A two-step design of experiments approach to investigate the simultaneous effects of ion-pairing and chemical enhancers to improve the permeability of lornoxicam in a topical hydrogel patch

Huu-Manh Nguyen1, The-Khang Duong1, Van-Khuyen Nguyen1, Thi-Khanh-Ly Nguyen1, Thi-Hoang-Yen Dong2, Canh-Hung Nguyen1, Nguyen-Thach Tung1
1Department of Pharmaceutics, Hanoi University of Pharmacy, Hoan Kiem, Vietnam
2Department of Pharmaceutics, Thai Nguyen University of Medicine and Pharmacy, Thai Nguyen, Vietnam

Tóm tắt

A two-step experimental design was used to develop a lornoxicam (LOR)-loaded topical hydrogel patch. We specifically focused on the simultaneous effect of the ion pair formation agent (triethanolamine [TEA]) and the chemical enhancer (cremophor RH40 [RH40]) on flux and conducted physicochemical studies and skin physiology assessments to obtain further information. Drug-in-adhesive patches were fabricated using a micrometer-adjustable film applicator. The applied Design of Experiments (DoE) approach consisted of the Fractional Factorial Resolution V + design and the Central Composite Face design established by the MODDE® 12.0 software. Molecular-level drug-excipient interactions were investigated using infrared (IR) and proton nuclear magnetic resonance (1H NMR) spectroscopy. The effects on skin physiological function was assessed using DermaLab Combo. DoE results revealed that TEA enhanced flux by 3.14-fold, whereas RH40 reduced it by 4.62-fold. The addition of RH40 resulted in the disappearance of the proton peak within the region of 12–13 ppm, suggesting competition for hydrogen bonding with LOR between TEA and RH40. The optimized formulation (4% TEA, 0% RH40, and 0.2% Al(OH)3) increased skin hydration by 6.20-fold. Opposing effects of TEA and RH40 on skin elasticity were observed. Expected flux and adhesion strength for the optimized formulation were 7.18 µg·cm–2·h–1 and 11.79 mJ, respectively. Our understanding of the conflicting effects of TEA and RH40 has been advanced. The integrated use of the two-step DoE, physicochemical studies, and skin physiology assessments was proven to be effective in elucidating the simultaneous effects of different permeation-modifying strategies on patches, thus having substantial value for the successful execution of future research endeavors.

Tài liệu tham khảo

Ahmed MO, Al-Badr AA (2011) Lornoxicam. Profiles Drug Subst Excip Relat Methodol 36:205–239 Al-Lawatia H, Binkhathlan Z, Lavasanifar A (2019) Nanomedicine for the effective and safe delivery of non-steroidal antiinflammatory Drugs: a review of preclinical research. Eur J Pharm Sci 142:179–194 Alexander H, Brown S, Danby S, Flohr C (2018) Esearch techniques made simple: Transepidermal Water loss measurement as a Research Tool. J Invest Dermatol 138:2295–2300 Attimarad M (2010) Rapid Rp HPLC method for quantitative determination of lornoxicam in tablets. J Basic Clin Pharm 1:115–118 Bond JR, Barry BW (1988) Limitations of Hairless Mouse skin as a model for in Vitro Permeation studies through Human skin: hydration damage. J Invest Dermatol 90:486–489 Borumand M, Sibilla S (2014) Daily consumption of the collagen supplement pure gold Collagen® reduces visible signs of aging. Clin Interv Aging. https://doi.org/10.2147/CIA.S65939 Brockmann W, Hüther R (1996) Adhesion mechanisms of pressure sensitive adhesives. Int J Adhes Adhes 16:81–86 Cristofoli M, Kung C-P, Hadgraft J, Lane ME, Sil BC (2021) Ion pairs for transdermal and dermal drug delivery: a review. Pharmaceutics. https://doi.org/10.3390/pharmaceutics13060909 Do T-P-C, Nguyen D-C, Nguyen T-D, Bui Q-D, Nguyen C-H et al (2021) The design of Experiment Approach, Rheology for optimization of a topical anti-inflammatory and analgesic cream. Curr Drug Deliv 18:1303–1313 Elder DP, Holm R, Diego, HLd (2013) Use of pharmaceutical salts and cocrystals to address the issue of poor solubility. Int J Pharm 453:88–100 Elias PM, Gruber R, Crumrine D, Menon G, Williams ML et al (2014) Formation and functions of the corneocyte lipid envelope (CLE). Biochim Biophys Acta 1841:314–318 Eriksson L, Johansson E, Kettaneh-Wold N, Wikstrom C, Wold S (2000) Design of experiments, principles and applications. Umetrics Academy Feldstein MM, Siegel RA (2012) Molecular and nanoscale factors governing pressure-sensitive adhesion strength of viscoelastic polymers. J Polym Sci B Polym Phys 50:739–772 Fini A, Fazio G, Gonzalez-Rodriguez M, Cavallari C, Passerini N et al (1999) Formation of ion-pairs in aqueous solutions of diclofenac salts. Int J Pharm 187:163–173 U.S. Food and Drug Administration (2012) Guidance for Industry - Q8, Q9, & Q10: Questions and Answers - Appendix: Q&As from Training Sessions (Q8, Q9, & Q10 Points to Consider). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8-q9-q10-questions-and-answers-appendix-qas-training-sessions-q8-q9-q10-points-consider. Accessed August 2012 Frew J, Penzi L, Suarez-Farinas M, Garcet S, Brunner PM et al (2021) The erythema Q-score, an imaging biomarker for redness in skin inflammation. Exp Dermatol 30:377–383 Gondaliya D, Pundarikakshudu K (2003) Studies in Formulation and Pharmacotechnical evaluation of controlled release Transdermal Delivery System of Bupropion. AAPS PharmSciTech. https://doi.org/10.1208/pt040103 Gutschke E, Bracht S, Nagel S, Weitschies W (2010) Adhesion testing of transdermal matrix patches with a probe tack test– in vitro and in vivo evaluation. Eur J Pharm Biopharm 75:399–404 Habeeb MM (1997) Spectroscopic studies of proton transfer equilibria in hydrogen bonded complexes. Appl Spectrosc Rev 32:103–140 Hanbali OAA, Khan HMS, Sarfraz M, Arafat M, Ijaz S et al (2019) Transdermal patches: design and current approaches to painless drug delivery. Acta Pharm 69:197–215 Hashmat D, Shoai MH, Ali FR, Siddiqui F (2020) Lornoxicam controlled release transdermal gel patch: design, characterization and optimization using co-solvents as penetration enhancers. PLoS ONE. https://doi.org/10.1371/journal.pone.0228908 Hu Y, Wu Y-Y, Xia X-J, Wu Z, Liang W-Q et al (2011) Development of drug-in-adhesive transdermal patch for α-asarone and in vivo pharmacokinetics and efficacy evaluation. Drug Deliv 18:84–89 Hua W, Fan L-M, Dai R, Luan M, Xie H et al (2016) Comparison of two series of non-invasive instruments used for the skin physiological properties measurements: the DermaLab® from Cortex Technology vs. the series of detectors from courage & Khazaka. Skin Res Technol 23:70–78 Hudson RA, Scott RM, Vinogradov SN (1972) Hydrogen-bonded complex-ion-pair equilibriums in 3,4-dinitrophenol-amine-aprotic solvent systems. J Phys Chem 76:1989–1993 Jiang Q, Wang J, Ma P, Liu C, Sun M et al (2017) Ion-pair formation combined with a penetration enhancer as a dual strategy to improve the transdermal delivery of meloxicam. Drug Deliv and Transl Res 8:64–72 Joseph J, N, VHB, D, RD (2018) Experimental optimization of Lornoxicam liposomes for sustained topical delivery. Eur J Pharm Sci 112:38–51 Jung E, Lee EY, Choi H-K, Ban S-J, Choi S-H et al (2015) Development of drug-in-adhesive patch formulations for transdermal delivery of fluoxetine: in vitro and in vivo evaluations. Int J Pharm 487:49–55 Katona G, Sipos B, Ambrus R, Csóka I, Szabó-Révész P (2022) Characterizing the drug-release enhancement effect of surfactants on Megestrol-acetate-loaded granules. Pharmaceuticals. https://doi.org/10.3390/ph15020113 Khan RU, Shah SU, Rashid SA, Naseem F, Shah KU et al (2022) Lornoxicam-Loaded Chitosan-Decorated Nanoemulsion: Preparation and in Vitro evaluation for enhanced Transdermal Delivery. Polymers. https://doi.org/10.3390/polym14091922 Kováčik A, Kopečná M, Vávrová K (2020) Permeation enhancers in transdermal drug delivery: benefits and limitations. Expert Opin Drug Deliv 17:145–155 Kraus CA (1956) The Ion-Pair Concept: its evolution and some applications. J Phys Chem 60:129–141 Lane ME (2013) Skin penetration enhancers. Int J Pharm 447:12–21 Lee J-H, Lee T-H, Shim K-S, Park J-W, Kim H-J et al (2017) Effect of crosslinking density on adhesion performance and flexibility properties of acrylic pressure sensitive adhesives for flexible display applications. Int J Adhes Adhes 74:137–143 Li M, Wang Q, Chen N, Yao S, Sun X et al (2022) Probing Pharmaceutical strategies to promote the skin delivery of Asiatic Acid from hydrogels: Enhancement effects of Organic Amine counterions, Chemical Enhancers, and Microneedle pretreatment. Pharmaceutics. https://doi.org/10.3390/pharmaceutics14112532 Lim D-H, Do H-S, Kim H-J, Bang J-S, Yoon G-H (2007) Preparation of SIS/SBS-based UV-cross-linkable pressure-sensitive adhesives using the thiol-ene reaction. J Adhes Sci Technol 21:589–603 Lindh JD, Bradley M (2015) Clinical effectiveness of moisturizers in atopic dermatitis and related disorders: a systematic review. Am J Clin Dermatol 16:341–359 Martínez-Cifuentes M, Cardona W, Saitz C, Weiss-López B, Araya-Maturana R (2017) A study about Regioisomeric hydroquinones with multiple intramolecular hydrogen bonding. Molecules. https://doi.org/10.3390/molecules22040593 Mitragotri S (2002) A theoretical analysis of permeation of small hydrophobic solutes across the stratum corneum based on scaled particle theory. J Pharm Sci 91:744–752 Motekaitis RJ, Martell AE (1984) Complexes of aluminum(III) with hydroxy carboxylic acids. Inorg Chem 23:18–23 Ngawhirunpat T, Worachun N, Opanasopit P, Rojanarata T, Panomsuk S (2013) Cremophor RH40-PEG 400 microemulsions as transdermal drug delivery carrier for ketoprofen. Pharm Dev Technol 18:798–803 Nguyen D-C, Dang Q-A, Nguyen T-D, Bui V-T, Chi S-C et al (2023) DoE-based formulation, physicochemical properties, and anti-inflammatory investigation of a topical patch preparing by partially neutralized polyacrylate-based adhesive hydrogel. Mater Today Commun. https://doi.org/10.1016/j.mtcomm.2023.105606 Nijhawan M, Santhosh A, Babu PRS, Subrahmanyam CVS (2013) Solid state manipulation of lornoxicam for cocrystals - physicochemical characterization. Drug Dev Ind Pharm doi. https://doi.org/10.3109/03639045.2013.804834 Nogami H, Nagai T, Suzuki A (1965) Studies on powdered preparations. 13. Reaction between dried aluminum hydroxide gel and organic acid. Chem Pharm Bull 13:1387–1391 Nokhodchi A, Shokri J, Dashbolaghi A, Hassan-Zadeh D, Ghafourian T et al (2003) The enhancement effect of surfactants on the penetration of lorazepam through rat skin. Int J Pharm 250:359–369 Panchaxari DM, Pampana S, Pal T, Devabhaktuni B, Aravapalli AK (2013) Design and characterization of diclofenac diethylamine transdermal patch using silicone and acrylic adhesives combination. DARU J Pharm Sci Doi. https://doi.org/10.1186/2008-2231-21-6 Pastore MN, Kalia YN, Horstmann M, Roberts MS (2015) Transdermal patches: history, development and pharmacology. Br J Pharmacol 172:2179–2209 Peperkamp K, Verhulst AC, Tielemans HJP, Winters H, Dalen D et al (2019) The inter-rater and test‐retest reliability of skin thickness and skin elasticity measurements by the DermaLab Combo in healthy participants. Skin Res Technol 25:787–792 Pinkus H (1973) Lichenoid tissue reactions. A speculative review of the clinical spectrum of epidermal basal cell damage with special reference to erythema dyschromicum perstans. Arch Dermatol 107:840–846 Pregosin PS (2009) NMR spectroscopy and ion pairing: measuring and understanding how ions interact. Pure Appl Chem 81:615–633 Rigg PC, Barry BW (1990) Shed snake skin and hairless mouse skin as model membranes for human skin during permeation studies. J Invest Dermatol 94:235–240 Sanphui P, Tothadi S, Ganguly S, Desiraju GR (2013) Salt and cocrystals of Sildenafil with Dicarboxylic acids: solubility and pharmacokinetic advantage of the Glutarate Salt. Mol Pharm 10:4687–4697 Shapetko NN, Shigorin DN (1968) NMR study of intramolecular hydrogen bond protons in quinoid structures. J Struct Chem 8:474–476 Sintov AC, Botner S (2006) Transdermal drug delivery using microemulsion and aqueous systems: influence of skin storage conditions on the in vitro permeability of diclofenac from aqueous vehicle systems. Int J Pharm 311:55–62 Soema PC, Willems G-J, Jiskoot W, Amorij J-P, Kersten GF (2015) Predicting the influence of liposomal lipid composition on liposome size, zeta potential and liposome-induced dendritic cell maturation using a design of experiments approach. Eur J Pharm Biopharm 94:427–435 Taevernier L, Wynendaele E, D’Hondt M, Spiegeleer BD (2015) Analytical quality-by-design approach for sample treatment of BSA-containing solutions. J Pharm Anal 5:27–32 Vakalopoulos KA, Wu Z, Kroese L, Kleinrensink G-J, Jeekel J et al (2015) Mechanical strength and Rheological properties of tissue adhesives with regard to Colorectal AnastomosisAn Ex vivo study. Ann Surg 261:323–331 Wang M, Fang L, Ren C, Li T (2008) Effect of ion-pairing and enhancers on scutellarin skin permeability. J Pharm Pharmacol 60:429–435 Wang J, Zhang H, An D, Yu J, Li W et al (2014) Rheological characterization of Cataplasm bases composed of cross-linked partially neutralized Polyacrylate Hydrogel. AAPS PharmSciTech 15:1149–1154 Wang Q, Zhang Y, Zhang X, Li Q, Huang M et al (2022) A study of the mechanism and separation of structurally similar phenolic acids by commercial polymeric ultrafiltration membranes. Membranes. https://doi.org/10.3390/membranes12030285 Xi H, Wang Z, Chen Y, Li W, Sun L et al (2012) The relationship between hydrogen-bonded ion-pair stability and transdermal penetration of lornoxicam with organic amines. Eur J Pharm Sci 47:325–330 Yang J, Zhu Y, Diao Y, Yin C (2018) Rheological and mechanical analyses of Felbinac cataplasms by using Box–Behnken Design. Pharmaceutics. https://doi.org/10.3390/pharmaceutics10030088 Yang J, Bai R, Chen B, Suo Z (2019) Hydrogel Adhesion: a Supramolecular Synergy of Chemistry, Topology, and mechanics. Adv Funct Mater. https://doi.org/10.1002/adfm.201901693 Zayed MA, El-Dien FAN, Mohamed GG, El-Gamel NEA (2007) FTIR, magnetic, mass spectral, XRD and thermal studies of metal chelates of tenoxicam. J Mol Struct 841:41–50 Zhao X, Liu JP, Zhang X, Li Y (2006) Enhancement of transdermal delivery of theophylline using microemulsion vehicle. Int J Pharm 327:58–64 Zhao H, Liu C, Quan P, Wan X, Shen M et al (2017) Mechanism study on Ion-pair complexes Controlling skin permeability: Effect of Ion-pair dissociation in the viable epidermis on Transdermal Permeation of Bisoprolol. Int J Pharm 532:29–36