Acta pharmaceutica Nordica最新文献

The in vitro dissolution rates of enteric-coated pellets and tablets containing dexchlorpheniramine maleate (DCPM) were obtained using the USP XXI paddle and a flow-through method. Pellets were produced by extrusion and spheronization. Tablets were produced by direct compaction, and by wet granulation. The products were coated with different amounts of Eudragit L30D using fluid-bed technology. Onset of release, determined by fitting of the Weibull function, was the only factor found to be affected by the amount of coating of the tablets. For pellets, both onset of release and dissolution rate showed significant differences. Scanning electron microscopy was used to study the effect of different dissolution media on the coating. Acidic medium was found to alter the coating surface, but the coating did not rupture during the time used in this study.

Bioreversible derivatization of cimetidine to afford more lipophilic prodrugs was performed by N-acyloxymethylation of its imidazole group as well as by N-acylation with various chloroformates. Both the N-acyloxymethyl and N-alkoxycarbonyl derivatives were readily hydrolyzed to cimetidine in human plasma and in rat liver homogenate. The pH-rate profiles for the hydrolysis of the derivatives were derived at 60 degrees C. The derivatives were all more lipophilic than the parent drug as determined by partition experiments in octanol-aqueous buffer systems. In vitro studies using the modified Ussing-chamber technique showed that some derivatives possessed increased permeability coefficients for the transport across the rat jejunum relative to cimetidine. The results obtained suggest that these derivatives may be useful to improve the biomembrane transport characteristics of the hydrophilic cimetidine.

Various carboxylic acid and carbonate esters of the opioid analgesic ketobemidone were prepared and assessed as potential prodrugs with the aim of obtaining a ketobemidone formulation suitable for buccal or sublingual absorption. The chemical stability, enzymatic hydrolysis and lipophilicity characteristics of the esters were studied using HPLC assay procedures. All esters were rapidly hydrolyzed in human plasma, the half-lives ranging between 0.03 and 1.8 min. A marked enzymatic hydrolysis took place in whole human saliva, the half-lives of hydrolysis being in the range 3-295 min. All esters were more lipophilic than the parent ketobemidone, as determined by octanol-buffer partition experiments and by reversed-phase column chromatography. The relatively high resistance of the sterically hindered 3,3-dimethylbutyryl ester to undergo hydrolysis in saliva combined with its facile plasma-enzyme catalyzed conversion and high lipophilicity makes this ester the most promising prodrug candidate for buccal delivery.

The kinetics of hydrolysis of acyclovir was studied in 0.01-0.5 M hydrochloric acid solutions (pH 0.5-2.2) at 80 degrees C. The hydrolytic cleavage of the 9-C-N bond in acyclovir to give guanine was found to proceed almost quantitatively (greater than 90%) as evidenced by HPLC analysis. The rate of hydrolysis was subject to apparent specific acid catalysis, the specific hydrogen ion catalytic rate constant being 4.9 x 10(-2) M-1 min-1 at 80 degrees C and mu = 0.5. The possible significance of acid-catalyzed hydrolysis for the stability of acyclovir during its transit through the stomach after peroral administration was found to be negligible. A novel 4-(morpholinomethyl)benzoate ester prodrug of acyclovir was found to be three times more stable in acidic solutions than acyclovir itself despite the ester group being an additional site of degradation. The dominating degradation reaction of the ester was found to be cleavage of the 9-C-N bond. The higher stability of the ester was ascribed to the greater electron-withdrawing effect of the ester group relative to the hydroxyl group which decreases the tendency of the 9-C-N bond to be ruptured by an A-1 mechanism.

A series of alkylthiolated 2,3-dicyano-1,4-benzoquinones was synthesized and tested for the effects on the respiratory chain in beef heart mitochondria as an antimetabolite of ubiquinones (coenzyme Q). It was proved that these analogs are among the best inhibitors of both succinate oxidase and NADH oxidase systems. The introduction of a 2,3-dicyano group to the quinone ring was found to be more favorable for inhibitory activity than 2,3-dimethoxy, 2,3-dimethyl groups and bicyclic quinones such as 2,3-ethylenedioxy-1,4-benzoquinones and 1,4-naphthoquinones. The inhibitory activity was minimally sensitive to the length of the alkylthio side-chain. On the other hand, the difference spectra of reduced minus oxidized forms of cytochromes were investigated to identify the inhibitory site, suggesting that alkylthiolated 2,3-dicyano-1,4-benzoquinones inhibit at sites between the substrates (succinate and NADH) and cytochrome b, and at the site after cytochrome a + a3 in the respiratory chain.

Small molecular weight aliphatic dicarboxylic acids, i.e. dimethylmalonic acid, diethylmalonic acid and maleic acid, afford greater than 35% reduction in serum cholesterol and triglycerides levels in CF1 mice at 20 mg/kg/day, i.p. Furthermore, these agents lowered greater than 40% serum cholesterol levels in rat after oral administration at 20 mg/kg/day. Dimethylmalonic and diethylmalonic acids lowered rat serum triglyceride levels by at least 23%. Rat tissue lipids, e.g. liver, small intestinal mucosa and aorta wall, were reduced in concentration and fecal lipids were elevated by dimethyl- and diethylmalonic acids. Rat serum lipoproteins after 14 days of treatment demonstrated reduction of VLDL and LDL cholesterol levels with elevated HDL cholesterol levels by dimethylmalonic and maleic acids. The agents also inhibited de novo hepatic enzyme activities, specifically mitochondrial citrate exchange, acetyl-CoA synthetase, ATP-dependent citrate lyase, acyl-CoA:cholesterol acyltransferase, cholesterol-7 alpha-hydroxyase, sn-glycerol-3-phosphate acyltransferase and phosphatidate phosphohydrolase, which would result in the reduction of de novo synthesis of fatty acids, cholesterol and triglycerides.

Although it is well-known that N-substituted phthalamic acid derivatives are readily hydrolyzed in acidic aqueous solution due to intramolecular catalysis by the neighbouring carboxy group, sparse information is available on the degradation behaviour in neutral solutions. A recent publication [5] has claimed that N-(3-bromopropyl)phthalamic acid is very easily hydrolyzed in mildly alkaline solutions by an intramolecular catalytic effect of the ionized carboxy group. In this study, the degradation behaviour of N-(2-bromoethyl)phthalamic acid (I), N-(3-bromopropyl)phthalamic acid (II) and various other N-alkyl and N-aryl substituted phthalamic acid derivatives were examined with the primary aim of assessing their degradation rate at physiological pH. Whereas the compounds I and II were indeed found to be easily degraded in neutral aqueous solutions, the degradation was not due to hydrolysis of the amide bond as previously claimed but rather to an intramolecular displacement reaction of the bromo group by the amide moiety, as evidenced by HPLC analysis of the rection products. The other phthalamic acid derivatives studies showed a very high stability in neutral and alkaline solution. It is concluded that phthalamic acid derivatives are too stable chemically and enzymatically to be considered as prodrug forms for primary or secondary amines.

Receptor compartments can be hydrophilic or hydrophobic. The hydrophobic character can be revealed from the logarithmic relationship between the octanol-water partition coefficient (Po/w) and the equipotent equilibrium concentration (Cw) measured in the water compartment (Franke: Theoretical Drug Design Methods. Elsevier, Amsterdam 1984). For activation of the sensory irritant receptor during exposure to airborne chemicals the Cw values at equilibrium can be obtained from the gas or vapour concentrations [( A]a) and the water-gas partition coefficients (Pw/g). However, if the octanol-gas partition coefficients (Po/g) are used, the analysis can be carried out directly from the gas or vapour concentrations. The thermodynamic activity can also be used to reveal whether the environment of the receptor is hydrophobic or not. We have adapted Franke's theory to a series of homologous airborne sensory irritants. Our results suggest that the environment of the sensory irritant receptor is likely to be a hydrophobic site within the polar part of the nerve membrane. The extended theory is general and it is therefore suggested that it applies to other airborne exposure concentrations which are in equilibrium with a hydrophobic receptor.

Kneaded mixtures of a basic drug, meclizine dihydrochloride (MZ), and a neutral drug, prednisolone (PN), with low molecular gelatin at the weight ratio of 1:1 were prepared, and their in vitro dissolution and in vivo absorption behaviour were examined. The dissolution rate of drugs from the kneaded mixtures was significantly faster than that of the drugs themselves. The low molecular gelatin enhanced the dissolution rate of MZ and PN by improving the wettability of the drug particles without any interaction in solution and the solid state. After oral administration of the kneaded mixture to beagle dogs, the initial serum concentration was significantly higher than that of the drug alone. However, the AUC value of the drug from the kneaded mixture was almost same as that of drug alone.

Thirty-four batches of heparin formulations were tested for vasodepressor activity in the anaesthetized cat in accordance with pharmacopoeial requirements. Batches containing chlorobutanol as preservative exerted hypotensive effects, similar to that of 0.1 microgram of histamine/kg, but the average heparin formulation without preservative also caused significant lowering of blood pressure. This effect was reduced by a histamine-H1-receptor antagonist. Heparin formulations, like histamine, caused contraction of the isolated guinea pig ileum which may indicate contamination with up to about 0.1 microgram histamine per 5000 IU of heparin. Using radioligand assays for substance P (SP) and vasoactive intestinal polypeptide (VIP), formulations of heparins of porcine intestinal origin were found not to inhibit 125I-BH-SP binding but some batches moderately reduced binding of 125I-VIP consistent with a maximal contamination with 50-100 ng of VIP per 5,000 IU. The results may have clinical implications for high-dose heparin therapy in connection with thoracic surgery. The results may also provide an argument for retaining the vasodepressor test in pharmacopoeial monographs for heparins.