K. C. Sung

Mucoadhesive buccal disks for novel nalbuphine prodrug controlled delivery: effect of formulation variables on drug release and mucoadhesive performance

The objective of this work was to assess the effects of drug solubility and loading percent, as well as Carbopol 934/hydroxypropylcellulose (CP/HPC) ratio, on drug release and mucoadhesive performance of the nalbuphine prodrug loaded buccal disks. Drug release rates for the disks were found to be a function of drug solubility, with higher drug release rates for disks loaded with more hydrophilic prodrugs and an increased amount of beta-cyclodextrin. The drug release rates increased with loading percents for nalbuphine hydrochloride, whereas an opposite drug release trend was observed for disks loaded with nalbuphine enanthate, which can be explained by the diffusional drug release mechanism. The CP/HPC ratio affected release rates of nalbuphine enanthate, whereas the ratio had no impact on the release of nalbuphine hydrochloride. Within the 2 days of experiment time, all formulations attached well to the porcine buccal tissues, indicating those formulation variables had no influence on the mucoadhesive performance of CP/HPC-based buccal disks.

Controlled release of nalbuphine prodrugs from biodegradable polymeric matrices: influence of prodrug hydrophilicity and polymer composition

Abstract The objective of this work was to assess the effects of nalbuphine prodrug hydrophilicity and lactide/glycolide copolymer ratio on drug release from lactide/glycolide based polymeric matrices. A panel of four nalbuphine prodrugs with various ester chains were incorporated into poly ( d,l -lactide) based matrices by using the solvent evaporation method. Drug release rates for the matrices were found to be a function of prodrug hydrophilicity, with higher drug release rates for matrices with more hydrophilic prodrugs. Data analysis using the Higuchi expression indicated that the release of various prodrug from poly ( d,l -lactide) based matrices was consistent with a diffusion mechanism. The prodrug release rate constants derived from the Higuchi expression correlated well with prodrug solubilities. In the second part of the study, the effect of lactide/glycolide copolymer ratio on nalbuphine propionate release was studied. The drug release rate and matrix hydration rate were found to be a function of copolymer ratio, with faster drug release and matrix hydration for matrices with lower lactide/glycolide ratio copolymers. The nalbuphine propionate release profiles fit well to the Higuchi expression, indicating that drug release from the Poly ( d,l -lactide-co-glycolide) based matrices was consistent with a diffusion mechanism. The drug release rates correlated well with matrix hydration rates, suggesting that different polymer compositions may attribute to various matrix hydration and therefore affect drug release from the PLGA matrices.

Delivery of nalbuphine and its prodrugs across skin by passive diffusion and iontophoresis.

The in vitro transport of nalbuphine (NA) and its prodrugs across various skins was investigated in order to assess the effects of prodrug lipophilicity on passive as well as iontophoretic permeation. The passive diffusion of NA and its prodrugs increased with the drug lipophilicity. Iontophoresis significantly increased the transport of NA and its prodrugs; the enhancement ratio was highest for NA and decreased as the drug lipophilicity increased. Measurements using intact and stratum corneum (SC)-stripped skins showed that the SC was the major skin diffusion barrier for the passive permeation of NA and nalbuphine pivalate (NAP). The iontophoretic permeation of NA and NAP across intact and SC-stripped skins indicated that the SC layer was not rate-limiting for the permeation of NA, but remained the rate-limiting barrier for transdermal permeation of NAP. Permeation studies using SC-stripped and delipidized skins suggested that the intercellular pathway was the predominant route for the passive permeation of NA and NAP as well as the iontophoretic permeation of NAP across the SC. The relative rates of passive and iontophoretic permeation across Wistar rat skins demonstrated that a significant amount of NA may permeate skin via the appendageal routes, whereas NAP permeated predominantly through the lipid matrix.

Lipid nanoparticles with different oil/fatty ester ratios as carriers of buprenorphine and its prodrugs for injection

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.

Transdermal delivery of nalbuphine and its prodrugs by electroporation.

The aim of this study was to assess the effects of electroporation on transdermal permeation of nalbuphine (NA) and its prodrugs. The permeation characteristics were investigated under various electrical factors and skin barriers to elucidate the mechanisms involved in transdermal delivery of NA and its prodrugs by skin electroporation. The in vitro permeation studies were performed using side-by-side diffusion cells. The various electrical factors investigated were pulse voltage, pulse duration and pulse number; the different skin barriers studied were intact hairless mouse skin, stratum corneum (SC)-stripped skin, delipid skin as well as furry Wistar rat skin. The prodrugs were fully converted to parent drug after skin permeation. Application of electroporation significantly enhanced transdermal permeation of NA and its prodrugs. The enhancement ratios were highest for NA and the four prodrugs showed the similar permeability after electroporation. The permeation amounts of NA and its prodrugs may be increased by application of higher pulse voltage, pulse duration as well as pulse number. Various kinetics and mechanisms were observed for the permeation of the hydrophilic NA and lipophilic nalbuphine enanthate through different skin barriers by applying electroporation. This study demonstrated that electroporation may enhance and control transdermal permeation of NA and its prodrugs. The results also indicated that the physicochemical properties of prodrug had significant effects on kinetics as well as mechanisms of transdermal permeation by electroporation.

Controlled release of nalbuphine propionate from biodegradable microspheres : In vitro and in vivo studies

The objective of this work was to assess the in vitro characteristics, in vivo pharmacokinetics and in vivo pharmacodynamics of nalbuphine propionate (NAP)-loaded microspheres. An oil-in-water solvent evaporation method was used to incorporate NAP into poly (d,l-lactide-co-glycolide) (PLGA)-based microspheres. The morphology of the microspheres were evaluated using scanning electron microscopy which showed a spherical shape with smooth surface. A prolonged in vitro drug release profile was observed, with approximately 71.1% of incorporated drug released in 96 h. The release profile fit well to the Baker and Lonsdales spherical matrix model, suggesting the release of NAP from microspheres was consistent with a diffusion mechanism. The in vivo pharmacokinetic studies after subcutaneous injection of NAP-loaded microsphere showed a sustained plasma nalbuphine (NA)-time profile, with 100% relative bioavailability comparing to the AUC obtained after intravenous injection. The in vitro release pattern correlated well with the in vivo pharmacokinetic profile. The pharmacodynamic studies evaluated using paw pressure model also showed a prolonged pharmacological response after injection of microspheres. A linear correlation between the percent analgesic effect and the logarithm of plasma NA concentration was obtained, suggesting the pharmacological response can be reflected by plasma drug concentration. This correlation may be utilized for evaluating the pharmacological responses of various NA and its prodrug-based formulations with known plasma NA concentrations.

The effects of iontophoresis and electroporation on transdermal delivery of buprenorphine from solutions and hydrogels

The in‐vitro permeation of buprenorphine across skin was investigated to assess the effects of iontophoresis and electroporation on drug permeation from solutions as well as from hydrogels. Iontophoresis (0.3 mA cm−2) increased the buprenorphine permeation from solution by a factor of 14.27 as compared with passive diffusion; the application of electroporation increased the buprenorphine permeation from solutions by a factor of 8.45. The permeation experiments using cellulose membrane and stratum corneum (SC)‐stripped skin as permeation barriers suggested that the enhancement with iontophoresis was primarily due to strong electrophoretic drift of buprenorphine molecules, whereas the enhancement seen with electroporation was mainly attributed to the creation of transient aqueous pores in the SC layer. Application of high‐voltage pulses followed by iontophoresis resulted in a shorter permeation onset time from both solutions and hydrogels as compared with iontophoresis or electroporation alone. The charge repulsion between buprenorphine and chitosan vehicles as well as the competition effects of counter‐ions for carboxymethylcellulose (CMC)‐based polymers may account for the different permeation rates under electrical field. This study demonstrates the feasibility of using hydrogels for delivery of buprenorphine under the application of iontophoresis or electroporation, separately or together.

Biodegradable polymeric microspheres for nalbuphine prodrug controlled delivery : in vitro characterization and in vivo pharmacokinetic studies

The objective of this work was to study the in vitro characteristics as well as in vivo pharmacokinetic performance of a series nalbuphine (NA) prodrug-loaded microspheres. An oil-in-water solvent evaporation method was used to incorporate the various NA prodrugs into poly(D,L-lactide-co-glycolide) (PLGA)-based microspheres. The morphology of microspheres under the scanning electron microscopy (SEM) revealed a spherical shape with smooth surface. Drug release rates for the microspheres were found to be a function of prodrug hydrophilicity, with higher drug release rates for microspheres loaded with more hydrophilic prodrugs. The release profiles fit well to the Baker and Lonsdales spherical matrix model, suggesting the drug release from microspheres was consistent with a diffusion mechanism. The in vivo pharmacokinetic studies after s.c. injection of microspheres into rabbits showed sustained plasma NA-time profiles, with approximately 104.7, 67.2, and 41.0% relative bioavailability for microspheres loaded with nalbuphine propionate (NAP), nalbuphine pivalate (NPI), and nalbuphine decanoate (NDE), respectively. The in vitro release characteristics correlated well with the in vivo pharmacokinetic profiles. The results indicated that the prodrug hydrophilicity had significant effects on the in vitro as well as in vivo drug release kinetics. The present study demonstrates the feasibility of using biodegradable polymeric microspheres for controlled delivery of NA prodrugs.

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 ∼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‐, α‐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.

Skin permeation of buprenorphine and its ester prodrugs from lipid nanoparticles: lipid emulsion, nanostructured lipid carriers and solid lipid nanoparticles

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.