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The release of a drug having low solubility in a certain pH range from controlled-release microspheres using tetraglycerol pentastearate and tetraglycerol monostearate in combination as the matrix base showed pH dependence. Trepibutone, an acidic drug having lower solubility in an acidic medium, was released pH-independently from the microspheres which incorporated magnesium oxide, a solid base. It might have resulted from the pH inside the matrix being kept in an optimum range for drug release due to the incorporation of a solid base. On the other hand, the addition of water soluble acidic or basic excipients was ineffective to achieve pH-independent release. For papaverine, a basic drug, pH-independent drug-release characteristics could be achieved by adding Eudragit L100-55, an enteric polymer. It is thought that the enteric polymer increased the pores for drug release by dissolving in a higher pH range, where the solubility of papaverine is low, and thereby made the release pH-independent. Further, selecting a polyglycerol ester of a fatty acid with an appropriate hydrophile-lipophile balance as the matrix could yield a drug with the desired release rate at any pH.

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An oral controlled-release drug delivery system based on microspheres of polyglycerol esters of fatty acids (PGEFs), was applied to an anti-hypertensive, delapril hydrochloride. The in-vitro release profile was controlled by selecting a PGEF with an appropriate hydrophilic-lipophilic balance value for the matrix. The microspheres from which 80% of the drug was released in 6 h were orally administered to rats. The plasma concentration of the active metabolite was sustained after administration of the microspheres in comparison with administration of a solution. The in-vivo release profile was in good agreement with the in-vitro release profile. When the microspheres were administered, the pharmacological effect of delapril hydrochloride on the angiotensin I-induced pressor response was also sustained showing consistency with the plasma concentration-time curve.

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We performed a pharmacokinetic analysis of the blood thiamin profile after oral administration of thiamin tetrahydrofurfuryl disulfide (TTFD) to healthy adults. To distinguish between thiamin derived from TTFD ingestion and that from previous dietary intake, the baseline thiamin level was subtracted from the apparent blood vitamin levels measured after administration. Following administration of 100 mg of TTFD, the peak blood thiamin level was almost 10 times the baseline level and the blood thiamin profile could be simulated by a two-compartment model to obtain reasonable pharmacokinetic parameters. When the blood thiamin profile for a 10-mg dose of TTFD was estimated using scaled-down pharmacokinetic parameters derived at the 100-mg dose level, a reasonable fit for the raw data obtained at 10-mg dose was obtained. Therefore, the parameters derived from the data at a dose of 100 mg appeared to be reliable. Since even 180 mg of TTFD is completely absorbed and the absorption ratio is independent of the dose, it can be concluded that gastrointestinal absorption of TTFD is good within the dose range.

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The absorption mechanisms of gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417) and thyrotropin-releasing hormone (TRH) were studied in the rat. In situ absorption experiments were carried out by the radioimmunoassay, and experiments using everted sacs of small intestine were by radioactivity measurements with 14C-labeled DN-1417 or 3H-labeled TRH in the low concentration range of drug and by a high pressure liquid chromatography in the rather high concentration range of drug. The site specificity of absorption in the small intestine of rats could not be found with DN-1417, whereas TRH-T was absorbed from only the upper part of small intestine. Dose-proportional absorption of DN-1417 was observed in experiments of in situ as well as in vitro. Dose-proportional transfer of DN-1417 through the everted small intestine was also found within the concentration range from 120 ng/ml to 27 mg/ml, whereas the transfer ratio of TRH decreased with increase in the concentration of TRH. DN-1417 transfer from mucosal to serosal fluid was not inhibited by the replacement of medium Na ions by K ions, pretreatment of intestinal mucosa with HgCl2, the existence of an oligopeptide, or the existence of beta-lactam antibiotics which had been reported to be absorbed by active transport or carrier-mediated transport systems. While, TRH transfer was inhibited by the replacement of medium Na ions by K ions, pretreatment of intestinal mucosa with HgCl2, the existence of an oligopeptide, and the existence of beta-lactam antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS)

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Plasma levels of gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417), an analog of thyrotropin-releasing hormone, were determined by a radioimmunoassay after oral or intravenous administration in rats and dogs. A pharmacokinetic analysis after intravenous injection revealed biphasic elimination of the plasma concentration following a two compartment open model with half lives in alpha-phase of 2.0 min and beta-phase of 19.2 min in rats, and half lives in alpha-phase of 4.0 min and beta-phase of 33.0 min in dogs. Absolute bioavailabilities when administered orally the solution of DN-1417 after 24 h fasting in rats and dogs were 1 and 10%, respectively. The bioavailability was observed to be unchanged at the dose up to 500 mg/kg in rats and at the dose up to 100 mg/dog in dogs. Thus, the absorption of DN-1417 in rats and dogs was proportional to the dose. On the other hand, the absolute bioavailabilities after meal in dogs were 7.9% at the dose of 20 mg/dog and 7.2% at the dose of 2 mg/dog, whereas in the 24 h fasting condition they were 15.7 and 12.0%, respectively, showing the decrease in absorption with food ingestion. These phenomena are somewhat different from the absorption of thyrotropin-releasing hormone.

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Intestinal absorption mechanisms of thyrotropin-releasing hormone (TRH) following the oral administration of TRH-tartrate (TRH-T) were studied in animals. When TRH-T was orally administered to rats or beagle-dogs, absorption of TRH showed apparent saturation and decreased with food ingestion. TRH is very stable against gastrointestinal digestive enzymes, homogenized intestine and epithelial cells. First pass effect in the liver was not observed in beagle-dogs. Absorption site specificity was found in rats, namely TRH can be absorbed from only the upper part of the small intestine. A saturation phenomenon was also observed in in situ and everted sac experiments. TRH absorption was inhibited by the existence of oligopeptides and some beta-lactam antibiotics that had been reported to be absorbed by active transport or carrier-mediated transport systems. The transfer of TRH from mucosal to serosal solutions was inhibited by the replacement of medium Na ions by K ions and by the existence of oligopeptides. The transfer rate from serosal side to mucosal side was much slower than that from mucosal side to serosal side. These results suggested that there should be a certain carrier-mediated transport system in the absorption process of TRH.

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Quantitative blood levels of thyrotropin-releasing hormone (TRH) were determined by a sensitive and specific radioimmunoassay after oral administration or intravenous injected of thyrotropin-releasing hormone tartrate monohydrate (TRH-T) in the rat, dog and human. A pharmacokinetic analysis after intravenous injection of the drug revealed biphasic elimination of the whole blood concentration following a two-compartment open model with a half-life in alpha-phase of 2.6 min and beta-phase of 4.6 min in the rat (dose: 500 micrograms/kg); a half-life in alpha-phase of 3.2 min and beta-phase of 18.1 min in the beagle-dog (dose: 146 micrograms/dog); a half-life in alpha-phase of 4.0 min and beta-phase of 20.4 min in the human (dose: 730 microgram/human). The absolute bioavailability of TRH after oral administration of TRH-T solution in 24 h fasting rats were 1.5, 0.4, and 0.2% at 29.2, 146, and 730 mg/kg dosing levels, respectively (e.q. 20, 100, 500 mg/kg of TRH) compared with i.v. injection (dose: 500 microgram/kg). In beagle-dogs, they were 12.6, 9.8, 5.6, and 3.5% at 2.92, 14.6, 29.2, and 146 mg/dog dosing levels, respectively (e.q., 10, 20, and 100 mg/dog at TRH) compared with i.v. injection (dose: 146 micrograms/dog). Those of after meal in beagle-dogs were 6.0 and 2.3% at 2.92 and 29.2 mg/dog dosing levels (e.q. 2, and 20 mg/dog of TRH). Thus, TRH absorption showed apparent saturation and was decreased by food ingestion. The absolute bioavailability in the humans, who were administered 11.7 mg TRH-T (2.92 mg/tablet X four, e.q. 8 mg of TRH) two hours after meal, was 2.0% on the average, and thyroid stimulating hormone levels were significantly increased by oral administration of TRH-T tablets.

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A radioimmunoassay was developed for the measurement of exogenous thyrotropin-releasing hormone (TRH) in the whole blood of rats, beagle-dogs and humans. Even at low temperature, TRH is degraded so quickly in the whole blood that stabilization of TRH in the blood is necessary. For this purpose, the direct extraction with methanol and concentration before the radioimmunoassay was satisfactorily performed. The method is highly sensitive so that a lower quantifiable concentration of 20 pg/ml was detectable, and good reproducibility and standard errors of less than 10% from triplicate standard curves were obtained. At low concentration of TRH, the effect of food ingestion and volume of whole blood on the sensitivity of the radioimmunoassay was observed and thin layer chromatographic treatment improved it.

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Three poorly soluble drugs (chloramphenicol, phenacetin and prednisolone) were compressed into tablets of 10% drug content on a physical testing instrument at three different compression pressures. The dissolution profiles were determined by a modification of the U.S.P. method for drug suspensions, granules before compression, disintegrated and intact tablets. By comparison of the dissolution rates for disintegrated tablets with those for granules before compression, or suspensions, it is possible to separate the change in particle size during compression from the pressure-dependent dissolution behaviour of intact tablets. A comparative measurement of dissolution for disintegrated tablets with that for granules provides a useful method for elucidating the particle bonding or cleavage within the tablet during compression.

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Three size fractions for each of three poorly soluble drugs were compressed into 10 mm diameter tablets of four different dilution ratios. The compression was carried out on a physical testing instrument at four compression levels of 49.0, 98.1, 196.2 and 294.3 MN m-2. The effect of drug content and drug particle size on the change in particle size during tableting was examined by the determination of the dissolution rate for disintegrated tablets. A linear relation was obtained when plotting 1n(T80%) versus drug content. There was a critical particle size where the phenomena of cleavage and bonding during tableting balanced each other, but this varied with drug content.

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To elucidate the effect of particle shape on the dissolution profile of a powder, an equation was derived for the dissolution of powders whose particles are rectangular parallelepipeds and log-normally distributed by introducing three-dimensional parameters instead of diameter in the Brooke equation for the spherical powder dissolution. By using some hypothetical values for constants in the equation, it is shown that the smallest side length, alphao does greatly affect the dissolution profile but that the other two side lengths, and betaalphao, do not, even with rather large values of alpha and beta. Nonisotropic dissolution also is discussed.

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A theoretical equation to describe the drug dissolution from a tablet was derived by combining and equation for the disintegration rate of a tablet with an equation for the dissolution of particles. The theory is based on the assumptions that: (a) dissolution occurs only from the particles released in a medium by tablet disintegration, (b) the number of particles released into a medium obeys the equation N = NO(T/Td)m, and (c) the dissolution of particles, which are spherical in shape, is represented by the equation previously given by Brooke. Tablet dissolution versus time plots, obtained by calculating the equation with a computer, gave an S-shaped curve between the dissolution curve for particles starting at time zero and the curve for particles starting at the tablet disintegration time. The joint influences of disintegration and particle dissolution on the overall tablet dissolution profile also were examined. When dissolution of powders was rapid, disintegration of a tablet directly influenced its dissolution. When powders intrinsically dissolved slowly, the effect of disintegration on the tablet dissolution profile was slight.

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