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.     

Absorption enhancement of polypeptide drugs by cyclodextrins. I. Enhanced rectal absorption of insulin from hollow-type suppositories containing insulin and cyclodextrins in rabbits.

The absorption of insulin (from porcine pancreas) from the rectum of rabbits after the administration of hollow-type suppositories containing insulin and five kinds of cyclodextrins (CyDs) was investigated. Three types of suppositories were employed: suppository I containing insulin (approximately 26 IU/mg) and various amounts of each CyD in citric buffer solution at pH 3.0 or powder in its cavity, suppository II containing CyD without insulin, and suppository III containing insulin without CyD. Without CyD, the insulin and glucose levels in plasma were unchanged, whereas a significant increase in the plasma insulin concentration and a marked decrease in the glucose levels were found following simultaneous administration of insulin and CyDs by suppository I. The enhancing effect of CyD on rectal insulin absorption (absorption-enhancing effect) by chemically modified CyDs (heptakis(2,6-di-O-methyl)-beta-CyD (DM-beta-CyD) and 2-hydroxypropyl-beta-CyD (HP-beta-CyD)) was higher than those by natural CyDs (alpha-, beta-, and gamma-CyD). The area under the plasma concentration-time curve (AUC) and Cmax of insulin significantly decreased with the preadministration (administration of CyD 6, 24 and 48 h before rectal insulin administration) of DM-beta-CyD. The absorption-enhancing effect disappeared 24 h after preadministration. These results suggest that CyDs enhance insulin absorption from the rectum, and that attenuation of the membrane transport barrier function in the rectum recovers at a maximum of 24 h after administration of CyDs.     

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.     

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.     

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.     

Effect of glycyrrhizinate on dissolution behavior and rectal absorption of amphotericin B in rabbits.

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.     

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.     

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.     

Percutaneous absorption of ketoprofen from acrylic gel patches containing d-limonene and ethanol as absorption enhancers.

The percutaneous absorption of ketoprofen (KPF) from gel patches containing d-limonene and ethanol was investigated in rats. Plasma levels of KPF varied with the kind of polymers which constitute the gel patch, and the highest level was observed when the copolymer of ethylacrylate (EA) and diethyleneglycolmethacrylate (DEGMA) was used as a vehicle. The amount of KPF permeating through the rat skin from the gel patch was well correlated with that of ethanol. Permeations were enhanced with increase in the amount of d-limonene distributed from the vehicle to the skin tissue. The amount of d-limonene accumulated in the skin varied greatly with the kind of polymers; the highest accumulation was observed with the EA-DEGMA copolymer, and decreased with increasing affinity of d-limonene to the polymers. The reason EA-DEGMA copolymer showed the highest percutaneous absorption of KPF from gel patches containing d-limonene may be the hydrophilic nature of this polymer which showed the lowest affinity to d-limonene.