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At least 145 records · Page 8Linked to original sources

PubMed2003

[Construction of an anti-apoptosis CHO cell line for biopharmaceutical production].

Mammalian cells are prone to apoptosis when cultured in large scale for production of biopharmaceuticals. And this will reduce production duration and result in high cost of production. Apoptosis is triggered by various factors, and delicately regulated by a set of genes. Bcl-2, a component integrated in mitochondria membrane, is an important member of these genes. By maintaining the integrity of mitochondria membrane, Bcl-2 keeps cytochrome C from releasing into cytoplasm, and thus blocks the activation of caspases, and subsequent onset of apoptosis. Over-expression of Bcl-2 has proven to be useful in blocking apoptosis in various cell lines, including CHO, hybridoma, myeloma, lymphoma and insect cells. Ammonia, a metabolite of cultured cells, however, showed apparent pro-apoptosis activity. In living cells, ammonia can be utilized by glutamine synthetase (GS) to synthesize glutamine, and thus lower the concentration of ammonia in medium, and its negative effects. Glutamine is essential to living cells. If not added into medium, glutamine can only be synthesized by GS, which makes GS a qualified selection marker. This marker can be used for gene amplification by adding into medium increased concentration of MSX, an inhibitor of GS. In this study, we over-expressed Bcl-2 using GS amplification in a recombinant CHO cell line stably expressing human interferon-beta. The modified cell line, with higher expression of Bcl-2 and lower production of ammonia, exhibited good anti-apoptosis quality and higher interferon-beta production in continuous culture.

Animals↗

PubMedDate not supplied

[In vitro and in vivo biopharmaceutical evaluation of lorazepam commercial tablets].

OBJECTIVE: Lorazepam (LZM) is a broadly used tranquillizer for the treatment of anxiety. Tavor is one of the most diffused registered drug products containing LZM. Lots of generic drug products containing LZM have been registered in Italy by several pharmaceutical groups and are present in the Italian market. Due to the wide medical prescription of products containing LZM, it seemed interesting, from a technological and biopharmaceutical point of view, to perform a comparative bioequivalence evaluation of a trade marked and generic tablet formulations containing LZM available in the Italian market. MATERIALS AND METHODS: The trial vas carried out on four preparations, including Tavor (1 mg) as reference product and three generics named A, B and C. In vitro technological parameters (dissolution, uniformity of content, uniformity of weight) and in vivo (pharmacokinetic on rabbit) studies were performed. RESULTS: All the examined brands passed technological tests according the European Pharmacopeia 5th ed. and USP25. Tavor ensures a faster dissolution behaviour than the tree generics in vitro. All the pharmacokinetic parameters were within the prescriptions of EMEA, even if the reference product showed the highest values of AUC0-infinity and of Cmax. CONCLUSIONS: Obtained results show that Tavor ensures a faster dissolution behaviour than the tree generics in vitro. Moreover, considering the pharmacokinetic data, it is possible to suppose that the generics B and C are not able to provide the same therapeutic effect as the reference product.

Analysis of Variance↗

PubMed2006

Rapid in vivo dissolution of ketoprofen: implications on the biopharmaceutics classification system.

The aim of this paper was to investigate the in vivo dissolution behavior of ketoprofen, a Class II drug according to the Biopharmaceutics Classification System (BCS), in the upper small intestine of dogs. An intubations method was used, where no blocking balloons were used to prevent luminal drug transport along the GI tract. Our design allowed the drug to be transported freely to more distal parts of the GI tract and also, it was supported by a pharmacokinetic study. Pharmacokinetic parameters of ketoprofen were determined in dogs after administering approximately 0.27 mg kg(-1) (solution) or approximately 1.47 mg kg(-1) (suspension) in oral bolus doses. There were not statistical significant differences in plasma concentrations for both formulations, either in the maximum concentrations C(max) or AUC following oral dose administration. The rapid disappearance of ketoprofen from the intestinal lumen, reflected by low mass recovery in the supernatant and sediment of the collected intestinal fluid samples, in comparison to that recovery of the non-absorbable marker phenol red, suggests that ketoprofen is emptying into the small intestine and is rapidly dissolved and absorbed. In this study, the in vivo results clearly show that the absorption rate of ketoprofen is not dissolution limited; therefore ketoprofen would be essentially equivalent to Class I drugs and could be considered for waiver of bioavailability and bioequivalence testing.

Animals↗

PubMedDate not supplied

[The oral liquid form of vinburnine: biopharmaceutics].

Biopharmaceutic comparison is achieved between commercialized capsules of vinburnine and drops dosage form intended for geriatric pharmacotherapy. Drug bioavailability of vinburnine seems saved, if not significantly increased by the new formulation, in spite of the very important, and well known interindividual variations of vincamine drug products. Only the absorption rate seems statistically increased by drops.

Administration, Oral↗

PubMedDate not supplied

Biopharmaceutical aspects of ritodrine retard in pregnant women.

Biopharmaceutical aspects of the new sustained-release formulation of ritodrine, a tocolytic agent, were studied in 9 patients with preterm labour. A mean bioavailability of 26% (range 22%-32%) was estimated after the 4th day of treatment (steady state). A.U.C.'s from oral administration were found to correlate well with those measured in i.v. therapy in the same patients (r = 0.92; p = 0.0004). It was concluded that differences in bioavailability of ritodrine-retard are small enough to enable clinicians, using this sustained release preparation, to make fair estimations of the oral dosage, needed to replace the initial i.v. treatment.

Administration, Oral↗

PubMed1987

[Biopharmaceutical and clinico-pharmacological research on the intramammary preparation Cephamasten].

An animal drug formula, Cephamasten, for intramammary application in the treatment of mastitis-affected cows, ewes, and goats in the lactation period was worked out on the base of microbiologic, technologic, biopharmaceutic, and clinico-pharmacologic studies. Its active ingredient was the Pharmachim cephalexin-monohydrate. The consistence of Cephamasten has proved suitable for intracisternal introduction. It is tolerated well within the udder of cows, and it rapidly releases the antibiotic incorporated in it. The milk of the treated quarters has proved free from cephalexin after the 72nd hour of the last infusion. Cephamasten has shown high effectiveness in the treatment both of the preclinical and of the acute clinical mastitis. In the first case best results were obtained with the twofold treatment at a 24-hour interval, and in the second case--with the sixfold treatment at 12-hour intervals (intracisternal introduction of the preparation). In the case of generalized mastitis, in dependence on the severity of the process Cephamasten is to be applied at 4-6-12 intervals along with frequent milking and the parenteral application of other agents.

Animals↗

PubMed1984

Practical application of the concept of mean times in biopharmaceutics.

The "concept of mean times" (1) in combination with the "method of moments" (3, 4) provides a practical basis for handling biopharmaceutical problems. This holds for in vitro, in vitro/in vivo and in vivo situations. Using several examples, it was demonstrated that questions concerning the comparability of in vitro dissolution models and their in vivo relevance can be answered, and that the rate of bioavailability can be evaluated exactly.

Animals↗

PubMed1984

The rabbit as an experimental model for biopharmaceutical studies following rectal administration of theophylline.

In order to find a suitable animal model for biopharmaceutical studies after rectal application of theophylline, the pharmacokinetics of theophylline following the administration in rabbits of three different rectal preparations were examined and compared with those of the oral and i. v. route. No significant formulation related impact from the studied rectal dosage forms on the bioavailability of the drug was found. However, the unexpected rapid achievement of peak serum concentration after insertion of the suppository lacked any correlation with human experiments. It was concluded that the evaluation of rectal theophylline medication for man cannot directly be based on the data obtained from rabbits.

Administration, Oral↗

PubMed1980

Biopharmaceutic evaluation of etofylline clofibrate and its drug formulation.

The biopharmaceutic criteria of Duolip and its active principle, 1-(theophyllin-7-yl)-ethyl-2-[2-(p-chlorophenoxy)-2-methylpropionate] (etofylline clofibrate, ML 1024), are described. ML 1024 was found to be practically insoluble in water at pH values ranging from 2 to 7.4 and in human serum. A very low dissolution rate of the drug from the capsule preparation was found in artificial gastric and intestinal fluid, along with little cleavage to the individual components clofibric acid and etofylline. The particle size was mainly less than 40 micrometers. For the classification of granules the granule size, the angle of repose (tan alpha), the flow time, the stamp volume and the packing factor were determined.

Biopharmaceutics↗

PubMedDate not supplied

[The pharmacokinetic and biopharmaceutical evaluation of the new tranquilizer gidazepam].

The pharmacokinetics of the new tranquilizer gidazepam and its desalkyl metabolite was studied in rats. Some biopharmaceutical characteristics of the agents under study were defined. Gidazepam was found to have much advantage over the principal active ingredient (desalkylgidazepam) in its higher bioavailability. The methodological approaches developed by the authors to evaluate the efficacy of gidazepam may be applied in designing novel drugs.

Animals↗

PubMed1997

Characterization and establishment of specifications for biopharmaceuticals.

This paper describes the role of product characterization and product specifications in the context of an overall control strategy. Due to advances in analytical characterization and biotechnology manufacturing methods, product characterization can now be used as an effective means of assessing the impact of manufacturing process changes on product quality, safety and efficacy, hence obviating the need for repeating clinical testing each time a manufacturing process change is made. The ICH specifications guidance document can serve a key role in harmonising test requirements and regulatory practices with regard to produce characterization. Consumers, regulatory agencies, and biopharmaceutical manufacturers all stand to benefit from this harmonization process.

Biopharmaceutics↗

PubMed1976

[The role of biopharmaceutical parameters in drug development (author's transl)].

The biopharmaceutical factors, which influence the interaction between dosage form and drug activity, extend from the mode of application, through chemical and physical properties of the active constituent, to the final product, including the excipients and manufacturing processes involved. In recent years, important strides have been made in this field, which improve drug safety. This has consequently influenced and enlarged the present scope of pharmaceutical technology drug research.

Biological Availability↗

PubMed1999

Strategies for analysis and structure characterization of glycans/proteoglycans by capillary electrophoresis. Their diagnostic and biopharmaceutical importance.

Proteoglycans are key biological macromolecules that, via their glycan constituents, participate and regulate several cellular events and physiopathological processes. Refined structures of their highly anionic glycan chains, involving sulphation pattern and uronic acid distribution through the polymeric chain, determine the interactions of proteoglycans with matrix effector molecules and are responsible for numerous effects. Analysis and structural characterization of glycans are, therefore, essential in understanding the biological functions of proteoglycans. Capillary electrophoresis with its high resolving power and sensitivity may successfully be used for the fine chemical characterization of components present in low amounts and to overcome limitations due to low amount/volume of biologic samples available. This technique is also friendly to the user and to the environment, since a very small amount of solvents (a few microL) is required. In this review the strategies used to analyse and characterize the structure of glycan chains of proteoglycans are summarized. They involve capillary electrophoretic analysis of depolymerized acidic glycan chains using specific enzymes and analysis of intact chains. The importance of this type of analysis in biologic samples and tissues and its possible diagnostic and biopharmaceutical use are also discussed.

Carbohydrate Conformation↗

PubMed1994

A biopharmaceutic approach in designing a controlled release tablet of sodium monofluorophosphate: 1. In vitro and in vivo studies in beagle dogs.

The purpose of this study was to develop a controlled release tablet (CRT) of sodium monofluorophosphate (NaMFP) based on biopharmaceutic and pharmacokinetic principles. NaMFP was introduced in the early eighties to treat osteoporosis. The required dose size (200 mg of NaMFP) and time of drug delivery (8.3 h) were theoretically determined based on the pharmacokinetic parameters of fluoride (F-). A CRT was formulated with ethyl cellulose (EC) by the direct compression method. The ratio of drug to polymer was adjusted 1:1, after studying the in vitro release profiles. The release mechanism from the developed dosage form followed the square root of time relationship. This dosage form was evaluated for its in vivo performance in dogs. The pharmacokinetics of F-, after the IV and PO administration of NaMFP, was determined to standardize the animal model. F- followed a two-compartment model and no significant differences were found between the two routes of administration. The bioavailability in dogs was only 60%. The reason for this poor bioavailability was postulated to be the delivery of drug extended beyond the principal sites of absorption of the gastrointestinal tract. Hence, we decided to characterize the absorption sites of NaMFP and to modify the CRT.

Analysis of Variance↗

PubMed2003

Characterization of dexloxiglumide in vitro biopharmaceutical properties and active transport.

The objective of this work was to characterize dexloxiglumide biopharmaceutical properties in vitro and relate these characteristics to its in vivo absorption performance, and to assess dexloxiglumide interaction with P-glycoprotein (P-gp) and MRP1 to anticipate its drug interaction potential. Dexloxiglumide aqueous solubility was moderate and pH dependent. Dexloxiglumide exhibited moderate Caco-2 permeability that was polarized, concentration dependent, and pH dependent. The apical-to-basolateral (AP-BL) permeability at pH 5 [14.5 (+/-1.8) x 10(-6) cm/s] was 2-fold higher than at pH 7.5 [7.24 (+/-0.27) x 10(-6) cm/s]. Neutral and ionized dexloxiglumide species displayed permeabilities of 30.8 (+/-8.4) x 10(-6) cm/s and 9.03 (+/-1.31) x 10(-6) cm/s, respectively. The transport of dexloxiglumide across MDR1-MDCK (P-gp overexpressing Madine Darby canine kidney cells) monolayers was polarized, with a BL-AP/AP-BL permeability ratio of 9.35 (+/-0.73), which was reduced to 1.03 (+/-0.03) by P-gp inhibition. Rhodamine 123 efflux was reduced by dexloxiglumide from 4.06 (+/-0.34) to 2.84 (+/-0.15) across Caco-2 monolayers, and from 17.3 (+/-0.9) to 8.26 (+/-1.38) across MDR1-MDCK monolayers, further indicating dexloxiglumide interaction with P-gp. Additionally, P-gp ATPase activity increased with dexloxiglumide concentration. Dexloxiglumide was effluxed from MRP1-NIH3T3 cells (NIH-3T3 cells expressing the multidrug resistance-associated protein 1). Dexloxiglumide increased MRP1-substrate fluorescein uptake 4-fold, and fluorescein increased dexloxiglumide uptake 1.8-fold. Overall, in vitro transport studies indicate dexloxiglumide to be moderately soluble and moderately permeable, which is in agreement with the incomplete oral absorption of dexloxiglumide. In vitro, dexloxiglumide was moderately modulated by P-gp and MRP1, which provides a rationale for the design of drug interaction studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1981

Carbamazepine: a clinical biopharmaceutical study.

In a biopharmaceutical study of carbamazepine, the F-CBZ, DAK preparation, which contained small particles with minor variation in size, had a more rapid dissolution rate than Tegretol, which contained larger particles of more variable size. Accordingly, carbamazepine had a more rapid absorption rate from F-CBZ, DAK than from Tegretol in a comparative absorption test involving single-dose administration of 200 mg to 8 healthy volunteers. The clinical significance of the difference in absorption rates for the steady state levels of carbamazepine and carbamazepine-10,11-epoxide, and the frequency of side-effects in relation to tablet intake, were evaluated in a double-blind, randomized, double-dummy cross-over trial of 35 days' duration, in 21 well-adjusted epileptic patients. 9 patients were treated with Tegretol alone and 12 with Tegretol combined with other antiepileptic drugs. A lower steady state plasma level of carbamazepine was found at 08.00 h during treatment with F-CBZ, DAK in comparison with Tegretol. The difference was small. There was no difference in the type and frequency of side-effects or seizures between the 2 preparations. The frequency of epileptic fits was not correlated with the plasma level of carbamazepine or the epoxide. Side-effects, however, had a tendency to be correlated with the concentration of the epoxide. Thus, the particle size influenced the absorption rate of carbamazepine, without having a significant correlation wih the frequency of side-effects. The difference in the minimum plasma level of carbamazepine between treatments with the two preparations was modest, and appeared to be without clinical significance.

Adult↗

PubMed1992

Biopharmaceutical evaluation of ibufenac, ibuprofen, and their hydroxyethoxy analogs in the rabbit eye.

Two new structural analogs, 2-(4-hydroxyethoxyphenyl)acetic acid [R3] and 2-(4-hydroxyethoxyphenyl)propionic acid [R4], along with their parent compounds, ibufenac and ibuprofen, were evaluated for their biopharmaceutical properties. The analogs represented substitution of the lipophilic isobutyl side chains of ibufenac and ibuprofen with hydrophilic hydroxyethoxy side chains. Anti-inflammatory activity was evaluated by administering drugs topically to inhibit inflammation induced by using either clove oil or arachidonic acid. The rank order of activity was ibufenac approximately equal to ibuprofen > R3 approximately equal to R4. The new compounds, R3 and R4, were highly water soluble (> 60-fold) and partitioned less (< 1/1500-fold) into the lipid phase when compared to ibufenac and ibuprofen. R3 and R4 each had apparent corneal permeability coefficients of 6 x 10(-6) cm/sec, whereas ibufenac and ibuprofen yielded values of about 22 x 10(-6) cm/sec. In an ocular pharmacokinetic study in the rabbit eye, constant concentrations of each compound were maintained on the cornea in a cylinder or well fixed to the cornea, resulting in a constant input rate. This method circumvented parallel loss routes at the absorption site including nasolacrimal drainage. From area calculations the dispositions of the compounds within the eye were described by mean residence times, steady state volumes of distributions, and clearance rates. R3 and R4 were more slowly absorbed, retained within eye tissues longer, and were cleared more slowly from the eye than ibufenac and ibuprofen. The aqueous humor concentration-time profiles were also computer-fitted to equations representing classical pharmacokinetic models. For ibufenac and ibuprofen, the entire cornea was assumed to be the net barrier for entry into the anterior chamber. Whereas, for R3 and R4, the corneal epithelium and endothelium were presumed to be the diffusional barriers into and out of the stroma, the latter treated as a compartment. Aqueous humor concentrations of each drug fit the models reasonable well and agreed with conclusions made from the use of area calculations. The drop volume method was used to measure the surface tension of each compound. Both ibufenac and ibuprofen were considerably more surface active than R3 or R4. The greater surface tension measured for ibufenac and ibuprofen correlated to the subjective observations of ocular discomfort for these drugs.

Administration, Topical↗

PubMed1993

Biocontainment design considerations for biopharmaceutical facilities.

This article highlights biocontainment design considerations for biopharmaceutical manufacturing facilities. The major focus of this report is on industry's use and interpretation of the regulations with specific design recommendations for a Biosafety Level 2--Large-Scale physical containment level as described by the National Institutes of Health Guidelines.

Accidents, Occupational↗