Formulation and Evaluation of Microneedle Based Transdermal Drug Delivery System by Using Antihypertensive Drug

1.1. Transdermal drug delivery system:

Definition – Transdermal drug delivery system is defined as self-contained, self-discrete dosage forms, which when applied to the intact skin deliver the drug at a controlled rate to the systemic circulation. ^(1,2) Transdermal drug delivery (TDD) is a route of drug delivery for treating or preventing disease by absorbing drugs through the skin, permeating into the skin and further into the blood circulation. TDD avoids first-pass effects, prolongs the action of drugs with short half-lives through slow release and avoids fluctuations in blood levels, reduces side effects and improves patient compliance. The stratum corneum barrier plays a key role in TDD, and many methods have been used to improve the efficiency of TDD, including the use of chemical penetration enhancers and different physical enhancement approaches, such as micro-needling, iontophoresis, electroporation, laser ablation and ultrasound facilitation. ⁽³⁾

1. 2.  Microneedle Based Transdermal Drug Delivery Systems:

In recent years, microneedles have gained widespread interest in TDD and have shown Brilliant achievements in delivering both chemical small molecules and biomacromolecules whilst being minimally invasive and painless. ^(4,5) Microneedles usually consist of micrometer-sized needles (50–900 µm in length) in the form of microneedle arrays that can successfully penetrate. the stratum corneum and deliver drugs in a minimally invasive manner below the stratum corneum without damaging blood vessels and nerves in the dermis ^(6,7), improving patient compliance and allowing drugs exposed in the epidermis or dermis to be rapidly absorbed by surrounding capillaries and lymph nodes. ^(8-10) Microneedles or Micro-needle patches or Microarray patches are micron-scaled medical devices used to administer vaccines, drugs, and other therapeutic agents.⁽¹¹⁾ While microneedles were initially explored for transdermal drug delivery applications, their use has been extended for the intraocular, vaginal, transungual, cardiac, vascular, gastrointestinal, and intracochlear delivery of drugs.⁽¹²⁾ Microneedles are constructed through various methods, usually involving photolithographic processes or micro moulding. These methods involve etching microscopic structure into resin or silicon in order to cast microneedles. Microneedles are made from a variety of material ranging from silicon, titanium, stainless steel, and polymers. Some microneedles are made of a drug to be delivered to the body but are shaped into a needle so they will penetrate the skin. Stimuli-responsive microneedles are advanced devices that respond to environmental triggers such as temperature, pH, or light to release therapeutic agents. The arrays are applied to the skin of patients and are given time to allow for the effective administration of drugs. Microneedles are an easier method for physicians as they require less training to apply and because they are not as hazardous as other needles, making the administration of drugs to patients safer and less painful while also avoiding some of the drawbacks of using other forms of drug delivery, such as risk of infection, production of hazardous waste, or cost. ⁽¹³⁾

1.3. Types of Microneedles:

As aforementioned, a microneedle is a micron-sized needle with a height of 10–2000 µm, and width of 10–50 µm, and are widely used in transdermal drug delivery systems to the advantage of safe, painless, convenient, non-invasive and efficient drug delivery.50- 51 Microneedles can create pores on the skin and enable the drug to penetrate through the epidermis layer to the dermal tissue directly. Unlike regular hypodermic needles, the microneedle has the ability to improve patient compliance as it does not hurt nerves. What is more, the microneedle delivery system delivers drugs transdermally, hereby improving the bioavailability of drugs via avoiding hepatic first pass metabolism. The drug delivery mechanisms of these microneedles (respectively) are the “poke and patch” approach, the “coat and poke” approach, the “poke and release” approach, and the “poke and flow” approach. We will subsequently introduce each type of microneedle in more detail, along with examples of successful use cases of each. ^(14,17) Morphologically, microneedles are classified into five types namely:

1. Solid microneedles
2. Coated microneedles
3. Dissolving microneedles
4. Hollow microneedles
5. Hydrogel-Forming microneedles.

1.4. Advantages of Microneedle Patch:

1. Minimally invasive
2. Pain-free
3. Enhanced drug absorption
4. Reduced dosing frequency
5. Improved patient compliance
6. Large molecules can be administered
7. Painless administration of the active pharmaceutical Ingredient
8. First-pass metabolism is avoided
9. Faster healing at injection site than with a hypodermic needle,
10. Decreased microbial penetration as compared with a hypodermic needle, the microneedle punctures only the epidermis
11. Specific skin area can be targeted for desired drug delivery enhanced drug efficacy may result in dose reduction
12. Good tolerability without long-term oedema or erythema
13. Rapid drug delivery can be achieved by coupling the microneedles with other technologies. ⁽¹⁸⁾

1.5. Disadvantages of Microneedle:

1. Careful use of the device may be needed to avoid particles ‘bouncing off’ the skin surface.
2. The thickness of the stratum cornea and other skin layers varies between individuals and so penetration depth of particles could vary too.
3. The external environment, like hydration of the skin, could affect delivery.
4. Repetitive injection may collapse the veins.
5. The tip of the microneedle may break off and remain within the skin on removal of the patch. ⁽¹⁹⁾

1.6. Material Compositions of Microneedles:

Microneedles can be made from various different materials, each yielding different characteristics and these materials can be used to prepare different kinds of microneedles via different methods. ⁽²⁰⁾ The materials of microneedles can be divided into various types:

1. Metal materials
2. Inorganic materials
3. Polymer materials
4. Glass materials
5. Ceramic materials.

1.7. Various Methodologies/Techniques:

There are Various Methodologies/Techniques involved in Microneedles Applications is as follows:

1.7.a. Poke with patch or poke and flow approach:

It involves pressing of solid microneedles array on the skin to produce microspores followed by the application of patch or liquid formulation containing therapeutic agent. The microspores formed allow the easy passage of drug in to the deeper tissues of the skin.

1.7.b. Coat and poke approach:

In this method, microneedle array is first coated with drug and then inserted into skin. Upon insertion, the drug-coated on the microneedles dissolves in the aqueous pores followed by permeation in to the surrounding skin tissues and microcirculation.

1.7.c. Scratch and patch approach:

It is a variation of poke and patch approach, where microneedle array is scraped over the skin and then applying patch or liquid formulation.

1.7.d. Dip and scrape:

In this approach, microneedles are first dipped into drug solution and then scraped across the skin surface to leave behind the drug within micro abrasions created by the needles.

1.7.e. Poke and release approach:

In this approach, the drug can be encapsulated within soluble sugar or biodegradable polymeric microneedles, followed by the insertion into the skin to achieve either fast or controlled drug release. Poke with flow: In this approach, hollow microneedle array is pressed on the skin to create micro-channels in the skin followed by infusion of liquid formulations in to deeper skin tissues across the needle pores. ⁽²¹⁾

2. Preformulation Studies:

Preformulation studies are investigations of the physical and chemical properties of a timolol maleate, such as organoleptic properties, solubility, melting point, and compatibility with polymer by using FTIR spectroscopy. Analytical method development: A simple, accurate, and precise UV-visible spectrophotometric method was developed and validated for the quantitative estimation of timolol maleate in accordance with ICH guidelines. The goal is to generate data that informs formulation design and development, resulting in a stable, safe, and effective drug product.

2.1. Fabrication of microneedle patch:

For formulation of microneedle patch Polymers like PVA, PVP K30, HPMC E4M, HPMC K4M, Plasticizers like Glycerin, PEG 400 and drug (Timolol maleate) was used. Aqueous blend of polymer and drug were used to fabricate microneedle patches by using different plasticizers with constant volume, as Specified in (Table no. 1 & 2). by observing each formulation, the best formulation batch was optimized.

Table No.1: Formulation of timolol maleate loaded microneedle patches by using Glycerin as plasticizer

Table No. 2: Formulation of timolol maleate loaded microneedle patches by using PEG 400 as plasticizer.

86.5 mg of timolol maleate and varying amounts of polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP K30) in ration 9:1 were dissolved in same volumes of distilled water and ethanol in ration 1:1 by keeping glycerin amount constant (as shown in table no. 3), then applying gentle heat using water bath. Distilled water and ethanol was selected as solvent owing to better solubility of drug in it. These polymer matrix solutions were transferred into ABS micromolds, and allowed to dry in vacuum desiccator for 24 h. After 24 h, microneedle patches were retrieved from micromolds and preserved in a moisture resistant container along with silica.

Table No.3: Formulation of Microneedle patch by increasing concentration of PVA: PVP K30 (9:1)