Orally disintegrating tablets and orally disintegrating mini tablets – novel dosage forms for pediatric use

The oral administration route is considered to be the most widely used route because of its convenience of administration and manufacturing. Dosage forms, like orally disintegrating tablets (ODTs), mini tablets, and orally disintegrating mini tablets (ODMTs), are recognized as promising for use in pediatric patients. ODTs are known to be suitable drug delivery systems, especially for pediatric patients, because of their rapid disintegration properties, use without water, and no swallowing problems. In addition, in recent years, a new formulation approach has been developed. ODMTs, are the newest drug delivery systems. They combine the advantageous properties of ODTs and the small size of mini tablets, aimed for pediatric use. These tablets, which can be formulated as 2–4?mm in diameter, are known as drug delivery systems that have children acceptability age as low as 6-months old. The fact that the ODTs and the ODMTs can be formulated with acceptable flavors for children further increases the importance of these carrier systems in the treatment. The objective of this article is to highlight the development of ODTs and mini-ODTs, their significance, ideal characteristics, various techniques, and aspects related to design and formulation, marketed preparations, and future perspectives, especially for the pediatric patients.     

Representative Scale-Down Lyophilization Cycle Development Using a Seven-Vial Freeze-Dryer (MicroFD®)

We have implemented the use of a small-scale, 7-vial Micro Freeze Dryer (MicroFD^®; Millrock Technology, Inc.) that has the capability to accurately control heat transfer during lyophilization. We demonstrate the ability to fine-tune the MicroFD^® vial heat transfer coefficient (K_v) to match the K_v of vials in a LyoStar III laboratory-scale unit. When the MicroFD^® is run under conditions that match the K_v of the LyoStar III, the resulting lyophilization performance between scales results in equivalent product temperature profiles and critical quality attributes for the same drying process. The proposed workflow demonstrates how exploitation of K_v control in the MicroFD^® enables cycle development of at-scale lyophilization processes using only 7 product vials. By changing the MicroFD^® K_v, laboratory and, potentially, manufacturing cycles may be simulated using only 7 product vials for tremendous active pharmaceutical ingredient savings, as long as at-scale heat transfer coefficients are well characterized.     

Development of Solid Dispersion by Hot Melt Extrusion Using Mixtures of Polyoxylglycerides With Polymers as Carriers for Increasing Dissolution Rate of a Poorly Soluble Drug Model

Various polyoxylglycerides have been researched extensively in the development of solid dispersions (SDs) for bioavailability enhancement of poorly water-soluble drugs. However, because of their low melting points (40°C-60°C), SDs produced are usually soft and semisolid. The objective of present study was to prepare SDs of a Biopharmaceutical Classification System class II drug, carvedilol, in mixtures of stearoyl polyoxylglycerides (Acconon^® C-50; m.p. ～50°C) with polymers by hot melt extrusion to obtain free-flowing powder upon grinding. Miscibility of carvedilol with Kollidon^® VA64, hydroxypropyl methylcellulose acetate succinate, and Klucel^? EXF was first evaluated by film casting, and Kollidon^® VA64 was selected for further study. SDs containing 5%-20% carvedilol, 0%-20% Acconon^® C-50, and the remaining Kollidon^® VA64 were prepared for hot melt extrusion. SDs were characterized by differential scanning calorimetry and powder X-ray diffraction analysis, and dissolution tests were conducted in 250 mL of pH 6.8 phosphate buffer by filling powders in capsules. Carvedilol was miscible with all polymers tested up to 50% and remained amorphous in SDs. The drug release from formulations containing 20% carvedilol and 0, 5%, 10%, and 20% Acconon^® C-50 were 30%, 30%, 70%, and 90%, respectively, in 60 min. SDs containing carvedilol and Acconon^® C-50, up to 20% each, as well as Kollidon^® VA64, were physically stable after 3 months of storage at 25°C/60% relative humidity.     

马来酸依那普利叶酸对H型高血压大鼠血管平滑肌细胞GRP94和caspase-12的表达影响

目的 观察同型半胱氨酸（Homocysteine,Hcy）对自发性高血压（SHR）大鼠动脉血管平滑肌细胞内质网应激相关因子葡萄糖调节蛋白94（GRP94）和半胱氨酸门冬氨酸特异性蛋白酶12（caspase-12）表达变化的影响及马来酸依那普利叶酸片对其的干预机制.方法 将36只成年雄性SHR大鼠随机等分为3组,即对照组、蛋氨酸组和依叶片（马来酸依那普利叶酸片）组,每组12只.喂养8周后检测血清Hcy浓度,测定平均动脉压（MAP）,测量主动脉中层的厚度;检测CRP94和caspase-12的表达水平.结果 蛋氨酸组与对照组相比,MAP无差异（P＆gt;0.05）,血清Hcy浓度明显增高（P〈0.01）,主动脉中层厚度、CRP94和caspase-12蛋白表达量显著增加（P〈0.05）;依叶片组与蛋氨酸组相比,血清Hcy明显降低（P〈0.01）,MAP、血管平滑肌中层厚度、CRP94和caspase-12蛋白表达量显著降低（P〈0.05）.结论 高Hcy可加重高血压动脉血管平滑肌细胞内质网应激反应,导致CRP94表达增加及caspase-12的活化增高,从而加重血管损伤,导致血管重构;马来酸依那普利叶酸片可能通过下调血浆Hcy浓度和降低血压来抑制内质网应激,从而逆转Hcy对高血压血管平滑肌细胞的损伤作用.     

吲达帕胺联合依那普利治疗糖尿病合并高血压的可行性研究

目的：分析吲达帕胺联合依那普利治疗糖尿病合并高血压的临床效果及可行性;方法：随机将我院收治的70例患者分为对照组和观察组,对照组主要采用依那普利治疗,观察组在对照组治疗的基础上加用吲达帕胺治疗,观察两组患者血糖、血钾、血压水平,以及治疗效果;结果：血钾、血糖方面,两组患者治疗前后检测比较,P＞0.05;治疗后,观察组血糖低于对照组,两组比较,P＜0.05;血压方面,两组患者的舒张压和收缩压均有所下降,观察组下降效果优于对照组,两组比较,P＜0.05;观察组血压控制的总有效率为85.71%,对照组为65.71%,两组比较差异显著具有统计学意义(P＜0.05)。结论：对糖尿病合并高血压患者行吲达帕胺联合依那普利治疗效果显著,不良反应少,安全性和可行性较高。     

依那普利对犬急性右心室心肌梗死心源性休克血流动力学指标的作用

目的观察依那普利、单纯补液对急性右心室心肌梗死(RVMI)心源性休克时血流动力学指标的作用。方法结扎犬冠状动脉造成大面积RVMI并发心源性休克模型。随机分为对照组、补液组、依那普利组。观察各组正常时、梗死后即刻及给药后即刻、1h、1周时点的平均动脉压(MAP)、心排血量(CO)、右心房压力(RAP)、右心室收缩压(RVSP)等血流动力学指标,并评价疗效。结果快速补液后,RAP进一步升高,加重了血流动力学变化。依那普利治疗后RAP降低,CO增加,血流动力学变化得以改善。结论大面积RVMI心源性休克时,快速扩容治疗在RAP≥13mmHg时会进一步损害左、右心室功能,依那普利可降低右心后负荷,增加CO,能有效纠正休克。     

氯沙坦、依那普利及其合用对腹主动脉缩窄型高血压大鼠的影响

目的　探讨依那普利、氯沙坦及其合用对腹主动脉缩窄型高血压大鼠血压、心肌肥厚程度和心肌组织丝裂原活化蛋白激酶 (MAPK)的活性及表达的影响。方法　采用腹主动脉缩窄型高血压大鼠模型 ,然后将动物随机分为 7组 (n均 =6 )。分别为氯沙坦 (10 mg· kg- 1 · d- 1 )组 ,氯沙坦 (30 mg· kg- 1 · d- 1 )组 ,依那普利 (4mg· kg- 1 · d- 1 )组 ,依那普利 (12 mg· kg- 1· d- 1 )组 ,依那普利合用氯沙坦 (4m g· kg- 1· d- 1和 10 m g· kg- 1· d- 1 )组和安慰剂组。以假手术组作对照。给药 5周后测定左心室重量与体重比值、平滑肌肌动蛋白表达和 MAPK蛋白表达变化。结果　与假手术组比较 ,大鼠腹主动脉缩窄术后 6周血压明显升高 ,心肌组织发生明显肥厚 ,平滑肌肌动蛋白和 MAPK蛋白表达增高 (P<0 .0 1)。与安慰剂组比较 ,氯沙坦、依那普利及其合用可降低平均动脉血压 ,减轻心肌肥厚 ,同时降低平滑肌肌动蛋白和 MAPK蛋白表达 (P<0 .0 1) ,且氯沙坦、依那普利的作用呈剂量依赖性。与单用氯沙坦或依那普利比较 ,氯沙坦和依那普利合用可进一步降低平均动脉血压、减轻心肌肥厚和 MAPK蛋白表达 (P <0 .0 5 )。结论　 MAPK是介导高血压心肌肥厚的重要信号分子。氯沙坦、依那普利均能减轻心肌肥厚和 MAPK蛋白?     

解酒药改善心肌梗死后心力衰竭大鼠心脏功能的观察研究

目的观察使用解酒药是否能改善心肌梗死后心力衰竭大鼠的心脏功能。方法将60只体重相近的成年雄性SD大鼠采用冠状动脉结扎法建立急性心肌梗死模型后,随机分为4组,灌胃不同药物,分别为阴性对照生理盐水组(0.3ml/(kg.d)),阳性对照依那普利组(10mg/(kg.d)),解酒药组(0.3g/(kg.d))以及解酒药和依那普利联合用药组(0.3g/(kg.d)解酒药加10mg/(kg.d)依那普利)。所有大鼠术后每组每天定时进行药物干预,并每周定时测量体重。术后4周采集超声心动图各参数(室间隔厚度、后壁厚度、左室舒张末内径、左室收缩末内径、左室短轴缩短率、左室射血分数)来评价大鼠的心功能。结果与术前相比,术后4周解酒药组和联合用药组大鼠的体重无明显变化,而依那普利组和生理盐水组大鼠体重上升。术后4周心脏超声结果显示:与生理盐水组比较,依那普利组、解酒药组和联合用药组的左室射血分数、左室短轴缩短率均有升高(P<0.05),但三组间无显著性差异;而室间隔厚度、后壁厚度、左室舒张末内径、左室收缩末内径等参数,四组间无显著性差异。结论解酒药能有效改善心肌梗死后心力衰竭的大鼠心功能。     

血脂紊乱对大鼠动脉p27表达水平的影响

目的观察高脂血症对大鼠主动脉p27表达的影响,初步探讨其在动脉硬化过程中的作用机制。方法将30只SD大鼠随机分为正常对照组、高脂血症组和高脂血症依那普利治疗(依那普利)组各10只。各组大鼠用酶比色法检测血TC、TG、LDL-C和HDL-C浓度;用HE染色法观察主动脉病理改变,测量主动脉壁内层、中层厚度;用逆转录聚合酶链反应(RT-PCR)检测血管组织p27 mRNA的表达强度,用免疫印迹法(Western blot)检测p27蛋白的表达强度。结果高脂血症组大鼠血TC、TG、LDL-C浓度均高于正常对照组(均为P0.01),HDL-C浓度低于正常对照组(P0.01),依那普利可在一定程度上降低血脂水平,但差异无统计学意义。高脂血症组血管壁内层和中层厚度明显高于对照组[血管壁内层厚度:正常对照组(2.69±0.13)μm比高脂血症组(2.77±0.16)μm,P0.05;血管壁中层厚度:正常对照组(209.38±11.30)μm比高脂血症组(247.14±11.64)μm,P0.01],组织p27 mRNA和p27蛋白表达水平较对照组明显降低[p27 mRNA/GAPDH mRNA:正常对照组(0.57±0.08)比高脂血症绢(0.14±0.02),P0.05;p27蛋白:正常对照组(0.42±0.05)比高脂血症组(0.10±0.02),均为P0.05];依那普利组血管壁厚度较高脂血症组减小(P0.05),p27 mRNA和p27蛋白的表达水平明显上调[p27 mRNA/GAP-DHmRNA:高脂血症组(0.14±0.02)比依那普利组(0.38±0.05);p27蛋白:高脂血症组(0.10±0.02)比依那普利组(0.35±0.06),均为P0.05]。结论 p27在高脂血症大鼠血管组织呈低水平表达,依那普利可使其表达增加,p27可能参与了抑制动脉硬化的进展。     

Update on antifungal agents for paediatric patients

Paediatric age groups display important differences in host biology, predisposing conditions, epidemiology and presentation of fungal infections relative to the adult population. During the past decade, several new antifungal agents have been developed. Although not all of these agents are yet approved for children, the paediatric development of antifungal agents has moved forwards in an exemplary manner. Invasive fungal infections will remain important causes of morbidity and mortality in immunocompromised paediatric patients. Whereas the availability of new therapeutic options is an important advance, antifungal therapy has become increasingly complex, and a thorough understanding of the available antifungal armamentarium is essential for the successful management of the individual patient. This article provides an update on the pharmacokinetics, safety and dosing of antifungal agents in paediatric patients, and their clinical indications.