DISSOLVABLE MICRONEEDLES: APPLICATIONS AND OPPORTUNITIES

SKIN

Citation: Kim JD, Jeong DH, “Dissolvable Microneedles: Applications and Opportunities”. ONdrugDelivery Magazine, Issue 84 (Mar 2018), pp 24-29.

Jung Dong Kim and Do Hyeon Jeong discuss dissolvable microneedle technology and its myriad uses. The authors go on to explain the potential dissolvable microneedles offer in the medical and pharma sectors, including opportunities to serve unmet needs.

INTRODUCTION

The microneedle was originally developed as a way to deliver active ingredients painlessly into the skin. At present, many companies are trying to develop drug-loaded dissolvable polymer microneedle products for the treatment or prevention of various diseases.1-5

Dissolvable polymer microneedles are made by mixing active ingredients with dissolvable polymers to create a micron-sized needle shape that naturally dissolves away after skin insertion. These offer various advantages:

• First, the microneedle is a less painful way of delivering active ingredients compared with the syringe. This can potentially improve the quality of life for those who would otherwise need frequent injections.
• Second, the dissolvable microneedle is an environmentally friendly solution, leaving no dangerous or wasteful products behind, such as needles or glass, because microneedles dissolve into the skin after insertion.
• Third, cold-chain supply costs are reduced, because the solid state of the dissolvable microneedle enables greater stability during the distribution of various biopharmaceuticals without the need for refrigeration.6-11

Many researchers are developing techniques used in the production of dissolvable microneedles, such as micromoulding, drawing lithography, droplet-born air blowing (DAB) and centrifugal lithography.6,12-14 Micromoulding and DAB techniques are already applied in the manufacture of commercial products, such as the skincare patch. However, pharmaceutical dissolvable microneedle products have not yet been commercialised despite more than fifteen years of research and development.15-18

RAPHAS’ DAB TECHNOLOGY

The DAB process was developed in 2013 to reduce the time required for microneedle fabrication and to allow for gentle fabrication conditions, without the use of UV irradiation or heat. The DAB microneedle array fabrication process occurs by dispensing viscous polymer solution by symmetric air blowing. This property of DAB makes it possible to fabricate microneedles in a few minutes, without loss of activity in ingredients which are sensitive to heat or UV light.

“Raphas has registered a total of 24 DAB technology-related patents around the world, including in the US, Japan, China, and the EU…”

The main advantage of this technique is its simplicity, but there are many hidden mechanical and rheological technologies that are utilised in the successful mass production of dissolvable microneedles.13 Additionally, DAB technology does not need to change any equipment to manufacture diverse patch patterns. Raphas has developed various microneedle patch designs using this advantage of DAB technology.

Raphas has registered a total of 24 DAB technology-related patents around the world, including in the US, Japan, China, and the EU. Raphas’s DAB process has also received cosmetic GMP certifications from the ISO and medical device GMP from the Korean Ministry of Food and Drug Safety (MFDS) on microneedle patch products (Figure 1). Moreover, various Raphas products have been certified by the agencies of the EU, China, Brazil, the US and more.

Figure 1: (A) ISO 22716 certification for GMP relating to cosmetic biodegradable microneedle patches and (B) GMP certification for Raphas’ medical device.

SKINCARE APPLICATIONS

Raphas manufactures skincare microneedle patch products using hyaluronic acid as a matrix material. These skincare products contain various active ingredients with proven effectiveness. Raphas produces them to order from various brands in an “original development manufacturing” system. Most of these sales are for the overseas market, especially to the US and Japan. Sales of Raphas’ dissolvable microneedle products totalled more than 12 million pouches (two patches per pouch) from 2013 to 2017.

Raphas continues to work closely with and support companies selling their own products with the selection of active ingredients, product design, testing and other new product development. In order to better serve as a manufacturer, Raphas launched its own brand, Acropass, to prove the efficacy and improve the quality of new products.

In addition, these products are very safe for the skin because they do not contain any preservatives. There were no significant side-effects after using Raphas’ skincare products; this was tested by 25 clinical studies performed according to the good clinical practice guidelines of the Korean MFDS. Also, there were no significant side-effects reported from consumers after using Raphas products.

Wrinkle Treatment

Facial wrinkles are representative of skin ageing caused by reduction of skin elasticity and degradation of the extracellular matrix (ECM). Raphas has commercialised various wrinkle treatment microneedle patch products with a plethora of cosmetic companies. The matrix material of this microneedle is hyaluronic acid, which has been used as moisturising and filling agent for many cosmetic products. This hyaluronic acid based microneedle has wrinkle treatment efficacy by itself. Additionally, this product could be combined with a cream or essence type product for better wrinkle treatment efficacy.19,20

Epidermal growth factor (EGF) loaded microneedles showed significant wrinkle treatment efficacy after applying every day for 10 days (Figure 2a). This product also showed significant wrinkle treatment efficacy after applying twice a week for four weeks (Figure 2c).21

Figure 2: Clinical trial results for wrinkle care efficacy of EGF loaded microneedle patch, with (A) once daily application for 10 days and (B) twice weekly application for 4 weeks. (C) Clinical efficacy of new wrinkle care product after 2 hours of application.

Recently, a new wrinkle care product has been prepared and finished clinical trials. This new product is composed of three major active ingredients. One of the major ingredients is acetyl octapeptide-3 which targets the inhibition of wrinkle formation and is very similar to botulinum toxin in terms of immediate efficacy. The other two ingredients, providing the long-term efficacy, are ascorbyl glucoside and sodium cyclic lysophosphatidic acid, which encourages the skin’s natural rejuvenation process.

Figure 2c shows a clinical result which indicates wrinkle improvement efficacy after two hours of application; the peak of observed eye wrinkle was significantly decreased after 2 hours of using the product. These results indicate that this new product has fast-onset efficacy for wrinkle treatment.

Trouble Cure

Trouble Cure is a product for restoring acne affected skin quickly without leaving scars (Figure 3a). This product can help people manage acne efficiently and hygienically. The microneedle contains antimicrobial and anti-inflammatory ingredients within the hyaluronic acid backbone structure. The length of the microstructure is around 500 μm so that the active ingredient can be directly transferred to the hair follicle region where the bacterium causes the acne.

Figure 3: (A) Trouble Cure product. (B) Clinical efficacy of Trouble Cure for acne treatment. Red circle shows the Trouble Cure-treated area.

After application, an anti-inflammatory ingredient is delivered into the skin to suppress the inflammation of the acne, and an added antimicrobial ingredient helps to inhibit the activity of inflammation-causing bacteria. The antimicrobial ingredient is a peptide that is effective against antibiotic-resistant strains.

In general, the antimicrobial peptide is inactive at physiological salt concentrations and is rapidly degraded by proteolytic enzymes present in serum and the digestive tract.22,23 Therefore, it is difficult to show efficacy at target area when used as ointment or cream formulation. However, Trouble Cure can deliver the antimicrobial peptide directly into the target region via the microneedle patch without loss of activity.

Clinical trial results showed that more than 90% of subjects had improved skin condition after four days from the first application of the product, which proved to be safe, without adverse skin reactions during the test (Figure 3b). In addition, this product is designed to be used hygienically with alcohol swabs and individual packaging to prevent secondary contamination occurring whilst managing the acne.

Spot Eraser

Skin whitening and brightening products are used for various hyperpigmentory disorders. Skin whitening ingredients usually act as tyrosinase inhibition to block the synthesis of melanin from melanocyte.24,25

Figure 4: (A) Spot Eraser product. (B) Clinical efficacy of Spot Eraser on the post-inflammatory hyperpigmentation two weeks on from the end of four weeks of application once every other day. Blue circle shows the Spot Erasertreated area.

Raphas has developed a novel concept for a topical whitening product by the name of Spot Eraser (Figure 4a). This product can treat topical hyperpigmented spots by inhibiting the multi-pathway of hyperpigmentation using tranexamic acid, niacinamide, ascorbic acid and arbutin. Tranexamic acid can inhibit melanogenesis through the activation of autophagy in a melanoma cell line. Niacinamide reduces cutaneous pigmentation by inhibiting melanosome transfer. Ascorbic acid is a strong antioxidant that can inhibit melanin oxidation to keep the melanin in a relatively brighter colour form. Arbutin is a glycosylated hydroquinone which can inhibit tyrosinase activity.

Clinical results for Spot Eraser showed significant efficacy in terms of post-inflammatory hyperpigmentation after a single application every two days for four weeks, and observing for an additional two weeks without further applications (Figure 4b). Clinical results also showed a significant decrease in melasma area and severity index (MASI). These results indicate the Spot Eraser could be a good solution for the topical treatment of hyperpigmentation.

MEDICAL DEVICE APPLICATIONS

Drug Absorption Enhancer

Therapass is a dissolvable microneedle product composed of hyaluronic acid (Figure 5a). This product does not contain any active ingredients. It enhances skin absorption of ointment, such as topical steroids, when applied to the skin after ointment application (Figure 5b).

Figure 5: (A) Therapass: Dissolvable microneedle based medical device. (B) Mechanism of Therapass as an enhancer of ointment absorption.

Although topical steroids have been used as a general treatment for a variety of skin diseases, some patients, such as prurigo nodularis patients, do not sufficiently respond to the strong steroids, possibly due to the thickened skin leading to a low drug penetration rate. However, the efficacy of topical steroids could be enhanced via a microneedle patch by physically penetrating the thickened skin. Dermatologists have performed clinical trials using this product for two kinds of skin diseases, psoriasis and prurigo nodularis.

“The efficacy of topical steroids could be enhanced via a microneedle patch by physically penetrating the thickened skin…”

Prurigo nodularis is a skin disease characterised by itchy nodules which are distributed in symmetric and bilateral manner.26 Patients often scratch these nodules and it causes permanent changes to the skin, including hyperkeratosis, hyperpigmentation and skin thickening. A topical steroid, with moderate to high potency, is the standard therapeutic agent, and it is the most widely practiced treatment method. However, the efficacy of topical steroids can be dependent upon the thickness of the lesion. Microneedle based therapy can help to overcome this problem. In the clinical study, microneedle-assisted delivery showed significantly enhanced efficacy of the topical steroid, decreasing the area and height of nodules (p <0.05) compared with topical steroid alone.

Psoriasis is a chronic, inflammatory skin disease, which decreases quality of life, and affects roughly 2-4% of the population.27 There is no cure for psoriasis, however, treatments such as topical steroids can help control the symptoms. In a clinical study in psoriasis patients, the median decrease of modified Psoriasis Area Severity Index (mPASI; range 0 to 12), which is a sum of scores for plaque thickness, scaliness and redness, was 60% after one week’s application of the microneedle patch.28 This result shows that use of the microneedle patch significantly enhances the therapeutic effects of topical steroids and shows fast onset for the topical psoriasis treatment compared with conventional application of topical steroids on the region (p <0.001).

Diagnosis

The microneedle can be used in diagnostics as a minimally invasive patient monitoring tool. Previous studies have focused on hollow microneedle based blood or interstitial fluid extraction for glucose sensing or disease marker diagnosis.29-32 However, hydrogel microneedle-based in vivo diagnosis showed the possibility for a user friendly and comfortable disposable microneedle patch sensor.33,34 Although research has shown the potential for a microneedle-based diagnostic application, no such product has yet been commercialised.

Raphas has begun researching disposable microneedle patch sensors using DAB technology with other partners, looking to overcome the obstacles to commercialisation, including manufacturing cost and sensitivity.

PHARMACEUTICAL APPLICATIONS

Dissolvable microneedle based pharmaceutical products are yet to be commercialised. However, many dissolvable microneedle companies, including Raphas, are developing various pharmaceutical products for various diseases. Raphas is currently developing products for Alzheimer’s disease, osteoporosis, immunotherapy and others.

Alzheimer’s Disease

Alzheimer’s disease is a chronic neurodegenerative disease which causes difficulty in remembering recent events. Donepezil tablets are a widely used oral administration for Alzheimer’s disease, and clinical studies have shown modest benefits in cognition and/or behaviour.35

“Dissolvable microneedle based pharmaceutical products are yet to be commercialised. However, many dissolvable microneedle companies, including Raphas, are developing various pharmaceutical products for various diseases…”

However, there is an unmet need for a new administration route of donepezil because of adverse effects in the gastrointestinal (GI) tract and patients with dysphagia.36 Raphas and its partners have been co-developing a donepezil-loaded microneedle patch to overcome the problems inherent to the current dosage form. An IND application will be submitted to the Korean MFDS for the clinical study of this product during the first half of this year.

Osteoporosis

Many elderly people suffer from osteoporosis, a disease which causes chronic bone weakness. Parathyroid hormone injection is the only US FDA approved bone building medication for the treatment of advanced osteoporosis, requiring a once daily injection, which can adversely affect quality of life. Therefore, various companies such as Zosano Pharma, Corium and 3M are developing parathyroid hormone-loaded microneedles. Raphas has been developing this formulation with the support of the Korean government for the past two years, and an IND application will be submitted this June.

Immunotherapy

Allergen-specific immunotherapy (SIT) is an effective treatment for allergy-related symptoms, such as atopic dermatitis (AD). However, frequent clinical visits over a three-year period, as well as looming adverse events, tend to discourage patient compliance.

Raphas has been developing a house dust mite (HDM) allergen-loaded microneedle patch for HDM-SIT of AD, and this microneedle patch showed a similar efficacy to a ten times higher dosage delivered via subcutaneous injection.37

RAPHAS’ FUTURE PLANS

Raphas plans to expand its business area beyond the cosmetic market to include medical devices and pharmaceuticals. Recently, Raphas started research into vaccine-loaded microneedle patch development with a multinational vaccine company and constructed a new building to setup GMP facilities for clinical studies. Additionally, Raphas is continuing to develop various medical products, such as a dementia treatment patch, hormonal therapy patch, and immunotherapy patch, using DAB technology.

The foundation of Raphas is closely connected with the aspirations of professional researchers into drug delivery systems. Raphas believes that this remarkable method for enjoying “a healthier life, without pain” is the future of drug delivery systems. Raphas will open up the road to this treatment for everyone in the world.

REFERENCES

1. McAllister DV et al, “Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: novel fabrication methods and transport studies”. Proc Natl Acad Sci, 2003, Vol 100(24), pp 13755-13760.
2. Ito Y et al, “Self-dissolving microneedles for the percutaneous absorption of EPO in mice”. J Drug Target, 2006, Vol 14(5), pp 255-261.
3. Lee JW, Park JH, Prausnitz MR, “Dissolving microneedles for transdermal drug delivery”. Biomaterials, 2008, Vol 29(13), pp 2113-2124.
4. Prausnitz MR, Langer R, “Transdermal drug delivery”. Nat Biotechnol, 2008, Vol 26(11), pp 1261-1268.
5. Bal SM et al, “Microneedle-Based Transcutaneous Immunisation in Mice with N-Trimethyl Chitosan Adjuvanted Diphtheria Toxoid Formulations”. Pharm Res, 2010, Vol 27(9), pp 1837-1847.
6. Park JH, Allen MG, Prausnitz MR, “Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery”. J Control Rel, 2005, Vol 104(1), pp 51-66.
7. Park JH, Allen MG, Prausnitz MR, “Polymer microneedles for controlled-release drug delivery”. Pharm Res, 2006, Vol 23(5), pp 1008-1019.
8. Gill HS et al, “Effect of microneedle design on pain in human subjects”. Clin J Pain, 2008, Vol 24(7), pp 585-594.
9. Sullivan SP, Murthy N, Prausnitz MR, “Minimally invasive protein delivery with rapidly dissolving polymer microneedles”. Adv Mater, 2008, Vol 20(5), pp 933-938.
10. Sullivan SP et al, “Dissolving polymer microneedle patches for influenza vaccination”. Nat Med, 2010, Vol 16(8), pp 915-920.
11. Lee JW et al, “Dissolving microneedle patch for transdermal delivery of human growth hormone”. Small, 2011, Vol 7(4), pp 531-539.
12. Lee K et al, “Drawing lithography: three-dimensional fabrication of an ultra-high-aspect-ratio microneedle”. Adv Mater, 2010, Vol 22(4), pp 483-486.
13. Kim JD et al, “Droplet-born air blowing: Novel dissolving microneedle fabrication”. J Control Rel, 2013, Vol 170(3), pp 430-436.
14. Yang H et al, “Centrifugal Lithography: Self-Shaping of Polymer Microstructures Encapsulating Biopharmaceutics by Centrifuging Polymer Drops”. Adv Healthcare Mater, 2017, Vol 6(19)
15. Ito Y et al, “Feasibility of microneedles for percutaneous absorption of insulin”. Eur J Pharm Sci, 2006, Vol 29(1), pp 82-88.
16. Indermun S et al, “Current advances in the fabrication of microneedles for transdermal delivery”. J Control Rel, 2014, Vol 185, pp 130-138.
17. Schoellhammer CM, Blankschtein D, Langer R, “Skin permeabilization for transdermal drug delivery recent advances and future prospects”. Exp Opin Drug Deliv., 2014, Vol 11(3), pp 393-407.
18. Nguyen TT, Park JH, “Human studies with microneedles for evaluation of their efficacy and safety”. Exp Opin Drug Deliv, 2017, Vol 30, pp 1-11.
19. Hong JY et al, “Efficacy and safety of a novel, soluble microneedle patch for the improvement of facial wrinkle”. J Cosmet Dermatol, 2017, Oct 7.
20. Kim S et al, “Enhanced Transdermal Delivery by Combined Application of Dissolving Microneedle Patch on Serum-Treated Skin”. Mol Pharm 2017, Vol 14(6), pp 2024-2031.
21. Park J et al, “Efficacy of Biodegradable Microneedle Patches on Periorbital Wrinkles”. Korean J Dermatol, 2014, Vol 52(9), pp 597-607.
22. Goldman MJ, Anderson GM, Stolzenberg ED, “Human betadefensin- 1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis”. Cell, 1997, Vol 88, pp 553-560.
23. Sieprawska-Lupa M et al, “Degradation of human antimicrobial peptide LL-37 by Staphylococcus aureus-derived proteinases”. Antimicrob Agents Chemother, 2004, Vol 48(12), pp 4673-4679.
24. Cabanes J, Chazarra S, Garcia- Carmona F, “Kojic acid, a cosmetic skin whitening agent, is a slowbinding inhibitor of catecholase activity of tyrosinase”. J Pharm Pharmacol, 1994, Vol 46(12), pp 982-985.
25. Chang TS, “An updated review of tyrosinase inhibitors”. Int J Mol Sci, 2009, Vol 10(6), pp 2440-2475.
26. Lee MR, Shumack S, “Prurigo nodularis: a review”. Australas J Dermatol, 2005, Vol 46(4), pp 211-218; pp 219-220.
27. Parisi R et al, “Global epidemiology of psoriasis: a systematic review of incidence and prevalence”. J Invest Dermatol, 2013, Vol 133(2), pp 377-385.
28. Lee JH et al, “A hyaluronic acid-based microneedle patch to treat psoriatic plaques: A pilot open trial”. Br J Dermatol, 2018, Vol 178, pp 24-25.
29. Zimmerman S et al, “A microneedlebased glucose monitor: fabricated on a wafer-level using in-device enzyme immobilization”. TRANSDUCERS 2003 – The 12th International Conference on Solid-State Sensors, Actuators and Microsystems, 2003, Vol 1, pp 99-102.
30. Mukerjee E et al, “Microneedle array for transdermal biological fluid extraction and in situ analysis”. Sens Actuators, A, 2004, Vol 114, pp 267-275.
31. Wang PM, Cornwell M, Prausnitz MR, “Minimally invasive extraction of dermal interstitial fluid for glucose monitoring using microneedles”. Diabetes Technol Ther, 2005, Vol 7(1), pp 131-141.
32. Li CG et al, “One-touch-activated blood multidiagnostic system using a minimally invasive hollow microneedle integrated with a paperbased sensor”. Lab Chip, 2015, Vol 15(16), pp 3286-3292.
33. Donnelly RF et al, “Hydrogelforming microneedles increase in volume during swelling in skin, but skin barrier function recovery is unaffected”. J Pharm Sci, 2014, Vol 103, pp 1478-1486.
34. Romanyuk AV et al, “Collection of analytes from microneedle patches”. Anal Chem, 2014, Vol 86(21), pp 10520-10523.
35. Steele LS, Glazier RH, “Is donepezil effective for treating Alzheimer’s disease?”. Can Fam Physician, Vol 45, pp 917-919.
36. Affoo RH et al, “Swallowing dysfunction and autonomic nervous system dysfunction in Alzheimer’s disease: a scoping review of the evidence”. J Am Geriatr Soc, 2013, Vol 61(12), pp 2203-2213.
37. Kim JH et al, “Successful transdermal allergen delivery and allergen-specific immunotherapy using biodegradable microneedle patches”. Biomat, 2018, Vol 150, pp 38-48.