口服固体制剂原辅料相容性研究进展

对近年来国内外在原辅料相容性方面的研究进行综述,以便于制剂工作者更好地进行处方设计。笔者首先分析了口服固体制剂原辅料发生不相容的原因,随后对各种原辅料相互作用进行了深入的阐述,并列举了近年来研究的成果;随后对影响原辅料相互作用的外界因素进行了分析和列举;最后对近年来采用的原辅料相容性研究手段进行了综述,为今后更好地开展此类研究提供参考。     

固体制剂工艺对药物晶型的影响

综述了固体制剂加工生产各因素对药物晶型的影响。指出精制、粉碎、制粒、干燥和压片都可能引起药物晶型发生变化,从而影响药物的生物利用度和治疗的有效性。     

热熔制粒在口服固体制剂中的应用

目前,多种不同的热熔制粒方法在颗粒荆、片剂、胶囊剂等口服固体制剂的制备中得以应用。本文综述了热熔制粒法的特点、设备、黏合剂、应用、发展趋势、产业化的关键问题及解决途径,重点介绍了具有不同溶解性、起关键作用的低熔点黏合剂。     

口服固体制剂掩味技术的研究进展

综述各种新兴口服固体制剂掩味技术的原理、特点及制备过程,并简述口服掩味技术评价方法的最新进展。口服固体制剂中许多药物由于受到不良口味的影响,致使病人的用药顺应性差、临床应用受限。近年来在使用矫味剂、麻痹剂等掩味手段的基础上产生了许多新兴的掩味技术,如喷动床包衣、粉末包衣和盐析包衣等。     

Ionization States in the Microenvironment of Solid Dosage Forms: Effect of Formulation Variables and Processing

Purpose Evaluation of the effect of formulation composition and processing variables on the microenvironment in solid dosage forms, based on ionization of indicator probes.Materials and Methods Sulfonephthalein indicators were intimately mixed with individual excipients, binary excipient mixtures or multi-component blends by the solvent deposition method. Diffuse reflectance visible spectroscopy of these solids provided a measure of indicator ionization extent. Indicator solution studies yielded equations relating solution pH to the ratio of the absorbance signals of the ionized to that of the unionized form, for each indicator. These equations and the spectral data of the indicator-treated solids were used to calculate an acidity function, ‘pH_eq’ for the solids. The ionization of incorporated probes was also monitored during various stages of simulated pharmaceutical processing viz. wet and dry mixing.Results The pH_eq provided a measure of the physicochemical environment experienced by the probe in the solid. The surface nature of formulation components and their surface area available for interaction influenced the overall properties of the final blend. The extent of probe ionization varied at different stages of a simulated wet mixing–drying process. The pH of the excipient suspension was not a good predictor of the probe ionization in the final dried solid. Indicator ionization is expected to be influenced by the microenvironmental acidity, polarity and ionic strength. Individual excipient properties contributed to the overall microenvironment in powder mixtures even when dry mixed at low water contents.Conclusions The environment experienced by a drug in the final solid dosage form will be influenced by the nature of the excipients, the extent of their surfaces available for interaction, surface modification during processing and the amount and nature of solvent used.     

Simultaneous In Vivo Visualization and Localization of Solid Oral Dosage Forms in the Rat Gastrointestinal Tract by Magnetic Resonance Imaging (MRI)

Purpose. Bioavailability of orally administered drugs is much influenced by the behavior, performance and fate of the dosage form within the gastrointestinal (GI) tract. Therefore, MRI in vivo methods that allow for the simultaneous visualization of solid oral dosage forms and anatomical structures of the GI tract have been investigated. Methods. Oral contrast agents containing Gd-DTPA were used to depict the lumen of the digestive organs. Solid oral dosage forms were visualized in a rat model by a ¹H-MRI double contrast technique (magnetite-labelled microtablets) and a combination of ¹H- and ¹⁹F-MRI (fluorine-labelled minicapsules). Results. Simultaneous visualization of solid oral dosage forms and the GI environment in the rat was possible using MRI. Microtablets could reproducibly be monitored in the rat stomach and in the intestines using a ¹H-MRI double contrast technique. Fluorine-labelled minicapsules were detectable in the rat stomach by a combination of ¹H- and ¹⁹F-MRI in vivo. Conclusions. The in vivo ¹H-MRI double contrast technique described allows solid oral dosage forms in the rat GI tract to be depicted. Solid dosage forms can easily be labelled by incorporating trace amounts of non-toxic iron oxide (magnetite) particles. ¹H-MRI is a promising tool for observing such pharmaceutical dosage forms in humans. Combined ¹H- and ¹⁹F-MRI offer a means of unambiguously localizing solid oral dosage forms in more distal parts of the GI tract. Studies correlating MRI examinations with drug plasma levels could provide valuable information for the development of pharmaceutical dosage forms.     

口服固体制剂中泛昔洛韦与乳糖的美拉德反应研究

目的 考察泛昔洛韦与乳糖在口服固体制剂中产生美拉德反应的条件,建立美拉德反应产物(Maillard reaction productions,MRPs)的监测方法,指导制剂开发。方法 参照美拉德反应机制和固体制剂生产工艺,选择水分、温度和时间作为主要研究条件,采用目视法和差示扫描量热法对美拉德反应进行初步评价;采用HPLC和LC-MS对MRPs进行鉴别和质控。结果 在水分 ≤ 10%、温度 ≤ 90℃时,泛昔洛韦与乳糖相容性良好,且不产生美拉德反应;并可采用HPLC对MRPs进行质控。结论 泛昔洛韦在口服固体制剂处方工艺开发与乳糖联用时,应进行水分和温度的控制,降低产生美拉德反应的风险。     

FDA《根据BCS豁免速释固体口服制剂体内生物利用度和生物等效性研究的指导原则》介绍

美国食品药品管理局于2017年12月发布了《根据生物药剂学分类系统豁免速释固体口服制剂体内生物利用度和生物等效性研究指导原则》的正式版本。该指导原则指出原料药属于生物药剂学分类系统（BCS）1类（而且制剂是速溶的）和3类（而且制剂是极速溶的）的速释（IR）固体口服制剂的生物利用度（BA）或生物等效性（BE）研究可获得豁免。正式版本对2015年草案版做了许多修订。详细介绍该指导原则的正式版本并标明约30处修订。该指导原则对我国IR固体口服制剂BA或BE研究的豁免和监管有重要参考价值。     

The Selection of a Pharmaceutical Salt—The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance

A roadmap for the selection of a pharmaceutical salt form for a development candidate is presented. The free base of the candidate did not have sufficient chemical stability for development. The initially selected salt form turned out to be undevelopable because it was unstable during scale-up synthesis and storage. The rationale for the new solid form screening and the criteria for selection are discussed. Before the final selection, the pH solubility profiles of the 2 new salts, a benzoate and a besylate, were compared. Atypical solubility behavior was observed for the benzoate salt in hydrochloric acid with and without normal saline. A scheme is proposed illustrating how the pKas of the counterion and active pharmaceutical ingredient, the medium composition, and final pH affect the solubility and solution equilibria of the 2 selected salt forms. This scheme also includes the equilibria between solution and solid phases in different pH ranges. The pharmaceutical importance of this research is that it sheds light on how the acidity of the counterion can affect the solubility of the selected salt form in the gastric environment. With a well-designed formulation strategy, this property potentially can be translated to optimal biopharmaceutical performance of the drug product.