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Gastrointestinal absorption characteristics of drugs in lipid-containing oral dosage forms were studied in rats. A new antiinflammatory agent 1-cyclopropyl-4-phenyl-6-chlor-2 (1H)-quinazolinone (SL-512) was selected as a model of hardly water soluble drugs. Medium chain triglyceride (MCT), medium chain monoglyceride (MCM), and corn oil were used as models of well-digestible lipids, and N-α-methylbenzyllinoleamide (MBLA) for that of hardlydigestible ones. Absorption of orally dosed SL-512 strongly depended on the dose volume of lipid vehicles. Larger volume of lipids (≤100 mcl/rat) delayed absorption of SL-512 due to larger remaining of SL-512 both in the stomach and in the intestine. The gastric retension was also affected by the fluidity of lipids employed. In smaller volume of lipids (5-20 mcl/rat), which has not been examined in previous papers in spite of its compatibility to human clinical dose volume, the amount of intestinal remaining was much less than that of gastric remaining of the preparation. In experiments designed to minimize intestinal remaining of SL-512, serum level of the drug calculated by using gastric emptying rate instead of absorption rate was found to be in good accordance with that of experimental value.

A novel method for evaluation of oral lipid formulation in rats, which enabled us to reduce the dose level to 2 mcl/rat with satisfactory acuracy, was presented. The dose level was fairly comparable to that of clinical unit dose such as a soft capsule on mcl/kg (lipid dose/body weight) basis. By using this method, lipid-containing oral dosage forms were evaluated. A new antiinflammatory agent 1-cyclopropyl-4-phenyl-6-chlor-2(1H)-quinazolinone (SL-512) was selected as a model of poorly water soluble drug. A medium chain triglyceride was mostly used as a lipid vehicle. It was demonstrated that the characteristics of the lipid formulation could be estimated by measuring the gastric emptying rate of the drug or sometime combined with the intestinal remaining of the drug in rats. These results basically consisted of those obtained from 20 mcl/rat dosing experiments previously reported. It was newly found that by reducing the dose level to 2 mcl/rat, the drug absorption was less affected by the dosage form factors such as the drug concentration in the preparation or the digestibility of lipid vehicle. It was also shown by this method that compared with an aqueous suspension, the drug absorption of the lipid formulation was less variable and less affected by the concomitant food intake.

The correlation between the dissolution rate and bioavailability of griseofulvin tablets was studied in stomach-emptying-controlled rabbits and in humans. Three different test tablets, each consisting of two dose levels (62.5 or 125 mg) of griseofulvin, were used. The dissolution rates in 0.5 hr were approximately 75, 40, and 12%. With oral administration at 62.5 mg/rabbit, the ratio of peak plasma level, Cmax, was 1.00:0.66:0.40 and that of the area under the curve (AUC) was 1.00:0.73:0.46 for the three tablets. The corresponding C'max ratio was 1.00:0.74:0.34 and the AUC ratio was 1.00:0.72:0.33 in humans at the dose level of 500 mg. A good correlation was observed for the rank order of Cmax and AUC between rabbits and humans, but such a correlation was not seen between in vivo data and in vitro data at a larger dose of 125 mg/rabbit. This finding was attributable to the dose, which exceeded the GI drug dissolution or absorption capacities. These results suggest that the stomach-emptying-controlled rabbit is useful for evaluating oral dosage forms for human use and that dose level selection is important in the bioavailability study of a barely water-soluble drug.

A novel procedure to control the stomach emptying rate in rabbits is presented. Rabbits were given a special solid diet for 1 week and then the gastric contents were washed out with saline. Then the rabbits were muzzled to prevent coprophagy during the night. Fifty grams of special soft diet given to the “stomach‐emptying‐controlled” rabbit transferred exponentially from the stomach into the small intestine and almost disappeared from the stomach within 5 hr. Griseofulvin, indomethacin, or nalidixic acid was administered in a hard gelatin capsule or tablet, with subsequent feeding of a special soft diet. Good correlations were observed between the plasma level‐time curves of these drugs in the stomach‐emptying‐controlled rabbits and in human subjects.

The drug absorption characteristics of a lipid-containing oral dosage form were studied in human subjects and rats. Diazepam was employed as a model drug and medium-chain triglyceride (MCT) was used as a model lipid. When administered orally to four human subjects, there was no significant difference between diazepam soft capsules and tablets in the average plasma levels of the drug, due to a large intersubject variation. However, when administered to an individual subject repeatedly, the soft capsules showed the tendency of faster drug absorption and superior reproducibility in the plasma level-time curve, suggesting a more uniform drug absorption rate compared with the tablets. The mechanism of this effect was further investigated in the rat model dosing a small amount (2μl/rat) of MCT solution or aqueous suspension. After oral administration, the retention of diazepam in the small intestine was quite small compared with that in the stomach, suggesting the importance of the gastric disappearance rate in drug absorption from these preparations. The gastric drug disappearance rate of MCT solution was faster and significantly less variable than that of the aqueous suspension, which was considered to be the main cause of the more uniform drug absorption rate of the oral diazepam-MCT preparations. It is suggested that diazepam, though it is a weak base, was emptied from the stomach mostly while retained in the lipid, and thus was affected by the movement of MCT in the GI tract.

The α and β forms of chloramphenicol palmitate (CPP) crystals were successfully obtained in similar particle sizes by utilizing wet micronization. Comparisons of the absorbability of CPP suspensions of the above crystals using conventionally fasted rabbits were unsuccessful because of the low plasma level after dosing the β form (less than 1 μg/ml). Plasma levels were then compared by dosing CPP suspensions of the α and β forms to stomach-emptying-controlled (SE-controlled) rabbits in a crossover manner. Compartive absorption studies were also performed in the SE-controlled rabbits with a capsule form of CP and suspensions of CPP in the α and β forms. It was demonstrated that absorption occurred in the order CP>CPP (α form)>CPP (β form). The correlation between in vitro extent of hydrolysis and in vivo absorbability in terms of AUC is discussed. These results suggest that the SE-controlled rabbit is a very useful animal model for preliminary bioavailability studies on oral dosage forms for human clinical use.

The effect of stomach-emptying control on the physiological state of rabbits was examined. An improved"cangue method"for stomach-emptying control is described and compared with the previously reported"muzzle method."The increment of rabbit body weight indicated that pre-feeding of the special solid diet to rabbits in both methods did not affect their physiological state. Physiological normality of these rabbits was also confirmed in terms of urine pH and packed cell volume. The cangue method was found to be superior to the muzzle method as regards easy operation, the prevention of coprophagy and negligible damage to the stomach during the process of gastric lavage. Analysis of hemocytological and clinico-biochemical data suggested that the physiological state of rabbits is hardly affected by stomach-emptying control using either method.

Complexes of bencyclane fumarate (Ben) with cyclodextrins (CDs) were newly prepared and their characteristics were studied from a pharmaceutical viewpoint. The results of differential scanning calorimetry (DSC), X-ray diffractometry and thin-layer chromatography (TLC) were consistent with the formation of inclusion complexes. Water solubility of Ben-CDs were 2- to 8-fold lager than that of Ben. The stability of Ben in acidic media (pH 1.2) was considerably improved by complex formation with β-CD or γ-CD. Apparent first-order rate constants [h-1] of hydrolysis of Ben were 6.5×10-2, 5.5×10-2, 1.0×10-2 and 1.7×10-2 for Ben, Ben-α-CD, Ben-β-CD and Ben-γ-CD, respectively. The intrinsic bitter taste of Ben was significantly reduced by inclusion complexation with CDs. Thus, there are clear pharmaceutical advantages of Ben-CD compared with Ben. In addition, a novel animal test method, which is helpful for studying astringent bitter-tasting drugs, is proposed.

The usefulness of stomach-emptying-(SE-) controlled rabbits for GI absorption studies of relatively water-soluble drugs was investigated, employing aminopyrine and sulfisoxazole as model drugs. When aminopyrine was administered, similar plasma level-time curves were obtained in both SE-controlled and conventionally fasted rabbits. In the case of sulfisoxazole, the time required to reach the peak plasma level was much longer in conventionally fasted rabbits than in the SE-controlled group. It was concluded that use of conventionally fasted rabbits for GI absorption studies should be limited to work on water-soluble drugs.