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At least 559 records · Page 31Linked to original sources
PubMed1992

Biopharmaceutical explanation for the topical activity of 6-hydroxyethoxy-2-benzothiazolesulfonamide in the rabbit eye.

6-Hydroxyethoxy-2-benzothiazolesulfonamide (compound 1), 6-hydrogen-2-benzothiazolesulfonamide (compound 2) and ethoxzolamide (compound 3) are carbonic anhydrase inhibitors, of which only compound 1 is active in lowering intraocular pressure when administered to the rabbit eye. They were compared for potency by inhibiting carbonic anhydrase I (CAase I) using the pH stat procedure. No differences were detected. Binding affinity and number of binding sites were identical; only a single binding site was operative. 14C-labelled compound 1 was used to measure the presence of an ocular metabolite which ranged from 17 to 57% in cornea, iris/ciliary body and aqueous humor. By maintaining drug solutions on either the corneal or conjunctival/scleral surfaces of the eye of anesthetized rabbits for 120 minutes, steady state concentrations of compounds 1-3 were determined in cornea, aqueous humor and iris/ciliary body. It was concluded that compound 1 penetrated both routes equally well and also accumulated at the active site in considerably higher concentrations than compounds 2 and 3. Compounds 2 and 3 did not accumulate in the iris/ciliary body nor did compound 3 penetrate the conjunctival/scleral route very well, approximately 5-20 fold lower than from the corneal route.

Administration, Topical↗
PubMed1993

Biopharmaceutical characterisation of a low-dose (75 mg) controlled-release aspirin formulation.

The release of aspirin from a 75 mg controlled-release formulation, designed to inhibit maximally thromboxane A2 production while sparing stimulated prostacyclin biosynthesis, was characterised in healthy subjects. The calculated in vivo release rate of aspirin matched the design goal of approximately 10 mg h(-1). The C(max) of aspirin associated with the controlled-release formulation was lowered 15-fold relative to a solution formulation of the same dose. The bioavailability of aspirin (based on salicylate concentrations) from the controlled-release formulation was approximately 90% relative to the solution, and drug release was not affected by co-administration of a standard breakfast.

Adolescent↗
PubMed1994

Biopharmaceutical aspects of tolfenamic acid.

The pharmacokinetics of tolfenamic acid is well described by a two-compartment model with relatively short half-lives (T/2 beta 1-2 hours) and tolfenamic acid is highly protein-bound with small volumes of distribution. It is cleared relatively fast (150-200 ml/min), mainly by hepatic metabolism and the metabolites are renally cleared as glucuronic acid conjugates. The peroral absorption is good and the peroral bioavailability is about 75%, as first pass metabolism accounts for about 20%. Tolfenamic acid shows linear pharmacokinetics and during multiple dosage regimen, i.e. thrice daily, no accumulation beyond the second dose is observed. The bioavailability in dependence of age and disease has been studied and only in the case of severe liver or kidney impairment, a change in dosage regimen seems warranted. The development of different formulations will be outlined, mainly on rectal delivery, on sustained release and rapid release oral formulations, on topical ointment, and on parenteral delivery. The problems with tolfenamic acid in pharmaceutical formulation caused mainly by poor solubility will be discussed. Formulations ready for the market now or very soon are Clotam capsules (tablets). Clotam retard tablets, Clotam suppositories, and Clotam oral suspension, whereas rapid tablets, topical ointments, and parenteral formulations need further development to be ready for marketing in the years to come.

Absorption↗
PubMed2005

Proteomic profiling of recombinant Escherichia coli in high-cell-density fermentations for improved production of an antibody fragment biopharmaceutical.

By using two-dimensional polyacrylamide gel electrophoresis, a proteomic analysis over time was conducted with high-cell-density, industrial, phosphate-limited Escherichia coli fermentations at the 10-liter scale. During production, a recombinant, humanized antibody fragment was secreted and assembled in a soluble form in the periplasm. E. coli protein changes associated with culture conditions were distinguished from protein changes associated with heterologous protein expression. Protein spots were monitored quantitatively and qualitatively. Differentially expressed proteins were quantitatively assessed by using a t-test method with a 1% false discovery rate as a significance criterion. As determined by this criterion, 81 protein spots changed significantly between 14 and 72 h (final time) of the control fermentations (vector only). Qualitative (on-off) comparisons indicated that 20 more protein spots were present only at 14 or 72 h in the control fermentations. These changes reflected physiological responses to the culture conditions. In control and production fermentations at 72 h, 25 protein spots were significantly differentially expressed. In addition, 19 protein spots were present only in control or production fermentations at this time. The quantitative and qualitative changes were attributable to overexpression of recombinant protein. The physiological changes observed during the fermentations included the up-regulation of phosphate starvation proteins and the down-regulation of ribosomal proteins and nucleotide biosynthesis proteins. Synthesis of the stress protein phage shock protein A (PspA) was strongly correlated with synthesis of a recombinant product. This suggested that manipulation of PspA levels might improve the soluble recombinant protein yield in the periplasm for this bioprocess. Indeed, controlled coexpression of PspA during production led to a moderate, but statistically significant, improvement in the yield.

Bacterial Proteins↗
PubMed1983

Biopharmaceutical evaluation of 'Osmosin'.

'Osmosin' is an osmotically-controlled oral drug delivery system which presents a saturated solution of sodium indomethacin trihydrate (105.4 mg), equivalent to 85 mg indomethacin, to the gastro-intestinal tract at a constant rate of 7 mg per hour, with a release time of 10 to 12 hours. Drug delivery is not influenced by pH or gastro-intestinal motility. The bioavailability and functionality of 'Osmosin' have been studied after single-dose and after repeated administrations in man. Its performance was compared to that after intravenous administration and various capsule regimens of indomethacin. In both studies, comparable urinary excretion and renal clearance for all oral regimens indicated that like amounts of drug were available for absorption from 'Osmosin' and 'Indocid' capsules. This comparability was verified by the fact that indomethacin is 85% bioavailable from 'Osmosin' compared to intravenous or oral regimens (75 mg given as one dose of 3 X 25 mg capsules or 25 mg 3-times). Drug is absorbed at a constant rate for about 4 hours after 'Osmosin' administration. Indomethacin plasma profiles on an 'Osmosin' 12-hourly regimen were different from typical indomethacin capsule regimens (25 mg at 0, 4, 8 hours; 75 mg at 12 hours or 50 mg at 0, 4 and 14 hours daily). Indomethacin plasma levels from 'Osmosin' were more uniform and sustained, demonstrating more even distribution of drug with time. The constant-rate delivery of sodium indomethacin trihydrate to the gastro-intestinal tract from 'Osmosin' controls the rate of drug absorption, prolongs the effective half-life of drug in plasma, does not inhibit the efficiency of absorption, but does significantly decrease the extremes in plasma level fluctuation noted with conventional dosage forms.

Absorption↗
PubMed2001

The biopharmaceutical aspects of nasal mucoadhesive drug delivery.

Nasal drug administration has frequently been proposed as the most feasible alternative to parenteral injections. This is due to the high permeability of the nasal epithelium, allowing a higher molecular mass cut-off at approximately 1000 Da, and the rapid drug absorption rate with plasma drug profiles sometimes almost identical to those from intravenous injections. Despite the potential of nasal drug delivery, it has a number of limitations. In this review, the anatomy and physiology of the nasal cavity, as well as ciliary beating and mucociliary clearance as they relate to nasal drug absorption, are introduced. The rationale for nasal drug delivery and its limitations, some factors that influence nasal drug absorption, and the experimental models used in nasal drug delivery research are also reviewed. Nasal mucoadhesion as a promising method of nasal absorption enhancement is discussed, and factors that influence mucoadhesion, as well as safety of nasal mucoadhesive drug delivery systems are reviewed in detail. Nasal drug administration is presently mostly used for local therapies within the nasal cavity. Anti-allergic drugs and nasal decongestants are the most common examples. However, nasal drug administration for systemic effects has been practised since ancient times. Nasally-administered psychotropic drugs by native Americans, the use of tobacco snuffs, and nasal administration of illicit drugs such as cocaine are all well known (Illum & Davis 1992). Nowadays, the nasal cavity is being actively explored for systemic administration of other therapeutic agents, particularly peptides and proteins (Illum 1992; Edman & Björk 1992), as well as for immunization purposes (Lemoine et al 1998). To better understand the basis for nasal drug absorption and factors that can influence it, a brief review of the anatomy and physiology of the nose is appropriate.

Administration, Intranasal↗
PubMed1997

Biopharmaceutical studies on drug/conjugated-metabolite interactions. III. Effect of acetaminophen sulfate and its positional isomers on the pharmacokinetics of acetaminophen in rats.

The effect of three positional isomers, o-, m- and p-acetylaminophenyl sulfate (AOAPS, AMAPS and APAPS (acetaminophen sulfate), respectively), on the pharmacokinetics of acetaminophen (APAP) was investigated in rats. All of the intravenously administered positional isomers were rapidly eliminated from plasma, and approximately 80% of the dose was excreted in an unchanged form in the urine within 4 h, while biliary excretions represented a small percent of the doses. Following the intravenous bolus injection of APAP, plasma elimination of APAP was accelerated and the distribution volume of APAP was increased under a steady state concentration (about 10 microg APAP eq/ml) of AOAPS or APAPS, but not AMAPS, as compared with saline infusion. Total body clearances of APAP were increased from 18.3 ml/min/kg for the control to 23.9 and 26.9 ml/min/kg for AOAPS and APAPS coadministration, respectively. AOAPS and APAPS competitively displaced the serum protein binding of APAP, while AMAPS had little effect. The distribution volume of unbound APAP was anomalously increased by APAPS, while it was not affected by AOAPS or AMAPS. Tissue-to-plasma concentration ratios of APAP were significantly increased by APAPS in the liver, kidney and brain, while they were only slightly increased by AOAPS. It was suggested that APAPS has not only the displacing activity of serum protein binding but also other specific effectiveness on the distribution of APAP.

Acetaminophen↗
PubMed1987

Biopharmaceutical characteristics of a suppository base containing poly (oxyethylene)-poly (oxypropylene) copolymer, Unilube. I. Effects of a suppository base containing Unilube 70DP-950B on release and rectal absorption of aminopyrine in rabbit.

The rectal absorption of aminopyrine (AP) from a three-component-system suppository base (TCS), which is a mixture of oleaginous base, water-soluble base and the poly-(oxyethylene) poly-(oxypropylene) block copolymer, Unilube, was investigated. Albino rabbits were used as the animal model. The bioavailability of oleaginous base and water-soluble base (polyethylene glycol 4000) were 44.3% and 82.6%, respectively. The time to reach maximum plasma concentration (Tmax) of the oleaginous and the water-soluble bases were 21.0 +/- 8.2 min and 33.0 +/- 16.4 min, respectively. When TCS was used, its Tmax was 30 min and increasing the amount of Unilube in the base from 5% (w/w) to 20% (w/w) decreased the bioavailability from 100.4% to 47.2%. The softening temperature of TCS was 55-57 degrees C. Collectively, TCS containing 5% of Unilube gave significantly higher bioavailability than the other bases without softening until 57 degrees C. Also, the results of the two different release tests were compared with the results of an animal experiment in this paper.

Animals↗
PubMed1982

Biopharmaceutical studies on hydantoin derivatives. II. Pharmacokinetics and bioavailability of hydantoin derivatives in dogs.

Pharmacokinetics and bioavailability for the 1-benzenesulfonylhydantoin derivatives and 1-unsubstituted hydantoin derivatives were evaluated from the plasma concentrations after oral and intravenous administrations to dogs. Apparent volume of distribution of the 1-benzenesulfonylhydantoin derivatives was about 0.25 l/kg, while that of the 1-unsubstituted hydantoin derivatives was about 1.3 l/kg. The result suggests that introduction of the benzenesulfonyl group at 1-position of the hydantoin ring has marked effect on the distribution into the fluids and tissues of the body. Bioavailabilities of sodium 5,5-diphenylhydantoin and sodium 1-benzenesulfonyl-5,5-diphenylhydantoin exceeded those of their corresponding free forms. The results were well explicable in terms of the excellent dissolution behaviours of the salt forms. The bioavailabilities of 5-ethyl-5-phenylhydantoin and 1-benzenesulfonyl-5-ethyl-5-phenylhydantoin were almost perfect. The results suggest that the dissolution rate is a rate-determining step in the bioavailability of the derivatives having two phenyl groups at 5-position of the hydantoin ring, irrespective of the presence of the benzenesulfonyl group at 1-position.

Administration, Oral↗
PubMed1982

Biopharmaceutical studies on hydantoin derivatives. III. Physico-chemical properties, dissolution behavior, and bioavailability of the molecular compound of 1-benzenesulfonyl-5,5-diphenylhydantoin and antipyrine.

Physico-chemical properties, dissolution profiles, and bioavailability of the molecular compound composed of equimolar amount of 1-benzenesulfonyl-5, 5-diphenylhydantoin (BSDH) and antipyrine were studied. The spectral and thermal analyses suggest that the intermolecular force in the molecular compound is attributed to the hydrogen bond between 3-NH of BSDH and 5-C = 0 of antipyrine. In the aqueous media, the molecular compound decomposed to the constituents and there was no interaction between them. The dissolution behavior of BSDH from the molecular compound was characteristic, the high supersaturation being present for a long time, while the dissolution of antipyrine from the molecular compound was slow and continued for a long time. The dissolution profile of the molecular compound was truly reflected on the bioavailability in dogs. With respect to BSDH, the rate and the extent of bioavailability of the molecular compound were excellent. On the other hand, the absorption of antipyrine from the molecular compound was sustained for a long time. BSDH and antipyrine had no influence one another on the intrinsic rate constant of transport through the intestinal membrane and on the pharmacokinetic constants such as the volume of distribution and the elimination rate constant.

Administration, Oral↗
PubMed1984

Biopharmaceutical studies on hydantoin derivatives. IV. Factors affecting bioavailability of 5,5-diphenylhydantoin in dog.

Several factors affecting the bioavailability of 5,5-diphenylhydantoin (I) and its sodium salt (I-Na) were examined in dogs in relation to meal and following results were obtained. The bioavailability of I was not appreciably affected by the volume of coadministered water in the range of 30-120 ml. The bioavailability of I was most excellent when I was administered 0.5 h after meal. Food intake 0.5 h after drug administration enhanced appreciably the bioavailability, but that 2 h after drug administration did hardly affect the bioavailability. The extent of bioavailability of I-Na was almost 100% of the dose in the range of 100-400 mg/dog when it was administered 0.5 h after meal. While, when I-Na was administered in the fasting state, the extent of bioavailability was about 60% of the dose. Food-induced enhancement of the bioavailability of I was independent of the food constituents. The bioavailability of I was increased about 1.5-fold and 2-fold with 10-fold increase in the specific surface area of I, in the nonfasting and the fasting states, respectively. In the experiments using the dogs with the chronically implanted fistula in the common bile duct, it was found that the bile was not a major factor contributing to the food-induced enhancement of the bioavailability of I. There was a good correlation between the bioavailability of I in dog and that in man.

Adult↗
PubMed1985

Preparation and biopharmaceutical evaluation of microcapsules of ampicillin.

Microencapsulation of ampicillin, an orally administered antibiotic, with different viscosity grades of ethyl cellulose was studied. The preparation of microcapsules was done as follows; the mixture of ethyl cellulose-CH2Cl2-ampicillin was dispersed in purified water containing 0.5% (w/w) sodium lauryl benzenesulfonate, and then CH2Cl2 was dried out by elevating the temperature. The dissolution curves for the release of ampicillin from microcapsules prepared using the four different viscosity grades of ethyl cellulose were quite different. The release of ampicillin increased with decreasing ethyl cellulose viscosity. The evaluation of prepared microcapsules was made using gastric-emptying-controlled rabbits. The plasma concentration of ampicillin obtained by the administration of microcapsules showed a significant sustained-release pattern. The area under the plasma concentration curve (AUC) of ampicillin obtained after a single oral administration of microcapsules prepared using 10 cps ethyl cellulose was 1.8 times greater than that obtained after double oral administration of powder. This fact will be caused by the delaying of gastric-emptying, intestinal-transit and dissolution of ampicillin there. It was confirmed that a large number of microcapsules still remained in the stomach and each microcapsules still contained ampicillin at 24 h after dosing from the experiment using gastric-emptying-controlled rabbits.

Ampicillin↗
PubMed1985

Biopharmaceutical evaluation of methylcellulose as an excipient for nitroglycerin tablets.

To examine the bioavailability of nitroglycerin in sublingual tablet, 5 healthy adult volunteers underwent simultaneous sublingual administration of a tablet prepared with methylcellulose and a tablet prepared with lactose containing 0.15 mg of nitroglycerin and 0.15 mg of nitroglycerin-15N3, respectively. In 4 of 5 volunteers, no difference in plasma concentration determined by gas chromatography-mass spectrometry (GC-MS) was observed between 2 tablets described above, so it was well accepted that nitroglycerin in tablets prepared with methylcellulose had a similar bioavailability to that in tablets prepared with lactose. The simultaneous administration of the 2 nitroglycerin tablets to a healthy volunteer, one of which containing the drug labeled with a stable isotope followed by GC-MS assay, seems to be the most suitable method for a precise comparison of bioavailability of the formulations.

Adult↗
PubMed1986

Biopharmaceutical studies on hydantoin derivatives. V. Pharmacokinetics and pharmacodynamics of 5,5-diphenylhydantoin and 1-benzenesulfonyl-5,5-diphenylhydantoin.

Disposition of 1-benzenesulfonyl-5,5-diphenylhydantoin (II) having a potent anti-inflammatory activity was compared with that of 5,5-diphenylhydantoin (I), an antiepileptic drug, in order to elucidate whether the pharmacodynamic difference between them can be explained by their physicochemical and pharmacokinetic properties. After oral administration of I-14C to rats, radioactivity was distributed in all tissues including the brain, whereas after II-14C administration, the concentrations of radioactivity in most tissues were lower than those in plasma. The results were consistent with the finding obtained by whole-body autoradiography which revealed that after oral administration of II-14C to rats, radioactivity was not transferred into brain but was significantly transferred into inflamed tissues. Brain/plasma concentration ratio of I was about 1.3, whereas that of II was about 0.05. Plasma protein binding of I having pKa value of 8.30 was about 88%, whereas that of II having pKa value of 4.89 was about 99%. The changes in physicochemical properties due to introduction of a benzenesulfonyl group into the hydantoin ring may be responsible for the difference in the disposition between I and II. When II was cerebroventricularly administered to mice, it showed a potent anti-convulsant activity against maximal electroshock seizure, the activity being comparable to that for I. This indicates that the earlier failure to demonstrate the activity of II in a routine screening test for antiepileptic drugs was due to the inability of II to penetrate the blood-brain barrier and to achieve effective concentration in the brain. II was found to inhibit the biosynthesis of prostaglandin. These findings along with the physicochemical properties suggest that although II does not fall structurally under any category of anti-inflammatory drugs the mechanism of action may be similar to that for non-steroidal acidic anti-inflammatory drugs.

Administration, Oral↗