Rectal absorption of omeprazole from suppositories in rabbits

Rectal absorption of omeprazole, a proton pump inhibitor, from suppositories was studied in rabbits. The suppositories were prepared by the conventional melting method with two types of bases, water-soluble polyethylene glycol (PEG) 4000 and oil-soluble Witepsol H15 bases, and administered intrarectally (ir) to rabbits at a dose of 10 mg omeprazole/kg. The plasma omeprazole concentration-time profiles of the two suppositories were compared with those following intravenous (iv) administration of the same dose. There were no significant differences between the two suppositories in bioavailabilities and peak plasma concentrations (C_max). Bioavailabilities and C_max of PEG- and Witepsol suppositories were 30.3 and 33.9%, and 7.0 and 5.6 μg/ml, respectively. However, PEG suppository showed significantly (P<0.05) shorter time to reach peak plasma concentration (T_max), mean absorption time (MAT) and mean residence time in the plasma (MRT) than Witepsol suppository. The T_max MRT and MAT were 25.0, 83.0 and 38.5 min for PEG suppository, but were 90.0, 122.5 and 78.0 min for Witepsol suppository, respectively. These differences between the two suppositories could be explained by the difference in the in vitro dissolution rates between the suppositories. The dissolution of omeprazole from PEG suppository was reportedly much faster than that from Witepsol suppository. It suggests that plasma profiles of omeprazole, especially C_max, MAT and MRT, could be controlled by modifying thein vitro dissolution rate of the drug from the suppositories. Above results suggest that rectal suppository is worth developing as an alternative dosage form of omeprazole to the conventional oral preparations which need sophisticated treatments, such as enteric coating, to prevent acid degradation of the drug in the stomach fluid.     

Rectal absorption of morphine from controlled release suppositories

The absorption profiles and bioavailability of morphine in human volunteers (n = 13) were described after oral administration of MS Contin tablets and rectal administration of a newly developed controlled release suppository. By manipulating the viscosity of fatty suppository base an entirely identical cumulative morphine input could be obtained compared with oral dosing.     

Rectal absorption of insulin suppositories in rabbits

When insulin solutions (100 U kg^?1) at various pH values were placed in the rectum of rabbits, a large decrease in blood glucose concentration was observed except at the pH close to the iso-electric point of insulin. The effect of surface-active agents on the rectal absorption of insulin was examined by measuring the blood glucose concentration after the administration of 2 or 5 U kg^?1. Non-ionic ether type, anionic, cationic and amphoteric surfactants as well as bile acids increased the absorption. The optimal effect with suppositories was reached with the addition of 1% polyoxyethylene (9) lauryl alcohol ether. Insulin suppositories containing agents enhancing rectal absorption were compared with the insulin for intravenous, intramuscular and subcutaneous injection. The changes of blood glucose and plasma immuno-reactive insulin concentration after rectal administration of insulin were similar to those after intravenous injection.     

Absorption of phenytoin from rectal suppositories formulated with a polyethylene glycol base

STUDY OBJECTIVE: To compare phenytoin pharmacokinetics following administration of an oral suspension and a rectal suppository formulated with a polyethylene glycol base. DESIGN: Unblinded, single-dose, randomized, crossover trial. SETTING: University-affiliated pharmacokinetics and biopharmaceutics laboratory. SUBJECTS: Six healthy subjects. INTERVENTION: Subjects were given a single 200-mg dose of phenytoin as an oral suspension and a rectal suppository separated by a 1-week washout. MEASUREMENTS AND MAIN RESULTS: Blood for plasma phenytoin concentrations was obtained at baseline and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. Plasma was analyzed by high-performance liquid chromatography (coefficient of variation < 6%) for total phenytoin concentration. Phenytoin maximum concentration (Cmax), time to Cmax (Tmax), time to first measurable concentration (Tlag), and area under the curve from time zero to time of last measurable concentration (AUClast) were estimated for oral and rectal administration by WinNonlin (v 1.1) and compared using Wilcoxon's signed rank test (p<0.05 for statistical significance). Two subjects did not have detectable plasma phenytoin concentrations after rectal administration. For the other four subjects, median rectal Cmax was significantly lower than oral Cmax (0.4 vs 1.9 microg/ml, p=0.028), median rectal Tmax did not differ from oral Tmax (11.9 vs 8.0 hrs, p=0.465), and median rectal AUClast, although highly variable, was significantly lower than oral AUClast (5.4 vs 36.2 microg x hr/ml, p=0.046). No Tlag was seen after oral administration, but with rectal administration the median Tlag was 2 hours. The estimated relative bioavailability of rectal phenytoin suppositories based on AUC0-24 was 4.7%, with individual values ranging from 0-58.3%. CONCLUSION: It appears that absorption of phenytoin from polyethylene glycol rectal suppositories in healthy subjects is highly variable and unpredictable. Thus this formulation is not recommended.     

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.     

Effect of drug solubility on in vitro availability rate from suppositories with polyethylene glycol excipients

Factors involved in the availability mechanism of different drugs from suppositories with polyethylene glycol (PEG) excipients were studied using an in vitro model of the rectal compartment with a porous membrane simulating the rectal barrier. Different from lipophilic excipients, the drug is released as a consequence of the progressive dissolution of PEG into the intrarectal aqueous phase. Drug concentration in this small intrarectal phase produces the gradient against the large volume of the plasmatic phase, which regulates the diffusion rate through the barrier. As with lipophilic excipients, drug solubility in water was found to be an important factor influencing suppository release rate. Nevertheless, PEG influenced in vitro drug availability considerably, by increasing both drug solubility and dissolution rate. The osmotic effect of PEG in the intrarectal compartment influenced the increase in volume of the aqueous phase. The results, compared with those obtained from suppositories with a lipophilic excipient, show a higher dissolution rate from PEG excipient, but a higher diffusion rate across the barrier did not always correspond. Drugs less soluble in water showed a greater availability from PEG suppositories. On the contrary the more soluble drugs were less available.     

Correlations between physical and drug release characteristics of polyethylene glycol suppositories.

The mechanical strength and elastic moduli of blocks of polyethylene glycol with a range of molecular weights were determined. A rotating-basket dissolution test was used to measure the release characteristics of prednisolone from similar blocks. The effects of blending bases of different molecular weight and of the addition of water also were determined. Linear relationships were found for the mechanical strength, molecular weight, and release rate, but no simple relationship could be observed for the elastic moduli.     

吲哚美辛栓诱发直肠出血

患者男,45岁。因“自服氧化乐果后呼吸困难14d,鲜血便1d”,于2004年9月26日收入住院。患者原有乙肝病毒携带史20余年,肝功能正常;无痔疮病史。本次乐果中毒后先在当地医院救治,并使用机械通气,抗炎,营养支持等治疗;近1周来,患者出现持续高热,曾多次应用吲哚美辛(消炎痛)栓肛塞退热处理。入院当天在当地医院解大量鲜血便,约1000mL,原因不明。给予快速输血补液后转入本院。入院时查体:T38.2℃,BP110/60mmHg(1mmHg=0.133kPa),HR120次/min,神志清楚,轻度贫血貌,皮肤巩膜无黄染,气管切开,机械通气,两肺可闻及痰鸣音以及湿性啰音,心律齐,腹部…     

Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine

Purpose. To investigate the effect of co-administered polyethylene glycol 400 (PEG 400), a pharmaceutical excipient previously shown to accelerate small intestinal transit, on the absorption characteristics of ranitidine from the gastrointestinal tract. Methods. Ten healthy male volunteers each received, on two separate occasions, an immediate-release pellet formulation of ranitidine (150 mg) encapsulated within a hard gelatin capsule and a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). The liquid preparations were also radiolabelled with indium-111 to allow their transit through the gastrointestinal tract to be followed using a gamma camera. On a further occasion an intravenous injection of ranitidine (50 mg) was administered. Blood samples were taken over a 12 h period on each study day to allow a ranitidine plasma and subsequent absorption rate profile to be generated for each oral formulation. Urine was collected for 24 h and assessed for PEG 400 concentration. Results. The absolute bioavailability of ranitidine from the pellet formulation was significantly reduced by 31% (from 51% to 35%) and small intestinal liquid transit time was significantly shortened by 37% (from 226 min to 143 min) as a consequence of PEG 400 in the test preparation. PEG 400 also affected the rate of ranitidine absorption, with major differences noted in the mean absorption time and C_max parameters. The appearance of double peaks were less evident in the ranitidine pharmacokinetic profiles in the presence of PEG 400, and little or no correlation was observed between the absorption of ranitidine and PEG 400. Conclusions. These results clearly demonstrate that PEG 400 adversely influences the gastrointestinal absorption of ranitidine. This in turn has ramifications for the use of PEG 400 as a pharmaceutical excipient in oral formulations.     

Release and rectal absorption of ethosuximide from suppositories in rabbits

Ethosuximide was formulated in different suppository bases. In vitro release experiment demonstrated more rapid and higher release of the drug from water soluble polyethylene glycol (PEG) bases than from Witepsol fatty bases. Rectal administration in PEG 400:4000 and 400:6000 to rabbits gave high plasma levels where Cmax was 45.66 and 42.66 micrograms.ml-1, respectively; while, in the presence of Witepsol E76 and W35 it was 34.00 and 28.33 micrograms.ml-1, respectively. The systemic availability was 89.39%, 82.72%, 58.80% and 47.45% when the bases were PEG 400:4000, PEG 400:6000, Witepsol E76 and Witepsol W35, respectively.     

Rectal absorption of steroids

The investigations were designed to evaluate the systemic absorption of two steroids from suppositories. The suppositories containing either 3H-hydrocortisone (1 mg) or 3H-prednisolone-21-hexanoate (1 mg) were administered to a group of 4 baboons restrained in chairs. The levels of radio-activity in the plasma and urine were measured up to 120 h following rectal administration, and these levels were compared with those of a subsequent intravenous administration (1 mg each). The results show that both hydrocortisone (H) and prednisolone-21-hexanoate (P) are rapidly (tmax = 2-3 h) and significantly (H: 60-78%, P: 47-58%) absorbed from suppositories and thus can also cause systemic effects.     

Rectal absorption of oxcarbazepine

Physicians regularly challenge the hospital pharmacy departments to find alternative routes for the administration of drugs, which can't be withhold, e.g. antiepileptic drugs. In our hospital we were confronted with the question whether it was possible to administer oxcarbazepine rectally. In the present report data on the absorption of rectally administered oxcarbazepine is presented. No therapeutic bloodlevels were attained after rectal administration. Administration via the oral route, however, gave within the same period of time a therapeutic bloodlevel. It is concluded that the absorption after rectal administration of oxcarbazepine at least in this dose and frequency used is too low to justify application in practice.