Microneedle-Based Transdermal Delivery of Lovastatin for Enhanced Wound Healing: A Review

Abstract

Microneedle-mediated transdermal drug delivery (TDD) has emerged as a promising alternative to conventional oral and injectable dosage forms. This minimally invasive technology offers several advantages, including painless administration, enhanced patient compliance, and circumvention of first-pass hepatic metabolism, thereby improving drug bioavailability. Microneedles can effectively breach the stratum corneum without stimulating pain receptors or causing tissue damage, enabling efficient drug transport into systemic circulation. Lovastatin, a widely used lipid-lowering agent, has recently garnered attention for its additional wound healing properties. However, its poor aqueous solubility and limited skin permeability restrict its therapeutic efficiency through traditional routes. Microneedle systems offer an innovative platform to overcome these limitations by enhancing the systemic availability of lovastatin, particularly for wound management. This review highlights the fundamental concepts, types, fabrication techniques, and materials used in microneedle systems. It further explores current advancements in microneedle- based delivery of lovastatin, supported by preclinical and clinical findings, and evaluates the potential of these systems to transform transdermal drug delivery in modern therapeutics.

Keywords

Introduction

Fig. 1: Types of wounds

Fig. 2: Structure of skin

Fig. 3: Penetration routes: a) Intercellular, b) transcellular and c) transappendageal pathways

Microneedle drug delivery system

The position and size of the skin make it an appropriate, non-invasive site for the delivery of therapeutic drugs as well as the collection of interstitial fluid samples for the identification of biomarkers. MN-based delivery and sampling are essentially non- invasive, painless, self-administered methods that replace hypodermic needles and improve patient compliance. Microneedles (MNs) are made utilizing a variety of constituent materials with a range of patterns and shapes, from metals and glass to polymers and hydrogels, in conjunction with a variety of delivery methods, as a result of the field's increased research activity over the past few decades.17

Four of the approaches—poke and patch (solid MNs), coat and poke (coated MNs), poke and flow (hollow MNs), poke and dissolve (dissolving MNs), and poke and release (hydrogel-forming MNs)—were first suggested, with one more developed later.18,19

Solid microneedles penetrate the stratum corneum to enhance drug delivery to the dermis, improving bioavailability. They are especially effective for vaccines due to their strong and lasting immune response. Compared to hollow types, they are simpler to manufacture, mechanically stronger, and can be made from materials like silicon, metals, or polymers.20

Hollow microneedles contain an internal channel to deliver or store liquid drugs, making them ideal for high- dose or high molecular weight formulations. They offer controlled release, are suitable for vaccines, and allow pressure-based drug flow similar to hypodermic needles. Their design supports both burst and sustained drug delivery.20

Coated Microneedle (CMN)

Coated microneedles are solid needles layered with a drug solution. They deliver small drug doses rapidly and are useful for proteins and DNA. Though minimally invasive and effective—comparable to intradermal vaccines—they pose risks of cross-contamination if drug residues remain on the needle tips.20

Dissolving Microneedle (DMN)

Dissolving microneedles are made of water-soluble materials that release drugs as the needles break down in the skin. Suitable for single-step administration of macromolecules, they offer fast release and patient-friendly use. However, they require precise insertion and have slower dissolution rates, which can limit efficiency.20

Table 1: Methods for preparation of microneedle

Materials used in the preparation of microneedle

The principal factor driving MN manufacture is their unbreakable and pliable skin penetration. The MN manufacturing difficulty has been addressed by taking into account a number of elements, including material, manufacturing process, and design. Different kinds of MNs have been fabricated using a range of materials. Polymers, metals, ceramics, and silicon are a few examples of these materials.

Advantages of Microneedles

• When compared to discomfort from a hypodermic needle, the intensity of pain from a microneedle patch ranges from 5% to 40%.
• A microneedle patch can release the medication for up to a week at a predetermined rate and under regulated conditions.
• Using a microneedle, medications that are prone to first-pass metabolism can be administered.
• Microneedles enhance the permeation of drug 4 times than passive diffusion.
• Patients who are unconscious or unable to take the formulation orally may be treated using a microneedle patch.

Applications of Microneedle drug delivery system.

1. Oligonucleotide Delivery

Microneedles, especially solid types made of titanium or stainless steel, improve the delivery of short DNA/RNA strands by enabling better skin penetration. Combined with iontophoresis, they enhance intracellular uptake more effectively than traditional methods.

2. Vaccine Therapy

Microneedles deliver vaccines with better immune response and lower doses compared to injections. Hollow and dissolving types were successful in delivering DNA vaccines for influenza, rabies, and anthrax, showing higher antibody levels and better patient comfort.

3. Peptide Delivery

Microneedles overcome enzymatic degradation of peptides like desmopressin and cyclosporin A, ensuring better skin penetration and release. Polymer-based microneedles have also been engineered to treat conditions like keloids by delivering specific peptide blockers.21

4. Hormone Delivery

Microneedles significantly enhance transdermal delivery of hormones like insulin and parathyroid hormone. They can be combined with smart materials or glucose-sensing systems for responsive delivery, showing faster absorption and reduced blood glucose levels.

5. Cosmetic Delivery

Used in skincare, microneedles improve the delivery of cosmetic agents like retinyl retinoate and ascorbic acid. E-rollers and nanoliposomes help deliver these ingredients deeper into the skin for better anti-aging and pigmentation control effects.

6. Lidocaine Delivery

Microneedles coated with lidocaine offer rapid and painless local anesthesia, with quicker onset than topical creams. PEG-lidocaine dispersions show better penetration within minutes, making them ideal for minor procedures.

7. Pain Therapy

Microneedles filled with pain relievers like meloxicam provide fast, localized relief. They offer higher drug deposition, especially for neuropathic pain, by targeting receptors without systemic side effects or skin irritation.

8. Ocular Drug Delivery

In ophthalmology, microneedles combined with iontophoresis enhance drug delivery to the posterior eye segment, allowing over 30% of nanoparticles to reach target areas, improving treatment for conditions like macular degeneration.22

9. Cancer Therapy

Microneedles are used for localized delivery of anticancer agents like 5-fluorouracil and tamoxifen. They increase drug permeability in tumors like melanoma and breast cancer while minimizing systemic side effects.

10. Clinical Trials and Safety

Clinical studies show microneedles cause minimal pain and no skin irritation. Participants preferred them over hypodermic needles. Trials for lidocaine and psoriasis treatment confirmed faster drug action and improved outcomes with daily use.

DRUG PROFILE

Lovastatin: A Multifunctional Lipid-Lowering Agent with Therapeutic Potential in Wound Healing

Lovastatin is a widely prescribed statin drug primarily used for lowering cholesterol levels. Beyond its lipid-lowering capabilities, it exhibits promising properties including bone regeneration, anti-inflammatory action, and enhancement of wound healing, particularly when delivered through novel systems such as microneedle patches. This section provides a comprehensive overview of the physicochemical, pharmacokinetic, and pharmacodynamic characteristics of lovastatin along with dosage and storage information.

Lovastatin is a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl- coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate — a key step in cholesterol biosynthesis. Originally developed as a lipid- lowering agent, recent studies have highlighted its broader therapeutic potential, including effects on bone tissue regeneration, fracture healing, and cutaneous inflammation.

Structure of lovastatin

Physicochemical Properties of Lovastatin

Pharmacological Profile

Pharmacodynamics

Lovastatin belongs to BCS Class II, characterized by poor solubility and high permeability. It effectively reduces levels of total cholesterol, low-density lipoprotein cholesterol (LDL- C), apolipoprotein B (apoB), non-HDL-C, and triglycerides (TG), while modestly increasing high-density lipoprotein cholesterol (HDL-C). It is commonly used for the treatment and prevention of cardiovascular conditions.

Pharmacokinetics

Lovastatin (branded as Mevacor) is a fungal metabolite derived from Aspergillus terreus. It is a lipophilic prodrug that undergoes first-pass hepatic metabolism. It inhibits cholesterol biosynthesis by competitively blocking HMG-CoA reductase, leading to reduced intracellular cholesterol and increased uptake of LDL-C by the liver. This action helps in lowering cardiovascular risk, especially in patients with Type 2 diabetes and those with a history of cardiac events.

Storage Conditions

Lovastatin should be stored between 5°C and 30°C, preferably in tightly sealed containers. Under these conditions, the tablets remain stable for up to 24 months from the date of manufacture. Optimal storage is at room temperature, between 20°C and 25°C.

Dosage Guidelines

The recommended dosage of lovastatin ranges from 10 to 80 mg/day, typically administered twice daily. The starting dose may be gradually increased in 20 mg increments, with a maximum dose of 80 mg/day.

CONCLUSION

Lovastatin holds considerable promise in wound healing applications, particularly for managing diabetic ulcers, owing to its ability to modulate VEGF expression, promote angiogenesis, and exert anti-inflammatory effects. Despite these therapeutic benefits, its clinical use in topical formulations is hindered by poor aqueous solubility and limited skin permeability. Microneedle-based drug delivery systems offer an innovative and effective solution to these limitations by enabling targeted, controlled, and enhanced transdermal delivery of lovastatin. The selection of appropriate polymers, microneedle geometry, and fabrication techniques plays a critical role in optimizing drug delivery performance. As research in this area advances, microneedle-mediated systems are poised to transform the landscape of wound care therapeutics. Continued interdisciplinary efforts are necessary to refine fabrication technologies, ensure safety and patient compliance, and facilitate clinical translation, ultimately paving the way for commercial adoption and improved patient outcomes.

REFERENCES

1. Tottoli, E., M.,; Dorati, R.; Genta, I.; Chiesa, E.; Pisani, S.; Conti, B., Skin wound healing process and new emerging technologies for skin wound care and regeneration. Pharmaceutics 2020, 12 (8), 735.
2. Velnar, T.; Bailey, T.; Smrkolj, V., The wound healing process: an overview of the cellular and molecular mechanisms. Int. J. Med. Res. 2009, 37 (5), 1528-1542.
3. Wigand, M.; Göde, U.; Linger, F.; Dunker, I., Normal wound healing of the paranasal sinuses: clinical and experimental investigations. Eur. Arch. Oto-Rhino-L EUR Arch Oto- Rhino-L 1991, 248 (7), 390-394.
4. Bhowmik, D., Recent advances in novel topical drug delivery system. J. Pharm. Innov. 2012, 1 (9).
5. Blakytny, R.; Jude, E., The molecular biology of chronic wounds and delayed healing in diabetes. Diabet. Med. 2006, 23 (6), 594-608.
6. Zhao, Z.; Chen, Y.; Shi, Y., Microneedles: a potential strategy in transdermal delivery and application in the management of psoriasis. RSC Advances 2020, 10 (24), 14040-14049.
7. Guillot, A. J.; Cordeiro, A. S.; Donnelly, R. F.; Montesinos, M. C.; Garrigues, T. M.; Melero, A., Microneedle-based delivery: An overview of current applications and trends. Pharmaceutics 2020, 12 (6).
8. Dang, N.; Liu, T. Y.; Prow, T. W., Chapter seventeen - nano- and microtechnology in skin delivery of vaccines. In Micro and Nanotechnology in Vaccine Development, Skwarczynski, M.; Toth, I., Eds. William Andrew Publishing: 2017; pp 327-341.
9. Henry, S.; McAllister, D. V.; Allen, M. G.; Prausnitz, M. R., Microfabricated microneedles: A novel approach to transdermal drug delivery. Journal of Pharmaceutical Sciences 1998, 87 (8), 922-925.
10. Lau, S.; Fei, J.; Liu, H.; Chen, W.; Liu, R., Multilayered pyramidal dissolving microneedle patches with flexible pedestals for improving effective drug delivery. Journal of Controlled Release 2017, 26, 113-119.
11. Pradeep Narayanan, S.; Raghavan, S., Fabrication and characterization of gold-coated solid silicon microneedles with improved biocompatibility. The International Journal of Advanced Manufacturing Technology 2019, 104 (9), 3327-3333.
12. Xie, L.; Zeng, H.; Sun, J.; Qian, W., Engineering microneedles for therapy and diagnosis: A survey. 2020, 11 (3), 271.
13. Gill, H. S.; Prausnitz, M. R., Coated microneedles for transdermal delivery. J Control Release 2007, 117 (2), 227-37.
14. McGrath, M. G.; Vrdoljak, A.; O'Mahony, C.; Oliveira, J. C.; Moore, A. C.; Crean, A. M., Determination of parameters for successful spray coating of silicon microneedle arrays. Int J Pharm 2011, 415 (1-2), 140-9.
15. Chen, J.; Qiu, Y.; Zhang, S.; Yang, G.; Gao, Y., Controllable coating of microneedles for transdermal drug delivery. Drug Development and Industrial Pharmacy 2015, 41 (3), 415-422.
16. Kim, Y. C.; Park, J. H.; Prausnitz, M. R., Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev 2012, 64 (14), 1547-68.
17. Vaccines and immunization. https://www.who.int/health-topics/vaccines-and- immunization (accessed Jan 14).
18. Prausnitz, M. R., Microneedles for transdermal drug delivery. Adv Drug Deliv Rev 2004, 56 (5), 581-7.
19. Mansoor, I.; Liu, Y.; Häfeli, U. O.; Stoeber, B. In Fabrication of hollow microneedle arrays using electrodeposition of metal onto solvent cast conductive polymer structures, 2013 Transducers & Eurosensors XXVII: The 17th International Conference on Solid- State Sensors, Actuators and Microsystems (TRANSDUCERS & EUROSENSORS XXVII), 16-20 June 2013; 2013; pp 373-376.
20. Thakur, R. R. S.; Tekko, I. A.; Al-Shammari, F.; Ali, A. A.; McCarthy, H.; Donnelly, R. F., Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery. Drug Delivery and Translational Research 2016, 6 (6), 800-815.
21. Dabholkar N, Gorantla S, Waghule T, Rapalli VK, Kothuru A, Goel S, Singhvi G.
22. Lin W, Cormier M, Samiee A, Griffin A. Transdermal delivery of antisense oligonucleotides with microprojection patch (Macroflux (R)) technology. Pharmaceutical research. 2001 Dec 1;18(12):1789.