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Results for “Biopharmaceutics”

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At least 19 recordsLinked to original sources

PubMed2026

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↗

PubMed1976

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↗

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↗

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↗

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↗

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↗

PubMed1990

Biochemical and biopharmaceutical properties of macromolecular conjugates of uricase with dextran and polyethylene glycol.

Uricase (UC) was conjugated with dextran and polyethylene glycol and their biochemical and biopharmaceutical properties were studied. UC-dextran conjugates (UC-D) synthesized by four methods, periodate oxidation, cyanogen bromide, carbodiimide and cyanuric chloride largely retained the UC enzymatic activity depending on the extent to which they modified amino groups. The periodate oxidation method seemed best because it gave a conjugate with high yield and satisfactory activity retention. The conjugate of UC with activated polyethylene glycol (UC-PEG2) was also obtained with high yield but the remaining activity was somewhat lower than those of dextran conjugates at the same modification extent. UC-D and UC-PEG2 showed sustained enzymatic activity in plasma after intravenous injection to rats. The advantage of chemical modification of proteins, especially with dextran, by the periodate oxidation method for preparation of a protein-delivery system was thus suggested.

Animals↗

PubMed1992

Pharmaceutical and biopharmaceutical quality of a sustained release carbamazepine preparation: a contribution to quality assurance.

Side effects observed during treatment with non-sustained release carbamazepine preparations are often due to the steep rise in plasma carbamazepine concentrations. To maintain plasma levels with only minor fluctuations between narrow limits, sustained release formulations have been developed which release the active constituent at a constant rate which is not too high. Bioavailability tests (single dosage, crossover design) and several investigations into the dissolution profile were carried out on three test batches of a sustained release carbamazepine preparation (Timonil 300 retard). The aim was a release model which, in the context of quality assurance, would not only facilitate reliable statements with regard to batch conformity, but would also be validated in respect of pharmacokinetic parameters such as rate of absorption and bioavailability. Correlations between mean dissolution times (MDT) and mean absorption times (MAT) at level B were found [Skelly et al. 1990]. A dissolution test differing from the pharmacopoeial tests was selected, which permitted the assessment of both batch conformity and biopharmaceutical batch quality.

Absorption↗

PubMed1976

[The role of biopharmaceutical parameters in drug development (author's transl)].

The biopharmaceutical factors, which influence the interaction between dosage form and drug activity, extend from the mode of application, through chemical and physical properties of the active constituent, to the final product, including the excipients and manufacturing processes involved. In recent years, important strides have been made in this field, which improve drug safety. This has consequently influenced and enlarged the present scope of pharmaceutical technology drug research.

Biological Availability↗

PubMed1992

Biopharmaceutical evaluation of ibufenac, ibuprofen, and their hydroxyethoxy analogs in the rabbit eye.

Two new structural analogs, 2-(4-hydroxyethoxyphenyl)acetic acid [R3] and 2-(4-hydroxyethoxyphenyl)propionic acid [R4], along with their parent compounds, ibufenac and ibuprofen, were evaluated for their biopharmaceutical properties. The analogs represented substitution of the lipophilic isobutyl side chains of ibufenac and ibuprofen with hydrophilic hydroxyethoxy side chains. Anti-inflammatory activity was evaluated by administering drugs topically to inhibit inflammation induced by using either clove oil or arachidonic acid. The rank order of activity was ibufenac approximately equal to ibuprofen > R3 approximately equal to R4. The new compounds, R3 and R4, were highly water soluble (> 60-fold) and partitioned less (< 1/1500-fold) into the lipid phase when compared to ibufenac and ibuprofen. R3 and R4 each had apparent corneal permeability coefficients of 6 x 10(-6) cm/sec, whereas ibufenac and ibuprofen yielded values of about 22 x 10(-6) cm/sec. In an ocular pharmacokinetic study in the rabbit eye, constant concentrations of each compound were maintained on the cornea in a cylinder or well fixed to the cornea, resulting in a constant input rate. This method circumvented parallel loss routes at the absorption site including nasolacrimal drainage. From area calculations the dispositions of the compounds within the eye were described by mean residence times, steady state volumes of distributions, and clearance rates. R3 and R4 were more slowly absorbed, retained within eye tissues longer, and were cleared more slowly from the eye than ibufenac and ibuprofen. The aqueous humor concentration-time profiles were also computer-fitted to equations representing classical pharmacokinetic models. For ibufenac and ibuprofen, the entire cornea was assumed to be the net barrier for entry into the anterior chamber. Whereas, for R3 and R4, the corneal epithelium and endothelium were presumed to be the diffusional barriers into and out of the stroma, the latter treated as a compartment. Aqueous humor concentrations of each drug fit the models reasonable well and agreed with conclusions made from the use of area calculations. The drop volume method was used to measure the surface tension of each compound. Both ibufenac and ibuprofen were considerably more surface active than R3 or R4. The greater surface tension measured for ibufenac and ibuprofen correlated to the subjective observations of ocular discomfort for these drugs.

Administration, Topical↗

PubMed1991

Calibration and validation of linearity in chromatographic biopharmaceutical analysis.

Calibration in chromatographic biopharmaceutical analysis is a major determinate of method performance and many methods have been proposed to evaluate an appropriate calibration model, to determine the linear range and to evaluate the goodness of fit. Ten chromatographic bioanalytical methods have been evaluated in this work by observation of concentration-response curves, linearity plots, calculation of concentration residuals, correlation coefficients and lack of fit analysis. These methods were applied to univariant linear regression, weighted regression, polynomial regression and power fit models in order to determine the most appropriate way to establish and evaluate calibration functions. It was found that weighted linear regression provided the most appropriate calibration function for eight of the 10 methods studied, whereas unweighted regression and the power fit model proved appropriate for one each of the other two methods. The choice of calibration function was best accomplished through observation of calculated concentration residuals. Linearity and sensitivity plots were of little value for assessment of linearity through the selected calibration range if conventional (+/- 5%) tolerance limits are employed. Validation of the calibration model can be accomplished by demonstrating the concentration residuals and the slope of the log concentration-log response plots are within reasonable tolerance limits or by lack of fit analysis. Correlation coefficients were demonstrated to be of little value for this purpose and the quadratic approach to linearity validation was in disagreement with other methods in four of the 10 methods evaluated.

Calibration↗

PubMed1991

Quantitation of DNA and protein impurities in biopharmaceuticals.

The development of drugs and biologicals for human injection generated from recombinant DNA and hybridoma technologies has resulted in new standards for product purity. We discuss the regulatory position relative to impurities in these biopharmaceuticals, focusing on the analytical goals for quantitation. Current methods for making these measurements are reviewed, and a new system designed for improved analysis is described. Assay results for both contaminating DNA and proteins are presented.

Chemistry, Pharmaceutical↗

PubMedDate not supplied

A total organic carbon analysis method for validating cleaning between products in biopharmaceutical manufacturing.

The validation of cleaning procedures for biopharmaceutical products produced by recombinant DNA (rDNA) technology presents a diverse analytical challenge. This is because of the need for quantitation of a broad range of potential residual cellular components, including proteins, carbohydrates, and nucleic acids, as well as trace levels of detergents at various manufacturing stages. The validation of a Total Organic Carbon (TOC) analysis method for use in cleaning validation studies is presented. The method has a limit of detection of approximately 0.1 ppm, with a limit of quantitation of 0.5 ppm. TOC analysis has an accuracy of 50 to 70% or better in the 0.5- to 10-ppm range and demonstrates an overall variability of approximately 5%. The method is broadly applicable to a variety of impurities and contaminants that are likely to be encountered following the manufacture of rDNA products.

Asepsis↗

PubMed1991

[Biopharmaceutical importance of pharmaceutical aids in drug prescribing with special reference to rectal administration].

Based on literary sources, the medical and pharmaceutical significance of vehicles and additives, which play an ever-increasing role in the production of all drug forms, is discussed. Then the groups of additives used in the production of suppositories are described partly on the basis of our own experiences, and their biopharmaceutical significance is evaluated.

Drug Compounding↗

PubMed1990

[Biopharmaceutical study of aminophenazone-containing suppositories. 2. Results of in vitro drug release and in vivo drug absorption].

Ten kinds of surface active ingredients of Th. Goldschmidt AG. (Essen-FRG) in concentrations of 5% were mixed with Witepsol W 35 and Massa Estarinum 299 suppository masses of Hüls-Troisdorf AG. Werk (Witten-FRG) which are official in Hungary. According to the authors the above tensides, which have been used advantageously first of all in ointments, creams and cosmetic preparations, can also be applied in rectal preparations. In the publication of two parts it has been established that these ingredients influence physical parameters of suppositories beneficially. They always increase significantly in vitro diffusion values and in some cases with order of magnitude. Massa Estarinum 299 containing 5% of Emulgator BTO proved to be the best in case of chosen suppositories containing aminophenazone. Correlation between in vitro and in vivo investigations has shown the importance of correct selection of base and ingredient materials in biopharmaceutical work.

Aminopyrine↗

PubMed1990

Sub-femtomole quantitation of proteins with Threshold, for the biopharmaceutical industry.

The Threshold system provides for rapid quantitation of a variety of analytes at sub-femtomole levels, which is fewer than 6 x 10(8) molecules. The operating principles of the measurement system will be described, including the means for chemical modulation of the signal and the subsequent signal detection utilizing a proprietary silicon sensor. The Immuno-Ligand Assay is a universal ligand-binding assay system which provides quantitative measurement of proteins (including antibodies) in a variety of biological media. Assay performance will be described, along with data demonstrating sensitivity, precision and accuracy, for a variety of analytes of interest to the biopharmaceutical industry.

Animals↗