R. T. Calvert

'In vivo' disintegration of hard gelatin capsules in fasting and non-fasting subjects

Abstract The dispersion of hard gelatin capsules in the stomach has been followed using a model formulation consisting of an ion exchange resin labelled with a gamma-emitting isotope and monitoring externally with a gamma camera. Capsule formulations were prepared giving both slow and fast in vitro disintegration times. Little dispersion of the capsule contents occurred in fasting subjects, whereas after food, the dispersion was more in keeping with the in vitro disintegration times. Gastric emptying curves could be related to the behaviour of the capsule in the stomach. In one case, the capsule lodged in the oesophagus and gradually emptied its contents into the stomach.

The effect of diphenhydramine alone and in combination with ethanol on histamine skin response and mental performance

SummaryThe effects of diphenhydramine and diphenhydramine plus ethanol on response to intradermal histamine and on mental performance were assessed in twelve male volunteers. A significant impairment of histamine skin response was found with diphenhydramine. This response was unaffected by ethanol. Ethanol improved performance with a tracking test compared with diphenhydramine alone, the effect was not potentiated by the combination. None of the treatments had a significant effect on a digit symbol substitution test. Co-administration of ethanol and diphenhydramine caused greater impairment of performance in a serial seven subtraction test than diphenhydramine alone. There was no correlation between central and peripheral effects of the antihistamine.

Estimation of the degree of binding of tetracyclines in human plasma

The binding of tetracyclines in human plasma has been studied extensively since bound antibiotic can be considered to be temporarily inactive (Kunin, Craig & others, 1973). Table 1 lists the available data for the four tetracyclines of greatest clinical importance. Although these data show plasma binding to be significant the variation in the values quoted for each drug is such as to make a reliable estimate impossible. The values for percentage binding of tetracycline, for example, range from 24 to 64% (Table 1) whereas the percentage of free (and therefore active) doxycycline could be 9 or 27 % of the total drug in the plasma (Table 1). Furthermore, some of the concentrations used (Table 1) have been markedly higher than the therapeutic concentration of 0.8 to 5.0 pg ml-l (Fabre, Milek & Kaliopoulos, 1971). Because of this confusion we have re-examined the binding of these four tetracyclines in human plasma at concentrations covering the therapeutic range. Samples (as hydrochlorides) of tetracycline and doxycycline were gifts from Pfizer (Lot Nos. 203-71716 and 305-58708 respectively), oxytetracycline was purchased from Sigma (Lot No. 41C-0800) and minocycline from Cyanamid (Batch 205). The two methods most suitable for evaluating drug binding in plasma are ultrafiltration and equilibrium dialysis, the latter method was used in this work since we found the tetracyclines bind extensively and variably to ultrafiltration membranes which may account for some of the variation in previously reported values (Table 1). In contrast, only relatively low binding (6%) of tetracyclines to the equilibrium dialysis apparatus occurred and this was corrected for by sampling from both sides of the membrane. The same basic procedure was used for each tetracycline: a solution of the drug in pooled citrated human plasma ( 5 ml) was dialysed against sterile Ssrensens phosphate buffer (pH 7.4 5 mi) using a Perspex dialysis cell and sterile, washed Visking membrane. The pH of the buffer is critical since the degree of binding is known to vary with pH

Investigations of the biosynthesis of novobiocin

The biosynthesis of novobiocin was investigated using isotopically labelled compounds. The amino‐group of the coumarin unit was found to be derived from tyrosine, other typical 7‐oxycoumarin precursors were not incorporated into the coumarin unit of novobiocin, 4′‐hydroxyphenylpyruvate was a better precursor of the substituted benzoic acid unit than was 4′‐hydroxycinnamic acid. A biosynthetic route to this unit of novobiocin is suggested. Synthetic pathways for 2′,4′‐dihydroxyphenylalanine‐1‐14C and 4‐hydroxybenzaldehyde‐U‐14C are reported for the first time.

Bioavailability of griseofulvin from a novel capsule formulation.

The in vivo availability of griseofulvin from a novel formulation has been compared with the micronized powder. The formulation technique involves the conversion of the hydrophobic surface of the drug to a hydrophilic one by treatment with a film forming polymer. This enhances the wettability of the power, and increases its dissolution rate. The results of the in vivo study show the formulation technique has increased the rate and extent of bioavailability of griseofulvin when compared with the non‐treated powder.

Stability of drugs in the presence of pharmaceutical colours

Department of Pharmacy, University of Manchester, Manchester M13 9PL. U. K . Colours are used in pharmaceuticals both for aesthetic value and identification purposes. For the colouring of tablet sugar coats, lakes are coming increasingly popular as they offer advantages over water soluble dyes in speed of application and colour uniformity. Although the colour stability of dyes and lakes has been studied (Goodhart, Lieberman & others, 1963, interaction between colours and drugs has received little attention. The following report deals with the degradation of phenylbutazone in the presence of pharmaceutical lakes. F.D & C Red 2 Lake (Amaranth), F.D & C Red 3 Lake (Erythrosin), F.D & C Yellow 5 Lake (Tartrazine) and F.S & C Yellow 6 Lake (Sunset Yellow) may be used in combination to give a colour suitable for the sugar coating of phenyl-butazone tablets. Suspensions, in Sorensen’s phosphate buffer (pH 7.4), of the individual lakes were prepared and stored in subdued light. Solutions of phenylbutazone were similarly prepared. Mixtures of phenylbutazone and the lakes were exposed, in 1 cm quartz cells, to unfiltered light from a 300 W projector bulb, situated 50cm from the cell. At various time intervals, the cell was removed from the beam, and the phenylbutazone concentration measured spectrophotometrically at 264 nm. Corrections were applied for absorbance due the lake, and interference from the degradation product (Beckstead, Kaistha & Smith, 1968). Under the conditions used, phenylbutazone alone, and in the presence of amaranth, tartrazine and sunset yellow was stable. In the presence of erythrosin, degradation of the phenylbutazone occurred, the rate constants for the degradation of a 0.001 % solution being dependent on the concentration of lake as shown in Table 1. ROSALIND BAUGH, R. T. CALVERT AND J. T. FELL