Feasibility of transdermal delivery of prazosin hydrochloride

Preformulation studies were conducted to determine the feasibility of a transdermal dosage form of prazosin hydrochloride (PZHC1). A target PZHC1 skin flux of 6.3 μg/cm²/h was set to attain a steady-state plasma concentration of 10 ng/ml (from a 20-cm² skin area). The octanol/water partition coefficient of the drug and its solubility in water, phosphate-buffered saline (pH 7.4), and propylene glycol were measured. PZHC1 flux through human cadaver skin was determined with and without 3% (w/v) azone as a penetration enhancer. The epidermis was found to be the rate-limiting barrier for the permeation of PZHC1 through the human cadaver skin. Transdermal delivery of prazosin may be feasible with a suitable penetration enhancer.     

Synthesis and evaluation of N-acetylprolinate esters - novel skin penetration enhancers

A series of N-acetylproline esters (alkyl side chain length, 5-18) were synthesized and tested for potential skin penetration enhancement activity using modified Franz diffusion cells and hairless mouse skin as the penetration barrier. Benazepril and hydrocortisone were used as model drugs and were applied as saturated solutions in propylene glycol. The enhancers were added at a concentration of 5% (w/v). Drug flux, permeability coefficient and enhancement ratios for permeability coefficient were determined. Azone was used as the positive control. While all the compounds tested increased the skin penetration of hydrocortisone, the 5- and 8- carbon esters had no significant effect on the skin penetration of benazepril. The highest fluxes were obtained with 11, 12, and 18-carbon esters and they were comparable to Azone. There was no significant difference between the fluxes obtained with 2 and 5% (w/v) concentrations of the 12-carbon ester on hydrocortisone permeation. The 16-carbon ester, where ethanol was used as a cosolvent, significantly increased the fluxes of both the drugs compared to the control. Differential scanning calorimetric studies suggested that the enhancers may be acting on the lipids of the stratum corneum and their effect was similar to that of Azone. The membrane/vehicle partition coefficient studies indicated an increase in benazepril partition coefficient with enhancer treatment compared to the control. Maximum flux increase was obtained with the 11 and 12 carbon (alkyl chain length) esters for both benazepril and hydrocortisone. The 18- carbon ester which has a cis-double bond in the alkyl side chain, also increased the flux significantly.     

The effect of sorption promoters on percutaneous permeation of a model zwitterion baclofen

In vitro percutaneous penetration of baclofen, a model zwitterion, in the presence of penetration enhancers was investigated to better characterize a porous polar pathway of diffusion across the stratum corneum. The following sorption promoters were studied: DMSO, urea, propylene glycol (PG), sodium lauryl sulphate (SLS), ethanol 95%, Azone, oleic acid (OA) and OA/PG system. No significant increase of penetration or skin accumulation of baclofen was observed when DMSO, urea, PG, Azone or OA were used. The presence of SLS or OA/PG in the vehicle resulted in high penetration rates and uptake of baclofen but this effect was observable only after 30 h and was accompanied with signs of the barrier damage. Ethanol 95% was the only vehicle which promoted baclofen penetration despite its lower solubility in this solvent which is attributed to new pore formation. Penetration rate and skin accumulation of the zwitterion depend on its solubility in the vehicle.     

Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin

Mannitol, hydrocortisone and progesterone were selected as model penetrants to assess the mode of action of eight potential penetration enhancers in human skin. Their partition coefficients, octanol: water and stratum corneum: water were measured and correlated with their postulated routes of penetration through human skin. The results suggest that mannitol penetrated via a polar route, hydrocortisone by a mainly lipid route and progesterone via a lipid pathway but its penetration rate was probably affected by aqueous layers. From permeation studies through cadaver skin in which an in-vivo mimic method was used, it was concluded that the penetration enhancers fell into three main categories: solvents which enhanced permeation of polar and non-polar compounds e.g. 2-pyrrolidone, N-methylpyrrolidone, N-methylformamide and propylene glycol plus Azone; enhancers which preferentially affected the polar route e.g. propylene glycol plus decylmethylsulphoxide, and accelerants which mainly modified the non-polar route e.g. propylene glycol plus oleic acid, propylene glycol alone and, to a limited extent, water.     

Studies on the In-vitro Percutaneous Penetration of Indomethacin from Gel Systems in Hairless Mice

The influence of co-solvents on the in-vitro percutaneous penetration of indomethacin from gel systems was studied using a simplex lattice experimental design. Gel formulations were prepared by gelling the vehicle mixture of water, either alcohol or isopropanol and either propylene glycol or PEG 400 with 1% w/w Carbomer 940. Hairless mouse skin was employed as the barrier in a Franz-type diffusion cell. The penetration rates at steady state for seven formulations were fitted to a polynomial equation based on this simple lattice method and a three-dimensional plot was constructed. The formulation having the maximal penetration rate was determined to be the vehicle with a solvent ratio of water: alcohol: propylene glycol equal to 15:33:52, and which possessed a solubility parameter of 15 and a drug solubility of around 10 mg mL^?1. When the solubility parameter of the vehicle was > 15, the drug solubility increased. However, the penetration rate decreased with an increasing solubility parameter. For those vehicles with a solubility parameter < 15, both the drug solubility and the penetration rate decreased with a decrease in the solubility parameter. There was shown to be an approximately 20-fold increase in the relative enhancement factor when using both alcohol and isopropanol, but only a threefold increase for both propylene glycol and PEG 400, when compared with water.     

Improvement of clonazepam release from a Carbopol hydrogel.

The performance of Tween 80, Tween 60, oleic acid, oleyl alcohol and Azone as enhancers of clonazepam permeation from a Carbopol hydrogel through a cellulose nitrate membrane was investigated. The effect of incorporating methyl beta-cyclodextrin (DS 1.8) in combination with clonazepam as a solid phase into some vehicles was also tested. In vitro release studies were carried out with a Sartorius apparatus and the following parameters were evaluated: drug solubility in the vehicle; partition coefficient of the drug between lauryl alcohol (the solvent which impregnates the membrane) and the vehicle; steady state flux; permeability constant; diffusion coefficient; lag time. The release kinetics followed a nearly zero-order pattern, although the diffusion-controlled mechanism might also have been operative. Maximum drug release (2.5 times that of the gel base) was achieved for the formulation containing clonazepam and methyl beta-cyclodextrin in a 1:1 (mol/mol) ratio as a solid phase, in a vehicle composed of water, propylene glycol, Tween 80 and Azone at a mass fraction of 43%, 50%, 2% and 5%, respectively.     

Differences in penetration-enhancing effect of Azone through excised rabbit, rat, hairless mouse, guinea pig and human skins

The transdermal delivery of dihydroergotamine (DHE), from propylene glycol formulations with and without 6.0% laurocapram (Azone), and the penetration enhancing effect of Azone were evaluated in vitro on excised rabbit, rat, hairless mouse, guinea pig and human skins utilizing improved Franz diffusion cells. The steady-state flux of DHE from the propylene glycol formulation without Azone were 0.045, 0.270, 0.395, 0.128 and 10.035 μg/cm² per h across excised human, rat, guinea pig, rabbit and hairless mouse, respectively. Under the influence of the enhancer, Azone increased DHE penetration through excised skin of the various species used in this study in the following order: rabbit skin > human skin > rat skin > guinea pig skin > hairless mouse skin. The maximum enhancement factor of Azone (251.47) was obtained across rabbit skin and the minimum enhancing effect (14.44) was observed in the case of hairless mouse skin. The enhancement factor of Azone across human skin was 54.56. These results show that animal skins are poor models for human skin under the conditions used. The lag time of DHE, from the propylene glycol formulation containing 6.0% Azone, through human skin was longer than the lag times across all other skin species tested in this investigation.     

Percutaneous Absorption of Nicardipine and Ketorolac in Rhesus Monkeys

Vehicle effects on the percutaneous absorption of nicardipine base, nicardipine hydrochloride, ketorolac acid, and ketorolac tromethamine were determined using the rhesus monkey as an in vivo model for human skin penetration. Vehicles investigated included blends of propylene glycol, trimethylene glycol, ethanol, Azone, Tween 20, water, and long-chain fatty acids. Formulations were prepared such that the compound dose, application area, and percentage saturation of the compound in the vehicle were held constant. Variations in absorption of the compounds were therefore attributable to vehicle effects. Each formulation was applied to three monkeys for a period of 24 hr using 10 Hill Top Chambers. Plasma samples were taken at appropriate intervals for 36 to 48 hr. The results indicated that trimethylene glycol and Tween 20 did not enhance absorption of the test compounds despite claims by other investigators. Azone and ethanol provided moderate enhancement of both the rate and the extent of absorption, while long-chain fatty acids in combination with propylene glycol significantly enhanced penetration. In general, higher fluxes were observed with the more lipophilic compounds nicardipine base and ketorolac acid as compared to the hydrochloride and tromethamine salts.     

氯诺昔康凝胶剂的研制

目的制备氯诺昔康凝胶剂,考察其体外经皮渗透性。方法采用紫外分光光度法测定氯诺昔康的表观溶解度和油水分配系数,采用Franz扩散池考察载药凝胶剂的体外经皮渗透性,以6 h累积渗透量为指标,采用正交试验设计筛选最佳处方,探讨了卡波姆浓度、氮酮及丙二醇用量对氯诺昔康凝胶剂经皮渗透的影响,并考察其局部刺激性。结果氯诺昔康在水、pH 6.8和pH 7.4磷酸盐缓冲液中的表观溶解度分别为8.65,86.0和324.0μg/mL,油水分配系数为1.52;正交试验优化的最佳处方为:含0.75%卡波姆、30%丙二醇、4%月桂氮卓酮。制备的凝胶剂外观细腻,黏度适宜,pH值为6.8~7.0,体外经皮渗透实验结果符合零级动力学方程,家兔各涂药部位无水疱、疹块、红肿等现象。结论氯诺昔康凝胶剂制备工艺简单,质量可控。     

促渗剂对奥沙普秦体外经皮渗透的影响

目的 研究几种常用促渗剂对奥沙普秦体外经皮渗透的影响。方法 用紫外分光光度法检测浓度,采用改进Franz扩散池,比较几种常用促渗剂对奥沙普秦渗透速率的影响。结果 氮酮(Azone)单独使用不能明显提高奥沙普秦的渗透速率(P>0.05),而丙二醇、薄荷醇、Azone 丙二醇(1:1)、丙二醇 薄荷醇(1:1)能显著提高奥沙普秦的渗透速率(P<0.01)。结论 丙二醇、薄荷醇、Azone 丙二醇(1:1)、丙二醇 薄荷醇(1:1)可作为促渗剂用于奥沙普秦经皮吸收制剂。     

Terbutaline Transdermal Delivery: Preformulation Studies and Limitations of In-vitro Predictive Parameters

A transdermal dosage form of terbutaline may be useful to prevent nocturnal wheezing by providing prolonged duration of action. It will also improve patient compliance and bioavailability. Controlled input of the drug would be an additional advantage as this will reduce the intersubject variablity. Preformulation studies were conducted to determine the feasibility of a transdermal dosage form of terbutaline. The drug solubility in propylene glycol was 6.3 mg mL^?1. The apparent partition coefficient (n-octanol/deionized-water, pH 6.5) of terbutaline was 0.03. A pH-partition coefficient (octanol/buffer) profile indicated that the partition coefficient values were 0.02, 0.05 and 04 in buffers of pH 3, 7.4 and 9, respectively. The required drug flux through the human skin to attain therapeutic concentrations in the blood was calculated to be 3.3 μg cm^?2 h^?1 for a 10-cm² transdermal delivery system. Rabbit, guinea-pig and human skin was tested as the penetration barrier using modified Franz diffusion cells. Terbutaline flux values through the rabbit and guinea-pig skin were 8.3 and 7.7 μg cm^?2 h^?1, respectively. The flux through human full-thickness skin and human epidermis were 0.6 and 3.6 μg cm^?2 h^?1. Azone (3% w/v), a skin penetration enhancer, significantly increased the drug flux through all the membranes tested. Based on these studies, transdermal delivery of terbutaline appears to be promising.     

改善美洛昔康体外经皮渗透的研究

目的:研究几种常用促渗剂对美洛昔康体外经皮渗透的影响,改善美洛昔康体外经皮.方法:用紫外分光光度法检测浓度,采用改进Franz扩散池,比较几种常用促渗剂对美洛昔康渗透速率的影响.结果:氮酮(Azone)单独使用不能明显提高美洛昔康的渗透速率(P>0.05),而丙二醇.薄荷醇、丙二醇 Azone(1:1),丙二醇 薄荷醇(1:1)能显著提高美洛昔康的渗透速率(P<0.01).结论:丙二醇、薄荷醇、丙二醇 Azone(1:1)、丙二醇 薄荷肆(1:1)可作为促渗剂用于美洛昔康经皮吸收制剂.     

Vehicle effect on topical drug delivery. III. Effect of Azone on the cutaneous permeation of metronidazole and propylene glycol

The ability of Azone (1-dodecylazacycloheptan-2-one), a novel penetration enhancer, to increase the percutaneous delivery of metronidazole has been investigated, across full thickness human skin in vitro. A finite dose technique was used employing several vehicles. Azone at a concentration of 1% was found to be as effective as 5% and 10% concentrations in achieving enhanced transport of metronidazole. The presence of propylene glycol was found to be necessary for maximal enhancement, and the penetration of this compound was also found to be markedly enhanced by Azone. The delivery of metronidazole within the first 20 h of the experiments was increased about 25 times in the presence of 1% Azone. Repeated doses of the drug after a single dose of Azone indicated that the effect of Azone on the skin remains after several days.     

透皮促进剂对白花前胡甲素体外经皮渗透的影响

目的:考察透皮促进剂对白花前胡甲素(dl-praeruptorin A,Pd-Ia)体外经皮渗透的影响。方法:采用改进的Franz扩散池,以大鼠离体皮肤为渗透屏障,用高效液相色谱法对Pd-Ia进行含量测定,考察月桂氮酮(Azone)及1%Azone与不同浓度丙二醇(PG)混合物对Pd-Ia透皮吸收的影响。结果:使用Azone对Pd-Ia有促透作用,1%Azone效果较好,平均渗透速率达到4.064μg.cm-2.h-1;1%Azone与15%PG合用促透效果最好,平均渗透速率达到4.889μg.cm-2.h-1,且与单用1%Azone有显著性差异(P<0.05)。结论:1%Azone与15%PG合用时,含0.5%Pd-Ia溶液体外渗透具有最大促透效果,体现出协同作用。     

Use of an in Vitro Model for the Assessment of Muscle Damage from Intramuscular Injections: in Vitro-in Vivo Correlation and Predictability with Mixed Solvent Systems

The potential of binary mixtures of propylene glycol–water, ethanol–water, and polyethylene glycol 400–water to cause skeletal muscle damage (myotoxicity) following intramuscular injection was examined with an in vitro model using the isolated rat muscle. At moderate concentrations (20–40%, v/v) of the organic cosolvent, the order of myotoxicity was propylene glycol > ethanol polyethylene glycol 400. The in vitro results were then compared with in vivo toxicity in rabbits after injection of normal saline, 40% (v/v) polyethylene glycol 400, 40% (v/v) propylene glycol, indocyanine green in normal saline, and indocyanine green in 40% (v/v) propylene glycol. Employing the area under the creatine kinase activity curve from 0 to 72 hr as the index of skeletal muscle damage, an excellent in vitro–in vivo correlation was observed. The basic myotoxicity relationships obtained from the binary cosolvent systems were then used to examine the myotoxicity of ternary organic cosolvent mixtures. Several mixed solvent systems with the same theoretical molar solubilization power for a model compound, diazepam, were selected to determine (1) if myotoxicity can be reduced by changing the composition of the ternary mixtures and (2) if myotoxicity of the individual components is additive. For the solvent systems containing propylene glycol, ethanol, and water, the total myotoxicity equaled the sum of the individual myotoxicity of each component. In contrast, for the solvent systems containing polyethylene glycol 400, the total myotoxicity was only half of the sum of individual toxicities. These results suggest that polyethylene glycol 400 in mixed cosolvent systems might have a protective effect on the myotoxicity generated by intramuscular injections.     

The Effect of Ultrasound on the in Vitro Penetration of Ibuprofen Through Human Epidermis

The objective of this study was to develop an in vitro method to investigate the effect of ultrasound on the in vitro absorption of ibuprofen from a propylene glycol/water vehicle through human epidermis. A diffusion cell was modified so ultrasound could be applied to the vehicle and skin. Since ultrasound can increase the temperature underneath the area of application, control representing temperature effects ran concurrently to the ultrasound experiment. The results demonstrate that ultrasound can increase the penetration of ibuprofen through human skin. This increase in diffusion was greater than for controls where an equivalent increase in temperature was utilized. The results also indicate that evaporation of vehicle components may alter the skin/vehicle partition coefficient, decreasing the effects of ultrasound on the penetration of ibuprofen through the skin.     

Influence of propylene glycol as cosolvent on mechanisms of drug transport from hydrogels

The in vitro penetration of topical glucocorticoids (GC) betamethasone 17-valerate (BMV), hydrocortisone 17-butyrate (HCB) and hydrocortisone (HC) into an artificial lipid acceptor and excised human skin was examined using binary hydrogels with varying propylene glycol (PG) content. The relationship between the physicochemical properties of the model drugs in binary PG/water mixtures and the rate and extent of their penetration into artificial lipid membranes was studied. As a function of the drug solubility and partition behavior between lipid acceptor and PG/water mixtures, two directions were found in which PG affects the penetration of the GCs used. The lipophilic BMV, providing a higher solubility in the acceptor lipid than in PG/water mixtures of the formulations, penetrates thermodynamically controlled. In this case, PG acts only as cosolvent. For the more hydrophilic HC with higher solubilities in PG/water mixtures than in the acceptor medium, the amount penetrated increases with increasing PG content of the formulation. This result is surprising because of the expectation that the rate and extent of penetration decrease with decreasing partition coefficients. PG penetrates rapidly into the artificial acceptor and into excised human skin. It acts as both cosolvent and enhancer. In the case of HC transport, the enhancer effect is supposed to be a solvent drag effect of PG. HCB seems to penetrate thermodynamically controlled up to 40% PG. However, if PG contents of 60 and 80% are used in the gels the drag transport mechanism dominates. The results obtained from the studies with the lipophilic acceptor membranes were confirmed using excised human skin.     

自制复方特比萘酚软膏渗透促进剂的研究

目的 筛选并确定自制复方特比萘酚软膏中的渗透促进剂.方法 采用体外经皮渗透试验,使用立式Franz扩散池,接收液为60％聚乙二醇400-40％生理盐水,渗透膜为SD大鼠腹部皮肤,筛选最适渗透促进剂.结果10％丙二醇对复方特比萘芬软膏的促渗作用明显大于15％丙二醇,对比氮酮和丙二醇的促渗效果,10％丙二醇优于3％氮酮.结...     

胰岛素体外透皮特性研究

目的 考察胰岛素透皮吸收特性及透皮促进剂对其透皮行为的影响。方法 通过V-C扩散池，用紫外分光光度法测定胰岛素的透皮吸收动力特性及透皮促进剂的促进作用。结果 胰岛素经离体小鼠、家兔、大鼠和人体皮肤的渗透系数分别为16．37，17．54，8．23和9．15。而氮酮(Azone)、冰片、油酸有明显的促透作用，其中3％的Azone和2％的冰片使渗透系数分别增加了4．9和6．1倍。结论 胰岛素在大鼠皮肤中渗透系数与人体皮肤接近，冰片和Azone具有促进药物渗透作用。     

Effect of propylene glycol,Azone and n-decylmethyl sulphoxide on skin permeation kinetics of 5-fluorouracil

The effect of propylene glycol (PG), azone (LDA) and n-decylmethyl sulfoxide (LDB) on the permeation course of fluorouracil through the hairless mouse skin was studied. Steady-state fluxes and permeability coefficients were measured in buffer solutions and in systems containing the enhancing agents. The permeation rates of fluorouracil have been shown to be highly pH dependent in the pH range of 5–9, the rate decreases with an increase in pH. The solubility of fluorouracil in pure propylene glycol at equilibrium measured by the solubility method was found to be 2.2 mg · ml^?1 at 25°C which is a relatively low value as compared to the solubility in water. The effect of various concentrations of propylene glycol in aqueous donor solutions on the drug permeation rate was examined at pH's 5.7 and 9.0. It was found that propylene glycol decreases the permeation flux when increasing concentrations are added to the aqueous pH 5.7 system; however, at pH 9, a strong enhancement effect was shown. PG was also found to decrease the drug reservoir in the hairless mouse skin e.g. 8.4 and 2.8 mg · (mg skin)^?1 for buffer pH 9 and PG/aqueous solution pH 9 systems, respectively. The concentration dependent enhancement effects of azone and n-decylmethyl sulfoxide have been measured. Both have been found to be potent enhancing agents. However, at relatively low concentrations such as 5%, Azone induced a 50-fold and n-decylmethyl sulfoxide only a two-fold enhancement of the drug steady-state flux. At high concentrations as much as 40%, n-decylmethyl sulfoxide appears to be more effective than Azone. The fluxes measured with these systems were 0.21, 0.17 and 0.003 mg · cm^?2 · h^?1 for the n-decylmethyl sulphoxide, Azone and PG/H₂O systems, respectively.