INTRODUCTION:

Rheumatoid arthritis is a chronic inflammatory condition that affects the hands, foot, and joints. The immune system of the body destroys its own tissue, including joints, in rheumatoid arthritis¹. Internal organs are attacked in extreme cases. Joint linings are impacted by rheumatoid arthritis, which results in painful swelling. Joint deformity and bone degradation are brought on by the chronic inflammation brought on by rheumatoid arthritis. Rheumatoid arthritis has no known cure; however, physiotherapy and medication can reduce the disease's course. Rheumatoid arthritis is treated with anti-rheumatic medications (DMARDS)².

Mechanism of rheumatoid arthritis:

Rheumatoid arthritis is an auto immune and inflammatory disease, which means that your immune system attacks healthy cells in your body by mistake, causing inflammation (painful swelling) in the affected parts of the body. RA mainly attacks the joints. Citrullination of cellular proteins, which leads to rheumatoid arthritis, mediated by genetic and environmental factors. These antigens are taken up by antigen-presenting cells and transported to lymph nodes, where they activate CD4 and T cells through the CD28-CD80 pathway and other pathways, leading to the differentiation of synovial CD4 and T cells into T helper cells. The CD4 and T helper cells secrete INF-alpha and lymphotoxin-beta, which activate B cells, which then differentiate into autoantibody-producing plasma cells, which produce the RF factor and anti-ccp cells, which cause synovial damage. T cells also secrete INF-alpha and IL-17, which can form macrophages, which in turn cause synovial inflammation and TNF-alpha, which causes bone avulsions. The treatment to rheumatoid arthritis must block the production of the COX1 and COX2enzymes, TNF-alpha, INF-alpha, and interleukin synthesis, all of which are released by T cells. NSAIDS, corticosteroids, glucocorticoids, DMARDs, biological agents, etc. are among the medications used to treat rheumatoid arthritis that suppress the synthesis of COX1 and COX2³

Stages of treatment that have to be given to Rheumatoid Arthritis⁴:

Rheumatoid arthritis is caused by enzyme activity of proteins, these leads to induce the TNF-α and lymphotoxin-B which increases in rheumatic factor. This leads to inflammation of synovial membrane causing rheumatoid arthritis. Disease modified anti-rheumatic drugs which blocks the T cells to convert to TNF-α cells leads to decrease the disease. The Tcells forms the macrophages and fibroblasts which causes the bone destruction, synovial inflammation, cartilage damage leading to rheumatoid arthritis. Corticosteroids are used to suppress the immune cells (Tcells) and leads to inhibit the mechanism of conversion of T cells to macrophages, decreasing the inflammation. NSAIDS are used to inhibit COX-1 and COX-2 enzymes (which is prone for prostaglandins synthesis leading to inflammation) and decrease the pain.

Alternative treatments for Rheumatoid arthritis:

Rheumatoid arthritis is treated using alternative methods, including:

1. Ayurvedic

2. Naturopathy

3. Chinese medicine

4. Acupuncture

5. Hydration therapy etc.

1. Ayurvedic treatment⁵:

Herbs and dietary supplements are frequently used in Ayurvedic medicine.

· Boswellia serrata⁶:

The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in medicines since time immemorial. Gum- resin extracts of Boswellia serrata have been traditionally used in folk medicines for centuries to treat various chronic inflammatory diseases. The sinous part of Boswellia serrata possess monoterpenes, diterpenes, triterpens, tetraterpens, tetracyclic, triterpenic acids β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-and four major pentacyclic acids responsible for the inhibition of pro-inflammatory enxymes. Out of these four boswellic acids, acetyl-11-keto-β bosewellic acid is most potent inhibitor of 5-lipooxgenese, an enzyme responsible for inflammation.

· Garlic⁷:

Garlic was observed in a murine macrophages cell line infected with Leishmania that advanced glycation end products induced IL-12 production and, in addition, INF-γ and inducible nitric oxide synthase were overexpressed. However, in peripheral blood monocytes, AGE upregulated IL-10 and decreased IL-12 production, which might cause downregulation of proinflammatory cytokines TNF-α, IL-6, INF-γ, and IL-2 by T cells and it acts as negative feedback in the signalling proinflammatory response.

· Ginger:

The activity of Zingiber officinale as an anti-inflammatory agent. Ginger treated cells showed similar inhibition effect to betamethasone by inhibiting production of cytokines IL-1, IL-6, TNF-∝ indicating anti-inflammatory effect. Ginger extract is used for the inhibition of the COX-2 enzyme, 8-paradol and 8-shagol are the major phytoconstituents of ginger significantly reduces the activity of COX-2 enzyme. 8-paradol and 8-shogaol exhibited their effect to COX-2 by lipophilicity of the alkyl side chain, substitution pattern of hydroxy and carbonyl groups on the side chain.

· Castor Oil:

Castor oil is a mix of triglycerides consisting of mainly ricinolein, linoleic acid, oleic acid, palmitic acid, stearic acid, dihydroxy stearic acid and traces of other fatty acid. Ricinoleic acid is the main component of castor oil, ricinus communis L. (family Euphorbiaceous), famous as ‘castor oil plant’, are traditionally used to treat inflammation. Ricinus communis is a tropical flowering plant that is widely cultivated in Asian countries. Studies on Ricinus communis leaves have shown anti-oxidant, antibacterial, hepatoprotective anti-nociceptive effect acts as osteoarthritic, rheumatoid arthritis, cancer

· Tee Tree Oil:

tea tree oil is composed of terpene hydrocarbons, mainly mono terpenes, sesquiterpens and alcholos. Tea tree oil acts as anti-septic, anti-microbial, anti-inflammatory agents. Anti-inflammatory activity of tea tree oil is inhibiting the production of inflammatory mediator tumor necrosis factor [TNF-∝], interleukins-1β, IL-10. Terpenes present in tea tree oil diminish the production of TNF-∝, IL-β, IL-10 by lipopolysaccharide activated monocytes.

· Oregano Oil:

oregano oil is composed of γ-terpenes, linalool, carvacrol, thymol etc. Terpenes such as thymol and carvacrol acetate reduces the production of tumor necrosis factor-∝[TNF-∝], interleukin-1β. Oregano oil acts as anti-inflammatory agent and reduces the COX-2 mRNA expression and reduces the rheumatoid arthritis.

2. Naturopathy⁸:

The musculoskeletal system as a whole is much improved by naturopathy treatment for arthritis and other musculoskeletal conditions. Some Nature Cure offers naturopathic treatment for gout and other musculoskeletal conditions. Muscles, tendons, ligaments, nerves, discs, joints and other elements of the musculoskeletal system might malfunction for many reasons.

Therapies include naturopathy.

· Massage:

· mud treatment

· heliotherapy

· hydrotherapy

· yoga

3. Chinese Treatment⁹:

Rheumatoid arthritis is cured by Chinese medicine. Rheumatoid arthritis can be treated using Chinese herbs. Rheumatoid arthritis has been effectively treated with traditional Chinese medicine (TCM). A TCM treatment plan for RA uses the Qingre Huoxue decoction (QRHXD) and Qingre Huoxue external preparation (QRHXEP). Few studies have examined the good and safety QRHXD vs traditional synthetic disease-modifying antirheumatic medications (csDMARDs) are used for active RA to date. Chinese patients with active RA participated in a multicenter, double-blind, randomized controlled experiment to evaluate this.

4. Acupunture¹⁰:

A form of Chinese traditional medicine with a long history is acupuncture. Fine needles are inserted into pressure points on the body in various locations by acupuncturists. It is claimed that this procedure will relax the body and improve blood flow. Good energy is said to flow through "qi" (pronounce it "chee") in Chinese culture. It is obstructed by something called "bi." The needles release the bi and allow the qi to expand. Endorphins are said to be released throughout the treatment. These are organic hormones that lessen pain perception. Acupuncture has the ability to alleviate pain, it is not likely to considerably reduce inflammation. The most of people either don't feel the needles or only experience a very slight prick. According to reports, the arrows or needles are as thin as a human hair strand.

Acupuncture is sometimes used for the treatment of anxiety, migraines and back pain in addition to joint discomfort. Inflammation in the joints or upper neck caused by rheumatoid arthritis (RA) may result in pain there. Acupuncture may be an option for those who suffer from the illness to find relief. If they want to avoid needles, some people choose acupressure as an alternative. Deep pressure is applied to the same pressure points during acupressure.

5. Hydration therapy:

Exercise you do in a pool is called hydrotherapy, often known as water or aquatic treatment. The depth of the water should be between your waist and shoulders and it should be warm. You've probably seen a particular form of hydrotherapy if you've ever attended a water aerobics class at a recreation centre. Typically, a personal trainer or fitness professional is in charge of this type of class. Under the direction of a physio therapist, then you can also practise hydrotherapy. In this situation, you might utilise a treadmill or stationary cycle while swimming in the pool, Hydrotherapy is used by patients to cure musculoskeletal disorders, enhance circulation, induce relaxation and alleviate anxiety, pain and depression in addition to overall fitness.

Novel approaches used for rheumatoid arthritis¹¹:

· Nano particles

· Dendrimes

· Lipogleosomes

· Emulgels

· Microemulsions

· Micelles

· Liposomes

· Niosomes

· Transferosomes

· Ethosomes

· Aspasomes

· Ufasomes

Rheumatoid arthritis novel dosage forms:

Nanoparticle¹²:

Rheumatoid arthritis is treated with nanoparticle systems, which are mostly based on polymers. To extend the time that a medicine is in use and to control how rapidly it is delivered, several scientists use PLGA nanoparticles. It has been discovered that PLGA Betamethasone systems are significantly more effective at reducing the inflamed condition when supplied intravenously to arthritic rats and mice. In adjuvant induced arthritis (AIA) rats showed that a nanogel ointment containing solid ketoprofen nanoparticles with a mean particle size of 83 nm had anti-inflammatory benefits. For the treatment of RA, FDA used both gold and metallic nanoparticles. However, it mostly favours metallic nanoparticles for passive targeting in RA.

Dendrimers¹³:

Dendrimers are multifunctional macromolecules with regularly spaced branches, commonly referred to as cascade molecules. Its globular form and uniquely branching structure produce a large number of surface groups it can be altered to serve as a template to drug delivery and so boost drug loading. The therapeutic effects of dendrimers have been investigated during the production of folic acid and methotrexate-conjugated poly (amid amine) dendrimers to the exact targeted activation of macrophages using collagen induced arthritis CIA (complete abrogation) mice. Methotrexate combined with amino groups of dendrimers which is exposed to blood circulation before being injected into the infected regions resulted in low body weight in CIA mice because of its more cationic charge density.

Niosomes¹⁴

Niosomes can be defined as microscopic lamellar molecule formed by the mixture of cholesterol, non ionic surfactant and charge-inducing agent. These molecules comprise both hydrophilic and hydrophobic moites interacting with herbal constituents of varying solubilites, Noisome loaded with drugs for dermal application are aimed to preferentially show interaction with the inflamed tissue without exerting an immediate action. Adsorption and fusion of nio some on the surface of skin leading to high thermodynamic activity gradient of drug at the interface which is the driving force for permeation of lipophilic drug.

Emulgels¹⁵:

The PH, stability, in-vitro permeation, and skin irritation test are done to generate emulgels. By applying the carrageenan-induced paw edema technique on Wistar rats. Studies were done to assess the formulations' ability to reduce inflammation both in vivo and in vitro. The scientists discovered that nimesulide emulgels had a permeation rate of 54%, indicating better drug release without causing skin inflammation, although to the promoted nimesulide gel, which has a penetration rate of 44% at 30 minutes. Additionally, compared to commercial formulations, it has 86% medication loading capacity, which is appropriate for having a potent anti-inflammatory effect. Emulgels function well because they hasten the release of drugs at desired location.

Microemulsion¹⁶:

The micro emulsion was applied topically and colloidal dispersions made thermodynamically stable systems are applied to the areas of inflammation that are impacted. Its averages of the cumulative percentages are extremely high, and its particle sizes range from 10 to 100 nm. Researchers claimed that in comparison to the drug's traditional cream and suspension, the micro-emulsion version of tenoxicam showed a greater cumulative percent. The oral formulation of tenoxicam (TNX), which is a substance that was made with Tween 80, ethanol, and oleic acid that is intended to lessen inflammation. Tenoxicam can now be applied topically to treat a number of inflammatory conditions with improved formulations. It reduces inflammation better and has higher cumulative percentage values and due to its low viscosity, a gelling agent is required.

Micelles¹⁷:

The drug delivery method for treating RA uses micelles. Since micelle stability is an important factor to consider. The stability and solubility were tested, they were made using PEG phospholipids, which are frequently used to encapsulate medications. Gastrointestinal vasoactive peptide which activates Synovial macrophage is mostly brought on by receptor overexpression. Micelles formulated by adding drug, phospholipid these preparations are administered to arthritis-affected rats and have a higher ability to reduce inflammation. Similar to this, when given to arthritis-prone rats, camptothecin micelles reduced inflammation in contrast to free camptothecin.

Liposomes¹⁸:

In an effort to increase the effectiveness of RA conditions, many liposomal systems that were intravenously administered and collected in the synovial membrane of the RA patient's joints. These included cationic liposomes, immunoliposomes, liposomes with superoxide dismutase, lactoferrin, clondronate-loaded liposomes and stealth liposomes. Rats prone to arthritis are given cholesterol-based liposomes that have been enclosed with clondronate. These remedies lessen inflammation and help to stop bone resorption. Liposome clondronate is used to reduce macrophages in the synovium. The generated liposome lessens toxicity and joint inflammation in contrast of free medications. Numerous benefits of liposomes include increased therapeutic index and effectiveness as well as reduced toxicity of encapsulated drug.

Aspasomes¹⁹:

Ascrobyl palmitate, combined with cholesterol and charged lipid, forms multilayer vesicles called aspasomes that are used in drug encapsulation. Methotrexate aspasomes are commercially accessible and used to treat rheumatoid arthritis.

Invasomes ²⁰:

As opposed to other typical vesicles, which are formed of phospholipids, ethanol, and a terpene or a blend of terpenes in their structure, invasomes are a novel vesicular system that play a significant role in improving the transdermal penetration of active pharmacological molecules.These ingredients had good penetration qualities and served as an effective transdermal penetrator. Invasomes are soft liposomal vesicles that contain minute amounts of ethanol and terpenes and act as possible carriers with enhanced skin penetration.

Transferosomes²¹:

Transdermal distribution is excellent for transferosomes because they contain complex vesicles processing on aqua cores encircled by complex of bilayer of lipids. Transferosomes are made of a natural amphiphilic lipid and a biocompatible surfactant. Other names for transferosomes include elastic vesicles, ultradeformable vesicles and ultradeformable liposomes. Due to the flexibility of skin, transfersomes can fit through pores that are many times smaller than its own. As a result, when applied non-occlusively, they can improve skin penetration.

Ufasomes ²²:

The vesicles of unsaturated fatty acids, or ufasomes are confined to a pH range between 7-9 and closed lipid bilayers of suspension made by fatty acids and their ionized species. Ufasomes with lipid carriers that bind to the skin's surface and permit lipid exchange across the stratum corneum's outermost layers are one potential drug delivery method. Ufasomes, is combination to liposomes and niosomes, have been developed for their ability to deliver medicines, proteins, peptides, and other substances topically.

Updates on research available in novel drug delivery systems for rheumatoid arthritis

Carrier type	Drug or products	Inference	Reference
Solid lipid Nanoparticle	Methotrexate	A cancer and rheumatoid arthritis medication is methotrexate. A micro-emulsification solidification process was used to create the SLN dispersions with MTX, stearic acid, and soy lecithin in the ratios of 1:4:1, 1:4:1.5, and 1:4:2, sodium taurodeoxycholate, and distilled water. MTX-SLN particles with MTX-Stearic acid-Soya lecithin—1:4:2—were created, and the results show that they have an average size of 270 nm and a 51.3% drug entrapment. It took until the 15th hour to achieve the in-vitro release. According to the pharmacokinetic analysis, MTX solution had a shorter half-life and greater MRT than SLNs. These findings unequivocally demonstrate that SLNs are a promising sustained release medication targeting method and that MTX-SLNPs increase regulatory T cells while decreasing pathogenic Th17 cells and pro-inflammatory compounds like TNF. These findings suggest the potential of MTX-NPs to treat the arthritis.	23
Ethosomes	Ibuprofen	Ibuprofen ethosomal gel was prepared by using thin film hydtration method it consist of 10% drug, 2.5% phospholipid, ethanol and water is used, in in-vivo studies the transdermal application of this ibuprofen ethosomal gel shows the plasma concentrations were achieved half-n-hour and reached a Cmax of 74.11±18.52 g/ml after 2 hours.the oral administred values are less when compared transdermal and these gel was tested on rats to see the antipyretic activity and the obtained values indicating the ethosomal gel of ibuprofen's safety.	24
Nano emulsion	ibuprofen	Ibuprofen nano emulasion was prepared by high speed homozenation method Nanoemulsions containing 2%ibuprofen, various oil:surfactant ratios (10:90, 20:80 and 30:70) and 80% of water were selected from the ternary system of PKOE/Cremophor EL/water and prepared by the phase inversion composition (PIC) method. Ibuprofen 2% PKOE nanoemulsions were effectively created. We produced droplet sizes below 50 nm and polydispersity indices below 0.2. stability of nanoemulsions system was improved by the adding of 2% ibuprofen. And it is easily penetrate through human skin.	25
Liposomes	celecoxib	liposomes are formulated by thin film method. Phosphatidylcholine and cholesterol were dissolved in the chloroform-methanol (1:1) and 5 mg celecoxib and 10ml of ethanol was used. The vesicles were obtained and liposomes with this concentration gives high entrapment efficiency.	26
Aspasomes	methotrexate	Methotrexate's rheumatoid arthritis activity and ascorbyl palmitate's antioxidant action was assessed. Ascorbic acid-6-palmitate, cholesterol, dicetyl phosphate( 45:45:10) choloroform and methanol is used in preparation.The antioxidant potency of aspasome was much better than that of ascorbic acid and skin permeation enhancing property indicating a promising future for aspasome in transdermal route.	27
Transferosomes	imatinib	Imatinib-loaded transfersomes (imatinib-TFS) were prepared by the film-hydration method. The 5mg imatinib, 20-25mg soyalecithin(4:1,7:1,10:1), tween 80 and span 80 is used in the formulation, in-vitro drug release studies and ex-vivo skin permeations are done. The optimized imatinib-TFS formulation incorporated into the Carbopol 940 gel showed enhanced flux of imatinib through the rat skin as compared to imatinib-gel. Animal studies also exhibited improved paw inflammation in the group treated with imatinib-TFS-Gel, gives the good permeation results.	28
Ufasomes	Methotrxate	Methotrexate, oleic acid, span80 are used in the preparation of fatty acid vesicles by thin film hydration method, 9:1,8:2,7:3,6:4,5:5 ratios of oelic acid and methotrexate is used and incorporated in to the carbapol gel, in-vitro drug release studies are done, these ufasomes obtained using oleic acid, a safe surfactant widely, applied nonocclusively, improve in vitro skin delivery of MTX compared to either aqueous solution or normal liposomes. The enhanced accumulation of MTX within the skin might help to optimize targeting of this drug, modern topical application of MTX is used in the treatment of RA.	29

REFERENCE

1. Firestein GS. Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis Rheum. 1996; 39(11): 1781-90. doi: 10.1002/art.1780391103.

2. Spandana K, Varun Teja Chary, Shivani. M, Rheumatoid arthritis, Research Journal of Pharmaceutical Dosage Forms and Technology, 2019; Vol. 11(02), doi: 10.5958/0975-4377.2019.00021.1.

3. D Kilimozhi, V Parthasarathy and N Amuthavalli, Effect of Delonix elata on Adjuvant Induced Arthritis in Rats - A Radiographic Densitometric Analysis, Research J. Pharmacology and Pharmacodynamics 2009; 1(1): 25-30.

4. Siddhesh Gosavi, Pranali Joshi, Vidur Bhogate, Sairaj Gawade, Pooja Sangelkar, Shraddha Kanekar, Comparative Study on Treatment of Rheumatoid Arthritis, 2021; Vol. 11(01), doi: 10.5958/2231-5713.2021.00002.7.

5. Park J., and Ernst, E. Ayurvedic medicine for rheumatoid arthritis: A systematic review. Seminars in Arthritis and Rheumatism,2005;34(5), 705–713. doi:10.1016/j.semarthrit.2004.11.005.

6. Trapti Rastogi, Deepali S Ghorpade, UA Deokate and SS Khadabadi, Studies on Antimicrobial Activity of Boswellia serrata, Moringa oleifera and Vitex negundo: A comparison, Research Journal of Pharmacognosy and Phytochemistry.2009; 1(1), 75-77.

7. Sankalp Goswami, Prachi Sharma and Yogesh Shivhare, Phytopharmaceuticals as Cosmetic Agents: A Review, Research J. Topical and Cosmetic, 2011;Sci. 2(1): Jan. – June,page 11-13.

8. Dunn, J. M., and Wilkinson, J. M. Naturopathic management of rheumatoid arthritis. Modern Rheumatology,2005;15(2), 87–90. doi:10.3109/pl00021706.

9. Zhang, P., Li, J., Han, Y., Wei Yu, X., and Qin, L. Traditional Chinese medicine in the treatment of rheumatoid arthritis: a general review. Rheumatology International, 2010;30(6), 713–718. doi:10.1007/s00296-010-1370-0

10. Casimiro, L., Barnsley, L., Brosseau, L., Milne, S., Robinson, V., Tugwell, P., and Wells, G. Acupuncture and electroacupuncture for the treatment of RA. The Cochrane Database of Systematic Reviews. 2002; doi:10.1002/14651858.cd003788.

11. Kanchan R Pagar, Sarika V Khandbahale, A Review on Novel Drug Delivery System: A Recent Trend, 2019; Vol. 09(02), DOI: 10.5958/2231-5713.2019.00023.0.

12. Sarika V. Khandbahale1, Prof.Dr.R.B.Saudagar, Nanoparticle- A Review, 2017;Vol. 7(3), doi: 10.5958/2231-5659.2017.00026.

13. Bosch, X.Dendrimers To Treat Rheumatoid Arthritis. ACS Nano,2011; 5(9), 6779–6785. doi:10.1021/nn203190x.

14. Shashikant Chandrakar and Swarnalata Saraf, Niosome - A Versatile Tool in Transdermal Drug Delivery, Pharmaceutical Dosage Forms and Technology. 2009; vol 1(1), 01-04.

15. Sharma, V., Nayak, S. K., Paul, S. R., Choudhary, B., Ray, S. S., and Pal, K, Emulgels. Polymeric Gels,2018; 251–264. doi:10.1016/b978-0-08-102179-8.00009-0.

16. Chen, H., Chang, X., Weng, T., Zhao, X., Gao, Z., Yang, Y., … Yang, X. A study of microemulsion systems for transdermal delivery of triptolide. Journal of Controlled Release,2004, 98(3), 427–436. doi:10.1016/j.jconrel.2004.06.001.

17. Chunhong Li, Hanmei Li, Qin Wang, Meiling Zhou, Man Li, Tao Gong, Zhirong Zhang, Xun Sun pH-sensitive polymeric micelles for targeted delivery to inflamed joints,, 2017;vol 246,133–141, https://doi.org/10.1016/j.jconrel.2016.12.027.

18. Raghavendra Babu N, Padmavathi.Y, Priyanka.S, Ravi Kumar.P, Development of Sensitive Spectrophotometric Method for Analysis of Darifenacin Hydrobromide Liposomes in Rat Plasma, 2017; Vol. 7(1), doi: 10.5958/2231-5675.2017.00008.4.

19. Tahani Saeedi, Hadil Faris Alotaibi, Polina Prokopovich, Polymer colloids as drug delivery systems for the treatment of arthritis,2020; vol 285, https://doi.org/10.1016/j.cis.2020.102273.

20. Shweta Jain, Shalini Tripathi, Pushpendra Kumar Tripathi, Invasomes: Potential vesicular systems for transdermal delivery of drug molecules, 2021; vol 61, https://doi.org/10.1016/j.jddst.2020.102166.

21. Chando Anita, Momin Munira, Quadros Mural, Lalka Shaily, Topical nanocarriers for management of Rheumatoid Arthritis: A review, 2021; vol 141, https://doi.org/10.1016/j.biopha.2021.111880.

22. Lakshmi,V Sree, Manohar, R Deepa, Mathan, S, Dharan, Shaiju S, Ufasomes: A Potential Vesicular Carrier System,2020; Vol. 12(10), 1332-1335.

23. Ruckmani K., Sivakumar M., and Ganeshkumar, P. A.Methotrexate Loaded Solid Lipid Nanoparticles (SLN) for Effective Treatment of Carcinoma. Journal of Nanoscience and Nanotechnology,2006; 6(9), 2991–2995. doi:10.1166/jnn.2006.457.

24. Margarita Shumilov, Ronny Bercovich, Shaher Duchi, Denzie Ainbinder, and Elka Touitou, ibuprofen transdermal ethosomal gel: characterization and efficiency in animal model, 2010; vol.6, 569-576.

25. Norazlinaliza salim, Maria Jose DGarcia-Celma, Elvaira Escribano, Jordi Nolla, Mertixell Llinas, Mahiran Basri, Conxita Solans, Tharwat F Tadros, formulation of nanoemulsion containing inuprofen by PIC method for topical delivery 2018; S172-S179.

26. Eskandar Moghimipour, Anayatollah Salami and Mahsa Monjezi, Formulation and Evaluation of Liposomes for Transdermal Delivery of Celecoxib 2015 Feb; 10(1): e17653. doi: 10.17795/jjnpp-17653.

27. Saikat Ghosh,Biswajit Mukherjee, Shreyasi Chaudhuri, Tanushree Roy, Alankar Mukherjee, and Soma Sengupta, Methotrexate Aspasomes Against Rheumatoid Arthritis: Optimized Hydrogel Loaded Liposomal Formulation with In Vivo Evaluation in Wistar Rats 2017; DOI: 10.1208/s12249-017-0939-2.

28. Somayeh Taymori, Valiollah Hajishemi, majid Tabbakhian and Massoud Torkashvand. Preparation and Evaluation of Imatinib Loaded Transfersomal gel for the Treatment of Rheumatoid Arthritis 2021; 20(4): 33–46. doi: 10.22037/ijpr.2021.115481.15394.

29. Sharma, A., and Arora, S. Formulation and In Vitro Evaluation of Ufasomes for Dermal Administration of Methotrexate. ISRN Pharmaceutics, 2012;1–8. doi:10.5402/2012/873653.

Received on 12.06.2023 Modified on 07.08.2023

Research J. Science and Tech. 2023; 15(4):225-232.

DOI: 10.52711/2349-2988.2023.00039