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At least 253 records · Page 14Linked to original sources
PubMed2002

Formulation and biopharmaceutical issues in the development of drug delivery systems for antiparasitic drugs.

The development of really new antiparasitic drugs to market level is a very rare event. A large number of lead structures have already been screened and discarded, the market is large but poor, and the administrative barriers are increasingly high and costly. Novel antiparasitics must not only be better, they must also be substantially safer than the existing repertoire. There are two major aspects to drug development. One is the strategy of pathogen-specific biochemical intervention, the other the strategy of optimal formulation and application. This review focuses on the latter. In finding and adapting innovative and "intelligent", i.e. parasite- and disease-specific formulations and delivery systems, established but deficient drugs might be optimised, enhancing their efficiency and reducing negative side effects at relatively low cost. Further, many promising new ideas are severely hampered by the low water solubility of the antiparasitic drug. Here as well, some of the innovative drug formulation and delivery systems discussed below might offer highly efficient, while technologically simple, solutions.

Animals↗
PubMed2006

A decision-support model for evaluating changes in biopharmaceutical manufacturing processes.

A simulation is described that evaluates the impacts of altering bio-manufacturing processes. Modifications designed to improve production levels, times and costs were assessed, including increasing feed volumes/titres, replacing initial downstream stages with packed or expanded bed affinity steps and removing ion exchange steps. Options were evaluated for manufactured product mass, COG, batch times and development costs and timescales. Metrics were combined using multi-attribute-decision-making techniques generating a single assessment metric for each option. The utility of this approach was illustrated by application to an FDA-approved process manufacturing rattlesnake anti-venom (Protherics U.K.). Currently, ovine serum containing anti-venom IgG is purified by precipitation/centrifugation, prior to antibody proteolysis by papain. An ion exchanger removes F(C), before affinity chromatography yields the final anti-venom. An expanded bed affinity column operating with an 80% higher IgG titre, 66% higher feed volume and without the ion exchanger delivered the best multi-attribute-decision-making value, potentially providing the most desirable alternative.

Biopharmaceutics↗
PubMed1994

The search for novel microbial fine chemicals, agrochemicals and biopharmaceuticals.

An ever-increasing number of fine chemicals and enzymes is now produced based on microbial biotechnology. Microbial products generally display desired chirality, are biodegradable and are produced from renewable (agro)-substrates. Bioconversion reactions, based on the use of (immobilised) biocatalysts (cell or enzymes), yield interesting regio- and enantioselective molecules under mild reaction conditions, starting from racemic precursors. Furthermore these bioprocesses have a positive environmental impact. Ingenious screening procedures for novel microbial primary and secondary metabolites, bioactive peptides, proteins and enzymes reveal that only the tip of the iceberg has been explored. Examples of such novel microbial products pertain to enzymes, enzyme-inhibitors, biopolysaccharides, bio-plastics, bioactive peptides, bacteriocins, targeted toxins, alkaloids, steroids, immunomodulators, vaccines, antibiotics and lantibiotics, biopesticides, vitamins and related growth factors, amino acids and specialty sugars, polyols and organic acids, biomagnets, bioflavours and biopigments. Several trends are discussed which are now in vogue to detect novel useful compounds from microbes. Examples are given of those microbial metabolites and enzymes, which have attracted industrial interest.

Amino Acid Sequence↗
PubMed1996

Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption.

For almost a half century scientists have striven to develop a theoretical model capable of predicting oral drug absorption in humans. From the pH-partition hypothesis to the compartmental absorption and transit (CAT) model, various qualitative/quantitative approaches have been proposed, revised and extended. In this review, these models are classified into three categories; quasi-equilibrium models, steady-state models and dynamic models. The quasi-equilibrium models include the pH-partition hypothesis and the absorption potential concept, the steady-state models include the film model and the mass balance approaches, and the dynamic models include the dispersion, mixing tank and CAT models. The quasi-equilibrium models generally provide a basic guideline for understanding drug absorption trends. The steady-state models can be used to estimate the fraction of dose absorbed. The dynamic models predict both the fraction of dose absorbed and the rate of drug absorption and can be related to pharmacokinetic models to evaluate plasma concentration profiles.

Administration, Oral↗
PubMed1987

Quantification of tamoxifen and N-desmethyltamoxifen in human plasma by high-performance liquid chromatography, photochemical reaction and fluorescence detection, and its application to biopharmaceutic investigations.

The anticancer drug tamoxifen and its major metabolite N-desmethyltamoxifen are quantified in human plasma down to subnanogram amounts by high-performance liquid chromatography. Plasma is alkali-buffered and extracted with hexane. The organic solvent is evaporated and the residue dissolved in the mobile phase. An aliquot is sampled automatically and chromatographed. The analytes are detected after postcolumn UV irradiation and rearrangement to substituted phenanthrenes by their intense fluorescence. Precise handling of exact volumes facilitates external calibration. Statistical data for precision and accuracy are given and illustrate reliable quantification. The method is applied to the samples of a clinical study, and the pharmacokinetic parameters of both analytes are presented. The novel design of the photochemical reactor is discussed, with respect to peak broadening and photochemical recovery. The measured peak broadening is smaller than theoretically predicted, owing to non-helical coiling.

Biopharmaceutics↗
PubMedDate not supplied

Biopharmaceutical studies on crude drug preparations. I: Permeation of paeonol in a decoction and dry extract of Paeonia suffruticosa root cortex using an absorption simulator.

The permeation behavior of paeonol, one active constituent of a crude Chinese drug called Moutan Cortex, through an artificial gastric lipid barrier was examined in vitro using an absorption simulator in order to clarify how the administered form influenced the bioavailability of paeonol from a crude preparation. Paeonol concentrations were determined by a high-performance liquid chromatographic method developed during this study. Paeonol showed greater permeation from artificial gastric juice into artificial plasma when it was applied as a decoction or freeze-dried extract of Moutan Cortex than when applied as purified paeonol alone.

Absorption↗
PubMed1990

French and/or European perspectives on biopharmaceutical characterization of drug dosage forms.

In order to bring definitions of drug dosage forms up to date, it was necessary for the French Pharmacopoeia to propose assays allowing the quality control of the dosage forms to be based on the kinetics of drug release in vitro. Currently, five examples can be cited of dosage forms that can be characterized by release in vitro. (1) Oral solid dosage forms--for tablets, all the parameters of powders before compression (e.g., flowability, tableting properties) are being studied in addition to the dissolution tests, (2) Rectal dosage forms--the disintegration test of suppositories will be discarded and a new dissolution test using a special flow-through cell is now being studied. (3) Inhalations--since particle diameter is the most important factor for inhalation activity, a method has been developed to give the correct answer to this question. (4) Modified release drug dosage forms--these have been defined separately from the conventional forms. For the peroral route, they are: (i) accelerated release drug dosage forms, (ii) sustained release drug dosage forms and (iii) delayed release drug dosage forms. To emphasize the differences in the release kinetics, use of the paddle method, well known in the USP, and the flow-through cell has been suggested and described in the European Pharmacopoeia. Some associations and/or in vitro-in vivo correlations have increased the interest in the last method. (5) Transdermal delivery systems--these are defined separately from plaster and sticking-plaster. The use of a cell method was suggested to study the drug release and some comparisons between different techniques are presented.

Biopharmaceutics↗
PubMed2005

Regulatory perspectives from Japan - comparability of biopharmaceuticals.

In Japan there is no official guideline about comparability assessment of biotechnological products at present. However, there is some notifications which should be referred to, when the manufacturer changes the manufacturing process. Here, regulatory perspectives from Japan on the comparability assessment are presented. When establishing the comparability of biotechnological products derived from different manufacturing processes and the validity of modified manufacturing process, rational step-by-step approaches based on both product and process aspects would be useful. At first, relevant physicochemical and biological properties of products including purity, impurity profiles and stability should be compared before and after the manufacturing change, depending on the type and nature of the desired products. It is also necessary to examine the capacities of the new manufacturing process for ensuring the consistent production of the active protein product as well as the anticipated elimination of potential impurities and contaminants. Further relevant assessment of preclinical and clinical comparability of product may be necessary in some cases.

Biological Products↗
PubMed2005

Protein aggregation and its inhibition in biopharmaceutics.

Protein aggregation is arguably the most common and troubling manifestation of protein instability, encountered in almost all stages of protein drug development. Protein aggregation, along with other physical and/or chemical instabilities of proteins, remains to be one of the major road barriers hindering rapid commercialization of potential protein drug candidates. Although a variety of methods have been used/designed to prevent/inhibit protein aggregation, the end results are often unsatisfactory for many proteins. The limited success is partly due to our lack of a clear understanding of the protein aggregation process. This article intends to discuss protein aggregation and its related mechanisms, methods characterizing protein aggregation, factors affecting protein aggregation, and possible venues in aggregation prevention/inhibition in various stages of protein drug development.

Biopharmaceutics↗
PubMed2003

Production of supercoiled multimeric plasmid DNA for biopharmaceutical application.

Production of nucleic acids as an active pharmaceutical ingredient (API) in gene therapy and genetic vaccination is gaining more and more importance. Non-viral vectors like plasmid DNA are currently investigated in various clinical trials. Supercoiled multimeric plasmids are of particular interest for pharmaceutical purpose because they contain multiple copies of a therapeutic gene and can therefore be more efficient vectors. A process for the preparation of Escherichia coli strains replicating dimers, trimers, and tetramers of a 4.6 kb plasmid is presented. Cultivation of these clones on semi-defined glycerol medium in a 7 l bioreactor shows structural stability of dimers and trimers during the whole cultivation process. Plasmid concentrations and selectivities are compared to the corresponding cultivation with the plasmid monomer. Cultivation of the tetramer replicating strain shows a disintegration of the plasmid multimer and reconstitution of the monomer and smaller multimers.

Biopharmaceutics↗
PubMed2005

Determination of thio-based additives for biopharmaceuticals by pulsed electrochemical detection following HPLC.

Pulsed electrochemical detection (PED) following liquid chromatographic separation has been applied to the direct (i.e., without derivatization) determination of two major sulfur-containing compounds used as pharmaceutical additives, isopropyl-thio-beta-D-galactopyranoside (IPTG) and monothioglycerol (MTG). Limits of detection of IPTG and MTG were found to be 1 ppb (0.2 pmol, 50 microL) and 0.2 ppb (0.1 pmol, 50 microL), respectively, using optimized potential-time waveforms applied to a Au electrode. In addition to high sensitivity as compared to optical detection, the simultaneous detection of free thiols and disulfides can be used to study the kinetics of these conversions, as is shown for MTG. A practical application of HPLC-PED is demonstrated in determining MTG in a pharmaceutical formulation. The high selectivity of PED for thiocompounds reduces sample preparation and produces simpler chromatograms in a variety of matrices.

Biopharmaceutics↗
PubMed2004

Plant-based production of biopharmaceuticals.

Plants are now gaining widespread acceptance as a general platform for the large-scale production of recombinant proteins. The first plant-derived recombinant pharmaceutical proteins are reaching the final stages of clinical evaluation, and many more are in the development pipeline. Over the past two years, there have been some notable technological advances in this flourishing area of applied biotechnology, as shown by the continuing commercial development of novel plant-based expression platforms. There has also been significant success in tackling some of the limitations of plant bioreactors, such as low yields and inconsistent product quality, that have limited the approval of plant-derived pharmaceuticals.

Biological Factors↗
PubMed2004

On risk and plant-based biopharmaceuticals.

Research into plant-based expression of pharmaceutical proteins is proceeding at a blistering pace. Indeed, plants expressing pharmaceutical proteins are currently being grown in field environments throughout the USA. But how are these plants and proteins being assessed for environmental risk and how are they being regulated? Here, we examine the applicability of the risk assessment paradigm for assessing human and ecological risks from field-grown transgenic plants that express pharmaceutical proteins.

Biopharmaceutics↗
PubMed2005

Biopharmaceutical production in plants: problems, solutions and opportunities.

There are major structural differences between plant and mammalian N-linked glycans, with those from plants being immunogenic in most laboratory mammals and eliciting glycan-specific IgE and IgG antibodies in humans, when delivered parenterally. However, because humans are constantly exposed to plant glycoproteins in the diet, glycosylated plant-made pharmaceuticals (PMPs) should be acceptable for topical and oral administration. To exploit fully the potential that plants offer for the production of therapeutic proteins for parenteral administration, it might be necessary to inhibit plant-specific post-translational modifications to obtain "humanized" non-immunogenic N-glycans on PMPs. The benefits that could accrue are lower manufacturing costs, relative to mammalian cell culture, and a reduced risk of transmission of mammalian pathogens.

Biological Products↗
PubMed2003

Improvement of physicochemical and biopharmaceutical properties of theophylline by poly(ethylene glycol) conjugates.

In the present paper two theophylline esters with poly (ethylene glycol) (PEG) and methoxy poly (ethylene glycol) (mPEG) were prepared. Quantitative yields of the pure products were obtained. Unlike the free drug, the drug-polymer conjugates are freely water-soluble at room temperature. In vitro release experiments in aqueous buffer demonstrate that both conjugates are stable in buffer of pH 7.4 and 1.2. In vivo release studies after oral administration of theophylline conjugates demonstrate a good release of parent drug.

Animals↗
PubMed2000

Developing efficient strategies for the generation of transgenic cattle which produce biopharmaceuticals in milk.

At the close of the millennium, a revolution in the treatment of disease is taking shape due to the emergence of new therapies based on human recombinant proteins. The ever-growing demand for such pharmaceutical proteins is an important driving force for the development of safe and large-scale production platforms. Since the efficacy of a human protein is generally dependent on both its amino acid composition as well as various post-translational modifications, many recombinant human proteins can only be obtained in a biologically active conformation when produced in mammalian cells. Hence, mammalian cell culture systems are often used for expression. However, this approach is generally known for limited production capacity and high costs. In contrast, the production of (human) recombinant proteins in milk of transgenic farm animals, particularly cattle, presents a safe alternative without the constraint of limited protein output. Moreover, compared to cell culture, production in milk is very cost-effective. Although transgenic farm animal technology was still in its infancy a decade ago, today it is on the verge of fulfilling its potential of providing therapeutic proteins that can not be produced otherwise in sufficient quantities or at affordable cost. Since 1989, we have been at the forefront of this development, as illustrated by the birth of Herman, the first transgenic bull. In this communication, we will present an overview of approaches we have taken over the years to generate transgenic founder animals and production herds. Our initial strategies were based on microinjection; at the time the only viable option to generate transgenic cattle. Recently, we have adopted a more powerful approach founded on the application of nuclear transfer. As we will illustrate, this strategy presents a breakthrough in the overall efficiency of generating transgenic animals, product consistency, and time of product development.

Animals↗