药用辅料的不良反应及其安全性管理

药用辅料系药物制剂中除活性成分以外所有物料的统称,其功能除赋形外,还能保持或增加活性成分的稳定性和生物利用度。据估计,现有40余类上千种药用辅料,如溶剂、吸附剂、防腐剂、着色剂、矫味剂、增稠剂、抗氧剂等;另外,近年还出现一些新型辅料。辅料相对于活性成分而言,是一种惰性物质。然而,现有资料证明,许多辅料可引起不良反应,如丙二醇致溶血、苯甲醇致喘息综合征等。药用辅料的安全性涉及其毒性、质量和不正确使用。临床医师应了解与辅料相关的不良反应,药品管理部门也应加强辅料的安全性管理以利于维护患者安全。     

Skin absorption of volatile oils. Pharmacokinetics

Volatile oils are frequently employed in the local treatment of pain. 1,8-Cineole, the principal component of eucalyptus oil, was used as a model substance to determine whether this active component can be detected in effective amounts at the target area in the skeletal muscles after dermal application. The investigation showed surprisingly large differences depending on the manner of application. The relative bioavailability of the model substance 1,8-cineole obtained by using an applicator was 320% as compared with that obtained by using an occlusive dressing. This has practical effects on the dosage and on the frequency of application.     

Direct compression high functionality excipient using coprocessing technique: a brief review

Tablets are still the most commonly used dosage form because of the ease of manufacturing, convenience in administration, accurate dosing and excellent stability. Direct compression is the preferred method for the preparation of tablets. However, it has been estimated that less than 20 percent of the active pharmaceutical ingredients (API) can be processed into tablets via direct compression since the majority of API lack the flow, cohesion or lubricating properties required for direct compression. Increasing trends toward direct compression suggests the need for development of high functional excipients. High functionality of excipients can be obtained by development of new excipients or by particle engineering of existing excipients. Particle engineering using coprocessing provides a way to obtain an excipient with high functionality. Coprocessed excipients are the mixture of two or more excipients interacting at sub-particle level; that can provide an excipient with improved functionality as well as masking undesirable properties. Coprocessing is very cost effective method of providing high functional excipient. The present review discusses the advantages of coprocessed excipients, role of material science in coprocessing, methods of coprocessing of excipients and properties of various coprocessed excipients available in the market.     

Excipients as stabilizers

Excipients are better known as promoters of degradation than as stabilizers of drug substances. This is not surprising. Functional groups or residues in excipients can have the propensity to interact with labile active ingredients, with attendant loss of molecular integrity or other changes in quality. Thus, the canon of work on excipients as stabilizers is not extensive. Nevertheless, possibilities exist to capitalize on our knowledge of how a drug substance degrades, and of the properties and composition of excipients, to convert unstable drugs into viable products. This article discusses such approaches to product stabilization.     

共处理技术制备直接压片高功能辅料的方法及应用进展

片剂因剂量准确、服用方便、质量稳定被广泛应用.粉末直接压片工艺是制备片剂较为简便的方法.然而,受粉体流动性、可压性、稀释潜力等性质的影响,目前只有不到20％的活性药物成分(API)可通过粉末直接压片工艺制备成片剂.应用颗粒工程学,通过共处理技术将两种或多种辅料在颗粒水平上相结合,可改善辅料的性能,进而满足直接压片法对粉体性质的要求.本文讨论了共处理技术制备直接压片高功能辅料的优势、共处理技术常规方法并例举了已经上市的直接压片高功能辅料及其应用前景,为共处理技术制备高功能辅料应用于粉末直接压片工艺提供思路.     

The safety of pharmaceutical excipients

The most important part of a medicine as far as its weight is concerned, is constituted by its excipients, which have the important functions of guaranteeing the dosage, stability and bioavailability of the active principle. The components employed as excipients must present the characteristics required by their technological function but, as with any substance administered to man, they must also correspond to suitable safety requirements. In fact, in the past the importance of evaluating the possible adverse effects of excipients was underestimated, because their inertia and innocuity were taken for granted. The safety profile of these substances is more deeply researched as regards the toxicological aspect only if they are also employed in the food industry (anti-oxidants, sweeteners, colouring agents, etc.). Indeed, in this case, the International Toxicological Committees (among which the Joint Expert Committee on Food Additives, a mixed committee of the WHO/FAO) demand thorough studies in laboratory animals, with the intent of protecting the consumer's safety. Tackling the question of the toxicity of excipients thoroughly is not a simple matter for several reasons: the large number of substances on the market and the diversity of their chemical profiles, their sources, their technological functions, and the presence of secondary products and/or contaminants that may be the true causes of adverse effects. In this article we shall review the principal classes of excipients and their respective side effects. Then we shall proceed to their toxicological evaluation, giving examples of: (a) intrinsic toxicity, or adverse effects that may be encountered in the whole population; and (b) specific toxicity, which manifests only in people who are carriers of a transmissible disease or who are genetically predisposed, such as people with allergies and intolerances.     

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Metformin Hydrochloride

Data are examined regarding possible waiver of in vivo bioequivalence testing (i.e. biowaiver) for approval of metformin hydrochloride (metformin) immediate-release solid oral dosage forms. Data include metformin's Biopharmaceutics Classification System (BCS) properties, including potential excipient interactions. Metformin is a prototypical transporter-mediated drug and is highly soluble, but only 50% of an orally administered dose is absorbed from the gut. Therefore, metformin is a BCS Class III substance. A BCS-based approval approach for major changes to marketed products and new generics is admissible if test and reference dosage forms have the identical active pharmaceutical ingredient and if in vitro dissolution from both are very rapid (i.e. at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Recent International Council for Harmonisation BCS guidance indicates all excipients for Class III biowaivers are recommended to be qualitatively the same and quantitatively similar (except for preservatives, flavor agents, colorant, or capsule shell or film coating excipients). However, despite metformin being a prototypical transporter-mediated drug, there is no evidence that commonly used excipients impact metformin absorption, such that this restriction on excipients for BCS III drugs merits regulatory relief. Commonly used excipients in usual amounts are not likely to impact metformin absorption.     

口腔膜剂的研发及应用

膜剂系指药物与适宜的成膜材料经加工制成的膜状制剂,可供口服、皮肤或黏膜外用.本文着重介绍了口腔膜剂的生产工艺、包装和性能评价方法,综述了其开发、应用现状和发展前景.     

Ensuring Product Stability – Choosing the Right Excipients

The stability of pharmaceuticals is an important product quality attribute. Of the known factors affecting stability, moisture is often perceived as the most common cause of drug degradation by hydrolysis or other reactions facilitated by moisture as a medium. Excipients are a critical entity in formulations to enable drug delivery as well as efficient manufacture of pharmaceutical dosage forms. Yet to this end, there is limited application and understanding of the role of excipients in protecting moisture sensitive drugs. An improved understanding of moisture-excipient interactions is important when selecting excipients for formulations containing moisture sensitive drugs. This review outlines the role of excipients as a moisture protectant in oral solid dosage forms. It focuses on the moisture interactions of excipients in order to highlight the potential of certain excipients as moisture protectants. More specifically, the mechanisms by which excipients can reduce drug degradation (e.g. acting as a physical barrier, reducing moisture availability and mobility) are discussed. A summary of analytical tools to evaluate moisture-excipient interactions is also provided.     

A Nitrite Excipient Database: A Useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products

N-Nitrosamine risk assessment and control have become an integral part of pharmaceutical drug product development and quality evaluation. Initial reports of nitrosamine contamination were linked with the drug substance and its manufacturing process. Subsequently, the drug product and aspects of the formulation process have shown to be relevant. Regarding specific formulation contributions to nitrosamine content in a product, one risk lies in possible interactions between nitrosating agents, derived from nitrite in excipients, and vulnerable amines, either present as moieties of the active molecule or as impurities / degradants. However, the limited validated information on nitrite levels in excipients available until now, has been an obstacle for scientists to assess the risk of nitrosamine formation in pharmaceutical products. This has driven the creation of a database to store and share such validated information. The database, maintained by Lhasa Limited, constitutes a central platform to hold the data donated by the pharmaceutical company members on the nitrite concentrations in common excipients measured with validated analytical procedures. The goal of this data sharing initiative is to provide a common framework to contextualize and estimate the risk posed by presence of nitrites to contribute to the formation of nitrosamines in drug products. The major findings from the database analyses are: (1) average nitrite content and batch to batch variance differ among excipients, (2) for solid dosage forms, the nitrite contribution is dominated by the highest formula % excipients, e.g., the fillers (diluents), which are typically used in larger proportion, and are characterized by low nitrite levels and low variability, leading to an average value of 1 µg/g nitrite in a typical formulation, (3) substantial differences in average nitrite content in batches from different excipient vendors potentially reflecting differences in source materials or processing methods for excipient manufacturing. That final point suggests that future selection of raw materials or processing by excipient manufacturers may help reduce nitrite levels in finished drug product formulations, and thus the overall risk of nitrosamine formation in cases where the product contains vulnerable amines.     

Modification of drug release with application of pharmaceutical technological methods]

Pharmaceutical technological methods, which enable the development of controlled release, prolonged action solid oral dosage forms, are of great importance. The purpose of our study was to apply these methods and evaluate the prepared samples. The first type of the samples were individually coated separated particles, prepared by mixing with lubricant to built up a lubricant film layer on the surface of the drug crystals. The next group of the samples were separately coated particles--wall material was wax--prepared using the following two technologies: fluidisation atomisation process and hot-melt coating. The third group of the samples was the matrix type, where the core material was mixed into the molten mass of the thermosoftening natural coating material or into some synthetic polymer film material. In some cases several surface active agents were added to the molten mixture to achieve a modification in the drug release process and the examined parameters of the samples. For the comparative evaluation of the prepared dosage forms drug release determination and kinetical analysis of the process were maintainly used. The surface morphology was examined on the base of scanning electronmicroscopic and optical microscopic studies. Among the physical and physico-chemical studies particle size analysis was carried out and dynamic contact angles of the solid samples as well as the surface tension decreasing effect was measured to determine the modifying properties of surface active excipients. To sum up, our results demonstrate that the economical and environmentally acceptable melt coating technology was justified as applicable advantageously in a large number of cases for the development of controlled release devices of highly watersoluble drug, even the medical substance is an organic compound having adjustable thermostability.     

Role of water in the physical stability of solid dosage formulations

The interaction of moisture with pharmaceutical solids is highly crucial to an understanding of water-based processes, for example, manufacturing processes or prediction of solid dosage form stability and shelf life. Both the active pharmaceutical ingredient (API) and excipients in the formulation have different moisture sorption properties that can result in unexpected processing-induced phase transitions and they can affect solid-state phase transitions in the final dosage forms. The character of excipient effects on the stability of formulation. Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The aim of the present study was to investigate the water sorption properties of different excipients, model the sorption isotherms, examine the phase transitions, and identify differences of excipients in solid dosage form stability using dynamic vapor sorption analysis, near-infrared spectroscopy, and X-ray diffraction methods. The thermal processing was carried out with a variable temperature X-ray powder diffractometer to compare the dehydration behavior of wet excipients and evaluate solid-state properties during heating. These results showed that despite some limitations, moisture sorption isotherms of excipients are useful in predicting solid-state stability, interactions at early stages of formulation development, and effects of moisture on physicochemical properties of the final dosage forms.     

Preformulatory research on model soft gel capsule containing liquid filling with constant ibuprofen content

Research was conducted into the influence of pharmaceutical excipients on model soft gel capsules filling containing ibuprofen. The HPLC method was employed to assess the changes of active substance content and level of impurities depending on excipients of soft gel capsule filling. HPLC analysis after 6 months stability tests was conducted and active substance content and the level of impurities were assessed in soft gelatin capsules to evaluate the influence of excipients of the shell on tested parameters. Obtained results were determining the purpose application of ibuprofen containing soft gelatin capsules and implementing new drug to the market.     

Nanosizing for oral and parenteral drug delivery: a perspective on formulating poorly-water soluble compounds using wet media milling technology

A significant percentage of active pharmaceutical ingredients identified through discovery screening programs is poorly soluble in water. These molecules are often difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues, e.g. poor bioavailability, lack of dose proportionality, slow onset of action and other attributes leading to poor patient compliance. In addition, for parenteral products, these molecules are generally administered with co-solvents and thus have many undesirable side effects. Wet media milling is one of the leading particle size reduction approaches that have been successfully used to formulate these problematic compounds. The approach is a water-based media milling process where micron-sized drug particles are shear-fractured into nanometer-sized particles. Nanoparticle dispersions are stable and typically have a mean diameter of less than 200 nm with 90% of the particles being less than 400 nm. The formulation consists only of water, drug and one or more GRAS excipients. Drug concentrations approaching 300-400 mg/g can be targeted with the use of minimal amounts stabilizer. Typically, on average, the drug to stabilizer ratio on a weight basis ranges from 2:1 to 20:1. These liquid nanodispersions exhibit acceptable shelf-life and can be post-processed into various types of solid dosage forms. Nanoparticulate-based drug products have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routes of administration can be identified with milligram quantities of drug substance providing the discovery scientist an alternate avenue for screening and identifying superior leads. In the last few years, formulating poorly water soluble compounds as nanosuspensions has evolved from a conception to a realization. The versatility and applicability of this drug delivery platform are just beginning to be realized.     

The Effects of Pharmaceutical Excipients on Gastrointestinal Tract Metabolic Enzymes and Transporters—an Update

Accumulating evidence from the last decade has shown that many pharmaceutical excipients are not pharmacologically inert but instead have effects on metabolic enzymes and/or drug transporters. Hence, the absorption, distribution, metabolism, and elimination (ADME) of active pharmaceutical ingredients (APIs) may be altered due to the modulation of their metabolism and transport by excipients. The impact of excipients is a potential concern for Biopharmaceutics Classification System (BCS)-based biowaivers, particularly as the BCS-based biowaivers have been extended to class 3 drugs in certain dosage forms. The presence of different excipients or varying amounts of excipients between formulations may result in bio-inequivalence. The excipient impact may lead to significant variations in clinical outcomes as well. The aim of this paper is to review the recent findings of excipient effects on gastrointestinal (GI) absorption, focusing on their interactions with the metabolic enzymes and transporters in the GI tract. A wide range of commonly used excipients such as binders, diluents, fillers, solvents, and surfactants are discussed here. We summarized the reported effects of those excipients on GI tract phase I and phase II enzymes, uptake and efflux transporters, and relevant clinical significance. This information can enhance our understanding of excipient influence on drug absorption and is useful in designing pharmacokinetic studies and evaluating the resultant data.     

Drug excipients

The therapeutical use of drugs involves the application of dosage forms, serving as carrier systems together with several excipients to deliver the active ingredient to the site of action. Drug delivery technology combines an understanding of medicinal chemistry and pharmacology with the skill of formulation, aiming the preparation of improved pharmaceuticals. The recently introduced Biopharmaceutical Classification System provides guidance for dosage form design, taking the molecular and physico-chemical properties of drugs into consideration through their solubility and permeability characteristics. Pharmaceutical excipients used for oral dosage form have been traditionally assumed as being inert. However, recent experience and new results have shown that they can interact with the active drug ingredient, affecting its dissolution, absorption and bioavailability. Classification of the excipients is based on their role in the pharmaceutical formulation and on their interactions influencing drug delivery, based on their chemical and physico-chemical properties. The main classes are the antioxidants, coating materials, emulgents, taste- and smell-improvers, ointment bases, conserving agents, consistency-improvers and disintegrating materials. Some of the excipients may serve multiple purposes; for example, methylcellulose is a coating material, is applied in the preparation of suspensions, to increase viscosity, as a disintegrating agent or binder in tablets. The aim of this paper is to review the drug-excipients with respect to their chemistry, importance and interactions altering the pharmacokinetics of the drug substances. Emphasis will be given to two major classes of excipients: the antioxidants and disintegrants (substances facilitating disintegration of the drug tablets in the gastro-intestinal tract). Details will be given on the mechanisms through which they can alter drug effectiveness and tolerance, and control their application. Examples and references will be given for their analysis.     

An overview of the different excipients useful for the direct compression of tablets

The humble tablet dosage form still accounts for more than 80% of all dosage forms administered to man. This review will outline the various excipients that have been used as fillers in direct compression formulations, with particular emphasis on what is expected from such excipients in terms of their functionality. It is intended that this overview (which is by no means exhaustive) will serve as an 'aide-memoire' to the formulation scientist.     

List of Reviewers

This literature review presents hydrolysis of active pharmaceutical ingredients as well as the effects on dosage form stability due to hydrolysis of excipients. Mechanisms and measurement methods are discussed and recommendations for formulation stabilization are listed.     

Hydrolysis in pharmaceutical formulations

This literature review presents hydrolysis of active pharmaceutical ingredients as well as the effects on dosage form stability due to hydrolysis of excipients. Mechanisms and measurement methods are discussed and recommendations for formulation stabilization are listed.     

Application of UV Imaging in Formulation Development

Efficient drug delivery is dependent on the drug substance dissolving in the body fluids, being released from dosage forms and transported to the site of action. A fundamental understanding of the interplay between the physicochemical properties of the active compound and pharmaceutical excipients defining formulation behavior after exposure to the aqueous environments and pharmaceutical performance is critical in pharmaceutical development, manufacturing and quality control of drugs. UV imaging has been explored as a tool for qualitative and quantitative characterization of drug dissolution and release with the characteristic feature of providing real-time visualization of the solution phase drug transport in the vicinity of the formulation. Events occurring during drug dissolution and release, such as polymer swelling, drug precipitation/recrystallization, or solvent-mediated phase transitions related to the structural properties of the drug substance or formulation can be monitored. UV imaging is a non-intrusive and simple-to-operate analytical technique which holds potential for providing a mechanistic foundation for formulation development. This review aims to cover applications of UV imaging in the early and late phase pharmaceutical development with a special focus on the relation between structural properties and performance. Potential areas of future advancement and application are also discussed.