吲哚美辛水凝胶贴剂小鼠体外透皮性能研究

目的：通过研究不同促透剂对吲哚关辛水凝胶贴剂透皮性能的影响,遴选在特定栽药剂量时具有最佳促透效果的促透剂,并与市售贴剂进行比较,对吲哚美辛水凝胶贴剂的体外透皮性能进行评价。方法：采用改良Franz透皮扩散池,以离体小鼠背部皮肤为透皮屏障,在最佳载药量选用不同浓度的氮酮、油酸、丙二醇以及三者组成的二元或三元组合为促透剂,在规定时间点测定吲哚美辛的累积透过百分率以及单位面积累积透过量。结果：与空白对照组相比,当氮酮与油酸单独应用时,二者均没有明显的促透作用;当选用二元促透剂联合应用时,油酸与丙二醇联用能够明显促进吲哚美辛的经皮渗透（P〈0．05）;当选用三元促透剂时促透效果更好,单位面积累积透过量最高可达234．4μg·cm^-2,24h内药物累积透过百分率明显高于市售贴剂。结论：氮酮、油酸、丙二醇三者联合应用可作为吲哚关辛贴剂的理想促透剂。吲哚关辛水凝胶贴剂是具有应用价值的新型经皮控释制剂。     

The Experimental Evaluation and Molecular Dynamics Simulation of a Heat-Enhanced Transdermal Delivery System

Transdermal delivery systems are useful in cases where preferred routes such as the oral route are not available. However, low overall extent of delivery is seen due to the permeation barrier posed by the skin. Chemical penetration enhancers and invasive methods that disturb the structural barrier function of the skin can be used to improve transdermal drug delivery. However, for suitable drugs, a fast-releasing transdermal delivery system can be produced by incorporating a heating source into a transdermal patch. In this study, a molecular dynamics simulation showed that heat increased the diffusivity of the drug molecules, resulting in faster release from gels containing ketoprofen, diclofenac sodium, and lidocaine HCl. Simulations were confirmed by in vitro drug release studies through lipophilic membranes. These correlations could expand the application of heated transdermal delivery systems for use as fast-release-dosage forms.     

Transdermal siRNA-TGFβ1-337 patch for hypertrophic scar treatment

Hypertrophic scarring (HSc) is a fibroproliferative disorder of the dermis characterized by erythematous, swollen, and pruritic lesions of healing skin. An increased understanding of the role of TGFβ1 in the development of HSc provides the potential for treating HSc by down-regulating TGFβ1 expression. siRNAs that effectively interfered with TGFβ1 expression were screened. It was concluded that the siRNA-TGFβ1-337 was able to effectively down-regulate TGFβ1 expression in HSc fibroblasts. The effects of siRNA-TGFβ1-337 on cell proliferation, cell cycle, and apoptosis of HSc fibroblasts were investigated. It was shown that it inhibited cell proliferation, arrested cells in the G1 stage of the cell cycle, and induced apoptosis of HSc fibroblasts. The transdermal patch of siRNA-TGFβ1-337 was a combination of siRNA-TGFβ1-337 and a pressure-sensitive adhesive hydrogel. The treatment effects of the transdermal patch were assessed in an animal model established by transplanting human HSc to nude mice. Decreased expression of TGFβ1 was observed with treatment with the transdermal siRNA-TGFβ1-337 patch. Consequently, the treatment resulted in type I collagen down-regulation and regularly arranged scar fibroblasts being significantly reduced and undergoing apoptosis; the scar size was decreased significantly. Thus, our findings indicate that a transdermal siRNA-TGFβ1-337 patch is a potential treatment for hypertrophic scars.     

Design and Characterization of an Adhesive Matrix Based on a Poly(Ethyl Acrylate, Methyl Methacrylate)

The main issue in the development of transdermal patches made of poly(ethyl acrylate, methyl methacrylate) (Eudragit NE 40D, PMM) is the shrinkage phenomenon during the spreading of the latex onto the release liner. To solve this problem, the latex is usually freeze-dried and then re-dissolved in an organic solvent (method 1). To simplify the production process, we prepared an adhesive matrix by adding to the commercial PMM latex a plasticizer and an additive (anti-shrinkage agent) that avoids the shrinkage of the water dispersion spread onto the release liner (method 2). In some cases the active ingredient itself, such as potassium diclofenac (DK) and nicotine (NT), works as anti-shrinkage agent. In this work, the effects of the preparation method, types and concentrations of the plasticizer (triacetin and tributyl citrate) on the adhesive properties of the transdermal patches were investigated. The adhesive properties of the prepared patch were determined by texture analysis, peel adhesion test and shear adhesion. The PMM/plasticizer interactions were evaluated by ATR-FTIR spectroscopy. Furthermore, the in vitro skin permeation profiles of DK and NT released from the patch were determined by Franz cell method. Generally speaking, the variables that mainly modify the adhesive properties are the concentration and type of the plasticizer. The skin permeation profiles of DK and NT from the patch prepared by method 2 overlapped with those obtained with the commercial products. The results underline that the PMM latex can be used conveniently in the development of transdermal patches.     

回顾性分析与评价麻醉性镇痛药的应用情况和发展趋势

目的:神经系统药物是各治疗领域中增长最快的领域,其增速与心脑血管领域和抗肿瘤领域相当,麻醉镇痛类药物则是其中的首类药物。本文主要分析本院麻醉性镇痛药(narcotic analgesics,NALG)应用的现状及趋势,并行客观评价。方法:回顾性分析2010年~2012年第三军医大学第二附属医院麻醉性镇痛药品的种类、用量、金额、用药频度等,并进行归类统计、比较和分析。结果:经过数据统计分析,结果表明注射剂型药物多为住院患者使用,其他口服或透皮贴剂的门诊用量较大。其中,临床应用以芬太尼类居首。羟考酮缓释片的用量排名有明显的上升趋势。结论:当前麻醉性镇痛药的应用情况基本合理,但为创建无痛医院仍需进一步完善科学用药管理与监督,并提高合理用药水平。医院麻醉性镇痛药应注重以改善患者健康为目的,建立以患者为中心的用药指标,最大限度地减轻患者的痛苦。     

蛋白质和多肽药物长效性研究进展

基于分子生物学和重组技术的发展,蛋白质和多肽已经成为一类重要的药物,但是其稳定性差,生物利用率低,半衰期短等问题也日益受到关注。本文重点介绍了一些新的给药途径和给药系统,例如鼻腔、颊等给药途径以及黏膜给药系统、透皮给药系统、缓控释技术等给药系统的进展。综述了对于蛋白质和多肽药物进行定点突变和化学修饰,以达到增加其长效性的一些新方法。     

The Melanogenesis-Inhibitory Effect and the Percutaneous Formulation of Ginsenoside Rb1

Ginsenoside Rb1 (Rb1) is the most predominant ginsenoside isolated from the roots of ginseng (Panax ginseng C. A. Meyer). This compound is active in various human biological pathways that are involved in human collagen synthesis and inhibition of cell apoptosis. In this study, the skin-whitening effects of Rb1 were investigated in B16 melanoma cells. Our results showed that Rb1 inhibited melanogenesis in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16 cells in a dose-dependent manner, which collectively indicated that Rb1 may have skin-whitening effects and may be formulated into skin-whitening products for skin care. Accordingly, a ginsenoside collagen transdermal patch was developed as a vehicle to topically deliver Rb1 into pig skin. The percutaneous permeation, retention within skin, and release in vitro of Rb1 from seven transdermal patch formulas were studied. It was determined that the best formula for ginsenoside collagen transdermal patch is made of protein collagen hydrolysate powder (PCHP) 2.0% (w/w), methyl cellulose (MC) 0.5% (w/w), polyethyleneglycol 6000 (PEG6000) 0.5% (w/w), ginsenoside 0.036% (w/w), azone 0.4% (v/w), menthol 0.20% (w/w), and water.     

Discovery of transdermal penetration enhancers by high-throughput screening

Although transdermal drug delivery is more attractive than injection, it has not been applied to macromolecules because of low skin permeability. Here we describe particular mixtures of penetration enhancers that increase skin permeability to macromolecules (approximately 1-10 kDa) by up to approximately 100-fold without inducing skin irritation. The discovery of these mixtures was enabled by an experimental tool, in vitro skin impedance guided high-throughput (INSIGHT) screening, which is >100-fold more efficient than current tools. In vitro experiments demonstrated that the mixtures delivered macromolecular drugs, including heparin, leutinizing hormone releasing hormone (LHRH) and oligonucleotides, across the skin. In vivo experiments on hairless rats with leuprolide acetate confirmed the potency and safety of one such mixture, sodium laureth sulfate (SLA) and phenyl piperazine (PP). These studies show the feasibility of using penetration enhancers for systemic delivery of macromolecules from a transdermal patch.     

经皮给药纳米载体及靶向系统治疗类风湿关节炎研究进展

类风湿关节炎(RA)是全世界难治性自身免疫疾病,其治疗药物虽不断发展,但病灶药物浓度达不到有效水平导致药物疗效不理想或存在各种毒副反应,因此,基于新技术、新方法研究开发针对RA的安全、高效新型制剂是必要的。研究表明,纳米技术的运用可提高药物生物利用度,经皮给药可改善口服和注射带来的毒副作用。对近年来基于经皮给药系统治疗RA利用的纳米载体进行综述,并阐述在RA病理特征中运用到的靶向策略,思考透皮制剂的改进方法,探讨新型纳米制剂研究现状及存在的问题,从而为制备新型透皮纳米制剂提供参考。     

The Transdermal Patches for Site-Specific Delivery of Letrozole: A New Option for Breast Cancer Therapy

The aim of this work was to evaluate capability of site-specific delivery of a transdermal patch through determination of letrozole in local tissues disposition in female mice. After transdermal administration, the letrozole levels in skin, muscle, and plasma were 10.4–49.3 μg/g, 1.64–6.89 μg/g, and 0.35–1.64 μg/mL, respectively. However, after the mice received letrozole suspension, the drug concentration of plasma and muscle were 0.20–4.80 μg/mL and 0.15–2.38 μg/g. There was even no drug determined in skin through all experiments. Compared with oral administration, the transdermal patch for site-specific delivery of letrozole could produce high drug concentrations in skin and muscle and meanwhile obtain low drug level in plasma. These findings show that letrozole transdermal patch is an appropriate delivery system for application to the breast tumor region for site-specific drug delivery to obtain a high local drug concentration and low circulating drug concentrations avoiding the risk of systemic side effects.     

<Emphasis Type="Italic">In vitro</Emphasis> Enhancement of Lactate Esters on the Percutaneous Penetration of Drugs with Different Lipophilicity

Lactate esters are widely used as food additives, perfume materials, medicine additives, and personal care products. The objective of this work was to investigate the effect of a series of lactate esters as penetration enhancers on the in vitro skin permeation of four drugs with different physicochemical properties, including ibuprofen, salicylic acid, dexamethasone and 5-fluorouracil. The saturated donor solutions of the evaluated drugs in propylene glycol were used in order to keep a constant driving force with maximum thermodynamic activity. The permeability coefficient (K _p), skin concentration of drugs (SC), and lag time (T), as well as the enhancement ratios for K _p and SC were recorded. All results indicated that lactate esters can exert a significant influence on the transdermal delivery of the model drugs and there is a structure-activity relationship between the tested lactate esters and their enhancement effects. The results also suggested that the lactate esters with the chain length of fatty alcohol moieties of 10–12 are more effective enhancers. Furthermore, the enhancement effect of lactate esters increases with a decrease of the drug lipophilicity, which suggests that they may be more efficient at enhancing the penetration of hydrophilic drugs than lipophilic drugs. The influence of the concentration of lactate esters was evaluated and the optimal concentration is in the range of 5∼10 wt.%. In sum, lactate esters as a penetration enhancer for some drugs are of interest for transdermal administration when the safety of penetration enhancers is a prime consideration.     

丁丙诺啡透皮贴剂控制肩周炎患者疼痛的效果观察

目的:探讨丁丙诺啡透皮贴剂治疗肩关节周围炎的患者对于疼痛的缓解效果和肩关节活动功能的改善作用。方法:搜集本院近5年来门诊就诊及住院治疗的肩周炎患者152例,全部患者均规范化按照VAS评分使用镇痛药物。其中,78例患者在达到中度及以上疼痛水平时,额外加用丁丙诺啡透皮贴剂。每隔3月通过电话随访量化患者疼痛评分变化情况,门诊随访检查患者肩关节活动功能,并使用Constant-Murley肩关节功能评分量表进行数字化评估。结果:152例肩周炎患者在治疗观察期间,疼痛及肩关节活动功能均有一定程度的缓解和改善,在观察期末,平均Constant-Murley肩关节功能评分保持于80分水平。在治疗观察期内,外用丁丙诺啡透皮贴的患者在6-18月期间时,Constant-Murley肩关节功能评分上升速度明显高于对照组(P0.05)。结论:丁丙诺啡透皮贴剂可以加快肩周炎患者的康复速度,提升肩周炎患者在治疗期间的生活质量。     

Development and Evaluation of α-Asarone Transdermal Patches Based on Hot-Melt Pressure-Sensitive Adhesives

A hot-melt, pressure-sensitive adhesive (HMPSA) based on styrene–isoprene–styrene was prepared, and its compatibility with various transdermal penetration enhancers was investigated. The effect of penetration enhancers on the adhesion properties of HMPSA was also studied. A drug-in-adhesive patch was formulated using α-asarone as a model drug, and penetration enhancers were screened by an in vitro transdermal study across excised pig skin. The pharmacokinetics in rabbits was also studied. The results show that HMPSA was miscible with most penetration enhancers (azone, menthol, isopropyl myristate, 1-methyl-pyrrolidinone, N,N-dimethylformamide, oleic acid), apart from propylene glycol. Penetration enhancers had a plasticizer-like effect that decreased the peel strength and shear strength of HMPSA. A combination of 1% oleic acid and 4% menthol had the highest in vitro penetration rate and was selected for patch preparation. The patch formulation was optimized by replacing some of the plasticizer by penetration enhancers to achieve good adhesion and effective transdermal flux. The final patch showed a high efficiency, with a relative bioavailability of 1,494%. This suggests that HMPSA may be a promising material for drug-delivery patches.     

Analysis of Bitter Almonds and Processed Products Based on HPLC-Fingerprints and Chemometry

In the processing field, there is a saying that “seed drugs be stir-fried”. Bitter almond (BA) is a kind of seed Chinese medicine. BA need be used after being fried. To distinguish raw bitter almonds (RBA) from processed products and prove the rationality of “seed drugs be stir-fried”, we analyzed the RBA and five processed products (scalded bitter almonds, fried bitter almonds, honey fried bitter almonds, bran fried bitter almonds, bitter almonds cream) using RP-HPLC fingerprints and chemometric methods. The similarity between RBA and processed products was 0.733∼0.995. Hierarchically clustered heatmap was used to evaluate the changes in components. Principal component analysis (PCA) was used for classification, and all samples are distinguished according to RBA and five processing methods. Six chemical markers were obtained by partial least squares discriminant analysis (PLS-DA). The content and degradation rate of amygdalin and β-glucosidase activity were determined. Compared with RBA, the content and degradation rate of amygdalin, and β-glucosidase activity were increased in bitter almonds cream. The content and degradation rate were decreased, and β-glucosidase was inactivated in other processed products. The above results showed that stir-frying had the best effect. The results showed that processing can ensure the stability of RBA quality, and the saying “seed drugs be stir-fried” is reasonable.     

生物相容透皮给药微针治疗浅表肿瘤

复杂的肿瘤微环境导致抗肿瘤药物在肿瘤组织内递送效率低下，严重阻碍了药物对浅表肿瘤的治疗效果。生物相容透皮给药微针凭借较高的机械强度，刺穿皮肤角质层，将微针内的药物递送至浅表肿瘤组织内，提高生物利用度，改善静脉注射、口服给药的肝肾毒性等问题。本文介绍了生物相容透皮给药微针的设计及其在癌症化疗、光动力治疗、光热治疗、免疫治疗、基因治疗等领域的研究进展，对浅表肿瘤的微创、局部递药和精准、高效治疗具有重要指导意义。     

Ethno biological usage of zoo products in rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most common autoimmune disorder which causes swelling, redness, pain, stiffness, restriction of limb movements, decreases life expectancy and early death of the patients. Available drugs include non steroidal anti-inflammatory and analgesics, disease modifying anti-rheumatic drugs and steroids (glucocorticoids etc). All these drugs have their own limitations such as gastrointestinal irritations, cardiovascular problems, and drug dependency. Search for alternative therapy from natural products are being ventured throughout the world. Zoo therapy in arthritis, a common practice of the ancient times that have been mentioned in traditional and folk medicine. The scientific basis of some of the zoo products are being explored and have been showing promising results in experimental rheumatoid arthritis. These therapies have minimum side effects and many of them have potential to give rise to drug development clues against rheumatoid arthritis. The present review is an effort to establish the folk and traditional treatment of rheumatoid arthritis using zoo products.     

Development of a Discriminative <Emphasis Type="Italic">In Vitro</Emphasis> Release Test for Rivastigmine Transdermal Patches Using Pharmacopeial Apparatuses: USP 5 and USP 6

The aim of this study was to develop and validate a discriminating in vitro release test to evaluate rivastigmine transdermal patches. The Exelon® Patch was chosen as a model transdermal product. The studies of in vitro release were designed to determine the impact of the official apparatus chosen (USP apparatus 5 and USP apparatus 6), the rotation speed, and the dissolution medium characteristics on the rivastigmine release profile from transdermal patches. Patches with different drug release profiles were tested in order to evaluate the discriminating power of the in vitro release test developed and validated. Variables such as the apparatus type, the dissolution medium, and the rotation speed have a significant influence on the drug release characteristics from a transdermal patch. The in vitro release methodologies using the USP apparatus 5 at 50 rpm and USP apparatus 6 at 25 rpm using the medium phosphate-buffered saline pH 7.4 were considered discriminative and adequate to characterize the rivastigmine (RV) release from a commercial transdermal patch, Exelon® Patch.     

Formulation development and in vitro and in vivo evaluation of membrane-moderated transdermal systems of ampicillin sodium in ethanol: pH 4.7 buffer solvent system

The objective of the present study was to develop membrane-moderated transdermal systems of ampicillin sodium and to evaluate them with respect to various in vitro and in vivo parameters. The membrane-type transdermal systems were prepared using a drug with various antinucleant polymers— hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), cellulose acetate phthalate, chitosan, sodium alginate (SA), and sodium carboxymethylcellulose—in an ethanol: pH 4.7 buffer volatile system by the solvent evaporation technique with HPMC as the rate-controlling membrane for all the systems. The swelling properties of the polymers were studied, and drug-polymer interaction studies were performed. The patches were subjected to various physicochemical studies, in vitro release studies, permeation studies, and skin irritation studies. The best patch among the formulations was selected for further in vivo studies. Compared to the other patches, SA exhibited the highest moisture content at 16%; a 21% moisture uptake was found with MC. The release and permeation of the drug from the SA patch was found to be the maximum. The in vivo study of the SA patch exhibited a peak plasma concentration C_max of 126 μg/mL at T_max 4 hours. Hence, it can be concluded that hydrophilic ampicillin sodium can be developed as a transdermal delivery system with SA that is an alternative to intravenous administration and has minimal adverse effects. Published: January 26, 2007     

Physical Characterization of a New Skin Bioadhesive Film

Physical properties (roughness, gloss, mechanical, surface topography and adhesive) of a bioadhesive film for the transdermal delivery of drugs and its interactions with a skin model surface were studied. Roughness is a measurement of the small-scale variations in the height of a physical surface. No significant differences in Ra between the “x” and “y” dimensions for both the skin model and patch were detected, due to uniformity in their production. Scanning electron microscope pictures showed small particles projected from the film. Those particles resulted in increasing roughness and surface area. For the patch, gloss values measured at 20° were 6.0 ± 0.9 and at 60°, 32.2 ± 2.2 gloss units, respectively, indicating a semi-gloss material. Concerning the mechanical properties, the tensile strength of the film resulted four- to sevenfold greater than the peel force from the model skin used, indicating the suitability of the film for skin application. The adhesion to skin model depended on the amount of water used for film application and on the elapsed time between film application and removal. Finally, the model skin that was invented by Charkoudian can be used as an alternative to costly and highly variable human skin substrates since it possesses human topography.     

多瑞吉在带状疱疹疼痛治疗阿片类药物转换中的应用

目的:探讨多瑞吉在带状疱疹疼痛治疗阿片类药物转换中的应用。方法:选择37例住院治疗的带状疱疹疼痛患者,年龄>45岁、VAS评分≥4分、所有病人常规抗病毒治疗、增加免疫力等常规治疗,予硬膜外腔置管间断注入消炎镇痛药物并持续泵吗啡,根据疼痛调整至止痛剂量,转换为多瑞吉贴剂后出院。疼痛控制后逐渐减药,每半个月减量半贴多瑞吉,对病人的疼痛评分、生活质量及并发症进行评估。结果:有1例病人应药物副反应出组,其余病人硬膜外泵吗啡后均在一周左右控制疼痛,等效转换为多瑞吉,定时定量减药,无疼痛反复,成瘾戒断等情况。结论:带状疱疹疼痛采用硬膜外间断注药持续泵吗啡迅速达到无痛后,转换为等效剂量的多瑞吉,定时定量减药,安全有效。