Development of methotrexate-loaded cubosomes with improved skin permeation for the topical treatment of rheumatoid arthritis

Applied Nanoscience - Tập 9 - Trang 1781-1796 - 2019
Kumar Janakiraman1, Venkateshwaran Krishnaswami1, Vaidevi Sethuraman1, Vijaya Rajendran1, Ruckmani Kandasamy1
1Centre for Excellence in Nanobio Translational Research (CENTRE), Department of Pharmaceutical Technology, University College of Engineering, Anna University, Tiruchirapalli, India

Tóm tắt

Methotrexate-loaded cubosomes (MTCs) were developed to provide relief from pain/joint stiffness, by affording stable methotrexate concentration at the targeting sites through sustained pattern by non-invasive skin route with enhanced permeation upon skin, for the treatment of rheumatoid arthritis. Non-ionic surfactant poloxamer 188 works to enhance the permeation of methotrexate. The results of FT-IR analysis indicates the compatibility nature of methotrexate (MT), poloxamer 188 and cetyl palmitate selected for the formulation. Different ratios of poloxamer 188 and cetyl palmitate were utilized to formulate using emulsification process. The selected MTCs showed particle size of around 626.13 ± 14.15 nm with charge of around − 6.29 ± 1.07 mV with cubic morphology. The encapsulation efficiency of MTCs was found to be 92.94 ± 0.9%. The in vitro MT release from MTCs conducted for 12 h revealed a sustained release pattern. The non-crystalline nature of MTCs was confirmed by XRD analysis. The in vitro anti-inflammatory effect of MTCs showed enhanced anti-inflammatory effect 11.9% compared to diclofenac sodium 10.4%. Ex vivo skin permeation analysis in excised skin of wistar albino rats showed 2.50 ± 0.3 ng of MT permeation within 2 h followed by 8.80 ± 5.2 ng within 12 h without any skin irritation. In addition, histopathological evaluation supported with fluorescent microscopic analysis of FITC-labeled MTCs confirmed the superior permeation enhancement of MTCs. The thermal stimulus time (TST) as studied by rat tail flick method indicates the enhancement of TST in case of MTCs (5.63 ± 0.21 s) compared to standard diclofenac gel (2.70 ± 0.20 s)/blank formulation (2.45 ± 0.23 s), which indicates the superior analgesic effect of the developed MTCs. The inflammed paw thicknesses were measured for CFA-induced arthritic rats which get reduced from day 1 (1.47 cm) to (1.03 cm) day 15 for MTCs-treated groups that were imaged by animal imaging system. Thus, the MTCs may act as a promising system for the treatment of RA upon topical application.

Tài liệu tham khảo

Abitha MH, Mathew F (2015) Formulation and evaluation of nanoparticles as sustained release topical formulation containing non-steroidal anti-inflammatory drug. World J Clin Pharmacol Micrbiol Toxicol 1(3):35–42 Ahmad A, Abuzinadah MF, Alkreathy HM, Banaganapalli B, Mujeeb M (2018) Ursolic acid rich Ocimum sanctum L. leaf extract loaded nanostructured lipid carriers ameliorate adjuvant induced arthritis in rats by inhibition of COX-1, COX-2, TNF-α and IL-1: pharmacological and docking studies. PLoS One 13(3):e0193451 Amodwala S, Kumar P, Thakkar HP (2017) Statistically optimized fast dissolving microneedle transdermal patch of meloxicam: a patient friendly approach to manage arthritis. Eur J Pharm Sci 104:114–123 Azizi M, Esmaeili F, Partoazar A, Ejtemaei Mehr S, Amani A (2017) Efficacy of nano and microemulsion-based topical gels in delivery of ibuprofen: an in-vivo study. J Microencapsul 34:195–202 Azmi ID, Wu L, Wibroe PP, Nilsson C, Ostergaard J, Sturup S, Gammelgaard B, Urtti A, Moghimi SM, Yaghmur A (2015) Modulatory effect of human plasma on the internal nanostructure and size characteristics of liquid-crystalline nanocarriers. Langmuir 31(18):5042–5049 Bhalekar MR, Upadhaya PG, Madgulkar AR (2016) Fabrication and efficacy evaluation of chloroquine nanoparticles in CFA induced arthritic rats using TNF-α Elisa. Eur J Pharm Sci 84:1–8 Bhaskar K, Anbu J, Ravichandiran V, Venkateswarlu V, Rao YM (2009) Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in-vitro, ex-vivo and in-vivo studies. Lipids Health Dis 8:6 Bhoyar N, Giri TK, Tripathi DK, Alexander A, Azuddin (2012) Recent advances in novel drug delivery system through gels: review. J Biol Pharm Allied Sci 2(2):21–39 Bodratti AM, Alexandridis P (2018) Formulation of poloxamers for drug delivery. J Funct Biomater 9(1):11 Boilard E, Blanco P, Nigrovic PA (2012) Platelets: active players in the pathogenesis of arthritis and SLE. Nat Rev Rheumatol 8(9):534–542 Bonabello A, Galmozzi MR, Canaparo R, Isaia GC, Serpe L, Muntoni E, Zara GP (2003) Dexibuprofen (S(+)-isomer ibuprofen) reduces gastric damage and improves analgesic and anti-inflammatory effects in rodents. Anesth Analg 97:402–408 Chopra A, Shankar S (2012) Biosimilar DMARD in rheumatology: a general perspective with focus on India. Indian J Rheumatol 7(2):89–96 Choudhary N, Bhatt LK, Prabhavalkar KS (2018) Experimental animal models for rheumatoid arthritis. Immunopharmacol Immunotoxicol 40(3):193–200 Chuang SY, Lin CH, Huang TH, Fang JY (2018) Lipid-based nanoparticles as a potential delivery approach in the treatment of rheumatoid arthritis. Nanomaterials 8:42 Ci L, Huanga Z, Liu Y, Liu Z, Wei G, Lu W (2017) Amino-functionalized poloxamer 407 with both mucoadhesive and thermo sensitive properties: preparation, characterization and application in a vaginal drug delivery system. Acta Pharmaceutica Sinica B 7(5):593–602 Cronstein BN (1996) Molecular therapeutics. Arthritis Rheum 39(12):1951–1960 Cronstein B (2010) How does methotrexate suppress inflammation? Clin Exp Rheumatol 28(61):S21–S23 Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH (2001) Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 60:729–735 Dave V, Yadav RB, Kushwaha K, Yadav S, Sharma S, Agrawal U (2017) Lipid-polymer hybrid nanoparticles: development & statistical optimization of norfloxacin for topical drug delivery system. Bioact Mater 2:269–280 De Lathouder S, Gerards AH, de Groot ER, Valkhof MG, Dijkmans BA, Aarden LA (2004) Bioassay for detection of methotrexate in serum. Scand J Rheumatol 33:167–173 Dhanka M, Shetty C, Srivastava R (2017) Injectable methotrexate loaded polycaprolactone microspheres: physicochemical characterization, biocompatibility, and hemocompatibility evaluation. ‎Mater Sci Eng C 81:542–550 Duan W, Li H (2018) Combination of NF-kB targeted siRNA and methotrexate in a hybrid nanocarrier towards the effective treatment in rheumatoid arthritis. J Nanobiotechnol 16:58 Ekambaram S, Perumal SS, Subramanian V (2010) Evaluation of antiarthritic activity of Strychnos potatorum Linn seeds in Freund’s adjuvant induced arthritic rat model. BMC Complement Altern Med 10:1–9 Elmowafy M, Samy A, Abdelaziz AE, Shalaby K, Salama A, Raslan MA, Abdelgawad MA (2017) Polymeric nanoparticles based topical gel of poorly soluble drug: formulation, ex-vivo. and in-vivo evaluation. BJBAS 6(2):184–191 El-Sayed MM, Hussein AK, Sarhan HA, Mansour HF (2017) Flurbiprofen-loaded niosomes-in-gel system improves the ocular bioavailability of Flurbiprofen in the aqueous humor. Drug Dev Ind Pharm 43(6):902–910 Escandell JM, Recio MC, Manez S, Giner RM, Cerda Nicolas M, Rios JL (2007) Cucurbitacin reduces the inflammation and bone damage associated with adjuvant arthritis in lewis rats by suppression of tumor necrosis factor-in T lymphocytes and macrophages. J Pharmacol Exp Ther 320(2):581–590 Favalli EG, Biggioggero M, Crotti C, Becciolini A, Raimondo MG, Meroni PL (2018) Sex and management of rheumatoid arthritis. Clin Rev Allergy Immunol 55(156):1–13 Ferreira M, Silva E, Barreiros L, Segundo MA, Costa Lima SA, Reis S (2016) Methotrexate loaded lipid nanoparticles for topical management of skin-related diseases: design, characterization and skin permeation potential. Int J Pharm 512(1):14–21 Garg NK, Singh B, Tyagi RK, Sharma G, Katare OP (2016) Effective transdermal delivery of methotrexate through nanostructured lipid carriers in an experimentally induced arthritis model. Colloids Surf B 147:17–24 Gerards AH, de Lathouder S, de Groot ER, Dijkmans BAC, Aarden LA (2003) Inhibition of cytokine production by methotrexate. Rheumatology 42:1189–1196 Ghosh S, Mukherjee B, Chaudhuri S, Roy T, Mukherjee A, Sengupta S (2017) Methotrexate aspasomes against rheumatoid arthritis: optimized hydrogel loaded liposomal formulation with in-vivo evaluation in wistar rats. AAPS PharmSciTech 19(3):1320–1336 Gupta AK, Parasar D, Sagar A, Choudhary V, Chopra BS, Garg R, Ashish, Khatri N (2015) Analgesic and anti-inflammatory properties of gelsolin in acetic acid induced writhing, tail immersion and carrageenan induced paw edema in mice. PLoS One 10(8):e0135558 Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe D, Bombardier C (2016) Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged cochrane systematic review and network meta-analysis. BMJ 353:i1777 Hescot S, Amazit L, Lhomme M, Travers S, DuBow A, Battini S, Boulate G, Namer IJ, Lombes A, Kontush A, Imperiale A, Baudin E, Lombes M (2017) Identifying mitotane-induced mitochondria-associated membranes dysfunctions: metabolomic and lipidomic approaches. Oncotarget 8(66):109924–109940 Jenning V, Gohla S (2000) Comparison of wax and glyceride solid lipid nanoparticles. Int J Pharm 196:219–222 Kang Q, Liu J, Zhao Y, Liu X, Liu XY, Wang YJ, Mo NL, Wu Q (2018) Transdermal delivery system of nanostructured lipid carriers loaded with Celastrol and Indomethacin: optimization, characterization and efficacy evaluation for rheumatoid arthritis. Artif Cells Nanomed Biotech. https://doi.org/10.1080/21691401.2018.1503599 Kapral T, Stamm T, Machold KP, Montag K, Smolen JS, Aletaha D (2006) Methotrexate in rheumatoid arthritis is frequently effective, even if re-employed after a previous failure. Arthritis Res Ther 8:R46 Kaur A, Bhoop BS, Chhibber S, Sharma G, Gondil VS, Katare OP (2017) Supra molecular nano-engineered lipidic carriers based on diflunisal-phospholipid complex for transdermal delivery: QbD based optimization, characterization and preclinical investigations for management of rheumatoid arthritis. Int J Pharm 533(1):206–224 Khurana S, Bedi PM, Jain NK (2013) Preparation and evaluation of solid lipid nanoparticles based nanogel for dermal delivery of meloxicam. Chem Phys Lipids 175:65–72 Kimura Y, Shibata M, Tamada M, Ozaki N, Arai K (2017) Pharmacokinetics of morphine in rats with adjuvant-induced arthritis. In Vivo 31(5):811–817 Kraan MC, Smeets TJ, van Loon MJ, Breedveld FC, Dijkmans BA, Tak PP (2004) Differential effects of leflunomide and methotrexate on cytokine production in rheumatoid arthritis. Ann Rheum Dis 63:1056–1061 Lee SJ, Lee A, Hwang SR, Park JS, Jang J, Huh MS, Jo DG, Yoon SY, Byun Y, Kim SH, Kwon IC, Youn I, Kim K (2014) TNF-α gene silencing using polymerized siRNA/thiolated glycol chitosan nanoparticles for rheumatoid arthritis. ASGCT 22(3):397–408 Levy RA, de Jesus GR, de Jesus NR, Klumb EM (2016) Critical review of the current recommendations for the treatment of systemic inflammatory rheumatic diseases during pregnancy and lactation. Autoimmun Rev 15(10):955–963 Mahajan TD, Mikuls TR (2018) Recent advances in the treatment of rheumatoid arthritis. Curr Opin Rheumatol 30(3):231–237 Mahdi HJ, Khan NAK, Asmawi MZB, Mahmud R, A/L Murugaiyah V (2018) In-vivo anti-arthritic and anti-nociceptive effects of ethanol extract of Moringa oleifera leaves on complete Freund’s adjuvant (CFA)-induced arthritis in rats. Integr Med Res 7:85–94 Majithia V, Geraci SA (2007) Rheumatoid arthritis: diagnosis and management. Am J Med 120:936–939 McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7(6):429–442 Nagai N, Yoshioka C, Ito Y (2015) Topical therapies for rheumatoid arthritis by gel oinments containing Indomethacin nanoparticles in adjuvant-induced arthritis rat. J Oleo Sci 64(3):337–346 Pandey A, Mittal A, Chauhan N, Alam S (2014) Role of surfactants as penetration enhancer in transdermal drug delivery system. J Mol Pharm Org Process Res 2(2):113 Patel J, Patel B, Banwait H, Parmar K, Patel M (2011) Formulation and evaluation of topical aceclofenac gel using different gelling agent. IJDDR 3(1):156–164 Patel D, Dasgupta S, Dey S, Ramani YR, Ray S, Mazumder B (2012) Nanostructured lipid carriers (NLC)-based gel for the topical delivery of aceclofenac: preparation, characterization, and in-vivo evaluation. Sci Pharm 80:749–764 Peng X, Zhou Y, Han K, Qin L, Dian L, Li G, Pan X, Wu C (2015) Characterization of cubosomes as a targeted and sustained transdermal delivery system for capsaicin. Drug Des Dev Ther 9:4209–4218 Peresin MS, Habibi Y, Zoppe JO, Pawlak JJ, Rojas OJ (2010) Nanofiber composites of polyvinyl alcohol and cellulose nanocrystals: manufacture and characterization. Biomacromolecules 11(3):674–681 Prey S, Paul C (2009) Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review. BJD 160:622–628 Rein P, Mueller RB (2017) Treatment with biologicals in rheumatoid arthritis: an overview. Rheumatol Ther 4(2):247–261 Rosenblatt KM, Bunjes H (2017) Evaluation of the drug loading capacity of different lipid nanoparticle dispersions by passive drug loading. Eur J Pharm Biopharm 117:49–59 Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, Elkins-Melton M, Outman R, Allison JJ, Suarez Almazor M, Bridges SL, Chatham WW, Hochberg M, Maclean C, Mikuls T, Moreland LW, O’dell J, Turkiewicz AM, Furst DE (2008) American college of rheumatology 2008 recommendations for the use of non-biologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 59(6):762–784 Salah S, Mahmoud AA, Kamel AO (2017) Etodolac transdermal cubosomes for the treatment of rheumatoid arthritis: ex-vivo permeation and in-vivo pharmacokinetic studies. Drug Deliv 24(1):846–856 Severino P, Souto EB, Pinho SC, Santana MH (2013) Hydrophilic coating of mitotane-loaded lipid nanoparticles: preliminary studies for mucosal adhesion. Pharm Dev Technol 18(3):577–581 Shah RM, Eldridge DS, Palombo EA, Harding IH (2016) Microwave-assisted formulation of solid lipid nanoparticles loaded with non-steroidal anti-inflammatory drugs. Int J Pharm 515(1–2):543–554 Shelke SJ, Shinkar DM, Saudagar RB (2013) Topical gel: a novel approach for development of topical drug delivery system. IJPT 5(3):2739–2763 Shin SC, Cho CW, Oh IJ (2001) Effects of non-ionic surfactants as permeation enhancers towards piroxicam from the poloxamer gel through rat skins. Int J Pharm 222:199–203 Shinde CG, Venkatesh MP, Pramod Kumar TM, Shivakumar HG (2014) Methotrexate: a gold standard for treatment of rheumatoid arthritis. J Pain Palliat Care Pharmacother 28:351–358 Sierra EE, Brigle KE, Spinella MJ, Goldman D (1997) pH dependence of methotrexate transport by the reduced folate carrier and the folate carrier and the folate receptor in L1210 leukemia cells. Biochem Pharmacol 53:223–231 Sivaraman A, Banga AK (2017) Novel in situ forming hydrogel microneedles for transdermal drug delivery. Drug Deliv Transl Res 7(1):16–26 Smith EW, Maibach HI (2005) Percutaneous penetration enhancers. CRC Press, Boca Raton Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, Emery P, Gaujoux-Viala C, Gossec L, Nam J, Ramiro S, Winthrop K, de Wit M, Aletaha D, Betteridge N, Bijlsma JW, Boers M, Buttgereit F, Combe B, Cutolo M, Damjanov N, Hazes JM, Kouloumas M, Kvien TK, Mariette X, Pavelka K, van Riel PL, Rubbert-Roth A, Scholte-Voshaar M, Scott DL, Sokka-Isler T, Wong JB, van der Heijde D (2010) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 69:964–975 Stanos SP (2007) Topical agents for the management of musculoskeletal pain. J Pain Symptom Manag 33(3):342–355 Sung YK, Cho SK, Kim D, Won S, Choi CB, Bang SY, Hong SJ, Kim HA, Koh EM, Lee HS, Suh CH, Yoo DH, Bae SC (2017) Characteristics and outcomes of rheumatoid arthritis patients who started bio similar infliximab. Rheumatol Int 37(6):1007–1014 Suto B, Berko S, Kozma G, Kukovecz A, Budai-Szucs M, Eros G, Kemeny L, Sztojkov-Ivanov A, Gaspar R, Csanyi E (2016) Development of ibuprofen-loaded nanostructured lipid carrier-based gels: characterization and investigation of in vitro and in vivo penetration through the skin. Int J Nanomedicine 11:1201–1212 Szekanecz Z, Koch AE (2016) Successes and failures of chemokine-pathway targeting in rheumatoid arthritis. Nat Rev Rheumatol 12(1):5–13 Tekeoglu I, Gurol G, Harman H, Karakece E, Ciftci IH (2016) Overlooked hematological markers of disease activity in rheumatoid arthritis. Int J Rheum Dis 19(11):1078–1082 Tomescu A, Sirbu R, Paris S, Cadar E, Erimia CL, Tomescu CL (2016) Methotrexate therapy in obstetrical diseases. Eur J Interdiscip stud 2(1):9–16 Van den Bemt BJ, Zwikker HE, van den Ende CH (2012) Medication adherence in patients with rheumatoid arthritis: a critical appraisal of the existing literature. Expert Rev Clin Immunol 8(4):337–351 Wang X, Yan X, Wang F, Ge F, Li Z (2018) Role of methotrexate chronotherapy in collagen induced rheumatoid arthritis in rats. Z Rheumatol 77(3):249–255 Wessels JAM, Huizinga TWJ, Guchelaar HJ (2008) Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology 47:249–255 Yazici S, Yazici M, Erer B, Erer B, Calik Y, Ozhan H, Ataoglu S (2010) The platelet indices in patients with rheumatoid arthritis: mean platelet volume reflects disease activity. Platelets 21:122–125 Yu Z, Lv H, Han G, Ma K (2016) Ethosomes loaded with cryptotanshinone for acne treatment through topical gel formulation. PLoS One 11(7):e0159967 Zeb A, Qureshi OS, Kim HS, Cha JH, Kim HS, Kim JK (2016) Improved skin permeation of methotrexate via nanosized ultra deformable liposomes. Int J Nanomed 11:3813–3824