Pharmaceutica acta Helvetiae最新文献

A semi-physiological pharmacostatistical model was developed and used to study the manner in which intra-individual variability in hepatic clearance is transmitted to the area-under the plasma concentration-time curve from zero to infinity (AUC) of a drug and its metabolite. In order to clarify the effects, the model contained no other sources of variability. As the drug's hepatic extraction ratio increased, the coefficient of variation (CV) of the AUC of the drug increased, whereas that of the metabolite decreased. The AUC of the metabolite increased as the drug's non-hepatic clearance increased. In contrast, at low extraction ratios, the CV of the AUC of the drug decreased as the drug's non-hepatic clearance increased. At high extraction ratios, the CV of the AUC of the drug was insensitive to the contributions of other forms of clearance. The results suggest that under certain circumstances, smaller samples sizes could be used in bioequivalence studies for highly variable drugs if the test were based on the metabolite rather than the parent drug.

A simple selective kinetic method for the assay of nalidixic acid in solid state and pharmaceutical preparations is described. The reaction of nalidixic acid with persulfate in alkaline medium was carried out at 75°C. The correlation coefficient was found to be 1.0000. The activation parameters and the factor of the linear least square equation were calculated. The proposed method is suitable to determine nalidixic acid in the range 10–120 μg/ml.

Imidazolylpropylguanidines are potent histamine H₂ receptor agonists and act as inotropic vasodilators. A large series of 141 derivatives was tested in the isolated guinea pig atrium and submitted to CoMFA. Since all compounds are full agonists, pD₂ values reflect H₂ receptor binding. Hydrophobicity was considered as Σf of the variable structural moiety, calculated by the Leo–Hansch method. Preliminary Hansch analysis with Σf, (Σf)² and indicator variables showed that pD₂ additively depends on contributions of certain substructures and has a hydrophobic optimum. For CoMFA, all 3D structures were optimized and aligned. Partial Least Squares analysis of pD₂ as function of steric and electrostatic field variables and of Σf and (Σf)² led to models with r² of 0.78 with and 0.93 without hydrophobicity. Results indicate a parabolic dependence of pD₂ on hydrophobic effects. The 3D distribution of field influences on pD₂ suggests a model (shape and electrostatic potential) of the binding site. The role of branching and different substituent effects of a first and a second ring indicate that adequately branched structures induce a conformational change of the binding site enabling a favourable accommodation of the second ring with various substituents.

Blood lipid levels in rats with hyperlipidemia resulting from high-fat feeding were determined after oral administration of hydroalcoholic extract and polyphenolic fraction of Dracocephalum kotschyi leaves. Administration of the hydroalcoholic extract and polyphenolic fraction produced a significant decrease of blood triglyceride, total cholesterol and LDL-cholesterol levels. HDL-cholesterol level was significantly increased.

A new formulation of topical tretinoin–minoxidil solution was prepared and the chemical stability of tretinoin was studied for 6 months at 4°C. A reversed phase high performance liquid chromatography (HPLC) method was developed for determination of tretinoin using cyanocobalamine as an internal standard. Tretinoin was shown that to be stable for at least 6 months used refrigerated storage conditions.

The physical and physicochemical properties of three lots of high-viscosity hydroxypropylcellulose (HPC) (two lots from a Japanese supplier and one lot from a US supplier) were compared. The drug-release properties of theophylline matrix tablets prepared with the different polymers were also investigated. HPCs from the two suppliers showed clear differences in molecular weight, molecular structure, particle size distribution, particle shape, and water affinity. Furthermore, clear differences were observed in the time-course of drug release from tablets made with the different polymers. The differences in basic physical and physicochemical properties of the HPCs affect compression behaviour, the capacity for and time-course of water uptake, and the rheological properties of aqueous dispersions, which explains the observed differences in time-course of drug release. Molecular weight and particle size distribution are particularly important determinants of drug release properties. Abnormally rapid drug release was observed from tablets prepared with relatively small amounts of the highest-molecular-weight highest-particle-size HPC. This result, together with the fact that the time-course of drug release differs markedly between matrix tablets prepared with HPCs that come from different suppliers but that are nominally interchangeable (at least according to the criteria given in the US Pharmacopoeia), suggests that these two properties (mean molecular weight and particle size distribution) are of value for quality control of HPCs destined for use in the manufacture of matrix tablets.

Bilayered osmotically controlled Gastrointestinal Therapeutic System of atenolol has been obtained by using cellulose acetate pseudolatex prepared by polymer emulsification method. Various factors such as orifice size, coating thickness, amount and nature of polymeric excipients, and amount of osmotic agent influence the drug release from GITS. Therefore, in the present study a 7-factor, 12-run Plackett–Burman screening design was employed to evaluate the formulation variables for atenolol GITS coated with CA pseudolatex. The variables studied were orifice size, %coating weight gain, amounts of sodium chloride, Polyox® N80 and 303, and Carbopol® 934P and 974P on drug release. The screening design has revealed that orifice size, %coating weight gain and amount of Carbopol® 934P have prominent influence on in-vitro atenolol release. The response variable was cumulative percent atenolol released (Y) in 24 h with constraints on percent release at 2, 6, 12 and 18 h. The polynomial equation obtained was Y₂₄=149.82−0.13X₁−0.34X₂+0.06X₃−0.13X₄−0.23X₅−76.25X₆−2.46X₇. The results indicated that the drug release under constrained conditions was influenced by the factors with decreasing order of importance as %coating weight gain>Carbopol® 934P>Polyox® N80>Carbopol® 974P>Polyox® 303>amount of sodium chloride>orifice size.

Various diester analogues of nifedipine in which the ortho nitrophenyl group at position 4 is replaced by 1-methyl-2-methylsulfonyl-5-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists on guinea-pig ileal smooth muscle. Nifedipine was used as a standard. Compound 6n was found to be the most active.

The purpose of this study was to evaluate the possible advantages of floating and high-density dosage forms and their influence on pharmacokinetic parameters. Atenolol was chosen as a model drug because of its poor absorption in the lower gastrointestinal tract. Three formulations containing 25 mg atenolol, a floating multiple-unit capsule, a high-density multiple-unit capsule, and an immediate-release tablet were compared with respect to estimated pharmacokinetic parameters. The two multiple-unit dosage forms were composed of compressed minitablets and had sustained release properties. The bioavailability of the two gastroretentive preparations with sustained release characteristics was significantly decreased when compared to the immediate-release tablet. The floating minitablets seemed to be retained longer in the stomach than the high-density dosage form. The first atenolol concentration detectable in the plasma and the time to peak T_max were delayed for the floating dosage form. For the parameters C_max and AUC_0–∞, the lower limit of the 90% confidence interval was outside the bioequivalence range (0.80–1.25). This study showed that it was not possible to increase the bioavailability of a poorly absorbed drug such as atenolol using gastroretentive formulations. Atenolol absorption was delayed and the maximum plasma concentration was diminished.

The dissolution behavior of poorly water-soluble anti-schistosomal drug, praziquantel (PZQ) from coprecipitates (dispersions) and physical mixtures of the drug with polyvinylpyrrolidone (PVP) was characterized. The dissolution data obtained for different PZQ–PVP systems covering a range of drug loading from 10% to 100% w/w of PZQ in 10% increments were used in order to compare the release kinetics between the mixtures and the coprecipitates. The parameters estimated from release models showed that the coprecipitates exhibited an increase in the release rate in relation to intact PZQ but to a lesser extent than the equivalent physical mixtures. Furthermore, they exhibited different release behavior than the physical mixtures. According to solubility studies of PZQ in the presence of PVP the formation of a PZQ–PVP complex can be assumed. This hypothesis led to consistent interpretations of the dissolution profiles. In the coprecipitates the presence of PVP led to near zero-order release. The release kinetics were interpreted in terms of critical percolation thresholds according to the percolation theory.