Enhanced percutaneous permeability of nicardipine hydrochloride by carvone across the rat abdominal skin

The purpose of this study was to investigate the effect of carvone on the permeation of nicardipine hydrochloride across the excised rat abdominal epidermis from 2% w/w hydroxypropyl cellulose (HPC) gel system. The HPC gel formulations containing nicardipine hydrochloride (1% w/w) and selected concentrations of carvone (0 to 12% w/w) were prepared, and evaluated for drug content, stability of the drug, and in vitro permeation of the drug through excised rat abdominal epidermis. The HPC gel was found to contain 99.98 to 101.6% of nicardipine hydrochloride, and the drug was found to be stable in the HPC gels. The permeation flux of nicardipine hydrochloride across rat epidermis was increased markedly by the addition of carvone to the HPC gels. A maximum flux of nicardipine hydrochloride (243.95.70 ± 1.90 µg/cm²/hr) was observed with an enhancement ratio of 7.9 when carvone was incorporated at a concentration of 12% w/w in the HPC reservoir system. The differential scanning calorimetry and Fourier transform-infrared data indicated that carvone increased the permeability of nicardipine hydrochloride across the rat epidermis by partial extraction of lipids in the stratum corneum. The results suggest that carvone may be useful for enhancing the skin permeability of nicardipine hydrochloride from transdermal therapeutic system containing HPC gel as a reservoir.     

Effects of some hydrophilic permeation enhancers on the absorption of bepridil through excised human skin

The permeation of Bepridil through excised human skin was measured from vehicles composed of various mixtures of aqueous buffer and the permeation enhancers ethanol, DMSO or DMF. Only DMSO was found to act as a true permeation enhancer for the drug, the magnitude of its action depending on its concentration in the vehicle. At concentrations greater than 50% DMSO the permeability coefficient of the drug was increased over and above that which could be accounted for by changes in partitioning of the drug between vehicle and skin. The effects of ethanol could be related to changes in the measured skin/vehicle partition coefficients of the drug. DMF showed a complicated, concentration dependent influence on permeation.     

Effects of some hydrophilic permeation enhancers on the absorption of bepridil through excised human skin

Abstract

The permeation of Bepridil through excised human skin was measured from vehicles composed of various mixtures of aqueous buffer and the permeation enhancers ethanol, DMSO or DMF. Only DMSO was found to act as a true permeation enhancer for the drug, the magnitude of its action depending on its concentration in the vehicle. At concentrations greater than 50% DMSO the permeability coefficient of the drug was increased over and above that which could be accounted for by changes in partitioning of the drug between vehicle and skin. The effects of ethanol could be related to changes in the measured skin/vehicle partition coefficients of the drug. DMF showed a complicated, concentration dependent influence on permeation.     

Evaluation of the percutaneous absorption of chlorpromazine from PLO gels across porcine ear and human abdominal skin

Objective: The overall objective of this work is to determine the percutaneous absorption of chlorpromazine hydrochloride from pluronic lecithin organogels (PLO gels) and verify the suitability of topically applied chlorpromazine hydrochloride PLO gels for use in hospice patients for relieving symptoms such as vomiting and nausea during the end stages of life.

Methods: PLO gels of chlorpromazine hydrochloride were prepared using isopropyl palmitate (IPP) or ricinoleic acid (RA) as oil phase. In vitro percutaneous absorption of chlorpromazine hydrochloride was assessed through porcine ear and human abdominal skin. Further, the theoretical steady state plasma concentration (C_ss) of chlorpromazine was calculated from the flux values.

Results: The pH, viscosity, and stability of both PLO gels prepared with IPP and RA were comparable. The thixotropic property of RA PLO gel was found to be better than that of IPP PLO gel. The permeation of chlorpromazine hydrochloride was higher from RA PLO gel than from IPP PLO gel and pure drug solution. Theoretical C_ss of chlorpromazine from pure drug solution, IPP PLO gel and RA PLO gel were found to be 1.05, 1.20, and 1.50?ng/ml, respectively. PLO gels only marginally increased the flux and theoretical C_ss of chlorpromazine.

Conclusion: From this study, it is clearly evident that PLO gels fail to achieve required systemic levels of chlorpromazine following topical application. Chlorpromazine PLO gel may not be effective in treating nausea and vomiting for hospice patients with swallowing difficulties.     

In vitro release and diffusion studies of promethazine hydrochloride from polymeric dermatological bases using cellulose membrane and hairless mouse skin

The study was designed to investigate the feasibility of developing a transdermal drug dosage form of promethazine hydrochloride (PMH). The in vitro release and diffusion characteristics of PMH from various dermatological polymeric bases were studied using cellulose membrane and hairless mouse skin as the diffusion barriers. These included polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), cross-linked microcrystalline cellulose, and carboxyl methyl cellulose sodium (Avicel CL-611), and a modified hydrophilic ointment USP. In addition, the effects of several additive ingredients known to enhance the drug release from topical formulations were evaluated. The general rank order for the drug release from these formulations using cellulose membrane was observed to be PEG > HMPC > Avicel CL-611 > hydrophilic ointment base. The inclusion of the additives had little or no effect on the drug diffusion from these bases, except for the hydrophilic ointment formulation containing 15% ethanol, which provided a significant increase in the drug release. However, when these formulations were studied for drug diffusion through the hairless mouse skin, the Avicel CL-611 base containing 15% ethanol exhibited the optimum drug release. The data also revealed that this formulation gave the highest steady-state flux, diffusion, and permeability coefficient values and correlated well with the amount of drug release.     

Percutaneous absorption of captopril from hydrophilic cellulose derivatives through excised rabbit skin and human skin

The purpose of this investigation was to evaluate the influence of percutaneous absorption of captopril from hydrophilic cellulose derivatives gel bases (carboxymethylcellulose sodium [CMC], hydroxypropylcellulose [HPC] and hydroxylpropylmethylcellulose [HPMC]. The effects of various types and concentrations of penetration enhancers on captopril percutaneous absorption from HPC gel through rabbit skin were evaluated and selected to obtain some optimal formulations for penetration study through human chest skin. Then the required flux (1488 microg/hr) for captopril transdermal drug delivery system to maintain the therapeutic minimum effective concentration through human skin was used to evaluate the development of the optimal formulations. The results indicated that the minimum administered areas for therapeutic minimum effective concentration of captopril (cap) gel containing decanol (dec) were 10.4 cm2 (5% cap, 7% dec) and 7.6 cm2 (7% cap, 7% dec). These areas were within acceptable range, so these formulations can possibly be developed for a transdermal drug 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.     

In vitro percutaneous absorption of genistein from topical gels through human skin

The objective of this study was to formulate genistein as a topical gel with various penetration enhancers for increased permeation and retention in human skin. The high performance liquid chromatography assay method was validated for precision and reproducibility. The intra-day and inter-day precision as represented by the coefficient of variation (CV) of the peak areas were <0.44% and <0.67%, respectively. Further, the reproducibility was demonstrated by the CV of the assay at different genistein concentrations, which were <1.64%. Genistein was subjected to various stress conditions to obtain basic information on the appropriate pH and aqueous vehicle for formulating topical gels. Genistein was highly stable under neutral and oxidative conditions, but degraded to highly polar and nonpolar compounds under basic and acidic conditions, respectively. Menthol produced a 9- and 22-fold increase in the flux and skin retention of genistein, respectively, after 24?h of gel application as compared with the control (no enhancer). Cineole showed an approximately 7-fold increase in flux, but skin retention did not increase significantly. Transcutol increased the flux and skin retention of genistein by 5- and 7-fold, respectively. When Transcutol was formulated with Lauroglycol, there was a 13- and 9-fold increase in the flux and skin retention, respectively. Incorporation of penetration enhancers into the topical gel increased the skin permeation of genistein, so that the target delivery rate for its therapeutic effects can be achievable based on the in vitro human skin data generated in this study.     

In vitro percutaneous absorption of genistein from topical gels through human skin

The objective of this study was to formulate genistein as a topical gel with various penetration enhancers for increased permeation and retention in human skin. The high performance liquid chromatography assay method was validated for precision and reproducibility. The intra-day and inter-day precision as represented by the coefficient of variation (CV) of the peak areas were <0.44% and <0.67%, respectively. Further, the reproducibility was demonstrated by the CV of the assay at different genistein concentrations, which were <1.64%. Genistein was subjected to various stress conditions to obtain basic information on the appropriate pH and aqueous vehicle for formulating topical gels. Genistein was highly stable under neutral and oxidative conditions, but degraded to highly polar and nonpolar compounds under basic and acidic conditions, respectively. Menthol produced a 9- and 22-fold increase in the flux and skin retention of genistein, respectively, after 24?h of gel application as compared with the control (no enhancer). Cineole showed an approximately 7-fold increase in flux, but skin retention did not increase significantly. Transcutol increased the flux and skin retention of genistein by 5- and 7-fold, respectively. When Transcutol was formulated with Lauroglycol, there was a 13- and 9-fold increase in the flux and skin retention, respectively. Incorporation of penetration enhancers into the topical gel increased the skin permeation of genistein, so that the target delivery rate for its therapeutic effects can be achievable based on the in vitro human skin data generated in this study.     

Effect of lateral diffusion on the percutaneous absorption of micro-particles

The rate of percutaneous absorption of micro-particles is very important due to its effects on human health. In this study, a new approach is proposed to investigate both the lateral and the longitudinal diffusions during the absorption of a micro-particle. The results of the current 2D model are compared with the results of a previous 1D model. According to the results, the influence of lateral diffusion on the rate of percutaneous absorption is important, especially for the lipohilic materials. On the other words, the difference between the results of the two models is more significant, at lower values of the ratio of viable-epidermis-diffusivity to the stratum-corneum-diffusivity (D_VE/D_SC), or at lower values of the viable epidermis to the stratum corneum partition-coefficient (k_VE/k_SC). For instance, when D_VE/D_SC equals to 1 and k_VE/k_SC is 0.33, for a particle with a radius of 10?µm, the steady-state-molar-flux estimated by the 2D model is 2.37 times greater than that estimated by the 1D model. Hence, the lateral diffusion should be taken into account in the percutaneous absorption of micro-particles.     

The effects of pH and chemical enhancers on the percutaneous absorption of indomethacin

The absorption of indomethacin through excised hairless mouse skin from aqueous solution was determined at different pH values. We found that the rate of its absorption increased with decreasing pH. Its distribution coefficient in octanol-phosphate buffer was also pH dependent. Furthermore, the change of permeability coefficient with pH correlated well with the distribution coefficient by a two-degree polynominal equation. The individual incorporation of five chemical enhancers into a polymeric patch at optimal pH resulted in an increase or decrease in the in vitro absorption rate and in the amount absorbed during the first 24 hours depending on the enhancer and its concentration used. Both sodium cholate at 4 and 6 %, and sodium lauryl sulfate at 4 % increased the absorption rate about four to seven times compared to the control. The in vivo absorption using rabbits from patch containing 6% sodium cholate also showed an increase in rate and the AUC compared to that from the control; however, the extent of the increase was much less compared to that obtained from the in vitro study. The stability of this drug in aqueous solution was also studied as a function of pH. It was confirmed that indomethacin was more stable at lower pH values. The pH-rate constant profile also indicated a specific base catalysis for its degradation at pH above 6.5. Due to its small solubilities at lower pHs, an optimal pH near 5 was suggested for the preparation of a transdermal delivery system for indomethacin.     

Effect of urea and pantothenol on the permeation of progesterone through excised rat skin from polymer matrix systems

Standard in vitro permeation experiments, using excised rat skin, were carried out to establish the release profile and permeation behavior of progesterone from polymethacrylate (PMA), polyvinylpyrrolidon (PVP), and polyvinylalcohol (PVA) transdermal systems. Data obtained show significant differences in release characteristics from each polymer systems. The greatest amount of progesterone was released from the PVA system. The influence of urea and pantothenol on progesterone release was also investigated. Release data were compared with the permeation rates of progesterone across excised rat skin. The highest permeation rates were measured from PVA matrices containing 5% urea (860 ± 138 μg/cm²; cumulative amount permeated in 24 hr) and from PVP matrices containing 6% pantothenol (660 ± 73 μg/cm²; cumulative amount permeated in 24 hr). A good correlation between release and permeation data was found with the polymer matrices; however, this was not the case when additives were included.     

Transdermal delivery of tadalafil. I. Effect of vehicles on skin permeation

Transdermal delivery that avoids the presystemic disposition can provide an alternative to oral administration of tadalafil. Accordingly, the aim of this study was to select the best vehicle as the first step in optimization of tadalafil transdermal delivery. The vehicles were used neat or in selected binary combinations and were evaluated for drug solubilization and transdermal delivery. The drug solubility in pure vehicles were ranked as polyethylene glycol (PEG) 400 > propylene glycol (PG) > ethanol > ethyl oleate (EO) > isopropyl myristate (IPM) > water. The solubility in binary systems containing ethanol at 2:1 ratios with EO or IPM was greater than that obtained with pure ethanol, EO, or IPM. This effect could be due to the cosolvency effect. The transdermal drug delivery from pure vehicles was ranked as IPM > EO > ethanol > PG > PEG > water. The delivery from binary mixtures of ethanol with either IPM or EO was higher than that obtained from pure solvents with the delivery increasing with increasing ethanol concentration in the mixtures. The delivery from binary mixtures was synergistic rather than additive. The study thus demonstrated a potential of tadalafil transdermal delivery. Binary combinations of ethanol with either IPM or EO provided the first step forward toward the development of transdermal delivery system for tadalafil.     

The effect of mixed-solvent and terpenes on percutaneous absorption of meloxicam gel

The purpose of the present study was to develop the meloxicam transdermal dosage form. The response surface methodology was used to obtain an appropriate mixed-solvent system of pH-7.4 buffer and ethanol for preparing meloxicam hydrogel. The enhancement effects of terpenes on drug precautious absorption were evaluated via in vitro and in vivo study. The result showed that the solubility of meloxicam was dependent on the pH value of buffer solution. The mixed-solvent system of pH-7.4 buffer and ethanol had a synergistic effect on the increase of drug solubility. The highest solubility was obtained in the ratio of 50/50 pH 7.4 buffer/ethanol. A series of terpenes were used as enhancer for improving the penetration rate of meloxicam. The penetration rates were significantly increased by about 70-593 fold and the lag times were shortened from 7.92 to 0.17 hr by enhancer incorporation. Among these terpenes, menthol showed the greatest effect. In vivo penetration study, the AUC(48h) was increased by about 1.7 fold by the addition of 5% menthol as enhancer.     

In vivo absorption study of ritodrine hydrochloride in the buccal administration to rats

Background: Although ritodrine (RD)-hydrochloride (HCl), named RD-HCl, is widely used in the treatment of premature labor by intravenous prolonged infusion or frequent oral dosing of tablets, those administrations often lower patients’ quality of life (QOL) or cause undesirable side effects, such as tachycardia; therefore, in this study, the potential usefulness of buccal administration as a novel administration method was examined in vivo.

Method: First, the HPLC method was assessed for the determination of plasma RD concentration. Then, after RD-HCl solution in saline was administered intravenously (1?mg/kg), intragastrically (10?mg/kg) or buccally (10?mg/kg) in rats, the plasma concentration–time profiles were investigated, and the absorption extent and rate compared.

Results: The present modified determination method by HPLC with fluorescence detection (Ex. 278?nm, Em. 306?nm) was suitable to analyze the plasma level at 8–200?ng/mL. Buccal administration gave the best plasma concentration–time profile for maintenance of an effective plasma level and fewer side effects. Absorption rates calculated by deconvolution also supported better sustained absorption in buccal dosing.

Conclusion: Buccal application of RD-HCl was demonstrated to be a potentially useful dosing method in the treatment of premature labor with RD-HCl.     

Enhancing effects of chitosan and chitosan hydrochloride on intestinal absorption of berberine in rats

Berberine chloride (BBR) is a plant alkaloid that has been used for centuries for treatment of inflammation, dysentery, and liver diseases. It is poorly absorbed from the gastrointestinal (GI) tract and its various clinical uses are limited because of its poor bioavailability. The object of the present study was to investigate the absorption enhancing effect of chitosan on BBR. Mixtures of BBR and chitosan were prepared and the absorption enhancement was investigated in rats. The results showed a dose-dependent absorption enhancement produced by chitosan. Formulations containing 0.5%, 1.5%, and 3.0% chitosan resulted in improvement of AUC_{0–36 h} values by 1.9, 2.2, 2.5 times. The absorption enhancing ability of chitosan may be due to its ability to improve the BBR paracellular pathway in the intestinal tract. Chitosan hydrochloride, a salt of chitosan, was also investigated in this study. However, the addition of 2.0% and 3.3% chitosan hydrochloride to BBR solution did not produce any increase in either C_max or AUC_{0–36 h} of BBR. Subsequent solubility studies suggested that the reduced berberine chloride solubility in chitosan hydrochloride may limit the enhancement ability. This study showed that the optimum formulation producing the highest BBR absorption is the BBR solution containing 3.0% chitosan.     

Enhancing effects of chitosan and chitosan hydrochloride on intestinal absorption of berberine in rats

Berberine chloride (BBR) is a plant alkaloid that has been used for centuries for treatment of inflammation, dysentery, and liver diseases. It is poorly absorbed from the gastrointestinal (GI) tract and its various clinical uses are limited because of its poor bioavailability. The object of the present study was to investigate the absorption enhancing effect of chitosan on BBR. Mixtures of BBR and chitosan were prepared and the absorption enhancement was investigated in rats. The results showed a dose-dependent absorption enhancement produced by chitosan. Formulations containing 0.5%, 1.5%, and 3.0% chitosan resulted in improvement of AUC(0-36 h) values by 1.9, 2.2, 2.5 times. The absorption enhancing ability of chitosan may be due to its ability to improve the BBR paracellular pathway in the intestinal tract. Chitosan hydrochloride, a salt of chitosan, was also investigated in this study. However, the addition of 2.0% and 3.3% chitosan hydrochloride to BBR solution did not produce any increase in either C(max) or AUC(0-36 h) of BBR. Subsequent solubility studies suggested that the reduced berberine chloride solubility in chitosan hydrochloride may limit the enhancement ability. This study showed that the optimum formulation producing the highest BBR absorption is the BBR solution containing 3.0% chitosan.     

基于吸收光谱技术的皮肤胆固醇无创检测系统设计

利用STM32微处理器,设计了一种基于吸收光谱技术的皮肤胆固醇无创检测系统,通过微型光谱仪获得有色产物的吸收光谱信息,间接得到人体皮肤胆固醇相对含量。本系统设计了一款高精度可调LED恒流源,LED光强的波动范围控制在±1%以内。还设计了一种结构简单、试剂用量少、不需要确切的检测试剂体积的液体限位装置,实现被测液体浓度的准确测量。通过检测梯度浓度CuSO4溶液,验证了系统应用于不同浓度溶液定量检测的准确性。采用本系统对动脉粥样硬化性疾病患者和对照人群的皮肤胆固醇进行检测,检测结果在统计学上有显著性差异,初步验证系统可用于人体皮肤胆固醇的检测。     

Effects of excited-state absorption on two-photon absorbing materials

Many chromophores with a large two-photon absorptive cross section are hybrid materials where the two-photon absorption (TPA) is coupled to an excited-state absorption (ESA). We develop a numerical technique to investigate hybrid two-photon processes in nonlinear absorbers. Our numerical method compares well with published results. In addition to customary calculation of the transmission curve, we demonstrate the importance of the ESA following the TPA, which may cause significant temporal and radial distortion. We also show that improvements in the transmission can result in significant radial and temporal pulse distortion, which may actually reduce the material effect.