In Vitro-In Vivo Correlation of Buprenorphine Transdermal Systems Under Normal and Elevated Skin Temperature.

PURPOSE: Application of external heat using a heating pad over buprenorphine transdermal system, Butrans® has been shown to increase systemic levels of buprenorphine in human volunteers. The purpose of this study was to perform in vitro permeation studies at normal as well as elevated temperature conditions to evaluate the correlation of in vitro data with the existing in vivo data. METHODS: In vitro permeation tests (IVPT) were performed on human skin from four donors. The IVPT study design was harmonized to a previously published clinical study design and skin temperature was maintained at either 32 ± 1 °C or 42 ± 1 °C to mimic normal and elevated skin temperature conditions, respectively. RESULTS: IVPT studies on human skin were able to demonstrate heat induced enhancement in flux and cumulative amount of drug permeated from Butrans® which was reasonably consistent with the corresponding enhancement observed in vivo. Level A in vitro-in vivo correlation (IVIVC) was established using unit impulse response (UIR) based deconvolution method for both baseline and heat arms of the study. The percent prediction error (%PE) calculated for AUC and Cmax values was less than 20%. CONCLUSIONS: The studies indicated that IVPT studies performed under the same conditions as those of interest in vivo may be useful for comparative evaluation of the effect of external heat on transdermal delivery system (TDS). Further research may be warranted to evaluate factors, beyond cutaneous bioavailability (BA) assessed using an IVPT study, that can influence plasma exposure in vivo for a given drug product.

Understanding Formulation and Temperature Effects on Dermal Transport Kinetics by IVPT and Multiphysics Simulation.

PURPOSE: It is often unclear how complex topical product formulation factors influence the transport kinetics through skin tissue layers, because of multiple confounding attributes. Environmental factors such as temperature effect are also poorly understood. In vitro permeation testing (IVPT) is frequently used to evaluate drug absorption across skin, but the flux results from these studies are from a combination of mechanistic processes. METHOD: Two different commercially available formulations of oxybenzone-containing sunscreen cream and continuous spray were evaluated by IVPT in human skin. Temperature influence between typical skin surface temperature (32°C) and an elevated 37°C was also assessed. Furthermore, a multiphysics-based simulation model was developed and utilized to compute the flux of modeled formulations. RESULTS: Drug transport kinetics differed significantly between the two drug products. Flux was greatly influenced by the environmental temperature. The multiphysical simulation results could reproduce the experimental observations. The computation further indicated that the drug diffusion coefficient plays a dominant role in drug transport kinetics, influenced by the water content which is also affected by temperature. CONCLUSION: The in vitro testing and bottom-up simulation shed insight into the mechanism of dermal absorption kinetics from dissimilar topical products.

Effect of Controlled Heat Application on Topical Diclofenac Formulations Evaluated by In Vitro Permeation Tests (IVPT) Using Porcine and Human Skin.

PURPOSE: Heat therapy is widely used for pain relief and may unintentionally be used in conjunction with pain relieving topical formulations. The purpose of this study was to evaluate the influence of heat on the permeation of diclofenac through porcine and human skin, comparing four marketed products. METHODS: In vitro permeation tests (IVPT) were performed on porcine skin from a single miniature pig and human skin from three donors. Skin temperature was maintained at either 32 ± 1°C or 42 ± 1°C to mimic normal and elevated skin temperature conditions, respectively. RESULTS: IVPT studies on porcine and human skin were able to demonstrate heat-induced enhancement in flux and cumulative amount of drug permeated from the four diclofenac products. The pivotal data showed the most significant heat-induced enhancement for the solution, followed by the patch and two gels in decreasing order of significance based on p values. Diclofenac solution showed the highest flux and cumulative amount permeated at both baseline and elevated skin temperature compared to the patch and gels. CONCLUSIONS: The studies demonstrated that exposure to heat can alter drug permeation from topical formulations, but the increased levels are not expected to lead to systemic concentrations that are of concern. Formulation design and excipients can influence drug permeation at elevated skin temperature.

The Sensitivity of In Vitro Permeation Tests to Chemical Penetration Enhancer Concentration Changes in Fentanyl Transdermal Delivery Systems.

Chemical penetration enhancers (CPEs) are frequently incorporated into transdermal delivery systems (TDSs) to improve drug delivery and to reduce the required drug load in formulations. However, the minimum detectable effect of formulation changes to CPE-containing TDSs using in vitro permeation tests (IVPT), a widely used method to characterize permeation of topically applied drug products, remains unclear. The objective of the current exploratory study was to investigate the sensitivity of IVPT in assessing permeation changes with CPE concentration modifications and subsequently the feasibility of IVPT's use for support of quality control related to relative CPE concentration variation in a given formulation. A series of drug-in-adhesive (DIA) fentanyl TDSs with different amounts of CPEs were prepared, and IVPT studies utilizing porcine and human skin were performed. Although IVPT could discern TDSs with different amounts of CPE by significant differences in flux profiles, maximum flux (Jmax) values, and total permeation amounts, the magnitudes of the CPE increment needed to see such significant differences were very high (43-300%) indicating that IVPT may have limitations in detecting small changes in CPE amounts in some TDSs. Possible reasons for such limitations include formulation polymer and/or other excipients, type of CPE, variability associated with IVPT, skin type used, and disrupted stratum corneum (SC) barrier effects caused by CPEs.

On the Road to Development of an in Vitro Permeation Test (IVPT) Model to Compare Heat Effects on Transdermal Delivery Systems: Exploratory Studies with Nicotine and Fentanyl.

PURPOSE: At elevated temperatures, the rate of drug release and skin permeation from transdermal delivery systems (TDS) may be higher than at a normal skin temperature. The aim of this study was to compare the effect of heat on the transdermal delivery of two model drugs, nicotine and fentanyl, from matrix-type TDSs with different formulations, using in vitro permeation tests (IVPT). METHODS: IVPT experiments using pig skin were performed on two nicotine and three fentanyl TDSs. Both continuous and transient heat exposures were investigated by applying heat either for the maximum recommended TDS wear duration or for short duration. RESULTS: Continuous heat exposure for the two nicotine TDSs resulted in different effects, showing a prolonged heat effect for one product but not the other. The Jmax enhancement ratio due to the continuous heat effect was comparable between the two nicotine TDS, but significantly different (p < 0.05) among the three fentanyl TDSs. The Jmax enhancement ratios due to transient heat exposure were significantly different for the two nicotine TDSs, but not for the three fentanyl TDSs. Furthermore, the transient heat exposure affected the clearance of drug from the skin depot after TDS removal differently for two drugs, with fentanyl exhibiting a longer heat effect. CONCLUSIONS: This exploratory work suggests that an IVPT study may be able to discriminate differences in transdermal drug delivery when different TDS are exposed to elevated temperatures. However, the clinical significance of IVPT heat effects studies should be further explored by conducting in vivo clinical studies with similar study designs.

Microneedle-assisted percutaneous delivery of naltrexone hydrochloride in yucatan minipig: in vitro-in vivo correlation.

Although microneedle-assisted transdermal drug delivery has been the subject of multiple scientific investigations, very few attempts have been made to quantitatively relate in vitro and in vivo permeation. The case of naltrexone hydrochloride is not an exception. In the present study, a pharmacokinetic profile obtained following a "poke and patch" microneedle application method in the Yucatan minipig is reported. The profile demonstrates a rapid achievement of maximum naltrexone hydrochloride plasma concentration followed by a relatively abrupt concentration decline. No steady state was achieved in vivo. In an attempt to correlate the present in vivo findings with formerly published in vitro steady-state permeation data, a diffusion-compartmental mathematical model was developed. The model incorporates two parallel permeation pathways, barrier-thickness-dependent diffusional resistance, microchannel closure kinetics, and a pharmacokinetic module. The regression analysis of the pharmacokinetic data demonstrated good agreement with an independently calculated microchannel closure rate and in vitro permeation data. Interestingly, full-thickness rather than split-thickness skin employed in in vitro diffusion experiments provided the best correlation with the in vivo data. Data analysis carried out with the model presented herein provides new mechanistic insight and permits predictions with respect to pharmacokinetics coupled with altered microchannel closure rates.

Advanced harmonization techniques result in accurate establishment of in vitro-in vivo correlations for oxybenzone from four complex dermal formulations with reapplication.

Due to high variability during clinical pharmacokinetic (PK) evaluation, the prediction of in vivo exposure from in vitro absorption testing of topical semisolid and liquid dermal products has historically proven difficult. Since absorption from unoccluded formulations can be influenced by environmental factors such as temperature and humidity, maximal effort must be placed on the harmonization of experimental parameters between in vitro and in vivo testing conditions to establish accurate in vitro/in vivo correlations (IVIVC). Using four different sunscreen formulations as a model, we performed in vitro permeation testing (IVPT) studies with excised human skin and maintained strict harmonization techniques to control application time, occlusion, temperature, and humidity during in vivo human serum PK evaluation. The goal was to investigate if increased control over experimental parameters would result in decreased inter-subject variability of common topical formulations leading to acceptable IVIVC establishment. Using a deconvolution-based approach, excellent point-to-point (Level A correlation) IVIVC for the entire 12-h study duration was achieved for all four sunscreen formulations with < 10% prediction error of both area under the curve (AUC) and peak concentration (Cmax) estimation. The low variability of in vivo absorption data presents a proof-of-concept protocol design for testing of complex semisolid and liquid topical formulations applied over a large surface area with reapplication in a reliable manner. This work also presents the opportunity for expanded development of testing for the impact of altered temperature and humidity conditions on product absorption in vivo with a high degree of precision.

Prescriber Perspectives on Biosimilar Adoption and Potential Role of Clinical Pharmacology: A Workshop Summary.

The approval and adoption of biosimilar products are essential to contain increasing healthcare costs and provide more affordable choices for patients. Despite steady progress in the number of the US Food and Drug Administration (FDA) biosimilar approvals over the years, biosimilar adoption in the United States has been slow and gradual, largely driven by payers rather than clinicians. In order to better understand the barriers to biosimilar adoption in the clinic, the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) and the FDA jointly hosted a virtual workshop on April 13, 2022, titled "Biosimilars: A Decade of Experience and Future Directions - Strategies for Improving Biosimilar Adoption and the Potential Role of Clinical Pharmacology." This summary documents the experiences of four leading academic clinicians with specialties in oncology, rheumatology, gastroenterology, and endocrinology and their perspectives on how to increase biosimilar adoption, including the role of clinical pharmacology. Besides systemic changes in pricing and reimbursement, there is a need for additional education of a broad range of providers, including advanced care practitioners, and patients themselves. Educational efforts highlighting the rigor of the studies that support the approval of biosimilars-including the clinical pharmacology studies-and the benefits of biosimilars, can play a major role in improving biosimilar acceptance.

Evaluation of in vitro/in vivo correlations for three fentanyl transdermal delivery systems using in vitro skin permeation testing and human pharmacokinetic studies under the influence of transient heat application.

The value of developing an in vitro/in vivo correlation (IVIVC) is substantial in biopharmaceutical drug development because once the model is developed and validated, an in vitro method may be used to efficiently assess and predict drug product performance in vivo. In this study, three bioequivalent, matrix-type, fentanyl transdermal delivery systems (TDS) were evaluated in vitro using an in vitro permeation test (IVPT) and dermatomed human skin, and in vivo in human pharmacokinetic (PK) studies under harmonized study designs to evaluate IVIVC. The study designs included 1 h of transient heat application (42 ± 2°C) at either 11 h or 18 h after TDS application to concurrently investigate the influence of heat on drug bioavailability from TDS and the feasibility of IVPT to predict the effects of heat on TDS in vivo. Level A (point-to-point) and Level C (single point) IVIVCs were evaluated by using PK-based mathematical equations and building IVIVC models between in vitro fraction of drug permeation and in vivo fraction of drug absorption. The study results showed that the three differently formulated fentanyl TDS have comparable (p > 0.05) heat effects both in vitro and in vivo. In addition, the predicted steady-state concentration (Css) from in vitro flux data and the observed Css in vivo showed no significant differences (p > 0.05). However, the effects of heat on enhancement of fentanyl bioavailability observed in vivo were found to be greater compared to those observed in vitro for all three drug products, resulting in a weak prediction of the impact of heat on bioavailability from the in vitro data. The results from the current work suggest that while IVPT can be a useful tool to evaluate the performance of fentanyl TDS in vivo with a relatively good predictability at a normal temperature condition and to compare the effect of heat on drug delivery from differently formulated TDS, additional testing measures would enhance the ability to predict the heat effects in vivo with a lower prediction error.

Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers.

CONTEXT: The nonpsychoactive cannabinoid, cannabidiol (CBD), has great potential for the treatment of chronic and 'breakthrough' pain that may occur in certain conditions like cancer. To fulfill this goal, suitable noninvasive drug delivery systems need to be developed for CBD. Chronic pain relief can be best achieved through the transdermal route, whereas 'breakthrough' pain can be best alleviated with intranasal (IN) delivery. Combining IN and transdermal delivery for CBD may serve to provide patient needs-driven treatment in the form of a nonaddictive nonopioid therapy. OBJECTIVE: Herein we have evaluated the IN and transdermal delivery of CBD with and without permeation enhancers. MATERIALS AND METHODS: In vivo studies in rats and guinea pigs were carried out to assess nasal and transdermal permeation, respectively. RESULTS: CBD was absorbed intranasally within 10 minutes with a bioavailability of 34-46%, except with 100% polyethylene glycol formulation in rats. Bioavailability did not improve with enhancers. The steady-state plasma concentration of CBD in guinea pigs after transdermal gel application was 6.3 +/- 2.1 ng/mL, which was attained at 15.5 +/- 11.7 hours. The achievement of a significant steady-state plasma concentration indicates that CBD is useful for chronic pain treatment through this route of administration. The steady-state concentration increased by 3.7-fold in the presence of enhancer. A good in vitro and in vivo correlation existed for transdermal studies. CONCLUSION: The results of this study indicated that CBD could be successfully delivered through the IN and transdermal routes.

In vitro skin diffusion study of pure forskolin versus a forskolin-containing Plectranthus barbatus root extract.

An in vitro skin diffusion study of pure forskolin (1) versus a 1-containing Plectranthus barbatus root extract (P. barbatus extract) in hairless guinea pig skin and human skin in a flow-through diffusion cell system was conducted and is being reported for the first time. Both topical agents were formulated in a solution of 70% ethanol and 30% propylene glycol (v/v). The results showed that forskolin can be delivered through the stratum corneum and that the flux of this compound was enhanced when 1 was delivered as a constituent of the P. barbatus extract as compared to an equivalent amount in pure form. These results suggest that the P. barbatus extract used contains permeation enhancement activity from other compound(s) contained in the crude root extract. It is possible that P. barbatus root extract may be used as an economical source of 1 to perform topical chemical manipulation of pigmentation in high-risk populations.

In vivo evaluation of a transdermal codrug of 6-beta-naltrexol linked to hydroxybupropion in hairless guinea pigs.

6-Beta-naltrexol is the major active metabolite of naltrexone, NTX, a potent mu-opioid receptor antagonist used in the treatment of alcohol dependence and opioid abuse. Compared to naloxone, NTX has a longer duration of action largely attributed to 6-beta-naltrexol. This study was carried out in order to determine percutaneous absorption of a transdermal codrug of naltrexol, 6-beta-naltrexol-hydroxybupropion codrug (CB-NTXOL-BUPOH), in hairless guinea pigs as well as to evaluate the safety of 6-beta-naltrexol for development as a transdermal dosage form. This codrug may be useful in the simultaneous treatment of alcohol dependence and tobacco addiction. The carbonate codrug traversed the skin at a faster rate than 6-beta-naltrexol. 6-Beta-naltrexol equivalent steady state plasma concentrations of 6.4 ng/ml were obtained after application of the codrug as compared to 1.2 ng/ml from 6-beta-naltrexol base. The steady state plasma concentration of hydroxybupropion after codrug application was 6.9 ng/ml. Skin sensitization and irritation tested in the hairless guinea pigs using the Buehler method revealed that 6-beta-naltrexol had no skin sensitizing potential. The method was validated with a known sensitizer, p-phenylenediamine, which induced sensitization in 90% of the animals. 6-beta-Naltrexol caused only mild transient skin irritation after the initial application of the patch. During subsequent applications, erythema was slightly increased but no skin damage was observed. In conclusion, a transdermal codrug of 6-beta-naltrexol could be a viable alternative treatment for alcohol and opiate abuse.

In vitro-in vivo correlations for nicotine transdermal delivery systems evaluated by both in vitro skin permeation (IVPT) and in vivo serum pharmacokinetics under the influence of transient heat application.

The in vitro permeation test (IVPT) has been widely used to characterize the bioavailability (BA) of compounds applied on the skin. In this study, we performed IVPT studies using excised human skin (in vitro) and harmonized in vivo human serum pharmacokinetic (PK) studies to evaluate the potential in vitro-in vivo correlation (IVIVC) of nicotine BA from two, matrix-type, nicotine transdermal delivery systems (TDS). The study designs used for both in vitro and in vivo studies included 1h of transient heat (42±2°C) application during early or late time periods post-dosing. The goal was to evaluate whether any IVIVC observed would be evident even under conditions of heat exposure, in order to investigate further whether IVPT may have the potential to serve as a possible surrogate method to evaluate the in vivo effects of heat on the bioavailability of a drug delivered from a TDS. The study results have demonstrated that the BA of nicotine characterized by the IVPT studies correlated with and was predictive of the in vivo BA of nicotine from the respective TDS, evaluated under the matched study designs and conditions. The comparisons of single parameters such as steady-state concentration, heat-induced increase in partial AUCs and post-treatment residual content of nicotine in TDS from the in vitro and in vivo data sets showed no significant differences (p≥0.05). In addition, a good point-to-point IVIVC (Level A correlation) for the entire study duration was achieved by predicting in vivo concentrations of nicotine using two approaches: Approach I requiring only an in vitro data set and Approach II involving deconvolution and convolution steps. The results of our work suggest that a well designed IVPT study with adequate controls can be a useful tool to evaluate the relative effects of heat on the BA of nicotine from TDS with different formulations.

Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle.

Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, has received attention for therapeutic potential in treating neurologic and psychiatric disorders. Recently, CBD has also been explored for potential in treating drug addiction. Substance use disorders are chronically relapsing conditions and relapse risk persists for multiple reasons including craving induced by drug contexts, susceptibility to stress, elevated anxiety, and impaired impulse control. Here, we evaluated the "anti-relapse" potential of a transdermal CBD preparation in animal models of drug seeking, anxiety and impulsivity. Rats with alcohol or cocaine self-administration histories received transdermal CBD at 24 h intervals for 7 days and were tested for context and stress-induced reinstatement, as well as experimental anxiety on the elevated plus maze. Effects on impulsive behavior were established using a delay-discounting task following recovery from a 7-day dependence-inducing alcohol intoxication regimen. CBD attenuated context-induced and stress-induced drug seeking without tolerance, sedative effects, or interference with normal motivated behavior. Following treatment termination, reinstatement remained attenuated up to ≈5 months although plasma and brain CBD levels remained detectable only for 3 days. CBD also reduced experimental anxiety and prevented the development of high impulsivity in rats with an alcohol dependence history. The results provide proof of principle supporting potential of CBD in relapse prevention along two dimensions: beneficial actions across several vulnerability states and long-lasting effects with only brief treatment. The findings also inform the ongoing medical marijuana debate concerning medical benefits of non-psychoactive cannabinoids and their promise for development and use as therapeutics.

Intranasal absorption of Delta(9)-tetrahydrocannabinol and WIN55,212-2 mesylate in rats.

The aim of this study was to examine the potential of the nasal route for systemic delivery of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and WIN55,212-2 mesylate. Anesthetized rats were surgically prepared to isolate the nasal cavity, into which Delta(9)-THC (10 mg/kg) or WIN55,212-2 (150 microg/kg) in propylene glycol alone or propylene glycol and ethanol (9:1) were administered. Rats were also administered Delta(9)-THC (1 mg/kg) and WIN55,212-2 (150 microg/kg) intravenously in order to determine absolute bioavailabilities of the nasal doses. Plasma Delta(9)-THC and WIN55,212-2 concentrations were determined by liquid chromatography/mass spectroscopy (LC/MS). The pharmacokinetics of the drugs after intranasal administration was best described by a one-compartment model with an absorption phase. WIN55,212-2 was absorbed more rapidly (T(max)=0.2-0.3h) than Delta(9)-THC (T(max)=1.5-1.6h) and to a higher extent than Delta(9)-THC. Addition of ethanol (10%) to the formulations had no significant effect on the C(max) after nasal administration (p>0.05). Furthermore, it had no significant effect on the absolute bioavailability (F(abs)): F(abs)=6.4+/-2.4% and 9.1+/-3.0% for Delta(9)-THC in propylene glycol, with and without ethanol, respectively. For WIN55,212-2, F(abs)=49.9+/-6.9% (propylene glycol alone) and 56.6+/-14.1% (propylene glycol with 10% ethanol). The results of the study showed that systemic delivery of Delta(9)-tetrahydrocannabinol and WIN55,212-2 could be achieved following nasal administration in rats.

LC-MS determination of fentanyl in human serum and application to a fentanyl transdermal delivery pharmacokinetic study.

AIM: Fentanyl is an opioid agonist used for acute and chronic pain management. In this report, a highly sensitive and simple LC-MS/MS method using Hydrophilic Interaction Chromatography (HILIC) column was validated and used for fentanyl quantification in human serum. RESULTS: The isocratic mobile phase was composed of acetonitrile: 10 mM ammonium formate buffer (pH = 3.2; 90:10, v/v). The assay was linear over a concentration range of 10-10,000 pg/ml. The accuracy of the validation method ranged from 93.2 to 107%, and the precision was within 6.4%. Fentanyl was stable during short- and long-term storage. CONCLUSION: The assay has been successfully applied to serum samples obtained from healthy subjects of a fentanyl transdermal pharmacokinetic study.

A fully validated LC-MS/MS method for simultaneous determination of nicotine and its metabolite cotinine in human serum and its application to a pharmacokinetic study after using nicotine transdermal delivery systems with standard heat application in adult smokers.

A sensitive and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous determination of nicotine and its main metabolite cotinine in human serum samples. Liquid-liquid extraction using ethyl acetate was employed for serum sample extractions. Chromatographic separation was achieved on Phenomenex Luna(®) HILIC column (150 mm x 3.0mm, 5 µm). Isocratic elution was performed using acetonitrile:100mM ammonium formate buffer (pH=3.2) (90:10, v/v) as the mobile phase, at a flow rate of 0.4 mL/min. Tandem mass spectrometric detection was employed at positive electrospray ionization in MRM mode for the determination of both nicotine and cotinine and their stable isotope labeled internal standards. Analysis was carried out in 8 min over a concentration range of 0.26-52.5 ng/mL and 7.0-1500 ng/mL for nicotine and cotinine, respectively. The assay was validated according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained; the accuracy ranged between 93.39% and 105.73% for nicotine and between 93.04% and 107.26% for cotinine. No significant matrix effect was observed. Stability assays indicated both nicotine and cotinine were stable during sample storage, preparation and analytical procedures. The method was successfully applied to biological samples obtained from a pharmacokinetic study conducted in adult smokers to investigate heat effect on nicotine and cotinine serum levels after nicotine transdermal delivery system (TDS) application.

Norelgestromin/ethinyl estradiol intravenous infusion formulation optimization, stability and compatibility testing: A case study to overcome polysorbate 80 interference in chromatographic analysis.

Norelgestromin/ethinyl estradiol is a progestin/estrogen combination hormonal contraceptive indicated for the prevention of pregnancy in women. The very poor solubility and wettability of these drugs, along with their high potency (adsorption issues), give rise to difficulties in designing intravenous (IV) formulations to assess absolute bioavailability of products containing both drugs. The purpose of this study was to develop an IV formulation, evaluate its stability under different conditions and evaluate its compatibility with IV sets for potential use in absolute bioavailability studies in humans. Also, a selective high-performance liquid chromatography (HPLC) method for quantification of ethinyl estradiol and norelgestromin in polysorbate 80 matrix was developed and validated. Norelgestromin/ethinyl estradiol IV solution was prepared using sterile water for injection with 2.5% ethanol and 2.5% polysorbate 80 as a cosolvent/surfactant system to obtain a final drug solution of 25µg ethinyl estradiol and 252µg norelgestromin from a concentrated stock drug solution. The stabilities of the concentrated stock and IV solutions were assessed after storing them in the refrigerator (3.7±0.6°C) and at room temperature (19.5±0.5°C), respectively. Additional studies were conducted to examine the stability of the IV solution using an Alarias(®) low sorbing IV administration set with and without an inline filter. The solution was allowed to drip at 1mL/min over a 60min period. Samples were obtained at the beginning, middle and end of the 60min duration. The chemical stability was evaluated for up to 10 days. Norelgestromin and ethinyl estradiol concentration, purity, and degradant levels were determined using the HPLC method. The norelgestromin/ethinyl estradiol IV formulation met the chemical stability criteria when tested on day 1 through day 9 (216h). Norelgestromin concentrations assayed in stock and IV solutions were in the range of 90.0-98.5% and 90.9-98.8% after 9 days, respectively. As for ethinyl estradiol, the assayed concentrations were in the range of 91.8-100.9% and 92.7-100.8% for the stock and IV solutions, respectively. The administration set was found to be compatible with both drugs; the assayed concentrations were in the range of 99.2-100.3% for norelgestromin and 96.3-102.7% for ethinyl estradiol, but the inline filter showed some adsorption of ethinyl estradiol; where the assayed concentrations were in the range of 98.1-99.8% for norelgestromin and 95.9-97.4% for ethinyl estradiol. The present study provided evidence supporting the suitability of an intravenous formulation for norelgestromin/ethinyl estradiol using ethanol/polysorbate 80 as a cosolvent/surfactant system. Both IV and concentrated stock solutions when stored at room temperature and refrigeration, respectively, were found to be chemically stable up to 9 days. These results indicated that this formulation is chemically stable and can be used over the time period tested. This IV formulation can be used to evaluate the absolute bioavailability of products containing norelgestromin and ethinyl estradiol provided that microbial testing of the IV formulation is performed.

In vivo evaluation of 3-O-alkyl ester transdermal prodrugs of naltrexone in hairless guinea pigs.

Naltrexone (NTX) is a potent competitive antagonist with high affinity for the mu-opioid receptor. Therapeutically, NTX is used for the treatment of alcohol dependence and opioid addiction; however, it does not have the ideal physicochemical properties necessary to achieve therapeutic plasma concentrations via the transdermal route. The aim of the present investigation was to evaluate the in vivo transdermal delivery of three 3-O-alkyl ester prodrugs of NTX, including NTX-3-O-acetate (ACE-NTX), NTX-3-O-propionate (PROP-NTX), and NTX-3-O-hexanoate (HEX-NTX) in hairless guinea pigs. The pharmacokinetic parameters for NTX and the 3-O-alkyl ester prodrugs of NTX were determined after intravenous drug administration and topical drug application of transdermal therapeutic systems (TTS) in guinea pigs. The results of the in vivo studies showed mean steady-state plasma concentrations of NTX from NTX, ACE-NTX, PROP-NTX and HEX-NTX at 4.2, 25.2, 16.0, and 8.3 ng/mL, respectively. These NTX plasma concentrations were maintained for 48 h. The results of these in vivo studies demonstrated that ACE-NTX and PROP-NTX prodrugs of NTX were the most promising drug candidates for transdermal delivery.

Bioconversion of naltrexone and its 3-O-alkyl-ester prodrugs in a human skin equivalent.

The purpose of this study was to compare the percutaneous absorption and bioconversion of naltrexone (NTX), naltrexone-3-O-valerate (VAL), and naltrexone-3-O-(2'-ethylbutyrate) (ETBUT) in a human skin equivalent model (EpiDerm) and in fresh human skin in vitro. NTX diffusion and metabolism to 6-beta-naltrexol (NTXol) were quantitated and compared in the EpiDerm and in excised fresh human skin. VAL and ETBUT diffusion and bioconversion studies were also completed in EpiDerm. Naltrexone bioconverted to levels of 3+/-2% NTXol in the EpiDerm and 1+/-0.5% in fresh human skin. VAL hydrolyzed rapidly in the EpiDerm and mainly (93+/-4%) NTX was found in the receiver compartment, similar to human skin. More intact ETBUT permeated the EpiDerm tissue compared to VAL, and only 15+/-11% NTX was found in the receiver. Significantly higher fluxes of NTX and the prodrugs were observed with the EpiDerm compared to human skin. A similar flux enhancement level was observed for VAL, compared to NTX base, in the EpiDerm and the human skin. Metabolically active human epidermal models like EpiDerm are useful as an alternative experimental system to human skin for prediction of topical/transdermal drug/prodrug bioconversion.