Formulation and Evaluation of Hydrophilic Polymer Based Methotrexate Patches: In Vitro and In Vivo Characterization

This study attempted to develop and evaluate controlled-release matrix-type transdermal patches with different ratios of hydrophilic polymers (sodium carboxymethylcellulose and hydroxypropyl methylcellulose) for the local delivery of methotrexate. Transdermal patches were formulated by employing a solvent casting technique using blends of sodium carboxymethylcellulose (CMC-Na) and hydroxypropylmethylcellulose (HPMC) polymers as rate-controlling agents. The F1 formulated patch served as the control formulation with a 1:1 polymer concentration. The F9 formulation served as our optimized formulation due to suitable physicochemical properties yielded through the combination of CMC-Na and HPMC (5:1). Drug excipient compatibilities (ATR-FTIR) were performed as a preformulation study. The ATR-FTIR study depicted great compatibility between the drug and the polymers. Physicochemical parameters, kinetic modeling, in vitro drug release, ex vivo drug permeation, skin drug retention, and in vivo studies were also carried out for the formulated patches. The formulated patches exhibited a clear, smooth, elastic nature with good weight uniformity, % moisture uptake, drug content, and thickness. Physicochemical characterization revealed folding endurance ranging from 62 ± 2.21 to 78 ± 1.54, tensile strength from 9.42 ± 0.52 to 12.32 ± 0.72, % swelling index from 37.16 ± 0.17 to 76.24 ± 1.37, and % drug content from 93.57 ± 5.34 to 98.19 ± 1.56. An increase in the concentration of the CMC-Na polymer (F9) resulted in increased drug release from the formulated transdermal patches. Similarly, drug permeation and retention were found to be higher in the F9 formulation compared to the other formulations (F1–F8). A drug retention analysis revealed that the F9 formulation exhibited 13.43% drug retention in the deep layers of the skin compared to other formulations (F1–F8). The stability study indicated that, during the study period of 60 days, no significant changes in the drug content and physical characteristics were found. ATR-FTIR analysis of rabbit skin samples treated with the formulated transdermal patches revealed that hydrophilic polymers mainly affect the skin proteins (ceramide and keratins). A pharmacokinetic profile revealed Cmax was 1.77.38 ng/mL, Tmax was 12 h, and t1/2 was 17.3 ± 2.21. In vivo studies showed that the skin drug retention of F9 was higher compared to the drug solution. These findings reinforce that methotrexate-based patches can possibly be used for the management of psoriasis. This study can reasonably conclude that methotrexate transdermal matrix-type patches with CMC-Na and HPMC polymers at different concentrations effectively sustain drug release with prime permeation profiles and better bioavailability. Therefore, these formulated patches can be employed for the potential management of topical diseases, such as psoriasis.

[1]  M. Akhlaq,et al.  Transdermal delivery of gatifloxacin carboxymethyl cellulose-based patches: Preparation and characterization , 2021 .

[2]  Khalid Rehman Hakeem,et al.  Olive Oil Based Methotrexate Loaded Topical Nanoemulsion Gel for the Treatment of Imiquimod Induced Psoriasis-like Skin Inflammation in an Animal Model , 2021, Biology.

[3]  V. Andonova,et al.  Lipid Nanoparticulate Drug Delivery Systems: Recent Advances in the Treatment of Skin Disorders , 2021, Pharmaceuticals.

[4]  A. Azad,et al.  Ethyl Cellulose and Hydroxypropyl Methyl Cellulose Blended Methotrexate-Loaded Transdermal Patches: In Vitro and Ex Vivo , 2021, Polymers.

[5]  Xiguang Chen,et al.  Systematic comparisons of dissolving and swelling hyaluronic acid microneedles in transdermal drug delivery. , 2021, International journal of biological macromolecules.

[6]  M. Kwon,et al.  Recent advances in transdermal drug delivery systems: a review , 2021, Biomaterials Research.

[7]  K. Marina,et al.  Formulation, Optimization and in vitro Evaluation of Apremilast Nanoemulgel for Topical Delivery , 2021, International Journal of Pharmaceutical Investigation.

[8]  J. Kennedy,et al.  Electro-hydrodynamic assisted synthesis of lecithin-stabilized peppermint oil-loaded alginate microbeads for intestinal drug delivery. , 2021, International journal of biological macromolecules.

[9]  G. Rohith,et al.  Influence of chitosan thioglycolic acid conjugate in improving bioavailability of an antiparkinson drug; Rasagiline Mesylate from transdermal patch , 2021, Drug development and industrial pharmacy.

[10]  Mariappan Rajan,et al.  Progress in natural polymer engineered biomaterials for transdermal drug delivery systems , 2021 .

[11]  A. Dash,et al.  Liposomes and transferosomes: a breakthrough in topical and transdermal delivery. , 2021, Therapeutic delivery.

[12]  G. Stamatas,et al.  The stratum corneum water content and natural moisturization factor composition evolve with age and depend on body site , 2021, International journal of dermatology.

[13]  J. Xia,et al.  Two cases of refractory erythrodermic psoriasis effectively treated with secukinumab and a review of the literature , 2021, Dermatologic therapy.

[14]  M. Shoaib,et al.  Formulation development and evaluation of drug-in-adhesive-type transdermal patch of metoclopramide HCl , 2021, Polymer Bulletin.

[15]  V. Thakur,et al.  New Horizons in Hydrogels for Methotrexate Delivery , 2020, Gels.

[16]  P. Turnbaugh,et al.  Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation. , 2020, Cell host & microbe.

[17]  J. Keller Sodium Carboxymethylcellulose(CMC) , 2020 .

[18]  P. Hunter,et al.  Our natural “makeup” reveals more than it hides: Modeling the skin and its microbiome , 2020, Wiley interdisciplinary reviews. Systems biology and medicine.

[19]  A. Mujumdar,et al.  Synthesis and evaluation of luliconazole loaded biodegradable nanogels prepared by pH-responsive Poly (acrylic acid) grafted Sodium Carboxymethyl Cellulose using amine based cross linker for topical targeting: In vitro and Ex vivo assessment , 2020 .

[20]  M. A. Farooq,et al.  An overview of hydrogels and their role in transdermal drug delivery , 2020 .

[21]  F. Guardiola,et al.  Influence of skin wounds on the intestinal inflammatory response and barrier function: Protective role of dietary Shewanella putrefaciens SpPdp11 administration to gilthead seabream (Sparus aurata L.). , 2020, Fish & shellfish immunology.

[22]  M. Furue,et al.  Interleukin-17A and Keratinocytes in Psoriasis , 2020, International journal of molecular sciences.

[23]  A. Azad,et al.  Carboxymethyl fenugreek galactomannan-g-poly(N-isopropylacrylamide-co-N,N'-methylene-bis-acrylamide)-clay based pH/temperature-responsive nanocomposites as drug-carriers. , 2020, Materials science & engineering. C, Materials for biological applications.

[24]  C. Liu,et al.  Kaempferol attenuates imiquimod‐induced psoriatic skin inflammation in a mouse model , 2019, Clinical and experimental immunology.

[25]  Muhammad Farhan,et al.  Engineering and characterisation of BCG-loaded polymeric microneedles , 2019, Journal of drug targeting.

[26]  O. Ahmed,et al.  Development of an optimized avanafil-loaded invasomal transdermal film: ex vivo skin permeation and in vivo evaluation. , 2019, International journal of pharmaceutics.

[27]  István Antal,et al.  Microparticles, Microspheres, and Microcapsules for Advanced Drug Delivery , 2019, Scientia Pharmaceutica.

[28]  M. Talamonti,et al.  Pharmacotherapeutic management of psoriasis in adolescents and children , 2019, Expert opinion on pharmacotherapy.

[29]  E. A. McBride,et al.  A Survey of Rabbit Handling Methods Within the United Kingdom and the Republic of Ireland , 2019, Journal of applied animal welfare science : JAAWS.

[30]  M. Ghorab,et al.  Buccoadhesive gel of carvedilol nanoparticles for enhanced dissolution and bioavailability , 2018, Journal of Drug Delivery Science and Technology.

[31]  L. S. Taylor,et al.  Pharmaceutical Applications of Cellulose Ethers and Cellulose Ether Esters. , 2018, Biomacromolecules.

[32]  A. Zeb,et al.  Improved skin permeation of methotrexate via nanosized ultradeformable liposomes , 2016, International journal of nanomedicine.

[33]  P. Uzor,et al.  Perspectives on Transdermal Drug Delivery , 2011 .

[34]  Rakesh Patel,et al.  Formulation and evaluation of transdermal patch of Aceclofenac , 2009 .

[35]  M. Rao,et al.  Characterization and Ex vivo Studies of Nanoparticle Incorporated Transdermal Patch of Itraconazole , 2020 .

[36]  G. Aggarwal,et al.  Development Of Topical Gel Of Methotrexate Incorporated Ethosomes And Salicylic Acid For Treatment Of Psoriasis. , 2019, Pharmaceutical nanotechnology.

[37]  O. S. Fowler,et al.  Structure and functions of the skin. , 1844 .