Novel Gastroretentive Dosage Forms: Evaluation of Gastroretentivity and Its Effect on Levodopa Absorption in Humans

Purpose. To design novel expandable gastroretentive dosage forms (GRDFs) and evaluate their gastroretentive properties. Then, to assess the pharmacokinetics of levodopa compounded in such a GRDF in healthy volunteers. Methods. Thin (<0.07 cm), large-dimensioned ( 5 × 2.1 cm), multilayer dosage forms (DFs) with different rigid polymeric matrices and mechanical properties were folded into gelatin capsules and were administered to healthy volunteers with a light breakfast. GRDF unfolding and physical integrity were evaluated in vitro and in vivo (by gastroscopy and radiology). The pharmacokinetics of levodopa-GRDF were compared to Sinemet CR^® in a crossover design. Results. The combination of rigidity and large dimension of the GRDFs was a decisive parameter to ensure prolonged gastroretentivity ( 5 h). Large-dimension DFs lacking rigidity had similar gastroretentivity as a nondisintegrating tablet (10 mm). The GRDFs rapidly unfolded and maintained their mechanical integrity. The absorption phase of levodopa was significantly prolonged following GRDF administration in comparison to Sinemet CR^®. Conclusions. The combination of size and rigidity of the novel GRDF enables a significant extension of the absorption phase of a narrow absorption window drug such as levodopa. This approach is an important step toward the implementation of such GRDFs in the clinical setting.     

囊泡载体制剂在经皮给药系统中治疗皮肤病的潜在应用

本文综述了脂质体、传递体、醇质体、非离子表面活性剂囊泡四种囊泡载体的组成、特征以及其制剂在经皮给药系统中治疗几种皮肤病的应用,为今后的研究提供思路。     

Nanoparticles and microparticles for skin drug delivery

Skin is a widely used route of delivery for local and systemic drugs and is potentially a route for their delivery as nanoparticles. The skin provides a natural physical barrier against particle penetration, but there are opportunities to deliver therapeutic nanoparticles, especially in diseased skin and to the openings of hair follicles. Whilst nanoparticle drug delivery has been touted as an enabling technology, its potential in treating local skin and systemic diseases has yet to be realised. Most drug delivery particle technologies are based on lipid carriers, i.e. solid lipid nanoparticles and nanoemulsions of around 300 nm in diameter, which are now considered microparticles. Metal nanoparticles are now recognized for seemingly small drug-like characteristics, i.e. antimicrobial activity and skin cancer prevention. We present our unpublished clinical data on nanoparticle penetration and previously published reports that support the hypothesis that nanoparticles > 10 nm in diameter are unlikely to penetrate through the stratum corneum into viable human skin but will accumulate in the hair follicle openings, especially after massage. However, significant uptake does occur after damage and in certain diseased skin. Current chemistry limits both atom by atom construction of complex particulates and delineating their molecular interactions within biological systems. In this review we discuss the skin as a nanoparticle barrier, recent work in the field of nanoparticle drug delivery to the skin, and future directions currently being explored.     

Influence of Formulation,Receptor Fluid,and Occlusion,on in Vitro Drug Release from Topical Dosage Forms,Using an Automated Flow-Through Diffusion Cell

An automated flow-through diffusion cell apparatus was used for comparing the release rates of a naphthoic acid derivative, CD 271, from different topical formulations. The influence of the following parameters on CD 271 release from the formulations was investigated: receptor fluid composition, occlusion, weight of tested formulation, and dosage form type. The amount of tested formulation was shown to have no significant effect on the apparent release constant and lag time for an anionic oil-in-water emulsion and an aqueous gel. Occlusion affected drug release from the different dosage forms. Thus, occlusion increased CD 271 pharmaceutical availability for a lotion and a hydroalcoholic gel containing 0.1% of sol-ubilized drug. The release profile of CD 271 from the formulations was highly dependent on the receptor fluid composition. Drug release was dramatically enhanced with n-octanol as compared to an aqueous solution of surfactant. Using occlusive or nonocclusive procedures, CD 271 apparent release constant and lag time were found to be highly dependent on the type of tested formulation. The flow-through diffusion cell proposed in the present study allows an accurate comparison of drug release characteristics from prototype topical formulations and therefore represents a valuable tool for formulation research or quality control process.     

Transdermal and dermal delivery of adefovir: Effects of pH and permeation enhancers

The objective of this work was to investigate feasibility of transdermal and dermal delivery of adefovir (9-(2-phosphonomethoxyethyl)adenine), a broad-spectrum antiviral from the class of acyclic nucleoside phosphonates. Transport of 2% adefovir through and into porcine skin and effects of various solvents, pH, and permeation enhancers were studied in vitro using Franz diffusion cell. From aqueous donor samples, adefovir flux through the skin was 0.2-5.4 microg/cm2/h with greatest permeation rate at pH 7.8. The corresponding adefovir skin concentrations reached values of 120-350 microg/g of tissue. Increased solvent lipophilicity resulted in higher skin concentration but had only minor effect on adefovir flux. A significant influence of counter ions on both transdermal and dermal transport of adefovir zwitterion was observed at pH 3.4. Permeation enhancer dodecanol was ineffective, 1-dodecylazepan-2-one (Azone) and dodecyl 2-(dimethylamino)propionate (DDAIP) showed moderate activity. The highest adefovir flux (11.3+/-3.6 microg/cm2/h) and skin concentration (1549+/-416 microg/g) were achieved with 1% Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium 5-(dodecyloxycarbonyl)pentylcarbamate) at pH 4. This study suggests that, despite its hydrophilic and ionizable nature, adefovir can be successfully delivered through the skin.     

Influence of adsorbents in transdermal matrix patches on the release and the physical state of ethinyl estradiol and levonorgestrel

The drug release from medium molecular weight polyisobutene patches containing adsorbates (drug content: 0.2% ethinyl estradiol, 1.0% levonorgestrel; adsorbent content: 20%, w/w) increased in the order of no adsorbent < titanium dioxide < MCC < crospovidone. This was attributed to differences in drug crystallinity which increased in the order of crospovidone (crystal free) < MCC < titanium dioxide < no adsorbent and the water uptake which increased in the order of no adsorbent (0.1%) = titanium dioxide (0.1%) < MCC (1.6%) < crospovidone (4.8%) at 90% rh. Patches containing adsorbates onto crospovidone were investigated in detail. Increasing the adsorbate’s drug loading increased the drug release up to a crospovidone content of 15% (w/w). Patches were crystal free for crospovidone contents ?10% (w/w), which corresponds to a drug loading of crospovidone of 12% (w/w). In conclusion, the incorporation of drug adsorbates onto crospovidone into patches based on polyisobutene significantly increased the drug release (approximately 9.1 times for ethinyl estradiol and 15.4 times for levonorgestrel) and prevented drug recrystallization.     

新给药系统的工程化——新制剂及制造装置

药物制剂国家工程研究中心创建10年来积累了制剂工程的较丰富经验，并对如下系列的科研项目进行了研究开发与工程化的全过程运转——（1）缓控释颗粒的挤出．滚圆．气流包衣；（2）口腔生物黏附片；（3）渗透泵控释片；（4）透皮给药；（5）可生物降解注射微球；（6）缓释混悬剂；（7）脂质体；（8）植入小粒。不同剂型的多种药物及相应生产设备已经产业化。     

Transdermal Permeation and Skin Retention of Diclofenac and Etofenamate/Flufenamic Acid From Over-the-Counter Pain Relief Products

Topical pain relief products differ in the type of drug, concentration, and formulation. All these factors influence the drug transit through the skin barrier, and its eventual retention in the skin as a reservoir for subsequent release. In addition, the drug potency can be different, which is important for the product efficacy. We studied here ex vivo human skin permeation and retention of five over-the-counter NSAID gels containing 2.32% diclofenac (DIC) and 5–10% etofenamate (ETF). The potency of the permeated/retained drug amounts were compared using a composite parameter, the Index of Relative Topical Anti-inflammatory Activity (IRTAA), which is calculated as the product of the skin permeation/retention and the drug relative potency. The IRTAAs of the DIC gel were 94–667-fold higher and 72–208-fold higher for transdermal delivery and skin retention, respectively, than IRTAAs of the ETF gels. These superior IRTAAs indicate that DIC delivered by this topical formulation would achieve a higher bioactivity and would form a potent drug reservoir relevant for its subsequent long-lasting release.     

Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin

The purpose of this study was to develop novel dissolving microneedle arrays fabricated from hyaluronic acid (HA) as a material and to improve the transdermal permeability of relatively high molecular weight drugs. In this study, fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4 kDa (FD4) was used as a model drug with a relatively high molecular weight. The microneedle arrays significantly increased transepidermal water loss (TEWL) and reduced transcutaneous electrical resistance (TER), indicating that they could puncture the skin and create drug permeation pathways successfully. Both TEWL and TER almost recovered to baseline levels in the microneedle array group, and relatively small pathways created by the microneedles rapidly recovered as compared with those created by a tape stripping treatment. These findings confirmed that the microneedle arrays were quite safe. Furthermore, we found that the transdermal permeability of FD4 using the microneedle arrays was much higher than that of the FD4 solution. Furthermore, we found that the microneedle arrays were much more effective for increasing the amount of FD4 accumulated in the skin.These findings indicated that using novel microneedle arrays fabricated from HA is a very useful and effective strategy to improve the transdermal delivery of drugs, especially relatively high molecular weight drugs without seriously damaging the skin.     

Modeling Drug Absorption from the Dermis after an Injection

A dermal absorption model for small and macromolecules was previously proposed by Ibrahim et al. This model estimated absorption of therapeutics from the dermal tissue based on their molecular size and protein binding through blood and lymphatics. Blood absorption followed a two-pore theory and the lymphatic absorption was limited by the constant lymphatic flow rate. Current work builds on this steady-state concept by modeling the absorption from the dermis immediately after an injection is given (unsteady state). An injection in the dermis creates a localized pressure gradient which resolves itself over time. This phenomenon is captured in the model to estimate the impact of injection volume on the absorption rate constant. Blood absorption follows the two-pore theory but is time-dependent and the lymphatic absorption is determined based on valve opening and pressure driven convective flow, returning to steady-state as the molecule is absorbed. A direct comparison of the steady-state analysis, experimental data and the current model is made. The results indicate that accounting for the localized time-varying pressure can better predict the experimental absorption rate constants. This work significantly improves the existing understanding of macromolecule uptake from the interstitial fluid following intradermal injection.     

聚合物胶束在经皮给药系统中的应用

摘 要 目的：综述聚合物胶束作为药物载体在经皮传递系统中的应用进展。方法: 根据国内外发表的最新文献,对聚合物胶束的制备方法、促进皮肤渗透的机制、释药过程及其在经皮给药系统中的应用进行分析与讨论。结果: 聚合物胶束具有增加难溶性药物的溶解度,促进药物的经皮吸收等作用,作为药物载体在经皮传递系统的应用越来越广泛。结论:聚合物胶束可作为药物载体被广泛用于经皮给药系统的研究中,具有较好的发展前景。     

石杉碱甲透皮控释贴片对小鼠学习记忆的改善作用

目的：观察石杉碱甲透皮控释贴片（Hup-ATDDS)对正常小鼠及记忆障碍模型小鼠学习记忆功能的影响。方法：跳台试验测定Hup-ATDDS对正常小鼠学习成绩的影响;建立东莨菪碱记忆获得障碍模型及亚硝酸钠记忆巩固障碍模型。采用一次性训练的空间辨别反应实验-电迷宫实验和一次性学习的回避性条件反射试验-跳台试验测定小鼠记忆功能,观察Hup-ATDDS对其影响。结果：Hup-ATDDS53.4μg/只对正常小鼠跳台试验有促进学习成绩作用。对1mg/kg东莨菪碱引起的记忆获得障碍及120mg/kg亚硝酸钠产生记忆巩固障碍有明显的反转作用。结论：石杉碱甲透皮控释贴片具有较好的促进正常小鼠及记忆障碍小鼠的学习记忆功能作用。     

马钱子碱双层聚合物可溶性微针的制备及其在不同载药方式下的体外经皮渗透性研究

目的:制备马钱子碱(Bru)双层聚合物可溶性微针,并考察其在不同载药方式下的体外经皮渗透特性。方法:以微针揭膜难易程度、阵列完整性、气泡量、针型、针尖硬度、背衬韧性等为考察指标分别筛选微针的针尖材料和背衬材料,并以微针形态为考察指标筛选基质溶胀方法和干燥方法,然后采用两步法制备双层聚合物可溶性微针,并进行表征和安全性评价。通过Franz扩散池法考察针尖载药、背衬载药、全载药Bru双层聚合物可溶性微针的体外经皮渗透特性,绘制体外透皮曲线并计算累积渗透量(Q)和累积渗透率。结果:优选的双层聚合物可溶性微针的制备工艺为以硫酸软骨素-聚乙烯吡咯烷酮K30(1∶1,m/m)作为针尖材料,15%聚乙烯醇作为背衬材料,在4℃冰箱静置1 h进行基质溶胀,干燥器室温干燥24 h。所制微针阵列完整,机械性能良好,能成功刺穿铝箔和大鼠皮肤,微针处理后皮肤在6 h内即可恢复到原来的状态。体外透皮试验结果显示,微针递药可大大提高Bru的经皮累积渗透量,针尖材料可在10 min内溶解并释放药物;针尖载药微针在8 h内基本释放完全,Q_{8 h}为102.185μg/cm²,累...     

蜂蜜的抗菌特性及其在医学上的应用

利用蜂蜜的抗菌特性治疗各种疾病或创伤是蜂蜜开发中一个比较热门的方向。本文对蜂蜜可能的抗茼机理(高渗、酸性环境和抗菌组分)以及蜂蜜中的抗菌组分(过氧化氢和非过氧化氢类)作了阐述，对利用蜂蜜抗菌特性开发产品(创伤敷料、口腔保健和胃药开发)作了探讨。     

Alternative Manufacturing Concepts for Solid Oral Dosage Forms From Drug Nanosuspensions Using Fluid Dispensing and Forced Drying Technology

Flexible manufacturing technologies for solid oral dosage forms with a continuous adjustability of the manufactured dose strength are of interest for applications in personalized medicine. This study explored the feasibility of using microvalve technology for the manufacturing of different solid oral dosage form concepts. Hard gelatin capsules filled with excipients, placebo tablets, and polymer films, placed in hard gelatin capsules after drying, were considered as substrates. For each concept, a basic understanding of relevant formulation parameters and their impact on dissolution behavior has been established. Suitable matrix formers, present either on the substrate or directly in the drug nanosuspension, proved to be essential to prevent nanoparticle agglomeration of the drug nanoparticles and to ensure a fast dissolution behavior. Furthermore, convection and radiation drying methods were investigated for the fast drying of drug nanosuspensions dispensed onto polymer films, which were then placed in hard gelatin capsules. Changes in morphology and in drug and matrix former distribution were observed for increasing drying intensity. However, even fast drying times below 1 min could be realized, while maintaining the nanoparticulate drug structure and a good dissolution behavior.     

Combined effect of liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate in rat skin

In this report, we investigated the combined effect of drug liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate (ISN) in rat abdominal skin in vitro. Occlusive application of both liposomal and aqueous ISN solution, with and without addition of 5% glycerol, showed that drug liposomalization and addition of glycerol has far-reaching implications for ISN permeation and accumulation in 4 and 8 weeks old rat abdominal skin. Using 8 weeks old rat abdominal skin, the optimal concentration of glycerol to be added to liposomal ISN was found to be 5%. The ISN mean values permeated through and accumulated in stripped 8 weeks old rat abdominal skin from those formulations described above were not significant different, which might indicate the combined effect of glycerol and liposomal ISN resides solely in the stratum corneum (SC). Based on previous reports, the enhancement effect of glycerol might be due to an increase in the SC hydration, and perhaps due to subtle changes in the lipid organization caused by penetration of liposomal lipids within the SC intercellular spaces. These data might provide evidence that glycerol action on SC is useful to facilitate skin permeation and accumulation of drugs formulated in liposome.     

Simultaneous In Vivo Visualization and Localization of Solid Oral Dosage Forms in the Rat Gastrointestinal Tract by Magnetic Resonance Imaging (MRI)

Purpose. Bioavailability of orally administered drugs is much influenced by the behavior, performance and fate of the dosage form within the gastrointestinal (GI) tract. Therefore, MRI in vivo methods that allow for the simultaneous visualization of solid oral dosage forms and anatomical structures of the GI tract have been investigated. Methods. Oral contrast agents containing Gd-DTPA were used to depict the lumen of the digestive organs. Solid oral dosage forms were visualized in a rat model by a ¹H-MRI double contrast technique (magnetite-labelled microtablets) and a combination of ¹H- and ¹⁹F-MRI (fluorine-labelled minicapsules). Results. Simultaneous visualization of solid oral dosage forms and the GI environment in the rat was possible using MRI. Microtablets could reproducibly be monitored in the rat stomach and in the intestines using a ¹H-MRI double contrast technique. Fluorine-labelled minicapsules were detectable in the rat stomach by a combination of ¹H- and ¹⁹F-MRI in vivo. Conclusions. The in vivo ¹H-MRI double contrast technique described allows solid oral dosage forms in the rat GI tract to be depicted. Solid dosage forms can easily be labelled by incorporating trace amounts of non-toxic iron oxide (magnetite) particles. ¹H-MRI is a promising tool for observing such pharmaceutical dosage forms in humans. Combined ¹H- and ¹⁹F-MRI offer a means of unambiguously localizing solid oral dosage forms in more distal parts of the GI tract. Studies correlating MRI examinations with drug plasma levels could provide valuable information for the development of pharmaceutical dosage forms.     

Inter- and intra-individual variability in human skin barrier function: A large scale retrospective study

In vitro transepidermal tritiated water flux measurements are frequently used to evaluate skin barrier integrity for quality control purposes. However, research in this area to date has been largely based upon small-scale studies, each involving relatively few skin permeation measurements. In order to enhance our understanding in this area, we have conducted a much larger scale retrospective statistical analysis of tritiated water k_p values. These values reflected the permeability of 2400 skin samples that were derived from 112 female volunteers over a 4 year period. It was found that the population of tritiated water k_p values constituted a positively skewed, non-Normal distribution. Mean k_p was 2.04 × 10⁻³ cm/h while the 95th percentile was 4.50 × 10⁻³ cm/h. Both values are higher than those reported in previous smaller studies. Hence, our study indicates that previously suggested upper limits for tritiated water flux are too low and that they be revised upwards to a value of 4.5 × 10⁻³ cm/h. Analysis was also performed on smaller data subsets allowing inter-individual and intra-individual comparisons. For intra-individual k_p variability, site-related differences yielded a non-Normal, positively skewed pattern in most individuals. Inter-individual variability was Normally-distributed and showed scatter that was much smaller in magnitude.     

青藤碱透皮给药与西医治疗膝关节滑膜炎患者的临床效果分析与比较

目的探讨不同治疗方法治疗膝关节滑膜炎的临床效果。方法将2012年2月～2013年2月收治的60例膝关节滑膜炎患者随机分成两组,对照组30例采用基础治疗加用双氯芬酸二乙胺乳膏剂外涂,观察组30例采用基础治疗加用青藤碱透皮给药。结果观察组疗效明显高于对照组,差异有统计学意义（P〈0.05）。观察组关节疼痛、肿胀及活动受限的改善程度均优于对照组。结论青藤碱具有抗感染、镇痛、抗风湿、免疫抑制等作用,透皮给药可直接作用于病变部位,两者结合使药物在深部组织发挥作用,作用机制明确,疗效明显优于常规的西医治疗。     

Enhancing effect of pyrrolidone derivatives on transdermal drug delivery II. Effect of application concentration and pre-treatment of enhancer

We compared the enhancing effects of 1-methyl- (I), 1-hexyl- (II) and 1-lauryl-2-pyrrolidone (III) on the penetration of phenolsulfonphthalein (Phenol red) as a model for a non-absorbable drug. Using the in vitro penetration technique and excised rat skin, the enhancers were applied at various concentrations. An increase in enhancer concentration was found to increase the flux and skin accumulation, and shorten the lag time for steady-state penetration of Phenol red. The enhancing effects of II and III ceased at 0.1 mmol/ml. Penetration for enhancers was found to increase with their own concentrations. Pre-treatment with enhancer for 5 h shortened the lag time for steady-state penetration of Phenol red. Removal of II from the donor side after pre-treatment decreased its enhancing effect. Enhancer III still showed an effect after removal.