New Approach for the Application of USP Apparatus 3 in Dissolution Tests: Case Studies of Three Antihypertensive Immediate-Release Tablets

The USP Apparatus 3 is a compendial dissolution Apparatus that has been mainly used to assess the performance of modified-release drug products. However, this Apparatus can be applied to dissolution testing of immediate-release tablets as well, with several advantages such as lower consumption of dissolution media, reduced setup time in quality control routine, and minimized hydrodynamic issues. In this work, three immediate-release (IR) tablets containing antihypertensive drugs of different Biopharmaceutic Classification System (BCS) classes were evaluated in order to assess the possible interchangeability between the official dissolution method using typical USP Apparatus 1 or 2 and the proposed methods using USP Apparatus 3. Depending on the selection of the appropriate operational conditions, such as dip rate and sieve mesh size, it was observed that USP Apparatus 3 could provide similar dissolution profiles compared to USP Apparatus 1 or 2 to the drug products tested. In addition, USP Apparatus 3 avoided conning issues related to USP Apparatus 2. The successful application of USP Apparatus 3 in dissolution tests for IR drug products depends on the definition of specific test conditions for each product, considering all the equipment variables, as well as drug and formulation characteristics.     

In Vitro Dissolution of Generic Immediate-Release Solid Oral Dosage Forms Containing BCS Class I Drugs: Comparative Assessment of Metronidazole,Zidovudine, and Amoxicillin Versus Relevant Comparator Pharmaceutical Products in South Africa and India

Biowaivers are recommended for immediate-release solid oral dosage forms using dissolution testing as a surrogate for in vivo bioequivalence studies. Several guidance are currently available (the World Health Organization (WHO), the US FDA, and the EMEA) where the conditions are described. In this study, definitions, criteria, and methodologies according to the WHO have been applied. The dissolution performances of immediate-release metronidazole, zidovudine, and amoxicillin products purchased in South African and Indian markets were compared to the relevant comparator pharmaceutical product (CPP)/reference product. The dissolution performances were studied using US Pharmacopeia (USP) apparatus 2 (paddle) set at 75 rpm in each of three dissolution media (pH1.2, 4.5, and 6.8). Concentrations of metronidazole, zidovudine, and amoxicillin in each dissolution media were determined by HPLC. Of the 11 metronidazole products tested, only 8 could be considered as very rapidly dissolving products as defined by the WHO, whereas 2 of those products could be considered as rapidly dissolving products but did not comply with the f₂ acceptance criteria in pH 6.8. All 11 zidovudine products were very rapidly dissolving, whereas in the case of the 14 amoxicillin products tested, none of those products met any of the WHO criteria. This study indicates that not all generic products containing the same biopharmaceutics classification system (BCS) I drug and in similar strength and dosage form are necessarily in vitro equivalent. Hence, there is a need for ongoing market surveillance to determine whether marketed generic products containing BCS I drugs meet the release requirements to confirm their in vitro bioequivalence to the respective reference product.KEY WORDS: BCS, dissolution testing, generic drug, immediate-release solid oral dosage forms, WHO criteria     

The next generation of PPAR drugs: do we have the tools to find them?

Agonists of PPARalpha and PPARgamma are currently approved for use in treating, respectively, dyslipidemia and type 2 diabetes. Agonists of PPARbeta/delta are currently in development by several pharmaceutical companies. Despite their therapeutic importance, there are dose limiting side effects associated with PPAR drug treatments, thus a new generation of safer PPAR drugs are being actively sought after. In this review we will discuss the side effects associated the PPARs, how the current drugs in clinical development were discovered and new concepts in how to screen for PPAR drugs.     

Unlocking the potential of natural products in drug discovery

The natural product specialized metabolites produced by microbes and plants are the backbone of our current drugs. Despite their historical importance, few pharmaceutical companies currently emphasize their exploitation in new drug discovery and instead favour synthetic compounds as more tractable alternatives. Ironically, we are in a Golden Age of understanding of natural product biosynthesis, biochemistry and engineering. These advances have the potential to usher in a new era of natural product exploration and development taking full advantage of the unique and favourable properties of natural products compounds in drug discovery.     

Natural products as a screening resource

Natural products have been the most productive source of leads for new drugs, but they are currently out of fashion with the pharmaceutical industry. New approaches to sourcing novel compounds from untapped areas of biodiversity coupled with the technical advances in analytical techniques (such as microcoil NMR and linked LC-MS-NMR) have removed many of the difficulties in using natural products in screening campaigns. As the 'chemical space' occupied by natural products is both more varied and more drug-like than that of combinatorial chemical collections, synthetic and biosynthetic methods are being developed to produce screening libraries of natural product-like compounds. A renaissance of drug discovery inspired by natural products can be predicted.     

Advanced lipid technology

Abstract

Phospholipids and cholesterols are being spotlighted as raw materials for preparing liposomes, one of the key compounds for drug delivery systems (DDS), and as base compounds for converting water-soluble drugs to fat-soluble drugs. Other applications of phospholipids also are being explored. Nippon Fine Chemical, aware of the future of such lipids, has developed new processes for synthesizing and purifying phospholipids and is supplying them on an industrial scale. These products – used worldwide – are highly regarded as raw materials for preparing liposomes. In particular, Nippon Fine Chemical’s innovative research led to the development of “Presome®”, a base agent that facilitates the preparation of liposome solutions. To further this research, Nippon Fine Chemical has established an “Advanced Lipid Technology”.     

Biological screening of natural products and drug innovation in China

Natural products have been applied to human healthcare for thousands of years. Drug discovery in ancient times was largely by chance and based on clinical practices. As understanding of therapeutic benefits deepens and demands for natural products increase, previously serendipitous discoveries evolve into active searches for new medicines. Many drugs presently prescribed by physicians are either directly isolated from plants or are artificially modified versions of natural products. Scientists are looking for lead compounds with specific structures and pharmacological effects often from natural sources. Experiences and successes of Chinese scientists in this specialized area have resulted in a number of widely used drugs. The tremendous progress made in life sciences has not only revealed many pathological processes of diseases, but also led to the establishment of various molecular and cellular bioassays in conjunction with high-throughput technologies. This is advantageous and permits certain natural compounds that are difficult to isolate and purify, and compounds that are difficult to synthesize, to be assayed. The transition from traditional to empirical and to molecular screening will certainly increase the probability of discovering new leads and drug candidates from natural products.     

Development and Evaluation of a Novel Modified-Release Pellet-Based Tablet System for the Delivery of Loratadine and Pseudoephedrine Hydrochloride as Model Drugs

Modified-release multiple-unit tablets of loratadine and pseudoephedrine hydrochloride with different release profiles were prepared from the immediate-release pellets comprising the above two drugs and prolonged-release pellets containing only pseudoephedrine hydrochloride. The immediate-release pellets containing pseudoephedrine hydrochloride alone or in combination with loratadine were prepared using extrusion–spheronization method. The pellets of pseudoephedrine hydrochloride were coated to prolong the drug release up to 12 h. Both immediate- and prolonged-release pellets were filled into hard gelatin capsule and also compressed into tablets using inert tabletting granules of microcrystalline cellulose Ceolus KG-801. The in vitro drug dissolution study conducted using high-performance liquid chromatography method showed that both multiple-unit capsules and multiple-unit tablets released loratadine completely within a time period of 2 h, whereas the immediate-release portion of pseudoephedrine hydrochloride was liberated completely within the first 10 min of dissolution study. On the other hand, the release of pseudoephedrine hydrochloride from the prolonged release coated pellets was prolonged up to 12 hr and followed zero-order release kinetic. The drug dissolution profiles of multiple-unit tablets and multiple-unit capsules were found to be closely similar, indicating that the integrity of pellets remained unaffected during the compression process. Moreover, the friability, hardness, and disintegration time of multiple-unit tablets were found to be within BP specifications. In conclusion, modified-release pellet-based tablet system for the delivery of loratadine and pseudoephedrine hydrochloride was successfully developed and evaluated.     

Terpenoid biotransformations by Mucor species

Terpenoids are natural products of great interest due to their widespread use in agrochemicals, drugs, fragrances, flavouring and pigments. Biocatalysts are increasingly being used in the search for new derivatives with improved properties especially to obtain structurally novel leads for new drugs which are difficult to obtain using conventional organic chemical methods. This review, covering up to the end of 2012, reports on the application of Mucor species as catalysts in terpenoid biotransformation to obtain new drug targets, enhance pharmacological activity or decrease the unwanted effects of starting material.     

Drug discovery prospect from untapped species: indications from approved natural product drugs

Due to extensive bioprospecting efforts of the past and technology factors, there have been questions about drug discovery prospect from untapped species. We analyzed recent trends of approved drugs derived from previously untapped species, which show no sign of untapped drug-productive species being near extinction and suggest high probability of deriving new drugs from new species in existing drug-productive species families and clusters. Case histories of recently approved drugs reveal useful strategies for deriving new drugs from the scaffolds and pharmacophores of the natural product leads of these untapped species. New technologies such as cryptic gene-cluster exploration may generate novel natural products with highly anticipated potential impact on drug discovery.     

Literature Mining for the Discovery of Hidden Connections between Drugs,Genes and Diseases

The scientific literature represents a rich source for retrieval of knowledge on associations between biomedical concepts such as genes, diseases and cellular processes. A commonly used method to establish relationships between biomedical concepts from literature is co-occurrence. Apart from its use in knowledge retrieval, the co-occurrence method is also well-suited to discover new, hidden relationships between biomedical concepts following a simple ABC-principle, in which A and C have no direct relationship, but are connected via shared B-intermediates. In this paper we describe CoPub Discovery, a tool that mines the literature for new relationships between biomedical concepts. Statistical analysis using ROC curves showed that CoPub Discovery performed well over a wide range of settings and keyword thesauri. We subsequently used CoPub Discovery to search for new relationships between genes, drugs, pathways and diseases. Several of the newly found relationships were validated using independent literature sources. In addition, new predicted relationships between compounds and cell proliferation were validated and confirmed experimentally in an in vitro cell proliferation assay. The results show that CoPub Discovery is able to identify novel associations between genes, drugs, pathways and diseases that have a high probability of being biologically valid. This makes CoPub Discovery a useful tool to unravel the mechanisms behind disease, to find novel drug targets, or to find novel applications for existing drugs.     

Leishmania: role of P glycoprotein in drug resistance and reversion strategies

Protozoan parasites are important causative agents of morbidity and mortality throughout the world--a problem further complicated by the emergence of drug resistance in these parasites. Mechanisms of drug resistance include the following: decreased uptake of the drug into the cell, loss of drug activation, alterations in the drug target, and over-expression of a well-known multiple drug transporter proteins. In this review, two critical components of resistance are stressed: (1) the role of ATP binding cassette proteins, such as P-glycoproteins, in mediating drug resistance in Leishmania and other protozoans, followed by development of cross-resistance to many structurally and functionally unrelated drugs, and (2) some concepts concerning the reversal mechanism of multidrug resistance by drugs and natural products. Several modulators or chemosensitizers alter the capacity of P-glycoproteins to maintain subtoxic intracellular drug concentrations. Calcium channel blockers such as verapamil act in this mode; however, high concentrations are required for an efficient and effective inhibition and, in addition, produce undesirable side effects. The discovery of new, natural product modulators of P-glycoproteins is stressed. This category of modulators offer potentially improved efficacy and lowered toxicity for the mammalian host.     

Natural products as catalysts for innovation: a pharmaceutical industry perspective

Natural products are evolutionarily designed and chemically distinct from most synthetic library molecules. In addition to their role as drugs, they are successfully used as molecular probes to identify disease relevant targets. Novel natural products are still routinely discovered from traditional sources through cultivation of microorganisms. Complementary approaches based on genome sequence information and subsequent annotation of biosynthetic pathways are emerging technologies. However, to be of practical use for drug discovery, these concepts must be advanced beyond their current state.     

Advanced protein formulations

It is well recognized that protein product development is far more challenging than that for small‐molecule drugs. The major challenges include inherent sensitivity to different types of stresses during the drug product manufacturing process, high rate of physical and chemical degradation during long‐term storage, and enhanced aggregation and/or viscosity at high protein concentrations. In the past decade, many novel formulation concepts and technologies have been or are being developed to address these product development challenges for proteins. These concepts and technologies include use of uncommon/combination of formulation stabilizers, conjugation or fusion with potential stabilizers, site‐specific mutagenesis, and preparation of nontraditional types of dosage forms—semiaqueous solutions, nonfreeze‐dried solid formulations, suspensions, and other emerging concepts. No one technology appears to be mature, ideal, and/or adequate to address all the challenges. These gaps will likely remain in the foreseeable future and need significant efforts for ultimate resolution.     

Identifying Novel Drug Indications through Automated Reasoning

Background

With the large amount of pharmacological and biological knowledge available in literature, finding novel drug indications for existing drugs using in silico approaches has become increasingly feasible. Typical literature-based approaches generate new hypotheses in the form of protein-protein interactions networks by means of linking concepts based on their cooccurrences within abstracts. However, this kind of approaches tends to generate too many hypotheses, and identifying new drug indications from large networks can be a time-consuming process.

Methodology

In this work, we developed a method that acquires the necessary facts from literature and knowledge bases, and identifies new drug indications through automated reasoning. This is achieved by encoding the molecular effects caused by drug-target interactions and links to various diseases and drug mechanism as domain knowledge in AnsProlog, a declarative language that is useful for automated reasoning, including reasoning with incomplete information. Unlike other literature-based approaches, our approach is more fine-grained, especially in identifying indirect relationships for drug indications.

Conclusion/Significance

To evaluate the capability of our approach in inferring novel drug indications, we applied our method to 943 drugs from DrugBank and asked if any of these drugs have potential anti-cancer activities based on information on their targets and molecular interaction types alone. A total of 507 drugs were found to have the potential to be used for cancer treatments. Among the potential anti-cancer drugs, 67 out of 81 drugs (a recall of 82.7%) are indeed known cancer drugs. In addition, 144 out of 289 drugs (a recall of 49.8%) are non-cancer drugs that are currently tested in clinical trials for cancer treatments. These results suggest that our method is able to infer drug indications (original or alternative) based on their molecular targets and interactions alone and has the potential to discover novel drug indications for existing drugs.     

纳米混悬药物传递系统研究进展

在新药研发过程中,约有40%的药物存在溶解性差的问题,限制了药物的开发与应用。纳米混悬剂是20世纪末发展起来的一种纳米药物传递系统,可增加难溶性药物的溶解度和溶出速率、改变药物的体内药物动力学特征、提高口服生物利用度、安全性和有效性。纳米混悬剂不但适用于水溶性差的药物,而且适用于水溶性、脂溶性均较差的药物,其制备方法主要包括"bottom up"和"top down"两种。本文从纳米混悬剂的特点、理论基础、专利技术及应用等方面对纳米混悬剂的研究进展进行了综述。纳米混悬剂对改善难溶性药物的溶出、吸收,提高难溶性药物的有效性、安全性等方面具有显著优势,且适合工业化生产,已有越来越多的产品问世。纳米混悬技术是未来药物传递系统的发展方向之一,将具有良好的应用前景。     

Implementing quality by design for biotech products: Are regulators on track?

Quality by design (QbD) is an innovative approach to drug development that has started to be implemented into the regulatory framework, but currently mainly for chemical drugs. The recent marketing authorization of the first monoclonal antibody developed using extensive QbD concepts in the European Union paves the way for future further regulatory approvals of complex products employing this cutting-edge technological concept. In this paper, we report and comment on insights and lessons learnt from the non-public discussions in the European Medicines Agency's Biologicals Working Party and Committee for Medicinal Products for Human Use on the key issues during evaluation related to the implementation of an extensive QbD approach for biotechnology-derived medicinal products. Sharing these insights could prove useful for future developments in QbD for biotech products in general and monoclonal antibodies in particular.     

Implementing quality by design for biotech products: Are regulators on track?

Quality by design (QbD) is an innovative approach to drug development that has started to be implemented into the regulatory framework, but currently mainly for chemical drugs. The recent marketing authorization of the first monoclonal antibody developed using extensive QbD concepts in the European Union paves the way for future further regulatory approvals of complex products employing this cutting-edge technological concept. In this paper, we report and comment on insights and lessons learnt from the non-public discussions in the European Medicines Agency''s Biologicals Working Party and Committee for Medicinal Products for Human Use on the key issues during evaluation related to the implementation of an extensive QbD approach for biotechnology-derived medicinal products. Sharing these insights could prove useful for future developments in QbD for biotech products in general and monoclonal antibodies in particular.     

Ethno biological usage of zoo products in rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most common autoimmune disorder which causes swelling, redness, pain, stiffness, restriction of limb movements, decreases life expectancy and early death of the patients. Available drugs include non steroidal anti-inflammatory and analgesics, disease modifying anti-rheumatic drugs and steroids (glucocorticoids etc). All these drugs have their own limitations such as gastrointestinal irritations, cardiovascular problems, and drug dependency. Search for alternative therapy from natural products are being ventured throughout the world. Zoo therapy in arthritis, a common practice of the ancient times that have been mentioned in traditional and folk medicine. The scientific basis of some of the zoo products are being explored and have been showing promising results in experimental rheumatoid arthritis. These therapies have minimum side effects and many of them have potential to give rise to drug development clues against rheumatoid arthritis. The present review is an effort to establish the folk and traditional treatment of rheumatoid arthritis using zoo products.     

生物医药关键技术发展趋势

近年来,生物医药研究人员正在药物的设计、发现、试验、制备,以及检测技术、其他诸如纳米、信息、光学等高技术的融合应用方面致力于更新观念的研究开发,并已取得众多突破,在相关领域形成新的技术趋势。在药物设计方面,随着遗传信息方面的研究进展越来越快,核酸为靶的药物设计已成为新的热点;在疫苗方面,基因疫苗的研制已成为新方向,其技术应用趋向可调控、更安全、更高效生产等,科研人员同时还致力于解决基因疫苗的安全性;在治疗方面,抗体工程和组织工程分别成为药物治疗和组织器官再造的热点;新型药物输送技术正成为业界追逐的目标,药物传输公司正在开发多技术平台,提高药物的效能,减少不良反应和降低成本;药物安全问题已在全球范围内达成共识,美、英、日、欧盟等国均在积极开展药物安全性方面的研究,开发药物安全监测系统;疾病诊断与检测的新技术表现为更高效、准确、快速、早期的趋势,科研人员同时还致力于降低诊断检测产品的价格,以使更多人受益;IT技术、光电技术、纳米技术等新技术正被积极应用于生物医药领域,为大型制药公司和生物技术公司提供药物发现、设计、毒性研究等更新途径的新技术系统。