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PubMed2006

Classification of torasemide based on the Biopharmaceutics Classification System and evaluation of the FDA biowaiver provision for generic products of CLASS I drugs.

The biopharmaceutical properties of an in-house developed new crystal modification of torasemide (Torasemide N) were investigated in comparison with the most well known crystal modification form of torasemide (Torasemide I) in order to classify the drug according to the Biopharmaceutics Classification System (BCS), and to evaluate the data in line with current US Food and Drug Administration (FDA) guidance (with biowaiver provision for Class I drugs) to determine if the biowaiver provision could be improved. The solubility profiles of Torasemide I and Torasemide N were determined, and tablets prepared from both forms of the drug were studied for in-vitro release characteristics in media recommended by the current FDA guidance for biowaiver of generic products, and in other media considered more appropriate for the purpose than the ones recommended by the FDA. Two separate bioequivalence studies in healthy humans (following oral administration) were performed with two test products (both prepared from Torasemide I) against a single reference product (prepared from Torasemide N). The absorption profiles of the drug from the tablets were determined by deconvolution for comparison with the in-vitro release profiles to determine the appropriateness of some dissolution media for predicting in-vivo performance and to determine the comparative rate and extent of absorption. The drug was absorbed from the tested products quickly and almost completely (about 95% within 3.5 h of administration). However, one test product failed to meet the bioequivalence criteria and had a significant initial lower absorption rate profile compared with the reference product (P< or =0.05), whereas the other product was bioequivalent and had a similar absorption profile to the reference product. A dissolution medium at pH 5.0, in which torasemide has minimum solubility, was found to be more discriminatory than the media recommended by the FDA. Torasemide has been classified as a Class I drug according to the BCS up to a maximum dose of 40 mg and the data suggest that the current FDA guidance could be improved by giving more emphasis to selection of appropriate dissolution media than is given in its current form for approving biowaiver to generic products of Class I drugs.

Area Under Curve↗

PubMed1989

[Biopharmaceutical aspects of a chemical approach to drug delivery: macromolecule-drug conjugates].

Some recent advances pertaining to the biopharmaceutical aspects of drug delivery are briefly given, followed by a review of the current status of the application of soluble macromolecular carriers for drug delivery. The dextran conjugates were selected as model compounds to demonstrate the implications of the biopharmaceutical approach in the design, evaluation, and delivery of macromolecular conjugates.

Animals↗

PubMed1990

Biopharmaceutical payment and coverage: are cost control policies too restrictive? Industrial Biotechnology Association.

The use of recombinant DNA technology and monoclonal antibody technology has led to a variety of new "biopharmaceuticals" that aid the body in fighting disease. We are already seeing improvements in patients' quality of life as a result of these new technologies. Often, we also see a lowering of health care costs due to preventing or shortening hospital stays and the reduction of the need for other health care expenditures. However, it is important to recognize that there is also the possibility of an increase in health care costs as the new drugs enable people to live longer, and thus possibly consume more health care services. In recent years, a rising concern has been voiced about the rapid increase in health care spending. Despite vital health and economic benefits made possible by new pharmaceuticals, spending on drugs is a relatively small portion of total health care expenditures. As consumers demand access to high-quality health care, the issue of reimbursement has become highly controversial. As we stated earlier, we recognize that HCFA and other third-party payers have a legitimate interest in attempting to control health care expenditures. However, we are aware that restrictive policies on drug coverage and payment could deprive patients of access to medically necessary therapies and, ultimately, reduce biopharmaceutical manufacturers' revenues to the point where future research is hampered or halted.

Biotechnology↗

PubMed2001

[Biopharmaceutical considerations of dissolution testing used as a prognostic tool for oral drug adsorption].

Drug dissolution is a prerequisite to drug absorption and in vivo effectiveness for almost all drugs given in oral solid dosage forms. Drug absorption depends on the dissolution and solubilization of the drug under physiological conditions, and the permeability across the gastrointestinal tract. Because of the critical nature of the first steps, in vitro dissolution may be relevant to the prediction of biological response. Dissolution tests are applied to choose between formulation factors, assess the lot-to-lot quality of a drug product according to the biobatch; and ensure continuing product quality and performance after certain changes (e.g. in the formulation and manufacturing process, site of manufacture, scale-up). The recently developed Biopharmaceutical Classification System (BCS) has several benefits for recognizing how dissolution tests can be designed and which physiological factors have to be taken into consideration for the in vitro evaluation of solid dosage forms. Choice of test conditions (composition, volume and hydrodynamics of dissolution medium) should be based on where the drug is best absorbed in the gastrointestinal tract, and on whether it is administered in fasted or fed state. Duration of test and physiologically representative media can be selected to simulate gastric and intestinal environments according to the permeability profile of the drug, but mimicking in vivo hydrodynamics remains problematic and further research is required. To provide a basis for predicting the likelihood of achieving a successful in vivo-in vitro correlation, this review summarizes the biopharmaceutical considerations of in vivo drug release in accordance with the BCS.

Administration, Oral↗

PubMed2004

HepeX-C (XTL Biopharmaceuticals).

XTL Biopharmaceuticals is developing HepeX-C, a combination of two antibodies (HCV-AB68 and HCV-AB65) as a potential therapy for hepatitis C virus infection. By September 2003, phase II trials of HCV-AB68 alone had been conducted and XTL Biopharmaceuticals announced that it planned to conduct a phase I study of the antibody combination.

Animals↗

PubMedDate not supplied

Sensor-based system for rapid and sensitive measurement of contaminating DNA and other analytes in biopharmaceutical development and manufacturing.

The Threshold System provides for rapid and highly sensitive measurements of a variety of analytes at low concentration. The operating principles of the measurement system, including signal detection utilizing a proprietary silicon sensor, are described. The first application to run on the Threshold System is a quantitative assay for picogram levels of total DNA. This assay is of great value for monitoring levels of contaminating DNA in purified and in-process biopharmaceuticals. After sample pretreatment, the total assay time is less than two hours. The assay performance characteristics are described, along with data demonstrating sensitivity, precision, and accuracy. Pretreatment procedures for biopharmaceutical proteins are discussed. Two additional applications on Threshold are introduced. First, a universal ligand-binding assay system provides quantitative measurement of antigens or antibodies, in a variety of biological media, with speed, sensitivity, and precision. Second, preliminary results of rapid DNA-probe measurements on Threshold are presented.

Biosensing Techniques↗

PubMed1985

Biopharmaceutic and pharmacokinetic aspects of vincamine HCl.

Vincamine HCl was biopharmaceutically and pharmacokinetically evaluated. For biopharmaceutical characterization of the drug the apparent lipoid/water partition coefficient (APC), pKa, extent of protein (bovine) binding and the erythrocyte (human) uptake were determined. Vincamine has an APC of 2.05, a pKa of 6.17, is 64% bound to plasma proteins, and is about 6% bound to erythrocytes. Because the gerbil was used as model in pharmacodynamic studies, the pharmacokinetic drug disposition was determined in this species and compared to parameters reported in the literature for other species. The terminal half-life is about 1 hour, the apparent volume of distribution 2.9 L/kg, and the total clearance is about 33.3 ml/min/kg. The parameters are comparable to other species including man. The brain concentration is about 5-fold that in plasma. A therapeutic steady state concentration for effectiveness in gerbils has been estimated to be 0.02 mcg/ml.

Animals↗

PubMed1996

The safety of biopharmaceutical products--a personal viewpoint.

There are now published guidelines dealing with the production of cytokines, monoclonal antibodies and other therapeutic proteins made by applying biotechnological procedures. Strict conformity with these guidelines will undoubtedly yield safe products, but the question can be asked whether all the tests now specified are really essential in relation to the actual risks involved. During many years of experience with some of these biopharmaceutical products, problems which might on theoretical grounds have occurred have in practice not been encountered. Should biopharmaceuticals still be subjected to a much more intense scrutiny than is given to most other medicinal products? Has the time come to review current control procedures? Unnecessary tests increase the cost of products, and may make them too expensive to be available to millions of people who would benefit from their use.

Biological Products↗

PubMed1998

Imaging of cells by autofluorescence: a new tool in the probing of biopharmaceutical effects at the intracellular level.

The success of biopharmaceuticals relies on the ability to have reliable probes to interpret their mechanisms of action in situ at the intracellular level in terms of cell organelles and microcompartments. One of the most effective probes is the endogenous coenzyme NAD(P)H and its fluorescence transients obtained by the microinjection or perfusion of metabolic intermediates and modifiers, in the presence of drugs and inhibitors. The approach in fluorescence microtopography and microspectrofluorimetry is based on the premise that natural cell fluorescence (autofluorescence) holds a decisively greater potential in unravelling intracellular physiopathological processes than extrinsic fluorescence or artificial pseudocolouring. The mounting as a detector of a cooled charge-coupled device camera or alternatively of a non-cooled camera in conjunction with an image intensifier or an investigator (i.e. frame scan accumulator) to enhance sensitivity makes possible the detection of the low-quantum-yield NAD(P)H fluorescence at a level comparable to images previously obtained with high-quantum-yield fluorochromes. The modulation of mitochondrial autofluorescence by rotenone, carbonyl cyanide p-trifluoromethoxyphenylhydrazone and oligomycin, and of cytoplasmic and nuclear autofluorescence by glucose and iodacetamide in CV-1 kidney epithelial cells, Ehrlich-Lettre hypotetraploid CCL77 cells and Saccharomyces cerevisiae, provides examples of the usefulness of fluorescence imaging in the study of biopharmaceuticals. The method goes beyond NAD(P)H to the multiplicity of extrinsic and intrinsic probes already available or in development.

Cell Line↗

PubMed1996

Five modified numerical deconvolution methods for biopharmaceutics and pharmacokinetics studies.

Four improved finite-difference numerical deconvolution methods and one nonlinear regression numerical deconvolution method are proposed and implemented using IMSL/IDLTM. These five numerical deconvolution methods are evaluated using simulated data generated with and without added noise under six different dosing cases. Comparisons between these methods are made in terms of the superimposability of the calculated cumulative amount of drug released or absorbed-time profiles with the theoretical data. The results indicate that the proposed fixed step number equal step length numerical deconvolution method is simple and accurate and therefore is appropriate for pharmacokinetic and biopharmaceutic studies. When an analytic function is legitimate to represent the drug input rate, the nonlinear regression numerical deconvolution method will yield enhanced numerical accuracy and stability.

Absorption↗

PubMed2003

Development of the second-order derivative UV spectrophotometric method for direct determination of paracetamol in urine intended for biopharmaceutical characterisation of drug products.

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 (lambda 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 lambdazc. 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 2Dlambdazc. The proposed method enables determination of total paracetamol in urine directly and simply by reading the 2Dlambdazc 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).

Acetaminophen↗

PubMed2001

Economic comparison between conventional and disposables-based technology for the production of biopharmaceuticals.

Time to market, cost effectiveness, and flexibility are key issues in today's biopharmaceutical market. Bioprocessing plants based on fully disposable, presterilized, and prevalidated components appear as an attractive alternative to conventional stainless steel plants, potentially allowing for shorter implementation times, smaller initial investments, and increased flexibility. To evaluate the economic case of such an alternative it was necessary to develop an appropriate costing model which allows an economic comparison between conventional and disposables-based engineering to be made. The production of an antibody fragment from an E. coli fermentation was used to provide a case study for both routes. The conventional bioprocessing option was costed through available models, which were then modified to account for the intrinsic differences observed in a disposables-based option. The outcome of the analysis indicates that the capital investment required for a disposables-based option is substantially reduced at less than 60% of that for a conventional option. The disposables-based running costs were evaluated as being 70% higher than those of the conventional equivalent. Despite this higher value, the net present value (NPV) of the disposables-based plant is positive and within 25% of that for the conventional plant. Sensitivity analysis performed on key variables indicated the robustness of the economic analysis presented. In particular a 9-month reduction in time to market arising from the adoption of a disposables-based approach, results in a NPV which is identical to that of the conventional option. Finally, the effect of any possible loss in yield resulting from the use of disposables was also examined. This had only a limited impact on the NPV: for example, a 50% lower yield in the disposable chromatography step results in a 10% reduction of the disposable NPV. The results provide the necessary framework for the economic comparison of disposables and conventional bioprocessing technologies.

Antibodies, Bacterial↗

PubMed1990

Pharmacokinetic and biopharmaceutic aspects of once daily treatment with metoprolol CR/ZOK: a review article.

In the development of a new controlled release preparation and its subsequent assessment there are a number of factors that need to be considered both related to the drug itself and to the pharmaceutical preparation. This review describes the biopharmaceutical and pharmacokinetic properties of metoprolol CR/ZOK, a recently introduced formulation of a widely used beta 1-selective adrenoceptor antagonist intended for once daily usage. The metoprolol CR/ZOK preparation provides reproducible dissolution and absorption properties resulting in stable plasma concentrations with minimum fluctuations over a 24-hour dosage interval. This has been shown in extensive studies comprising over 200 healthy volunteers. Considerations for a new drug preparation such as bioavailability and variability in relation to a standard treatment and the clinical significance of taking the drug with food and in increasing doses, are potential concerns that do not seem to be a problem for the therapeutic use of metoprolol CR/ZOK. Furthermore, the pharmacokinetic data achieved in young healthy subjects appear to be relevant for the treatment of patients, as shown by the consistent plasma concentration profiles obtained in elderly and in hypertensive patients.

Biopharmaceutics↗

PubMed2004

Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: verapamil hydrochloride, propranolol hydrochloride, and atenolol.

Literature data related to the Biopharmaceutics Classification System (BCS) are presented on verapamil hydrochloride, propranolol hydrochloride, and atenolol in the form of BCS-monographs. Data on the qualitative composition of immediate release (IR) tablets containing these active substances with a Marketing Authorization (MA) in the Netherlands (NL) are also provided; in view of these MA's the assumption was made that these tablets were bioequivalent to the innovator product. The development of a database with BCS-related data is announced by the International Pharmaceutical Federation (FIP).

Administration, Oral↗

PubMed2005

Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride.

Literature data on the properties of chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride related to the Biopharmaceutics Classification System (BCS) are reviewed. The available information indicates that these chloroquine salts can be classified as highly soluble and highly permeable, i.e., BCS class I. The qualitative composition of immediate release (IR) tablets containing these Active Pharmaceutical Ingredients (APIs) with a Marketing Authorization (MA) in Belgium (BE), Germany (DE), Finland (FI), and The Netherlands (NL) is provided. In view of these MA's and the critical therapeutic indication of chloroquine, it is assumed that the registration authorities had evidence that these formulations are bioequivalent to the innovator. It is concluded that IR tablets formulated with these excipients are candidates for a biowaiver.

Antimalarials↗

PubMed1979

Differential thermal, solubility, and aging studies on various sources of digoxin and digitoxin powder: biopharmaceutical implications.

Unlike most organic compounds, both digoxin and digitoxin melted over a wide temperature range, with the widest range being 88 and 33 degrees for both compounds, respectively. Furthermore, the melting ranges varied markedly among several untriturated powders obtained from commercial sources and after recrystallization. Trituration produced dramatically sharper and generally lower melting temperatures. Apparent equilibrium solubility also varied considerably among different untriturated compounds. Correlation between solubility and final melting temperature was found. Results from dynamic solubility studies were used to explain the failure of trituration to enhance the apparent equilibrium solubility in certain samples. Storage at room temperature increased the melting points and decreased aqueous solubilities. Several reasons such as the presence of polymorphic and amorphous forms, crystal defects, impurities, and solvate formation were postulated to explain the findings. In a preliminary study, the in vitro dissolution rates of two commercial tablet products stored at elevated temperatures for 4-8 weeks progressively decreased. Biopharmaceutical implications and areas for further studies are discussed.

Biopharmaceutics↗

PubMed1989

Control of pharmaceutical properties of soybean trypsin inhibitor by conjugation with dextran. II: Biopharmaceutical and pharmacological properties.

Biopharmaceutical and pharmacological properties of the Kunitz-type soybean trypsin inhibitor (STI)-dextran conjugate (STI-D) were studied. Dextran having a molecular weight of approximately 10,000 was covalently attached to the STI molecule by periodate oxidation. The STI-polyethylene glycol (PEG) conjugate (STI-PEG) was also tested for comparison. After iv injection to mice, native STI showed rapid elimination of activity from plasma (t 1/2 = 2 min), and approximately 60% of the dose was excreted in urine within 1 h after injection. On the other hand, STI-D was slowly cleared from plasma and its urinary excretion was restricted. The STI-PEG conjugate showed a pharmacokinetic behavior similar to that of STI-D. Pharmacological activities of native and modified STI were evaluated by two animal experimental models; that is, trypsin-induced shock in mice and acute pancreatitis in rats. In mice, shock induced by iv injection of trypsin was inhibited by the iv pretreatment with native STI, but the effect was observed for only 1 h. The STI-D conjugate showed a superior inhibitory effect on trypsin-induced shock to that of STI alone at the same dose, and this effect continued for 5 h. A similar effect was also observed in mice given an iv injection of STI-PEG. In rats with acute pancreatitis, no significant therapeutic effect was shown by the iv treatment with native STI, as well as saline treatment. On the other hand, the iv treatment with STI-D at the same dose as STI lowered the mortality of the rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Using empirical Bayes methods in biopharmaceutical research.

A compound sampling model, where a unit-specific parameter is sampled from a prior distribution and then observed are generated by a sampling distribution depending on the parameter, underlies a wide variety of biopharmaceutical data. For example, in a multi-centre clinical trial the true treatment effect varies from centre to centre. Observed treatment effects deviate from these true effects through sampling variation. Knowledge of the prior distribution allows use of Bayesian analysis to compute the posterior distribution of clinic-specific treatment effects (frequently summarized by the posterior mean and variance). More commonly, with the prior not completely specified, observed data can be used to estimate the prior and use it to produce the posterior distribution: an empirical Bayes (or variance component) analysis. In the empirical Bayes model the estimated prior mean gives the typical treatment effect and the estimated prior standard deviation indicates the heterogeneity of treatment effects. In both the Bayes and empirical Bayes approaches, estimated clinic effects are shrunken towards a common value from estimates based on single clinics. This shrinkage produces more efficient estimates. In addition, the compound model helps structure approaches to ranking and selection, provides adjustments for multiplicity, allows estimation of the histogram of clinic-specific effects, and structures incorporation of external information. This paper outlines the empirical Bayes approach. Coverage will include development and comparison of approaches based on parametric priors (for example, a Gaussian prior with unknown mean and variance) and non-parametric priors, discussion of the importance of accounting for uncertainty in the estimated prior, comparison of the output and interpretation of fixed and random effects approaches to estimating population values, estimating histograms, and identification of key considerations in the use and interpretation of empirical Bayes methods.

Bayes Theorem↗