In vitro permeation screening of a new formulation of thiocolchicoside containing various enhancers

Thiocolchicoside, a muscle relaxant agent with anti-inflammatory and analgesic actions, also is used topically for the treatment of muscular spasms and for rheumatologic, orthopedic, and traumatologic disorders. In this study, thiocolchicoside was formulated to use as foam to avoid contact with the afflicted area during the spreading phase. To enhance drug penetration, various enhancers were added to the base formulation. The tested enhancers were ethoxyethylendiglycol (Transcutol ® ), highly purified phosphatidylcholine (Lipoid S20), capsaicin, propylene glycol dipelargonate (DPPG), and glycolysed ethoxylated glycerides (Labrafil M1944 CS). The transdermal absorption of the tested formulations containing enhancers, in comparison with base formulation, was evaluated in vitro through rat skin using standard Franz diffusion cells. Base formulation was found to have a higher permeation profile than the simple aqueous and hydroalcoholic solutions of the drug, meaning that the base formulation by itself enhances the drug permeation. Among the tested formulations, only the formulation containing DPPG/ethanol was found to be statistically different, showing an enhancement factor of 3.58. In the same experimental session, Muscoril ® ointment, the commercially available pharmaceutical product containing the same thiocolchicoside concentration (0.25%), also was tested. The formulation containing DPPG/ ethanol showed a 4.86 times increase of permeability constant in comparison with Muscoril ® ointment. The formulation containing DPPG/ethanol as an enhancer could be a good candidate for a new topical foam, considering its good characteristics of permeability and compliance.     

In Vitro and Ex Vivo Permeation Studies of Etodolac from Hydrophilic Gels and Effect of Terpenes as Enhancers

Etodolac, a highly lipophilic anti-inflammatory drug, is widely used in rheumatoid arthritis usually at an oral dose of 200 mg twice daily. The commonest side effects during therapy with etodolac is generally gastrointestinal disturbances these are usually mild and reversible but in some patients are peptic ulcer and severe gastrointestinal bleeding. To eliminate these side effects and obtain high drug concentration at the application side, dermal application of etodolac seems to be an ideal route for administration. Hydrophilic gel formulations of etodolac were prepared with carboxymethylcellulose sodium. The effect of different terpenes (anethole, carvacrol, and menthol) as an enhancer on the percutaneous absorption of etodolac was also investigated. Permeation studies were carried out with unjacketed modified horizontal diffusion cells through cellulose membrane and rat skin. In vitro studies with cellulose membrane showed that all formulations presented the same drug release profile (p > 0.05). Ex vivo studies with excised rat skin revealed that etodolac was released and penetrated into rat skin quickly. Anethole, a hydrophobic terpene, enhanced the absorption of etodolac significantly (p < 0.05). This result is consistent with the fact that hydrophobic terpenes are effective on the percutaneous absorption of lipophilic drugs. Menthol and carvacrol, hydrophilic terpenes, did not enhance the absorption of etodolac. The lipophilicity of the enhancers seems an important factor in promoting penetration of etodolac through the skin. Since etodolac creates gastrointestinal disturbances, topical formulations of etodolac in gel form including 1% anethole could be an alternative.     

中药复方制剂心安康贴剂的透皮吸收促进剂选择研究

目的：对中药复方制剂心安康贴剂的透皮吸收促进剂的选择进行研究。方法：采用Franz渗透扩散装置的气相色谱法，进行了大鼠皮肤贴剂的体外释放与渗透试验，对氮酮、十六醇、月桂醇硫酸钠，丙二醇4种透皮吸收促进剂单独应用和任意两种舍用的促进效果进行考察。结果：氮酮和丙二醇以2％：15％褥合，促进效果最强。结论：透皮促进剂对中药贴剂中的成分有较好的促透作用。     

In Vitro Permeation Studies of Nanoemulsions Containing Ketoprofen as a Model Drug

We prepared a nanoemulsion system with benzyl alcohol/ ethanol/Solutol/smash^® HS 15 /water. Ketoprofen was used as a model drug in this study. The nanoemulsions of this system evidenced a high degree of stability. The droplet diameter did not change over a period of at least 3 months. The nanoemulsion containing 4% benzyl alcohol evidenced a permeation rate higher than was observed with the 1% and 2% nanoemulsions. Also the nanoemulsion containing 1% Solutol^® HS 15 provided a permeation rate higher than was seen with the 2% and 4% nanoemulsions. All ketoprofen-loaded nanoemulsions enhanced the in vitro permeation rate through mouse skins as compared to the control.     

渗透促进剂对利多卡因经皮渗透的促进作用

考察了7种渗透促进剂对利多卡因游离碱的促渗作用，并提出了一促渗作用参数对油溶性和水溶性促渗剂的促渗作用进行系统比较，结果发现渍溶性促渗剂的促渗作用强于水溶性促渗剂（P＜0．05），但对药物经皮渗透的滞后时间无改善作用，水溶性促渗剂可使滞后时间有所缩短。     

Enhanced Permeation of an Antiemetic Drug from Buccoadhesive Tablets by Using Bile Salts as Permeation Enhancers: Formulation Characterization,In Vitro,and Ex Vivo Studies

Buccal bioadhesive bilayer tablets of prochlorperazine maleate were designed and formulated by using buccoadhesive polymers such as hydroxypropylmethyl cellulose, Carbopol 934P, and sodium alginate. Physicochemical characteristics like the uniformity of weight, hardness, thickness, surface pH, drug content, swelling index, microenvironment pH, in vitro drug release, and in vivo buccoadhesion time of the prepared tablets were found to be dependent on the type and composition of the buccoadhesive materials used. The effect of bile salts on the permeation was studied through porcine buccal mucosa and it was found that out of three bile salts incorporated (sodium glycholate, sodium taurocholate, and sodium deoxycholate), sodium glycholate enhanced the permeation rate of prochlorperazine maleate by an enhancement factor of 1.37.     

白头翁素贴片的制备与体外经皮渗透试验

目的制备白头翁素贴片，为白头翁素经皮制剂的开发提供依据。方法采用Eudragit E100为骨架材料，流涎工艺制备骨架型贴片。以HPMC醇性凝胶为储库递质，EVA为控释膜，热封法制备储库型贴片。采用TK 6A型透皮扩散仪，用人皮进行体外渗透实验；采用高效液相色谱法测定各时间点接受室中药物浓度，求算经皮渗透的相关参数。结果白头翁素骨架型贴剂经皮给药的稳态透皮速率［(1.72±0.02) mg·(cm2) 1·h 1］是其饱和水溶液的1.47倍，是储库型贴剂的2.30倍。结论白头翁素骨架型贴剂制备简单，具有较高的经皮渗透速率，有望开发成一种新型的经皮给药制剂。     

增渗剂和离子导入对尼莫地平体外经皮渗透性的影响

研究了增渗剂和离子导入技术对尼莫地平（ＮＭ）体外经皮渗透性的作用,渗透促进剂如３％和５％月桂氮卓酮及１０％油酸的２０％丙二醇溶液能增加药物的渗透性（Ｐ＜００５）,其增渗比分别为４６６、４３９及１２６４．离子导入技术能够显著增加药物的渗透性（Ｐ＜００１）,渗透比为８０３．同时表明１０％油酸和３％的月桂氮卓酮丙二醇溶液与离子导入并用,渗透比为１５、８５、８９２．     

不同促渗剂对马钱子碱贴剂体外透皮吸收的影响

目的:研究不同促渗剂对马钱子碱贴剂体外透皮促渗作用的影响.方法:采用不同浓度、不同种类促渗剂制备马钱子碱贴剂;采用改良Franz扩散池,以离体雄性大鼠皮肤为模型,通过高效液相色谱法测定药物浓度,拟合马钱子碱透皮吸收的累积透过量和透过速率.结果:以3%氮酮制备的马钱子碱贴剂具有较好的体外透过速率及累积透过量;促渗剂合用时...     

In Vitro Skin Permeation and Bioassay of Chlorhexidine Phosphanilate,a New Antimicrobial Agent

An in vitro technique was developed to study the permeation and antimicrobial activity of graded concentrations of a new antibacterial agent, chlorhexidine phosphanilate (CHP), in cream formulations using Franz diffusion cells. Formulations containing from 0.2 to 2% CHP were quantitatively applied to intact excised skin and to skin from which the stratum corneum and partial epidermis had been enzymatically removed. Receptor fluids from diffusion cells were sampled over time and assayed by HPLC methods for chlorhexidine and phosphanilic acid; 24- and 48-hr samples of the diffusate from studies with damaged skin were also bioassayed using clinical isolates of appropriate microbial species. Through intact skin almost no permeation of CHP was observed over 48 hr. The failure of CHP to penetrate intact human skin suggests that normal stratum corneum is the rate-limiting barrier to penetration by this antimicrobial agent. In damaged skin lacking stratum corneum barrier, the release of CHP from the formulation becomes the rate-determining step. Coincident with penetrating damaged skin, CHP dissociates, and the molar ratio of the chlorhexidine and phosphanilate moieties in the diffusate changes to favor phosphanilic acid. The extent of changes in the permeation rates of both moieties of CHP was directly related to the CHP concentration in cream. Both CHP moieties were found to reach equilibrium in the dermis within 24 hr after application. It was also observed that CHP creams down to 0.2% concentration yielded diffusates with activity exceeding the minimum inhibitory concentration of all test microorganisms within 24 hr.     

Formulation,Characterization, and In Vitro Evaluation of Bioadhesive Gels Containing 5-Fluorouracil

The objective of this study was to prepare and evaluate in vitro the bioadhesive gels of 5-Fluorouracil (FU) for the treatment of oropharyngeal cancer. In preformulation study, the physicochemical interactions between FU and polymers were investigated by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectrophotometry, and differential scanning calorimetry (DSC). According to FTIR, XRD, and DSC studies, the drug did not show any evidence of an interaction with the polymers used and was present in an unchanged state. The gel formulations containing FU were prepared by using Poloxamer 407, HPMC K 15 M, and Gantrez® S-97 (polymethylvinylether-co-maleic anhydride). The formulations contained Poloxamer 407 (16–18% w/w) either alone or in combination with HPMC K 15 M and Gantrez® S-97. The bioadhesiveness of the gels was found to increase with increasing proportion of HPMC K 15 M and Gantrez® S-97. In vitro release studies indicated that release could be sustained up to 8 hr. The permeability coefficients (Kp) of gel across cellulose membrane and buccal mucosal membrane were 1.06 × 10^?4 cm/s and 3.94 × 10^?5 cm/s, respectively, and differed significantly (p < 0.05). Increasing temperature increased the drug release by increasing drug diffusion despite increase in viscosity. The pH of the release medium showed a very slight effect on the release of FU. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer–Peppas model and the drug release kinetics primarily as non-Fickian diffusion.     

Studies on Optimizing In Vitro Transdermal Permeation of Ondansetron Hydrochloride Using Nerodilol,Carvone, and Limonene as Penetration Enhancers

The present investigation was carried out to formulate a terpene-based hydroxypropyl cellulose (HPC) gel drug reservoir system for its optimal transdermal permeation of ondansetron hydrochloride. The HPC gel formulations containing ondansetron hydrochloride (3% w/w) and selected concentrations of either nerodilol (0% w/w, 1% w/w, 2% w/w, 3% w/w, and 4% w/w), carvone (0% w/w, 2% w/w, 4% w/w, 8% w/w, and 10% w/w), or limonene (0% w/w, 2% w/w, 3% w/w, and 4% w/w) were prepared and subjected to in vitro permeation of the drug across rat epidermis. All the 3 terpene enhancers increased the transdermal permeation of ondansetron hydrochloride. The optimal transdermal permeation was observed with 3% w/w of nerodilol (175.3 ± 3.1 μg/cm^2.h), 8% w/w of carvone (87.4 ± 1.6 μg/cm^2.h), or 3% w/w of limonene (181.9 ± 0.9 μg/cm^2.h). The enhancement ratio (ER) in drug permeability with 3% w/w nerodilol, 8% w/w carvone, and 3% w/w limonene were 21.6, 10.8, and 22.5, respectively, when compared with that obtained without a terpene enhancer (control). However, there was 1.04-, 2.09-, and 2.17-fold increase in the optimal drug flux obtained with carvone, nerodilol, and limonene, respectively, when compared with the desired drug flux (84 μg/cm^2.h). It was concluded that the HPC gel drug reservoir systems containing either 3% w/w nerodilol or 3% w/w limonene act as optimal formulations for use in the design of membrane-controlled transdermal therapeutic system (TTS) of ondansetron hydrochloride.     

不同透皮促进剂对双氯芬酸钾凝胶体外透皮效果的影响研究

目的:考察氮酮(Azone)、丙二醇(PG)、油酸(OA)3种透皮促进剂一元、二元、三元联合对双氯芬酸钾凝胶的体外促透作用。方法:配制以下13种含不同透皮促进剂的双氯芬酸钾凝胶处方:空白,3%Azone,5%OA,12%PG,6%PG+2.5%OA,12%PG+5%OA,1.5%Azone+2.5%OA,1.5%Azone+6%PG+5%OA,1.5%Azone+12%PG,3%Azone+5%OA,3%Azone+6%PG,3%Azone+6%PG+5%OA,3%Azone+12%PG,以透皮速率J等为指标,采用改良的Franz扩散池,以离体人皮肤为透皮屏障,测定并计算双氯芬酸钾凝胶加入上述不同透皮促进剂处理后药物的透皮性能。结果:与空白组比较,其它各组J值均升高,其中以3%Azone+12%PG组的J值最高,达10.253 0μg.cm-2.h-1。结论:3种透皮促进剂对双氯芬酸钾凝胶均有不同程度促透效果,但以Azone和PG二元联用效果最佳。     

A New Formulation of Fenofibrate: Suprabioavailable Tablets

Summary

The rationale for, and development of, a new suprabioavailable fenofibrate tablet formulation is described. The new suprabioavailable tablet formulation combines wellestablished micronisation technology with a new micro-coating process. The new formulation provides more predictable and reliable drug absorption. Owing to the strong relationship between the fenofibrate dissolution performance and its oral bioavailability, equivalent plasma levels of active principal are achieved at a lower dose, with less inter-subject variability and a reduced food effect. The new suprabioavailable tablet may, therefore, be a more efficient and better tolerated formulation.     

Mechanism of In Vitro Percutaneous Absorption Enhancement of Carvedilol by Penetration Enhancers

The effect of penetration enhancers like tulsi (basil) oil, eucalyptus oil, clove oil, black cumin oil, oleic acid and Tween 80 on the percutaneous absorption of model lipophilic drug-carvedilol was investigated using excised rat abdominal skin. Transdermal flux, permeability coefficient and enhancement factor were calculated for each penetration enhancer. Black cumin oil (5% v/v) was selected on the basis of its highest enhancement in permeation and was evaluated further for its mode of action using DSC, FTIR and histological studies. The results indicated that the oil shows its action by extraction of lipids from stratum corneum as well as by loosening the hydrogen bonds between ceramides subsequently leading to fluidization of the lipid bilayer.     

In Vitro Skin Permeation of Osthol from Hydro-Alcohofic Gel Formulations

Aim To evaluate the in vitro percutaneous absorption behavior of osthol from a series of hydro-alcoholic gel formulations containing three penetration enhancers through excised human skin (stratum cormeum and epidermis,SCE). Methods Excised human skin was mounted in Franz-type diffusion cells. The samples withdrawn from the receptor cell were analyzed for osthol content by high-performance liquid chromatography (HPLC). Results The enhancers azone, menthol and chenopodium increased the osthol percutaneous steady-state fluxes 3.12, 2.00 and 1.25 times those of the enhancer-free formulations (controls), separately. Conclusions The main enhancement mechanism of the skin penetration enhancers azone, menthol and chenopodium is to destroy the barrier fimction of stratum corneum, reducing the resistance of drug transport through the skin and increasing the diffusion coefficients of osthol.     

蛇床子素凝胶药物经皮吸收的体外研究

目的体外测定含有渗透促进剂的蛇床子素凝胶经人体皮肤的吸收.方法以离体人皮肤为渗透模型,应用Franz扩散池进行实验.样品以高效液相法测定蛇床子素的含量.结果与对照组相比,渗透促进剂Azone、薄荷醇、土荆芥油可以使得蛇床子素的稳态流量分别提高3.12、2.00、1.25倍.结论三种渗透促进剂的作用机理为破坏了皮肤角质层的屏障作用,降低了药物的扩散阻力,因而提高了蛇床子素的扩散系数.     

An In Vitro Pulmonary Permeation System with Simulation of Respiratory Dynamics

To study the effect of respiration on transpulmonary permeation kinetics of drugs, an in vitro pulmonary permeation system, which consists of a setup for the simulation of respiratory dynamics, was developed. The system is composed of four major components: a pair of horizontal-type half-cells, a model air–blood barrier, an instrument for the application and regulation of respiratory pressure, and a pressure monitoring system. Calibration studies were performed and results showed that the primary respiration parameters (the peak inspiration pressure, respiratory frequency, and the percent inspiration time) can be controlled at a reproducible manner. This system appears to simulate very well the respiratory dynamics observed normally under physiologic conditions. After calibration, the system was utilized to characterize and quantitate the effect of respiration on the transpulmonary permeation of drugs using progesterone as the model drug. The results showed that progesterone permeability is increased as much as 1.8–5.6 folds by application of a respiratory pressure, depending on the combination of respiration parameters. Further studies demonstrated that the enhancement in pulmonary permeation triggered by respiratory pressure is resulted from the stretching of the lung tissue, not by the pressure gradient itself. The observations lead to the conclusion that the system developed in this investigation is a useful in vitro tool for studying the kinetics of pulmonary drug permeation under a physiologically simulating respiratory dynamics. The studies have provided scientific evidence for demonstrating that respiration is an important factor in determining the kinetics of transpulmonary drug permeation through possible alteration in the properties of the air–blood barrier.     

Transdermal Delivery of Carvedilol Containing Glycyrrhizin and Chitosan as Permeation Enhancers: Biochemical,Biophysical, Microscopic and Pharmacodynamic Evaluation

The present study was aimed at unveiling the influence of glycyrrhizin and chitosan on rat epidermis and to correlate these effects with percutaneous permeation characteristics of carvedilol. The permeation of carvedilol across excised rat epidermis was significantly higher (p < 0.05) when glycyrrhizin, chitosan, or glycyrrhizin–chitosan mixture was used as a donor vehicle as compared to propylene glycol:ethanol (7:3) mixture. Epidermis obtained after 12 hr treatment of viable rat skin with a glycyrrhizin–chitosan mixture showed significantly higher (p < 0.05) permeability to carvedilol as compared to that after treatment with glycyrrhizin or chitosan alone. Further, the application of patches containing glycyrrhizin–chitosan mixture resulted in sustained release of carvedilol, which was able to control the hypertension in deoxycorticosterone acetate induced hypertensive rats through 28 hr. Estimation of microconstituents in rat epidermis revealed maximum extraction of cholesterol, sphingosine, and triglycerides after treatment with glycyrrhizin–chitosan mixture. This was manifested in altered lipid and protein-specific thermotropic transitions. Further, increase in intercellular space, disordered lipid structure and corneocyte detachment as observed in SEM and TEM suggests great potential of glycyrrhizin for use as a percutaneous permeation enhancer.