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The aim of this study was to develop and characterize lipid nanoparticle systems for the transdermal delivery of buprenorphine and its prodrugs. A panel of three buprenorphine prodrugs with ester chains of various lengths was synthesized and characterized by solubility, capacity factor (log K'), partitioning between lipids and water and the ability to penetrate nude mouse skin. Colloidal systems made of squalene (lipid emulsion, LE), squalene + Precirol (nanostructured lipid carriers, NLC) and Precirol (solid lipid nanoparticles, SLN) as the lipid core material were prepared. Differential scanning calorimetry showed that the SLN had a more-ordered crystalline lattice in the inner matrix compared to the NLC. The particle size ranged from 220-300 nm, with NLC showing the smallest size. All prodrugs were highly lipophilic and chemically stable, but enzymatically unstable in skin homogenate and plasma. The in vitro permeation results exhibited a lower skin delivery of drug/prodrug with an increase in the alkyl chain length. SLN produced the highest drug/prodrug permeation, followed by the NLC and LE. A small inter-subject variation was also observed with SLN carriers. SLN with soybean phosphatidylcholine (SLN-PC) as the lipophilic emulsifier showed a higher drug/prodrug delivery across the skin compared to SLN with Myverol, a palmitinic acid monoglyceride. The in vitro permeation of the prodrugs occurred in a sustained manner for SLN-PC. The skin permeation of buprenorphine could be adjusted within a wide range by combining a prodrug strategy and lipid nanoparticles.

Buprenorphine is a promising drug for the treatment of chronic pain and opioid dependence. The aim of the present work was to evaluate the feasibility of lipid nanoparticles with different oil/fatty ester ratios for injection of buprenorphine. To improve the release properties and analgesic duration of the drug, ester prodrugs were also incorporated into the nanoparticles for evaluation. Linseed oil and cetyl palmitate were respectively chosen as the liquid lipid and solid lipid in the inner phase of the nanoparticulate systems. Differential scanning calorimetry (DSC) was performed, and the particle size, zeta potential, molecular environment, and lipid/water partitioning were determined to characterize the state of the drug/prodrug and lipid modification. The in vitro release kinetics were measured by a Franz assembly. DSC showed that systems without oil (solid lipid nanoparticles, SLNs) had a more ordered crystalline lattice in the inner matrix compared to those with oil (nanostructured lipid carriers, NLCs and lipid emulsion, LE). The mean diameter of the nanoparticles ranged between 180 and 200nm. The in vitro drug/prodrug release occurred in a delayed manner in decreasing order as follows: SLN>NLC>LE. It was found that the release rate was reduced following an increase in alkyl ester chains in the prodrugs. The in vivo antinociception was examined by a cold ethanol tail-flick test in rats. Compared to an aqueous solution, a prolonged analgesic duration was detected after an intravenous injection of buprenorphine-loaded SLNs and buprenorphine propionate (Bu-C3)-loaded NLCs (with 10% linseed oil in the lipid phase). The Bu-C3 in NLCs even showed a maximum antinociceptive activity for 10h. In vitro erythrocyte hemolysis and lactate dehydrogenase (LDH) release from neutrophils demonstrated a negligible toxicity of these carriers. Our results indicate the feasibility of using lipid nanoparticles, especially SLNs and NLCs, as parenteral delivery systems for buprenorphine and its prodrugs.

Background: A long-acting analgesic may be particularly desirable in patients suffering from long-lasting pain. The aim of the study was to evaluate the antinociceptive effect of a novel depot of buprenorphine decanoate and its metabolic profiles in human and animal blood., Methods: Following their intramuscular injections in guinea pigs, the antinociceptive effects of the novel depot of buprenorphine decanoate (in oil) and the traditional dosage form of buprenorphine HCl (in saline) were evaluated. An in vitro metabolic study of buprenorphine decanoate in human and animal blood was also carried out. The antinociception of drugs was evaluated using the plantar test. The blood concentrations of drugs were assayed using a high performance liquid chromatography., Results: We found that both the buprenorphine HCl (in saline) and buprenorphine decanoate (in oil) produced dose-related antinociceptive effect but of different duration of action. Under an equi-mole basis of 0.6 micromol/kg, the durations of action of buprenorphine HCl and decanoate were 4 and 72 h, respectively. In in vitro metabolic study in human and animal bloods, buprenorphine decanoate was totally converted to buprenorphine. Buprenorphine decanoate is a prodrug of buprenorphine., Conclusions: Intramuscular injection of the depot of buprenorphine decanoate in guinea pigs produced a dose-related long-lasting antinociceptive effect which was much longer than that of the traditional dosage form of buprenorphine HCl. Moreover, buprenorphine decanoate is a prodrug of buprenorphine.

An analgesic with a prolonged duration may be desirable in patients with long-lasting pain. In this study, we evaluated the antinociceptive effects and durations of action of three novel depots of buprenorphine esters buprenorphine propionate, enanthate, and decanoate given by IM injection, in rats. The pharmacokinetic profiles of buprenorphine in blood after IM injection of these depots were also evaluated. Antinociception was evaluated using the plantar test. Buprenorphine concentrations in blood were assayed using high-performance liquid chromatography. We found that the traditional form of buprenorphine HCl (in saline) produced a dose-related antinociceptive effect. A dose of 0.6 micromol/kg buprenorphine HCl (in saline) produced a significant antinociceptive effect lasting 5 h. The same dose of buprenorphine base, propionate, enanthate, and decanoate (in oil) also produced a significant antinociceptive effect with longer durations of action of 26, 28, 52, and 70 h, respectively. The pharmacokinetic studies demonstrated that all the buprenorphine esters were prodrugs of buprenorphine. We conclude that the novel depots of buprenorphine prodrugs: buprenorphine propionate, enanthate, and decanoate produced a long-acting antinociceptive effect after IM injection in rats.

Buprenorphine is a promising new pharmacotherapy for the management of physical dependence to opioids. The aim of the study was to evaluate the duration of action of several novel depots of buprenorphine in the treatment of physical dependence to morphine in mice. Following intramuscular injection, the duration of action of several novel oil-based depots of buprenorphine base in morphine-dependent mice were evaluated. The traditional dosage form of buprenorphine hydrochloride in saline was used as control. We found that the depot of buprenorphine base in sesame oil produced a dose-related long-lasting effect. On an equimolar basis of 6 micromol kg(-1), its effect was 5.7-fold longer than that of buprenorphine hydrochloride in saline. When prepared in several other oleaginous vehicles (castor oil, cottonseed oil, peanut oil and soybean oil), buprenorphine base also produced a long-lasting effect, which was similar to buprenorphine base in sesame oil. In conclusion, buprenorphine base, when prepared in oleaginous vehicles and injected intramuscularly in mice, produced a long-lasting effect on physical dependence to morphine.

Background: Buprenorphine is a potent analgesic. Extending its duration of action would make buprenorphine more valuable for clinical use. The depot formulation with prodrug design is a method used to prolong the duration of a short-acting drug. The aim of this study was to design and develop an esterification method to synthesize the prodrugs of buprenorphine and also to find out the detailed chemical characteristics of these prodrugs., Methods: A method of esterification was used. Buprenorphine prodrugs were synthesized by esterizing buprenorphine with various fatty acids and then purified by silica-gel column chromatography. The chemical structures of the prodrugs were affirmed by infrared, nuclear magnetic resonance and gas chromatography/mass spectrometries., Results: Six ester-type prodrugs of buprenorphine were successfully synthesized: buprenorphine propionate, pivalate, benzoate, valerate, enanthate, and decanoate., Conclusions: A proper method for esterification of buprenorphine was developed. Six ester-type prodrugs of buprenorphine were successfully synthesized and the detailed chemical characteristics of these prodrugs were put forward.

A rapid, sensitive, precise and accurate high-performance liquid chromatographic assay with fluorescence detection was developed for the simultaneous determination of buprenorphine and buprenorphine propionate in human and animal blood. Buprenorphine propionate was also proven to be a prodrug of buprenorphine. It was comprised of only a one-step extraction procedure with ethyl acetate and normal-phase chromatography on a Betasil Silica column. The recoveries of buprenorphine and buprenorphine propionate were above 84%. Calibration graphs were linear for buprenorphine over the concentration range 2-1500 ng/ml and for buprenorphine propionate over the concentration range 20-1500 ng/ml with a coefficient of variation, both within- and between-day, or less than 10% at any level. The limits of quantitation of buprenorphine and buprenorphine propionate in human or animal blood were 2.0 and 20 ng/ml, respectively, based on a single-to-noise ratio of 3. The method has been successfully applied to pharmacokinetic studies of buprenorphine and buprenorphine propionate in rabbits. The results demonstrated that buprenorphine propionate was rapidly and totally converted to its parent drug, buprenorphine, following intravenous administration. Buprenorphine propionate is a prodrug of buprenorphine.

Background: A long-acting analgesic may be particularly desirable in patients with long-lasting pain. In order to provide a long-acting analgesic effect, a novel buprenorphine ester, buprenorphine palmitate, was synthesized in our laboratory. The aim of the study was to evaluate whether the ester had a long-lasting effect., Methods: The antinociceptive effects (dose-range studies) of buprenorphine HCl and buprenorphine palmitate were evaluated using the plantar test in Sprague-Dawley rats., Results: We found that intramuscular injection of buprenorphine HCl 0.05, 0.1 and 1 micromol/kg in rats produced dose-related antinociceptive effects of 2, 3, and 4 h, respectively. Intramuscular injection of buprenorphine palmitate 1, 5, and 10 micromol/kg also produced dose-related antinociceptive effects of 72, 76 and 78 h, respectively. On an equimolar basis of 1 micromol/kg, the durations of action of intramuscular buprenorphine HCl and buprenorphine palmitate were 4 and 72 h, respectively., Conclusions: Intramuscular injection of buprenorphine palmitate in rats produced a long-lasting antinociceptive effect which was much longer (18-fold) than did intramuscular buprenorphine HCl.

Background: A long-acting analgesic is particularly desirable in patients with long-lasting pain. In order to prolong the duration of action of a potent analgesic, buprenorphine, a buprenorphine ester (buprenorphine benzoate) was synthesized in our laboratory. The aim of the study was to evaluate whether the ester form could have a long-lasting effect., Methods: Two studies were carried out. In study 1, we evaluated the antinociceptive effect of buprenorphine HCI at dosage of 0.05, 0.1, and 0.6 micromol/kg. In study 2, we evaluated the antinociceptive effect of buprenorphine benzoate at dosage of 0.6 micromol/kg. Male Sprague-Dawley rats (n = 12 in each group of different treatment) were used and the antinociceptive effects of the testing compounds were evaluated using the plantar test (a thermal test)., Results: Intramuscular injection of buprenorphine HCI at dosage of 0.05, 0.1, and 0.6 micromol/kg in rats produced dose-related antinociceptive effects with duration of action of 3, 4, and 4 h, respectively. Intramuscular injection of buprenorphine benzoate at 0.6 micromol/kg produced a duration of action of 48 h., Conclusions: Intramuscular injection of buprenorphine benzoate in rats produced a longer duration of action, which is 12-fold longer than that of buprenorphine HCI.