Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Abstract

Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5-1.0ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2-0.3ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5-1.0ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene prodrugs and that the pharmacokinetic profile of nalmefene can be tuned by varying the length of the alkyl group.

<p>Development Of Novel Liposome-Encapsulated Combretastatin A4 Acylated Derivatives: Prodrug Approach For Improving Antitumor Efficacy</p>

“…The results suggest that longer modified acyl chains for CA4 were associated with slower release rates in vitro. The results are consistent with those previously reported 29. This may be attributed to the increased lipid solubility of the obtained compound in parallel with the increase in the modified fatty acid chain for CA4.…”

“…Obviously, the release rate was as follows: CA4-6-L>CA4-10-L>CA4-14-L>CA4-16-L>CA4-18-L. The results suggest that longer modified acyl chains for CA4 were associated with slower release rates 29 This may be attributed to the increased lipid solubility of the obtained compound in parallel with the increase in the modified fatty acid chain for CA4. Of note, higher lipid solubility indicates more challenging separation from the liposome.…”

“…In this study, we synthesized a series of CA4 prodrugs with fatty chains attached at the 3′-position of the CA4 B-ring varying in length (ie, 6, 10, 14, 16, and 18 carbons) as a model drug, and prepared the prodrugs as liposomes to study the release of the parent drug. To the best of our knowledge, this was the first study to investigate the in vitro release and conversion of CA4-prodrug lipid in plasma with regard to the length of the fatty chain 24,27–29. In addition, the in vitro experiments were designed to investigate the relationship between the release trend and in vivo pharmacokinetics, biodistribution, and antitumor effect.…”

“…To the best of our knowledge, this was the first study to investigate the in vitro release and conversion of CA4-prodrug lipid in plasma with regard to the length of the fatty chain. 24,[27][28][29] In addition, the in vitro experiments were designed to investigate the relationship between the release trend and in vivo pharmacokinetics, biodistribution, and antitumor effect. This approach evaluates a suitable preparation for CA4 prodrug and provides a reference for other drugs.…”

Lipid–Drug Conjugate for Enhancing Drug Delivery

“…These lipoprotein carriers can be used to facilitate the delivery and cellular uptake of the LDC in tumor cells with overexpressed lipoprotein receptors. Other reported delivery carriers and formulations for LDCs include mesoporous silica nanoparticles, 133 sesame seed oil injections, 88 lipid nanocapsule hydrogels, 134 and extended release injectable formulations. 89 …”