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Selected AbstractsThe New European Medicines Agency Guideline on the Investigation of BioequivalenceBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2010José Augusto Guimarães Morais Several new features have been added to this guideline, as well as changes aimed at improving the clarity of the guidance provided. The first issue to be addressed was to limit the scope of the guideline to bioequivalence studies for immediate release dosage forms with systemic action. Therefore, the guideline refers to bioequivalence alone. Moreover, the new definition of Generic Medicinal Product has been incorporated. Clearer guidance covering more specific cases is now given on sections such as: fed/fasting conditions, use of metabolite data, enantiomers and strength to be used in the bioequivalence study. Steady-state design is now restricted and other designs, such as parallel group design, replicate design and two-stage design, are now incorporated in a more explicit form. New practical guidance on Highly Variable Drug Products and Narrow Therapeutic Index Drugs has been incorporated. The possibility for a biowaiver based on the Biopharmaceutics Classification System is now more explicit for Class I drugs and can be extended to Class III drugs under restricted conditions. We are aware that the initial goal of providing a very specific and clear guidance on these issues has not been entirely achieved, mainly because it is almost impossible to cover all individual cases and predict every possible situation that may arise. Demonstration of bioequivalence will still require in many instances a case by case approach. [source] Commercial manufacturing scale formulation and analytical characterization of therapeutic recombinant antibodiesDRUG DEVELOPMENT RESEARCH, Issue 3 2004Reed J. Harris Abstract Stable therapeutic antibody dosage forms present production technology challenges, particularly when high-concentration formulations are needed to meet the elevated dose requirements that are generally required for successful antibody therapy. Solid dosage forms, such as lyophilized powders, are generally more stable than liquid formulations. High-concentration drug products can be achieved by reconstitution of the lyophilisate in a smaller volume than its initial (pre-lyophilization) volume, but requires a significant vial overfill. High-concentration liquid formulations are becoming feasible as new techniques and technologies become available. Analytical methods to detect subtle molecular variations have been developed to demonstrate manufacturing consistency. Some molecular heterogeneity is contributed by conserved sites, such as Asn297 glycosylation and the loss of heavy chain C-terminal Lys residues. Characteristics that affect potency, stability, or immunogenicity must be elucidated for each therapeutic antibody. Drug Dev. Res. 61:137,154, 2004. © 2004 Wiley-Liss, Inc. [source] Quantifying Components of Drug Expenditure Inflation: The British Columbia Seniors' Drug Benefit PlanHEALTH SERVICES RESEARCH, Issue 5 2002Steven G Morgan Objective. To quantify the relative and absolute importance of different factors contributing to increases in per capita prescription drug costs for a population of Canadian seniors. Data Sources/Study Setting. Data consist of every prescription claim from 1985 to 1999 for the British Columbia Pharmacare Plan A, a tax-financed public drug plan covering all community-dwelling British Columbians aged 65 and older. Study Design. Changes in per capita prescription drug expenditures are attributed to changes to four components of expenditure inflation: (1) the pattern of exposure to drugs across therapeutic categories; (2) the mix of drugs used within therapeutic categories; (3) the rate of generic drug product selection; and (4) the prices of unchanged products. Data Collection/Extraction Methods. Data were extracted from administrative claims files housed at the UBC Centre for Health Services and Policy Research. Principal Findings. Changes in drug prices, the pattern of exposure to drugs across therapeutic categories, and the mix of drugs used within therapeutic categories all caused spending per capita to increase. Incentives for generic substitution and therapeutic reference pricing policies temporarily slowed the cost-increasing influence of changes in product selection by encouraging the use of generic drug products and/or cost-effective brand-name products within therapeutic categories. Conclusions. The results suggest that drug plans (and patients) would benefit from more concerted efforts to evaluate the relative cost-effectiveness of competing products within therapeutic categories of drugs. [source] Quality specifications for peptide drugs: a regulatory-pharmaceutical approachJOURNAL OF PEPTIDE SCIENCE, Issue 11 2009Valentijn Vergote Abstract Peptide drugs, as all types of pharmaceuticals, require adequate specifications (i.e. quality attributes, procedures and acceptance criteria) as part of their quality assurance to ensure the safety and efficacy of drug substances (i.e. active pharmaceutical ingredients) and drug products (i.e. finished pharmaceutical dosage forms). Compendial monographs are updated regularly to keep up with the most recent advances in peptide synthesis (e.g. reduced by-products) and analytical technology. Nevertheless, currently applied pharmacopoeial peptide specifications are barely harmonized yet (e.g. large differences between the European Pharmacopoeia and the United States Pharmacopeia), increasing the manufacturers' burden of performing analytical procedures in different ways, using different acceptance criteria. Additionally, the peptide monographs are not always consistent within a single pharmacopoeia. In this review, we highlight the main differences and similarities in compendial peptide specifications (including identification, purity and assay). Based on comparison, and together with additional information from peptide drug substance manufacturers and public evaluation reports on registration files of non-pharmacopoeial peptide drugs, a consistent monograph structure is proposed. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. [source] A critical assessment of the ICH guideline on photostability testing of new drug substances and products (Q1B): Recommendation for revisionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2010Steven W. Baertschi Abstract The ICH guideline on photostability (ICH Topic Q1B) was published in November 1996 and has been implemented in all three regions (US, EU, and Japan). The guideline describes a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution, but it does not cover the photostability of drugs under conditions of patient use. The pharmaceutical industry now has considerable experience in designing and carrying out photostability studies within the context of this guideline, and issues have been identified that would benefit from the revision process. The purpose of this commentary is to accomplish the following: (i) highlight issues proposed for consideration in the ICH revision process, (ii) offer a rationale for why these issues may compromise the design of a testing protocol and/or the results of the testing program, and (iii) provide recommendations for clarification of the guideline. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2934,2940, 2010 [source] Biowaiver monographs for immediate release solid oral dosage forms: Doxycycline hyclate,,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2010E. Jantratid Abstract Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing doxycycline hyclate are reviewed. According to the Biopharmaceutics Classification System (BCS), doxycycline hyclate can be assigned to BCS Class I. No problems with BE of IR doxycycline formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low. Doxycycline has a wide therapeutic index. Further, BCS-based dissolution methods have been shown to be capable of identifying formulations which may dissolve too slowly to generate therapeutic levels. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing doxycycline hyclate as the single Active Pharmaceutical Ingredient (API) provided that (a) the test product contains only excipients present in doxycycline hyclate IR solid oral drug products approved in the International Conference on Harmonization (ICH) or associated countries; and (b) the comparator and the test products comply with the BCS criteria for "very rapidly dissolving" or, alternatively, when similarity of the dissolution profiles can be demonstrated and the two products are "rapidly dissolving.". © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1639,1653, 2010 [source] Non-invasive systemic drug delivery: Developability considerations for alternate routes of administrationJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2010Neil R. Mathias Abstract Over the past few decades alternate routes of administration have gained significant momentum and attention, to complement approved drug products, or enable those that cannot be delivered by the oral or parenteral route. Intranasal, buccal/sublingual, pulmonary, and transdermal routes being the most promising non-invasive systemic delivery options. Considering alternate routes of administration early in the development process may be useful to enable new molecular entities (NME) that have deficiencies (extensive first-pass metabolism, unfavorable physicochemical properties, gastro-intestinal adverse effects) or suboptimal pharmacokinetic profiles that are identified in preclinical studies. This review article describes the various delivery considerations and extraneous factors in developing a strategy to pursue an alternate route of administration for systemic delivery. The various delivery route options are outlined with their pros and cons; key criteria and physicochemical attributes that would make a drug a suitable candidate are discussed; approaches to assess delivery feasibility, toxicity at the site of delivery, and overall developability potential are described; and lastly, product trends and their disease implications are highlighted to underscore treatment precedence that help to build scientific rationale for the pursuit of an alternate route of administration. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1,20, 2010 [source] Biowaiver monographs for immediate release solid oral dosage forms: Quinidine sulfate,,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2009S. Grube Abstract Literature data are reviewed relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing quinidine sulfate. Quinidine sulfate's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. The available data are not fully conclusive, but do suggest that quinidine sulfate is highly soluble and moderately to highly permeable and would likely be assigned to BCS Class I (or at worst BCS III). In view of the inconclusiveness of the data and, more important, quinidine's narrow therapeutic window and critical indication, a biowaiver based approval of quinidine containing dosage forms cannot be recommended for either new multisource drug products or for major postapproval changes (variations) to existing drug products. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2238,2251, 2009 [source] Biowaiver monographs for immediate release solid oral dosage forms: Diclofenac sodium and diclofenac potassium,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2009B. Chuasuwan Abstract Literature data are reviewed regarding the scientific advisability of allowing a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing either diclofenac potassium and diclofenac sodium. Within the biopharmaceutics classification system (BCS), diclofenac potassium and diclofenac sodium are each BCS class II active pharmaceutical ingredients (APIs). However, a biowaiver can be recommended for IR drug products of each salt form, due to their therapeutic use, therapeutic index, pharmacokinetic properties, potential for excipient interactions, and performance in reported BE/bioavailability (BA) studies, provided: (a) test and comparator contain the same diclofenac salt; (b) the dosage form of the test and comparator is identical; (c) the test product contains only excipients present in diclofenac drug products approved in ICH or associated countries in the same dosage form, for instance as presented in this paper; (d) test drug product and comparator dissolve 85% in 30 min or less in 900 mL buffer pH 6.8, using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm; and (e) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1206,1219, 2009 [source] Biowaiver monographs for immediate release solid oral dosage forms: AciclovirJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2008J. Arnal Abstract Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing (biowaiver) for the approval of immediate release (IR) solid oral dosage forms containing aciclovir are reviewed. Aciclovir therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) studies were also taken into consideration in order to ascertain whether a biowaiver can be recommended. According to the Biopharmaceutics Classification System (BCS) and considering tablet strengths up to 400 mg, aciclovir would be BCS Class III. However, in some countries also 800 mg tablets are available which fall just within BCS Class IV. Aciclovir seems not to be critical with respect to a risk for bioinequivalence, as no examples of bioinequivalence have been identified. It has a wide therapeutic index and is not used for critical indications. Hence, if: (a) the test product contains only excipients present in aciclovir solid oral IR drug products approved in ICH or associated countries, for instance as presented in this article; and (b) the comparator and the test product both are very rapidly dissolving, a biowaiver for IR aciclovir solid oral drug products is considered justified for all tablet strengths. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5061,5073, 2008 [source] Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride,,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2008C. Becker Abstract Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing ethambutol dihydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ethambutol dihydrochloride is a Biopharmaceutics Classification System (BCS) Class III drug with permeability properties approaching the border between BCS Class I and III. BE problems of ethambutol formulations containing different excipients and different dosages forms have not been reported and hence the risk of bioinequivalence caused by excipients is low. Ethambutol has a narrow therapeutic index related to ocular toxicity. However, as long as the prescribers' information of the test product stipulates the need for regular monitoring of ocular toxicity, the additional patient risk is deemed acceptable. It is concluded that a biowaiver can be recommended for IR solid oral dosage forms provided that the test product (a) contains only excipients present in ethambutol IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) complies with the criteria for "very rapidly dissolving" and (c) has a prescribers' information indicating the need for testing the patient's vision prior to initiating ethambutol therapy and regularly during therapy. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1350,1360, 2008 [source] Conference report: Bio-International 2005JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2007Kamal K. Midha Abstract This is a summary report of the International Pharmaceutical Federation/Board of Pharmaceutical Sciences (FIP/BPS) international conference, Bio-International 2005, which was held October 24,26, 2005 at the Royal Pharmaceutical Society, in London, UK. Bioequivalence (BE) issues related to multisource locally delivered topical dosage forms, oral inhalation drug products, highly variable drug products (HVDP), and endogenously occurring drugs were discussed. The conference also focused on alternate approaches to assess BE for some of these drug products. Pharmacokinetic (PK) approaches like, dermatopharmacokinetics (DPK) for dermatological topical dosage forms, scaled average BE (s-ABE) where within-subject variability is considered for estimation of 90% confidence intervals to document BE for highly variable drugs (HVD) were recommended. In addition, issues and difficulties related to the BE assessment of oral inhalation products, role, and appropriateness of metabolites in BE assessment, importance of base line correction in BE assessment of endogenously occurring drugs, and waiver of BE study requirements for certain drugs based on a Biopharmaceutics Classification System (BCS), were also discussed. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 747,754, 2007 [source] Stability profiles of drug products extended beyond labeled expiration datesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2006Robbe C. Lyon Abstract The American Medical Association has questioned whether expiration dating markedly underestimates the actual shelf life of drug products. Results from the shelf life extension program (SLEP) have been evaluated to provide extensive data to address this issue. The SLEP has been administered by the Food and Drug Administration for the United States Department of Defense (DOD) for 20 years. This program probably contains the most extensive source of pharmaceutical stability data extant. This report summarizes extended stability profiles for 122 different drug products (3005 different lots). The drug products were categorized into five groups based on incidence of initial extension failures and termination failures (extended lot eventually failed upon re-testing). Based on testing and stability assessment, 88% of the lots were extended at least 1 year beyond their original expiration date for an average extension of 66 months, but the additional stability period was highly variable. The SLEP data supports the assertion that many drug products, if properly stored, can be extended past the expiration date. Due to the lot-to-lot variability, the stability and quality of extended drug products can only be assured by periodic testing and systematic evaluation of each lot. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1549,1560, 2006 [source] Tetrazole compounds: The effect of structure and pH on Caco-2 cell permeabilityJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2006Amber M. Young Abstract A tetrazole ring is often used in drug discovery as a replacement for the carboxylic acid group. Previous work indicates that compounds containing a tetrazole moiety show asymmetric permeability in Caco-2 cells characteristic of an efflux transporter substrate. The aim of this study is to determine which transporters are responsible for polarization of transport of tetrazole-containing compounds in Caco-2 cells. Results indicate that only select compounds with tetrazole moieties display asymmetric transport. Three compounds (two commercial drug products and one druglike structure) were selected for further studies. Losartan appears to be primarily a P-glycoprotein (P-gp) substrate, as previously reported, but MRP inhibitors such as MK-571 and rifampicin also affect the difference between apical to basolateral and basolateral to apical transport. Pemirolast and phenyltetrazole derivative C are sensitive to P-gp inhibition, but transport seems to be mediated by one or more of the MRP family of transporters. Additionally, lowering the pH from 7.4 to 4.0 eliminates the polarization of permeability in Caco-2 cells. These studies indicate that some tetrazole compounds are susceptible to efflux, therefore caution should be used when choosing an appropriate functional group to replace carboxylic acids when synthesizing a drug candidate. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:717,725, 2006 [source] Biowaiver monographs for immediate release solid oral dosage forms: Ibuprofen,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2005H. Potthast Abstract Literature data are reviewed on the properties of ibuprofen related to the biopharmaceutics classification system (BCS). Ibuprofen was assessed to be a BCS class II drug. Differences in composition and/or manufacturing procedures were reported to have an effect on the rate, but not the extent of absorption; such differences are likely to be detectable by comparative in vitro dissolution tests. Also in view of its therapeutic use, its wide therapeutic index and uncomplicated pharmacokinetic properties, a biowaiver for immediate release (IR) ibuprofen solid oral drug products is scientifically justified, provided that the test product contains only those excipients reported in this paper in their usual amounts, the dosage form is rapidly dissolving (85% in 30 min or less) in buffer pH 6.8 and the test product also exhibits similar dissolution profiles to the reference product in buffer pH 1.2, 4.5, and 6.8. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2121-2131, 2005 [source] Pharmacokinetic aspects of biotechnology productsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2004Lisa Tang Abstract In recent years, biotechnologically derived peptide and protein-based drugs have developed into mainstream therapeutic agents. Peptide and protein drugs now constitute a substantial portion of the compounds under preclinical and clinical development in the global pharmaceutical industry. Pharmacokinetic and exposure/response evaluations for peptide and protein therapeutics are frequently complicated by their similarity to endogenous peptides and proteins as well as protein nutrients. The first challenge frequently comes from a lack of sophistication in various analytical techniques for the quantification of peptide and protein drugs in biological matrices. However, advancements in bioassays and immunoassays,along with a newer generation of mass spectrometry-based techniques,can often provide capabilities for both efficient and reliable detection. Selection of the most appropriate route of administration for biotech drugs requires comprehensive knowledge of their absorption characteristics beyond physicochemical properties, including chemical and metabolic stability at the absorption site, immunoreactivity, passage through biomembranes, and active uptake and exsorption processes. Various distribution properties dictate whether peptide and protein therapeutics can reach optimum target site exposure to exert the intended pharmacological response. This poses a potential problem, especially for large protein drugs, with their typically limited distribution space. Binding phenomena and receptor-mediated cellular uptake may further complicate this issue. Elimination processes,a critical determinant for the drug's systemic exposure,may follow a combination of numerous pathways, including renal and hepatic metabolism routes as well as generalized proteolysis and receptor-mediated endocytosis. Pharmacokinetic/pharmacodynamic (PK/PD) correlations for peptide and protein-based drugs are frequently convoluted by their close interaction with endogenous substances and physiologic regulatory feedback mechanisms. Extensive use of pharmacokinetic and exposure/response concepts in all phases of drug development has in the past been identified as a crucial factor for the success of a scientifically driven, evidence-based, and thus accelerated drug development process. Thus, PK/PD concepts are likely to continue and expand their role as a fundamental factor in the successful development of biotechnologically derived drug products in the future. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2184,2204, 2004 [source] Near infrared spectroscopy in the development of solid dosage formsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2007Eetu Räsänen The use of near infrared (NIR) spectroscopy has rapidly grown partly due to demands of process analytical applications in the pharmaceutical industry. Furthermore, newest regulatory guidelines have advanced the increase of the use of NIR technologies. The non-destructive and non-invasive nature of measurements makes NIR a powerful tool in characterization of pharmaceutical solids. These benefits among others often make NIR advantageous over traditional analytical methods. However, in addition to NIR, a wide variety of other tools are naturally also available for analysis in pharmaceutical development and manufacturing, and those can often be more suitable for a given application. The versatility and rapidness of NIR will ensure its contribution to increased process understanding, better process control and improved quality of drug products. This review concentrates on the use of NIR spectroscopy from a process research perspective and highlights recent applications in the field. [source] Nanotechnology advances in controlled drug delivery systemsPHYSICA STATUS SOLIDI (C) - CURRENT TOPICS IN SOLID STATE PHYSICS, Issue 12 2008C. Kiparissides Abstract Nanotechnology advances in drug delivery deal with the development of synthetic nanometer sized targeted delivery systems for therapeutic agents of increased complexity, and biologically active drug products. Therapeutic systems in this class are up to a million times larger than classical drugs like aspirin. Being larger there is more scope for diversity and complexity, which makes their protection much more challenging and their delivery more difficult. Their increased complexity however, gives these systems the unique power to tackle more challenging diseases. Targeted delivery systems can have multiple functions, a key one being their ability to recognize specific molecules which can be located either on the membrane of target cells, or in specific compartments within the cell. A challenging objective of targeted drug delivery is the development of innovative multidisciplinary approaches for the design, synthesis and functionalization of novel nanocarriers for targeted delivery of protein/peptide (P/P) drugs via oral, pulmonary and nasal administration routes as well as the fabrication of "smart" miniaturized drug delivery devices able to release a variety of drugs on demand. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] The journey of Indian GLP programme,looking back and forwardQUALITY ASSURANCE JOURNAL, Issue 1 2009V. Amalan Stanley Abstract The Indian GLP (Good Laboratory Practice) compliance monitoring programme has successfully brought the task of implementing the programme to the foreground where full OECD (Organization for Economic Cooperation and Development) membership is about to happen. It has been a long journey, more than five years for the programme to arrive at this juncture, succeeding through sheer commitment and will of the Science and Technology initiatives under which the programme has been implemented. Considering the spontaneous and natural challenges that are bound to make the effort of implementing the GLP compliance programme tougher for any country, the progress made by the Indian GLP programme can be considered very rapid. Though the dawn of full OECD membership for the Indian GLP programme is imminent the paper deals with the details of the journey it has traveled so far and the challenges ahead, commending the commitment of the efforts of the GLP MA (Monitoring Authority) as well as the preparedness of the test facilities. This paper discusses the GLP policy aspects that favoured the growth of the programme among non-member adherents, such as the allowance for getting GLP certification by GLP MA abroad. It also deals with the challenge of harmonizing the policies of the internal agencies that have direct influence on the implementation of the GLP programme, other than legalizing the GLP aspects as there are various government departments in India dealing with the regulatory aspects of specific drug products for human use or that are of chemical in origin. There are data requirements made mandatory by these institutions on pre-clinical or non-clinical safety evaluation of those products, which invariably necessitate studies conducted in compliance with the principles of GLP. The paper concludes with the emphasis that there is a primary need for harmony as well as legal or judicial underpinnings under the umbrella of a national GLP Monitoring Authority, a gray area to be essentially tackled with foresight, to earn credibility on the international front. Copyright © 2009 John Wiley & Sons, Ltd. [source] Analysis of the composition of immunoconjugates using size-exclusion chromatography coupled to mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 13 2005Alexandru C. Lazar Recombinant monoclonal antibody drug products play an increasingly important role in the treatment of various diseases. Antibodies are large, multi-chain proteins and antibody preparations often contain several molecular variants, which renders them heterogeneous. The heterogeneity is further increased in immunoconjugates prepared by covalently linking several drug molecules per antibody molecule. As part of the product characterization, the molecular weights of the antibodies or their drug conjugates need to be measured. Electrospray ionization mass spectrometry (ESI-MS) is well suited for the analysis of recombinant antibodies and immunoconjugates. Sample preparation is an important element of ESI-MS analysis, in particular samples need to be freed of interfering charged species, such as salts and buffer components. In this paper, Amicon centrifugal filters, reversed-phase high-performance liquid chromatography (HPLC), and size-exclusion HPLC were evaluated for sample desalting. Size-exclusion HPLC, using aqueous acetonitrile as the mobile phase, directly coupled to ESI-MS provided the best performance and was optimized for the study of immunoconjugates. The results showed that antibodies carrying covalently linked maytansinoid molecules generated charge envelope profiles that differ from those of the non-conjugated antibody. For the determination of the distribution of the various conjugate species in an immunoconjugate sample prepared by randomly linking in the average 3.6 drug molecules per antibody molecule, the experimental conditions needed to be carefully selected to allow acquisition of the whole spectrum containing the charge envelopes of all species. Copyright © 2005 John Wiley & Sons, Ltd. [source] Variability and Impact on Design of Bioequivalence StudiesBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2010Achiel Van Peer Revisions of the regulatory guidance are based upon many questions over the past years and sometimes continuing scientific discussions on the use of the most suitable statistical analysis methods and study designs, particularly for drugs and drug products with high within-subject variability. Although high within-subject variability is usually associated with a coefficient of variation of 30% or more, new approaches are available in the literature to allow a gradual increase and a levelling off of the bioequivalence limits to some maximum wider values (e.g. 75,133%), dependent on the increase in the within-subject variability. The two-way, cross-over single dose study measuring parent drug is still the design of first choice. A partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability are proposed for drugs with high within-subject variability. In case of high variability, more regulatory authorities may accept a two-stage or group-sequential bioequivalence design using appropriately adjusted statistical analysis. This review also considers the mechanisms why drugs and drug products may exhibit large variability. The physiological complexity of the gastrointestinal tract and the interaction with the physicochemical properties of drug substances may contribute to the variation in plasma drug concentration-time profiles of drugs and drug products and to variability between and within subjects. A review of submitted bioequivalence studies at the Food and Drug Administration's Office of Generic Drugs over the period 2003,2005 indicated that extensive pre-systemic metabolism of the drug substance was the most important explanation for consistently high variability drugs, rather than a formulation factor. These scientific efforts are expected to further lead to revisions of earlier regulatory guidance in other regions as is the current situation in Europe. [source] Skin disposition of menthol after its application in the presence of drug substancesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2008Krzysztof Cal Abstract Many drug products that are applied onto the skin contain menthol. Menthol plays a dual role in the analgesic and anti-inflammatory drugs: it causes cooling and local anesthetic effects and, being a penetration enhancer, it increases the skin permeation of the drug substances. However, there are no data concerning the skin penetration of menthol after its application in the most commonly used vehicles and in the presence of drug substances. Therefore, this study evaluated the ex vivo skin disposition of menthol after application of the commercially available drug products containing aluminum acetotartrate, methyl salicylate, ibuprofen and naproxen, using full human-skin mounted in flow-through diffusion cells. After 15, 30 and 60,min of application, the skin was progressively tape-stripped into three fractions of stratum corneum and the remaining epidermis with dermis. The content of menthol in the skin layers was determined by GC method. Varying degrees of penetration of menthol into the skin layers was observed, depending on its amount in the vehicle and the presence of drug substance. In the presence of aluminum acetotartrate, the skin penetration of menthol was limited only to the outer fraction of the stratum corneum. In the case of drug products containing naproxen, the concentration of the drug substance significantly influenced the skin penetration of menthol. Copyright © 2008 John Wiley & Sons, Ltd. [source] Development of the second-order derivative UV spectrophotometric method for direct determination of paracetamol in urine intended for biopharmaceutical characterisation of drug productsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2003Jelena Paroj Abstract Paracetamol is a widely used nonsalicylate analgesic and antipyretic drug. The existing methods for the determination of paracetamol in biological fluids are mainly HPLC techniques, although there are some reported methods based on spectrophotometric determinations. However, all these methods involve some extraction or derivatisation procedures. In the present study the UV spectra of investigated samples were recorded over the wavelength range 220,400 nm (, step 0.21 nm; scan speed 60 nm/min) and second-order derivative spectra were calculated. Second-order derivative spectra of different blank urine samples displayed the presence of a zero-crossing point at 245,247 nm defined as ,zc. The zero-order absorption spectra of paracetamol in water displays maximum absorbance at 243 nm, while in second derivative spectra, a minimum peak at 246 nm was observed. Therefore, the application of zero-crossing technique to the second-derivative UV absorption spectrum should be useful for the determination of paracetamol using 2D,zc. The proposed method enables determination of total paracetamol in urine directly and simply by reading the 2D,zc of the diluted samples. The obtained results were in good accordance with published data on cumulative urinary excretion after per oral administration of paracetamol obtained applying different spectrophotometric methods of determination. It could be useful for biopharmaceutical characterisation of drug products (monitoring of the levels of paracetamol in urine in bioavailability testing, for the evaluation of in vitro,in vivo correlation and screening of different formulations during drug product development). Copyright © 2003 John Wiley & Sons, Ltd. [source] | ||||||||||||||||