Innovative Technology in Sildenafil Cream Developed for Women

What "Black Technologies" are Used in the Sildenafil Cream Developed for Women?

Background

Sildenafil citrate (commonly known as "Viagra," brand name: Viagra®) is a phosphodiesterase type 5 (PDE-5) inhibitor, approved by the FDA in 1998 for the treatment of erectile dysfunction (ED) in men. Normally, when men experience sexual stimulation, nitric oxide is released and activates guanylate cyclase, which increases the levels of cGMP. The mechanism of PDE5 inhibitors is to block the activity of PDE5, preventing the degradation of cGMP. Research has shown that similar NO-cGMP biological pathways exist in female genital tissues. PDE5 isoenzymes are expressed in the vascular smooth muscle cells of the female clitoral corpora, vagina, and labia minora, and the related changes after sexual stimulation play a core role in mediating female sexual arousal response. Female sexual arousal disorder (FSAD) shares similar pathophysiology with ED, manifested as the persistent or recurrent inability of women to achieve or maintain sufficient genital arousal during sexual activity, which often causes distress or difficulty in sexual relationships.

Strategic Science & Technologies, LLC (SST), a biotechnology company based in Cambridge, Massachusetts, is at the clinical stage with an innovative KNOSISTM local drug delivery technology. The company has developed a 3.6% sildenafil cream using this technology, designed for local application to the vulva and vaginal tissues. The cream aims to improve FSAD-related physical arousal symptoms by promoting vasodilation and increasing blood flow to genital tissues, while avoiding the systemic side effects of oral sildenafil. SST has entered into a global exclusive licensing agreement with Dare Bioscience for this product, which has completed Phase IIb clinical trials. According to Dare Bioscience's announcement, the company plans to meet with the FDA in Q4 2023 to review Phase IIb study data and discuss the design of Phase III clinical trials. If successful, the company aims to obtain FDA approval for the 3.6% sildenafil cream for the treatment of FSAD in women using the 505(b)(2) pathway, leveraging existing safety and efficacy data of sildenafil, making it the first FDA-approved product for treating FSAD in women.

Clinical Research Status

Phase I Clinical Trial

The Phase I clinical trial of 3.6% sildenafil cream was conducted on 20 healthy postmenopausal women. The results showed that, at clinically relevant doses, the local application of sildenafil cream was safe and well-tolerated, with subjects reporting that the product was easy to use and absorbed well. After a single dose of 1g, 2g, and 4g of 3.6% sildenafil cream, sildenafil successfully penetrated the vulvar skin and vaginal epithelium into the systemic circulation (Figure 1). No significant systemic or skin-related adverse reactions were observed at 1g and 2g doses, suggesting that the cream has good tolerability and no systemic side effects typical of oral PDE5 inhibitors (blood drug concentrations were significantly lower than those observed with oral sildenafil in men).

Phase IIa Clinical Trial

The Phase IIa clinical trial involved 15 premenopausal and 16 postmenopausal women with FSAD. The study found that, compared to a placebo cream, sildenafil cream increased blood flow to genital tissues. Thermographic studies in healthy women showed a significant increase in genital temperature after the use of sildenafil cream, with a statistical difference from the placebo within 15 minutes post-application, indicating a positive effect on genital blood flow.

Phase IIb Clinical Trial

The Phase IIb clinical trial of 3.6% sildenafil cream was a multicenter, double-blind, placebo-controlled study that evaluated the efficacy and safety of the cream in premenopausal women with FSAD. The results showed that the cream achieved the primary endpoint and demonstrated clinically meaningful benefits in patients with FSAD or FSAD with reduced desire. Significant improvements were observed in arousal sensations, desire, orgasm, as well as in sexual dysfunction-related stress, guilt, and embarrassment.

About KNOSISTM Local Drug Delivery Technology

By delivering the drug locally to the treatment site, local drug delivery can minimize systemic exposure and potentially relieve symptoms more quickly, resulting in more direct therapeutic effects. Most charged drugs (such as sildenafil) have difficulty penetrating the stratum corneum. Studies have shown that drugs that form two or more hydrogen bonds with the stratum corneum are not easily able to penetrate the active epidermis and dermis. However, once a drug penetrates the stratum corneum and reaches the active epidermis and dermis, it is easier for the drug to diffuse into deeper tissues, producing therapeutic effects at the intended site of action. Fick's first law indicates that the penetration of drugs through the stratum corneum is related to their thermodynamic activity, and charged drugs can have their thermodynamic activity enhanced by adding high concentrations of ionic salts (such as sodium chloride, potassium chloride, etc.) in the formulation. High ionic concentrations also prevent the drug from forming hydrogen bonds with the stratum corneum, facilitating its entry into deeper tissues.

KNOSIS™ technology is an innovative drug delivery method developed by Eric T. Fossel, a scientist at Strategic Science & Technologies, LLC (SST). Due to the presence of the stratum corneum, the success of local drug delivery therapies is mostly limited to small, uncharged molecules. SST's proprietary local delivery technology overcomes these challenges through at least two novel features. First, KNOSIS™ technology creates an unfavorable biophysical environment for the active pharmaceutical ingredient (API), increasing its free energy and generating a positive chemical potential that drives the API from the delivery vehicle into the tissue. Second, this novel formulation prevents the API from forming hydrogen bonds with the stratum corneum, as hydrogen bonding inhibits the ability of the API to penetrate into the tissue. These two complementary actions help SST achieve the desired local therapeutic effect in the target tissue, while minimizing or eliminating systemic side effects due to the extremely low amount of the drug entering the bloodstream.

According to Eric T. Fossel's patent US10898489B2, two key excipients are used in the topical formulation containing PDE5 inhibitors (such as sildenafil): L-arginine and ionic salts (such as sodium chloride, potassium chloride, etc.). L-arginine itself acts as a nitric oxide donor and is used to increase local blood flow at the application site, enhancing the delivery effect of the drug formulation and aiding in percutaneous absorption. The ionic salts in the formulation create a high ionic strength environment, making the environment chemically and/or energetically unfavorable for the PDE5 inhibitors (such as sildenafil) to exist in the vehicle, thus promoting the migration of the drug from the vehicle to the skin tissue. In addition, the high concentration of salts in the formulation prevents the API from forming hydrogen bonds with the stratum corneum, increasing the percutaneous delivery efficiency. 

The patent describes that this cream is prepared by mixing the aqueous phase and the oil phase to form an emulsion. The drug is added to the corresponding phase according to its solubility, and the pH and temperature are adjusted. Emulsifiers are used to prevent high salt concentrations from destabilizing the emulsion, and after mixing, the formulation is cooled to form a cream. Homogenization treatment can also be performed. This specific ingredient combination (such as xanthan gum, propylene glycol, and Tween 20 surfactants) helps stabilize the cream at high temperatures (such as 40°C or higher) for several days or even weeks, with synergistic effects that improve thermal stability and reduce phase separation.