基于AQbD理念的吡罗昔康凝胶体外释放研究

目的 基于分析方法质量源于设计（AQbD）理念，建立并优化吡罗昔康凝胶体外释放实验（IVRT）。方法 建立分析目标、确定关键分析属性［体外释放速率（IVRR）、初始采样时间累积释放量（Q₀）、释放度］；基于先前的知识与经验，从分析目标中推导出有影响的方法变量，并利用石川图进行系统总结，对影响的变量进行风险等级评估，筛选出关键方法变量（膜的种类、释放介质的种类、上样量）；对2种上样量（150、300 mg）、3种释放介质（0.9% NaCl溶液、pH 5.5的磷酸盐缓冲液和pH 7.2的磷酸盐缓冲液）和3种膜［混合纤维素膜（MCE）、聚醚砜膜（PES）、聚四氟乙烯膜（PTFE）］进行2×3×3全析因实验设计，采用扩散池法进行IVRT，将各时间点样品进行HPLC定量分析，进一步计算Q₀、释放度和IVRR。利用JMP Pro软件对实验结果进行建模分析，筛选最优参数。参考美国食品药品监督管理局（FDA）、欧洲药品管理局（EMA）要求对建立的IVRT进行膜惰性验证，释放介质验证，线性、精密度和重复性考察，敏感性和特异性考察及耐用性考察。结果 吡罗昔康凝胶 IVRT 采用静态垂直扩散池（扩散面积 1.767 cm²，接收池体积 12 mL），温度 32 ℃，转速 600 r·min^-1，释放介质为 pH7.2磷酸盐缓冲液、膜为 MCE、上样量为 300 mg，取样时间为 0.5、1.0、2.0、3.0、4.0、5.0、6.0 h，取样方式为全部取样。方法学验证均符合要求。结论 所建立的吡罗昔康凝胶IVRT可靠、耐用、具有区分力。     

硅橡胶质量参数与氟尿嘧啶植入剂释放度的相关性研究

目的 分析硅橡胶分子量及黏度特性对氟尿嘧啶植入剂释放度的影响。方法 依据GN/T21863-2008标准和《中国药典》对不同批号硅橡胶的分子量分布和黏度进行检测,记录数均分子量、分子量分布和黏度,采用相同制剂工艺制备20份不同硅橡胶的小试样品,依据国家药品标准WS1-（X-103）-2005Z对小试样品的释放度进行检测,以数均分子量（X₁）、分子量分布（X₂）和黏度（X₃）作为X变量,以120 h释放度结果作为Y变量,使用Minitab 16.0软件进行多元回归分析,确定硅橡胶关键质量参数。结果 多元回归分析表明,数均分子量和黏度参数是关键质量参数（P<0.05）,分子量分布为非关键质量参数（P>0.05）;120 h释放度的线性回归方程：Y=-0.3+3.76 X₁+0.267X₃。结论 硅橡胶数均分子量和黏度是影响氟尿嘧啶植入剂释放度的关键质量参数,产品生产过程中应依据制剂工艺参数对硅橡胶的制备进行严格控制,从而最大程度降低硅橡胶对产品质量稳定性造成的影响。     

盐酸羟考酮缓释片体外一致性评价研究

目的 建立盐酸羟考酮缓释片释放曲线测定方法和有关物质检测方法,评价自制制剂和原研制剂释放曲线的相似性和有关物质杂质谱的一致性。方法 用4种释放介质[水、盐酸（pH 1.2）、乙酸盐缓冲液（pH 4.0）和磷酸盐缓冲液（pH 6.8）]分别考察自制盐酸羟考酮缓释片和原研制剂的释放情况,并通过计算相似因子（f₂）评价溶出曲线的相似性;优化有关物质检查色谱条件,使14-羟可待因酮、氢可酮达到基线分离,对比研究自制盐酸羟考酮缓释片与原研制剂的有关物质,进行杂质谱研究。结果 自制制剂与原研制剂在4种释放介质中释放曲线的f₂均>50,表明2种制剂体外释放行为相似,且两者的有关物质杂质谱基本一致,表明2种制剂质量基本一致。结论 建立的释放曲线、有关物质测定方法准确、可靠,可为盐酸羟考酮缓释片的仿制药一致性评价提供参考。     

外用半固体制剂质量研究与体外评价技术进展

外用半固体制剂用途广泛,但处方、制剂特性复杂,工艺参数控制难度高,微小的处方工艺变化都可能导致产品质量的显著差异,其与吸入制剂、透皮贴剂等都属于研发难度大,在审评过程中需要根据具体品种个性化考虑的复杂制剂。能区分不同处方和工艺,且具有体内外相关性的体外评价研究,可以更好地满足外用半固体制剂的质量研究和审评技术要求。本文以复杂制剂的研究为重点,在查阅国内外相关的文献报道和政策法规的基础上,参考国内外监管机构对外用半固体制剂的评价要求和品种指南(product-specific guidances, PSGs),结合自身研究工作的发现和思考,综述了外用半固体制剂的应用、政策法规以及质量控制等方面的现状,着重对如何建立科学的外用半固体制剂的体外评价体系进行了探讨,初步分析了外用半固体制剂建立体内外相关性的技术难点,期望为外用半固体仿制药开发及产品变更研究提供借鉴。     

126种外用固体和半固体制剂药品说明书调查分析

目的为改进和完善外用固体和半固体制剂药品说明书提供建议,以促进其安全、合理使用。方法搜集某三级医院药房及2家社会连锁药店外用固体和半固体制剂共126个品种的药品说明书,将西药制剂和中成药制剂说明书分别统计,对其完整性、规范性进行分析。结果在126种西药和中成药说明书中,缺项较多的10个项目分别是:不良反应5.49%和68.57%;禁忌症27.47%和51.43%;注意事项2.20%和17.14%;孕妇及哺乳期妇女用药73.62%和100.00%;儿童用药80.22%和100.00%;老人用药83.52%和100.00%;药物相互作用72.53%和97.14%;药物过量89.01%和100.00%;药理/毒理作用65.93%和94.28%;药代动力学80.22%和100.00%。西药药品说明书的标注项目质量优于中成药制剂。结论外用固体和半固体制剂药品说明书的内容标注仍然存在不规范问题,特别是中成药说明书更需要完善和改进。     

局部药用凝胶剂的研究新进展和新应用

凝胶剂（Gel）是指药物与能形成凝胶剂的辅料制成的均一、混悬或乳剂型的乳胶稠厚液体或半固体制剂.凝胶剂作为新型的药物制剂,广泛用于缓释、控释及脉冲释放等新型给药系统,可分为全身用凝胶剂和局部用凝胶剂两类.     

尼美舒利固体分散体的非pH依赖性释放研究

目的以尼美舒利为难溶弱酸性模型药物,研究提高该类药物释放速率的方法。方法以聚乙二醇6000(PEG6000)为载体,采用熔融法制备尼美舒利固体分散体;测定含不同碱化剂(包括NaOH、KOH、Ca(OH)2、Na2CO3、CaCO3)的尼美舒利固体分散体中药物的释放速率。结果加入碱化剂能显著增加尼美舒利在蒸馏水中的释放度,碱化剂不同,药物的释放度不同;碱化剂的碱性越强,分散体的颜色越深,其吸湿性也相对越大。结论在尼美舒利PEG6000固体分散体中加入碱化剂可显著改善该类药物的体外释放特点,并呈现明显的非pH依赖性。     

挤出滚圆法制备尼群地平缓释微丸的处方因素考察

目的 对影响药物释放的处方因素进行考察.方法 以微晶纤维素（MCC）为成型辅料，乙基纤维素（EC）为缓释材料，可溶性高分子材料为致孔剂，乳糖、十二烷基硫酸钠（SDS）及崩解剂为释药速度调节剂，采用挤出滚圆法制备尼群地平固体分散体及微丸，通过体外释放度试验对各辅料的种类及用量进行详细考察。结果 在尼群地平含量为10％的前提下，EC（10cps）用量在20％左右有一定的缓释作用；致孔剂采用PVPkm用量应在5％以下；崩解剂种类及用量对微丸中药物的释放影响显著，4％～12％的交联羧甲基纤维素钠（CCNa）可使药物释放较为完全；乳糖及SDS对药物释放无明显影响，用量分别为20％和4％较佳；成球辅料MCC型号为AvicelPH101。结论 采用上述处方，可制得体外释放度符合要求的尼群地平缓释微丸。     

世界口腔溶膜生产技术开发新进展

口腔溶膜的生产可通过各种方法进行,例如溶剂铸造,热熔挤压,半固态铸造,固体分散挤压,辗压。以下讨论了这些方法和评价溶膜的各种参数。口腔薄膜或口腔溶膜（ODFs）提供了活性药物成分（API）在舌头上的快速释放。口腔溶膜（ODFs）提供了对口     

双嘧达莫缓释微丸的研制及其体外释放特性

目的：制备双嘧达莫pH非依赖型缓释微丸，使药物释放不受胃肠道pH值变化及个体差异的影响。方法：采用固体分散技术，将药物与联合载体（Eudragit L、EC和PEG 6000）的混和有机液喷包于微晶纤维素（MCC）空白丸芯上形成膜衣骨架型共沉淀物结构，以正交设计进行处方优化，考察不同pH条件下缓释微丸的释放特性。结果：缓释微丸的体外药物释放呈pH非依赖型释放特征，符合一级动力学方程。结论：具有溶解度pH依赖性的药物，以固体分散技术处理，通过不同性质载体的调节作用，可以制成pH非领带型的缓释制剂。     

A comprehensive approach to qualify and validate the essential parameters of an in vitro release test (IVRT) method for acyclovir cream, 5%

The rate of release of an active pharmaceutical ingredient (API) from a topical semisolid dosage form can be influenced by its physical and structural properties. An In Vitro Release Test (IVRT) is an established method to characterize this rate of API release and compare the underlying sameness in product quality characteristics. The purpose of this work was to validate an IVRT method to compare acyclovir cream, 5% products. However, despite widespread use of the IVRT since 1997, there has been no established approach to validate an IVRT method. Our approach included: 1) qualification of the diffusion cell apparatus, 2) qualification of the laboratory, 3) validation of the HPLC analytical method, and 4) validation of numerous critical parameters of the IVRT method, itself, and resulted in a comprehensive and successful IVRT method validation. Subsequent to the IVRT validation work described here, the U.S. Food and Drug Administration (FDA) drafted a guidance on the development and validation of an IVRT method for acyclovir cream, 5%. Although there are notable differences between our approach and the approach in that guidance, this report illustrates how many of the same essential qualification parameters and validation concepts were considered and systematically addressed in our approach to IVRT validation.     

Active compounds release from semisolid dosage forms

The aim of this paper is to review all the aspects of the in vitro release testing (IVRT) from semisolid dosage forms. Although none of the official dissolution methods has been specified for use with semisolid dosage forms, their utility for assessing release rates of drugs from semisolid dosage forms has become a topic of considerable interest. One can expect to overcome such complexity in the future, when the official “Topical and Transdermal Drug Products—Product Performance Tests” will be published in an issue of the Pharmacopeial Forum. Many factors such as type of the dissolution medium, membrane, temperature, and speed have an influence on the mechanism and kinetics of the release testing from gels, creams, and ointments; therefore, those parameters have been widely discussed.     

Investigation of the utility of an in vitro release test for optimizing semisolid dosage forms

Current literature indicates that an in vitro release test (IVRT) can serve as a research tool during the course of developing topical formulations. The purpose of this study was therefore to investigate the ability of an IVRT to select the topical semisolid formulations with the most rapid release rate of the model drug ketoprofen from two closely related hydrogels in a simulated product development process. Two glycols with distinct differences in their physical-chemical properties, Transcutol P (ethoxydiglycol) and propylene glycol, were incorporated into Carbopol 980 and Poloxamer 407 formulations. The release rate of ketoprofen was determined utilizing different receptor media and conditions, i.e., phosphate buffer pH 7.4, isopropyl myristate (IPM), and a combination of an IPM soaked membrane and phosphate buffer (pH 7.4) as receptor fluid. The results indicated that the conditions chosen could affect greatly the conclusions concerning the formulations. The only observable trend was that Transcutol P-containing formulations tended to permit a faster ketoprofen release than propylene glycol-containing formulations when utilizing IPM as a receptor component. This was attributed to the mutual miscibility of Transcutol P in IPM. It can be concluded that, for the purpose of formulation screening in the early phases of product development, an IVRT will only be useful for predicting the amount of drug available for absorption if the receptor medium has properties that closely mimic human skin. These results illustrate the importance of selecting suitable receptor components and indicate that it may be necessary to consider alternatives to the commonly used synthetic membranes.     

Investigation of the Utility of an In Vitro Release Test for Optimizing Semisolid Dosage Forms

Current literature indicates that an in vitro release test (IVRT) can serve as a research tool during the course of developing topical formulations. The purpose of this study was therefore to investigate the ability of an IVRT to select the topical semisolid formulations with the most rapid release rate of the model drug ketoprofen from two closely related hydrogels in a simulated product development process. Two glycols with distinct differences in their physical–chemical properties, Transcutol P (ethoxydiglycol) and propylene glycol, were incorporated into Carbopol 980 and Poloxamer 407 formulations. The release rate of ketoprofen was determined utilizing different receptor media and conditions, i.e., phosphate buffer pH 7.4, isopropyl myristate (IPM), and a combination of an IPM soaked membrane and phosphate buffer (pH 7.4) as receptor fluid. The results indicated that the conditions chosen could affect greatly the conclusions concerning the formulations. The only observable trend was that Transcutol P-containing formulations tended to permit a faster ketoprofen release than propylene glycol-containing formulations when utilizing IPM as a receptor component. This was attributed to the mutual miscibility of Transcutol P in IPM. It can be concluded that, for the purpose of formulation screening in the early phases of product development, an IVRT will only be useful for predicting the amount of drug available for absorption if the receptor medium has properties that closely mimic human skin. These results illustrate the importance of selecting suitable receptor components and indicate that it may be necessary to consider alternatives to the commonly used synthetic membranes.     

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.     

Reliability and Reproducibility of Vertical Diffusion Cells for Determining Release Rates from Semisolid Dosage Forms

Purpose USP has formed Advisory Panels to ensure the integrity of laboratory procedures for non-oral routes of administration and expects that the panels will recommend performance tests (performance qualification, PQ) for these dosage forms as well as performance verification tests (PVT) for those PQ tests. An integral part of PQ is PVT, in which a standard formulation is first tested in a metrologically sound collaborative study to set acceptance criteria. Individual laboratories can then test the performance of their product by comparing their results to those obtained from the USP collaborative study. These studies are guided by metrological principles, e.g., those of the International Organization for Standardization (ISO) 43-1, which succinctly states that “one of the main uses of proficiency testing schemes is to assess laboratories’ ability to perform tests competently.” Materials and methods Four laboratories conducted two collaborative studies to determine the reliability and reproducibility—understood in metrological terms—of release rates from semisolid dosage forms using the vertical diffusion cell (VDC). Results The experiments reported here from the second study found that the major contributor to variability is the interlaboratory component that may include intermediate precision considerations other than analyst. Because all laboratories used the same model equipment, one might expect that the observed reproducibility CV was lower than if the laboratories used different models or equipment made by different manufacturers. Also, more variability was observed with the creams than the other dosage forms. Conclusions The results from the preliminary collaborative study found inconsistency among the laboratories. After operator training, the results from the second study were more consistent, suggesting the initial results were associated with variations among the laboratories in performing the methods and procedures and conducting the protocols. Those results emphasize that although the in vitro release procedure is simple and reproducible, training is needed. The data presented suggest that testing of in vitro release by VDCs should be considered as a PVT for topical semisolid dosage forms. Thus, a standard semisolid product is needed, along with a means for setting acceptance criteria. The SUPAC-SS Guidance may be helpful in the latter regard.     

French and/or European perspectives on biopharmaceutical characterization of drug dosage forms

In order to bring definitions of drug dosage forms up to date, it was necessary for the French Pharmacopoeia to propose assays allowing the quality control of the dosage forms to be based on the kinetics of drug release in vitro. Currently, five examples can be cited of dosage forms that can be characterized by release in vitro. (1) Oral solid dosage forms--for tablets, all the parameters of powders before compression (e.g., flowability, tableting properties) are being studied in addition to the dissolution tests, (2) Rectal dosage forms--the disintegration test of suppositories will be discarded and a new dissolution test using a special flow-through cell is now being studied. (3) Inhalations--since particle diameter is the most important factor for inhalation activity, a method has been developed to give the correct answer to this question. (4) Modified release drug dosage forms--these have been defined separately from the conventional forms. For the peroral route, they are: (i) accelerated release drug dosage forms, (ii) sustained release drug dosage forms and (iii) delayed release drug dosage forms. To emphasize the differences in the release kinetics, use of the paddle method, well known in the USP, and the flow-through cell has been suggested and described in the European Pharmacopoeia. Some associations and/or in vitro-in vivo correlations have increased the interest in the last method. (5) Transdermal delivery systems--these are defined separately from plaster and sticking-plaster. The use of a cell method was suggested to study the drug release and some comparisons between different techniques are presented.     

The Use of Modeling Tools to Drive Efficient Oral Product Design

Modeling and simulation of drug dissolution and oral absorption has been increasingly used over the last decade to understand drug behavior in vivo based on the physicochemical properties of Active Pharmaceutical Ingredients (API) and dosage forms. As in silico and in vitro tools become more sophisticated and our knowledge of physiological processes has grown, model simulations can provide a valuable confluence, tying-in in vitro data with in vivo data while offering mechanistic insights into clinical performance. To a formulation scientist, this unveils not just the parameters that are predicted to significantly impact dissolution/absorption, but helps probe explanations around drug product performance and address specific in vivo mechanisms. In formulation, development, in silico dissolution-absorption modeling can be effectively used to guide: API selection (form comparison and particle size properties), influence clinical study design, assess dosage form performance, guide strategy for dosage form design, and breakdown clinically relevant conditions on dosage form performance (pH effect for patients on pH-elevating treatments, and food effect). This minireview describes examples of these applications in guiding product development including those with strategies to mitigate observed clinical exposure liability or mechanistically probe product in vivo performance attributes.     

A Review of Disintegration Mechanisms and Measurement Techniques

Pharmaceutical solid dosage forms (tablets or capsules) are the predominant form to administer active pharmaceutical ingredients (APIs) to the patient. Tablets are typically powder compacts consisting of several different excipients in addition to the API. Excipients are added to a formulation in order to achieve the desired fill weight of a dosage form, to improve the processability or to affect the drug release behaviour in the body. These complex porous systems undergo different mechanisms when they come in contact with physiological fluids. The performance of a drug is primarily influenced by the disintegration and dissolution behaviour of the powder compact. The disintegration process is specifically critical for immediate-release dosage forms. Its mechanisms and the factors impacting disintegration are discussed and methods used to study the disintegration in-situ are presented. This review further summarises mathematical models used to simulate disintegration phenomena and to predict drug release kinetics.     

Perspectives on Physicochemical and <Emphasis Type="BoldItalic">In Vitro</Emphasis> Profiling of Ophthalmic Ointments

Ophthalmic ointments are unique in that they combine features of topical drug delivery, the ophthalmic route and ointment (semisolid) formulations. Accordingly, these complex formulations are challenging to develop and evaluate and therefore it is critically important to understand their physicochemical properties as well as their in vitro drug release characteristics. Previous reports on the characterization of ophthalmic ointments are very limited. Although there are FDA guidance documents and USP monographs covering some aspects of semisolid formulations, there are no FDA guidance documents nor any USP monographs for ophthalmic ointments. This review summarizes the physicochemical and in vitro profiling methods that have been previously reported for ophthalmic ointments. Specifically, insight is provided into physicochemical characterization (rheological parameters, drug content and content uniformity, and particle size of the API in the finished ointments) as well as important considerations (membranes, release media, method comparison, release kinetics and discriminatory ability) in in vitro release testing (IVRT) method development for ophthalmic ointments.

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Graphical Abstract Summary of the physicochemcial profiling and in vitro drug release testing (IVRT) for ophthalmic ointments.