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.     

Transforming Lipid-Based Oral Drug Delivery Systems into Solid Dosage Forms: An Overview of Solid Carriers, Physicochemical Properties, and Biopharmaceutical Performance

The diversity of lipid excipients available commercially has enabled versatile formulation design of lipid-based drug delivery systems for enhancing the oral absorption of poorly water-soluble drugs, such as emulsions, microemulsions, micelles, liposomes, niosomes and various self-emulsifying systems. The transformation of liquid lipid-based systems into solid dosage forms has been investigated for several decades, and has recently become a core subject of pharmaceutical research as solidification is regarded as viable means for stabilising lipid colloidal systems while eliminating stringent processing requirements associated with liquid systems. This review describes the types of pharmaceutical grade excipients (silica nanoparticle/microparticle, polysaccharide, polymer and protein-based materials) used as solid carriers and the current state of knowledge on the liquid-to-solid conversion approaches. Details are primarily focused on the solid-state physicochemical properties and redispersion capacity of various dry lipid-based formulations, and how these relate to the in vitro drug release and solubilisation, lipid carrier digestion and cell permeation performances. Numerous in vivo proof-of-concept studies are presented to highlight the viability of these dry lipid-based formulations. This review is significant in directing future research work in fostering translation of dry lipid-based formulations into clinical applications.     

Use of microwave in processing of drug delivery systems

Microwave has received a widespread application in pharmaceuticals and food processing, microbial sterilization, biomedical therapy, scientific and biomedical analysis, as well as, drug synthesis. This paper reviews the basis of application of microwave to prepare pharmaceutical dosage forms such as agglomerates, gel beads, microspheres, nanomatrix, solid dispersion, tablets and film coat. The microwave could induce drying, polymeric crosslinkages as well as drug-polymer interaction, and modify the structure of drug crystallites via its effects of heating and/or electromagnetic field on the dosage forms. The use of microwave opens a new approach to control the physicochemical properties and drug delivery profiles of pharmaceutical dosage forms without the need for excessive heat, lengthy process or toxic reactants. Alternatively, the microwave can be utilized to process excipients prior to their use in the formulation of drug delivery systems. The intended release characteristics of drugs in dosage forms can be met through modifying the physicochemical properties of excipients using the microwave.     

Functions of lipids for enhancement of oral bioavailability of poorly water-soluble drugs

Lipid-based formulations encompass a diverse group of formulations with very different physical appearance, ranging from simple triglyceride vehicles to more sophisticated formulations such as self-emulsifying drug delivery systems (SEDDS). Lipid-based drug delivery systems may contain a broad range of oils, surfactants, and co-solvents. They represent one of the most popular approaches to overcome the absorption barriers and to improve the bioavailability of poorly water-soluble drugs. Diversity and versatility of pharmaceutical grade lipid excipients and drug formulations as well as their compatibility with liquid, semi-solid and solid dosage forms make lipid systems most complex. Digestion of triglyceride lipids, physicochemical characteristics and solubilisation of lipid digestion products as well as intestinal permeability are some of the variable parameters of such formulations. Furthermore, among the factors affecting the bioavailability of the drug from lipid-based formulations are the digestion of lipid, the mean emulsion droplet diameter, the lipophilicity of the drug and the type of lipids. The solubility of the Active Pharmaceutical Ingredient in the Lipid System, the desorption/sorption isotherm and the digestibility of lipid vehicle are important issues to be considered for formulations of isotropic lipid formulations. This review also describes the fate of lipid formulations in the gut and the factors influencing the bioavailability from lipid-based formulations. Novel formulation systems and currently marketed products conclude this review.     

Compritol 888 ATO: a multifunctional lipid excipient in drug delivery systems and nanopharmaceuticals

Introduction: Compritol® 888 ATO is a lipid excipient that is generally used in cosmetic industry as a surfactant, emulsifying agent and viscosity-inducing agent in emulsions or creams. Based on its chemical composition, Compritol 888 ATO is a blend of different esters of behenic acid with glycerol.

Areas covered: Recently, there has been great interest in the multiple roles that Compritol 888 ATO plays in various pharmaceutical delivery systems. Accordingly, this review aimed at summarizing the current and potential applications of Compritol 888 ATO in various drug delivery areas.

Expert opinion: Different researches have highlighted the feasibility of using Compritol 888 ATO as a lubricant or coating agent for oral solid dosage formulations. It has also been explored as a matrix-forming agent for controlling drug release. At present, the most common pharmaceutical application of Compritol 888 ATO is in lipid-based colloidal drug delivery system such as solid lipid microparticles, solid lipid nanoparticles and nanostructured lipid carriers. Although, Compritol 888 ATO has acceptable regulatory and safety profiles and although the number of articles that emphasize on its applicability as an innovative excipient in pharmaceutical technology is continuously increasing, it is not widely used in the pharmaceutical market products and its use is limited to its sustain release ability in extended release tablets.     

Lipid-based formulations for oral administration of poorly water-soluble drugs

Lipid-based drug delivery systems have shown great potentials in oral delivery of poorly water-soluble drugs, primarily for lipophilic drugs, with several successfully marketed products. Pre-dissolving drugs in lipids, surfactants, or mixtures of lipids and surfactants omits the dissolving/dissolution step, which is a potential rate limiting factor for oral absorption of poorly water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form has a pronounced effect on the biopharmaceutical aspects of drug absorption and distribution both in vitro and in vivo. The aim of this review is to provide an overview of the different lipid-based dosage forms from a biopharmaceutical point of view and to describe effects of lipid dosage forms and lipid excipients on drug solubility, absorption and distribution.     

Excipients with specialized functions for effective drug delivery

INTRODUCTION: There is a growing need for the development of pharmaceutical excipients that could improve product performance and overcome the shortcomings of new drug moieties, such as their poor solubility and membrane permeability, as well as to aid with modern manufacturing processes. AREAS COVERED: Different types of functional excipients are discussed in this paper, in terms of their roles in modern dosage forms to optimize drug delivery and manufacturability. Functions of specialized excipients that are covered in this article include the enhancement of drug membrane permeability, the improvement of drug solubility and stability, the regulation of drug release in response to feedback mechanisms and assistance with the production of dosage forms. EXPERT OPINION: Modern drug delivery systems rely on sophisticated excipients with multiple functions to improve overall product performance. The excipient market is expected to grow substantially with emerging trends in the development of these advanced drug delivery systems.     

Chitosan and Its Use as a Pharmaceutical Excipient

Chitosan has been investigated as an excipient in the pharmaceutical industry, to be used in direct tablet compression, as a tablet disintegrant, for the production of controlled release solid dosage forms or for the improvement of drug dissolution. Chitosan has, compared to traditional excipients, been shown to have superior characteristics and especially flexibility in its use. Furthermore, chitosan has been used for production of controlled release implant systems for delivery of hormones over extended periods of time. Lately, the transmucosal absorption promoting characteristics of chitosan has been exploited especially for nasal and oral delivery of polar drugs to include peptides and proteins and for vaccine delivery. These properties, together with the very safe toxicity profile, makes chitosan an exciting and promising excipient for the pharmaceutical industry for present and future applications.     

Emulsion forming drug delivery system for lipophilic drugs

In the recent years, there is a growing interest in the lipid-based formulations for delivery of lipophilic drugs. Due to their potential as therapeutic agents, preferably these lipid soluble drugs are incorporated into inert lipid carriers such as oils, surfactant dispersions, emulsions, liposomes etc. Among them, emulsion forming drug delivery systems appear to be a unique and industrially feasible approach to overcome the problem of low oral bioavailability associated with the BCS class II drugs. Self-emulsifying formulations are ideally isotropic mixtures of oils, surfactants and co-solvents that emulsify to form fine oil in water emulsions when introduced in aqueous media. Fine oil droplets would pass rapidly from stomach and promote wide distribution of drug throughout the GI tract, thereby overcome the slow dissolution step typically observed with solid dosage forms. Recent advances in drug carrier technologies have promulgated the development of novel drug carriers such as control release self-emulsifying pellets, microspheres, tablets, capsules etc. that have boosted the use of "self-emulsification" in drug delivery. This article reviews the different types of formulations and excipients used in emulsion forming drug delivery system to enhance the bioavailability of lipophilic drugs.     

Approaches for the development of solid and semi-solid lipid-based formulations

Interest in Lipid Based Drug Delivery (LBDD) has developed over the past decade fuelled by a better understanding of the multiple roles lipids may play in enhancing oral bioavailability. Moreover, the emergence of novel excipients with acceptable regulatory and safety profiles coupled with advances in formulation technologies have greatly improved the potential for successful lipid based formulations. With the growing interest in this field, there is an increasing need for guidelines in excipient selection and characterization; material handling, formulation design, and processing techniques to obtain effective and patient-compliant dosage forms. The aim of this review is to present the recent approaches in selecting the most appropriate lipid system(s); methods for characterization of their behavior in vitro and in vivo; and the current formulation and processing techniques to obtain various solid dosage forms.     

Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies

Oral lipid-based drug delivery systems may include a broad range of oils, surfactants, and cosolvents. This diversity makes comparison of lipid-based formulations difficult. Although the relationship between formulation and drug absorption is understood at a conceptual level, performance in vivo cannot be predicted with confidence at present. The Lipid Formulation Classification System (LFCS) identifies the factors which are likely to affect performance in vivo. There is now a need to establish performance criteria which will facilitate in vitro-in vivo correlation studies. In this review we discuss the properties of excipients, and identify criteria for selection of excipients for lipid-based formulations. Excipients are discussed in the context of the LFCS, our existing knowledge of the fate of these materials during dispersion and digestion, and the likely consequences of their use in formulations. We outline the formulation strategies that can be used for each type of lipid formulation, and suggest a framework for the in vitro testing of each type. Finally we address the choice of lipid formulations in relation to the physicochemical properties of the drug.     

Equivalence-by-Design: Targeting <Emphasis Type="BoldItalic">In Vivo</Emphasis> Drug Delivery Profile

In the United States (U.S.), drug products are considered therapeutically equivalent if they meet regulatory criteria of pharmaceutical equivalence and bioequivalence. These requirements can be traced back to 1977 when the U.S. Food and Drug Administration (FDA) published the regulations on bioavailability and bioequivalence. Over the years, to keep up with the advancement in science and technology, the FDA has been constantly updating the regulatory approaches to assessing and ensuring equivalence. In view of the recent growth in novel pharmaceutical dosage forms and delivery systems, this paper examines the current framework for documentation of therapeutic equivalence and explores the opportunities of further advancing equivalence methods for complex drug products. It is proposed that equivalence may be established by matching the in vivo drug delivery profile (iDDP) between drug products in comparison. This can be achieved by characterizing the iDDP of the reference formulation with application of an equivalence-by-design approach for pharmaceutical development. Critical variables can be identified to serve as in vitro markers or biomarkers for mapping the desired drug delivery profile in vivo. A multidisciplinary approach may be necessary to develop these markers for characterization of iDDPs. The opinions expressed in this article do not necessarily represent the views or policies of the U.S. Food and Drug Administration     

药物与辅料相容性研究进展

目的对药物与辅料的相容性及相互作用机制和研究方法进展作概述和分析。方法结合近年来国内外相关文献进行评述和展望。结果药物与辅料的相互作用可改变药物活性分子的理化性质,影响药物的稳定性和有效性。结论药物与辅料的相容性研究对制剂处方设计、提高制剂质量和安全性至关重要,药物与辅料相容性及作用机制研究的方法有热分析法、光谱法、色谱法等,可根据试验目的和要求选择适宜的分析方法。     

Biopharmaceutical challenges associated with drugs with low aqueous solubility--the potential impact of lipid-based formulations

The percentage of new chemical entities synthesised with low aqueous solubility and high therapeutic efficacy is growing, this presents major challenges for the drug delivery scientists. The role of physicochemical properties in identification of suitable drug candidates for oral lipid-based delivery systems is discussed. A knowledge of the interplay of physicochemical and biopharmaceutical drug properties with the physiological environment of the gastro-intestinal tract (GIT), as a prerequisite to successful formulation design, is reviewed. The importance of excipient selection with an emphasis on bioactive excipients is stressed. The need for more examples of in vitro-in vivo correlations as a means of maximizing the development potential and commercial future for lipid-based formulations, and, promoting confidence within the industry for these delivery systems is highlighted.     

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.     

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.     

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.     

Impact of Excipient Interactions on Solid Dosage Form Stability

Drug-excipient interactions in solid dosage forms can affect drug product stability in physical aspects such as organoleptic changes and dissolution slowdown, or chemically by causing drug degradation. Recent research has allowed the distinction in chemical instability resulting from direct drug-excipient interactions and from drug interactions with excipient impurities. A review of chemical instability in solid dosage forms highlights common mechanistic themes applicable to multiple degradation pathways. These common themes include the role of water and microenvironmental pH. In addition, special aspects of solid-state reactions with excipients and/or excipient impurities add to the complexity in understanding and modeling reaction pathways. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes. Recent developments in the understanding of degradation pathways further impact methodologies used in the pharmaceutical industry for prospective stability assessment. This paper discusses these emerging aspects in terms of limitations of drug-excipient compatibility studies, emerging paradigms in accelerated stability testing, and application of mathematical modeling for prediction of drug product stability.     

Mechanoradical-Induced Degradation in a Pharmaceutical Blend during High-Shear Processing

Mechanically generated radicals were shown to affect short-term stability of a model pharmaceutical formulation during high-shear processing. A formulation containing an oxidatively sensitive drug, either amorphous or crystalline, and a polymeric excipient was high-shear mixed and the resulting short-term degradation was determined with HPLC. High-shear mixing of the excipients was also carried out before drug addition to isolate effects on excipients versus those directly on the drug. Short-term drug stability was found to be strongly dependent on the amount of shear added to excipients prior to drug addition, regardless of morphology. A mechanism for the observed degradation based on mechanically generated radicals from microcrystalline cellulose is proposed. These results indicate that excipient high-shear exposure needs to be considered in regards to drug stability.     

Mechanoradical-induced degradation in a pharmaceutical blend during high-shear processing

Mechanically generated radicals were shown to affect short-term stability of a model pharmaceutical formulation during high-shear processing. A formulation containing an oxidatively sensitive drug, either amorphous or crystalline, and a polymeric excipient was high-shear mixed and the resulting short-term degradation was determined with HPLC. High-shear mixing of the excipients was also carried out before drug addition to isolate effects on excipients versus those directly on the drug. Short-term drug stability was found to be strongly dependent on the amount of shear added to excipients prior to drug addition, regardless of morphology. A mechanism for the observed degradation based on mechanically generated radicals from microcrystalline cellulose is proposed. These results indicate that excipient high-shear exposure needs to be considered in regards to drug stability.