The delivery and antinociceptive effects of morphine and its ester prodrugs from lipid emulsions.

Long-acting analgesia is critical for patients suffering from long-acting pain. The purpose of this study was to develop lipid emulsions as parenteral drug delivery systems for morphine and its ester prodrugs. Morphine prodrugs with various alkyl chain lengths, including morphine propionate (MPR), morphine enanthate (MEN), and morphine decanoate (MDE), were synthesized. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were quickly hydrolyzed to the parent drug when exposed to esterase and plasma. Lipid emulsions were prepared using phosphatidylethanolamine (PE) as an emulsifier, while squalene was used as an inner oil phase. Drug release was found to be a function of the drug/prodrug lipophilicity, with a lower release rate for more-lipophilic drug/prodrugs. The inclusion of morphine and its prodrugs into lipid emulsions retarded their release. Lipid emulsions, which incorporated cholesterol, generally exhibited a drug/prodrug release comparable to that of emulsions without co-emulsifiers. Pluronic F68 (PF68) further slowed down the release of morphine and its prodrugs from the emulsions. The antinociceptive activity through the parenteral administration of these emulsions was examined using a cold ethanol tail-flick study. Compared with an aqueous solution, a prolonged analgesic duration was detected after application of the drug/prodrug emulsions. Incorporation of co-emulsifiers such as PF68 and cholesterol further increased the duration of action. The combination of prodrug strategy and lipid emulsions may be practically useful for improving analgesic therapy with morphine.

Ester prodrugs of morphine improve transdermal drug delivery: a mechanistic study.

Two alkyl esters of morphine, morphine propionate (MPR) and morphine enanthate (MEN), were synthesized as potential prodrugs for transdermal delivery. The ester prodrugs could enhance transdermal morphine delivery. The mechanisms of this enhancing effect were elucidated in this study. Both prodrugs were more lipophilic than their parent drug as evaluated by the skin/vehicle partition coefficient (log P) and capacity factor (log K'). The in-vitro skin permeation of morphine and its prodrugs from pH 6 buffer was in the order of MEN > MPR > morphine. MPR and MEN respectively enhanced the transdermal delivery of morphine by 2- and 5-fold. A contrary result was observed when using sesame oil as the vehicle. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were readily hydrolysed to the parent drug when exposed to skin homogenate and esterase. Approximately 98% MPR and approximately 75% MEN were converted to morphine in an in-vitro permeation experiment. The viable epidermis/dermis contributed to a significant resistance to the permeation of ester prodrugs. According to the data of skin permeation across ethanol-, alpha-terpineol-, and oleic acid-pretreated skin, MEN was predominantly transported via lipid bilayer lamellae in the stratum corneum. The intercellular pathway was not important for either morphine or MPR permeation.

Submicron lipid emulsion as a drug delivery system for nalbuphine and its prodrugs.

This study investigates the submicron lipid emulsion as a potential parenteral drug delivery system for nalbuphine and its ester prodrugs. Submicron emulsions were prepared using egg phospholipid as the main emulsifier, various co-emulsifiers were also incorporated, including Brij 30, Brij 98, and stearylamine. Squalene as the oil phase formed stable emulsions with small particles. Drug release was affected by incorporating various co-emulsifiers and drugs with various lipophilicity. The loading of nalbuphine into lipid emulsions resulted in the slower and sustained release of nalbuphine. Lipid emulsions containing Brij 98 could further enhance the release of prodrugs as compared to the aqueous solution (control) especially for nalbuphine enanthate (NAE). Hemolysis caused by the interaction between erythrocytes and lipid emulsions was investigated. Brij 30 and Brij 98 could shield the hemolytic activity of phospholipids in the oil/water interface, decreasing the acute toxicological potential of the emulsions. The in vivo analgesic activity of various emulsions was examined by a cold ethanol tail-flick test. The analgesic duration and potency were significantly increased by incorporating nalbuphine and NAE into Brij 98-containing emulsions. There was no need for nalbuphine benzoate (NAB) to show a controlled delivery manner by encapsulating into emulsions, since NAB itself could prolong the analgesic duration of nalbuphine due to the slow enzyme degradation. The in vivo analgesic activity correlated well to the profiles of in vivo pharmacokinetic profiles. The study demonstrates the feasibility of using submicron lipid emulsion as the parenteral drug delivery system for nalbuphine and its prodrugs.