Sustained-release Suppositories Research Articles

Development and Evaluation of Micropelleted Sustained-Release Suppositories of Terbutaline Sulfate

Terbutaline sulfate (TS), a β2 agonist, was fabricated in the form of micropelleted sustained-release suppositories. Micropellets of TS using Eudragit RS100 were prepared by emulsification-solvent evaporation technique and were incorporated into suppositories (PEG 4000 as base) by fusion method. Physical, in vitro and in vivo evaluations were carried out for both conventional (PEG 4000 base) and micropelleted sustained-release suppositories and were compared. Micropellets were scanned using electron microscopy to see the surface structure before and after the in vitro dissolution.

Application of curdlan to controlled drug delivery. III. Drug release from sustained release suppositories in vitro.

The use of curdlan, a natural beta-1,3-glucan, in the preparation of sustained release suppositories was studied in vitro. To prepare the suppositories, indomethacin, prednisolone or salbutamol sulfate was mixed with curdlan gel. Preparation conditions, including heating time and curdlan concentrations of 5 and 10%, had little effect on the drug release. The tonicity (hypotonic or isotonic) of the media for the suppository preparation and for in vitro drug release study also had little effect on drug release. However, the heating temperature during gel preparation, the drug amount in the suppository and the type of release media did affect drug release. It was found that drug release was sustained and diffusion-controlled in the three drugs. And finally, curdlan can be applicable for use in a sustained release suppository.

Bioavailability of sustained release indomethacin suppositories containing polycarbophil

The bioavailability of indomethacin from polyethylene glycol base, commercial suppositories Indocid ∗, MSD and from polyethylene glycol base containing 5, 6 and 8% of polycarbophil, with the purpose of obtaining a controlled release suppositories, was determined in dogs. The results show that polycarbophil as a bioadhesive increased absorption and improved the bioavailability of indomethacin where the areas under the curves for the commercial suppositories and those containing 0, 5, 6 and 8% polycarbophil were 19.5, 14.9, 31.2, 21.4 and 21.2 μ h ml −1, respectively. The maximum plasma concentration ( C max) and the time to reach C max ( t max) were 4.76, 2.98, 4.50, 2.36 and 1.29 μg/ml and 1, 1, 1, 1 and 12 h for the commercial suppositories and those containing 0, 5, 6 and 8% polycarbophil, respectively. The data indicate that as the polycarbophil concentration increased from 0 to 5% in the polyethylene glycol suppositories, the plasma levels and bioavailability improved significantly ( p < 0.1, Student's t-test), whereas on increasing from 5 to 6 and 8% the plasma levels and bioavailability decreased significantly ( p < 0.05). At 8% polycarbophil concentration, sustained release suppositories were produced but a decrease in plasma levels was observed.

Ketoprofen sustained-release suppositories containing hydroxypropylmethylcellulose phthalate in polyethylene glycol bases

In this study, conventional and sustained-release suppositories of ketoprofen (KP) were prepared and the effects of suppository bases and the inert matrix material (hydroxypropylmethylcellulose phthalate, HP 55) on in vitro release of ketoprofen suppositories were investigated. Suppositories containing 100 mg ketoprofen were prepared by the fusion method. Witepsol H15, Massa Estarinum B, and polyethylene glycols (PEG) were used as examples of hydrophobic and hydrophilic bases, respectively. Sustained-release suppositories of KP were prepared by using HP 55. Weight variation, content uniformity, breaking (hardness) and melting range tests were then conducted on these formulations. In vitro release and diffusion rate tests were also carried out according to the USP XXII basket method and the Muranishi method, respectively. The results show that the rate of release of KP is very slow for Witepsol H15 and Massa Estarinum B bases. However, KP was released very rapidly from the PEG bases in the conventional suppositories. On the other hand, HP 55 might be useful as a vehicle for sustained release preparations of ketoprofen in suppository form. It was shown from the kinetic assessment of release data that the best fit was achieved with zero-order kinetics.

ウイテプゾール，エチレン‐酢酸ビニル共重合体混合系新規基剤を用いたプロゲステロン坐剤

A sustained release suppository containing progesterone (mixed suppository) was prepared to treat the luteal phase defect. A mixture of ethylene-vinyl acetate copolymer (EVA) and Witepsol-W35 was used as the suppository base. Characteristics of the mixed suppositories using various types of EVA were compared with those of Witepsol-W35 alone (control suppository).Determined as physical characteristics were hardness, DSC peak temperature, heat of fusion and release profiles of progesterone. Furthermore, the plasma concentration profiles of progesterone observed from suppositories were measured in rabbits. The sustained release of progesterone from the mixed suppository was observed in the beads cylindrical filter method.When the mixed suppositories were administered to the vagina of rabbits, some part of the suppository remained after 3 hours though nothing remained the control suppository.The Pharmacokinetic parameters obtained from the plasma concentration profiles suggested the sustained release property of progesterone in the biophase when the mixed suppository was administered. With this mixed suppository, the concentrations of progesterone in the vagina, cervical canal and uterus at 3 hours after the administration were higher than those of the control suppository.These results suggest that the mixed suppository could be useful as a dosage form for replacement therapy of progesterone.

大学病院におけるモルヒネ製剤使用量の推移

We surveyed the amount of morphine preparations used at our hospital, the Hospital of Toyama Medical and Pharmaceutical University, including both marketed preparations and the sustained release suppository which we prepare here at our pharmacy. For oral dosage, the amount of controlled release morphine tablet used rapidly increased, while morphine HC1 powder decreased dramatically. As for the amount of suppositories being used, the morphine HCl suppository as well as that of the sustaind release suppository tends toward a slight increase. Since more morphine is expected to be used, it is essential for pharmacists to contribute to a more appropriate clinical use of morphine.

Rectal absorption of Zidovudine

Rectal absorption of Zidovudine (3′-azido-3′-deoxythymidine, AZT) was investigated in order to determine the feasibility of developing AZT suppositories. Although the small intestine shows a higher absorption rate than the stomach and large intestine in rats, considerable absorption of AZT was observed from the lower large intestine (8 cm above the anus). A sustained-release suppository was prepared by direct compression of hydroxypropyl cellulose (HPC) with AZT. During in vivo experiments in rats, this suppository (10 mg or 37.5 μmol AZT/kg) maintained constant plasma levels above 1 μM for more than 6 h. The results suggest that suppositories can prove useful as an alternative dosage form of AZT administration.

ＭＳコンチン錠を包含する新しい徐放性坐剤によるとう痛治療の可能性について

ＭＳコンチン錠を包含する新しい徐放性坐剤によるとう痛治療の可能性について

アルギン酸含有モルヒネ持続性坐剤によるとう痛管理の臨床的評価

The rapid initial absorption and the subsequent prolonged absorption of morphine were obtained simultaneously by using sustained-release suppository (MA), which can be prepared simply by mixing sodium alginate with morphine hydrochloride in VOSCO® H-15 base, in rabbits. The clinical effects of MA were evaluated in patients with severe pain such as the terminal cancer patients. Of 35 patients receiving MA, 21 and 13 could achieve acceptable analgesia on a twice and a once daily dose schedule, respectively. Conventional morphine suppository without alginic acid, however, relieved pain only for 8 hours on the same single-dose. The efficacy of MA is also supported by the sustained plasma morphine level in six female operating patients receiving MA. The MA dosing interval lengthened to every 12 to 24 hours resulted in a decrease in the total daily morphine requirement below 40 mg, The clinically desirable sedation was obtained during night and day in all patients, and the side effects such as vomitting and constipation observed in 29 percent of the patients were mild and controlled by simptomatic treatment. The advantage of less frequent dosing by MA may lead to improvement of the quality of life of terminal patients with pain.

ウサギに３種類の坐剤を投与した際のモルヒネの体内動態

We prepared three kinds of morphine suppositories: HE was based on the equivalent mixture of Witepsol H-15 and E-75; S was based on Witepsol S-55 alone; MSC contained controlled-release morphine tablet (MS Contin) in the same base as HE. The pharmacokinetics after rectal administration of the preparations was investigated in rabbits. We found that HE had short Tmax (10min) and that the sustained release continued around 6hr after administration. The extent of bioavailability (BA) of HE was 43.4%, and the plasma concentration of morphine was higher than orally administered MS Contin tablet, throughout the observation period. S had a high BA (95.1%) but Cmax (446.2ng/ml) was too high judged from some risk of adverse effect or dependence. Thus we considered it is not appropriate for clinical use. On the other hand, MSC had longer Tmax (150min). The plasma concentration 12hr after administration was around half the Cmax and the sustained release was found to be good. The MSC's BA also showed high value and only a little dispersion (78.3±6.6%). The cumulative absorption-time profiles of MSC in vivo approximated to the morphine-release behavior of MS Contin tablets in vitro.From the facts described above we conclude:1. We can expect the same or more analgesic effect from HE than oral MS Contin tablets.2. MSC is a good sustained-release morphine suppository which can be expected to be useful for cancer pain therapy, through every 12-hr administration.

Sustained Release Suppository of Sodium Diclofenac: use of Water Absorbable Polymer

AbstractThe investigation on the usefulness of water absorbable polymer (Poys® SA-20) for the preparation of sustained release suppository was performed. To prepare the sustained release suppository, sodium diclofenac solution is absorbed into the sphere polymer, and the particles of the polymer after dryness are suspended in the melted triglyceride suppository base, followed by solidification. The sustained release of sodium diclofenac from the suppository was confirmed by the in vitro release study with slow release of sodium diclofenac and by the in vivo absorption study in dogs with an avoidance of transient high plasma diclofenac concentration and a prolong of plasma diclofenac concentration.

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.

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.

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.

Evaluation of sustained-release suppositories containing microencapsulated theophylline and oxyphenbutazone

Microencapsulation of theophylline and oxyphenbutazone using ethylcellulose was carried out by a simple coacervation method. To control the release of theophylline and oxyphenbutazone the microcapsule surfaces were modified by dry-blending each drug with a carboxyvinyl polymer by pulverization in an electrical mixer before encapsulation. Suppositories containing pure theophylline or oxyphenbutazone as well as microencapsulated theophylline and oxyphenbutazone were prepared by the fusion method. The release rate of theophylline and oxyphenbutazone decreased as the content of coacervation-inducing agent polyethylene was increased except at a concentration of 1% polyethylene in case of oxyphenbutazone microcapsules. The release rates of theophylline and oxyphenbutazone from suppositories containing these microcapsules were in accordance with the results of the dissolution rates of drugs. On the other hand, suppositories containing microcapsulated carboxyvinyl-polymer-modified drugs showed a pseudo-zero-order release profile. The surface modification of drug particles with carboxyvinyl polymer before encapsulation is a good method to prepare sustained release suppositories containing theophylline and oxyphenbutazone microcapsules.

Study on absorption of indomethacin from sustained-release suppositories containing hydrogenated soybean lecithin in rabbits.

The absorption of indomethacin (IM) from suppositories containing hydrogenated soybean lecithin (HL) after rectal administration in rabbits was investigated with the aim of producing sustained-release suppositories. The suppositories were prepared by the fusion method with IM, HL and Witepsol H-15 (H-15). The IM release rate from the suppositories (IM 10 mg, HL 200 mg, total weight 1 g) was faster than that of the control suppositories without HL. The release of IM from the suppositories (IM 10 mg, HL 300 mg or 350 mg) showed slow-release profiles. In absorption studies in rabbits, sustained-plasma levels of IM were obtained when suppositories having an HL content of more than 300 mg were administered. The suppositories composed of Witepsol E-85 (melting point approximately 43 degrees C), 10 mg of IM, and 200 mg of HL, showed slow-release profiles in the release test, but did not show sustained plasma levels of IM in the absorption test. These results indicate that sustained-release suppositories able to release IM gradually from the surface of the suppositories can be obtained when HL, IM and H-15, whose melting point is lower than body temperature, are used in the preparation of the suppositories, provided that the HL content is high enough in relation to IM.

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.

Clinical investigation of sodium diclofenac sustained-release suppositories

Sustained release suppositories of sodium diclofenac (SR-Supp) were evaluated in 8 patients who were in pain. In terms of the study of plasma diclofenac concentration profiles in 4 healthy male humans, plasma diclofenac concentrations of more than 50 ng/ml were maintained for 8 h in one subject, for 9 h in another, and for more than 12 h in two others after administration of a Sr-Supp containing 50 mg sodium diclofenac. In the clinical investigations of SR-Supp, 8 patients having chronic rheumatoid arthritis with severe pain were treated with SR-Supp. Plasma diclofenac concentrations in patients were determined only at 4 h after administration of SR-Supp, but in all cases, they correlated well with the values obtained in healthy subjects. The effect of SR-Supp in alleviating pain was sustained for 10 h or more, and allowed the patients to sleep comfortably through the night.

Evaluation of indomethacin sustained-release suppositories prepared with a methacrylic acid-methacrylic acid methyl ester copolymer-polyethylene glycol 2000 solid matrix.

Indomethacin (IM) sustained-release suppositories were prepared by using a solid matrix of methacrylic acid-methacrylic acid methyl ester copolymer (Eudragit L100[○!R] : EL) as a poorly water-soluble carrier and polyethylene glycol 2000 (PEG 2000) as a readily water-soluble carrier. The rate of IM release from EL-PEG 2000 matrix suppositories decreased with increase of the EL content. The sustained release of IM from these matrix suppositories was attributed to the development of a network structure of EL. Rectal administrations of the matrix suppositories in rabbits resulted in good characteristics for sustained release. The extent bioavailability of the 20% EL-PEG 2000 matrix suppositories (EL-20) was about 50%.