A Smart and Potential approach for Transdermal Drug Delivery using Microneedles: A Review

 

Neha Sharma*, Tarun Kumar Sharma, Dr. Vinay Pandit, Dr. M. S Ashawat

Department of Pharmaceutics, Laureate Institute of Pharmacy, Kathog, Jawalamukhi,

Kangra (H.P.) 177101, India.

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

 

ABSTRACT:

Transdermal drug delivery system used to transport the drug across the skin deep into systemic circulation. The main advantages of Transdermal drug delivery system improved patient compliance, sustained release, avoidance of gastric irritation, as well as elimination of pre-systemic first-pass effect. But most of therapeutic agents is limited due to thickness of stratum corneum, which act as a barrier for the delivery of various drug molecules and only few molecules are able to reach the action site. Microneedles are the new form of delivery system, which are used to increase the delivery of drug through this route and overcoming the number of problems related to conventional drug delivery system the main aim of this review to focus on new innovation in transdermal drug delivery systems. In the microneedle drug delivery system, the skin is temporarily broken, that creating micron size pathways that deliver the sufficient amount of drug directly into the stratum corneum from which the drug can directly go into the systemic circulation. In this review, we describe different type of microneedles can be solid, coated, dissolving and biodegradable microneedles and their method of fabrication. Microneedles can be manufactured in different forms like hollow, solid, and dissolving. Also describe materials used for fabrication, fabrication techniques, methodology of drug delivery such as Poke and patch, Coat and poke, Poke and release, Poke and flow and evaluation parameters.

 

KEYWORDS: Transdermal delivery, Microneedles, Stratum corneum, biodegradable microneedles, Biocompatibility.

 

 

 

INTRODUCTION:

Drug delivery through transdermal route across the skin gives the most convenient route for delivery of various drug into the systemic circulation and it developed for controlled drug delivery system. Transdermal drug delivery system is a system which delivers the drug effectively across the skin1.

 

Nowadays, the transdermal route becomes the most successful and creative focus for research in drug delivery, with around 40% of the drug candidate being under clinical examination related to dermal systems. The innovation has a proven record of FDA approval since the first transdermal patch was approved in 19812. The effectiveness of transdermal delivery is limited by the poor permeability of the uppermost layer of skin stratum corneum which is the outmost layer and the primary transport barrier3. These types of drug delivery systems are preferred because they have several advantages over the conventional drug delivery system like mask the unpleasant taste of the drug, avoids fast pass metabolic activities and also helpful in giving the immediate response of the drug by steady release. And it is more effective and safer for drug administration. In TDDS, the drug is administrated by different pathways like transcellular and paracellular routes4. In both the route the drug is delivered to the site of action by simple diffusion. The other important pathway is by micro-needling through microchannels5.

 

Microneedles (MNs):

Microneedle based technique is an emerging and invasive mode of drug delivery6. The microneedles (MNs) are studied by various researchers for delivering drugs through the transdermal route for overcoming the limitations of conventional delivery. Microneedle is a device consists of needles of micron size, which are arranged on a patch. Considering the problems of the both hypodermic needle and the transdermal patch, the microneedle drug delivery system was developed and is thought to be a mixture of both. The main problem associated with TDDS is that most of the drug molecules not easily to cross the skin membrane. Researchers have developed a microneedle, which allow hydrophilic molecules, high molecular weight drugs cross the stratum corneum. Delivery of drugs using the microneedle allows the drug molecules to cross the stratum corneum layer. The advantages of this technology are the faster onset of action, better patient compliance, self-administration, improved permeability and efficacy7,8. Microneedles is transdermal system, which consisting of number if micro structured projection coated with drug. Microneedles are applied on skin to provide intradermal delivery of active ingredient. Microneedles are small hypodermic needles. Microneedle length ranges from 1-100 microns and 1 micron in diameter.

 

Salient features of microneedle drug delivery technology7:

·       Self administration.

·       Cost effective.

·       Good stability.

·       Rapid onset of action.

 

Advantages,9,10,11:

1.     Minimum pain and irritation by this route.

2.     Bypass first pass metabolism.

3.     High molecular weight drug can deliver.

4.     Healing is much faster than conventional delivery.

5.     Target drug delivery is possible.

6.     These are capable of very accurate dosing.

7.     Good stability and enhanced drug efficacy may result in dose reduction.

8.     Skin area can be targeted for desired drug delivery in specific area.

9.     Drug can be administered at constant rate for a longer period.

10. Good reproducibility.

 

Disadvantages12,13,14:

1.     Hydration of skin may affect the drug delivery.

2.     Irritation at the site of application.

3.     It may cause problem if microneedles may break and remain in the skin while removing the patch.

4.     Sterility of the drug product might be a problem if not carefully handled.

5.     Skin irritation may result because of allergy or sensitive skin.

 

Mechanism of drug delivery:

Drug delivery through the topical route follows the simple diffusion mechanism. In the microneedle drug delivery system, the skin is temporarily broken. A microneedle device is prepared by arranging hundreds of microneedles in areas on a tiny patch (the same as that of a normal transdermal patch available in the market) in order to deliver a sufficient amount of drug across the skin into systemic circulation. It punctures the stratum corneum thus bypassing the barrier membrane. In the upper dermis layer drug is placed and which shows the pharmacological effect15. The Mechanism of drug delivery through microneedles is shown in Fig. 1.

 

Fig. 1: Mechanism of drug delivery by microneedle device:

(1) Microneedle device with drug solution; (2) Device inserted into the skin; (3) Temporary mechanical disruption of the skin; (4) Releasing the drug in the epidermis; (5) Transport of drug to the site of action16.

 

Types of Microneedle:

Order of MNs relies upon their method of drug delivery. Solid MNs don't contain any medication and are only used to punch the skin. Another application of the drug formulation required post installing and withdrawal of solid MNs. Extra use of the medication detailing is required post addition and evacuation of strong MNs. Conversely, the presence of a drag, as on account of empty MNs, or covering strong MNs with drug definition empowers MN application and medication conveyance in a solitary advance. Medications can likewise be consolidated in a biodegradable grid. This dispose of the need to actually eliminate any leftovers. At the point when two MN exhibits are mounted on one another to improve entrance, they structure quickly isolating MNs17.

 

Solid MNs:

Solid MNs are a mixture of solitary uniform material with microscale distensions and do not contain any API or excipient related to the exhibit. They are commonly utilized as skin pre-treatment. After inclusion and evacuation, the tips of these MNs produce micron-sized pores on the skin surface. When the formulation is applied over the pores, they facilitate the permeation of drugs into the skin either for local or systemic action. The formulation can be in the form of a topical patch or a semisolid composition like gel, ointment, cream, or lotion18,19.

 

Hollow MNs:

Hollow MNs similar to hypodermic infusions, with a particular element of micron range size. They involve a conductor at the focal point of every projection. They are used for the infusion of liquid formulations into the skin20,21,22.

 

Coated MNs:

They are solid MNs coated with drug formulation, which fills the need of medication conveyance valuable to puncturing of the skin. After the inclusion of MNs, the coating dissolves in the skin and MNs are removed23,24,25.

 

Dissolvable/biodegradable/hydrogel-forming MNs:

MNs can be made out of water-dissolvable or biodegradable materials like polymers or sugars that encapsulate the medication inside the MN network or matrix. These MNs after application totally degrade in the skin, consequently delivering the encapsulates drug payload, and give up no hazardous remainders26,27. In the case of hydro gel MNs, the needle tips of polymer swell by absorbing body liquid to give drug discharge. They additionally make channels all the while, and along these lines permit the medication delivered from supply to enter the microcirculation. They leave none or inconsequential polymer residue after expulsion from the skin28.

 

Rapidly separating MNs:

This type of MNs consists of a water-soluble network of the drug. It is mounted on another cluster made out of an insoluble polymer that fills in as the spacer which helps to conquer skin deformation during inclusion. During insertion in the skin, the drug-loaded MNs interact with interstitial fluid and dissolve in the fluid. The remainder patches can be stripped off against the skin29,30.

 

Fig. 2: Different types of microneedles

(a) Solid microneedles use poke with patch approach, are used for pre-treatment of the skin; (b) Coated microneedles use coat and poke approach, and coating of drug solution is applied on the needle surface; (c) Dissolving microneedles are made of biodegradable polymers; (d) Hollow microneedles are filled with the drug solution and deposit the drug in the dermis15.

 

Materials used for fabrication:

Different types of material are used for the preparation of MNs. The material used should be inert in nature, absence of immunogenicity, high tensile strength, non-brittle nature, good mechanical strength, low corrosion rate, biocompatibility, stability, ease of availability, and low cost31.

 

Silicon:

The first microneedle was made up of silicon in the 1990s12. The nature of silicon is anisotropic and the structure is crystalline. Its properties depend on the alignment in the crystal lattice, which shows different elasticmoduli32,33. Silicon is flexible in nature which producing needles of different sizes and shapes. The attractive physical properties make it a versatile material. Silicon substances can be precisely manufactured and are capable of batch production. High cost of silicon and its time-consuming process limits its use in microneedle. Silicon has some biocompatibility issues because silicon is brittle, some part may crack and remain in the skin and causing some health problem34.

 

Metal:

Various types of metal is used for the manufacturing of MNs. The most commonly used metal are stainless steel, titanium, palladium, nickel, cobalt alloys, platinum, alloys, and gold32. Metal has good mechanical strength, high tensile strength and biocompatible. Which allows easy penetration through the stratum corneum or skin. Metals are stronger than silicon so more suitable than silicon and it avoids breaking so it is inferior than silicon MNs35,36. Stainless steel was the first metal used for the production of microneedle and titanium is the best alternative for stainless steel32,36,37.

 

Silica Glass:

Glass is inert but brittle and various geometries are manufactured which are penetrating into a stratum corneum38,39,40. The Disadvantage of silica glass is brittle in nature and breakage of the needle tip in the skin which causesinflammation41.

 

Carbohydrate:

Various sugar is used for the production of MNs such as maltose, trehalose, raffinose, mannitol, xylitol, galactose42 and most common is maltose43. These MNs have the ability to punch through the skin44. sugar face some limitations such as instability, required high temperature for processing and rapid resealing of pores32,44.

 

Ceramic:

The most commonly used material is alumina, calcium phosphate and calcium sulphate. Alumina is chemical resistance and stable due to highly energetic ionic and covalent bonds between AI and O45,46,47.

 

Polymers:

A Number of polymers is used for the manufacturing of MNs such as hydroxypropyl methylcellulose48, hyaluronicacid49, carboxymethycellulose (CMC), alginates, or synthetic polymers like poly (methylvinyl ether/maleic anhydride) i.e. GantrezVR50, polystyrene, polyvinyl alcohol, polyvinylpyrrolidone (PVP)51, polylactic acid, polyglycolic acid and their copolymers (poly (lactic-co-glycolic acid) [PLGA])52. Polymers is used to produce biodegradable and hydrogel-forming MNs. These polymers have advantage of biodegradable nature and biocompatibility30,53,54,55.

 

FABRICATION TECHNIQUES:

The material utilized for manufacturing governs the fabrication technique. The Solvent casting method is used for the preparation of MNs from film-forming polymers that can be effectively molded into the ideal structure. Materials like metals and silicon require complex strategies. It is important for the technique to have high exactness, accuracy, reproducibility, and vigor. Table 1. summarizes the methods of fabrication and the types of MNs produced by them56.

 

Table 1: Fabrication method of MNs and the type of needles produced.

S. No.

Method of fabrication

Type of microneedles produced

1

Laser cutting

Solid metallic

2

Laser ablation

Solid metallic

3

Vapor deposition

Solid silicon

4

Photolithography

Dissolvable/hydrogel forming, solid ceramic, hollow type

5

Deep X-ray lithography

Dissolvable/hydrogel forming, hollow type

6

Dry etching

Solid silicon, hollow type

7

Wet etching

Hollow type, Solid silicon, solid metallic,

8

Pulling pipettes

Hollow glass

9

Metal electroplating

Solid metallic, hollow type

10

Spraying

Spraying

11

Drawing lithography

Dissolvable/hydrogel forming, hollow type

12

Micromolding and melt casting

Dissolvable/hydrogel forming, solid ceramic

13

Droplet born air blowing

Dissolvable/hydrogel forming

14

Two photon polymerizations

Dissolvable/hydrogel forming, solid ceramic, hollow type

15

Dipping

Coated type

16

Microstereolithography

Solid silicon, solid metallic

 

METHODOLOGY FOR DRUG DELIVERY:

Various strategies are employed to use the microneedles for TDDS.

These include57

·       Poke and patch

·       Coat and poke

·       Poke and release

·       Poke and flow

 

Poke and patch:

It includes puncturing a variety of solid microneedles into the skin followed by application of the drug patch at the treated site. Transport of drug across the skin can happen by diffusion or possibly by iontophoresis if an electric field isapplied58. This strategy was additionally attempted to separate the interstitial liquid to quantify the glucose level by the non-invasive method59.

 

Coat and poke:

In this methodology, needles are first coated with the drug and afterward embedded into the skin for drug release by dissolution. The whole drug to be conveyed is covered on the needle it self60. The dip and scrape approach is a variation of this methodology, where microneedles are initial dipped into a drug solution and afterward scratched over the skin surface to give up the medication inside the miniature scraped areas made by the needles58. A restricted amount of medication could be coated over the microneedles (just around 1 mg) and broad enhancement was needed for uniform covering in this 'coat and jab' approach.

 

Poke and release:

This method involves the release of the encapsulated drug into the skin from MNs. The MNs made up of polymers and sugar that degrades or dissolves the drug after administration. The Advantage of the ‘poke and release’ method was that the drug release could be moderate as per the requirement using a number of polymers and polysaccharides61.

 

Poke and flow:

In this method skin is disrupter by external pressure and then the drug is flows through hollow microneedles from the reservoir in the patch62. A huge amount of drug can be administered by poke and flow method.

 

The above approaches can be employed to deliver drugs either systemically or at a local action.

 

Fig. 3: Method for drug delivery by microneedles:

(a) ‘poke and patch’ using solid microneedles, (b) ‘coat and poke’ using coated solid microneedles, (c) ‘poke and release’ using polymeric microneedles, (d) ‘poke and flow’ using hollow microneedles63.

 

Evaluation parameters:

There is two types of evaluation parameters i.e. In vitro and In vivo. They are64,65:

To insert the microneedles the different mediums like menthol and agarose gel are used In vitro study of microneedles. The In vitro test is utilized to decide the characters of a new test device. The principle target of this type of In vitro involves optimization of microneedles, assessment quality of microneedle, discovering penetration force and bending force, assurance of dissolution rate of coating materials, assessment of the effectiveness of drug delivery.

 

Various methods are:

Method A: This method describes the efficacy of microneedles. In this method microneedles are study with polydimethylsiloxane biochip and black ink is injected by microneedle into the Petridish, which contains menthol. For this purpose, the right triangular microneedles and isosceles triangular microneedles with 8.5 and 15 tip taper angles and 9.5 and 30 tip taper angles respectively have been used.

 

Method B: Rhodamine B-dye infused into microneedles to 1% agarose gel to assess the penetration force and flow of solution after penetrating into 1% agarose gel.

 

Method C: In this method, we insert microneedle into porcine cadaver skin and pig cadaver skin from 10s-20s and 5min are evaluated by this method. The delivery efficiency and dissolution rate of coating materials is determined using this method, which are coated on microneedles tip with vitamin B and calcein.

 

In vivo study:

In vivo investigation of microneedles is conducting a preclinical study on mice, guinea pigs and monkey etc. are utilized. The primary target of the In vivo study is the assurance of safety and toxicity of the tested compound. In vivo testing of microneedles of incorporate to perform skin toxicity test, mechanical stability, penetrating force in various skin, bending and breaking force, assurance of different parameters like skin sensitization, chronic dermal toxicity, carcinogenicity.

 

Method A: Method A used to determine the penetration force into the skin. This method is tested by injecting a microneedle into the tail of hairless mice.

 

Method B: This method is used to determine the penetrating force and bending breakage force. The testing of microneedles is done by injecting a Rhodamine B dye to hairless tailed mice and mice is also anaesthetized for this test.

 

Method C: In this method administration of Ovalbumin, a model protein antigen into a hairless guinea pig with the help of solid metal microneedles with the rate of 20μg ovalbumin in 5s up to 80μg and this method is used for the evaluation of vaccine delivery by microneedles.

 

Method D: In this method hollow and solid microneedle are used to deliver the Anthrax vaccine that contain recombinant protective antigen of Bacillus anthracis and this method involved the use of rabbits for vaccine delivery.

 

Approved products60,66,67,68:

Product name

Company Name

Application

Dermaroller®

Dermaroller® Germany, White Lotus

Improve skin texture, treat scars and hyperpigmentation.

C-8 (Cosmetic type)

The Dermaroller Series by Anastassakis K.

Used to enhance penetration of topical agents

CIT-8 (Collagen Induction Therapy

The Dermaroller Series by Anastassakis K.

Used in collagen induction and skin remodeling.

MF-8 type

The Dermaroller Series by Anastassakis K.

Treat scars.

MS-4

The Dermaroller Series by Anastassakis K.

Used on facial acne scars

MicroHyala®

CosMed transdermal drug Delivery

Wrinkle treatment

LiteClear®

Nanomed skincare

Treats acne and skin blemishes

Soluvia®

Sanofi Pasteur Europe

Influenza vaccination

h-patch

Valeritas

To deliver drugs in subcutaneous tissue (insulin)

Microstructured transdermal

System

3M

To deliver biologics and other small molecules

Micro-Trans

Valeritas Inc., USA

Drug is deliver into a dermis

Onvax Becton

Dickinson, USA

Use for delivery of vaccines.

AdminPen

AdminMed, USA

Liquid pharmaceutical formulation or cosmetics

NanoCare

NanoPass Inc.

Used for rejuvenation of skin and to boosts the cosmetic effect of topical applications.

 

CONCLUSION:

Transdermal drug delivery is a suitable choice to improve the bioavailability and increment the scope of the drug. It is a convenient route of administration of a variety of drugs. microneedles are used to increasing the permeability of skin through transdermal patches. Now a day microneedle proved to be an effective novel drug delivery system. The various drugs are administering by microneedles get the desired action. And day by day new development is carried out.

 

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Received on 11.01.2021            Modified on 21.02.2021

Accepted on 12.03.2021     ©Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 2021; 11(2):113-120.

DOI: 10.52711/2231-5659.2021-11-2-4