DRUG DELIVERY - Advancements in Transdermal Delivery Systems: A Focus on Invisicare® Technology for Obesity Treatment

INTRODUCTION

Skin penetration of drugs is a complex field with much on-going research. The function of skin is to not allow significant penetration of materials from outside the body and to conserve materials inside the body, particularly water.¹ Successful transder­mal delivery is also reliant on the characteristics of the drug for­mulation. The addition of alcohols, surfactants, moisturizers, fatty acids, and other fatty substances increase the skin’s permeability to drugs allowing transdermal delivery. Following successful pen­etration through the skin barrier, the therapeutic compound enters circulation by the bloodstream, allowing for systemic distribution throughout the body.² A transdermal delivery method may be de­sirable over conventional routes, ie, oral or injection due to the avoidance of systemic side effects from first-pass metabolism and greater patient compliance.³ Transdermal delivery offers a prom­ising alternative to drug delivery, but traditionally faces limitations in drug molecular weight and throughput. Skinvisible Pharma­ceuticals, Inc. has made significant progress in this field with its proprietary Invisicare^® polymer delivery system. This technology has demonstrated potential in the transdermal administration of glucagon-like peptide-1 (GLP-1) agonists and cannabinoid re­ceptor type 1 (CB-1) antagonists, primarily targeting obesity man­agement and other conditions requiring glucose regulation. Of particular interest is the recent provisional patent application for transdermal obesity and glucose-controlling agents utilizing the Invisicare system. This development represents a promising av­enue for non-invasive administration of metabolic regulators.

Invisicare polymer delivery technology represents a patented innovation in the field of topical and transdermal drug delivery systems, leveraging over 2 decades of pharmaceutical research and development. This proprietary formulation is designed to en­hance the efficacy and controlled release of active pharmaceuti­cal ingredients (APIs) when applied to the skin with topical or transdermal delivery; whichever is required. The technology forms a protective bond that holds ingredients on skin resisting rub-off and wash-off, is non-occlusive, and allows for normal skin respi­ration and perspiration. The Invisicare technology shows potential use in various transdermal applications, including Skinvisible’s new development in the field of obesity. By utilizing a proprietary series of penetrators and limiting the development to small mol­ecules (generally conceded < 1000 g/mole), Skinvisible has suc­cessfully delivered a series of active ingredients, including obesity focused actives.

Obesity in the US has topped 40%.⁴ This is the highest obe­sity has ever been in the US. Obesity contributes to hypertension and type 2 diabetes among other issues. Fad diets have failed as most regain the weight lost from dieting. Americans are not able to push themselves away from the table. Obesity is not limited to a certain age, social class, or ethnicity, and it is not just an Amer­ican problem.⁵ While lifestyle modifications, such as moderating food intake and increased exercise, remain a cornerstone of treatment, recent advancements have introduced pharmacolog­ical therapies as a valuable adjunct designed to promote weight loss.

There are three basic targets for anti-obesity drugs. Targets include CB1 antagonists effecting the CB1 endocannabinoid re­ceptor, GLP-1 (Glucagon like peptide) agonists, and Sodium glu­cose cotransporter 2 (SGLT-2) inhibitors. Some of the obesity drugs available decrease appetite while others increase insulin secretion to lower blood sugar levels and protein bound glucose (A1-C). The SGLT-2 drugs inhibit reabsorption of sugar by the kidneys.

OBESITY DRUG DELIVERY METHODS

A number of obesity medications are delivered subcutaneously with newer de­velopments providing oral administration. Current subcutaneous obesity drugs, while effective, are associated with several draw­backs. These include patient discomfort due to frequent injections, potential injec­tion site reactions, and the need for proper storage and handling of injectable med­ications.⁶ Additionally, the invasive nature of subcutaneous administration can lead to reduced patient compliance, potentially compromising treatment efficacy. Oral ad­ministration has the drawback of first-pass through the liver that can increase toxicity and decrease the concentration of drug in the bloodstream. Oral administration may also cause interactions with food in the gut and nausea.⁷ The great wish of many seems to be a system that can dispense these drugs safely and with reduced toxic­ity; a system such as transdermal delivery.

Transdermal delivery has been around for many years and in many forms.⁸ The major difficulty for transder­mal delivery is overcoming the skin’s nat­ural ability to prevent materials from entering or leaving the body. This can be achieved through active delivery (ie, mi­croneedles) and passive delivery (ie, skin penetrators). Most of the active delivery methods rely on disruption of the skin’s structure to greater or lesser degrees per­mitting passage of the drug into the body.

While only small molecules <1000 g/mol can pass through the skin, there are many smaller molecules potentially useful in the treatment of obesity that have mo­lecular weights less than 1000 g/mol. Many of these are currently being tested for efficacy and safety. It is also believed transdermal systems cannot deliver high drug throughput necessary for therapeutic efficacy.⁹

While traditional transdermal systems have faced challenges in deliver­ing high drug throughput necessary for therapeutic efficacy, recent advancements by Skinvisible Pharmaceuticals show very promising results, with a high ratio of re­lease over extended periods.

For 25 years Skinvisible Pharmaceuti­cals, Inc. has developed topical delivery systems for cosmeceuticals, prescription, and non-prescription drugs. Most recently, because of the emerging prominence of the endocannabinoid system, and the heightened interest in obesity drugs, the company has modified the system for transdermal delivery and have demon­strated enhanced drug permeation and in­creased bioavailability.

INVISICARE^® TRANSDERMAL DELIVERY

The Invisicare technology is character­ized as a high-performance polymer tech­nology that enhances dermal and transdermal drug delivery. Its key features include controlled release of active ingre­dients without an initial burst effect, im­proved skin adherence, and potential enhancements in efficacy, safety, and pa­tient satisfaction. It is not an encapsulation, patch, or liposome technology. The tech­nology is protected by patents, patent applications, and trade secrets, covering all formulations developed using Invisicare.

Skinvisible filed a provisional patent application in May 2024, covering formu­lations that leverage the company’s propri­etary delivery technology for the transdermal administration of obesity drugs titled Transdermal Delivery Compo­sition for Delivery of CB-1 Receptor Antag­onists and/or GLP-1 Receptor Agonists, and Method of Delivery. In June 2024, a second upgraded patent application was submitted encompassing a wider range of active ingredients and additional condi­tions beyond obesity that can benefit from glucose-controlling agents, such as dia­betes. The additional application is titled Transdermal Delivery Composition for De­livery of at Least One Glucose Controlling Agent, and Method of Delivering at Least One Glucose Controlling Agent. The com­pany’s proprietary drug delivery technol­ogy is at the heart of this innovation, demonstrating its ability to maximize trans­dermal delivery of various drugs through the skin without the use of a patch or other active penetration mechanism (ie, no mi­croneedles). This patent filing ushers in a new era of efficient and convenient obesity drug delivery solutions.

Central to the Invisicare system is a mixture of three or more commercially ac­cessible polymers. The smallest polymer has a molecular weight of ~17,000 g/mol, which is too large to pass through the skin. As the Invisicare polymer is a complex and not a compound, toxicity of the final composition is the same as the components utilized, which are all commonly used or considered GRAS. A proprietary combination of permeation enhancers is incorporated into the solution to get the desired penetration. No me­chanical penetration enhancers are used.

TRANSDERMAL OBESITY FORMULATION DEVELOPMENT

Skinvisible has developed and contin­ues to develop various transdermal formu­lations using its Invisicare technology and a glucose controlling agent, including a GLP-1 agonist, CB-1 antagonist, or SGLT-2 inhibitor. Along with long-term stability testing, Skinvisible analyses the potential permeation of these active ingredients through the analytical method: Franz cell diffusion analysis. The Franz diffusion cells were utilized to assess the compound’s ability to penetrate a model membrane, simulating percutaneous absorption. This in-vitro methodology provides valuable in­sights into the pharmacokinetic properties and potential efficacy of these actives for transdermal administration.

In conjunction with the Franz diffusion cells, cellulose membranes were utilized, and 0.05 M Phosphate Buffered 0.9% Saline at a pH of 7.0 was used in the re­ceiver chamber. This was followed by High Pressure Liquid Chromatography (HPLC) of the effluents on a C18 column with methanol plus 0.1% formic acid and water plus 0.1% formic acid in varying ratios ac­cording to the active analyzed.

TRANSDERMAL RESULTS

Skinvisible conducted Franz diffusion cell permeation studies to evaluate the transdermal delivery potential of three novel cannabinoid receptor type 1 (CB1) antagonists and one GLP-1 agonist. The results of the GPL-1 agonist tested (Danuglipron) are highlighted in Figure 1.

Figure 1 shows permeation of Danuglipron (FW = 555.6 g/mol). The curve is clearly exponential, more complex kinetics than seen with the smaller mole­cules (data not shown). The curve perfectly fit two parameter exponential statistics with R and R2 = 1.00. Danuglipron after 6 hours show permeation of 1.51×10-2 mm/cm2. Figure 2 shows the percentage release over 6 hours. Over 6 hours, the average permeation (release) of three readings at the 6-hour time point was 99.56%; approximately 17% per hour.

SUMMARY & CONCLUSION

In conclusion, the novel transdermal delivery system demonstrates significant potential for the administration of glucose-controlling agents in obesity management. The data presented here, combined with the company’s additional transdermal studies, suggest this system may offer a competitive alternative to traditional routes of administration, such as injection, oral delivery, patches, and microneedles. While further research will be valuable to fully characterize this delivery system in the context of obesity treatment, the current findings provide a strong foundation for future clinical applications. These promis­ing results pave the way for continued de­velopment and optimization of this innovative approach to drug delivery in metabolic disorders, and perhaps broader application in other disorders in which small molecules are used, potentially offering improved treatment op­tions for patients in the future.

REFERENCES

1. Kligman AM. What is the ‘true’ function of skin? Experimental Dermatology. 2002;11(2): 159-87.
2. Singh I, Morris AP. Performance of transdermal therapeutic systems: Effects of biological factors. International Journal of Pharmaceutical Investigation. 2011;1(1):4-9.
3. Yu YQ, et al. Enhancing Permeation of Drug Molecules Across the Skin via De­livery in Nanocarriers: Novel Strategies for Effective Transdermal Applications. Frontiers in Bioengineering and Biotechnology. 2021 Mar 29;9:636296.
4. Farberman R, Kelley B. The State of Obesity 2020: Better Policies for a Healthier America. Trust for America’s Health. 2020.
5. Ashour MM, et al. Anti-Obesity Drug Delivery Systems: Recent Progress and Challenges. Pharmaceutics. 2023 Nov;15(11):2635.
6. St Clair-Jones A, et al. Understanding and Minimising Injection-Site Pain Follow­ing Subcutaneous Administration of Biologics: A Narrative Review. Rheumatology and Therapy. 2020 Dec;7(4):741-757.
7. Ramadon D, et al. Enhancement strategies for transdermal drug delivery systems: Current trends and applications. Drug Delivery and Translational Research. 2022;12(4):758-791.
8. Paudel KS, Milewski M, et al. Challenges and opportunities in dermal/transder­mal delivery. Therapeutic Delivery. 2010 July;1(1):109-131.
9. Salamanca CH, Barrera-Ocampo A, Lasso JC, Camacho N, Yarce CJ. Franz Diffusion Cell Approach for Pre-Formulation Characterisation of Ketoprofen Semi-Solid Dosage Forms. Pharmaceutics. 2018 Sep 11;10(3):148.

Dr. James A. Roszell earned his PhD in Chemistry from The University of Memphis. He has over 35 years of experience in product formulation, experimental design, analysis, and method validation. Since joining Skinvisible in 1998, he has been responsible for research and development of the company’s patented technology, related polymer delivery vehicles, product formulations, and compositions. He is a joint contributor to Skinvisible’s initial technology patent and responsible for over 20 additional patents related to Invisicare technology. Prior to joining Skinvisible, he was a research chemist in the Cancer Research Laboratory in the V.A. Hospital in Memphis, TN. and a research chemist in the Respiratory Carcinogenesis Program at the V.A. Hospital, Tampa, FL. He has been the Director of Research and Development for Super Tech Products and Biochemical Industries. His invaluable chemical and scientific expertise are key factors in Skinvisible’s innovative technological achievements.

Doreen McMorran serves as the Vice President of Business Development at Skinvisible Pharmaceuticals, Inc. In this role, working in conjunction with the company’s research and development department, she spearheads the company’s research-driven product development strategies and technology/product out-licensing initiatives. Concurrently, she holds the positions of Chief Operating Officer and Chief Financial Officer at Ovation Science Inc. She brings over 25 years of experience in the medical and pharmaceutical sectors to her roles. Before joining Skinvisible Pharmaceuticals, Inc., she spent 6 years marketing and selling to international dermatology and skincare companies. She also provided medical education, both traditional and online, for physicians and consumers. Her career includes 6 years in the pharmaceutical industry, as well as senior management positions at various healthcare companies, where she focused on business development, new product development, sales, marketing, and operations. She earned her Bachelor of Commerce degree with Honors.