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At least 847 records · Page 47Linked to original sources
PubMed2002

Release of ketoprofen enantiomers from HPMC K100M matrices--diffusion studies.

Sustained release formulations of ketoprofen elaborated with HPMC K100M were studied to test the hypothesis that chiral excipients can stereoselectively affect the release of the racemic drug. The differences observed in the percentage released between enantiomers show the existence of a chiral interaction between ketoprofen and HPMC K100M. HPMC interacts preferably with the S-enantiomer, although the enantioselectivity observed was not relevant from biopharmaceutical and clinical points of view. Diffusion studies were carried out in membrane diffusion cells to simplify the excipient-drug system and hence to analyze only the influence of diffusion process on the stereoselectivity. The results obtained show that the absence of the erosion process strengthens the enantiomeric differences observed in the drug release from tablets. Another objective of this work was to study the influence of formulation pH on the 'in vitro' release profile of ketoprofen. The amount and the release mechanism of ketoprofen from formulations elaborated are conditioned mainly by the pH of the matrix.

Algorithms↗
PubMed2000

Rapid assessment of drug metabolism in the drug discovery process.

For a few years, in vitro models have been used as part of high-throughput screening (HTS) programs to characterize metabolic stability, drug permeability and drug solubility. This has allowed the rapid selection of lead candidates based not only on pharmacological endpoints but also on biopharmaceutical specifications. What has now become clear is that the huge amount of data produced to sort series of compounds has a limited predictive value when used to predict human pharmacokinetic parameters. More complex in vitro tests together with some simple in vivo tests used as validation steps have been developed in order to provide absolute data that may be used as a complement to lead selection providing reliable predictions not only of human pharmacokinetics but also of potential drug-drug interactions. These models may be used as part of selective drug screening (SDS) programs. Further advances in analytical and in vitro techniques will see some of these models shifting from SDS to HTS programs putting the emphasis on the use of expert systems and physiologically based pharmacokinetic models (PBPK) to provide meaningful endpoint data.

Animals↗
PubMed2005

Assessment of the feasibility of oral controlled release in an exploratory development setting.

Controlled release (CR) formulations have generally been considered as follow-ons to conventional immediate release formulations to manage the life cycle of a product. Although significant opportunities exist to use CR as an enabling technology for certain exploratory drug candidates, they have not been fully exploited. However, progress made in assessing CR feasibility based on the physicochemical and biopharmaceutical properties of the drug, together with advances made in understanding the various CR technologies and developing formulations in a fast and efficient manner, have increasingly made it possible to consider CR in an exploratory development setting.

Administration, Oral↗
PubMedDate not supplied

Antibodies and genetically engineered related molecules: production and purification.

Antibodies and antibody derivatives constitute 20 % of biopharmaceutical products currently in development, and despite early failures of murine products, chimeric and humanized monoclonal antibodies are now viable therapeutics. A number of genetically engineered antibody constructions have emerged, including molecular hybrids or chimeras that can deliver a powerful toxin to a target such as a tumor cell. However, the general use in clinical practice of antibody therapeutics is dependent not only on the availability of products with required efficacy but also on the costs of therapy. As a rule, a significant percentage (50-80%) of the total manufacturing cost of a therapeutic antibody is incurred during downstream processing. The critical challenges posed by the production of novel antibody therapeutics include improving process economics and efficiency, to reduce costs, and fulfilling increasingly demanding quality criteria for Food and Drug Administration (FDA) approval. It is anticipated that novel affinity-based separations will emerge from the development of synthetic ligands tailored to specific biotechnological needs. These synthetic affinity ligands include peptides obtained by synthesis and screening of peptide combinatorial libraries and artificial non-peptidic ligands generated by a de novo process design and synthesis. The exceptional stability, improved selectivity, and low cost of these ligands can lead to more efficient, less expensive, and safer procedures for antibody purification at manufacturing scales. This review aims to highlight the current trends in the design and construction of genetically engineered antibodies and related molecules, the recombinant systems used for their production, and the development of novel affinity-based strategies for antibody recovery and purification.

Animals↗
PubMedDate not supplied

Stable, long-term bacterial production of soluble, dimeric, disulfide-bonded protein pharmaceuticals without antibiotic selection.

Numerous biopharmaceuticals and other recombinant biotechnology products are made in prokaryotic hosts. However, bacterial production of native, biologically active eukaryotic proteins is rarely possible for disulfide-bonded and/or multisubunit proteins. We previously described the production of soluble, native disulfide-bonded dimeric proteins in the Escherichia coli cytoplasm (Miele et al., 1990; Mantile et al., 1993). Native, biologically active proteins with up to six disulfide bonds have been produced with our expression system (Garces et al., 1997). However, plasmid instability during induction limited its usefulness. We now report the stable, high-level expression of soluble, disulfide-bonded human uteroglobin without antibiotic selection. We designed a new vector containing a multifunctional stabilization region that confers complete plasmid stability and increased protein yields without copy number increases. Recombinant expression remains fully inducible after long-term continuous culture in nonselective liquid medium (at least 260 generations). This system may significantly expand the applications of bacterial expression to recombinant production of soluble, bioactive proteins for biochemical studies and biopharmaceutical/industrial purposes. As a result of the very broad activity spectrum of the stabilization region we selected, its use could be extended to bacterial hosts other than enterobacteria.

Anti-Bacterial Agents↗
PubMed2001

An extended point-area deconvolution approach for assessing drug input rates.

PURPOSE: To describe an extended point-area deconvolution approach for evaluating drug input rates based on the application of piecewise cubic polynomial functions. METHODS: Both the nonimpulse response data and the impulse reference data were independently represented by the piecewise cubic polynomials to obtain interpolations, numerical integration, and reduced step size for the staircase input rates. A moving average algorithm was employed to compute the input rate estimates. The method was illustrated using data from preclinical and human studies. Simulations were used to examine the effects of data noise. RESULTS: In all cases examined, the piecewise cubic interpolation functions combined with the moving average algorithm yielded estimates that were reasonable and acceptable. Compared to the standard point-area approach based on the trapezoidal rule, the present method resulted in estimates that were closer to the expected values. CONCLUSIONS: The point-area deconvolution analysis is one of the preferred approaches in assessing pharmacokinetic and biopharmaceutic data when it is undesirable to assume the functional forms of the input processes. The present method provides improved performance and greater flexibility of this approach.

Absorption↗
PubMed1991

One-sided and two-sided tests and p values.

Several considerations for the use of one-sided and two-sided tests are discussed: the inferential posture of the design of a study, the level of stringency for supporting a conclusion, the style for reporting p values, the perspective for interpreting results in the opposite direction to the one initially expected, and the role of confidence intervals. The suggestions for addressing these issues for confirmatory biopharmaceutical studies with one-sided objectives are as follows: 1. Clear documentation of the one-sided inferential posture of a study in its protocol. 2. Sufficient sample size for at least moderate power for evaluation with two-sided stringency. 3. Use of one-sided p values to express direction of results together with distinct flags for those which are suitably extreme to support inferences for the target direction or to merit description for the opposite direction. 4. Interpretation of opposite direction results in a post hoc, exploratory, descriptive way rather than inferentially. 5. Provision of one-sided confidence intervals to clarify the nature of one-sided inferences. Alternatively, for academic studies where publication with an inferential posture is of interest for either potential direction of findings, two-sided methods are typically useful. An underlying reason for this is the adjustment provided by two-sided methods for the multiplicity in the two complementary one-sided counterparts that they encompass.

Biopharmaceutics↗
PubMed2003

Issues of simultaneous tests for noninferiority and superiority.

In simultaneous testing for noninferiority and superiority, Morikawa and Yoshida (Morikawa, T., Yoshida, M. (1995). A useful testing strategy in phase III trails: Combined test of superiority and test of equivalence. J. Biopharmaceutical Statistics 5:297-306) argue that multiplicity adjustment is not necessary by using the closed testing (CT) principle. In fact, using the same argument, no multiplicity adjustment is necessary in simultaneous testing of any number of nested null hypotheses. However, simultaneous testing of many nested null hypotheses is problematic in a confirmatory trial because such simultaneous testing is similar to post-hoc specification of the null hypothesis. Thus, simultaneous testing for noninferiority and superiority may be viewed as an initial step towards exploratory analysis and may be best used cautiously in confirmatory evaluation.

Biopharmaceutics↗
PubMed1999

Interfacial adsorption of polymers and surfactants: implications for the properties of disperse systems of pharmaceutical interest.

This review considers basic aspects of the interfacial adsorption of polymers and surfactants, with particular reference to the relevance of these processes for the formulation of pharmaceutical disperse systems. First, we discuss different approaches to the interpretation of adsorption isotherms, paying particular attention to systems containing more than one adsorbate. Second, we consider the implications of adsorption for the properties of suspensions, emulsions, and colloidal systems, particularly as regards the use of polymers and surfactants for stabilizing disperse systems, for controlling flocculation, and for modifying the biopharmaceutical behavior of colloidal drug carriers. Finally, we present a number of representative examples of the importance of adsorption of macromolecules in pharmaceutical systems.

Absorption↗
PubMed2003

Double liposomes: hypoglycemic effects of liposomal insulin on normal rats.

The biopharmaceutical characteristics of double liposomes (DLs) containing insulin were examined, and the usefulness of DLs in combination with aprotinin is discussed. Encapsulation of insulin was influenced by lipid composition, and the highest efficiency was observed with positively charged liposomes. Insulin encapsulated in liposomes, especially in DLs, was protected from enzymatic proteolysis. A portion of insulin molecules was adsorbed on the surface of the membrane when liposomes were prepared using a lipid with a positive charge and was degraded by enzymes. Remarkable hypoglycemic effects were observed after intragastric administration of DLs containing insulin at a dose of 20 IU/kg to normal male Wistar rats. The highest mean relative efficacy to administration was obtained with insulin-loading DLs containing aprotinin as a protease inhibitor. These results suggest that DLs are applicable as an oral dosage form for peptide drugs such as insulin etc., especially in combination with protease inhibitors.

Animals↗
PubMedDate not supplied

Pharmacological update on new infusion drugs.

Ongoing clinical research and development of new infusion medications can challenge the infusion specialist's knowledge base in daily practice. This article reviews new and soon-to-be marketed infusion drugs, with an emphasis on biopharmaceuticals. The author also discusses mechanisms of action, drug interactions, side effects, and infusion specialist interventions for safe administration of these medications.

Anti-Bacterial Agents↗
PubMed1975

Cornea preparation for in vitro bio-pharmaceutical evaluation of ophthalmic dosage forms.

A system has been developed for a specific biopharmaceutical purpose: testing for ophthalmic preparations, the influence of formulation on drug transport through the cornea. The apparatus is a lucite cell, divided in two compartments by a clamped rabbit cornea. Physiological conditions are ensured by a supply of oxygenated perfusion medium. They are monitored by electrical conductivity and corneal thickness measurements. Reliability of the system was tested in a set of experiments.

Animals↗
PubMed2005

There are no useful CYP3A probes that quantitatively predict the in vivo kinetics of other CYP3A substrates and no expectation that one will be found.

The search for a substrate that may serve as a probe to quantitatively predict the in vivo kinetics of cytochrome P450 3A (CYP3A) drugs has been of particular interest because more than half of all human drugs appear to be substrates for this enzyme. Even three closely related 1,4-benzodiazepines-alprazolam, midazolam, and triazolam-are inadequate probes to predict the pharmacokinetics of each other in an individual. If these drugs--all metabolized through the same CYP3A pathways in humans, all FDA Biopharmaceutical Classification System Class 1 compounds exhibiting high solubility and high permeability and thus unaffected by transporter differences--cannot quantitatively predict the pharmacokinetics of their closely related congeners, there is little hope that any quantitative CYP3A probe will ever be found.

Alprazolam↗
PubMedDate not supplied

The pathologist and toxicologist in pharmaceutical product discovery.

Significant change is occurring in the drug discovery paradigm; many companies are utilizing dedicated groups from the toxicology/ pathology disciplines to support early stage activities. The goal is to improve the efficiency of the discovery process for selecting a successful clinical candidate. Toxicity can be predicted by leveraging molecular techniques via rapid high-throughput, low-resource in vitro and in vivo test systems. Several important activities help create a platform to support rapid development of a new molecular entity. The proceedings of this symposium provide excellent examples of these applied concepts in pharmaceutical research and development. Leading biopharmaceutical companies recognize that a competitive advantage can be maintained via rapid characterization of animal models, the cellular identification of therapeutic targets, and improved sensitivity of efficacy assessment. The participation of the molecular pathologist in this quest is evolving rapidly, as evidenced by the growing number of pathologists that interact with drug discovery organizations.

Animals↗
PubMed2005

Determination of intraluminal theophylline concentrations after oral intake of an immediate- and a slow-release dosage form.

The purpose of this study was to evaluate a protocol which enables determining luminal drug concentrations after oral drug administration in man. Human intestinal fluids were aspirated from two sampling sites (duodenum and jejunum) at different time points after oral intake of theophylline; an immediate- and a slow-release dosage form were used to demonstrate the feasibility of discriminating between different formulations. Osmolarity and pH of the aspirates were measured and theophylline concentrations were determined by HPLC-UV. After intake of the immediaterelease formulation of theophylline, duodenal maximum concentrations up to 3 mM were reached within 30 min. Theophylline appeared to be almost completely absorbed before it reached the second sampling site in the jejunum, as observed jejunal concentrations were lower than 10% of the maximal duodenal concentrations. These results are in agreement with fast dissolution and fast absorption through the intestinal mucosa, which could be expected as theophylline belongs to class I of the Biopharmaceutical Classification System. In contrast to the immediate-release formulation, administering the slow-release dosage form resulted in a gradual appearance of theophylline, reaching maximal intestinal concentrations below 300 muM. The proposed methodology can be used to assess luminal drug concentrations and to monitor the time- and site-dependent composition of intestinal fluids after intake of an oral dosage form. This approach may contribute to a better understanding of the behaviour of oral drug formulations in the gastrointestinal tract and may be exploited to further unravel the complexity of the gastrointestinal absorption process. In addition, knowledge of luminal drug concentrations may assist in the selection of drug concentrations applied in in-vitro permeability assays.

Administration, Oral↗
PubMedDate not supplied

Biotechnology and Medicare's new technology policy: lessons from three case studies.

Biotechnology has figured prominently in recent Medicare coverage and payment policies. Biotech treatments push policy boundaries for several reasons: They attract strong patient demand; they often treat rare or life-threatening diseases; they may have uncertain evidence of health benefits; and they are often costly. This paper considers case studies of Medicare coverage for off-label uses of biotech cancer drugs and payments for anemia biopharmaceuticals. The cases suggest Medicare's ongoing challenge to balance access considerations, the role and strength of evidence, and cost consequences of new treatments.

Anemia↗
PubMed2003

A modified two-portion absorption model to describe double-peak absorption profiles of ranitidine.

BACKGROUND: The pharmacokinetics of oral drugs exhibiting double peaks cannot be adequately described by using conventional compartmental models. OBJECTIVE: To propose and evaluate a modified two-portion absorption model based on physiological and biopharmaceutical considerations to describe the double-peak concentration-time curve of ranitidine. MODEL DESIGN: The proposed model assumes that oral ranitidine is absorbed sequentially in two portions due to delayed gastric emptying, and thus includes a gut compartment in addition to the central and peripheral compartments. METHODS: Validation of the model was performed with respect to structural identifiability, parameter estimability and model applicability. Using initial estimates of parameters obtained from previous intravenous data, the model was used to fit oral ranitidine data from six subjects who manifested clear double-peak concentration-time profiles as well as from six subjects who showed irregular but apparent single-peak concentration-time curves. RESULTS: Based on goodness-of-fit criteria, the model fitted well for both double-peak and single-peak concentration-time curves of ranitidine (for the two groups: weighted residual sum of squares, 0.044 +/- 0.027 and 0.054 +/- 0.036; correlation between observed and model predicted concentrations, 0.995 +/- 0.003 and 0.995 +/- 0.005). Simulation studies with concentrations generated with 10% normally distributed random error showed that all model fitted parameters had good accuracy and reasonable precision. The mean percentage bias ranged from -7.0 to 28.6%, and the coefficient of variance was within 30% for the majority of parameters compared with the theoretical values. CONCLUSION: The modified two-portion absorption model may afford a useful approach to characterise the absorption phase and estimate pharmacokinetic parameters for drugs with two absorption peaks.

Adult↗