Controlled-release Suppository Research Articles

Morphine in cancer pain: controlledrelease suppositories have advantages

Morphine in cancer pain: controlledrelease suppositories have advantages

Steady‐State Pharmacokinetic Evaluation of a Novel, Controlled‐Release Morphine Suppository and Subcutaneous Morphine in Cancer Pain

Although the oral route is the preferred method for morphine administration for cancer pain, many patients will require an alternate route of administration at some point during their illness. The authors studied the steady-state pharmacokinetics of morphine after administration of a novel, controlled-release suppository (MS-CRS) and subcutaneous morphine in a randomized, double-blind, two-way crossover evaluation in 10 patients with cancer pain. When administered at a 2.5:1 analgesic ratio, MS-CRS given every 12 hours showed an equivalent extent of absorption compared with subcutaneous morphine given every 4 hours (AUC0-12, 132.5 +/- 30.1 versus 123.8 +/- 27.3 ng.h.mL-1, P = not significant [NS]). Peak morphine concentrations were lower, time of peak was later, and percent fluctuation less after MS-CRS than after subcutaneous morphine (Cmax, 14.7 +/- 2.9 versus 29.9 +/- 5.4 ng/mL, P = .0110; tmax, 3.33 +/- 0.75 versus 2.22 +/- 0.15 hours, P = .0160; fluctuation, 122 +/- 71 versus 356 +/- 123%, P = .00160). Relative bioavailability of MS-CRS using the 2.5:1 analgesic ratio was 105%, and bioavailability from data dose normalized without regard to route specificity in metabolism was 42%. For both routes of administration there was a significant linear relationship between morphine dose and AUC (MS-CRS, r = .8568, P = .0032; subcutaneous morphine, r = .8314, P = .0055). MS-CRS morphine provides a pharmacokinetic profile consistent with dosing every 12 hours; at steady state, the extent of absorption is comparable with that of subcutaneous morphine when administered at a 2.5:1 dose ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Design of Novel Controlled-Release Suppositories Containing Polyglycerol Ester of Fatty Acid.

A novel controlled release suppository consisting of Witepsol H15 as a triglyceride base and polyglycerol ester of fatty acid (PGEF) has been designed and developed. The addition of PGEF to Witepsol H15 resulted in an increase in the solid fat index (SFI), which is correlated with melting point and apparent viscosity, of the Witepsol H15-PGEF (H15-PGEF) mixed base in a similar manner to the case of Witepsol H15-Witepsol E85 (H15-E85) mixed base. In the in vitro release tests, the release rate of Brilliant Blue from the H15-PGEF mixed base was reduced with increase of PGEF content, indicating that the drug release rate from the H15-PGEF mixed base depended on SFI. The change in the drug release rate from the H15-PGEF mixed base with temperature in release tests ranging from 36°C to 39°C was small, whereas the release rate in the H15-E85 mixed base changed significantly with temperature. These changes in drug release rate with temperature in the H15-E85 and H15-PGEF mixed bases were found to be attributable to the variation of SFI of both the mixed bases. In addition, the change in SFI during storage at 30°C in the H15-PGEF mixed base was relatively small as compared with that of the H15-E85 mixed base. From these results, the H15-PGEF mixed base is expected to be useful for stable controlled release suppositories.

Pharmacokinetics of two novel rectal controlled-release morphine formulations

Administration of morphine by the oral route is not possible in cancer patients who are unable to swallow or are intolerant of oral morphine. Thus, there is a need for reliable alternate routes of drug administration. We compared the bioavailability of two prototype 30-mg morphine sulfate controlled-release suppository formulations (high and low viscosity) with 30-mg oral controlled-release morphine sulfate tablets in a 14-subject single-dose randomized, three-way crossover study. Venous blood samples were obtained immediately prior to and for 24 hr following each dose. Morphine concentrations were determined by radioimmunoassay. Compared with oral controlled-release morphine, the high- and low-viscosity suppository formulations had significantly greater bioavailability (AUC 0–24 72.7± 13.2 for the oral preparation versus 98.6±35.7 and 105.8±37.3 ng · hr/mL for the suppositories, respectively, P < 0.05), later peak concentration (t max 2.3±0.8 versus 3.1±2.3 and 5.0±1.5 hr, respectively, P < 0.05), and longer half-value duration (4.3±1.6 versus 10.4±5.5 and 9.5±4.3 hr, respectively, P < 0.05). Peak concentration for the high-viscosity suppository formulation (C max 7.75±2.66 ng/mL) was significantly lower than the low-viscosity suppository (C max 9.23±2.85 ng/mL) and the oral tablet (C max 10.4±2.78 ng/mL) formulations ( P < 0.05). The increased bioavailability observed with the two controlled-release suppositories may be the result of partial avoidance of hepatic biotransformation with rectal administration.