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In the healthcare setting, the handling of clinical preparations is essential for the development of tailor-made pharmaceutical agents. However, during the design and development of new clinical formulations, pharmacists may encounter various questions and problems related to handling the formulations, such as a lack of knowledge of and experience in prescription design. In addition, if pharmacists require assistance to solve problems, it is rare to find a person with sufficient knowledge of and experience with the formulation in their facilities, and there are few connections among facilities; therefore, in practice, no consultants are available for advice. Universities may play an important role in solving this problem. We believe that it would be beneficial for both clinical practitioners and universities to develop a plan-do-check-action (PDCA) cycle that brings needs, problems, and questions from clinical sites to universities where research is conducted and the results are fed back to the clinics. This complements one of the major missions of universities as research institutes, which is to compile evidence. For new drug candidates that require a high degree of support from universities, the demonstration of sufficient safety information to warrant clinical trials and subsequent drug development will increase pharmacists' awareness of drugs and lead to uptake of formulations. This paper introduces the case for clinical formulation design in universities as part of the C (check) element of the PDCA cycle and how this corresponds to the needs of the pharmaceutical industry.

A vaginal suppository containing ulinastatin (UTI) was developed as a hospital pharmacy product from UTI injection solution and Witepsol® S-55. After mixing at 50°C for 0-8 h, UTI suppositories were prepared, which had good UTI content uniformity. Because 2% surfactant was contained in S-55, the UTI injection solution formed a water-in-oil type emulsion as a suppository base. The measured residual moisture content (loss on drying (LOD)) in the prepared vaginal suppositories decreased as the mixing time increased, but their hardness (hardness test (HT)) increased. Near (N) IR spectra of UTI suppositories were measured after mixing for 0-8 h. The best calibration models to predict the HT and LOD of the suppositories were determined based on the NIR spectra by the leave-one-out method in a partial least-squares regression analysis (PLS). The validation result indicated that PLS models for HT and LOD were obtained based on the spectra treated by a combination of smoothing and normalized, respectively, and the model consisted of three latent variables. The plots between the predicted and measured pharmaceutical properties (HT and LOD) based on the calibration data were superimposed with those of the external validation data. The developed NIR spectroscopy method was applied to the preparation process monitoring for UTI vaginal suppositories. In the prepared vaginal suppositories, the predicted LOD decreased as the mixing time increased, and the measured LOD values superimposed well with the predicted values. In contrast, the predicted HT increased as the mixing time increased, and the measured values superimposed with the predicted values.

Hospital preparations (HPs) prepared by hospital pharmacists have contributed to advanced medical care which is custom tailored to various and individual medical needs. Advanced pharmaceutical knowledge and skills are needed to properly prepare HPs. Hospital pharmacists have inherited formulations and the skills to prepare them from their predecessors. However, there has been an ongoing decrease in the number of HPs prepared in hospitals due to an increase in the availability of commercial formulations. Despite this trend, it is not acceptable for hospital pharmacists to lack experience when a doctor requests an original HP. We often refer to "The Hospital Preparation Casebook" when HPs are prepared. However, evidence for drug management and clinical evaluation of HPs in the book are frequently insufficient; it is difficult to keep the information up to date. Therefore, we consider that it is the role of universities to support the supply and usage of HPs in cooperation with hospital pharmacists and pharmacies. Here we report a trial that adopted a physicopharmaceutical approach to developing a HP of a mianserin hydrochloride suppository.

Cancer patients often report a decreased quality of life due to cancer-related pain, especially neuropathic pain, which is difficult to manage and often develops resistance to morphine. Thus a supplementary analgesic can play an important role in the treatment of cancer-related pain. Carbamazepine (CBZ), for example, can be effective, but only if the patient can take medication orally because it is limited to oral administration. In this study we investigated the efficacy of a suppository containing CBZ tablet in hospital preparations. We selected a base for the suppository of either polyethylene glycol (P), Witepsol VOSCO(®) H-15 (H), or Witepsol VOSCO(®) S-55 (S). Six to eight in vitro and in vivo groups were divided randomly based on route of administration and treatment: intravenous (i.v.), per os (p.o.), and intrarectal administration (i.r.) (composed of CBZ powder and tablet formulations, CBZp and CBZt) prepared in either a base of P, H, or S (CBZp/P, CBZp/H, CBZp/S, CBZt/P, CBZt/H, and CBZt/S). The hardness levels of the CBZt suppository group were significantly lower than the CBZp suppository group. The drug release profiles of the CBZt suppository group were high in order of P, H, and S; there were no significant differences between these groups and the CBZp suppository group. The maximum drug concentration time levels of the CBZt suppository group significantly increased compared with the p.o. group. These two groups had equivalent maximum drug concentration and bioavailability levels. These results suggest that a suppository containing CBZ tablet can be useful for hospital preparations.

The suppository preparation, which can improve the absorption of poorly absorbable drugs safer than commercially available suppositories, was developed by utilizing sodium laurate and taurine. Additionally, the novel oral absorption-improving system was also established by utilizing polyamines and bile acids. Furthermore, to evaluate the efficacy of these new formulations and estimate the absorbability of new drug candidates in humans, the in vitro prediction system utilizing an isolated human intestinal tissues was developed and successfully predicted the fraction of dose absorbed for several model drugs. These findings would contribute to the development of new dosage forms and new drugs for oral administration.

A traditional Chinese herbal medicine, Kampo medicine, maoto, has been widely used in the treatment of febrile symptoms caused by viral infection. This herbal extract granule for oral use, however, is not well accepted by infants or young children due to its unpleasant taste and odor. Therefore, we prepared Kampo medicine, maoto, suppository and investigated the pharmaceutical and clinical efficacy of the suppository. Kampo medicine, maoto, granules were micro-pulverized and homogeneously dispersed into Hosco-H15 to prepare suppositories containing 0.25 to 1.0 g herbal extract by the conventional fusion method. Content of l-ephedrine, an index compound of Kampo medicine, maoto, in the extract granules and suppositories was determined by using a high performance liquid chromatographic method. Physicochemical experiments revealed that the suppository containing 0.5 g herbal extract had the most suitable melting point of 34 degrees C. Contents of l-ephedrine in the suppository were constant, 93-96% of those in the same amount of the extract granules in different three lots. Upper and lower portions of the suppository had the same content of l-ephedrine. The suppository maintained more than 95% of l-ephedrine content through 6 months at 4 degrees C, room temperature and 40 degrees C, although maldistribution of the extract constituent was observed after storage at 40 degrees C. The suppository was administered to 21 pediatric febrile patients at a dose of 1/3 to 2 full pieces depending on their body weight and physical status. Significant reduction (p

Progesterone (P) is an important hormone for the establishment of pregnancy, and its administration is useful for luteal insufficiency. Considering the problems of commercially available oral and injection drugs, hospital-formulated vaginal suppositories are clinically used. However, since the half-life of P suppositories is short, it is difficult to maintain its constant blood concentration. To sustain drug efficacy and prevent side-effects, we are attempting to develop sustained-release suppositories by examining the degree of sustained-release of active ingredients. In this study, we examined the combinations of granulation methods and release systems for the preparation of sustained-release granules of P, and produced 13 types of sustained-release granules. We also examined the diameter, content, and dissolution of each type of granules, and confirmed that the sustained-release of all types of granules was satisfactory. Among the sustained-release granules, we selected granules with a content and a degree of sustained-release suitable for sustained-release suppositories.

We previously reported that the fatty base suppository containing sodium laurate (C12) and taurine (Tau) (C12-Tau suppository) could enhance the colonic absorption of rebamipide, a poorly water-soluble and poorly absorbable drug, without any serious mucosal damages in rats. In the preset study, in order to make C12-Tau suppositories available for practical use, the scaling-up studies of animal and formulation size were performed, compared with the suppositories containing sodium caprate (C10) (C10 suppository) at the same amounts as those contained in the commercial products. Twenty-mg C12 improved the dissolution of rebamipide from suppository remarkably and the addition of 30-mg Tau only slightly decreased the dissolution rate. The absorption of rebamipide from rabbit rectum was more markedly improved by suppositories containing C12 than C10 suppositories. Although Tau tended to attenuate the absorption-enhancing effect of C12, several C12-Tau suppositories kept high bioavailability values, which were much higher than control. Histopathological studies showed that Tau exerted the cytoprotective action and that C12-Tau suppositories were better than C10 suppositories in safety. Considering the balance between efficacy and safety, the suppository containing 10- or 20-mg C12 with 30-mg Tau is better than C10 suppositories as commercial products and could be promising for practical use in human.

The use of snail mucin motifs as rectal absorption enhancer for insulin has been evaluated. The mucin motifs were extracted from the giant African snail Archachatina marginata by differential precipitation with acetone. The mucin motifs were found to have a molecular weight of 5780 Da and an isoelectric point of 3.4. At the concentrations evaluated, the mucin exhibited rectal absorption enhancing property for the administration of insulin in rats. The % basal blood glucose level of the rats that received the batch of suppositories containing no mucin were consistently above 100% except at the ninetieth minute when it came down slightly to 97.2%. Rats dosed with the batch containing 7%w/w suppositories showed the greatest blood glucose reduction with mean % basal blood glucose concentration of 61.2%. Batches of the suppository containing 5% and 7% mucin showed more marked and consistent lowering in blood glucose concentration than the other batches containing lower amounts of the rectal absorption enhancer. The batch with 7% mucin reduced the basal glucose level to 44% within 2 h of administration of the glycero-gelatin suppository loaded mucin.

Salazosulfapyridine (SASP) is widely used orally and rectally in the treatment of ulcerative colitis. SASP is mainly metabolized by hydrolysis and the main active metabolite, 5-aminosalicylic acid (5-ASA), has an antiinflammatory effect. In the present study, we prepared suppositories containing 6.5 mmol of SASP and an enema containing 6.5 mmol of 5-ASA. We measured the concentrations of SASP and its various metabolites, 5-ASA, sulfapyridine (SP), acetylated metabolite of SP (Ac-SP), and N-acetyl-5-ASA (Ac-5-ASA), in the serum and urine after a single administration of each preparation to healthy male volunteers. When the SASP suppository was administered, the maximum concentration (Cmax) of SASP and Ac-5-ASA was 2.5+/-0.4 and 0.5+/-0.2 microM and the time to Cmax (Tmax) was 5 and 12 h, respectively. The Cmax value of SP, which causes side effects, was one-half of that of the parent compound. No 5-ASA in the serum was observed. When the 5-ASA enema was administered, Cmax and Tmax values of 5-ASA and Ac-5-ASA were 5.8+/-2.0 and 13.3+/-3.6 microM and 1 and 7 h, respectively. The area under the serum concentration-time curve (AUC) of SASP was 27.4+/-4.8 microM x h, a finding similar to that of 5-ASA after the administration of the 5-ASA enema (29.4+/-11.1 microM x h). The percentage of urinary recovery of SASP 24 h after administration of the SASP suppository was approximately 0.2%. These results indicate that SASP administered rectally is almost completely hydrolyzed in the colon and that 5-ASA is partially absorbed from the small intestine in unchanged form. On the other hand, approximately 0.3% of 5-ASA was recovered in the urine in unchanged form after the administration of the 5-ASA enema, whereas the urinary recovery of Ac-5-ASA was more than 10%. The present findings suggest that 5-ASA has favorable absorptive properties and can be expected to have systemic action after rectal administration of a 5-ASA enema.

The effect of insulin suppositories containing different amounts and concentrations of sodium salicylate (50, 100 mg) and polyoxyethylene-9-lauryl ether (POELE 1, 3, 4%), respectively, on the plasma glucose concentration of diabetic beagle dogs was investigated after rectal administration. Comparison of the effects of these formulations was made with that produced after subcutaneous insulin injections. Insulin suppositories containing sodium salicylate (50 mg) produced a maximum reduction of plasma glucose concentration (Cmax) of 55 +/- 11%, an area under the curve (AUC) of 252 +/- 59% reduction h; and a relative hypoglycemia (RH) of 49 +/- 12% relative to subcutaneous injection of insulin (4 U/kg). Increasing sodium salicylate to 100 mg/suppository did not improve the hypoglycemic effect of insulin suppositories further. Investigation of the influence of insulin suppositories containing different concentrations of the nonionic surfactant POELE (1, 3, 4%) showed that; the suppositories containing the lowest concentration (1%) produced the highest hypoglycemic effect with a Cmax of 68%, AUC of 332 +/- 67% reduction h, and RH of 55 +/- 11%. Incorporation of sodium salicylate 50mg in insulin suppositories containing 1% POELE did not improve further the effects found with these suppositories. In conclusion, a relative hypoglycemic effect of about 50-55% can be achieved using insulin suppositories containing Witepsol W35 as a base, insulin (5 U/kg), and sodium salicylate (50 mg) or POELE (1%) as rectal absorption enhancers.

New types of diclofenac sodium suppositories known to control a drug release function for hospital preparations were developed based on a concept of the drug delivery system. Hard fat (Witepsol) used as a base of the suppository consists of a mixture of triglycerides, diglycerides and monoglycerides, and each Witepsol is characterized by its physicochemical properties. Authors disclosed that the amount of drug release measured in the commercially available diclofenac sodium suppositories decreased at a low temperature (36 degrees C). Mixed types of diclofenac sodium suppositories consisting of Witepsol W35 and Witepsol E85 as a base were also prepared and their drug release functions investigated in vitro and in vivo. The in vitro drug release properties changed with the mixing ratios of the two bases and with the temperature of the fluid tested. The amount of released diclofenac sodium increased with increases of both the ratio of Witepsol W35 in the suppository and the temperature of the test fluid. Moreover, several processes causing these phenomena were evidenced by the image analysis. The in vivo absorption of diclofenac sodium was found to be also influenced by these factors. Consequently, it is predicted that such factors as the ratio of Witepsol W35 in the suppository and the temperature will influence the drug absorption and the pharmacological effect of diclofenac sodium suppositories.

A suppository of zonisamide (ZNS) was investigated from the viewpoint of pharmaceutical evaluation, pharmacokinetics and pharmacological effect. Two types of ZNS suppositories were prepared. One used Witepsol (H-15 : S-55=3 : 1) as a lipophilic base and the other polyethylene glycol (PEG, 4000 : 1500=4 : 1) as a hydrophilic base. The in vitro release rate of ZNS from the PEG suppository was significantly rapid compared with that of ZNS from Witepsol. Male Wistar rats were administered ZNS (20 mg/kg) using an intravenous, oral or rectal (PEG or Witepsol) route. The absorption of ZNS from the PEG suppository was more rapid than that of ZNS from the Witepsol suppository or from the oral preparation. The peak plasma concentration (Cmax) after a rectal administration of ZNS with Witepsol or PEG suppository was significantly higher than that after the oral administration of ZNS. However, the bioavailability of the three preparations was approximately 100%. Male ICR mice were administered ZNS (80 mg/kg) using the oral or rectal (PEG or Witepsol) route. A positive correlation was observed between the electroshock seizure (ES) threshold and ZNS concentration in plasma or brain. Further, there was no significant difference in the ES threshold or the ZNS concentration in plasma or brain among the three preparations. These results indicate that a ZNS suppository is a very useful preparation from the viewpoint of both pharmacokinetics and pharmacological action.

Pharmacokinetics of morphine and its glucuronides in plasma were studied after rectal administration of hollow-type oleaginous suppositories containing kneading mixtures of morphine hydrochloride, alpha-cyclodextrin, and/or xanthan gum in rabbits. In combination with xanthan gum, alpha-cyclodextrin reduced the first-pass metabolism of morphine in the rectal mucosa and by the liver and improved the apparent rectal bioavailability of the opioid about 4 fold. In vitro permeation studies using an isolated rectal mucosal preparation of rabbits revealed that alpha-cyclodextrin increased the transepithelial conductance and facilitated the transport of morphine through the rectal mucosa. Furthermore, alpha-cyclodextrin facilitated its own mucosal permeation and reduced the glucuronidation of morphine during the passage through the rectal mucosa, probably through restricting the formation of a catalytic complex of morphine with glucuronyltransferases, rather than because of the enzyme saturation. The present data suggest that alpha-cyclodextrin in combination with xanthan gum is particularly effective in improving the rectal bioavailability of morphine from hollow-type suppositories.

The oral bioavailability of tacrolimus is low and varies considerably in humans due to first-pass metabolism by cytochrome P450 (CYP) 3A4 and the active efflux mediated by P-glycoprotein. This study was undertaken to elucidate the usefulness of rectal administration of tacrolimus as an alternative route to improve its bioavailability. Tacrolimus powder was suspended in a suppository base (witepsol H-15) and the tacrolimus suppository was inserted into the anus of the rats. For comparison, tacrolimus was suspended in 0.5% sodium methylcellulose solution and administered orally to rats. The dose of tacrolimus was fixed to 2 mg/kg. Blood samples were collected periodically up to 24 h after dosing, and tacrolimus concentrations were assayed by microparticle enzyme immunoassay. The whole blood concentrations of tacrolimus after rectal administration were much greater than those after oral administration. The C(max) and AUC(0-24 h) values after rectal administration were 3.9- and 6.9-fold greater than those after oral administration, respectively. These results clearly suggest a possibility that rectal administration of tacrolimus is capable of improving its bioavailability and cutting the costs of tacrolimus treatment.

The effect of the viscosity of sodium hyaluronate solution on the rectal absorption of morphine was determined in rabbits. Hollow-type suppositories containing 10 mg morphine in viscous sodium hyaluronate solution of various mean molecular weights (MWs) were prepared. Rectal absorption of morphine in the sodium hyaluronate solution (MW 2.1 x 10(6) daltons) was dependent on sodium hyaluronate concentrations in the range of 0.1 to 3% (w/v). Bioavailability after rectal administration of morphine in 0.1% sodium hyaluronate solution is consistent with that of morphine solution in the absence of sodium hyaluronate and the sustained-release plasma profile was observed for morphine in 3% sodium hyaluronate solution. Administration of hollow-type suppositories containing 10 mg morphine in 1% sodium hyaluronate solution resulted in the highest bioavailability of approximately 2-fold that after administration of morphine in physiological saline solution. Five kinds of sodium hyaluronate solution with MWs of 2.4 x 10(5), 1.0 x 10(6), 1.8 x 10(6) and 2.1 x 10(6) daltons and respective viscosities of 70, 3.3 x 10(3), 3.2 x 10(6), 5.1 x 10(3) and 5.7 x 10(3) cP (20 degrees C) were examined. Optimal viscosity of the sodium hyaluronate solution was found to enhance rectal morphine absorption. These results indicate that the selection of relevant viscosity of the sodium hyaluronate solution may contribute to the improvement of bioavailability of morphine on rectal administration.

The pharmacokinetics of RK-28 [1-(4-hydroxy-2-butenoxy)methyl-2-nitroimidazole], a new hypoxic cell radiosensitizer, was studied following intravenous, oral, and rectal administration to rabbits. After an oral administration of RK-28 solution, the plasma concentration of RK-28 was considerably lower than that after intravenous administration through all time periods, and the absolute bioavailability was a mere 4.2%. It was presumed that a specific acid-catalized decomposition of RK-28 progressed in the stomach, and also, the absorbed RK-28 suffered first-pass effects in the liver. In contrast, the absolute bioavailability following the rectal administration of a solidified RK-28 suppository preparation was significantly increased in comparison with that obtained by other administration routes. Also, RK-28 emulsion suppositories were prepared by emulsifying various amounts of the drug with 1-hexadecanol and hydrogenated castor oil (HCO 60) at 80 degrees C, and these were administered into the rabbit rectum. The resulting absolute bioavailability was 91% for the RK-28 emulsion suppository and 86.9% for an RK-28 emulsion suppository containing small amounts of Eudispert hv. These values were better than those in rats. The rectal administration of the RK-28 emulsion suppository containing small amounts of Eudispert hv showed a preferable plasma concentration-time pattern that reflects on radiation therapy.

The bioavailability of bumetanide following the oral administration of tablets, or the rectal administration of either macrogol suppositories or suppositories with and without weak acids were evaluated in human subjects. The absorption of bumetanide from those suppositories containing bumetanide without weak acids (control suppositories) was extremely poor, while the absorption from those suppositories containing citric acid or tartaric acid was enhanced. The mean area under the plasma concentration-time curve (AUC) following the rectal administration of the suppositories containing citric acid and tartaric acid was 52 and 62%, respectively, of that following the oral administration. On the other hand, the absorption rate constant (ka) and the mean residence time (MRT) following the rectal administration of the suppositories containing weak acids increased significantly compared to those administered orally. The time (Tmax) required to achieve the maximum plasma concentration (Cmax) in the plasma following the rectal administration of the suppositories containing weak acids was significantly shortened compared to the time of those administered orally. These results indicated that the bumetanide contained in the suppositories containing weak acids might be absorbed rapidly after administration. The diuretic effect of bumetanide following the oral and rectal administration was also evaluated. Sufficient diuretic effects were obtained following the rectal administration of the suppositories containing weak acids.

The bioavailability of morphine after rectal administration using three types of suppositories containing morphine hydrochloride (10 mg) in different added forms was evaluated in rabbits. Three types of suppositories were constructed with a base material (Witepsol H-15): a conventional suppository containing morphine hydrochloride mixed with a base material, a hollow-type suppository containing morphine in an aqueous solution in its cavity, and a hollow-type suppository containing morphine as a powder (hydrochloride salt) in its cavity. The plasma concentrations of morphine and its metabolites, morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G), were determined. The mean AUC0-6 of morphine after rectal administration of the hollow-type suppository containing powdered morphine was significantly higher than that after the administration of a conventional suppository, whereas the mean AUC0-6 of M-3-G was lower than that after administration of a conventional suppository. The mean AUC0-6 of M-6-G by a hollow-type suppository containing powdered morphine was higher than that by a conventional suppository. Although the mean AUC0-6 ratio of M-3-G to morphine after administration of a conventional suppository was three times larger than that of a hollow-type suppository containing powdered morphine, the mean AUC0-6 ratios of M-6-G to morphine after use of the three types of suppositories were all approximately 1.0. This study demonstrates that the hollow-type suppository containing powdered morphine is a more effective rectal dosage vehicle than the conventional suppository.

The in vitro release of bumetanide from macrogol suppositories with and without weak acids (citric acid and tartaric acid) was studied. The release of bumetanide was not affected when weak acids were added to the suppositories. The in vivo rectal absorption of bumetanide from the suppositories was evaluated in rabbits. The bioavailability (absolute), expressed as the ratio of the area under the plasma concentration-time curve (AUC) following oral administration of bumetanide, was 39% that of intravenous administration. The value in bumetanide following rectal administration of the suppositories without weak acids was 32%. Each absolute bioavailability following rectal administration of the suppositories with 5% citric acid and 5% tartaric acid was 52% and 42%, respectively. These values were significantly larger than those of rectal administration of the suppositories without weak acids. Particularly, the bioavailability following rectal administration of the suppositories containing citric acid was significantly different from even those of oral administration. The absorption rate constants of bumetanide from the suppositories with weak acids were significantly larger than those following oral administration. These results indicated the possibilities of the rectal route of administration of drugs which are weak organic acids and show low or variable bioavailability following oral administration.

cis-Diamminedichloroplatinum (II) (cisplatin: CDDP) suppositories containing NaCl at different concentrations were prepared as a local chemotherapeutic agent for the treatment of uterine endometrial carcinoma and were administered to rabbits implanted with uterine VX2 tumor. The intrauterine CDDP histological level, as well as the antitumor effects and side effects of the suppositories to the liver and kidney were studied. The results showed high intrauterine tissue CDDP level in all suppository administrations. In particular, the NaCl-added suppositories enhanced the intrauterine CDDP level. As for antitumor effects, while the tumor growth rate of the NaCl-added suppository group was likely to be suppressed, the suppositories could not suppress tumor growth completely. The plasma platinum (Pt) level was 1.5 micrograms/ml or less and that of the liver and kidney was as low as 0.31 to 0.48 micrograms/g. No difference in levels depending on NaCl concentration was observed, nor was any abnormality found in the biochemical analysis including glutamate oxaloacetate transaminase (GOT) and blood urea nitrogen (BUN). Histopathological study revealed the degeneration of tumor cells in the NaCl-added suppository group. Minimal congestion and hemorrhage were observed in the endometria, possibly resulting from CDDP. By adding NaCl to CDDP suppositories, the uterine CDDP level and antitumor effects increased while no serious renal dysfunction was noted. Therefore, we conclude that NaCl-added CDDP suppositories are a useful local chemotherapy for endometrial carcinoma.

The effects of dipotassium glycyrrhizinate (GLYK) on the dissolution behavior and bioavailability of amphotericin B (AMB) were investigated. The mixtures of AMB and GLYK were prepared at different molar ratios by lyophilization. Lyophilization resulted in amorphous AMB either alone or in the mixture. Dissolution rates of AMB of the mixtures were markedly faster than that of lyophilized AMB alone, which was followed by a decrease of dissolution. The initially-enhanced dissolution rate was likely to be due to the improvement of surface wettability of drug particles with GLYK rather than the amorphous state of AMB. A phase solubility study of AMB with GLYK indicated that the increasing solubility was caused by micellar solubilization. The in vitro release rate of AMB from suppositories containing the lyophilized mixtures was significantly accelerated by increasing the amount of GLYK. The rectal absorption of AMB from suppositories containing either the drug alone, a physical mixture or a lyophilized mixture was studied using rabbits. The absorption of the mixture (AMB/GLYK = 1/9) was about 35 times greater in the area under the serum concentration-time curve (0-24 h) than that of lyophilized AMB alone. These results suggest that GLYK is useful for improving the dissolution property of AMB and the bioavailability of the drug incorporated in suppositories.

To improve the rectal delivery of an anti-inflammatory drug, biphenylylacetic acid (BPAA), the use of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and heptakis (2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) was investigated. Inclusion complex formations of BPAA with both beta-CyDs in a molar ratio of 1:1 in water were ascertained, and their stability constants were determined. The dissolution of BPAA in water and the release of BPAA from an oleaginous suppository (Witepsol H-5) were significantly increased by beta-CyDs, depending on the magnitude of the stability constants of the water-soluble complexes. However, the serum levels of BPAA after rectal administration of the suppositories containing BPAA or its beta-CyDs complexes in rats increased in the order of BPAA alone much less than DM-beta-CyD less than or equal to HP-beta-CyD complex. The in situ recirculation study revealed that the greater the stability constant of the complex, the lesser was the absorption of BPAA from the rectal lumen of rats under the solution state. Both in vivo and in situ studies demonstrated that rather high amount of HP-beta-CyD (about 20% of dose) was absorbable from the rat's rectum, compared with DM-beta-CyD (less than 5% of dose), suggesting the possibility of the permeation of BPAA through the rectal membrane in the form of HP-beta-CyD complex. Furthermore, DM-beta-CyD and HP-beta-CyD significantly reduced the irritation of the rectal mucosa caused by BPAA after the administration of the suppositories to rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Poly (vinylalcohol) (PVA) emulsion gel suppositories were prepared by a given cycle of freezing and thawing. Oil phase and emulsifying agent used were Panacete 800 and a series of Pluronic L-44, respectively. The effects of polymerization degree of PVA on the gel strength and the drug release were investigated. Drug release from PVA emulsion gel suppository was compared with that from a conventional suppository. The structure of gel was observed by using a scanning electron microscope. The gel strength increased when PVA emulsion gel suppository was prepared with Panacete 800 and Pluronic L-44. The drug release of hydrophilic and hydrophobic drugs from the suppository was in agreement with a zero-order release profile. When oil phase was added into PVA gel suppository, PVA fiber became thin and the network of PVA fiber became dense.

Cisplatin (CDDP) has attracted attention as a chemotherapeutic agent for the treatment of uterine endometrial carcinoma but causes serious side effects, including renal toxicity. CDDP suppositories containing NaCl at different concentrations were prepared to enhance the efficacy and to reduce the side effects of CDDP. The release characteristics, melting point and viscosity of the suppositories were first studied. The rate of CDDP release increased as the NaCl concentration increased: it was 12% 12 h after administration of suppositories containing no NaCl, but 32% with 0.2% NaCl. The melting point was raised by addition of NaCl: 35.5 degrees C without NaCl and 36.5 degrees C with 0.2% NaCl. Addition of 0.2% NaCl doubled the viscosity. Clinically, the suppository containing 0.06% NaCl was given to 3 patients with endometrial carcinoma twice a week for 3 weeks to examine serum CDDP levels and endometrial absorption. Patients with endometrial carcinoma showed different peak plasma platinum (Pt) levels which were as low as 0.12, 0.06 and 0.22 micrograms Pt/ml with similar patterns of change in the level. Radiographic analysis revealed many Pt particles in sections of necrosed endometria after 21d of the treatment. No side effects of CDDP were found in biochemical testing or subjective symptoms.

Analgesic activity of morphine administered rectally as a suppository was investigated in rats in order to ascertain analgesic activity of morphine suppository. Morphine hydrochloride given rectally as a suppository produced analgesic activity in a dose-related manner in the tail pressure and acetic acid-induced writhing tests, and its potency (ED50 = about 17 and 0.689 mg/kg, respectively) was approximately twice that of morphine hydrochloride administered orally as an aqueous solution. The analgesic action was as durable as that of oral morphine, but its onset was faster. The plasma and brain levels of morphine reached peak until 30 min after rectal administration of morphine suppository, and these time-courses approximately corresponded with that of the analgesic action. These results suggest that morphine given rectally to rats as a suppository produces analgesic action equivalent or superior to orally administered morphine after absorption from the rectum.

We prepared indomethacin (IM) sustained-release suppositories using sugar ester (SE) as an additive. The suppositories were prepared by the fusion method with IM, SE, and Witepsol[○!R] H-15 (H-15) and their availablities in vitro and in vivo were evaluated mainly by the drug release test and the absorption test in rabbits, respectively. The softening point of the suppositories increased with increasing SE content. In the release test with the Muranishi method, slow-release profiles were obtained when the SE content was more than 52.5%. The absorption of IM from these suppositories, however, was very little. In the other release test, e.g. immersion method with guaze, all of the suppositories with SE showed slow-release profiles, and the drug release rates clearly depended on the SE content. The drug was released from the suppositories by the following leaching-type mechanism proposed by Higuchi. The suppository with a 30% SE content showed a sustained-plasma level of IM, but the other suppositories did not. It was concluded that an appropriate content of SE (i.e. 30%) in the suppository base was required to obtain sustained-release because it reasonable regulated the infiltration of rectal fluid into the suppository and the mechanical strength of the suppository against disintegration.

Bioavailabilities of morphine after rectal administration of three different morphine.HCl suppositories were evaluated in dogs, whose rectum was lavaged or non-lavaged. The suppositories were prepared with three fatty bases (Witepsol H-15, Witepsol W-35, Suppocire AT) by the fusion method. The release of morphine from the suppositories was examined after stored for two weeks at 30 degrees C. The plasma concentrations of morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were determined by high-performance liquid chromatography. The bioavailabilities of morphine after rectal administration were compared with those after intravenous and oral administration of morphine++.HCl solution. In the case of rectal lavaged dogs, the plasma levels of morphine after rectal administration of morphine.HCl solution were higher than those after oral administration of morphine.HCl solution. The release of morphine from Witepsol H-15 suppository was more rapid than those from other suppositories. Morphine after rectal administration of Witepsol H-15 suppository was rapidly absorbed in the rectum, and the inter-animal variation of its plasma levels was smaller than those of other suppositories. In rectal non-lavaged dogs, the bioavailabilities of morphine after rectal administration of morphine.HCl solution and suppositories decreased more than those of rectal lavaged dogs. Although the bioavailability of morphine after rectal administration of morphine.HCl was decreased by the influence of contents in the rectum, morphine from Witepsol H-15 suppository was more rapidly absorbed in the rectum, and the inter-animal variation of its plasma levels was smaller. These results indicate that, among their suppositories, Witepsol H-15 suppository is available for the terminal care of malignant disease.

The absorption characteristics of azasetron, a serotonin type 3 (5-HT3) receptor antagonist which is used for the treatment of chemotherapy-induced emesis and nausea, were investigated in rabbits. The serum concentrations of azasetron following rectal administration as a suppository increased rapidly and showed the mean tmax value of 0.18 h. The concentrations were greater after rectal administration than those after oral administration. The absolute bioavailability was significantly different between the rectal, 52.9% and oral doses, 21.6%. The mean Cmax and tmax values after the rectal dose were 904.8 ng/ml and 0.18 h, respectively, whereas those after the oral dose averaged 124.7 ng/ml and 0.85 h, respectively. These results indicate that azasetron is absorbed to a greater extent and more rapidly into the systemic circulation via the rectum than via the intestine in rabbits. Consequently, the suppository form of azasetron hydrochloride may be feasible for the treatment of chemotherapy-induced acute emesis and nausea.

Capric acid (C10) enhanced the absorption of cefoxitin sodium in a concentration-dependent manner following the rectal administration as a suppository in rats. The optimal concentration of C10 was 13%. C10 administered as a suppository also reduced rectal membrane resistance (Rm), showing that the above enhancing effect was induced by widening the paracellular pathway. Both the enhancing effect on the absorption and the reducing effect on Rm were inhibited by W7, an inhibitor of myosin light chain kinase. These results supported that, as shown in the in vitro Caco-2 cell system, the C10 effect on the paracellular pathway is due to activating the contraction of Ca(2+)-calmodulin-dependent actin filament.

Rectal absorption of 32-mer phosphorothioate deoxynucleotides (S-Oligo) in the rat was attempted with the aid of a suppository containing oleic acid and a surfactant. Although, the suppository without adjuvant did not show detectable blood levels, that containing over 10% oleic acid enabled the absorption of S-Oligo with t max at 2h postdosing.

The absorption of carbamazepine (CBZ) after rectal administration in the form of a suppository was studied in rats. CBZ suppositories were prepared with Witepsol H-15 (H-15), Witepsol S-55 (S-55) or polyethylene glycol 6000 (PEG) bases by moulding procedure. An in vitro investigation was undertaken using a dissolution apparatus. The in vitro dissolution rate of CBZ showed marked differences among the bases in the order PEG > H-15 > S-55. An in vivo study demonstrated marked differences in the time required to reach peak plasma concentration (Tmax) of CBZ after rectal and oral administration: the absorption of CBZ from PEG base was the most prolonged among these bases (in the order PEG > H-15 > S-55 > ORAL). Comparison of the area under the plasma concentration-time curve (AUC) of CBZ after rectal administration of the three different suppositories with those after intravenous and oral administration showed no significant differences in the AUC among the five preparations. These results suggest the possibility that CBZ suppositories can replace oral treatment for epilepsy.

Diethylethoxymethylene malonate (DEEMM) and diethyl maleate (DEM) enhanced the rectal absorption of cefmetazole in rats when studies were carried out using in vivo, in situ rectal loop and in vitro rectal everted sac method. Since an increase of cefmetazole transport was found when concentration of nonprotein sulfhydryls in rectal tissue was decreased by the presence of either DEEMM or DEM in the study using in vitro everted sac method and the enhancement of cefmetazole absorption by the coadministration of either DEEMM or DEM was suppressed by the treatment with dimercaprol, membrane permeability of rectal tissue seems to be regulated by the concentration of nonprotein sulfhydryls in rectal tissue. On the other hand, it was also found that there were differences between the action of DEEMM and the action of DEM from the following two results : 1) enhancing action of DEEMM was suppressed by the presence of calcium ion in microenema while action of DEM was not so much influenced, and 2) DEEMM enhanced the rectal absorption of lysozyme in rabbits but DEM did not.

1-(2-Tetrahydrofuryl)-5-fluorouracil (FT-207) concentrations in lymph and plasma were measured after rectal administration of three types of suppositories containing FT-207. The suppositories used in this study were prepared from polyacrylic acid aqueous gel bases, emulsion type bases and a commercial fat base, witepsol w-35. Both aqueous gel and emulsion type suppositories were superior to the suppositories from witepsol with regard to FT-207 concentration in lymph and plasma. The addition of aqueous gel to the polyacrylic acid aqueous gel was found to be effective for the lymph transport from the aqueous gels. Polyacrylic acid aqueous gel containing 1% glycyrrhizin was better than other suppositories. Solidification of the emulsion type bases are also investigated, and it is suggested that these may be better substitutes of the oily suppository.

Rectal absorption of diclofenac (DC) and its salts with sodium (DCNa), L-arginine (DC-Arg), L-lysine (DC-Lys), and L-histidine (DC-His) was studied in dogs, rabbits and rats. Plasma levels of unchanged DC were measured by high performance liquid chromatography. Both the bioavailability and the plasma peak level of DC-Lys were the largest among the salts studied. The bioavailability of DCNa on oral administration in terms of plasma levels of DC was observed to be much larger than after rectal administration of DC but it was of the same order as those of rectal administration of DCNa, DC-Arg, and DC-His. The extents of bioavailabilty in rabbits and in rats were similar, but considerably better than that in dogs. The irritative effects of DC salts on the rectal mucosa in rats were studied by gross and light microscopic examinations following the administration of suspensions in 1% methyl cellulose solution. DC-Arg showed the weakest irritation of the rectal mucosa, and the irritation caused by 20% suspension was equivalent to that of 5% suspension of DCNa. The protective effects of counter ions against the histological damage caused by DC to the rectal mucosa increased in the order or sodiumglysinegarginine. From these results, it appears that the basic amino acid salts of DC may be useful as rectal delivery preparations for clinical use.

Indomethacin (IM) slow-release suppositories were prepared using hydrogenated soybean lecithin (HL) as an additive. The suppositories were prepared by the fusion method with IM, HL and Witepsol H-15. The suppositories were evaluated by in vitro release testing, X-ray diffractometry, differential scanning calorimetry and penetrometry. IM existed in an amorphous state in the suppositories.The melting point and hardness of the suppositories increased with increasing HL content. Slow release from suppositories in which the IM content was 10 mg was obtained when the HL content was over 300 mg. When the IM content was 20 mg, the HL content required to obtain the slow-release profile was more than 600 mg. The slow-release suppositories did not melt or disintegrate entirely in the test solution in the cylindrical cell of the releasing apparatus in the course of testing. It was considered that IM dissolved gradually from the surface of the suppositories, because HL at the levels giving slow release of IM made the suppositories hard.

Phenobarbital was dissolved faster from a β-cyclodextrin complex than from phenobarbital powder, and it was released faster from suppositories containing its β-cyclodextrin complex than from those containing phenobarbital powder. After rectal administration of the suppository containing the β-cyclodextrin complex to rabbits, the blood concentration of the drug was higher than that following administration of the phenobarbital suppository. Since β-cyclodextrin tended to retard absorption of the drug in solution from the rectum, enhanced absorption of the drug from the complex was attributed to fast release from the suppository due to rapid dissolution.

The promoting effects of sodium salts of N-acyl-L-phenylalanines, p-substituted benzoic acids, saturated straight-chain fatty acids, saturated straight-chain α-bromofatty acids and N-acyl-N-methylglycines on the rectal absorption of sodium ampicillin (ABPC Na) were investigated in rats. The absorption-promoting effect of each carboxylic acid sodium salt was found to be parabolically correlated with its lipo-hydrophilic character (log P). The optimal log P value (log P0) of carboxylic acids exerting the maximum rectal absorption-promoting effect was in the range of 4.2-4.8. Among these carboxylic acids, sodium caprate was selected for examination of its rectal absorption-promoting action on four penicillins (ampicillin, sulbenicillin, piperacillin and mezlocillin) and eight cephalosporins (cephacetrile, ceftizoxime, cephalothin, cefazolin, cefmetazole, cefotiam, cefoperazone and cefpiramide). The extents of rectal absorption of the β-lactam antibiotics coadministered with sodium caprate were found to correlate well with the permeability of the drugs to cellulose membrane.

Releases of indomethacin from commercial witepsol suppositories were investigated by JP XI paddle, Muranishi and dialysis tubing methods. The drug was scarcely released from most of the suppositories by the paddle method at 37°C although it was released at 39°C. The release behaviors of suppositories differed greatly between the Muranishi and dialysis tubing methods. The melting points of suppositories correlated significantly with the release rates by the dialysis tubing method but not with those by the Muranishi method. The release rates by the Muranishi method were jelayed by increasing the fluid volume in the cylindrical cell and the releases by the dialysis tubing method were inhibited by adding aqueous medium into the tubing. The bioavailabilities from two and three of the products were estimated in rabbits and pigs, respectively, and the results correlated well with the release rates determined by the dialysis tubing method but poorly with those by the Muranishi method.

The rheological characteristics of emulsion bases must be chosen so as to produce a suppository having optimum physical, chemical and pharmacological properties. In this study, we measured some rheological characteristics of the emulsion in order to find favorable physicochemical conditions for the preparation of emulsion-type bases. The suppository consisted of Witepsol S-55, aqueous polymer, Amisoft surfactant and water. The preparation procedure was that described in our previous paper. The vicosity and visco-elasticity of suppository bases were measured with a Vismetron and an RM-1 or RV-12 type rheometer. Amisofts had excellent rheological properties as surfactants for emulsion-type suppository bases, as compared with sodium dodecyl sulfate or Tween 80. The activation energy of viscosity increased gradually at first and then sharply with increasing volume concentration of the dispersed phase after passing through the 50% point. The change in the activation energy was substantial when the volume concentration rose over 60%.

With the aim of developing a dosage form for the treatment of carcinoma colli, stick-like preparations containing bleomycin hydrochloride (BLM), carboquone (CQ), and 5-fluoro-uracil (5-FU) held in a mixture of hydroxypropyl cellulose (HPC) and Carbopol 934 (CP) were prepared and clinically tested in volunteers suffering from carcinoma colli after various in vitro tests. The results of preliminary tests of drug release using the agar gelbed method indicated that the addition of sodium lauryl sulfate enhanced the release of CQ, but the effect was not very great. Therefore, in order to enhance the release of CQ, the contents of HPC in the base and CQ were increased. The preparations of BLM and 5-FU of 2 mm diameter showed faster drug release than those of 4 mm diameter according to the Kerami filter method. In the preparations of 4 mm diameter, the release of CQ took place at almost the same rate as that of BLM, i. e., about 40% within 24 hr, due to the modification of the formula for the preparation of CQ. In the case of the preparation of 5-FU, the release was so rapid that about 100% of the drug was released within 24 hr. The present Kerami filter method seemed suitable and convenient for measuring the drug release from the present dosage forms. Clinical examination indicated the stick-like shape of the present dosage form to be favorable for the treatment of foci in the cervical canal. A high percentage of complete disappearance of the cancerous focus was obtained for patients of stage 0 in the cases of BLM and 5-FU, and a similar result was obtained for stage Ia in the case of CQ.

The effect of gel preparation on the rate of absorption of a rectally administered insulin which was suspended in a polyacrylic acid aqueous gel base (0.1%, pH 6.5) was investigated in the alloxan diabetic rats and rabbits. The preparation was administered into the in situ rectal loop in rats or infused directly into the rectum in rabbits, and the change in the blood glucose level and plasma insulin value was taken as a measure to evaluate the rate of rectal absorption of insulin. The blood glucose lowering effect in both rats and rabbits was dose-dependent, namely, a slight effect was observed at 1 IU/kg followed by a significant effect with 3 and 5 IU/kg, and a sharp hypoglycemic effect was recorded with 10 IU/kg which lasted for 5 hr. The plasma insulin level exhibited a rapid increase at 30 minutes after the dosing of the insulin by the polyacrylic acid aqueous gel base. However, the plasma level quickly diminished in 1 hr. Contrary to our expectation, an addition of a non-ionic surfactant such as Tween 80 under pH 4--8 did not show further enhancement of the absorption. In an attempt to simulate a clinical condition in which insulin was given after a meal, the insulin gel was administered into the rectal loop in diabetic rats following the i.v. injection of glucose. A satisfactory result was obtained in which 5 IU/kg dose was able to suppress a rise in the blood glucose after the glucose loading.

Dissolution and permeation patterns of phenobarbital (PB) from basic amino acid and choline salts of PB indicated that drug dissolution from the salts was faster than that of PB itself. Release of the drug from Vosco H15 suppositories containing the salts was faster than that from the suppository containing PB itself. After rectal administration of suppositories containing the salts to rabbits, the blood levels were significantly (p < 0.05) higher than those following administration of the suppository containing PB itself during a period from 30 min to 2 h.