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 permeation study of hinokitiol: effects of vehicles and enhancers

In vitro permeation of hinokitiol (HKL) through hairless mouse skin was investigated using a diffusion cell. Either propylene glycol (PG) or ethanol (EtOH) was used as a vehicle for HKL. After applying the HKL solutions of 0.5%. 1%, 2%, and 5% onto the skin, the amount of HKL transferred through the skin into the receptor solution, phosphate-buffered saline (PBS, pH7.4), was determined at a predetermined time intervals for 18 hr using a high performance chromatography (HPLC). EtOH was more effective than PG in terms of in vitro permeation of HKL. This is possibly because EtOH acts as a permeation enhancer. Another reason would be related to the higher thermodynamic activity of HKL in ethanol. To investigate the effect of an enhancer on the in vitro permeation, oleyl alcohol, 1-dodecyl-2-pyrrolidone (DP), and lauric acid were used as enhancers. Each was added to the HKL solution (1%) so that the concentration of the enhancer was 1%. Among the enhancers, DP was the most effective and it enhanced the permeation of HKL approximately 5-10 times.     

Effect of chemical enhancers and iontophoresis on thiocolchicoside permeation across rabbit and human skin in vitro

The aim of this work was to study the permeation of thiocolchicoside across the skin in vitro. The effect of the chemical enhancer lauric acid and the physical technique of iontophoresis was investigated. Permeation experiments were performed in vitro using rabbit ear skin as barrier. The effect of lauric acid at different concentrations (2% and 4%) and of the vehicle (water, ethanol, or ethanol/water) was investigated. The primary effect of lauric acid was on the partitioning parameter, whereas the diffusive parameter did not change significantly. When human epidermis was used, the permeation parameters were generally lower, although not significantly different from rabbit ear skin. The data obtained with full-thickness human skin indicate that, despite the hydrophilic nature of thiocolchicoside, the resistance to drug transport is not limited to the stratum corneum, but that the underlying dermal tissue can also contribute. Iontophoresis enhanced the flux of thiocolchicoside compared with the passive control. The mechanism by which iontophoresis enhanced thiocolchicoside transport across the skin was electroosmosis. The permeation of thiocolchicoside across the skin can be enhanced using chemical or physical penetration enhancers.     

Effect of enhancers and retarders on percutaneous absorption of flurbiprofen from hydrogels

The effect of enhancers/retarders on the transdermal absorption of flurbiprofen from cellulose hydrogels was studied in vitro. The release rate of flurbiprofen and the viscosity of hydrogel matrices were also examined. The flux of flurbiprofen from cellulose hydrogels approximated that from aqueous buffers, whereas the skin reservoir of flurbiprofen was lower with hydrogels. Incorporation of the cosolvents, propylene glycol (PG) and ethanol, did not significantly increase skin absorption of flurbiprofen. Ethanol even reduced the skin reservoir of the drug. Oleic acid, an unsaturated fatty acid, produced the largest skin reservoir of the drug when incorporated into the hydrogels. D-Limonene, a cyclic monoterpene, showed the greatest ability to enhance the flux of flurbiprofen. However, phospholipids as retarders markedly reduced the skin absorption of flurbiprofen. The mechanisms by which enhancers/retarders govern flurbiprofen permeation were elucidated by in vitro permeation studies using various skin types (enhancers/retarders-pretreated skin, stratum corneum (SC)-stripped skin, and delipidized skin) and histological examination. The results suggest different mechanisms and skin structural modifications caused by different enhancers/retarders.     

Effect of permeation enhancers and organic acids on the skin permeation of indapamide

The aim of present study was to investigate the transdermal properties of indapamide and to explore the efficacy of various permeation enhancers and organic acids with regard to the percutaneous absorption of indapamide. Permeation experiments were performed in vitro, using rat abdominal skin as a barrier. In the permeation studies, 2-chamber diffusion cells were used. The results obtained indicate that N-dodecylazepan-2-one, N-methyl-2-pyrrolidone, menthol and oleic acid had a strong enhancing effect on the permeation of indapamide and N-dodecylazepan-2-one exhibited the most potent enhancing effect. All eight of the organic acids chosen had a potent enhancing effect on the permeation of indapamide across rat abdominal skin. Among the organic acids examined, lactic acid had the greatest enhancing effect. The formation of an ion-pair between indapamide and organic acids may be responsible for the enhanced skin permeation of indapamide. Although the exact reason remains unknown, it is worth carrying out further investigations.     

In vitro permeation studies of nanoemulsions containing ketoprofen as a model drug

We prepared a nanoemulsion system with benzyl alcohol/ ethanol/Solutol/smash(R) 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(R) 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.     

In vitro skin permeation of estradiol from various proniosome formulations

The objective of this work was to assess the in vitro characteristics, in vivo pharmacokinetics and in vivo pharmacodynamics of nalbuphine propionate (NAP)-loaded microspheres. An oil-in-water solvent evaporation method was used to incorporate NAP into poly (d,l-lactide-co-glycolide) (PLGA)-based microspheres. The morphology of the microspheres were evaluated using scanning electron microscopy which showed a spherical shape with smooth surface. A prolonged in vitro drug release profile was observed, with 71.1% of incorporated drug released in 96 h. The release profile fit well to the Baker and Lonsdale's spherical matrix model, suggesting the release of NAP from microspheres was consistent with a diffusion mechanism. The in vivo pharmacokinetic studies after subcutaneous injection of NAP-loaded microsphere showed a sustained plasma nalbuphine (NA)-time profile, with 100% relative bioavailability comparing to the AUC obtained after intravenous injection. The in vitro release pattern correlated well with the in vivo pharmacokinetic profile. The pharmacodynamic studies evaluated using paw pressure model also showed a prolonged pharmacological response after injection of microspheres. A linear correlation between the percent analgesic effect and the logarithm of plasma NA concentration was obtained, suggesting the pharmacological response can be reflected by plasma drug concentration. This correlation may be utilized for evaluating the pharmacological responses of various NA and its prodrug-based formulations with known plasma NA concentrations.     

Preparation,characterization and in vitro intestinal absorption of a dry emulsion formulation containing atorvastatin calcium

A redispersible dry emulsion (DE) formulation of atorvastatin calcium (AC) was developed to enhance the in vitro dissolution of AC, thereby increasing its gastrointestinal absorption. The spray-drying technology was used where Plurol Oleique CC 497 was chosen as the oil phase. Effects of carriers, surfactants, and homogenizers on the characteristics of DE containing AC were systematically investigated. The final formulation consisted of dextrin and Poloxamer 188 as carrier and surfactant, respectively, and was homogenized by a high pressure homogenizer before spray drying. The in vitro release of AC from the optimized DE was significantly higher than that of pure AC powder (76% vs. 30% at 24 hr). The in vitro intestinal absorption of AC from the DE formulation was 0.77 μg/cm² at 2 hr, which was a 2.33-fold increase compared to the pure unformulated AC powder. These results suggest that the oral dry emulsion formulation could improve the intestinal absorption of AC.     

Vehicle effects on in vitro skin permeation of and stratum corneum affinity for model drugs caffeine and testosterone

The effects of Labrasol (LBS) (glycolysed ethoxylated C₈/C₁₀ glycerides), Labrafil (LBF) (glycolysed ethoxylated glycerides), Transcutol (TSC) (diethylene glycol monoethyl ether) and DPPG (propylene glycol dipelargonate) on the flux across excised human skin of the lipophilic testosterone (TST) and the hydrophilic caffeine (CAF) and on the affinity of the human stratum corneum for these drugs are compared taking propylene glycol (PG) and liquid petrolatum (LP) as reference vehicles. DPPG and LBF enhance CAF flux relative to PG while LBS and TSC increase the stratum corneum affinity for TST relative to LP. However, the materials tested enhance neither the flux of nor the stratum corneum affinity for both drugs with respect to either reference. On the other hand, a saturated solution of DPPG in PG enhances both properties for both drugs relative to PG. Such effects are ascribed to the ability of DPPG to interact with the lipid bilayers and to that of PG to promote DPPG penetration into stratum corneum and to create interaction sites in such a tissue.     

促渗剂对氟比洛芬体外经皮渗透的影响

目的研究不同的促渗剂对氟比洛芬体外经皮渗透的促渗作用。方法采用TK-6A型透皮扩散仪,用人皮进行体外经皮渗透实验,考察不同的促渗剂[二甲基亚砜、月桂醇、丙二醇、月桂氮酮(氮酮)、尿素、油酸]及其组合对氟比洛芬体外透皮吸收的促渗作用,以HPLC法测定各时间点接受室中药物浓度,求算透皮吸收的有关参数,比较各促渗剂的促渗作用。结果15%二甲基亚砜、3%氮酮、1%尿素可使氟比洛芬经皮渗透速率分别提高1.8,1.5,1.1倍,促渗剂联用取得的促渗效果更佳,5%油酸 20%丙二醇 1%尿素可使该药物的经皮渗透速率提高6倍。结论单用促渗剂对氟比洛芬经皮渗透促渗效果有限,促渗剂联合使用可以显著提高氟比洛芬经皮渗透速率。     

6种促进剂对西替利嗪体外经皮渗透的影响

目的 :研究 6种不同的促进剂对西替利嗪体外经皮渗透的促进作用。方法 :用Valia Chien水平扩散池 ,选择了丙二醇、月桂氮芯卓 酮 (azone)、柠烯 (dipentene)、水杨酸甲酯、含 10 %薄荷脑的丙二醇、含 10 %樟脑的丙二醇作为促进剂 ,采用离体SD大鼠腹部皮肤用促渗剂预处理的方式 ,建立以去氯羟嗪为内标的反相离子对高效液相色谱法 ,测定接收液中西替利嗪的含量。结果 :除丙二醇和水杨酸外其余几种促进剂对西替利嗪体外经皮渗透都有显著的促进作用 (P <0 .0 1)。以含 10 %薄荷脑的丙二醇的促渗效果最好。结论 :月桂氮芯卓 酮、柠烯、薄荷脑、樟脑可以作为促渗剂用于西替利嗪经皮吸收制剂     

Epithelial transport of Noscapine across cell monolayer and influence of absorption enhancers on in vitro permeation and bioavailability: implications for intestinal absorption

Abstract

The purpose of this study was to investigate the permeation of Noscapine (Nos) across the Caco-2 and Madin–Darby canine kidney (MDCK) cell monolayers and to evaluate the influence of absorption enhancers on in vitro and in vivo absorption of Nos. The bidirectional transport of Nos was studied in Caco-2 and MDCK cell monolayers at pH 5.0–7.8. The effect of 0.5% w/v chitosan (CH) or Captisol (CP) on Nos permeability was investigated at pH 5.0 and 5.8. The effect of 1–5% w/v of CP on oral bioavailability of Nos (150?mg/kg) was evaluated in Sprague–Dawley rats. The effective permeability coefficients (P_eff) of Nos across Caco-2 and MDCK cell monolayers was found to be in the order of pH 5.0?>?5.8?>?6.8?>?7.8. The efflux ratios of P_eff?<?2 demonstrated that active efflux does not limit the absorption of Nos. The use of CH or CP have shown significant (***, p?<?0.001) enhancement in P_eff of Nos across cell monolayer compared with the control group. The CP (1–5% w/v) based Nos formulations resulted in significant (***, p?<?0.001) increase in the bioavailability of Nos compared with Nos solution. The use of CP represents viable approach for enhancing the oral bioavailability of Nos and reducing the required dose.     

In vitro evaluation of a series of azone analogs as dermal penetration enhancers: III. Acyclic amides

A scries of acyclic amides was synthesized and tested for enhancement properties using excised hairless mouse skin and hydrocortisone 21-acetate as the model drug. All compounds were applied at 0.4 M (or at their respective saturation solubilities) in propylene glycol. Azone (0.4 M) was used as a standard enhancer. Enhancement ratios were calculated for flux, 24 h diffusion cell receptor concentrations (Q₂₄) and 24 h full-thickness mouse skin steroid content. Enhancer 5 showed the highest activity for flux (35.22-fold over control), 24 h receptor concentration (79.86-fold over control) and skin drug content (4.3-fold over control). These enhancement ratios were higher than those for Azone which were 19.51, 38.30 and 1.5-fold over control, respectively. Enhancers 4, 10 and 11 showed similar Q₂₄ values to Azone, and 3, 9 and 10 increased skin steroid content to a greater extent than Azone.     

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.     

In vitro and in vivo evaluations of the efficacy and safety of skin permeation enhancers using flurbiprofen as a model drug

The efficacy and safety of commonly used enhancers were systemically evaluated by in vitro and in vivo methods in this study. Flurbiprofen was used as the model drug to examine the enhancing capacity of these enhancers. Both in vitro permeation by Franz cells and in vivo kinetics of skin disposition were performed to determine the flurbiprofen permeation by enhancers. Unsaturated fatty acids showed the greatest enhancement of flurbiprofen permeation. The enhancing effect of D-limonene was slightly lower than that of the fatty acids. Azone and L-alpha-lecithin even reduced the skin deposition by flurbiprofen application. In vitro prostaglandin E(2) (PGE(2)) release by cell culture, in vivo transepidermal water loss (TEWL) and colorimetry, and skin morphological changes were determined to examine the irritation of the skin by enhancers. The results showed that skin disruption and inflammation did not necessary correspond to the enhancing efficiency of the enhancers. Moreover, some discrepancies were observed in these irritant profiles when using various methods. The fatty acids generally showed the most irritating properties, followed by Azone, D-limonene, and L-alpha-lecithin. A complete portrait of the efficacy and safety of commonly used enhancers was therefore established in this study.     

不同透皮促进剂对马钱子碱体外透皮吸收的影响

目的考察不同透皮促进剂对马钱子碱体外透皮吸收的影响。方法采用改良Franz扩散池,选用离体猪耳朵皮为屏障,考察不同类型的透皮促进剂对马钱子碱体外透皮吸收速率、增渗倍数等参数的影响。结果除吐温-80外,各透皮促进剂均能提高马钱子碱的透皮速率,促透能力由弱至强依次为桉叶素<油酸<氮酮<肉豆蔻酸异丙酯<柠檬烯。结论本研究可为马钱子碱外用剂型的选择与优化提供指导。     

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。     

渗透促进剂对葛根素角膜透过性的影响

目的研究葛根素(puerarin)的角膜透过性,为其处方设计提供理论基础。方法采用体外扩散实验以林格溶液为扩散介质考察在多种渗透促进剂条件下PUE的离体兔眼角膜透过性。结果10 g.L-1吐温80和5 g.L-1乙二胺四乙酸二钠(EDTA)分别使PUE的表观渗透系数增加到1.69和2.10倍,与对照组呈现显著性差异(P<0.01),而20 g.L-1羟丙基-β-环糊精(HP-β-CD)与1 g.L-1月桂氮卓酮(azone)未能显著增大PUE的表观渗透系数(P>0.05);5 g.L-1乙二胺四乙酸二钠(EDTA-2Na),10 g.L-1吐温80能显著缩短PUE透过角膜的滞后时间(P<0.01);而20 g.L-1羟丙基-β-环糊精(HP-β-CD)与1 g.L-1月桂氮卓酮(azone)未能显著缩短PUE的滞后时间(P>0.05);所有渗透促进剂对眼组织均没有显著刺激性。结论5 g.L-1的EDTA-2Na能够显著增加PUE的表观渗透系数并能显著缩短其角膜透过时间,且对角膜无明显刺激性。     

促渗剂对祖师麻总香豆素体外经皮渗透的影响

目的:研究几种常用促渗剂对祖师麻总香豆素体外经皮渗透的影响.方法:采用Tp-5智能扩散仪,离体SD大鼠腹部皮肤为渗透屏障,以累计渗透量为指标,用HPLC法测定有效成分祖师麻甲素的浓度.结果:氮酮、冰片合用丙二醇可作为促渗剂,用于祖师麻总香豆素经皮吸收制剂,且氮酮合用丙二醇效果最好.结论:为研发祖师麻经皮给药制剂提供了实验依据.     

透皮促进剂对肤康祛斑凝胶体外透皮吸收的影响

目的考察透皮促渗剂对肤康祛斑凝胶的主药熊果苷体外经皮渗透的影响。方法对优化后的肤康祛斑凝胶处方,以大鼠离体皮肤作为渗透屏障,用高效液相色谱法测定凝胶中熊果苷经皮透入接收液含量。考察氮酮、氮酮-薄荷油、氮酮-冰片作为促渗剂对熊果苷透皮吸收的影响。结果肤康祛斑凝胶中熊果苷的体外累积渗透率符合Weibull分布,以氮酮-薄荷油作为促渗剂的处方中,熊果苷累积渗透率最高,渗透促进剂的促透效果为:氮酮-薄荷油>氮酮-冰片>氮酮。结论以氮酮-薄荷油作为促渗剂,对熊果苷有较好的促渗作用。