Development and in vitro evaluation of diltiazem hydrochloride transdermal patches based on povidone-ethylcellulose matrices

To select a suitable formulation for the development of transdermal drug-delivery system of diltiazem hydrochloride. Transdermal patches of the drug, employing different ratios of polymers, ethylcellulose (EC), and povidone (PVP) were developed and evaluated for the potential drug delivery using depilated freshly excised abdominal mouse skin. The influence of different film compositions on in vitro drug permeation into receptor fluid were studied using a modified Franz diffusion cell. The cumulative amount of drug was found to be proportional to the square root of time, i.e., Higuchi kinetics. From this study, it was concluded that the films composed of povidone:ethylcellulose (1:2) should be selected for the development of transdermal drug-delivery system of diltiazem hydrochloride, using a suitable adhesive layer and backing membrane, for potential therapeutic use.     

Magnetophoresis in combination with chemical enhancers for transdermal drug delivery

Purpose: The objective of the present work was to investigate the effect of combination of a novel physical permeation enhancement technique, magnetophoresis with chemical permeation enhancers on the transdermal delivery of drugs.

Methods: The in vitro drug transport studies were carried out across the freshly excised abdominal skin of Sprague-Dawley rats using transdermal patch systems (magnetophoretic and non-magnetophoretic) of lidocaine hydrochloride (LH). LH gel prepared using hydroxypropyl methylcellulose (HPMC) was spread over the magnets as a thin layer. To investigate the effect of chemical permeation enhancers, menthol, dimethyl sulfoxide, sodium lauryl sulfate and urea (5% w/v) were incorporated in the gels prior to loading on the patch system.

Results: The flux of lidocaine from magnetophoretic patch was ~3-fold higher (3.07?±?0.43 µg/cm²/h) than that of the control (non-magnetophoretic patch) (0.94?±?0.13 µg/cm²/h). Incorporation of chemical permeation enhancers in the gel enhanced the magnetophoretic delivery flux by ~4 to 7-fold.

Conclusions: The enhancement factor due to combination of chemical permeation enhancer was additive and not synergistic. Mechanistic studies indicated that magnetophoresis mediated drug delivery enhancement was via appendageal pathway.     

The effect of component of microemulsion for transdermal delivery of nicardipine hydrochloride

Purpose: Nicardipine hydrochloride has been used widely for the treatment of angina pectoris and hypertension. Because of its extensive first pass metabolism after oral administration, the transdermal administration of nicardipine microemulsions was developed in this study. Methods: Microemulsions consisted of isopropyl myristate (IPM), surfactant mixture of Tween 80/Span 80 and/or Tween 80/Span 20, co-surfactant (ethanol) and aqueous phase. Pseudo-ternary phase diagrams were constructed using water titration method. The effect of component of microemulsion on the percutaneous absorption of drug was evaluated by in vitro permeation study. Results: The area of microemulsion isotropic region in the presence of ethanol was comparably larger in the absence of ethanol. The mean droplet size of nicardipine microemulsions ranged from 70 to 123 nm. With addition of ethanol, the droplet size became smaller. The permeation rate and extent of nicardipine microemulsion transport across rat skin was affected by the components of microemulsion. Nicardipine microemulsion had higher flux at surfactant mixture with lower hyrophile-lipophile balance (HLB) value and Tween content. Conclusions: The microemulsion consisted of 52% IPM, 35% surfactant mixture and 13% water had higher permeation rate through rat skin above 122.53±1.87 μg/cm2/h and was expected to develop a transdermal delivery system.     

Evaluation of the transdermal permeation behavior of Proterguride from drug in adhesive matrix patches through hairless mouse skin

The transdermal in vitro permeation behavior of the highly potent dopamine agonist Proterguride was investigated using hairless mouse skin as a model membrane. Drug in adhesive matrix formulations based on different types of pressure-sensitive adhesives (Eudragit® E 100 and Gelva®7883 as acrylates, Oppanol® B 15 SFN as polyisobutylene, and BioPSA® 7-4202 as silicone) with a drug load of 3% by weight were manufactured. All patches were examined for drug crystallization by polarized microscopy immediately after the manufacturing process and after storage for 30 days in sealed aluminium laminate bags at ambient temperature and at 40°C, respectively. Furthermore, the influence of the drug load in acrylate-based formulations onto the steady-state flux of Proterguride was examined. The Eudragit® E 100 system delivered a significantly higher steady-state flux than the systems based on Oppanol® B 15 SFN and also a somewhat higher steady-state flux than the Gelva®-based patch. An addition of 10% by weight of the crystallization inhibitor povidone 25 did not significantly influence the steady-state flux of Proterguride from acrylate matrices. The lipophilic silicone and polyisobutylene adhesives facilitated drug crystallization within the short storage periods at both conditions, probably due to the absence of povidone 25, which was incompatible with these polymers. Varying the drug load in acrylate-based formulations led to a linear increase of the steady-state flux until the steady-state flux of Proterguride leveled off and the patches tended to drug crystallization. It was found that Gelva®-based patches show good physical stability, good skin adhesion, and moderate flux values and, thus, can be evaluated as a basis for a suitable formulation for the transdermal administration of Proterguride.     

Development of matrix patches for transdermal delivery of a highly lipophilic antiestrogen

The aim of this study was to develop matrix-type transdermal systems (TDSs) containing the highly lipophilic (log P = 5.82) antiestrogen (AE) and the permeation enhancers propylene glycol and lauric acid. For that purpose, permeation of AE from various adhesive matrices through excised skin of hairless mice was evaluated. It was found that pretreatment of the skin with permeation enhancers raised the transdermal flux of subsequently applied antiestrogen. Highest steady-state transdermal fluxes (1.1 µg cm^-2 h^-1) were obtained from Gelva®, polyacrylate adhesive, followed by 0.55 µg cm^-2 h^-1 from Oppanol® polyisobutylene, 0.31 µg cm^-2 h^-1 from BIO-PSA® silicone, and 0.12 µg cm^-2 h^-1 from Sekisui polyacrylate matrices. In order to develop TDS with high content of fluid permeation enhancer propylene glycol, two different strategies were investigated. One strategy was the addition of hydroxypropyl cellulose (HPC) as thickening agent to Gelva matrices. This allowed for propylene glycol loading levels of up to 30%, resulting in transdermal AE fluxes of 0.09 µg cm^-2 h^-1. On the other hand, a fleece-laminated backing foil was loaded with the described permeation enhancer formulation and laminated with polyacrylate adhesive layer, resulting in transdermal AE fluxes of 0.06 µg cm^-2 h^-1. However, application of these TDSs on skin pretreated with permeation enhancers raised the fluxes to 2.6 µg cm^-2 h^-1 from Gelva/HPC and 0.46 µg cm^-2 h^-1 from fleece/Sekisui.     

The effect of clove oil on the transdermal delivery of ibuprofen in the rabbit by in vitro and in vivo methods

The study was designed to evaluate skin permeation enhancement effect of essential oils from Eugenia caryophyllata (clove oil) in rabbits and to compare the in vitro absorption and in vivo permeation using ibuprofen as a model drug. The in vitro results indicated a significant permeation enhancement effect of the clove oil. The group with 1% oil appeared to the flux (239 μg/cm²/hr), and 3% oil was 293 μg/cm²/hr to some extent similar with 2% azone group (327 μg/cm²/hr). The enhancement ratio of clove oil was 7.3. In vivo results also demonstrated that clove oil showed a significant permeation enhancement effect, but the enhancement of clove oil was relatively weak than in vitro. The group with 3% oil exhibited the higher value of area under the curve (AUC) of 80.8 μg/mL·hr, which was 2.4 times the high of control. The AUC value of 3% oil group was similar to that of 2% azone group (89.8 μg/mL·hr). The GC-MS results indicated eugenol and acetyleugenol identified from clove oil might mainly contribute to enhance in vitro and in vivo absorption of ibuprofen because of its large quantities (90.93%).     

Transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers

The effects of vehicles and penetration enhancers on the in vitro permeation of ondansetron hydrochloride (OS) across dorsal hairless mouse skins were investigated. Various types of vehicles, including ester, alcohol, and ether and their mixtures were used, and then a series of fatty acids and fatty alcohols were employed as enhancers. Among pure vehicles used, water and ethanol showed high permeation fluxes, which were 48.2 ± 23.7 and 41.9 ± 17.9 µg/cm² per h, respectively. Even though propylene glycol monocaprylate (PGMC) alone did not show a high permeation rate, the skin permeability of OS was increased by the addition of diethylene glycol monoethyl ether (DGME); the highest flux was achieved at 40% of DGME. Also, the combination of PGMC and ethanol (80:20) or PGMC and propylene glycol (PG) (60:40) increased the permeation flux by six- and two-fold, respectively, compared to PGMC alone. The synergistic enhancement was also obtained by using PG-oleyl alcohol (OAl) cosolvent. The greatest flux was attained by the addition of unsaturated fatty acids at 3% concentration to PG. The enhancement factors with the addition of oleic acid or linoleic acid to PG were about 1250 and 450, respectively. But saturated fatty acids failed to show a significant enhancing effect. When the PGMC-DGME (60:40) cosolvent system was used as a vehicle, all fatty acids, including unsaturated fatty acids, failed to show significant enhancing effects. The results indicate that the combinations of oleic acid, linoleic acid, or oleyl alcohol with PG, or PGMC-DGME (60:40) cosolvent could be used for the design of the OS transdermal system.     

Formulation,characterization and clinical evaluation of propranolol hydrochloride gel for transdermal treatment of superficial infantile hemangioma

The objective of the present study is to formulate and characterize propranolol hydrochloride (PPL?·?HCl) gel, and to evaluate the efficacy of this formulation in transdermal treatment for superficial infantile hemangioma (IH). The transdermal PPL?·?HCl gel was prepared by a direct swelling method, which chose hydroxypropyl methylcellulose (HPMC) as the matrix and used terpenes plus alcohols as permeation enhancer. Permeation studies of PPL?·?HCl were carried out with modified Franz diffusion cells through piglet skin. Our results pointed to that among all studied permeation enhancers, farnesol plus isopropanol was the most effective combination (Q_24, 6027.4?±?563.1?μg/cm², ER, 6.8), which was significantly higher than that of control gel (p?相似文献   

Damar Batu as a novel matrix former for the transdermal drug delivery: in vitro evaluation

Purpose: Damar Batu (DB) is a novel film-forming biomaterial obtained from Shorea species, evaluated in this study for its potential application in transdermal drug delivery system. Methods: DB was characterized initially in terms of acid value, softening point, molecular weight (M_w), polydispersity index (M_w/M_n), and glass transition temperature (T_g). Neat, plasticized films of DB were investigated for mechanical properties. The biomaterial was further investigated as a matrix-forming agent for transdermal drug delivery system. Developed matrix-type transdermal patches were evaluated for thickness and weight uniformity, folding endurance, drug content, in vitro drug release study, and skin permeation study. Results: On the basis of in vitro drug release and in vitro skin permeation performance, formulation containing DB/Eudragit RL100 (60 : 40) was found to be better than other formulations and was selected as the optimized formulation. IR analysis of physical mixture of drug and polymer and thin layer chromatography study exhibited compatibility between drug and polymer. Conclusion: From the outcome of this study, it can be concluded that applying suitable adhesive layer and backing membrane-developed DB/ERL100, transdermal patches can be of potential therapeutic use.     

Proniosomal gel-mediated transdermal delivery of bromocriptine: in vitro and ex vivo evaluation

Vesicular systems endow large opportunities for the transdermal delivery of therapeutics. The present study was designed to investigate the potential of a novel class of vesicular system ‘proniosome’ as a carrier for transdermal delivery of bromocriptine (BCT). Proniosome formulations were prepared by the coacervation-phase separation method and the influence of factors like surfactant type and its amount, lipid concentration, cholesterol amount and drug content were studied. Span 60 was the most appropriate surfactant, and yielded vesicle size and percentage encapsulation efficiency of 1.3 µm and 98.9%, respectively. The developed system was characterised w.r.t. morphology, transition temperature, drug release, skin permeation and skin irritancy. Proniosomes exhibited a sustained release pattern of BCT in vitro. Skin permeation study revealed high penetration of proniosomes with sustained release of BCT through rat skin. The optimised proniosomal formulation showed enhanced transdermal flux of 16.15 μg/cm²/h as compared to 3.67 μg/cm²/h for drug dispersion. The developed formulations were observed as non-irritant to the rat skin and were found as quite stable at 4 and 25 °C for 90 days w.r.t. vesicle size and drug content. The dried proniosomal formulation could act as a promising alternative to niosomes and preferably for transdermal delivery of BCT.     

Transfersomes--a novel vesicular carrier for enhanced transdermal delivery: development, characterization, and performance evaluation

This work describes the use of a novel vesicular drug carrier system called transfersomes, which is composed of phospholipid, surfactant, and water for enhanced transdermal delivery. The transfersomal system was much more efficient at delivering a low and high molecular weight drug to the skin in terms of quantity and depth. In the present study transfersomes and liposomes were prepared by using dexamethasone as a model drug. The system was evaluated in vitro for vesicle shape and size, entrapment efficiency, degree of deformability, number of vesicles per cubic mm, and drug diffusion across the artificial membrane and rat skin. The effects of surfactant type, composition, charge, and concentration of surfactant were studied. The in vivo performance of selected formulation was evaluated by using a carrageenan-induced rat paw edema model. Fluorescence microscopy by using rhodamine-123 and 6-carboxyfluorescein as fluorescence probe was performed. The stability study was performed at 4°C and 37°C. An in vitro drug release study has shown a nearly zero order release of drug and no lag phase. The absence of lag phase in comparison to liposomes and ointment is attributed to the greater deformability, which may account for better skin permeability of transfersomes. In vivo studies of transfersomes showed better antiedema activity in comparison to liposomes and ointment, indicating better permeation through the penetration barrier of the skin. This was further confirmed through a fluorescence microscopy study. Finally, it may be concluded from the study that complex lipid molecules, transfersomes, can increase the transdermal flux, prolong the release, and improve the site specificity of bioactive molecules.     

Preparation, evaluation, and NMR characterization of vinpocetine microemulsion for transdermal delivery

A novel microemulsion was prepared to increase the solubility and the in vitro transdermal delivery of poorly water-soluble vinpocetine. The correlation between the transdermal permeation rate and structural characteristics of vinpocetine microemulsion was investigated by pulsed field gradient nuclear magnetic resonance (PFG-NMR). For the microemulsions, oleic acid was chosen as oil phase, PEG-8 glyceryl caprylate/caprate (Labrasol®) as surfactant (S), purified diethylene glycol monoethyl ether (Transcutol P®) as cosurfactant (CoS), and the double-distilled water as water phase. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation. The effects of various oils and different weight ratios of surfactant to cosurfactant (S/CoS) on the solubility and permeation rate of vinpocetine were investigated. Self-diffusion coefficients were determined by PFG-NMR in order to investigate the influence of microemulsion composition with the equal drug concentration on their transdermal delivery. Finally, the microemulsion containing 1% vinpocetine was optimized with 4% oleic acid, 20.5% Labrasol, 20.5% Transcutol P, and 55% double-distilled water (w/w), in which drug solubility was about 3160-fold higher compared to that in water and the apparent permeation rate across the excised rat skin was 36.4 ± 2.1 µg/cm²/h. The physicochemical properties of the optimized microemulsion were examined for the pH, viscosity, refractive index, conductivity, and particle size distribution. The microemulsion was stable after storing more than 12 months at 25°C. The irritation study showed that the optimized microemulsion was a nonirritant transdermal delivery system.     

新型水溶性壳聚糖盐酸盐微球的制备与表征

以水溶性壳聚糖盐酸盐为原料,戊二醛为交联剂,采用乳化交联法制备了壳聚糖盐酸盐微球。通过多种理化手段检测及体外MG63细胞共培养对壳聚糖盐酸盐微球的形貌结构、尺寸大小、粒径分布、成球机理、结晶度、热稳定性及细胞相容性进行了测试及表征,并与普通酸溶性壳聚糖制备的微球进行比较。结果表明水溶性壳聚糖盐酸盐与戊二醛通过Schiff碱反应产生交联,易成球,球形圆整光滑;粒径分布较窄,粒径约为5～10μm;微球结晶度较低,其热稳定性较壳聚糖盐酸盐原料和酸溶性壳聚糖微球均有提高;细胞相容性良好。该微球表现出与酸溶性壳聚糖微球相似的理化性质,但因其原料为水溶性,微球制备条件更为温和,在药物载体研究领域有望得到更广泛的应用。     

Evaluation and controlled release characteristics of modified xanthan films for transdermal delivery of atenolol

The present study was performed to evaluate the possibility of using modified xanthan films as a matrix system for transdermal delivery of atenolol (ATL), which is an antihypertensive drug. Acrylamide was grafted onto xanthan gum (XG) by free radical polymerization using ceric ion as an initiator. Fourier transform infrared spectroscopy and differential scanning calorimetry indicated the formation of the graft copolymer. The obtained graft copolymer was loaded with ATL and films were fabricated by solution casting method for transdermal application. Various formulations were prepared by varying the grafting ratio, drug loading, and different penetration enhancers. The formulations prepared were characterized for weight, thickness uniformity, water vapor transmission rate, and uniformity in drug content of the matrix. All the thin films were slightly opaque, smooth, flexible, and permeable to water vapor, indicating their permeability characteristics suitable for transdermal studies. Fourier transform infrared spectroscopy and differential scanning calorimetry studies indicated no significant interactions between drug and polymer. Drug is distributed uniformly in the matrix but showed a slight amorphous nature. Drug-loaded films were analyzed by X-ray diffraction to understand the drug polymorphism inside the films. Scanning electron microscopic studies of the placebo and drug-loaded films demonstrated a remarkable change in their surface morphology. The skin irritation tests were performed in mice and these results suggested that both placebo and drug-loaded films produced negligible erythema and edema compared to formalin (0.8% v/v) as the standard irritant. The in vitro drug release studies were performed in phosphate buffer saline using a Keshary-Chien diffusion cell. Different formulations were prepared and variations in drug release profiles were observed. Release data were analyzed by using the Ritger and Peppas equation to understand the mechanism of drug release as well as the estimation of n values, which ranged between 0.41 and 0.53, suggesting a Fickian diffusion trend.     

In vitro release studies on matrix type transdermal drug delivery systems of naltrexone and its acetyl prodrug

Matrix type acrylic adhesive transdermal patches of naltrexone (NTX) and its 3-O-acetyl ester prodrug were prepared and evaluated for drug content, thickness, and in vitro release characteristics. Among the four DURO-TAK adhesive polymers (87-2516, 87-2054, 87-2501, and 87-2582) tested, 87-2516 proved to be the most suitable and compatible polymer for the transdermal delivery of NTX from NTX and prodrug patches. A linear relationship was observed for release flux (F) and cumulative amount (Mt) values versus 1%, 2%, and 3% drug loading at equimolar levels. The release of NTX from the patches showed a good correlation (R2>0.99) for Mt vs. square root t profiles, indicating that a Higuchian matrix diffusion mechanism of drug release from the transdermal adhesive patches was obtained. Overall, the amounts of NTX released from the prodrug patches were significantly higher than from the NTX patches, at all three drug loading levels.     

The effects of pressure-sensitive adhesives and solubilizers on the skin permeation of testosterone from a matrix-type transdermal delivery system

Matrix-type transdermal delivery systems of testosterone (TS) were formulated with three different pressure-sensitive adhesives (PSA). The effects of PSA, skin permeation enhancers, and solubilizers on the rat skin permeation rate of TS were systematically investigated. Without a solubilizer, the skin permeation rate of TS reached its maximum value when only 2% of TS was loaded in the matrix and the crystal formation in the matrix was very rapid and severe. Two surfactants differing in their hydrophile-lipophile balance (HLB) number were, therefore, considered. Span 80, which was of the lower HLB number, was more effective than Tween 80 in increasing the solubility, and thereby increasing the permeation rate of TS. Moreover, the concentrations of both the solubilizer and the skin permeation enhancer affected the skin permeation rate. Thus, the highest skin permeation rate (4.14 µg/cm²/hr) was achieved when 2% TS was loaded in DuroTak® 87-2516 together with 10% Span 80 and 3% dodecylamine, the permeation enhancer. In vivo study showed that the application of an experimental patch on rat abdominal skin resulted in a prompt and significantly higher plasma concentration of TS than that of a commercial product (Testoderm®) designed to apply on the scrotal skin. The area under the curve (AUC) increased linearly as the loading dose of TS increased up to 6%. Thus, based on these results, a non-scrotal matrix-type transdermal delivery system of TS could be developed.     

On the characterization of medicated plasters containing NSAIDs according to novel indications of USP and EMA: adhesive property and in vitro skin permeation studies

This work aims to establish if the assays recently introduced by EMA (Guideline on quality of transdermal patches-draft) and USP (Specific tests for transdermal delivery systems) to characterize transdermal patches (TP) are suitable for medicated plasters (MP). Six approved MP differing for type and characteristics of adhesive and backing layer were selected and characterized in terms of adhesive performances by tack, shear adhesion, peel adhesion and release liner removal tests and in vitro skin permeation. As far as the adhesive properties are concerned, the major drawback is related to the measurement of shear adhesion of MP made of an adhesive hydrogel and/or a stretchable backing layer which could be solved by reducing the applied load. Moreover, a concern on the mass balance prescribed by EMA draft for the acceptance of the results of in vitro penetration studies remains. Indeed, the acceptance range is narrow than that reported by Ph. Eur. requirement for uniformity of content. Finally, a novel calculation for evaluating the in vitro efficiency of MP in releasing the loaded drug through the skin was proposed.     

Synchronized and controlled release of metformin hydrochloride/glipizide from elementary osmotic delivery

Abstract

The combination of metformin hydrochloride (MTF) and glipizide (GLZ) is second-line medication for diabetes mellitus type 2 (DMT2). In the present study, elementary osmotic pump ( EOP) tablet is designed to deliver the combination of MTF and GLZ in a sustained and synchronized manner. By analyzing different variables of the formulation, sodium hydrogen carbonate is introduced as pH modifier to improve the release of GLZ, while ethyl cellulose acts as release retardant to reduce the burst release phase of MTF. A two-factor, three-level face-centered central composite design (FCCD) is applied to investigate the impact of different factors on drug release profile. Compared with conventional tablets, the EOP tablet demonstrates a controlled release behavior with relative bioavailability of 99.2% for MTF and 99.3% for GLZ. Data also shows EOP tablet is able to release MTF and GLZ in a synchronized and sustained manner both in vitro and in vivo.     

Enhanced stability and permeation potential of nanoemulsion containing sefsol-218 oil for topical delivery of amphotericin B

Aim: To characterize the enhanced stability and permeation potential of amphotericin B nanoemulsion comprising sefsol-218 oil at varying pH and temperature of aqueous continuous phase.

Methodology: Several batches of amphotericin B loaded nanoemulsion were prepared and evaluated for their physical and chemical stability at different pH and temperature. Also, a comparative study of ex vivo drug permeation across the albino rat skin was investigated with commercial Fungisome® and drug solution at 37?°C for 24?h. The extent of drug penetrated through the rat skin was thereby evaluated using the confocal laser scanning microscopy (CLSM).

Results and conclusions: The optimized nanoemulsion demonstrated the highest flux rate 17.85?±?0.5?µg/cm²/h than drug solution (5.37?±?0.01?µg/cm²/h) and Fungisome® (7.97?±?0.01?µg/cm²/h). Ex vivo drug penetration mechanism from the developed formulations at pH 6.8 and pH 7.4 of aqueous phase pH using the CLSM revealed enhanced penetration. Ex vivo drug penetration studies of developed formulation comprising of CLSM revealed enhanced penetration in aqueous phase at pH 6.8 and 7.4. The aggregation behavior of nanoemulsion at both the pH was found to be minimum and non-nephrotoxic. The stability of amphotericin B was obtained in terms of pH, optical density, globular size, polydispersity index and zeta potential value at different temperature for 90 days. The slowest drug degradation was observed in aqueous phase at pH 7.4 with shelf life 20.03-folds higher when stored at 4?°C (3.8 years) and 5-fold higher at 25?°C (0.951 years) than at 40?°C. The combined results suggested that nanoemulsion may hold an alternative for enhanced and sustained topical delivery system for amphotericin B.     

Simultaneous estradiol and levonorgestrel transdermal delivery from a 7-day patch: in vitro and in vivo drug deliveries of three formulations

A new drug-in-adhesive transdermal patch was developed to deliver both estradiol and levonorgestrel through the skin over a 7-day period, but at different rates. This report elucidates the in vitro and in vivo biopharmaceutical studies that were necessary during the development of this product. Three test patches had to be manufactured, all delivering estradiol at the same rate, but delivering levonorgestrel at three different rates so that a levonorgestrel dose response could be studied in the clinic. An in vitro hairless mouse skin model (HMS) using modified Franz diffusion cells was used to select the test products delivering levonorgestrel in the order of 1:2:3. HMS experiments also demonstrated that the presence of estradiol did not affect the flux of levonorgestrel. Two in vivo studies in postmenopausal women showed that at steady state (four weeks of once-weekly dosing) the three test products all delivered estradiol at comparable rates. Similarly, the levonorgestrel deliveries for the three test products were in the order expected. The target fluxes of both drugs were achieved in these three test products by varying the drug loads and patch size. That this approach was successful is evidence of the value of using the HMS penetration experiments in transdermal product development and should provide useful insights for other formulations having to develop complex systems. One of the test products is now marketed as Climara Pro^TM.