Development and evaluation of new multiple-unit levodopa sustained-release floating dosage forms

This work relates to the development and the in vitro evaluation of sustained-release minitablets (MT), prepared by melt granulation and subsequent compression, which are designed to float over an extended period of time. Levodopa was used as a model drug. The importance of the composition and manufacturing parameters of the MT on their floating and dissolution properties was then examined. The investigation showed that MT composition and MT diameter had the greatest influence on drug release, which was sustained for more than 8h. By using the same formulation, the best floating properties were obtained with 3mm MT prepared at low compression forces ranging between 50 and 100N. Their resultant-weight (RW) values were always higher than those obtained with a marketed HBS dosage form within 13h. When they were filled into gelatin capsules, no sticking was observed. By evaluating the dissolution profiles of levodopa at different pH values, it was found that dissolution profiles depend more on the prolonged-release ability of Methocel K15M than on the pH-dependent solubility of levodopa. Finally, the robustness of the floating MT was assessed by testing the drug release variability in function of the stirring conditions during dissolution tests.     

Development and evaluation of sustained-release propranolol wax microspheres

To obtain a sustained-release dosage form with a lack of gastric unwanted effects, wax microspheres containing propranolol (I) were prepared by a congealable dispersion microencapsulation technique. The effects of the process variables; type of wax, speed of emulsification, amount of drug loaded, type and amount of emulsifier, were studied on the entrapment efficiency, angle of repose, dissolution efficiency (DE), in-vitro drug release and mean particle size of (I) microspheres, by a factorial design. The results showed that changes in the amount of emulsifier (Tween), 0.04% and 0.08%, the type of Tween (80 and 20) and the wax type; beeswax or ceresine, caused a significant decrease in the entrapment efficiency. All the variables had an effect on the angle of repose and particle size of the (I) microspheres. The only significant parameter affecting the DE was the nature of the wax. The drug release in pH 6.8 was affected by all the variables except the amount of emulsifier. The formulation with a 0.25:4 ratio of drug:ceresine wax and 0.04% of Tween 80 in 600 rpm emulsification speed showed a suitable multiparticulate delivery system for the retarded dissolution of entrapped active ingredients, allowing absorption only in the intestinal tract.     

Development and evaluation of sustained-release propranolol wax microspheres

To obtain a sustained-release dosage form with a lack of gastric unwanted effects, wax microspheres containing propranolol (I) were prepared by a congealable dispersion microencapsulation technique. The effects of the process variables; type of wax, speed of emulsification, amount of drug loaded, type and amount of emulsifier, were studied on the entrapment efficiency, angle of repose, dissolution efficiency (DE), in-vitro drug release and mean particle size of (I) microspheres, by a factorial design. The results showed that changes in the amount of emulsifier (Tween), 0.04% and 0.08%, the type of Tween (80 and 20) and the wax type; beeswax or ceresine, caused a significant decrease in the entrapment efficiency. All the variables had an effect on the angle of repose and particle size of the (I) microspheres. The only significant parameter affecting the DE was the nature of the wax. The drug release in pH 6.8 was affected by all the variables except the amount of emulsifier. The formulation with a 0.25:4 ratio of drug:ceresine wax and 0.04% of Tween 80 in 600 rpm emulsification speed showed a suitable multiparticulate delivery system for the retarded dissolution of entrapped active ingredients, allowing absorption only in the intestinal tract.     

An overview of preparation and evaluation sustained-release injectable microspheres

Recently, sustained-release injectable microspheres as a novel parenteral administration system have been interested on for many years, due to the excellent advantages when compared to traditional dosage forms: less administration frequency, lower adverse side effects and no need for a surgical procedure. Therefore, major progresses in the development of another successful marketed sustained-release injectable formation have been made, but most investigations are merely limited in laboratory levels; in addition, few reports focus on giving some positive guidance to launch these novel microspheres into market. This review addressed some commonly used polymers, preparation methods and sterilization processes relating to biodegradable microspheres. Moreover, the processes for measuring the sustained-release behaviour of this novel system are summarized in this report, including the methods to determine the in vitro and in vivo release behaviours and the strategies to analyse the in vitro and in vivo correlations.     

Preparation and in-vitro evaluation of sustained-release metoclopramide hydrochloride microspheres

Abstract

Sustained-release metoclopramide microspheres were successfully prepared using cellulose propionate polymer at 1:2 drug to polymer ratio employing solvent evaporation technique and using acetone as the polymer solvent. The prepared microspheres at three stirring speeds were characterized with regard to their drug content, particle size distribution, surface topography using SEM and their release profiles at two different pHs at 37°C. The surface of all samples was smooth with very few irregular elevations or depressions. The average particle size decreases as the rotational speed increases and was found to be 1320, 774 and 345 μm at 600, 900 and 1200rpm, respectively. The average % drug entrapped was found to be 90.5, 100.1 and 60.0% at 600, 900 and 1200 rpm, respectively. Small differences in the release rate were observed due to different rotation speeds with an apparent lower dissolution for batches produced at 1200 rpm probably due to the properties of the coat. The effect of storage under accelerated conditions for 10 weeks on the release characteristics of these microspheres was also studied. The release properties of the microspheres did not change after storing them at 40°C/80% relative humidity for 10 weeks.     

A new multiple-unit oral floating dosage system. I: Preparation and in vitro evaluation of floating and sustained-release characteristics.

A multiple-unit type of oral floating dosage system, (a new type of floating pills which generate carbon dioxide gas) has been prepared in order to prolong the gastric emptying time (GET) of the preparation. The floating ability and the sustained-release characteristics of the system have been elucidated in vitro. The system was composed of sustained-release pills as seeds and double layers on the sustained-release pills. The inner layer was an effervescent layer containing both sodium bicarbonate and tartaric acid. The outer layer was a swellable membrane layer containing mainly polyvinyl acetate and purified shellac. When the system was immersed in water, it formed swollen pills, like balloons, with a density much lower than 1.0 g/mL. The reaction was due to carbon dioxide gas generated by neutralization in the effervescent layer with the diffusion of water through the swellable membrane layer. The system was floating completely within approximately 10 min and approximately 80% remained floating over a period of 5 h irrespective of pH and viscosity of the test medium. While the system was floating, a drug (p-aminobenzoic acid) was released. The release rate of the drug from the system was zero order and depended on the sustained-release characteristics of the sustained-release seeds composing the system. The release rate was not affected by the amount of the swellable membrane layer up to 13% (w/w).     

APT011缓释微球的制备及体外评价（英文）

本研究目的在于制备新的神经激肽-1受体拮抗剂—APT011缓释注射微球,并对其理化性质、体外释放及初步稳定性进行评价。首先采用W/O/W复乳溶剂挥发法制备载药微球,并用正交设计实验优化处方工艺。显微观察结果显示该载药微球为球形,圆整度好;平均粒径为90μm,粒径分布均匀;粉末X-衍射结果表明APT011在微球内部以无定型形式存在; DSC结果表明药物APT011与空白微球无明显相互作用。此外,载APT011微球具有明显的缓释效果,可持续释放2个月。初步稳定性结果表明在40°C和光照条件下,微球的载药量与突释效应没有明显改变。上述结果说明,载APT011微球具有优良的理化性质、缓释特性和初步稳定性,具有进入临床的潜力。     

马来酸曲美布汀胃漂浮缓释片的处方筛选及体外评价

目的筛选马来酸曲美布汀胃漂浮缓释片的处方,并评价其漂浮和体外释放特性。方法用正交实验设计对片剂处方进行筛选与优化,制备马来酸曲美布汀胃漂浮缓释片,测定其体外释药与漂浮特性。结果优选的处方为每片含HPMC800030 mg,CMC-Na 30 mg,十六醇70 mg,CaCO330 mg。该处方片剂在硬度为3-4 kg时漂浮性好,体外持续释药达6 h以上,符合Higuchi模型。结论该片剂具漂浮、缓释作用,制备工艺简单。     

Development of oral drug delivery system using floating microspheres

Floating acrylic resin microspheres with an internal hollow structure were prepared by a solvent diffusion and evaporation method. The yield of microspheres depended on the diffusion rate of ethanol and/or isopropanol in the organic phase. They were successfully produced when amixture of ethanol and isopropanol was used instead of ethanol alone. The mixing ratioof components in the organic phase affected the size and the yield of microspheres and the best results were obtained at the volume ratio of ethanol:isopropanol:dichloromethane (8:2:5). Direct introduction of the organic phase into the aqueous phase through aglass tube alsosignificantly improved the yield by avoiding the contact of organic phase with the surface of water. The optimum rotation speed and temperature were 250rpm and 25 C, respectively. Several different drugs with various physico-chemical properties were used as model drugs for encapsulation and release tests. When a drug had low solubility in dichloromethaneandhighsolubilityin both water and amixture of ethanol/isopropanol, the loading efficiency was the lowest. The release profiles were significantly different depending on the solubility of a drug in the release medium and the physico-chemical properties of an encapsulated drug.     

Development of oral drug delivery system using floating microspheres

Floating acrylic resin microspheres with an internal hollow structure were prepared by a solvent diffusion and evaporation method. The yield of microspheres depended on the diffusion rate of ethanol and/or isopropanol in the organic phase. They were successfully produced when a mixture of ethanol and isopropanol was used instead of ethanol alone. The mixing ratio of components in the organic phase affected the size and the yield of microspheres and the best results were obtained at the volume ratio of ethanol:isopropanol:dichloromethane (8:2:5). Direct introduction of the organic phase into the aqueous phase through a glass tube also significantly improved the yield by avoiding the contact of organic phase with the surface of water. The optimum rotation speed and temperature were 250 rpm and 25 degrees C, respectively. Several different drugs with various physico-chemical properties were used as model drugs for encapsulation and release tests. When a drug had low solubility in dichloromethane and high solubility in both water and a mixture of ethanol/isopropanol, the loading efficiency was the lowest. The release profiles were significantly different depending on the solubility of a drug in the release medium and the physico-chemical properties of an encapsulated drug.     

Development and evaluation of sustained-release clonidine-loaded PLGA microparticles

This work describes the encapsulation of a small, hydrophilic molecule (clonidine) into a PLGA matrix to provide sustained release over more than one month after intra-articular administration. The microparticles were prepared using a double emulsion (w(1)/o/w(2)) method followed by evaporation of the organic solvent. To optimize the efficiency of encapsulation and the mean size of the microparticles, which was targeted around 30μm, the following parameters were modulated: the viscosity and the volume of the organic phase, the molecular weight of the polymer, the volume of the internal and external aqueous phases, the drug loading, the concentration of surfactant, and the stirring parameters. Blends of polymers characterized by different molecular weights (34000-96000Da) as well as copolymers of PLGA-PEG were used to enhance the entrapment of the drug. The pH of the aqueous phases was adjusted to obtain suitable encapsulation efficiency. Characterization was made of the physico-chemical properties of the microparticles, such as their crystallinity (DSC and PXRD) and microstructure (SEM). When performing in vitro dissolution studies, controlled release for up to approximately 30days was achieved with several of the formulations developed. Diffusion was found to be the dominant drug release mechanism at early time points.     

亮丙瑞林缓释微球的研究

目的 :制备收率及包封率高、可持续释药 3mo的亮丙瑞林微球。方法 :以生物可降解聚合物聚乳酸 (PLA)为载体 ,采用W /O/W复乳 液中干燥法制备缓释亮丙瑞林微球 ,以包封率及收率为指标 ,用正交设计对微球处方工艺进行优化 ,并考察微球的体外释放及体内药效。结果 :经优化得到的亮丙瑞林微球收率及包封率分别为 6 8%和 6 5 %。在选择的释放条件下 ,至 10 5d时 ,累积释放 88%。给予成熟雄性大鼠 10 0 μg·kg- 1·d- 1单剂量皮下注射 ,12h内出现睾酮迅速升高 ,3d内降至 0 .1μg·L- 1以下 ,并维持低睾酮水平 10 5d。结论 :制备的亮丙瑞林微球能产生持续长时间的缓释作用     

Development and in vitro characterization of floating sustained-release drug delivery systems of polyphenols

Abstract

The aim of this study was to develop and characterize floating stomach-retentive matrix tablets that will deliver polyphenols in a controlled release manner. The tablets were prepared by direct compression. A number of polymers were examined and egg albumin was chosen in light of a better performance in terms of floating behavior and decomposition time. Dissolution studies for three representative polyphenols loaded into a number of formulations were performed using the “f₂” factor in order to compare release profiles of different polyphenols and formulations. The release data showed a good fit into the power law equation and zero-order kinetics has been determined for some of the systems. Erosion and textural analysis studies revealed that higher concentration of egg albumin results in a higher gel strength that is less susceptible to erosion, potentially leading to a prolonged delivery time of drug. The ability of egg albumin-based tablets to resist high mechanical forces was also determined, while comparison to cellulose-derived polymers revealed that the latter have a much lower ability to resist the same forces. The developed delivery system has the potential to increase the efficacy of the therapy for various pathological stomach conditions and to improve patient compliance.     

尼莫地平缓释水凝胶微球的制备

目的:研究瓜尔胶-丙烯酰胺接枝聚合物水凝胶微球的制备工艺,并以尼莫地平为模型药物考察其体外释放特性.方法:选择搅拌速度、交联剂用量、聚合物浓度、乳化剂用量、油/水比5个因素作为考察对象,通过L16(45)正交设计实验优化制备工艺,并在电镜下观察微球形态,用HPLC法测定微球的载药量及累计释药量.结果:5因素对微球制备工艺的影响依次为交联剂用量＞乳化剂用量＞聚合物浓度＞搅拌速度＞水/油比.经过优选制得的尼莫地平水凝胶徽球,球形度较好,表面较光滑,载药量为(1.40±0.27)%.体外释药结果表明,一级动力学方程及Higuchi方程均能较好地对其进行拟合.结论:本法工艺稳定可行,所得尼莫地平水凝胶微球具有良好的缓释效果.     

长春西汀s-PLGA长效缓释微球的体内外评价

目的:本研究以星状聚乳酸羟基乙酸共聚物(star poly D,L-lactide-co-glycolide,s-PLGA)为载体制备长春西汀长效缓释微球,对其体内外性质进行评价。方法:采用开环聚合法制备s-PLGA,以此作为载体材料,采用乳化-溶剂挥发法制备长春西汀s-PLGA长效缓释微球(VIN-MS),并对其包封率、粒径和体内外性质进行了考察。结果:本研究制备的VIN-MS的平均粒径为(18±2)μm,包封率为62.20%,载药量为37.43%。扫描电镜观察结果表明,微球外观圆整、均匀,流动性好,分散性好。体外释放结果表明,VIN-MS具有明显的缓释特性,其突释率为6.96%。体内结果表明,VIN-MS制剂体内周期能维持15 d,与长春西汀普通注射剂相比,VIN-MS的曲线下面积(AUC)和平均滞留时间(MRT)分别是普通注射剂的40倍和38倍。结论:长春西汀s-PLGA长效缓释微球的成功制备将有利于脑血管病的治疗。     

A new multiple-unit oral floating dosage system. II: In vivo evaluation of floating and sustained-release characteristics with p-aminobenzoic acid and isosorbide dinitrate as model drugs.

In a previous study, we developed a multiple-unit type of oral floating dosage system, which is a new type of floating pill composed of both an effervescent layer and a swellable membrane layer coated on sustained-release pills. The system was shown to have excellent floating ability and sustained-release characteristics in vitro, irrespective of the pH and viscosity of the medium. In the present study, the floating ability and the sustained-release characteristics of the system in the gastrointestinal tract have been evaluated in vivo. In beagle dogs and humans in the fed state, most of the new type of pills containing barium sulfate were floating in the stomach at 10 min, and they kept floating for at least 3 h after administration (observed by periodic X-ray photographs), while some control pills without the effervescent layers were already transited into the small intestine by 3 h. Moreover, in order to evaluate the sustained-release characteristics of the drug from the new type of floating pills, p-aminobenzoic acid (PABA), with a limited absorption site, and isosorbide dinitrate (ISDN), with wide absorption sites in the gastrointestinal tract, were employed as model drugs. Floating pills of the new type, with the same sustained-release rate as that of non-floating pills (control pills) were prepared. In beagle dogs in the fed state, the new type of floating pills containing PABA showed higher plasma PABA levels at 5 and 6 h after dosing and 1.61 times greater AUC than the control pills.(ABSTRACT TRUNCATED AT 250 WORDS)     

当归多糖铁胃内漂浮缓释片的处方筛选及体外评价

目的:研究当归多糖铁胃内漂浮缓释片(APIC-FSRT)的制备工艺及释放机理.方法:采用均匀设计优化处方,以丙烯酸树脂Ⅱ,羟丙基甲基纤维素,聚维酮等为辅料,全粉末直接压片.结果:筛选出体外释放10 h,漂浮达12 h的最优化处方,其释放曲线符合Higuchi方程.结论:为制备当归多糖铁胃内漂浮缓释片提供依据.