A Novel Technique for Intra Transdermal Delivery of Drugs – Coated Polymeric Needles

A. Lakshmi Usha¹*, M. Kusuma Kumari¹, E. Radha Rani¹, A.V.S. Ksheera Bhavani²

¹Department of Pharmaceutics, Maharajah’s Collage of Pharmacy, Vizianagaram, A. P., India.

²Department of Pharmaceutics, Sri Venkateswara College of Pharmacy, Madhapur, Hyderabad, Telanaga.

*Corresponding Author E-mail: alakshmiusha@gmail.com

ABSTRACT:

The barrier properties of the topmost layer of the skin, stratum corneum have significant limitations for successful systemic delivery of a wide range of therapeutic molecules, especially macromolecules and genetic material. One solution is to utilize microneedles (MNs), which are capable of painlessly traversing through the stratum corneum and directly translocating protein drugs into the systemic circulation. This strategy involves the use of micron sized needles fabricated from different materials and using different geometries to create transient aqueous conduits across the skin. Microneedles in isolation, or in combination with other enhancing strategies, have been shown to dramatically enhance the skin permeability of numerous therapeutic molecules including biopharmaceuticals either in vitro, ex vivo or in vivo. MNs can be designed to incorporate appropriate structural materials as well as therapeutics or formulations with tailored physicochemical properties. This platform technique has been applied to deliver drugs both locally and systemically in applications ranging from vaccination to diabetes and cancer therapy. As an alternative to hypodermic needles, coated polymer microneedles (MNs) are able to deliver drugs to subcutaneous tissues after being inserted into the skin. The dip-coating process is a versatile, rapid fabricating method that can form coated MNs in a short time. However, it is still a challenge to fabricate coated MNs with homogeneous and precise drug doses in the dip-coating process. This review article focuses on recent and potential future developments in microneedle technologies. This will include the detailing of progress made in microneedle design, an exploration of the challenges faced in this field and potential forward strategies to embrace the exploitation of microneedle methodologies, while considering the inherent safety aspects of such therapeutic tools. The clinical potential and future translation of MNs are also discussed.

KEYWORDS: Transdermal drug delivery, microneedle, Hydrogel-forming, safety, vaccination, drug monitoring, public perception.

INTRODUCTION:

Transdermal drug delivery is clinically superior to traditional, invasive injections. Protein drug transportation across the skin avoids the hepatic first-pass metabolism and is delivered in the systemic circulation at a pharmacologically relevant rate.

The skin is the largest organ in the body that protects the internal organs. It also plays an important role in preventing the entry of toxic chemicals and exit of water and other essential endogenous substances in the body. [1] The complex structure and large surface area is challenging for drugs and vaccines to cross the skin in therapeutically large amounts. The major barrier in the skin stratum corneum (SC), which is the outermost layer of the skin. The SC is 10–15μm thick and is made up of 15–20 corneocyte layers. [2] It is made up of corneocytes embedded in an intercellular lipid matrix. The layer below the  stratum corneum is a viable epidermis (VE) which is a cellular, avascular tissue measuring 50–100μm thick. The VE is composed of keratinocytes and approximately 40% protein, 40% water and 15%–20% lipids. The basal layer of the epidermis consists of cells which form the most important structural and functional connection to the dermis below. The stratum corneum and viable epidermis together form complete epidermis [3]. Only compounds which can pass through SC, diffuse living epidermis and pass through the upper part of the papillary dermis have the potential to reach circulation and exhibit systemic effects. The dermis consists of blood vessels, lymphatic nerves, and various skin appendages. Hypodermis, below the reticular dermis has a thickness of several millimeters and is composed of fat microtubules, fibrous collagen, blood vessels, and lymphatic nerves. Recent advances in transdermal drug delivery therefore have intensified the need for strategies to overcome the SC barrier function in order to facilitate rapid and effective permeation of a broader range of molecules, including macromolecular therapeutics and genetic materials [4]. Such strategies to overcome the SC barrier properties namely via optimization of the drug formulation or alteration of the SC barrier function, can be achieved by one of two main approaches - either by chemical or physical methods. Conventional transdermal delivery strategies, well established for small molecules, are focused on optimization of drug formulation. For macromolecules such as protein/peptide drugs, optimisation of the formulations done by encapsulating macromolecules in a vesicular carrier such as liposomes, chemical modification for synthesising more lipophilic analogues, or incorporating chemical penetration enhancers and proteolytic enzymes inhibitors. However, as this approach does not significantly disrupt the skin barrier, its application might be limited to only small peptides. Other transdermal delivery technologies rely on manipulating the SC barrier properties by application of physical energy, or by physical abruption of the SC and, finally, by controlled removal of the SC so that permeation of drug molecules could be increased [5].

Fig. 1: Strategies to facilitate transportation of macromolecules through the skin

In the current days, Microneedles (MN) are being utilized to enhance transdermal delivery of small and large molecules. The emergence of microfabrication manufacturing technology over the past decades, led to the development of Microneedles. Transdermal MN’s enhances drug delivery across the skin by creating micron sized pores in the skin [6]. They are ideal as they adhere to a patient’s skin as they do not stimulate nerves that are associated with pain. MN’s improve patient compliance when they are given to patients with needle phobia. They more likely applied as patches because of their painlessness. When MN’s are fabricated in arrays with a backing that can be applied to the skin like a bandage, the device is called a MN patch. MN’s are mainly divided into four categories [7]

· Hallow

· Solid

· Coated

· Dissolving

Different types of Microneedles are depicted in the figure below:

Fig. 2: Drug relese from different types of Microneedle

Fig. 3: Schematic representation of four different MN application methods used to facilitate drug delivery transdermally.

From the above figure we can describe:

a. Solid MN’s for increasing the permeability of a drug formulation by creating micro-holes across the skin.

b. Coated MN’s for rapid dissolution of the coated drug into the skin.

c. Dissolvable MN’s for rapid or controlled release of the drug incorporated within the microneedles.

d. Hollow MN’s are used to puncture the skin and enable release of a liquid drug following active infusion or diffusion of the formulation through the needle bores.

Microneedle Arrays:

MN array consists of micron-sized projections assembled typically on one side of a supporting base or patch. These micro projections generally range from as short as 25μm to as long as 2,000μm in length. The first concept of MN drug delivery device was studied in 1971 in a United States Patent in which the inventors, Gerstel and Place, used the term ‘puncturing projections’ to describe this invention However, the first serious discussions and proof-of-concept analyses of MN emerged in the late 1990s, when Henry demonstrated the use of silicon MN to successfully facilitate the delivery of a model drug, Calcein, across human skin [8]. It was believed that, revolution in the microelectronics industry leading to the advent of microfabrication technology enabled the evolution of manufacturing facilities necessary to produce such micro conduits. Since then, a large growing body of literature has investigated various microfabrication methodologies utilized in the manufacture of MN arrays from numerous materials. These materials have included silicon, metals such as stainless steel, palladium, nickel and titanium, carbohydrates including galactose, maltose and polysaccharide, glass and various polymers. In addition, MN arrays have been produced in various shapes and sizes. These microstructures may be in the form of needle, microblades, and blunt projections or shaped in an arrow-head [9]. MN’s have shown to effectively enhance the delivery of many therapeutic molecules across biological membranes including skin, mucosal tissue and sclera. It was suggested that MN arrays can be used for transportation of macromolecules and possibly supramolecular complexes and microparticles apart from small molecular weight API’s. MN’s can be administered easily and patient-friendly administration of therapeutics across the skin at low cost with potential efficacy as a parenteral route is possible 10]. Geometric modulations of MN’s and simple alteration in drug formulations can result in controlled drug deposition within targeted skin layers. MN’s have been penetrating through the skin and crossing the SC into the viable epidermis, avoiding contact with nerve fibers and blood vessels that reside primarily in the dermal layer. Therefore, the use of MN’s is to provide pain-free, minimally invasive means of delivering small and large molecular weight APIs by preventing bleeding at the application site. Over the last decade, extensive research has been carried out concerning MN’s design by using a large number of techniques and fabrication methods. More importantly, enhancement of delivery of drug and a wide variety of biomolecules of various physicochemical properties has been demonstrated in in vitro, ex vivo and in vivo experiments, using a broad variety of device designs [11].

Fig 3: Microneedle Array

Delivery strategies of MN’s:

The first strategy of Microneedle mediated transdermal and dermal drug delivery is via the use of solid MN’s, which are also termed as “poke with patch” approach. Upon removal of the Microneedle, transient microchannels are created on the skin within which a conventional drug formulation is subsequently applied. The movement of molecules through these microchannels occurs via passive diffusion. The drug formulation serves as an external drug reservoir and can be in the form of a transdermal patch, solution, cream, gel etc. The solid MN’s however, have certain limitations such as it requires a two-step application process which may lead to practicality issues for the eventual end-users [12]. Coated MNs are prepared by coating a drug formulation onto the microstructures prior to application. When Microneedle arrays are inserted into the skin, drug will be deposited in the skin following the dissolution of the drug coating material. This drug delivery strategy is termed “coat and poke” i.e. MN’s function by creating micropores in the skin, followed by dissolution of the MN’s when they come in contact with the skin interstitial fluid. The use of hollow MN’s is that it promotes continuous delivery of a particular medication via the injection of a fluid formulation containing the medication of choice through the hollow needle bore-opening into the skin [13].

Coated MN’s:

Coated MN’s are fabricated using silicon or metal and the drug in return is loaded onto individual needles of the MN array in a dry state as a coating layer. After inserting the coated MN’s into the skin, the drug is rapidly released into the tissue. Coated MN’s offer advantages such as they can be applied simply in one-step whereas uncoated solid MN’s require a two-step approach. Coated MN’s have been considered as attractive candidates for rapid cutaneous delivery of macromolecules such as vaccines, proteins, peptides and DNA to the skin [14]. However, one major limiting factor of drug delivery is that only limited amount of drug can be coated onto the miniscule surface area of the MN structures. This therefore suggests that delivery via coated MN’s is restricted only to potent molecules/drugs so as to ensure optimal drug delivery without compromising the mechanical strength of the needles which is required to achieve insertion into the skin. Furthermore, the optimization of MN coating methods and formulation characteristics suffers from issues such as ensuring consistency, uniformity, reproducibility and stability of the MN drug coating materials while minimizing drug loss during the coating process. In addition to this loss of drug coating material from the MN surface occurs prior to insertion into the skin i.e. during handling must be prevented [15].

Coating methodologies:

A number of methodologies have been developed and adapted successfully to coat all the individual MN shafts encompassing a MN array with particular drug compounds.

Micron scale dip coating process:

Micronscale dip-coating process proposed by Gill and Prausnitz was successfully applied for the deposition of a variety of molecules differing in physicochemical properties onto the surface of MN’s. The two most important parameters affecting the dip-coating process are surface tension and viscosity of the formulation. Gill and Prausnitz demonstrated that reduction in surface tension by the addition of surfactants and increase in viscosity of the coating solution by the addition of viscosity enhancers resulted in uniform and thick drug coatings onto MN’s [16]. Coating solutions with lower surface tensions were determined to facilitate good wetting and decreased speed of film formation on the MN surface. In contrast, higher viscosity results in reduced contact angle of the coating solution resulting in increased volume of liquid film adherence to the MN have and increased residence time of the film on the MN surface. The versatility of this coating technique was demonstrated by coating MN’s with a hydrophobic molecule such as curcumin, in addition to the model proteins, BSA and insulin, in either organic or aqueous-based coating solutions. The investigators then proposed a novel approach where drug could be deposited within holes created in the centre of the MN’s. In the most complex design, a drug layering approach was adopted. The holes in the centre of the MN, termed pockets, were selectively filled with a drug formulation and a protective layer composed of biodegradable polymer polylactic-co-glycolic acid (PLGA), was coated onto the surface of the MN shaft. Finally, a second layer of drug was deposited onto the MN [17].

Gas Jet Process:

Chen et al. proposed a novel coating technique utilizing gas jet to distribute coating solution evenly onto the surface of individual MN shafts. The microprojection patch was composed of densely packed solid silicon MN’s of heights of 30, 60 or 90 μm [18]. The coating solution was applied onto the patch with the help of a gas jet (6-8 m/s) at an incident angle of 20°. Gas jet is used to distribute and quickly dry the formulation onto the entire patch. The proposed method is used for uniform coating of a variety of compounds like OVA, rhodamine-labelled dextran, ethidium bromide on short and densely packed microprojections [19].

Gene delivery:

The use of coated MN for delivery of genetic materials for various clinical indications like genetic immunizations has been reported by Pearton. In this study, genetic material, in particular plasmid DNA (pDNA), was dry-coated onto in-plane stainless steel MN’s of 750 μm in length. The reliable loading capacity of pDNA onto the MN’s, its stability and the capability of the MN’s to penetrate the skin was reflected by successful gene expression in excised, but viable human cutaneous tissue [20]. However, the study highlighted the need to further investigate the dissolution characteristics of this coated pDNA prior to investigation in a live animal model. More recently, the same research group also demonstrated successful proof-of-concept gene silencing using steel MN coated with small interfering RNA [21].

Vaccine delivery:

Coated MN’s have been extensively studied to facilitate transcutaneous vaccination. An abundance of immune-presenting cells (APCs) makes the skin an extremely attractive site for antigen presentation. Antigens can be introduced into the skin via coated MN’s to target Langerhans cells in the epidermis or dendritic cells in the dermis in order to induce a more pronounced immune response [22]. The limited drug quantities that can be coated onto MN’s does not in fact hinder their application in vaccine delivery as only minute quantities of antigen are necessary to elicit an immune response. Stability concerns associated with conventional injectable vaccines such as the need for the cold chain preservation of vaccine potency during storage and transport is a critical issue [23]. The storage of vaccines in a dry state coated onto MN arrays may circumvent this issue however as it allows the preservation of vaccine stability to a greater extent than storage in the form of an injectable. Most importantly, coated MN-mediated vaccinations manufactured from different fabrication materials (metals or polymer), with or without adjuvant and/or in combination with other enhancing technologies have been demonstrated to induce superior or comparable immunogenicity with attractive advantages of dose sparing compared to the conventional vaccination routes such as subcutaneous or intramuscular administration [24].

Recent developments in Coated Microneedles:

The pharmacokinetics and pharmacodynamics of parathyroid hormone (PTH, 4.1 kDa) microneedle-mediated delivery in humans was studied. The microneedle arrays consisting of titanium microneedles coated with PTH (20 to 40 micrograms) attached to an adhesive patch. The patch is applied with a hand-held and reusable applicator. A once-daily subcutaneous injection of FORTEO®, which is used as a therapy for advanced osteoporosis in men and postmenopausal women, served as a reference for the evaluation of the coated microneedle system performance with a wear time of 30 mins [25]. Clinical studies in post-menopausal women demonstrated that the microneedle system achieved shorter t_max of approximately 8 mins compared to 24 mins for SC injection. The terminal half-life after SC injection was longer compared to microneedle delivery, and implied flip-flop kinetics. The relative bioavailability of the PTH microneedle patch ranged from 40% to 80%. Interestingly, these differences were believed to be dictated by application to different anatomical body sites and not by the patch performance inconsistency, with the highest relative exposure that was obtained from the abdomen, followed by upper arm, and the lowest from the thigh. In each case, the residual PTH found on the microneedle array after application was < 20 %. Dose-proportional increase in the AUC was observed in the clinic [26]. The inter-subject and intra-subject variability seen in the PTH-patch and FORTEO were comparable. Pharmacodynamically, the PTH coated microneedle produced dose-proportional increase in the bone mineral density. The magnitude of this effect was higher compared to FORTEO and might be related to different PK achieved with the application of PTH microneedle. Moisture and oxygen-devoid packaged PTH microneedle patches were found to be stable in room temperature for 2 years, which is a significant advantage over FORTEO that needs to be stored at 5°C to 8°C [27].

Another study was carried involving the Zosano microneedle patch system. In this study, the stability and preclinical performance of erythropoietin coated microneedles was evaluated in rats. Pharmacokinetic profiles obtained following SC and microneedle assisted administration of EPO were alike and resulted in t_max of 6 to 12 hrs and a terminal elimination half-life of 9 to 12 hrs. A linear AUC dose-response curve was achieved within 7 to 200-microgram dose range tested. Moreover, the relative bioavailability of EPO after microneedle administration was comparable to that obtained following SC injection [28].

Zhang investigated the potential of Lidocaine coated microneedles for local analgesic action in domestic swine. This study was unique because here, an attempt was made to use the microneedles to enhance local (dermal) delivery of a therapeutic agent. He used 3MN’s 500 micrometer-long solid microneedles, termed sMTS, dip-coated with aqueous lidocaine (234 Da) solution. The local lidocaine concentration, obtained at the treatment site immediately following microneedle application was higher than the estimated level needed for analgesia and was maintained for an hour when co-administered with vasoconstrictive Lidocaine [29].

CONCLUSION:

Since conception in the late 1990’s, the MN field has continued to evolve and improve, with superior manufacturing materials, fabrication methods, and designs appearing within the scientific and patent literature. The introduction of biodegradable, polymeric MN devices may herald a new area in the development of MN technology, overcoming a number of disadvantages of previous MN designs [30]. Firstly, solid MN devices may suffer from the fact that silicon is not a biomaterial with an established safety profile thus leading to concerns over the potential skin problems that could arise if breakage of silicon or metal MN’s occurred. Secondly, the use of a solid, non-drug coated MN devices requires a two-step application process, which is undesirable, particularly when made at home where a dosage form may not be positioned exactly over the area of skin where MN puncture was performed [31]. Whilst coated MN devices may overcome this issue, accurate MN coating is a difficult process, which requires considerable research effort which must be optimized on a drug-to-drug basis. Furthermore, a coated MN device is only capable of delivering up to a maximum of 1mg of drug as a bolus dose only [32]. Although hollow MN’s offer the potential for continuous infusion, or as required dosing of a drug solution, central outlets may become blocked by compressed dermal tissue following MN insertion. The major advantages of polymeric MN systems include the possibility of loading a drug to be delivered into the MN matrix for release in skin by biodegradation or dissolution in skin interstitial fluid and, in many cases, their biocompatibility and biodegradability [33]. Furthermore, the ability to produce MN devices from aqueous polymeric blends at ambient conditions, without the need for a heating step, could prove to be a notable advantage in preserving the stability of an incorporated drug, particularly in the case of protein/peptide and vaccine delivery [34].

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Received on 30.05.2020            Revised on 15.06.2020

Accepted on 01.07.2020      ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2020; 10(4):289-295.

DOI: 10.5958/2231-5713.2020.00048.3