INTRODUCTION:

Transdermal drug delivery (TDDS) is the delivery of drugs through a superficial lipophilic layer of the skin (stratum corneum) which is about 10-15μm thick. This protective barrier limits the delivery of small molecules and biologics. The therapeutics can be delivered to the target areas and blood using a needle and the syringes that are capable to beat the barriers associated with TDDS. However, syringe-based injections decrease patient compliance, they are painful and necessitate trained medical practitioner for administration. Moreover, these injections may cause infections and

injuries (needle stick type), and generate high volumes of non-biodegradable dissipate [1,2].

Nowadays, the use of biotherapeutic agents has been increasing tremendously to treat different types of diseases, such as malignancy, infectious diseases, etc [3]. A range of biologics like proteins, peptides, vaccines, hormones, and antibody therapies have progressed widely in the efficacious treatment of these diseases previously not effectively managed by small molecule drugs. Compared with conventional therapeutics, biologics have many advantages including high activity, high specificity, and typically are effective at low concentrations. Besides, biologics degrade into amino acids which are far less biologically harmful than the toxic metabolites. Despite the above benefits, large molecules (biologics) limited their delivery using a traditional hypodermic needle and syringe model. Biotherapeutics, even under extremely controlled environments, are highly prone to degradation. Besides, pH variation, and alteration in ionic and osmotic pressure, and shear stress on the formulation causes structural changes resulting in loss of biological activities [4].Furthermore, one of the important shortcomings in the use of biotherapeutic is the lack of suitable drug delivery platforms available for biologic drugs. Therefore, to beat the above problems, new strategies are developed using non-invasive and minimally invasive techniques [1,2].

A variety of formulation options including pulmonary and nasal delivery, etc have been introduced for conveying the biologics (proteins, peptides, monoclonal antibodies). However, these approaches have been unsuccessful in turning into widely accepted within the pharmaceutical industry and remained in the area of research driven by curiosity. Besides, large costs associated with the initial production of biotherapeutic agents, such as antibodies, and vaccines have made more costly for these treatment choices [3].As such, this expense and associated drawbacks have resulted in then necessitate developing appropriate delivery systems that exhibit high dose-delivery efficiency. Besides, selective biotherapeutics such as monoclonal antibodies is limited to the traditional hypodermic needle and syringe model.

Microneedle (MN) technology is one of the potential approaches for the transdermal delivery of biotherapeutic agents. MNs are microdimensional protrusions arranged on a supporting base plate that can penetrate the skin’s SC barrier and provide access for drugs to dermal tissue. MNs for transdermal delivery penetrate the skin to upper layers of the dermis, causing no pain or bleeding and are ideal for patient adherence as they are doing not stimulate nerves [4].Besides, it improves patient compliance as a patient with needle phobia is more likely to use the patch due to its painlessness. Moreover, MNs are capable to improve the stability of biologics. Therefore, MNs could be a promising approach for the transdermal delivery of biologics. The present review is mainly focusing on the delivery of biologics using MNs, mechanisms of drug delivery through MNs, types of MNs, and material used for their fabrication. Moreover, the challenges associated with the delivery of biologics, different biologics delivered through MNs and research completed, and clinical trials and safety are also discussed.

Mechanism of drug delivery through MNs:

The drug is delivered topically following the diffusion mechanism. The delivery of drugs using MNs is mainly associated with momentary disruption of the skin. The hundreds of MNs are arranged in arrays on a tiny patch to convey a sufficient amount of drug to get a desired therapeutic response. MN bypasses the barrier layer and pierces directly into the stratum corneum. The drug is deposited directly in the outermost (epidermis or upper dermis) layer of the skin that then reaches the systemic circulation and shows a therapeutic response upon entering the site of action [5].The drug delivery mechanism through microneedles is featured in Figure 1.

Figure 1: Mechanism of drug delivery through MN device: (A) MN device with drug solution, (B) Device inserted into the skin, (C) Momentary mechanical disruption of the skin, (D) Releasing the drug in the epidermis, (E) Drug transport to the site of action [5].

Types of microneedles:

Broadly, drug delivery using various types of MNs has been classified into five approaches. In the case of MNs patch, MNs are fabricated in arrays on a backing that can be applied resembling to bandage on the skin [6]. The four other categories of MNs (Figure 2) include hollow, solid, coated, and polymeric [5]. Solid MNs are free of drugs and are merely used to nudge the skin. For reference, the presence of a hole, as in the case of hollow MNs, or the coating with drug formulations of solid MNs, allows the application of MN and the delivery of drugs in a single stage. Drugs may likewise be fused into a biodegradable matrix that prevents any remains from having to be physically removed.

Polymeric MN platforms found to be potential in the conveyance of enormous amounts of the drug. The delivery of large molecular weight biologics like monoclonal antibodies generally required in high doses, therefore, it is difficult to deliver them using solid and coated MNs technologies. These solid and coated MN technologies due to their limited dose are reasonable for the conveyance of potent biologics such as vaccines [7, 8].

Figure 2: Different types of microneedles: (A) Solid MN, (B) Coated MN, (C) Dissolving MN, (D) Hollow MN [6].

Solid microneedles:

Solid MNs are an array of a sole homogeneous material with micron-scale protrusions, and with the absence of drug or excipients on the array, and used for skin pre-treatment. The tip of these MNs can generate micron-sized pores on the skin surface after its insertion and removal where the formulation is to be applied that facilitates the permeation of drugs into the skin either for site-specific or systemic effect. It can be formulated in the form of a topical patch or a semi-solid composition such as gel, ointment, cream, or lotion [9].

Hollow microneedles:

Hollow MNs have a close resemblance to hypodermic injections, with a distinctive feature of micron range size. They are employed mainly to permeate liquid formulations from a drug reservoir into the skin [10].

Coated microneedles:

They are types of solid MNs in which appropriate drug formulation is coated over it that serves the aim of drug delivery supplementary to the piercing of the skin. The coating disintegrates (dissolves) in the skin following MNs are inserted, after which the MNs are removed [11].

Dissolvable/ Biodegradable/ Hydrogel forming microneedles:

In these sorts of MNs, the drug is exemplified inside the MNs lattice composed of water-soluble and biodegradable type of materials like polymers or sugars. The complete degradation or dissolution of MNs occurs in the skin after application, thereby releasing the embodied drug payload, and leaving no hazardous remnants behind [12]. On account of hydrogel-forming MNs, the needle tips of polymer swell by engrossing body fluid to provide drug release. They also simultaneously build conduits and thus allow the drug released from the reservoir to reach the microcirculation. After removal from the skin, they leave zero or negligible residue of a polymer [13].

Rapidly separating microneedles:

This type of MNs comprises a water-soluble lattice epitomizing the drug. This water-soluble lattice containing the drug is mounted on the second array consisting of an insoluble polymer that serves as the spacer to overcome skin deformation during insertion. The therapeutics-loaded MNs undergo dissolution upon injection into the skin following its contact with interstitial fluid and [14].

Materials used for microneedles fabrication:

Wide ranges of materials from metal to polymers are used for manufacturing MNs. The different ideal features of materials used to prepare MNs include inert and non-brittle nature, absence of immunogenicity, high tensile strength, good mechanical strength, low corrosion rate, biocompatibility, stability, ease of availability and low cost, etc. The various materials and techniques used in the manufacture of MNs along with their merits and demerits are depicted in Table 1.

Silicon:

It tends to be utilized to make solid, hollow and coated MNs [15]. Silicon gives generous mechanical strength to MNs that help it to effectively penetrate the skin and extensively used to achieve efficient transdermal drug delivery [16]. Besides, it can be used for fabricating MNs with varied shapes and heights. However, the most important limitations of silicon are its high cost, and intricate fabrication requirements, long fabrication times, and sophisticated multi-step processing. Moreover, the safety issue is of major importance due to the practicable fracture of MNs in the skin. Despite the above drawbacks silicon has been widely used for enhancing and facilitating transdermal drug delivery [17,18].

Metals:

The metals (stainless steel, titanium, palladium, nickel, platinum, alloys, and gold) are extensively used for the production of MNs. The main purpose of metals is to manufacture solid hollow MNs and as a base of the coated MNs. The metals provide desirable mechanical properties and high tensile strength which enable easy penetration through stratum corneum [19-23].

Amongst the available metals, stainless steel is generally utilized while platinum and palladium are rarely used for manufacturing MNs. Nonetheless, the main impediment of stainless steel is a higher rate of corrosion than titanium alloys. Titanium alloys posses’ stronger mechanical strength compared to stainless steel. In the case of nickel, there is a necessity to take special precautions due to their biocompatibility issues [24].

Glass:

It is used for manufacturing glass MNs of assorted geometries which successfully pierce through stratum corneum. The hollow type MNs is commonly fabricated using glass. The glass used is both silica and borosilicate. The borosilicate glass has demonstrated good biocompatibility. But, the important problem allied with glass (silica) MNs are the chances of causing inflammation and granulomas by the plausibility of breakage of needle tips due to its delicate nature [25,26].

Ceramics:

These materials are utilized to make solid, hollow, or coated forms of MNs. The generally utilized materials comprise alumina, calcium phosphate, and calcium sulfate. In any case, alumina is profoundly biocompatible; having been exposed to manual compression force it has been appeared to surrender to brittle crack. In spite of the fact that calcium phosphate and calcium sulfate are biocompatible, the capacity to withstand fracture has been demonstrated when injected into porcine skin. Ormoc ® is considered safe to use and is highly biocompatible [27,28].

Polymers:

The natural and synthetic polymers are employed for the production of hydrogel-forming MNs. The important advantages offered by polymers are biodegradability and biocompatibility. The frequently employed polymers are hydroxypropyl methylcellulose (HPMC), hyaluronic acid, carboxymethyl cellulose, alginates or synthetic polymers like poly (methyl vinyl ether/maleic anhydride) i.e. Gantrez, polystyrene polyvinyl alcohol, PVP (polyvinylpyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA) and their copolymers (PLGA) [29,30].

Sugars:

Sugars (maltose, trehalose, raffinose, mannitol, xylitol, and galactose) produce MNs that can pierce through stratum corneum. The major drawbacks associated with sugar use are, however instability, the need for high processing temperatures, and rapid pore resealing, etc [31].

Table 1: Different materials and techniques used for the fabrication of MNs

Fabrication technique	Material(s) used	Advantages	Limitations in scale-up
Micropipette pulling	Borosilicate glass	Cost-effective	Excessive calibration required and time consuming [32]
Casting	Sodium alginate, PLGA, Hyaluronic acid, etc.	Cost-effective; multiple needles can be produced from same micro-mold	Complex MN designs not achievable; post processing required; limited to solid MNs [33, 34]
Injection molding	Polycarbonate, cyclic olefin copolymer	Low post processing	Drying processes may take time; wear and tear of molds over time [35]
Hot embossing	PMMA, PLGA	Low post processing	Temperature-sensitive drugs cannot be loaded [36]
Investment molding	Cyclic olefin copolymer, PLGA	Hollow MNs can be prepared	MN design limitations [37]
Filling mold cavities with atomized spraying	PLGA, PVP	High temperature not needed; viscosity independent spraying	Continuous process needed [38]
Photo polymerization	PVP, PEG 600 diacrylate, gelatin methacryloyl	Higher strength of needles produced	High cost; crosslinking conditions may need to be maintained [39]
Stereolithography	Gantrez, class I resin, dental SG	High precision; fine detaining	Material fragility; high cost machinery; mass production not impossible [40]
Fused deposition modeling	PLA	Cost-effective; ease of manufacture	Limited material choices; higher temperature needed [41]
Drawing lithography	SU-8, maltose	Different MN shapes possible	Limited material choices; higher temperature needed [41]
Photolithography	Poly ethylene glycol diacrylate, CMC	Efficient process; dimensional control	Expensive; clean and darkroom requirement; material limitations [42]
Continuous liquid interface production	Trimethyl olpropane triacrylate	Tunable geometries; mold independent; single-step process	Limited material options, costly [43]
Two-photon polymerization	Ormocer	Good resolution; scalable	Limited to photosensitive materials [44]
Micromilling	PMMA, metals	High precision; good material choices	Costly; sophisticated machinery; specific cuts not possible [45]
Micromachining	Stainless steel	Complex MN designs achievable	Costly; requires sophisticated equipment; limited to metals [46]

Potential challenges in delivery of biologics (Protein) through MNs:

The proteins are important material that can play noteworthy roles like enzymatic catalysis, cellular regulation, biological scaffold, and molecular transportation in the body. Protein drugs are used in the treatment of cancer, as a vaccinations, and genetic disorders. The different types of protein delivered by using MNs are proteins with enzymatic or regulatory activity, vaccines, antibodies, etc. However, applications of therapeutic proteins in transdermal delivery are constrained due to their intrinsic properties [47,48].

The delivery of proteins using MNs is associated with different challenges such as the requirement of more time to close the pores that may cause irritation and infection at the site, affecting delivery. The sterility of the microneedles is an imperative concern for clinical applications and related products. Besides, the protein denaturation during storage or administration may influence therapeutic and vaccination efficiency. Cellular permeability is another chief challenge linked with the molecular size of proteins/peptides [49,50].

Additionally, the bioavailability of proteins administered using MN is also limited by protease hydrolytic attacks in the skin and blood. Therefore, the above problems necessitate the design of proper formulations using suitable material that help to conserve protein reliability and as well as improve delivery efficiency [51,52].

Furthermore, the hydrophilic nature of proteins makes them impermeable across the skin because of the lipophilic nature of stratum corneum. Therefore, numerous enhancement techniques like chemical enhancers, iontophoresis, microneedles, electroporation, sonophoresis, thermal ablation, laser ablation, radiofrequency ablation, and noninvasive jet injector’s had come in existence for the delivery of proteins by overcoming the skin barrier. Protein/drug formulation layered solid microneedles have been also reported to offer encouraging results.

Different proteins (biologics) delivered through MNs

Proteins with enzymatic or regulatory activity:

The kinds of proteins with enzymatic or regulatory activity including insulin, desmopressin, erythropoietin, lysozyme, glucagon, glucagon-like peptide-1 (GLP-1), parathyroid hormone (PTH), growth hormone and etanercept has been delivered successfully using MNs technology [53]. Several studies reported more stability of proteins in the solid-state during thermal processing than in the aqueous solution [54,55]. Martanto and co-workers have developed solid MN for transdermal delivery of insulin. The in vivo studies demonstrated better transdermal insulin delivery and lowered blood glucose levels (80% or more) in diabetic hairless rats [56]. The proteins (BSA and lysozyme, etc) incorporated in a carboxy methyl cellulose (CMC)-based MNs observed to be stable even after two months of storage.

Antibodies:

Monoclonal antibodies (mAbs) are one of the important biologics used to target certain cells and regulate the immune system by recognition of receptor-binding domains of protein ligands. Moreover, the mAbs showed their applicability in both diagnostic and therapy. Recently, researchers have investigated the applicability of MN-mediated transdermal techniques to deliver monoclonal antibodies. However, the major challenges in antibody delivery are deactivation of proteins, loss of efficacy, risks of immunogenicity, and immune complex hypersensitivity. Therefore, it is essential to maintain the stability of antibodies in MN formulations to avoid such undesirable effects. To this end, studies have shown that more than 80% of monoclonal immunoglobulin G (IgG) was recovered with stable tertiary confirmation after the dissolution of hyaluronan (HA)-based dissolvable MNs [57]. Courtenay et al. delivered bevacizumab (BVZ), a recombinant humanized monoclonal antibody transdermally using MNs. Both dissolving and hydrogel-forming microneedles were developed by them for BVZ delivery. In vivo pharmacokinetic study of hydrogel-forming, MNs showed Cmax (358.2±100.4ng/mL), Tmax 48 h, AUC (44357±4540), and, (Css 942±95 ng/mL,) revealing the potential for these devices to provide sustained delivery of antibody therapeutics to the lymph and systemic circulation [58].

Vaccines:

The vaccine is a biological formulation used to provide active acquired immunity against specific pathogenic infections or disease. However, vaccines available currently are limited to subcutaneous injection only. Therefore, MNs laden with antigenic therapeutics have been studied to provoke momentous antibody and cell-mediated immune responses. The noteworthy benefit of MN vaccine over injectable soluble antigens includes the successful incorporation of antigen to skin-inhabitant antigen-presenting cells (dendritic cells) resulting in effective topical immunization. In addition, MN matrix biomaterials possess natural immunogenicity and therefore could act as an adjuvant to boost the immune responses. For instance, PLGA could advance antigen-specific antibody and the assistant T cell-dependent humoral responses against a co-delivered antigen. Moreover, HA is involved in the regulatory functions of T cells in the peripheral blood. A superior comprehension of the vaccine stability throughout the fabrication, storage, and administration process is essential for future optimization [59].

The CMC and trehalose-based dissolvable MN patch was used to deliver the influenza vaccine. Improved viral protein stability and protective immunity were observed with the MN injection vaccine than a solution-based intramuscular injection of vaccine. Besides, trehalose surface coated MN displayed a stabilizing effect on the hemagglutinin activity of the inactivated influenza virus. Similarly, a recombinant protective antigen given through dissolvable MNs displayed remarkable immune response than in vivo (intramuscular or intradermal injection) in rats [60]. Moreover, Rodgers and co-workers did intradermal vaccination (heat-inactivated bacteria) using a dissolving microneedle patch. The mice vaccinated with P. aeruginosa MNs exhibited significantly (p=0.0059) lower bacterial load in mice lungs compared to their unvaccinated counterparts suggesting the prospective of dissolving MNs for intradermal vaccination with heat-inactivated bacteria [61]. In a recent study, sucrose and CMC-based MN patch designed to embed a standard dose of the measles vaccine and were tested in rhesus macaques. Also, Ali and co-workers developed a polymeric microneedle for DNA vaccination delivery of novel 30 amino acid cationic peptide delivery sequences (RALA) against cervical cancer. This MN demonstrated delayed TC-1 tumour commencement in a prophylactic model, and slowed tumour growth remarkably in a therapeutic model of vaccination when compared to intramuscular vaccination [62]. The different biologics delivered using MNs are depicted in Table 2.

Table 2: Different biologics delivered using MNs

MN type	Polymer matrix	Protein drug	Significance
Coated MN	Sucrose	Ovalbumin (OVB)	Improved transport of OVB through skin [63]
	Polysorbate 20	Desmopressin (DSP)	Significantly improved bioavailability (80%) of DSP [64]
	Polysorbate 20	Parathyroid hormone (PTH)	High ambient-temperature storage stability [65]
	Sodium poly(styrene sulfonate)	OVB	In vivo study demonstrated rapid release (within 3 min) of OVB [66]
	Polyethylene/polyisobutylene	OVB	Increased immune responses up to 50-fold at 1 and 5μg dose of OVB transdermally than subcutaneous or intramuscular route [67]
	Carboxymethylcellulose / chitosan	Bovine serum albumin (BSA)	Reduced water sensitivity while maintaining the main functional characteristics, showed sustained release of BSA [68]
	Polydi(carboxylatophenoxy)phosphazene	Horseradish peroxidase (HDP)	Improved protein stability [69]
	Polydi(carboxylatophenoxy)phosphazene	Hepatitis B surface antigen (HBSA)	Showed 10-fold higher immune responses with dose of 20 μg compared to intramuscular injection of same dose [70]
Dissolvable or Degradable MNS	Carboxymethylcellulose (CMC)/ trehalose	Human growth hormone (HGH)	Retention of functional activity and improved storage stability up to 15 months at room temperature [71]
	CMC	BSA	Retention of significant enzymatic activity (96%) after 2 months storage at room temperature [72]
	CMC	Lysozyme (LZ)	Showed sustained release of LZ for hours to days [72]
	Chondroitin sulfate	Erythropoietin (EPO)	Improved absorption rate of EPO into the systemic circulation [73]
	Chondroitin sulfate	Insulin	Exhibited sustained release of insulin [74]
	Dextran	EPO	Improved bioavailability of EPO [75]
	Galactose	BSA	Significantly improved penetration [76]
	Hyaluronic acid	Influenza hemagglutinin (IH)	Significantly enhanced immune responses against infectious diseases [77]
	Hyaluronic acid	Humanized monoclonal IgG1	Exhibited rapid dissolution in the skin and increased protein stability [78]
	Maltose	Biotinylated anti-human IgG	Significantly improved percutaneous delivery [79]
	PLGA/CMC	BSA	Controlled release of BSA for hours to months [80]
	Poly(methylvinyl--ethercomaleic acid)	Insulin	Significantly increased insulin transport across the neonatal porcine skin [81]
Bio-responsive MN	Poly(vinylpyrroli-done)	Sulforhodamine B; inactivated influenza virus	Improved immunogenicity [79]
	Starch / gelatin	Insulin	Pharmacodynamic and pharmacokinetic results showed a similar hypoglycemic effect (92% bioavailability) in rats from insulin-loaded microneedles and a subcutaneous injection of insulin, improved stability at 25 or 37°C for 1 month [82]
	Starch / gelatin	Leuprolide acetate	Improve systemic absorption efficiency [78]
	Silk / poly(acrylic acid)	OVB	Enhanced immune responses and exhibited a initial burst release (70%) over the course of 2 h with sustained release of the remaining 30% over the next 5-6 days [83]
	Hyaluronic acid	Insulin	MN showed significantly faster response rate to hyperglycemic levels than pH-sensitive-based glucose responsive formulations and higher in vivo stability of insulin in MN [84]
	Hyaluronic acid	anti-PD-1 antibody	Demonstrated sustained release and enhanced retention of checkpoint inhibitors in the tumor microenvironment [85]
	Hyaluronic acid / dextran	Anti-PD-1; anti-CTLA-4 antibody	In vivo studies using mouse models with melanoma showed that a single administration of the MN patch inhibited tumor growth superior to those obtained with intratumor (i.t.) injection of the same dose [86]

Table 3: MNs for delivery of biologics in clinical trials

Company name	Delivery approach	Biologics	Indication	Clinical phase
Emory	Microneedle patch	Fluvirin: H1N1, H3N2, B vaccine strain	Flu vaccine	Phase I
University of Lausanne	DebioJect microneedles	Pasteur rabies vaccine (inactivated)	Rabies vaccine	Phase I
Fluzone Intradermal (Sanofi)	BD Soluvia microinjection system for intradermal injection	Four strains of attenuated live virus: A(H1N1), A(H3N2), B Yamagata lineage, B Victoria lineage	Flu vaccine	-
IPOL (NanoPass)	NanoPass MicronJet 600 microneedle device	Inactivated polio vaccine	Polio vaccine	Phase II
ASP0892 (Astellas)	NanoPass MicronJet technology	Single multivalent peanut lysosomal associated membrane protein DNA plasmid	Peanut allergy vaccine	Phase I
HDM-SPIRE (Circassia)	NanoPass MicronJet technology	House dust mite synthetic peptide immuno-regulatory epitopes	Dust mite allergy vaccine	Phase II

Clinical trials and safety:

A lot of preclinical and clinical studies were carried out on microneedles developed for delivery of biologics with the objectives to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity in healthy volunteers. The delivery of trivalent influenza vaccine with the help of dissolving microneedles has used 40 patients during clinical trials. The results displayed that MN injection did not cause severe adverse reactions and immune responses. Currently, NCT03607903 (Humira, AbbVie) is an MNs consisting of adalimumab used for treating juvenile idiopathic arthritis an auto-immune/auto-inflammatory diseases with the objective to compare the pain perception and acceptability of MN-based delivery of single dose (40 mg) of adalimumab subcutaneously (SC) and intradermally (ID) in healthy adult volunteers. Some MNs for delivery of biologics are progressed in clinical are presented in Table 3.

CONCLUSION:

MN concept is one of the stepping stones to improve the transdermal delivery of biologics. MN is a minimally invasive, safe, and easy technique for transdermal delivery of drugs which can bypass first-pass effects. Different types of materials are used for the fabrication of MNs desired for the delivery of specific therapeutics. Several biologics such as proteins, vaccines, and antibodies are found to be potent for the treatment of cancer, infectious diseases, etc. However, many potential challenges associated with the transdermal delivery of biologics are skin barriers, biologics stability, etc. Therefore, MNs are found to be a suitable approach for their delivery. Different types of MNs such as dissolving and hydrogel-forming MN arrays have been formulated and used to bypass the skin’s barrier function and deliver biologics effectively.

Though the microneedle approach is being applied to a number of drugs (small molecules and biologics), but it has to encounter various challenges before it can release to the market. The foremost problems allied with microneedles technology include skin allergy, redness, and irritation. Moreover, several further studies are necessary for elucidating the mechanisms of induced immune protection and patient acceptability profiles, etc. Although vaccine delivery using MNs through the oral cavity or eyes has not been studied as broadly as the skin and none are in the clinical trials yet, and in the future, the successful administration of vaccines with microneedles in other areas of the body can be expected. Besides, these MNs for vaccination are phase II or III of clinical trials, therefore additional research is needed so that the delivery of vaccines by microneedles enters the final stages of clinical trials and eventually become commercialized. In the future, improved delivery of biologics using microneedles could be a keystone all over the world.

COMPETING INTEREST:

The authors declare that they have no competing interests.

ABBREVIATIONS:

BSA: Bovine serum albumin; BVZ: bevacizumab; CMC: Carboxymethylcellulose; CLSM: Confocal laser scanning microscopy; DCs: dendritic cells; GLP-1: Glucagon-like peptide-1; HA: Hyaluronic acid; HPMC: Hydroxypropyl methylcellulose; ID: Intradermal; IgG: Immunoglobulin G; MN: Microneedle; MNDDS: Microneedle drug delivery system; OVB: Ovalbumin; PVP: polyvinylpyrrolidone; PLA: Polylactic acid; PGA: Polyglycolic acid; PTH: Parathyroid hormone; PLGA: Poly (lactic-co-glycolic acid); PMMA: Polymethyl methacrylate; PVA: Polyvinylpyrrolidone; PEG: Polyethylene glycol; PLA: Polylactic acid; SC: Stratum corneum. SU-8: Epoxy-based negative photoresist.

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Received on 24.09.2020 Revised on 19.10.2020

Asian J. Pharm. Res. 2021; 11(1):46-54.

DOI: 10.5958/2231-5691.2021.00010.1