In order to bring definitions of drug dosage forms up to date, it was necessary for the French Pharmacopoeia to propose assays allowing the quality control of the dosage forms to be based on the ...kinetics of drug release in vitro. Currently, five examples can be cited of dosage forms that can be characterized by release in vitro. (1) Oral solid dosage forms--for tablets, all the parameters of powders before compression (e.g., flowability, tableting properties) are being studied in addition to the dissolution tests, (2) Rectal dosage forms--the disintegration test of suppositories will be discarded and a new dissolution test using a special flow-through cell is now being studied. (3) Inhalations--since particle diameter is the most important factor for inhalation activity, a method has been developed to give the correct answer to this question. (4) Modified release drug dosage forms--these have been defined separately from the conventional forms. For the peroral route, they are: (i) accelerated release drug dosage forms, (ii) sustained release drug dosage forms and (iii) delayed release drug dosage forms. To emphasize the differences in the release kinetics, use of the paddle method, well known in the USP, and the flow-through cell has been suggested and described in the European Pharmacopoeia. Some associations and/or in vitro-in vivo correlations have increased the interest in the last method. (5) Transdermal delivery systems--these are defined separately from plaster and sticking-plaster. The use of a cell method was suggested to study the drug release and some comparisons between different techniques are presented.
In order to assess the extent and the rate of absorption in bioavailability studies, area under the curve (AUC), experimental maximum concentration (Cmax) and experimental time to reach Cmax (Tmax), ...are used. But when slow-release formulations are considered, the drug concentration-time curves usually show multiple peaks, and it is difficult to compute a Cmax and Tmax value. In case a Cmax value is computed, important variability in this parameter results in high values in the residual variance of the ANOVA test. So in order to decrease the high variability, average parameters: average concentration (Cav), average maximum concentration (Cmax,av) and Cmax,av x 100/Cav (%Cmax,av), are proposed. These new parameters were applied in a bioavailability study of slow-release amitriptyline formulation.
In a French region where farmer's lung (FL) is common, we determined the prevalence of FL precipitins in dairy farmers and analyzed the relation between the presence of FL precipitins and the ...clinical probability of the disease. All the exposed dairy farmers of both sexes (n = 2555) from five districts of the Doubs department were asked to respond to a medical and professional questionnaire. A total of 1763 (69%) farmers agreed to participate. Precipitins tests were conducted in 551 (31%) farmers who showed any respiratory symptom and in a random sample of 100 asymptomatic farmers. Serum for each farmer was analyzed by both double diffusion and immunoelectrophoresis against Micropolyspora faeni (MF) and extracts of moldy hay (HE) from Doubs. The 651 farmers were then divided into four groups (G 1-4) with a decreasing probability of FL (G1: typical FL symptoms; G4: asymptomatic farmers). The estimated prevalence of precipitins in the whole population was as follows: 1) by double diffusion, against HE: 83%, against MF: 27%; 2) by immunoelectrophoresis, against HE: 26%, against MF: 19%. There was a close "linear" relation between the prevalence of precipitins detected by immunoelectrophoresis against HE and the symptoms: 51% in G1, 36% in G2, 29% in G3, and 13% in G4. Precipitins detected by immunoelectrophoresis were also related to exposure and geography (more immunization in tableland area than in plain or mountain area). Presence of precipitins detected by double diffusion was not related to symptoms, exposure, or geography.
Abstract
The work reported here describes the improvement of an industrial production of tablets formed by direct compression. This formulation contained 50% active substance of plant origin as a ...nonhygroscopic powder. The first step was to evaluate a number of direct compression excipients in preformulation tests and then make up a basic formulation providing tablets with correct characteristics. The second step was the optimization of the initial formulation using a two-level factorial experimental design. This enabled the best formulations to be selected objectively.
The effect of food on the bioavailability of the antidiabetic drug metformin (Glucophage, Lipha Laboratories) was investigated in patients at steady-state. Seventeen diabetic patients (5 males and 12 ...females) treated with a long-term metformin therapy received their morning dose after an overnight fasting or after each of four types of breakfast: low protein, low fat, low carbohydrate or standard. Mean (+/- SD) and median areas under the serum concentration curves (AUC), maximum concentrations (Cmax) and time to reach the Cmax (Tmax) were calculated. Compared to fasting conditions, AUC and Cmax for metformin were bioequivalent after the four types of breakfast except the low fat (high carbohydrate) diet which had results slightly reduced (90% CI = 0.76-0.90). The intraindividual variability was calculated and found to be lower than the interindividual variability.
Several studies have been devoted to cross-linked sodium chondroitin sulphate (SCS), in the context of numerous strategies attempting to target the colon for the absorption or the therapeutic action ...of a drug. SCS, a glycosaminoglycan presenting a specific degradation in the colon, is in fact soluble in water and its use as drug carrier at such a distance from the digestive tube necessitates its hydrophobisation. One method described in the literature consists in manufacturing a three-dimensional network by cross-linking with bifunctional compounds. However, all the structural characterisations carried out on the products resulting from the catalysed treatments of SCS with diaminoalkanes demonstrate that there are no cross-linking bridges between the polymer chains. Moreover, treated SCS-based tablets containing theophylline as model drug lead in vitro to dissolution profiles which are identical to those obtained with the non-treated SCS. We were therefore unable to find the announced results using the method described.
Abstract
A novel method is described that simplifies in vitro dissolution tests of programmerelease drug dosage forms. It is based on a single solid reagent that affords immediate stepped-pH ...conditions using a single unitization to model the physiological gradient. Six pharmaceutical products were tested using two methods; the paddle method and the through flow cell method. The dissolution efficiencies obtained with the proposed reagent were identical to those obtained with classical buffers used in dissolution tests. Varying dissolution parameters (paddle rotation rate, flow rate in the through flow cell, use of surfactants) gave closely similar results for the two pH stepping methods but with the added advantage of a single medium.
Seventeen diabetic patients (5 males and 12 females) treated with long-term metformin therapy received their morning dose after an overnight fast or after one of four types of breakfast: low protein, ...low fat, low carbohydrate or standard. Mean (+/- SD) and median areas under the serum concentration curves (AUC), maximum concentrations (Cmax) and time to reach the maximum concentrations (tmax) were calculated for the major biological parameters (glycemia, C-peptide, insulin and glucagon levels). None of the diets were bioequivalent to the fasting condition and only the low carbohydrate diet gave comparable results. A strong relationship was found between the carbohydrate intake (in g) and the AUC of the various markers except glucagon.
The sustained release properties of an indomethacin hard-gelatin capsule formulated with saturated polyglycolysed glycerides (Gelucire®) were demonstrated in vivo. Indomethacin was selected as a ...model drug with very poor solubility in water and acidic media. It is known to exhibit high intersubject variability because of enterohepatic circulation. The formulation, which in vitro showed an erosion-controlled release, was compared in six human volunteers in the fed state by using a randomized cross-over design, to a standard multiple-unit diffusion-controlled pellet capsule. Close action period values (time duration with plasma levels higher than 0.5 μg/ml) were found for the test and the reference formulation (5.2 and 5.7 h). The time to reach peak tmax appeared slightly shorter for the test preparation (1.75 h) than for the reference formulation (2.67 h), but the difference was not statistically significant because of the high intersubject variability (non-parametric Wilcoxon matched pair test). Again, due to the small number of subjects entered in the study (insufficient for a real bioequivalence study) equivalence could not be accepted in terms of extent and rate of absorption based on the decision procedures involving the 90% confidence interval and the two one-sided t-tests. The mean maximum plasma concentrations Cmax were 3.35 and 2.82 μg/ml for the test and the reference formulation respectively, with the corresponding values of the area under the plasma concentration-time curve AUC amounting to 10.14 and 11.38 μg h/ml. However, a simulation on 24 subjects (3 repetitions of the same data) would lead to bioequivalence of the two preparations. As for other corrosion-controlled forms, drug release from the proposed Gelucire® formulation was very sensitive to hydrodynamic conditions, leading to poor in vitro-in vivo correlation, when comparison is made with a reference formulation characterized by a diffusion-controlled release. Finally, it was concluded that erosion-controlled release formulations are especially suitable for drugs, such as indomethacin, that have low solubility in water or acidic media. More generally, sustained release hard gelatin capsules with thermosetting excipients is very versatile and their preparation is very straightforward.
