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PubMed1993

Biopharmaceutics of didanosine in humans and in a model for acid-labile drugs, the pentagastrin-pretreated dog.

Didanosine is a purine nucleoside analogue approved for the treatment of human immunodeficiency virus infection. It is extremely unstable at pH values less than 3 and requires protection against gastric acid-induced hydrolysis. Beagle dogs pretreated with pentagastrin, an analogue of gastrin that reproducibly stimulates gastric acid secretion, have been used to screen different didanosine formulations. The absolute bioavailability of didanosine from a saline solution decreased from approximately 43% in untreated dogs to 8% after pretreatment with pentagastrin. Administration of buffered solution of didanosine to untreated and pretreated dogs yielded bioavailability estimates of 37 and 30%, respectively. In humans, the bioavailability from a similar buffered solution was approximately 40%. Pentagastrin-pretreated dogs were used to evaluate four new products relative to a citrate-phosphate buffer sachet, the formulation selected for large-scale clinical trials in humans. Two of these new formulations, a chewable tablet and an antacid suspension, were more bioavailable then the reference sachet. This also proved to be true in man, necessitating an adjustment in the dose of didanosine when administered as the chewable tablet. Dogs pretreated with pentagastrin accurately predicted the improved bioavailability of new didanosine formulations prior to clinical use. This animal model may be helpful in evaluating the biopharmaceutics of other acid-labile drugs.

Adult↗

PubMed1985

[Biopharmaceutics of ophthalmic drugs].

The importance of biopharmaceutics in the development of ophthalmic drugs is pointed out. Ophthalmic drugs have to be stable, sterile, well tolerated and effective. The constraints resulting from these requirements limit the number of pharmaceutical presentations. The development of pilocarpine eye drops is taken as an example to illustrate how difficult it is to satisfy Goldmann's criteria of stability, sterility, tolerance, and efficacy simultaneously. A rapid and sensitive ocular tolerance test for the selection of the most favorable formulations is proposed as a means of counteracting the present shortage of screening tests. Additionally, the physiological, physicochemical, and pharmaceutical factors are discussed which can influence the drugs' passage through the cornea and consequently increase or decrease their efficacy. Two examples, taken respectively from the aqueous solutions and lipophilic gels, demonstrate the importance of pharmaceutical and biological availability as well as the present tendency toward optimization in the development of ophthalmic preparations.

Biopharmaceutics↗

PubMed2006

In vitro display technologies reveal novel biopharmaceutics.

Display technologies are fundamental to the isolation of specific high-affinity binding proteins for diagnostic and therapeutic applications in cancer, neurodegenerative, and infectious diseases as well as autoimmune and inflammatory disorders. Applications extend into the broad field of antibody (Ab) engineering, synthetic enzymes, proteomics, and cell-free protein synthesis. Recently, in vitro display technologies have come to prominence due to the isolation of high-affinity human antibodies by phage display, the development of novel scaffolds for ribosome display, and the discovery of novel protein-protein interactions. In vitro display represents an emerging and innovative technology for the rapid isolation and evolution of high-affinity peptides and proteins. So far, only one clinical drug candidate produced by in vitro display technology has been approved by the FDA for use in humans, but several are in clinical or preclinical testing. This review highlights recent advances in various engineered biopharmaceutical products isolated by in vitro display with a focus on the commercial developments.

Biopharmaceutics↗

PubMedDate not supplied

Flow cytometry in the preclinical development of biopharmaceuticals.

Novel biomarkers are often required in the preclinical development of biopharmaceuticals in order to characterize pharmacologic and toxicologic effects and to establish pharmacodynamic and pharmacokinetic relationships. Flow cytometry is uniquely suited for measurement of these biomarkers. Large numbers of single cells in a heterogeneous population can be rapidly identified and characterized with high accuracy and reproducibility. Cells are not damaged by the detection system and can be subsequently sorted for further morphologic or functional analysis. The availability of clinical instruments and a wide range of fluorescent probes have made this technology applicable for use in toxicologic clinical pathology. Flow cytometry has played an integral role in the development of a monoclonal antibody to human CD4 (keliximab, IDEC-CE9.1, SB 210396). Lymphocyte subset analysis and assays for expression, coating, and modulation of human CD4 were used for sequential assessment of the pharmacologic activity of keliximab in transgenic mice expressing human CD4.

Animals↗

PubMed1996

The physicochemical and biopharmaceutical properties of fragmented keratin as a new drug carrier.

Two types of fragmented keratin were prepared from buffalo horn and hoof using savinase and Na2S, and their physicochemical and biopharmaceutical properties were examined in mice. The number-average molecular weight of enzymatically fragmented keratin (E-FK), chemically fragmented keratin (C-FK), and fragmented gelatin (FG) were 8000, 33,000, and 6600, respectively. The systematic acute toxicity of FKs was significantly low. Moreover, the immunogenicity of FKs was significantly lower than that of superoxide dismutase. FKs and FG were partially hydrolyzed by trypsin. FKs were digested easily by alpha-chymotrypsin, but FG underwent less hydrolysis under the same conditions. FKs were bound to plasma proteins, including albumin, and also to some proteins in liver and kidney homogenates. In plasma, E-FK was hydrolyzed slowly, but in liver and kidney homogenates it showed slightly faster hydrolysis. In contrast, FG was not hydrolyzed in any of the media used here. After intravenous administration of FKs and FG to mice, these molecules were rapidly eliminated from the plasma. E-FK and C-FK were taken up into the kidneys (CLuptake, kidney; 10,400, 11,600 microliters/h/g), and then gradually excreted in urine. FG was excreted rapidly into urine (CLurine; 6360 microliters/h). Interestingly, C-FK was also taken up into the liver (CLliver; 4820 microliters/h). These results indicated that fragmented keratins are biodegradable materials and might be used as new types of liver- and kidney-specific targeting carriers.

Amino Acids↗

PubMed2004

Classification of loratadine based on the biopharmaceutics drug classification concept and possible in vitro-in vivo correlation.

Loratadine was studied both in vitro and in vivo (in healthy humans) to classify it according to the Biopharmaceutics Classification System (BCS) in order to gain more understanding of the reasons for its highly variable nature with respect to plasma time profiles, and to determine the most appropriate dissolution test conditions for in vitro assessment of the release profile of the drug from solid dose forms. Based on the solubility of loratadine determined under various pH conditions and its permeability through Caco-2 monolayers, loratadine was classified as a Class II drug. Plasma profiles were predicted by convolution analysis using dissolution profiles obtained under various pH and hydrodynamic conditions as the input function and plasma time data obtained from a syrup formulation as the weighting function. The predicted profiles based on dissolution studies done at gastric pH values were in reasonable agreement with the mean bio-data suggesting dissolution testing should be done at gastric pH values. However, the bio-data were highly variable and it is suggested this may be due, at least in part, to high individual gastric pH variability and dissolution occurring in the intestine on some occasions, and therefore, dissolution testing should also be done in simulated intestinal fluid.

Area Under Curve↗

PubMed1986

Biopharmaceutical characterization of 450191-S, a ring-opened derivative of 1,4-benzodiazepine. I. Active metabolite levels in rat plasma.

5-[(2-Aminoacetamido)methyl]-1-[p-chloro-2-(o-chlorobenzoyl)phenyl ]-N,N-dimethyl-1 H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-S), a sleep inducer, is a ring-opened derivative of 1,4-benzodiazepine and has been reported to be activated by intestinal aminopeptidases. In order to determine the biopharmaceutical significance of 450191-S as the ring-opened derivative of 1,4-benzodiazepine, we examined plasma levels of active metabolites in rats following oral administration of 450191-S or its primary active metabolite, 8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazolo [1,5-a] [1,4]benzodiazepine-2-carboxamide (M-1). By increasing the dose of 450191-S, the plasma level of the active metabolites increased dose-dependently, which appeared to be due to saturation of hepatic elimination. The areas under the plasma concentration-time curves of active metabolites at a dose of 30 mg/kg of 450191-S were 2- to 20-fold higher than those at the same dose of M-1 administration per se. These results appeared to be attributable to the presence of a labile precursor of M-1, desglycylated 450191-S, which could avoid extensive first-pass extraction by the liver. In conclusion, the results suggested that 450191-S is superior to M-1, since the former maintained higher plasma levels of the active metabolites.

Animals↗

PubMed1990

Biochemical and biopharmaceutical properties of macromolecular conjugates of uricase with dextran and polyethylene glycol.

Uricase (UC) was conjugated with dextran and polyethylene glycol and their biochemical and biopharmaceutical properties were studied. UC-dextran conjugates (UC-D) synthesized by four methods, periodate oxidation, cyanogen bromide, carbodiimide and cyanuric chloride largely retained the UC enzymatic activity depending on the extent to which they modified amino groups. The periodate oxidation method seemed best because it gave a conjugate with high yield and satisfactory activity retention. The conjugate of UC with activated polyethylene glycol (UC-PEG2) was also obtained with high yield but the remaining activity was somewhat lower than those of dextran conjugates at the same modification extent. UC-D and UC-PEG2 showed sustained enzymatic activity in plasma after intravenous injection to rats. The advantage of chemical modification of proteins, especially with dextran, by the periodate oxidation method for preparation of a protein-delivery system was thus suggested.

Animals↗

PubMedDate not supplied

Insurers' strategies for managing the use and cost of biopharmaceuticals.

This paper examines strategies under development by health insurers to manage biopharmaceuticals, as their use spreads beyond rare diseases and academic sub-specialists to common conditions and community-based practices. Emphasis is placed on medical management (formulary placement and prior authorization), network design (physician contracting and drug distribution), and benefit design (coinsurance and annual payment limits). Contemporary initiatives are modest in ambition but potentially lay the foundation for a framework that balances access to innovation with affordability in this dynamic industry.

Biopharmaceutics↗

PubMed2006

Feasibility of biowaiver extension to biopharmaceutics classification system class III drug products: cimetidine.

BACKGROUND: The extension of biowaivers (drug product approval without a pharmacokinetic bioequivalence study) to drugs belonging to Class III of the Biopharmaceutics Classification System (BCS) is currently a subject of much discussion. OBJECTIVES: To assess the relationship between in vitro dissolution characteristics and in vivo absorption performance of immediate-release (IR) products containing cimetidine, a BCS Class III compound, in human subjects. To evaluate the feasibility and appropriateness of an extension of the biowaiver concept to BCS Class III compounds. STUDY DESIGN AND PARTICIPANTS: BCS-conform dissolution tests were carried out on ten marketed cimetidine products from Thailand and Germany, as well as cimetidine tablet formulations containing cimetidine 400mg manufactured by direct compression using methacrylate copolymer (Eudragit) RS PO) as a release-retarding agent to yield three batches with significantly different release profiles. Twelve healthy male subjects were enrolled in a randomised, open-label, single-dose schedule based on a five-way Williams' design balanced for carryover effects. Subjects received the following treatments, with 1-week washout periods between: (i) Tagamet 400mg tablet; (ii) 7.5% methacrylate copolymer cimetidine tablet; (iii) 15% methacrylate copolymer cimetidine tablet; (iv) 26% methacrylate copolymer cimetidine tablet; and (v) Tagamet (300 mg/ 2 mL) intravenous injection. The area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) and AUC from time zero to infinity (AUC(infinity)), peak plasma concentration (C(max)), absolute bioavailability (F) and mean residence time (MRT) were evaluated and statistically compared among formulations. In vitro-in vivo correlation (IVIVC) analysis was then applied to elucidate the overall absorption characteristics of each tablet formulation. RESULTS: The release properties of the ten marketed cimetidine products were shown to comply with current US FDA criteria for rapidly dissolving drug products. As expected, the in vitro dissolution profiles of the cimetidine tablets containing different percentages of methacrylate copolymer differed considerably from one another. However, in vivo results showed no significant difference in AUC(12), AUC(infinity), C(max) and F between the tablets manufactured with methacrylate copolymer and the innovator. The MRT values obtained from 26% methacrylate copolymer tablets were significantly longer than for the other two methacrylate copolymer formulations and the Tagamet tablets. Furthermore, IVIVC analysis showed that the 26% methacrylate copolymer tablets exhibited dissolution rate-limited absorption, whereas the other formulations showed permeability rate-limited absorption. CONCLUSION: The results of the present study indicated that the absorption of cimetidine from IR tablets is, in general, limited by permeability rather than dissolution. IVIVC analysis demonstrated that only when the release was deliberately retarded (tablets containing 26% methacrylate copolymer), did the dissolution represent the rate-limiting step to drug absorption. On the in vitro side, it seems that 85% dissolution within 30 minutes, as currently required by the US FDA Guidance, is more than sufficient to guarantee bioequivalence of IR cimetidine products. For cimetidine and other BCS Class III drugs with a similar intestinal absorption pattern, application of the biowaiver concept seems to present little risk of an inappropriate bioequivalence decision.

Adult↗

PubMed2006

Biopharmaceutical therapeutics for asthma remodeling.

Current asthma therapy is aimed at controlling disease symptoms. A subset of asthma patients remains symptomatic despite optimal therapy indicating that an unmet medical need exists for these patients. Innovative therapeutics are needed to treat the unmet need in asthma and biopharmaceutical approaches may provide an opportunity for identifying these agents. It is proposed that airway remodeling contributes to asthma symptoms and this feature of disease pathology may be a target for future therapies. The current review focuses on the contribution of one feature of airway remodeling, subepithelial fibrosis, towards disease and highlights some of the mechanisms that may contribute to this feature of airway remodeling. Further, some potential molecular targets are identified for consideration for therapeutic intervention.

Animals↗

PubMed1994

Biopharmaceutical evaluation of salicylazosulfanilic acid as a novel colon-targeted prodrug of 5-aminosalicylic acid.

A prodrug of 5-aminosalicylic acid (5-ASA), salicylazosulfanilic acid (SASA), which consists of sulfanilic acid linked to 5-ASA through an azo-linkage was newly synthesized. Biopharmaceutical properties of SASA were evaluated in comparison with those of salicylazosulfapyridine (SASP) in rats. Since SASA is much more hydrophilic than SASP, the absorption of SASA from the small intestine was less in comparison with SASP. When SASA and SASP were incubated with the rat intestinal contents under anaerobic conditions, both compounds were stable in the small-intestinal contents, but were rapidly degraded to 5-ASA in the cecal and the colonic contents. The degradation to 5-ASA by the large-intestinal contents was suppressed by the pretreatment with kanamycin sulfate, suggesting that the bioconversion of SASA is mediated by the intestinal microflora similarly to that of SASP and that SASA is also a prodrug of 5-ASA. After the oral administration, 5-ASA was found neither in the stomach nor in the small intestine in case of both prodrugs. Most of the prodrugs were transferred to the lower intestine where they were degraded to 5-ASA. The recovery of SASA including the metabolites from the gastrointestinal tract at four hours after the oral administration was significantly greater than that of SASP. Accordingly, SASA is free from the liberation of sulfapyridine, the adverse effect moiety of SASP, and less absorbable in the small intestine. Thus, the beneficial characteristics of SASA as an excellent colon-targeted prodrug of 5-ASA were clarified.

Administration, Oral↗

PubMed2001

Biopharmaceutical statistics in a pharmaceutical regulated environment: past, present, and future.

The practice of statistics in the pharmaceutical industry has changed markedly over the last 25 years. This paper examines the evolution of clinical trial statistics in relationship to advances in statistical methodology and computational power as well as the changing regulatory environment. The current role of the biopharmaceutical statistician is assessed along with the drivers for future change.

Biopharmaceutics↗

PubMedDate not supplied

Biopharmaceutical assessment of eye drops containing aloe (Aloe arborescens Mill.) and neomycin sulphate.

The subject of the studies was eye drops made of aloe, containing the group of aloe chemical substances of anti-inflammatory use and neomycin sulphate. The aim of the studies was to evaluate the permeability of biologically active aloe substances, determined as aloenin, through synthetic lipophilic and hydrophilic membranes in a standard perfusion apparatus and in vitro verification of the transport possibilities of these substances through the isolated cornea of pig's eye. The permeability process of biologically active aloe substances determined as aloenin, through synthetic lipophilic and hydrophilic membranes, was analyzed using the first-order kinetics. Estimated quotas of permeability rate constant show that the investigated chemical compounds of aloe, included in the eye drops, diffused through the applied membranes. The studies of permeability through isolated pig's cornea proved that biologically active aloe substances could not overcome this biological barrier. On the basis of biopharmaceutical studies it can be concluded that the eye drops containing aloe and neomycin sulphate, due to the lack of permeating abilities through the eye cornea, should be particularly useful in the treatment of inflammations and infections of external parts of the eye, such as conjuctiva, eyelid edges, lacrimal sac and cornea.

Aloe↗

PubMed2003

Immunogenicity of biopharmaceuticals. The European perspective.

In 1993 a Concerted EU Action was started to coordinate research concerning the immunogenicity of biopharmaceuticals bringing together researchers from academia and industry. The main topic of this concerted action has been interferon alpha. The factors influencing its immunogenicity were studied. Blind panel testing of patients' sera showed large differences in reported titres as an important variable in different studies. The EMEA has requested the three marketing authorization holders of interferon beta to develop a common assay for antibodies to this product. The status of this project will be discussed. The occurrence of about 30 cases of pure red cell aplasia related to antibodies induced by erythropoietin treatment will also be reported.

Biological Factors↗

PubMed2003

Hydrogels based on the chemically crosslinked polyacrylic acid: biopharmaceutical characterization.

This study is an attempt of biopharmaceutical characterization of hydrogels based on crosslinked polyacrylic acid (PAA). Macrodiisocyanates (MDIC) or oligomethanediisocyanate (DO) were used as crosslinking agents. The drug release rate from such hydrogels is determined by the density of the net and is lowered by a decrease in the PAA : MDIC mass ratio. The increase of the drug concentration in the matrix improved the release process. The drug release from the hydrogels was found to be pH dependent.

Acetaminophen↗

PubMedDate not supplied

Process and product monitoring of recombinant DNA-derived biopharmaceuticals with high-performance capillary electrophoresis.

High-performance capillary electrophoresis (HPCE) has emerged over the past 20 years as a powerful multidimensional separation tool that is orthogonal to HPLC and comparable to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) slab gel methods. HPCE is most frequently applied in the QC release testing of recombinant DNA-derived protein and monoclonal antibody (MAb) biopharmaceuticals. HPCE is a rugged and robust separation tool that can be used like HPLC to monitor the purification process, as well as to analyze bulk drug and drug substances. Examples of the practical applications of the predominant free-solution capillary electrophoresis (FSCE) and capillary gel electrophoresis (CGE) formats of HPCE, applied for process monitoring and product monitoring of recombinant protein and MAb biotherapeutics, are presented. HPCE has been applied in FSCE mode to monitor the purification of the rDNA-derived protein, recombinant human interleukin-4 (rhIL4). FSCE is demonstrated to be a robust method that can be used to monitor multiple column chromatographic purification processes, such as immobiilized metal-ion affinity chromatography (IMAC), ion exchange chromatography (IEC), and size exclusion chromatography (SEC) columns. The FSCE data are used to pool fractions to carry forward for further purification. The FSCE method is compared to the corresponding RP-HPLC method for rhIL4. HPCE has been applied in the CGE mode to monitor the purification of an rDNA-derived IgG4 MAb. CGE is demonstrated to be a convenient and rapid method to profile the purification process, compare purification processes, and provide a fingerprint of the MAb bulk drug that is useful for determining purity and lot-to-lot consistency. The practical advantages and limitations of CGE for process monitoring and product monitoring of MAbs are presented. The CGE method is compared to the high-performance SEC separation of the MAb under nondenaturing (HP-SEC) and denaturing (HP-DSEC) conditions and to SDS-PAGE gels for the analysis and characterization of MAb bulk drugs.

Antibodies, Monoclonal↗

PubMed1992

Pharmaceutical and biopharmaceutical quality of a sustained release carbamazepine preparation: a contribution to quality assurance.

Side effects observed during treatment with non-sustained release carbamazepine preparations are often due to the steep rise in plasma carbamazepine concentrations. To maintain plasma levels with only minor fluctuations between narrow limits, sustained release formulations have been developed which release the active constituent at a constant rate which is not too high. Bioavailability tests (single dosage, crossover design) and several investigations into the dissolution profile were carried out on three test batches of a sustained release carbamazepine preparation (Timonil 300 retard). The aim was a release model which, in the context of quality assurance, would not only facilitate reliable statements with regard to batch conformity, but would also be validated in respect of pharmacokinetic parameters such as rate of absorption and bioavailability. Correlations between mean dissolution times (MDT) and mean absorption times (MAT) at level B were found [Skelly et al. 1990]. A dissolution test differing from the pharmacopoeial tests was selected, which permitted the assessment of both batch conformity and biopharmaceutical batch quality.

Absorption↗