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PubMed1987

The metabolism and biopharmaceutics of spironolactone in man.

Spironolactone, a competitive aldosterone antagonist, has been used for almost 30 years in those disorders associated with primary or secondary hyperaldosteronism. This review is confined to its metabolism and biopharmaceutics in man. Spironolactone undergoes extensive metabolism with no unchanged drug appearing in the urine. Its metabolites can be divided into two main categories: those in which the sulfur of the parent molecule is removed and those in which the sulfur is retained. The dethioacetylated metabolite canrenone, belonging to the former category, was long considered to be the major active metabolite of spironolactone. For this reason pharmacokinetic studies have focussed on its kinetic behaviour. However, pharmacodynamic studies indicated that canrenone could only partly explain spironolactone's action. Furthermore, with the advent of modern high-performance liquid chromatographic techniques to measure canrenone concentrations, it was shown that previously employed assay techniques were unspecific and consequently considerably overestimated true canrenone levels. Recently, it was demonstrated that after a single oral dose of spironolactone, 7 alpha-thiomethylspirolactone is the main metabolite and that unchanged spironolactone reaches maximum serum concentrations which are in the same order of magnitude as canrenone. Both spironolactone and 7 alpha-thiomethylspirolactone are known to possess anti-mineralocorticoid activity, and they may be mainly responsible for the activity of spironolactone. It also appears likely that endocrine side effects of spironolactone, such as gynaecomastia, are mediated by these sulfur-containing compounds. The oral absorption of spironolactone is improved by using micronized drug or inclusion complexes of spironolactone with cyclodextrins. Concomitant food intake has also been shown to enhance the bioavailability, by increasing the absorption and decreasing the first-pass effect of spironolactone.

Aged↗

PubMed2006

Taking advantage of viral immune evasion: virus-derived proteins represent novel biopharmaceuticals.

In healthy individuals, natural and adaptive immune responses are able to control virus entry into the host. In particular, CD8(+)-mediated cytotoxicity, sustained by the intervention of CD4+ cells, represents the major key event leading to virus eradication. On the other hand, viruses are able to evade from host immune response via several mechanisms, and special emphasis will be placed on hepatitis C virus and chronic Epstein-Barr infections also in view of personal data. Virokines, viroreceptors, and serpins greatly contribute to viral immune escape, and, among virokines, interleukin (IL)-10 has been object of intensive studies. Finally, all these products have been used as biopharmaceuticals, and, for instance, viral IL-10, chemokine-binding proteins, and serpins exhibit in animal models immunosuppressive, anti-inflammatory, and antiatherogenic activities. As far as their use in human trials is concernded, many cautions are required in order to avoid deleterious side effects and, in particular, the purity of the product, its route and frequency of administration, as well as the immune status of the patient should be taken into serious account.

Antiviral Agents↗

PubMed2005

Stability assessment of pharmaceuticals and biopharmaceuticals by isothermal calorimetry.

The assessment of stability (of actives, excipients and/or formulated products) is an important, and often time-consuming, part of pharmaceutical product development. Conventionally, HPLC is used to quantify the concentrations of a parent compound and any degradation products as a function of storage time. HPLC, however, is relatively insensitive to small changes in concentration and it is often the case that stability assays are conducted under stress conditions, in order to accelerate any degradation processes. The Arrhenius relationship is then employed to give an initial prediction of stability under storage conditions while long-term studies, under storage conditions, are conducted to confirm these predictions. The properties of isothermal calorimetry, such as its intrinsic sensitivity to small changes in heat and invariance to the physical form of a sample, make it ideally suited for stability assessment because it obviates the need for an Arrhenius analysis. In addition, the ability to conduct titration or gas perfusion experiments vastly increases its range of applications. Recent advances in instrumental design and data analysis have made it easier to analyse data quantitatively for complex systems. It is the purpose of this review to highlight some of these developments, discuss them in the context of pharmaceutical and biopharmaceutical examples and explore some of the future challenges and applications of the technique.

Biological Products↗

PubMed1999

Why do we still use serum in the production of biopharmaceuticals?

Eukaryotic cells, in general, require serum for growth in vitro. Serum is a complex mixture of a large number of constituents, so the addition of serum introduces an ambiguous factor into cell cultivation. However, many commercially available sera are of a high uniform quality. Of these, foetal bovine serum is the most frequently used and is capable of supporting the growth of a wide variety of eukaryotic cells. However, with the identification of essential growth factors and nutrients required by different cells, several very effective serum-free media have been formulated. The use of these serum-free media is limited to a very narrow range of cells. Regulatory constraints generally make it impractical and uneconomic to alter existing biopharmaceutical production processes in which serum is used as a raw material.

Animals↗

PubMed1999

A universal virus inactivant for decontaminating blood and biopharmaceutical products.

Removal of virus infectivity from blood and biopharmaceutical products prepared from blood is an issue of considerable importance. Irrespective of the methods that are chosen it is vital that the biological activity of the product is not impaired. For blood and unfractionated plasma or serum, the problem is even more challenging. Selective inactivation of the genome is the key step in the preparation of killed virus vaccines. Imines have been used for more than 30 years for the preparation of inactivated foot-and-mouth disease virus vaccines without any evidence of survival of virus infectivity. Moreover, the immunogenicity of the virus is unimpaired. Viruses belonging to all the recognised families can be inactivated by imines. The biological properties of several proteins, including the cell growth-promoting factors in calf serum, are not impaired using conditions which ensure the inactivation of > 10(15) infectious units of poliovirus and foot-and-mouth disease virus (FMDV). Moreover, both viruses can be inactivated by imines at 4 degrees C, thus providing a method for removing infectivity from protein preparations which are unstable at higher temperatures. The mechanism by which FMDV is inactivated has been studied. We found that the RNA extracted from the virus after inactivation at 4 degrees C was not degraded and contained no hidden breaks but nevertheless was non-infectious. However, it could be amplified by PCR using primers corresponding to the gene coding for a portion of the viral RNA polymerase, but not from that coding for VP1, one of the structural proteins, showing that alteration of a base or bases had occurred in that region.

Animals↗

PubMed2000

[Biopharmaceutics of local anesthetic-cyclodextrin complexes following loco-regional administration].

In the research of new dosage forms improving the therapeutic index of local anesthetics, we studied cyclodextrins, cyclic oligosaccharides forming soluble inclusion complexes with various lipophilic drugs. Complexes between bupivacaine and hydroxypropyl-B-cyclodextrin, bupivacaine and sulfobutyl ether-7-B-cyclodextrin were studied in vivo, using an epidural and a perineural (sciatic) model, respectively. Biopharmaceutics and pharmacodynamics of bupivacaine were evaluated in the rabbit. In both models, only systemic absorption rate of bupivacaine was decreased upon complexation, not the quantity absorbed. Complexation with cyclodextrins could be a promising drug delivery system to improve the therapeutic index of local anesthetics.

Anesthetics, Local↗

PubMed2003

NicVAX (Nabi Biopharmaceuticals).

Nabi Biopharmaceuticals is developing NicVAX, a proprietary vaccine designed as a potential therapeutic to prevent and treat nicotine addiction.

Clinical Trials, Phase I as Topic↗

PubMed2005

Validation of peptide mapping with electrospray mass spectrometry for recombinant proteins of biopharmaceutical interest and its applications as an identity test and a characterization tool.

In this paper, the steps required to validate a liquid chromatography peptide mapping method with mass spectrometric detection (LC-MS) for use as an identity test and characterization tool are presented. All aspects of peptide mapping are evaluated and optimized, including protein sample preparation (protein reduction, alkylation and enzymatic digestion), high performance liquid chromatography (HPLC) separation of the resulting peptides, and the use of a mass spectrometric detection. In addition, the validation of a single quadruple MS detector is described and the implementation of on-line electrospray ionization MS (ESI-MS) as an adjunct detector to support the investigation of peak differences is presented. Applications of peptide mapping with tandem MS using an electrospray ion-trap instrument throughout the biopharmaceutical product development cycle are discussed, including assessing protein product heterogeneity derived from post-translational modifications (e.g. multiple N- or C-termini, deamidation, oxidation and glycosylation) and protein degradation.

Peptide Mapping↗

PubMed2006

[The importance of micronization in the design of dosage forms I. Theoretical and biopharmaceutical aspects].

The role of micronization is growing considering the optimization of the physicochemical characteristics of drug, dissolution enhancement and ensuring appropiate bioavailability. The importance of micronization can be understood on the basis of Noyes-Whitney equation, where the particle characteristics influence the active surface contacting with the dissolution medium, theoretically the solubility, and the boundary layer around the particle under certain hidrodynamic conditions. To adjudge the possibilities and limits of micronization concerning the dosage form design and preparations based on innovative pharmaceutical technology, it is necessary to take the detailed theoretical, physiological and biopharmaceutical aspects into consideration.

Biological Availability↗

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↗

PubMed1995

Biopharmaceutic characteristics of a new extended-release theophylline formulation (Uni-Dur).

BACKGROUND: There is a close relationship between improvement in airway function and the plasma concentration of theophylline, as well as between rapidly rising plasma theophylline concentrations and increased frequency of undesired effects. Development of pharmaceutical formulations and prescribed dosage intervals for theophylline dosage forms should therefore be directed toward providing the most stable plasma concentrations attainable. OBJECTIVE: To characterize the steady-state biopharmaceutic profile of Uni-Dur following once-daily or twice-daily administration. METHODS: Twenty-four adult male volunteers with average theophylline clearance (3.0 and 5.5 L.h-1) received three treatments on separate occasions: Uni-Dur 800 mg once-daily, Uni-Dur 400 mg twice-daily, and Uniphyl 800 mg once-daily. Treatments were taken after a meal for five days with at least 1 week washout between treatment periods. Trough blood samples were collected prior to the AM dose on days 3, 4, and 5, and at specified intervals up to 48 hours after the AM dose on day 5 for subsequent determination of theophylline concentrations in plasma. RESULTS: The area under the plasma concentration-time curve (AUC; microgram.mL-1.h) for theophylline over 24 hours on day 5 was 187 for Uni-Dur 800 mg once-daily, 187 for Uni-Dur 400 mg twice-daily, and 172 for Uniphyl 800 mg once-daily; the peak plasma concentrations were 10.4, 9.4, and 11.0 micrograms.mL-1 and the trough concentrations were 5.5, 7.2, and 3.5 micrograms.mL-1, respectively; fluctuation index (peak minus trough divided by trough) was 78%, 16%, and 231%, respectively. No further accumulation of theophylline occurred after day 3. No serious nor severe adverse events were reported during any treatment. CONCLUSIONS: Uni-Dur is an extended-release formulation that provides stable plasma concentrations of theophylline over a 24-hour period with less fluctuation than observed with a once-daily reference formulation. In subjects with normal theophylline clearance, Uni-Dur administered twice-daily provided remarkably stable theophylline plasma concentrations over a 24-hour period. Absorption of theophylline from Uni-Dur was not affected by food, and no evidence of dose-dumping was observed. Uni-Dur should provide efficacious theophylline therapy with minimal adverse events in patients with symptoms of asthma and reversible bronchospasm associated with chronic bronchitis and emphysema.

Adult↗

PubMed1995

In vitro biopharmaceutical investigation of antacid activity in standard dissolution test apparatus.

The pH stat titration and the Rossett-Rice test used especially for the reaction kinetical and in vitro biopharmaceutical investigation of antacids were standardized applying the U.S.P. Dissolution Test Apparatus with paddle stirring element. The developed "artificial stomach" is suitable to simulate also the gastric emptying. The in vitro model may give a new alternative for the in vitro evaluation of antacid effectiveness, because this standardized method may perfectly eliminate the deficiencies of the earlier test prescriptions.

Aluminum Hydroxide↗

PubMedDate not supplied

Role of quality control in validation of biopharmaceutical processes: case example of clean-in-place (CIP) procedure for a bioreactor.

If ever clear instruction and close teamwork is needed, it is in the validation of manufacturing processes. All members of the Validation Team need to understand how the Quality Control testing fits into the overall validation work plan. This affords the team members the opportunity to understand how data will be used and avoids a situation where the test results either invalidate or inadequately support the validation plan. A case example is presented for an approach used to validate Clean-in-Place (CIP) procedures for 1600 L bioreactors which are operated on a campaign basis for multi-biopharmaceutical synthesis.

Chromatography, High Pressure Liquid↗

PubMed1996

Transmissible encephalopathies and biopharmaceutical production.

The use of post-mortem tissues as sources for the production of biologicals, vaccines and feedstuffs has led to the transmission or generation of transmissible encephalopathies in some recipients. For example, the use of pituitary-derived human growth hormone and gonadotropins has resulted in the transmission of Creutzfeldt-Jakob disease to other humans [1], the use of formalin-inactivated sheep brain as a source for louping ill vaccine led to the transmission of scrapie to over 1,000 sheep from one vaccine lot [2], and the use of rendered products from ruminant carcasses in the domestic animal food chain led to the emergence and epizootic of bovine spongifrom encephalopathy in the United Kingdom [3]. Infection with transmissible encephalopathies by iatrogenic or other mechanisms is difficult to predict or control. The characteristics of these pathogens do not permit easy detection, clearance, or inactivation in routine biopharmaceutical production environments.

Animals↗

PubMed1998

Appropriate mammalian expression systems for biopharmaceuticals.

Process development for biopharmaceuticals is dictated by product quality, drug safety and economy of the manufacturing process. Not surprisingly, these factors also play a key role in the evaluation of mammalian cell expression systems to be used in the production of pharmacologically active glycoproteins. To date, the most prominent candidates for efficient expression of glycoproteins are mammalian cell lines such as mouse fibroblast cells (C 127-BPV), Chinese hamster ovary cells (CHO-DHFR, CHO-NEOSPLA, CHO-GS), mouse myeloma cells (NSO-GS) as well as transgenic animals carrying c-DNA or genomic DNA which codes for the protein of interest. The expression titer in the case of glycoproteins is mainly determined by the promoter construct, the site of integration into the chromosome, the copy number and the type of protein in question. Based on expression titer, CHO-NEOSPLA and NSO-GS expression systems are most effective in the production of monoclonal antibodies and, to a lesser extent, of recombinant DNA derived proteins. However, based on overall product yield, expression of recombinant DNA derived proteins in transgenic animals is by far the most promising system. Therefore, for proteins required in large quantities, transgenic expression systems offer an attractive choice. However, cost of goods for products for which the dosage or the overall annual quantities are low, is dominated by downstream processing, filling, lyophilization and packaging and not by the fermentation process. Such proteins are preferentially produced by classical mammalian cell culture systems. Concerns which have to be addressed with respect to drug safety in the transgenic animal approach are the size of the herd, genetic stability from animal to animal, variation in productivity and in impurity profiles during lactation periods, microbial, viral, mycoplasma and prion contaminants, the dependence on health status and the life span of the animal. In a number of cases glycosylation of the protein is relevant for the prevention of immunogenicity of the protein, the pharmacological activity, the pharmacokinetic profile, solubility and stability against proteolysis. The glycosylation pattern, depending on protein structure, is influenced by the enzymatic system of the host cell as well as by fermentation conditions. Therefore, selection of host cells and culture conditions must take into account the requirement for a specific and stable glycosylation pattern. For the assessment of glycovariants, a number of protein analytical methods such as peptide mapping, isoelectric focusing, oligosaccharide mapping, MALDI-TOF (matrix assisted laser desorption mass spectrometry-time of flight), capillary electrophoresis and specific potency assays are available. In our experiments, glycosylation of proteins expressed in CHO cells was demonstrated to be very stable. Only extreme process times, cultivation methods and ammonium ion concentrations had an influence on the glycosylation profile. Among the three products investigated--tissue plasminogen activator (t-PA), interferon omega and soluble intercellular adhesion molecule (s-ICAM)--t-PA expressed the most stable glycosylation pattern. Only at extreme ammonium concentrations an increase of mannose-5 structures was observed, whereas biantennary complex structures were reduced. On the other hand, interferon omega and s-ICAM showed greater susceptibility to increased ammonium concentrations and to adherent cultivation. Such conditions induced quantitative changes to the glycosylation pattern favoring the appearance of higher branched structures. Short cultivation times resulted in more heterogenous oligosaccharide structures. Since the glycosylation of the three proteins is different in the same host cell, the amino acid sequence of the protein apparently influences the glycosylation pattern and its sensitivity to culture conditions. In NSO-mouse myeloma cells, production of s-ICAM is two times as high as in CHO cells

Animals↗