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A Review on Bi-layered Suppositories

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European Journal of Scientific Research
ISSN 1450-216X / 1450-202X Vol. 146 No 1 June, 2017, pp.45 - 54
http://www. europeanjournalofscientificresearch.com

A Review on Bi-layered Suppositories

Muaadh A. Mohamed Ali

Department of Pharmaceutical Sciences, Faculty of Pharmacy
University of Science and Technology, Taiz, Yemen
E-mail: [email protected]
Tel: +967734733054

Abstract

In the last decade, interest in developing a combination of two or more drugs in a

single dosage form has increased in the pharmaceutical industry, promoting patient
convenience and compliance. Bi-layered suppository can be an attractive option to avoid
chemical incompatibilities between drugs by physical separation, and to enable the
development of different drug release profiles (immediate release with extended release).
Bi-layered suppository is a novel pharmaceutical technology for the successful
development of controlled release formulation along with various features to provide a way
of the successful drug delivery system. Therapeutic strategies based on rectal delivery of
bi-layered suppositories are gaining more acceptance among researchers due to a
confluence of factors, including advanced delivery strategies, patient compliance and
combination therapy.

Keywords: Bi-layered Suppository, Combination Therapy, Controlled Release,

Evaluation of Bi-layered Suppositories

1. Introduction
Though the oral route is the most common and the easiest way to administer a drug, it suffers from
some drawbacks such as its non-suitability when quick onset of action is required. Further, many
patients find it difficult to swallow solid dosage forms such as tablets and capsules, resulting in a high
incidence of non-compliance and ineffective therapy. The rectal route for drug administration was
proven to be advantageous over other routes because of the reduced side effects such as gastrointestinal
irritation and the avoidance of pH conditions, gastrointestinal enzymes, disagreeable taste and first pass
effect (Jannin et al, 2014; Ryu et al, 1999; Samy et al, 2000; Tukker, 2009).
A conventional suppository generally consists of an active ingredient loaded into an inert base,
which may be either a rigid or semi-rigid base. It offers an alternate form of oral medication for
systemic action in patients who are in coma or who cannot tolerate oral medication due to periodical
episodes of nausea and vomiting or pathological conditions of the gastrointestinal tract. After
administration, the role of the suppository is to liberate the active ingredient, either by melting due to
body temperature or by dissolving in the local mucosal fluids, depending on the nature of the
suppository base, and then to release the active ingredient to produce a local effect or to move to the
mucosal barriers into the systemic circulation to produce a pharmacological effect (Gupta, 2007;
Hermann, 1995; Taha et al, 2004).
Combinational therapy has been found to have various advantages over monotherapy such as
problems of dose-dependent side effects are minimized, a low-dose combination of two different
agents reduces the dose-related risk and the addition of one agent may counteract some deleterious
A Review on Bi-layered Suppositories 46

effects of the other. The use of a combination of two active ingredients or the same active ingredient
with different release rate to optimize therapy and to improve patient compliance has increased steadily
over the years (Abebe et al, 2014; Bangalore et al, 2007). When two or more active ingredients are
needed to be administered simultaneously and they are incompatible, the best option would be the
multi-layered technology.
Bi-layered suppository is a novel technology for the development of a combination of two or
more active ingredients in a single dosage form for sequential release of these drugs and to avoid
incompatibility between them (Marsovna et al, 2015; Mohamed Ali, 2017). On the other hand, in case
of the conventional dosage forms, there will be a wide range of fluctuations in the drug concentration
in the blood stream and tissues, which therefore results in unwanted toxicity and low efficiency. This
factor such as repetitive dosing and unpredictable absorption led to the concept of controlled drug
delivery systems. The goal in designing controlled delivery systems is to reduce the frequency of the
dosing or to increase the effectiveness of the drug by localization at the site of action, reducing the dose
required or providing uniform drug delivery whilst also providing greater patient compliance and
convenience. The primary objective of controlled release drug delivery is to ensure safety and to
improve efficacy of drugs as well as patient compliance (Singh et al, 2011).
Bi-layered suppositories have enabled the development of controlled delivery of drugs with
modified release profiles by combining layers with various release patterns, or by combining slow-
release with immediate-release layers. Formulation of layers from different suppository bases, allows
manipulation of drug release. The release characteristic of active ingredients could be modulated as fast
or prolonged release by using a different base in each layer of the suppository to enable the
development of different drug release profiles (Chicco et al, 1999; Realdon et al, 1997; Yahagi et al,
1999). In addition, number of polymers are available for the preparation to act as adhesive enhancing
promoters or controlled drug release materials. The addition of Carbopol 934P together with antiemetic
drug such as ramosetron HCl in witepsol H15 could enhance the drug bioavailability with sustained
release behavior (Yahagi et al, 2000). Polycarbophyl, hydroxypropyl methyl cellulose (HPMC),
Hydroxypropylcellulose (HPC), xanthan gum or sodium salt with calcium salt could retain the drug
release in this area (Ceschel et al, 2001; Iwata et al, 1997; Phaechamud et al, 2013).
This article provides an overview of bi-layered suppository technology, highlighting the main
benefits of this type of rectal dosage forms. In addition, several aspects relevant to bi-layered
suppository are addressed, including ideal characteristics, preparation, challenges during development,
in vitro evaluation and advancement in the field of bi-layered suppositories.

1.1. Objectives for Designing of Bi-layered Suppositories

The main objectives for designing bi-layered suppositories is to administer fixed dose combinations of
different drugs, to separate the incompatible drugs from each other, and to control the delivery rate of
either single or two different drugs.

1.2. Benefits Offered by Bi-layered Suppositories

In general, suppositories offer great microbial and chemical stability, do not require sterile conditions
and are, therefore, less expensive to manufacture and better patient compliance is achieved due to its
ease of administration. Suppositories are also able to mask the bitter taste and bad odour of drugs by
rectal administration.
Bi-layered suppositories have some key advantages compared to conventional mono-layer
suppositories. For instance, repetitive dosing is required in conventional dosage forms which can be
avoided with bi-layered suppositories by sequential release of two drugs and incompatibility between
two or more drugs can be avoided by physical separation. In addition, bi-layered suppositories have
enabled the development of controlled delivery of active pharmaceutical ingredients by combining
layers with various release patterns, or by combining slow release with immediate-release layers in a
single dosage form (Chicco et al, 1999; Mohamed Ali, 2017; Realdon et al, 1997; Yahagi et al, 1999).
47 Muaadh A. Mohamed Ali

Therefore, two different active ingredients or the same active ingredient can be delivered at differing
rates in a single suppository.

1.3. Disadvantages of Bi-layered Suppositories

The formulation and production of bi-layered suppositories can be associated with the common bi-
layer problems, such as layer separation during and after the various stages of production, insufficient
hardness, inaccurate individual layer weight control, cross-contamination between the layers, reduced
yield, etc. (Abebe et al, 2014). Although the general suppository manufacturing principles remain the
same, there is much more to consider, since making bi-layered suppositories involves multiple, often
incompatible products, additional equipment, and many formulation and operation challenges. In
addition, development of two layers implies additional time spent on formulation, analysis and
validation. Therefore, bi-layered suppositories are much expensive compared to conventional or single
layered suppositories. Further, bioavailability problems occur with drugs of poor wetting and slow
dissolution properties. Therefore, it is critical to optimize these factors to enable the design of a robust
product and process.

1.4. Ideal Characteristics of Bi-layered Suppositories

Bi-layered suppository should be elegant and free of defects like chips, cracks, discoloration, and
contamination. It should have the required chemical and physical stability to maintain its physical
attributes over time and must be able to release the medicinal agents in a desired, predictable and
reproducible manner. In addition, bi-layered suppositories should have sufficient mechanical strength
to withstand mechanical shock during its production, packaging, shipping and dispensing (Allen,
2008; Mohamed Ali, 2017).

2. Advancement in the Field of Bi-layered Suppositories

Drug release from suppositories and subsequent absorption through the rectum involves several stages,
starting from suppository melting or softening at rectal temperature, followed by drug migration
through the suppository mass and its transfer from the suppository surface to the rectal environment,
and finally drug solubilization in rectal fluids and drug permeation across the rectal membrane
(Realdon et al, 1997).
Drug solubility, particle size of a dispersed drug, and excipient characteristics such as melting
temperature, fusion rate, viscosity at rectal temperature, hydrophilic-lipophilic characteristics have a
crucial role in release rate of a drug dose from suppositories and the rate of drug absorption
(Bornschein et al, 1980; Minkov et al, 1984). It has been shown that higher drug solubility in the
vehicle results in slower drug release and reduced drug absorption from the dosage form. This is
attributed to the tendency of the drug to be retained in the base (Shangraw and Walkling, 1971; Pagay
et al, 1974). The same drug dose is therefore able to produce a different therapeutic response when
included in excipients with different properties. Furthermore, the excipient properties can affect not
only the rate, but also the extent of absorption, especially for drugs that undergo saturable presystemic
metabolism. For such drugs, the magnitude of the first-pass effect could vary with the drug release rate
from the suppositories.
Bi-layered suppository has been specifically developed for many purposes such as providing of
two different release rates or dual release of a drug from a single dosage form. Again a combination of
the two drugs is feasible with bi-layered suppositories to maximize their individual therapeutic effect and
minimize side effects. Various advances in bi-layered suppository technology has been shown in Table 1.
A Review on Bi-layered Suppositories 48

Table 1: Lists of Various Advances Made in Bi-layered Suppositories

Author(s) Active ingredient(s) Rational Year Ref no.

Mohamed Ali Paracetamol and Metoclopramide HCl Combination therapy 2017 [21]
Marsovna et al. Paracetamol and Licorice Extract Combination therapy 2015 [18]
Phaechamud et al. Propranolol HCl Sustained release 2013 [24]
Probiotic (lactobacillus sp.) and Combination therapy (vaginal route) 2012 [16]
Kale et al. Prebiotic (organic acid)
Ramadan Diclofenac sodium Bioavailability improvement 2012 [25]
Lactobacilli and antibacterial herbal Combination therapy (vaginal route) 2011 [23]
Pashayan extracts
Soliman et al. Theophylline Fast release performance 2000 [33]
Chicco et al. Paracetamol Bioavailability improvement 1999 [8]
Yahagi et al. Lidocaine Bioavailability improvement 1999 [38]
Iwata et al. Progesterone Sustained release 1997 [13]
Paracetamol, aminophenazone and Modulating drug release 1997 [27]
Realdon et al. aminophylline
Deshmukh and Diazepam Fast release performance 1989 [9]
Thwaites

Realdon et al (1997) showed that by using in different ratios of two excipients with different
characteristics in superimposed layers, it was possible to modulate the drug release kinetics in relation
to the required therapeutic response. Four different types of Witepsol bases (H12, H15, S55 and W35)
were used in the study to modulate the release kinetics of paracetamol, aminophenazone and
aminophylline by using a pair of Witepsol bases each time with different characteristics in
superimposed layers between which the drug is distributed and regulating the reciprocal ratio between
the two suppository fractions.
A sustained release suppository containing progesterone with a double-layered structure was
prepared for the treatment of the luteal phase defect by Iwata et al (1997). Hydroxypropylcellulose
(HPC) and Carbopol 934P were used as bases of the inner layer and Witepsol W35 was used as a base
of the outer layer. When the suppositories were administered into the vagina of rabbits, they showed a
sustained release property and a rapid rise in the serum concentration more than an ordinary Witepsol
suppository.
The studies carried out by Chicco et al (1999) on two layered excipient suppositories of
paracetamol prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-
releasing one, i.e. Witepsol H15 and W35, respectively, showed that a proper combination of fast
paracetamol releasing excipient H15 and slow releasing excipient W35 could give an optimized plasma
profile and the drug release from this dosage form seemed to be controllable by varying the ratio of the
two excipient layers. An in vivo investigation of paracetamol availability was carried out on eight
healthy volunteers, comparing the two formulations. The comparison between the two different
formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an
increase in the extent of drug absorption from the layered excipient suppository. It was also
hypothesized that the enhanced paracetamol availability could be due to a liver bypass mechanism
offered by layered suppository.
Usually, suppositories move to the upper rectum after administration while dissolving or
melting, and this is disadvantageous for the drugs which accept first-pass effect considerably. To avoid
the first-pass effect, drugs released from suppositories should be absorbed into the lower rectum.
Yahagi et al (1999) attempted to restrict drug absorption from suppositories to the lower rectum by
preparing mucoadhesive double-phased suppositories using Witepsol H15 as a base, and Carbopol
934P and white beeswax as additives. Carbopol 934P has a mucoadhesive property and beeswax gives
the suppositories stiffness. Double-phased suppositories consisting of a front layer containing l0%
Carbopol 934P and 20% beeswax and a terminal layer containing lidocaine and various amounts of
Carbopol were prepared. Lidocaine was selected as a model drug which undergoes first-pass effect,
and plasma concentrations of lidocaine and its metabolites were measured. The results showed that
49 Muaadh A. Mohamed
Mohamed Ali

double-phased
phased suppository with both rectal stagnation and moderate drug release property facilitates
drug absorption in the lower rectum effectively. These results suggest that the double-phased
double
mucoadhesive suppositories may be useful for improving
improving bioavailabilities of drugs with significant
first-pass
pass effect like lidocaine.
The same results were concluded by Ramadan (2012).(2012) Double-phased
Double phased suppositories consist of a
mucoadhesive front layer containing wax and a mucoadhesive terminal layer containing
containing the drug were
prepared and evaluated in rats. The anchoring, adhesive phase strictly limits the absorption of the drug
in the lower rectum and the formulation of the terminal layer modulates drug release properties. The
results revealed that the double-
dou -phased
phased suppository with both rectal residence and moderate drug
release properties facilitated drug absorption in the lower rectum effectively and improved the
bioavailability of diclofenac sodium which has a significant first–pass
first pass effect.
Vaginal double
double-layered
layered suppositories were fabricated to load probiotics (lactobacilli) in the core
and antibacterial herbal extract in the outer layer for simultaneous treatment of bacterial vaginosis and
vagina recolonization by lactobacilli (Pashayan,
Pashayan, 2011).
2011 . The combination
combination of Novata ABPH in the core
and Witepsol H15 in the outer layer as bases was a more suitable vehicle for the preparation of this
double-layered
layered vaginal suppository.
Rectal double-layered
double layered suppositories containing paracetamol in the first layer and
metoclopramide HCl in the second layer by the fusion method using cocoa butter, witepsol W35 and
different grades of polyethylene glycol (PEG400, PEG4000, and PEG6000) were developed and
evaluated by Mohamed
Mohamed Ali li (2017).
(2017). PEGs based suppositories had better release profiles than
suppositories prepared from fatty bases for paracetamol; while fatty bases suppositories showed better
release profiles than PEGs based formulations for metoclopramide HCl. The addition of PEG 400 to
PEG 4000 and PEG 6000 bases showed a significant effect on the release of both two drugs from the
tested suppositories. The prepared double-layered
double layered suppositories may be more suitable than
conventional formulations for the treatment of migraine by the sequential release of the two drugs,
enhancing
hancing the release of drugs administered rectally and improving bioavailability of drugs with
significant first-pass
first pass effect to get a rapid pharmacological effect.

3. Preparation of Bi-layered
Bi layered Suppositories
The simple bi-layered
bi layered suppository is prepared with one layer of drug for immediate release with the
second layer designed to release the same or different drug, either as a conventional release of a second
dose or in an extended release form. Figure 1 shows
shows the general structure of bi-layered
bi layered suppositories.

Figure 1: Schematic Illustration of Bi-layered

Bi layered Suppository

To obtain these bi-layered

bi layered suppositories, two distinct masses with each of selected excipients
containing the same or different drug are prepared by melting the excipients of each layer separately at
a suitable temperature to obtain two fractions. Then, the
the drug is uniformly dispersed. The first layer is
prepared by partially filling the mould with a first fraction of the mass in a predetermined volume.
When it gets solidified, the second fraction is added into the same mould to get a second layer and
A Review on Bi-layered
Bi layered Suppositories 50

cooling
cooling them again to room temperature. An additional intermediate layer of inert base may also be
included into separate two incompatible drugs to minimize the area of contact between the two layers
(Yahagi
Yahagi et al, 1999).
1999)
Another structure of bi-layered
bi layered suppository,
suppository, which consist of core and outer layers was
developed as seen in figure 2. There are two methods to prepare such suppositories. In the first method,
bi layered suppositories are prepared using two metal molds with different hole size. The core bases
bi-layered
have
ave higher temperature of melting than the bases of the outer layer. The core layer is prepared by
melting suppository base over the water bath. Then, drug and other additives are added into the melted
base with gentle stirring until a homogeneous mass was obtained. The mixture is poured into the mold
with small holes at a temperature just above the congealing point of the suppository base and cooled.
The melted base of the outer layer is prepared and homogenized. Then, the cores are fixed xed on the
needles in the centre of the larger mold, the outer layer mixture is added and then cooled (Pashayan,
Pashayan,
2011)
2011).

Figure 2: Schematic Illustration of Bi-layered

Bi layered Suppository with Outer and Inner Layers
L

In the second method, the suppository base is melted on a water bath and then mixed with drug
and the mixture is filled into the stainless steel suppository mold to form an outer layer. This mold
composed of the stainless steel rods to place into the outer layer component during setting to form
mold cavity and then the rods are removed before the inner layer component is subsequently filled into
the created cavity (Phaechamud
Phaechamud et al, 2013).
2013)

4. Main Evaluation Methods of Bi-layered

Bi layered Suppositories
4.1. General Appearance
The general appearance of a suppository,
suppository, its visual identity and overall elegance are essential for
consumer acceptance. The suppositories are examined with the naked eye (subjective evaluation) to
assess the homogeneity of surface appearance and colour for the absence or presence of smoothness
smoothness or
gritty conditions, fissuring, pitting, fat blooming, exudation and migration of the active ingredients.

4.2. Size and Shape

The size and shape of the suppository can be dimensionally described by measuring the width and
length, monitored and controlled.

4.3. Uniformity of Weight

Twenty suppositories are selected at random, weighed and the average weight is calculated. There must
be not more than 2 suppositories differ from the average weight by more than 5% and no suppository
differs from the average weight by more than 10 % (British Pharmacopoeia, 1998).
51 Muaadh A. Mohamed Ali

4.4. Mechanical Strength (Hardness)

The ability of the suppository to withstand the hazards of packing, transportation and handling before
usage depends on its mechanical strength (hardness). The hardness of randomly selected suppositories
can be measured by Monsanto or Erweka hardness tester. The weight required for a suppository to
collapse is recorded in kilograms (Allen, 2008; Sankar et al, 2012).

4.5. Melting Point Estimation

Melting point is a measure of the time taken for the entire suppository to melt or disperse when
immersed in a water bath maintained at 37 ± 1oC (Allen, 2008; Ranjita and Kamalinder, 2010).

4.6. Disintegration Time Test

The disintegration time is a critical factor in the determination of the release rate of the active
ingredient(s) from the suppository. The disintegration times can be recorded utilizing USP tablet
disintegration apparatus (Janicki et al, 2001). During this test, the time taken for the suppository to
melt or disperse is measured when immersed in a water bath maintained at constant temperature (37 ±
1oC). The time required for the suppository to melt or disperse in the surrounding water is noted.

4.7. Dissolution Rate Studies

The ability of the formulations to release the active ingredient(s) when administered is evaluated using
the dissolution rate studies. Many research groups described a number of in vitro dissolution
techniques for determination of the dissolution rate of drug substances from suppositories in the
literature (Realdon et al, 1997; Yahagi et al, 1999; Hargoli et al, 2013; Sznitowska and Stokrocka,
2007; Medina et al, 2014; Asikoglu et al, 1995; Vidras et al, 1982; Krasowska and Krowczynski,
1996). Dissolution studies for suppositories are commonly performed by the USP basket method (USP
Apparatus 1) and in a less extent with the USP paddle method (USP Apparatus 2) (Hargoli et al, 2013;
Medina et al, 2014; Asikoglu et al, 1995). On the other hand, dialysis methods and flow-through cell
method (USP Apparatus 4) has also been considered as an alternative to USP vessels systems (Realdon
et al, 1997; Sznitowska and Stokrocka, 2007; Medina et al, 2014; Vidras et al, 1982; Krasowska and
Krowczynski, 1996).
According to the USP basket method, the USP rotating basket dissolution apparatus is used for
the determination of release rates of drug from the suppository. Each suppository is placed in a basket
and lowered into a flask containing of dissolution medium The basket is rotated at 50-100 rpm at a
constant temperature 37 ± 0.5oC. At different time intervals the definite sample size are withdrawn and
immediately replaced with drug-free dissolution medium. Then, drug concentration is measured using
a suitable technique.

4.8. Stability
To achieve the objectives of bi-layered suppositories, it is imperative that their quality and the
performance be maintained over the expiration period. During the stability studies, drug products need
to be observed closely and tested periodically to ensure that their integrity is preserved throughout their
shelf life and they perform in a predictable manner. The bi-layered suppositories are packed in suitable
packaging and stored under the following conditions for a period as prescribed by ICH guidelines for
accelerated studies. The suppositories should be withdrawn periodically and analyzed for physical
characterization (Visual defects, mechanical strength, melting, disintegration time and dissolution rate,
etc.) and drug content (Sankar et al, 2012; Soremekun et al, 2012).
A Review on Bi-layered Suppositories 52

5. Conclusion
Bi-layered suppository is improved beneficial technology when compared to single layered
suppository. It provides one of the important design approaches where two or more incompatible drugs
can be incorporated into a single unit. Bi-layered suppository is suitable for sequential release of two
drugs, with different indication, in combination and also for sustained release suppository in which one
layer is immediate release as initial dose and second layer is maintenance dose.
The objective of the dosage form is to ensure that the drugs available to its citizen are not only
safe and effective, but are also properly manufactured and packaged to meet the established quality
target product profile over its shelf life. Therefore, to develop a robust bi-layered suppository a
complete understanding must be developed through the application of scientific tools to produce
suppositories with desired characteristics such as sufficient mechanical strength, optimum release
profiles, stability and shelf life.

References
[1] Abebe, A., I. Akseli, O. Sprockel, N. Kottala, and A.M. Cuitiño, 2014. “Review of bilayer
tablet technology”, International Journal of Pharmaceutics, 461(1-2), pp. 549-558.
[2] Allen, L.V.Jr., 2008. “Suppositories”, Pharmaceutical Press, London, pp 141-143.
[3] Asikoglu, M., G. Ertan, and G. Cosar, 1995. “The release of isoconazole nitrate from different
suppository bases: in-vitro dissolution, physicochemical and microbiological studies”, Journal
of Pharmacy and Pharmacology, 47(9), pp. 713-716.
[4] Bangalore, S., G. Kamalakkannan, S. Parkar, and F.H. Messerli, 2007. “Fixed-dose
combinations improve medication compliance: a meta-analysis”, The American journal of
medicine, 120, pp. 713–719.
[5] Bornschein, M., A. Grohmann, and R. Voigt, 1980. “On the action of various factors on the
liberation from suppositories”, Pharmazie, 35(12), pp. 772-776.
[6] British Pharmacopoeia, 1998. Vol. I&II. Her Majesty’s Stationery Office. London .
[7] Ceschel, G.C., P. Maffei, S.L. Borgia, C. Ronchi, and S. Rossi, 2001. “Development of
mucoadhesive dosages form for vaginal administration”, Drug Development and Industrial
Pharmacy, 27(6), pp. 541-547.
[8] Chicco, D., I. Grabnar, A. Skerjanec, D. Vojnovic, V. Maurich, N. Realdon, E. Ragazzi, A.
Belic, R. Karba, and A. Mrhar, 1999. “Correlation of in vitro and in vivo paracetamol
availability from layered excipient suppositories”, International Journal of Pharmaceutics,
189(2), pp. 147–160.
[9] Deshmukh, A.A., and P.M. Thwaites, 1989. “In vitro release of diazepam from conventional
and double-layer polyethylene glycol suppositories”, Drug Development and Industrial
Pharmacy, 15(8), pp. 1289-1307.
[10] Gupta, P.J., 2007. “Suppositories in anal disorders: a review”, European Review for Medical
and Pharmacological Sciences, 11, pp. 165-170.
[11] Hargoli, S., J. Farid, S.H. Azarmi, S. Ghanbarzadeh, and P. Zakeri-Milani, 2013. “Preparation
and In Vitro Evaluation of Naproxen Suppositories”, Indian Journal of Pharmaceutical
Sciences, 75(2), pp. 143-148.
[12] Hermann, T.W., 1995. “Recent research on bioavailability of drugs from suppositories”,
International Journal of Pharmaceutics, 123, pp. 1-11.
[13] Iwata, M., Y. Takahashi, S. Shirotake, T. Yamamoto, K. Takayama, Y. Machida, F. Hirahara,
K. Minaguchi, and T. Nagai, 1997. “Sustained release double-layered progesterone suppository
for luteal support therapy”, Yakugaku Zasshi, 117(9), pp. 629-635.
[14] Janicki, S., M. Sznitowska, W. Zebrowska, H. Gabiga, and M. Kupiec, 2001. “Evaluation of
paracetamol suppositories by pharmacopoeial dissolution test-comments on methodology”,
European Journal of Pharmaceutics and Biopharmaceutics, 52(2), pp. 249-254.
53 Muaadh A. Mohamed Ali

[15] Jannin, V., G. Lemagnen, P. Gueroult, D. Larrouture, and C. Tuleu, 2014. “Rectal route in the
21century to treat children”, Advanced Drug Delivery Reviews, 73, pp. 34-49.
[16] Kale, V., M. Patil, and S. Yadav, 2012. “Preparation and evaluation of Novel Vaginal Pessaries
of Lactobacilli”, International Journal of Drug Development and Research, 4(3), pp. 97-103.
[17] Krasowska, H., and L. Krowczynski, 1996. “The effect of inclusion complexation and surface
active agent addition on suppository release characteristics of ketoprofen and fenbufen”.
Pharmazie, 51(5), pp. 353-357.
[18] Marsovna, A.G., Z.S. Kedelevna, and P.G. Petrovna, 2015. “The development technologies of
double layer suppositories on the basis of licorice extract and paracetamol”, Journal of
Pharmacy and Pharmacology, 3, pp.531-537.
[19] Medina, J.R., A.R. Padilla, M. Hurtado, A.R. Cortés and A.M. Domínguez-Ramírez, 2014. “In
vitro release of ketoprofen suppositories using the USP basket and the flow-through cell
dissolution methods”, Pakistan Journal of Pharmaceutical Sciences, 27(3), pp. 453-458.
[20] Minkov, E., N. Lambov, D. Kirchev, I. Bantutova, and J. Tencheva, 1984. “Biopharmaceutical
investigations of rectal suppositoires. Part 1. Pharmaceutical and biological availability of
theophylline”, Die Pharmazie, 39(4), pp. 242-243.
[21] Mohamed Ali, M.A., 2017. “Preparation and In vitro Evaluation of Paracetamol and
Metoclopramide HCl Double-layered Suppositories for Migraine Treatment”, Journal of
American Science, 13(4), pp. 43-50.
[22] Pagay, S.N., R.I. Poust, and J.L. Colaizzi, 1974. “Influence of vehicle dielectric properties on
acetaminophen bioavailability from polyethylene glycol suppositories”, Journal of
Pharmaceutical Sciences, 63(1), pp. 44–47.
[23] Pashayan, M.M., 2011. “Formulation and investigation of vaginal double layer suppositories
containing lactobacilli and herbal extracts”, The New Armenian Medical Journal, 5(2), pp. 54-59.
[24] Phaechamud, T., P. Chomto, T. Srichan, and C. Savedkairop, 2013. “Role of Xanthan Gum on
Propranolol HCl Release from Single and Double Layered Suppositories”, Research Journal of
Pharmaceutical, Biological and Chemical Sciences, 4(1), pp.1034-1044.
[25] Ramadan, A.A., 2012. “Preparation, characterization and in-vivo evaluation of double-phased
mucoadhesive suppositories containing diclofenac in rats”, Journal of Applied Sciences
Research, 8(2), pp. 746-752.
[26] Ranjita, S., and S. Kamalinder, 2010. “In vitro release of paracetamol from suppocire
suppositories: role of additives”, Malaysian Journal of Pharmaceutical Sciences, 8(1), pp. 57-71.
[27] Realdon, N., E. Ragazzi, M.D. Zotto, and G.D. Fini, 1997. “Layered excipient suppositories:
the possibility of modulating drug availability”, International Journal of Pharmaceutics, 148,
pp. 155-163.
[28] Ryu, J.M., S.J. Chung, M.H. Lee, C.K. Kim, and C.K. Shim, 1999. “Increased bioavailability of
propranolol in rats by retaining thermally gelling liquid suppositories in the rectum”, Journal of
Controlled Release, 59(2), pp.163‑172.
[29] Samy, E.M., M.A. Hassan, S.S. Tous, and C.T. Rhodes, 2000. “Improvement of availability of
allopurinol from pharmaceutical dosage forms I - suppositories”, European Journal of
Pharmaceutics and Biopharmaceutics, 49(2), pp.119-127.
[30] Sankar, V.R., Y.D. Reddy, G.H. Reddy, and G.S.K. Reddy, 2012. “Formulation and In-vitro
characterisation of sustained release metronidazole cocoa butter suppositories”, Inventi Impact:
Pharm Tech, 2012(4), 275-280.
[31] Shangraw, R.F., and W.D. Walkling, 1971. “Effect of vehicle dielectric properties on rectal
absorption of acetaminophen”, Journal of Pharmaceutical Sciences, 60(4), pp. 600–602.
[32] Singh, P., S. Kumar, V.K. Shukla, G. Sharan, P. Verma, and S. Dey, 2011. “Bilayer and
Floating-Bioadhesive tablets. Innovative approach to Gastroretention”, Journal of Drug
Delivery and Therapeutics, 1(1), pp. 32-35.
A Review on Bi-layered Suppositories 54

[33] Soliman, S.A., M.A.F. Gadalla, and V.F. Naggar, 2000. “Formulation, in vitro and in vivo
evaluation of fast release double layer theophylline suppositories”, Acta Pharmaceutica, 50(4),
pp. 315-328.
[34] Soremekun R.O., B.O. Silva, F. Tayo, and C.I. Igwilo, 2012. “Formulation of quinine
suppository for initiation of early treatment of malaria – a preliminary study”, MalariaWorld
Journal, 3(14), pp. 1-7.
[35] Sznitowska, M., and M. Stokrocka, 2007. “Determination of diclofenac released from
suppositories using UV spectrophotometry, spectra derivative spectrophotometry and HPLC”,
Acta Poloniae Pharmaceutica, 63(5), pp. 401-405.
[36] Taha, E.I., A.A. Zaghloul, A.M. Samy, S. Al-Saidan, A.A. Kassem, and M.A. Khan, 2004.
“Bioavailiabilty assessment of salbuthamol sulphate suppositories in human volunteers”,
International Journal of Pharmaceutics, 279, pp. 3-7.
[37] Tukker, J., 2009. “Rectal and vaginal drug delivery”. In: Aulton M.E., ed. Pharmaceutics, the
Science of Dosage Form Design. Churchill Livingstone. Edinburgh, UK, pp. 534-543.
[38] Yahagi, R., H. Onishi, and Y. Machida, 1999. “Preparation and Evaluation of double-phased
mucoadhesive suppositories of lidocaine utilizing Carbopol® and white beeswax”, Journal of
Controlled Release, 61, pp.1-8.
[39] Yahagi, R., Y. Machida, H. Onishi, and Y. Machida, 2000. “Mucoadhesive suppositories of
ramosetron hydrochloride utilizing Carbopol®”, International Journal of Pharmaceutics,
193(2), pp. 205-212.
[40] Vidras, N.J., V.E. Reid, N.R. Bohidar, and F.M. Plakogiannis, 1982. “Medicament release from
suppository bases I: Physicochemical characteristics and bioavailability of indomethacin in
rabbits”, Journal of Pharmaceutical Sciences, 71(8), pp. 945-949.

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