madman
Super Moderator
Evaluation of an Anhydrous Permeation‑Enhancing Vehicle for Percutaneous Absorption of Hormones (2022)
Guiyun Song · Daniel Banov · Hui Song · Yi Liu · Kendice Ip· August S. Bassani · Benigno C. Valdez
Abstract
The efficiency and safety of hormone delivery through the skin partly depend on the appropriate choice of vehicle and the type of formulation. The present study reports the skin cytotoxicity, irritancy, and safety of a newly developed anhydrous permeation-enhancing base (APEB) and the percutaneous absorption of progesterone, testosterone, estriol, and estradiol in APEB formulations. Using the human skin EpiDerm model, cell death was not observed after 4 h of exposure to APEB and was 48% after 24 h, indicating its mild to non-irritating property. APEB did not change the expression level of skin cell proliferation markers including PCNA, MCL-1, iNOS, and NFκB proteins, and apoptosis was minimal after 8-h exposure. The in vivo skin irritation and sensitization evaluation of APEB using a Human Repeat Insult Patch Test showed no adverse reaction of any kind during the course of the study. These results indicate the safety of APEB on skin tissues. The hormone percutaneous absorption was performed using human cadaver abdomen skin tissues and the Franz diffusion system, and hormone concentrations were determined by ELISA. Absorption was observed as early as 2 h of application and accumulated after 24 h to 2851±66 ng/cm2, 2338±594 ng/cm2, 55±25 ng/cm2, and 341±122 ng/cm2 for progesterone, testosterone, estriol, and estradiol, respectively. A steady flux rate of absorption of the hormones was observed within 24 h of application. These results suggest that APEB can be used as a vehicle to deliver these hormones through the skin and into the bloodstream for hormone replacement therapy.
Introduction
Hormones are body chemical messengers secreted by the endocrine glands directly into the bloodstream to the targeted organ/tissue. Hormone deficiency affects development, growth, metabolism, homeostasis, and sexual function among others [1]; hence, hormone replacement therapy (HRT) is used for the management of its symptoms. Replacement therapies for progesterone, estrogen, and/or testosterone are commonly used to treat menopausal symptoms such as hot flashes, night sweats, bone loss and fracture, vaginal discomfort, and mood and depressive disorders. The efficiency and safety of HRT partly depend on the method of delivery including oral, injection, nasal spray, or topical [2].
The inherent limitations of oral and parenteral delivery of hormones are usually overcome by transdermal delivery through percutaneous absorption. The latter method is a noninvasive self-administration with predictable pharmacokinetics and potentially better bioavailability because it avoids first-pass metabolism by the liver with a fast onset of action [3]. For example, transdermal administration of progesterone and estrogen reduces the risk of venous thromboembolism compared with the oral route [4]. Oral formulations of testosterone have been linked with liver toxicity and fluctuations in testosterone levels [5] whereas testosterone transdermal gels and liquids provide more consistent serum testosterone levels [6]. The guideline from the National Institute for Health and Care Excellence (NICE) suggests that transdermal HRT is more cost-effective and efficacious than oral HRT for hot flushes and night sweats [7]. A common adverse effect of these transdermal formulations includes application site reactions, which underscores the importance of developing compounding bases for these hormones with improved safety.
Custom-formulated/compounded hormone preparations have become an alternative to FDA-approved drug products because they are tailored to fit a unique need of a patient including avoidance of a possible allergic reaction to an inactive ingredient, provision of an exact dose that may not be commercially available, preference for a certain flavor and texture, and access to discontinued or out-of-stock medications. Drug compounding is a valuable treatment option for patients who do not have access to a commercial drug that meets their individual needs [8]. Recent reviews of the literature show the clinical and therapeutic values of compounded progesterone, testosterone, estrogen, and other hormones in HRT [9, 10]. A potential factor that contributes to the efficacy of these compounded HRT is the base composition.
In the search for an optimized vehicle for topical hormone delivery, an anhydrous permeation-enhancing base (APEB, also called PCCA VersaBase® Anhydrous HRT [11]) was selected to evaluate the percutaneous absorption of progesterone, testosterone, estriol, and estradiol. Progesterone has been shown to be percutaneously absorbed using a similar vehicle called VersaBase® Cream (VBC), a topical cream base that simulates the natural moisturizing barrier of the skin through its emulsion system [12–15]. Compared with VBC which contains water, APEB has a water activity below 0.6 (Aw < 0.6), which is considered an anhydrous base [11–13]. It uses a unique, patent-pending delivery system designed to improve the solubility of lipophilic molecules, such as hormones.
In the present study, the skin cytotoxicity, irritancy, and safety of APEB and the percutaneous absorption of progesterone, testosterone, estriol, and estradiol in this base were determined using an in vitro dermatomed skin model.
Materials and Methods
Compounded Topical Formulation
The compounded formulation used in this study contained either APEB or VBC with 10% progesterone USP (PCCA Special Micronized), 0.1% testosterone USP Micronized CIII (Yam, PCCA), or 0.1% estriol/0.1% estradiol USP micronized (PCCA).
Results
*APEB is Non‑cytotoxic
*Progesterone in APEB is Percutaneously Absorbed
*Testosterone Has Similar Absorption Profiles in APEB and VBC Formulations
*APEB Facilitates Absorption of Estriol and Estradiol
Discussion
The demand for efficacious, safe, and convenient topical HRT continues to increase. In this study, APEB developed especially for topical hormone delivery is characterized. The results suggest that APEB is safe for dermal application, and the base facilitates the percutaneous permeation of the hormones, suggesting that despite the anhydrous property of the vehicle, the lipophilic hormones are released from the base and permeate through the skin.
*The study has its own limitations including the number of samples used in the in vitro evaluations and the number of human subjects in the HRIPT analysis. Better statistical power and more significant results are obtained with greater numbers. In vitro evaluations cannot fully reproduce the complexity of biological systems, and the results are considered only a prediction of the in vivo skin absorption [36]. Moreover, anatomical site, skin hydration, and age of the person are important factors that may affect the skin absorption of hormones compounded in APEB [37]
Although a clinical trial for hormone delivery using APEB as a vehicle is warranted, compounding pharmacists and physicians will now have a better option in using APEB for compounded topical hormones for HRT. Based on the need of the pharmacy compounding industry to focus on the role of water activity in establishing beyond-use dates for compounded medications, the described efficient percutaneous absorption of progesterone, testosterone, estriol, and estradiol in APEB formulations indicates that this base can be used to maximize efficiency.
Conclusions
The in vitro and in vivo results of this study suggest that APEB is non-toxic to human skin cells and can be used as an effective vehicle for topical hormone delivery. APEB facilitates the percutaneous absorption of progesterone, testosterone, estriol, and estradiol without quick peaking or declining, which is one of the desired characteristics of an ideal hormone delivery base. Based on the presented results, APEB could provide a reliable option to compounding pharmacists, and practitioners may also consider these formulations as a viable route of hormone administration for patients undergoing HRT.
Guiyun Song · Daniel Banov · Hui Song · Yi Liu · Kendice Ip· August S. Bassani · Benigno C. Valdez
Abstract
The efficiency and safety of hormone delivery through the skin partly depend on the appropriate choice of vehicle and the type of formulation. The present study reports the skin cytotoxicity, irritancy, and safety of a newly developed anhydrous permeation-enhancing base (APEB) and the percutaneous absorption of progesterone, testosterone, estriol, and estradiol in APEB formulations. Using the human skin EpiDerm model, cell death was not observed after 4 h of exposure to APEB and was 48% after 24 h, indicating its mild to non-irritating property. APEB did not change the expression level of skin cell proliferation markers including PCNA, MCL-1, iNOS, and NFκB proteins, and apoptosis was minimal after 8-h exposure. The in vivo skin irritation and sensitization evaluation of APEB using a Human Repeat Insult Patch Test showed no adverse reaction of any kind during the course of the study. These results indicate the safety of APEB on skin tissues. The hormone percutaneous absorption was performed using human cadaver abdomen skin tissues and the Franz diffusion system, and hormone concentrations were determined by ELISA. Absorption was observed as early as 2 h of application and accumulated after 24 h to 2851±66 ng/cm2, 2338±594 ng/cm2, 55±25 ng/cm2, and 341±122 ng/cm2 for progesterone, testosterone, estriol, and estradiol, respectively. A steady flux rate of absorption of the hormones was observed within 24 h of application. These results suggest that APEB can be used as a vehicle to deliver these hormones through the skin and into the bloodstream for hormone replacement therapy.
Introduction
Hormones are body chemical messengers secreted by the endocrine glands directly into the bloodstream to the targeted organ/tissue. Hormone deficiency affects development, growth, metabolism, homeostasis, and sexual function among others [1]; hence, hormone replacement therapy (HRT) is used for the management of its symptoms. Replacement therapies for progesterone, estrogen, and/or testosterone are commonly used to treat menopausal symptoms such as hot flashes, night sweats, bone loss and fracture, vaginal discomfort, and mood and depressive disorders. The efficiency and safety of HRT partly depend on the method of delivery including oral, injection, nasal spray, or topical [2].
The inherent limitations of oral and parenteral delivery of hormones are usually overcome by transdermal delivery through percutaneous absorption. The latter method is a noninvasive self-administration with predictable pharmacokinetics and potentially better bioavailability because it avoids first-pass metabolism by the liver with a fast onset of action [3]. For example, transdermal administration of progesterone and estrogen reduces the risk of venous thromboembolism compared with the oral route [4]. Oral formulations of testosterone have been linked with liver toxicity and fluctuations in testosterone levels [5] whereas testosterone transdermal gels and liquids provide more consistent serum testosterone levels [6]. The guideline from the National Institute for Health and Care Excellence (NICE) suggests that transdermal HRT is more cost-effective and efficacious than oral HRT for hot flushes and night sweats [7]. A common adverse effect of these transdermal formulations includes application site reactions, which underscores the importance of developing compounding bases for these hormones with improved safety.
Custom-formulated/compounded hormone preparations have become an alternative to FDA-approved drug products because they are tailored to fit a unique need of a patient including avoidance of a possible allergic reaction to an inactive ingredient, provision of an exact dose that may not be commercially available, preference for a certain flavor and texture, and access to discontinued or out-of-stock medications. Drug compounding is a valuable treatment option for patients who do not have access to a commercial drug that meets their individual needs [8]. Recent reviews of the literature show the clinical and therapeutic values of compounded progesterone, testosterone, estrogen, and other hormones in HRT [9, 10]. A potential factor that contributes to the efficacy of these compounded HRT is the base composition.
In the search for an optimized vehicle for topical hormone delivery, an anhydrous permeation-enhancing base (APEB, also called PCCA VersaBase® Anhydrous HRT [11]) was selected to evaluate the percutaneous absorption of progesterone, testosterone, estriol, and estradiol. Progesterone has been shown to be percutaneously absorbed using a similar vehicle called VersaBase® Cream (VBC), a topical cream base that simulates the natural moisturizing barrier of the skin through its emulsion system [12–15]. Compared with VBC which contains water, APEB has a water activity below 0.6 (Aw < 0.6), which is considered an anhydrous base [11–13]. It uses a unique, patent-pending delivery system designed to improve the solubility of lipophilic molecules, such as hormones.
In the present study, the skin cytotoxicity, irritancy, and safety of APEB and the percutaneous absorption of progesterone, testosterone, estriol, and estradiol in this base were determined using an in vitro dermatomed skin model.
Materials and Methods
Compounded Topical Formulation
The compounded formulation used in this study contained either APEB or VBC with 10% progesterone USP (PCCA Special Micronized), 0.1% testosterone USP Micronized CIII (Yam, PCCA), or 0.1% estriol/0.1% estradiol USP micronized (PCCA).
Results
*APEB is Non‑cytotoxic
*Progesterone in APEB is Percutaneously Absorbed
*Testosterone Has Similar Absorption Profiles in APEB and VBC Formulations
*APEB Facilitates Absorption of Estriol and Estradiol
Discussion
The demand for efficacious, safe, and convenient topical HRT continues to increase. In this study, APEB developed especially for topical hormone delivery is characterized. The results suggest that APEB is safe for dermal application, and the base facilitates the percutaneous permeation of the hormones, suggesting that despite the anhydrous property of the vehicle, the lipophilic hormones are released from the base and permeate through the skin.
*The study has its own limitations including the number of samples used in the in vitro evaluations and the number of human subjects in the HRIPT analysis. Better statistical power and more significant results are obtained with greater numbers. In vitro evaluations cannot fully reproduce the complexity of biological systems, and the results are considered only a prediction of the in vivo skin absorption [36]. Moreover, anatomical site, skin hydration, and age of the person are important factors that may affect the skin absorption of hormones compounded in APEB [37]
Although a clinical trial for hormone delivery using APEB as a vehicle is warranted, compounding pharmacists and physicians will now have a better option in using APEB for compounded topical hormones for HRT. Based on the need of the pharmacy compounding industry to focus on the role of water activity in establishing beyond-use dates for compounded medications, the described efficient percutaneous absorption of progesterone, testosterone, estriol, and estradiol in APEB formulations indicates that this base can be used to maximize efficiency.
Conclusions
The in vitro and in vivo results of this study suggest that APEB is non-toxic to human skin cells and can be used as an effective vehicle for topical hormone delivery. APEB facilitates the percutaneous absorption of progesterone, testosterone, estriol, and estradiol without quick peaking or declining, which is one of the desired characteristics of an ideal hormone delivery base. Based on the presented results, APEB could provide a reliable option to compounding pharmacists, and practitioners may also consider these formulations as a viable route of hormone administration for patients undergoing HRT.
