OPTIMIZATION OF PROCESS PARAMETERS FOR ENHANCING THE SKIN PERMEATION EFFICIENCY OF NISOLDIPINE LOADED ULTRA DEFORMABLE VESICLES IN TRANSDERMAL PATCHES

D. MAHESWARA REDDY; MOTHILAL M.

doi:10.22159/ijap.2024v16i6.52019

Authors

D. MAHESWARA REDDY SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur-603203, Tamilnadu, India https://orcid.org/0000-0002-5422-5710
MOTHILAL M. Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur-603203, Tamilnadu, India https://orcid.org/0000-0003-0451-2890

DOI:

https://doi.org/10.22159/ijap.2024v16i6.52019

Keywords:

Drug permeation, Hypertension management, Nisoldipine, Transdermal patches, Transferosomes

Abstract

Objective: The study aimed to address the limitations of oral delivery and enhance the bioavailability of nisoldipine (NSD) through the development of transferosomal transdermal patches containing ultra-deformable transferosomes.

Methods: NSD, known for its low oral bioavailability and adverse effects, was encapsulated in transferosomes using a thin film hydration method. 17 formulations were made using Box Behnken Design, varying Dipalmitoylphosphatidylcholine (DPPC), span-80, and stirring speed, and were evaluated for vesicle size, Polydispersity Index (PDI), and Entrapment Efficiency (EE%). The optimal formulation, selected based on these parameters, was combined into Transdermal Patches (TPs). The patches underwent extensive testing for physicochemical properties, in vitro and ex-vivo permeation, and skin irritancy.

Results: The results showed transferosomes with Vesicle Sizes (VS) ranging from 124±2.25 to 400±1.55 nm and EE% from 52.88±0.23 to 90.01±1.58%, with Zeta Potentials (ZP) between-48 to-20 mV. The patch thickness (0.66±0.02 mm) and weight per square inch (382.1±1.69 mg) showed consistent manufacturing, while the Water Vapor Transmission Rate (WVT) (1.54±0.01g/m²/24h), low moisture content (1.07±0.01%), and regulated moisture absorption (3.78±0.01%) maintained formulation stability. In vitro and ex-vivo permeation indicated superior drug permeation for transferosomal patches (NP) compared to plain nisoldipine patches (NP-N), with permeation directly proportional to PEG-400 concentration. Additionally, the transferosomal patches were found to be free from skin irritation.

Conclusion: The optimized Niosoldipine transferosomal patch (NP-3) composition displays good folding endurance (FE) 97.67±0.47, required for transdermal systems, and successfully allows drug permeation (DP) at 86.39±2.64% in a short timescale. Hence, the study concludes that transferosomal patches of NSD offer a promising approach for effective transdermal delivery, potentially improving hypertension management by providing a controlled and prolonged drug release.

Downloads

Download data is not yet available.

References

Godfraind T. Discovery and development of calcium channel blockers. Front Pharmacol. 2017 May 29;8:286. doi: 10.3389/fphar.2017.00286, PMID 28611661.

Dens JA, Desmet WJ, Coussement P, DE Scheerder IK, Kostopoulos K, Kerdsinchai P. Long term effects of nisoldipine on the progression of coronary atherosclerosis and the occurrence of clinical events: the NICOLE study. Heart. 2003;89(8):887-92. doi: 10.1136/heart.89.8.887, PMID 12860866.

Preeti SS, Sambhakar S, Malik R, Bhatia S, Harrasi AA, Saharan R. Lipid horizons: recent advances and future prospects in LBDDS for oral administration of antihypertensive agents. Int J Hypertens. 2024;2024(1):2430147. doi: 10.1155/2024/2430147, PMID 38410720.

Pepine CJ, Cooper DE Hoff RM, Weiss RJ, Koren M, Bittar N, Thadani U. Comparison of effects of nisoldipine extended-release and amlodipine in patients with systemic hypertension and chronic stable angina pectoris. Am J Cardiol. 2003;91(3):274-9. doi: 10.1016/s0002-9149(02)03154-5, PMID 12565082.

Dole R, Kothapally D, Chukkala S, Thatipelli RC. Approaches to improve oral bioavailability of antihypertensive drugs: a mini review. J Drug Delivery Ther. 2023;13(5):73-7. doi: 10.22270/jddt.v13i5.5814.

Chu PC, Liao MH, Liu MG, LI CZ, Lai PS. Key transdermal patch using cannabidiol-loaded nanocarriers with better pharmacokinetics in vivo. Int J Nanomedicine. 2024 May 16;19:4321-37. doi: 10.2147/IJN.S455032, PMID 38770103.

Fernandez Garcia R, Lalatsa A, Statts L, Bolas-Fernandez F, Ballesteros MP, Serrano DR. Transferosomes as nanocarriers for drugs across the skin: quality by design from lab to industrial scale. Int J Pharm. 2020 Jan 5;573:118817. doi: 10.1016/j.ijpharm.2019.118817, PMID 31678520.

Narvekar MN, Redkar MM, Bhosale MN. Self-assembled ultradeformable phospholipid vesicles with edge activators for delivery of transcutaneous bioactives. Indo Am J Pharm Res. 2019;9(12):543-52.

Kumar PK, Kumar RS. Review on transferosomes and transferosomal gels. J Pharm Res Int. 2021;33(43B):114-26. doi: 10.9734/jpri/2021/v33i43B32532.

Wang J, Zhao Y, Zhai B, Cheng J, Sun J, Zhang X. Phloretin transfersomes for transdermal delivery: design optimization and in vivo evaluation. Molecules. 2023;28(19):6790. doi: 10.3390/molecules28196790, PMID 37836633.

Jain AK, Kumar F. Transfersomes: ultradeformable vesicles for transdermal drug delivery. Asian J Biomater Res. 2017;3:1-3.

Rajkumar J, Sree Lakshmi RK, Vineesha S. A new approach to transdermal drug delivery using transfersomes based nano encapsulation: a research update. Asian J Pharm Res Dev. 2022;10(1):64-70. doi: 10.22270/ajprd.v10i1.1082.

Sun Y, Zhang Y, Liu X, Tingting Y, Shen L, YE D. The preparation of high minoxidil loaded transfersomes and its gel for effective topical treatment of alopecia. J Drug Deliv Sci Technol. 2023 Jun;84:104458. doi: 10.1016/j.jddst.2023.104458.

Shravani Y, Ahad HA, Haranath C, Gari Poojitha B, Rahamathulla S, Rupasree A. Past decade work done on cubosomes using factorial design: a fast track information for researchers. Int J Life Sci Pharm Res. 2021;11(1):124-35. doi: 10.22376/ijpbs/lpr.2021.11.1.P124-135.

Mundarinti SH, Ahad HA. Past decade attempts on gastro retentive microspheres using factorial design: comprehensive literature. Int J Pharm Phytopharm Res. 2021;11(2):24-30. doi: 10.51847/XqUtLso9HJ.

Priyanka NV, Neeraja P, Mangilal T, Kumar MR. Formulation and evaluation of gel loaded with microspheres of apremilast for transdermal delivery system. Asian J Pharm Clin Res. 2019;12(2):411-7. doi: 10.22159/ajpcr.2019.v12i2.29374.

Choudhury D, Dutta KN, Kalita R. A review on transdermal patches used as an anti-inflammatory agent. Asian J Pharm Clin Res. 2021;14(12):21-6. doi: 10.22159/ajpcr.2021.v14i12.43277.

Simrah HA, Hafeez A, Usmani SA, Izhar MP. Transfersome an ultra deformable lipid-based drug nanocarrier: an updated review with therapeutic applications. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(2):639-73. doi: 10.1007/s00210-023-02670-8, PMID 37597094.

Qosimah D, Widyarti S, Beltran M, Rifa IM. Improved cellular immunity and increased insulin in streptozotosin-induced mice using ethanol coriander (Coriandrum sativum) extract. Res J Pharm Technol. 2021;14(7):3689-94. doi: 10.52711/0974-360X.2021.00638.

Fouziya B, Abdul Ahad H, Swamy Charan D, Sri Vidya J, Chandana Reddy U, Nandini Reddy P. Fabrication and evaluation of cefpodoxime proxetil niosomes. Asian J Pharm Technol. 2022;12(2):109-12. doi: 10.52711/2231-5713.2022.00018.

Todke P, Polaka S, Raval N, Gondaliya P, Tambe V, Maheshwari R. Transfersome embedded gel for dual mechanistic delivery of anti-psoriatic drugs to dermal lymphocytes. J Microencapsul. 2022;39(6):495-511. doi: 10.1080/02652048.2022.2116119, PMID 35993180.

Riccardi D, Baldino L, Reverchon E. Liposomes transfersomes and niosomes: production methods and their applications in the vaccinal field. J Transl Med. 2024;22(1):339. doi: 10.1186/s12967-024-05160-4, PMID 38594760.

Haranath C. Recent advances in lipid-based nanovesicles for transdermal drug delivery. J Med Pharm Allied Sci. 2022 Dec 31;11(6):5375-81. doi: 10.55522/jmpas.V11I6.4273.

Abd El-Alim SH, Kassem AA, Basha M, Salama A. Comparative study of liposomes ethosomes and transfersomes as carriers for enhancing the transdermal delivery of diflunisal: in vitro and in vivo evaluation. Int J Pharm. 2019 May 30;563:293-303. doi: 10.1016/j.ijpharm.2019.04.001, PMID 30951860.

Amos WB, White JG. How the confocal laser scanning microscope entered biological research. Biol Cell. 2003;95(6):335-42. doi: 10.1016/s0248-4900(03)00078-9, PMID 14519550.

Teng X, LI F, LU C. Visualization of materials using the confocal laser scanning microscopy technique. Chem Soc Rev. 2020;49(8):2408-25. doi: 10.1039/C8CS00061A.

Waheed A, Aqil M, Ahad A, Imam SS, Moolakkadath T, Iqbal Z. Improved bioavailability of raloxifene hydrochloride using limonene containing transdermal nano-sized vesicles. J Drug Deliv Sci Technol. 2019 Aug;52:468-76. doi: 10.1016/j.jddst.2019.05.019.

Balata GF, Faisal MM, Elghamry HA, Sabry SA. Preparation and characterization of ivabradine HCl transfersomes for enhanced transdermal delivery. J Drug Deliv Sci Technol. 2020 Dec;60:101921. doi: 10.1016/j.jddst.2020.101921.

Kumar Jyothika LS, Abdul Ahad H, Haranath C, Kousar S, Pal Gowd HD, Halima Sadiya S. Types of transdermal drug delivery systems: a literature report of the past decade. RJPDFT. 2022;14(2):157-62. doi: 10.52711/0975-4377.2022.00025.

Mehra V, Pai A, B Bhat B, Ram HNA, Kamath BV. Prospective potential of enzymes from novel bacillus sonorensis: insights into the structural aspects industrial and therapeutic significance. Res J Pharm Technol. 2023;16(10):4671-6. doi: 10.52711/0974-360X.2023.00759.

Sarmah PJ, Kalita B, Sharma AK. Transfersomes based transdermal drug delivery: an overview. IJAPR. 2013;4(12):2555-63.

Babu GN, Muthukarupan M, Ahad HA. Neem fruit mucilage impact on acyclovir release at different intervals: a central composite design screening. Int J Pharm Res Allied Sci. 2021;10(4):131-41. doi: 10.51847/Uh1ekmZM0d.

Wong WF, Ang KP, Sethi G, Looi CY. Recent advancement of medical patch for transdermal drug delivery. Medicina (Kaunas). 2023;59(4):778. doi: 10.3390/medicina59040778, PMID 37109736.

Yilmaz EG, Ece E, Erdem O, Es I, Inci F. A sustainable solution to skin diseases: ecofriendly transdermal patches. Pharmaceutics. 2023;15(2):579. doi: 10.3390/pharmaceutics15020579, PMID 36839902.

Chaurasiya P, Ganju E, Upmanyu N, Ray SK, Jain P. Transfersomes: a novel technique for transdermal drug delivery. J Drug Delivery Ther. 2019;9(1):279-85. doi: 10.22270/jddt.v9i1.2198.

Ghosh S, Basak A. Design fabrication in-vitro and ex-vivo permeation study nisoldipine (nsp) loaded slns by modified solvent diffusion method. Res J Pharm Technol. 2024;17(5):2327-38. doi: 10.52711/0974-360X.2024.00365.

Islam N, Irfan M, Zahoor AF, Iqbal MS, Syed HK, Khan IU. Improved bioavailability of ebastine through development of transfersomal oral films. Pharmaceutics. 2021;13(8):1315. doi: 10.3390/pharmaceutics13081315, PMID 34452276.

Ahad A, Al Jenoobi FI, Al Mohizea AM, Aqil M, Kohli K. Transdermal delivery of calcium channel blockers for hypertension. Expert Opin Drug Deliv. 2013;10(8):1137-53. doi: 10.1517/17425247.2013.783562, PMID 23527660.

Pandit AP, Omase SB, Mute VM. A chitosan film containing quercetin loaded transfersomes for treatment of secondary osteoporosis. Drug Deliv Transl Res. 2020;10(5):1495-506. doi: 10.1007/s13346-020-00708-5, PMID 31942700.

Naji GH, Al Gawhari FJ. Evaluation of types and concentration of bile salts impact on physical properties of nisoldipine loaded bilosomes. Pharmacia. 2024 Feb;71(4):1-7. doi: 10.3897/pharmacia.71.e116917.

Sharma G, Sharma A. Recent insights on drug delivery system in hypertension: from bench to market. Curr Hypertens Rev. 2023;19(2):93-105. doi: 10.2174/1573402119666230707120846, PMID 37550916.

Varia U, Joshi D, Jadeja M, Katariya H, Detholia K, Soni V. Development and evaluation of ultra deformable vesicles loaded transdermal film of boswellic acid. Futur J Pharm Sci. 2022;8(1):39. doi: 10.1186/s43094-022-00428-2.

Fitri AM, Elim D, Mahfud MASB, Sultan NAF, Saputra MD, Afika N. Polymeric hydrogel-forming microneedle mediated transdermal delivery of sildenafil citrate from direct compressed tablet reservoir for potential improvement of pulmonary hypertension therapy. International Journal of Pharmaceutics. 2023 Jan 25;631:122549. doi: 10.1016/j.ijpharm.2021.122549.

Khatoon K, Rizwanullah M, Amin S, MIR SR, Akhter S. Cilnidipine loaded transfersomes for transdermal application: formulation optimization in vitro and in vivo study. J Drug Deliv Sci Technol. 2019;54:101303. doi: 10.1016/j.jddst.2019.101303.

Dudhipala N, Phasha Mohammed R, Adel Ali Youssef A, Banala N. Effect of lipid and edge activator concentration on development of aceclofenac loaded transfersomes gel for transdermal application: in vitro and ex vivo skin permeation. Drug Dev Ind Pharm. 2020;46(8):1334-44. doi: 10.1080/03639045.2020.1788069, PMID 32598194.

Mazhar D, Haq NU, Zeeshan M, Ain QU, Ali H, Khan S. Preparation characterization and pharmacokinetic assessment of metformin HCl loaded transfersomes co-equipped with permeation enhancer to improve drug bioavailability via transdermal route. J Drug Deliv Sci Technol. 2023 Jun;84:104448. doi: 10.1016/j.jddst.2023.104448.

Mahmood S, Chatterjee B, Mandal UK. Pharmacokinetic evaluation of the synergistic effect of raloxifene loaded transfersomes for transdermal delivery. J Drug Deliv Sci Technol. 2021;63:102545. doi: 10.1016/j.jddst.2021.102545.

Majukar S, Dandagi P, Kurangi B. Design and characterization of transfersomal patch of aceclofenac as a carrier for transdermal delivery. IOSR JPBS. 2019;9(1):1138-47. doi: 10.9790/3008-090103113847.

Sapkota R, Dash AK. Liposomes and transferosomes: a breakthrough in topical and transdermal delivery. Ther Deliv. 2021;12(2):145-58. doi: 10.4155/tde-2020-0122, PMID 33583219.

Oyarzun P, Gallardo Toledo E, Morales J, Arriagada F. Transfersomes as alternative topical nanodosage forms for the treatment of skin disorders. Nanomedicine. 2021;16(27):2465-89. doi: 10.2217/nnm-2021-0335.

Patil P, Nene S, Shah S, Singh SB, Srivastava S. Exploration of novel drug delivery systems in topical management of osteoarthritis. Drug Deliv Transl Res. 2023;13(2):531-46. doi: 10.1007/s13346-022-01229-z, PMID 36031671.

Lin SY. Thermoresponsive gating membranes embedded with liquid crystal(s) for pulsatile transdermal drug delivery: an overview and perspectives. J Control Release. 2020;319:450-74. doi: 10.1016/j.jconrel.2019.12.046, PMID 31901369.

Yuan M, Niu J, Xiao Q, YA H, Zhang Y, Fan Y. Hyaluronan modified transfersomes based hydrogel for enhanced transdermal delivery of indomethacin. Drug Deliv. 2022;29(1):1232-42. doi: 10.1080/10717544.2022.2053761, PMID 35403516.

Ruan J, Liu C, Song H, Zhong T, Quan P, Fang L. Sustainable and efficient skin absorption behaviour of transdermal drug: the effect of the release kinetics of permeation enhancer. Int J Pharm. 2022;612:121377. doi: 10.1016/j.ijpharm.2021.121377, PMID 34915145.

Altun E, Yuca E, Ekren N, Kalaskar DM, Ficai D, Dolete G. Kinetic release studies of antibiotic patches for local transdermal delivery. Pharmaceutics. 2021;13(5):613. doi: 10.3390/pharmaceutics13050613, PMID 33922739.

Shivalingam MR, Balasubramanian A, Ramalingam K. Formulation and evaluation of transdermal patches of pantoprazole sodium. Int J App Pharm. 2021;13(5):287-91. doi: 10.22159/ijap.2021v13i5.42175.

Matharoo N, Mohd H, Michniak Kohn B. Transferosomes as a transdermal drug delivery system: dermal kinetics and recent developments. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2024;16(1):e1918. doi: 10.1002/wnan.1918, PMID 37527953.

Jatav VS, Saggu JS, Sharma AK, Sharma A, Jat RK. Design development and permeation studies of nebivolol hydrochloride from novel matrix-type transdermal patches. Adv Biomed Res. 2013;2(1):62. doi: 10.4103/2277-9175.115813, PMID 24223377.

Deng P, Athary Abdulhaleem MF, Masoud RE, Alamoudi WM, Zakaria MY. Employment of PEGylated ultra deformable transferosomes for transdermal delivery of tapentadol with boosted bioavailability and analgesic activity in post-surgical pain. Int J Pharm. 2022 Nov 25;628:122274. doi: 10.1016/j.ijpharm.2022.122274, PMID 36228884.

Patel RP, Patel G, Baria A. Formulation and evaluation of transdermal patch of aceclofenac. Int J Drug Del. 2009 Jul;1(1):41-51. doi: 10.5138/ijdd.2009.0975.0215.01005.

Gannu R, Vamshi Vishnu Y, Kishan V, Madhusudan Rao Y. Development of nitrendipine transdermal patches: in vitro and ex vivo characterization. Curr Drug Deliv. 2007;4(1):69-76. doi: 10.2174/156720107779314767.

Parhi R, Padilam S. In vitro permeation and stability studies on developed drug-in-adhesive transdermal patch of simvastatin. Bull Fac Pharm Cairo Univ. 2018;56(1):26-33. doi: 10.1016/j.bfopcu.2018.04.001.

Tawfeek HM, Abdellatif AA, Abdel Aleem JA, Hassan YA, Fathalla D. Transfersomal gel nanocarriers for enhancement the permeation of lornoxicam. J Drug Deliv Sci Technol. 2020;56:101540. doi: 10.1016/j.jddst.2020.101540.

Gupta R, Kumar A. Transfersomes: the ultra deformable carrier system for non-invasive delivery of drug. Curr Drug Deliv. 2021;18(4):408-20. doi: 10.2174/1567201817666200804105416.

Bindu H, Radha. Design and in vivo evaluation of naproxen-loaded transferosomal gel for transdermal delivery. Int J App Pharm. 2024;16(2):272-84. doi: 10.22159/ijap.2024v16i2.49562.

Tiwari G, Tiwari R, Singh R, Rai AK. Ultra-deformable liposomes as flexible nanovesicular carrier to penetrate versatile drugs transdermally. NANOASIA. 2020;10(1):12-20. doi: 10.2174/2210681208666180820145327.

Nayak D, Tippavajhala VK. A comprehensive review on preparation, evaluation and applications of deformable liposomes. Iran J Pharm Res. 2021;20(1):186-205. doi: 10.22037/ijpr.2020.112878.13997, PMID 34400952.

Badr Eldin SM, Ahmed OA. Optimized nano transfersomal films for enhanced sildenafil citrate transdermal delivery: ex vivo and in vivo evaluation. Drug Des Dev Ther. 2016 Apr 5;10:1323-33. doi: 10.2147/DDDT.S103122.

Abdallah MH, Abu Lila AS, Shawky SM, Almansour K, Alshammari F, Khafagy ES. Experimental design and optimization of nano-transfersomal gel to enhance the hypoglycemic activity of silymarin. Polymers. 2022;14(3):508. doi: 10.3390/polym14030508, PMID 35160498.

Gayathri H, Sangeetha S. Design and development of tofacitinib citrate loaded transferosomal gel for skin cancer by box-behnken design doe approach. Int J Health Sci. 2022;6:3119-40. doi: 10.53730/ijhs.v6nS6.10118.

Rajpurohit M, Patil A, MV, Urolagin D, Saeed M, Ahmad I. Fabrication and characterisation of nabumetone transferosomal gel for effective topical delivery. J Mol Struct. 2024 Sep 15;1312:138430. doi: 10.1016/j.molstruc.2024.138430.

Das B, Nayak AK, Mallick S. Thyme oil containing fluconazole loaded transferosomal bigel for transdermal delivery. AAPS Pharm Sci Tech. 2023;24(8):240. doi: 10.1208/s12249-023-02698-2, PMID 37989918.