In Vivo Evaluation of Pindolol Multi-Unit Dosage Forms

Abstract

Pindolol, a beta adrenoceptor agent, is effective in the treatment of hypertension in daily doses ranging from 10 to 45 mg. The drug shows pH dependent solubility and a modified multi unit controlled release formulation was assessed for efficacy in vivo in healthy male human volunteers. An open blind comparative crossover study of the controlled release formulation was carried out with a conventional formulation. The treated quotients and the ratio between the maximal plasma concentration were calculated to assess the efficacy of the formulations.     

Assessment of Disintegration and Dissolution of Dosage Forms In Vivo Using Gamma Scintigraphy

Abstract

The measurements of the in vitro rate of disintegration and dissolution of dosage forms are considered to be the most available predictors of the behaviour of dosage forms and the plasma concentration - time profile. However, the interaction of the formulation with physiological processes has shown that prediction of bioavailability by such simple tests is inadequate and has highlighted the need to establish methodology which would enable the determination of in vivo rates of dissolution and disintegration. Over the past ten years, the technique of gamma scintigraphy has made a significant contribution to the understanding of the behaviour of formulations in the body. This review provides an overview of the technique and its advantages and limitations in pharmaceutical research, together with illustrations showing some of the applications in the measurement of disintegration and dissolution of dosage forms.     

Studies of Floating Dosage Forms of Furosemide: In Vitro and In Vivo Evaluations of Bilayer Tablet Formulations

For the purpose of enhancement the bioavailability of furosemide (FR), a floating dosage form with controlled release of FR was designed in this study. Because of the lower solubility of active material in the gastric medium, it was first enhanced by preparing an inclusion complex of FR with beta-cyclodextrin (β-CD) in a 1:1 proportion using the kneading method. Following the design of dosage form, bilayer floating tablets were prepared. After dissolution rate studies were performed using the continuous flow-through cell method, the formulation that provided delivery of active material near the target profile was given to six healthy male volunteer subjects, and in vivo tests were performed. It was determined by radiographs that floating tablets prepared by adding BaSO₄ stayed in the stomach for 6 hr. Further, values of the area under the plasma concentration-time curve (AUC) obtained with the floating dosage form were about 1.8 times those of the conventional FR tablet in blood analyses; maximum and minimum plasma concentrations were also found to be between the desired limits. In urine analyses, the peak diuretic effect seen in classical preparations was decreased and prolonged in floating dosage forms. Also, a considerably significant correlation was detected between in vivo results and in vitro data of the dissolution rate, and it was concluded that the modified continuous flow-through cell method is usable for in vitro dissolution rate tests of floating dosage forms.     

Ketoprofen Suppository Dosage Forms: In Vitro Release and in Vivo Absorption Studies in Rabbits

In vitro release of ketoprofen from suppository bases and in vivo absorption in rabbits were studied. Suppositories containing 50 mg of ketoprofen were prepared using theobroma oil, esterified (c₁₀–c₁₈) fatty acids, and polyethylene glycol 1000 bases. The displacement values of the drug were determined and found to be of the order of theobroma oil > esterified (c₁₀–c₁₈) fatty acids and polyethylene glycol 1000 bases. The suppository hardness data revealed that the theobroma oil base produced relatively brittle suppositories. Using the USP dissolution method, the release of ketoprofen was observed to be greatest from polyethylene glycol 1000 suppositories. With the dialysis technique, the maximum release of drug was obtained from theobroma oil suppository containing polysorbate 40 at a 6% level. Selected suppository formulations were evaluated for rectal absorption studies in rabbits. The in vivo data showed that the optimum drug absorption took place from the polyethylene glycol 1000 base and theobroma oil formulation containing 6% polysorbate 40.     

Evaluation of Dosage Forms. VI. Studies of Commercial Oxyphenbutazone Tablet Dosage Forms

Dissolution-dialysis studies of commercial tablets of oxyphenbutazone were carried out to establish the applicability of this technique for the in vitro evaluation of oxyphenbutazone dosage form. While disintegration time and dissolution rate studies did not give a true indication of bioavailability, an excellent correlation was obtained between the dialysis rate constant K and the pharmacokinetic parameters AUC and C_max.     

In Vitro and Invivo Evaluation of Some Fast Release Dosage Forms of Hydrochlorothiazide

The utilization of ternary sugar solid dispersion and solvent deposition systems for increasing the dissolution rate of hydrochlorothiazide (hot) were investigated. The dispersion systems were prepared by the fusion method using various combinations of mannitol and sorbitol, and urea and polyethylene glycol 4000 (peg 4000) were used for comparison. An 1:2 mixture of sorbitol-mannitol was found to be an excellent carrier. The dissolution rate of this sample was closely comparable to that of hot-peg 4000 solid dispersions. Drug-urea eutectic mixtures were inferior to both the sugar and polymer dispersions. Solvent deposition systems of hot with microfine cellulose and potato starch gave higher dissolution rates at the initial sampling times. It is proposed that solid dispersion systems of this drug may prove to be valuable. Tablets fabricated from fast-release hot granules showed better in vivo results than a marketed tablet. A linear relationship was observed between in vitro-in vivo data of some of the products.     

In Vitro and Invivo Evaluation of Some Fast Release Dosage Forms of Hydrochlorothiazide

Abstract

The utilization of ternary sugar solid dispersion and solvent deposition systems for increasing the dissolution rate of hydrochlorothiazide (hot) were investigated. The dispersion systems were prepared by the fusion method using various combinations of mannitol and sorbitol, and urea and polyethylene glycol 4000 (peg 4000) were used for comparison. An 1:2 mixture of sorbitol-mannitol was found to be an excellent carrier. The dissolution rate of this sample was closely comparable to that of hot-peg 4000 solid dispersions. Drug-urea eutectic mixtures were inferior to both the sugar and polymer dispersions. Solvent deposition systems of hot with microfine cellulose and potato starch gave higher dissolution rates at the initial sampling times. It is proposed that solid dispersion systems of this drug may prove to be valuable. Tablets fabricated from fast-release hot granules showed better in vivo results than a marketed tablet. A linear relationship was observed between in vitro-in vivo data of some of the products.     

Quantitative Evaluation of Different Dosage Forms of Ampicillin

Abstract

The bioavailability of five different commercial brands of ampicillin was examined. The absorption of each dosage form was compared in a crossover study of twelve healthy volunteers (6 males and 6 females). Urinary excretion rates were also employed to evaluate the absorption process. Statistical analysis of the results was carried out to evaluate the significance of differences between dosage forms and subjects. The statistical analysis indicated no significant differences between different tested brands of ampicillin, while the differences between subjects were significant. Comparison between the two different genders indicated no significant differences between the male and female subjects.     

Quantitative Evaluation of Different Dosage Forms of Ampicillin

The bioavailability of five different commercial brands of ampicillin was examined. The absorption of each dosage form was compared in a crossover study of twelve healthy volunteers (6 males and 6 females). Urinary excretion rates were also employed to evaluate the absorption process. Statistical analysis of the results was carried out to evaluate the significance of differences between dosage forms and subjects. The statistical analysis indicated no significant differences between different tested brands of ampicillin, while the differences between subjects were significant. Comparison between the two different genders indicated no significant differences between the male and female subjects.     

In Vitro/in Vivo Evaluation Of A Liquid Sustained Release Dosage Form Of Chlorpheniramine

Abstract

Chlorpheniramine-resin complexes were coated with cellulose acetate butyrate to yield microcapsules with a geometric mean diameter of 346 μm. In vitro release rate of chlorpheniramine declined with increasing microcapsule size. Release of chlorpheniramine from the micropcapsules was faster in simulated gastric fluid (pH 1.2) than in simulated intestinal fluid (pH 7.5). A Chlorpheniramine solution administered by rapid intravenous injection to dogs exhibited a two phase decline in plasma drug concentration. A peroral solution resulted in a rapid rise to a peak followed by a sharp decline in plasma chlorpheniramine concentration. Peroral administration of a microcapsule suspension caused a rapid rise in plasma concentration, but prevented the fast decline.     

In Vitro/in Vivo Evaluation Of A Liquid Sustained Release Dosage Form Of Chlorpheniramine

Chlorpheniramine-resin complexes were coated with cellulose acetate butyrate to yield microcapsules with a geometric mean diameter of 346 μm. In vitro release rate of chlorpheniramine declined with increasing microcapsule size. Release of chlorpheniramine from the micropcapsules was faster in simulated gastric fluid (pH 1.2) than in simulated intestinal fluid (pH 7.5). A Chlorpheniramine solution administered by rapid intravenous injection to dogs exhibited a two phase decline in plasma drug concentration. A peroral solution resulted in a rapid rise to a peak followed by a sharp decline in plasma chlorpheniramine concentration. Peroral administration of a microcapsule suspension caused a rapid rise in plasma concentration, but prevented the fast decline.     

Bioavailability of Cephalexine Dosage Forms

The bioavailability of 3 brands of cephalexine (tablets, capsules and suspension) using a solution as a reference standard was evaluated in 8 healthy volunteers in a crossover design. Single oral doses of each product were administered at intervals of 1 week. Statistical analysis of the cumulative urinary amount of cephalexine excreted after 12 h, indicated no significant differences among them. Moment analysis was used to estimate the mean dissolution and mean absorption time, showing that dissolution is the rate limiting step in tablets and capsules.     

Bioavailability of Cephalexine Dosage Forms

Abstract

The bioavailability of 3 brands of cephalexine (tablets, capsules and suspension) using a solution as a reference standard was evaluated in 8 healthy volunteers in a crossover design. Single oral doses of each product were administered at intervals of 1 week. Statistical analysis of the cumulative urinary amount of cephalexine excreted after 12 h, indicated no significant differences among them. Moment analysis was used to estimate the mean dissolution and mean absorption time, showing that dissolution is the rate limiting step in tablets and capsules.     

Disintegrants in Solid Dosage Forms

Abstract

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

Disintegrants in Solid Dosage Forms

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

Carbamazepine Modified Release Dosage Forms

Abstract

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid – methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Carbamazepine Modified Release Dosage Forms

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid - methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Characterization of the In Vitro Dissolution of Some Commercial Sustained Release Theophylline Dosage Forms

A dissolution study of five commercial sustained release theophylline dosage forms, concerning their pH dependency, is described. The experiment was carried out in a flow through dissolution apparatus, at constant pH and at pH gradient, being the pH values of 1, 2, 6, 5 and 7, 5. In both cases, they were treated in terms of the dissolution profile and the dissolution rate, complemented with the dissolution efficiency at pH gradient in order to make a correlation with the in vivo experiments that will be done in the future. The absorbance was measured at a wavelength of 264 nm. According to the results obtained, was selected the best pharmaceutical form, concerning the pH dependency and taking as a basis, just, the in vitro experiments.