Oromucosal multilayer films for tailor-made,controlled drug delivery

Introduction: The oral mucosa has recently become increasingly important as an alternative administration route for tailor-made, controlled drug delivery. Oromucosal multilayer films, assigned to the monograph oromucosal preparations in the Ph.Eur. may be a promising dosage form to overcome the requirements related to this drug delivery site.

Areas covered: We provide an overview of multilayer films as drug delivery tools, and discuss manufacturing processes and characterization methods. We focus on the suitability of characterization methods for particular requirements of multilayer films. A classification was performed covering indication areas and APIs incorporated in multilayer film systems for oromucosal use in order to provide a summary of data published in this field.

Expert opinion: The shift in drug development to high molecular weight drugs will influence the field of pharmaceutical development and delivery technologies. For a high number of indication areas, such as hormonal disorders, cardiovascular diseases or local treatment of infections, the flexible layer design of oromucosal multilayer films provides a promising option for tailor-made, controlled delivery of APIs to or through defined surfaces in the oral cavity. However, there is a lack of discriminating or standardized testing methods to assess the quality of multilayer films in a reliable way.     

马来酸依那普利叶酸片对H型高血压患者的血压及血清Hcy水平的影响

目的:探讨马来酸依那普利叶酸片对H型高血压患者血压及血清Hcy水平的影响。方法:117例H型高血压患者随机分为A、B、C 3组,每组39例。A组给予复方制剂马来酸依那普利叶酸片10 mg/0.8 mg/d;B组给予马来酸依那普利片10 mg/d+叶酸片0.8 mg/d;C组仅给予马来酸依那普利片10 mg/d。3组均连续服用12个月。观察治疗前及治疗后第3、6、9、12个月3组患者血压及同型半胱氨酸(Hcy)水平的变化。结果:治疗后第3、6、9、12个月,3组收缩压、舒张压均较治疗前显著降低(P<0.01),但3组间比较差异均无统计学意义(P>0.05)。治疗后第6、9、12个月,A、B两组Hcy水平较治疗前明显降低(P<0.01),且显著低于C组(P<0.01);治疗后第12个月,A组Hcy水平低于B组,差异有统计学意义(P<0.05)。A、C组脑卒中发生率比较差异有统计学意义(P<0.05)。结论:马来酸依那普利叶酸片能有效控制H型高血压患者的血压,降低Hcy水平,降低此类患者脑卒中的发生率。     

依那普利叶酸片对H型高血压左室肥厚患者心血管事件及心功能指标的影响

目的：研究依那普利叶酸片对H型高血压左室肥厚患者心血管事件及心功能指标的影响。方法选取2012年9月至2013年9月收入我院的H型高血压左室肥厚患者100例为研究对象,分为治疗组和对照组,每组各50例。对照组口服依那普利,治疗组口服依那普利叶酸片,2组均治疗12个月。治疗前后检测患者血浆同型半胱氨酸（ Hcy）水平、心功能及左室射血分数、主要心血管事件发生率及不良反应发生情况。结果治疗前,2组患者收缩压（ SBP ）、舒张压（ DBP ）差异无统计学意义（P＞0．05）,治疗后,2组SBP、DBP均显著降低（P＜0．05）,且治疗组降压效果更加明显。治疗前,2组患者血浆Hcy水平比较未见统计学差异（P＞0．05）,治疗后,2组血浆Hcy水平均显著降低（P＜0．05）,且治疗组降低更加明显。治疗后,治疗组和对照组患者E／A值,分别由0．65±0．09和0．64±0．13上升到0．93±0．14和0．77±0．12,治疗前后,2组E／A值比较差异均有统计学意义（P＜0．05）;治疗后,与对照组相比,治疗组患者E／A值显著升高,2组相比差异具有统计学意义（P＜0.05）。治疗后,治疗组和对照组的左室射血分数（ LVEF）值分别由64．64±1．19和65．11±1．47上升到69．43±1．40和66．95±1．38,治疗前后2组LVEF差异具有统计学意义（P＜0．05）;治疗后,与对照组相比,治疗组LVEF值显著升高,2组相比差异具有统计学意义（P＜0．05）。患者随访时间2～12个月,平均随访时间（7．53±3．74）个月。随访过程中,对照组出现7例主要心血管事件,其中4例脑卒中,2例心肌梗死,1例心血管病死亡,无主要心血管事件生存率为86．0％。治疗组共发生3例主要心血管事件,其中2例脑卒中,1例心肌梗死,无主要心血管事件生存率为94．0％。与对照组比较,治疗组无主要心血管事件生存率显著提高,2组相比差异具有统计学意义（P＜0．05）。结论依那普利叶酸片降压及降低血浆Hcy、逆转左室肥厚作用更强,心血管事件发生率更低,其疗效显著强于依那普利,有效保护心脏。     

Release studies of undecylenoyl phenylalanine from topical formulations

The aim of this study was to characterize the stability of new vehicles for the undecylenoyl phenylalanine that is used as skin-lightening agent in the melasma treatment. The purpose of this research was also to analyse the release kinetics of phenylalanine derivative from topical preparations through different synthetic membranes. Topical formulations such as two different macroemulsions, hydrogels (based on carbomer and hydroxyethylcellulose) and microemulsions were characterized in terms of stability by laser diffraction method. Additionally, multiple light scattering assessed the stability of macroemulsions. The release rates of active substance through different membranes (such as Cuprophan, nitrocellulose, cellulose acetate and Strat-M) were determined using enhancer cell. In order to explain the mechanism of release process the results were fitted with different kinetic models. New stable vehicles for Ude-Phe were successfully obtained. The results proved that the membrane structure had the influence on the release rate of undecylenoyl phenylalanine. The slowest release rate of Ude-Phe was observed when Strat-M membrane was applied. The highest amount of active substance was released from the hydrogel based on carbomer. The release of undecylenoyl phenylalanine from both macroemulsions and hydrogel based on hydroxyethylcellulose followed the Higuchi model. Whereas the release results of Ude-Phe from both microemulsion-based hydrogels and carbomer hydrogel can be described by using Korsmeyer-Peppas model. Hydrogels and microemulsion-based hydrogels could be recommended as proper vehicles for the derivative of phenylalanine.     

珍菊降压片联合依那普利治疗原发性高血压的临床研究

目的探讨珍菊降压片联合马来酸依那普利片治疗原发性高血压的临床疗效。方法选取2014年6月—2017年6月在首都医科大学附属北京世纪坛医院治疗的高血压患者134例为研究对象,所有患者根据治疗方案的差别分为对照组和治疗组,每组各67例。对照组口服马来酸依那普利片,2片/次,1次/d。治疗组在对照组基础上口服珍菊降压片,1片/次,3次/d。两组患者连续治疗2个月。观察两组的临床疗效,比较两组的血压变化和血管内皮功能改善情况。结果治疗后,对照组和治疗组的总有效率分别为74.63%、91.04%,两组比较差异有统计学意义(P0.05)。治疗后,两组收缩压(SBP)、舒张压(DBP)均显著下降,同组治疗前后比较差异有统计学意义(P0.05);且治疗组血压明显低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组一氧化氮(NO)、降钙素基因相关肽(c GRP)水平显著升高,内皮素(ET)水平显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组血管内皮功能指标明显优于对照组,两组比较差异具有统计学意义(P0.05)。结论珍菊降压片联合马来酸依那普利片治疗原发性高血压具有较好的临床疗效,可改善血管内皮功能,安全性较好,具有一定的临床推广应用价值。     

10 years EU regulation of pediatric medicines – impact on cardiovascular drug formulations

Introduction: Child-appropriate drug formulations are mandatory for an efficient and safe drug therapy in children. Since the implementation of supportive legislations development of novel drug formulations has significantly been enforced despite the fact that children are a heterogeneous group of patients with varying needs according to age, maturation and disease.

Areas covered: In this review, recent advances and current strategies are evaluated how to overcome the specific hurdles in pediatric drug development. For cardiovascular diseases as an example, EMA’s decisions on pediatric investigation plans (PIPs) have been evaluated. New developments with innovative platform technologies such as mini-tablets and orodispersible preparations have been identified indicating a clear shift from liquid preparations to small-sized solid (multiparticulate) or orodispersible dosage forms. Reasons for this shift of paradigm are discussed.

Expert opinion: Innovative platform technologies for solid drug dosage forms such as mini-tablets, orodispersible tablets or film preparations will continue to conquer the pharmaceutical market. Still, there are some major issues to be resolved, e.g. how to ensure quality of the new dosage forms and dose accuracy in flexible dosing, but the governmental incentives will continue to accelerate development of pediatric medicines and will bridge the still existing gaps in the near future.     

马来酸依那普利片稳定性研究

目的 提高马来酸依那普利片的稳定性。方法 将马来酸依那普利原料和碳酸氢钠以1:3的摩尔比溶解在水中,作为粘合剂使用。结果 通过原辅料相容性试验表明,处理后的API与各辅料相容性较好,杂质没有明显变化;通过制剂的加速6个月试验表明：杂质C由0.15%增长至0.61%,杂质D由未检出增长到0.48%;通过长期12个月的数据表明：杂质C由0.15%增长至0.42%,杂质D由未检出增长至0.1%。结论 通过原辅料相容性和稳定性考察结果显示,该工艺有效解决了马来酸依那普利制剂稳定性不好的问题。     

Stochastic Multiscale Heat Transfer Analysis of Heterogeneous Materials with Multiple Random Configurations

This study presents a new stochastic multiscale analysis approach to analyze the heat transfer performance of heterogeneous materials with random structures at different length scales. The heterogeneities of the materials are taken into account by periodic layouts of unit cells, consisting of randomly distributed inclusion dispersions and homogeneous matrix on the microscale and mesoscale. Based on the reiterated homogenization, a novel unified micro-meso-macro stochastic multiscale formulation is established and the scale gap is correlated by means of two-scale asymptotic expansions. Also, the stochastic multiscale formulae for computing the effective thermal property and temperature field are derived successively. Then, the stochastic prediction algorithm coupled with the finite element method is brought forward in details. The accuracy of the implemented stochastic multiscale analysis is verified by comparing the results against the experimental data for three scales heterogeneous materials with several different material combinations. The comparison demonstrates the usability of the proposed stochastic multiscale method for the determination of the thermal behaviors. This study offers a unified multiscale framework that enables heat transfer behavior analysis of heterogeneous materials with multiple random configurations.     

Role of medium-chain fatty acids in the emulsification mechanistics of self-micro-emulsifying lipid formulations

Purpose

The objective of the present study was to design and develop stable o/w microemulsions comprising Miglyol 812, Imwitor 988 and Tagat TO as a non ionic surfactant. This was based on particle size measurements and phase behavior studies. The empirical role of incorporating medium-chain mono/di-glycerides in the lipid matrix in the mechanistic processes of emulsification was also established in various simulating physiological conditions.

Methods

The efficiency of self-emulsification was evaluated under conditions of varying key compositions in the lipid mixtures; oil, cosurfactant and surfactant. Droplet diameter was measured using laser diffraction and light scattering techniques. Equilibrium phase studies were performed and phase boundaries were determined for the lipid–water systems.

Results

Microemulsion systems were produced from blends of Miglyol 812, Imwitor 988 and Tagat TO. An optimized formulation consisted of {Miglyol 812/Imwitor 988} and Tagat TO spontaneously self-emulsified in water producing dispersions with droplet diameters of ∼50 nm. Phase equilibrium diagrams have revealed significant enhancement in the water-solubilized region (L₂) without any presence of liquid crystalline materials.

Conclusions

Potential SMEDDS formulations for the bioavailability enhancement of poorly water-soluble compounds were developed by mixing blends of {Miglyol 812/Imwitor 988} and Tagat TO as a non-ionic surfactant. ‘Diffusion and stranding’ appears to be the dominant mechanism of emulsification.     

吸入制剂肺部沉积量测定的方法学研究进展

目的:介绍吸入制剂肺部沉积量的不同测定方法,为相关研究提供参考和思路。方法:采用文献检索的方式,搜索Pubmed、中国知网和万方数据库的相关文献,对其进行整理和分析,并将不同测定方法按其特点分类介绍。结果:吸入剂的肺部沉积量可通过影像学和非影像学方法来测定。影像学方法包括二维γ显像法、单光子发射计算机断层扫描(SPECT)、正电子发射断层扫描(PET)等;非影像学方法包括活性炭阻断法及尿排泄法。非影像学方法可使患者免受电离辐射的影响,而影像学方法可提供更多的局部沉积量信息。结论:不同测定方法均有其优势与局限性。目前国外监管部门较为认可的方法为γ显像法和非影像学方法,但部分非影像学方法在我国并未得到广泛应用,相信其在以后的应用会有所增加。