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At least 865 records · Page 48Linked to original sources

PubMed2002

[Transgenic cattle constitute a breakthrough in production of innovative medicine. From milk to medicine].

The continuously increasing demand for biomolecules, e.g. human proteins, for applications in human health care, is one of the main driving forces for the development of safe, large-scale production systems. One very promising approach is the production of biomolecules in the milk of transgenic cattle. By using nuclear transfer technology, transgenic cattle can be generated in a very safe and efficient manner, thereby offering a significant time reduction when compared to conventional breeding methods. As a result, that the transgenic cattle platform offers an efficient, safe and cost-effective method for producing large amounts of biopharmaceuticals, which is essential to the development of innovative health care products.

Animal Husbandry↗

PubMed2002

Formulation approaches for orally administered poorly soluble drugs.

Despite having pharmacodynamic or target activity, many drugs fail in the drug development process due to poor bioavailability, and presently marketed conventional dosage forms of poorly soluble drugs employ high doses leading to potential toxicity. The introduction of the Biopharmaceutic Classification System (BCS) has provided a basis to categorize drugs based on the two major parameters affecting absorption, solubility and permeability. Several techniques can be employed to enhance the absorption and bioavailability of poorly soluble and poorly permeable drugs based on the BCS concept. This article is an attempt to summarize the development of various formulation approaches that are currently employed to enhance bioavailability of orally administered poorly soluble drugs.

Biopharmaceutics↗

PubMed2004

[Analysis of the items of pharmaceutics of Chinese medicine accepted and supported by NSFC in recent 5 years].

In this article, the items from 1999 to 2003 of pharmaceutics of Chinese medicine accepted and supported by subject of traditional Chinese medicine, No.9 department of life science, national natural science foundation of China (NSFC) have been reported, in several aspects, such as extracting process, preparation, biopharmaceutics, pharmacokinetic, etc. The problems in these items have also been analyzed briefly.

Biopharmaceutics↗

PubMedDate not supplied

Determination of "extractables" on polymer materials by means of HPLC-MS.

In biopharmaceutical processes, in the area of food and medical technology a variety of devices is used. These devices consist of various polymers. The detection and identification of potential extractables from these polymers during application are requested by the regulatory bodies. For risk and toxicity assessment, both identification and quantification of extractables are necessary. This article describes the development of a LS-MS methodology transfered from an established HPLC-UV-VIS method for full extractables analysis of sterile-grade filtration cartridges.

Biopharmaceutics↗

PubMed1978

[In vitro and in vivo investigations with different nitrofurantoin formulations (author's transl)].

In vitro dissolution tests and biopharmaceutical investigations on healthy test persons were carried out with 4 different galenic tablet formulations. Three of these formulations were prepared by a special galenic process, the fourth corresponded to the usual tablet formulations. It was shown that the dissolution behaviour of the formulations in vitro, in accordance with the specifications of the American Pharmacopoeia (USP XIX), does not correlate with the parameters found in vivo. However, if the formulations in vitro are checked with the Sartorius model according to Stricker, correlations can be found with the in vivo behaviour of nitrofurantoin. A linear relationship was achieved by the special galenic formulation directly regulating the pharmacokinetic behaviour of nitrofurantoin. The known biological scatter of nitrofurantoin was strongly reduced by this process. The amount of the substance still present and circulating in the body creating the side effects could be reduced to a minimum. All facts considered, the therapeutic safety is also ensured.

Adult↗

PubMed1984

Moment analysis in vivo and in vitro.

Moments are quantities that can be calculated either directly from empiric observations or from model equations that describe observed time-dependent events. The analysis of empirically obtained moments provides insight into the mean duration and into the time profile of the underlying processes. The rules of their assessment and analysis are the same for pharmacokinetic and for pharmaceutical observations. Examples are given that show the power of moment analysis in pharmacokinetic experiments in vivo and in pharmaceutical dissolution testing in vitro. The method can be used for evaluation of in vivo/in vitro correlations in biopharmaceutics.

Animals↗

PubMed1984

[Use of foaming and nonfoaming gentamycin tablets in treating cows with chronic endometritis].

Biopharmaceutic and therapeutic investigations were carried out with foaming and nonfoaming gentamycin sulfate tablets. The experiments were conducted with a total of 100 cows affected with chronic inflammation of the uterus. Both types of tablets, containing 30,000 IU of gentamycin sulfate each were introduced into the uterus via Andreev's catheter, bimanually or by means of a vaginal speculum and Albrechtzen's clamp, at the rate of 10. Followed up were the serum levels, the excretion with the milk, and the content in the uterine secretion of gentamycin after using the tablets. There was no statistically significant difference in the serum levels of gentamycin as initiated by the two types of tablets. In milk the peak values reached 0.02 micrograms/cm3, and in uterine washings (with 15 cm3 isotonic solution of sodium chloride) the proper levels were established up to 74nd hour. Demonstrated was the therapeutic effect in the treatment of cows with chronic endometritis - 77.4 per cent with the use of foaming and 71.4 per cent with the use of nonfoaming tablets. There was also a rising trend with the conception rate in the treatment of sterile cows (otherwise having no signs of uterine inflammation) with the use of nonfoaming tablets of gentamycin sulfate at the rate of 5, introduced 24 hours after insemination.

Animals↗

PubMed1994

Introduction to gene technology.

The increased use of biotechnology for numerous categories of common products (pharmaceuticals, foods, agricultural chemicals, etc.) has an ever increasing impact on our society. In the medical/pharmaceutical field, biotechnology signifies a drastic change in the approach to drug discovery, research and development, diagnosis, and disease management. The basis of replication, transcription, translation, recombinant DNA technology, and production of altered genes are defined. Examples of biopharmaceuticals, i.e., enzymes or regulators of enzyme activity, hormones or hormone-like growth factors, cytokines, vaccines, monoclonal antibodies, and gene transfer in humans are discussed.

Animals↗

PubMed1993

Studies on the reliability of a novel absorption-lipophilicity approach to interpret the effects of the synthetic surfactants on drug and xenobiotic absorption.

Some theoretical principles of the absorption/lipophilicity approach, which attempts to explain the effects of the synthetic surfactants on xenobiotic and drug intestinal absorption, are reviewed and experimentally checked by examining the correlations obtained between "in situ" absorption constants, ka, found in rat colon, and "in vitro" lipophilicity indexes, K', for two compound series (secondary aliphatic amines and phenylalkylamines) in the absence and in the presence of the nonionic surfactant Polysorbate 80, in the intestinal perfusion fluid. Evidence is given for the following actions of the synthetic surfactant: at its critical micelle concentration (CMC), it increases the polarity of the absorbing membrane and, at the same time, it disrupts the aqueous stagnant diffusion layer adjacent to the mucosal barrier. When a supramicellar concentration (SMC) is used, the above actions are almost totally masked by the micellar solubilization of the tested amines, which decreases their absorption constants relative to those found at CMC, as markedly as solute lipophilicity increases. As a consequence of these actions, the correlations between ka and K', which are clearly hyperbolic in free solution, become potential in the presence of the surfactant at its CMC, whereas at SMC a bilinear correlation is obtained. Absorption via lipophilic ionized species seems to take place for both compound series. Mathematical and physicochemical interpretations of this behaviour are outlined, and biopharmaceutical implications of these phenomena are discussed.

Amines↗

PubMed1997

Raw material considerations.

Raw materials (RM) testing and control strategy form a major part of the foundation of a well-characterized protein (WCP) or biopharmaceutical. Raw materials may be present in the final vial as excipients or may have product contact earlier in processing. Manufacturers of WCPs should use a scientific approach to set acceptance criteria and test methods for bulk raw materials which are not present in dosage forms in substantial amounts. These methods and standards should enable the procurement of specified RMs which enable the reliable preparation of a product which consistently meets its quality attributes. Manufacturers of WCPs must use available pharmacopoeial standards for excipients and bulk process RMs which cannot be substantially removed during purification or other processing steps. Manufacturers should support efforts to harmonize pharmacopoeial standards for excipients.

Biopharmaceutics↗

PubMed1997

Comparison of population pharmacokinetic modeling methods using simulated data: results from the Population Modeling Workgroup.

Statistical modeling methods have had increasing use in drug disposition studies, both to estimate pharmacokinetic parameters and to develop regression models that relate these parameter estimates to patient characteristics. These methods are particularly flexible as they allow non-linearity and sparse within-patient information. In the past few years, multiple analysis methods have become available, but there is a lack of systematic comparisons of their estimates on the same data sets. Two simulated data sets were therefore developed by the Population Modeling Workgroup of the Biopharmaceutical Section of the American Statistical Association. We analysed these data sets using seven population modeling programs, some of which contain multiple analysis methods. Although each data set represents a single replicate from a given model and data collection design, the results suggest that the behaviour of some methods differs from that of the others.

Anti-Arrhythmia Agents↗

PubMedDate not supplied

A framework establishing clear decision criteria for the assessment of drug efficacy.

Much has been published on various aspects of data analysis and reporting from clinical trials within the biopharmaceutical environment. This ranges from regulatory guidelines on the format and content of registration dossiers to recommendations on data presentation and the statistical methodologies that are appropriate for the diverse types of data one observes in clinical trials. Little has been written about designing a clinical trial analysis and reporting package that focuses on the decisions that must be made throughout the drug development process. Pharmaceutical companies today are under enormous pressure to develop drugs quickly and (cost-) efficiently. Because of this, drugs often move into the later phases of drug development before evidence from prior phases is completely understood. This provides a challenge to clinical trialists to design and execute a clinical trial programme which can expedite drug development. The statistician, as a clinical trialist, must strive to determine the optimum analytical methodology that facilitates decision making for this clinical trial programme. This paper proposes a new framework for the assessment of efficacy in drug development called the 'one programme, one p-value' framework. This framework will accelerate drug development by providing clear criteria for the decisions which must be made along the way. The 'one programme, one p-value' framework is based on the notion that the clinical trial programme comprises exploratory and confirmatory phases. The use of the likelihood function in the exploratory phase facilitates the decision whether (or when) to move into the confirmatory phase. The confirmatory phase consists of one confirmatory trial with a single hypothesis test of the drug's efficacy; hence 'one p-value'. Sponsor interaction with regulatory agencies is necessary at each decision point. Finally, the paper considers how analysis and reporting of efficacy data can be accomplished from a clinical trial programme as described.

Clinical Trials as Topic↗

PubMed1999

Serum protects protein-free competent Chinese hamster ovary cells against apoptosis induced by nutrient deprivation in batch culture.

The development of serum- and protein-free Chinese hamster ovary (CHO) cell cultures is a high priority for the production of biopharmaceuticals. Protein-free competent CHO cells lines have been previously constructed by two different methods-metabolic engineering with cell-cycle regulatory proteins and long-term selective adaptation. Apoptosis was present in both cell lines during protein-free, static-batch culture as a result of nutrient deprivation, and glucose deprivation alone was a potent inducer of apoptosis compared to the depletion of other nutrients such as amino acids. By adding back serum to the cultures during batch growth or nutrient deprivation, it was shown that unidentified survival factors in serum can greatly reduce apoptosis in protein-competent cell lines in all phases of the culture. Both observations contrast to previous reports for hybridoma cells, in which amino acids were the key determinants of apoptosis and serum had no additional antiapoptotic effect. Serum's protective effect against CHO cell death in batch culture was multifaceted and complex: (1) 10% FBS increased cell viability to >99% during exponential growth from roughly 75-90%, (2) 5-10% fetal bovine serum (FBS) reduced specific glucose consumption rates in both cell lines by 40%, thereby delaying the onset of apoptosis caused by glucose deprivation, and (3) 5% FBS reduced the specific cell death rate by 65% during a 3-d lactate-consumption phase characterized by substantial abortive proliferation, in which the cells both proliferated and died at a constant rate. The benefit of serum on cell production over the various phases of batch growth was combined into a single parameter by integrating the viable cell concentration vs. time profile (termed here as cumulative volumetric viable cell-time, VCTvol). Despite the ability of both cell lines to grow indefinitely without any exogenous growth factors, the addition of serum resulted in a 2. 3-fold increase in the VCTvol. Thus, it is clear that there is much room for improvement of protein-free CHO cell lines despite their adequate growth competence, and new strategies different from those successfully used for hybridomas may be necessary to combat CHO cell apoptosis.

Animals↗

PubMed1999

Bicarbonate concentration and osmolality are key determinants in the inhibition of CHO cell polysialylation under elevated pCO(2) or pH.

Accumulation of CO(2) in animal cell cultures can be a significant problem during scale-up and production of recombinant glycoprotein biopharmaceuticals. By examining the cell-surface polysialic acid (PSA) content, we show that elevated CO(2) partial pressure (pCO(2)) can alter protein glycosylation. PSA is a high-molecular-weight polymer attached to several complex N-linked oligosaccharides on the neural cell adhesion molecule (NCAM), so that small changes in either core glycosylation or in polysialylation are amplified and easily measured. Flow-cytometric analysis revealed that PSA levels on Chinese hamster ovary (CHO) cells decrease with increasing pCO(2) in a dose-dependent manner, independent of any change in NCAM content. The results are highly pH-dependent, with a greater decrease in PSA at higher pH. By manipulating medium pH and pCO(2), we showed that decreases in PSA correlate well with bicarbonate concentration ([HCO(3)(-)]). In fact, it was possible to offset a 60% decrease in PSA content at 120 mm Hg pCO(2) by decreasing the pH from 7.3 to 6.9, such that [HCO(3)(-)] was lowered to that of control (38 mm Hg pCO(2)). When the increase in osmolality associated with elevated [HCO(3)(-)] was offset by decreasing the basal medium [NaCl], elevated [HCO(3)(-)] still caused a decrease in PSA, although less extensive than without osmolality control. By increasing [NaCl], we show that hyperosmolality alone decreases PSA content, but to a lesser extent than for the same osmolality increase due to elevated [NaHCO(3)]. In conclusion, we demonstrate the importance of pH and pCO(2) interactions, and show that [HCO(3)(-)] and osmolality can account for the observed changes in PSA content over a wide range of pH and pCO(2) values.

Animals↗

PubMed2000

Protein modification during antiviral heat bioprocessing.

Heat treatment is routinely used in the preparation of therapeutic protein biopharmaceuticals as a means of viral inactivation. However, in undertaking virucidal heat treatments, a balance must be found between the bioprocessing conditions, virus kill, and the maintenance of protein integrity. In this study, we utilize a simple model protein, hen egg-white lysozyme, to investigate the relationship between antiviral bioprocess conditions (protein formulation and temperature) and the extent and type of protein modification. A variety of industrially relevant wet- and dry-heat treatments were undertaken, using formulations that included sucrose as a thermostabilizing excipient. Although there was no evidence of lysozyme aggregation or crosslinking during any of the heat treatments, using liquid chromatography-electrospray ionization-mass spectroscopy (LC-ESI-MS) and peptide mapping we show that protein modifications do occur with increasingly harsh heat treatment. Modifications were predominantly found after wet-heat treatment, the major covalent modification of lysozyme under these conditions being glycation of Lys(97), by either glucose or fructose derived from hydrolyzed sucrose. The extent of sucrose hydrolysis was itself dependent on both the duration of heat treatment and formulation composition. Advanced glycation end products (AGEs) and additional unidentified products were also present in protein samples subjected to extended heat treatment. AGEs were derived primarily from initial glycation by fructose and not glucose. These findings have implications for the improvement of bioprocesses to ensure protein product quality.

Carbohydrates↗

PubMed2000

Part II. Overexpression of bcl-2 family members enhances survival of mammalian cells in response to various culture insults.

A number of bioreactor configurations have been developed for the manufacture of products from mammalian cell hosts. Even in the most efficient of these, however, problems such as nutrient exhaustion, growth factor deprivation, and toxin accumulations may arise. Consequently, the current effort focused on the feasibility of overexpressing anti-apoptosis genes in baby hamster kidney (BHK) and Chinese hamster ovary (CHO) cells as a means of limiting cell death upon exposure to three such insults. Extended periods of glucose deprivation, serum withdrawal, and treatment with ammonium chloride each caused significant damage, often apoptotic in nature, to BHK and CHO cells, typically rendering cultures completely nonviable. The overexpression of bcl-2 and bcl-x(L), however, was able to abrogate the cell death in BHK cultures, though to varying degrees. For instance, the presence of Bcl-2, which did little to suppress apoptosis upon glucose deprivation, significantly improved the viabilities of these cells during serum withdrawal. In contrast, bcl-x(L) overexpression provided BHK cells with enhanced protection in the absence of glucose, allowing cultures to remain viable throughout the entire three week study. CHO cultures, on the other hand, displayed similar trends in survival in response to both glucose and serum deprivation. During these studies, Bcl-x(L) was consistently able to afford cells the highest degree of protection, though Bcl-2 also enhanced culture viabilities and viable numbers. Death suppression following exposure to 50 mM ammonium chloride was observed to a limited extent in both BHK and CHO cells overexpressing bcl-2 and bcl-x(L). However, even during such harsh treatment, Bcl-x(L) was able to enhance the survival of both cultures, providing CHO cells with viable numbers that were nearly 20-fold that of the controls after five days of exposure. Furthermore, the extensions in cell survival provided by the anti-apoptosis gene products enabled the recovery of many of the cultures during rescue attempts in which the death-inducing stimulus was removed. Clearly, engineering cells to better withstand and recover from the insults common during the large scale cultivation of mammalian cells has a number of potential applications in the biopharmaceutical industries where cell death can limit culture productivities.

Animals↗

PubMedDate not supplied

Use of capillary electrophoresis for the characterization of human serum albumin heterogeneity.

Human serum albumin (HSA) is used in large amounts as an excipient in many biopharmaceutical formulation to prevent loss of the active ingredient through adsorption and/or degradation. Traditionally, iso-electric focusing has been used to demonstrate charge heterogeneity in HSA preparations. In an effort to develop new methods for the analysis of formulation components, a capillary zone electrophoresis method was developed for the analysis of HSA. Under initial separation conditions using untreated silica capillaries and 20 mM sodium phosphate, pH 6.0 as electrophoretic buffer, HSA migrated as a single peak. Addition of 1,4-diaminobutane allowed separation of several components which could be further resolved by varying the buffer pH. Optimal separation conditions were attained at 5 mM 1,4-diaminobutane and pH 8.5. The reproducibility of the separation conditions was verified by using capillaries from a different manufacturer. A comparative analysis of HSA preparations from different manufacturers provided evidence that the method may be used to qualitatively differentiate individual preparations. The analysis of rhEPO formulations, composed largely of HSA, showed levels of heterogeneity comparable to that of HSA preparations. Electrospray ionisation mass spectrometry (ESA-MS) was used as an independent method to confirm the heterogeneous nature of HSA.

Electrophoresis, Capillary↗

PubMed2000

Lymphatic transport of proteins after subcutaneous administration.

This mini-review summarizes the relevant literature regarding the lymphatic transport of proteins after subcutaneous administration. A review of the physiology of the lymphatics and inherent anatomical differences between blood and lymph capillaries is presented followed by a brief overview of the general characteristics of protein absorption and bioavailability following S.C. injection. A description of factors known to directly affect the lymphatic uptake of macromolecules follows and is supported by representative data from this laboratory. A brief perspective on the importance of lymphatic uptake and transport in understanding the biopharmaceutical properties of protein drugs and potentially targeting the lymphatics is presented.

Animals↗