Abstract
Purpose
We fabricated and characterized polyvinyl alcohol (PVA)-based dissolving microneedles (MNs) for transdermal drug delivery of apomorphine hydrochloride (APO), which is used in treating the wearing-off phenomenon observed in Parkinson’s disease.
Methods
We fabricated MN arrays with 11 × 11 needles of four different lengths (300, 600, 900, and 1200 μm) by micromolding. The APO-loaded dissolving MNs were characterized in terms of their physicochemical and functional properties. We also compared the pharmacokinetic parameters after drug administration using MNs with those after subcutaneous injection by analyzing the blood concentration of APO in rats.
Results
PVA-based dissolving MNs longer than 600 μm could effectively puncture the stratum corneum of the rat skin with penetrability of approximately one-third of the needle length. Although APO is known to have chemical stability issues in aqueous solutions, the drug content in APO-loaded MNs was retained at 25°C for 12 weeks. The concentration of APO after the administration of APO-loaded 600-μm MNs that dissolved completely in skin within 60 min was 81%. The absorption of 200-μg APO delivered by MNs showed a Tmax of 20 min, Cmax of 76 ng/mL, and AUC0–120 min of 2,829 ng・min/mL, compared with a Tmax of 5 min, Cmax of 126 ng/mL, and AUC0–120 min of 3,224 ng・min/mL for subcutaneous injection. The bioavailability in terms of AUC0–120 min of APO delivered by MNs was 88%.
Conclusion
APO-loaded dissolving MNs can deliver APO via skin into the systemic circulation with rapid absorption and high bioavailability.
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Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311:1670–83. https://doi.org/10.1001/jama.2014.3654.
Dawson VL, Dawson TM. Promising disease-modifying therapies for Parkinson’s disease. Sci Transl Med. 2019;11:eaba1659. https://doi.org/10.1126/scitranslmed.aba1659.
McFarthing K, Buff S, Rafaloff G, Dominey T, Wyse RK, Stott SRW. Parkinson’s disease drug therapies in the clinical trial pipeline: 2020. J Parkinsons Dis. 2020;10:757–74. https://doi.org/10.3233/JPD-202128.
Carbone F, Djamshidian A, Seppi K, Poewe W. Apomorphine for Parkinson’s disease: efficacy and safety of current and new formulations. CNS Drugs. 2019;33:905–18. https://doi.org/10.1007/s40263-019-00661-z.
Boyle A, Ondo W. Role of apomorphine in the treatment of Parkinson’s disease. CNS Drugs. 2015;29:83–9. https://doi.org/10.1007/s40263-014-0221-z.
Sam E, Jeanjean AP, Maloteaux JM, Verbeke N. Apomorphine pharmacokinetics in parkinsonism after intranasal and subcutaneous application. Eur J Drug Metab Pharmacokinet. 1995;20:27–33. https://doi.org/10.1007/BF03192285.
Zaleska B, Domzał T. Apomorphine in treatment of Parkinson’s disease with fluctuations. Neurol Neurochir Pol. 1999;33:1297–303.
Rossi P, Colosimo C, Moro E, Tonali P, Albanese A. Acute challenge with apomorphine and levodopa in parkinsonism. Eur Neurol. 2000;43:95–101. https://doi.org/10.1159/000008142.
Pietz K, Hagell P, Odin P. Subcutaneous apomorphine in late stage Parkinson’s disease: a long term follow up. J Neurol Neurosurg Psychiatry. 1998;65:709–16. https://doi.org/10.1136/jnnp.65.5.709.
Liu KS, Sung KC, Al-Suwayeh SA, Ku MC, Chu CC, Wang JJ, et al. Enhancement of transdermal apomorphine delivery with a diester prodrug strategy. Eur J Pharm Biopharm. 2011;78:422–31. https://doi.org/10.1016/j.ejpb.2011.01.024.
Peira E, Scolari P, Gasco MR. Transdermal permeation of apomorphine through hairless mouse skin from microemulsions. Int J Pharm. 2001;226:47–51. https://doi.org/10.1016/s0378-5173(01)00759-1.
Li GL, de Vries JJ, van Steeg TJ, van den Bussche H, Maas HJ, Reeuwijk HJ, et al. Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment. J Control Release. 2005;101:199–208. https://doi.org/10.1016/j.jconrel.2004.09.011.
Li GL, Danhof M, Frederik PM, Bouwstra JA. Pretreatment with a water-based surfactant formulation affects transdermal iontophoretic delivery of R-apomorphine in vitro. Pharm Res. 2003;20:653–9. https://doi.org/10.1023/a:1023211219118.
Ingrole RSJ, Azizoglu E, Dul M, Birchall JC, Gill HS, Prausnitz MR. Trends of microneedle technology in the scientific literature, patents, clinical trials and internet activity. Biomaterials. 2021;267:120491. https://doi.org/10.1016/j.biomaterials.2020.120491.
Prausnitz MR. Engineering microneedle patches for vaccination and drug delivery to skin. Annu Rev Chem Biomol Eng. 2017;8:177–200. https://doi.org/10.1146/annurev-chembioeng-060816-101514.
Tuan-Mahmood TM, McCrudden MT, Torrisi BM, McAlister E, Garland MJ, Singh TR, et al. Microneedles for intradermal and transdermal drug delivery. Eur J Pharm Sci. 2013;50:623–37. https://doi.org/10.1016/j.ejps.2013.05.005.
Hirobe S, Azukizawa H, Hanafusa T, Matsuo K, Quan YS, Kamiyama F, et al. Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. Biomaterials. 2015;57:50–8. https://doi.org/10.1016/j.biomaterials.2015.04.007.
Rouphael NG, Paine M, Mosley R, Henry S, McAllister DV, Kalluri H, et al. The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial. Lancet. 2017;390:649–58. https://doi.org/10.1016/S0140-6736(17)30575-5.
Palylyk-Colwell E, Ford C. A transdermal glucagon patch for severe hypoglycemia. In: CADTH Issues in Emerging Health Technologies. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health. 2016;159
Ameri M, Daddona PE, Maa YF. Demonstrated solid-state stability of parathyroid hormone PTH(1–34) coated on a novel transdermal microprojection delivery system. Pharm Res. 2009;26:2454–63. https://doi.org/10.1007/s11095-009-9960-9.
Rapoport AM, Ameri M, Lewis H, Kellerman DJ. Development of a novel zolmitriptan intracutaneous microneedle system (Qtrypta™) for the acute treatment of migraine. Pain Manag. 2020;10:359–66. https://doi.org/10.2217/pmt-2020-0041.
van der Maaden K, Jiskoot W, Bouwstra J. Microneedle technologies for (trans)dermal drug and vaccine delivery. J Control Release. 2012;161:645–55. https://doi.org/10.1016/j.jconrel.2012.01.042.
Birchall JC. Microneedle array technology: the time is right but is the science ready? Expert Rev Med Devices. 2006;3:1–4. https://doi.org/10.1586/17434440.3.1.1.
Al-Ghananeem AM. Transdermal delivery of apomorphine using microneedles. Patent. 2010;No. WO2010022326A2
Lee KJ, Jeong SS, Roh DH, Kim DY, Choi HK, Lee EH. A practical guide to the development of microneedle systems - in clinical trials or on the market. Int J Pharm. 2020;573:118778. https://doi.org/10.1016/j.ijpharm.2019.118778.
Hiraishi Y, Nakagawa T, Quan YS, Kamiyama F, Hirobe S, Okada N, et al. Performance and characteristics evaluation of a sodium hyaluronate-based microneedle patch for a transcutaneous drug delivery system. Int J Pharm. 2013;441:570–9. https://doi.org/10.1016/j.ijpharm.2012.10.042.
Ronnander JP, Simon L, Koch A. Transdermal delivery of sumatriptan succinate using iontophoresis and dissolving microneedles. J Pharm Sci. 2019;108:3649–56. https://doi.org/10.1016/j.xphs.2019.07.020.
Abdelghany S, Tekko IA, Vora L, Larrañeta E, Permana AD, Donnelly RF. Nanosuspension-based dissolving microneedle arrays for intradermal delivery of curcumin. Pharmaceutics. 2019;11:308. https://doi.org/10.3390/pharmaceutics11070308.
Wu D, Katsumi H, Quan YS, Kamiyama F, Kusamori K, Sakane T, et al. Permeation of sumatriptan succinate across human skin using multiple types of self-dissolving microneedle arrays fabricated from sodium hyaluronate. J Drug Target. 2016;24:752–8. https://doi.org/10.3109/1061186X.2016.1154565.
Ronnander P, Simon L, Spilgies H, Koch A, Scherr S. Dissolving polyvinylpyrrolidone-based microneedle systems for in-vitro delivery of sumatriptan succinate. Eur J Pharm Sci. 2018;114:84–92. https://doi.org/10.1016/j.ejps.2017.11.031.
Tas C, Joyce JC, Nguyen HX, Eangoor P, Knaack JS, Banga AK, et al. Dihydroergotamine mesylate-loaded dissolving microneedle patch made of polyvinylpyrrolidone for management of acute migraine therapy. J Control Release. 2017;268:159–65. https://doi.org/10.1016/j.jconrel.2017.10.021.
Spierings EL, Brandes JL, Kudrow DB, Weintraub J, Schmidt PC, Kellerman DJ, et al. Randomized, double-blind, placebo-controlled, parallel-group, multi-center study of the safety and efficacy of ADAM zolmitriptan for the acute treatment of migraine. Cephalalgia. 2018;38:215–24. https://doi.org/10.1177/0333102417737765.
Nomoto M, Kubo S, Nagai M, Yamada T, Tamaoka A, Tsuboi Y, et al. A randomized controlled trial of subcutaneous apomorphine for Parkinson disease: a repeat dose and pharmacokinetic study. Clin Neuropharmacol. 2015;38:241–7. https://doi.org/10.1097/WNF.0000000000000111.
Ando D, Miyazaki T, Yamamoto E, Koide T, Izutsu KI. Chemical imaging analysis of active pharmaceutical ingredient in dissolving microneedle arrays by Raman spectroscopy. Drug Deliv Transl Res. 2022;12:426–34. https://doi.org/10.1007/s13346-021-01052-y.
Donnelly RF, Majithiya R, Singh TR, Morrow DI, Garland MJ, Demir YK, et al. Design, optimization and characterisation of polymeric microneedle arrays prepared by a novel laser-based micromoulding technique. Pharm Res. 2011;28:41–57. https://doi.org/10.1007/s11095-010-0169-8.
Matsuo K, Yokota Y, Zhai Y, Quan YS, Kamiyama F, Mukai Y, et al. A low-invasive and effective transcutaneous immunization system using a novel dissolving microneedle array for soluble and particulate antigens. J Control Release. 2012;161:10–7. https://doi.org/10.1016/j.jconrel.2012.01.033.
Ozawa A, Sakaue M. New decolorization method produces more information from tissue sections stained with hematoxylin and eosin stain and masson-trichrome stain. Ann Anat. 2020;227:151431. https://doi.org/10.1016/j.aanat.2019.151431.
Naito C, Katsumi H, Suzuki T, Quan YS, Kamiyama F, Sakane T, et al. Self-dissolving microneedle arrays for transdermal absorption enhancement of human parathyroid hormone (1–34). Pharmaceutics. 2018;10:215. https://doi.org/10.3390/pharmaceutics10040215.
Zhu Z, Luo H, Lu W, Luan H, Wu Y, Luo J, et al. Rapidly dissolvable microneedle patches for transdermal delivery of exenatide. Pharm Res. 2014;31:3348–60. https://doi.org/10.1007/s11095-014-1424-1.
Chen YL, Shi L, Agbo F, Yong SH, Tan PS, Ngounou Wetie AG. LC-MS/MS simultaneous quantification of apomorphine and its major metabolites in human plasma: application to clinical comparative bioavailability evaluation for the apomorphine sublingual film and a subcutaneous product. J Pharm Biomed Anal. 2020;190:113493. https://doi.org/10.1016/j.jpba.2020.113493.
Netsomboon K, Partenhauser A, Rohrer J, Elli Sündermann N, Prüfert F, Suchaoin W, et al. Preactivated thiomers for intranasal delivery of apomorphine: in vitro and in vivo evaluation. Eur J Pharm Biopharm. 2016;109:35–42. https://doi.org/10.1016/j.ejpb.2016.09.004.
Teodorescu M, Bercea M, Morariu S. Biomaterials of PVA and PVP in medical and pharmaceutical applications: perspectives and challenges. Biotechnol Adv. 2019;37:109–31. https://doi.org/10.1016/j.biotechadv.2018.11.008.
Larrañeta E, Lutton REM, Woolfson AD, Donnelly RF. Microneedle arrays as transdermal and intradermal drug delivery systems: materials science, manufacture and commercial development. Mater Sci Eng R Rep. 2016;104:1–32. https://doi.org/10.1016/j.mser.2016.03.001.
Nguyen HX, Bozorg BD, Kim Y, Wieber A, Birk G, Lubda D, et al. Poly (vinyl alcohol) microneedles: fabrication, characterization, and application for transdermal drug delivery of doxorubicin. Eur J Pharm Biopharm. 2018;129:88–103. https://doi.org/10.1016/j.ejpb.2018.05.017.
Arya J, Henry S, Kalluri H, McAllister DV, Pewin WP, Prausnitz MR. Tolerability, usability and acceptability of dissolving microneedle patch administration in human subjects. Biomaterials. 2017;128:1–7. https://doi.org/10.1016/j.biomaterials.2017.02.040.
Zhang XP, Wang BB, Li WX, Fei WM, Cui Y, Guo XD. In vivo safety assessment, biodistribution and toxicology of polyvinyl alcohol microneedles with 160-day uninterruptedly applications in mice. Eur J Pharm Biopharm. 2021;160:1–8. https://doi.org/10.1016/j.ejpb.2021.01.005.
Chen BZ, Ashfaq M, Zhang XP, Zhang JN, Guo XD. In vitro and in vivo assessment of polymer microneedles for controlled transdermal drug delivery. J Drug Target. 2018;26:720–9. https://doi.org/10.1080/1061186X.2018.1424859.
Oh JH, Park HH, Do KY, Han M, Hyun DH, Kim CG, et al. Influence of the delivery systems using a microneedle array on the permeation of a hydrophilic molecule, calcein. Eur J Pharm Biopharm. 2008;69:1040–5. https://doi.org/10.1016/j.ejpb.2008.02.009.
Yan G, Warner KS, Zhang J, Sharma S, Gale BK. Evaluation needle length and density of microneedle arrays in the pretreatment of skin for transdermal drug delivery. Int J Pharm. 2010;391:7–12. https://doi.org/10.1016/j.ijpharm.2010.02.007.
Römgens AM, Bader DL, Bouwstra JA, Baaijens FPT, Oomens CWJ. Monitoring the penetration process of single microneedles with varying tip diameters. J Mech Behav Biomed Mater. 2014;40:397–405. https://doi.org/10.1016/j.jmbbm.2014.09.015.
Loizidou EZ, Williams NA, Barrow DA, Eaton MJ, McCrory J, Evans SL, et al. Structural characterisation and transdermal delivery studies on sugar microneedles: experimental and finite element modelling analyses. Eur J Pharm Biopharm. 2015;89:224–31. https://doi.org/10.1016/j.ejpb.2014.11.023.
Jung EC, Maibach HI. Animal models for percutaneous absorption. J Appl Toxicol. 2015;35:1–10. https://doi.org/10.1002/jat.3004.
Liu S, Jin MN, Quan YS, Kamiyama F, Kusamori K, Katsumi H, et al. Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin. Eur J Pharm Biopharm. 2014;86:267–76. https://doi.org/10.1016/j.ejpb.2013.10.001.
Verbaan FJ, Bal SM, van den Berg DJ, Groenink WH, Verpoorten H, Lüttge R, et al. Assembled microneedle arrays enhance the transport of compounds varying over a large range of molecular weight across human dermatomed skin. J Control Release. 2007;117:238–45. https://doi.org/10.1016/j.jconrel.2006.11.009.
Glatte P, Buchmann SJ, Hijazi MM, Illigens BM, Siepmann T. Architecture of the cutaneous autonomic nervous system. Front Neurol. 2019;10:970. https://doi.org/10.3389/fneur.2019.00970.
Jackson EA, Neumeyer JL, Kelly PH. Behavioral activity of some novel aporphines in rats with 6-hydroxydopamine lesions of caudate or nucleus accumbens. Eur J Pharmacol. 1983;87:15–23. https://doi.org/10.1016/0014-2999(83)90045-6.
Ang ZY, Boddy M, Liu Y, Sunderland B. Stability of apomorphine in solutions containing selected antioxidant agents. Drug Des Devel Ther. 2016;10:3253–65. https://doi.org/10.2147/DDDT.S116848.
Burkman AM. Some kinetic and thermodynamic characteristics of apomorphine degradation. J Pharm Sci. 1965;54:325–6. https://doi.org/10.1002/jps.2600540242.
Kim J, Gao Y, Zhao Z, Rodrigues D, Tanner EEL, Ibsen K, et al. A deep eutectic-based, self-emulsifying subcutaneous depot system for apomorphine therapy in Parkinson’s disease. Proc Natl Acad Sci U S A. 2022;119:e2110450119. https://doi.org/10.1073/pnas.2110450119.
Ito Y, Yoshimura M, Tanaka T, Takada K. Effect of lipophilicity on the bioavailability of drugs after percutaneous administration by dissolving microneedles. J Pharm Sci. 2012;101:1145–56. https://doi.org/10.1002/jps.22814.
Liu S, Jin MN, Quan YS, Kamiyama F, Katsumi H, Sakane T, et al. The development and characteristics of novel microneedle arrays fabricated from hyaluronic acid, and their application in the transdermal delivery of insulin. J Control Release. 2012;161:933–41. https://doi.org/10.1016/j.jconrel.2012.05.030.
Bhadale RS, Londhe VY. A comparison of dissolving microneedles and transdermal film with solid microneedles for iloperidone in vivo: a proof of concept. Naunyn Schmiedeberg's Arch Pharmacol. 2023;396:239–46. https://doi.org/10.1007/s00210-022-02309-0.
Agbo F, Isaacson SH, Gil R, Chiu YY, Brantley SJ, Bhargava P, et al. Pharmacokinetics and comparative bioavailability of apomorphine sublingual film and subcutaneous apomorphine formulations in patients with Parkinson’s disease and “OFF” episodes: results of a randomized, three-way crossover, open-label study. Neurol Ther. 2021;10:693–709. https://doi.org/10.1007/s40120-021-00251-6.
Agbo F, Crass RL, Chiu YY, Chapel S, Galluppi G, Blum D, et al. Population pharmacokinetic analysis of apomorphine sublingual film or subcutaneous apomorphine in healthy subjects and patients with Parkinson’s disease. Clin Transl Sci. 2021;14:1464–75. https://doi.org/10.1111/cts.13008.
Hirobe S, Azukizawa H, Matsuo K, Zhai Y, Quan YS, Kamiyama F, et al. Development and clinical study of a self-dissolving microneedle patch for transcutaneous immunization device. Pharm Res. 2013;30(10):2664–74. https://doi.org/10.1007/s11095-013-1092-6.
Katsumi H, Tanaka Y, Hitomi K, Liu S, Quan YS, Kamiyama F, et al. Efficient transdermal delivery of alendronate, a nitrogen-containing bisphosphonate, using tip-loaded self-dissolving microneedle arrays for the treatment of osteoporosis. Pharmaceutics. 2017;9:29. https://doi.org/10.3390/pharmaceutics9030029.
Kim JY, Han MR, Kim YH, Shin SW, Nam SY, Park JH. Tip-loaded dissolving microneedles for transdermal delivery of donepezil hydrochloride for treatment of Alzheimer’s disease. Eur J Pharm Biopharm. 2016;105:148–55. https://doi.org/10.1016/j.ejpb.2016.06.006.
Dul M, Alali M, Ameri M, Burke MD, Craig CM, Creelman BP, et al. Assessing the risk of a clinically significant infection from a microneedle Array patch (MAP) product. J Control Release. 2023;361:236–45. https://doi.org/10.1016/j.jconrel.2023.07.001.
McCrudden MT, Alkilani AZ, Courtenay AJ, McCrudden CM, McCloskey B, Walker C, et al. Considerations in the sterile manufacture of polymeric microneedle arrays. Drug Deliv Transl Res. 2015;5(1):3–14. https://doi.org/10.1007/s13346-014-0211-1.
Ripolin A, Quinn J, Larrañeta E, Vicente-Perez EM, Barry J, Donnelly RF. Successful application of large microneedle patches by human volunteers. Int J Pharm. 2017;521:92–101. https://doi.org/10.1016/j.ijpharm.2017.02.011.
Li W, Li S, Fan X, Prausnitz MR. Microneedle patch designs to increase dose administered to human subjects. J Control Release. 2021;339:350–60. https://doi.org/10.1016/j.jconrel.2021.09.036.
Goud KY, Mahato K, Teymourian H, Longardner K, Litvan I, Wang J. Wearable electrochemical microneedle sensing platform for real-time continuous interstitial fluid monitoring of apomorphine: toward Parkinson management. Sens Actuators B Chem. 2022;354:131234. https://doi.org/10.1016/j.snb.2021.131234.
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This research was supported by JSPS KAKENHI (Grant Number JP22K15350) and AMED (Grant Number JP22mk0101193).
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D.A. designed the projects, performed the experiments, directed the research, and wrote the manuscript. A.O. and M.S. performed histological experiments. E.Y., T.M., T.K., Y. S., and K.I. assisted in writing the manuscript. All the authors reviewed the manuscript.
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Ando, D., Ozawa, A., Sakaue, M. et al. Fabrication and Characterization of Dissolving Microneedles for Transdermal Drug Delivery of Apomorphine Hydrochloride in Parkinson’s Disease. Pharm Res 41, 153–163 (2024). https://doi.org/10.1007/s11095-023-03621-x
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DOI: https://doi.org/10.1007/s11095-023-03621-x