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Fabrication of Tip-Dissolving Microneedles for Transdermal Drug Delivery of Meloxicam

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Abstract

Dissolving microneedles (MNs) offered a simple, minimally invasive method for meloxicam (MX) delivery to the skin. However, the fabrication of dissolving MNs still faced some challenges, such as significant time consumption, loss of drug activity, and difficulty in regulating MN drug loading. To address these issues, we developed the tip-dissolving (TD) MNs. Several kinds of drugs were encapsulated successfully, and the quantity of MX ranged from 37.23 ± 8.40 to 332.53 ± 13.37 μg was precisely controlled. The effects of fabrication process on biomacromolecules stability were studied, and it was found that tyrosinase kept 90.4% activity during the fabrication process. The whole process for the fabrication of MNs only takes approximately 1 h. In order to further evaluate the potential of the TD MNs, MX TD MNs were prepared for in vitro release experiments, in vivo release experiments, safety evaluation, pharmacokinetic studies, and pharmacodynamic studies. The results demonstrated that MX TD MNs offered several advantages, including rapid release of the encapsulated drug (91.72% within 30 min), efficient drug delivery to skin (79.18%), no obvious skin irritation, decent relative bioavailability (122.3%), and strong anti-inflammatory and analgesic effects. Based on these results, we envisage that the TD MNs have promising potential for transdermal drug delivery of MX.

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References

  1. Degner F, Sigmund R, Zeidler H. Efficacy and tolerability of meloxicam in an observational, controlled cohort study in patients with rheumatic disease. Clin Ther. 2000;22(4):400–10. https://doi.org/10.1016/S0149-2918(00)89009-8.

    Article  CAS  PubMed  Google Scholar 

  2. Senna GE, Passalacqua G, Dama A, Crivellaro M, Schiappoli M, Bonadonna P, et al. Nimesulide and meloxicam are a safe alternative drugs for patients intolerant to nonsteroidal anti-inflammatory drugs. Eur Ann Allergy Clin Immunol. 2003;35(10):393–6.

    PubMed  Google Scholar 

  3. Pairet M, van Ryn J, Schierok H, Mauz A, Trummlitz G, Engelhardt G. Differential inhibition of cyclooxygenases-1 and -2 by meloxicam and its 4′-isomer. Inflamm Res. 1998;47(6):270–6. https://doi.org/10.1007/s000110050329.

    Article  CAS  PubMed  Google Scholar 

  4. Distel M, Mueller C, Bluhmki E, Fries J. Safety of meloxicam: a global analysis of clinical trials. Br J Rheumatol. 1996;35(Suppl 1):68–77. https://doi.org/10.1093/rheumatology/35.suppl_1.68.

    Article  CAS  PubMed  Google Scholar 

  5. Lanes SF, Rodrigeuz LA, Hwangg E. Baseline risk of gastrointestinal disorders among new users of meloxicam, ibuprofen, diclofenac, naproxen and indomethacin. Pharmacoepidemiology and drug safety. 2000;9(2):113–7. doi: https://doi.org/10.1002/(SICI)1099-1557(200003/04)9:2<113::AID-PDS478>3.0.CO;2–2.

  6. Chen J, Gao Y. Strategies for meloxicam delivery to and across the skin: a review. Drug Delivery. 2016;23(8):3146–56. https://doi.org/10.3109/10717544.2016.1157839.

    Article  CAS  PubMed  Google Scholar 

  7. Altman RD, Barthel HR. Topical therapies for osteoarthritis. Drugs. 2011;71(10):1259–79. https://doi.org/10.2165/11592550-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  8. Wiechers JW. The barrier function of the skin in relation to percutaneous absorption of drugs. Pharmaceutisch weekblad Scientific edition. 1989;11(6):185–98. https://doi.org/10.1007/BF01959410.

    Article  CAS  PubMed  Google Scholar 

  9. YC A, Choi JK, Choi YK, Ki HM, Bae JHA. Novel transdermal patch incorporating meloxicam: in vitro and in vivo characterization. Int J Pharm. 2010;385(385):12–9.

    Google Scholar 

  10. Badran MM, Taha EI, Tayel MM, Al-Suwayeh SA. Ultra-fine self nanoemulsifying drug delivery system for transdermal delivery of meloxicam: dependency on the type of surfactants. J Mol Liq. 2014;190(190):16–22. https://doi.org/10.1016/j.molliq.2013.10.015.

    Article  CAS  Google Scholar 

  11. Pathan I, Mangle M, Bairagi S. Design and characterization of nanoemulsion for transdermal delivery of meloxicam. Analytical. Chem Lett. 2016:286–95.

  12. Sareen R, Kumar S, Gupta GD. Meloxicam carbopol-based gels: characterization and evaluation. Current Drug Delivery. 2011;8(4):407–15. https://doi.org/10.2174/156720111795768013.

    Article  CAS  PubMed  Google Scholar 

  13. Duangjit S, Obata Y, Sano H, Onuki Y, Opanasopit P, Ngawhirunpat T, et al. Comparative study of novel ultradeformable liposomes: menthosomes, transfersomes and liposomes for enhancing skin permeation of meloxicam. Biol Pharm Bull. 2014;37(2):239–47. https://doi.org/10.1248/bpb.b13-00576.

    Article  CAS  PubMed  Google Scholar 

  14. Fang JY, Sung KC, Wang JJ, Chu CC, Chen KT. The effects of iontophoresis and electroporation on transdermal delivery of buprenorphine from solutions and hydrogels. J Pharm Pharmacol. 2002;54(10):1329–37. https://doi.org/10.1211/002235702760345392.

    Article  CAS  PubMed  Google Scholar 

  15. Kim TY, Kim YI, Seo SK, Kim SH, Yang KH, Shin SC. Anti-Hyperalgesic effects of meloxicam hydrogel via phonophoresis in acute inflammation in rats; comparing systemic and topical application. Biomol Ther. 2009;17(3):305–10. https://doi.org/10.4062/biomolther.2009.17.3.305.

    Article  CAS  Google Scholar 

  16. Garland MJ, Migalska K, Mahmood TMT, Singh TRR, Woolfson AD, Donnelly RF. Microneedle arrays as medical devices for enhanced transdermal drug delivery. Expert Rev Med Devices. 2011;8(4):459–82. https://doi.org/10.1586/erd.11.20.

    Article  CAS  PubMed  Google Scholar 

  17. Henry S, Mcallister DV, Allen MG, Prausnitz MR. Microfabricated microneedles: a novel approach to transdermal drug delivery. J Pharm Sci. 1998;87(8):922–5. https://doi.org/10.1021/js980042+.

    Article  CAS  PubMed  Google Scholar 

  18. Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery ☆. Adv Drug Deliv Rev. 2012;64(14):1547–68. https://doi.org/10.1016/j.addr.2012.04.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Donnelly RF, Garland MJ, Morrow DIJ, Migalska K, Singh TRR, Majithiya R, et al. Optical coherence tomography is a valuable tool in the study of the effects of microneedle geometry on skin penetration characteristics and in-skin dissolution. J Control Release. 2010;147(3):333–41. https://doi.org/10.1016/j.jconrel.2010.08.008.

    Article  CAS  PubMed  Google Scholar 

  20. Kaushik S, Hord AH, Denson DD, Mcallister DV, Smitra S, Allen MG, et al. Lack of pain associated with microfabricated microneedles. Anesth Analg. 2001;92(2):502–4. https://doi.org/10.1213/00000539-200102000-00041.

    Article  CAS  PubMed  Google Scholar 

  21. Witting M, Obst K, Pietzsch M, Friess W, Hedtrich S. Feasibility study for intraepidermal delivery of proteins using a solid microneedle array. Int J Pharm. 2015;486(1–2):52–8. https://doi.org/10.1016/j.ijpharm.2015.03.046.

    Article  CAS  PubMed  Google Scholar 

  22. Chen J, Qiu Y, Zhang S, Yang G, Gao Y. Controllable coating of microneedles for transdermal drug delivery. Drug Dev Ind Pharm. 2013;41(3):415–22. https://doi.org/10.3109/03639045.2013.873447.

    Article  PubMed  Google Scholar 

  23. Gill HS, Prausnitz MR. Coating formulations for microneedles. Pharm Res. 2007;24(7):1369–80. https://doi.org/10.1007/s11095-007-9286-4.

    Article  CAS  PubMed  Google Scholar 

  24. Khan H, Mehta P, Msallam H, Armitage D, Ahmad Z. Smart microneedle coatings for controlled delivery and biomedical analysis. J Drug Target. 2014;22(9):790–5. https://doi.org/10.3109/1061186X.2014.921926.

    Article  CAS  PubMed  Google Scholar 

  25. Chen JQY, Zhang S, Gao Y. Dissolving microneedle-based intradermal delivery of interferon-α-2b. Drug Dev Ind Pharm. 2016;42(6):890–6. https://doi.org/10.3109/03639045.2015.1096282.

    Article  CAS  PubMed  Google Scholar 

  26. Jun H, Han MR, Kang NG, Park JH, Park JH. Use of hollow microneedles for targeted delivery of phenylephrine to treat fecal incontinence. J Control Release. 2015;207:1–6. https://doi.org/10.1016/j.jconrel.2015.03.031.

    Article  CAS  PubMed  Google Scholar 

  27. Lutton REM, Larrañeta E, Kearney MC, Boyd P, Woolfson AD, Donnelly RFA. Novel scalable manufacturing process for the production of hydrogel-forming microneedle arrays. Int J Pharm. 2015;494(1):417–29. https://doi.org/10.1016/j.ijpharm.2015.08.049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ahmad Z, Stride E, Edirisinghe M. Novel preparation of transdermal drug-delivery patches and functional wound healing materials. J Drug Target. 2009;17(9):724–9. https://doi.org/10.3109/10611860903085386.

    Article  CAS  PubMed  Google Scholar 

  29. Amodwala S, Kumar P, Thakkar HP. Statistically optimized fast dissolving microneedle transdermal patch of meloxicam: a patient friendly approach to manage arthritis. Eur J Pharm Sci. 2017;104:114–23. https://doi.org/10.1016/j.ejps.2017.04.001.

    Article  CAS  PubMed  Google Scholar 

  30. Larrañeta E, Stewart S, Fallows SJ, Birkhäuer LL, Mccrudden MTC, Woolfson AD, et al. A facile system to evaluate in vitro drug release from dissolving microneedle arrays. Int J Pharm. 2016;497(1):62–9. https://doi.org/10.1016/j.ijpharm.2015.11.038.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Vijaya Kumar SG, Mishra DN. Preparation, characterization and in vitro dissolution studies of solid dispersion of meloxicam with PEG 6000. Yakugaku Zasshi. J Pharm Soc Japan. 2006;126(8):657–64. https://doi.org/10.1248/yakushi.126.657.

    Article  Google Scholar 

  32. Chang J-S, P-C W, Huang Y-B, Tsai Y-H. In-vitro evaluation of meloxicam permeation using response surface methodology. J Food Drug Anal. 2006;14(3)

  33. Momtaz S, Lall N, Basson A. Inhibitory activities of mushroom tyrosine and DOPA oxidation by plant extracts. S Afr J Bot. 2008;74(4):577–82. https://doi.org/10.1016/j.sajb.2008.02.005.

    Article  CAS  Google Scholar 

  34. Winter CAREA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Exp Biol Med. 1962;111(3):544–7. https://doi.org/10.3181/00379727-111-27849.

    Article  CAS  Google Scholar 

  35. Millan MJ. Serotonin and pain: evidence that activation of 5-HT 1A receptors does not elicit antinociception against noxious thermal, mechanical and chemical stimuli in mice. Pain. 1994;58(1):45–61. https://doi.org/10.1016/0304-3959(94)90184-8.

    Article  CAS  PubMed  Google Scholar 

  36. Kitchen I, Green PG. Differential effects of di-isopropylfluorophosphate poisoning and its treatment on opioid antinociception in the mouse. Life Sciences. 1983;33(Suppl 1):669–72.

    Article  CAS  PubMed  Google Scholar 

  37. Donnelly RF, Morrow DI, Singh TR, Migalska K, Mccarron PA, O’Mahony C, et al. Processing difficulties and instability of carbohydrate microneedle arrays. Drug Dev Ind Pharm. 2009;35(10):1242–54. https://doi.org/10.1080/03639040902882280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chu LY, Choi SO, Prausnitz MR. Fabrication of dissolving polymer microneedles for controlled drug encapsulation and delivery: bubble and pedestal microneedle designs. J Pharm Sci. 2010;99(10):4228–38. https://doi.org/10.1002/jps.22140.

    Article  CAS  PubMed  Google Scholar 

  39. Hong X, Wei L, Wu F, Wu Z, Chen L, Liu Z, et al. Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine. Drug Des Dev Therap. 2013;7(3):945–52.

    Google Scholar 

  40. Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360(16):1613.

    Google Scholar 

  41. Cohn D, Salomon AH. Designing biodegradable multiblock PCL/PLA thermoplastic elastomers. Biomaterials. 2005;26(15):2297–305. https://doi.org/10.1016/j.biomaterials.2004.07.052.

    Article  CAS  PubMed  Google Scholar 

  42. Chu LY, Prausnitz MR. Separable arrowhead microneedles. J Controll Release Off J Controll Release Society. 2011;149(3):242–9.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Natural Science Foundation of Fujian Province (Grant No. 2015J05167), the Education Department of Fujian Province (Grant No. JZ160470), the Program for Distinguished Young Talents in Fujian Province University, Putian University (Grant Nos. 2014052 and 2015075), and Training Program of Innovation and Entrepreneurship for Undergraduates (Grant Nos. 201711498004, 201711498055, and 201711498070).

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Authors and Affiliations

  1. School of Pharmacy and Medical Technology, Putian University, 351100, Fujian, China

    Jianmin Chen, Weiyue Huang, Ziyao Huang, Shiqi Liu, Yaling Ye, Qinglian Li & Meiping Huang

  2. Key Laboratory of Pharmaceutical Analysis and Laboratory Medicine (Putian University), Fujian Province University, Fujian, China

    Jianmin Chen

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  1. Jianmin Chen
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Correspondence to Jianmin Chen.

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Chen, J., Huang, W., Huang, Z. et al. Fabrication of Tip-Dissolving Microneedles for Transdermal Drug Delivery of Meloxicam. AAPS PharmSciTech 19, 1141–1151 (2018). https://doi.org/10.1208/s12249-017-0926-7

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