INTRODUCTION:

When it comes to medication distribution via the skin, hypodermic needles and dermal lotions are the most often employed methods. Patients dislike needles because of the discomfort they cause, and topical medications have lower bioavailability. The skin is the primary barrier for medication delivery via the topical route^1,2. MNs are a harmless and non-invasive technique of medication administration or sample that may skip the stratum corneum belonging to skin without activating neurons, causing itching, or developing infections^3,4.

These small gadgets allow illness detection and regulate testing that extends past viruses to bacterial illnesses and medical crises, with point-of-care patch tests substituting time-consuming and costly facility testing. As a result, there is an increasing interest in tiny patches containing large scale polymer MNs^5,6, with the point-of-care quick diagnostic industry alone expected to increase to $50.6 by the year 2025⁷.

Precise medication administration is performed by depositing the medication composition on a solid MN or integrating the medication of biodegradable-matrices, which allows the medication to be released through the skin. MNs can carry bio therapeutic agents such as insulin⁸ and vaccines in addition to APIs^9-12.

Because the passage ways are far bigger than the conventional bioactive molecules, micro-needle distribution is not limited by molecular size. Micro-needles of diverse materials, shapes, and dimensions (50-900m height, 2000mm 2 surface area) have been created using several micro fabrication processes¹³.

Fig. 1: Depicts a contrast between micro-needles and standard injection distribution methods.

Categorization of Micro-Needles:

Micro-needles can be generally categorised based on their distribution profile or the substance utilised in their production.

A) Depending on medication delivery differences:

Micro-needles might be solid, hollow, dissolving, or coated micro-needles.

1. Solid Micro-needles:

Solid micro-needles are often used to pre-treat the skin by creating holes. The needles' pointed heads pierce the skin, creating micron-sized pathways via which the medication immediately penetrates the skin layers upon administration of a medication patch, boosting penetration. The medication is absorbed by the capillaries and has a widespread impact. It can also be utilised for a local impact¹⁴. As micro channels are formed, they operate on a 'poke and patch' basis. These micro channels improve medication penetration by allowing formulations to diffuse straight into the skin layer. Micro pores created by micro needles persisted on rat skin for at least 72 hours following micro needle application when kept under occlusive circumstances, including occlusive tape^15,16. The 'scrape and patch' technique is a variant on the traditional solid micro needle procedure in which micro needles, micro blades, or micro projections are scraped across the skin to create micro-abrasions. Medication solutions contained inside a patch are subsequently administered to these micro projections¹⁷.

Fig. 2: Solid micro-needles

2. Hollow micro-needles:

Such micro-needle devices are smaller versions of standard hypodermic needles¹⁸. A vacant area within the hollow micro-needle is occupied with the medication dispersion or solution. They are pierced at the tips. The medicine is immediately injected into the epidermis or higher dermis layer after being inserted into the skin. It is primarily utilised for high-molecular-weight molecules like oligo-nucleotides, vaccines and proteins¹. A pressure-driven movement of liquid mixture is used to distribute drugs¹⁹. This approach can carry significant dosages into the dermal membrane²⁰.

Fig. 3: Hollow micro needles

3. Coated microneedles:

Coated microneedles operate on the 'coat and poke' concept. These MNs are made out of a foundation of solid microneedles that have been coated with medication solutions or dispersions. Various ways for coating microneedles have been investigated^21-23. Further dissolving of the medication from the layer occurs, and the medication is swiftly supplied. The quantity of medicine that may be deposited is determined by the width of the coating layer and the needle size, which is typically quite small²⁴. Dip coating is the main prevalent approach, but it is complex because of the necessity for accurate control to ensure that the Micro needles are inserted precisely in the dipping solution²³.

Fig. 4: Dip coating technology was used to coat micro needles

The medication can readily penetrate coated micro needles. The medicine dissolves quickly in the skin, causing a quick commencement of effect. By repeating the process, the width of the coating can be increased. Nevertheless, it is not suited for medication preparation coating.owing to dosage limits, administration necessitates a big dose^25,26.

Fig. 5: Coated micro needles

5. Dissolving micro needles:

The 'poke and release' concept govern the operation of dissolving micro needles. In comparison to other micro needles, they are simple to make as well as utilise. They sure have gotten a lot of attention in past few years²⁷. Micro needles can be produced from water-soluble or disposable substances that contain medications and have enough mechanical strength to pierce the skin²⁸. Dissolving micro needles are generally produced utilising a solvent casting process and a water-solvable compostable polymer. Biodegradable polymers derived from cellulose, like methyl cellulose and carboxy methyl cellulose, are commonly utilised. Saccharides (such as sucrose and trehalose) are also added in the micro needles; these enhance product breakdown and stabilise molecules^29,30. Because of the polymer's bio compatability and breakdown within the skin, it is among the finest options for lengthy treatment with enhanced patient satisfaction¹.

Fig. 6: Dissolving Micro needles

B) Depending on various materials selected:

Based on the form or constituents of the patch, micro needles are made of a variety of ingredients ranging from metal to polymer. In general, micro needle substances should be strong enough to penetrate the skin³¹. MNs can be made of polymers, silicone, metals or ceramics. Construction materials have been divided into two categories: non-degradable and degradable. Ceramics, metals, and silicone are examples of non-biodegradable substances, whereas polysaccharides and biodegradable polymers are examples of degradable polymers.

1. Non-degradable Materials:

a) Metals: Soluvia® was one among the first micro needle-dependent products to be commercialised. Micronjet, a silicone dependent product, was introduced into market as well³². Because metallic substances have significant mechanical and tensile strength, they may readily penetrate into the skin. These are utilised in the manufacture of coated, hollow, and solid micro needles³³. They offer excellent mechanical qualities as well as biocompatibility. Metals are robust sufficiently to prevent breaking and so more suited for micro needle manufacture than silicon. Stainless steel was the very first metal utilised in the manufacture of microneedles³⁴. Laser cutting, metal electroplating, 3D laser ablation and wet etching are all fabrication processes¹⁹. The AdminPen®, which ranges in length from 600 to 1500 m, is an example of a commercial scale hollow stainless steel microneedle³⁵.

b) Silicone: Silicone has been studied for almost twenty years and is among the main regularly utilised materials for micro needle devices³⁶. In the nineties, the first silicon micro needle was created³⁷. Silicon has a crystalline structure and is anisotropic in character. Its characteristics are determined by the crystal lattice orientation, which exhibits distinct elastic properties (50 to 180 GPa). Silicon's high cost and lengthy sophisticated production process limit its application in micro needle technology. Furthermore, because to the fragile nature of silicon, certain parts may shatter and stay in the skin, creating some medical complications^38-40. Silicone MN arrays have the potential to be employed as main moulds in micromolding⁴¹.

Fig. 7: Silicone micro needle array template

c) Ceramic: Alumina (Al2O3) is mostly utilised for its chemical tolerance. Due to the extremely energetic ionic and covalent connections formed among Al and O atoms, this produces a stable oxide⁴². Ceramic substances have been employed in medicine distribution for many years. Porous ceramic micro needles allow medications to be absorbed and diffused instantly after interposition in the linked pores. Because of their inherent porosity, micro needles may load medicines without extra processing^43,44. Calcium sulphate di-hydrate [Gypsum (CaSO4 0.2H2O)] and calcium phosphate di-hydrate [Brushite (CaHPO4.2H2O)] are two more forms of ceramics utilised⁴⁵. Ormocer®, an organically engineered ceramic, has been employed in past years. It is a cross-linked copolymer in 3 dimensions⁴⁶.

d) Synthetic polymers: Various synthetic polymers, including as polyvinyl alcohol and polyvinyl pyrrolidone, have been investigated for use in MNs. Poly methyl methacrylate is a biocompatible polymer utilized in MN arrays⁴⁷.

2. Degradable materials:

a) Natural: Carbohydrates are viable resources for the manufacture of micro needles. Among the most essential characteristics of carbs is their low cost and safety⁴⁸. They are not only biocompatible, but additionally have a minimal toxic-effects. Some carbs are considered to be extremely strong. Every one of these substances are affordable and quickly biodegradable³⁹. Maltose is among the greatest often utilised sugars⁴⁹. Additional sugars and polysaccharides, such as mannitol, trehalose, sucrose, xylitol, and galactose, might also be employed⁵⁰.

b) Synthetic:

MNs have been created using a wide range of synthetic macromolecular materials. Polylactic-co-glycolic acid, polyglycolic acid (PGA), and polylactic acid are additional examples of these materials^51,52. MNs regulate medication flow in these sorts of products, and that is dependent on the makeup of the MN components^53,54.

Fabrication Techniques:

The fabrication or production procedure for micro needles is determined by the kind, shape, and substance of the microneedle⁵⁵.

Micro-Needle Evaluation Methods:

A) Characterization Methods: The medicine can be placed onto or into the micro needles in suspension encapsulated (nano particles, liposomes, nano liposomes etc.)⁵⁹. The polymer solution can be applied to the medication as a coating or as a patch. Based on the kind of formulation employed in the micro needles, several physicochemical characterizations such as viscosity, poly dispersity index, particle size, and zeta potential can be tested for loaded medication⁶⁰. For a patch that is applied following pre-treatment, medication dispersion, attachment, and penetration tests are done. Dynamic light scattering, X-ray scattering, and TEM can be used to determine the size, internal structure, and crystallinity of liposomes or nano carriers. Medication dispersion and micro needle stability may be examined at various temperatures, pH levels, and simulated in-vivo physiological settings (cell line or tissues). Additional experiments on developed micro needles include solubility investigations, medication composition, in-vitro release tests, and biocompatibility studies^61,62.

B) Dimensional Analysis: To examine the needle geometry and quantify the tip radius, length, and height of the micro needle, many approaches are utilised. The most prevalent techniques are optical and electrical microscopy. The analysis of a 3D image provides a more accurate view of needle shape and aids in product testing. This was accomplished using a SEM and a con-focal laser microscope. SEM creates a picture of a sample by scanning it with a focused stream of electrons that interact with the atoms in the sample and produce different signals that provide information about the sample's surface topography and composition. High-resolution pictures are produced using con-focal laser microscopes^63,64.

C) Insertion forces or mechanical properties: A micro needle must be sharp and narrow enough to effectively pierce the skin while yet being robust enough not to break once inside the skin. The force at which the micro needle loses structural integrity and the insertion force are two critical elements in the safe and efficient design of micro needles. The 'safety factor' is the ratio of these two forces. The ratio should be as high as feasible⁶⁵.

D) In-vitro skin permeation studies: The diffusion cell equipment is employed to determine drug penetration through the skin. Pig ear skin is primarily employed in the experiment which is positioned between the receptor and donor section. The cumulative permeation profiles of treated and untreated skin are compared.

E) In-vivo animal model studies: The study can make use of hairless rats. To anaesthetize the animal, a proper procedure must be applied. Trans-epidermal water loss (TEWL), which is assessed before and after micro needling, is one of the characteristics examined. This parameter is measured with a Delfin Vapometer⁶⁶.

F) Skin healing process: Whenever a micro needle gadget is placed into the skin and withdrawn after therapy, it leaves micron-sized holes. It might take some time to reseal these pores. These holes must be resealed as soon as possible to avoid infection. The time it takes for the skin to regain its barrier characteristics is critical. Electrical impedance measurements can be used to investigate pore resealing. Depending on whether the skin is blocked and the shape of the needle, recovery time might range from 2 to 40 hours. Pore resealing can also be studied using TEWL and tissue staining^67,68.

G) Skin infection and irritation: When the skin is subjected to diverse environmental pressures, it develops a variety of defence systems to defend itself. Micro needle usage might induce mild to moderate skin irritation or allergies in those with sensitive skin⁶⁹. There is redness, discomfort, and swelling. Itching might cause pain in patients. Unless the needles are sterile, holes formed by introducing micro needles into the skin can be a source of infection. While the holes generated by micro needles are much smaller than those created by hypodermic needles, they allow for less germ penetration⁶⁷.

H) Pain: Since micro needles do not reach pain receptors deep within the dermis, they generate less discomfort than hypodermic needles. The number of micro needles on a patch, the length of the micro needle, and the tip angle or needle shape all influence pain intensity⁶⁷. Gill et al. confirmed that micro needles are less painful than a hypodermic needle of 26 gauge. The shorter and fewer the micro needle on the patch, the less painful the therapy⁷⁰.

Applications of Polymeric Micro Needles:

1. Oligo-nucleotide Delivery:

Oligonucleotides are short pieces of DNA or RNA. It is challenging to deliver oligonucleotides to their intracellular location of action. As a result, numerous ways for improving delivery were identified. Using a micro needle, an effort was made to administer 20-merphosphorothioated oligodeoxynucleotide. The poke with patch method was used to deliver oligonucleotides using solid micro needles made of stainless steel or titanium. When compared to undamaged skin, more medication was observed to reach the site of action. Iontophoresis combined with a micro needle technique produced better outcomes than iontophoresis alone^2,71.

2. Vaccine treatment:

A vaccination is a biological product. It offers active acquired immunity to a specific illness. Vaccination is a destroyed or weakened virus, pathogenic microorganism, its toxins, or one of its surface proteins. Vaccination treatment boosts the body's immune system and protects against future microorganism encounters. In vaccine treatment, the micro needle method was proven to be successful^67,68.

A micro needle was used to administer the DNA vaccination. Immune responses seen were far superior to those obtained with standard doses⁷². An attempt was also made to construct a micro needle patch for delivering influenza vaccination⁷³. When the medicine is delivered by hollow micro needles rather than intramuscular injection, a lower dosage is required. The use of hollow micro needles to administer anthrax and rabies vaccines was also investigated³⁸.

3. Peptide administration:

When peptides are taken orally, they are destroyed enzymatically. Transdermal administration prevents this, although less peptide may pass the skin. Peptide administration through micro needles can aid overcome peptide skin penetration. Desmopressin is a peptide hormone that is synthesised from vasopressin. It is used to compensate for low vasopressin levels. This medicine is used to treat diabetes insipidus, childhood bedwetting, and haemophilia A. The use of micro needle delivery to distribute desmopressin was explored, and it was shown that micro needle distribution was safer and more efficient than conventional ways². Cyclosporin A is a water-insoluble, high-molecular-weight cyclic peptide used to treat a variety of skin conditions. Molding was used to create dissolving micro needles carrying cyclosporine a that were 600m long and 250m broad. Fabricated micro needles containing 10% cyclosporine. A were forced into the pig skin for 60 minutes, resulting in the dissolution of approximately 65% of the micro needle with 346.5 g drug delivery⁷⁴.

4. Hormone administration:

Insulin is a kind of peptide hormone. The medicine is employed to treat high blood sugar. It was discovered that delivering insulin by micro needle lowers blood glucose levels more effectively⁷⁵. Clinical studies with parathyroid hormone (I-34) coated micro needles revealed 3 times shorter T_max and 2 times shorter apparent T1/2 when compared to traditional injection therapy⁷⁶. These investigations shown that micro needles may be used effectively for hormone treatment. Furthermore, by using appropriate polymers, they can be changed for long-term activity⁷⁷.

5. Ocular Transmission:

Targeted medication delivery can treat a wide range of posterior segment conditions. Nano particles were delivered through the supra choroidal space using iontophoresis. The particles were observed to localise at the injection site in the absence of iontophoresis. More than 30% of nano particles were transported to the posterior portion of the eye when coupled with microneedles⁷⁸.

CONCLUSION:

Silicon was used to make the first micro needle. A research was done to determine whether or not micro needles can be utilised to deliver medications more effectively through the skin. Originally, permeation tests were performed on cadaver skin to see whether big molecules such as albumin and insulin could pass through the skin when micro needles were used. Subsequent research revealed that micro needles transmit big molecules more effectively.

Polymeric micro needles (MNs) are an effective method for delivering tiny chemical molecules to big complex bio therapeutics with proven clinical effectiveness. MNs-based medication delivery through the skin addresses the shortcomings of oral and parental routes and is designed for self-administration at home. The success of polymer MN development is heavily reliant on the kind of polymer utilised (one polymer or a combination of polymers), biocompatibility with the medication, design, and mechanical strength of the MN. Fundamental research and commercialization projects must be coupled to accelerate the manufacture of polymeric MNs on a wide scale, with more work necessary to set sterilising guidelines and raise awareness of the long-term harmful consequences of polymeric MNs in regenerative medicine.

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Received on 16.05.2023 Modified on 07.02.2024

Asian J. Res. Pharm. Sci. 2024; 14(3):236-242.

DOI: 10.52711/2231-5659.2024.00039