Skin Penetration Study
PDLabs’ Transdermal Verapamil Gel 15% formulation utilized in the PDLabs’ sponsored clinical studies was evaluated by Dow Pharmaceutical Sciences. The bioavailability of this topically applied drug formulation of verapamil HCl was assessed utilizing an in vitro percutaneous absorption test. Radiolabeled (3H) verapamil HCl absorption was measured utilizing Bronaugh flow-through diffusion cells and evaluated for potential effectiveness in the topical treatment of Peyronie’s.
Human abdominal skin was dosed with the subject formulation, and the absorption characteristics were evaluated after exposure to the human skin sample for 24 hours. Samples were collected every six hours during the 24 hour period. The kinetic profile of the drug’s penetration was studied by plotting dose penetration vs. time. Epidermal, dermal, and receptor solution samples were assessed. 87.58% of the applied dose was recovered. The receptor solution concentration correlates with the amount of drug systemically available following the application of a clinically relevant dose to normal, non-occluded skin.
The PDLabs’ 15% Transdermal Verapamil HCl compound resulted in very low levels in the receptor solution (0.028%). This predicts very low levels of verapamil HCl systemic exposure following topical application which is one desired characteristic of the product since the targeted area of treatment lies very close to the dermis of the skin. Additionally untoward systemic effects are minimized. Dermal and epidermal levels of deposition suggest that the vehicle and the drug to a large degree partition in the epidermis thereby creating a significant reservoir for sustained release of verapamil HCl from human skin without the use of mechanical depots of drug such as those manufactured in sustained release patches.
This combination of high dose loading and high epidermal deposition, following the application to skin indicate that the PDLabs formulation of 15% verapamil HCl should result in effective, sustained delivery of the verapamil HCl to the Peyronie’s plaque.
Martin, et al, reported that the transdermal application of verapamil gel to the penile shaft fails to infiltrate the tunica albuginea ( The Journal of Urology, Vol. 168, 2483-2485, December 2002). The results of this study were analyzed by pharmacology experts and found to be seriously flawed for several reasons: The medication used was an illegally made, counterfeit gel that was not obtained from PDLabs, only eight patients were studied, and the medication was only appplied twice before the samples were taken in surgery. It is highly unlikely that two applications would result in equilibration between epidermal tissue and the tunica albuginea. Application occurred over only the sides of the penile shaft and not the entire penile shaft.
Furthermore, few details are provided concerning active ingredient, and no information is provided regarding whether verapamil or verapamil hydrochloride was used. Verapamil hydrochloride is preferred due to its stability. Verapamil base is unstable. The authors refer to the medication as “verapamil gel”. Drug vehicle selection and compounding technique are critical. The vehicle must be designed to traverse the stratum corneum to the extent that it reaches subdermal connective tissue but at the same time minimizes systemic absorption.
The compounding procedure must be reproducible and must provide a product of consistent characteristics such as viscosity, particle size, pH, and appearance. Stability of compounded verapamil is a problem, and it must be protected from light to prevent degradation, and packaged in a material that is non-reactive chemically or physically to the active ingredient or any ingredient of the drug vehicle. The authors state that it is unlikely that verapamil would be found in fibrotic scar tissue. However, treating fibrotic connective tissue is the essence of transdermal treatment and should lead to remodeling of fibrotic tissue by retarding the production of fibroblasts at the site of injury along with the maturation of fibroblast collagenase.
Verapamil is extensively metabolized by cytochrome P4503A4, and only 3-4 percent is excreted unchanged in the urine. Based on the reported urinary concentration of 46 ng/mL, and using data provided by Saseen, et. al.,* the back extrapolated plasma concentration would have to be 1400 ng/mL to achieve the reported urinary concentration, and the estimated dose to produce this plasma concentration is approximately equivalent to an oral dose of 960mg. daily. The observed urinary verapamil is most likely due to contamination. Only 40mg was reported to have been applied. Furthermore, no information is provided concerning the sensitivity and specificity of the assay. Apparently, no blank samples were run to determine if interfering substances were present in the analyzed samples. Another potential problem is the site of tunica sampling and the site of drug application. Based on the description, the two sites were not in close proximity. This study does not provide definitive evidence of the lack of verapamil penetration to the tunica. These discrepancies were reported to the Journal editor and published in the May, 2005 Journal of Urology.