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At least 829 records · Page 46Linked to original sources
PubMed1996

Adventitious agents from animal-derived raw materials--a method of risk assessment.

The use of animal-derived raw materials in biopharmaceutical manufacture has a long history. On a risk/benefit basis the use of these raw materials has certainly been beneficial. With proper precautions animals will continue to be the source of raw material for many years to come. As scientific sophistication increases, continuing examination of animal-derived raw material sourcing is important. Even as biopharmaceutical production has made significant progress so has the quality and safety of available animal-derived supplements. It is now possible to perform a reasonable assessment of risk as it relates to adventitious agents. An easy-to-use, preliminary risk-assessment exercise will be discussed. It will allow users of animal-derived raw materials to make more informed decisions regarding the need and type of pre-use processing before the final risk/benefit analysis. Areas to be assessed include geographical origin, age and species of animal, method of harvesting, and anatomical origin of the material.

Abattoirs↗
PubMed2005

Biowaiver monographs for immediate release solid oral dosage forms: ranitidine hydrochloride.

Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate release (IR) solid oral dosage forms containing ranitidine hydrochloride are reviewed. According to the current Biopharmaceutics Classification System (BCS), ranitidine hydrochloride should be assigned to Class III. However, based on its therapeutic and therapeutic index, pharmacokinetic properties and data related to the possibility of excipient interactions, a biowaiver can be recommended for IR solid oral dosage forms that are rapidly dissolving and contain only those excipients as reported in this study.

Administration, Oral↗
PubMed2005

Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen.

Literature data are reviewed on the properties of ibuprofen related to the biopharmaceutics classification system (BCS). Ibuprofen was assessed to be a BCS class II drug. Differences in composition and/or manufacturing procedures were reported to have an effect on the rate, but not the extent of absorption; such differences are likely to be detectable by comparative in vitro dissolution tests. Also in view of its therapeutic use, its wide therapeutic index and uncomplicated pharmacokinetic properties, a biowaiver for immediate release (IR) ibuprofen solid oral drug products is scientifically justified, provided that the test product contains only those excipients reported in this paper in their usual amounts, the dosage form is rapidly dissolving (85% in 30 min or less) in buffer pH 6.8 and the test product also exhibits similar dissolution profiles to the reference product in buffer pH 1.2, 4.5, and 6.8.

Administration, Oral↗
PubMed2005

Cationic analog of deoxycholate as an oral delivery carrier for ceftriaxone.

A great number of currently available drugs and those being developed that fall under the class III of the BCS (biopharmaceutical classification system) possess high therapeutic potential but cannot be delivered by peroral absorption. In this study, we synthesized a cationic analog of deoxycholic acid and evaluated its efficacy as a potential oral drug carrier for anionic BCS class III drugs using ceftriaxone as a model drug. Cationic deoxycholylethylamine (DCEA), one of cationic analogs of deoxycholic acid, was synthesized and made into physical complexes at varied molar ratios with an anionic ceftriaxone. These drug complexes were formulated with propylene glycol and their oral bioavailabilities were evaluated. The results of the partition coefficient study revealed a highly water soluble ceftriaxone that became more hydrophobic as the molar ratio of the carrier in the complex increased. When the ceftriaxone/DCEA formulation was administered into a nonclosed segment of duodenum of rats, C(max) (the maximum drug concentration in plasma) and AUC (area under the curve) were significantly increased and its bioavailability was increased up to 70%. Therefore, the new cationic carriers proposed in this study could improve the absorption of BCS class III drugs in the intestine with maintaining their full biological activity.

Animals↗
PubMed2007

Conference report: Bio-International 2005.

This is a summary report of the International Pharmaceutical Federation/Board of Pharmaceutical Sciences (FIP/BPS) international conference, Bio-International 2005, which was held October 24-26, 2005 at the Royal Pharmaceutical Society, in London, UK. Bioequivalence (BE) issues related to multisource locally delivered topical dosage forms, oral inhalation drug products, highly variable drug products (HVDP), and endogenously occurring drugs were discussed. The conference also focused on alternate approaches to assess BE for some of these drug products. Pharmacokinetic (PK) approaches like, dermatopharmacokinetics (DPK) for dermatological topical dosage forms, scaled average BE (s-ABE) where within-subject variability is considered for estimation of 90% confidence intervals to document BE for highly variable drugs (HVD) were recommended. In addition, issues and difficulties related to the BE assessment of oral inhalation products, role, and appropriateness of metabolites in BE assessment, importance of base line correction in BE assessment of endogenously occurring drugs, and waiver of BE study requirements for certain drugs based on a Biopharmaceutics Classification System (BCS), were also discussed.

Administration, Inhalation↗
PubMed2006

Types of filtration.

There are a multitude of filter designs and mechanisms utilized within the biopharmaceutical industry. Prefilters are commonly pleated or wound filter fleeces manufactured from melt-blown random fiber matrices. These filters are used to remove a high contaminant content within the fluid. Prefilters have a large band of retention ratings and can be optimized to all necessary applications. The most common application for prefilters is to protect membrane filters, which are tighter and more selective than prefilters. Membrane filters are used to polish or sterilize fluids. These filters need to be integrity testable to assess whether or not they meet the performance criteria. Cross-flow filtration can be utilized with micro- or ultrafiltration membranes. The fluid sweeps over the membrane layer and therefore keeps it unblocked. This mode of filtration also allows diafiltration or concentration of fluid streams. Nanofilters are commonly used as viral removal filters. The most common retention rating of these filters is 20 or 50 nm.

Biopharmaceutics↗
PubMedDate not supplied

In vitro/in vivo correlations: scientific implications and standardisation.

In vitro/in vivo correlations and the parameters that should be correlated have now been well defined in the USP and FDA working group proposals. Among the three levels of correlation defined, Level A is the most interesting one. In this paper, the Level A correlation is studied from a mathematical and a biopharmaceutical point of view. The conditions that must be met before attempting to establish correlations and the place of in vitro/in vivo correlation in modified release drug dosage form development are discussed. To establish in vitro/in vivo correlations requires a strict development methodology in order to obtain them in the most favourable conditions. In vitro/in vivo correlations should be sought as early as possible during the dosage form development (a priori correlations). If the formulation has been undertaken first and correlations sought on the finished product from subsequent in vitro tests, the predictive power of these correlations (a posteriori correlations) is thus limited and they require additional validation.

Animals↗
PubMed2006

Oral absorption of poorly water-soluble drugs: computer simulation of fraction absorbed in humans from a miniscale dissolution test.

PURPOSE: The purpose of this study was to develop a new system for computer simulation to predict fraction absorbed (F(a)) of Biopharmaceutical Classification System (BCS) class II (low solubility-high permeability) drugs after oral administration to humans, from a miniscale dissolution test. METHODS: Human oral absorption of 12 lipophilic drugs was simulated theoretically by using the dissolution and permeation parameters of the drugs. A miniscale dissolution test and a solubility study were carried out in a conventional buffer and a biorelevant medium (pH 6.5). A dissolution parameter, which can simulate in vivo dissolution, was obtained from the in vitro dissolution curve. Human intestinal permeability was estimated assuming that the permeation was limited by diffusion through the unstirred water layer. The F(a) in humans was predicted and then compared with clinical data. RESULTS: The dissolution and solubility of most model drugs were faster and higher in a biorelevant medium than in a conventional buffer. The simulated absorption was limited by the drug dissolution rate and/or solubility. Predicted F(a) was significantly correlated with clinical data (correlation coefficient r2 = 0.82, p < 0.001) when the dissolution profiles in biorelevant medium were used for the simulation. CONCLUSIONS: This new system quantitatively simulated human absorption and would be beneficial for the prediction of human F(a) values for BCS class II drugs.

Absorption↗
PubMed2005

The protein structure of recombinant human lactoferrin produced in the milk of transgenic cows closely matches the structure of human milk-derived lactoferrin.

Human lactoferrin (hLF) is an iron-binding glycoprotein involved in the host defence against infection and excessive inflammation. As the availability of (human milk-derived) natural hLF is limited, alternative means of production of this biopharmaceutical are extensively researched. Here we report the crystal structure of recombinant hLF (rhLF) expressed in the milk of transgenic cows at a resolution of 2.4 A. To our knowledge, the first reported structure of a recombinant protein produced in milk of transgenic livestock. Even though rhLF contains oligomannose- and hybrid-type N-linked glycans next to complex-type glycans, which are the only glycans found on natural hLF, the structures are identical within the experimental error (r.m.s. deviation of only 0.28 A for the main-chain atoms). Of the differences in polymorphic amino acids between the natural and rhLF variant used, only the side-chain of Asp561 could be modeled into the rhLF electron density map. Taken together, the results confirm the structural integrity of the rhLF variant used in this study. It also confirms the validity of the transgenic cow mammary gland as a vehicle to produce recombinant human proteins.

Animals↗
PubMed1994

Updated clinical safety experience with fluvastatin.

Clinical experience with fluvastatin in > 1,800 North American patients treated for an average of 61 weeks has shown it to be safe and well tolerated. Frequencies of transaminase and creatine kinase elevations compare favorably with those observed during long-term administration of other 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Further, whereas frank rhabdomyolysis has been encountered with treatment with all other HMG-CoA reductase inhibitors, this syndrome has not been observed to date with fluvastatin in studies here or abroad; a single case of myopathy, which was probably related to physical exertion, was reported in a patient receiving fluvastatin. Although dyspepsia was observed more commonly in fluvastatin patients the incidence, along with that of other adverse events (e.g., headache), and the number of treatment discontinuations proved statistically indistinguishable from those of placebo controls. Whether the favorable safety profile of fluvastatin is related to this synthetic agent's unique biopharmaceutical profile is a matter of ongoing long-term inquiry.

Anticholesteremic Agents↗
PubMed2005

The role of formulation in insulin comparability assessments.

The concept of comparability can be applied when changes are made to manufacturing processes for biotechnology products subsequent to pivotal clinical trial studies. For many process changes, comparability can be demonstrated based entirely on relevant in vitro data provided that a detailed knowledge of the process/product exists, suitable analytical methodology is employed, and historical data are available for the assessment. Insulin provides an excellent model system to illustrate many important considerations when dealing with comparability exercises for biotechnology products. The physicochemical properties of insulin demonstrate the numerous chemical reactions and physical transformations that are exclusive to proteins. These properties are heavily influenced by formulation conditions and must be carefully evaluated when process changes are made. In addition, physical and chemical testing performed on representative formulations can provide valuable insight when assessing the comparability between pre- and post-change materials. This paper reviews our experience with manufacturing changes involving insulin emphasizing the important role of formulation in the comparability exercise for protein biopharmaceuticals.

Biopharmaceutics↗
PubMed2006

An integrated early formulation strategy--from hit evaluation to preclinical candidate profiling.

The selection of a suitable vehicle for preclinical compound profiling is a very important task during the early developmental phases to ensure the quality of candidates and the speed of compound progression. Apart from biopharmaceutical and pharmaceutical technical considerations, i.e. solubility/dissolution improvement or route of application, other aspects have to be taken into account, as well: (i) availability and quality of the compound, (ii) tolerability of the vehicle in the selected animal model, (iii) developmental possibilities, i.e. whether the formulation can be transformed into a clinical one. The approach described in this paper is based on results of team collaboration between functions involved in the conduct of animal experiments (Pharmacology, Pharmacokinetics, Toxicology, and Pharmaceutical Sciences). Very early in vivo studies should be performed with dissolved API as available information on solid-state characteristics is usually limited at this time. Later studies should be performed with developable formulations, taking into consideration pharmacological, toxicological, and pharmaceutical requirements. At this stage, delivery strategies (i.e. advanced formulations and/or alternative routes of administration) should be considered, as well. In addition, a minimum level analytical characterization of compounds and formulations used in animal studies is required to explain unexpected results.

Animals↗
PubMed2005

In situ and in vivo efficacy of peroral absorption enhancers in rats and correlation to in vitro mechanistic studies.

The present investigation attempts to increase intestinal permeability and hence absorption of biopharmaceutic classification system (BCS) Class III (cefotaxime sodium (CX)) and Class IV (cyclosporin A (CSA)) drugs by employing certain absorption enhancers. Drugs were co-perfused with sodium caprate (SC, 0.25% w/v), piperine (P, 0.004% w/v) and sodium deoxycholate (SD, 1.0% w/v) separately in rat in situ single pass intestinal perfusion model. These additives increased intestinal permeability (P(app)) and absorption rate constant (K(a)) up to two and fourfold, respectively. SC exhibited substantial absorption enhancement of both CX and CSA, while SD and P enhanced absorption of CX and CSA, respectively. Co-administration of SC significantly enhanced peroral bioavailability of CX (from 29.4 +/- 1.7 to 69.6 +/- 3.2) and CSA (from 18.4 +/- 15.6 to 49.6 +/- 25.1) in rats, while P increased bioavailability of CSA (from 18.4 +/- 15.6 to 33.1 +/- 17.7). Transmission electron microscopy of intestinal mucosa revealed that SC and SD act on lipid and protein domains of absorptive membrane. P showed no effect on intestinal P(app) and oral bioavailability of CX but has a profound effect on CSA, a known P-glycoprotein (P-gp) substrate. These results indicated that P enhances intestinal absorption of CSA by modulating P-gp mediated efflux transport. Release of lactate dehydrogenase in situ from intestinal mucosa in the presence of absorption enhancer was taken as index of its local toxicity. All the absorption enhancers showed significantly less release of LDH compared to positive control, sodium dodecyl sulfate (60% w/v). Overall, the data indicate that the features of these commonly used food ingredients or endogenous bile salts can effectively improve bioavailability of various BCS Class III and Class IV drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Absorption enhancement, mechanistic and toxicity studies of medium chain fatty acids, cyclodextrins and bile salts as peroral absorption enhancers.

The objective of the present investigation was to evaluate an oral 'drug delivery' approach, which involves co-administration of absorption enhancers (AEs). The representative low permeable hydrophilic (biopharmaceutic classification system (BCS) Class III) drugs used in the study comprised of cefotaxime sodium and ceftazidime pentahydrate, whereas low permeable lipophilic (BCS Class IV) drugs include cyclosporin A and lovastatin. AEs from three different chemical classes, namely, medium chain fatty acids (sodium caprylate and caprate), cyclodextrins (beta-cyclodextrin, hydroxypropyl beta-cyclodextrin) and bile salts (sodium cholate and deoxycholate) were evaluated for absorption enhancement efficacy, mechanism of action and toxicity using in vitro everted intestinal sac model. These AEs were found to enhance intestinal permeability of drugs from 2- to 27-fold. Light microscopy studies of intestinal sac incubated with AEs for 120 min revealed morphological changes in absorptive mucosa and rank order of toxicity were cyclodextrins>bile salts congruent with medium chain fatty acids. Fluorescence polarization studies indicated that brush bordered membrane vesicles labeled with lipophilic (DPH, 12AS) and hydrophilic dyes (ANS), when treated with AEs exhibited concentration and time dependent decrease in fluorescence polarization. Total protein released in presence of AEs was more than control but considerably less than EDTA (0.58% w/v), which is known to cause toxic release of proteins from cell. Overall, AEs were found to significantly enhance drug permeability by decreasing lipid membrane fluidity and/or interacting with hydrophilic domains of membrane, and has the potential to improve oral delivery.

Animals↗
PubMed2005

Validation of the 96 well Caco-2 cell culture model for high throughput permeability assessment of discovery compounds.

The use of Caco-2 cells for permeability screening of discovery compounds is quite well established and serves as the "method-of-choice" across the pharmaceutical industries worldwide. The typical permeability-screening model involves growing cells on a 12 well or 24 well transwell format. In this manuscript, we report the use of Caco-2 cells grown on 96 well transwell plates for screening of discovery compounds to assess their permeability characteristics. A set of standard compounds (marketed compounds) belonging to the various class of Biopharmaceutics Classification System (BCS) were used to assess the utility of the 96 well Caco-2 cells. Extensive validations were also performed with approximately 160 Bristol-Myers Squibb (BMS) discovery compounds by comparing the permeability values in the 96 well Caco-2 cells with the in-house 24 well Caco-2 cells. Functional Caco-2 cells with intact monolayers could be established in the 96 well format using optimized seeding and culturing conditions. The permeability of BCS compounds in the 96 well format was found to be comparable to the permeability in 24 well format. Similarly, there was very good correlation (R2=0.93) between the two formats for the extensive validation performed with in-house discovery compounds. The validated 96 well Caco-2 cell system presents a very attractive permeability screening tool that can perform much more efficiently than the conventional 12 well or 24 well systems while providing the same high quality permeability screening data.

Automation↗
PubMed2004

Simultaneous estimation of pharmacokinetic properties in mice of three anti-tubercular ethambutol analogs obtained from combinatorial lead optimization.

Integrating combinatorial lead optimization of [1,2]-diamine core structure based on ethambutol with high-throughput screening has led us to focus on three promising analogs (SQ37, SQ59 and SQ109) as potential anti-tubercular drug candidates from thousands of synthesized diamine analogs for further characterization of their biopharmaceutical and pharmacokinetic properties by using liquid chromatography/tandem mass spectrometry (LC/MS/MS) and cassette dosing for pharmacokinetic screening. Simultaneous separation of the three analogs was achieved on reversed phase HPLC using a gradient mobile phase composed of MeOH/CH(3)COONH(4) (5mM)/trifluoroacetic acid: 80/20/0.1 (v/v/v). After extraction with acetonitrile from biomatrices, samples were analyzed on the LC/MS/MS system in the positive mode using an electrospray ion source. The retention time for the analogs ranged from 3.70 to 4.48 min. Incubation of SQ37 with plasma at 37 degrees C for 6h resulted in its degradation in human and rat plasma (20-35%), but no significant degradation was observed in mouse and dog plasma. SQ59 was relatively stable in the plasma of the four species. SQ109 was degraded in human and dog plasma (30-40%), but stable in mouse and rat plasma during the 6h incubation. A rapid multiple pharmacokinetic screening was taken by cassette dosing of the three analogs to mice and simultaneous analysis of their plasma concentrations. The analogs showed large Vd(ss) ranging from 11,300 (SQ37), 12,800 (SQ109) to 63,900 ml/kg (SQ59). The clearance ranged from 3240 (SQ109), 3530 (SQ37) and 8043 ml/kg/h (SQ59). The elimination t(1/2) ranged from 4.4 to 21.1h dependent on the routes. The oral bioavailability was 5.1 (SQ59), 20.1 (SQ37) and 7.8% (SQ109), respectively. Both SQ37 and SQ109 possess good pharmacokinetic properties.

Animals↗
PubMed2003

Viral leads for chemokine-modulatory drugs.

The chemokine system, which controls leukocyte trafficking, provides several potentially very attractive anti-inflammatory drug targets. However, the complexity and redundancy of this system makes it very difficult to exploit through classical drug discovery. Despite this, viruses have millions of years of experience in manipulating this system. For example, virally encoded "biopharmaceuticals"--chemokines and chemokine binding proteins--demonstrate the effectiveness of blocking a carefully selected group of chemokine receptors and how the local immune response can be changed from one dominated by Th1 cells to one dominated by Th2 cells by targeting specific chemokine receptors. The crucial importance of the binding of chemokines to glycosaminoglycans to produce their effects is also highlighted by viruses that produce binding proteins to disrupt the gradient of chemokines, which guides the direction leukocyte migration.

Animals↗
PubMed2000

Statistical testing of drug accumulation in skin tissues by linear regression versus contents of stratum corneum lipids.

This investigation is a contribution to standardization in in vitro drug penetration measurements using excised human skin and to statistical treatment of the observations. The wide variations observed in measurements of drug accumulation in and drug permeation through the stratum corneum are caused not only by analytical errors but also by the variability of the horny layer lipid composition. The last-mentioned systematic influence can be compensated for by stepwise (multiple) linear regression using the contents of the main lipid classes as independent variables. In consequence, the S.E. of estimate given by the regression calculation is lower than the S.E. of the means of the observations. Significant differences in drug quantities accumulated in skin tissues (stratum corneum and dermis) are sensitively detected by Chow's F-test of structural change. Accumulation data of flufenamic acid and hydrocortisone penetrated from different bases are given as examples. The calculation mode is exemplarily explained and discussed. The results of the test for structural change, two-independent-groups t-test and paired-samples t-test are compared. The F-test of structural change proves to be a helpful statistical method suitable to the assessment of biopharmaceutical quality parameters and to measurements using biological materials.

Administration, Topical↗