INTRODUCTION:

Dissolving microneedles offer a less painful method of delivering active ingredients compared to traditional hypodermic needles, potentially improving the quality of life for individuals requiring frequent injections. These environmentally friendly microneedles dissolve into the skin after use, leaving no harmful waste behind. They also reduce cold-chain supply costs due to their solid state, which enhances stability. Typically composed of solid materials coated with water-soluble formulations, dissolving microneedles release their drug payload into the skin upon insertion, either through dissolution or degradation.¹

Fabrication techniques focus on mechanical strength, material choice, and tip sharpness to ensure easy insertion into tissues. Various materials such as silicon, polymers, metals, and ceramics are used in their production.^2,3 Microneedles can be used for a range of drug delivery applications, including transdermal, ocular, oral mucosal, gastrointestinal, ungual, and vaginal administration. Different types of microneedles, including solid removable, dissolving, hollow, coated, and hydrogelforming⁴, offer unique mechanisms of drug delivery enhancement. Research into extending microneedle applications to other organs and tissues, such as the oral cavity⁵, gastrointestinal tract⁶, nails⁷, and eyes⁸, shows promise in expanding their utility beyond transdermal delivery. Overall, microneedles represent a versatile and promising approach to drug delivery, with ongoing advancements driving their adoption in various medical contexts. The oral route stands as the most commonly utilized method for drug delivery, owing to its simplicity and cost-effectiveness (no specialized personnel required).^9,10 Oral solid forms such as tablets and capsules generally boast good physicochemical stability and ease of dosing. Yet, these formulations encounter hurdles that may hinder drug bioavailability, including the hepatic first-pass effect, complex formation, hydrolysis by gastric pH, and malabsorption due to diseases or surgeries.^11-14 Patient adherence to therapeutic guidelines poses another challenge¹⁵, particularly among children and the elderly, leading to the development of alternative oral liquid formulations.¹⁶ Efforts to optimize these forms often focus on prolonging drug release to reduce administration frequency.¹² However, these formulations are technologically complex and susceptible to degradation, potentially compromising efficacy or safety.

Figure 1. Types of microneedles, step-by-step process of their application, and corresponding mechanisms of drug delivery across a tissue barrier.

MICRONEEDLES – BASED DRUG DELIVERY APPROACHES:

“The efficacy of microneedle array (MNA) drug delivery hinges on crucial factors, primarily revolving around MNA design (including shape, size, geometry, and fabrication materials and methods) and the nature of the active ingredient being delivered.Various approaches can be categorized as: ‘penetrate and seal,’ ‘penetrate and flow,’ ‘encapsulate and penetrate,’ and ‘penetrate and release.¹³

Solid Microneedles for “Poke and Patch”:

The “penetrate and seal” method involves using solid MNA to create microchannels in the skin, reaching deep layers of the epidermis. This process enhances the passive transport of drugs through the skin by disrupting the main barrier, the stratum corneum.^14,16Its simplicity in terms of technology makes it appealing, especially for easy implementation in clinical settings. However, this technique is not without controversy and has several drawbacks. One major limitation is that the micropores remain open for a limited time, potentially halting the delivery of the active substance prematurely. Studies have shown that barrier properties are restored within 2 hours after microneedle treatment. Yet, this timeframe can be extended up to three days under occlusive conditions using formulations like patches or tapes¹⁷, albeit at the cost of increased infection risk.¹⁸

Microneedle – Based Drug Delivery Approaches:-

Various approaches can be categorized as: ‘penetrate and seal,’ ‘penetrate and flow,’ ‘encapsulate and penetrate,’ and ‘penetrate and release.¹⁹

Solid Microneedles for “Poke and Patch”:

The “penetrate and seal” method involves using solid MNA to create microchannels in the skin, reaching deep layers of the epidermis. This process enhances the passive transport of drugs through the skin by disrupting the main barrier, the stratum corneum.^20,21 This approach entails two steps: firstly, the MNA puncture the epidermis and are then removed, followed by the application of the drug in a conventional form (solution, cream, or patch), serving as an external drug reservoir.²²Its simplicity in terms of technology makes it appealing, especially for easy implementation in clinical settings.Yet, this timeframe can be extended up to three days under occlusive conditions using formulations like patches or tapes²³, albeit at the cost of increased infection risk.²⁴

Coated Microneedles for “Coat and Poke”:

Another method using robust MNA involves the “encase and puncture” technique, where the surface of the solid microneedles is covered with a drug or vaccine-containing substance.²⁵ This approach facilitates drug diffusion from the encasing layer to the deeper layers of the epidermis upon MNA insertion (Figure 3).²⁶ However, there are certain limitations associated with the encasing process that affect its efficacy. For example, the amount of drug that can be enclosed within the encasing layer is relatively limited. Additionally, the thickness of the encasing material may reduce the sharpness of the microneedles and affect their ability to penetrate the skin.^27,28

Dissolving and Hydrogel-Forming Microneedles for “Poke and Release”:

Water-soluble and biodegradable materials are commonly used in the production of dissolving MNA, allowing drugs to be loaded and released as the MNA dissolve after insertion.^29.30 This approach offers several advantages over the “poke and patch” method. Dissolving microneedles can provide controlled drug release over an extended period by regulating the dissolution rate of the matrix formulation used in the MNA. Additionally, it simplifies the drug administration process to a single step, as the MNA can penetrate the skin

Hollow Microneedles for “Poke and Flow”:

The “poke and flow” strategy was developed to deliver drug solutions into the skin, resembling hypodermic injections but addressing their drawbacks.^31,32 In this method, microneedles serve a similar function to hypodermic needles, facilitating the administration of drug formulations after skin penetration.

Preparation of Dissolving microneedles:

Water-soluble microneedles consist of materials, primarily polymers such as polyvinyl alcohol, carboxymethyl cellulose, and dextran, along with biodegradable polymers like polylactic acid, chitosan, and polyglycolic acid or polylactide-co-glycolide (PLGA).³³ Unlike coated and polymer microneedles, dissolving microneedles are designed to fully dissolve in the skin, eliminating any sharps waste afterward. They are typically fabricated on flat, cylindrical, or planar substrates and are pressed into the skin in unison. These microneedles not only penetrate the skin but also act as carriers for drug delivery into the tissue, allowing for precise dosage administration. Each array can accommodate up to 1mg of drug.³⁴

Fabrication Process:

The materials for dissolving microneedles are typically produced through a photolithographic and micromolding procedure. This process involves utilizing thick photoresist polymer SU-8 and poly-methyl-methacrylate (PMMA), with light path control being a crucial aspect of the photolithographic process.³⁵

Lithography Techniques:

Drawing Lithography: This method relies on the stretching deformation of polymeric or biodegradable polymeric material from a 2-dimensional to a 3-dimensional structure. The process involves dispensing melted polymer or dissolving material onto a fixed plate and elongating it by drawing pillars on the upper-moving plate. The viscosity of the polymer or dissolving material is gradually increased by cooling until it reaches the glass transition temperature, resulting in a solid polymeric material suitable for skin piercing. This method minimizes waste of dissolving polymeric material as drops are dispensed directly onto the plate. However, it is not suitable for thermolabile antigens due to high transition and melting temperatures.^36-38

Deep X-ray Lithography:

This method produces dissolving microneedles with sharp tips using short wavelength x-rays and high photon energy. While effective, it suffers from the same limitations as UV lithography regarding fixed substrates and x-ray sources. Control over the dissolution rate of the polymethylmethacrylate (PMMA) resist is achieved by regulating the absorbed dose with double exposure.⁴⁹

Droplet Air Blowing Method:

In this technique, droplets of plain polymer or dissolving material solution and drug solution are dispensed onto two plates, which are then brought into contact and withdrawn to produce dissolving microneedles of the required lengths. Air flow is used to dry the polymer or biodegradable solutions, resulting in dissolving microneedle patches or arrays on each plate.⁴⁰

Molding and Casting:

This approach involves fabricating dissolving microneedles of desired shapes and structures by changing the mold structures and/or casting materials. Silicon, metal, and polymers are commonly used as base materials for microneedle production. Silicon base micromolds are fabricated by deep-reactive ion etching, while metal base micromolds are produced by electroplating metal onto silicon microneedle masters. Polymeric base micromolds are made using a mechanical micromilling process with polydimethylsiloxane (PDMS).

Coating Methods:

Coating can be performed by dipping the casting solution into a large bath or by layer-by-layer coating techniques. Coating formulations should be water-soluble and compatible with industrial pharmaceutical manufacturing processes. Various materials, such as polymethylmethacrylate, poly(lactic-co-glycolic acid) (PLGA), carboxymethyl cellulose, hyaluronic acid, and sugars, can be used to make solid and dissolving microneedles.⁴¹

Drug Coating Formulation:

Dissolving microneedle coating formulations are typically applied by dip coating or spreading drug solution onto microneedle surfaces. The coating process should not damage the drug and must be compatible with industrial pharmaceutical manufacturing processes. The formulation should be water-soluble to ensure rapid and complete dissolution into the skin, and the coating solution excipients and solvent should be safe for human use.

Hollow Dissolving Microneedles:

Similar to hypodermic needles, hollow dissolving microneedles are fabricated to optimize drug delivery into the skin or other tissues. They can modulate pressure and flow rate for slow infusion or time-varying delivery. Hollow dissolving microneedles can also serve as channels for drug diffusion into the skin from a non-pressurized drug reservoir.⁴²

EVALUATION OF MICRONEEDLES:

Characterization Methods:

Drug Loading:

The drug can be loaded into dissolving microneedles in various forms such as suspension, dispersion, or encapsulated forms like liposomes, nanoparticles, and nanoliposomes. Physicochemical characterization methods including polydispersity index, viscosity, and zeta potential are evaluated based on the type of formulation used. Drug release, adhesion, and permeation tests are conducted before and after treatment. The size, internal structure, and crystallinity of liposomes or nanocarriers are analyzed using techniques such as dynamic light scattering, X-ray scattering, transmission electron microscopy, and optical coherence tomography (OCT).

Dimensional Evaluation:

Various methods are employed to assess the geometry of the microneedles and measure parameters such as tip radius, length, and height. Common methods include optical or electrical microscopy. Analysis of 3D images provides a comprehensive understanding of needle geometry and aids in quality control. Scanning Electron Microscopy (SEM), multiphoton microscopy, and confocal laser microscopy are utilized for detailed visualization. SEM utilizes a focused beam of electrons to generate images of the sample surface topography and composition, while confocal laser microscopy produces high-resolution images.

In-vitro Skin Permeation Studies:

Techniques for testing skin permeation include measurements of transepidermal water loss (TEWL)⁴³ and electrical resistance⁴⁴. Instruments such as the Delfin Vapometer are used to measure skin penetration. Additionally, diffusion cell apparatus is employed to assess drug permeation through the skin. Cumulative permeation profiles of microneedle-treated and untreated skin are compared. Various dyes, such as trypan blue, methylene blue, and gentian violet, are utilized to examine microneedle delivery properties.⁴⁵

APPLICATION OF MICRONEEDLE DRUG DELIVERY SYSTEM:

Parenteral administration is typically preferred for certain medications like proteins, antibodies, antigens, and other biotechnological active ingredients.^46,47 These substances are usually not well absorbed orally due to their molecular weight and sensitivity to degradation. Various methods of encapsulation, particularly in nano or microparticles, have been developed to address these challenges. These molecules are prime candidates for transdermal delivery via microneedles. This section provides an overview of the main types of drugs studied for transdermal administration using microneedle arrays (MNA) and their applications.⁴⁸

Immunization:

“Vaccination through the skin via transdermal administration is an area of growing interest due to the presence of specialized immune cells like dendritic and Langerhans cells in the epidermis. These cells play a crucial role in initiating immune responses⁴⁹by uptaking and presenting antigens to other immune cells. Various types of microneedle arrays (MNAs), including dissolving, hollow, and coated ones, have been explored as delivery systems for vaccines. Ovalbumin (OVA)⁵⁰is frequently used as a model antigen in studies involving MNAs. For instance, Du et al. developed a hollow MNA to deliver OVA-loaded nanoparticles along with poly(I:C),⁵¹ which induced a robust immune response in a murine model. Similarly, McCrudden et al. utilized dissolving MNAs to deliver OVA, resulting in significant humoral and cellular immune responses in mice.⁵²

Therapeutic Proteins:

Bovine serum albumin (BSA) is often utilized as a prototype protein for transdermal drug delivery of therapeutic proteins using microneedles.⁵² Cheung et al. employed the focused ion beam technique (FIB) to fabricate microneedles and enhance BSA absorption via the “poke and patch” method. Their findings indicated that BSA absorption through the skin necessitates prior stratum corneum perforation using MNA to establish pathways for protein passage.⁵³ Immunoglobulins are frequently used to treat conditions involving antibody production deficits, typically administered via injection. Several research groups have explored the potential of MNA administration instead. Mönkäre et al. loaded monoclonal IgG (10% w/w) into dissolving HA MNA, successfully reaching the epidermis of ex vivo human skin.^54-56

Insulin:

Insulin has been extensively studied for delivery through routes other than subcutaneous injection. In the realm of microneedle array (MNA) technology, Lee et al. developed dissolving MNAs made of gelatin and CMC, concentrating insulin in the needle tip to enhance transdermal delivery,⁵⁷ Ex vivo experiments demonstrated release and skin penetration of insulin, with in vivo bioavailability reaching 95.6% and 85.7%, respectively.⁵⁸ Yu et al. designed MNAs containing insulin and glucose oxidase-loaded nanovesicles, which responded to local hypoxia induced by glucose oxidation, achieving effective and controlled blood glucose regulation in diabetic animal models.⁵⁹

Vitamins:

Various demographic groups face significant risks of experiencing vitamin deficiency.^60-62 These MNAs exhibited a five-fold improvement in delivery efficacy compared to a transdermal cream with chemical permeation enhancers. Particularly, the delivery efficiency was 81.08% for the MNA and only 16.28% for the transdermal cream.^63,64

Antibiotics:

Using controlled-release drug delivery systems for antibiotic administration could reduce dosage frequency, aiding in the battle against antibiotic resistance.⁸⁹In vivo studies demonstrated that while intramuscular injections yielded higher plasma concentrations initially, MAPs provided more consistent levels over time, extending the therapeutic effect and reducing administration frequency.⁶⁵ Another study by Lee et al. focused on bleomycin-coated MAPs, showcasing efficient drug delivery into porcine skin. Pharmacokinetic analysis in rats highlighted prolonged drug release and a longer half-life compared to conventional subcutaneous injections.⁶⁶

Natural Compounds:

Certain natural compounds exhibit anti-inflammatory, anti-carcinogenic, anti-microbial, and antioxidant properties, making them candidates for diverse therapeutic uses.⁶⁸A significant increase in quercetin release from lipid nanoparticles after microneedle pre-treatment, with twofold higher penetration into the stratum corneum and fivefold higher penetration into the epidermis compared to untreated skin. Overall, these findings underscore the potential of MNAs as a promising approach for improving the transdermal delivery of bioactive compounds.^69-71

Cosmeceuticals:

Currently, cosmeceuticals undergo extensive clinical trials when combined with MNA.⁷² This is primarily due to MNA’s ability to deliver active ingredients to the viable epidermis and the simpler regulatory processes compared to medicinal products. Another study by Lee et al. demonstrated the skin barrier restoration and moisturizing properties of horse oil-loaded dissolving HA MNA, resulting in improved skin elasticity and moisture content over four weeks.⁷³

Table 1: Summary of Microneedles in Pharmaceutical Science

S. No.	Researcher years	Title of Research	Findings	Ref. No.
1	Lulu et al. 2024	Dissolving microneedle to improve transdermal delivery of terbinafine for treatment of onychomycosis	The topical formulation of antifungal agents has demonstrated prominent success in treating fungal infection.	70
2	Shahbazi et al. 2023	Recent approaches for enhancing the performance of dissolving microneedles in drug delivery applications	Dissolving microneedles (dMNs) are promising versatile drug delivery systems for the transdermal delivery	71
3	Tejashree et al. 2019	A smart approach and increasing potential for transdermal drug delivery system	The most widely used methods for transdermal administration of the drugs are hypodermic needles, topical creams, andtransdermal patches.	72
4	Darji et al. 2018	Excipient Stability in Oral Solid Dosage Forms: A Review	The choice of excipients constitutes a major part of preformulation and formulation studies during the preparation of pharmaceutical dosage forms.	10
5	Bhatnagar et al./2017	Microneedles in the Clinic.	Reduction in the dimensions of hypodermic needle to micron-scale size has gained tremendous interest among researchers.	25
6	Goyal et al. 2016	Nanoparticles and nanofibers for topical drug delivery	This review provides the first comprehensive overview of the use of both nanoparticles and nanofibers for topical drug delivery. Researchers have explored the use of nanotechnology, specifically nanoparticles and nanofibers, as drug delivery systems for topical and transdermal applications.	19
7	McCrudden et al. 2015	Laser-engineered dissolving microneedle arrays for protein delivery: potential for enhanced intradermal vaccination	Aimed to highlight the utility of novel dissolving microneedle (MN)-based delivery systems for enhanced transdermal protein delivery	46
8	Okebukola et al. 2014	Vitamin E supplementation in people with cystic fibrosis	People with cystic fibrosis are at an increased risk of fat-soluble vitamin deficiency including vitamin E.	57
9	Mahadevan et al. 2013	PDMS embedded microneedles as a controlled release system for the eye	To demonstrate intraocular drug delivery using a novel device fabricated by embedding hollow glass microneedles within a soft and flexible poly (dimethylsiloxane) (PDMS) substrate for ease of device insertion into the eye.	73
10	Patel et al. 2012	Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye	This study seeks to determine the intraocular pharmacokinetics of molecules and particles injected into the suprachoroidal space of the rabbit eye in vivo using a hollow microneedle.	74
11	Sullivan et al. 2010	Dissolving polymer microneedle patches for influenza vaccination	Influenza prophylaxis would benefit from a vaccination method enabling simplified logistics and improved immunogenicity without the dangers posed by hypodermic needles.	35
13	Donnelly et al. 2009	Microneedle arrays allow lower microbial penetration than hypodermic needles in vitro	In this study we determined, for the first time, the ability of microorganisms to traverse microneedle-induced holes using two different in vitro models.	75

CONCLUSION:

As a novel technology, dissolving microneedles offer advantages such as painless and swift delivery compared to other systemic administration methods. They have shown significant progress in various fields including immunobiologicals, disease diagnosis, long-term treatment, and cosmetics. However, there is still a pressing need for the development of wearable and smart devices to facilitate long-term disease management. Economic cosmetic products utilizing dissolving microneedles may experience rapid growth and expanded opportunities in the coming decades. Overall, dissolving microneedles hold great promise for biomedical applications. Wearable devices incorporating dissolving microneedle patches are anticipated to seamlessly integrate disease diagnosis and treatment in the near future.

REFERENCES:

1. Yeu-Chun Kim, Jung-Hwan Park, Mark R, Prausnitz. Microneedles for drug and vaccine delivery.Adv Drug Deliv Rev. 2012; 64(14): 1547-1568.

2. Shayan Fakhraei Lahiji, Youseong Kim, Geonwoo Kang Suyong Kim, Seunghee Lee, Hyungil Jung. Tissue Interlocking Dissolving Microneedles for Accurate and Efficient Transdermal Delivery of Biomolecules. J. Bio.Sci. 2019; 21(3): 211223.

3. Shayan Fakhraei Lahiji, Youseong Kim, Geonwoo Kang, Suyong Kim, Seunghee Lee, Hyungil Jung. Tissue Interlocking Dissolving Microneedles for Accurate and Efcient Transdermal Delivery of Biomolecules. Scientific Reports. 2019; 9: 7886.

4. Bariya, S.H., et al. Microneedles: an emerging transdermal drug delivery system. Journal of Pharmacy and Pharmacology. 2012; 64(1): 11-29.

5. Serpe, L., et al. Influence of salivary washout on drug delivery to the oral cavity using coated Microneedles: An in vitro Evaluation. European Journal of Pharmaceutical Sciences. 2016; 93: 215-223.

6. Traverso, G., et al., Microneedles for drug delivery via the gastrointestinal tract. Journal of Pharmaceutical Sciences. 2015. 104(2): 362-367.

7. Chiu, W.S., et al. Drug delivery into microneedle-porated nails from nanoparticle reservoirs. Journal of Controlled Release. 2015; 220: 98-106.

8. Thakur Singh, R.R., et al. Minimally invasive microneedles for ocular drug delivery. Expert Opinion on Drug Delivery, 2016: p. 1-13.

9. MacGregor, R.R.; Graziani, A.L. Oral Administration of Antibiotics: A Rational Alternative to the Parenteral Route. Clin. Infect. Dis. 1997; 24: 457–467.

10. Darji, M.A.; Lalge, R.M.; Marathe, S.P.; Mulay, T.D.; Fatima, T.; Alshammari, A.; Lee, H.K.; Repka, M.A.; Narasimha Murthy, S. Excipient Stability in Oral Solid Dosage Forms: A Review. AAPS Pharm Sci Tech. 2018; 19: 12–26.

11. Davis, S.S.; Hardy, J.G.; Fara, J.W. Transit of Pharmaceutical Dosage Forms through the Small Intestine. Gut. 1986; 27: 886–892.

12. Maderuelo, C.; Lanao, J.M.; Zarzuelo, A. Enteric Coating of Oral Solid Dosage Forms as a Tool to Improve Drug Bioavailability. Eur. J. Pharm. Sci. 2019; 138: 105019.

13. Prausnitz, M.R. Engineering Microneedle Patches for Vaccination and Drug Delivery to Skin. Annu. Rev. Chem. Biomol.Eng. 2017; 8: 177–200.

14. Li, W.-Z.; Huo, M.-R.; Zhou, J.-P.; Zhou, Y.-Q.; Hao, B.-H.; Liu, T.; Zhang, Y. Super-Short Solid Silicon Microneedles For Transdermal Drug Delivery Applications. Int. J. Pharm. 2010; 389: 122–129.

15. Gupta, J.; Gill, H.S.; Andrews, S.N.; Prausnitz, M.R. Kinetics of Skin Resealing after Insertion of Microneedles In Human Subjects. J. Control. Release. 2011; 154: 148–155.

16. Larrañeta, E.; Lutton, R.E.M.; Woolfson, A.D.; Donnelly, R.F. Microneedle Arrays as Transdermal andIntradermal Drug Delivery Systems: Materials Science, Manufacture and Commercial Development. Mater. Sci. Eng. R Rep. 2016; 104: 1–32.

17. Kalluri, H.; Banga, A.K. Formation and Closure of Microchannels in Skin Following Microporation. Pharm. Res. 2011: 28: 82–94.

18. Donnelly, R.F.; Singh, T.R.R.; Alkilani, A.Z.; McCrudden, M.T.C.; O’Neill, S.; O’Mahony, C.; Armstrong, K.; McLoone, N.; Kole, P.; Woolfson, A.D. Hydrogel-Forming Microneedle Arrays Exhibit Antimicrobial Properties: Potential for Enhanced Patient Safety. Int. J. Pharm. 2013; 45: 76–91.

19. Goyal, R.; Macri, L.K.; Kaplan, H.M.; Kohn, J. Nanoparticles and Nanofibers for Topical Drug Delivery. J. Control. Release. 2016: 240: 77–92.

20. Li, S.; Li, W.; Prausnitz, M. Individually Coated Microneedles for Co-Delivery of Multiple Compounds with Different Properties. Drug Deliv. Transl. Res. 2018; 8: 1043–1052.

21. Iliescu, F.; Dumitrescu-Ionescu, D.; Petrescu, M.; Iliescu, C. A Review on Transdermal Drug Delivery Using Microneedles: Current Research and Perspective. Ann. Acad. Rom. Sci. Series Sci. Technol. Inf. 2014; 7: 7–34.

22. Koutsonanos, D.G.; del Pilar Martin, M.; Zarnitsyn, V.G.; Sullivan, S.P.; Compans, R.W.; Prausnitz, M.R.; Skountzou, I. Transdermal Influenza Immunization with Vaccine-Coated Microneedle Arrays. PLoS ONE. 2009; 4: e4773.

23. Rodgers, A.M.; McCrudden, M.T.C.; Vincente-Perez, E.M.; Dubois, A.V.; Ingram, R.J.; Larrañeta, E.;Kissenpfennig, A.; Donnelly, R.F. Design and Characterisation of a Dissolving Microneedle Patch for Intradermal Vaccination with HeatInactivated Bacteria: A Proof of Concept Study. Int. J. Pharm. 2018; 549: 87–95.

24. Lee, W.-J.; Han, M.-R.; Kim, J.-S.; Park, J.-H. A Tearable Dissolving Microneedle System for Shortening Application Time. Expert Opin. Drug Deliv. 2019; 16: 199–206.

25. Bhatnagar, S.; Dave, K.; Venuganti, V.V.K. Microneedles in the Clinic. J. Control. Release. 2017; 260: 164–182.

26. Martanto, W.; Moore, J.S.; Kashlan, O.; Kamath, R.; Wang, P.M.; O’Neal, J.M.; Prausnitz, M.R. Microinfusion Using Hollow Microneedles. Pharm. Res. 2006; 23: 104–113.

27. 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 Design, Development and Therapy. 2013; 7: 945.

28. Sixing Yang, Yan Feng, Lijun Zhang, Nixiang Chen, Weien Yuan, Tuo Jin. A scalable fabrication process of Polymer Microneedles. Int J Nanomed. 2012; 7:1415-1422.

29. Xiaoxiang He, Jingyao Sun, Jian Zhuang, Hong Xu, Ying Liu, Daming Wu. Microneedle System for Transdermal Drug And Vaccine Delivery: Devices, Safety, and Prospects, Dose-Response: Int. J Phar. 2019; l(3): 1-18.

30. Jeong Woo Lee, Mee-Ree Han, Jung-Hwan Park. Polymer microneedles for transdermal drug delivery, Journal of Drug Targeting, 2013; 21(3): 211-223.

31. Leo ne M, Monkare J, Bouwstra JA, Kersten G. Dissolving Microneedle Patches for Dermal Vaccination, Pharm Res. 2017; 17: 222.

32. Chong In Shin, Seong Dong Jeong, Sanoj Rejinold N, Yeu-Chun Kim. Microneedles for vaccine delivery: challenges and Future perspectives, Ther. Deliv. 2017; 8(6): 447-460.

33. Shayan Fakhraei Lahiji, Youseong Kim, Geonwoo Kang, Suyong Kim, Seunghee Lee, Hyungil Jung. Tissue Interlocking Dissolving Microneedles for Accurate and Efcient Transdermal Delivery of Biomolecules. Scientific Reports. 2019; 9: 7886.

34. Kim JD, Kim M, Yang H, Lee K, Jung H. Droplet-born Air blowing: Novel dissolving microneedle fabrication. Contrl. Rel. 2013; 170(3): 430-436.

35. Sullivan SP, Koutsonanos DG, del Pilar Martin M. Dissolving polymer microneedle patches for influenza Vaccination. Nat Med. 2010; 16(8): 915-920.

36. Wang PM, Cornwell M, Hill J, Prausnitz MR. Precise Microinjection into skin using hollow microneedles. J InvestDermatol. 2006; 126(5): 1080-1087.

37. Sivamani RK, Stoeber B, Liepmann D, Maibach HI. Microneedle penetration and injection past the stratum Corneum inHumans. Journal of Dermatological Treatment. 2009; 20: 156-9.

38. Gittard SD, Chen B, Xu H, Ovsianikov A, Chichkov BN, Monteiro-Riviere NA et al. The effects of geometry on Skin Penetration and failure of polymer microneedles. Journal of Adhesion Science and Technology. 2013; 27(3): 227-243.

39. Choi SO, Kim YC, Park JH, Hutcheson J, Gill HS, Yoon YK et al. An electrically active microneedle array for Electroporation. Biomed. Biomedical Microdevices. 2010; 12: 263-73.

40. Patel, A.; Cholkar, K.; Mitra, A.K. Recent Developments in Protein and Peptide Parenteral Delivery Approaches. Ther.Deliv. 2014; 5: 337–365.

41. Bull, S.P.; Hong, Y.; Khutoryanskiy, V.V.; Parker, J.K.; Faka, M.; Methven, L. Whey Protein Mouth Drying Influenced By Thermal Denaturation. Food Qual. Prefer. 2017; 56 (Pt B): 233–240.

42. Muheem, A.; Shakeel, F.; Jahangir, M.A.; Anwar, M.; Mallick, N.; Jain, G.K.; Warsi, M.H.; Ahmad, F.J. A Review on The Strategies for Oral Delivery of Proteins and Peptides and Their Clinical Perspectives. Saudi Pharm. J. 2016; 24: 413–428.

43. Collin, M.; Milne, P. Langerhans Cell Origin and Regulation. Curr. Opin. Hematol. 2016: 23; 28–35.

44. Van der Maaden, K.; Jiskoot, W.; Bouwstra, J. Microneedle Technologies for (Trans) Dermal Drug and Vaccine Delivery. J. Control. Release. 2012; 161: 645–655.

45. Du, G.; Hathout, R.M.; Nasr, M.; Nejadnik, M.R.; Tu, J.; Koning, R.I.; Koster,A.J.; Slütter, B.; Kros, A.; Jiskoot, W.; et al. Intradermal Vaccination with Hollow Microneedles: A Comparative Study Of Various Protein Antigen and Adjuvant Encapsulated Nanoparticles. J. Control. Release. 2017; 266: 109–118.

46. McCrudden, M.T.C.; Torrisi, B.M.; Al-Zahrani, S.; McCrudden, C.M.; Zaric, M.; Scott, C.J.; Kissenpfennig, A.; McCarthy, H.O.; Donnelly, R.F. Laser-Engineered Dissolving Microneedle Arrays for Protein Delivery: Potential for Enhanced Intradermal Vaccination. J. Pharm. Pharmacol. 2015; 67: 409–425.

47. Van der Maaden, K.; Jiskoot, W.; Bouwstra, J. Microneedle Technologies for (Trans) Dermal Drug and Vaccine Delivery. J. Control. Release. 2012; 161: 645–655.

48. Cheung, K.; West, G.; Das, D.B. Delivery of Large Molecular Protein Using Flat and Short Microneedles Prepared UsingFocused Ion Beam (FIB) as a Skin Ablation Tool. Drug Deliv. Transl. Res. 2015; 5: 462–467.

49. Courtenay, A.J.; McCrudden, M.T.C.; McAvoy, K.J.; McCarthy, H.O.; Donnelly, R.F. Microneedle-Mediated Transdermal Delivery of Bevacizumab. Mol. Pharm. 2018; 15: 3545–3556.

50. Chen, J.; Qiu, Y.; Zhang, S.; Gao, Y. Dissolving Microneedle-Based Intradermal Delivery of Interferon-α-2b Drug Dev. Ind. Pharm. 2016; 42: 890–896.

51. Ie, X.; Pascual, C.; Lieu, C.; Oh, S.; Wang, J.; Zou, B.; Xie, J.; Li, Z.; Xie, J.; Yeomans, D.C.; et al. Analgesic MicroneedlePatch for Neuropathic Pain Therapy. ACS Nano. 2017; 11: 395–406.

52. Resnik, D.; Možek, M.; Peˇcar, B.; Janež, A.; Urbanˇciˇc, V.; Iliescu, C.; Vrtaˇcnik, D. In Vivo Experimental Study Of Noninvasive Insulin Microinjection through Hollow Si Microneedle Array. Micromachines (Basel). 2018; 9: 40.

53. Lee, I.-C.; Lin, W.-M.; Shu, J.-C.; Tsai, S.-W.; Chen, C.-H.; Tsai, M.-T. Formulation of Two-Layer Dissolving Polymeric Microneedle Patches for Insulin Transdermal Delivery in Diabetic Mice. J. Biomed. Mater. Res. A. 2017; 105: 84–93.

54. Chen, M.-C.; Ling, M.-H.; Kusuma, S.J. Poly-γ-Glutamic Acid Microneedles with a Supporting Structure Design as aPotential Tool for Transdermal Delivery of Insulin. Acta Biomater. 2015; 24: 106–116.

55. Dong, R.; Sun, S.; Liu, X.-Z.; Shen, Z.; Chen, G.; Zheng, S. Fat-Soluble Vitamin Deficiency in Pediatric Patients With Biliary Atresia. Gastroenterol. Res. Pract. 2017; 2017: 7496860.

56. Godala, M.; Materek-Ku´smierkiewicz, I.; Moczulski, D.; Rutkowski, M.; Szatko, F.; Gaszy ´nska, E.; Tokarski, S.; The Risk of Plasma Vitamin A, C, E and D Deficiency in Patients with Metabolic Syndrome:A Case-Control Study.

57. Okebukola, P.O.; Kansra, S.; Barrett, J. Vitamin E Supplementation in People with Cystic Fibrosis. Cochrane Database Syst. Rev. 2014; CD009422.

58. Kim, H.-G.; Gater, D.L.; Kim, Y.-C. Development of Transdermal Vitamin D3 (VD3) Delivery System UsingCombinations of PLGA Nanoparticles and Microneedles. Drug Deliv. Transl. Res. 2018: 8: 281–290.

59. Vora, L.K.; Donnelly, R.F.; Larrañeta, E.; González-Vázquez, P.; Thakur, R.R.S.; Vavia, P.R. Novel Bilayer Dissolving Microneedle Arrays with Concentrated PLGA Nano-Microparticles for Targeted Intradermal Delivery: Proof of Concept. J. Control. Release. 2017; 265: 93–101.

60. Hutton, A.R.J.; Quinn, H.L.; McCague, P.J.; Jarrahian, C.; Rein-Weston, A.; Coffey, P.S.; Gerth-Guyette, E.; Zehrung, D.; Larrañeta, E.; Donnelly, R.F. Transdermal Delivery of Vitamin K Using Dissolving Microneedles For the Prevention Of Vitamin K Deficiency Bleeding. Int. J. Pharm. 2018; 541: 56–63.

61. Ramöller, I.K.; Tekko, I.A.; McCarthy, H.O.; Donnelly, R.F. Rapidly Dissolving Bilayer Microneedle Arrays—A Minimally Invasive Transdermal Drug Delivery System for Vitamin B12. Int. J. Pharm. 2019; 566: 299–306.

62. Risbud, M.V.; Bhonde, R.R. Polyacrylamide-Chitosan Hydrogels: In Vitro Biocompatibility and Sustained AntibioticRelease Studies. Drug Deliv. 2000; 7: 69–75.

63. Risbud, M.V.; Bhonde, R.R. Polyacrylamide-Chitosan Hydrogels: In Vitro Biocompatibility and Sustained Antibiotic Release Studies. Drug Deliv. 2000; 7: 69–75.

64. González-Vázquez, P.; Larrañeta, E.; McCrudden, M.T.C.; Jarrahian, C.; Rein-Weston, A.; Quintanar-Solares, M.; Zehrung, D.; McCarthy, H.; Courtenay, A.J.; Donnelly, R.F. Transdermal Delivery of Gentamicin Using Dissolving Microneedle Arrays for Potential Treatment of Neonatal Sepsis. J. Control. Release. 2017; 265: 30–40.

65. Bose, S.; Kaur, A.; Sharma, S. A review on advances of sustained release drug delivery system. Int. Res. J.Pharm. 2013; 4: 1–5.

66. Gao, X.; Patel, M.G.; Bakshi, P.; Sharma, D.; Banga, A.K. Enhancement in the Transdermal and Localized Delivery of Honokiol Through Breast Tissue. AAPS PharmSciTech. 2018; 19: 3501–3511.

67. Puri, A.; Nguyen, H.X.; Banga, A.K. Microneedle-Mediated Intradermal Delivery of Epigallocatechin-3-Gallate. Int. J.Cosmet. Sci. 2016; 38: 512–523.

68. Kochhar, J.S.; Tan, J.J.Y.; Kwang, Y.C.; Kang, L. Recent Trends in Microneedle Development & Applications in Medicine and Cosmetics (2013–2018). In Microneedles for Transdermal Drug Delivery; Kochhar, J.S., Tan, J.J.Y.,Kwang, Y.C., Kang, L., Eds.; Springer International Publishing: Cham, Germany. 2019; 95–144.

69. Lee, C.; Eom, Y.A.; Yang, H.; Jang, M.; Jung, S.U.; Park, Y.O.; Lee, S.E.; Jung, H. Skin Barrier Restoration and Moisturization Using Horse Oil-Loaded Dissolving Microneedle Patches. Skin Pharmacol. Physiol. 2018; 31:163–171.

70. Lulu An , Yuanyuan Wang, Jiaan Wu, Xiaoping Liu, Mei Liu, Siyue Kan, Yan Li, Yongyong Li , Jingwen Tan, Lianjuan Yang .Dissolving microneedle to improve transdermal delivery of terbinafine for treatment of onychomycosis. Journal of Drug Delivery Science and Technology. 2024; 95: 105537.

71. Tomás Bauleth-Ramos, Nesma El-Sayed, Flavia Fontana, Maria Lobita, Mohammad-Ali Shahbazi , Hélder A.Santos.Recent approaches for enhancing the performance of dissolving microneedles in drug delivery applications. Science Direct. 2023; 63: 239-287.

72. Tejashree Waghule, Gautam Singhvi, Sunil Kumar Dubey, Murali Monohar Pandey, Gaurav Gupta, Mahaveer Sing et al. Microneedles: A smart approach And increasing potential for Transdermal drug delivery System. Biomed & Pharmtherapy. 2019; 109:1249-1258.

73. Mahadevan, G.; Sheardown, H.; Selvaganapathy, P. PDMS Embedded Microneedles as a Controlled Release System for The Eye. J. Biomater. Appl. 2013; 28: 20–27.

74. Patel, S.R.; Berezovsky, D.E.; McCarey, B.E.; Zarnitsyn, V.; Edelhauser, H.F.; Prausnitz, M.R. Targeted Administration into the Suprachoroidal Space Using a Microneedle for Drug Delivery to the Posterior Segment of the Eye. Investig. Ophthalmol. Vis. Sci. 2012; 53: 4433–4441.

75. Donnelly, R.F.; Singh, T.R.R.; Tunney, M.M.; Morrow, D.I.J.; McCarron, P.A.; O’Mahony, C.; Woolfson, A.D. Microneedle Arrays Allow Lower Microbial Penetration Than Hypodermic Needles In Vitro. Pharm. Res. 2009; 26: 2513–2522.

Received on 15.05.2024 Modified on 19.06.2024

Res. J. Pharma. Dosage Forms and Tech.2024; 16(3):268-274.

DOI: 10.52711/0975-4377.2024.00042