Micro-needles as an effective drug delivery system and associated patents in pharmaceutical field: A Review

Abstract

Microneedles (MNs) are the most interesting and minimally invasive technique in pharmaceutical drug delivery systems. Recently researchers have concluded that MNs can be prominent future methods. Depending on the unique properties of MNs, they can be used widely in drug delivery systems. This delivery method has improved drug delivery avoiding many hurdles that were linked with the conventional system. The principal mechanism involved is temporarily damaging the skin layer; hence micron-size pores are created, which help the drug to reach the targeted site without any complications.  The popularity of MNs in pharmaceutical and biomedical research is growing exponentially as it offers easy delivery of bio-actives to the specific site with minimal invasion.  Several numbers of molecules are delivering via MNs, such as hormones, vaccines, and peptides. In this review, the efficiency of Micro-needle, their fabrication materials, as drug delivery carriers, and various associated patents are discussed.

References

1. Dugam S, Tade R, Dhole R, Nangare S. Emerging era of microneedle array for pharmaceutical and biomedical applications: recent advances and toxicological perspectives. Future Journal of Pharmaceutical Sciences. 2021 Dec; 7(1):1-26.
2. Nangare S, Tade RS, Dugam S, Shitole MM. Progress in erectile dysfunction therapy via drug delivery system. Thai Journal of Pharmaceutical Sciences (TJPS). 2020 Jun 15; 44(2).
3. Barry BW. Novel mechanisms and devices to enable successful transdermal drug delivery. European journal of pharmaceutical sciences. 2001 Sep 1; 14(2):101-14.
4. Tabassum N, Sofi A, Khuroo T. Microneedle technology: a new drug delivery system. Int J Res Pharm Biomed Sci. 2011; 2(1):59-62.
5. Donnelly RF, Singh TR, Woolfson AD. Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety. Drug delivery. 2010 May 1; 17(4):187-207.
6. Mogusala NR, Devadasu VR, Venisetty RK. Fabrication of microneedle molds and polymer based biodegradable microneedle patches: a novel method. American Journal of Drug Delivery and Therapeutics. 2015; 2(2).
7. Prausnitz MR, Mitragotri S, Langer R. Current status and future potential of transdermal drug delivery. Nature reviews Drug discovery. 2004 Feb; 3(2):115-24.
8. Xie L, Zeng H, Sun J, Qian W. Engineering microneedles for therapy and diagnosis: a survey. Micromachines. 2020 Mar; 11(3):271.
9. Du G, Sun X. Current advances in sustained release microneedles. Pharmaceutical Fronts. 2020 Mar; 2(01):e11-22.
10. Verbaan FJ, Bal SM, Van den Berg DJ, Groenink WH, Verpoorten H, Lüttge R, Bouwstra JA. Assembled microneedle arrays enhance the transport of compounds varying over a large range of molecular weight across human dermatomed skin. Journal of Controlled Release. 2007 Feb 12; 117(2):238-45.
11. Waghule T, Singhvi G, Dubey SK, Pandey MM, Gupta G, Singh M, Dua K. Micro needles: A smart approach and increasing potential for transdermal drug delivery system. Biomedicine & pharmacotherapy. 2019 Jan 1; 109:1249-58.
12. Larraneta E, Lutton RE, Woolfson AD, Donnelly RF. Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development. Materials Science and Engineering: R: Reports. 2016 Jun 1; 104:1-32.
13. Hong X, Wei L, Wu F, Wu Z, Chen L, Liu Z, Yuan W. Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine. Drug design, development and therapy. 2013; 7: 945.
14. Niinomi M, Nakai M. Titanium-based biomaterials for preventing stress shielding between implant devices and bone. International journal of biomaterials. 2011 Jan 1; 2011.
15. Pignatello R, editor. Biomaterials: applications for Nanomedicine. BoD–Books on Demand; 2011 Nov 16.
16. Gittard SD, Narayan RJ, Jin C, Monteiro-Riviere NA, Ovsianikov A, Chichkov BN, Stafslien S, Chisholm B. Pulsed laser deposition of antimicrobial silver coating on Ormocer (registered) microneedles. Biofabrication (Online). 2009 Dec 15; 1.
17. Perennes F, Marmiroli B, Matteucci M, Tormen M, Vaccari L, Di Fabrizio E. Sharp beveled tip hollow microneedle arrays fabricated by LIGA and 3D soft lithography with polyvinyl alcohol. Journal of Micromechanics and Micro engineering. 2006 Jan 25;16(3):473.
18. Aoyagi S, Izumi H, Isono Y, Fukuda M, Ogawa H. Laser fabrication of high aspect ratio thin holes on biodegradable polymer and its application to a microneedle. Sensors and Actuators A: Physical. 2007 Sep 12;139(1-2):293-302.
19. Park JH, Allen MG, Prausnitz MR. Polymer microneedles for controlled-release drug delivery. Pharmaceutical research. 2006 May;23(5):1008-19.
20. Chu LY, Choi SO, Prausnitz MR. Fabrication of dissolving polymer microneedles for controlled drug encapsulation and delivery: bubble and pedestal microneedle designs. Journal of pharmaceutical sciences. 2010 Oct 1;99(10):4228-38.
21. Donnelly RF, Majithiya R, Singh TR, Morrow DI, Garland MJ, Demir YK, Migalska K, Ryan E, Gillen D, Scott CJ, Woolfson AD. Design, optimization and characterisation of polymeric microneedle arrays prepared by a novel laser-based micro moulding technique. Pharmaceutical research. 2011 Jan;28(1):41-57.
22. Miyano T, Tobinaga Y, Kanno T, Matsuzaki Y, Takeda H, Wakui M, Hanada K. Sugar micro needles as transdermic drug delivery system. Biomedical Micro devices. 2005 Sep; 7(3):185-8.
23. Mao J, Wang H, Xie Y, Fu Y, Li Y, Liu P, Du H, Zhu J, Dong L, Hussain M, Li Y. Transdermal delivery of rapamycin with poor water-solubility by dissolving polymeric microneedles for anti-angiogenesis. Journal of Materials Chemistry B. 2020; 8(5):928-34.
24. Nguyen HX, Banga AK. Enhanced skin delivery of vismodegib by microneedle treatment. Drug delivery and translational research. 2015 Aug; 5(4):407-23.
25. Katsumi, H., Liu, S., Tanaka, Y., Hitomi, K., Hayashi, R., Hirai, Y., Kusamori, K., Quan, Y.S., Kamiyama, F., Sakane, T. and Yamamoto, A., 2012. Development of a novel self-dissolving microneedle array of alendronate, a nitrogen-containing bisphosphonate: evaluation of transdermal absorption, safety, and pharmacological effects after application in rats. Journal of pharmaceutical sciences, 101(9), pp.3230-3238.
26. Sharma D. Micro needles: an approach in transdermal drug delivery: a Review. Pharma Tutor. 2018 Jan 1; 6(1):7-15.
27. Akhtar N. Micro needles: an innovative approach to transdermal delivery–a review. Int. J. Pharm. Pharm. Sci. 2014; 6(4):18-25.
28. Suzuki M, Takahashi T, Aoyagi S. 3D laser lithographic fabrication of hollow microneedle mimicking mosquitos and its characterisation. International Journal of Nanotechnology. 2018; 15(1-3):157-73.
29. Cheung K, Han T, Das DB. Effect of force of microneedle insertion on the permeability of insulin in skin. Journal of diabetes science and technology. 2014 May; 8(3):444-52.
30. Larraneta E, Lutton RE, Woolfson AD, Donnelly RF. Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development. Materials Science and Engineering: R: Reports. 2016 Jun 1; 104:1-32.
31. Narayanan SP, Raghavan S. Fabrication and characterization of gold-coated solid silicon microneedles with improved biocompatibility. The International Journal of Advanced Manufacturing Technology. 2019 Oct; 104(9):3327-33.
32. Manoj VR, Manoj HI. Review on transdermal microneedle-based drug delivery. Asian J Pharm Clin Res. 2019; 12(1):18-29.
33. Bora P, Kumar L, Bansal AK. Microneedle technology for advanced drug delivery: Evolving vistas. Review Article, Deaprtment of Pharmaceutical Technology, NIPER, CRIPS. 2008 Jan; 9(1).
34. Lin W, Cormier M, Samiee A, Griffin A, Johnson B, Teng CL, Hardee GE, Daddona PE. Transdermal Delivery of Antisense Oligonucleotides with Microprojection Patch (Macroflux®) Technology. Pharmaceutical research. 2001;18(12):1789-93.
35. Prausnitz MR. Engineering microneedle patches for vaccination and drug delivery to skin. Annual review of chemical and biomolecular engineering. 2017 Jun 7;8:177-200.
36. Mikszta JA, Alarcon JB, Brittingham JM, Sutter DE, Pettis RJ, Harvey NG. Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery. Nature medicine. 2002 Apr;8(4):415-9.
37. Mistilis MJ, Bommarius AS, Prausnitz MR. Development of a thermostable microneedle patch for influenza vaccination. Journal of pharmaceutical sciences. 2015 Feb 1; 104(2):740-9.
38. Rodgers AM, Courtenay AJ, Donnelly RF. Dissolving microneedles for intradermal vaccination: manufacture, formulation, and stakeholder considerations. Expert opinion on drug delivery. 2018 Nov 2; 15(11):1039-43.
39. Zhu DD, Zhang XP, Yu HL, Liu RX, Shen CB, Zhang WF, Cui Y, Guo XD. Kinetic stability studies of HBV vaccine in a microneedle patch. International journal of pharmaceutics. 2019 Aug 15; 567:118489.
40. Littauer EQ, Mills LK, Brock N, Esser ES, Romanyuk A, Pulit-Penaloza JA, Vassilieva EV, Beaver JT, Antao O, Krammer F, Compans RW. Stable incorporation of GM-CSF into dissolvable microneedle patch improves skin vaccination against influenza. Journal of Controlled Release. 2018 Apr 28; 276:1-6.
41. Ali R, Mehta P, Arshad MS, Kucuk I, Chang MW, Ahmad Z. Transdermal microneedles—a materials perspective. Aaps PharmSciTech. 2020 Jan; 21(1):1-4.
42. Jeong HR, Kim JY, Kim SN, Park JH. Local dermal delivery of cyclosporin A, a hydrophobic and high molecular weight drug, using dissolving microneedles. European Journal of Pharmaceutics and Biopharmaceutics. 2018 Jun 1; 127:237-43.
43. Martanto W, Davis SP, Holiday NR, Wang J, Gill HS, Prausnitz MR. Transdermal delivery of insulin using microneedles in vivo. Pharmaceutical research. 2004 Jun; 21(6):947-52.
44. Li QY, Zhang JN, Chen BZ, Wang QL, Guo XD. A solid polymer microneedle patch pretreatment enhances the permeation of drug molecules into the skin. Rsc Advances. 2017;7(25):15408-15.
45. Jung JH, Chiang B, Grossniklaus HE, Prausnitz MR. Ocular drug delivery targeted by iontophoresis in the suprachoroidal space using a microneedle. Journal of Controlled Release. 2018 May 10; 277:14-22.
46. Thakur RR, Tekko IA, Al-Shammari F, Ali AA, McCarthy H, Donnelly RF. Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery. Drug delivery and translational research. 2016 Dec; 6(6):800-15.
47. Than A, Liu C, Chang H, Duong PK, Cheung CM, Xu C, Wang X, Chen P. Self-implantable double-layered micro-drug-reservoirs for efficient and controlled ocular drug delivery. Nature communications. 2018 Nov 6; 9(1):1-2.
48. Ali R, Mehta P, Arshad MS, Kucuk I, Chang MW, Ahmad Z. Transdermal microneedles—a materials perspective. Aaps Pharmscitech. 2020 Jan; 21(1):1-4.
49. Kang-Mieler JJ, Rudeen KM, Liu W, Mieler WF. New Ocular Drug Delivery Systems. In Macular Surgery 2020 (pp. 577-591). Springer, Singapore.
50. Cha KJ, Kim T, Park SJ, Kim DS. Simple and cost-effective fabrication of solid biodegradable polymer microneedle arrays with adjustable aspect ratio for transdermal drug delivery using acupuncture microneedles. Journal of Micromechanics and Micro engineering. 2014 Oct 16; 24(11):115015.
51. Mishra RK, Mohan AV, Soto F, Chrostowski R, Wang J. A microneedle biosensor for minimally-invasive transdermal detection of nerve agents. Analyst. 2017; 142(6):918-24.
52. Sharma S, El-Laboudi A, Reddy M, Jugnee N, Sivasubramaniyam S, El Sharkawy M, Georgiou P, Johnston D, Oliver N, Cass AE. A pilot study in humans of microneedle sensor arrays for continuous glucose monitoring. Analytical Methods. 2018; 10(18): 2088-95.
53. Gowers SA, Freeman DM, Rawson TM, Rogers ML, Wilson RC, Holmes AH, Cass AE, O’Hare D. Development of a minimally invasive microneedle-based sensor for continuous monitoring of β-lactam antibiotic concentrations in vivo. ACS sensors. 2019 Apr 5; 4(4):1072-80.
54. Sharma S, Takagi E, Cass T, Tsugawa W, Sode K. Minimally invasive microneedle array electrodes employing direct electron transfer type glucose dehydrogenase for the development of continuous glucose monitoring sensors. Procedia technology. 2017 Jan 1; 27:208-9.
55. Skoog SA, Miller PR, Boehm RD, Sumant AV, Polsky R, Narayan RJ. Nitrogen-incorporated ultrananocrystalline diamond microneedle arrays for electrochemical biosensing. Diamond and Related Materials. 2015 Apr 1; 54:39-46.
56. Keum DH, Jung HS, Wang T, Shin MH, Kim YE, Kim KH, Ahn GO, Hahn SK. Microneedle Biosensor for Real‐Time Electrical Detection of Nitric Oxide for In Situ Cancer Diagnosis During Endomicroscopy. Advanced healthcare materials. 2015 Jun; 4(8):1153-8.
57. Kearney MC, Caffarel-Salvador E, Fallows SJ, McCarthy HO, Donnelly RF. Microneedle-mediated delivery of donepezil: potential for improved treatment options in Alzheimer’s disease. European Journal of Pharmaceutics and Biopharmaceutics. 2016 Jun 1; 103:43-50.
58. Lee HJ, Son Y, Kim D, Kim YK, Choi N, Yoon ES, Cho IJ. A new thin silicon microneedle with an embedded microchannel for deep brain drug infusion. Sensors and Actuators B: Chemical. 2015 Mar 31; 209:413-22.
59. van der Maaden K, Jiskoot W, Bouwstra J. Microneedle technologies for (trans) dermal drug and vaccine delivery. Journal of controlled release. 2012 Jul 20; 161(2):645-55.
60. Cheung K, West G, Das DB. Delivery of large molecular protein using flat and short microneedles prepared using focused ion beam (FIB) as a skin ablation tool. Drug delivery and translational research. 2015 Aug; 5(4):462-7.
61. Mönkäre J, Nejadnik MR, Baccouche K, Romeijn S, Jiskoot W, Bouwstra JA. IgG-loaded hyaluronan-based dissolving microneedles for intradermal protein delivery. Journal of controlled release. 2015 Nov 28; 218:53-62.
62. Machekposhti SA, Soltani M, Najafizadeh P, Ebrahimi SA, Chen P. Biocompatible polymer microneedle for topical/dermal delivery of tranexamic acid. Journal of Controlled Release. 2017 Sep 10; 261:87-92.
63. Hirobe S, Otsuka R, Iioka H, Quan YS, Kamiyama F, Asada H, Okada N, Nakagawa S. Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo. Life sciences. 2017 Jan 1; 168:24-7.
64. Chandrashekar BS, Yepuri V, Mysore V. Alopecia areata-successful outcome with microneedling and triamcinolone acetonide. Journal of cutaneous and aesthetic surgery. 2014; 7(1):63.
65. Alsantali A. Alopecia areata: a new treatment plan. Clinical, cosmetic and investigational dermatology. 2011; 4:107.
66. Mohammed YH, Yamada M, Lin LL, Grice JE, Roberts MS, Raphael AP, Benson HA, Prow TW. Microneedle enhanced delivery of cosmeceutically relevant peptides in human skin. PloS one. 2014 Jul 17; 9(7):e101956.
67. Pan J, Ruan W, Qin M, Long Y, Wan T, Yu K, Zhai Y, Wu C, Xu Y. Intradermal delivery of STAT3 siRNA to treat melanoma via dissolving microneedles. Scientific reports. 2018 Jan 18; 8(1):1-1.
68. Nangare S, Dhananjay B, Mali R, Shitole M. Development of novel freeze-dried mulberry leaves extract-based transfersomal gel. Turk J Pharm Sci. https://doi. org/10.4274/tjps. 2019 Dec 5; 98624.
69. Park JH, Allen MG, Prausnitz MR. Biodegradable polymer Microneedles: fabrication, mechanics and transdermal drug delivery. Journal of controlled release. 2005 May 5; 104(1):51-66
70. Ramadan E, Borg T, Abdelghani GM, Saleh NM. Transdermal microneedle-mediated delivery of polymeric lamivudine-loaded nanoparticles. J. Pharm. Technol. Drug Res. 2016 Mar 30; 5(1).
71. Yu J, Zhang Y, Gu Z. Glucose-responsive insulin delivery by microneedle-array patches loaded with hypoxia-sensitive vesicles. In Biomedical Nanotechnology 2017 (pp. 251-259). Humana Press, New York, NY.
72. Zhao Z, Chen Y, Shi Y. Microneedles: a potential strategy in transdermal delivery and application in the management of psoriasis. RSC Advances. 2020; 10(24):14040-9.
73. Niu L, Chu LY, Burton SA, Hansen KJ, Panyam J. Intradermal delivery of vaccine nanoparticles using hollow microneedle array generates enhanced and balanced immune response. Journal of controlled release. 2019 Jan 28; 294:268-78.
74. Vemulapalli V, Yang Y, Friden PM, Banga AK. Synergistic effect of iontophoresis and soluble Microneedles for transdermal delivery of methotrexate. Journal of Pharmacy and Pharmacology. 2008 Jan; 60(1):27-33.
75. Du H, Liu P, Zhu J, Lan J, Li Y, Zhang L, Zhu J, Tao J. Hyaluronic acid-based dissolving microneedle patch loaded with methotrexate for improved treatment of psoriasis. ACS applied materials & interfaces. 2019 Oct 25; 11(46):43588-98
76. Nguyen HX, Banga AK. Delivery of methotrexate and characterization of skin treated by fabricated PLGA micro needles and fractional ablative laser. Pharmaceutical research. 2018 Mar; 35(3):1-20.
77. Korkmaz E, Friedrich EE, Ramadan MH, Erdos G, Mathers AR, Ozdoganlar OB, Washburn NR, Falo Jr LD. Therapeutic intradermal delivery of tumor necrosis factor-alpha antibodies using tip-loaded dissolvable microneedle arrays. Acta biomaterialia. 2015 Sep 15; 24:96-105.
78. Wang C, Ye Y, Hochu GM, Sadeghifar H, Gu Z. Enhanced cancer immunotherapy by micro needle patch-assisted delivery of anti-PD1 antibody. Nano letters. 2016 Apr 13; 16(4):2334-40.
79. Naguib YW, Kumar A, Cui Z. The effect of Micro needles on the skin permeability and antitumor activity of topical 5-fluorouracil. Acta Pharmaceutica Sinica B. 2014 Feb 1; 4(1):94-9.
80. Bhatnagar S, Kumari P, Pattarabhiran SP, Venuganti VV. Zein micro needles for localized delivery of chemotherapeutic agents to treat breast cancer: drug loading, release behavior, and skin permeation studies. AAPS Pharm SciTech. 2018 May; 19(4):1818-26.
81. Ye Y, Wang C, Zhang X, Hu Q, Zhang Y, Liu Q, Wen D, Milligan J, Bellotti A, Huang L, Dotti G. A melanin-mediated cancer immunotherapy patch. Science immunology. 2017 Nov 10; 2(17).
82. Zhao X, Li X, Zhang P, Du J, Wang Y. Tip-loaded fast-dissolving micro needle patches for photodynamic therapy of subcutaneous tumor. Journal of controlled release. 2018 Sep 28; 286:201-9.
83. Nguyen HX, Bozorg BD, Kim Y, Wieber A, Birk G, Lubda D, Banga AK. Poly (vinyl alcohol) micro needles: fabrication, characterization, and application for transdermal drug delivery of doxorubicin. European journal of pharmaceutics and biopharmaceutics. 2018 Aug 1; 129:88-103.
84. Lan X, She J, Lin DA, Xu Y, Li X, Yang WF, Lui VW, Jin L, Xie X, Su YX. Micro needle-mediated delivery of lipid-coated cisplatin nanoparticles for efficient and safe cancer therapy. ACS applied materials & interfaces. 2018 Sep 11; 10(39):33060-9.
85. Dong L, Li Y, Li Z, Xu N, Liu P, Du H, Zhang Y, Huang Y, Zhu J, Ren G, Xie J. Au nanocage-strengthened dissolving micro needles for chemo-photothermal combined therapy of superficial skin tumors. ACS applied materials & interfaces. 2018 Mar 1; 10(11):9247-56.
86. Jain AK, Lee CH, Gill HS. 5-Aminolevulinic acid coated microneedles for photodynamic therapy of skin tumors. Journal of Controlled Release. 2016 Oct 10; 239:72-81.
87. Chen MC, Lin ZW, Ling MH. Near-infrared light-activatable microneedle system for treating superficial tumors by combination of chemotherapy and photothermal therapy. ACS nano. 2016 Jan 26;10(1):93-101.
88. Donnelly RF, Morrow DI, McCarron PA, Woolfson AD, Morrissey A, Juzenas P, Juzeniene A, Iani V, McCarthy HO, Moan J. Micro needle-mediated intradermal delivery of 5-aminolevulinic acid: potential for enhanced topical photodynamic therapy. Journal of Controlled Release. 2008 Aug 7; 129(3):154-62.
89. Yu J, Zhang Y, Ye Y, Isanti R, Sun W, Ranson D, Ligler FS, Buse JB, Gu Z. Micro needle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proceedings of the National Academy of Sciences. 2015 Jul 7; 112(27):8260-5.
90. Chen W, Tian R, Xu C, Yung BC, Wang G, Liu Y, Ni Q, Zhang F, Zhou Z, Wang J, Niu G. Micro needle-array patches loaded with dual mineralized protein/peptide particles for type 2 diabetes therapy. Nature communications. 2017 Nov 24; 8(1):1-1.
91. Lee H, Choi TK, Lee YB, Cho HR, Ghaffari R, Wang L, Choi HJ, Chung TD, Lu N, Hyeon T, Choi SH. A graphene-based electrochemical device with thermo responsive micro needles for diabetes monitoring and therapy. Nature nanotechnology. 2016 Jun; 11(6):566-72.
92. Singh A, Yadav S. Micro needling: advances and widening horizons. Indian dermatology online journal. 2016 Jul; 7(4):244.
93. Hong X, Wei L, Wu F, Wu Z, Chen L, Liu Z, Yuan W. Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine. Drug design, development and therapy. 2013; 7:945.
94. Dugam S, Tade R, Dhole R, Nangare S. Emerging era of microneedle array for pharmaceutical and biomedical applications: recent advances and toxicological perspectives. Future Journal of Pharmaceutical Sciences. 2021 Dec; 7(1):1-26.
95. Kaspar RL, Speaker T, inventors; TRANSDERM Inc, assignee. Delivery of botulinum with microneedle arrays. United States patent application US 15/331,469. 2017 Jul 27.
96. Kaushik S, Hord AH, Denson DD, McAllister DV, Smitra S, Allen MG, Prausnitz MR. Lack of pain associated with microfabricated microneedles. Anesthesia & Analgesia. 2001 Feb 1; 92(2):502-4.
97. 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 Jun 1; 128:1-7.
98. https://www.clinicaltrials.gov/ct2/results