Testosterone Therapy for Late-Onset Hypogonadism: A Clinical, Biological, and Analytical Approach Using Compounded Testosterone 0.5-20% Topical Gels.

Testosterone is integral to men's sexual and overall health, but there is a gradual decline in the ageing male. The topical administration of testosterone is a valuable option as a supplement (replacement) therapy to alleviate hypogonadal symptoms. The clinical efficacy of a compounded testosterone 5% topical gel was assessed retrospectively in a male patient in his seventies by evaluating the laboratory testing of the serum total testosterone and the results of a validated androgen deficiency questionnaire. After treatment, the patient's hypogonadal symptoms improved and the serum total testosterone level achieved was considered clinically optimal. The skin permeation of the testosterone topical gel (biological testing) was evaluated in vitro using the Franz finite dose model and human cadaver skin, and it is shown that testosterone can penetrate into and through ex vivo human skin. Testosterone therapy is often prescribed for extended periods, and consequently, it is crucial to determine the beyond-use date of the compounded formulations. The analytical testing involved a valid, stability-indicating assay method for compounded testosterone 0.5% and 20% topical gels. This multidisciplinary study shows evidence supporting topically applied testosterone's clinical efficacy and the compounded formulations' extended stability. Personalized, topical testosterone therapy is a promising alternative in current therapeutics for hypogonadal patients.

In vitro evaluation of the percutaneous absorption of progesterone in anhydrous permeation-enhancing base using the Franz skin finite dose model and mass spectrometry.

Progesterone is used for hormone replacement therapy through various routes of administration. This study was conducted to (a) evaluate the stability of progesterone in a proprietary anhydrous permeation-enhancing base (APEB) and the efficiency of its skin permeation, and (b) determine the appropriateness of mass spectrometry as a method of analysis for permeated progesterone. Using a proven stability-indicating ultra-performance liquid chromatographic method, the compounded hormone (100 mg progesterone/g APEB gel) was determined to be physically and chemically stable at room temperature for six months. Skin permeation analysis using the Franz skin finite dose model and mass spectrometry imaging showed an optical density of 1699 for the permeated progesterone compounded in APEB and 550 for the permeated progesterone in a water containing VBC, which is a statistically significant different (P = 0.029). The study suggests that APEB can be used as a compounding base for effective skin permeation of progesterone, and mass spectrometry is a reliable method for visualization and quantitative analysis of permeated progesterone.

Evaluation of the in vitro human skin percutaneous absorption of ketoprofen in topical anhydrous and aqueous gels.

BACKGROUND: Ketoprofen is a nonsteroidal anti-inflammatory drug used for the treatment of acute and chronic pain associated with inflammatory conditions. This study aims to evaluate the in vitro percutaneous absorption of ketoprofen 10% formulated in proprietary anhydrous and aqueous gels using the Franz skin finite dose model. MATERIALS AND METHODS: The anhydrous gel was initially characterized for cytotoxicity using EpiDerm skin tissue model by cell proliferation assay and Western blot analysis. The Ultra Performance Liquid Chromatography method for measuring ketoprofen was validated and the stability of ketoprofen 10% in the anhydrous gel formulation was evaluated at 5°C and 25°C for 181 days. The percutaneous absorption of ketoprofen was determined using donated human skin. The tissue sections were mounted within Franz diffusion cells. A variable finite dose of each ketoprofen formulation in either anhydrous or aqueous gel was applied to the skin sections and receptor solutions were collected at various time points. RESULTS: Cell proliferation assay showed minimal cell death when EpiDerm skin tissue was exposed to the anhydrous gel for 24 h; the levels of protein markers of cell proliferation were not affected after 17-h exposure. Ketoprofen was stable in the anhydrous gel when stored at 5°C and 25°C. When compounded in the anhydrous and aqueous gels, ketoprofen had mean flux rate of 2.22 and 2.50 µg/cm2 /h, respectively, after 48 h. The drug was distributed to the epidermis and dermis sections of the skin. Both the anhydrous and aqueous gels facilitated the percutaneous absorption of ketoprofen without statistically significant differences. CONCLUSION: The anhydrous gel can be used as a base to facilitate the transdermal delivery of ketoprofen. Although the anhydrous and aqueous gels can deliver a similar amount of ketoprofen, the anhydrous gel (water activity below 0.6) allows for extended default beyond-use-date of compounding preparations.

Analysis of the Physical Characteristics of an Anhydrous Vehicle for Compounded Pediatric Oral Liquids.

The paucity of suitable drug formulations for pediatric patients generates a need for customized, compounded medications. This research study was set out to comprehensively analyze the physical properties of the new, proprietary anhydrous oral vehicle SuspendIt® Anhydrous, which was designed for compounding pediatric oral liquids. A wide range of tests was used, including sedimentation volume, viscosity, droplet size after dispersion in simulated gastric fluid, microscopic examination and content uniformity measurements to evaluate the properties of the anhydrous vehicle. The results showed that the vehicle exhibited consistent physical properties under varying conditions and maintained stability over time. This can be attributed to the unique blend of excipients in its formulation, which not only maintain its viscosity but also confer thixotropic behavior. The unique combination of viscous, thixotropic and self-emulsifying properties allows for rapid redispersibility, sedimentation stability, accurate dosing, potential drug solubility, dispersion and promotion of enhanced gastrointestinal distribution and absorption. Furthermore, the vehicle demonstrated long-term sedimentation stability and content uniformity for a list of 13 anhydrous suspensions. These results suggest that the anhydrous oral vehicle could serve as a versatile base for pediatric formulation, potentially filling an important gap in pediatric drug delivery. Future studies can further investigate its compatibility, stability and performance with other drugs and in different clinical scenarios.

Evaluation of an Anhydrous Permeation-Enhancing Vehicle for Percutaneous Absorption of Hormones.

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.

Beyond-use Date of Trimix: A Reproducible Stability Study Using Bracketing Design.

Trimix is a widely prescribed penile injection for patients with erectile dysfunction and is only available as a compounded medication. The instability of alprostadil, one of the major ingredients of Trimix, has been a limiting factor in its utilization. There are published stability data for Trimix formulations that have been used to establish a beyond-use-date. However, a robust bracketed study that is shown to be reproducible is highly desirable and meaningful. The purpose of this study was to test the reproducibility of a bracketed stability study when the preparations were made by two different entities to provide beyond-use date information of Trimix preparations that cover a wide range of strengths. A validated stability indicating method was used to compare the stability of a bracketed Trimix - alprostadil 5 µg/mL to 45 µg/mL, papaverine 15 mg/mL to 30 mg/mL, and phentolamine 0.4 mg/mL to 5 mg/mL, and a single-strength preparation containing alprostadil 30 µg/mL, papaverine 30 mg/mL, and phentolamine 2 mg/mL that were compounded and stored following the same methods and conditions, but at two different practice settings. Beyond-use dates of 60 days and 64 days at cold temperature were obtained for the two preparations from two different settings. The consistent results confirmed the reproducibility of the bracketing designs used to determine the beyond-use dates of Trimix. The clinical value of these results stems from the availability of accurate and widely applicable stability data that can be referenced to establish beyond use dates of a number of Trimix preparations with various strength combinations.

Evaluation of the Efficacy and Stability of Compounded Pentoxifylline-containing XemaTop for Psoriasis.

Psoriasis is an inflammation-mediated skin disorder for which an efficacious topical treatment is yet to be identified. A new compounded topical formulation containing 10% pentoxifylline in XemaTop base was recently developed for psoriasis. Prior to its use in humans, an in vitro evaluation was performed to determine its efficacy in attenuating molecular markers associated with psoriasis using a three-dimensional psoriasis tissue model. After 5 days of topical exposure to the formulation, the levels of inflammatory cytokines IL-1ß, IL-6, and GM-CSF decreased by 20%, 94%, and 96%, respectively. The production of pro-collagen type I and fibronectin essential for cellular proliferation was also significantly inhibited with a concomitant thinning of the epidermis. These results suggest that 10% pentoxifylline in XemaTop is efficacious in inhibiting the biomarkers associated with psoriasis. Pentoxifylline in XemaTop was stable within 91 days when stored under refrigerated or ambient conditions. These biochemical and stability studies suggest that 10% pentoxifylline in XemaTop may be evaluated now in psoriasis patients.

In vitro evaluation of Naltrexone HCl 1% Topical Cream in XemaTop™ for psoriasis.

Psoriasis is a multifactorial skin disease involving abnormal cell proliferation and inflammation; an efficacious topical treatment is yet to be identified. A formulation containing 1% Naltrexone HCl in XemaTop™ base was compounded, characterized and evaluated in vitro as a possible treatment for psoriasis. A three-dimensional psoriasis tissue model was exposed to the formulation for 2 or 5 days and analyzed for the level of markers of cellular proliferation, and inflammatory cytokine IL-6. Using immunohistochemical staining, the level of Ki67 protein significantly decreased in the drug-treated tissues. Western blot analysis showed 86% and 53% down-regulation of other proliferation markers PCNA and CYCLIN D1, respectively, after 5-day exposure. The pro-survival Wnt/ß-catenin pathway was compromised as indicated by 57% decrease in the level of ß-CATENIN and down-regulation of its down-stream targets including CYCLIN D1 (decreased by 53%), c-MYC (63%), c-JUN (92%) and MET (96%) proteins. Likewise, the PI3K/AKT/mTOR pathway was significantly inhibited by 1% Naltrexone HCl in XemaTop™, suggesting protein synthesis was affected. The production of IL-6 was inhibited by 70% in drug-treated tissues. These results suggest that the compounded drug is efficacious in down-regulating molecular markers associated with the pathogenesis of psoriasis. Low-dose Naltrexone in XemaTop™ was stable within 180 days when stored under refrigerated or ambient conditions. These results provide a basis for a clinical evaluation of 1% Naltrexone HCl in XemaTop™ in psoriasis patients.

Physicochemical Stability of Extemporaneously Prepared Methylcobalamin Injections in the Presence and Absence of Preservative and the Impact of Light Exposure.

Methylcobalamin, one of the two active forms of vitamin B12, is the most effective analog in permeation and in transportation of neurons in subcellular organelles. Formulations of methylcobalamin are only commercially available in a few countries, which make them inaccessible for most patients. Extemporaneously prepared injections become the only option for those patients. The objective of this work is to study the physical and chemical (ultrahigh- performance liquid chromatography stability-indicating method) stabilities of methylcobalamin injections in the presence and absence of preservative during 181 days (considering the stability limit as 90% of initial concentration of methylcobalamin). The light exposure stability of injections in amber serum vials or clear syringes, solution in amber or clear glassware under typical pharmacy, clinical, and laboratory settings are also presented. Methylcobalamin injections, regardless of the concentrations and inactive ingredients, remained stable for at least 181 days at room temperature when stored in amber serum vials and protected from light. These experimental data suggested that the methylcobalamin injection solutions should be protected from light completely and light exposure in pharmacy, clinical, and laboratory setting should be minimized.

Physical and Chemical Stability of Estriol 0.025% to 1% Vaginal Creams (VersaBase).

Estrogen replacement therapy is often recommended when female patients present with lower than normal physiologic levels, such as patients going through menopause. The physical and chemical stability of estriol 0.25 mg/g and 10 mg/g vaginal creams (VersaBase) was tested over a period of 182 days, at room temperature and refrigerated conditions, in order to determine the corresponding beyond-use date. The physical characterization consisted in observing all samples for color/appearance and odor, and testing for pH, whereas the chemical characterization consisted in ultra-performance liquid chromatography assay testing. Both vaginal creams were proven physically and chemically stable, and the ultra-performance liquid chromatography method was proven stability indicating. As a result, the beyond-use date of the estriol 0.025% to 1% vaginal creams (VersaBase), in electronic mortar and pestle plastic jars, is six months at both room temperature and refrigerated conditions.

Physical and Chemical Stability of Budesonide Mucoadhesive Oral Suspensions (MucoLox).

Budesonide is a corticosteroid that has been shown effective in the treatment of eosinophilic esophagitis, but there are currently no commercial medicines to treat this chronic allergic/immune condition, despite its prevalence in the U.S. Therefore, pharmaceutical compounding is the alternative choice to meet the therapeutic need of eosinophilic esophagitis patients. Two budesonide mucoadhesive oral suspensions (1 mg/10 mL and 2 mg/10 mL) were developed using the compounding vehicle MucoLox, a proprietary mucoadhesive polymer blend that promotes mucosal adhesion. The physical and chemical stability of the oral suspensions was tested over a period of 182 days, at room temperature and refrigerated conditions, in order to determine the corresponding beyond-use date. The physical characterization consisted in observing all samples for color/appearance and odor, and testing for pH and density, whereas the chemical characterization consisted in ultra-performance liquid chromatography assay testing. Both oral suspensions were proven physically and chemically stable, and the ultra-performance liquid chromatography method was proven stability indicating. As a result, the beyond-use date of the budesonide 1-mg/10-mL and 2-mg/10-mL mucoadhesive oral suspensions (MucoLox), in amber plastic bottles, is six months at both room temperature and refrigerated conditions.