注射用奈达铂的制备及质量研究

目的 对注射用奈达铂的制备工艺及质量检测进行研究.方法 对使用的溶剂和赋形剂进行筛选,确定处方,并通过对pH值范围、活性炭用量和冻干工艺进行筛选,确定其制备工艺;采用高效液相色谱法测定制剂的含量和有关物质.结果 最佳处方为奈达铂50 mg,右旋糖酐150 mg,乙醇适量.pH值范围为6.5～7.5,活性炭用量0.1％;最佳冻干过程为--40℃预冻6h,18 h内升温至25℃,25℃再干燥4h.结论 本品制备工艺可靠,适于工业化生产,质量可控.     

5-氟尿嘧啶壳聚糖纳米粒冻干粉的制备

目的 为研究5-氟尿嘧啶壳聚糖纳米粒冻干粉的制备工艺,提高5-氟尿嘧啶壳聚糖纳米粒的稳定性。方法 首先制备5-氟尿嘧啶壳聚糖纳米粒,并以外观和再分散性为指标,进行单因素考察并利用正交实验优化工艺。结果 5-氟尿嘧啶壳聚糖纳米粒冻干粉的最佳制备工艺为预冻时间24 h、冻干保护剂为甘露醇、用量为80 mg、浓度为10%。冻干前后包封率差异无统计学意义（P>0.05）,冻干后的粒径和冻干前相比有一定增大。结论 5-氟尿嘧啶壳聚糖纳米粒冻干粉有望成为新剂型。     

巴豆总蛋白质提取工艺优选

摘 要 目的: 优选巴豆总蛋白质的最佳提取工艺。 方法: 以巴豆总蛋白得率为评价指标,采用单因素和正交试验考察提取溶剂、料液比、提取溶剂pH、提取转速及时间对得率的影响并确定最佳提取工艺。结果:单因素试验结果表明,以PBS缓冲液提取、转速8 000 r·min^-1、料液比1∶70、时间15 min、提取溶剂pH为8.0时,巴豆总蛋白质得率最高。正交试验得出各因素对巴豆总蛋白质得率的影响程度大小依次为：pH＞提取转速＞料液比＞时间,巴豆总蛋白质的最佳工艺条件为：PBS缓冲液pH为8.0,料液比1∶70、提取转速8 000 r·min^-1,提取时间20 min。结论:通过单因素试验和正交试验确定了巴豆总蛋白质的最佳提取工艺,该工艺操作简单、省时,为巴豆蛋白质的进一步深层次研究提供了基础。     

HPLC法测定注射用卡非佐米的含量

摘 要 目的：建立高效液相色谱法测定注射用卡非佐米含量的方法。方法: 使用Waters symmetry C₁₈（250 mm×4.6 mm, 5 μm）色谱柱,样品溶剂为甲醇,流动相为0.05%三氟乙酸水-乙腈（57∶43）,流速为1.0 ml·min^-1,波长210 nm,柱温25℃,进样体积10 μl。结果: 结果卡非佐米线性范围为120～600 μg·mL^-1(r=0.999 7),平均回收率为100.4%,RSD为0.24%（n=9）。结论:本方法能够快速有效地测定注射用卡非佐米的含量。     

注射用奥扎格雷钠细菌内毒素检查方法研究

目的：探讨注射用奥扎格雷钠细菌内毒素检查方法替代家兔热原检查法的可行性。方法：采用2个不同厂家的鲎试剂,用凝胶法进行干扰预试验及干扰试验;用灵敏度为0.5EU·mL^-1鲎试剂和0.8mg·mL-1的奥扎格雷钠溶液进行细菌内毒素检查。结果：注射用奥扎格雷钠稀释到0.8mg·mL^-1时,对鲎试剂与内毒素的凝集反应无干扰作用;样品的细菌内毒素限值确定为0.625EU·mL^-1。结论：注射用奥扎格雷钠可用细菌内毒素检查法替代原有的家兔热原检查法。     

基于生物指标与理化指标结合模式指导的加味甘麦大枣颗粒精制纯化工艺

目的 优选加味甘麦大枣颗粒的精制纯化工艺。方法 以药效为指标,确定制剂的精制纯化工艺路线;以甘草苷转移率为定量指标,甘草、合欢皮、地龙的薄层色谱为定性指标优选制剂的工艺参数。结果 最佳精制纯化工艺：水煎煮液浓缩至相对密度为1.10（60℃）,加乙醇至50%,搅拌速率300 r·min^-1,静置24 h。结论 制定的制剂工艺可行,保证了制剂的有效稳定。     

不同处方工艺的注射用尼麦角林质量及稳定性对比研究

目的 确定影响注射用尼麦角林质量及稳定性的因素,为本品处方工艺及质量控制提供依据。方法 采用不同处方、冻干工艺制备样品,进行不同温度下稳定性考察,以有关物质为指标,评价不同温度对产品稳定性的影响。结果 产品处方、水分及温度均会对注射用尼麦角林的稳定性造成影响。结论 水分和温度是影响注射用尼麦角林质量稳定性的主要因素,处方差异对稳定性的影响较小。     

多指标综合评分法优化痛风巴布剂的醇提工艺

目的 优选痛风巴布剂的最佳提取工艺。方法 以青藤碱、总生物碱的含量和干浸膏得率为评价指标,采用正交设计试验,考察乙醇浓度、乙醇用量、提取时间和提取次数对提取结果的影响,确定痛风巴布剂处方药材的最佳提取工艺。结果 痛风巴布剂的最佳提取工艺为65%乙醇,提取3次,每次6倍量溶剂,提取总时间为1.5 h,在该工艺条件下得到的青藤碱含量、总生物碱含量和干浸膏得率分别为2.79 mg·g^-1、1.22%和13.06%。结论 优选的醇提工艺稳定、可行。     

注射用克林霉素磷酸酯降压物质检查法的研究

目的 建立注射用克林霉素磷酸酯降压物质检查法。方法 通过对注射用克林霉素磷酸酯与组织胺对照品引起麻醉猫血压下降程度比较的研究,确定其降压物质检查法的限值。结果 注射用克林霉素磷酸酯降压物质检查限值确定为5 mg·kg^-1较为合理。结论 注射用克林霉素磷酸酯降压物质检查拟定方法符合规定,方法可行。     

注射用益气复脉(冻干)HPLC指纹图谱研究

目的 建立注射用益气复脉(冻干)的HPLC指纹图谱,并建立评价其质量的指纹图谱分析方法。方法 采用HPLC法,色谱柱为Waters Symmetry^® C₁₈柱(250 mm×4.6 mm,5 μm);流动相为乙腈-0.01%磷酸水溶液梯度洗脱;检测波长203 nm;柱温32 ℃。结果 建立了注射用益气复脉(冻干)中人参皂苷类、五味子木质素类的指纹图谱,并建立了3种指纹图谱分析评价方法。结论 建立的注射用益气复脉(冻干)指纹图谱的重复性、稳定性好,采用夹角余弦法与相关系数法从两个不同的角度评价指纹图谱,可以有效地反映益气复脉的质量,两者差异不大,而采用欧氏距离法却无法获得两张图谱的真实相似程度,无法给出直观的综合质量评价结果。     

不同冻干保护剂对利巴韦林冻干粉针的影响研究

目的研究Emprove低内毒素蔗糖、无水乳糖、Emprove低内毒素葡萄糖、Emprove低内毒素甘露醇、Emprove低内毒素山梨醇、Emprove低内毒素氯化钾、Emprove低内毒素甘氨酸7种不同类型常用冻干保护剂对利巴韦林冻干粉针性能的影响。方法以外观和复溶效果为指标,考察了预冻时间、冻干保护剂用量、冻干时间的影响。测定了空白粉针剂和利巴韦林粉针剂冻干后含水量、p H值和利巴韦林质量分数。结果以无水乳糖为冻干保护剂,预冻时间6 h,冻干时间9 h,保护剂用量4%;以Emprove低内毒素氯化钾为冻干保护剂,预冻时间9 h,冻干时间9 h,保护剂用量4%;以Emprove低内毒素甘露醇为冻干保护剂,预冻时间6 h,冻干时间6 h,保护剂用量4%;以Emprove低内毒素甘氨酸为冻干保护剂,预冻时间12 h,冻干时间9 h,保护剂用量4%。所得冻干粉针外观饱满、平整,迅速、完全复溶。结论无水乳糖、Emprove低内毒素氯化钾、Emprove低内毒素甘露醇、Emprove低内毒素甘氨酸4种冻干保护剂更适合制备利巴韦林冻干粉针,可为水溶性药物冻干粉针剂的制备提供了参考。     

不同冻干保护剂对硼替佐米冻干粉针的影响研究

目的研究Emprove低内毒素蔗糖、Emprove低内毒素甘露醇、Emprove低内毒素甘氨酸3种不同类型冻干保护剂对硼替佐米冻干粉针性能的影响。方法以硼替佐米冻干粉针和空白冻干粉针的外观和复溶效果为指标,考察预冻时间、冻干保护剂用量、冻干时间、叔丁醇体积分数的影响。比较了硼替佐米冻干粉针和空白冻干粉针的含水量、p H值和硼替佐米的质量分数。结果 3种冻干保护剂均能在适宜条件下制备硼替佐米冻干粉针,以Emprove低内毒素蔗糖为冻干保护剂,预冻时间24 h,用量15%,冻干时间15 h,叔丁醇体积分数40%;以Emprove低内毒素甘露醇为冻干保护剂,预冻时间6 h,用量4%,冻干时间6 h,叔丁醇体积分数40%;以Emprove低内毒素甘氨酸为冻干保护剂,预冻时间6 h,用量4%,冻干时间6 h,叔丁醇体积分数20%;所得产品饱满、平整,完全复溶。冻干后含水量5%,p H值和硼替佐米的质量分数变化不显著。结论 Emprove低内毒素蔗糖、Emprove低内毒素甘露醇、Emprove低内毒素甘氨酸均适合用作硼替佐米冻干粉针剂制备的冻干保护剂,实验为难溶性药物冻干制剂的制备提供了参考。     

Application of freeze-drying in the development of oral drug delivery systems

ABSTRACT

Introduction: With continual focus on oral drug delivery systems (ODDS), the role of freeze-drying becomes increasingly valuable. While freeze-drying is fundamentally a desiccation process, the advantageous material properties attributed to freeze-drying extend far beyond the preparation of stable pharmaceutical products. The formulation and process variables are important considerations as they affect the final freeze-dried product characteristics. It is of interest to expound on the principles and effects of freeze-drying in the hope of introducing novel products for applications in the development of ODDS.

Areas covered: In this review, basic principles, general formulation and process variables associated with freeze-drying will be covered. The application of freeze-drying in 3 areas: modification of active ingredients, development of novel freeze-dried excipients and development of freeze-dried final dosage forms will be discussed.

Expert opinion: As a pharmaceutical unit operation, freeze-drying has created new dimensions in the area of oral drug delivery, where the properties of the drugs, excipients and characteristics of the final solid dosage form can be modified by the freeze-drying process. With the emergence of new applications, the role of freeze-drying technology in ODDS is indeed a relevant and promising one.     

丁香苦苷冻干粉针的处方优化及制备工艺的研究

目的:研究适合注射用丁香苦苷冻干粉针的处方配比和制备工艺。方法:以产品外观,复水性,含量等为指标,运用正交试验法优化其处方配比;采用真空冷冻干燥法制备其样品,用高效液相色谱法检测其含量,并对制备条件如装量、共晶点、预冻温度、升华温度、解吸温度等进行研究。结果:经优化,确定丁香苦苷含量为8%(A2),赋形剂用量为5%甘露醇(B2),装量为2.5mL(C3),西林瓶规格为7mL(D1);生产工艺为pH值为7.0,-45℃下预冻、-30℃下升华干燥和25℃时解吸干燥。结论:该工艺制备的丁香苦苷冻干粉针符合《中国药典》(2005版)冻干粉针的相关规定。     

Effect on the nasal bioavailability of co-processing drug and bioadhesive carrier via spray-drying

A mucoadhesive combination of a maize starch (Amioca^®, mainly consisting of amylopectine) and a cross-linked acrylic acid-based polymer (Carbopol^® 974P) was spray-dried with metoprolol tartrate (used as model molecule) in order to develop a powder suitable for nasal drug delivery via a one-step manufacturing process. The bioavailability of metoprolol tartrate after nasal administration of this powder to rabbits was compared with powders manufactured via other procedures: (a) freeze-drying of a dispersion prepared using the co-spray-dried powder, (b) freeze-drying of a dispersion prepared using a physical mixture of drug and mucoadhesive polymers. After co-processing via spray-drying a low bioavailability (BA 10.8 ± 2.3%) was obtained, whereas manufacturing procedures based on freeze-drying yielded a higher BA: 37.9 ± 12.8% using the co-processed powder and 73.6 ± 24.9% using the physical mixture. The higher bioavailability was due to the deprotonation of poly(acrylic acid) during neutralisation of the dispersion prior to freeze-drying. This induced repulsion of the ionised carboxyl groups and a lower interaction between poly(acrylic acid) and starch, creating a less compact matrix upon hydration of the polymer and allowing an easier escape of metoprolol tartrate from the matrix. This study showed that co-processing of a mucoadhesive Amioca^®/Carbopol^® 974P formulation with metoprolol tartrate via co-spray-drying did not provide any added value towards the bioavailability of the drug after nasal administration of the mucoadhesive powder.     

Pharmaceutical development of a parenteral lyophilized formulation of the investigational antitumor neuropeptide antagonist [Arg6, D-Trp7,9, MePhe8]-Substance P {6-11}

The aim of this study was to develop a stable parenteral dosage form for the investigational cytotoxic drug [Arg6, D-Trp7,9, MePhe8]-Substance P {6-11} (Substance P Antagonist G; Antagonist G). Antagonist G bulk drug was structurally and analytically characterized. The drug exhibits excellent aqueous solubility, although relatively poor aqueous stability characteristics. Lyophilization was, therefore, selected as the manufacturing process. Differential scanning calorimetry studies were conducted to determine the freeze-drying cycle parameters which resulted in a stable, lyophilized formulation of Antagonist G. The prototype, containing 50 mg Antagonist G per vial, was found to be the optimal formulation in terms of solubility, length of the freeze-drying cycle, stability, and dosage requirements in the planned phase I clinical trials. Quality control of the freeze-dried formulation showed that the manufacturing process does not change the integrity of Antagonist G. Shelf life studies demonstrated that the formulation is stable for at least 3 years, when stored at 2–8°C in a dark environment. Oxidative degradation products of Antagonist G were isolated and structurally characterized by mass spectrometry, nuclear magnetic resonance spectroscopy, and infrared spectroscopy.     

Spray-congealed microparticles for drug delivery – an overview of factors influencing their production and characteristics

Introduction: In any manufacturing process, the success of producing an end product with the desired properties and yield depends on a range of factors that include the equipment, process and formulation variables. It is the interest of manufacturers and researchers to understand each manufacturing process better and ascertain the effects of various manufacturing-associated factors on the properties of the end product. Unless the manufacturing process is well understood, it would be difficult to set realistic limits for the process variables and raw material specifications to ensure consistently high-quality and reproducible end products. Over the years, spray congealing has been used to produce particulates by the food and pharmaceutical industries. The latter have used this technology to develop specialized drug delivery systems.

Areas covered: In this review, basic principles as well as advantages and disadvantages of the spray congealing process will be covered. Recent developments in spray congealing equipment, process variables and formulation variables such as the matrix material, encapsulated material and additives will also be discussed.

Expert opinion: Innovative equipment designs and formulations for spray congealing have emerged. Judicious choice of atomizers, polymers and additives is the key to achieve the desired properties of the microparticles for drug delivery.     

Development of a Freeze-Dried Albumin-Free Formulation of Recombinant Factor VIII SQ

Purpose. To develop a stable freeze-dried formulation of recombinant factor VIII-SQ (r-VIII SQ) without the addition of albumin. Methods. Different formulations were evaluated for their protective effect during sterile filtration, freeze-thawing, freeze-drying, reconstitution and long term storage. Factor VIII activity (VIII:C), visual inspection, clarity, solubility, moisture content and soluble aggregates and/or fragments were assayed. Results. A combination of non-crystallising excipients (L-histidine and sucrose), a non-ionic surfactant (polysorbate 80) and a crystalline bulking agent (sodium chloride) was found to preserve the factor VIII activity during formulation, freeze-drying and storage. Calcium chloride was included to prevent dissociation of the heavy and light chains of r-VIII SQ. Sodium chloride was chosen as the primary bulking agent since the concentration of sodium chloride necessary for dissolution of r-VIII SQ in the buffer will inhibit the crystallization of many potential cake formers. It was found that L-histidine, besides functioning as a buffer, also protected r-VIII SQ during freeze-drying and storage. A pH close to 7 was found to be optimal. Some potential macromolecular stabilisers, PEG 4000, Haes^®-steril and Haemaccel^®, were evaluated but they did not improve the recovery of VII:C. The freeze-dried formulation was stable for at least two years at 7°C and for at least one year at 25°C. The reconstituted solution was stable for at least 100 hours at 25°C. Conclusions. The albumin-free formulation resulted in consistently high recovery of VII:C, very low aggregate formation and good storage stability. The stability of the reconstituted solution makes the formulation suitable for continuous administration via infusion pump. The formulation strategy described here may also be useful for other proteins which require a high ionic strength.     

Enhanced Aqueous Dissolution of a Poorly Water Soluble Drug by Novel Particle Engineering Technology: Spray-Freezing into Liquid with Atmospheric Freeze-Drying

Purpose. The purpose of this work was to investigate spray-freezing into liquid (SFL) and atmospheric freeze-drying (ATMFD) as industrial processes for producing micronized SFL powders with enhanced aqueous dissolution. Micronized SFL powders dried by ATMFD were compared with vacuum freeze-dried SFL powders. Methods. Danazol was formulated with polyvinyl alcohol (MW 22,000), polyvinylpyrrolidone K-15, and poloxamer 407 to produce micronized SFL powders that were freeze-dried under vacuum or dried by ATMFD. The powders were characterized using Karl-Fischer titration, gas chromatography, differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, surface area, and dissolution testing (SLS 0.75%/Tris 1.21% buffer media). Results. Micronized SFL powders containing amorphous drug were successfully dried using the ATMFD process. Micronized SFL powders contained less than 5% w/w and 50 ppm of residual water and organic solvent, respectively, which were similar to those contents detected in a co-ground physical mixture of similar composition. Micronized SFL powders dried by ATMFD had lower surface areas than powders produced by vacuum freeze-drying (5.7 vs. 8.9 m²/g) but significantly greater surface areas than the micronized bulk drug (0.5 m²/g) and co-ground physical mixture (1.9 m²/g). Rapid wetting and dissolution occurred when the SFL powders were introduced into the dissolution media. By 5 min, 100% dissolution of danazol from the ATMFD-micronized SFL powder had occurred, which was similar to the dissolution profile of the vacuum freeze-dried SFL powder. Conclusions. Vacuum freeze-drying is not a preferred technique in the pharmaceutical industry because of scalability and high-cost concerns. The ATMFD process enables commercialization of the SFL particle-engineering technology as a micronization method to enhance dissolution of hydrophobic drugs.