INTRODUCTION:

There has been a very vast growth in the development of biopharmaceutical products over the past two decades and most of these are administered by intravenous or subcutaneous injection. Chronic diseases, such as osteoporosis, diabetes, and growth hormone deficiency, are treated with therapeutic peptides and proteins and for a drug to be of clinical utility it required years of good patient compliance to attain its therapeutic effect. Thus, a patient- friendly drug delivery system would be desirable alternative for the patient⁽¹⁾. There is still a paucity of effective methods for administration of therapeutic proteins to patients. Drugs are conventionally delivered to the body either orally via pills or by means of injections using hypodermic needles. While these methods have historically been effective, they each have their own advantages and limitations.

Oral delivery is painless, however, much modern therapeutics such as proteins, peptides, and DNA based compounds cannot be delivered orally as they lose their activity either by enzymatic degradation in the gastrointestinal tract or by first- pass effects of the liver or they are poorly absorbed across the intestinal epithelium leading to low bioavailability. Transdermal drug delivery, which refers to the penetration of drugs across the skin, is an attractive alternative to deliver these modern biotherapeutics, as it is painless, can be self- administered in the GI tract and first- pass effects of the liver, and can allow for sustained drug delivery over extended periods of time. Transdermal patches have been developed to deliver drugs across the skin; however they can be applied to a limited number of drugs that are small enough and lipophilic enough to penetrate outermost barrier layer of the skin at therapeutic rates⁽²⁾. Consequently, micron- dimension needles called microneedles, which are long enough to pass the skins barrier, but short enough to avoid stimulating nerve endings have been developed to increase skin permeability to large and hydrophilic molecules while minimizing pain. For the Transdermal system to be most effective, the drug must penetrate the skin barrier and reach the targeted site in the concentration required to produce systemic action. In the modern therapy, increment of drug delivery across the human skin is very important. Due to the limitation of oral drug delivery and the pain related with the use of needles in case of injections, drug delivery research has tremendously oriented towards the trasdermal route. A variety of drugs has been reported to be delivered transdermally to overcome the limitations being exhibited by the classical oral, injectable and inhaler systems and about 74% of the drugs taken orally today are not found to be as effective as required. They can be fabricated out of metal, silicon dioxide, glass, fiber glass and so many other materials. They can also be solid or hollow. Solid microneedles are often coated with the drug that needs to be delivered to the body like Vitamin B and the hollow ones are used to deliver drugs Hollow microneedles can also be used to remove fluids from the body, e.g. Glucose for analysis. With respect to USA market of drugs which are under clinical evaluation, among 129 products, 51% of it corresponds to the transdermal or dermal systems. Across the world, the transdermal patch market has comprises of only 10 drugs i. e. Scopolamine, nitro- glycerine, tulobuterol, clonidine, estradiol, testosterone, fentanyl and nicotine with a lidocaine patch to be marketed very soon. The first transdermal system named as “ Transdermal- SCOP” was approved by FDA in 1979 for the prevention of nausea and vomiting⁽²⁾.

Objectives for the preparation of microneedles are:

1. Characterize skin repair responses to solid microneedle insertion to determine the extent of increased skin permeability coupled with predictions of pharmacokinetics of drug delivered through permeabilized skin.

2. Determine the effect of hollow microneedle- based infusion parameters in flow conductivity of skin and pain and thereby identify barriers to fluid flow into the skin from hollow microneedles.

3. Assess the safety and efficacy of systemic therapeutic effects through measurement of pharmacokinetic parameters, pain, irritation, and user preference for microneedle- based insulin delivery in type 1 diabetes subjects and,

4. Assess the safety and efficacy of local therapeutic effects through delivery of lidocaine to the skin⁽^3,4,5).

Microneedles are a diverse category of delivery technologies designed to access the intradermal cells. Some microneedle patches consist of tiny needles coated with vaccine, while others use the skins moisture to dissolve the vaccine into the intradermal layer. Hollow microneedles are a different type of device, using miniature needles attached to a regular syringe. Preclinical studies show great promise for application to a variety of vaccines.

Advantages:

1. The major advantage of microneedles over traditional needles is, when it is inserted into the skin it does not pass the stratum corneum, which is outer 10-15 um of the skin.

2. Improved patient compliance

3. Avoid first pass hepatic metabolism in comparison to oral drug delivery systems.

4. It also avoids gastrointestinal absorption and enzymatic or pH related deactivation, avoids gastrointestinal irritation and reduces fluctuations in plasma drug profile.

5. It enhances bioavailability as well as high concentrations of drugs delivered via this route can be localized at the site of action, thereby reducing the systemic drug levels and therefore also reducing the systemic side effects associated with the drug.

6. It is an attractive method to transport drug or biological compounds due its advantage in reducing the pain and inconvenient intravenous injections.

7. It has convenient route and can deliver therapeutic volumes/ doses of drug quickly with minimal discomfort.

8. It is simple, inexpensive and self administrable.

9. It can create sustained or bolus delivery profiles.

10. It has rapidly responsive pharmacokinetics and pharmacodynamics⁽^1,2,3).

Disadvantages:

1. Systems containing small sized molecules can only easily penetrate the skin.

2. It possesses local irritation, erythma, itching, and local oedema may be produces by the drug or other excipients at the site of application especially in the patch formulation.

3. Limited permeability across the skin may limit the delivery of number of

Drugs⁽^1,2,3).

Need for using microneedles:

Transdermal drug delivery is a non- invasive, user- friendly delivery method for therapeutics. However, its clinical use has found limited application due to the remarkable barrier properties of the outermost layer of skin, the stratum corneum. Physical and chemical methods have been developed to overcome this barrier and enhance the transdermal delivery of drugs. One of such techniques was the use of microneedles to temporarily compromise the skin barrier layer. this method combines the advantages of conventional injection needles and transdermal patches while minimizing their disadvantages. To increase skin permeability, a number of different approaches has been studied, ranging from chemical/ lipid enhancers to electric fields employing iontophorosis and electroporation to pressure waves generated by ultrasound or photoacoustic effects. When oral administration of drugs is not feasible due to poor drug absorption or enzymatic degradation in the gastrointestinal tract or liver, injection using a painful hypodermic needle is the most common alternative. An alternative approach involves creating larger transport pathways of microns dimensions using arrays of microscopic needles. These pathways are orders of magnitude bigger than molecular dimensions and, therefore, should readily permit transport of macromolecules, as well as possibly supramolecular complexes and microparticles. The combination of elastic liposomes and microneedles may provide higher and more stable transdermal delivery rates of drugs without the constraints of traditional diffusion- based transdermal devices, such as molecular size and solubility⁽^2,3,4).

Mechanism of working and design of microneedle patches:

Microneedle- based drug delivery systems can be applied to the delivery of microgram levels of small molecules or peptide through to delivery of hundreds of milligrams of high value formulations of proteins. Trasdermal delivery of the systematically acting drugs to the targeted tissues showed that the drugs must possess some physicochemical properties which act by facilitating the systemic absorption of drug across the skin and also enhance the drug uptake via capillary network into the dermal papillary layer. to overcome the limitations of transdermal system as well as to circumvent the barrier nature of stratum corneum, various approaches have been made to accomplish the main objective of permeation enhancement across the skin through transdermal route to increase the drug delivery.

The mechanism for delivery is not based on diffusion as it is in other transdermal drug delivery products. The drug, in the form of biomolecules, is encapsulated within the microneedles, which are then inserted into the skin in the same way a drug like nitrogycerine is released into the bloodstream from a patch. The needles dissolve within minutes, releasing the trapped cargo at the intended delivery site.

In microneedle devices, a small area is covered by hundreds of microneedles that pierce only the stratum corneum, thus allowing the drug to bypass this important barrier. The tiny needles are constructed in arrays to deliver sufficient amount of drug to the patient for the desired theraprutic response.

Hollow microneedles of various lengths ranging from 600-800 um have been studied to demonstrate the distribution of calcein and fluorescently labeled insulin within the epidermis and dermis in- vitro in hairless rat skin. Further 200 um long hollow microneedles have been shown to deliverer blue ink and fluorescent Lucifer yellow dye to a depth of 100 um under the skin of chicken thigh. Hollow microneedles have also been inserted into human cadaver sclera to deliver nanoparticles on the order of 280 nm⁽^4,5,6).

Mechanism of permeation: The mechanism of delivery via microneedles is based on mechanical disruption of the skin and application of the drug or vaccine within the epidermis, from where it can more readily reach its targeted site of action. The drug such as biomolecules is entrapped within the microneedles, which are then further inserted into the skin and released the drug into the blood stream. The needles dissolve within minutes, released the entrapped drug at the intended site of delivery⁽⁶⁾.

Fig. Mechanism of microneedles

Types of microneedles:

Microneedles are broadly classified into two types mainly. These are solid microneedles and hollow microneedles.

1. Solid microneedles- Solid microneedles are defined as the arrays of projections that are employed for creating holes in stratum corneum and are applied before the application of a drug then removed afterwards. These can be used by inserting the needles into the skin for specified time period. Solid microneedles can be prepare by coating with the drug and then inserted into the skin. After removal of the microneedle containing device, drug will remain deposited within the skin membranes. Erodible microneedles when inserted into the skin, dissolves and the drug can easily be loaded into the soluble needles.

2. Hollow microneedle- Studies in human cadaver tissues have demonstrated that the primary resistance to fluid flow to skin via microneedles resides within the skin and not the microneedles. Hollow microneedles were fabricated by pulling fire- polished type 1 borosilicate glass pipettes with a micropipette puller. The pulled needles were then beveled at a 30⁰ angle using a beveler producing hollow microneedles with an oval- shaped opening. Due to this oval shape, the effective radius of the needle opening was determined by averaging the lengths of the long and short axes of the needle tip opening.

3. Coated microneedles- Have also been studied in human cadaver sclera to show rapid delivery of sulforhodamine and BSA in less than 30 seconds. Insertion of microneedles coated with vitamin B, calcein and 1 um barium- sufate microparticles into porcine cadaver skin has shown rapid dissolution of the drug from the needle into the dermis within a matter of seconds.

4. Poly- lactide- co- glycolide microneedles- Using the poke and release approach have been shown to deliver calcein just below the dermal- epidermal junction in a controlled release manner to human cadaver skin. Depending on the encapsulation formulation, these needles could control times ranging from hours to months⁽^6,7).

Materials used for construction:

There are various materials used for the construction of microneedles. In that glass, silicon, metals such as stainless steel, solid or coat of gold over nickel, palladium, cobalt and platinum and biodegradable polymers are mostly preferred materials for the preparation of microneedles⁽^1,5).

Drug delivery method:

There are various strategies for the delivery of drug through microneedles as a transdermal drug delivery which includes;

1. Poke with patch approach

2. Biodegradable microneedles

3. Hollow microneedles

4. Dip and scrape

5. Coat and poke approach

Poke with patch approach:

It involves piercing an array of solid microneedles into the skin followed by application of the drug patch at the treated site. Transport of drug patch across skin can occur by diffusion or possibly by iontophoresis if an electric field is applied.

Biodegradable microneedles:

It involves encapsulating the drug within the biodegradable, polymeric microneedles, followed by the insertion into the skin for a controlled drug release.

Hollow microneedles:

It involves injecting the drug through the needle with a hollow bore. This approach is more reminiscent of an injection than a patch.

Dip and scrape:

Dip and scrape approach, where microneedles are first dipped into a drug solution and then scraped across the skin surface to leave behind the drug within the microabrasions created by the needles. The arrays were dipped into a solution of drug and scraped multiple times across the skin of mice in vivo to create microabrasions.

Coat and poke approach:

In this approach needles are first coated with the drug and then inserted into the skin for drug release by dissolution. The entire drug to be delivered is coated on the needle itself⁽^6,7,8)).

Formulation design parameters:

The general design parameters that are to be considered in the development of microneedles are that these should be capable enough to insert into skin without breakage. Polymers should be selected to have sufficient mechanical strength and should be biocompatible. They should not produce any pain. The geometry of the microneedle is also very important, where sharpness of tip strongly effects the microneedles insertion into skin. Micromolds were fabricated using photolithography and molding processes. To serve as microneedle matrix materials, ultra-low viscosity carboxymethylcellulose, amylopectin and bovine serum albumin were dissolved in deionized water. Water was then evaporated off until the concentration of solute was approximately 27 wt%, which resulted in a viscous hydrogel. Viscosity of concentrated hydrogels was measured using a Couette viscometer. Solute concentration was determined by measuring solution mass before and after evaporation⁽^1,8).

Characteristics of microneedles:

1. Dimensions of microneedles- The dimensions of microneedles can vary depending on the types of micro needles. Typical microneedle geometries may ranges from 150- 1500 microns in length, 50- 250 microns in base width, and 1- 25 microns in tip diameter. The tips of microneedles are of different shapes like triangular, rounded or arrow shaped. The hollow microneedle arrays are fabricated with lumen diameter of 30 um and height 250 um. Centre to centre hollow microneedle array 150 um and the axis of lumen is fabricated with the distance of 10 um to axis of outside column.

2. Control drug release- The microneedles should deliver the controlled amount of drug at a definite and predetermined rate.

3. Penetration- The microneedles should be able to penetrate the drug to the required depth in the tissues of the body. Painless insersions of microneedles into skin can be accomplished by gentle pushing, using approximately 10 Newton forces.

4. Ruggedness- microneedles developed must be capable of insertion deep into skin without breaking. They should be manufactured by taking optimum size and if they are too long, upper portion of microneedles may not have enough rigidity and could undergo breakage before penetration. They must be able to withstand the insertion force without delaminating or fracture⁽^1,7).

Evaluation parameters:

1. In- vitro study of microneedles

In vitro evaluation microneedles are accomplished by using various mediums like agarose gel and methanol to insert the microneedles. The main key objective of the microneedles, finding out the penetration force and bending force, evaluation of strength of microneedle, determination of the dissolution rate of coating material and the estimation of the efficiency of drug delivery.

2. In- vivo testing of microneedles

To conduct the in vivo preclinical study, generally mice, rabbits, guinea pigs, mouse and monkey etc. are used. The main motive of the in vivo testing is the determination of safety as well as toxicity of the tested compound. The key objective behind in vivo testing of the microneedles force in different skin, mechanical stability, bending breakage force, to perform various non- clinical safety study and pharmacological study, determination of various parameters like immunogenicity, genotoxicity, skin sensitization and allerginisation study, development toxicity, acte and chronic dermal toxicity and carcinogenicity.

3. Imaging and histology

Fluorescence micrographs of coated microneedles and histological skin sections were collected using an Olympus IX70 fluorescent microscope with a CCD camera. Digital X- ray imaging to detect barium sulfate was done using Faxitron MX 20 cabinet X- ray. Histological examination of cadaver skin was conducted on frozen sections.

4. Delivery from individual microneedles in vitro- single microneedles coated with calcein were inserted into porcine cadaver skin for 20 s and removed. For particle delivery, barium sulfate particles, or latex beads were inserted into porcein cadaver skin for 1 min. After removing the microneedles, the skin surface was examined by brightfield microscopy for coating residue. Porcein cadaver skin was then examined histologically to assess the extent of delivery of microneedle coatings into the skin⁽^1,9).

Application of microneedle patches:

Most bio therapeutic agents and vaccines are injected by the use of hypodermic needle. Use of injection possesses the advantage of providing a low- cost, rapid and direct way to deliver almost all types of molecules into the body. Microneedle patches are used to deliver the drugs having high molecular weight and which are hydrophilic in nature through the skin. There is a problem associated with the use of hypodermic needles that they cannot be easily used by patients themselves. A microneedles allows precise tissue localization of delivery, such as within the skin, the suprachoroidal space of the eye, and the cell nucleus. Conventional transdermal drug delivery system is limited by the barrier nature of the stratum corneum. Various chemical, biochemical and physical methods have been studied to enhance the skin permeability. Microneedles can also be employed for targeted vaccine delivery to antigen- presenting cells in the skin and is of keen interest nowadays. Microneedles, in comparison to all the methods, can be prepared as a low- cost patch that is simple for patients to apply for delivery of bio macromolecules like insulin, hormones, immunological cell, proteins and peptides. Microneedles have also gain prominent attention in the field of cosmetics and various cosmeceuticals have been used for the treatment of scars, acne, pigmentation and wrinkles as well as for skin toning⁽⁷⁾.

Anti- restenosis delivery

This can be deliver in the form of microneedle patch. This is the targeted drug delivery system. And can be used to treat the atherosclerosis.

Insulin delivery

This can be deliver as a microneedle patch. This can be used in the diabetic patients to reduced the glycerol level upto 80% within 4 hrs. and gives most prominent effect as compare to other marketed formulations.

Influenza vaccine delivery

This can be deliver with the help of microneedle patche and used to enhance immune response as compared to intramuscular injection.

Lidocaine hydrochloride delivery

This can be introduced used microneedle array and can be used for repeatable and robust penetration across stratum corneum and epidermis.

Naltrxone delivery

This can be deliver with the help of microneedle patch and can be used for enhanced the transdermal delivery.

Bovine serum albumin

This can be deliver using chitosan microneedle patch. This can be a promising devise for sustained delivery of macromolecules.

Recombinant human insulin delivery

This can be easily delivered through the microneedles hydrogel patch and can be used for sustained release of insulin.

Immunization or antigen delivery

This can be deliver using microneedle array patch system and can be used for effective immunization.

Desmopressin delivery

this can be introduced into the microneedle patch and can be used for enhanced bioavailability in the treatment of enuresis⁽⁸⁾.

Microneedle patches are also gaining increasing focus as an alternative method to deliver vaccine. Use of hollow microneedles in influenza vaccination has widespread clinical utility worldwide. In spite of drug delivery, microneedles are also used in bio-sampling, local call treatment etc. application of microneedles relies mainly on the function of the device that accelerate insertion of microneedles, its efficient infusion into the skin, followed by skin recovery, drug delivery, stability and storage in addition to lack of pain, skin infection and irritation, and also including drug safety and efficacy.

DNA vaccine delivery- This can be introduced using microneedle array and this has a potential to lower the doses and the number of boosters needed for immunization.

Oligonucleotide delivery

This can deliver using microneedle patch and can be used to increased the absorption of the molecules relative to the intact skin⁽⁹⁾.

CONCLUSION:

Microneedle is a novel approach which can be incorporated wither in the form of patch or in the form of array have been observed as a potential carrier for the delivery of numerous macromolecular drugs for the effective transdermal delivery. These painless systems are slowly gaining importance and would qualify to be one of the important devices for controlled drug release in future. Thus it was concluded that, these systems represented it to be an sufficient and superior carriers as compared to other needle based formulation for the transdermal delivery. Various research reports studies confirmed that microneedles are ought to be the prominent carriers for enhancing the permeation deep into the systemic circulation and providing a painless, effective and safe route for drug delivery.

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Received on 01.12.2015 Accepted on 18.12.2015

Asian J. Pharm. Tech. 2015; Vol. 5: Issue 4, Oct. - Dec., Pg 195-200

DOI: 10.5958/2231-5713.2015.00029.X