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Clinically established biodegradable long acting injectables: An

industry perspective

Christian Isalomboto Nkanga, Andreas Fisch, Mazda Rad-

Malekshahi, Marieta Duvnjak Romic, Birgit Kittel, Thomas
Ullrich, Jing Wang, Rui Werner Maçedo Krause, Sabine Adler,
Twan Lammers, Wim E. Hennink, Farshad Ramazani

PII: S0169-409X(20)30217-9
DOI: https://doi.org/10.1016/j.addr.2020.11.008
Reference: ADR 13677

To appear in: Advanced Drug Delivery Reviews

Received date: 8 October 2020

Revised date: 9 November 2020
Accepted date: 10 November 2020

Please cite this article as: C.I. Nkanga, A. Fisch, M. Rad-Malekshahi, et al., Clinically
established biodegradable long acting injectables: An industry perspective, Advanced
Drug Delivery Reviews (2020), https://doi.org/10.1016/j.addr.2020.11.008

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© 2020 Published by Elsevier.

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Clinically established biodegradable long acting

injectables: An industry perspective
Christian Isalomboto Nkanga1,2,3, Andreas Fisch3, Mazda Rad-Malekshahi4, Marieta Duvnjak
Romic3, Birgit Kittel5, Thomas Ullrich5, Jing Wang3, Rui Werner Maçedo Krause1, Sabine
Adler3, Twan Lammers6, Wim E. Hennink7, Farshad Ramazani3,*
1
Center for Chemico- and Bio-Medicinal Research (CCBR), Department of Chemistry, Rhodes
University, P.O. Box 94, Grahamstown 6140, South Africa.
2
Faculty of Pharmaceutical Sciences, University of Kinshasa, B.P. 212, Kinshasa XI, Democratic
Republic of the Congo
3
Technical Research and Development, Novartis Pharma AG, Basel 4002, Switzerland
4
Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Centre, Faculty of

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Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
5
Novartis Institute for Biomedical Research, Novartis Pharma AG, Basel 4002, Switzerland

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6
Department of Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany
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7
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the
Netherlands
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* Corresponding author: Tel.: +41 79 5922245, email: [email protected]
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Abstract:
Long acting injectable formulations have been developed to sustain the action of drugs in the
body over desired periods of time. These delivery platforms have been utilized for both
systemic and local drug delivery applications. This review gives an overview of long acting
injectable systems that are currently in clinical use. These products are categorised in three
different groups: biodegradable polymeric systems, including microparticles and implants;
micro and nanocrystal suspensions and oil-based formulations. Furthermore, the applications
of these drug delivery platforms for the management of various chronic diseases are
summarized. Finally, this review addresses industrial challenges regarding the development
of long acting injectable formulations.
Keywords:
Long acting injectables, extended release, drug delivery, PLGA microparticles, microspheres,

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implants, in situ forming implants, drug crystals, oil-based formulations, drug crystal
suspensions

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1. Introduction
Parenteral drug delivery systems have been developed for the treatment of numerous
diseases via different administration routes including intravenous (IV), subcutaneous (SC),
intramuscular (IM), epidural and intra-articular injection, as well as surgical insertion of
depots in the organ or tissue of interest [1–3]. For bioavailability of drug molecules,
parenteral delivery can provide specific advantages as compared to the oral route of
administration; due to the avoidance of the drug absorption step, as well as the
gastrointestinal enzyme degradation and liver first pass effect. Despite these advantages of
parenteral drug delivery, most drugs have to be frequently administrated in chronic diseases;
especially for drug molecules susceptible to rapid in vivo clearance, repeated injections are
required to maintain therapeutic levels throughout the treatment duration [4]. Such a high
dosing frequency markedly affects patient compliance, which further worsens in chronic
conditions like mental and hormone-dependent disorders, where medication is needed for

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several months to years.
The above limitations have encouraged the development of controlled release strategies that

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allow extending systemic drug exposure over prolonged periods of time following parenteral
administration of a single dose [5,6]. Over the past few years, the target for long acting
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injectable (LAI) formulations has been expanded from systemic to local drug delivery [7–9].
In this regard, the LAI formulations are directly injected in the proximity of the diseased
tissue, aiming for high drug exposure over a desired period in the target tissues and low
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systemic drug distribution.
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Up to now, several LAI technology platforms have found their way into the market. These
include polymeric particulate systems (i.e., microparticles and nanoparticles), implants, in
situ forming depots, suspensions of drug crystals, oil-based formulations of lipophilic
(pro)drugs and liposomes [9–11]. We here give an overview of clinically relevant LAI
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strategies, by grouping the above-mentioned technology platforms into three categories

namely: (i) microencapsulation, (ii) implantation and in situ forming depots (gels/implants)
and (iii) molecular (i.e., prodrugs) and particulate (i.e., micro/nanocrystals) drug
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modification. We next describe formulation characteristics and therapeutic strategies of

marketed biodegradable LAI products. Finally, challenges and perspectives regarding the
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development of LAI drug delivery systems are discussed. Due to their limited extended
release capacities, liposomal or polymeric nanoparticles are excluded from this review. Since
most of the LAI formulations are protected by patent right and there is limited data available
regarding their physicochemical characterizations (e.g., particle size distribution, implant
size, detailed information about polymer type etc.), only publicly available data are reported
in this review.
2. Overview of strategies for development of long acting injectables
Despite some technological challenges in the industrial development of injectable drug
products, which will be highlighted in this review, multiple sustained release platforms have
been successfully marketed. This section provides an overview of different strategies that
have led to the development of clinically used LAI drug products.
2.1. Microencapsulation

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The term ―microencapsulation‖ refers to engineering of particles with sizes between 1 and
1000 μm, where solid or liquid drug substances are entrapped either as a dispersed and/or
dissolved in a polymer matrix (microspheres), or as a core surrounded by a polymeric shell
(microcapsules) [12]. The polymers used for microencapsulation include both (semi)naturally
occurring (e.g., alginate, collagen, chitosan) or synthetic materials (based on e.g., copolymers
of lactic and glycolic acid (PLGA) [13]. These biomaterials have been employed to protect
the encapsulated drug substance from degradation and minimize its toxicity towards the
surrounding tissue, as well as tailoring the release and the therapeutic action of the loaded
drug molecules over prolonged periods (from days to months).
According to a PharmaCircle® search, conducted on the 1st of April 2020, the majority of
marketed LAI formulations are composed of polymeric materials among which PLGA is the
most frequently used one, accounting for 46% (22 drug products) of all marketed products
(Figure 1) [14]. PLGA is an aliphatic random co-polyester of lactic acid and glycolic acid,

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with different molecular weights, different ratios of glycolic to lactic acid, and different end
caps (acid or ester terminated), which translates into different degradation kinetics [15–19].

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PLGA has been formulated into microparticles (MPs) for delivery of different types of cargos
with tailorable extended drug release profiles [20–22].
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Figure 1. Marketed drug products and their percentage arising from different parenteral long
acting platforms based on the Pharmacircle® database (date of search: April 1st, 2020). The
present review deals with only brand-name formulations not generic medicines [14]
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The formulation techniques used in microencapsulation processes include coacervation or

phase separation, spray drying and solvent evaporation/extraction. [23]. Among these
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techniques, solvent evaporation/extraction is the most commonly used method for

microspheres preparation [16,17]. Depending on the aqueous solubility of the drug candidate,
the solvent evaporation/extraction process involves variable emulsification approaches, e.g.
single emulsion (oil-in-water (O/W)) and double emulsion methods (water-in-oil-in-water
(W/O/W) or solid-in-oil-in-water (S/O/W)) [4,24–26]. Figure 2 demonstrates the emulsion
solvent evaporation technique for PLGA microparticles manufacturing. Depending on the
method of manufacturing, both hydrophilic and lipophilic drugs can be loaded into PLGA
MPs [26]. In general, O/W is used for loading water insoluble drugs into PLGA MPs. A
double emulsion method (W/O/W), which needs to first emulsify drug aqueous solution in
the organic PLGA phase, followed by a second emulsification step of the primary emulsion
(i.e., W/O emulsion) in a second aqueous phase is used to load water soluble drugs. Several
reviews have discussed the strategies and challenges associated with microencapsulation of
small drug molecules [12,25–27], as well as peptides and proteins for extended release
purposes [5,28–32].

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Although successfully employed for LAI product development, microencapsulation

techniques are still facing multiple challenges such as controlling particle size and size
distribution, tailoring drug release, and ensuring stability of fragile biotherapeutics (e.g.,
pharmaceutical proteins and peptides, nucleic acid based drugs) [5,33]. MPs are formulated
into a size range of 10–250 µm (or ideally 10–125 µm) to allow injection through
conventional needles, reducing macrophage phagocytosis and local tissue inflammation
[12,34,35]. Although, small MPs (i.e., 2 µm) are shown to be efficient for delivery of
antibiotics into alveolar macrophages for the treatment of tuberculosis [36]. Small particles
size can be easily injected through a thin needle [37]. Furthermore, since a few big particles
can clog the needle a narrow particle size distribution offers the possibility to use thinner
needles, thereby reducing pain during administration. Traditional manufacturing techniques
normally produce MPs with a relatively broad size distribution, leading to poor injectability.
Novel technologies such as membrane emulsification and/or microfluidics have been
extensively investigated for production of mono-sized MPs for better injectability through

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smaller needles [13,38]. It has been further demonstrated that size is an important factor that
determines the release kinetics of loaded drugs [39,40]. A limited drug loading capacity of

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MP formulations (typically ˂ 25% w/w) represents another challenge, especially for actives,
which have a relatively low potency and thus require high dosing. This has a direct impact on
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clinical applicability due to the requirement for the concentration of the MPs suspension
(normally ˂ 40% w/v, as higher concentrations result in higher viscosity and thus poor
injectability), as well as the injection volume (e.g., limited to approx. 2 mL for IM and 0.1
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mL for intravitreal injections) which may affect the nominal dose.
Drug release from PLGA MPs can be tuned from a couple of days to months. Tailoring drug
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release can be done by manipulating PLGA molecular weight, the ratio of glycolic acid to
lactic acid, the end terminus of polymer (e.g., acid or ester terminated) [41], MPs size and
surface porosity [42], drug loading (ratio of drug to polymer), and adding other excipients
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[43,44]. In general, the drug can be loaded into PLGA MPs as molecularly dissolved or solid
dispersion. In case of molecularly dissolved systems, the drug is released mainly by diffusion
through the polymer matrix but for solid dispersed drugs, release is mainly governed by
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swelling, degradation and porosity of the polymeric matrix material. Most often, the
combination of diffusion and polymer degradation is responsible for release of the drug. In
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general, PLGA based MPs and implants demonstrate a tri-phasic drug release pattern,
characterized by a burst, sustained release, and a second burst release. The mechanisms of
drug release from PLGA-based MPs are comprehensively reviewed by Fredenberg et al. [45].
Microencapsulation technologies have been successfully applied to small molecules drugs but
formulating macromolecular therapeutics into PLGA MPs remains challenging. Proteins
structure is highly dependent on the environment and structural changes can affect their
biological activity. Denaturation of proteins can occur due to the method of manufacturing
and to incompatibility with PLGA. For example, proteins may undergo denaturation and
aggregation at the interface of oil and water during encapsulation into PLGA MPs using
double emulsion solvent evaporation method (W/O/W), and/or due to high shear stresses
used for emulsification [33,46]. Regarding incompatibility with PLGA, it is worth mentioning
that the acidic pH formed inside of MPs during bulk erosion may damage acid sensitive
proteins [47,48]. Another drawback of PLGA for protein and peptide delivery is acylation of
protein nucleophilic groups (e.g., N-terminal amino group, mercapto- side chain of cysteine
and primary amine side chain of lysine) with lactic and glycolic acid units [49–52]. No

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protein drug based on PLGA MPs is currently marketed. The only protein based PLGA
formulation that entered the pharmaceutical market was Nutropin Depot® (Genentech Inc.),
but its clinical use was discontinued due to manufacturing difficulties [10].
In spite of the above challenges, microencapsulation remains to be a promising strategy for
preparing LAI formulations [53]. There are many small molecules and peptides based PLGA
MPs presently used in the clinic [11,54]. These formulations are briefly described in section 3
of this review.

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Figure 2. Schematic image of emulsion solvent evaporation technique for PLGA

microparticles manufacturing. Upon administration, PLGA microparticles releases the drug
for a prolonged time. The combination of diffusion and polymer degradation is responsible
for release of the drug.
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2.2. Preformed and in situ forming implants

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Similar to MPs, implants are polymer-based LAI systems that have successfully entered the
pharmaceutical market. There are two main types of implants, i.e., preformed (or classical)
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implants (e.g., Zoladex®) and in situ forming implants/depots (e.g., Sustol®). The classical
implants are cylindrical solid rods with 10–35 mm length and 1–3 mm diameter, prepared by
melt extrusion either from biodegradable or non-biodegradable polymers for subcutaneous
administration [30,55]. Depending on their size, solid implants are administered either via
surgical insertion or SC injection using a large needle (e.g., 16-gauge needle, with outer and
inner diameter of 1.65 and 0.065 mm, respectively) [56]. For non-biodegradable implants,
surgical operation is typically required to remove the delivery system at the end of the
treatment. This highlights the advantage of biodegradable implants, which gradually degrade
into metabolizable monomers (e.g., PLGA degrades into lactic and glycolic acid) during the
release process. Apart from the need for surgical removal, another problem associated with
preformed implants is the painful and sometimes traumatizing influence that patients
experience due to the injections. As such, some of the advantages of classical implant
technology (e.g., simplicity, low cost, no size/dose restriction) are compromised [56,57].
The limitations of MPs and preformed implants have inspired scientists to develop in situ
forming implants/gels, which represent a relatively cheap, rapid and easy-to-use parenteral

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controlled release technology. In situ forming implants (ISFI) are biodegradable polymer-
based liquid or syringeable semisolid formulations that undergo spontaneous
solidification/gelation at the site of injection [58]. Depending on the formulation
composition, ISFI can form through precipitation (due to phase separation/solvent extraction
or sol-to-gel transformation induced by physiological temperature/pH), organo-gelling (due
to the thermo-sensitivity of hot melts or self-assembly of lyotropic liquid crystals in aqueous
medium) or cross-linking of monomer/polymer chains (in response to photo-irradiation or the
presence of ions or enzymes) [59]. Among these ISFI formation mechanisms, in situ
precipitation induced by solvent extraction/phase separation (SE/PS) represents the most
investigated approach which has brought products to the market [60].
The SE/PS implants are composed of a biodegradable water-insoluble polymer (e.g. PLGA)
dissolved in a water miscible organic solvent (e.g., N-methyl-2-pyrrolidone or dimethyl
sulfoxide), and the drug dissolved or dispersed as microcrystals in the polymer solution.

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Upon SC injection, the organic solvent is extracted from the organic sol, leading to polymer
precipitation and formation of a solid depot in which the drug is trapped. The encapsulated

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drug is then gradually released through diffusion and polymer degradation [61]. As
demonstrated in Figure 3, the use of simple and fast solid-liquid dissolution/dispersion steps
for manufacturing as well as conventional needles for injection, with no need for surgery,
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make ISFI an attractive parenteral LAI technology. It is worth mentioning that the used
organic solvents such as N-methyl-2-pyrrolidone (NMP) are associated with certain levels of
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local or systemic toxicity depending on the route of administration. According to USP, the
maximum daily exposure for NMP in pharmaceutical product is 5.3 mg/day [62]. Such
toxicity related issues may limit the development of NMP-based in situ forming gels for other
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applications. Dimethyl sulfoxide (DMSO) is class 3 organic solvent and its maximum daily
dose is 50 mg/day, which makes it attractive for development of in situ forming gels.
However, when higher amounts of organic solvents (beyond the daily tolerated limits) are
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needed in a formulation, further toxicological studies are required to ensure product safety.
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Figure 3. Schematic image of in situ forming gel manufacturing using PLGA polymer and N-
methyl-2-pyrrolidone (NMP). Upon administration, solvent extraction/phase separation
results in in situ gelation of the polymer which releases the drug for a prolonged time.
2.3. Molecular and particulate drug modification
2.3.1. Molecular drug modification (prodrugs)
The possibility for modification of drug substances at molecular and particulate levels has
launched several LAI technologies. One approach used for molecular modifications is
covalent attachment of a drug to a fatty acid chain. Prodrug formation using decanoate,
enanthate or caproate has already been established for oil-based LAI formulations. In this
context, fatty acids form an ester bond with the prodrug. In most cases, esterification of a
parent drug with a fatty acid chain not only increases its solubility in the oil formulation but
also enhances its partitioning in fatty tissues in the body, which leads to a sustained release

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kinetics [63]. Therefore, drug release can be controlled by both cleavage of a traceless linker,
mostly through hydrolysis of ester bond, and slow drug release from fatty tissues into the

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circulation. Oil-based parenteral formulations can be used for systemic drug delivery (e.g.,
IM or SC) or localized drug delivery (e.g. intra-articular delivery). Simple and cost-effective
manufacturing process is a unique feature of oil-based depot formulations [64]. Terminal
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sterilization is often performed using filtration as they can be easily filtered through 0.2
micron sterile filters [65]. Figure 4 is a schematic representation of oil-based formulations
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and their simple manufacturing steps.
Oil depot formulations are generally consisted of esterified drug, oil vehicle and benzyl
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alcohol. The oil vehicle is mainly composed of a vegetable oil like sesame oil, castor oil,
arachis oil, or fractionated coconut oil. Viscosity is a key parameter in selection of oil vehicle
as high viscose oils are not syringeable and therefor hard to be administered parenterally. On
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the other hand, low viscosity formulations generally speaking release the drug rapidly [66].
Benzyl alcohol as co-solvent increases not only oil solubility of the prodrug but also reduces
oil viscosity, which facilitates prodrug release from depots [67,68].
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As shown in Table 5 the octanol-water partitioning coefficient (log P) values of marketed oil-
based prodrug formulations are >3.8, suggesting that lipophilicity is a key factor in slowing
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down drug release from oil depots which can be obtained by increasing the length of fatty
acid chains extends [69]. Some of the important parameters for controlling drug release from
oil-based depots includes concentration of drug in the oil, the surface area of the oil depot, the
partition coefficient between oil depot and tissue fluid etc. After releasing prodrug from the
oil depot prodrug with low water solubility shows low tissues absorption and lymphatic
transport, whereas more water soluble prodrugs may diffuse directly to central blood
circulation where they can be hydrolysed by enzymatic and/or chemical routes into parent
drugs [70]. It is known that conversion of prodrug happens via carboxylesterases, which are
mainly present in the blood therefore the prodrug remains mainly intact in the site of injection
with less carboxylesterases [71]. Of special note, the rate of bioconversion of prodrug with a
long chain fatty acid to the parent drug is modulated by the chemistry of the ester linkage.
Slowly hydrolysing esters as compared to more rapidly hydrolysing esters provide time for
redistribution of prodrug and minimize burst release which may results in toxic peak
concentration [72,73]. Oil-based depot formulations are barely employed in recent clinical
trials (only one in phase III, i.e. Fulvestrant + Everolimus + Anastrozole Co-Therapy based

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on an oil formulation; developed by AstraZeneca and Novartis AG). The limited number of
ongoing clinical trials in this area might be due to the difficultly of tuning drug release
kinetics. Another promising drug derivatization strategy includes the conjugation of drug
molecules to a polymer carrier using a linker that slowly breaks in vivo to release unmodified
drug. An illustrative example of this technology is TransCon™ hGH, an investigational long-
acting prodrug of human growth hormone (hGH or somatropin) under development by
Ascendis Pharma A/S. TransCon hGH is a prodrug composed of somatropin transiently
conjugated to a methoxy polyethylene glycol (40 kDa) through a proprietary TransCon
linker. In this formulation system, the polymer carrier prolongs plasma circulation of hGH by
preventing its interactions with hGH receptors in tissues and hampering its renal clearance;
while the TransCon linker ensures sustained release of active hGH through slow
autohydrolysis occurring under normal physiological conditions [74]. Data from phase 2
clinical trials demonstrated that weekly administrations of TransCon hGH to children with
hGH deficiency exhibited hGH and insulin-like growth factor-1 levels similar to those of

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daily somatropin injections marketed as Genotropin (Pfizer) [75]. Based on clinical safety
and efficacy data, the U.S. Food and Drug Administration (FDA) has recently accepted the

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biologics license application of Ascendis Pharma for TransCon™ hGH against pediatric hGH
deficiency; but this therapy has not yet been approved for clinical use [76]. Although prodrug
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strategies clearly hold some promise for clinical development of long acting injectables, it is
important to note that this approach is not applicable to all drug molecules, especially in case
of lack of functional groups to be modified. For example, some drugs such as aripiprazole,
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olanzapine and risperidone do not possess hydroxyl group for esterification.
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Figure 4. Schematic image of oil-based formulation and simple manufacturing steps. Upon
administration, the prodrugs can be hydrolysis by enzymatic and/or chemical routes into
parent drugs in a prolonged time.
2.3.2. Particulate drug modification (micro/nano drug crystals)

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Physical modification of drug substances into particulate systems such as nano- or

microcrystals is a formulation strategy to develop long acting injectables (Figure 5). This
strategy is applicable for drugs with a very low aqueous solubility and their release from
crystals is mainly controlled by dissolution kinetics in the local tissue fluid and surface area
of drug crystals [77]. The manufacturing of nano and microcrystals can be achieved using
three approaches, namely the ―bottom-up‖ technique (e.g., crystallization of a drug from an
oversaturated organic solution), the ―top-down‖ approach (e.g., micronization of drug crystals
by milling or high-pressure homogenization), and a combination of both techniques. In the
bottom-up method, drugs are first dissolved in a good solvent, and the involved critical steps
(i.e., nucleation and crystal growth) are influenced by many factors (temperature, stirring and
evaporation rate, addition of non-solvents, geometry of the reactor etc.), resulting in poor
control of particle size and size distribution. Therefore, these methods are mainly used in the
food industry or as a pre-treatment of drugs for later top-down manufacturing. The top-down
technology has been successfully implemented for the preparation of nano- or micro-

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suspensions [78]. For example, wet media milling is a standard and established technology
for nanosuspension preparation [77].

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Drug crystal-based formulations are aqueous suspensions composed of poorly water-soluble
drug/prodrugs in the size range of micro- or nanoparticles, and minimal amounts of one or
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several stabilizing ingredients (e.g., polysorbates, povidones etc.). These formulations are
marketed in the form of either a lyophilized powder (e.g., Zyprexa Relprevv ®), which is
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reconstituted by diluent prior to injection, or in the form of aqueous suspension (e.g. Invega
Trinza®). Ready to use aqueous suspensions are preferred, but due to their limited stability,
they cannot be applied for all drugs and drug candidates. An unwanted phenomenon that can
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occur in aqueous crystal suspensions is the so-called Ostwald ripening, in which small drug
crystals dissolve and re-deposit on the surface of larger drug crystals [79,80]. Since reduction
of the number of small crystals and increase of overall particle size reduces the specific
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surface area of the drug crystal suspension, Ostwald ripening can slow down drug release
kinetics. This phenomenon is driven by drug solubility in the formulation, drug crystal
polydispersity level and time. Ostwald ripening can be accelerated by temperature
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fluctuations in the drug product during e.g., autoclaving or storage. High temperature
increases the solubility of drug crystals in the suspension especially smaller crystals dissolve
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and after autoclaving recrystallize on the surface of larger particles. Since temperature
cycling during autoclaving is highly standardized, drug crystal growth should be very
reproducible using this autoclaving sterilization method. Moreover, care has to be taken to
avoid so-called caking of the suspension, which is drug crystal sedimentation and
agglomeration at the bottom of vials. This phenomenon can happen in the bulk suspension
during manufacturing or in the vial during autoclaving or storage. Caking makes dosing
accuracy, resuspendability and injectability challenging. Temperature increase during
autoclaving not only temporarily increases drug solubility, but also reduces formulation
viscosity. Low viscosity accelerates drug crystal sedimentation in the vial and increases the
risk of aggregation of sedimented drug crystals in the cooling phase. Both Ostwald ripening
and caking can be minimized by optimization of the formulation composition to reduce drug
solubility, e.g., by reducing co-solvent or surfactant levels, addition of viscosity enhancers,
narrow particle size distribution and control of storage conditions of the drug product. The
optimal balance between those critical variables is important to enable easy resuspendability

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and injectability of the drug suspension through reasonably thin needles, e.g. 18-23 gauge
[77].
There are factors that slow down release or dissolution kinetics/extend drug release from
micronized suspensions, e.g., by increasing lipophilicity of drug (using insoluble salt,
chemical modification or co-crystal formation), change of particle size (nano to
microparticles) and suspension concentration [77]. Good examples of the application of
chemical modification and co-crystal technology for extending drug release based on
retarding the kinetics of dissolution are Kenalog® and Bicillin L-A®. Kenalog® is a
microcrystal formulation of poorly water-soluble triamcinolone acetonide. It is a chemical
derivative of triamcinolone by which two of its hydroxy groups are bound together with one
molecular equivalent of acetone as a so-called ketal. This covalent modification renders the
molecule more lipophilic and less water-soluble than triamcinolone (0.043 vs 0.847 mg/mL).
It has been shown that the micronized suspension of triamcinolone acetonide exhibited

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extended duration of pharmacological action in the body owing to the drug‘s low aqueous
solubility [81–84]. Bicillin L-A® is an aqueous drug co-crystal suspension of penicillin G
with benzathine (Bicillin L-A®) and it is monthly injected via the IM route for the treatment

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of syphilis and protection from group A streptococcal infections [85,86].
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Increasing suspension concentration and drug dose are other ways to extend the duration of
drug release. Invega Sustenna® is a nanosuspension of paliperidone palmitate with a
skipconcentration of 156 mg/mL that releases the active agent over one month in the body
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upon IM injection. Invega Trinza® is another drug product based on nanosuspension of
paliperidone palmitate with a suspension concentration of 312 mg/mL that releases the drug
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over 3 months upon IM injection [87]. By increasing suspension concentrations and

administration of higher doses, likely the compartment which is surrounding the crystal
suspension becomes saturated and drug release from nanoparticles is further extended. It has
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been shown that when a paliperidone palmitate nanosuspension is administered at doses that
were 3.5-fold higher than the corresponding dose for one-month release, the obtained plasma
concentrations were similar to the values observed for the one-month release formulation but
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now lasted up to three months instead of one month. Nanosuspensions of hydrophobic drugs
for parenteral delivery offer the advantage of high drug loading (high suspension
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concentration) which can be injected using small needle size (e.g., 22 or 23G) [88], thus
extending drug release due to higher local concentration and minimizing the risk of tissues
damage due to smaller needles size.

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Figure 5. Schematic image of micro/nano crystal suspension manufacturing. Drug release
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from crystals is mainly controlled by dissolution kinetics in the local tissue fluid and surface
area of drug crystals.
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3. Clinically established long acting parenteral formulations

Based on the different formulation strategies presented in the previous sections, several LAI
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parenteral formulations have been brought to the clinic, benefiting patients with chronic
diseases. We here categorize these products in three groups, namely biodegradable polymeric
systems (particularly, MPs and implants, oil-based formulations and drug crystal (nano and
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micro) suspensions.
3.1. Long acting biodegradable polymeric systems for parenteral use
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In the following section, LAI platforms based on biodegradable polymers are categorized into
PLGA-based and non-PLGA based systems. As shown in Figure 1, 46% of the presently
marketed LAI products are based on PLGA. Other polymers that are used in FDA approved
LAI drug delivery systems include sodium hyaluronate, poly[1,3-
bis(carboxyphenoxy)propane-co-sebacic-acid] (PCPP-SA), triethylene glycol
poly(orthoester) and a complex of anionic sodium carmellose (carboxymethyl cellulose) with
cationic abarelix acetate.
3.1.1. PLGA-based long acting biodegradable systems
The marketed products composed of PLGA-based MPs and implants are summarized in
Tables 1 and 2 and discussed in detail below.
Table 1. Marketed PLGA-based microparticle formulations
Register Drug Manufactu Indicatio Route of Dosin Log Water PLGA Highest Drug Annual
ed name rer n adminis g P solubili type dosage loadin sale (Year
interv ty (L/G g%(w

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 Journal Pre-proof

tration al (mg/m ratio) (mg) /w) 2019) M$

(week L)
)

Arestin® Minocycl OraPharma Gum subgingi 12 0.5 50.00 PLGA 1.0 Not 87
ine infection val found
hydrochl
oride

Bydureo Exenatide AstraZenec Type 2 SC 1 - 2.1 1.00 PLGA 2.0 5.0 549
n® a diabetes 75:25
mellitus

Lupron Leuprolid Takeda, Breast and IM 4–26 1.1 0.50 PLA* 45.0 17.0 887
Depot® e acetate Abbott prostatic
cancer

Nutropin Somatotr Genentech GH SC 4–5 - 5.00 Not 22.5 12.0 382 (Year
Depot® opin Inc. deficiency found 2005)

Risperda Risperido Alkermes & Schizophr IM 2 3.0 0.003 PLGA 52.0 32.9 688

of
l ne Janssen enia, 75:25
Consta® Psychotic
disorders

ro
Sandosta Octreotid Novartis Acromega IM 4 0.4 1.20 PLGA 30.0 4.17 1585
tin® e acetate ly, 55/45
LAR Carcinoid star
Tumors
-p polyme
r

Signifor®
re
Pasireotid Novartis Acromega IM 4 3.0 0.01 PLGA 60.0 25 72 (Year
LAR e ly 55/45 2018)
pamoate star
polyme
lP

r+
PLGA
50:50

Somatuli Lanreotid Ipsen Acromega IM 2 1.1 PLGA 30.0 24.6* 1154

na

ne® LA e acetate Pharma ly 75: 25 *

Biotech 0.50

Trelstar Triptoreli Debiophar Prostatic IM 4–26 1.7 Not 22.5 7.3 456
ur

®
LA n m, Ipsen, cancer found
pamoate Vifor 0.03
®
Vivitro Naltrexon Alkermes & Alcohol IM 4 1.9 1.63 PLGA 380.0 33.7 335
Jo

e Janssen Opioid 75:25

dependenc
e

Zilretta® Triamcin Flexion Pain killer intra- 12 2.5 0.04 PLGA 32.0 25.0 73
olone articular 75:25
acetonide

*poly(lactic acid) polymer (it is not known whether it is poly(L-Lactic acid) or poly(DL-
Lactic acid). Solubility and logP values obtained from drug bank [89]; **from FDA data base
[90]; other data are from PharmaCircle® data base [14]
3.1.1.1. Marketed long acting injectables based on PLGA microparticles
3.1.1.1.1. Arestin®
Arestin® is a ready-to-use single-dose cartridge containing minocycline-loaded PLGA
microspheres and available as a dry powder formulation. Arestin® is used as a supplementary
component of scaling and root planning procedures for the management of periodontitis. A
single subgingival injection of Arestin® MPs into periodontal pocket provides local sustained

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release of minocycline over 2 weeks [91]. In a study published by Persson et al. [92] the anti-
bacterial effects of Arestin® in a patient with peri-implantitis was assessed over 12 months.
Arestin® demonstrated significant decrease in bacterial load up to 180 days for most of the
investigated pathogens, including Tannerella forsythia, Porphyromonas gingivalis, and
Treponema denticola. The most sensitive pathogen to this therapy was Actinobacillus
actinomycetemcomitans [92]. The antimicrobial efficacy of Arestin® has been also reported
elsewhere [89,90].
3.1.1.1.2. Bydureon®
Bydureon® is a PLGA-based MPs formulation containing 5% (w/w) exenatide, a glucagon-
like peptide-1 (GLP-1) agonist that is used for type II diabetes. Several studies have
demonstrated that Bydureon® has much better hypoglycemic activity and fewer adverse
effects than twice-daily SC injection of the free drug 5-10 μg in solution [95,96]. Bydureon®
can also be used as combination therapy along with established oral antidiabetic drugs, such

of
as metformin and/or sulfonylurea [97,98]. Nevertheless, a single dose of Bydureon
administration exhibits an exenatide release over approximately 10 weeks. An initial release

ro
of exenatide can be observed possibly as a result of surface-bound exenatide on MP surface,
followed by a gradual release of exenatide from the MP matrix due to the hydration and
-p
erosion of PLGA. The gradual release phase shows two subsequent peaks of exenatide in
plasma at approximately week 2, and week 6 to 7, respectively [99]. Plasma concentration of
exenatide is gradually increased and maintained stable after 6 to 7 weeks at around 300 pg/ml
re
over weekly dosing intervals.
3.1.1.1.3. Lupron Depot®
lP

Lupron Depot® is a sterile PLGA MPs-based formulation that is separately filled with an
aqueous vehicle in a dual-chamber syringe. Several variants of Lupron Depot® are clinically
na

available containing different amounts of leuprolide acetate, including 7.5, 22.5, 30 and 45
mg that are administered via IM route in a dosing interval of 1, 3, 4 and 6 months,
respectively. The efficacy and safety of Lupron Depot® in hormonal and menstrual
ur

suppression in endometriosis patients have been demonstrated [100–104]. In addition, Lupron

Depot® was found to be efficacious against cognitive decline in Alzheimer‘s disease patients
Jo

under acetylcholinesterase inhibitor therapy [105]. This was explained by Lupron‘s potential
to suppress the peripheral circulating concentrations of gonadotropins and disrupt the
expression of the brain‘s GnRH receptors that are correlated to the areas of Alzheimer‘s
disease neuropathology [106] .
3.1.1.1.4. Nutropin Depot®
Nutropin Depot® is the only marketed long acting injectable formulations delivering a protein
drug, recombinant human growth hormone (rhGH), Somatotropin of rDNA origin. Nutropin
Depot® is administered via SC injection to children with GH deficiency in doses of 1.5 mg/kg
monthly or 0.75 mg/kg twice monthly. Kemp et al. [107] examined the pharmacokinetic and
pharmacodynamic response parameters after single or multiples doses of Nutropin Depot® in
138 prepubertal children with GH deficiency. Data analysis revealed that at least 50% of GH
exposure occurs within the first 48 hours after administration and the GH serum levels
remained above 1 μg/L to 11–14 days. Nutropin Depot® achieved serum peak levels similar
to those observed with daily injections of GH. Another clinical study demonstrated the
therapeutic potential of Nutropin Depot® in adults with GH deficiency at much lower single

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doses (0.25 mg/kg and 0.5 mg/kg) [108]. Despite its proven clinical efficacy, Nutropin
Depot® is not commercially available due to manufacturing issues [10], underlining the need
for further efforts in the PLGA-based formulations development addressing ER protein drug
delivery.
3.1.1.1.5. Risperdal Consta®
Risperdal Consta® is the first LAI antipsychotic formulation based on PLGA MPs. Risperdal
Consta® is administered via IM injection every two weeks for the treatment of schizophrenia
and other psychotic disorders, such as schizoaffective disorder or bipolar disorder [109]. A
double-blind study demonstrated the possibility of switching schizophrenia patients under
oral risperidone to long-acting one (Risperdal Consta®) without compromising the overall
treatment efficacy and safety, while improving patient adherence due to reduced dosing
frequency [110]. Despite the advantage of improved dosing rates, Risperdal Consta® remains
dependent on oral antipsychotic treatment, which is required in the first 3 weeks of treatment

of
to supplement long-acting risperidone. The use of additional supplement is due to the multi-
phasic release profile of Risperdal Consta®, exhibiting about 3.5% of initial release followed

ro
by a 3-week lag phase of any drug release and finally the actual release for two weeks [111].
This is a typical example of degradation-based drug release from PLGA microparticles
-p
known as bulk erosion [112]. This limitation inspired the development of Invega Sustenna®,
an aqueous nanocrystal suspension of the active metabolite of risperidone, paliperidone
palmitate, with a dose of 150 mg. In addition to efficacy, tolerability and safety profiles
re
comparable to Risperdal Consta®, Invega Sustenna® supplies effective plasma concentrations
rapidly and excludes the need for oral antipsychotic supplementation [113]. Further efforts
lP

have being being devoted to develop risperidone-loaded MPs with 4-week steady release
profiles to prevent extrapyramidal side effects and high-dosing frequency [111,114]. By
screening PLGA with different molecular weight and copolymer compositions , Su et al.
na

[111] reported zero-order release of risperidone from PLGA 50:50 for 20 days, which could
not be achieved using PLGA 75:25 (Risperdal Consta®). This is likely due to the 3 weeks lag
phase observed because of poor water penetration and slower biodegradation of the PLGA
ur

(75/25) matrix composed of higher ratio of lactic units. Such results encourage future
improvement of this clinically established PLGA formulation. This includes for instance
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thorough optimization of relevant formulation parameters (e.g., PLGA molecular weight and
composition) to improve the release kinetics of risperidone from PLGA MPs.
3.1.1.1.6. Sandostatin® LAR
Sandostatin® LAR is a PLGA-based MPs loaded with a synthetic somatostatin analog,
octreotide (as acetate salt). Similar to the endogenous somatostatin, octreotide can normalize
the levels of insulin-like growth factor-1 (IGF-1) and growth hormone (GH), thus
Sandostatin® LAR is prescribed for the management of symptomatic acromegaly and
neuroendocrine tumors [115]. Sandostatin® LAR demonstrated positive effects in both short-
and long-term symptomatic treatment of malignant carcinoid syndrome upon monthly IM
injections. Its efficacy and safety profiles were similar to those of thrice-daily SC injections
of octreotide solution and weekly-biweekly IM injections of lanreotide, a somatostatin analog
[116,117]. The IM administration of Sandostatin® LAR 20 mg every 4 weeks was found to be
as efficacious and safe as thrice-daily SC injections of octreotide 0.3–0.6 mg (Sandostatin®)
to acromegalic patients, explaining the added value of reduced dosing frequency [118–120].

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3.1.1.1.7. Signifor® LAR

Signifor® LAR is a PLGA-based MPs containing 25% (w/w) pasireotide pamoate as free-
base, a second-generation somatostatin analogue. Signifor® LAR has been established for
long-term management of symptomatic acromegaly, while pasireotide solution (Signifor®) is
a short-acting formulation daily administered via SC route. Signifor® LAR is administered
IM. on a monthly basis [121]. Signifor® LAR is specifically indicated for patients with
acromegaly that is resistant to the first-line acromegalic therapy, which is composed of first-
generation somatostatin analogue, such as Sandostatin® LAR (octreotide-loaded
microspheres) [122]. In a randomized clinical study, pharmacokinetics of Signifor® LAR
showed high plasma levels on day 1, after IM injection of MPs, followed by a decline in drug
release for a week and subsequent increase from week 1 to week 4. Steady-state drug release
was obtained from the 3rd month of the treatment (i.e., after three consecutive injections) and
lasted for 28 days [123].

of
3.1.1.1.8. Somatuline® LA
Somatuline® LA is an extended release PLGA-based MP formulation. Similar to octreotide,

ro
lanreotide is an octapeptide analogue of somatostatin, thus Somatuline® LA is prescribed for
the treatment of acromegaly with an administration frequency of every 2 weeks. Following
-p
IM injection, Somatuline® LA exhibits a biphasic release profile, characterized by a rapid
initial release within 1-2 hours reaching a plasma level of 8.5 ± 4.7 ng/mL, followed by a
re
slow release from around day 3-5 until day 14-21 featured by a plateau of a plasma
concentration of around 1 ng/mL. During the first day after injection, around 7% of the
lP

loaded lantrotide is released because of the presence of adsorbed lanreotide on the surface of
microspheres, likely due to inefficient washing step during manufacturing. Noteworthy,
lanreotide-loaded MPs exhibited favourable PK profiles in acromegaly patients. In addition, a
number of clinical trials showed efficacy of Somatuline® LA in normalising both GH and
na

IGF-1 levels in acromegaly patients. Even though each Somatuline® LA contains 40 mg

lanreotide, only 30 mg can be finally delivered to the patients, which is defined as the
effective dose, because of the loss during resuspension and administration process [124].
ur

3.1.1.1.9. Trelstar® LA
Jo

Trelstar® LA is composed of sterile lyophilized PLGA-microspheres loaded with triptorelin

pamoate, which is a synthetic analogue of luteinizing hormone-releasing hormone (LHRH).
Trelstar® LA is indicated for the management of prostatic cancer. The single-doses of
Trelstar® LA contains 3.75, 11.25 and 22.5 mg of triptoreline intended for IM administration
every 1, 3 and 6 months, respectively [125]. A few randomized studies have comparatively
investigated the ability of long-acting LHRH agonists (e.g. Trelstar® LA versus Lupron
Depot®, leuprolide acetate) to achieve androgen suppression in male patients with prostate
cancer. In a comparative clinical trial, Trelstar® LA 3.75 mg/month was found to be better in
normalizing castration levels of serum testosterone than Lupron Depot® 7.5 mg [126].
3.1.1.1.10. Vivitrol®
Vivitrol® is a PLGA microsphere formulation loaded with naltrexone, an opioid receptor
antagonist. Vivitrol® is administered via the IM route for the management of alcohol and
opioid dependence. The efficacy of naltrexone-loaded microspheres has been demonstrated in
several clinical trials, with much longer-lasting abstinence to and greater reduction in alcohol

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and opioid consumption/craving than placebo [127,128]. The successful development of

Vivitrol® provides a promising alternative to oral naltrexone formulations, while the latter
was limited by poor patient compliance despite its demonstrated ability to reduce alcohol and
opioid reinforcement [88,89]. Furthermore, oral administration of naltrexone thrice a week
causes high drug exposure to the gastrointestinal tract and high plasma peaks leading to
several adverse effects (such as skin rash, body aches or pain), thus discouraging the
treatment continuation, which limits the possibility of providing sufficient evidence of
clinical efficacy. In addition to the improved adherence, IM administration of naltrexone-
loaded microspheres (Vivitrol®) demonstrated better clinical effectiveness and tolerability
than oral dosage forms [129–131]. In healthy volunteers upon IM injection of Vivitrol®
(380 mg dose), an immediate burst release (1-2h after dosing) was observed, likely due to the
presence of pores in the surface of microparticles and maximum plasma concentration (C max)
reached at day 2 post dosing. After two weeks of extended drug release, naltrexone
concentrations in plasma declined. However, the mean plasma concentration of the drug

of
remained above 1 ng/mL for more than 35 days [132]. It was also found that a single IM
injection of Vivitrol® (380 mg dose) demonstrated 4-flod higher AUC28 as compared to

ro
50 mg/day of oral naltrexone administered for 28 days [132].
3.1.1.1.11. Zilretta®
-p
Zilretta® a dry powder composed of PLGA-based microspheres containing triamcinolone
acetonide for intra-articular (IA) injection. The FDA has recently approved Zilretta® for the
re
management of pain in osteoarthritis (OA) knee [133]. In a randomized phase III clinical
trial, it was shown that Zilretta® extended drug release up to 12 weeks as compared to only 6
lP

weeks extended release of triamcinolone microcrystal suspensions (40 mg) following IA

administration. Furthermore, Zilretta® significantly reduced pain, stiffness and physical
function as compared to 40 mg triamcinolone acetonide suspension and placebo [134].
na

Table 2. Marketed preformed implants and in situ forming implants

Registere Drug Manufactur Indicatio Route of Dosin L Water Delivery Highe Drug Annu
ur

d name er n administ g og solubili system st loadin al

ration interv P ty Dosea g sale
al (mg/m ge %(w/ (Year
(week) L) (mg) w) 2019)
Jo

M$
Atridox® Doxycy Atrix Periodonta subgingi 18 0. 50.00 Atrigel 50 10.0 Not
cline Laboratories l disease val 6 Delivery found
hyclate Inc. System with
PLA and
NMP
CiproScr Ciproflo Bioretec Ltd. Bone Intra- 42 0. 45*45mm, Not Not Not
ew® xacin infection bone 3 1.00 implantable found found found
in surgery insertion screws
comprised of
drug loaded
PLA

Leuprone Leuprol Novartis Breast and SC 4 and 1. 0.5 PLGA 50:50 5 Not Not
HEXAL® ide (Sandoz/Hex prostatic 13 1 or PLA found found
acetate al) cancer rodes
Ozurdex® Dexame Allergan Macular intravitre 26 1. 0.09 PLGA 50:50 0.7 Not 298
thasone edema, al 9 rodes found
non-
infectious
uveitis

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Suprefact Busereli Sanofi- Prostatic SC 8 and 0. 0.038 PLGA 75:25 9.45 20.0 Not
®
Depot n Aventis cancer 13 9 rodes found
acetate
Propel® Mometa Intersect Sinusitis Intra- 4 and 4. 0.02 PLGA 1.35 Not 109
and sone ethmoida 13 1 75:25 rodes found
Sinuva® furoate l or blend of
PLGA 50:
50 and PEG
rodes
SinoFuan 5- Simcere Cancer intraperit 2 - 1.00 A cylindrical 200 Not 18
®
fluorour Pharmaceuti oneal 0. PLGA found (year
acil cal Group 6 implants of 2013)
0.1~0.5 mm
diameters
Zoladex® Gosereli AstraZeneca Breast and SC 4 and 1. 0.05 PLGA rods 10.8 29.9 813
n prostatic 13 5
acetate cancer
Perseris® Risperid Indivior Inc Schizophr SC 4 3. 2.33 Atrigel 120 24.2 Not
one enia 1 Delivery found
System with

of
NMP and
PLGA 80:20
Eligard® Leuprol Tolmar Inc. Prostatic SC 4, 13, 1. 0.50 Atrigel 45 21.4 127

ro
ide cancer 18 and 1 Delivery
acetate 26 System with
NMP, PLGA
(50:50),
-p (75:25),
(85:15)
Scenesse® Afamel Clinuvel Erythropoi SC 8 1. 0.023 A rod 16 51.1 18
anotide Pharmaceuti etic 4 implant with
re
cals Ltd. protoporp 1.7 cm
hyria length, 1.45
mm diameter
lP

Solubility and logP values obtained from drug bank [89]; other data are from PharmaCircle ®
data base [14].
na

3.1.1.2. Marketed preformed and in situ forming implants based on PLGA polymer
3.1.1.2.1. Atridox®
ur

Atridox® is a subgingival in situ forming implant of the antibiotic doxycycline hyclate in

Atrigel® delivery technology. Atridox® is a single dose product presented in a two-syringe
Jo

mixing system. This system includes syringe A that contains Atrigel® matrix 450 mg, which
is an in situ gelling depot composed of 36.7% poly(DL-lactide) (PLA) dissolved in 63.3% N-
methyl-2-pyrrolidone, and syringe B that contains 50 mg doxycycline hyclate (equivalent to
42.5 mg doxycycline). The reconstituted product for subgingival administration is a pale-
yellow viscous liquid with 10% doxycycline hyclate indicated for periodontal patients every
4 months. In a clinical study it was demonstrated that local injection of Atridox® was as
effective in the treatment of periodontitis [135]. It was concluded that local administration of
Atridox®, as a less invasive technique, could be a good alternative to invasive approaches
such as scaling and root planning. Another clinical study performed by Zeidner et al. [136],
showed that a single SC administration of Atridox® was better prophylactic antibiotic option
than oral doxycycline in patients with Anaplasma phagocytophilum and Borrelia burgdorferi
co-infection. The review by Southard et al. [137] discusses in detail the full potential of
Atrigel® technology as well as the clinical findings that led to successful establishment of
Atridox® periodontal therapy.

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3.1.1.2.2. CiproScrew®
CiproScrew® is a biodegradable implant in the form of screw for fracture-fixation.
CiproScrew® is indicated for prevention of ciprofloxacin sensitive infections associated with
mechanical fixation of bone fractures, bone grafts and osteochondral fractures as well as
osteotomies and arthrodesis. Several studies demonstrated the potential of the screw to supply
local bactericidal tissue concentrations for about 42 weeks [138–142]. In a prospective
randomized trial, biodegradable poly(lactic acid) screws were as effective as stainless steel
screws resulted in an uncomplicated healing of patient‘s fibular fractures with no evidence of
osteolysis. In addition, no need for further screw removal in case of CiproScrew® was
required up on drug exhausting due its biodegradability, in contrast to stainless steel screws
suggesting CiproScrew® can be an excellent alternative to steel screws for bon fixation [141].
3.1.1.2.3. Leuprone® HEXAL®

of
Leuprone® HEXAL® is a preformed implant loaded with a gonadotropin-releasing hormone
agonist (leuprolide, also known as leuprorelin). Leuprone® HEXAL® is produced in the form

ro
of rods. Leuprolide is used as acetate and homogeneously dispersed in PLGA (50/50) or
poly(lactic acid) matrix, yielding Leuprone® HEXAL® 1- or 3-months implant, respectively
[143]. Leuprone® HEXAL® is injected subcutaneously into the anterior abdominal wall every
-p
1 or 3 months for the treatment of advanced hormone-dependent prostate cancer. Geiges et al.
[143] assessed the effects of leuprolide implants for testosterone suppression and
re
normalization of prostate specific antigen levels in a randomized, controlled study. The
efficacy and safety profiles of the implants in prostate cancer patients were found to be
lP

comparable to those of intramuscularly administered leuprolide MPs. The results provided

insights for clinical development of leuprolide implants, which offer the advantage as a
ready-to-use formulation (with no need for reconstitution as done for MPs). Moreover,
production of PLGA implant is simpler and involves less steps as compared to PLGA MPs.
na

3.1.1.2.4. Ozurdex®
Ozurdex® is a preformed rod-shaped implant composed of PLGA matrix containing
ur

dexamethasone, a synthetic glucocorticoid agent with anti-inflammatory activities. Ozurdex®

is used for the treatment of macula oedema, due to diabetes or retinal vein occlusion and non-
Jo

infectious uveitis [144]. Several studies have reported the clinical efficacy and safety profiles
of Ozurdex® [145–149]. Due to the long-lasting release behavior of implant (over 4–6
months), dexamethasone from Ozurdex® controls macula edema effectively with minimized
glucocorticoid-related adverse effects e.g., reduced risk for refractory intraocular pressure
augmentation or cataract [150]. Ozurdex® exhibits a typical three phase release profile,
known for PLGA MPs and implants, which leads to early substantial therapeutic effects
within the first 8 weeks of administration, followed by a relatively constant and moderate
effect [151]. Despite this multiphasic release, the long-term administration of Ozurdex®
remains effective in controlling diabetic macular edema with reduced adverse effects [152].
A case study in patients with retinal vein occlusions demonstrated that Ozurdex® improves
resolution of macular edema and enhances visual acuity [153].
3.1.1.2.5. Suprefact® Depot
Suprefact® Depot is a preformed rod-like PLGA implant comprising buserelin, a luteinizing
hormone-releasing hormone analogue. This implant is supplied with two different buserelin

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dosages, 6.3 and 9.45 mg, that are intended for prostate cancer therapy through SC injection
every 2 and 3 months, respectively [154]. Pettersson et al. [155] conducted a prospective
clinical study to determine the duration of androgen deprivation in prostate cancer patients.
The authors observed that a single administration of Suprefact® Depot 9.45 mg decreased the
serum testosterone levels below the lower castration limit for about 6 months, which holds
the promise for neoadjuvant therapy or long-term management of androgen deprivation.
3.1.1.2.6. Propel® and Sinuva®
The PROPEL® family is a group of sinus stents composed of a PLGA matrix loaded with
mometasone furoate, a corticosteroid anti-inflammatory agent. Intersect ENT manufactures
PROPEL® implants (PROPEL® for use in the ethmoid sinus, PROPEL Mini® for use in the
ethmoid sinus and frontal sinus ostia, PROPEL Contour® for use in the frontal sinus ostia and
maxillary sinus ostia) with diverse shapes based on PLGA including a blend of PLGA and
polyethylene glycol that are designated for different types of sinuses, but all containing 0.37

of
mg of mometasone furoate that releases the drug over a 1 month period in the body.
SINUVA® (indicated for use in adults with nasal polyps who have had previous ethmoid

ro
sinus surgery) is a newer PLGA sinus implant delivering a much higher dose of mometasone
furoate (1.35 mg) over a longer drug release duration of 3 months. Both the PROPEL® family
-p
and SINUVA® products are administrated using a special delivery system. For example, the
PROPEL® or PROPEL® Mini implant is inserted in the ethmoid cavity after endoscopic sinus
surgery for preventative control of postoperative obstruction and inflammation.
re
PROPELMini® acts as a sinus spacer and supplies slow and sustained release of mometasone
furoate to sinus mucosa for the management of chronic rhinosinusitis. In addition, as shown
lP

in Figure 6, due to its spring-like configuration, the inserted PROPEL® prevents lateralization
of the turbinate and the postoperative formation of granulation tissue and scarring [156].
na
ur
Jo

Figure 6. Image depicting the Propel® Mini implant applicator/delivery device and
schematically illustrating the implant when inserted in the inflamed sinus. The spring-like

20
 Journal Pre-proof

shape not only opens the sinus but also releases the corticosteroid drug over 30 days. Images
modified with permission from Intersect ENT [157]
3.1.1.2.7. SinoFuan®
SinoFuan® is a preformed PLGA based implant loaded with 5-fluorouracil, a metabolic
anticancer drug, that is intended for intraperitoneal insertion during surgical operation for
gastric cancer. In a clinical study, short-term safety of SinoFuan® implants upon resection of
primary liver cancer was investigated. These implants demonstrated to be safe with minimum
impact on liver biomarkers. The clinical findings have encouraged further investigations to
provide new clinical insights into the efficacy of SinoFuan® in hepatic cancer [158]. It has
been shown that 5-fluorouracil implants are nontoxic and can extend the survival rate of
advanced gastric cancer patients (3-year survival rate of 64.3% vs. 42.4%, P=0.018) [159]. In
a case study, a patient with history of peritoneal SinoFuan® implantation, the implant caused
local tissue necrosis and fibrotic lumps that overloaded the liver although it demonstrated

of
curative effect on the cancer. Analytical examination of the fibrotic mass showed that it
contained fluorouracil. This rare complication of SinoFuan® implants shows the need for

ro
better understanding the cause of this problem and improving the application of such
implants in different gastric cancer [160]. -p
3.1.1.2.8. Zoladex®
Zoladex® is a preformed cylindrical PLGA-based rod containing an agonist analogue of
re
luteinizing hormone-releasing hormone, indicated for the long-term management of breast
and prostate cancer. Zoladex® unit-dose is implanted via SC injection into the anterior
lP

abdominal wall every three-months (10.8 mg) or one-month (3.6 mg). The use of goserelin
acetate 3.6 mg implant was reported to be comparable to 3-months 10.8 mg dosage form, in
terms of both efficacy and safety [161,162]. Zoladex® 3.6 mg has shown some success as a
na

long-acting alternative therapy to surgical castration of patients with prostate cancer

[163,164]. In a clinical study by Ahmed et al. [165], monthly insertions of Zoladex® 3.6 mg
and constant infusion of goserelin over 60 days demonstrated similar effects on testosterone
ur

and luteinizing hormone control. In a randomized multi-center trial conducted in patients

with advanced prostate cancer, Zoladex® 3.6 mg exhibited much better tolerability than
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diethylstilbestrol 3 mg, a daily injectable analogue of luteinizing hormone-releasing hormone.

Irrespective of the goserelin acetate dosing, Zoladex® induces an increase in testosterone
levels in the first week of implantation, followed by a constant depletion and the castration
levels are obtained and maintained from the 4th week to week 18 [166–168]. Despite
differences in drug content, the two Zoladex® forms have similar drug release kinetics, and
their endocrinological and clinical effects are comparable [169]. Zoladex® 10.8 mg seems to
correspond well to 3-consecutive administrations of Zoladex® 3.6 mg, but further in vitro-in
vivo correlations studies would provide valuable insights for comparative assessment of these
two formulations. An interesting future area for exploitation of Zoladex® could be
combination therapies, associating long acting goserelin acetate with hormone replacement
therapy (i.e., using oestrogen-progestogen conjugate). A prospective placebo-controlled study
by Moghissi et al. [170] demonstrated that in endometriosis patients, the combination of
Zoladex® 3.6 mg monthly with oestrogen-progestogen conjugate 0.3–5 mg daily improves the
tolerability of each therapy, without any loss of efficacy. Using this combination regimen, the
authors observed a remarkable attenuation of the hypoestrogenic side effects of goserelin and
loss of bone mineral density due to the minimized hormone replacement.

21
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3.1.1.2.9. Eligard®
Similar to Atridox®, the design of Eligard® is also based on in situ forming gel (Atrigel®
formulation) that is loaded with leuprolide acetate for the treatment of advanced prostatic
cancer. Upon use, the Atrigel® delivery system (PLGA dissolved in NMP) is mixed with
leuprolide acetate powder, forming suspensions, which subsequently solidify as a depot in
vivo that regulates the release of leuprolide. [171]. Eligard® is available in different forms
varying in PLGA composition and drug contents [172]. Clinical studies showed that Eligard®
could sustain the release of leuprolide over the designed release duration (4 – 26 weeks
depending on the formulation used), with a constant leuprolide serum concentration from 0.1
- 2 ng/mL for all four dosages [172]. However, 3-5 hour after injection, a high burst release
was observed, ranging from 25.3 ng/mL for 7.5 mg Eligard® up to 150 ng/mL for 30 mg
Eligard®. Such initial release might be due to the slower and incomplete solid depot
formation in vivo, causing the ―free‖ leuprolide rapidly washed out form the depot. Another

of
issue for Eligard® is the use of the organic solvent N-methyl-2-pyrrolidone (NMP). Even
though NMP is used in many FDA approved products, it has a potential for causing local

ro
tissue irritation [173]. Thus, current research efforts are focused on development of in situ
forming gels from aqueous solution, triggered by body temperature or pH [174].
-p
3.1.1.2.10. Perseris®
Perseris® is another example of Atrigel® delivery system. Perseris® is releasing risperidone
re
for the treatment of schizophrenia in adults. Upon mixing, risperidone forms a suspension in
PLGA (L/G 80:20 molar ratio) and NMP-based Atrigel delivery system, which then forms a
solid depot in vivo. Similar to Eligard®, Perseris® also shows two peaks of risperidone in
lP

plasma. The first peak occurs after 4-6 hours post administration because of drug leakage
during the depot formation process (Cmax 10.9 ng/mL for 120 mg dose). Around day 10-14
post administration, a second peak was observed with a similar magnitude as the burst
na

release, which is likely due to onset of PLGA matrix degradation and bulk erosion [175].
3.1.1.2.11. Scenesse®
ur

Scenesse® is an afamelanotide (a melanocortin 1 receptor agonist) loaded PLGA rod implant

for relieving pain associated with phototoxic reactions from erythropoietic protoporphyria in
Jo

adult patients. Scenesse® is a single rod implant with a length of 1.7 cm and a diameter of
1.45 mm, containing afamelanotide. Upon implantation, Scenesse® showed a median Tmax of
36 hours, and the apparent half-life of afamelanotide was around 15 hours. Multiple clinical
trials, where more than 800 patients have been treated with Scenesse®, showed that the
formulation is well tolerated and reduces the incidence as well as the severity of phototoxic
reactions [176].

3.1.2. Marketed non-PLGA long acting parenteral formulations

This section discusses prolonged release parenteral formulations composed of polymers other
than PLGA, namely sodium hyaluronate, poly[1,3-bis(carboxyphenoxy)propane-co-sebacic-
acid (PCPP-SA), triethylene glycol poly(orthoester), etc. These polymers are potential
alternatives for PLGA, while sharing similar biocompatibility profiles and providing
controlled release over prolonged periods, for loading drug molecules that are incompatible

22
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with PLGA. Table 3 summarizes the marketed formulations of this category, and further
details are provided in the following paragraphs.
Table 3. Marketed non-PLGA long acting parenteral formulations
Registere Drug Manu Indicat Route Dosing Lo Water Type of carrier Highest Drug Annu
d name factur ion of interval g solubili system dosage loadin al sale
er admini (week) P ty (mg) g (Year
stratio (mg/m %(w/ 2019)
n L) w) M$

Somatro Somatro Biopar GH SC 1 N 5.00 Hyaluronate 24.0 Not Not

pin pin tners Deficie A found found
Biopartn and ncy,
ers® Turner
LG Syndro
Life me
Scienc
es, Ltd

of
Gliadel® Carmusti Eisai Gliobla SC - 1.5 4.00 Wafer made of 7.7 3.85 40
Wafer ne stoma Polifeprosan 20, (Year
multifo poly [bis 2007)

ro
rme (pcarboxyphenox
y)] propane and
-p sebacic acid in a
20:80 molar ratio,
diameter 1.45 cm,
thickness 1 mm
re
Sustol® Graniset Heron Vomiti SC 1 2.6 0.43 Biochronomer® 10.0 2 14
ron therap ng technology:
eutics (chemo tri(ethylene
lP

therapy glycol)
) poly(orthoester)
(TEG-POE), 392
mg, and
na

polyethylene
glycol
monomethyl
ether, 98 mg)
ur

Trivaris® Triamcin Allerg Intraoc intrvitr 3 and 6 2.5 0.04 2.3% (w/w ) 8.0 Not Not
olone an ular eal sodium found found
acetonid inflam hyaluronate;
Jo

e mation 0.63% sodium

chloride; 0.3%
sodium
phosphate,
dibasic; 0.04%
sodium
phosphate,
monobasic; and
water for
injection

Buvidal® Bupreno Camur Opioid SC 1 and 4 4.9 0.02 FluidCrystal 32.0 Not Not
rphine us AB depend Depot found found
hydrochl ence
oride

Plenaxis® Abarelix Specia Prostat IM 4 2.8 0.01 Abarelix/CMC 100.0 84 Not

lity e complex found
Europ cancer
ean
Pharm

23
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Somatuli Lanreoti Ipsen Acrom SC 4 1.1 0.50 Peptide self- 120.0 100 1154
ne de Pharm egaly assembly
Depot® acetate a
Biotec
h

Firmago Degareli Astell Prostat SC 4 and 14 3.1 0.02 Peptide self- 240.0 55.2 Not
n®, x acetate as e assembly found
cancer
Gonax®

Solubility and logP values obtained from drug bank [89]; other data are from PharmaCircle®
data base [14].
3.1.2.1. Somatropin Biopartners®
Somatropin Biopartners® (Decalge®) is a sustained-release formulation composed of MPs of

of
sodium hyaluronate (microgels) loaded with Somatropin, a recombinant human growth
hormone (rhGH). Somatropin Biopartners® is produced using spray-drying. This method was
found to be suitable for microgel preparation, and the bioactivity of the encapsulated rhGH

ro
was preserved conserved upon manufacturing. The formulation containing rhGH and sodium
hyaluronate in mass ratio of 1:1 exhibited constant increase in serum concentration in
-p
cynomolgus monkeys for 6 days [177]. The indications for Somatropin Biopartners® include
growth hormone deficiency and turner syndrome, which are both treated by weekly injections
of the microgels via SC route. A case study demonstrated that Somatropin Biopartners® 6 IU
re
(2 mg), that was administered weekly for 26 weeks, improved body composition and quality
of life without any significant adverse effects in adult patients with somatopause [178]. In
lP

another clinical study, the effect of extended release growth hormone therapy on survivor
patients with severe skin burn wound was investigated [179]. Somatropin Biopartners® 6 IU
was found to be effective and safe for 3 months treatment of sarcopenia (loss of muscle mass
na

due to severe burning), which previously required daily injection of rhGH 1 IU. In this
randomized study, Somatropin Biopartners® exhibited significant increase in oxygen
consumption, insulin-like growth factor I and adiponectin levels, with no remarkable effects
ur

on body weight, blood pressure, body fat content and bone mineral composition [179].
3.1.2.2. Gliadel® Wafer
Jo

Gliadel® Wafer is biodegradable implant with a diameter and thickness of 1.45 cm and 1 mm,
respectively. Each wafer is composed of polyanhydride copolymer 192.3 mg (polifeprosan
20), and 7.7 mg carmustine, an antineoplastic drug. Polifeprosan 20 is a biodegradable
polymer composed of poly [bis (p-carboxyphenoxy) propane:sebacic acid] in a molar ratio of
20:80 [180]. Regarding formulation of Gliadel®, it is worth mentioning that the drug was first
incorporated into polymeric MPs by spray-drying method, and then the preformed MPs were
compression-moulded to yield implantable wafers, as shown in Figure 7, to fill the resection
cavity after brain tumour surgery [181]. Gliadel® Wafer‘s biodegradability in human brain
was determined in a study that demonstrated degradation of about 70% of the polymeric
network within three weeks post implantation; but Wafer remnants were found to be present
up to 232 days during re-operation and autopsy. The composition of these remnants mainly
included water and monomeric components as well as traces of carmustine [182]. Following
surgical brain tumour resection, the implantation of up to 8 wafers alongside the wall of the
resection cavity allows to localize chemotherapy in the peritumoral surgical bed [183].
Gliadel® Wafer was tested in a randomized placebo-controlled, double-blind phase III trial
24
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using 240 patients intraoperatively diagnosed with initial malignant glioma [184]. Data
indicated that Gliadel® Wafer implantation on primary surgical resection is well tolerated, as
no systemic toxicities or adverse effects were observed, and does not necessitate another
surgery since the resultant local chemotherapy provides sufficient clinical benefits (with
death risk reduction of 29% for treated group). In another phase III clinical trial, Gliadel®
Wafer implanted at the resection cavity achieved 100-fold higher local concentrations than
systemic administration of carmustine formulation, thus providing enhanced site-specific
efficacy as well as reduced systemic toxicity, based on the undetectable drug levels in plasma
[185]. In addition, the authors observed a significantly longer median survival for the
treatment group (11 patients treated with Gliadel® Wafers) compared to the placebo group
(13 patients treated with placebo Wafers), 14.7 versus 9.5 months, respectively. For more
information about release and degradation of Gliadel® Wafers see our previous review study
[7].

of
ro
-p
re

Figure 7. Gliadel Wafers implanted into a tumour resection cavity upon brain tumour surgery
lP

[181]. Reproduced with Permission from Elsevier.

3.1.2.3. Sustol®
na

Sustol® is a compact kit consisting of a single-dose syringe that contains a sterile in situ
gelling viscous liquid. The main composition of Sustol® includes an antiemetic agent,
granisetron, and two biodegradable polymers triethylene glycol poly(orthoester) polymer and
ur

polyethylene glycol monomethyl ether (mPEG), respectively. Poly(orthoester) polymeric

matrix undergoes surface biodegradation. Surface erosion leads to controlled drug release and
Jo

maintaining neutral pH in the core of the matrix, which can be an advantage for loading pH
sensitive drugs. Polyethylene glycol is added to the triethylene glycol poly(orthoester)
polymer likely to dissolve the drug, lower the viscosity of the polymer for ease of injection
and facilitate drug release from the matrix. It has been shown that addition of 2 kDa mPEG
1% (w/w) to poly(orthoester) polymer significantly increases the release kinetics of model
drug from the matrix [186].
Sustol® is administered on a weekly basis, via SC injection into the upper arm or abdomen
that releases granisetron over more than 5 days. [187]. Sustol® is used for prevention of acute
and delayed nausea and vomiting due to highly or moderately emetogenic anticancer
chemotherapy or chemotherapeutic combination of anthracycline and cyclophosphamide
[188]. The Extended release formulation Sustol® after SC administration exhibits much
greater plasma half-life (26–28 hours) than IV and oral granisetron (i.e., 9 and 6 hours,
respectively) [189].
3.1.2.4. Trivaris®

25
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Trivaris® is a preservative-free gel of triamcinolone acetonide, a synthetic water-insoluble

glucocorticoid corticosteroid for intrvitreal injection[190,191]. A multicenter randomized
clinical trial demonstrated the efficacy of intravitreal triamcinolone injection in treating
vision loss associated with macular edema due to central retinal vein occlusion [192,193]. In
terms of safety, Trivaris® is preferred by many specialists over other preservative-containing
intravitreal formulations of triamcinolone (e.g. Kenalog® that contains benzylic alcohol, see
section 3.3), which expose to high risk for retinotoxicity [191,194]. Drug release from this
formulation is governed by dissolution kinetics and particle size of the drug rather than
hyaluronic acid polymer. Sodium hyaluronate is added to this composition most likely as
viscosity enhancer to enable better injectability. As compared to Kenalog® higher drug
concentration (40 mg/mL vs 80 mg/mL) is used in Trivaris® and therefore a viscosity
enhancer such as hyaluronic acid was used to minimize the sedimentation and enhances the
injectability. Particle size was found to be the key determining drug release duration of two
marketed long acting formulation of triamcinolone acetonide [195]. Particle size (X90) was

of
47 μm for Kenalog and 22 μm for Trivaris and therefore Kenalog showed longer drug
exposure in vitreous of rabbits.

ro
3.1.2.5. Buvidal® -p
Buvidal® is a pre-filled solution for extended release of buprenorphine, an opioid drug
indicated for opioid dependency. Buvidal® is based on FluidCrystal Depot technology, which
is a solution containing soybean phosphatidylcholine, glycerol dioleate and ethanol (weekly
re
dose) or NMP (monthly dose). Upon injection, ethanol is exchanged by water and the lipids
transform into a liquid crystalline gel structure encapsulating buprenorphine. Drug release is
lP

driven by gel matrix degradation, catalyzed by locally present lipase. After administration of
Buvidal®, a median Tmax of 24 hours and 6-10 hours was obtained with a complete absolute
bioavailability for the weekly and monthly dosage group, respectively. For the respective
na

dose interval 8–32 mg and the dose interval 64–128 mg, buprenorphine exposure is
proportionally increased with the given dose [196]. In a double-blind, double-dummy
randomized clinical trial, weekly and monthly SC buprenorphine depots (Buvidal®) were
ur

found to be noninferior to daily sublingual administrations of buprenorphine/naloxone

combination in 428 subjects with opioid use disorder treated over 24 weeks [197,198]. The
authors observed that 35.1% of the participants in the Buvidal® group tested negative in the
Jo

opioid urine testing, while only 28.4% in the daily sublingual buprenorphine group showed
negative urine screens.
3.1.2.6. Plenaxis®
Plenaxis® is based on the LEAP (Ligand Evolution to Active Pharmaceuticals) technology,
which combines the anionic polymer of sodium carmellose and the cationic abarelix acetate,
a synthetic peptide. Due to the electrostatic interactions of the two oppositely charged
molecules, they form a complex leading to precipitation. The precipitated complex is then
isolated, dried and milled to produce products with the desired particle size. The active
molecule, abarelix, is a gonadotropin releasing hormone receptor antagonists, thus Plenaxis®
is indicated for prostatic cancer. Each Plenaxis® complex contains 100 mg abarelix, and upon
use, the complex is reconstituted with 2.2 mL 0.9% sodium chloride solution into suspensions
that are monthly injected via the IM route. Following administration, abarelix is slowly
released reaching a mean peak concentration of 43.4 ng/mL approximately after 3 days post
administration [199].

26
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3.1.2.7. Somatuline ® Depot

Somatuline® Depot or Somatuline® Autogel is another version of lanreotide long acting
formulation indicated for the treatment of acromegaly with a dosing interval of 1 month.
Unlike Somatuline® LA that is based on PLGA MPs delivery system, Somatuline® Depot is a
carrier free system containing only water for injection and acetic acid for pH adjustment
based on peptide self-assembly technology. The success of Somatuline® Depot is based on a
liquid crystal technology, and lanreotide is believed to undergo self-assembly, forming
dimers firstly and finally nanotubes. The nanotubes are densely packed, contributing to a
smaller injection volume (max. 0.5 mL). Upon injection and contact with physiological
fluids, a local depot is formed sustaining the release of lanreotide via dissociation of peptide
monomers and dimers from nanofibers. In clinical studies, during the first day post dosing,
Cmax was obtained in the range of 4.3-8.4 ng/mL for the 60, 90 and 120 mg dose with a mean
absolute bioavailability of 73.4, 69.0, and 78.4%, respectively [200]. Lanreotide showed

of
sustained release with a half-life of 23 to 30 days and average serum concentrations > 0.9
ng/mL throughout 28 days for all dose groups. This product showed linear pharmacokinetics

ro
in repeated administration once every 28 days. Cmin, Cmax and AUC elevated in a dose-
dependent linear trend followed by reduction in GH levels in acromegalic patients. It is an
appealing technology since neither polymers nor other excipients are needed, however, the
-p
applied self-assembly process is only suitable for certain peptides [201,202].
Self- assembly in peptides is driven by several forces including van der Waals forces,
re
electrostatic interactions, hydrophobic interactions, hydrogen bonding and π–π stacking
(aromatic) interactions [203]. In lanreotide the main driving force for self-assembly is
lP

hydrogen bonding and π–π stacking interactions between its residues [204]. Up to now,
lanreotide is a unique example of a peptide with pharmacologic activity which has self-
assembling property while other self-assembling peptides with biological activity have been
na

developed based on conjugation of a assembling moiety, such as hydrocarbon chains, to

exploit hydrophobic interactions for assembling induction [205].
3.1.2.8. Firmagon® and Gonax® 3 Month Depot (Japan)
ur

Firmagon® and Gonax® 3 Month Depots are based on peptide self-assembly technology
Jo

which, provide sustained release of degarelix acetate, a gonadotropin releasing hormone

(GnRH) receptor antagonist, for 1 and 3 months, respectively [206]. Degarelix acetate has a
high-water solubility (100 mg/mL). However, when the concentrations are in the range of
0.1-10 mg/mL, the solution tends to form gels after certain time and dependent on the
concentration and temperature. The peptide self-assembly serves as a depot for sustained
release without the need of any polymers or additional treatment of the drug substance. The
only excipient for Firmagon® is mannitol, possibly as a bulking agent or stabilizer during
lyophilization. The PK behavior of degarelix extended release is strongly impacted by drug
concentration in the injection solution, since gel formation is concentration dependent.
Firmagon® is provided in 240 mg (given as two injections of 120 mg each reconstituted in 3
mL water for injection) as the starting dose, and then 80 mg (reconstituted in 4 mL water for
injection) is administrated as the maintenance dosage every 28 days. Before administration,
the drug powder is reconstituted with water for injection, followed by SC injection. Clinical
studies of Firmagon® in patients with prostate cancer, by using leuprolide 7.5 mg (Lupron
Depot®) as the control group, showed the efficacy of Firmagon® in suppressing testosterone

27
 Journal Pre-proof

secretion and maintaining such suppression to castration levels (testosterone ≤ 50 ng/dL)

during 12 months of treatment [206].
3.2. Marketed oil-based long acting parenteral formulations
As shown in Table 4, several oil-based parenteral formulations have reached pharmaceutical
market that demonstrates potential of the technology to achieve clinical success. The
following paragraphs provide key details about the marketed long acting parenteral oil-based
formulations.
Table 4. Marketed oil-based long acting parenteral formulations
Registered Drug Manufacture Indication Route Dosing log Water Highest Annual
name r of interv P solubility Dosage sale (Year
admin al (mg/mL) 2019) M$
istrati (week)
on

of
Androcur Cyprotero Bayer Cancer, IM 2 3.8 0.0010 100 Not found
Depot® ne acetate Prostate, Other mg/mL in
3 mL

ro
Clopixol Zuclopent H Lundbeck Schizophrenia, IM 4 7.4 0.0026 200 Not found
Depot® hixol A/S Maintenance -p mg/mL in
decanoate 10 mL

Delatestryl® Testostero Valeant Breast cancer IM 4 5.1 0.0004 200 2 (Year

ne and mg/mL in 2008)
re
enanthate hypogonadism 5 mL

Lyogen Fluphenazi H Lundbeck Psychotic IM 6 7.2 0.0002 25 mg/mL Not found

Depot® ne A/S Disorders, in 10 mL
lP

decanoate Other

Haldol Haloperido Johnson & Tourette's IM 3 7.2 0.0100 100 Not found
Depot® l decanoate Johnson syndrome, mg/mL in
Schizophrenia, 1 mL
na

Fluanxol Flupenthix H Lundbeck Schizophrenia, IM 4 7.2 0.0002 200 Not found

Depot® ol A/S Maintenance mg/mL in
decanoate 1-5 mL
ur

Makena® 17 Alpha- Lumara Preterm Birth IM 1 5.8 0.0008 250 122

hydroxypr Health mg/mL in
ogesterone 1-5 mL
Jo

caproate

Faslodex® Fulvestrant AstraZeneca Breast cencer IM 4 6.5 0.0067 50 mg/mL 892

Plc in 5 ml

Naldebain Dinalbuphi Lumosa Pain IM 1 5.3 0.0044 75 mg/mL Not found

ER® ne Therapeutics management in 2 mL
sebacate Co., Ltd.

Solubility and logP values obtained from drug bank [89]; other data are from PharmaCircle®
data base [14].
3.2.1. Androcur Depot®
Androcur Depot® is an oil-based solution in 3 mL ampoules, containing mainly castor oil and
cyproterone acetate, which is a derivative of progesterone with anti-androgen effects.
Androcur Depot® is developed for parenteral management of prostatic cancer. The same
dosing (300 mg IM) was as efficient as 50 mg tablets of cyproterone acetate administered
orally twice a day in the treatment of hot flush symptom, a hostile symptom associated with
antiandrogen therapy in prostatic cancer patients [207]. Similar studies reported that weekly

28
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IM injections of Androcur Depot® yielded the same plasma levels of cyproterone acetate as
50 mg tablets orally administered 4 to 8 times a day (200–400 mg/day) [208,209]. In other
words, one injection of Androcur Depot® (300 mg) is only 21% of the minimal oral dose (200
mg x 7 days) required for weekly management of prostatic cancer.
3.2.2. Clopixol Depot®
Clopixol Depot® is an oil-based formulation of zuclopenthixol decanoate, a neuroleptic agent,
composed of Viscoleo® a medium chain triglycerides/miglyols. Clopixol Depot® is indicated
for maintenance treatment of schizophrenia [210]. It is administered intramuscularly at the
dose of 200–400 mg every 2–4 weeks, depending on disease evolution and patient tolerance.
As a long-acting injectable formulation, Clopixol Depot® administered every two weeks (72
mg/2 weeks) exhibited sustained zuclopenthixol serum levels that were in the same range as
those observed with oral administrations of pure zuclopenthixol 4–30 mg on daily basis
[211]. Javed et al. [212] reported a significant reduction in self-harming behaviour of a 32-

of
years old woman following fortnight IM injection of Clopixol Depot® 400 mg.
3.2.3. Delatestryl®

ro
Delatestryl® is an injectable oil-based solution of testosterone enanthate, a testosterone
-p
prodrug dissolved in sesame oil. Delatestryl® is intended for the treatment of hormone
deficiency (male hypogonadism) [213], but some clinicians prefer using weekly SC injections
of 50 mg [214]. A 24-week multicenter, randomized, parallel-group study by Dobs et al.
re
[215] compared biweekly IM injection of Delatestryl® 200 mg with nightly topical
application of a testosterone-based transdermal gel 2.5 mg (Androderm®). It was found that
lP

the two treatments were efficacies in replacing testosterone in hypogonadal men [215].
However, 60% of patients reported skin irritation with topical Androderm® whereas IM
injection of LAI formulation exhibited 33% local reaction. But, unwanted increase in
na

haematocrit was higher for the IM group as compared to topically administered group (43
versus 15%) [215].
3.2.4. Fluanxol Depot®
ur

Fluanxol Depot® is composed of decanoic ester of flupenthixol, a neuroleptic thioxanthene,

Jo

dissolved in Viscoleo® for the treatment of schizophrenia. A comparative study revealed no

difference between serum levels of flupenthixol following IM injections of 20 and 100
mg/mL [216]. The lack of correlation between depot concentration and therapeutic response
cannot be explained by simple diffusion of lipophilic prodrug from oily depot to surrounding
tissues. However, it is likely due to metabolic breakdown of the formulation that takes place
in the local tissue or distribution of prodrug to blood circulation via lymphatic system and
converting to active drug by chemical or enzymatic rout. This similarity in depot properties
of the two formulations with different drug contents was supported by Kirk et al. [217], who
also observed similar serum concentrations with IM injections of 15–300 mg to different
individuals‘ groups (every 2, 3 and 4 weeks) for 4 months. It seemed that the administered
dose was enough to reach the maximal plasma level of 6 ng/mL on day 4–7 upon injection.
However, a significant difference was observed when comparing repeated daily oral
administrations with weekly IM injections of flupenthixol decanoate. Oral administrations
exhibited slow absorption, with quicker peak plasma concentrations (3–6 hours) and shorter
half-lives (19–39 hours) than those of the IM injections, respectively 3–5 day and 3–8 days
[218,219]. The intervention report by Mahapatra et al. [220] demonstrated no difference in

29
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clinical efficacy of flupenthixol decanoate IM depot in comparison with oral antipsychotics in

schizophrenia patients. The study revealed similar outcome in terms of survival, global
impression, relapse rate and leaving the study early.
3.2.5. Haldol Depot®
Haldol Depot® is an oil-based solution of haloperidol decanoate in sesame oil. Haldol Depot®
is used for the management of psychotic disorders (e.g. Tourette's syndrome, Schizophrenia).
The maximum plasma concentrations of haloperidol are obtained on around day 6 and its
half-life is approximately 3 weeks [213]. Using a three-year multisite study conducted at
various systems of schizophrenia care in the United States, Shi et al. [221] demonstrated a
clear difference between patients treated with haloperidol oral and those treated with
haloperidol depot, in terms of patient‘s characteristics and drug use patterns. The parenteral
formulation showed higher medication possession ratios, while oral administration
necessitated an augmentation and prolongation of the antipsychotic regimen. These efficacy-

of
and compliance-related observations were further confirmed by Zhu et al. [222]. These
authors demonstrated that schizophrenia patients can tolerate Haldol Depot® for much longer

ro
periods than oral administration of haloperidol (which can be subject to discontinuation
somewhere soon). -p
3.2.6. Lyogen Depot®
Lyogen Depot® is the ester of decanoic acid with fluphenazine (a piperazine phenothiazine),
re
dissolved in sesame oil. used for the treatment of chronic psychotic illness (schizophrenia).
Following Lyogen Depot® administration, the peak plasma concentrations of fluphenazine are
lP

observed within 8–24 hours, while the apparent half-life is about 14 days. The correlation
between dose and plasma concentration was found to be higher for the depot formulation than
after oral administration, which also exposes the drug to potential enzymatic deactivation in
na

the gut and first-pass metabolism in the liver [223]. However, the rapid increase in plasma
concentrations on day 1 of the first IM injection was associated with unwanted adverse
effects (including extrapyramidal symptoms), which were observed only temporarily due to
ur

the subsequent decrease and maintenance in plasma concentrations [224].

3.2.7. Makena®
Jo

Makena® is a solution of 17 α-hydroxyprogesterone caproate (a synthetic progestin) in castor

oil. It is administered for prevention of singleton spontaneous preterm birth in women. After
IM injection, the plasma concentration of the drug reaches 27.8 ng/mL after 4.6 days, with an
elimination half-life of 7.8 days [68]. A randomized and placebo-controlled trial investigated
the efficacy of Makena®. The weekly IM administration of Makena® 250 mg for 16–20
weeks, in 463 women with high risk of spontaneous preterm deliveries, demonstrated the
clinical long acting efficacy of the formulation and led to FDA-approval of Makena® [67].
3.2.8. Faslodex®
Faslodex® is fulvestrant injection in ethanol 96%, benzyl alcohol, benzyl benzoate and castor
oil. Fulvestrant is an estrogen receptor antagonist, which can downregulate the estrogen
receptor. Fulvestrant binds to the estrogen receptors in a competitive manner with a similar
level of affinity to estradiol. Faslodex® is indicated for the treatment of breast cancer in
postmenopausal women. Compared to IV or IM injection of fulvestrant, which is rapidly
cleared at a rate of 10.5 mL plasma/min/kg (similar to hepatic blood flow), Faslodex ® can

30
 Journal Pre-proof

maintain the plasma level of fulvestrant in a range of maximal 3-fold difference between peak
and trough concentation 28 ± 3 days post dosing. In a phase III open-label, randomized,
multicentre trial conducted over about 14.4 months, it was observed that monthly IM
administrations of Faslodex® 250 mg/mL were as effective as daily oral administrations of
anastrozole 1 mg in 451 postmenopausal women with hormone receptor-positive advanced
breast cancer [225]. In fact, data revealed similar clinical benefits from the two formulations;
with median times to progression of 5.5 and 5.1 months, and objective response rates of
20.7% and 15.7%, monthly fulvestrant and daily anastrozole, respectively.
3.2.9. Naldebain®
Naldebain® is a long acting formulation of nalbuphine, a semi-synthetic opioid, for pain
management. Naldebain® is a diester of sebacic acid and nalbuphine that yields the prodrug
dinalbuphine sebacate, which is slowly released into the blood stream and chemically and/or
enzymatically hydrolyzed to the parent drug, which exerts its analgesic effect [226]. In an

of
open-label phase I study, Naldebain® was IM injected to healthy volunteers by using 20 mg
nalbuphine HCl as the reference (20 mg, IM, Bain® by Genovate Biotechnology Co., Ltd,

ro
Taiwan). The bioavailability of nalbuphine from Naldebain® relative to that from nalbuphine
HCl was 85.4%. The mean absorption time of nalbuphine from Naldebain ® was 145.2 hours
-p
with a release duration of 6 days [227]. In the 6 center clinical studies, 221 patients received
treatment by Naldebain® or placebo, and extended analgesic effects were shown by
Naldebain®, with pain intensity significantly reduced through 48 hours and 7 days after
re
hemorrhoidectomy [228].
lP

3.3. Marketed long acting drug products based on drug crystal suspensions
Poorly water-soluble drug particles (drug crystals) may arise from co-crystallization and/or
particulate modification of drug substance. Owing to high drug concentrations commonly
na

used (200–400 mg/g), the use of drug crystal technology enhances bioavailability and drug
exposure irrespective of the administration route [77,229]. Despite the challenges associated
with tissue exposure to pure drug particles (which may cause local tissue damage in the case
ur

of irritative drugs such as non-steroidal anti-inflammatory drugs) [78], there have been
several regulatory approvals of drug crystal suspensions for long-term parenteral
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applications. Marketed parenteral micro and nanocrystal suspensions are summarized in

Table 5. Detailed descriptions of these products are provided in the following paragraphs.
Table 5. Marketed long-acting parenteral suspensions
Registered Drug Manufacture Indication Route of Dosin log Water Highest Annual
name r administr g P solubility Doseage sale
ation interv (mg/mL) (mg/mL) (year
al 2019)
(week M$
)
Agofollin Estradiol Biotika Hypoestrog SC 1 4.5 2-4 5 mg/mL
Depot® benzoate Bohemia enism in 2 mL

Aristada® and Aripiprazole Alkermes Schizophren IM 4-8 7.9 0.0002 275.83 189
Aristada lauroxil ia mg/mL in
InitioTM 2.4 mL
Betason L.A® Betamethasone Caspian Inflammator IM, intra- 2 1.8 0.066 6 mg/ml Not
Tamin y & allergic articular, in 1 mL found
Pharmaceutic states intrabursa
al Co. l or
intraderm

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al

Bicillin® L-A Penicillin G Pfizer Syphilis, IM 4 1.9 0.285 2400000 59

benzathine Prophylaxis IU in 4 (Year
mL 2007)
Depo-Medrol Methylpredniso Pfizer Epicondyliti intra- 1 2.6 0.019 10 mg/mL 469
/Lidocaine® lone acetate/ s, Others /peri- lidocaine
lidocaine articular hydrochlo
hydrochloride and intra- ride/40
bursal mg/mL
methylpre
dnisolone
acetate in
1-5 mL
Depo-subQ Medroxyproges Pfizer Contracepti IM 14 4.1 0.001 160 127
Provera 104® terone acetate on & mg/mL in (Year
and Depo- Endometrio 0.65 mL 2016)
Provera sis

of
Invega Paliperidone Janssen Schizophren IM 4 and 8.1 0.007 312 3330
Sustenna® palmitate Pharmaceutic ia 14 mg/mL in
and Invega als 0.875-

ro
Trinza® 2.625 mL
Kenalog® Triamcinolone Bristol-Myers Arthritis, IM, 1 2.5 0.04 80 mg/mL Not
acetonide Squibb inflammator intravitrea in 0.0625- found
y diseases
-p
l 2.5 mL

Zyprexa® Olanzapine Eli Lilly Schizophren IM 4 4.6 0.004 405 mg in 419

re
Relprevv® pamoate and_Co ia 1-2.7 mL
lP

Solubility and logP values obtained from drug bank [89]; other data are from PharmaCircle®
data base [14].
3.3.1. Agofollin Depot®
na

Agofollin Depot® is a microcrystalline aqueous suspension of estradiol benzoate, an

oestrogenic hormone synthesized by esterification of estradiol with benzoic acid. This ester
ur

derivative shows poor water solubility (2–4 mg/mL) and, as a prodrug, requires ester bond
hydrolysis for pharmacological action, which explains its long-acting profile. Agofollin
Depot® is supplied in ampoules containing 5 mg/mL for hormone therapy (i.e.,
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hypoestrogenism) by SC injection on a weekly basis. Due to its depot effect, SC

administration of estradiol benzoate 1 mg/week for 4 weeks was effective in inducing
significant changes in the bone blood flow and mineral content of the tibia in an in vivo study
on rats [230]. Similar results were obtained after SC administration of Agofollin Depot® at
the dose of 5 mg/kg body weight once a week [231,232]. Agofollin Depot® was also IM
administered at different doses. For example, IM injection of 10 mg/kg body weight in mice
twice a week was used for regulation of both serum leptin levels [233] and anterior pituitary
prolactin levels which was also achieved by IM injection of 1 mg twice a week in rats [234].

3.3.2. Aristada® and Aristada Initio®

Aristada® and Aristada Initio® are injectable suspensions for IM use, both delivering
aripiprazole lauroxil, an atypical antipsychotic, for the management of schizophrenia in
adults. Aristada Initio® (675 mg dose) is used as initial regimen in Aristada® based therapy in
combination with oral aripiprazole (30 mg dose), in conjunction with the first Aristada®

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injection[235,236]. Aripiprazole lauroxil is a prodrug of aripiprazole, which has a lower

aqueous solubility than aripiprazole (0.000237 and 0.00777 mg/mL, respectively) and allows
the preparation of a crystal suspension. After administration, the aripiprazole lauroxil crystal
suspension forms a local depot, resulting in sustained release of aripiprazole lauroxil over 4–8
weeks. The prodrug aripiprazole lauroxil is possibly first converted into N-hydromethyl
apripiprazole by enzyme-catalyzed hydrolysis and subsequently it is chemically hydrolysed
into aripiprazole. Aristada® and Aristada Initio® are not exchangeable because they have
different PK profiles in vivo. This difference in PK kinetics is likely caused by the smaller
particle size of Aristada Initio® suspension, which allows for quicker dissolution and faster
achievement of desirable aripiprazole levels [235–237]. The clinical efficacy and safety of
aripiprazole lauroxil depots has been demonstrated in randomized, double-blind, placebo-
controlled trials in schizophrenia or schizoaffective disorder patients [237,238]. For instance,
the clinical study by Meltzer et al. reported significant improvements in the positive and
negative syndrome scale from day 8 to 85 following gluteal monthly administration of 441–

of
882 mg of aripiprazole lauroxil to 623 patients with acute exacerbation of schizophrenia
[237].

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3.3.3. Betason L.A® -p
Betason L.A® is a long-acting injectable suspension of betamethasone, an anti-inflammatory
corticosteroid agent. Betason L.A® is supplied as a dual acting formulation in 1 mL ampoules
containing betamethasone acetate 3 mg and betamethasone (as disodium phosphate) 3 mg.
re
Owing to the anti-inflammatory and immunosuppressive activities of betamethasone, Betason
L.A® is used for multiple indications, such as inflammatory or allergic reactions, rheumatic
lP

disorders and for neoplastic diseases as a palliative treatment. Depending on the indications,
the administration of Betason L.A® is done through intramuscular, intra-articular, intrabursal
or intradermal injections. A pharmacokinetic study by Salem et al. [63] elucidated the
na

controlled release capabilities of this dual-acting suspension upon IM injection into healthy
human volunteers. The observed pharmacokinetic profiles demonstrated the prodrug nature
of hydrophobic betamethasone (acetate ester), which is responsible for extended release
ur

characteristics of the formulation while the soluble betamethasone (phosphate ester) releases
fast to achieve prompt onset of activity. A double-blind trial of intra-articular injections of
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betamethasone phosphate/betamethasone acetate suspension demonstrated an average

duration of about 14 days for symptoms of pain relief in patients suffering from rheumatoid
inflammations [239].
3.3.4. Bicillin® L-A
Bicillin® L-A is an aqueous suspension of penicillin G benzathine (600,000 units per 1 mL).
Penicillin G benzathine is a practically insoluble product, formed by co-crystallization of 2
molecules of penicillin G with one molecule of benzathine. Bicillin® L-A exhibits long-
lasting antibacterial effects due to slow dissolution of penicillin molecules from the almost
insoluble co-crystals. Bicillin® L-A 1.44 g (2.4 million units) is administered monthly by IM
injection for the management of primary or late syphilis (as a single immediate does or in
three doses, respectively). Bicillin® L-A is also used for the treatment and prophylaxis of
yaws and group A streptococcal pharyngitis associated with rheumatic fever and rheumatic
heart disease. The doses administered for these indications are 450 mg (0.6 million units) and
900 mg (1.2 million units) for children and adults, respectively [86].

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3.3.5. Depo-Medrol/Lidocaine®
Depo-Medrol/Lidocaine® is an injectable suspension containing methylprednisolone acetate
and lidocaine hydrochloride. Depo-Medrol/Lidocaine® is a LAI formulation intended for use
in inflammatory or rheumatic conditions requiring local glucocorticoid effects. Both doses
(0.1–2 mL) and parenteral routes of administration vary depending on the localization of
inflammation or rheumatism. When needed, Depo-Medrol/Lidocaine® is injected weekly via
intra-/peri-articular and intra-bursal routes or into the tendon sheath accordingly. Although
Depo-Medrol/Lidocaine® is a reputed long-acting formulation for localized anti-
inflammatory or anti-rheumatic management, there have been several cases of anaphylaxis
following its intra-articular injection [240,241]. The allergic reaction after injection can be
caused by sensitivity to the drug itself or excipients such carboxymethylcellulose or less
frequently polyethylene glycol [240], therefore further investigations are needed to
understand the cause of allergic reaction to ensure safe use of Depo-Medrol/Lidocaine®.

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3.3.6. Depo-subQ Provera 104®
Depo-subQ Provera 104® is a contraceptive formulation containing medroxyprogesterone

ro
acetate 104 mg/0.65 mL presented in a sterile prefilled and mono-dose injection system,
called Uniject®. Depo-subQ Provera 104® was developed from its parent formulation, namely
-p
Depo-Provera®, which was a 150 mg/mL solution of medroxyprogesterone acetate used for
IM contraception at the same dosing frequency (every three months). Apart from
re
convenience and easy administration, the use of SC injection (Depo-subQ Provera 104®)
offers several advantages including administration of only medroxyprogesterone acetate 104
lP

mg (instead 150 mg by IM) and reduced peak plasma concentrations. In comparative studies
between Depo-Provera® and Depo-subQ Provera 104®, the later demonstrated better
pharmacokinetic characteristics, including much stable sustained plasma levels of the drug, as
well as higher adherence and acceptability by the patients [242–248].
na

3.3.7. Invega Trinza® and Invega Sustenna®

Invega Trinza® is a sterile nanosuspension of paliperidone palmitate. The first registered
ur

paliperidone palmitate was Invega Sustenna®, a dose of 150 mg/ human that shows one
month release as compared to Invega Trinza® with a dose of 525 mg/human that is
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administered every three months [87]. The dose range for one-month injections is 50, 75,
100, or 150 mg/human whereas the dose range for three-month injections is 175, 263, 350, or
525 mg/human. Nanocrystal suspensions enables easy injection of high concentrated
suspensions e.g., in case of Invega Trinza® 525 mg drug is injected as single dose.
Noteworthy, paliperidone palmitate is a prodrug synthesized by esterification of paliperidone
with palmitic acid and particulate modification (nanosizing of the insoluble ester particles
using nanocrystal technology, wet media milling). Due to the limited solubility of
paliperidone palmitate nanocrystals and the necessity for ester bond hydrolysis (to free the
water soluble paliperidone), both the Invega Trinza® and Invega Sustenna® depots exhibit
sustained release following IM injection [88]. The time interval for Invega Trinza®
administration is 14 weeks for long-term management of symptomatic schizophrenia, which
is recommended only after at least 4-months treatment with Invega Sustenna® on a monthly
basis [87]. Following IM administration, the plasma concentration of the active metabolite
(paliperidone, which is 9-hydroxy-risperidone) is detectable after 1 day, and its half-life is
25–49 days [249], which results in a long-lasting pharmacological action. This extended

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release profile led to better tolerability, safety, convenience and compliance of antipsychotic
therapy, in comparison with oral administration [250].
3.3.8. Kenalog®
Kenalog® is an aqueous suspension of triamcinolone acetonide, a poorly water-soluble
derivative of triamcinolone, an anti-inflammatory drug. When compared to injectable
triamcinolone solution in a clinical study, triamcinolone acetonide LAI was associated with
less blood glucose elevation in patients with type-2 diabetes mellitus that were treated for
knee osteoarthritis as corticosteroids are known to increase blood glucose. Long acting
triamcinolone acetonide resulted in lower peak plasma levels and lower systemic exposure
compared to standard triamcinolone [251]. Similar systemic exposure of both triamcinolone
types was observed for patients with hip osteoarthritis [252]. Kenalog® is not only used for
the management of osteoarthritis; it is also administered via intravitreal injection for treating
vitreoretinal diseases such as refractory uveitis, diabetic retinopathy, retinal vein occlusion,

of
macular edema and degeneration. Despite the clinical successes reported, there have been
several safety issues related to intravitreal administration of Kenalog® when compared with

ro
preservative-free formulations of triamcinolone acetonide (e.g. Trivaris®) [194]. The
administration of Kenalog® was accompanied with retinal toxicity after 14 days, while
-p
triamcinolone acetonide suspended in non-preserved saline solution showed no toxicity after
3 months. Based on this observation, Lang et al. [253] suggested that the Kenalog® related
retinotoxicity could be due to one of its excipients, probably benzyl alcohol. This was
re
supported by Fong et al. [254], who observed much higher endophthalmitis incidence with
Kenalog® (benzyl alcohol 1.5%) than Kenacort-A (benzyl alcohol 1.0 %). Nevertheless, it
lP

must be mentioned that other factors such as particle size and shape, suspension
concentration, volume of injection may impact local tolerability of the formulation.
Therefore, further investigations led to revision of the composition of Kenalog® and
na

development of preservative-free formulations, such as Trivaris®.

3.3.9. Zyprexa® Relprevv®
ur

Zyprexa® Relprevv® is composed of microcrystalline powder of olanzapine pamoate

monohydrate for reconstitution. Upon reconstitution with its diluent, Zyprexa® Relprevv®
Jo

produces a suspension that remains homogeneously dispersed for 24 hours. The suspended
particles exhibit poor water solubility due to the hydrophobic nature of the prodrug/derivative
(olanzapine pamoate), the microcrystalline salt of olanzapine with pamoic acid. Following
IM injection, the driving forces for the release of the pharmacologically active drug
(olanzapine) from the depot include microcrystals dissolution of the salt into native
olanzapine and pamoic acid [249]. Since these processes occur slowly, a single dose of
Zyprexa® Relprevv® achieves sustained release of olanzapine over 4 weeks and maintains
plasma concentrations within the same therapeutic window as daily oral administrations
[255]. Zyprexa® Relprevv® is used for the treatment of schizophrenia at the dose of 150–300
mg every 2–4 weeks or 300–405 mg every 4 weeks [256].
4. Discussion and perspectives
The significance of LAI as a means to prolong the action of drugs in the body is well-
documented [7,8,257,258]. These delivery systems have a big impact on pharmaceutical
market with sale of approximately 16940 M$ in 2019 [14]. To date, the Food and Drug
Administration (FDA) has approved about 48 brand-name medicines based on biodegradable

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LAI delivery systems including PLGA MPs, implants, non-PLGA extended release depots,
crystal suspensions and oil-based formulations of lipophilic prodrugs [259]. Table 6
summarizes the strengths and weaknesses of different delivery systems that are presented and
discussed in this review.
In the past few decades, many LAI technologies have found their path into the clinic.
Nevertheless, the development of long-acting injectable products remains challenging and
usually takes long time, that is why they are usually introduced as life-cycle management
projects of existing immediate release therapies. Therefore, the following paragraphs
highlight some of challenges in the development of LAI systems in conjunction with the drug
attributes (e.g., potency, therapeutic index and stability), manufacturing and sterilization
protocols, syringeability/injectability, in vitro/in vivo release and in vivo local tolerability.
Table 6. Strengths and weaknesses of established LAI delivery systems

of
Formulation Strength Weakness

PLGA-based MPs • Drug release can be modulated • Gamma sterilization or aseptic

ro
(e.g., from weeks to months) production is required

• In principle it is possible to
-p • Not simple and rather expensive
load both hydrophilic and
hydrophobic drugs • High drug loading is challenging, ˃
50% of formulation is polymer
• Smooth and soft surface → low
re
risk of mechanical tissue • Difficult to scale up
irritation
lP

Preformed • Drug release can be modulated • Gamma sterilization or aseptic

implants to some extent production is required

• In principle it is possible to • Not simple and rather expensive

na

load both hydrophilic and

hydrophobic drugs • Invasive (in some cases surgical
procedures are required)
ur

• High drug loading is challenging ˃

50% of formulation is polymer
Jo

In situ forming • Drug release can be modulated • Limitation for using organic
implants to some extent solvents

• Simple and cost-effective • Limited options for tailoring drug

preparation methods release

• Filtration sterilization • High drug loading is challenging ˃

50% of formulation is polymer
• Easy scale up

Non-PLGA based • Polymers such as • Gamma sterilization or aseptic

systems poly(orthoester) polymers that production is required
degrade via surface erosion →
acid degradation in not • Not simple and rather expensive
accumulating in the delivery • Only few marketed products →
systems → compatible with limited knowledge available about
acid sensitive drugs

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versatility of this polymers

Crystal suspensions • Simple and cost-effective • Rough particle surface → high risk
preparation methods of mechanical tissue irritation

• Highest drug loaded carrier • Micronization is required

system → allowing high drug
dosing per volume • Gamma, heat sterilization or aseptic
manufacturing is required

• Limited options for tailoring drug

release e.g., by particle size tuning

Oil-based • Simple and cost-effective • Not possible for many drug

formulations preparation methods molecules to from prodrug (only
hydrophobic drug with functional
• Filtration sterilization groups)
• Easy scale up •

of
Limited options for tailoring drug
release

4.1. Drug substance attributes for LAI development

ro
-p
For LAI formulation, a drug candidate needs to be highly potent with slow plasma clearance
to enable lower frequency of dosing. In early phase of drug discovery, proper tool molecules
re
(drug like molecules) that are potent in vitro and can be produced in sufficient quantities are
usually selected for in vivo experiments. They are utilized to understand the extent and
duration of in vivo target engagement required for efficacy, this is first step to design a potent
lP

drug molecule [260]. For preparation of LAI, not only a drug candidate needs to be potent but
also needs to be loaded into a carrier system (e.g., PLGA MPs and implants) with high
loading capacity to supply the dose required for an extended period (i.e., weeks to months),
na

since the volume of injection is often limited depending on the site of injection.
Small drug molecules offer great opportunities to manipulate and tailor their physicochemical
properties. It is possible to design molecules that are suited for already established LAI
ur

technologies (e.g. encapsulation into PLGA MPs, oil/lipid-based formulations, or drug

substance micro- or nano-suspensions), in parallel to lead optimization in the research phase.
Jo

As an example, low aqueous solubility can be engineered in small molecules design by

providing high crystal lattice energy and/or poor hydration in aqueous environment. The
former category usually encompasses rigid and flat molecular structures that pack densely in
the crystals and provide strong intermolecular bonds via van der Waals interaction, π−π
stacking, and hydrogen bonding, while the latter class of poorly hydrated compounds
commonly features high lipophilicity [261–263]. A recent molecular study has established the
correlation between the number of aromatic rings in a drug molecule and its physicochemical
properties [264]; it was demonstrated that even within a defined lipophilicity range, increased
number of aromatic rings leads to decreased aqueous solubility. A medicinal chemist can
therefore build on distinct molecular features that drive the physicochemical profile towards a
desirable space. Early investigations on solid-state properties, such as crystallinity, melting
characteristics, polymorphism landscape, and physicochemical stability during milling
processes, are instrumental to compound triaging. For example, thermodynamic solubility
should be determined from a defined high-melting crystalline form in a biorelevant medium
to select suitable candidates for the generation of injectable micro- or nano-suspension
depots. A drug that is released from a depot carrier primarily via passive diffusion can be

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optimized towards low partitioning from the depot phase to the (aqueous) tissue
compartments, or by implementing high diffusion barriers (e.g. via large molecular size).
Finally, certain manufacturing processes, e.g. oil-in-water emulsification for the preparation
of PLGA microparticles, may require sufficient drug solubility in specific suitable organic
excipients.
The conventional early drug discovery toolbox must be therefore expanded by a solid set of
physicochemical assays, including differential scan calorimetry, X-ray powder diffraction,
granulometry, and thermodynamic solubility in customized media. Concerning the labor-
intensive process of physicochemical characterization, it is paramount important to start with
the need to generate reproducible crystallization protocols in the chemistry lab and culminate
in the delivery of a stable and well-defined injectable suspension to the in vivo pharmacology
group. It is imperative that selected candidates show exquisite potency in relevant biological
assays. This prerequisite will minimize the burden of injectable dose and volume, which can

of
both contribute to the safety and tolerability of the respective application. Figure 8 illustrates
how different pharmaceutical research disciplines can act together in an exemplary flowchart

ro
to ensure an optimal combination of drug molecule and LAI formulation that can be applied
in vivo. -p
re
lP
na
ur
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Figure 8. The interplay of pharmaceutical research disciplines in the early discovery of

candidates for LAI formulation development.
Further, an evaluation of successfully marketed injectable depot formulations shows that
most of the loaded drugs are highly lipophilic. Although poorly reputed for oral route of
administration, high lipophilicity appears to be beneficial for LAI systems. As shown in
Tables 1-5 and summarized in Figure 9, most of the marketed LAI drugs are poorly water-
soluble. Out of 48-marketed drug products presented in this review, only four formulations
contain drugs that are water-soluble. Therefore, we foresee drug lipophilicity not as a
limitation but rather as an opportunity for the development of LAI formulations.

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Figure 9. Solubility of drug molecules that have been used in clinically established LAI
formulations. Only 8% of drug molecules in marketed LAI formulations are water-soluble

of
based on USP solubility definition (i.e., 61% practically insoluble: <0.1 mg/mL, 27% slightly
soluble: 1-10 mg/mL, 8% soluble: 33-100 mg/mL and 4% very slightly soluble: 0.1 -1

ro
mg/mL).
For LAI formulation, a drug candidate needs to have broad therapeutic index to achieve
-p
efficacious concentrations without causing toxicity due to burst release or being non-
efficacious due to slow release phase. Zero order drug release kinetics is the most desired
release mechanism, but it is not easily achievable by current marketed delivery systems such
re
as biodegradable MPs/implants or drug crystals suspensions. In zero order pattern, the drug is
released at a constant rate for an extended period and the release kinetics is independent of its
lP

initial concentration. First order drug release is based on simple diffusion, dependent on the
initial drug concentration according to the Fick‘s second law. If the therapeutic window is
narrow, zero order release is a key to ensuring the drug concentration remains within the
na

therapeutic window for an extended time. However, for drug molecules that have broad
therapeutic window first order drug release remains a good alternative.
Physicochemical stability of drug candidate for the development of LAI formulation is very
ur

important, as most often manufacturing of such formulations involves harsh conditions such
as high temperature, dissolution in aqueous and/or organic solvents, chemical drug
interactions with the carrier components such as polymers (e.g., acylation). The FDA has
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approved a limited number of formulations based on biomaterials (such as PLGA and PEG)
available for development of LAI systems, which makes it difficult to find suitable carrier for
delivering delicate drug candidates such as macromolecular therapeutics. The drug and LAI
formulation needs to be stable upon terminal sterilization (e.g., gamma, x-ray, e-beam, heat
etc.), as discussed in the following paragraph.
4.2. Manufacturing processes for LAI development
Complex manufacturing processes are part of the factors that may hinder the development of
LAI formulation. For example, the development of PLGA MPs involves extensive process
development and scale-up from lab, pilot plant to manufacturing plant. For successful scale-
up, close collaboration and smooth handover between formulation scientists and
pharmaceutical engineers is required. Moreover, early investment in scalable equipment
(from lab scale through full production scale), implementation of process analytical
technology (PAT) tools for monitoring manufacturing of drug product and early
identification of critical process parameters make a vital combination for successful scale up

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manufacturing. According to pharmacopeia parenteral drug delivery systems must be

produced with high quality, purity, and sterility, including being essentially free from foreign
visible particles. Generally, drug product manufacturing to this standard is very challenging
and about 20% of drug product batch recalls is due to foreign visible particles contamination
[265]. In general, standard parenteral solutions are sterile filtrated and have low risk of
foreign particle contamination. However, parenteral suspensions, MPs and implants cannot
be sterile filtered. Therefore, strategies to control the level of foreign particles for drug
substance and in drug product manufacturing processes must be implemented. Considering
the above-mentioned parameters, when compared to standard parenteral formulations, the
development of LAI formulations is more complex, time consuming and expensive.
Preparation of parenteral suspension or implants under aseptic conditions has high production
costs, especially for early stage development of drug products. Therefore, terminal
sterilization is preferred to ensure sterility of the final drug product [266–269]. The

of
commonly employed terminal sterilization methods are by steam, dry heat, ethylene oxide
gas, x-ray, electron beam and γ- irradiation [270–272]. Among these methods, dry heat and

ro
steam sterilization are carried out at high temperature (e.g., 121°C) and therefore they are not
suitable for PLGA microparticles or implants as the glass transition of PLGA polymers is
often < 50°C, but they may be used for drug crystal suspension. Ethylene oxide may release
-p
toxic residues; therefore, it is not an option for terminal sterilization of drug products
[269,273–275]. Thus, γ-irradiation and x-ray irradiation are preferred methods for terminal
re
sterilization of PLGA MPs and implants due to their high efficiency and low thermal effects.
The γ-irradiation can efficiently treat a wide range of drug products composed of diverse
materials with different densities. X-ray irradiation is as efficient as γ-irradiation in addition
lP

to reducing processing times and potentially lower damage to the products. Electron beam on
the other hand has low penetrating effect and it is not a preferred option for the treatment of
parenteral drug product, but single used medical devices [276]. Although γ-irradiation is
na

widely used for terminal sterilization of parenteral products, including PLGA microparticles
and implants, it accelerates the cleavage of polymer ester bonds and generates free radical
and crosslinking [277,278]. Polymer chain cleavage due to sterilization can accelerate drug
ur

burst release. However, the impact of standard irradiation dose (i.e., 25 kGy) on molecular
weight reduction and consequently drug release is usually negligible. Nonetheless, some drug
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molecules are not stable against irradiation; therefore, it is important to evaluate the impact of
irradiation type/dose on the formulation in early stage of development.
4.3. Syringeability and injectability of LAI formulations
Efficient injection of parenteral formulations through conventional needles is crucial in
clinical translation of LAI. The ability of an injectable formulation to transfer from a vial
through a needle into a syringe is called syringeability, whereas the performance of a
formulation while being injected into the body is called injectability [279–281]. Particle size,
shape, density, viscosity and suspension concentration are important factors regarding the
syringeability and therefore injectability of parenteral formulations [282–284]. Large
particles or aggregates in the formulation often cause needle clogging. The needle clogging
can also occur due to bridging effect of the microspheres suspension with high polydispersity
while passing through the needle. Novel technologies such as membrane emulsification
and/or microfluidics enable production of mono-sized microspheres that are easily injectable
through smaller needle size as compared to polydisperse particles. Smaller needle size

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reduces the local tissue damage and associated pain, enhancing patient compliance [285].
Recently, Robert Langer and his colleagues [286] demonstrated that the geometry of the
syringe and needle plays an important role in injectability of the microparticle formulation.
Using a computational fluid dynamics (CFD) and experimental results, an injectable device
was designed to maximize the injectability in both in vitro and in vivo models. The custom-
made syringe and needle enabled a six-fold increase in injectability of PLGA MPs as
compared to commercial syringes with the same needle gauge. This study demonstrated a
framework for optimum injection of MPs and microcrystals-based drug delivery systems.
4.4. In vitro and in vivo release from LAI formulations
In vitro characterization of drug release is one of the most important tests during early and
late phase LAI development. A bio-indicative in vitro release set up can guide the
development team in terms of formulation selection and process optimization; batch-to-batch
quality control evaluation can serve as surrogate for bioequivalence trials at later stage if in

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vitro-in vivo correlation (IVIVC) is established. As the LAI field is still at the emerging stage,
there is no official guideline or requirement about in vitro release set up for specific type of

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delivery system. Recently, USP has published a draft informational chapter on ―In vitro
release test methods for parenteral drug preparations‖, discussing methods currently used for
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in vitro testing of injectable delivery systems [287]. Different experimental conditions (e.g.,
type of instrument, release medium composition and temperature) exhibit significant impact
on the release profile. Therefore, key product attributes [288], release mechanism (often
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multi-phased process e.g., burst, lag phase and steady release) [45] and environment that
influence drug release in vivo must be understood for successful in vitro method development
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[289,290]. Wide variety of techniques are utilized for release measurements, with continuous
flow (USP IV) and sample-and-separate approach being the most common ones. Sample-and-
separate methodology is convenient as it can be scaled-down to small volumes at early stage
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of development and is applicable for particulate-based delivery systems [291,292]. USP IV is

a compendial apparatus offering defined hydrodynamics, prevention of particle
agglomeration by application of glass beads and can be adapted for dialysis cell, which
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makes it suitable for evaluation of oil-based and nano-sized delivery systems [293–295]. USP
II apparatus with modifications designed especially for designated delivery system are also
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reported [296,297]. Release medium selection is another important parameter. Variants of

simulated biological fluids, with addition of proteins or enzymes representing different
tissues, are reported in the literature [298,299]. For analytical simplicity and reproducibility,
simple neutral buffers (pH 7.4) are the most used. As majority of LAI drugs have rather low
aqueous solubility, manipulation with pH, osmolality, temperature and addition of surfactants
are frequently required to achieve drug dissolution in reasonable time-frame [300–302].
When accelerating drug release in vitro, it is essential not to alter release mechanism, so that
obtained profiles are still representation of real-time in vivo release. As variations of medium
components often cause changes in release mechanism (e.g., polymer degradation in PLGA-
based delivery systems), additions of surfactants are preferred options for in vitro solubility
increase. The ultimate goal of the in vitro release method is to confirm the biorelevance and
later establishment of IVIVC. IVIVC is mathematical correlation between in vitro property of
the drug (e.g., in vitro release profile) and in vivo response (e.g., Cmax or AUC). In addition to
complex in vitro release mechanism of delivery systems, in vivo environment in terms of
(patho)physiology, metabolism and host response at specific administration site, pose another
challenge in successful IVIVC establishment [303]. Hand in hand with physiologically based

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pharmacokinetic (PBPK) modeling, IVIVC is still emerging with successful correlations

established based on animal data. The importance of understanding in vivo environment and
host response after intra muscular injection of crystalline suspension was investigated by
Darville et al. [304,305]. They discovered key role of macrophages surrounding suspension
depot and acting as additional phase/compartment of overall drug release/absorption. These
types of findings can help design meaningful in vitro release setup that can serve as basis for
IVIVC establishment. For PLGA-based systems, animal-based IVIVCs are published for
risperidone and leuprolide acetate microparticles [306] based on USP IV and sample-and-
separate approach, respectively. For the oil-based depot formulations, no information about
IVIVC attempts are publicly available. The reported established IVIVCs are of great
importance for formulation and physiology understanding. However, translation between
species remains a big gap. The published cases can serve as guidance during formulation
development, nevertheless, for establishment of IVIVC as substitution of in vivo studies
(bioequivalence, post approval changes), more understanding and human data must be

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provided and elaborated. Although much research is being conducted, the long acting
parenteral area is still at the emerging stage, and available knowledge and understanding are

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far from oral products, as most frequently used products. Further improvements in terms of in
silico and in vitro evaluation of LAI is needed to govern better understanding of delivery
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system and faster LAI development.
4.5. In vivo behavior and tolerance of LAI formulations
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For successful LAI development, it is important to understand the in vivo behavior of
delivery system upon administration [307–309]. The administration of LAI products leads to
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a cascade of events involving the innate and adaptive immune responses with the ultimate
goal to repair tissue injury (e.g., from injection or surgical implantation of the degradable
biomaterial) and to remove the foreign material by foreign body response (FBR). For
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biodegradable material, Anderson and Shives [310] have described the process in three
phases, from an acute initial response (phase 1) to more chronic responses of particle uptake
and breakdown (phase 2 &3). FBR is a complex dynamic process, which continues to be of
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interest in order to refine, optimize and control biocompatibility, degradation and rejection of
implants and biomaterials. In fact, immediately after tissue injury, proteins release from
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blood and extracellular matrix (ECM) triggers a signaling cascade (including the coagulation
system, cytokines and danger signals), leading to acute inflammation with neutrophils
(polymorphonuclear leukocytes, PMNs) as one dominant cell type involved. PMNs secrete
additional enzymes, ROS and cytokines to recruit more immune cells, including
lymphocytes, plasma cells, monocytes and macrophages. Over time, when initial tissue
damage is repaired, the process becomes more chronic, with macrophages as dominant cell
type. In a dynamic and complex interplay, macrophage signaling will further recruit
additional immune cells and more macrophages to boost phagocytosis for removal of the
foreign material. Depending on the ―digestibility‖ of the material and the nature of the
elicited chronic inflammation, macrophage fusion to foreign body giant cells (FBGCs),
activation of extracellular matrix and fibroblasts, granuloma and fibrous capsule formation
may occur at the site of depot or implant. In some cases, the extent of the inflammatory or
foreign body response may even lead to premature breakdown of the implant [311]. The
benign outcome and time course of the FBR will mainly depend on degradability of the
biomaterial and successful phagocytotic activity of macrophages and FBGCs. Poorly
digestible (or even indigestible) materials may lead to increased formation of FBGCs with

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reduced capacity for phagocytosis, while secretion of enzymes (like acid hydrolase), reactive
oxygen species (ROS) and protons is increased [312,313]. This phenomenon, referred to as
―frustrated phagocytosis‖, may ultimately enable degradation and resorption of materials
susceptible to these secretory products, and the FBR can resolve after full resorption
[312,314]. Particles having sizes < 5µm are taken up easily by phagocytosis [315]; and
therefore frequently linked to macrophage response, suggesting biodegradable materials of >
10 µm size to be able to escape the phagocytosis and control inflammation [13]. However,
this may only apply to spherical particles; since particle geometry and curvature, and tangent
angle during macrophage surface receptor contact play an even more important role
[316,317]. Additional properties (such as shape, scaffold [34] deformability, surface charge,
polarity, hydrophilicity, opsonisation and the type of interaction with different macrophage
surface receptors [318]) influence the elicited cytokine secretion to a more pro- or anti-
inflammatory response with different macrophage phenotypes [34]. Increased attention to
mechanistic understanding of phagocytosis and immunologic events of FBR has provided

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technological advances in biomedical applications [319] that will be crucial for future
development of slow release injectable implants, devices, and cell-based therapies. The

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summary of long acting parenteral drug development steps is depicted in Figure 10.
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Figure 10. The summary of important steps for LAI formulations development.
To wrap up this review, LAI formulations are more complex than standard injectable
solutions and therefore often have longer development timelines. Nevertheless, they can be
competitive due to noticeable clinical benefits and sustained sale over longer time since they
are not easy to copy. Most importantly LAI formulations are crucial for the patient
compliance in chronic diseases. As outlined above, the research team needs to work early on
with the development team to design a drug molecule that is both therapeutically efficient and
has suitable physicochemical characteristics to be formulated as LAI. In the past,
pharmaceutical companies used to introduce LAI projects as life-cycle management projects
of already existing immediate release therapies. But nowadays, the focus on the development
of LAI has changed to early-on involvement of the research and development teams working
closely to design an ideal drug molecule with suitable delivery system for LAI applications, a
promising approach that can significantly shorten development timelines.
5. Conclusion
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Long acting injectable formulations are developed to sustain the action of drugs in the body.
Evaluation of marketed injectable depot shows that most of the formulated drugs are potent,
physically and chemically stable with low water solubility and broad therapeutic window. To
shorten the duration of drug product development and increase the chance of success in
discovery projects, it is important to anticipate challenges such manufacturing issues (e.g.,
scale up production, sterilization, syringeability and injectability), IVIVC establishment, local
tolerability and in vivo fate of the formulations. Furthermore, early on collaboration between
research and development teams is required to design ideal drug molecules with suitable
delivery systems.
Acknowledgements
The authors acknowledge the support received from Next Generation Scientists Program
(Novartis Pharma AG, Basel). Christian I. Nkanga is grateful to the NGO Förderverein Uni
Kinshasa e. V.–BEBUC/Else-Kroener-Fresenius Stiftung & Holger-Poehlmann foundation

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for their advice.

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References:
[1] J.A.D. Sequeira, A.C. Santos, J. Serra, C. Estevens, R. Seiça, F. Veiga, A.J. Ribeiro,
-p
Subcutaneous delivery of biotherapeutics: challenges at the injection site, Expert Opin.
Drug Deliv. 16 (2019) 143–151. doi:10.1080/17425247.2019.1568408.
re
[2] W.Y. Lee, M. Asadujjaman, J.P. Jee, Long acting injectable formulations: the state of
the arts and challenges of poly(lactic-co-glycolic acid) microsphere, hydrogel,
organogel and liquid crystal, J. Pharm. Investig. 49 (2019) 459–476.
lP

doi:10.1007/s40005-019-00449-9.
[3] K. Chaudhary, M.M. Patel, P.J. Mehta, Long-Acting Injectables : Current P
na

erspectives and Future Promise, Crit. Rev. Ther. Drug Carrier Syst. 36 (2019) 137–
181.
[4] G. Ma, Microencapsulation of protein drugs for drug delivery : Strategy , preparation ,
ur

and applications, J. Control. Release. 193 (2014) 324–340.

doi:10.1016/j.jconrel.2014.09.003.
Jo

[5] Y. Shi, L. Li, Current advances in sustained-release systems for parenteral drug
delivery, Expert Opin. Drug Deliv. 5247 (2005). doi:10.1517/17425247.2.6.1039.
[6] D. Klose, F. Siepmann, K. Elkharraz, J. Siepmann, PLGA-based drug delivery
systems : Importance of the type of drug and device geometry, Int. J. Pharm. 354
(2008) 95–103. doi:10.1016/j.ijpharm.2007.10.030.
[7] F. Ramazani, C.F. Van Nostrum, G. Storm, F. Kiessling, T. Lammers, W.E. Hennink,
R.J. Kok, Locoregional cancer therapy using polymer-based drug depots, Drug Discov.
Today. 21 (2016) 640–647. doi:10.1016/j.drudis.2016.02.014.
[8] R. Narayanaswamy, V.P. Torchilin, Hydrogels and their applications in targeted drug
delivery, Molecules. 24 (2019). doi:10.3390/molecules24030603.
[9] R.V. Kalaydina, K. Bajwa, B. Qorri, A. Decarlo, M.R. Szewczuk, Recent advances in
―smart‖ delivery systems for extended drug release in cancer therapy, Int. J.
Nanomedicine. 13 (2018) 4727–4745. doi:10.2147/IJN.S168053.
[10] K. Park, S. Skidmore, J. Hadar, J. Garner, H. Park, A. Otte, B.K. Soh, G. Yoon, D. Yu,
44
 Journal Pre-proof

Y. Yun, B.K. Lee, X. Jiang, Y. Wang, Injectable, long-acting PLGA formulations:

Analyzing PLGA and understanding microparticle formation, J. Control. Release. 304
(2019) 125–134. doi:10.1016/j.jconrel.2019.05.003.
[11] H. Zhong, G. Chan, Y. Hu, H. Hu, D. Ouyang, A comprehensive map of FDA-
approved pharmaceutical products, Pharmaceutics. 10 (2018) 1–19.
doi:10.3390/pharmaceutics10040263.
[12] S. Shabee, H. Abadi, A. Moin, G. Hosahalli, Review Article : Fabricated
Microparticles : An Innovative Method to Minimize the Side Effects of NSAIDs in
Arthritis, Crit. Rev. Ther. Drug Carrier Syst. 33 (2016) 433–488.
[13] V. Tran, J. Benoît, M. Venier-julienne, Why and how to prepare biodegradable ,
monodispersed , polymeric microparticles in the field of pharmacy ?, Int. J. Pharm. 407
(2011) 1–11. doi:10.1016/j.ijpharm.2011.01.027.

of
[14] https://www.pharmacircle.com/info/. (Accessed on April 1, 2020).
[15] H.K. Makadia, S.J. Siegel, Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable

ro
Controlled Drug Delivery Carrier, Polymers 3 (2011) 1377–1397.
doi:10.3390/polym3031377. -p
[16] K.K. Chereddy, G. Vandermeulen, V. Préat, PLGA based drug delivery systems:
Promising carriers for wound healing activity, Wound Repair Regen. 24 (2016) 223–
236. doi:10.1111/wrr.12404.
re
[17] F. Sharifi, A. Otte, G. Yoon, K. Park, Continuous in-line homogenization process for
scale-up production of naltrexone-loaded PLGA microparticles, J. Control. Release.
lP

325 (2020) 347–358. doi:10.1016/j.jconrel.2020.06.023.

[18] V. Tran, J. Karam, X. Garric, J. Coudane, J. Benoît, C. N Montero-Menei, M. Venier-
na

Julienne, Protein-loaded PLGA-PEG-PLGA microspheres: a tool for cell therapy, Eur

J Pharm Sci. 45 (2012) 128-37. DOI: 10.1016/j.ejps.2011.10.030.
[19] F. Tamani, M.C. Hamoudi, F. Danede, J.F. Willart, F. Siepmann, J. Siepmann,
ur

Towards a better understanding of the release mechanisms of caffeine from PLGA

microparticles, J. Appl. Polym. Sci. 137 (2020) 1–12. doi:10.1002/app.48710.
Jo

[20] F. Ramazani, W. Chen, C.F. Van Nostrum, G. Storm, F. Kiessling, T. Lammers, W.E.
Hennink, R.J. Kok, Strategies for encapsulation of small hydrophilic and amphiphilic
drugs in PLGA microspheres: State-of-the-art and challenges, Int. J. Pharm. 499
(2016) 358–367. doi:10.1016/j.ijpharm.2016.01.020.
[21] F.Y. Han, K.J. Thurecht, A.K. Whittaker, M.T. Smith, Bioerodable PLGA-based
microparticles for producing sustained-release drug formulations and strategies for
improving drug loading, Front. Pharmacol. 7 (2016) 1–11.
doi:10.3389/fphar.2016.00185.
[22] E. Swider, O. Koshkina, J. Tel, L.J. Cruz, I.J.M. de Vries, M. Srinivas, Customizing
poly(lactic-co-glycolic acid) particles for biomedical applications, Acta Biomater. 73
(2018) 38–51. doi:10.1016/j.actbio.2018.04.006.
[23] P.L. Lam, R. Gambari, Advanced progress of microencapsulation technologies : In
vivo and in vitro models for studying oral and transdermal drug deliveries, J. Control.
Release. 178 (2014) 25–45. doi:10.1016/j.jconrel.2013.12.028.

45
 Journal Pre-proof

[24] J. Lee, H. Jin, H. Ji, S. Hang, E. Cho, H. Dong, B. Cheol, Marbo fl oxacin-
encapsulated microparticles provide sustained drug release for treatment of veterinary
diseases, Mater. Sci. Eng. C. 60 (2016) 511–517. doi:10.1016/j.msec.2015.12.004.
[25] S. Freitas, H.P. Merkle, B. Gander, Microencapsulation by solvent extraction /
evaporation : reviewing the state of the art of microsphere preparation process
technology, J. Control Release. 102 (2005) 313–332.
doi:10.1016/j.jconrel.2004.10.015.
[26] F. Ramazani, W. Chen, C.F. Van Nostrum, G. Storm, F. Kiessling, T. Lammers, W.E.
Hennink, R.J. Kok, Strategies for encapsulation of small hydrophilic and amphiphilic
drugs in PLGA microspheres : State-of-the-art and challenges, Int. J. Pharm. 499
(2016) 358–367. doi:10.1016/j.ijpharm.2016.01.020.
[27] C. Wischke, S.P. Schwendeman, Principles of encapsulating hydrophobic drugs in
PLA / PLGA microparticles, Int. J. Pharm. 364 (2008) 298–327.

of
doi:10.1016/j.ijpharm.2008.04.042.
[28] V.R. Sinha, A. Trehan, B iodegradable microspheres for protein delivery, J. Control.

ro
Release. 90 (2003) 261–280.
[29] F. Qi, J. Wu, H. Li, G. Ma, Recent research and development of PLGA / PLA
-p
microspheres / nanoparticles : A review in scienti fi c and industrial aspects, Front.
Chem. Sci. Eng. 13 (2018) 14–27 (2019). https://doi.org/10.1007/s11705-018-1729-4.
re
[30] M. Parent, C. Nouvel, M. Koerber, A. Sapin, P. Maincent, A. Boudier, PLGA in situ
implants formed by phase inversion: Critical physicochemical parameters to modulate
lP

drug release, J. Control. Release. 172 (2013) 292–304.

doi:10.1016/j.jconrel.2013.08.024.
[31] B. Gu, X. Sun, F. Papadimitrakopoulos, D.J. Burgess, Seeing is believing, PLGA
na

microsphere degradation revealed in PLGA microsphere/PVA hydrogel composites, J.

Control. Release. 228 (2016) 170–178. doi:10.1016/j.jconrel.2016.03.011.
ur

[32] Y. Yang, Q. Chen, J. Lin, Z. Cai, G. Liao, K. Wang, L. Bai, P. Zhao, Z. Yu, Recent
Advance in Polymer Based Microspheric Systems for Controlled Protein and Peptide
Delivery, Curr. Med. Chem. 26 (2019) 2285–2296.
Jo

doi:10.2174/0929867326666190409130207.
[33] M. Van De Weert, W.E. Hennink, W. Jiskoot, Protein instability in poly(lactic-co-
glycolic acid) microparticles, Pharm. Res. 17 (2000) 1159–1167.
doi:10.1023/A:1026498209874.
[34] T.B. Wissing, V. Bonito, E.E. van Haaften, M. van Doeselaar, M.M. Brugmans, H.M.
Janssen, C. V. Bouten, A.I. Smits, Macrophage-driven biomaterial degradation
depends on scaffold microarchitecture, Front. Bioeng. Biotechnol. 7 (2019).
doi:10.3389/fbioe.2019.00087.
[35] C. Foged, B. Brodin, S. Frokjaer, A. Sundblad, Particle size and surface charge affect
particle uptake by human dendritic cells in an in vitro model, Int. J. Pharm. 298 (2005)
315–322. doi:10.1016/j.ijpharm.2005.03.035.
[36] K. Makino, T. Nakajima, M. Shikamura, F. Ito, S. Ando, C. Kochi, H. Inagawa, G.I.
Soma, H. Terada, Efficient intracellular delivery of rifampicin to alveolar macrophages
using rifampicin-loaded PLGA microspheres: Effects of molecular weight and

46
 Journal Pre-proof

composition of PLGA on release of rifampicin, Colloids Surfaces B Biointerfaces. 36

(2004) 35–42. doi:10.1016/j.colsurfb.2004.03.018.
[37] K. Halasz, S.J. Kelly, M.T. Iqbal, Y. Pathak, V. Sutariya, Micro/Nanoparticle Delivery
Systems for Ocular Diseases, Assay Drug Dev. Technol. 17 (2019) 152–166.
doi:10.1089/adt.2018.911.
[38] W. Li, L. Zhang, X. Ge, B. Xu, W. Zhang, L. Qu, C.H. Choi, J. Xu, A. Zhang, H. Lee,
D.A. Weitz, Microfluidic fabrication of microparticles for biomedical applications,
Chem. Soc. Rev. 47 (2018) 5646–5683. doi:10.1039/c7cs00263g.
[39] N. Sharma, P. Madan, S. Lin, Effect of process and formulation variables on the
preparation of parenteral paclitaxel-loaded biodegradable polymeric nanoparticles: A
co-surfactant study, Asian J. Pharm. Sci. 11 (2016) 404–416.
doi:10.1016/j.ajps.2015.09.004.

of
[40] W. Chen, A. Palazzo, W.E. Hennink, R.J. Kok, Effect of particle size on drug loading
and release kinetics of gefitinib-loaded PLGA microspheres, Mol. Pharm. 14 (2017)
459–467. doi:10.1021/acs.molpharmaceut.6b00896.

ro
[41] N. Samadi, A. Abbadessa, A. Di Stefano, C.F. Van Nostrum, T. Vermonden, S.
Rahimian, E.A. Teunissen, M.J. Van Steenbergen, M. Amidi, W.E. Hennink, The
-p
effect of lauryl capping group on protein release and degradation of poly(d,l-lactic-co-
glycolic acid) particles, J. Control. Release. 172 (2013) 436–443.
re
doi:10.1016/j.jconrel.2013.05.034.
[42] F. Kazazi-Hyseni, M. Landin, A. Lathuile, G.J. Veldhuis, S. Rahimian, W.E. Hennink,
lP

R.J. Kok, C.F. Van Nostrum, Computer modeling assisted design of monodisperse
PLGA microspheres with controlled porosity affords zero order release of an
encapsulated macromolecule for 3 months, Pharm. Res. 31 (2014) 2844–2856.
na

doi:10.1007/s11095-014-1381-8.
[43] Y. Xu, C.S. Kim, D.M. Saylor, D. Koo, Polymer degradation and drug delivery in
PLGA-based drug–polymer applications: A review of experiments and theories, J.
ur

Biomed. Mater. Res. - Part B Appl. Biomater. 105 (2017) 1692–1716.

doi:10.1002/jbm.b.33648.
Jo

[44] G. Srikar, A.P. Rani, Study on influence of polymer and surfactant on in vitro
performance of biodegradable aqueous-core nanocapsules of tenofovirdisoproxil
fumarate by response surface methodology, Brazilian J. Pharm. Sci. 55 (2019) 1–11.
doi:10.1590/s2175-97902019000118736.
[45] S. Fredenberg, M. Wahlgren, M. Reslow, A. Axelsson, The mechanisms of drug
release in poly ( lactic-co-glycolic acid ) -based drug delivery systems — A review,
Int. J. Pharm. 415 (2011) 34–52. doi:10.1016/j.ijpharm.2011.05.049.
[46] E. Sah, H. Sah, Recent trends in preparation of poly(lactide-co-glycolide)
nanoparticles by mixing polymeric organic solution with antisolvent, J. Nanomater.
2015 (2015). doi:10.1155/2015/794601.
[47] W. Jiang, S.P. Schwendeman, Stabilization of a model formalinized protein antigen
encapsulated in poly(lactide-co-glycolide)-based microspheres, J. Pharm. Sci. 90
(2001) 1558–1569. doi:10.1002/jps.1106.
[48] G. Zhu, S.P. Schwendeman, Stabilization of proteins encapsulated in cylindrical

47
 Journal Pre-proof

poly(lactide-co- glycolide) implants: Mechanism of stabilization by basic additives,

Pharm. Res. 17 (2000) 351–357. doi:10.1023/A:1007513425337.
[49] F. Molavi, M. Barzegar-Jalali, H. Hamishehkar, Polyester based polymeric nano and
microparticles for pharmaceutical purposes: A review on formulation approaches, J.
Control. Release. 320 (2020) 265–282. doi:10.1016/j.jconrel.2020.01.028.
[50] M. van de Weert, W.E. Hennink, W. Jiskoot, Protein instability in PLGA MPs, Pharm.
Res. 17 (2000) 1159–1167. doi:10.1023/A:1026498209874.
[51] S.B. Murty, B.C. Thanoo, Q. Wei, P.P. DeLuca, Impurity formation studies with
peptide-loaded polymeric microspheres: Part I. In vivo evaluation, Int. J. Pharm. 297
(2005) 50–61. doi:10.1016/j.ijpharm.2005.02.035.
[52] S.B. Murty, J. Goodman, B.C. Thanoo, P.P. DeLuca, Identification of chemically
modified peptide from poly(D,L-lactide-co-glycolide) microspheres under in vitro

of
release conditions, AAPS PharmSciTech. 4 (2003) 392–405. doi:10.1208/pt040450.
[53] B. Gu, X. Sun, F. Papadimitrakopoulos, D.J. Burgess, Seeing is believing , PLGA

ro
microsphere degradation revealed in PLGA microsphere / PVA hydrogel composites,
J. Control. Release. 228 (2016) 170–178. doi:10.1016/j.jconrel.2016.03.011.
-p
[54] D.S. Pisal, M.P. Kosloski, S.V. Balu-Iyer, Delivery of Therapeutic Proteins, J. Pharm.
Sci. 99 (2010) 2557–2275. doi: 10.1002/jps.22054.
re
[55] S.A. Stewart, J. Domínguez-Robles, R.F. Donnelly, E. Larrañeta, Implantable
Polymeric Drug Delivery Devices: Classification, Manufacture, Materials, and Clinical
Applications, Polymers 10 (2018) 1379. doi:10.3390/polym10121379.
lP

[56] S. Kempe, K. Mäder, In situ forming implants — an attractive formulation principle

for parenteral depot formulations, J. Control. Release. 161 (2012) 668–679.
na

doi:10.1016/j.jconrel.2012.04.016.
[57] A. Alexander, J. Khan, S. Saraf, S. Saraf, thermosensitive injectable hydrogels for
biomedical applications, J. Control. Release. 172 (2013) 715–729.
ur

doi:10.1016/j.jconrel.2013.10.006.
[58] M. Voigt, M. Koerber, R. Bodmeier, Improved physical stability and injectability of
Jo

non-aqueous in situ PLGA microparticle forming emulsions, Int. J. Pharm. 434 (2012)
251–256. doi:10.1016/j.ijpharm.2012.05.029.
[59] P. Agarwal, I.D. Rupenthal, Injectable implants for the sustained release of protein and
peptide drugs, Drug Discov. Today. 18 (2013) 337–349.
doi:10.1016/j.drudis.2013.01.013.
[60] R. Vaishya, V. Khurana, S. Patel, A.K. Mitra, R. Vaishya, V. Khurana, S. Patel, A.K.
Mitra, Long-term delivery of protein therapeutics, Expert Opin. Drug Deliv. 5247
(2015). doi:10.1517/17425247.2015.961420.
[61] R. Raj, S. Thakur, H.L. Mcmillan, D.S. Jones, Solvent induced phase inversion-based
in situ forming controlled release drug delivery implants, J. Control. Release. 176
(2014) 8–23. doi:10.1016/j.jconrel.2013.12.020.
[62] https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/gc-467-
residual- solvents-ira-20190927.

48
 Journal Pre-proof

[63] I.I. Salem, N.M. Najib, Pharmacokinetics of Betamethasone After Single-Dose

Intramuscular Administration of Betamethasone Phosphate and Betamethasone
Acetate to Healthy Subjects, Clin. Ther. 34 (2012) 214–220.
doi:10.1016/j.clinthera.2011.11.022.
[64] S. Weng Larsen, C. Larsen, Critical factors influencing the in vivo performance of
long-acting lipophilic solutions-impact on in vitro release method design, AAPS J. 11
(2009) 762–770. doi:10.1208/s12248-009-9153-9.
[65] D.J. Burgess, A.S. Hussain, T.S. Ingallinera, M.L. Chen, Assuring quality and
performance of sustained and controlled release parenterals: Workshop report, AAPS
J. 4, 2 (2002).
[66] M. Thing, C. Larsen, J. Østergaard, H. Jensen, S.W. Larsen, In vitro release from oil
injectables for intra-articular administration: Importance of interfacial area, diffusivity
and partitioning, Eur. J. Pharm. Sci. 45 (2012) 351–357.

of
doi:10.1016/j.ejps.2011.12.006.
[67] E.D. Deeks, 17 a -Hydroxyprogesterone Caproate ( MakenaTM), In the Prevention of

ro
Preterm Birth, 13 (2011) 337–345, Auckland, New Zealand.
[68] M. Hines, .K.A. Lyseng-williamson, E.D. Deeks, A Guide to Its Use in the Prevention
-p
of Preterm Birth, Clinical Drug Investigation 33 (2013) 223–227. doi:10.1007/s40261-
013-0060-6.
re
[69] J.F. Remenar, Making the leap from daily oral dosing to long-acting injectables:
Lessons from the antipsychotics, Mol. Pharm. 11 (2014) 1739–1749.
lP

doi:10.1021/mp500070m.
[70] R.W. Kalicharan, P. Schot, H. Vromans, Fundamental understanding of drug
absorption from a parenteral oil depot, Eur. J. Pharm. Sci. 83 (2016) 19–27.
na

doi:10.1016/j.ejps.2015.12.011.
[71] R.W. Kalicharan, M.R. Bout, C. Oussoren, H. Vromans, Where does hydrolysis of
ur

nandrolone decanoate occur in the human body after release from an oil depot?, Int. J.
Pharm. 515 (2016) 721–728. doi:10.1016/j.ijpharm.2016.10.068.
Jo

[72] H.C. Detke, D.P. McDonnell, E. Brunner, F. Zhao, S. Sorsaburu, V.J. Stefaniak, S.A.
Corya, Post-injection delirium/sedation syndrome in patients with schizophrenia
treated with olanzapine long-acting injection, I: analysis of cases, BMC Psychiatry. 10
(2010) 43. doi:10.1186/1471-244X-10-43.
[73] D. Luedecke, D. Schoettle, A. Karow, M. Lambert, D. Naber, Post-Injection
Delirium/Sedation Syndrome in Patients Treated with Olanzapine Pamoate:
Mechanism, Incidence, and Management, CNS Drugs 29 (2015) 41–46. DOI
10.1007/s40263-014-0216-9.
[74] K. Sprogøe, E. Mortensen, D.B. Karpf, J.A. Leff, The rationale and design of
TransCon Growth Hormone for the treatment of growth hormone deficiency, Endocr.
Connect. 6 (2017) R171–R181. doi:10.1530/EC-17-0203.
[75] P. Chatelain, O. Malievskiy, K. Radziuk, G. Senatorova, M.O. Abdou, E.
Vlachopapadopoulou, Y. Skorodok, V. Peterkova, J.A. Leff, M. Beckert, Randomized
phase 2 study of long-acting transcon GH vs daily GH in childhood GH deficiency, J.
Clin. Endocrinol. Metab. 102 (2017) 1673–1682. doi:10.1210/jc.2016-3776.

49
 Journal Pre-proof

[76] https://www.biospace.com/article/releases/ascendis-pharma-a-s-announces-u-s-food-
and-drug-administration-fda-accepts-biologics-license-application-bla-for-transcon-
hgh-for-pediatric-growth-hormone-deficiency-ghd-
/#:~:text=TransCon%20hGH%20is%20an%20investigational,as%20a%20treatment%
20for%20GHD. (Accessed on 07 November 2020)
[77] E. Merisko-liversidge, G.G. Liversidge, Nanosizing for oral and parenteral drug
delivery : A perspective on formulating poorly-water soluble compounds using wet
media milling technology, Adv. Drug Deliv. Rev. 63 (2011) 427–440.
doi:10.1016/j.addr.2010.12.007.
[78] L. Gao, G. Liu, J. Ma, X. Wang, L. Zhou, X. Li, Drug nanocrystals : In vivo
performances, J. Control. Release. 160 (2012) 418–430.
doi:10.1016/j.jconrel.2012.03.013.
[79] H. Tsurusawa, J. Russo, M. Leocmach, H. Tanaka, Formation of porous crystals via

of
viscoelastic phase separation, Nat. Mater. 16 (2017) 1022–1028.
doi:10.1038/nmat4945.

ro
[80] X. Tan, Y. Zhong, L. He, Y. Zhang, G. Jing, S. Li, J. Wang, H. He, X. Tang,
Morphological and Crystalline Transitions in Monohydrous and Anhydrous
-p
Aripiprazole for a Long-Acting Injectable Suspension, AAPS PharmSciTech. 18
(2017) 1270–1276. doi:10.1208/s12249-016-0592-1.
re
[81] P.J. Missel, M. Horner, R. Muralikrishnan, Simulating dissolution of intravitreal
triamcinolone acetonide suspensions in an anatomically accurate rabbit eye model,
Pharm. Res. 27 (2010) 1530–1546. doi:10.1007/s11095-010-0163-1.
lP

[82] S. Mansoor, B.D. Kuppermann, M.C. Kenney, Intraocular sustained-release delivery

systems for triamcinolone acetonide, Pharm. Res. 26 (2009) 770–784.
na

doi:10.1007/s11095-008-9812-z.
[83] D. Veritti, A. Di Giulio, V. Sarao, P. Lanzetta, Drug safety evaluation of intravitreal
triamcinolone acetonide, Expert Opin. Drug Saf. 11 (2012) 331–340.
ur

doi:10.1517/14740338.2012.635141.
[84] K. Nan, S. Sun, Y. Li, J. Qu, G. Li, L. Luo, H. Chen, L. Cheng, Characterisation of
Jo

systemic and ocular drug level of triamcinolone acetonide following a single sub-
Tenon injection, Br. J. Ophthalmol. 94 (2010) 654–658. doi:10.1136/bjo.2009.172106.
[85] M.G. Pinette, K. Thayer, J.R. Wax, J. Blackstone, A. Cartin, Efficacy of intramuscular
penicillin in the eradication of group B streptococcal colonization at delivery, J Matern
Fetal Neonatal Med. 17 (2005) 333–335. doi:10.1080/14767050500132302.
[86] R. Wyber, K. Taubert, S. Marko, E.L. Kaplan, Benzathine Penicillin G for the
Management of RHD, Glob. Heart. 8 (2013) 227–234.
doi:10.1016/j.gheart.2013.08.011.
[87] M.O. Magnusson, M.N. Samtani, E.L. Plan, E.N. Jonsson, Population
Pharmacokinetics of a Novel Once-Every 3 Months Intramuscular Formulation of
Paliperidone Palmitate in Patients with Schizophrenia, Clin. Pharmacokinet. 56 (2017)
421–433. doi:10.1007/s40262-016-0459-3.
[88] M. Malamatari, K.M.G. Taylor, S. Malamataris, D. Douroumis, K. Kachrimanis,
Pharmaceutical nanocrystals : production by wet milling and applications, Drug

50
 Journal Pre-proof

Discov. Today. 23 (2018) 534–547. doi:10.1016/j.drudis.2018.01.016.

[89] https://www.drugbank.ca/. (Accessed on 15 April 2020)
[90] https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/022074Orig1s004.pdf.
(Accessed on 06 November 2020)
[91] I. Gibson, A. Momeni, M. Filiaggi, Minocycline-loaded calcium polyphosphate glass
microspheres as a potential drug-delivery agent for the treatment of periodontitis, J.
Appl. Biomater. Funct. Mater. 17 (2019). doi:10.1177/2280800019863637.
[92] G.R. Persson, G.E. Salvi, J.A. Lisa, Antimicrobial therapy using a local drug delivery
system ( Arestin ) in the treatment of peri-implantitis . I : microbiological outcomes,
Clin. Oral Impl. Res. 17 (2006) 386–393. doi:10.1111/j.1600-0501.2006.01269.x.
[93] T.E. Van Dyke, S. Offenbacher, L. Braswell, J. Lessem, Enhancing the value of
scaling and root-planing: arestin clinical trial results. J. Int. Acad. Periodontol. 4

of
(2002) 72–6.
[94] M. Torshabi, H. Nojehdehian, F. S. Tabatabae, In vitro behavior of poly-lactic-co-

ro
glycolic acid microspheres containing minocycline, metronidazole, and ciprofloxacin,
J Investig Clin Dent 8 (2017) e12201. doi: 10.1111/jicd.12201.
-p
[95] S. Lee, D.Y. Lee, Glucagon-like peptide-1 and glucagon-like peptide-1 receptor
agonists in the treatment of type 2 diabetes, Ann. Pediatr. Endocrinol. Metab. 1012
re
(2017) 15–26.
[96] K. Li, L. Yu, X. Liu, C. Chen, Q. Chen, J. Ding, Biomaterials A long-acting
lP

formulation of a polypeptide drug exenatide in treatment of diabetes using an

injectable block copolymer hydrogel, Biomaterials. 34 (2013) 2834–2842.
doi:10.1016/j.biomaterials.2013.01.013.
na

[97] M. Al-mrayat, V. Lawrence, M. Vloemans, Prolonged release exenatide gets the go-
ahead from NICE, Practical Diabetes 29 (2012) 86–88.
ur

[98] N.A. Painter, C.M. Morello, An Evidence-Based and Practical Approach to Using
Bydureon TM in Patients With Type 2 Diabetes, J. Am. Board Fam. Med. 26 (2013)
203–210. doi:10.3122/jabfm.2013.02.120174.
Jo

[99] Y. Cai, L. Wei, L. Ma, X. Huang, A. Tao, Z. Liu, W. Yuan, Long-acting preparations
of exenatide, Drug Des. Devel. Ther. 7 (2013) 963–970.
[100] J. Knittle, Lupron depot ( leuprolide acetate for depot suspension ) in the treatment of
endometriosis : a randomized , Fertil. Steril. 54 (1990) 419–427. doi:10.1016/S0015-
0282(16)53755-8.
[101] B.H. Woo, K.N.B.A. Dani, G. Jiang, B.C. Thanoo, P.P. Deluca, In Vitro
Characterization and in Vivo Testosterone Suppression of 6-Month Release Poly ( D,
L-Lactide ) Leuprolide Microspheres, Pharm. Res. 19 (4) (2002) 546–550.
[102] K.L. Parker, R.G. Baens-bailon, P.A. Lee, Depot Leuprolide Acetate Dosage for
Sexual Precocity, J. Clin. Endocrinol. Metab. 73 (2015) 50–52.
[103] S.A. Hild, M.L. Meistrich, R.P. Blye, J.R. Reel, L. Depot, C.-Ͼ.C.- The, Lupron Depot
Prevention of Antispermatogenic / Antifertility Activity of the Indenopyridine ,
CDB4022, in the Rat 1, Biol. Reprod. 172 (2001) 165–172.

51
 Journal Pre-proof

[104] J.R. Millam, H.L. Finney, Leuprolide Acetate Can Reversibly Prevent Egg Laying in
Cockatiels, Zoo Biol. 13 (1994) 149–155.
[105] R.L. Bowen, G. Perry, C. Xiong, M.A. Smith, C.S. Atwood, A Clinical Study of
Lupron Depot in the Treatment of Women with Alzheimer ‘ s Disease : Preservation of
Cognitive Function in Patients Taking an Acetylcholinesterase Inhibitor and Treated
with High Dose Lupron Over 48 Weeks, J. Alzheimers Dis. 44 (2015) 549–560.
doi:10.3233/JAD-141626.
[106] A.C. Wilson, M.S. Salamat, R.J. Haasl, K.M. Roche, A. Karande, S.V. Meethal, E.
Terasawa, R.L. Bowen, C.S. Atwood, Human neurons express type I GnRH receptor
and respond to GnRH I by increasing luteinizing hormone expression, J. Endocrinol.
191 (2006) 651–663. doi:10.1677/joe.1.07047.
[107] S.F. Kemp, P.J. Fielder, K.M. Attie, S.L. Blethen, E.O. Reiter, K.M. Ford, M. Marian,
L.N. Dao, H.J. Lee, P. Saenger, Pharmacokinetic and pharmacodynamic characteristics

of
of a long-acting Growth Hormone (GH) preparation (nutropin depot) in GH-deficient
children, J. Clin. Endocrinol. Metab. 89 (2004) 3234–3240. doi:10.1210/jc.2003-

ro
030825.
[108] D.M. Cook, B.M.K. Biller, M.L. Vance, A.R. Hoffman, L.S. Phillips, K.M. Ford, D.P.
-p
Benziger, A. Illeperuma, S.L. Blethen, K.M. Attie, L.N. Dao, J.D. Reimann, P.J.
Fielder, The pharmacokinetic and pharmacodynamic characteristics of a long-acting
growth hormone (GH) preparation (Nutropin Depot) in GH-deficient adults, J. Clin.
re
Endocrinol. Metab. 87 (2002) 4508–4514. doi:10.1210/jc.2002-020480.
[109] E.J. De Waal, W. Roosen, P. Vinken, J. Vandenberghe, P. Sterkens, L. Lammens,
lP

Mechanistic investigations on the etiology of Risperdal ® Consta ® -induced bone

changes in female Wistar Hannover rats, Toxicology. 299 (2012) 90–98.
doi:10.1016/j.tox.2012.05.007.
na

[110] P. Chue, M. Eerdekens, I. Augustyns, B. Lachaux, L. Eriksson, H. Pretorius, A.S.

David, P. Molc, Comparative efficacy and safety of long-acting risperidone and
risperidone oral tablets, Eur. Neuropsychopharmacol. 15 (2005) 111–117.
ur

doi:10.1016/j.euroneuro.2004.07.003.
[111] Z. Su, Y. Shi, L. Teng, X. Li, L. Wang, Q. Meng, L. Teng, Biodegradable poly ( D, --
Jo

co-glycolide ) ( PLGA ) microspheres for sustained release of risperidone : Zero-order

release formulation, Pharm Dev Technol. 16 (4) (2011) 377–384.
doi:10.3109/10837451003739297.
[112] F. Ramazani, W. Chen, C.F. Van Nostrum, G. Storm, F. Kiessling, T. Lammers, W.E.
Hennink, R.J. Kok, Formulation and characterization of microspheres loaded with
imatinib for sustained delivery, Int. J. Pharm. 482 (2015) 123–130.
doi:10.1016/j.ijpharm.2015.01.043.
[113] G. Pandina, R. Lane, S. Gopal, C. Gassmann-mayer, D. Hough, B. Remmerie, G.
Simpson, Progress in Neuro-Psychopharmacology & Biological Psychiatry A double-
blind study of paliperidone palmitate and risperidone long-acting injectable in adults
with schizophrenia, Prog. Neuropsychopharmacol. Biol. Psychiatry. 35 (2011) 218–
226. doi:10.1016/j.pnpbp.2010.11.008.
[114] T. An, J. Choi, A. Kim, J. Ho, Y. Nam, J. Park, H. Suh, C. Kim, S. Hwang, Sustained
release of risperidone from biodegradable microspheres prepared by in-situ

52
 Journal Pre-proof

suspension-evaporation process, Int. J. Pharm. 503 (2016) 8–15.

doi:10.1016/j.ijpharm.2016.02.023.
[115] H. Petersen, J. Bizec, H. Schuetz, M. Delporte, Pharmacokinetic and technical
comparison of Sandostatin ® LAR ® and other formulations of long-acting octreotide,
BMC Research Notes 4 (2011) 344.
[116] J. Garland, J.R. Buscombe, C. Bouvier, P. Bouloux, M. H. Chapman, A.C. Chow, N.
Reynolds , M.E. Caplin, Sandostatin LAR ( long-acting octreotide acetate ) for
malignant carcinoid syndrome : a 3-year experience, Aliment Pharmacol. Ther. 17
(2003) 437– 444. doi:10.1046/j.0269-2813.2003.01420.x.
[117] B. Astruc, P. Marbach, H. Bouterfa, C. Denot, M. Safari, A. Vitaliti, M. Sheppard,
Long-Acting Octreotide and Prolonged-Release Lanreotide Formulations Have
Different Pharmacokinetic Profiles, J. Clin. Pharmacol. 45 (2005) 836–844.
doi:10.1177/0091270005277936.

of
[118] P.H. Davies, S.E. Stewart, I. Lancranjan, M.C. Sheppard, P.M. Stewart, Long-term
therapy with long-acting octreotide ( Sandostatin-LAR ® ) for the management of

ro
acromegaly, Clin. Endocrinol. 48 (1998) 311–316.
[119] A.K. Fløgstad, J. Halse, S. Bakke, I. Lancranjan, P. Marbach, C.H. Bruns, J.A.K.
-p
Jervell, Sandostatin LAR in Acromegalic Patients : Long Term Treatment, J. Clin.
Endocrinol. Metab. 81 (1997) 23–28.
re
[120] P. Grass, P. Marbach, C. Bruns, I. Lancranjan, Sandostatin® LAR®
(microencapsulated octreotide acetate) in Acromegaly: pharmacokinetic and
lP

pharmacodynamic relationships, Metabolism 45 (8) (1996) 27–30.

[121] S. Fattah, D.J. Brayden, Progress in the formulation and delivery of somatostatin
analogs for acromegaly, Ther. Deliv. 8(10) (2017) 867–878.
na

[122] R. Gostelow, C. Scudder, S. Keyte, Y. Forcada, R.C. Fowkes, H.A. Schmid, D.B.
Church, S.J.M. Niessen, Pasireotide long-acting release treatment for diabetic cats with
ur

underlying hypersomatotropism, J. Vet. Intern Med. 31 (2017) 355–364.

[123] S. Petersenn, J. Bollerslev, A.M. Arafat, J. Schopohl, O. Serri, L. Katznelson, J.
Jo

Lasher, G. Hughes, K. Hu, G. Shen, K.H. Reséndiz, V. Giannone, A. Beckers,

Pharmacokinetics, pharmacodynamics, and safety of pasireotide LAR in patients with
acromegaly: A randomized, multicenter, open-label, phase i study, J. Clin. Pharmacol.
54 (2014) 1308–1317. doi:10.1002/jcph.326.
[124] Somatuline® LA [Product Leaflet]. Ipsen, Berkshire, UK. Initial Approval in 1998,
Revised in 2019, https://www.medicines.org.uk/emc/product/965/pil.
[125] R. Dreicer, D.F. Bajorin, D.G. Mcleod, D.P. Petrylak, J.W. Moul, New Data, New
Paradigms for Treating Prostate Cancer Patients—VI: Novel Hormonal Therapy
Approaches, Urology. 78 (2011) S494–S498. doi:10.1016/j.urology.2011.06.058.
[126] H. Lepor, Comparison of Single-Agent for Advanced Prostate Cancer, Rev. Urol. 7
(suppl 5) (2005) 3–12 –12.
[127] M. Haglund, L. Mooney, M. Gitlin, T. Fong, J. Tsuang, Vivitrol and Depression : A
Case Report and Review of the Literature, Addict. Disord. Their Treatment 13 (2014).
doi:10.1097/ADT.0000000000000051.

53
 Journal Pre-proof

[128] P.P. Lobmaier, N. Kunøe, M. Gossop, H. Waal, Naltrexone Depot Formulations for
Opioid and Alcohol Dependence : A Systematic Review, CNS Neurosci. Ther. 17
(2011) 629–636. doi:10.1111/j.1755-5949.2010.00194.x.
[129] B.A. Johnson, Naltrexone long-acting formulation in the treatment of alcohol
dependence, Ther. Clin. Risk Manag. 3 (2007) 741–749.
[130] B.P. Jarvis, A.F. Holtyn, S. Subramaniam, D.A. Tompkins, E.A. Oga, G.E. Bigelow,
K. Silverman, Extended-release injectable naltrexone for opioid use disorder : a
systematic review, Addiction 113 (2018) 1188–1209. doi:10.1111/add.14180.
[131] S.D. Comer, M.A. Sullivan, G.K. Hulse, Sustained-release naltrexone : novel treatment
for opioid, Expert Opin. Investig. Drugs 16 (8) (2007) 1285–1294.
[132] Y.Y. Syed, G.M. Keating, Extended-Release Intramuscular Naltrexone ( VIVITROL
Ò ): A Review of Its Use in the Prevention of Relapse to Opioid Dependence in

of
Detoxified Patients, CNS Drugs 27 (2013) 851–861. doi:10.1007/s40263-013-0110-x.
[133] J. Paik, S.T. Duggan, S.J. Keam, Triamcinolone Acetonide Extended-Release: A

ro
Review in Osteoarthritis Pain of the Knee, Drugs. 79 (2019) 455–462.
doi:10.1007/s40265-019-01083-3. -p
[134] V.B. Kraus, P.G. Conaghan, H.A. Aazami, P. Mehra, A.J. Kivitz, J. Lufkin, J. Hauben,
J.R. Johnson, N. Bodick, Synovial and systemic pharmacokinetics (PK) of
triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-
re
release microsphere-based formulation (FX006) or standard crystalline suspension in
patients with knee osteoarthritis (OA), Osteoarthr. Cartil. 26 (2018) 34–42.
lP

doi:10.1016/j.joca.2017.10.003.
[135] M.A. Javali, K.L. Vandana, A comparative evaluation of atrigel delivery system (10%
doxycycline hyclate) Atridox with scaling and root planing and combination therapy in
na

treatment of periodontitis: A clinical study, J. Indian Soc. Periodontol. 16 (2012) 43–

48. doi:10.4103/0972-124X.94603.
ur

[136] N.S. Zeidner, R.F. Massung, M.C. Dolan, E. Dadey, E. Gabitzsch, G. Dietrich, M.L.
Levin, A sustained-release formulation of doxycycline hyclate (Atridox) prevents
simultaneous infection of Anaplasma phagocytophilum and Borrelia burgdorferi
Jo

transmitted by tick bite, J. Med. Microbiol. 57 (2008) 463–468.

doi:10.1099/jmm.0.47535-0.
[137] G.L. Southard, R.L. Dunn, S. Garrett, The drug delivery and biomaterial attributes of
the ATRIGEL® technology in the treatment of periodontal disease, Expert Opin.
Investig. Drugs. 7 (1998) 1483–1491. doi:10.1517/13543784.7.9.1483.
[138] C. Castro, E. Sánchez, A. Delgado, I. Soriano, P. Núñez, M. Baro, A. Perera, C. Évora,
Ciprofloxacin implants for bone infection. In vitro-in vivo characterization, J. Control.
Release. 93 (2003) 341–354. doi:10.1016/j.jconrel.2003.09.004.
[139] M. Veiranto, P. Törmälä, E. Suokas, In vitro mechanical and drug release properties of
bioabsorbable ciprofloxacin containing and neat self-reinforced P(L/DL)LA 70/30
fixation screws, J. Mater. Sci. Mater. Med. 13 (2002) 1259–1264.
doi:10.1023/A:1021187331458.
[140] R.W. Bucholz, S. Henry, M.B. Henley, Fixation with bioabsorbable screws for the
treatment of fractures of the ankle, J. Bone Jt. Surg. - Ser. A. 76 (1994) 319–324.

54
 Journal Pre-proof

doi:10.2106/00004623-199403000-00001.
[141] D.B. Thordarson, M. Samuelson, L.E. Shepherd, P.F. Merkle, J. Lee, Bioabsorbable
versus stainless steel screw fixation of the syndesmosis in pronation-lateral rotation
ankle fractures: A prospective randomized trial, Foot Ankle Int. 22 (2001) 335–338.
doi:10.1177/107110070102200411.
[142] T.J. Mäkinen, M. Veiranto, J. Knuuti, J. Jalava, P. Törmälä, H.T. Aro, Efficacy of
bioabsorbable antibiotic containing bone screw in the prevention of biomaterial-related
infection due to Staphylococcus aureus, Bone. 36 (2005) 292–299.
doi:10.1016/j.bone.2004.11.009.
[143] G. Geiges, E. Schapperer, U. Thyroff-friesinger, Clinical development of two
innovative pharmaceutical forms of leuprorelin acetate, Ther. Adv. Urol. 5 (2013) 3–
10. doi:10.1177/1756287212471096.

of
[144] D. Herna, R. Clemente-toma, A.M. Duch-samper, Intracrystalline Ozurdex Ò :
therapeutic effect maintained for 18 months, Int. Ophthalmol. (2017) 3–7.
doi:10.1007/s10792-017-0780-3.

ro
[145] S. Pommier, S. Guigou, Long-Term Real-Life Efficacy and Safety of Repeated
Ozurdex ® Injections and Factors Associated with Macular Edema Resolution after
-p
Retinal Vein Occlusion : The REMIDO 2 Study, Ophthalmologica 236 (2016) 186–
192. doi:10.1159/000452896.
re
[146] J. Coca-robinot, B. Casco-silva, F. Armadá-maresca, J. García-martínez, Accidental
injections of dexamethasone intravitreal implant ( Ozurdex ® ) into the crystalline
lP

lens, Eur. J. Ophthalmol. 24 (4) (2014) 633–636. doi:10.5301/ejo.5000439.

[147] A. Chan, Critical appraisal of the clinical utility of the dexamethasone intravitreal
implant ( Ozurdex ® ) for the treatment of macular edema related to branch retinal
na

vein occlusion or central retinal vein occlusion, Clin. Ophthalmol. 5 (2011) 1043–
1049.
ur

[148] C. Aroney, S. Fraser-bell, E.L. Lamoureux, M.C. Gillies, L. Lyndell, E.K. Fenwick,
Vision-Related Quality of Life Outcomes in the BEVORDEX Study : A Clinical Trial
Comparing Ozurdex Sustained Release Dexamethasone Intravitreal Implant and
Jo

Bevacizumab Treatment for Diabetic Macular Edema, Invest. Ophthalmol. Vis. Sci. 57
(2019) 25–30. doi:10.1167/iovs.16-19729.
[149] M. Srour, G. Querques, N. Leveziel, J. Zerbib, Intravitreal dexamethasone implant
(Ozurdex ) for macular edema secondary to retinitis pigmentosa, Graefes Arch. Clin.
Exp. Ophthalmol. 251 (2013) 1501–1506. doi:10.1007/s00417-012-2249-4.
[150] G. Coscas, F. Coscas, I. Zucchiatti, A. Glacet-bernard, G. Soubrane, SD-OCT pattern
of retinal venous occlusion with cystoid macular edema treated with Ozurdex ®, Eur.
J. Ophthalmol. 21 (2011) 631–636. doi:10.5301/EJO.2011.7428.
[151] R. Mathew, E. Pearce, R. Muniraju, S. Sivaprasad, monitoring of Ozurdex for macular
oedema related to retinal vascular diseases : re-treatment strategy ( OCTOME Report 1
), Eye. 28 (2014) 318–326. doi:10.1038/eye.2013.287.
[152] M. Scaramuzzi, G. Querques, C. LA Spina, R. Lattanzio, F. Bandello, Repeated
intravitreal dexamethasone implant ( Ozurdex) for diabetic macular edema, Retina 35
(2015) 1216–1222.

55
 Journal Pre-proof

[153] A.V. Kulagina, O.G. Gusarevich, A.A. Gusarevich, P.A. Lebedev, A.D. Baltaks,
Clinical efficacy of dexamethasone intravitreal implant (Ozurdex) in patients with
retinal vein occlusions. Vestn. Oftalmol. 130,3 (2014) 49–53.
[154] L.G. Gomella, for Prostate Cancer : Is There a Best Castration Therapy ? Rev. Urol.
11(2) (2009) 52–60.
[155] B. Pettersson, E. Varenhorst, A. Petas, Duration of Testosterone Suppression after a 9 .
45 mg Implant of the GnRH-Analogue Buserelin in Patients with Localised Carcinoma
of the Prostate A 12-Month Follow-up Study, Eur. Urol. 50 (2006) 483–489.
doi:10.1016/j.eururo.2006.03.001.
[156] D.W. Kennedy, The PROPEL TM steroid-releasing bioabsorbable implant to improve
outcomes of sinus surgery, Expert Rev. Respir. Med. 6(5) (2012) 493–498.
[157] http://ir.intersectent.com/node/7251/html. (Accessed on 29 September 2020)

of
[158] J. Chen, J. Zhang, C. Wang, K. Yao, L. Hua, L. Zhang, X. Ren, Safety of implanting
sustained-release 5-fluorouracil into hepatic cross-section and omentum majus after

ro
primary liver cancer resection, Int. J. Immunopathol. Pharmacol. 29 (2016) 475–479.
doi:10.1177/0394632016648176. -p
[159] https://clinicaltrials.gov/ct2/show/NCT01317069. (Accessed on 17 April 2020)
[160] Y.Y. Shen, H.W. Qin, J.B. Zhang, Z.D. Wang, P. Li, K. Pang, B. Zhang, S. Li, K. Cui,
re
Fluorouracil implants caused a diaphragmatic tumor to be misdiagnosed as liver
metastasis: A case report, BMC Cancer. 16 (2016) 3–7. doi:10.1186/s12885-016-2778-
z.
lP

[161] D. Fontana, M. Mari, A. Martinelli, C. Boccafoschi, C. Magno, M. Turriziani, S.S.

Maymone, S. Cosciani Cunico, A. Zanollo, G. Montagna, M. Frongia, U. Jacobellis, 3-
na

Month Formulation of Goserelin Acetate (‗ Zoladex ‘ 10.8-mg Depot ) in Advanced

Prostate Cancer : Results from an Italian , Open, multicenter trial, Urol. Int. 70 (2003)
316–320. doi:10.1159/000070142.
ur

[162] B.J.A. Furr, F.G. Hutchinsonb, A biodegradable delivery system for peptides :
preclinical experience with the gonadotrophin-releasing hormone agonist, J. Control.
Jo

Release 21 (1992) 117–127.

[163] T. Kotake, M. Usami, T. Sonoda, M. Matsuda, E. Okajima, M. Osafune, K. Isurugi ,
H. Akaza, Y. Saitoh, LH-RH agonist, Zoladex (Goserelin), depot formulation in the
treatment of prostatic cancer. Randomized dose-finding trial in Japan, Am. J. Clin.
Oncol. 11 (Suppl 2) (1988) S108-111.
[164] A. Ward, B.J.A. Furr, B. Valcaccia, B. Curry, C.W. Bardin, G.L. Gunsalus, I.D.
Morris, Prolonged suppression of rat testis function by a depot formulation of Zoladex,
a GnRH Agonist, J. Androl 10 (1989) 478–486.
[165] S.R. Amhed, J. Grant, S.M. Shalet, A. Howell, S.D. Chowdhury, T. Weatherson, N.J.
Blacklock, Preliminary report on use of depot formulation of LHRH analogue ICI
118630 (Zoladex ) in patients with prostatic cancer, Br. Med. J. 290 (1985) 185–187.
[166] D.L. Citrin, M. Resnick, P. Guinan, N. Al-bussam, T.C. Gau, G.T. Kennealey, A
Comparison of Zoladex ® and DES in the treatment of advanced prostate cancer :
results of a randomized , multicenter trial, The Prostate 18 (1991) 139–146.

56
 Journal Pre-proof

[167] G.A. Dijkman, P. Fernandez Del Moral, J.W.M.H. Plasman, J.J.M. Kums, K.P.J.
Delaere, F.M.J. Debruyne, F.J. Hutchinson, B.J.A. Furr, A new extra long acting depot
preparation of the lhrh analogue Zoladex ®. First endocrinological and
pharmacokinetic data in patients with advanced prostate cancer, J. Steroid Biochem.
Molec. Biol 37 (6) (1990) 933–936.
[168] F.M.J. Debruyne, L. Denis, G.Lunglmayer, C. Mahler, D.W.W. Newling, B. Richards,
M.R.G. Robinson, P.H. Smith, E.H.J. Weil, P. Whelan, Long-term therapy with a
depotluteinizing hormone- releasing hormone analogue (Zoladex) in patients with
advanced prostatic carcinoma, J. Urol. 140 (1988) 775–777.
doi:10.1016/S00225347(17)41809-X.
[169] N.R. Zinner, M. Bidair, A. Centeno, K. Tomera, Similar frequency of testosterone
surge after repeat injections of goserelin (Zoladex) 3.6 mg and 10.8 mg: results of a
randomized open-label trial, Urology 64 (2004) 1177–1181.

of
doi:10.1016/j.urology.2004.07.033.
[170] K.S. Moghissi, W.D. Schlaff, D.L. Ofive, M.A. Skinner, H. Yin, Goserelin acetate

ro
(Zoladex) with or without hormone replacement therapy for the treatment of
endometriosis, Fertil Steril 69 (1998) 1056-1062.
-p
[171] Y. Pandya, D. Sisodiya, K. Dashora, Atrigel, Implants and Controlled Released Drug
Delivery System, Int. J. Biopharm. 5 (2014) 208–213.
doi:10.1056/NEJM197302222880814.
re
[172] ELIGARD ® [Product Leaflet]. Tolmar Pharmaceuticals, Inc. Fort Collins, Colorado.
Initial U.S. Approval in 2002, revised in 2019.
lP

[173] R.R.S. Thakur, H.L. McMillan, D.S. Jones, Solvent induced phase inversion-based in
situ forming controlled release drug delivery implants, J. Control. Release. 176 (2014)
na

8–23. doi:10.1016/j.jconrel.2013.12.020.
[174] S.R. Van Tomme, G. Storm, W.E. Hennink, In situ gelling hydrogels for
pharmaceutical and biomedical applications, Int. J. Pharm. 355 (2008) 1–18.
ur

doi:10.1016/j.ijpharm.2008.01.057.
[175] PERSERIS [Product Leaflet]. Indivior Inc. North Chesterfield, VA. Initial U.S.
Jo

Approval in 1993, revised in 2019.

[176] SCENESSE ® [Product Leaflet]. CLINUVEL, INC. West Menlo Park, CA. Initial
U.S. Approval in 2019, revised in 2019.
[177] S. Jin, S. Kwang, M. Jin, D. Hee, Y. Phil, Development of a novel sustained release
formulation of recombinant human growth hormone using sodium hyaluronate
microparticles, J. Control. Release 104 (2005) 323–335.
doi:10.1016/j.jconrel.2005.02.012.
[178] J.K. Park, C.O. Kim, S.W. Kim, C.Y. Lim, Y. Chung, Sustained-release recombinant
human growth hormone improves body composition and quality of life in adults with
somatopause, Letters to the Editor, JAGS 59 (5) (2011) 944–947.
[179] J. Kim, Y. Soo, K. Un, S. Young, J. Soo, C. Hoon, Growth Hormone &amp; IGF
Research Effects of sustained release growth hormone treatment during the
rehabilitation of adult severe burn survivors, Growth Horm. IGF Res. 27 (2016) 1–6.
doi:10.1016/j.ghir.2015.12.009.

57
 Journal Pre-proof

[180] A. Bregy, A.H. Shah, M. V Diaz, H.E. Pierce, P.L. Ames, D. Diaz, R.J. Komotar, The
role of Gliadel wafers in the treatment of high-grade gliomas, Expert Rev. Anticancer
Ther. 13(12) (2013), 1453–1461.
[181] J.B. Wolinsky, Y.L. Colson, M.W. Grinstaff, Local drug delivery strategies for cancer
treatment: Gels, nanoparticles, polymeric films, rods, and wafers, J. Control. Release.
159 (2012) 14–26. doi:10.1016/j.jconrel.2011.11.031.
[182] https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020637s026lbl.pdf.
(Accessed on 07 November 2020)
[183] R.R. Colen, P.O. Zinn, S. Hazany, D. Do-dai, J.K. Wu, K. Yao, J.J. Zhu, Magnetic
resonance imaging appearance and changes on intracavitary Gliadel wafer placement:
A pilot study, World J. Radiol. 3 (2011) 266–272.
[184] M. Westphal, D.C. Hilt, E. Bortey, P. Delavault, R. Olivares, P.C. Warnke, I.R.

of
Whittle, J. Ja skel inen, Z. Ram, A phase 3 trial of local chemotherapy with
biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary
malignant glioma, Neuro. Oncol. 5 (2003) 79–88. doi:10.1215/15228517-5-2-79.

ro
[185] A. Giese, T. Kucinski, U. Knopp, R. Goldbrunner, W. Hamel, H.M. Mehdorn, J.C.
Tonn, D. Hilt, M. Westpha, Pattern of recurrence following local chemotherapy with
-p
biodegradable carmustine ( BCNU ) implants in patients with glioblastoma, J.
NeuroOncol. 66 (2004) 351–360.
re
[186] J. Heller, J. Barr, S.Y. Ng, K.S. Abdellauoi, R. Gurny, Poly(ortho esters): Synthesis,
characterization, properties and uses, Adv. Drug Deliv. Rev. 54 (2002) 1015–1039.
lP

doi:10.1016/S0169-409X(02)00055-8.
[187] J. Vacirca, D. Caruana, G. Calcanes, M. Mosier, R. Boccia, Hydration requirements
with emetogenic chemotherapy : granisetron extended-release subcutaneous versus
na

palonosetron, Future Oncol. 14(14) (2018) 1387-1396.

[188] L.A. Raedler, Sustol (Granisetron) First Extended- Release 5-HT3 Receptor
ur

Antagonist Approved for the Prevention of Acute and Delayed CINV, Am. Health
Drug Benefits 10 (2017) 81–84.
[189] J. Gilmore, S.D. Amato, N. Griffith, L. Schwartzberg, Recent advances in antiemetics :
Jo

new formulations of 5HT 3 -receptor antagonists, Cancer Manag. Res. 10 (2018)

1827–1857.
[190] S.M. Couch, S.J. Bakri, Use of triamcinolone during vitrectomy surgery to visualize
membranes and vitreous, Clin. Ophthalmol. 2 (4) (2008) 891–896.
[191] S.M. Couch, S.J. Bakri, Intravitreal triamcinolone for intraocular in fl ammation and
associated macular edema, Clin. Ophthalmol. 3 (2009) 41–48.
[192] M.S. Ip, I.U. Scott, P.C. Vanveldhuisen, N.L. Oden, B.A. Blodi, M. Fisher, L.J.
Singerman, M. Tolentino, C.K. Chan, H.V. Gonzalez, A randomized trial comparing
the efficacy and safety of intravitreal triamcinolone with observation to treat vision
loss associated with macular edema secondary to central retinal vein occlusion: The
standard care vs corticosteroid for retinal vein occlusion (SCORE) Study Report 5,
Arch. Ophthalmol. 127(9) (2009) 1101–1114.
[193] M.S. Ip, N.L. Oden, I.U. Scott, P.C. Vanveldhuisen, B.A. Blodi, M. Figueroa, A.
Antoszyk, M. Elman, SCORE Study Report 3 Study Design and Baseline
58
 Journal Pre-proof

Characteristics, Ophthalmology 116 (2009) 1770–

1777.doi:10.1016/j.ophtha.2009.03.022.
[194] T.A. Albini, M.M. Abd-el-barr, P.E. Carvounis, M.N. Iyer, R.R. Lakhanpal, M.E.
Pennesi, P. Chevez-barrios, S.M. Wu, E.R. Holz, Long-term Retinal Toxicity of
Intravitreal Commercially Available Preserved Triamcinolone Acetonide ( Kenalog )
in Rabbit Eyes, Invest. Ophthalmol. Vis. Sci. 48 (2019) 390–395.
doi:10.1167/iovs.060145.
[195] J.E. Chang-Lin, M. Attar, A.A. Acheampong, M.R. Robinson, S.M. Whitcup, B.D.
Kuppermann, D. Welty, Pharmacokinetics and pharmacodynamics of a sustained-
release dexamethasone intravitreal implant, Investig. Ophthalmol. Vis. Sci. 52 (2011)
80–86. doi:10.1167/iovs.10-5285.
[196] Buvidal® [Product Leaflet]. Camurus AB, Lund, Sweden. Initial authorisation in
2018.

of
[197] M.R. Lofwall, S.L. Walsh, E. V. Nunes, G.L. Bailey, S.C. Sigmon, K.M. Kampman,
M. Frost, F. Tiberg, M. Linden, B. Sheldon, S. Oosman, S. Peterson, M. Chen, S. Kim,

ro
Weekly and monthly subcutaneous buprenorphine depot formulations vs daily
sublingual buprenorphine with naloxone for treatment of opioid use disorder a
-p
randomized clinical trial, JAMA Intern. Med. 178 (2018) 764–773.
doi:10.1001/jamainternmed.2018.1052.
re
[198] M. Chappuy, B. Trojak, P. Nubukpo, J. Bachellier, P. Bendimerad, G. Brousse, B.
Rolland, Prolonged-release buprenorphine formulations: Perspectives for clinical
practice, Therapies. (2020). doi:10.1016/j.therap.2020.05.007.
lP

[199] M. Ye, G. Bhat, K.A. Johnston, H. Tan, M. Garnick, Proprietary Rel-EaseTM drug
delivery technology: Opportunity for sustained delivery of peptides, proteins and small
na

molecules, Expert Opin. Drug Deliv. 3 (2006) 663–675.

doi:10.1517/17425247.3.5.663.
[200] SOMATULINE ® DEPOT [Product Leaflet]. Ipsen Pharma Biotech. Signes, France.
ur

Initial U.S. Approval in 2007, revised in 2019.

[201] A.I. Vinik, E.M. Wolin, N. Liyanage, E. Gomez-Panzani, G.A. Fisher, Evaluation of
Jo

Lanreotide Depot/Autogel Efficacy and Safety As A Carcinoid Syndrome Treatment

(Elect): A Randomized, Double-Blind, Placebo-Controlled Trial, Endocr. Pract. 22
(2016) 1068–1080. doi:10.4158/EP151172.OR.
[202] N. Kyriakakis, V. Chau, J. Lynch, S.M. Orme, R.D. Murray, Lanreotide autogel in
acromegaly - A decade on, Expert Opin. Pharmacother. 15 (2014) 2681–2692.
doi:10.1517/14656566.2014.970173.
[203] C.J.C. Edwards-Gayle, I.W. Hamley, Self-assembly of bioactive peptides, peptide
conjugates, and peptide mimetic materials, Org. Biomol. Chem. 15 (2017) 5867–5876.
doi:10.1039/c7ob01092c.
[204] C. Valéry, F. Artzner, B. Robert, T. Gulick, G. Keller, C. Grabielle-Madelmont, M.L.
Torres, R. Cherif-Cheikh, M. Paternostre, Self-Association Process of a Peptide in
Solution: From β-Sheet Filaments to Large Embedded Nanotubes, Biophys. J. 86
(2004) 2484–2501. doi:10.1016/S0006-3495(04)74304-0.
[205] D. Leite, E. Barbu, G. Pilkington, A. Lalatsa, Peptide Self-Assemblies for Drug

59
 Journal Pre-proof

Delivery, Curr. Top. Med. Chem. 15 (2015) 2277–2289.

doi:10.2174/1568026615666150605120456.
[206] Firmagon ® [Product Leaflet]. Ferring Pharmaceuticals Inc., Parsippany, NJ. Approval
in 2008, revised in 2020.
[207] I. Cervenakov, M. Kopecny, M. Jancar, D. Chovan, M. Mal‗a, I. Cerven, ‗ Hot flush ‘,
an unpleasant symptom accompanying antiandrogen therapy of prostatic cancer and its
treatment by cyproterone acetate, Int. Urol. Nephrol. 32 (2000) 77–79.
[208] T. Rabe, K. Grunwald, K. Feldmann, B. Rirnrzebarim, Treatment of
hyperandrogenism in women, Gynecol. Endocrinol. 10 (1996) Supp. 3, 1–44.
[209] A. Rost, M. Schmidt-Gollwitze, W. Hantelmann, W. Brosig, Cyproterone acetate,
testosterone , LH , FSH , and prolactin levels in plasma after intramuscular application
of cyproterone acetate in patients with prostatic cancer, The Prostate 2 (1981) 315–

of
322.
[210] A. Grinshpoon, M. Moskowitz, L. Palei, M. Mark, A. Valevski, A. Kreizman, A.

ro
Weizman, Zuclopenthixol , D1/ D2, antagonist , for treatment of chronic aggressive
schizophrenia and psychotic oligophrenic patients, Eur. Psychiatry 13 (1998) 273–275.
-p
[211] T. Aaes-Jurgensen, F. Bjerndal, U. Bartels, H.A.S. Lundbeck, D.K. Valby,
Zuclopenthixol levels in serum and breast milk, Psychopharmacology 90 (1986) 10–
11.
re
[212] Q. Javed, A. Chorghade, S. Javed, Y. Pervez, Reduction in self-harming behaviour
after zuclopenthixol decanoate, Prog. Neurol. Psychiatry (2014) 23–27.
lP

[213] R.G. Strickley, Solubilizing excipients in oral and injectable formulations, Pharm. Res.
21 (2) (2004) 201-230.
na

[214] J. Drouin, L‘hypogonadisme acquis: faut-il le traiter? Le Médecin du Québec 45 (3)

(2010) 37–42.
ur

[215] A.S. Dobs, A.W. Meikle, S. Arver, S.W. Sanders, K.I.M.E. Caramelli, N.A. Mazer,
Pharmacokinetics, efficacy, and safety of a permeation- enhanced testosterone
transdermal system in comparison with bi-weekly injections of testosterone enanthate
Jo

for the treatment of hypogonadal men, J. Clin. Endocrinol. Metab. 84 (10) (1999)
3469–3478.
[216] J.A. Stauning, L. Kirk, A. Jorgensen, Comparison of serum levels after intramuscular
injections of 2 % and 10 % cis(Z)-flupentixol decanoate in viscoleo to schizophrenic
patients, Psychopharmacology 72 (1979) 69–72.
[217] L. Kirk, A. Bilde, J.A. Stauning, B. Ahrensburg, A. Jørgensen, L. Kirk, A. Bilde, J.A.
Stauning, B. Ahrensburg, F. Depot, L. Kirk, A. Bilde, J.A. Stauning, B. Ahrensburg,
E. Petersen, A. Jorgensen, Serum concentrations of cis (Z) -flupentixol in patients
under maintenance treatment with cis (Z) - flupentixol decanoate : ( Fluanxol® Depot ,
Depixol® inj.) Serum concentrations of cis (Z) - flupen tixol in patients under
maintenance treatment with cis (Z) - flupentixol decanoate, Nord. Psykiatr. Tidsskr. 38
(5) (1984) 493-495. doi:10.3109/08039488409101893.
[218] A. Jorgensen, J. Andersen, N. Bjorndal, S.J. Dencker, L. Lundin, U. Malm, Serum
Concentrations of cis (Z) - Flupentixol and Prolactin in Chronic Schizophrenic Patients
Treated with Flupentixol and cis (Z) - Flupentixol Decanoate, Psychopharmacology 77
60
 Journal Pre-proof

(1982) 58–65.
[219] A. Jorgensen, Pharmacokinetic studies in volunteers of intravenous and oral cis (Z) -
flupentixol and intramuscular cis (Z) -flupentixol decanoate in Viscoleo ®, Eur. J.
Clin. Pharmacol. 360 (1980) 355–360.
[220] J. Mahapatra, S.N. Quraishi, A. David, S. Sampson, C.E. Adams, Flupenthixol
decanoate (depot) for schizophrenia or other similar psychotic disorders, Cochrane
Database Syst. Rev. 2014 (2014). doi:10.1002/14651858.CD001470.pub2.
[221] L. Shi, H. Ascher-Svanum, B. Zhu, D. Faries, W. Montgomery, S.R. Marder,
Characteristics and use patterns of patients taking first-generation depot antipsychotics
or oral antipsychotics for schizophrenia, Psychiatric Services 58 (2007) 482–488.
[222] B. Zhu, H. Ascher-Svanum, L. Shi, D. Faries, W. Montgomery, S.R. Marder, Time to
discontinuation of depot and oral first-generation antipsychotics in the usual care of

of
schizophrenia, Psychiatric Services 59 (2008) 315–317.
[223] T.R.E. Barnes, D.A. Curson, Long term depot antipsychotics: A risk-benefit

ro
assessment, Drug Safety 10 (1994) 464–479.
[224] J.M. Davis, L. Metalon, M.D. Watanabe, L. Blake, Depot antipsychotic drugs: Place in
-p
therapy, Drugs 47 (1994) 741–773.
[225] A. Howell, J.F.R. Robertson, J.Q. Albano, A. Aschermannova, L. Mauriac, U.R.
re
Kleeberg, I. Vergote, B. Erikstein, A. Webster, C. Morris, Fulvestrant, formerly ICI
182,780, is as effective as anastrozole in postmenopausal women with advanced breast
cancer progressing after prior endocrine treatment, J. Clin. Oncol. 20 (2002) 3396–
lP

3403. doi:10.1200/JCO.2002.10.057.
[226] C.J. Li, M.Y. Ku, C.Y. Lu, Y.E. Tien, W.H. Chern, J. ding Huang, In vitro and in vivo
na

release of dinalbuphine sebacate extended release formulation: Effect of the oil ratio
on drug release, Int. J. Pharm. 531 (2017) 306-312. doi:10.1016/j.ijpharm.2017.08.083.
[227] Y. en Tien, W.C. Huang, H.Y. Kuo, L. Tai, Y.S. Uang, W.H. Chern, J.D. Huang,
ur

Pharmacokinetics of dinalbuphine sebacate and nalbuphine in human after

intramuscular injection of dinalbuphine sebacate in an extended-release formulation,
Jo

Biopharm. Drug Dispos. 38 (2017) 494–497. doi:10.1002/bdd.2088.

[228] C.Y. Yeh, S.W. Jao, J.S. Chen, C.W. Fan, H.H. Chen, P.S. Hsieh, C.C. Wu, C.C. Lee,
Y.H. Kuo, M.C. Hsieh, W.S. Huang, Y.C. Chung, T.Y. Liou, H.H. Chiu, W.K. Tseng,
K.C. Lee, J.Y. Wang, Sebacoyl Dinalbuphine Ester Extended-release Injection for
Long-acting Analgesia, Clin. J. Pain. 33 (2017) 429–434.
doi:10.1097/AJP.0000000000000417.
[229] V.B. Junyaprasert, B. Morakul, Nanocrystals for enhancement of oralbioavailability of
poorly water-soluble drugs, Asian J. Pharm. Sci. 10 (2015) 13–23.
https://doi.org/10.1016/j.ajps.2014.08.005.
[230] J. Kapitola and J. Kubíóková, Estradiol Benzoate Decreases the Blood Flow through
the Tibia of Female Rats, Exp. Clin. Endocrinol. 96 (1990) 117–120.
[231] J. Kapitola, J. Andrie, J. Kubíková, Experimental and further findings on the inhibitory
effect of estradiol benzoate on the circulation and on 45 Ca and 3 H-proline
Incorporation in Rat Bones, Exp. Clin. Endocrinol. 100 (1992) 140–144.

61
 Journal Pre-proof

[232] J. Kapitola, J. Kubfckova, J. Andrle, Blood flow and mineral content of the tibia of
female and male rafs : changes following castration and / or administration of estradiol
or testosterone, Bone 16 (1995) 69–72.
[233] J. Nedvfdkovä, M. Haluzik, V. Schreiber, The decrease of serum leptin levels in
oestrogen-treated male mice, Physiol. Res. 46 (1997) 291–294.
[234] J. Nedvidkovâ, K. Pacâk, M. Haluzik, J. Nedvidek, V. Schreiber, The role of dopamine
in methylene blue-mediated inhibition of estradiol benzoate-induced anterior pituitary
hyperplasia in rats, Neurosci. Lett. 304 (2001) 194–198.
[235] ARISTADA INITIO TM [Product Leaflet]. Alkermes, Waltham, MA. Initial U.S.
Approval in 2015, revised in 2018.
[236] ARISTADA ® [Product Leaflet]. Alkermes, Waltham, MA. Initial U.S. Approval in
2015, revised in 2018.

of
[237] H.Y. Meltzer, R. Risinger, H.A. Nasrallah, Y. Du, J. Zummo, L. Corey, A. Bose, S.
Stankovic, B.L. Silverman, E.W. Ehrich, A randomized, double-blind, placebo-

ro
controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia, J. Clin.
Psychiatry. 76 (2015) 1085–1090. doi:10.4088/JCP.14m09741.
-p
[238] M.L. Hard, A. Wehr, L. von Moltke, Y. Du, S. Farwick, D.P. Walling, J. Sonnenberg,
Pharmacokinetics and safety of deltoid or gluteal injection of aripiprazole lauroxil
NanoCrystal ® Dispersion used for initiation of the long-acting antipsychotic
re
aripiprazole lauroxil , Ther. Adv. Psychopharmacol. 9 (2019) 204512531985996.
doi:10.1177/2045125319859964.
lP

[239] G. Husby, E Kass, K. Spongsveen, Comparative double-blind trial of intra-articular

injections of two long-acting forms of betamethasone, Scand J Rheumatology 4 (1975)
118–120.
na

[240] A. Borderé, A. Stockman, B. Boone, A. Franki, M.J. Coppens, J. Lambert, A case of

anaphylaxis caused by macrogol 3350 after injection of a corticosteroid, Contact
ur

Dermatitis. 67 (2012) 376–378. doi:10.1111/j.1600-0536.2012.02104.x.

[241] D.E. Moran, M.R. Moynagh, M. Alzanki, V.O. Chan, S.J. Eustace, Anaphylaxis at
Jo

image- guided epidural pain block secondary to corticosteroid compound, Skeletal

Radiol. 41 (2012) 1317–1318. doi:10.1007/s00256-012-1440-3.
[242] A.M. Kaunitz, P.D. Darney, D. Ross, K.D. Wolter, L. Speroff, Subcutaneous DMPA
vs . intramuscular DMPA : a 2-year randomized study of contraceptive efficacy and
bone mineral density, Contraception. 80 (2009) 7–17.
doi:10.1016/j.contraception.2009.02.005.
[243] S. Prabhakaran, A. Sweet, Self-administration of subcutaneous depot
medroxyprogesterone acetate for contraception : feasibility and acceptability,
Contraception. 85 (2012) 453–457. doi:10.1016/j.contraception.2011.09.015.
[244] C.B. Polis, G.F. Nakigozi, H. Nakawooya, G. Mondo, F. Makumbi, R.H. Gray,
Preference for Sayana ® Press versus intramuscular Depo-Provera among HIV-
positive women in Rakai , Uganda : a randomized, Contraception. 89 (2014) 385–395.
doi:10.1016/j.contraception.2013.11.008.
[245] J.D. Shelton, V. Halpern, Subcutaneous DMPA : a better lower dose approach,
Contraception. 89 (2020) 341–343. doi:10.1016/j.contraception.2013.10.010.
62
 Journal Pre-proof

[246] R.L. Williams, D.J. Hensel, J.D. Fortenberry, Self-administration of subcutaneous

depot medroxyprogesterone acetate by adolescent women, Contraception. 88 (2013)
401–407. doi:10.1016/j.contraception.2012.11.019.
[247] V. Halpern, S.L. Combes, L.J. Dorflinger, D.H. Weiner, D.F. Archer,
Pharmacokinetics of subcutaneous depot medroxyprogesterone acetate injected in the
upper arm, Contraception. 89 (2014) 31–35. doi:10.1016/j.contraception.2013.07.002.
[248] A. Beasley, K.O. Connell, S. Cremers, C. Westhoff, Randomized clinical trial of self
versus clinical administration of subcutaneous depot medroxyprogesterone acetate,
Contraception. 89 (2014) 352–356. doi:10.1016/j.contraception.2014.01.026.
[249] E. Ji, P. Sarmila, A. Myung, S. Kim, Long-acting injectable formulations of
antipsychotic drugs for the treatment of schizophrenia, Arch. Pharm. Res. 36 (2013)
651–659. doi:10.1007/s12272-013-0105-7.

of
[250] L. Alphs, C. Benson, K. Cheshire-Kinney, J.P. Lindenmayer, L. Mao, S.C. Rodriguez,
H. Starr, Real-world outcomes of paliperidone palmitate compared to daily oral
antipsychotic therapy in schizophrenia : a randomized , open-label , review board–

ro
blinded 15-month study, J. Clin. Psychiatry. 76 (5) (2015) 554-561.
[251] P.G. Conaghan, S.J. Russell, R. Sala, G. Habib, Q. Vo, R. Manning, A. Kivitz, Y.
-p
Davis, J. Lufkin, J.R. Johnson, S. Kelley, Triamcinolone acetonide extended-release
injectable suspension (TA-ER) is associated with reduced blood glucose elevation vs.
re
standard triamcinolone in type 2 diabetes mellitus patients with knee osteoarthritis: a
randomized, blinded, parallel-group study, Osteoarthr. Cartil. 26 (2018) S230.
doi:10.1016/j.joca.2018.02.481.
lP

[252] A. Kivitz, P. Mehra, P. Hanson, L. Levy, L. Kwong, A. Cinar, J. Lufkin, S. Kelley,

Safety and systemic exposure of triamcinolone acetonide following intra-articular
na

injection of triamcinolone acetonide extended-release or standard triamcinolone in

patients with hip osteoarthritis, Osteoarthr. Cartil. 27 (2019) S504–S505.
doi:10.1016/j.joca.2019.02.569.
ur

[253] Y. Lang, E. Zemel, B. Miller, I. Perlman, Retinal toxicity of intravitreal kenalog in

albino rabbits, Retina 27 (2007) 778–788.
Jo

[254] A.H.C. Fong, C.K.M. Chan , Presumed sterile endophthalmitis after intravitreal
triamcinolone (Kenalog)—More common and less benign than we thought? Asia. Pac.
J. Ophthalmol. 6 (2017) 45–49. doi:10.1097/APO.0000000000000194.
[255] J.T. Johnson, A.G. Everly, F.E.F. Kpakima, H.C. Detke, Postmortem redistribution of
olanzapine following intramuscular administration of olanzapine pamoate in dogs,
Forensic Sci. Int. 257 (2015) 353–358.
[256] N.K. Morton, D. Zubek, Psycho pharmacology adherence challenges and long-acting
injectable antipsychotic treatment in patients with schizophrenia, J. Psychosoc. Nurs.
51 (3) (2013) 13-18.
[257] J.D. Caplin, A.J. García, Implantable antimicrobial biomaterials for local drug delivery
in bone infection models, Acta Biomater. 93 (2019) 2–11.
doi:10.1016/j.actbio.2019.01.015.
[258] H. Deng, A. Dong, J. Song, X. Chen, Injectable thermosensitive hydrogel systems
based on functional PEG/PCL block polymer for local drug delivery, J. Control.

63
 Journal Pre-proof

Release. 297 (2019) 60–70. doi:10.1016/j.jconrel.2019.01.026.

[259] https://www.fda.gov/, (Accessed on 25 July 2020).
[260] W. Chen, Y. Wu, Y. Yue, J. Liu, W. Zhang, X. Yang, H. Chen, E. Bi, I. Ashraful, M.
Gratzel, L. Han, Translating Molecules into Medicines, Springer Nature, Switzerland
AG. 2017. doi:10.1007/978-3-319-50042-3.
[261] J.H. Fagerberg, O. Tsinman, N. Sun, K. Tsinman, A. Avdeef, C.A.S. Bergström, M.
Pharmaceut, Dissolution Rate and Apparent Solubility of Poorly Soluble Drugs in
Biorelevant Dissolution Media, Mol. Pharm. 7 (2010) 1419–1430.
[262] C.M. Wassvik, A.G. Holmen, P. , Rieke Draheim, Artursson, C.A.S. Bergström,
Molecular Characteristics for Solid-State Limited Solubility, J. Med. Chem. 51 (2008)
3035–3039.
[263] C.A.S. Bergström, C.M. Wassvik, K. Johansson, I. Hubatsch, Poorly soluble marketed

of
drugs display solvation limited solubility, J. Med. Chem. 50 (2007) 5858–5862.
[264] T.J. Ritchie, S.J.F. Macdonald, The impact of aromatic ring count on compound

ro
developability - are too many aromatic rings a liability in drug design?, Drug Discov.
Today. 14 (2009) 1011–1020. doi:10.1016/j.drudis.2009.07.014.
-p
[265] S. Bukofzer, J. Ayres, A. Chavez, M. Devera, J. Miller, D. Ross, J. Shabushnig, S.
Vargo, H. Watson, R. Watson, Industry perspective on the medical risk of visible
re
particles in injectable drug products, PDA J. Pharm. Sci. Technol. 69 (2015) 123–139.
doi:10.5731/pdajpst.2015.01037.
lP

[266] M.B. Sintzel, A. Merkli, C. Tabatabay, R. Gurny, Influence of Irradiation Sterilization

on Polymers Used as Drug Carriers- A Review. Drug Dev. Ind. Pharm. 23 (1997) 857–
878.
na

[267] S.E. Reinhold, K.G.H. Desai, L. Zhang, K.F. Olsen, S.P. Schwendeman, Self-healing
microencapsulation of biomacromolecules without organic solvents, Angew. Chemie -
Int. Ed. 51 (2012) 10800–10803. doi:10.1002/anie.201206387.
ur

[268] W. Jiang, R.K. Gupta, M.C. Deshpande, S.P. Schwendeman, Biodegradable

poly(lactic-co-glycolic acid) microparticles for injectable delivery of vaccine antigens,
Jo

Adv. Drug Deliv. Rev. 57 (2005) 391–410. doi:10.1016/j.addr.2004.09.003.

[269] C. Carrascosa, L. Espejo, S. Torrado, J.J. Torrado, Effect of γ-sterilization process on
PLGA microspheres loaded with insulin-like growth factor - I (IGF-I), J. Biomater.
Appl. 18 (2003) 95–108. doi:10.1177/088532803038026.
[270] C.Y. Hsiao, S.J. Liu, S. Wen-Neng Ueng, E.C. Chan, The influence of γ irradiation
and ethylene oxide treatment on the release characteristics of biodegradable
poly(lactide-co-glycolide) composites, Polym. Degrad. Stab. 97 (2012) 715–720.
doi:10.1016/j.polymdegradstab.2012.02.015.
[271] N. Faisant, J. Siepmann, J. Richard, J.P. Benoit, Mathematical modeling of drug
release from bioerodible microparticles: Effect of gamma-irradiation, Eur. J. Pharm.
Biopharm. 56 (2003) 271–279. doi:10.1016/S0939-6411(03)00104-8.
[272] N. Faisant, J. Siepmann, P. Oury, V. Laffineur, E. Bruna, J. Haffner, J.P. Benoit, The
effect of gamma-irradiation on drug release from bioerodible microparticles: A
quantitative treatment, Int. J. Pharm. 242 (2002) 281–284. doi:10.1016/S0378-

64
 Journal Pre-proof

5173(02)00188-6.
[273] D. Mohanan, B. Gander, T.M. Kündig, P. Johansen, Encapsulation of antigen in
poly(d,l-lactide-co-glycolide) microspheres protects from harmful effects of γ-
irradiation as assessed in mice, Eur. J. Pharm. Biopharm. 80 (2012) 274–281.
doi:10.1016/j.ejpb.2011.10.007.
[274] M. Igartua, R.M. Hernández, J.E. Rosas, M.E. Patarroyo, J.L. Pedraz, γ-Irradiation
effects on biopharmaceutical properties of PLGA microspheres loaded with SPf66
synthetic vaccine, Eur. J. Pharm. Biopharm. 69 (2008) 519–526.
doi:10.1016/j.ejpb.2007.12.014.
[275] I. Esparza, T. Kissel, Parameters affecting the immunogenicity of microencapsulated
tetanus toxoid, Vaccine. 10 (1992) 714–720. doi:10.1016/0264-410X(92)90094-Z.
[276] K.A. Hooper, J.D. Cox, J. Kohn, Comparison of the effect of ethylene oxide and γ-

of
irradiation on selected tyrosine-derived polycarbonates and poly(L-lactic acid), J.
Appl. Polym. Sci. 63 (1997) 1499–1510. doi:10.1002/(SICI)1097-
4628(19970314)63:11<1499::AID-APP12>3.0.CO;2-Y.

ro
[277] J.A. Bushell, M. Claybourn, H.E. Williams, D.M. Murphy, An EPR and ENDOR
study of γ- and β-radiation sterilization in poly (lactide-co-glycolide) polymers and
-p
microspheres, J. Control. Release. 110 (2005) 49–57.
doi:10.1016/j.jconrel.2005.09.009.
re
[278] B. Bittner, K. Mäder, C. Kroll, H.H. Borchert, T. Kissel, Tetracycline-HCl-loaded
poly(DL-lactide-co-glycolide) microspheres prepared by a spray drying technique:
lP

Influence of γ-irradiation on radical formation and polymer degradation, J. Control.

Release. 59 (1999) 23–32. doi:10.1016/S0168-3659(98)00170-9.
[279] S. Mitragotri, P.A. Burke, R. Langer, Overcoming the challenges in administering
na

biopharmaceuticals: Formulation and delivery strategies, Nat. Rev. Drug Discov. 13

(2014) 655–672. doi:10.1038/nrd4363.
ur

[280] R. Herrero-Vanrell, I. Bravo-Osuna, V. Andrés-Guerrero, M. Vicario-de-la-Torre, I.T.

Molina-Martínez, The potential of using biodegradable microspheres in retinal
diseases and other intraocular pathologies, Prog. Retin. Eye Res. 42 (2014) 27–43.
Jo

doi:10.1016/j.preteyeres.2014.04.002.
[281] F. Cilurzo, F. Selmin, P. Minghetti, M. Adami, E. Bertoni, S. Lauria, L. Montanari,
Injectability evaluation: An open issue, AAPS PharmSciTech. 12 (2011) 604–609.
doi:10.1208/s12249-011-9625-y.
[282] C. Berteau, O. Filipe-Santos, T. Wang, H.E. Roja, C. Granger, F. Schwarzenbach,
Evaluation of the impact of viscosity, injection volume, and injection flow rate on
subcutaneous injection tolerance, Med. Devices Evid. Res. 8 (2015) 473–484.
doi:10.2147/MDER.S91019.
[283] S. Puthli, P.R. Vavia, Stability studies of microparticulate system with piroxicam as
model drug, AAPS PharmSciTech. 10 (2009) 872–880. doi:10.1208/s12249-009-9280-
8.
[284] G.D. Chitnis, M.K.S. Verma, J. Lamazouade, M. Gonzalez-Andrades, K. Yang, A.
Dergham, P.A. Jones, B.E. Mead, A. Cruzat, Z. Tong, K. Martyn, A. Solanki, N.
Landon-Brace, J.M. Karp, A resistance-sensing mechanical injector for the precise

65
 Journal Pre-proof

delivery of liquids to target tissue, Nat. Biomed. Eng. 3 (2019) 621–631.

doi:10.1038/s41551-019-0350-2.
[285] E.B. Rodrigues, A. Grumann, F.M. Penha, H. Shiroma, E. Rossi, C.H. Meyer, V.
Stefano, M. Maia, O. Magalhaes, M.E. Farah, Effect of needle type and injection
technique on pain level and vitreal reflux in intravitreal injection, J. Ocul. Pharmacol.
Ther. 27 (2011) 197–203. doi:10.1089/jop.2010.0082.
[286] M. Sarmadi, A. Behrens, K. McHugh, H. Contreras, Z. Tochka, X. Lu, R. Langer, A.
Jaklenec, Modeling, design, and machine learning-based framework for optimal
injectability of microparticle-based drug formulations, Sci. Adv. 6 (2020) eabb6594.
doi:10.1126/sciadv.abb6594.
[287] USP, In Vitro Release Test Methods for Parenteral Drug Preparations <1001>, Pharm
Forum. Rockville, MD USP. 46 (2020).

of
[288] M. Kohno, J. V. Andhariya, B. Wan, Q. Bao, S. Rothstein, M. Hezel, Y. Wang, D.J.
Burgess, The effect of PLGA molecular weight differences on risperidone release from
microspheres, Int. J. Pharm. 582 (2020) 1–8. doi:10.1016/j.ijpharm.2020.119339.

ro
[289] H.M. Kinnunen, R.J. Mrsny, Improving the outcomes of biopharmaceutical delivery
via the subcutaneous route by understanding the chemical, physical and physiological
-p
properties of the subcutaneous injection site, J. Control. Release. 182 (2014) 22–32.
doi:10.1016/j.jconrel.2014.03.011.
re
[290] A.C. Doty, D.G. Weinstein, K. Hirota, K.F. Olsen, R. Ackermann, Y. Wang, S. Choi,
S.P. Schwendeman, Mechanisms of in vivo release of triamcinolone acetonide from
lP

PLGA microspheres, J. Control. Release. 256 (2017) 19–25.

doi:10.1016/j.jconrel.2017.03.031.
[291] T. Wang, P. Xue, A. Wang, M. Yin, J. Han, S. Tang, R. Liang, Pore change during
na

degradation of octreotide acetate-loaded PLGA microspheres: The effect of polymer

blends, Eur. J. Pharm. Sci. 138 (2019) 104990. doi:10.1016/j.ejps.2019.104990.
ur

[292] K. Nieto, S.R. Mallery, S.P. Schwendeman, Microencapsulation of amorphous solid

dispersions of fenretinide enhances drug solubility and release from PLGA in vitro and
in vivo, Int. J. Pharm. 586 (2020) 119475. doi:10.1016/j.ijpharm.2020.119475.
Jo

[293] N.P. Tipnis, J. Shen, D. Jackson, D. Leblanc, D.J. Burgess, Flow-through cell-based in
vitro release method for triamcinolone acetonide poly (lactic-co-glycolic) acid
microspheres, Int. J. Pharm. 579 (2020) 119130. doi:10.1016/j.ijpharm.2020.119130.
[294] B. Sterner, M. Harms, M. Weigandt, M. Windbergs, C.M. Lehr, Crystal suspensions of
poorly soluble peptides for intra-articular application: A novel approach for
biorelevant assessment of their in vitro release, Int. J. Pharm. 461 (2014) 46–53.
doi:10.1016/j.ijpharm.2013.11.031.
[295] A. Rawat, U. Bhardwaj, D.J. Burgess, Comparison of in vitro-in vivo release of
Risperdal® Consta® microspheres, Int. J. Pharm. 434 (2012) 115–121.
doi:10.1016/j.ijpharm.2012.05.006.
[296] N. Mertz, S.W. Larsen, J. Kristensen, J. Østergaard, C. Larsen, Long-Acting
Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation,
and In Vitro Release From Prodrug Suspension, J. Pharm. Sci. 105 (2016) 3079–3087.
doi:10.1016/j.xphs.2016.06.013.

66
 Journal Pre-proof

[297] G.F. Gao, M. Thurn, B. Wendt, M.J. Parnham, M.G. Wacker, A sensitive in vitro
performance assay reveals the in vivo drug release mechanisms of long-acting
medroxyprogesterone acetate microparticles, Int. J. Pharm. 586 (2020) 119540.
doi:10.1016/j.ijpharm.2020.119540.
[298] M.R.C. Marques, R. Loebenberg, M. Almukainzi, Simulated biological fluids with
possible application in dissolution testing, Dissolution Technol. 18 (2011) 15–28.
doi:10.14227/DT180311P15.
[299] S. Kollipara, R.K. Gandhi, Pharmacokinetic aspects and in vitro–in vivo correlation
potential for lipid-based formulations, Acta Pharm. Sin. B. 4 (2014) 333–349.
doi:10.1016/j.apsb.2014.09.001.
[300] J. Shen, K. Lee, S. Choi, W. Qu, Y. Wang, D.J. Burgess, A reproducible accelerated in
vitro release testing method for PLGA microspheres, Int. J. Pharm. 498 (2016) 274–
282. doi:10.1016/j.ijpharm.2015.12.031.

of
[301] K. Hirota, A.C. Doty, R. Ackermann, J. Zhou, K.F. Olsen, M.R. Feng, Y. Wang, S.
Choi, W. Qu, A.S. Schwendeman, S.P. Schwendeman, Characterizing release

ro
mechanisms of leuprolide acetate-loaded PLGA microspheres for IVIVC development
I: In vitro evaluation, J. Control. Release. 244 (2016) 302–313.
-p
doi:10.1016/j.jconrel.2016.08.023.
[302] A.C. Doty, Y. Zhang, D.G. Weinstein, Y. Wang, S. Choi, W. Qu, S. Mittal, S.P.
re
Schwendeman, Mechanistic analysis of triamcinolone acetonide release from PLGA
microspheres as a function of varying in vitro release conditions, Eur. J. Pharm.
Biopharm. 113 (2017) 24–33. doi:10.1016/j.ejpb.2016.11.008.
lP

[303] J. Shen, D.J. Burgess, In vitro-in vivo correlation for complex non-oral drug products:
Where do we stand?, J. Control. Release. 219 (2015) 644–651.
na

doi:10.1016/j.jconrel.2015.09.052.
[304] N. Darville, M. Van Heerden, D. Mariën, M. De Meulder, S. Rossenu, A. Vermeulen,
A. Vynckier, S. De Jonghe, P. Sterkens, P. Annaert, G. Van Den Mooter, The effect of
ur

macrophage and angiogenesis inhibition on the drug release and absorption from an
intramuscular sustained-release paliperidone palmitate suspension, J. Control. Release.
230 (2016) 95–108. doi:10.1016/j.jconrel.2016.03.041.
Jo

[305] N. Darville, M. Van Heerden, A. Vynckier, M. De Meulder, P. Sterkens, P. Annaert,

G. Van Den Mooter, Intramuscular administration of paliperidone palmitate extended-
release injectable microsuspension induces a subclinical inflammatory reaction
modulating the pharmacokinetics in rats, J. Pharm. Sci. 103 (2014) 2072–2087.
doi:10.1002/jps.24014.
[306] J. V. Andhariya, R. Jog, J. Shen, S. Choi, Y. Wang, Y. Zou, D.J. Burgess, In vitro-in
vivo correlation of parenteral PLGA microspheres: Effect of variable burst release, J.
Control. Release. 314 (2019) 25–37. doi:10.1016/j.jconrel.2019.10.014.
[307] T. Watanabe, N. Yamada, Y. Yoshida, O. Yamamoto, Granulomas induced by
subcutaneous injection of a luteinizing hormone-releasing hormone analog: A case
report and review of the literature, J. Cutan. Pathol. 37 (2010) 1116–1118.
doi:10.1111/j.1600-0560.2009.01456.x.
[308] R. Sakamoto, Y. Higashi, K. Mera, T. Kanekura, T. Kanzaki, Granulomas induced by
subcutaneous injection of leuprorelin acetate, J. Dermatol. 33 (2006) 43–45.

67
 Journal Pre-proof

doi:10.1111/j.1346-8138.2006.00008.x.
[309] K. Yasukawa, D. Sawamura, H. Sugawara, N. Kato, Leuprorelin acetate granulomas:
Case reports and review of the literature, Br. J. Dermatol. 152 (2005) 1045–1047.
doi:10.1111/j.1365-2133.2005.06341.x.
[310] J.M. Anderson, M.S. Shive, Biodegradation and biocompatibility of PLA and PLGA
microspheres, Adv. Drug Deliv. Rev. 64 (2012) 72–82.
doi:10.1016/j.addr.2012.09.004.
[311] M.J. Anderson, Biological responses to materials, Annu. Rev. Mater. Res. 31 (2009)
81–110.
[312] S. Franz, S. Rammelt, D. Scharnweber, J.C. Simon, Immune responses to implants - A
review of the implications for the design of immunomodulatory biomaterials,
Biomaterials. 32 (2011) 6692–6709. doi:10.1016/j.biomaterials.2011.05.078.

of
[313] J.M. Anderson, A. Rodriguez, D.T. Chang, Foreign body reaction to biomaterials,
Semin. Immunol. 20 (2008) 86–100. doi:10.1016/j.smim.2007.11.004.

ro
[314] M. Kalbacova, S. Roessler, U. Hempel, R. Tsaryk, K. Peters, D. Scharnweber, J.C.
Kirkpatrick, P. Dieter, The effect of electrochemically simulated titanium cathodic
-p
corrosion products on ROS production and metabolic activity of osteoblasts and
monocytes/macrophages, Biomaterials. 28 (2007) 3263–3272.
doi:10.1016/j.biomaterials.2007.02.026.
re
[315] J. Zandstra, C. Hiemstra, A.H. Petersen, J. Zuidema, M.M. van Beuge, S. Rodriguez,
A.A.R. Lathuile, G.J. Veldhuis, R. Steendam, R.A. Bank, E.R. Popa, Microsphere size
lP

influences the foreign body reaction, Eur. Cells Mater. 28 (2014) 335–347.
doi:10.22203/eCM.v028a23.
na

[316] D. Paul, S. Achouri, Y.Z. Yoon, J. Herre, C.E. Bryant, P. Cicuta, Phagocytosis
dynamics depends on target shape, Biophys. J. 105 (2013) 1143–1150.
doi:10.1016/j.bpj.2013.07.036.
ur

[317] J.A. Champion, S. Mitragotri, Role of target geometry in phagocytosis, Proc. Natl.
Acad. Sci. U. S. A. 103 (2006) 4930–4934. doi:10.1073/pnas.0600997103.
Jo

[318] P. Pacheco, D. White, T. Sulchek, Effects of Microparticle Size and Fc Density on

Macrophage Phagocytosis, PLoS One. 8 (2013) 1–9.
doi:10.1371/journal.pone.0060989.
[319] O. Veiseh, A.J. Vegas, Domesticating the foreign body response: Recent advances and
applications, Adv. Drug Deliv. Rev. 144 (2019) 148–161.
doi:10.1016/j.addr.2019.08.010.

68