基于QbD理念的药品质量分析研究新概念

本文阐述质量源于设计理念在药品质量评价分析中的应用基础,结合2010年全国评价性抽验的成效及特点,诠释质量源于设计理念在药品质量评价分析中的应用实践,展望质量源于设计理念在药品抽验工作计划、质量分析、质量再评价研究中的应用前景。     

基于质量风险管理的生物制药工艺验证策略

目的:根据美国、欧盟等药品监管部门以及ICH提出的基于生命周期的工艺验证方法,将风险管理运用到整个工艺验证的生命周期.方法:本文采用风险管理的方法对工艺设计阶段、工艺确认阶段以及持续工艺验证阶段进行了探讨.结果:证明基于风险的工艺开发和验证合并将产生更可靠、更持续可行的工艺,从而确保持续稳定地生产出符合预定用途和注册要求的药品.结论:通过符合更好的工艺实践,生物制药将进一步推动制药行业的发展.     

Assessment of the quality and structural integrity of a complex glycoprotein mixture following extraction from the formulated biopharmaceutical drug product

Biological drugs represent an important and rapidly growing class of therapeutics useful in the treatment of a variety of disorders ranging from cancer to inflammation to infectious diseases. Unlike single chemical entities, the recombinant production of these drugs in living cells confers considerable structural and chemical heterogeneity to the biologically derived protein product that constitutes the active pharmaceutical ingredient (API). In mammalian based expression systems, much of this diversity is conferred through heterogeneous protein glycosylation. These post-translational modifications can have significant effects on the structure, biological function, and pharmacological properties of the API. In addition, the bulk proteins that comprise the API are further formulated through the use of multiple excipients designed to ensure product stability, solubility, and lot-to-lot consistency. Unfortunately, these matrices can interfere with commonly available analytical methods used in the thorough chemical characterization of the biological drug product. At the same time, a demonstration of the suitable extraction of the bulk drug substance in a manner and form that does not destabilize the active ingredient or introduce any structural bias with direct reference to the original drug product is both critical and necessary. Here, we use recombinant human follicle stimulating hormone (follitropin alpha for injection) from a pharmaceutical source as an example to illustrate a suitable purification strategy to effectively extract the bulk drug substance from the formulated drug product with high purity and yield. We assess the suitability of this extraction method in preserving the structural integrity and overall quality of the drug substance relative to the formulated drug product, placing a particular emphasis on glycosylation as a key product attribute. In so doing, we demonstrate that it is possible to effectively extract the active pharmaceutical ingredient from a formulated biological drug product in a manner that is consequently sufficient for its use in comparability studies.     

Integrating genomics across drug discovery and development

The sequencing of the human genome was an exceptional achievement, but it was not an end in itself as it set the foundation for building new knowledge in biology and medicine. The laborious, multifaceted science of drug discovery and development also draws tremendous benefits from mining the human genome and exploiting the large palette of genomic technologies. This article discusses how diverse genomic tools have been used to date and how they will continue to be utilized in the future to impact drug discovery and development. Integrating genomics across drug discovery and development will undoubtedly help to shorten timelines, increase success rates at all stages and ultimately bring the right drugs to the right patients at the right times.     

Endocannabinoids: new targets for drug development

The possible therapeutic use of marijuana s active principles, the cannabinoids, is currently being debated. It is now known that these substances exert several of their pharmacological actions by activating specific cell membrane receptors, the CB1 and CB2 cannabinoid receptor subtypes. This knowledge led to the design of synthetic cannabinoid agonists and antagonists with high therapeutic potential. The recent discovery of the endocannabinoids, i.e. endogenous metabolites capable of activating the cannabinoid receptors, and the understanding of the molecular mechanisms leading to their biosynthesis and inactivation, opened a new era in research on the pharmaceutical applications of cannabinoids. Ongoing studies on the pathological and physiological conditions regulating the tissue levels of endocannabinoids, and on the pharmacological activity of these compounds and their derivatives, may provide a lead for the development of new drugs for the treatment of nervous and immune disorders, cardiovascular diseases, pain, inflammation and cancer. These studies are reviewed in this article with special emphasis on the chemical features that determine the interaction of endocannabinoids with the proteins mediating their activity and degradation.     

A new sensitive enzyme-linked immunosorbent assay (ELISA) for Alemtuzumab determination: development, validation and application

Alemtuzumab is a humanized (IgG(1)) rat monoclonal antibody to CD52 antigen and is currently used in the treatment of chronic lymphocytic leukemia (CLL) and other CD52-positive lymphoproliferative disorders. Various techniques have been developed to measure Alemtuzumab levels in human serum/plasma. The authors report on the validation of a very sensitive enzyme-linked immunosorbent assay (ELISA) to measure serum concentrations of the humanized IgG(1) using a rabbit polyclonal antibody specifically produced against the rat sequence of Alemtuzumab after papain digestion. The assay was successfully applied to test the serum samples of patients with B-lymphocyte CLL who received Alemtuzumab subcutaneously. This ELISA assay could be easily used to determine human serum levels of Alemtuzumab pre- and post-treatment to optimize dosing and scheduling and to study the relationship between dose and clinical response.     

磷酸二酯酶3：药物开发的新靶点

磷酸二酯酶（phosphodiesterase,PDE）是水解环磷酸腺苷（3’,5’-cyclic adenosine monophos-phate,cAMP）和环磷酸鸟苷（3’,5’-cyclicguanosine monophosphate,cGMP）重要的酶。其中,PDE3由2个基因组成,在体内广泛分布,其抑制剂在抗血小板聚集、扩张血管上起重要作用。研究显示,PDE3抑制剂具有神经保护作用,为寻找防治脑缺血的药物开辟了新的途径。     

Pioglitazone + metformin: new drug. A combination product to avoid

More serious adverse effects, and still no tangible proof of efficacy.     

Factors to consider when selecting a nebulizer for a new inhaled drug product development program

Introduction: Nebulizers are a common device choice for use when developing a new drug product, but the range of nebulizer devices available can make it difficult to select the right device. Increasingly, companies are only able to promote a drug with the device that was used during the development program; therefore, choosing the best device at an early stage is important in order to achieve commercial success. Selecting a device that is inappropriate for the intended drug can result in poor drug delivery from the nebulizer to the patient, which would have obvious implications for the development program. As device performance varies, it is important to ensure that the most appropriate device is chosen for the intended drug to ensure optimal drug delivery to the patient population.

Areas covered: In this review, the types of nebulizer devices available are highlighted, and the factors that should be taken into consideration when selecting the most appropriate device for a new drug are discussed. The review is broadly divided into drug, device, patient and trial characteristics.

Expert opinion: Efficient nebulizer devices that combine electronic monitoring capabilities as a form of telehealth are likely to provide superior drug delivery to patients and accurate clinical trial data. Their use in adaptive clinical trials may help to vastly reduce the time and costs associated with achieving drug approval.     

PROTAC technology: A new drug design for chemical biology with many challenges in drug discovery

Target Protein Degradation TPD is a new avenue and revolutionary for therapeutics because redefining the principles of classical drug discovery and guided by event-based target activity rather than the occupancy-driven activity. Since the discovery of the first PROTAC in 2001, TPD represents a rapidly growing technology, with applications in both drug discovery and chemical biology. Over the last decade, many questions have been raised and today the knowledge gained by each team has elucidated a number of them, although there is still a long way to go. The objective of this work is to present the challenges that the PROTAC strategy has very recently addressed in drug design and discovery by presenting extremely recent results from the literature and to provide guidelines in the drug design of new PROTACs as successful therapeutic modality for medicinal chemists.     

药物经济学——压缩新药研发成本的新动力

目的促进我国在新药研发中加强药物经济学的应用。方法综合国内外新药研发的现状,分析在新药研发阶段引入药物经济学的必要性以及可行性。结果与结论我国的药物经济学研究尚处在初级阶段,在新药研发中引入药物经济学还有待政府部门的规范和推动。     

Quality by design: understanding the product variability of a self-nanoemulsified drug delivery system of cyclosporine A

The objective of this work was to understand the product variability due to size and other characteristics of the SNEDDS by utilizing near infrared (NIR) and chemometric analysis, as well as several other well-known procedures. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsification region using CyA solutions in sweet orange oil (oily phase), Emulphor EL-620 (surfactant), and Capmul MCM-C8 (cosurfactant). The formulated SNEDDS were characterized by droplet size, turbidity, zeta potential, and Fourier transform infrared (FTIR) analysis. Drug release studies were performed by dissolution in conjunction with turbidimetry. Permeability studies were performed in a Franz diffusion cell assembly. The results indicated an optimum surfactant to cosurfactant ratio of 2:1. Above this ratio, the resultant nanoemulsions had a particle size of 10 nm and turbidity of 10 nephlometric units (NTU). All the prepared systems were positively charged. The FTIR spectra and the DSC thermograms obtained showed no incompatibility between the SNEDDS ingredients. Turbidity time profiles revealed three distinctive regions: lag phase, plateau, and pseudolinear phase. Emulsification rate was obtained from the corrected slope of the pseudolinear phase of the profile. Permeability data indicated that the product variability is more with smaller droplet size. The size of the droplets showed good correlation with NIR spectral data by partial least square (PLS) regression plots. In conclusion, this study demonstrated the ability to understand the impact of nanodroplets size on the SNEDDS variability by different product analyzing tools.     

Bioterrorism: a new frontier for drug discovery and development

Only a few years ago bioterrorism was considered a remote concern but today it has reached the forefront of the public imagination following recent terrorist attacks around the world. The disaster of September 11 2001, followed by anthrax letters sent via the US postal system, and now the renewed tension in the Middle East, have all brought the possibility of bioterrorism a little closer to reality. A number of biological agents could be used in a terrorist attack, including anthrax, botulinum, plague, smallpox, staphylococcal and streptococcal toxins, and the list of emerging pathogens is evolving rapidly. The serious diseases that these agents produce could cause considerable morbidity and mortality if used in a terrorist attack. This evolving threat presents the medical, public health and scientific communities with pressing challenges. The present research efforts in academia are primarily focused on the basic research on the pathogens that are considered to be bioweapons for terrorist attack. Thus, collaborative efforts between academic institutes, pharmaceutical industries and governmental agencies are warranted to translate basic research into drugs, vaccines and diagnostic tests. This review provides a brief overview of the threat from biological weapons and the current biodefense strategy to prevent and control outbreaks of diseases caused by intentional release of these bioweapons of mass destruction.     

Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption

For almost a half century scientists have striven to develop a theoretical model capable of predicting oral drug absorption in humans. From the pH-partition hypothesis to the compartmental absorption and transit (CAT) model, various qualitative/quantitative approaches have been proposed, revised and extended. In this review, these models are classified into three categories; quasi-equilibrium models, steady-state models and dynamic models. The quasi-equilibrium models include the pH-partition hypothesis and the absorption potential concept, the steady-state models include the film model and the mass balance approaches, and the dynamic models include the dispersion, mixing tank and CAT models. The quasi-equilibrium models generally provide a basic guideline for understanding drug absorption trends. The steady-state models can be used to estimate the fraction of dose absorbed. The dynamic models predict both the fraction of dose absorbed and the rate of drug absorption and can be related to pharmacokinetic models to evaluate plasma concentration profiles.     

The role of predictive biopharmaceutical modeling and simulation in drug development and regulatory evaluation

Advances in predicting in vivo performance of drug products has the potential to change how drug products are developed and reviewed. Modeling and simulation methods are now more commonly used in drug product development and regulatory drug review. These applications include, but are not limited to: the development of biorelevant specifications, the determination of bioequivalence metrics for modified release products with rapid therapeutic onset, the design of in vitro-in vivo correlations in a mechanistic framework, and prediction of food effect. As new regulatory concepts such as quality by design require better application of biopharmaceutical modeling in drug product development, regulatory challenges in bioequivalence demonstration of complex drug products also present exciting opportunities for creative modeling and simulation approaches. A collaborative effort among academia, government and industry in modeling and simulation will result in improved safe and effective new/generic drugs to the American public.     

microRNA——药物开发的新靶点

微小RNA(microRNA)是一类长约22 nt的非编码单链RNA,由前体经酶作用而得,它是细胞的内源性物质,普遍存在于动植物中,高度保守,在生命体的生长、发育、疾病发生发展的过程中起到了基因调控作用,它与重大疾病,如肿瘤、心脏疾病、神经性疾病等都有着密切的关联,因此成为新药开发的一个重要新靶点,以它为靶点的药物设计和药物研发工作也在不断探索中.本文就其研究的历史、生物合成和作用机制、生物功能、与疾病的关系以及以microRNA为靶点的药物设计的研究情况做一个简单的综述.     

Quality by design in formulation and process development for a freeze-dried, small molecule parenteral product: a case study

A case study has been developed to illustrate one way of incorporating a Quality by Design approach into formulation and process development for a small molecule, freeze-dried parenteral product. Sodium ethacrynate was chosen as the model compound. Principal degradation products of sodium ethacrynate result from hydrolysis of the unsaturated ketone in aqueous solution, and dimer formation from a Diels-Alder condensation in the freeze-dried solid state. When the drug crystallizes in a frozen solution, the eutectic melting temperature is above -5°C. Crystallization in the frozen system is affected by pH in the range of pH 6-8 and buffer concentration in the range of 5-50 mM, where higher pH and lower buffer concentration favor crystallization. Physical state of the drug is critical to solid state stability, given the relative instability of amorphous drug. Stability was shown to vary considerably over the ranges of pH and buffer concentration examined, and vial-to-vial variability in degree of crystallinity is a potential concern. The formulation design space was constructed in terms of pH and drug concentration, and assuming a constant 5 mM concentration of buffer. The process design space is constructed to take into account limitations on the process imposed by the product and by equipment capability.