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Current Applied Polymer Science, 2020, 4, 1-16 1
REVIEW ARTICLE

A Review On Expedient Assets Of Polymers Employed In Novel Topical

Formulation For Successful Treatment Of Arthritis
Suchitra Nishal1, Vikas Jhawat1,* and Parmita Phaugat1

1
School of Medical and Allied Sciences, GD Goenka University, Gurugram, India

Abstract: Background: Rheumatoid arthritis (RA) is an autoimmune ailment where the body's de-
fense system is violated by damaging its joints. In RA treatment strategies, attempts have been
made for oral, topical, and parenteral formulations with different drugs, but none of the formula-
tions could be regarded as the perfect dosage form. In the current review, the meticulous discussion
has been made on the suitability of novel topical formulations in the treatment of RA. Moreover,
the emphasis has been made on activities of biodegradable polymers such as hyaluronic acid,
lecithin, pluronic acid, chitosan, human serum albumin (HSA), and polylactide glycolic acid (PL-
ARTICLE HISTORY
GA) as well as their role in the management of RA.
Received: March 02, 2020
Revised: May 23, 2020 Objective: The study aimed to apprehend the role of polymeric materials in developing an ideal top-
Accepted: May 26, 2020
ical drug delivery system that can bestow targeted delivery, enhanced penetration of drugs, im-
DOI: proved stability of the formulation, and improved PKPD profile of the drugs.
10.2174/2452271604999200620184631

These polymers possess twofold functions, primarily by increasing skin penetration and secondari-
ly by improving joint mobility and cartilage regeneration. Furthermore, biocompatibility and
biodegradability are features that increase the use of the aforementioned polymers.

Results: The significant role of all the polymers in improving the conditions of bones and joints
suffering from rheumatoid arthritis has been demonstrated by various studies.

Keywords: Polymer, topical, biocompatible, biodegradable, cartilage regeneration, rheumatoid Arthritis.

1. INTRODUCTION establish pain and swell in the joints. In a quick period, hy-
pergenesis of the lining of synovia occurs, forming more
Arthritis is a chronic deteriorating systemic autoimmune
than ten folds of deep cells comprising type A and type B
ailment which is illustrated with unnecessary conscription of
synoviocytes. Some remarkable modifications made in con-
inflammation-causing bodies (likewise monocytes, T-lym-
text to the number and content of cells with the intrusion of
phocytes, macrophages, B- lymphocytes, and dendritic cells)
B cells, T cells, and plasma cells, are experienced by the sub
inside the synovial fluid, resulting into synovial hypergene- lining. High endothelial venules form by the transformation
sis, new blood cell formation and destruction in bone and of the synovial vessel to endothelial cells. The postcapillary
cartilage [1-3]. Thereby continual joint destruction and per- venules are observed in the inflamed non-lymphoid tissue as
manent deformity generally encompass minor junctions of well as secondary lymphoid tissue. Pannus, a provincial in-
feet and hands. Additionally, it can happen in other joints trusive synovial tissue, is a distinctive facet of RA (Fig. 1).
and remaining parts of the body like eyes, skin, heart, and Pannus is entangled with the disruptions of the joint, as ob-
lungs. Distinctive insignias and prodromes of arthritis em- served in RA [6].
brace severe joint ache, soreness with the rigidity of joints,
which either aggravate in the dawn or afterward resting peri- Numerous prominent elements responsible for the devel-
od. Rheumatoid arthritis, osteoarthritis, and psoriatic arthri- opment of RA can be categorized as preclinical, environmen-
tis are the common types of arthritis which are more preva- tal, and genetic. Preclinical elements indicate an augmented
lent throughout the world [3-5] level of associated biological indicators such as auto-anti-
bodies (IgM-Rheumatoid factor, Sa, p68, RA33, perinuclear
1.1. Pathophysiology of RA factor, and calpastatin) [7]. Major histocompatibility com-
plex (MHC) genes play a major role in genetic factors.
Tissue lump and accretion of fibrin are principal occur- HLA-DRB1 gene is the foremost and PADI, CTLA4, PTP-
ring events during the foremost weeks of RA, which can N22, CCRS6, CSF2, B3GNT2, PDE2A-ARAP1, ANXA3,
ARID5B, CD83, PLD4, and PTPN2 are the supporters. Alco-
* Address correspondence to this author at the School of Medical and Al-
hol intake, increased sodium feasting, autoimmune thyroid
lied Sciences, GD Goenka University, Gurugram, India; disease, schizophrenia, cigarette smoking, endometriosis,
E-mail: [email protected] and atopic dermatitis are environmental factors [8, 9].
2452-2716/20 $65.00+.00 © 2020 Bentham Science Publishers
2 Current Applied Polymer Science, 2020, Vol. 4, No. 0 Nishal et al.

Fig. (1). Anatomical Features of the Inflammatory Joint.

1.2. Treatment of Arthritis beans, and Curcuma longa, respectively. These medicaments
Curative therapy for arthritis primarily embraces slacken- can be delivered by different routes of administration [14,
ing joint edema, disguising joint pain, and synovitis, avert- 15].
ing the injury to joint and articular substructures, arresting
disease development, and restoration of complete activity of
joint. Numerous treatments are applied for achieving the NSAIDs
above-mentioned criteria, which can be described as medica- e.g.
tions for impeding disease growth, repressing the disease Indomethacin
symptoms, etc. The main goal in treating arthritis is to pre- DMARDs
vent any structural impairment and physical impediment Antioxidants
e.g.
[10]. Non-Steroidal Anti Inflammatory Drugs (NSAIDs), Methotrexate e.g. Curcumin
Disease Modifying Anti Rheumatic Drugs (DMARDs), corti- Treatments
costeroids, Janus Kinase inhibitors (JAKinibs), antioxidants for RA
and biologics can be employed for the preventive and cura- JAK Inhibitors
Biologics
tive therapy of arthritis (Fig. 2) [11-13]. e.g.
e.g. Rituximab
The ROS (reactive oxygen) and RNS (reactive nitrogen Tofacitinib
species) also have some role in the pathophysiology of RA. Corticosteroids
In ordinary circumstances, there exists a balance between e.g.
the endogenic defense mechanism of antioxidant and reac- Dexamethasone
tive species production. If this equilibrium gets disrupted,
then it can lead to oxidative stress, which further leads to a
disturbance in the cellular components. Antioxidants are Fig. (2). Representing Categories of Drugs Used in Treatment of
helpful to circumvent this imbalance by inactivating the reac- Rheumatoid Arthritis.
tive oxidant species in addition to inhibiting their produc-
tion. Antioxidants used can be enzymatic, non-enzymatic, or
1.3. Routes For Delivery of Therapeutic Agent
metabolic by nature. Astragalin, carnosol, chlorogenic acid,
and curcumin are some of the antioxidants obtained from dif- The selection of a suitable route for the administration of
ferent sources like rosa agrestis, rosemary/ sage, coffee/ drugs is critically essential, which needs to take into consi-
A Review On Expedient Assets Of Polymers Employed Current Applied Polymer Science, 2020, Vol. 4, No. 0 3

Table 1. Enlisting the patents on novel topical formulations

S.No. Topical Formulation Patent Number Year of Patent References

1. Emulgel WO 2016/038553 Al 2016 [27]
2. Nanogel US 2015/006.4254 A1 2015 [28]
3. Liposomal Gel INDIAN PATENT 251524 2012 [29]

Table 2. Illustrating the incorporation of therapeutic agents in topical drug delivery systems

S. No. Topical Formulation Therapeutic Agent Reference

Mefenamic Acid [32]
1. Emulgel
Dexibuprofen [33]
2. Nanogel Methotrexate [34]
Curcumin [35]
3. Nanoemulgel
Ginger Oil Extract [36]
Celecoxib [37]
4. Transferosomal Gel
Ibuprofen [38]
Methotrexate [39]
Methotrexate [40]
5. Liposomal Gel
Prednisolone [41]
Loperamide [42]
6. Niosomal Gel Thiocolchicoside [43]

deration factors like age and clinical condition of patients. mal gel. A wide range of therapeutic agents from varied
Many routes are employed for administering drugs, which in- sources have been incorporated in the aforementioned topi-
clude oral, buccal, intranasal, sublingual, intravenous, subcu- cal drug delivery systems (Table 2) [30, 31].
taneous, intramuscular, intramedullary, rectal, intrathecal,
All these formulations have proved their efficacy in im-
topical, and transdermal. In the present study, the impor-
proving the condition of joints infected with RA. Fabrication
tance and feasibility of the topical route for the delivery of
of the topical formulations comprises a catholic range of ex-
therapeutics for RA treatment are discussed [16-18].
cipients like polymers, solvents, surfactants, cosurfactants,
2. TOPICAL ROUTE: CRITICAL FOR TREATMENT stabilizers and gelling agents. Pandey et al., depicted in-
OF RA creased in vitro drug permeation, improved in vivo function-
ing, and steadiness of flurbiprofen by formulating pluronic
The topical route does not have the shortcomings of oral lecithin organogel [44]. Jain et al.,, formulated the solid
as well as parenteral route. Topical transport can be a poten- lipid nanoparticle of chondroitin sulfate-diacerine using
tial approach for drug delivery in joints locally. The first top- pluronic F 68 and soya lecithin as a surfactant which also
ical application of NSAIDs for osteoarthritis was approved augmented the permeability of the intestinal membrane and
in 2007, by the US FDA. Targeted assimilation of drugs at affinity among the intestinal membrane and lipid particles
the damaged tissue site results in minimal systemic contact, [45]. Khachatryan et al.,, formulated silver nanocrystals in
thereby, causing a decrease in the incidence of allied undesir- the hyaluronan lecithin matrix in which lecithin offered flexi-
able aftereffects perceived without harming the therapeutic ble, elastic foils, additional suitability for possible preven-
activity. Furthermore, it has been reported that topical admin- tive and curative appliances [46, 47]. Salwowska et al.,, indi-
istration of NSAIDs facilitates absorption into indigenous tis- cated the effect of the molecular size of HA on osteoarthritis
sues analogous to oral administration, displaying ≥ a 90% de- and rheumatic arthritis with an explanation of the mech-
cline in the peak systemic absorption [19-25]. Nagai et al.,, anism of analgesic and anti-inflammatory activity of HA
studied the treatment of rheumatoid arthritis using in- [48]. Bae et al.,, explained the role of HA in fostering the
domethacin nanoparticles in gel ointment form. They production of cartilage matrix; it develops the resilience and
suggested that topical delivery offered effective treatment ex- moisture of cartilage [49]. Neethu et al., evaluated the effi-
clusive of excessive systemic concentration of drugs [26]. ciency of chitosan hyaluronic acid hydrogel for cartilage re-
Numerous novel topical formulations are employed for RA pair but failed to retain the phenotype of allogeneic chondro-
treatment (Table 1). cytes entrapped inside the gels illustrated by the formation
For improvement of permeability and delivery of the of fibrocartilage [50]. Jung et al., formulated the injectable
therapeutic agent, enormous work has been done by research- hydrogel of piroxicam using high molecular weight
ers from all over the world. The conventional topical formu- hyaluronic acid and pluronic F-127, which exhibited sus-
lations like ointment, cream, emulsion, and gel are replaced tained release of drugs and provided increased mechanical
by the novel topical formulations such as emulgel, nanogel, strength [51]. Cai et al., devised gapmer antisense oligonu-
nanoemulgel, transferosomal gel, liposomal gel, and nioso- cleotides in HA-hydrogel possessing twofold modes of ac-
4 Current Applied Polymer Science, 2020, Vol. 4, No. 0 Nishal et al.

tion, one by binding with chondrocyte and other by gene si- of joints and cartilages infected with arthritis. Using differ-
lencing. Sustained release of COX-2 specific gapmers gave ent combinations and proportions of these polymers, various
rise to COX-2 silencing impression in chondrocytes of os- types of topical nanogel formulations can be prepared to im-
teoarthritis [52]. Lu et al., evaluated the antiapoptotic and an- part desired properties. The naturally originated polymeric
tiarthritic activity of carboxymethyl hexanoyl chitosan compounds accomplish countless effective roles for the de-
(CHC) and Low molecular weight Hyaluronic acid (LMW velopment of a drug delivery system [61]. Further, they also
HA) injectable gel by incorporating berberine into the gel. assist in the treatment of some diseases like arthritis, psoria-
The gel also prevented cartilage degeneration [53]. Lee et sis, cancers, and various skin problems. High drug loading,
al., described the use of tannic acid as an adjuvant in anti-in- compatibility, controlled release, target specificity, and non-
flammatory, anti-microbial, and antioxidant activity by for- lethality are prerequisites for the polymers [62]. Individual
mulating hydrogel with hyaluronic acid. TA also aids in the description of the polymers utilized for specific topical for-
improvement of the in vitro cellular reactions, embracing mulation for rheumatic arthritis is enlisted below:
cell attachment and propagation, exclusive of cytotoxicity
[54]. Kurakula et al.,, prepared proliposomal carbopol gel us- 3.1. Hyaluronic Acid
ing the varying concentration of lecithin and cholesterol of Hyaluronic acid is a natural polysaccharide isolated by
piroxicam, which decreased the dosing frequency in rheuma- scientists Meyer and Plamer in 1934 from bovine vitreous
toid arthritis and improved the steadiness of the gel [55]. humor. It is also known as hyaluronan and is made of repeat-
The current manuscript will describe the role of a variety of ing units of glucuronic acid-β-1, 3-N-acetyl glucosamine
polymeric materials employed for topical delivery of thera- joined through β-1,4 linkage of glycosidic bonds [47,
peutic agents for RA, which aid in the anti-arthritic activity 63-65]. HA is not synthesized by the Golgi apparatus. Its
of the therapeutic agents. synthesis convened on the inner surface of the cell mem-
brane, being a natural polymer found in many parts of the
3. POLYMERS body such as skin, vertebrae, etc. Biocompatibility, bio adhe-
The design and development of topical products require siveness, non-immunogenicity, non-toxicity, and biodegrada-
some essential qualities like the drug candidate having low bility are the assets of hyaluronic acid suitable for use as a
dose and molecular weight, short half-life, etc. The desired polymer in drug delivery systems. These properties have a
characteristics of novel topical formulations, such as en- wide opportunity in the arena of drug formulations and the
hanced penetration power and higher bioavailability of the cosmaceutical industry with the advantage of improved
permeability of drug, adhesion, and hydration of skin [48,
drug are accomplished by employing innumerable polymer-
50, 66]. Hyaluronic acid alone and in combination with
ic compounds. Hyaluronic acid, lecithin, pluronic acid, chi-
other natural polymers is useful in cartilage recovery as it is
tosan, PLGA, and HSA are the polymeric materials possess-
the part of cartilages. As per the study of Neethu et al., the
ing requisite qualities alone or in distinctive combinations.
hydrogel made by using a combination of hyaluronic acid
Above cited polymers are of natural origin and biodegrad-
with another natural polysaccharide is capable of retaining
able [56, 57]. These polymers aid in the development of nov-
more water and capturing cells which further make them an
el topical formulations by properties such as the controlled epitome for the renovation of cartilages [67-70]. The pres-
release of a drug, long-duration effect, low frequency of ap- ence of carboxylic acid, hydroxyl, and other operative func-
plication, synergistic effect to improve cartilage degenera- tional groups in HA renders it an appealing polymeric com-
tion, role in improving the permeability of the drugs, ad- pound for supplementary reformation [71].
vanced biocompatibility, easy degradation devoid of detri-
mental metabolites, easy to mold in the topical formulation 3.1.1. Role of HA in Management of Arthritis
and increased stability of the formulation. Retention of a
drug molecule in systemic circulation for comparatively HA exhibits various valuable effects on both rheumatoid
longer duration and delivery of the same to the target site arthritis and osteoarthritis. Osteoarthritis is characterized by
(i.el. inflamed tissue) are the two primary challenges for ef- a diminished amount of glucosamine glycan and amplified
fective delivery of therapeutic agents through oral route. Th- collagen degrading enzyme with proteoglycans. Free radi-
ese challenges can be met through designing a smart poly- cals of oxygen are prevalent during inflammation which can
meric topical drug delivery system such as stimuli-respon- be neutralized by high molecular weight hyaluronic acid.
sive substances that become responsive to surrounding stim- HA unveils analgesic activity by inhibiting apoptotic chon-
uli like redox potential, pH, temperature, and a dearth of oxy- drocytes and accelerating the proteoglycans [69, 70]. HA be-
gen. Innovative topical formulations are designed by employ- ing the structural constituent of synovial fluid and the articu-
ing pH gradient as the pH contour of the synovial fluid in lar cartilage, is involved in maintaining the lubrication of
joints and cartilages as well as provides physical resistance
RA infected tissues is substantially poorer as compared to
for the compaction drives. Hyaluronic acid with high molec-
normal fluid [57-59].
ular weight is more effective in promoting the viscoelastici-
In the present manuscript, it is being reviewed that differ- ty of synovial fluid (Fig. 3) [72-74]. This effect can be sus-
ent natural polymers employed in the development of topi- tained by maintaining the amount of HA at the synovial sur-
cal nanogel formulations exhibit a favorable impact on the face, which may further be achieved by making hydrogel us-
treatment of RA [60]]. These polymers help in the recovery ing HA binding peptides [75, 76].
A Review On Expedient Assets Of Polymers Employed Current Applied Polymer Science, 2020, Vol. 4, No. 0 5

Fig. (3). Mechanism of hyaluronic acid as visco-supplement.

Fig. (4). Describing Varied Functions of Hyaluronic Acid.

Degradation of HA can be prevented by using the ni- was used for augmentation in the propagation and delinea-
troxide-containing substance. Forsey et al., studied that an tion of osteoblast and similar cells. It also recovered the con-
improvement in lubrication between the cartilages can be structive and metabolic effects of bone in vitro as well as in
achieved by employing HA with lecithin derivative i.el. di- vivo conditions. It led to the new bone formation and ossifi-
palmitoyl phosphatidylcholine on a model damaged human cation by hastening the growth of the cells. The difficulty in
cartilage [77]. Growth and differentiation factor 5 (GDF-5) the release of GDF -5 to proper site and time alleviated by
6 Current Applied Polymer Science, 2020, Vol. 4, No. 0 Nishal et al.

making hydrogel with hyaluronic acid. Bae et al., reported bon compound. Lecithin is also a conventional phospholipid
up to 94% release of GDF-5 from the HA hydrogel over a having the eminent amount of phosphatidylcholine. These
period of 28 days. They also corroborated the hydrogel con- possess a similar polar head, however, varying fatty groups
taining HA and GDF-5 for its usefulness in osteogenesis by with hydrophilic and hydrophobic moieties, respectively.
employing the rabbit model [49]. Park et al., showed that This amphiphilic nature displays diverse thermotropic and ly-
HA and pluronic F-127 can be framed for injectable hydro- otropic phase configurations from solid to the liquid stage.
gel in which the pluronic, being, a surfactant can result in Mainly 3-D lamellar crystalline arrangement is exposed at
rapid erosion of hydrogel and consequently spout release of low-temperature conditions or hydrated state by the phospho-
the drug. This can be prevented by HA by promoting the in- lipids. Phospholipids are also capable of exhibiting gel-like
ter-crosslink of the micelles, further contributing to the tight state, 2-D lamellar state and other solid structures. The
packing of micelles of the pluronic over the gelation temper- phase transition of the phospholipids with variations in tem-
ature. This cross-linkage also aids in augmenting the me- perature is dependent on the characteristics and length of the
chanical strength of the gel [51]. Hyaluronic acid possesses chain. The phospholipids can make bilayer form after
varied functional attributes (Fig. 4). swelling in water and separate as monolayers when placed
in the oil. Thus it can be ascertained that the amphiphilic
Kim et al., investigated the use of HA as an apposite po-
lecithin molecule induces the polar molecule through the po-
lymer for executing ionic complexation with PEGylated
lar head and helps in dispersing non-polar drug molecules
TRAIL. The nanocomplex formed among PEGylated
through the nonpolar tail. Further, it also aids in captivating
TRAIL and HA originated as a valuable formulation for the
vitamins A, D, E, and K from our diet. This will further
treatment of RA as described by the results of the in vitro
boost up the bone as vitamin D and vitamin K are known to
study [78]. Cai et al., studied the hyaluronic acid (high
draft the bones [60, 82, 83].
molecular weight) hydrogel comprising the gapmer anti-
sense oligonucleotides that demonstrate the twin approach Lecithin serves as the predecessor for choline and acetyl-
that is binding to chondrocyte and by gene silencing. As per choline production so it may regulate the amount of acetyl-
this study, about a 14-day silencing effect on COX-2 was ob- choline available for the intracellular functions. Further-
served for 5-days persistent release of gapmer specific for more, it plays a role in the permeability of the cell mem-
COX-2. For this study, isogenic MCF-7 cells were em- brane. Lecithin is widely employed in cosmetics, food, and
ployed like the prototype. These synergistic effects develop pharmaceutical industry owing to its functional characteris-
into major monitors for osteoarthritis [52]. tics (Fig. 5) [84-88].

3.2. Lecithin
Lecithin is the inherent phospholipid component of ani- 1. Permeation
mals as well as plants. The possible sources of lecithin are enhancer
egg, bovine soya milk, rapeseed, and fish. Phospholipids be- 2. Nanostructured
Lipid Carrier
long to the lipids in having a polar head bearing the phos- 13. Nutritional
3. Solubility
phate linked to the hydrocarbon sequence of non-polar char- supplement,
enhancer
4. Spreading
acteristics. Attachment of distinct functional units (like phos- vitamin source
agent
phatidylcholine, phosphatidic acid, phosphatidylserine) to 14. Plasticizer
5. Coupling
the phosphate group of lecithin rendered it a structure with 15. Synergist
agent
variable characteristics. Animal lecithin (egg yolk) is quite Lecithin
expensive as compared to the plant (soya bean). The compo- Applications
sition of which is variable as per the method utilized for ex-
traction. Phosphatidylinositol, phosphatidylcholine, and 6. Emulsion
stabilizer
11. Antioxidant
phosphatidylethanolamine are the main phospholipids report- 7. Viscosity
12. Biologically
ed in lecithin [79, 80]. Lecithin procured from diverse active agent modifier
sources exhibits distinct properties which provide valuable 8. Catalyst
contributions to incongruent areas like pharmaceutical, cos- 9. Liposomal
encapsulating agent
metic, and food manufacturing [81].
10. Biodegradable
additive
3.2.1. Role of Lecithin in Management of Arthritis
Phospholipids are the chief constituent of cellular mem-
branes that exhibit an essential role in the metabolic activi- Fig. (5). Representing the extensive applications of Lecithin.
ties of organisms. Being a natural component of living or-
ganisms, the phospholipids can be used as a supplement to
treat diverse health problems without any hazardous effects. 3.3. Pluronic
Phosphatidylcholine, phosphatidic acid, phosphatidylserine, Pluronics are a triblock copolymer of poly (ethylene
and phosphatidyl-ethanolamine are the main classes of phos- oxide)-poly (propylene oxide)-poly (ethylene oxide) (PEO-P-
pholipids differing in chain length and saturation of the car- PO-PEO). These are also known as Synperonics, Kolliphor,
A Review On Expedient Assets Of Polymers Employed Current Applied Polymer Science, 2020, Vol. 4, No. 0 7

Fig. (6). Temperature related behavior of Pluronics.

Poloxamer 124
(Pluronic® L-44)

Poloxamer 184 Poloxamer 188

(Pluronic® L-64) (Pluronic® F-68)

Various
Forms of
Pluronics

Poloxamer 407
(Pluronic® F-127)

Fig. (7). Showing various grades of Pluronics.

and noticed in the year 1950. These are amphiphiles with ranged on the outer side and dehydrated PPO dwells in the
both polar and non-polar groups, which increase their sur- inner central hub. This whole process is termed as micelliza-
face-active properties. These do not possess any odor and tion resulting in a decline in the extent of hydration and in-
taste, having waxy granular white colored appearance with tensification in the hydrophobic property. This peak point
good flow properties [89, 90]. Depending on the number of that is the critical micellar concentration (CMC) is crucial
hydrophilic and hydrophobic units (PEO and PPO), the for micellization. The biological effects of pluronics are de-
pluronic polymers exhibit distinct properties. All the pluron- pendent on CMC [94-97]. Depending upon the grade of the
ics have different molecular weights and HLB despite simi- hydrophilic and hydrophobic unit of pluronics, they differ
lar chemical formula [91, 92]. These polymers can be mod- from each other (Fig. 7)
eled in diverse specialized forms varying from micelles to Hydrophilic or hydrophobic drug molecules can be easi-
gel reliant on temperature and concentration of a particular ly integrated into the composite of pluronic with other poly-
solvent system (Fig. 6) [93]. mers of suitable chemical nature. The drug release from this
When the temperature rises after Krafft Point or Critical composite is analyzed as a factor of pH and temperature [98,
Micelle Temperature (CMT), the hydrated PEO units are ar- 99]. Ur-Rehman et al.,, studied the effect of dimethyl
8 Current Applied Polymer Science, 2020, Vol. 4, No. 0 Nishal et al.

Body Weight
Reduction
Mineral
Antibacterial
Absorption

Anti-
Antioxidant Chitosan hyperlipidemic

Fig. (8). Describing Diverse Applications of Chitosan.

sulfoxide (DMSO) on the release of drug from Pluronic hibited anti-inflammatory action by impeding the cell aggre-
F127 gel and concluded that it affects the gel in a concentra- gation [105].
tion-dependent manner and at low concentration, it is safe to
use as a co-solvent as it showed no alteration in the gel be- 3.4. Chitosan
havior and release pattern of the drug. The integrative and Chitin is the natural source of chitosan by the process of
adsorptive nature of pluronics makes them beneficial in im- deacetylation. It consists of N-acetyl-D-glucosamine and D-
proving drug release as well as stability. These are capable glucosamine units. Chitosan is nontoxic, non-antigenic easi-
of adsorbing both hydrophilic and lipophilic molecules on ly bio adsorbed and biodegraded by lysozyme and chitinase
their surface. The presence of a hydrophobic block in the enzymes. The nanogel formed by employing chitosan
center permits the interface to the lipid compounds. They proves beneficial in the delivery of oligonucleotides, genes,
possess the ability to get adsorbed as well as to invade and drugs, etc [106, 107]. In addition to aid in drug delivery,
through oily films [94, 100]. Pluronic F-68 exhibits cells pro- chitosan also performs several other functions, as shown in
tective function and makes them invincible to any shear Fig. (8). Polysaccharides are employed for the treatment of
stress [101]. osteoarthritis. These polysaccharides are chondroitin sulfate,
hyaluronic acid, glucosamine, chitosan, heparin (Low Molec-
3.3.1. Role of Pluronics in Management of Arthritis ular Weight), alginate, xanthan gum, etc [60, 108].

The development of collagen and attachment of cells are 3.4.1. Role of Chitosan in Management of Arthritis
promoted by pluronic F127, which further enrich the process Oxidative stress is caused due to reactive oxygen species
of vascularization. So it may be said that pluronics may such as superoxide, radicals, peroxynitrite, hydrogen per-
prove a healthier drug delivery system for fostering the re- oxide, and hypochlorite and singlet oxygen. Overproduction
generation of inadequate vascular tissues like tendons, carti- of ROS makes the body's defense system helpless in con-
lages, bony tissues, and epithelial tissues [102]. Tharma- trolling the oxidative stress, which further results in several
lingam et al., investigated the effects of pluronic F68 on the diseases, for example, inflammation, rheumatoid arthritis,
CHO cell culture and reported that pluronic may be protec- dyslipidemia, cardiovascular diseases, and neurodegenera-
tive for the cells by making a fictitious barrier via adsorption tive ailments. Chitosan exhibits a hunting action over vari-
on the surface of cell membranes, and similarly by renewing ous free radical species bestowing therapeutic activity in con-
the dented cells. Along with the valuable effects on cells, trolling oxidative stress. In a study by Xie et al., it was ex-
they also reported the harmful effects like complicated elimi- plained that chitosan could exhibit activity as a scavenger of
nation of Pluronic F 68 in the course of retrieval of product ROS (Fig. 9) [109]. Chitosan plays a prodigious role in the
repair of cartilage and viscosupplementation. The hydrogel
and inhibitory action on a few cell lines. Further, they
made by dispersion of alginate–chitosan beads displayed im-
suggested lowering the amount of Pluronic F68 in the cul- provement in cartilage repair and a decline in the inflamma-
ture [103]. Curry et al., examined the usefulness of Pluronic tion of the synovial membrane of the rabbit model. The chi-
F68/ Poloxamer 188 in lowering the inflammation and dam- tosan-based hydrogel is capable of reinstating rheomorphic
age of tissues by employing replica of excitotoxic TBI in features of synovial fluid collected from patients of os-
rats. They described that it acts as a membrane-ordering teoarthritis equivalent to the synovial fluid of healthy per-
agent by augmenting the cell firmness and declining the sons. Consequently, this supports the accountability of chi-
membrane volatility [104]. Furthermore, poloxamer 188 ex- tosan for viscosupplementation [110].
A Review On Expedient Assets Of Polymers Employed Current Applied Polymer Science, 2020, Vol. 4, No. 0 9

Formation of NH3+ by
Formation of Stable
NH2 group upon
macromolecular
taking H+from
radicles by °OH upon
solution, further
reaction with free
addition reaction
NH2 group
with °OH

Deacetylation degree
Hydroxyl units react
and Molecular weight
with °OH thru H-
of chitosan reinforce
Scavenging
Modes of abstraction
Scavenging
Action of
Chitosan

Fig. (9). Describing various aspects of chitosan as a scavenger for ROS.

Fig. (10). Representing various aspects of Albumin.

Consequently, it is clear from the above-mentioned fig- mones, pH balancing and it also maintains osmotic pressure.
ure that the –OH (hydroxyl) group, OH and NH2 groups pre- HSA also supports the surrounding cells and tissues by deliv-
sent in polysaccharide unit of chitosan react with hydroxyl ering the metabolic byproducts i.el. amino acids [60]. The
free radical, free NH2 group and H+, OH respectively to form liver is the main site of synthesis for HSA, which is trans-
stable non-reactive compounds. But despite the valuable an- muted as pre-proalbumin from a single gene. Serine Pro-
tioxidant action of chitosan, their use is limited owing to tease present in the endoplasmic reticulum cleaves it from
N-terminal and further transfers it to the Golgi bodies before
their hydrophobicity [111].
secretion from the cell. HSA possesses the absolute molecu-
3.5. Human Serum Albumin (HSA) lar weight of 66700 Daltons. It has three domains i.el. do-
main I, II & III with two long and one short loop in each do-
Albumin is the most profusely found plasma protein. Al- main. Post-translational glycation, cysteinylation, S-guanyla-
bumin can be oval, bovine, and human serum, depending on tion, and dehydroalanine conversion are some of the meth-
the source. HSA exhibits many functional attributes in the bi- ods to alter the basic structure of HSA, which results in in-
ological system, for instance, a transporter for fatty acid, hor- creased absorption, bioavailability, and pharmacokinetic
10 Current Applied Polymer Science, 2020, Vol. 4, No. 0 Nishal et al.

properties [112]. Albumin plays valuable physiologic roles, gen type II and resistant apoptosis. Two micro RNAs such
for instance, it causes colloidal osmotic pressure, presents as miR146a and miR200b seemed to be expressed more by
nutrients for cells, performs solubilization of fatty acids, and LMWF5A, promoting its anti-inflammatory action. Along
plasma pH balancing. Along with these functions, albumin with this, it was also found regulating the anti-inflammatory
imparts fair stability above the extensive range of pH (4-9). prostaglandins [119]. The aforementioned upshots from dif-
It is thermostable upon heating at temperature 60 ºC for 10 ferent studies indicate the role of human serum albumin in
hrs, as well as violates the effect of denaturing agents and cartilage healing and the lessening of inflammation of joints.
solvents. Owing to the better stability and pharmacokinetic
properties of albumin, these can be employed as a carrier for 3.6. Poly Lactic-co-glycolide (PLGA)
diverse kind of drug molecules from different origin [113]. Lactic acid (A) and glycolic acid (B) are the integral
Albumin unveils diverse forms, properties, and mechanisms units of PLGA (Poly lactic-co-glycolide) present in varying
of carrying drugs (Fig. 10). ratios. It is the block polymer of repeating units of A & B,
The presence of hefty responsive groups (amino, thiol, such as AB, ABA & BAB [120]. It is prepared using lactic
and carboxylic acid group) on the surface of HSA makes and glycolic acid to carry out the direct polycondensation,
them suitable for binding to several drug molecules and tar- which can accomplish solution state or melt solid state. PL-
geted drug delivery by altering them covalently [56, 114]. GA is the FDA approved polymer that is biodegradable, bio-
Weber et al., described that 40% cross-linking of these compatible, and easy to be utilized in diverse drug delivery
groups by glutaraldehyde provides more stability of particles systems for a varied number of molecules like drugs [121],
as compared to 100% cross-linking. Treatment of albumin protein & peptides [122], plant materials [123, 124] and
with PEGs enhances the circulation as well as makes them RNA & DNA [125]. The PLGA in amorphous form is more
suitable for cancer treatment [115]. Ahmed & Husain ex- suitable as an excipient in controlled drug delivery forms
plained the role of nanoformulations of gold (AuNPs) and and as an antigen carrier for developing novel vaccines
silver (AgNPs) in inhibiting advanced glycation end-prod- [126]. The physicochemical properties of PLGA allow it to
ucts (AGEs) of HSA, which lowers the risk of various degen- get molded in any form and size for the encapsulation of any
erative disorders. AgNPs more strongly inhibits the AGEs as drug molecule. It has good broad-spectrum solubility in sol-
compared to AuNPs [116]. Das et al., demonstrated that bio- vents. Lactate, which is the hydrolytic product of PLGA,
compatible HSA nanoparticles formulated via an altered plays an important function in biochemical pathways like
method owned potential as a carrier for a hydrophobic drug anaerobic glycolysis and can augment physiological activi-
i.el. curcumin for enhancing its bioavailability [117]. HSA ties in various diseases [127]. The degradation of PLGA in
possesses different binding sites and helps in the solubiliza- water takes place employing hydrolysis of the ester bond. It
tion of hydrophobic drugs, which carries the drugs into the gets decomposed into harmless products i.el. water and car-
systemic circulation. It can also be utilized for targeted drug bon dioxide, which are further released from the body [128,
delivery. Arthritis is characterized by hypoalbuminemia, so 129]. Gentile et al., 2014 described the use of PLGA in bone
using HSA as a drug delivery carrier can supplement albu- tissue engineering and suitability of PLGA as scaffolds,
min as well as specifically deliver the drug [56, 60]. The ma- fibers, hydrogels, or microspheres for bone tissue regenera-
jor functions of albumin in the human body are to regulate tion. Further, they explained the role of two strategies i.el.
the colloidal osmotic pressure of blood and to transport a addition of hyaluronic acid and surface modification in the
wide range of drug molecules to their targets. PLGA scaffold for creating osteoconductive and osteoinduc-
tive slope for enhanced bone tissue regeneration. PLGA is
3.5.1. Role of HSA in Management of Arthritis available in a varied range of grades, depending on the ratio
Ren et al., described the potentials of albumin as a drug of lactide and glycolide units [130]. FDA and EMA provid-
carrier used in the treatment of rheumatoid arthritis. RA is ed approval to use PLGA in innumerable drug delivery meth-
recognized with the inflammation of joints and tissues, ods [131]. Chronopoulou et al., developed and characterized
which may lead to augmented fenestration of the vascular the PLGA sub-microcarriers, which are biodegradable by
cells. Past this, it becomes easy for the albumin dependent employing an osmosis-based method that possesses a permis-
delivery system to reach the location of inflammation [113]. sible drug loading efficiency up to 99% [132]. Wei et al., re-
HSA possesses an exceptional aptitude of binding to ROS, ported a Janus nanogel system for the delivery of taxol using
lipopolysaccharides, nitrogen reactive species, and bacterial a copolymer of PLGA–PEG–PLGA. This formulation in-
products, as well as entrap free radicals. This further res- hibits tumor growth as well as acts as a vehicle for transport-
trains the course of inflammation. Thus HSA serves as a ing other anticancer drugs. Furthermore, it can be freeze--
chief extracellular cover versus oxidative stress [118]. Bar- dried then stored as a powder, which can be suitably used
Or et al., showed the perspectives of low molecular weight with phosphate buffer solution [133].
fraction of commercial human serum albumin i.el.
3.6.1. Role of PLGA in Management of Arthritis
LMWF5A in the management of osteoarthritis of the knee
joint. As per the study, LMWF5A has been found to be con- Though PLGA is of synthetic origin yet, it is biocompati-
trolling the expression of SOX 9, and redifferentiation of fi- ble and biodegradable. These qualities make it useful as a
broblast-like chondrocytes into active chondrocytes, conse- drug delivery carrier for the treatment of several disease con-
quently leading to an augmented level of expression of colla- ditions. The scaffoldings of PLGA are useful in constructing
A Review On Expedient Assets Of Polymers Employed Current Applied Polymer Science, 2020, Vol. 4, No. 0 11

cartilage and restoration of damaged cartilages [134]. Wang tion of the joints. Several drug delivery systems have been
et al., confirmed by their in vitro study in the bone marrow developed for delivering the therapeutic agent to the target-
stem cells of rats that the PLGA scaffolds promoted differen- ed site. The topical route is favored owing to its less toxici-
tiation of the osteoblasts [135]. Fan et al., illustrated that the ty, ease of application, and targeted delivery but permeabili-
scaffold made by a combination of PLGA, gelatin, chon- ty through the skin, local incompatibility, and adverse ef-
droitin, and hyaluronate surfaced an innovative mode of aug- fects of polymeric materials used for topical drug delivery
menting the reparation of cartilages by maintaining the dif- systems may limit their use. To overcome this dilemma, a
ferentiation in mesenchyme stem cells [136]. Furthermore, range of natural and synthetic biodegradable and biocompati-
Ge et al., supported the fact of osteogenesis through the PL- ble polymers may be employed. As described above in the
GA scaffold by their investigation on the rabbit model. The manuscript, all the polymeric materials i.el. HA, lecithin,
authors described the considerate biocompatibility and os- pluronics, HSA, chitosan, and PLGA are biodegradable and
teoblastic proliferation and differentiation using 3D-printed biocompatible, accomplishing the requirements for the drug
PLGA scaffolds [137]. As described by a study conducted delivery system as well as promoting the therapeutic agents
by Shuqiang et al., PLGA scaffold aided in the healing of in healing the inflammation of joints and cartilages. These
bones in rabbits when employed as a carrier for osteogenic polymers exhibit remarkable properties that make them capa-
growth peptide [138]. In addition to this, Huang et al., evalu- ble of encapsulating the drug and releasing the drug in a con-
trolled manner without any noxious consequences. All the
ated the feasibility and stability of poly (b-hydroxybutyrate--
polymers act as an adjuvant in the treatment of arthritis and
co-b-hydroxy valerate) microspheres in the PLGA scaffold
encourage cartage regeneration in support of joint move-
for reinforcing bone reparation [139].
ment (Fig. 11). Upon accomplishment of the treatment, the
degradation pathways are also simple and are devoid of any
SUMMARY
detrimental metabolite. So this defines the effectiveness of
Rheumatoid arthritis is a prevailing disease in recent the above polymers to be used in a drug delivery system for
times characterized by degeneration and amplified inflamma- arthritis.

Fig. (11). Role of different polymers in the delivery of drugs for the treatment of arthritis.
12 Current Applied Polymer Science, 2020, Vol. 4, No. 0 Nishal et al.

Despite several valuable aspects of the aforementioned FUNDING

polymers, there may be some associated undesirable effects
None
that need to be optimized whenever these polymers are used
in the formulation designing. Hyaluronic acid is believed to CONFLICT OF INTEREST
be non-immunogenic and no serious side effects are ob-
served with this, but some cutaneous hypersensitive reac- The authors have no conflicts of interest, financial or
tions may occur in some groups of the population [140]. otherwise.
Bearing phospholipids as the main constituent, lecithin is
more prone to oxidative as well as hydrolytic degradation ACKNOWLEDGEMENTS
[141]. Pluronics suffer from the downside of rapid in vivo Declared none.
degradation, which can be overcome by cross-linking with
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