Enhancing effect of cyclodextrins on nasal absorption of insulin and its duration in rabbits.

The absorption of insulin (from porcine pancreas) in rabbits after the nasal administration of aqueous preparations containing insulin and five kinds of cyclodextrins (CyDs) in phosphate buffer solution at pH 7.0 was investigated. Without CyD, the insulin and glucose levels in plasma were unchanged, whereas a marked increase in the plasma levels of insulin and a decrease in glucose concentrations were observed following the simultaneous administration of insulin and CyD such as alpha- and heptakis (2,6-di-O-methyl)-beta-CyD (DM-beta-CyD). The largest enhancing effect on the nasal absorption of insulin was obtained by DM-beta-CyD. To evaluate the duration of the absorption-enhancing effect of CyDs, preadministration (administration of CyD 0.5, 6, 12 and 24 h before insulin administration) was performed. The area under plasma concentration-time curve (AUC) and Cmax of insulin significantly decreased with the preadministration of DM-beta-CyD 6, 12 and 24 h before nasal administration. The absorption-enhancing effect disappeared 24h after the preadministration. These findings demonstrate that CyDs enhance the nasal absorption of insulin, and the recovery of the membrane transport barrier function in nasal mucosa is achieved, at the latest, 24 h after the administration of CyDs.     

Enhanced rectal absorption of insulin in rabbits from hollow-type suppositories containing insulin and glyceryl-1-monooctanoate.

The absorption of two kinds of insulin (from porcine or bovine pancreas) from the rectum of rabbits after the administration of hollow-type suppositories containing insulin and glyceryl-1-monooctanoate (GMO) as an absorption-enhancing agent was investigated. Two types of suppositories were employed: type I containing insulin in an aqueous solution (approx. 25 IU/mg/100 microliters citric buffer solution at pH 3.0) in the cavity of the suppository and GMO mixed with a base material (Witepsol H-15), and type II containing insulin in a crystalline form in the same amount as in type I. Without GMO, the insulin and glucose levels in plasma were unchanged, whereas a marked increase in the plasma levels of insulin and a decrease of glucose concentrations were found following coadministration of insulin and GMO by the type I suppository. Similar enhancement of rectal absorption of insulin was obtained from porcine and bovine sources. In the case of the crystalline insulin, despite the use of the same amount of GMO, porcine insulin was more efficiently absorbed than bovine insulin by the type II suppository. GMO enhances the absorption of insulin in an aqueous solution or a crystalline form, and the dissolution rate of insulin may be an important factor in the rectal absorption of insulin.     

Enhancing effect of glyceryl-1-monooctanoate on the rectal absorption of gentamicin from hollow-type suppositories in rabbits

A hollow-type suppository containing gentamicin (GM) in its cavity was prepared using Witepsol H-15 (H-15) mixed with glyceryl-1-monooctanoate (MO) or MO alone in the body of the suppository (type I) and a suppository (type II) containing GM and MO in the cavity was constructed using H-15 in the body of the suppository. Without MO, GM (60 mg) was not absorbed (plasma GM levels less than 1 microgram/ml). However, the absorption of GM from the rectum of rabbits was enhanced by coadministered MO in types I and II. Even when the amount of GM was decreased to 6 mg (1/10), GM was observed in the plasma (Cmax, 3.5 +/- 0.3 micrograms/ml) after administration of the suppository made from MO mixed with H-15. The enhancing effect of MO on the rectal absorption of GM could not be further increased by incorporating an amount of MO larger than approximately 300 mg into the suppository. This study demonstrates that MO can be used in the two types of hollow suppositories as an effective enhancing agent of rectal absorption of poorly absorbed drugs such as GM.     

Indomethacin sustained-release suppositories containing sugar ester in polyethylene glycol base

Indomethacin (IM) sustained-release suppositories were prepared by the fusion method using sugar ester and polyethylene glycol 4000 (PEG). The suppositories were evaluated by in vitro release testing, X-ray analysis and in vivo absorption testing in rabbits. X-ray analysis showed that IM was amorphous in PEG-base suppositories. In a release test, slow-release was obtained when the sugar ester content of a suppository was 60%. The IM plasma level following the administration of the suppository was well sustained in the absorption test. The main slow-release mechanism is considered to be the release of IM from the matrix composed of sugar ester and PEG, which is represented by the Higuchi equation. A good correlation between the release test and the absorption test was obtained. It is considered that the amorphous state of IM in this type of sustained-release suppository would enhance the release and absorption of IM in the rectum of the rabbit, whose rectal fluid volume is small.     

Studies on sustained-release suppositories. I. Effect of alginic acid addition on rectal absorption of bacampicillin in rabbits

Sustained-release suppositories of bacampicillin (BAPC) were prepared by the use of the adduct which was precipitated from an aqueous solution containing BAPC and alginic acid (Alg). As the suppository base, Witepsol H-15 and macrogol were used. Absorptions of BAPC from the suppositories were prolonged in rabbits, but the bioavailabilities were decreased compared to that after administration of BAPC alone. However, these absorptions were improved enormously by the addition of surface-active agents, that is, an excellent prolonged absorption and high bioavailability were obtained. Interestingly, similar prolonged absorption could be obtained only by mixing Alg with BAPC in a suppository base. Further, this absorption rate was found to be controlled by the amount of Alg addition. The absorption profiles from a suppository containing the mixture differed from that containing the adduct in exhibiting both high plasma level and prolonged absorption. This may be due to simultaneous fast absorption of BAPC itself and formation of the adducts. Thus, it seemed that BAPC preparations containing Alg may be practically useful as a rectal preparation with prolonged action and giving a high plasma level.     

Enhancement effect of lauric acid on the rectal absorption of propranolol from suppository in rats.

In a previous paper, we have demonstrated that medium chain fatty acids significantly enhance the in vitro rectal absorption of propranolol (PL) and that the enhancement may be partly due to the formation of a complex with a fatty acid at a 1:1 molar ratio. To confirm in vivo the enhancement effect of lauric acid on PL absorption, PL suppositories with lauric acid at various molar ratios were administered to rat rectum. PL absorption from Witepsol and macrogol suppositories with lauric acid at a 1:1 molar ratio was much larger than that after PL alone and the 1:2 or 1:3 molar ratio ones. The bioavailability (BA) after administration of the 1:1 molar ratio suppository (PL, 4 mg/kg) was 1.6- and 2.1-fold for the Witepsol and macrogol formulations respectively, compared with that after PL alone. A similar result was obtained with the PL solid dispersion suppository with lauric acid at a 1:1 molar ratio, showing a 1.7-fold higher BA compared with PL alone. The release of PL from the macrogol suppository was significantly faster at a 1:1 molar ratio than that of other preparations, but not so in the solid dispersion suppository. There was not good agreement between the release rates of PL from the suppositories and the plasma levels after dosing. These results supported the concept that a portion of PL, by forming a 1:1 complex with lauric acid, would penetrate across the rectal mucosa more easily than PL alone.     

Studies on sustained-release suppositories. III. Rectal absorption of morphine in rabbits and prolongation of its absorption by alginic acid addition

Rectal absorption of morphine from various kinds of suppository bases was investigated. The extent of bioavailability of morphine by rectal administration varied with the bases used (30.5-97.5%), but every value was higher than that in the case of oral administration (13.5%). Witepsol bases were preferable to macrogol base for the rectal absorption of morphine. In particular, Witepsol S-55 or W-35 gave a higher plasma peak level than H-15 or E-75, whereas the difference in the mean residence times obtained from these bases could not be regarded as significant. Sustained-release suppositories of morphine could be prepared simply by mixing alginic acid (Alg) with morphine in a suppository base. Further, prolonged rectal absorption could be obtained by using these sustained-release suppositories, and the absorption rate was controlled by the amount of Alg added. It seems likely that the sustained release was due to the binding of morphine to Alg from the results of partition coefficient and binding ratio measurements in aqueous solution. The rapid initial absorption and the subsequent prolonged absorption of morphine simultaneously obtained from the morphine-Alg suppository may be useful in the clinical context.     

Preparation and characterization of insulin-loaded acrylic hydrogels containing absorption enhancers

The objectives of this study were to prepare insulin-loaded acrylic hydrogel formulations containing various absorption enhancers, to perform in vitro and in vivo characterization of these formulations, and to evaluate the factors which affecting insulin availability on rectal delivery of insulin using this hydrogel system. The acrylic block copolymer of methacrylic acid and methacrylate, Eudispert, was used to make the hydrogel formulations. As absorption enhancers, 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CyD), lauric acid (C12), or the sodium salt of C12 (C12Na), were incorporated into the hydrogels. In an in vitro release test, the release rate of insulin from the hydrogels decreased as the polymer concentration of the hydrogel increased. The addition of C12Na to the hydrogel further increased the insulin release rate, which was greater at higher concentrations of the enhancer. A portion of the C12Na was found to remain bound to the acrylic polymer in dissolution medium. Serum insulin levels were determined at various time points after the administration of insulin solution or insulin-loaded (50 units/kg body weight) Eudispert hydrogels containing 5% (w/w) of C12, C12Na, or DM-beta-CyD to in situ loops in various regions of the rat intestine. The most effective enhancement of insulin release was observed with formulations containing C12Na. The bioavailability of insulin from the hydrogels was lower than that from the insulin solutions. Hydrogel formulations containing 7% or 10% Eudispert remained in the rectum for 5 h after rectal administration. However, the 5% (w/w) C12Na solution stained with Evan's-blue had diffused out and the dye had reached the upper intestinal tract within 2 h. Finally, the rectal administration of insulin-loaded hydrogels, containing 4%, 7%, or 10% (w/w) Eudispert and 5% (w/w) of enhancer (C12, C12Na, or DM-beta-CyD) to normal rats was shown to decrease serum glucose concentrations. The greatest effect was found with insulin-loaded 7% (Eudispert) hydrogel containing C12Na which having cosiderable large insulin release rate and bioadhesive characteristics.     

Study of the interaction of clobazam with cyclodextrins in solution and in the solid state

Inclusion complexes of clobazam with alpha-, beta-, gamma-cyclodextrins (CyDs) and heptakis(2.6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) in aqueous solution and in the solid phase were studied by the solubility method, infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffractometry. In addition, inclusion complex of clobazam with heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin and the solid dispersion of clobazam with methyl cellulose (MC) in a ground mixture were investigated by IR, DSC and X-ray diffractometry. It was observed that DM-beta-CyD had the highest stability constant among the four CyDs in solution. Thermal and X-ray diffraction analyses showed that clobazam molecules existed in a molecularly dispersed state in the ground mixture of CyDs. Infrared spectra showed lower frequency shifts in the case of the ground mixtures of clobazam with natural CyDs, which can be attributed to the formation of hydrogen bonds between the two carbonyl groups of clobazam and hydroxyl groups of natural CyDs. In contrast, higher frequency shifts were observed in the case of the ground mixtures of clobazam with methylated CyDs and MC and these were considered to be due to the monomolecular dispersion of clobazam in a hydrophobic environment. The mode of interaction of clobazam with DM-beta-CyD was different from that with natural CyDs in the ground mixtures. Furthermore, the crystalline inclusion complex of clobazam with DM-beta-CyD was obtained by heating of the coprecipitate in vacuo at 120 degrees C for 1 h.     

Effect of cyclodextrins on biological membrane. II. Mechanism of enhancement on the intestinal absorption of non-absorbable drug by cyclodextrins.

The effects of two kinds of cyclodextrins (CyDs), alpha- and beta-CyD, on biological membranes were investigated by measuring changes in the absorption of a non-absorbable drug, sulfanilic acid (SA), from the rat small intestine, using in situ and in vitro experiments. After pretreatment with a mucolytic agent, N-acetyl-L-cysteine (N-Ac), only beta-CyD increased the absorption of SA significantly compared to the absorption without pretreatment. The mechanism of the enhancing effect of CyDs on the absorption of SA was discussed. Almost no morphological change in the small intestine was observed by pretreatment with N-Ac alone, N-Ac or alpha- or beta-CyD combinations. The liberation of membrane components differed among the CyDs, e.g., alpha-CyD selectively released phospholipid while beta-CyD released mainly cholesterol from the intestinal membrane. It is suggested that the interaction of membrane components with CyDs may be at least partly responsible for the enhanced absorption of SA. Moreover it was found from in vitro electrophysiological experiment, that the alteration in enhanced permeability caused by beta-CyD occurred primarily in the transcellular pathways, rather than in the paracellular pathways of the small intestine. These results suggest that the enhancement of intestinal absorption by beta-CyD, after removal of the mucin layer from the intestinal surface, is due to the interaction between the membrane components and CyD. This interaction would induce disorder in cell membrane lipid, resulting in the increased permeability of the transcellular route.     

Interactions of cyclodextrins with aromatic amino acids: a basis for protein interactions

Cyclodextrins (CyD) have proven effects on the stability of proteins and can be used in the formulation of aggregation prone therapeutic proteins. This effect stems from specific interactions between the CyD (preferably β-CyD) and solvent exposed amino acid residues. Here the interaction with hydrophobic aromatic amino acid residues stands out and the interaction between CyDs and these amino acid residues holds the key to understanding the observed effects, which CyDs exerts on proteins and peptides. Here we present a comparative study of the interactions between free and peptide bound aromatic amino acids and their derivatives with α, β and γ-CyDs using NMR spectroscopy. We propose a novel, quantitative means of assessing the penetration depth of guest molecules in CyD cavities, the penetration gauge Π, and apply it to the observed interaction patterns from ROESY NMR spectra. We demonstrate that the penetration depths of the aromatic rings within the CyDs rely highly on the nature of the remainder of the guest molecule. Thus the presence of charges, neighboring amino acids and the specific positioning on the surface of a protein highly influences the penetration depth and geometry of guest–CyD interactions.     

Studies on sustained-release suppositories. II. Evaluation of polymer electrolyte containing acidic groups for prolonged rectal absorption of bacampicillin in rabbits

Rectal absorption of bacampicillin hydrochloride (BAPC) was found to show the best bioavailability with Witepsol H-15 as suppository base among various Witepsol bases. However, an effective plasma concentration of drug (above 0.5 micrograms/ml) was only maintained for 2 h, so sustained-release suppositories of BAPC were studied. Bacampicillin reacts with acidic polymer electrolytes such as pectic acid (Pc), chondroitin sulfate (Cd) and precipitates as its adduct with the polymer in an aqueous solution. The dissolution rate of BAPC from the adducts in a solution was slower than that of BAPC itself. The absorptions of BAPC from the suppositories containing the adducts were prolonged, but the bioavailabilities were decreased compared to that from the suppository containing BAPC alone. Similar prolonged absorption could be obtained simply by mixing Pc or Cd with BAPC in a base. Further, the absorption rate was found to be controlled by the amount of the polymer addition, and both a high plasma level and excellent bioavailability were obtained. This desirable outcome may be due to the simultaneous occurrence of rapid absorption of BAPC itself and formation of the adducts.     

Effect of cyclodextrins on biological membrane. I. Effect of cyclodextrins on the absorption of a non-absorbable drug from rat small intestine and rectum

The effects of three kinds of cyclodextrins (CyDs), alpha-, beta- and gamma-CyD on biological membranes were investigated by changes in absorption of a non-absorbable drug, sulfanilic acid (SA), from the rat small intestine and rectum using an in situ perfusion technique. The absorption of SA from the intestine was slight and was not affected by the addition of CyDs. After pretreatment with a mucolytic agent, N-acetyl-L-cysteine (N-Ac), the absorption of SA was increased compared with SA alone in the presence of only beta-CyD. Similar treatment with sodium deoxycholate (SDC) and sodium lauryl sulfate (SLS) to gastro-intestinal membrane showed the enhanced absorption of SA by the addition of beta-CyD. The mucin layer on the surface of the gastro-intestinal membrane may play an important role in the absorption of drugs. On the other hand, enhanced absorption of SA from the rat rectum was not induced by beta-CyD with or without pretreatment with N-Ac, SDC or SLS. Simultaneously, the release of neutral sugars in the perfusate after treatment with adjuvants was also observed with N-Ac, SDC and SLS. These results indicate that the mucin layer works as a barrier to the increased absorption of SA by beta-CyD.     

Bioavailability of morphine in rabbits after rectal administration of suppository containing controlled release morphine tablet.

Two kinds of sustained release morphine suppositories have been prepared; one is an oleaginous base suppository (MSC) containing a controlled release morphine tablet (MST: MS Contin), and the other is a hollow-type suppository (MSCH) containing MST and morphine powder packed in its hollow space. In vitro release tests and in vivo rectal absorption experiments in rabbits were performed. The profiles of morphine release from MST and MSC in vitro were similar, and revealed that suppository bases had no effect on the release profile of morphine from the preparation. Morphine release from MSCH was rapid in the early phase, and then enclosed morphine was slowly and continuously released from MST. Phamacokinetics of morphine from the suppository were compared with the orally administered MST, and it was found that there was no difference in the maximum plasma concentration (Cmax) and the peak time (Tmax) between MSC and MST, but the mean residence time (MRT) of MSC was approximately three times longer than that of MST, and the extent of bioavailability (BA) of MSC was significantly larger than that of MST (71.6 +/- 14.2% and 11.9 +/- 4.0%, respectively). Cmax can be altered arbitrarily by changing the morphine content in the hollow space of MSCH. As in the case of MSC, the plasma concentration of morphine from MSCH was maintained. It is concluded from the above results that MSC is a satisfactory sustained release morphine suppository for the treatment of cancer pain, administering it twice a day, and that MSCH is effective due to its fast analgesic effect and sustained release nature not only for cancer pain but also for surgical operations.     

Thermo-reversible flurbiprofen liquid suppository with HP-β-CD as a solubility enhancer: improvement of rectal bioavailability

The purpose of this work was to develop a thermo-reversible flurbiprofen liquid suppository base composed of poloxamer and sodium alginate for the improvement of rectal bioavailability of flurbiprofen. Cyclodextrin derivatives such as α-, β-, γ-cyclodextrin and hydroxypropyl-β-cyclodextrin (HP-β-CD) were used to enhance the aqueous solubility of flurbiprofen. The effects of HP-β-CD and flurbiprofen on the physicochemical properties of liquid suppository were then investigated. Pharmacokinetic studies were performed after rectal administration of flurbiprofen liquid suppositories with and without HP-β-CD or after intravenous administration of commercial Lipfen^® (flurbiprofen axetil-loaded emulsion) to rats, and their pharmcokinetic parameters were compared. HP-β-CD decreased the gelation temperature and reinforced the gel strength and bioadhesive force of liquid suppository, while flurbiprofen was opposed to HP-β-CD. Thermo-reversible flurbiprofen liquid suppository showed the physicochemical properties suitable for rectal administration. The flurbiprofen liquid suppository with HP-β-CD showed significantly higher plasma levels, AUC and C_max of flurbiprofen than those of the liquid suppository without HP-β-CD, indicating that flurbiprofen could be well absorbed due to the enhanced solubility by formation of inclusion complex. Moreover, the flurbiprofen liquid suppository with HP-β-CD showed an excellent bioavailability in that the AUC of flurbiprofen after its rectal administration was not significantly different from that after intravenous administration of commercial Lipfen^®. It is concluded that HP-β-CD could be a preferable solubility enhancer for the development of liquid suppository containing poorly water-soluble drugs.     

Potential use of polypseudorotaxanes of pegylated polyamidoamine dendrimer with cyclodextrins as novel sustained release systems for DNA

In this study, we demonstrated the potential use of polypseudorotaxanes (PPRXs) of polyethylene glycol (PEG, molecular weight: 2000)-grafted polyamidoamine dendrimer (PEG-dendrimer) with cyclodextrins (CyDs) as novel sustained release systems for plasmid DNA (pDNA). PEG-dendrimer/pDNA complex formed PPRXs with α-CyD and γ-CyD solutions, but not with β-CyD solution. In the PEG-dendrimer/CyDs PPRXs systems, 17.9 mol of α-CyD and 8.8 mol of γ-CyD were involved in the PPRXs formation with one PEG chain by α-CyD and γ-CyD, respectively. In addition, the CyDs PPRX formation provided the sustained release of pDNA from PEG-dendrimer complex with pDNA at least 72 h in vitro. In addition, the release of pDNA from CyDs PPRX retarded as the dissolution medium volume decreased. These results suggest that the PEG-dendrimer/CyD PPRX systems can work as a sustained DNA release system, and the PPRX formation with CyDs may be useful as a sustained drug delivery technique for other pegylated polymers.     

Model Analysis for Oral Absorption of a Drug/Cyclodextrin Complex Involving Competitive Inclusion Complexes

The bioavailability parameters of a drug after oral administration of a preparation containing drug/CyD complexes may be modified by formation of competitive inclusion complexes. In this study, we examined the effects of competitors on drug permeation from its CyD complex through in-vitro artificial membranes and in-situ recirculation conditions, for comparison with the results under in-vivo conditions in the bile duct of cannulated rats. Phenacetin, an antipyretic, was used as a model drug, natural CyDs and maltosyl--CyD as host molecules, and benzoic acid derivatives, sodium taurocholate and acetaminophen as competitors. The in-vitro cellophane membrane permeation rate and the in-situ absorption rate of phenacetin were quantitatively predicted by theoretical calculation using the stability constants of drug/CyD and competitor/CyD complexes when CyD weakly interacts with membrane components in lower CyD concentrations (generally below 10 mM). The in-vivo absorption behavior was only qualitatively reproducible by the theoretical calculation, probably because of various physicochemical and physiological factors affecting the absorption. The present results may be useful not only for prediction of intestinal absorption of drugs from CyD preparations, but also for formulation design of CyD preparations containing multi-components.     

Design of polyvinyl alcohol hydrogel as a controlled-release vehicle for rectal administration of dl-propranolol-HCl and atenolol

Preparations of beta-blockers, propranolol-HCl and atenolol, in poly(vinyl alcohol) (PVA) hydrogel were designed for the therapeutic treatment of hypertension by transrectal delivery. In vitro release characteristics and plasma drug concentration profiles after rectal administration in rats and dogs were examined. The PVA hydrogels containing beta-blockers were prepared by a low-temperature crystallization method. The release of beta-blockers from hydrogel preparations was consistent with Fickian diffusion (Higuchi model); the drug release versus the square root of release time profile gave a straight line over 60% of the total release process. The release of beta-blockers from hydrogel preparations increased at higher concentrations of PVA in the hydrogel preparations and was not affected by the pH of hydrogel preparations. Plasma concentrations of beta-blockers after rectal administration of hydrogels were higher than those after administration of suppositories (Witepsol H-15) in rats and dogs. The drug plasma concentrations increased at higher concentrations of PVA in hydrogel preparations. In the case of propranolol, which is a hepatic high-clearance drug, area under the blood concentration curve, 0-8 h after rectal administration of a hydrogel preparation (20% w/w PVA, pH 7.0) was 2.16 times and 5.26 times higher than those obtained with Witepsol H-15 suppository and oral administration, respectively. Rectal administration with PVA hydrogels is a favorable route for a hepatic high-clearance drug such as propranolol.     

Circular dichroic investigation of factors that affect inclusion complexes of cyclodextrins as a drug carrier

Drug/cyclodextrin (CyD) inclusion complexes have become one of the most widely used approaches to increase aqueous solubility of poorly soluble drugs, to increase their bioavailability and stability, to reduce undesirable side effects and prevent drug–drug and drug–excipient interactions. Although drug molecules as well as CyDs exhibit detectable changes in their physicochemical properties upon complexation, to date, the interaction of CyDs with drugs is not well understood. So far, only few methods can be applied to obtain structural information on drug/CyD complexes. Circular dichroism spectroscopy (CD) has often been used to study molecular binding, nevertheless, rarely do these studies exploit the full potential of optical techniques. The objective of this article is to highlight important factors that affect drug/CyD binding interaction in particular β-CyD. On the basis of chirality, (S)-(+)-ibuprofen, meta-chlorobenzoic acid and aspirin were used to study binding interaction with β-CyD using CD. Based on CD equations for a simple 1:1 binding complex, the Levenberg–Marquadt non-linear equation was used for binding analysis and the production of simulated graphical presentations to explain the effect of various factors that influence the binding reaction and the binding curve. The results show reliability indicated by the binding constant which is in agreement with literature values. In addition, the effect of guest/host concentrations and the extent of binding on the inclusion complexes are elucidated with accuracy. This work provides useful information that can prove valuable in drug binding studies.     

Indomethacin sustained-release suppositories containing sugar ester

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 H-15 (H-15) and their availabilities 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 gauze, 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 reasonably regulated the infiltration of rectal fluid into the suppository and the mechanical strength of the suppository against disintegration.