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At least 1,693 records · Page 94Linked to original sources
PubMed2004

Validated RP-hPLC method for the assay of zalcitabine in drug substance, formulated products and human serum.

A HPLC method for zalcitabine determination in bulk form, pharmaceutical dosage forms and human serum has been developed and validated. The proposed method was conducted using a reverse phase technique, and UV monitoring at 265 nm. The mobile phase consisted of methanol: 0.01 M NaH2PO4 (85:15; v/v) adjusted to pH 4.62 with 1 M NaOH. The detector response was linear in the range of 0.015-50 microg mL(-1). The limit of detection and the limit of quantification of the procedure were 0.0066 microg mL(-1) and 0.022 microg mL(-1), respectively. The retention time was 2.5 min for zalcitabine and 3.5 min for the internal standard. No interferences from tablet additives were observed and analysing tablets containing zalcitabine proved the applicability of the method. This method was also applied for the determination of zalcitabine in spiked human serum samples.

Calibration↗
PubMed2006

Rapid colorimetric assay of diclofenac sodium tablets using 4-carboxyl-2,6-dinitrobenzene diazonium ion (CDNBD).

This study describes a novel simple, rapid and sensitive colorimetric assay method for diclofenac sodium tablets. The method is based on a simple aromatic ring derivatization technique using newly developed 4-carboxyl-2, 6-dinitrobenzenediazonium ion (CDNBD) as chromogenic derivatizing reagent with subsequent formation of an azo dye. The diazo coupling reaction was carried out between CDNBD and diclofenac. Optimization studies for time and temperature was conducted using the method of steepest ascent. The UV absorption spectrum was recorded and the stoichiometric ratio for the drug and reagent was done by continuous variation method. Optimal calibration range was fixed (1-way ANOVA) and then the method was applied to dosage form analysis. Comparison of dosage form analysis was done with the BP HPLC method. The diazo coupling reaction is very fast and optimization studies established an optimal reaction immediately after mixing the reaction mixture in a vortex mixer for 10 sec. A new absorption maximum (lambdamax) at 470 nm was selected as analytical wavelength. The assays were linear over 1.35-10.8 microg/ml of diclofenac and the reaction required a 2:1 reagent/drug stoichiometric ratio. The new method has a low limit of detection of 0.27 microg/ml, and was reproducible over a three-day assessment of precision (RSD 2.31%). The method has been successfully applied to the assay of diclofenac sodium slow-release tablets and found to be of equivalent accuracy (p>0.05) with the official (B.P 1998) HPLC method. The new method has distinct advantages of speed, simplicity, sensitivity, and more affordable instrumentation and could find application as a rapid analytical method for diclofenac sodium tablets.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

Enhanced bioavailability of piroxicam using Gelucire 44/14 and labrasol: in vitro and in vivo evaluation.

Piroxicam is a non-steroidal anti-inflammatory drug that is characterized by low solubility and high permeability. The purpose of the study was to investigate the in vitro and in vivo performance of the semi-solid dispersion prepared with Gelucire 44/14 and Labrasol into hard gelatin capsules (GL) for enhancing the dissolution rate of the drug. The results were evaluated by comparing with pure piroxicam filled into hard gelatin capsules (PP) and a commercially available tablet dosage form containing a piroxicam:beta-cyclodextrin complex (CD). The in vitro dissolution testing of the dosage forms was performed in different media (simulated gastric fluid, pH 1.2; phosphate buffers, pH 4.5 and 6.8; and water). Amongst the dosage forms, GL provided at least 85% piroxicam dissolution within 30 min in each of the media, behaving like a fast-dissolving immediate release drug product. Oral bioavailability of 20 mg piroxicam in GL, CD, and PP was compared after administration of a single dose to eight healthy volunteers. Three treatments were administered in crossover fashion, separated by a washout period of 2 weeks. Piroxicam was monitored in plasma by high-performance liquid chromatography. The apparent rate of absorption of piroxicam from GL (Cmax=2.64 micrograms/ml, tmax=82.5 min) was significantly higher than that of the PP (Cmax=0.999 micrograms/ml, tmax=144 min) (P<0.05) and similar to that of CD (Cmax=2.44 micrograms/ml, tmax=120 min) (P>0.05). The relative bioavailability values as the ratios of mean total AUC for GL relative to PP and CD, were 221 and 98.6%. Piroxicam is characterized by a slow and gradual absorption via the oral route and this causes a delayed onset of therapeutic effect. Thus, plain piroxicam preparations are not indicated for analgesia. The results of the in vivo study revealed that the GL dosage form would be advantageous with regards to rapid onset of action, especially in various painful conditions where an acute analgesic effect is desired.

Adult↗
PubMed2001

Modeling and comparison of dissolution profiles.

Over recent years, drug release/dissolution from solid pharmaceutical dosage forms has been the subject of intense and profitable scientific developments. Whenever a new solid dosage form is developed or produced, it is necessary to ensure that drug dissolution occurs in an appropriate manner. The pharmaceutical industry and the registration authorities do focus, nowadays, on drug dissolution studies. The quantitative analysis of the values obtained in dissolution/release tests is easier when mathematical formulas that express the dissolution results as a function of some of the dosage forms characteristics are used. In some cases, these mathematic models are derived from the theoretical analysis of the occurring process. In most of the cases the theoretical concept does not exist and some empirical equations have proved to be more appropriate. Drug dissolution from solid dosage forms has been described by kinetic models in which the dissolved amount of drug (Q) is a function of the test time, t or Q=f(t). Some analytical definitions of the Q(t) function are commonly used, such as zero order, first order, Hixson-Crowell, Weibull, Higuchi, Baker-Lonsdale, Korsmeyer-Peppas and Hopfenberg models. Other release parameters, such as dissolution time (tx%), assay time (tx min), dissolution efficacy (ED), difference factor (f1), similarity factor (f2) and Rescigno index (xi1 and xi2) can be used to characterize drug dissolution/release profiles.

Chemistry, Pharmaceutical↗
PubMed1993

Pharmacokinetics of diclofenac and misoprostol when administered alone or as a combination product.

The pharmacokinetics of a new diclofenac/misoprostol combination dosage form have been investigated. Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that has been commercially available for many years and its pharmacokinetics are well documented. Similarly, misoprostol is a prostaglandin analogue with well documented pharmacokinetics. It is available commercially as both an effective treatment for peptic ulceration and as prophylaxis of NSAID-induced gastric and duodenal damage. The aim of studies of the diclofenac/misoprostol combination dosage form has been to determine the potential for drug-drug interactions between the 2 drugs when they are coadministered. A single dose crossover study in young healthy volunteers showed no statistically significant differences between the plasma concentrations of either diclofenac or misoprostol when the drugs were each administered alone and those after administration of the combination dosage form. Although not statistically significant, slight variations in plasma diclofenac concentrations appeared to occur between dosage forms. Use of a replicate design study in which the same dosage of diclofenac was administered in 2 different treatment periods to elderly volunteers showed that this variation was due to interindividual variations in the disposition of diclofenac. The latter study had both single and multiple dose components and confirmed the lack of interaction between misoprostol and diclofenac at steady-state. Thus, diclofenac and misoprostol may be given in a combination dosage form without either drug altering the pharmacokinetics of the other.

Administration, Oral↗
PubMed2006

Pharmacokinetic/pharmacodynamic modeling of total lymphocytes and selected subtypes after oral budesonide.

In the present pharmacokinetic/pharmacodynamic (PK/PD) evaluation, cortisol, total lymphocytes, and lymphocyte subpopulations were monitored following single oral doses of two oral formulations of 3 mg budesonide (BUD) (Dosage Forms A and B) in order to assess the differential effects that BUD may have on cortisol suppression and the modulation of blood lymphocyte subtypes. On a single occasion, five subjects received one 3 mg capsule of Dosage Form A, four received three capsules of Dosage Form A (single dose of 9 mg), and five received three capsules of Dosage Form B (single dose of 9 mg). Placebo capsules were administered to six subjects in the study. Cortisol concentrations, total lymphocyte counts, and lymphocyte subpopulation counts for the CD3, CD4, CD8, CD19, and CD56/16 were fitted to an in direct PK/PD response model that described the effects of BUD on serum cortisol concentrations as well as the combined effects of BUD and cortisol on total lymphocytes and the CD3, CD4, CD8, CD19, and CD56/16 subtypes. Data were also analyzed using noncompartmental methods. The PK/PD model fitted the data with the exception of data for CD56/16. The IC(50) value for unbound BUD acting on total lymphocytes was 0.276 ng/ml while the IC(50) values for unbound BUD acting on lymphocyte subtypes ranged from 0.150 ng/ml for CD4 to 0.364 ng/ml for CD8. The IC(50) values for the effects of BUD on serum cortisol were lower (0.079 ng/ml). The results of PK/PD modeling and noncompartmental analysis indicate that BUD has a smaller effect on the CD8 subtype and larger effects on the CD4 and CD19 subtypes, relative to the effect on total lymphocytes, and that cortisol suppression, although not a direct immunological biomarker, may be a more sensitive marker for the systemic effect of corticosteroids.

Administration, Oral↗
PubMed1995

Regiospecific intestinal absorption of the HIV protease inhibitor L-735,524 in beagle dogs.

PURPOSE: To evaluate regional intestinal absorption and the feasibility of sustained release dosage form development for an HIV protease inhibitor, L-735,524, METHODS: L-735,524 free base or sulfate salt was administered orally as suspension, solution or in solid dosage forms to fasted or fed Beagle dogs. Delayed-release dosage forms with "slow" or "fast" in vitro dissolution rates were evaluated in vivo to assess plasma concentration profiles. In addition, drug was administered directly into the jejunum or colon of animals, and drug concentrations determined in portal circulation to characterize absorption from these sites. RESULTS: L-735,524 sulfate was well absorbed orally form a solution or capsule formulation if fasted animals' stomachs were preacidified with citric acid solution. A free base suspension, delivered in divided doses to fed animals, was also well absorbed. Prototype extended release dosage forms of L-735,524 produced a reduction in peak plasma levels but failed to prolong absorption and extend plasma concentrations compared to an immediate release capsule. Administration of L-735,524 sulfate solution (pH < 3) as bolus solution or by infusion into the jejunum resulted in rapid but incomplete absorption compared to oral gavage. The free base suspension (pH 6.5) delivered into jejunal or colonic regions did not produce measurable systemic plasma concentrations. CONCLUSIONS: Extended release formulations did not prolong absorption of L-735,524 in dogs. Optimal L-735,524 absorption was dependent on solubility in an acidic environment in the duodenum.

Administration, Oral↗
PubMed2003

Impact of physical properties of formulations on bioavailability of active substance: current and novel drugs with cyclosporine.

During the long period of cyclosporine-containing dosage forms development a lot of significant findings have been done especially in the field of drug delivery systems. Currently available drugs are based, from technological point of view, on self-dispersible drug delivery systems, which contain cyclosporine solved in pharmaceutically acceptable vehicle. One can find difference among particular systems: (a) at particle size distribution after dispergation; (b) at composition; and (c) at bioavailability of cyclosporine. As far as improvement of bioavailability between original brand leader formulation Sandimmune and recent brand leader formulation Neoral was followed by significant improvement in particle size distribution, it was generally assumed that the reason for this improvement have been found. Several other formulations, e.g. Consupren or SangCyA-self-dispersible systems, more or less correspond with above-mentioned theory that smaller is better and by this principle bridged liquid based dosage forms with solid dosage forms. Bioavailability of novel drug delivery system which gives coarse dispersion with average particle size between 1-150 microm when dispersed have been tested on healthy volunteers. No difference among pharmacokinetic parameters of novel drug delivery system and microemulsion system have been observed in spite of fact that average particle size of novel system is almost 1000x bigger.

Administration, Oral↗
PubMed1997

Mismatch of duodenal deliveries of dietary fat and pancreatin from enterically coated microspheres.

Gastric emptying of dietary fat is affected by both chemical and physical factors; but when ingested as a free oil or an aqueous emulsion, fat may empty most rapidly immediately after the meal. In contrast, gastric transit of 1- to 3-mm spheres (like those of enterically coated pancreatins) is known to vary inversely with sphere diameter; and spheres leave the stomach initially slowly, if their diameter is > or = 1.6 mm. Our objective was to determine whether 2-mm microspheres of Pancrease would empty much more slowly than free or emulsified oil and whether 1.2-mm microspheres of Creon would empty as fast as free oil. We used a gamma camera to track the concurrent gastric emptying of 123I-labeled oil and 113mIn-labeled spheres of Pancrease or Creon in pancreatic-insufficient subjects with cystic fibrosis who ingested 20 g of free oil in spaghetti meals or 20 g of oil emulsified in a milk meal. We found that either type of oil emptied rapidly initially but slowed later, whereas either dosage form emptied slowly initially but rapidly later. Unexpectedly, the smaller spheres of Creon emptied about the same as Pancrease did after the spaghetti meal. For example, 50% of oil but < 25% of either dosage form had left the stomach by 90 min after the meals. Both dosage forms were lipophilic, forming aggregates in vitro. We concluded that the gastric emptying of either dosage form frequently lagged behind the emptying of oil from ordinary meals. We speculated that the similar transits of the 1.2-mm Creon and the 2-mm Pancrease resulted from aggregation of these microspheres in the presence of free oil.

Adult↗
PubMed1997

The formulation of drug for ocular administration.

The different barriers that slow the penetration of active ingredients administered by the ocular route are described, and some novel dosage forms designed for this route are discussed. Both precorneal and corneal factors considerably restrict ocular penetration. The low bioavailability of classical ophthalmic dosage forms can be improved by several approaches, particularly by increasing the time the active ingredients remain in contact with the eye tissues. The new dosage forms are reviewed according to their type and their drug release mechanisms. The characteristics, advantages, and limitations of each are outlined. The potential of these dosage forms can be expected to enhance development. They offer prolonged effectiveness, reproducibility, fewer unwanted side effects, and improved tolerance.

Drug Administration Routes↗
PubMed2002

Determination of the binding parameter constants of Renagel capsules and tablets utilizing the Langmuir approximation at various pH by ion chromatography.

Sevelamer hydrochloride is a cross-linked polymeric amine; it is the active ingredient in Renagel capsules and tablets. Sevelamer hydrochloride is indicated for the control of hyperphosphatemia in patients with end-stage renal disease. The binding parameter constants of sevelamer hydrochloride were determined using the Langmuir approximation for three different dosage forms at pH 4.0, 5.5 and 7.0. The three dosage forms were Renagel 403 mg capsules, Renagel 400 mg tablets and Renagel 800 mg tablets. The results demonstrate the equivalency of all three dosage forms at each pH. The results also demonstrate a shift in the binding mechanism from pH 4.0 to 7.0.

Capsules↗
PubMed1990

[Evaluation of liposomal forms of rifampicin and prodigiozan in the treatment of experimental chronic tonsillitis].

Therapeutic effect of liposomal dosages of rifampicin and prodigiozan was studied on rabbits with simulated chronic tonsillitis in comparison to that of commercial ones of the drugs. The treatment schemes included daily intra-tonsillar++ injections of the dosage forms for 5 days. A high efficacy of their liposomal dosage forms in treatment of experimental chronic tonsillitis was confirmed microbiologically and immunologically. Approval of the liposomal dosage forms used in the therapy of patients with chronic tonsillitis requires clinical trials.

Adjuvants, Immunologic↗
PubMed1979

A priori lithium dosage regimen using population characteristics of pharmacokinetic parameters.

The important problem of initiation of long-term lithium treatment is tackled by means of the selection of an a priori dosage regimen based on the presumed efficacy of lithium and absence of toxicity. The pharmacokinetics of Li+ ion is represented by a four-compartment open model including the supposed first-order processes for the release of the active compound from the dosage form and its absorption. Experimental protocols for measurements of serum concentrations and of urinary amounts after single and multiple dosing to healthy volunteers were derived with several oral dosage forms. Estimation of the pharmacokinetic parameters for each subject made it possible to validate the model for the various dosage forms. The interindividual variability of these parameters is taken into account by estimating the characteristics of the statistical distribution for the whole population. A dosage regimen is considered optimum when serum concentration profiles at steady state range from the threshold of efficacy (0.8 mmol/liter) to the threshold of toxicity (2.0 mmol/liter). When the number of daily intakes is fixed, the search for the optimum dose for the whole population is effected by minimizing the expected value of the random variable which characterizes the risks of excursion out of the therapeutic range. By this means universal dosages are shown to be unsatisfactory. However, certain dosage regimens individualized with respect to the renal clearance value of lithium and based on two or three daily intakes can give excellent results even when conventional dosage forms are used.

Adolescent↗
PubMed1988

Gastric emptying rates of drug preparations. II. Effects of size and density of enteric-coated drug preparations and food on gastric emptying rates in humans.

Enteric-coated granules with different densities and tablets of different sizes were prepared in order to study the effect of these physical properties of dosage forms on the gastric emptying rates in humans. The effect of food on the gastric emptying rate was also studied. Aspirin contained in an enteric-coated product as a marker drug was used to determine the gastric emptying rate by measuring salicylates excreted into the urine. The larger the size of the dosage form, the larger were the values of parameters for estimating the gastric emptying rate such as tlag, tmax and the mean absorption time. There was a significant correlation between the gastric emptying rates and sizes of dosage forms. On the other hand, no effects of density of enteric-coated granules on the gastric emptying rate were observed. The gastric emptying of dosage forms of various sizes or densities tested were prolonged by food. However, the gastric emptying rate of granules was less affected by food than that of tablets.

Aspirin↗
PubMed1983

Innovations in drug delivery systems.

The history of pharmaceuticals has reflected a concern with the development of new chemical entities. Only recently has the importance of dosage form design been recognized as a vital component of effective therapy. Not only has the time and expense involved in the research of the new molecules escalated dramatically, but it has been discovered that many of these products might be improved through incorporation in rate-controlled dosage forms. Conventional formulations have provided vehicles with which to introduce agents into the body. New therapeutic systems offer great versatility since they permit localized treatment of specific tissues, sophisticated methods of animal experimentation, and controlled-release methods for systemic delivery. These new dosage forms are diverse, precise, and adaptable in many therapeutic situations. A membrane-controlled gastro-intestinal therapeutic (GIT) system resembling a conventional tablet in external appearance has recently been developed. This system is designed for the constant, controlled release over a period of 10 to 12 hours of drug in solution and uses osmotic activity as the source of energy. The GIT system, as used for 'Osmosin' (sodium indomethacin trihydrate), differs from conventional sustained-release and other controlled-release dosage forms in that the rate of release is not dependent upon pH to release the medication and is designed, therefore, to overcome the problems associated with unpredictable release patterns.

Animals↗
PubMed2002

The effect of food on the pharmacokinetics of nifedipine in two slow release formulations: pronounced lag-time after a high fat breakfast.

AIMS: The aim of this study was to investigate the effect of concomitant food intake on the bioavailability of two nifedipine containing modified release dosage forms for once daily administration. The clinical study was performed to investigate the in vivo relevance of pH-dependent differences in the in vitro release properties of the two dosage forms. METHODS: This was a randomized, open, 4-way crossover study in 24 healthy, male subjects. Following an overnight fast of 12 h single doses of Adalat OROS or Slofedipine XL were administered either in the fasted state or immediately after a high fat American breakfast. Nifedipine plasma concentrations in samples obtained until 48 h after drug administration were determined using a validated LC-MS/MS method. Calculation of pharmacokinetic parameters was conducted model-independently. The two dosage forms as well as the two administration conditions were compared by calculating point estimates and 90% confidence intervals for the relevant pharmacokinetic parameters. In vitro dissolution tests were performed using a paddle apparatus 3 acc. USP, a pharmacopoeial dissolution system consisting of reciprocating cylinders in flat-bottomed glass vessels, with various buffer systems covering the entire physiological pH-range of the gastrointestinal tract. RESULTS: After fasted administration the extent of bioavailability of nifedipine as characterized by AUC(0,infinity) was slightly lower for Slofedipine XL compared with Adalat OROS with a point estimate of 82.3% primarily resulting from pronounced differences in nifedipine concentrations during the first 15 h after administration. Accordingly, maximum plasma concentrations were lower after administration of Slofedipine XL compared with Adalat OROS (point estimate: 84.3%). Under fed conditions the differences in bioavailability between the two products as characterized by the pharmacokinetic parameters AUC(0,tn) and Cmax were greater than after fasting conditions with point estimates of 69.6% and 81.0%, respectively. However, most striking was a pronounced delay in nifedipine absorption observed under fed conditions after administration of Slofedipine XL which resulted in lag-times of more than 15 h in 15 out of 24 subjects. Owing to this lag-time under fed conditions the relative bioavailability of nifedipine from Slofedipine XL compared with Adalat OROS was only 28% over the intended dosing interval of 24 h. CONCLUSIONS: In this study a dosage form-dependent food interaction was observed which, under fed conditions, resulted in pronounced differences in the relative bioavailability of nifedipine between Slofedipine XL and Adalat OROS over the intended dosing interval of 24 h. The delay in nifedipine absorption when Slofedipine XL is administered after a high-fat breakfast may be explained by the formulation properties. Slofedipine XL is an erosive tablet with an acid resistant coating whereas Adalat OROS is designed with an osmotic push-pull system. Under fed conditions drug from the single unit enteric coated dosage form exhibits a delayed absorption probably due to an extensively prolonged gastric residence time which does not allow drug release, on the other hand the osmotically driven push-pull system is not sensitive to concomitant food intake. The observed phenomenon might be of therapeutic relevance. For example a change from taking Slofedipine XL in the fed to the fasted state might result in increased systemic concentrations of nifedipine.

Administration, Oral↗
PubMed2003

Dissolution and absorption modeling: model expansion to simulate the effects of precipitation, water absorption, longitudinally changing intestinal permeability, and controlled release on drug absorption.

A previously described model for simulating drug dissolution, absorption, and pharmacokinetics has been expanded beyond the original application of simulating immediate-release dosage forms to include simulation of drug precipitation, water absorption from the gastrointestinal tract, changing gastrointestinal permeability, disintegration, and controlled-release and dissolution from a GITS-type dosage form. A mathematical description of the model is presented as well as a retrospective analysis of nifedipine to demonstrate the utility of the model. The fourth-order Runge-Kutta numerical method was used to solve the series of coupled differential equations used to simulate the process of dissolution, absorption, and drug disposition. The model was able to simulate the clinically demonstrated effect for drug particle size on nifedipine plasma concentrations for an immediate-release dosage form. Further simulations indicated that drug particle size was less important for a GITS-type dosage form at a release rate of 1.7 mg/hr compared to rate of 17 mg/hr. Hypothetical calculations simulated the potential effect of drug precipitation, water absorption, and changing permeability on drug plasma concentrations. The expanded model increases the utility of a previously described model in providing guidance in drug development and selection.

Biological Availability↗
PubMed1986

Relative and absolute bioavailability of cibenzoline capsules and tablets in healthy subjects.

Eighteen healthy adult volunteers completed an open-label, four-way crossover study designed to determine the bioequivalency of 160-mg cibenzoline [2-(2,2-diphenylcyclopropyl)-4,5-dihydro-1H-imidazole] capsules and tablets, their relative bioavailability compared with an oral solution of the drug, as well as the absolute bioavailability of these dosage forms compared with an intravenous infusion of the drug. Blood samples obtained at specified times after drug administration were assayed for cibenzoline by HPLC, and pharmacokinetic parameters were estimated from the resulting plasma concentration-time profiles. Comparisons were made between the tablet and capsule to assess bioequivalency, between the solid dosage forms and a solution to assess relative bioavailability, and between the oral forms and an intravenous infusion to assess absolute bioavailability. The pharmacokinetic parameters for each oral dosage form were similar and ratios of mean parameters indicated that the solid dosage forms were bioequivalent and completely bioavailable relative to an oral solution. The ratios of the area under the plasma concentration-time profiles (AUC) for the capsule, tablet, and oral solution to that of the intravenous infusion were 0.85, 0.83, and 0.86, respectively, indicating that orally administered cibenzoline has an absolute bioavailability of approximately 85%.

Adult↗