Lipid Nano-System Based Topical Drug Delivery for Management of Rheumatoid Arthritis: An Overview

The overall purpose of rheumatoid arthritis (RA) treatment is to give symptomatic alleviation; there is no recognized cure for RA. Frequent use of potent drugs like non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs), lead to various adverse effects and patient compliance suffers. On the other hand, there are many drawbacks associated with traditional methods, such as high first pass, high clearance rate, and low bioavailability. Drug administration through the skin can be a promising alternative to cope with these drawbacks, increasing patient compliance and providing site-specific action. The stratum corneum, the uppermost non-viable epidermal layer, is one of the primary limiting barriers to skin penetration. Various nanocarrier technologies come into play as drug vehicles to help overcome these barriers. The nanocarrier systems are biocompatible, stable, and have a lower cytotoxic impact. The review discusses several lipid-based nanocarrier systems for anti-rheumatic medicines for topical administration it also discusses in-vivo animal models for RA and provides information on patents granted.


Introduction
Rheumatoid arthritis (RA) is an autoimmune, inflammatory disorder, characterized by polyarticular swelling in synovium tissue which leads to the destruction of articular cartilage. 1RA primarily targets the small diarthrodial joints of the hand and feet. 2 Immunological cells like macrophages, T, and B cells are found in synovium and involved in the production of several cytokinins, interleukins (IL-1B and IL-6), and tumor necrosis factor (TNF-alpha) on activation. 1 These inflammatory mediators and cytokine production results in progressive inflammation and joint swelling.Further, the production of TNF-alpha and IL-1B triggers enzyme metalloprotease and osteoclast production which results in bone erosion, and finally destruction of cartilage.This causes severe pain, swelling, bone stiffness, and destruction of functions. 1,3he conventional approaches for the management of RA include treatment with disease-modifying antirheumatic drugs (DMARDs) which improve functioning and slow down the process of joint damage.It includes drugs like methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine. 4Another treatment approach involves the use of corticosteroids, Non-steroidal anti-inflammatory drugs (NSAIDs; cyclooxygenase 2 inhibitors), and biological response modifiers (infliximab, adalimumab, etanercept, rituximab, abatacept, rituximab, tocilizumab, tofacitinib) for symptomatic action like pain and inflammation reduction. 5Although there are many advancements in RA therapies still safety and efficacy concerns limit their use. 1 Many adverse effects are associated with the drug used as cyclooxygenase-2 inhibitors have been withdrawn due to the serious cardiovascular toxicity associated with their use. 6Incidence of gastrointestinal (GI) distress (nausea, abdominal pain, diarrhea), rash/allergic reaction, bone marrow suppression, and hepatotoxicity, are higher with the use of methotrexate, leflunomide, and sulfasalazine.They are also associated with a high risk of cardiovascular disorders, fungal and viral infections with the occurrence of tuberculosis reactivation, herpes zoster, and hepatitis B/C.IL-17 inhibitors have been reported to cause inflammatory bowel disease. 7This all complications and adverse effects of drugs turn towards the development of novel carrier systems, with higher efficiency and safety.
Currently, topical drug delivery has gained wide attention as it is a non-invasive technique, has minimum side effects associated with the GI tract, avoids hepatic firstpass metabolism, and protects drugs from GI instability and enzymatic degradation.The major limitation of topical delivery is the permeation of the drug through the stratum corneum, which forms the uppermost layer of skin. 8To overcome these limitation various methods like iontophoresis, sonophoresis, electroporation, and microneedles, 9 has been used to some extent, coming to the lipid-based nanosystems like nanoemulsion, Pathogenesis of rheumatoid arthritis Genetic, environmental, and immunologic factors act as a trigger for RA disturbing the immune system functioning.As shown in Figure 1, a post-translational modification of amino acid arginine into citrulline that is citrullination process takes place, which is recognized as foreign antigen by the immune cells and stimulates the development of anticitrullinated peptide antibodies, or anti-cyclic citrullinated peptide (anti-CCP) autoantibodies. 10The citrulline containing protein such as filaggrin, type II collagen, and vimentin is recognized as a foreign antigen.These antigens are picked up by the antigen-presenting cells and are carried to the lymph nodes, where due to interaction between T-cell receptor and class II MHC-Peptide (major histocompatibility complex) antigen CD4 + T cells are activated, which then differentiates into T helper 1 (TH1) and T helper 17 cells (TH17).T H1 secrets Interferon-gamma TNF-alpha and Lymphotoxin B which activates macrophages and B-cells.B-cells then differentiate into plasma cells.These plasma cells secrete auto-antibodies like Rheumatoid factor (anti-IgM antibodies) and anticitrullinated peptide antibodies or anti-CCP antibodies.These T-cells and auto-antibodies enter into circulation reaching to joints.Rheumatoid factor forms a complex with Fc portion of altered IgG antibodies forming immune complexes.Anti-CCP targets citrullinated proteins.Now, this activated system destroys local tissue.Simultaneously T-effector cells stimulate synovial macrophages and fibroblasts to secrete proinflammatory mediators (like TNF-alpha, IL-1, and IL-6) which results in synovial inflammation and promotes angiogenesis to bring more inflammatory cells to the joints.Inflammatory cytokines increase the expression of receptor activator of nuclear factor κB (RANK) ligand (RANKL), on the surface of T-cells which brings about activation of osteoclasts.These activated osteoclasts cause bone destruction. 4The matrix metalloproteases secreted by synovial cells are involved in the destruction of cartilage. 8The overall pathogenesis, results in bone erosion, cartilage destruction, and inflamed condition.As depicted in Figure 2, the difference between normal and RA joints.The joint with RA shows inflammation on synovium or synovium membrane, thinning of cartilage, continuous erosion of bone and reduction in synovial fluid.

Conventional treatment for rheumatoid arthritis and their drawbacks
The widely used drugs of NSAIDs class to relieve pain and inflammation are most likely associated with undesirable side effects like ulcers, internal bleeding, kidney failure, and increased risk of a heart attack.They are also involved in the induction of reactive oxygen species resulting in increased oxidative stress in different tissues. 11NSAIDs and COX-2 inhibitors both are equally effective and are associated with an increased risk of GI, renal, and cardiovascular adverse effects. 12The study investigated by Combe et al 13 conclude that long-term use of etoricoxib, a COX inhibitor is associated with a greater risk of thrombotic events, renovascular adverse events, and GI intolerance. 13DMARDs plays important role in the treatment of RA, used as monotherapy or given in combination with glucocorticosteroids or NSAIDs drugs. 14The first choice from this category is methotrexate, many of these drug molecules like cyclosporine, gold, and D-penicillamine are associated with potential renal toxicity while drugs like methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, and infliximab have relatively low effect on renal function. 15,16They are also associated with side effects like liver and digestive organ dysfunction, stomatitis, and myelosuppression. 16ulfasalazine is mainly associated with adverse GI effects (e.g., nausea, vomiting, dyspepsia, anorexia), CNS effects (e.g., headache and dizziness), and rashes. 17The use of biological agents in RA is another treatment approach etanercept, infliximab, and adalimumab targets TNF and IL-1 activity, administered as monotherapy or given in combination with methotrexate. 18In addition to their side effects like bacterial and fungal infection, they are also associated with malignancy especially mon-Hodgkin's lymphoma. 16

Herbal medicine approach
According to the reported study, around 450 plant species belonging to 100 families are being traditionally used for arthritis management. 19There are many phytoconstituents or herbs reported for the management of RA some of them are Boswellia serrata (frankincense), Curcuma longa (turmeric), Eremostachys laciniata, Eucommia ulmoides, Matricaria chamomilla, Paeonia lactiflora, Withania somnifera (ashwagandha), Zingiber officinale, 20 Piper nigrum, Commiphora mukul, Pongamia pinnata, Betula platyphylla, 19 Nigella sativa (black cumin), Tinospora cordifolia (guduchi), Capsicum frutescens (cayenne), Allium sativum (garlic), Tripterygium wilfordii (thunder duke vine). 21Other traditional Chinese herbal medicines used in RA treatment are Angelica Sinensis Radix, Paeoniae Radix Alba, Ramulus Cinnamomi, Glycyrrhizae Radix et Rhizoma, and Clematidis Radix et Rhizoma, which shows improved treatment efficiency when given with DMARDs. 22There is very little information available on pharmacodynamics and pharmacokinetic potential of herbal drugs and the incidence of adverse effects like herbdrug and herb-herb interactions. 23On oral administration, these herbs may show drug-herb or herb-herb interactions which results in various side effects and may create a potential risk to the patient. 24Many of the studies have reported side effects associated with herbal drugs such as GI upset, dizziness, fatigue, male reproductive toxicity, and alteration in the female menstrual cycle.Other factors that limit their use is poor absorption, low bioavailability, rapid metabolism, and elimination of active component. 25n the other hand, the presence of multiple components in the herbal drugs, lack of standardization technique, and difficulties in the authentication of species as well as the presence of contaminants make it challenging to use. 23o avoid GI disturbances, first-pass effect, and to provide site-specific action various topical formulations were developed and studied. 26One of the studies conducted by Aiyalu et al 27 involves the development of containing Cardiospermum halicacabum and Vitex negundo leaf extracts loaded gel followed by evaluation of anti-arthritic activity using Freund's complete adjuvant induced arthritis method and concluded reduction in paw volume, TNF-α level with no agglutination in C-reactive protein and rheumatic factor, further histopathological examination justified anti-arthritic activity of herbal gel.

Lipid-based Nanomedicines as a topical treatment approach for RA
Recent approaches came up with the use of a topical route that provides non-invasive drug delivery and overcomes the drawbacks and adverse events associated with the conventional route, it also bypasses hepatic first-pass metabolism.Additionally, it is possible to deliver various drug molecules both hydrophilic and lipophilic. 28The stratum corneum (non-viable epidermis layer) is 5-20 μm thick, consisting of 10-15 layers of thick corneocytes, lipid matrix, corneodesmosomes, and a tight junction that makes stratum corneum acting as a barrier for drug penetration.
On the other hand, as shown in Figure 3 there are some proposed pathways for the molecule to cross the stratum corneum, which includes, 1. Paracellular (intercellular) pathway, the passage of the small lipophilic molecule through the lipid matrix which is in between the corneocytes.2. Transcellular (intracellular) pathway, the passage of the lipophilic molecule through the corneocytes by partitioning into lipophilic and hydrophilic domains.3. Transfollicular (shunt) pathway, involves the passage of drug molecules through sweat glands and hair follicles.
After crossing this non-viable layer (that is stratum corneum) it reaches to viable layer and passing through different layers it distributes into the dermal layer reaching the blood capillaries. 29Here, to make the molecule cross the barrier by incorporating it into a suitable carrier.Various nano lipid formulations mentioned in Figure 4, came into the picture which shows better penetration and prolonged residence time as compared to the conventional topical formulations. 8In addition these lipids also exhibit biocompatibility, increase adhesiveness with skin which in turn reduces water loss and promote skin hydration, and can also lead to lipid exchange between carriers and the outermost layer of skin, which encourages drug penetration. 30These systems are discussed further.

Nanoemulsion
These are thermodynamically stable, biphasic oil-inwater or water-in-oil type of dispersions stabilized by an emulsifier.The particle size of the dispersed phase ranges from 20 to 200 nm.Because of such small particle size, this system appears transparent. 31Nanoemulsion with drug delivery plays multiple roles that are the protection of the drug from degradation, carries both hydrophilic and lipophilic molecules in a single system, and can also provide control release action. 32Nano-sized dispersed phase in nanoemulsion makes the emulsion stable against sedimentation and creaming. 33It is found to be a promising alternative to improve penetration of poorly soluble drugs through the skin, both hydrophilic and hydrophobic drug molecules can be incorporated into it.It is challenging to use nanoemulsion topically due to its low viscous nature and inappropriate spreadability.Incorporating nanoemulsion into a gel can be a potential approach to overcome these challenges.Nanoemulgel is a nanoemulsion-based hydrogel that was developed, which shows improved spreadability and can also act as a drug reservoir to control the release of drug. 34okhale et al 35 formulated and evaluated Quercetinloaded nanoemulsion based gel for managing RA, the study conducted by using HIG-82 and RAW 264.7 cells showed a strong inhibitory effect on LPS-induced TNF-α production with no toxic effect on synoviocytes and also inhibited complete Freund's adjuvant induced paw edema in rats.Nanoemulsions can be also used for combination therapy, to deliver two drugs simultaneously.One of the studies, conducted by Poonia et al 36 revealed controlled drug release for up to 48 hr. and potential anti-arthritic activities with 78.76% inhibition in inflammation, accessed in rats when nanoemulsion loaded gel of two drugs that are Methotrexate and Resveratrol in combination, was investigated for transdermal use.
An advanced form of nanoemulsion drug delivery is the development of a Self-Nanoemulsifying drug delivery system, which has to cope with the limitations and certain stability issues like "Ostwald ripening" associated with the nanoemulsion system. 37These systems are a mixture of oil, drug, surfactant, and cosurfactant.These anhydrous preconcentrates of nanoemulsion turns into a nanoemulsion when they come in contact with the aqueous phase. 38A study carried out by Badran et al 39 reveals the development of a self-nano emulsifying drug delivery system loaded with Meloxicam for transdermal application for managing arthritic pain, this formulation has shown droplet size of about 14.41 ± 2.50 nm to 25.58 ± 2.33 nm (ultra-fine) with a higher release rate and 11.89 folds increase in drug permeation compared to control.Nanoemulsion can be a promising carrier system for the delivery of herbal and animal-origin drugs through the skin.A recent study conducted by Abbasifard et al 32 was based on the development of bee venom nanoemulsion which was evaluated for its penetration and activity to modulate serum levels of endothelin-1 (which is a proinflammatory factor that participates in RA pathogenesis) in collagen-induced RA model and found to have good skin permeation and showed a decrease in serum level of endothelin-1, because of anti-oxidant, anti-inflammatory and immunomodulatory effect of bee venom.Loading herbal drug extract in nanoemulsion is also found to be beneficial, Chandra et al, 40 to reduce the dose of ginger extract, a potent anti-inflammatory agent and to promote its drug delivery through the skin, incorporated ginger extract into a nanoemulsion and formulated as nanoemulgel which has improved transdermal absorption of the ginger extract. 40

Liposomes
Bilayered phospholipid vesicles, spherical in shape, with a self-closed structure having an aqueous core are called liposomes. 41They can encapsulate both hydrophilic and lipophilic molecules.Composed of phospholipids, cholesterol, and stabilizer and classified as unilamellar to multilamellar vesicles depending on their internal structure. 42They can serve as ideal carriers for most of the anti-rheumatic drugs because of their ability to show site-specific action, limiting the systemic exposure with low side effects. 43Bilayer structure can show fusion with the cell membrane, releasing liposomal contents. 44The phospholipids used can also act to increase the penetration through the skin, as it has a similar lipidic composition to that of the skin.They can also serve as a reservoir in the stratum corneum layer producing sustained-release action.Puglia et al 45 investigated in vivo drug release profile of indomethacin-loaded liposomes composed of dipalmitoyl-L-phosphatidylcholine and cholesterol, and found a more prolonged anti-inflammatory effect was observed with liposomal gel as compared to the gel without liposomes.This sustained action was probably because of the interaction of lipid vesicles and lipid in the stratum corneum, producing a depot.One of the studies, investigated to enhance the transdermal RA therapy by Shen et al 46 prepared a carbomer gel incorporated with methotrexate loaded thermal responsible flexible liposomes which have shown rapid drug release under thermal conditions and increased skin permeation as compared to free methotrexate.One of the studies held by Sharma et al 47 revealed the enhanced half-life of a drug with a significant reduction in inflammation and 1.5 folds increase in analgesic effect when studied on complete Freund's adjuvant-induced RA rat model, with aceclofenac cocrystal complexed with lysine and incorporated into liposomes and formulated as a gel when compared to marketed gel.
One of the important factors that affect vesicle to cross skin layers is the vesicle's composition.Many researchers have reported various carrier systems incorporating different components in it, which plays a vital role in crossing skin barriers and enhancing permeation through stratum corneum. 48

Glycerosomes
Glycerol is widely accepted for topical application and known to access deformability index which means it modifies the fluidity of liposomal bilayer vesicle which can increase its penetration through the skin. 49Glycerol at a concentration of 10%-30% v/v with phospholipids and cholesterol gives rise to glycerosomes which form a flexible vesicular structure with increased penetrating power as compared to liposomes.These systems are more stable than liposomes. 50Salem et al 51 conducted a study in which they have prepared celecoxib and cupferron glycerosomes for topical application, the results showed spherical morphology of drug-loaded glycerosomes with optimum particle size and high entrapment of about 89.66 ± 1.73%, 93.56 ± 2.87%, and showed significant drug release with high permeation and remarkable paw edema reduction as compared to control group.Drugs which possess limitations such as poor bioavailability on oral administration, or less lipophilic in nature, or undergo hydrolysis or efflux process can be most suitable to give via transdermal route, incorporating it in vesicular structure which promotes its penetration.One of the studies reported, by Zhang et al 52 formulation of glycerosomes loaded with paeoniflorin (monoterpene glucoside), which possess an anti-inflammatory and immunomodulatory activity for transdermal delivery resulted in enhanced accumulation in the synovium, elevated drug concentration at knee joint for a longer period, and with good skin biocompatibility.

Ufasomes
Synovial capsule barrier and skin barrier limit the efficacy of transdermal delivery.Addition of unsaturated fatty acids can overcome this barrier. 53As reported, unsaturated fatty acids by disrupting the tight junction or increasing the membrane fluidity can enhance skin permeation.The oleic acid and linoleic acid which are unsaturated fatty acids tend to form a vesicular structure when come in contact with the aqueous environment, these self-assembled nano-sizes are termed ufasomes. 54he formation of ufasomes takes place with unsaturated fats and their ionized species that are soaps and it is a pHdependent process. 55The process takes place at basic pH ranging from 7-9, as vesicle formation of unionized fatty acid and fully ionized groups occurs at this pH. 56These nanovesicles allow lipid exchange by getting attached to the skin surface. 57These are capable to carry drug molecules and increasing penetration efficiency across stratum corneum. 54Sharma and Arora 58 developed a gel containing oleic acid vesicle (ufasomes) loaded with methotrexate its In-vitro evaluation showed three to four folds higher permeation from that of plain gel, and 50% of the administered dose was detected in the skin from skin permeation assay.

Aspasomes
Vesicular structure made up of ascorbyl palmitate in combination with cholesterol and a negatively charged lipid that is dicetylphosphate is termed as aspasomes.These carriers possess inherent antioxidant properties due to the presence of ascorbyl palmitate. 59Ghosh et al 60 developed a methotrexate-loaded aspasome hydrogel which has shown in decline in rat paw diameter (21.25%), cartilage damage (84.4%), pannus formation (84.38%), inflammation (82.37%), and bone resorption (80.52%) when compared with arthritic control rat.

Proposomes
Propylene glycol plays a vital role to enhance skin permeation by solubilizing stratum corneum lipids.
Incorporating propylene glycol into a liposome can increase cutaneous and percutaneous drug penetration via the synergistic effect of propylene glycol and phospholipids.
So, this type of liposome is termed proposomes.Because of its more viscous and low volatile nature, it is also found to improve the stability of liposomes. 61Kathuria et al 62 developed tofacitinib (Janus kinase inhibitor) loaded proposomes for transdermal delivery and found that proposomes have shown enhanced permeation of tofacitinib by 4-11 folds and were stable for 6 months.

Transferosomes
A class of liposomes with highly deformable, elastic, and an ultra-flexible vesicular structure composed of phospholipids such as phosphatidylcholine and edge activators like sodium cholate, deoxycholate, Span 80, Tween 80 which increases the flexibility of vesicle by destabilizing lipid bilayers. 63These ultra-deformable nature of vesicles increases the ease of penetration through the skin by squeezing themselves through intracellular lipids of the stratum corneum and making the drug available to a deeper layer of skin. 64The formation of osmotic gradient at the application site across skin, assist penetration. 65They possess an ability to carry hydrophilic and hydrophobic moieties and can accommodate drug molecules with a wide range of solubility. 66Has a potential for surface modification for active targeting and can control the drug release.All these characteristics make it an ideal carrier. 65In a study conducted by Yuan et al, 67 showed the use of hygroscopic and biocompatible molecule that is Hyaluronic acid to modify the surface of transferosomes loaded with indomethacin resulted in superior drug penetration with sustaining the drug release. 67Preeti and Kumar 68 investigated soya phosphatidylcholine and sodium deoxycholate transferosomal gel of celecoxib, a cyclooxygenase -2 inhibitor for in vitro and ex vivo drug release and in vivo anti-inflammatory activity showed higher permeation tendency as compared to conventional gel for the management of RA.Another study conducted by Sarwa et al 69 found that capsaicin-loaded transferosomal gel showed 76.76% of drug release from the vesicular system in 24 hours as evident from confocal laser scanning micrographic study, with superior anti-arthritic activity as compared to marketed gel detected by in vivo studies. 69

Ethosomes
Ethanol affects the intercellular regions of the stratum corneum and acts as a permeation enhancer.The incorporation of ethanol in relatively high concentration with phospholipids and water forms a soft vesicular structure called an Ethosome.These carriers enhanced the delivery of drugs through the skin. 70,71The formation of vesicles with soft malleable structures relies on the fluidizing effect of ethanol on phospholipid bilayer.Concentrations of ethanol vary from 20-50%.As ethanol disturbs the stratum corneum bilayer by increasing its fluidity which eases the penetration of the ethosome, a fusion of those with the cell membrane in deeper skin layer triggers the drug release. 72Fan et al 73 explored the efficiency of tetrandrine-loaded ethosomes and studied drug deposition and drug flux across rat skin which was 1.7 and 2.4 folds higher than that of liposomes, respectively.This indicates that ethosomes as a promising vehicle for topical drug delivery.Another study conducted by Anjum et al 74 investigated the potential of ethosomes to deliver naproxen into deeper skin layers and, assessed the efficacy of naproxen ethosomal formulation using the carrageenan-induced rat paw edema model.Which was found to be more effective in inhibiting swelling paw edema as compared to marketed formulation.A nanoethosomal dispersion was developed for topical delivery of flufenamic acid was developed by Muslim and Maraie 75 which resulted in formation of stable formulation, with high entrapment and sustaining the action upto 24 hours after single administration.

Transethosomes
It is a combination of ethosomes and transethosomes, which shows a higher potential to permeate through skin layers.This system contains both an edge activator and ethanol which makes it easier to cross the skin barrier by squeezing through lipid layers of the stratum corneum using transdermal water gradient pressure. 56This system can be proven as more efficient to deliver medium to large size bioactive molecules. 76An edge activator (biocompatible surfactant) improves flexibility whereas ethanol deforms skin layers and adds up to vesicular fluidization. 77They can be loaded with both hydrophilic and lipophilic molecules. 78One of the studies held by Garg et al 79 describes the preparation of piroxicam-loaded transethosomes, which were then incorporated into the gel.The optimized batch showed entrapment efficiency of 68.434% with improved stability and drug permeation.RA is also accompanied by oxidative stress because of reactive oxygen species generated by neutrophils.The study explored by Song et al 80 to reduce this oxidative stress using transethosomes, transferosome's surface was decorated or covered with ascorbic acid forming an antioxidant surface.These transferosomes were loaded with sinomenine hydrochloride and revealed higher drug concentration in a synovial fluid resulting in higher penetration.

Niosomes
These are microscopic bilayer vesicular structures made up of a non-ionic surfactant and cholesterol arranged in such a manner that the outer and inner surface is hydrophilic area sandwiched lipophilic area between them. 81The non-ionic character plays vital role in drug delivery, with controlling the drug release and targeted action. 82Surfactant present act as a penetration enhancer by various mechanisms like altering the barrier functions of the skin, or by getting adsorbed at the interface. 83These vesicular carriers are biocompatible, biodegradable, relatively non-toxic, with an ability to entrap lipophilic, hydrophilic, and amphiphilic drug molecules, forming a suitable alternative to liposomal delivery. 84Auda et al 85 studied the anti-inflammatory activity of the drug celecoxib from different niosomal gel formulations using the carrageenan-induced rat paw edema method, results showed that there is significant anti-inflammatory activity (75.45%) of the poloxamer niosomal gel on rat paw edema with significant drug release of 72% after 12 hours.The niosomes of liposomes have physical stability issues, drug leakage during storage, and low encapsulation efficiency, which are overcome by preparing proniosomes. 86roniosomes are niosomal hybrid, which gets hydrated with water from skin layers under occlusion and get converted into niosomes, then permeates the skin barrier. 87hese formed niosomes are very similar to conventional niosomes. 88Alsarra et al 89 investigated ketorolac-loaded proniosomes and found that the niosomes produced upon hydration show 99% drug encapsulation and can be a promising vehicle for drug delivery.Ammar et al 90 developed a tenoxicam (NSAID) proniosomal gel which is found to be non-irritant with significantly higher anti-inflammatory and analgesic effects than that of oral marketed tenoxicam tablets.
A new form of vesicular carrier formed by addition of bile salts into a nonionic surfactant vesicles or niosomes called bilosomes. 91This type of vesicles is mostly preferred for oral vaccines, where the entrapped vaccine is protected from gut environment and enzymes due to presence of bile salts. 92Bile salts has the capability to penetrate the biological membrane, enhancing flexibility of vesicles and making it to penetrate deep layers of skin on topical application.Elkomy et al conducted a study where chitosan coated bilosomes were prepared encapsulated with berberine, an alkaloid having anti-rheumatic action.This bilosomes showed 83.8% of drug entrapment, enhanced skin permeation, with reduction in paw edema swelling. 93

Lipid nanoparticles systems
Solid lipid nanoparticles as the name indicated they are composed of single solid lipid or a mixture of solid lipid dispersed in an aqueous phase and stabilized by surfactant.The lipid phase is solid at room and body temperature. 94,95These are colloidal carriers with particle sizes ranging from 50 to 1000 nm, used to improve drug penetration through the skin The presence of solid lipid can prolong the drug release, to get sustain action.The lipids used are categorized as the "generally recognized as safe" (GRAS) category. 96The study conducted by Khurana et al 97 reported the potential of meloxicamloaded solid lipid nanoparticles-loaded gel and evaluated for its penetration and anti-inflammatory potential and found to have a potential to transport the drug to various skin layers with marked anti-inflammatory activity and excellent skin tolerability. 97The use of pure solid lipid in solid lipid nanoparticles tends to crystallize in a perfect crystalline structure after manufacturing, resulting in the expulsion of drugs and relatively low drug loading.Nanostructure lipid carriers are the second generation of solid lipid nanoparticles, composed of a liquid lipid along with solid lipid which avoids the formation of perfect crystal lattice which reduces drug expulsion and increases drug loading. 98The incorporation of liquid lipid increases the possibility of efficient entrapment of a drug that is more soluble in liquid lipid. 99These nanoparticles form a monolayered lipid film on the skin which blocks the water evaporation due to the occlusion effect resulting in increased skin hydration which assists drug penetration. 100u Y et al 101 developed triptolide loaded nanostructured lipid carrier for transdermal application which was evaluated for its encapsulation efficiency and drug loading, found to be 97.15% ± 9.46 and 10.35% ± 1.12, respectively with sustained release of drug and a significant reduction in knee edema in addition to marked anti-inflammatory effect by regulating the levels of TNF-α, IL-1β, and IL-6, reveled from in vivo studies.

Cubosomes
One of the lipid nanocarrier self-assembled system with non-lamellar, mesophasic nanostructure lyotropic liquid structure called cubosomes are also found suitable for topical delivery. 102As the name suggests lipids bilayers are arranged in a regular cubic form separated by interconnected aqueous channels.Lipids like monoolein, monolinolein, phytantriol, etc. are used. 103Monoolein, a blend of oleic glycerides and other unsaturated fats is the base for cubosome development. 104Their unique properties like high drug entrapment, high surface area, sustained release of drug and ability to encapsulate hydrophilic, lipophilic and amphiphilic drug molecules make it a suitable carrier.The study conducted by Gorantla et al, 105 showed developed cubosomes using glyceryl monooleate as liquid crystal structure forming material, incorporating tofacitinib is found to be suitable for transdermal application.Presence of oleic acid in glyceryl monooleate makes it more permeable through skin. 106here are many more studies carried over lipid-based nanocarriers, utilizing various systems with synthetic or natural phytoconstituents to deliver the drugs through skin layers by formulating as a hydrogel, cream, emulgel, etc which are tabulated in Table 1.

In vivo animal models for rheumatoid arthritis
To recognize drug targets for RA and test potential therapeutics animal models of arthritis are widely used. 126They represent an important tool for exploring and evaluating new treatment options and contribute to descriptive and in-vitro studies.Collagen-induced arthritis is the most widely used model as it required both T-cells and B-cells to autologous collagen II for disease manifestation and show immunological and pathological features like human RA. 127The other animal models used are summarized in Table 2.

Patents granted for rheumatoid arthritis
Several patents are been filed worldwide on treatment or diagnostic approaches for RA.Table 3 includes patents filed by various countries like the United States, Europe, Australia, China, etc.

Conclusion
Although there are several drugs available for use in RA treatment, however, none of the present pharmacotherapies have proven to be efficient in treating RA; they have several flaws that limit their efficiency.Drug delivery through the skin can be a promising strategy for the management of RA which has offered enticing possibilities for addressing the low bioavailability of certain oral medications, several side effects, and injection pain and discomfort.This review aimed to give an outline of the use of various lipid nanocarrier systems, including liposomes, The study concluded that Nanoemulgel loaded with Diflunisal ternary complex formulated with xanthum gum significantly enhances in-vitro permeation and showed improved anti-inflammatory activity.these lipid nanocarriers for drug administration through the skin is a valuable and promising approach.The review also highlights various studies conducted, giving a brief overview regarding the use of in-vivo arthritis models.

Figure 2 .
Figure 2. Condition in normal joint and rheumatoid arthritis joint

Figure 3 .
Figure 3. Proposed penetration pathways for lipid carriers to cross skin layers

Figure 4 .
Figure 4. Structural representation of various lipid-based nanocarrier systems

Table 1 .
A study was conducted on lipid nanocarrier delivery systems for drug delivery through the skin

Table 2 .
Commonly used Animal Models for Rheumatoid Arthritis.

Table 3 .
Patents on rheumatoid arthritis