Acta pharmaceutica Nordica最新文献

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.

In the seventies, it was shown that particles were generated in soft polyvinyl chloride (PVC) infusion fluid bags when they were shaken. In this investigation an exponentially modified log-normal distribution (EMLN) is fitted to the particle data. Using the formula for the volume of a sphere, the number-density distribution is converted into a volume-density distribution. The total particle load in the samples is estimated by integration for total particle volume. The results are expressed as volume concentration in plain SI-units (microliters/l). A four-factor analysis of variance demonstrates that the mechanism of the contamination process is most probably an emulsification of low molecular weight additives in the PVC plastic, i.e. di(2-ethylhexyl) phthalate (DEHP), epoxidized vegetable oils (EVO), and others.

The absorption of verapamil administered orally in chewing gum (23.4-29.7 mg) and perorally in tablets (80 mg) to seven healthy volunteers in a study using an open cross-over design, was compared. Following peroral administration the mean +/- SD AUC/D was (5.4 +/- 1.9) x 10(-3) micrograms ml-1 h per microgram dose and after administration of chewing gum (6.6 +/- 2.3) x 10(-3) micrograms ml-1 h per microgram dose (NS). The AUC ratio of verapamil to the metabolite norverapamil was 1.5 after oral and 0.8 after peroral administration, indicating that a part of the verapamil administered in chewing gum was absorbed through the oral mucosa.

Flumazenil, the first benzodiazepine antagonist to be marketed, is available only for intravenous injection (0.1 mg/ml). The half-life of the compound in plasma is short compared with that of the conventional benzodiazepines, and administration of the drug as a continuous infusion is therefore frequently required. However, the stability of flumazenil in infusion solution has not previously been known, which has meant that controlled studies of the drug in this administration form have been difficult to perform. In the present study, infusion solutions of flumazenil in concentrations of 1.0 and 5.0 micrograms/ml were produced and stored for periods of up to 9 months. The concentrations of the drug in the different solutions were determined by gas chromatography at defined intervals, and were found not to change during the study period. We conclude that the stability of flumazenil in infusion solution is satisfactory.

The purpose of this review is to introduce the investigators to sources of information and to guiding principles regarding the choice of animal models for experimental and clinical studies on intranasal application studies. It focuses also on the anatomical and physiological variations that can influence the selection of the correct animal model. A topical overview is given for following animal models which are all involved in intranasal drug or vaccine delivery research; dog, guinea pig, hamster, mouse, rabbit (in vivo and in situ), rat (in vivo, in vivo surgical and in situ) and sheep. In the selection of an animal model, both advantages and disadvantages must be considered. Small animals such as guinea pigs, hamsters, mice and rats, are easy to handle and inexpensive, but their nasal cavity is small and therefore preferred for absorption studies and for studying the influence of absorption promoters. Dogs, monkeys, sheep and rabbits are particularly useful in pharmacokinetic and formulation studies.

For many years, scientists in drug development have been blind to the 3-dimensional consequences of stereochemistry, mainly due to the problem of synthesis and analytical methodology. Now that new techniques are available for the resolution of racemic mixtures, there is an increasing pressure to only synthesise single enantiomers, and although guidelines on stereoisomers from the all regulatory agencies are awaited, there is already sufficient information to suggest that developmental studies on racemates will be greatly increased. There is often stereospecificity in pharmacology and toxicology, but this is frequently not the case for pharmacokinetics where enantiomeric differences may only play a relatively small contribution to overall drug activity, except for some exceptions (NSAI). Other chiral developments are discussed, for example, dextro fenfluramine from rac-fenfluramine, together with the ideas of what may be required for their registration.

Methadone administered in chewing gum in doses of 16.7-22.6 mg to seven patients in a study using an open balanced cross-over design, was compared with 20 mg of methadone given perorally as tablets. There was no significant difference in the AUC/D obtained after administration of chewing gum and tablets (p greater than 0.05). It is concluded that the chewing gum formulation should be considered for further testing with respect to suppression of abstinence syndrome in narcotic addicts.