[Biopharmaceutics. V. Biopharmaceutical stability and degradation].
Explore the source record for details and available documents.
Biopharmaceutics↗
SEARCH · Search PubMed
Results for “Biopharmaceutics”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Screening and characterization of biopharmaceuticals by high-performance capillary electrophoresis with laser-induced native fluorescence detection.
High-performance capillary electrophoresis (HPCE) with laser-induced native fluorescence (LIF) detection is used to address significant problems in the quality control of biopharmaceuticals. All of the biopharmaceuticals studied can be detected at subnanomolar levels with linear dynamic ranges of at least 3 orders of magnitude. HPCE/LIF can determine impurities in "purified" biopharmaceuticals present in amounts less than 0.01% (i.e., at 4 x 10(-11) M) that of the major component. With HPCE/LIF, detection sensitivity is thus no longer a concern in the assaying of active ingredients in biopharmaceutical dosage formulations. The peptide mapping of biopharmaceuticals present at 1 x 10(-7) M (or an injected limit of detection of 60 amol) is presented. Also, kinetic information on the reaction of a recombinant enzyme-drug with its substrate present at the micromolar level has been extracted from electropherograms acquired in real-time.
Biopharmaceutics↗
Host cell contaminant protein assay development for recombinant biopharmaceuticals.
The efficiency and consistency of a biopharmaceutical purification process determines drug quality, including which specific types and concentrations of residual host cell or process contaminants may remain. Commercial reagents and generic analytical methods are available for quantitating most of these contaminants. However, no generic assay is available for quantitation of the specific contaminant host cell proteins (HCPs) which are unique to a novel purification process. Because of this, proprietary reagents and assays must be developed for the quantitation of process-specific HCPs in each biopharmaceutical drug. The need to develop proprietary reagents which are both sensitive to, and specific for, potentially complex mixtures of unique contaminant proteins has defined what is acceptable methodology for development of quantitative HCP assays. Within the biopharmaceutical industry this need is most often satisfied by the development of multi-analyte HCP immunoassays based upon the null cell mock purification model. Confidence in the quantitative nature of a given HCP assay, and the validity of analytical measurement obtained by the assay, is dependent upon empirical demonstration of the unique stoichiometry of the HCP assay reagents. In conjunction with other analytical and validation methods, an HCP immunoassay may be thought of as a necessary quantitative tool for the optimization and validation of biopharmaceutical purification process efficiency and consistency, rather than as an end in itself.
Drug Contamination↗
Contribution of biopharmaceutics and pharmacokinetics to improve drug therapy.
Efficacy, safety and costs are the elements defining the quality of pharmacological therapy. Several clinical studies have shown the contribution of pharmacokinetics and biopharmaceutics to different treatment responses. During the past few years, new drugs with very interesting properties, such as good oral bioavailability, wide tissue distribution and slow elimination rate, have been introduced. It has allowed improvement in the patient's treatment, and has introduced new therapeutic possibilities. The development of new drug delivery systems has facilitated achieving certain pharmacodynamic effects and overcoming some pharmacokinetic disadvantages of conventional formulations. This achievement has been a biopharmaceutical challenge in answer to a clinical need. Therapeutic drug monitoring in wide populations has permitted improvements in the design of new dosage regimens in order to ameliorate the therapeutic efficacy for different groups of drugs: antibiotics, antineoplastics, cardiovascular agents etc. Pharmacokinetic criteria have to be considered as a clinical strategy to increase the accuracy when making decisions about dosage individualization. Individual patients, other patient populations, and also the use of usually unmonitored drugs, take advantage of therapeutic monitoring benefits. The contribution of biopharmaceutics and pharmacokinetics has been important for obtaining maximum efficacy with minimal side-effects and cost optimization.
Biopharmaceutics↗
Inducible flocculation in Komagataella phaffii enables enhanced biomass separation for biopharmaceutical production.
Biomass separation represents a critical bottleneck in Komagataella phaffii-based biopharmaceutical processes, as typically high cell densities of 40 - 50 % create significant operational, technical and economic challenges for harvest operations. Yeast cell aggregation (flocculation) provides a solution to accelerate cell sedimentation by increasing particle size, thus allowing to improve biomass-supernatant separation efficiency during both natural gravity settling and (continuous) centrifugation operations. This study demonstrates successful engineering of K. phaffii strains with an inducible flocculation phenotype using CRISPR/Cas9-based genome editing to integrate the Saccharomyces cerevisiae FLO1 (ScFLO1) gene under control of various regulatory elements, including methanol-inducible and derepressible promoters. Flocculation strength could be enhanced by implementing transcriptional positive feedback circuits based on the methanol-inducible AOX1 promoter. To address methanol-free production requirements, we developed alternative systems to retrofit PAOX1-based ScFLO1 expression and exploited the derepressible PDF promoter, offering broader compatibility with biopharmaceutical manufacturing facilities. Flocculating cells cultivated in a bioreactor demonstrated significantly improved sedimentation behavior, with considerably lower supernatant turbidity after short low-speed centrifugation or gravity sedimentation compared to non-flocculating controls. Crucially, cell flocculation had no negative impact on product amount and quality when expressing a multivalent NANOBODY® VHH molecule with pharmaceutical relevance. Thus, this work establishes the first genetically engineered flocculation system in K. phaffii compatible with recombinant protein production, providing the basis for an innovative approach to streamline harvest operations in biopharmaceutical processes.
Flocculation↗
Bioanalytic considerations for pharmacokinetic and biopharmaceutic studies.
The correct evaluation of pharmacokinetic and biopharmaceutic data can only be achieved if accurate analytic data are obtained. The accuracy of analytic data depends on the criteria used to validate the method. Consequently, careful scrutiny of drug stability, assay sensitivity, selectivity, recovery, linearity, precision, and accuracy is necessary for the proper interpretation of data. The importance of method validation and its influence on pharmacokinetic and biopharmaceutic data evaluation and interpretation will be discussed.
Biopharmaceutics↗
Importance of biopharmaceutics and pharmacokinetics in clinical medicine.
Despite the paucity of biopharmaceutic and pharmacokinetic data for many old drugs, these areas of scientific research have demonstrated an immense value in clinical medicine, and can be expected to expand man's knowledge of drug action and the influence of physiological function of drug disposition. Illustrated in this report are four major areas where biopharmaceutics and pharmaco-kinetics have contributed significantly to the field of medicine. Foremost among these contributions are: 1. the assessment of bioavailability and bioequivalence of new drugs and generic marketed drugs, respectively; 2. the pharmacolinetic characterization of new drugs and new drug delivery systems; 3. adjustment of dosing regimen; 4. assessment of kinetic profile of drugs in diseases state and dose adjustment thereof. Patient-drug pharmacokinetic profile designed to avoid toxicity is illustrated.
Animals↗
A pharmacokinetic approach to the establishment of biopharmaceutic characteristics of different acetylsalicylic acid formulations in man.
Eleven acetylsalicylic acid (ASA) formulations were administered to 26 healthy volunteers in a cross-over design. The properties of the preparations differed from conventional, effervescent, buffered to buccal. The objectives of this study were: Consideration of the general aspects of a biopharmaceutical study: which parameter for which biopharmaceutic characteristic? Measurement of the kinetic parameters of ASA: first-pass effect, mean residence time, mean appearance time, total body clearance, apparent volume of distribution, half-lives, etc. Comparison of the formulations. Most of the formulations yield mean residence times for ASA of 0.3-1.0 h, which do not differ significantly (p greater than 0.05). For most of the products the first-pass effect is about 40 per cent; the average values of the apparent volume of distribution and whole body clearance, corrected for the first-pass effect, are about 201 and 650 ml min-1, respectively. Peak levels are reached slowly for the buccal formulations, and rapidly for the buffered products. It is difficult, especially for ASA, to characterize the gastro-intestinal absorption with pharmacokinetic model parameters, because the first-pass effect is large and often elimination of ASA is faster than absorption. The model-independent approach has the special advantages of calculating reliable pharmacokinetic parameters, and creating theoretical possibilities to characterize the absorption patterns of the different formulations in a quantitative way. No significant differences in the values of the parameters are found between most of the formulations. The ASA first-pass effect is reasonably constant and buccal application has no advantage. Enteric coating of the outer layer of ASA formulations causes inconsistent absorption and may be categorized under 'artificial mistakes'.
Adolescent↗
Comparative biopharmaceutical performance of imipramine formulations in man.
The systemic availability of an investigational liquid formulation of imipramine was compared to that of a commercially available tablet (Tofranil) whose therapeutic efficacy has been established by usage. The experiment was conducted under controlled conditions and a balanced 2-by-2 crossover design was used to dissociate the significance of formulation effects from subject, group, and experimental period sources of variation. Pharmacokinetic interpretation and statistical analysis of plasma concentrations as a function of time and of systemic availability indicators reveal a nearly identical biopharmaceutical behavior for the two preparations. Significant differences (P less than 0.05) were found in the cumulative area under the plasma concentration--time curve (AUC) up to 4 hours after administration and the availability lag time, but not in the maximum plasma concentration, the time at which this concentration is reached, the first-order availability rate constant, and the AUC to infinity. These results collectively indicate a very similar biopharmaceutical performance, where the differences in the early AUC values are partly attributable to a longer availability lag time for the tablet formulation.
Adult↗
A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability.
A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes.(ABSTRACT TRUNCATED AT 250 WORDS)
Biological Availability↗
[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↗
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↗
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↗
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↗
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↗
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↗
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↗
Data-reduction problems in biopharmaceutics and pharmacokinetics.
The importance of the use of appropriate biostatistical methods is stressed. In this article some problems and common errors in the data-reduction methods applied in biopharmaceutical and pharmacokinetic research are discussed. A commonly used representation of a set of concentration-time curves is the so-called 'mean curve', a curve through the arithmetic means of concentrations at discrete time points. If individual curves are compared with the 'mean curve' it appears that important characteristics have disappeared while other, incorrect, characteristics have been created. Unreliable conclusions may result from this procedure. Rather every single concentration-time curve should be fitted by appropriate regression methods and the resulting parameters be considered as multiple characteristics of individual pharmacokinetic behaviour. In a second data-analysis step these parameters may be clustered into more or less homogeneous subgroups, which subsequently may be represented by a representative curve. Standard errors of the mean and confidence intervals based on standard errors of the mean instead of the standard deviation are often misused as dispersion measures to characterize the sample or population distribution. Standard errors of the mean and confidence intervals measure the precision of the mean of a sample and are sensitive to the sample size. Vertical bars (in curves) representing standard deviation, standard errors of the mean or confidence intervals suggest symmetrical distributions, but this is sometimes not justified. Deviations from normality appear to occur often. A simple graphical method to indicate the dispersion of non-normal sets is presented. Methods for the determination of confidence intervals for normal and non-normal distributions are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)
Biopharmaceutics↗