Release Naltrexone Research Articles

Design and Characterization of Chitosan-Based Smart Injectable Hydrogel for Improved Sustained Release of Antinarcotics.

The treatment adherence of narcotics-addicted individuals with reduced incidences of relapse can be enhanced by a sustained drug release formulation of antinarcotics. So far, different drug formulations have been reported with sustained drug release periods of 28 and 35 days. To further enhance this duration, different formulations of injectable hydrogels (IHs) have been developed by combining low molecular weight (LMW) and high molecular weight (HMW) chitosan (CS) with guar gum (GG) and crosslinking them by sodium bi phosphate dibasic. The structural, morphological, and physicochemical properties of LMW-CS IH, and HMW-CS IH were evaluated using Fourier transform infrared spectroscopy (FT-IR), thermo-gravimetric analysis (TGA), scanning electron microscopy (SEM), and rheological, swelling, and biodegradation analysis. The HMW-CS IH showed high crosslinking, increased thermal stability, high mechanical strength, elevated swelling, and low biodegradation. The antinarcotic drugs naltrexone (NTX) and disulfiram (DSF) were loaded separately into the HMW-CS IH and LMW-CS IH. The release of NTX and DSF was investigated in phosphate buffer saline (PBS) and ethanol (0.3%, 0.4%, and 0.5%) over a 56-day period using an UV spectrophotometer. The drug release data were tested in zero-order, first-order, and Korsemeyer-Peppas mathematical models. In PBS, all prepared formulations followed non-Fickian drug release, while in ethanol, only NTX HMW-CS IH followed non-Fickian release in all three different concentrations of ethanol.

Scanning Analysis of Sequential Semisolvent Vapor Impact To Study Naltrexone Release from Poly(lactide-co-glycolide) Microparticles.

Poly(lactide-co-glycolide) (PLGA)-based microparticle formulations have been a mainstay of long-acting injectable drug delivery applications for decades. Despite a long history of use, tools and techniques to analyze and understand these formulations are still under development. Recently, a new characterization method was introduced known as the surface analysis after sequential semisolvent impact using sequential semisolvent vapors. The vapor-based technique is named, for convenience, surface analysis of (semisolvent) vapor impact (SAVI). In the SAVI method, discretely controlled quantities of selected organic semisolvents in the vapor phase were applied to PLGA microparticles to track particle morphological changes by laser scanning confocal microscopy. Subsequently, the morphological images were analyzed to calculate mean peak height (Sa), core height (Sk), kurtosis (Sku), dale void volume (Vvv), the density of peaks (Spd), maximum height (Hm), and the shape ratio (Rs). Here, the SAVI method was applied to naltrexone-loaded microparticles manufactured internally and Vivitrol, a commercial formulation. SAVI analysis of these microparticles indicated that the two primary mechanisms controlling the naltrexone release were the formation of discrete, self-crystallized portions of naltrexone within the PLGA structure and the degradation of PLGA chains through nucleophilic substitution. The relatively higher amounts of naltrexone crystals resulted in prolonged release than lower amounts of crystals. Data from gel permeation chromatography, differential scanning calorimetry, and in vitro release measurements all point to the importance of naltrexone crystal formation. This study highlights the utility of SAVI for gaining further insights into the microstructure of PLGA formulations and using SAVI data to support research, product development, and quality control applications for microparticle formulations of pharmaceuticals.

Comparison of lipid liquid crystal formulation and Vivitrol® for sustained release of Naltrexone: In vitro evaluation and pharmacokinetics in rats

Camurus’ FluidCrystal® injection depot is a lipid liquid crystal (LLC) phase formation-based method, comprising of glycerol dioleate (GDO) and soy phosphatidylcholine (SPC), together with minute quantities of N-methyl-2-pyrrolidone solvent (NMP). The present study aimed to develop a method for LLC using sorbitan monooleate (LLC-SMO) instead of GDO to prepare a one-month sustained-release formulation of naltrexone (NTX) that is applied for the treatment of autism and treating alcohol dependence. The optical characteristics of the LLC were assessed by polarizing light microscopy (PLM) to reveal the presence of lamellar, hexagonal, and cubic mesophases. Furthermore, in vitro release of NTX and NMP, degradation, pharmacokinetics, and histopathology of LLC-GDO and LLC-SMO in rats were evaluated and compared to those of Vivitrol®. The PLM images revealed that the structure of LLC-SMO is hexagonal, similar to LLC-GDO. The in vitro release of NTX and its pharmacokinetic results in rats indicted that the LLC-SMO system is more uniform than LLC-GDO and Vivitrol® during 35 days. Histopathological results of LLC-GDO and LLC-SMO confirmed the biocompatibility of our LLC delivery systems. Taken together these data demonstrate that the LLC-SMO-based method, was efficient enough to sustain the release of NTX in vitro and in vivo, confirming the biocompatible nature of this delivery system.

Prescribers\u2019 satisfaction with delivering medications for opioid use disorder

BackgroundExpanding access to medications for opioid use disorder (MOUD), such as buprenorphine and extended release (XR) naltrexone, is critical to addressing the US opioid epidemic, but little is known about prescriber satisfaction with delivering these two types of MOUD. The current study describes the satisfaction of prescribers delivering buprenorphine and XR-naltrexone while examining whether satisfaction is associated with current patient census and organizational environment.MethodsAs part of a cluster randomized clinical trial (RCT) focused on expanding access to medication for opioid use disorder, 41 MOUD prescribers in Florida, Ohio, and Wisconsin completed a web-based survey. The survey included measures of prescriber satisfaction with delivering buprenorphine treatment and XR-naltrexone. In addition, the survey measured several prescriber characteristics and their perceptions of the organizational environment.ResultsPrescribers were generally satisfied with their work in delivering these two types of MOUD. Prescribers reporting a greater number of patients (r = .46, p = .006), those who would recommend the center to others (r = .56, p < .001), and those reporting positive relationships with staff (r = .56, p < .001) reported significantly greater overall satisfaction with delivering buprenorphine treatment. Prescribers who more strongly endorsed feeling overburdened reported lower overall buprenorphine satisfaction (r = -.37, p = .02). None of the prescriber characteristics or perceptions of the organizational environment were significantly associated with overall satisfaction with delivering XR-naltrexone treatment.ConclusionsThe generally high levels of satisfaction with both types of MOUD is notable given that prescriber dissatisfaction can lead to turnover and impact intentions to leave the profession. Future research should continue to explore the prescriber characteristics and organizational factors associated with satisfaction in providing different types of MOUD.RegistrationClinicalTrials.gov. NCT02926482. Date of registration: September 9, 2016. https://clinicaltrials.gov/ct2/show/NCT02926482.

Continuous in-line homogenization process for scale-up production of naltrexone-loaded PLGA microparticles

Injectable, long-acting drug delivery systems provide effective drug concentrations in the blood for up to 6 months. Naltrexone-loaded poly(lactide-co-glycolide) (PLGA) microparticles were prepared using an in-line homogenization method. It allows the transition from a laboratory scale to scale-up production. This research was designed to understand how the processing parameters affect the properties of the microparticles, such as microparticle size distributions, surface and internal morphologies, drug loadings, and drug release kinetics, and thus, to control them.The in-line homogenization system was used at high flow rates for the oil- and water-phases, e.g., 100 mL/min and 400 mL/min, respectively, to continuously generate microparticles. A high molecular weight (148 kDa) PLGA at various concentrations was used to generate oil-phases with a range of viscosities and also to compare with a 64 and 79 kDa at a single, high concentration. The uniformity of the microparticles was found to be related to the viscosity of the oil-phase. As the viscosity of the oil-phase increased from 52.6 mPa∙s to 4046 mPa∙s, the span value (a measure of uniformity) increased from 1.24 to 3.1 for the microparticles generated at the homogenization speed of 2000 RPM. Increasing the PLGA concentration from 5.58% to 16.85% showed a corresponding rise in the encapsulation efficiency from 74.0% to 85.8% and drug loading (DL) from 27.4% to 31.7% for the microparticles made with the homogenization speed of 2000 RPM. These increases may be due to a faster shell formulation, enabling PLGA microparticles to entrap more naltrexone into the structure. A higher DL, however, shortened the drug release duration from 56 to 42 days. The changes in morphology of the microparticles during different phases of the in vitro release study were also studied for three types of microparticles made with different PLGA concentrations and molecular weights. As PLGA microparticles went through structural changes, the surface showed raisin-like wrinkled morphologies within the first 10 days. Then, the microparticles swelled to form smooth surfaces. The in-line approach produced PLGA microparticles with a highly reproducible size distribution, DL, and naltrexone release rate.

Bioresponsive nanostructured systems for sustained naltrexone release and treatment of alcohol use disorder: Development and biological evaluation.

In this study, microemulsions capable of transforming into nanostructured hexagonal phase gels in vivo upon uptake of biological fluids for naltrexone prolonged release were investigated as a strategy for management of alcohol use disorder (AUD). Microemulsions were prepared using monoolein, tricaprylin, water and propylene glycol; after preliminary characterization, one formulation was selected, which contained 55% of monoolein-tricaprylin (M-55). This microemulsion displayed size below 200nm and Newtonian rheological behavior. Liquid crystalline gels formed in vitro upon 8h of contact with water following a second order kinetics. After 120h, <50% of naltrexone was released in vitro independently on drug loading (5 or 10%). In vivo, gels formed within 24h of M-55 subcutaneous administration, and persisted locally for over 30days providing slow release of the fluorescent marker Alexa fluor compared to a solution. Using the conditioned place preference paradigm, a test used to measure drug's rewarding effects, a single dose of M-55 containing 5% naltrexone reduced the time spent in the ethanol-paired compartment by 1.8-fold compared to saline; this effect was similar to that obtained with daily naltrexone injections, demonstrating the formulation efficacy and its ability to reduce dosing frequency. A more robust effect was observed following administration of M-55 containing 10% of naltrexone, which was compatible with aversion. These results support M-55 as a platform for sustained release of drugs that can be further explored for management of AUD to reduce dosing frequency and aid treatment adherence.

Hydrogels for diabetic eyes: Naltrexone loading, release profiles and cornea penetration.

Naltrexone (NTX) is a potent opioid growth factor receptor (OGFR) antagonist proved to be useful for treatment of ocular surface complications. The aim of this work was to explore the feasibility of designing NTX-imprinted 2-hydroxyethyl methacrylate-based hydrogels for sustained drug release on the ocular surface. Acrylic acid (AAc) and benzyl methacrylate (BzMA) were chosen as functional monomers able to form binding cavities mimicking OGFR binding sites for NTX. Imprinted hydrogels containing functional monomers loaded higher amounts of NTX compared to non-imprinted ones by simple soaking in drug aqueous solution. In addition, possibility of carrying out the loading and sterilization processes in one step was investigated. NTX release was evaluated both under agitated sink conditions and in a microfluidic flow chamber mimicking the hydrodynamic conditions of the eye, namely the small volume of lachrymal fluid and its renovation rate. Sustained release profiles together with adequate swelling degree (46 to 57% w/w), light transparency (over 85%) and oxygen permeability may make these hydrogels suitable candidates to NTX-eluting contact lenses. NTX-loaded and non-loaded discs successfully passed the chorioallantoic membrane test for potential ocular irritation and were cytocompatible with human mesenchymal stem cells. Finally, NTX-imprinted hydrogels tested in the bovine corneal permeability assay provided therapeutically relevant amounts of NTX inside the cornea, reaching drug levels similar to those attained with a concentrated aqueous solution in spite the discs showed sustained release.

Comparison of in-situ forming composite using PLGA-PEG-PLGA with in-situ forming implant using PLGA: In-vitro, ex-vivo, and in-vivo evaluation of naltrexone release

An in-situ forming composite (ISFC) of naltrexone (NTX) was prepared using PLGA-PEG-PLGA (triblock) and N-methyl-2-pyrrolidone (NMP) for decreasing the initial burst release. The supercritical CO2 method was used to achieve the ring-opening polymerization of the triblock. The Box-Behnken design was used to achieve the minimal initial burst release of NTX in the in-vitro release medium. In-vitro, ex-vivo, and in-vivo studies of the ISFC were compared with an in-situ forming implant (ISFI) composed of copolymer PLGA 504H. The equivalency of ISFC and Vivitrol® were compared by sampling the concentration of NTX in rabbit blood. The results of the in-vitro release evaluation showed that the initial burst release for the ISFC (5.69 ± 0.27%) was significantly lower than that for the ISFI (17.45 ± 1.07%). The Cmax of NTX (15.16 ± 2.46 ng/mL) from the ISFC was significantly (p < 0.05) lower than that of the ISFI (24.46 ± 2.9 ng/mL) and Vivitrol® (21.11 ± 2.89 ng/mL). The bioavailability and the range of serum concentration of NTX for the ISFC formulation was similar to that of Vivitrol®. The results suggested that the ISFC could be used as a new type of sustained-release formulation with a smaller initial burst release than the ISFI.

An in-situ forming implant formulation of naltrexone with minimum initial burst release using mixture of PLGA copolymers and ethyl heptanoate as an additive: In-vitro, ex-vivo, and in-vivo release evaluation

An in-situ forming implant formulation of naltrexone (NTX) was achieved based on a minimum initial burst release of NTX in the in-vitro release medium using a Box-Behnken design. Variables such as percent of copolymer by weight, copolymer composition (PLGA 756s: PLGA 504H), and percent ethyl heptanoate by weight as an additive in formulation were investigated. The in-vitro, ex-vivo, and in-vivo release of the optimized formulation was investigated. The rabbit-blood concentrations of the optimized formulation and Vivitrol® were compared to ensure their equivalency. The initial burst release of the optimized formulation in the in-vitro release over the first 24 h, 6.18 ± 0.91%, was significantly (p < 0.05) lower than that of the formulation containing 100% of PLGA 504H (17.45 ± 1.07%) and 100% of PLGA 756s (11.82 ± 1.03%). The Cmax of NTX (21.06 ± 2.9 ng/mL) from the optimized formulation was close to that of Vivitrol® (21.11 ± 2.89 ng/mL). Also, the absolute bioavailability (F) and the range of serum concentration of NTX (C) of the ISFI formulation (F = 18.29, C = 6.18–22.84) were similar to Vivitrol® (F = 16.83, C = 6.83–23.09). These results indicate that the optimized formulation can reach an effective therapeutic concentration for treating opioid and alcohol dependence.

Effect of combined naltrexone and bupropion therapy on the brain\u2019s functional connectivity

BackgroundThe control of food intake in environments with easy access to highly rewarding foods is challenging to most modern societies. The combination of sustained release (SR) naltrexone and SR bupropion (NB32) has been used in weight-loss and obesity management. However, the effects of NB32 on the brain circuits implicated in the regulation of food intake are unknown. Here we used functional connectivity density (FCD) mapping to evaluate the effects of NB32 on resting brain FC.MethodsThirty-six healthy women underwent magnetic resonance imaging (MRI) before and after 4-week treatment with NB32 (n = 16) or with placebo (n = 20). In each imaging visit, a 5-min resting-state functional MRI scan was conducted after 15 h of fasting. The FC of brain regions showing significant group effects on FCD were subsequently assessed using seed-voxel correlation analyses. We characterized the associations between FCD measures and craving control scores in the Control of Eating Questionnaire.ResultsAfter NB32 treatment, the group showed lower local and global FCD than the placebo group in the right superior parietal cortex and lower local FCD in the left middle frontal gyrus. Seed-voxel correlation analysis for the right superior parietal cortex seed demonstrated higher positive FC with the dorsal anterior cingulate gyrus (ACC), bilateral insula, and left superior parietal gyrus and stronger negative FC with right inferior frontal gyrus and right superior parietal cortices for the NB32 than the placebo group. Further, the NB32 group showed a significant correlation between local FCD change after treatment in left middle frontal gyrus and craving control scores (r = 0.519, p = 0.039).ConclusionsNB32 treatment decreased local and global FCD in superior parietal cortex and increased its connectivity with ACC (involved with saliency attribution), insula (interoception), and decreased local FCD in the medial prefrontal cortex (craving), which might underlie NB32 improved control over eating behaviors. ClinicalTrails.gov: NCT00711.

Development of combined encapsulated drug on the basis of naltrexone and disulfiram

In the article it is revealed the problem of choice of technology for obtaining the combined drug of prolonged action to ensure continuity of treatment process and relapse prevention of diseases such as drug dependence and alcoholism. In Ukraine and most of the world for the treatment of alcohol and drug dependencies are used disulfiram and naltrexone. In previous studies, the authors have demonstrated promising development of combined injectable drug of prolonged action based on these drugs. The aim of this study was to obtain the combined injectable drug of prolonged action, which would contain a combination of naltrexone and disulfiram for the treatment of combined alcohol and drug addictions by encapsulation method. The objects of our study served as naltrexone, disulfiram and excipients copolymers of lactic and glycolic acids with different ratios of elementary units, emulsifiers and solvents. Analysis of published data allowed us to determine the recommended therapeutic dose of 250 mg of disulfiram and 200 mg of naltrexone. Based on the information, obtained from patents, it is developed the methodology and conducted experiments to obtain encapsulated substances. Size of the emulsion droplets is regulated by rate of stirring: microscale capsules were formed at a speed of 1000 rev/min and nanoscale capsules were formed at speeds over 2,000 rev/min. Capsules were prepared separately from naltrexone and disulfiram in polymers with PLG (50 : 50) and PLG (70 : 30) with a ratio of polymer to the drug under 1 : 2. Morphological characteristics of microcapsules were determined by light microscopy. The methods of quantitative and qualitative determination of disulfiram in microcapsules are proposed. Prolonging the release of naltrexone is confirmed through test «Dissolution». Also, it is worked fundamental technological scheme of production. Advantages and disadvantages of the proposed technology are determined. To determine the toxicity and pharmacological activity of obtained microcapsules combined with alcohol and drug addiction it is started preclinical study (Wistar rats and white mice line Balb/c). By the results of this study it will be conducted preliminary comparative analysis of the pharmacological action of drugs Naltetlong and created combined encapsulated drug from naltrexone and disulfiram provided by this technology.

Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6β-naltrexol, using a novel LC Q-ToF MS assay

Naltrexone (NTX) is a long-acting opiate antagonist. Low-dose naltrexone (LDN) therapy has shown promising results in the treatment of several autoimmune disorders. Our aim was to formulate NTX into a cream for the delivery of LDN and develop an analytical technique for the quantification of NTX and its active metabolite 6-β-naltrexol (NTXol) during transdermal diffusion cell permeation studies. A 1% w/w NTX cream was formulated and drug permeation was examined over 24 h using static Franz diffusion cells mounted with pig skin. A Liquid Chromatography Quadrupole-Time of Flight Mass Spectrometry (LC-MS Q-ToF) method was developed for the detection of NTX and NTXol in the receptor solution, skin membrane and residual cream on the donor chamber after completion of the diffusion studies. The cream formulation exhibited steady state release of NTX over 24 h after an initial lag time of 2.74 h. The bioconversion of NTX to NTXol in the skin membrane was 1.1%. It was concluded that the cream may be an effective formulation for the sustained transdermal delivery of LDN. The novel LC Q-ToF MS method allowed the accurate measurement of NTX and NTXol levels across the diffusion cell assemblies and the quantification of NTX metabolism in the skin.

Opioid Antagonists

Opioid Antagonists

Heteroarm Star-Shaped Poly (N-isopropylacryamide-co-itaconic acid) Copolymer Prepared by Glucose Core as ATRP Initiator

Star-shaped temperature- and pH-sensitive poly (N-isopropylacryamide-co-itaconic acid) copolymer is synthesized by atom transfer radical polymerization (ATRP) using 1,2,3,4,6-penta-O-Isobutyrylbromide-α-D-glucose as 5-Arm ATRP Initiator. For ATRP of itaconic acid (IA), carboxylic groups of IA are protected via silylation by hexamethyldisilazane (HMDS) using Fe3O4 as a magnetic catalyst. The polymerization is carried out in 2-propanol/toluene 50:50 (v/v) mixed solvent at 90°C. Structure of copolymers is studied with FT-IR, 1H NMR, glass transition temperature (Tg), and scanning electron microscopy (SEM). Results of temperature, pH, and percentage variation on polymer structure and the effects on lower critical solution temperature (LCST), which is investigated with potentiometery and conductometry, show that LCST of copolymer is around body temperature and demonstrate the ability of this polymer in the design of controlled drug delivery systems. According to the obtained results from naltrexone release, the investigated star-shaped copolymer may have potential applications in the controlled release of drugs.

Thermosensitive Hydrogel Incorporating Microspheres for Injectable Implant Delivery of Naltrexone

Long-term drug delivery based on the injectable thermosensitive hydrogel is of great advantage to the administration of naltrexone, but the constant release is hard to reach due to the sol-gel transition and the high water content of the hydrogel. The aim of the present study is to develop an injectable implant delivery system by the incorporation of microspheres into thermosensitive hydrogel for the long-term constant release of naltrexone. Naltrexone was loaded in PLGA microsphere dispersed in the methylcellulose based thermosensitive sol, which formed the hydrogel containing the naltrexone-loaded microspheres at the body temperature. The presence of microsphere in the hydrogel delayed the sol-gel transition slightly but enhanced the mechanical strength of the hydrogel significantly. The microspheres degradation in water diffusion dominated phase was decelerated when they were embed in the hydrogel. The in vitro naltrexone release from the microsphere/hydrogel system showed an over 60 days constant release with no significant burst release, and the drug release rate was in proportion to the microsphere concentration in the hydrogel.

Synthesis of thermosensitive nanohydrogels by crosslinker free method based on N-isopropylacrylamide: Applicable in the naltrexone sustained release

A unique and rapid method was used to synthesize thermosensitive self-crosslinked nano (N-isopropylacrylamidevinylpyrrolidone-acrylamide) (NIPAAm-VP-AAm) terpolymers. Nanohydrogels were obtained within 30 min during a polymerization reaction with a convenient yield due to the high dilution of aqueous solution at an elevated temperature. Furthermore, hydrogen peroxide (H2O2) was employed for the first time as a safe initiator without any toxic segments for the thermosensitive polymer synthesis. Different nanohydrogels were obtained by modulating the molar ratio of monomers to initiators and their influences on the composition ratios, thermoresponsive behavior, size distribution, phase separation, and nanohydrogel drug release were investigated. As the synthetic route is crosslinker free, the obtained nanohydrogels can be introduced as a non-toxic efficient drug delivery system (DDS). The possibility of free radical formation on the PNIPAAm chains, which leads to the crosslinked structure, has been investigated theoretically by quantum mechanical calculations. The potential energy surface of the reaction was examined by changing the distance between the OH radical and the H atoms. Considering these calculations, the reaction can proceed from all pathways as it is observed experimentally. The average size of nanohydrogels, as revealed by dynamic light scattering (DLS) and transmission electronic microscopy (TEM), is <50 nm. Finally, naltrexone as an opiate antagonist was selected as a model drug for the investigation of nanohydrogel drug delivery capabilities. Nanohydrogels show sustained naltrexone release beyond 3 months without any initial burst release. Open image in new window

Will Abuse-Deterrent Formulations of Opioid Analgesics Be Successful in Achieving Their Purpose?

During the last 2 decades, there has been a dramatic increase in the use of strong opioids for chronic non-cancer pain. This increase has been accompanied by a steep increase in abuse, misuse, and both fatal and non-fatal overdoses involving prescription opioids. The situation is already alarming in the US. Prescription opioid-related harm is a complex, multifactorial issue that requires a multifaceted solution. In this respect, formulations of opioid analgesics designed to resist or deter abuse may be a useful component of a comprehensive opioid risk minimization programme. Such formulations have or are being developed. Abuse-resistant opioids include those that use some kind of physical barrier to prevent tampering with the formulation. Abuse-deterrent opioids are not necessarily resistant to tampering, but contain substances that are designed to make the formulation less attractive to abusers. This article focuses on two products intended to deter abuse that were reviewed by the US Food and Drug Administration (FDA). The first (Embeda®) consists of extended-release morphine with sequestered naltrexone, an opioid antagonist that is released if the tablet is compromised by chewing or crushing. Although Embeda® exhibited abuse-deterrent features, its label warns that it can be abused in a manner similar to other opioid agonists. Furthermore, tampering with Embeda® will result in the release of naltrexone, which may precipitate withdrawal in opioid-tolerant individuals. In March 2011, all dosage forms of Embeda® were recalled because the product failed to meet routine stability standards, and its return date to the market is currently unknown. The second product (Acurox®) was intended to be both tamper resistant and abuse deterrent. It consisted of an immediate-release oxycodone tablet with subtherapeutic niacin as an aversive agent and used a gel-forming ingredient designed to inhibit inhalation and prevent extraction of the drug for injection. The new drug application for Acurox® was rejected in 2010 by the FDA because of concerns about the potential abuse-deterrent benefits of niacin. While acknowledging that no one formulation can be expected to deter all types of opioid-abusive behaviours and no product is likely to be abuse proof in the hands of clear and determined abusers, the reductions in abuse these new products would provide may be an incremental step towards safer prescription opioids.

Morphine Sulfate and Naltrexone Hydrochloride Extended-Release Capsules: Naltrexone Release, Pharmacodynamics, and Tolerability

Background: Morphine sulfate and naltrexone hydrochloride extended-release capsules (EMBEDA, King Pharmaceuticals, Inc., Bristol, TN), indicated for management of chronic, moderate-to-severe pain, contain pellets of extended-release morphine sulfate with a sequestered naltrexone core (MS-sNT). Taken as directed, morphine provides analgesia while naltrexone remains sequestered; if tampered with by crushing, naltrexone is released to mitigate morphine-induced euphoric effects. While it is necessary to establish that formulations intended to reduce attractiveness for abuse are successful in doing so, it is also necessary to demonstrate that product therapeutic integrity is maintained for patients. Objectives: Data were reviewed from 3 studies to determine: 1) the quantity of naltrexone released when MS-sNT pellets are crushed (MS-sNTC) for at least 2 minutes with mortar and pestle); 2) the extent to which the naltrexone released upon crushing mitigated morphine-induced subjective effects; and 3) whether sequestered naltrexone precipitates opioid withdrawal when MSsNT is taken as directed. Methods: The naltrexone bioavailability study compared naltrexone release from MS-sNTC with that from whole intact MS-sNT capsules (MS-sNTW) and an equal naltrexone solution (NS) dose. Equivalent bioavailability was established if 90% confidence intervals (CIs) for geometric mean ratios (maximum plasma naltrexone concentration [Cmax] and area under the concentration-time curve extrapolated to infinity [AUC∞]) fell between 80% and 125%. The oral pharmacodynamic study assessed drug liking and euphoria and pharmacokinetic properties of MS-sNTC and MS-sNTW compared with morphine sulfate solution (MSS) and placebo. The 12-month, open-label (OL) safety study evaluated safety of MS-sNT administered orally as directed in patients with chronic, moderate-to-severe pain. Safety assessments included withdrawal symptoms based on the Clinical Opiate Withdrawal Scale (COWS). Results: Naltrexone from MS-sNTC met criteria for equivalent bioavailability to NS. Although morphine relative bioavailability was similar for MS-sNTC and MSS, mean peak (Emax) visual analog scale (VAS) scores for drug liking and Cole/Addiction Research Center Inventory Stimulation-Euphoria were significantly reduced for MS-sNTC vs MSS (P &lt; 0.001). In these 2 studies, a total of 6 participants had one measurement of plasma naltrexone after MS-sNTW that was above the lower limit of quantification. In the OL safety study, 72/93 participants (77%) had no quantifiable naltrexone concentrations. There was neither evidence of naltrexone accumulation for any participant nor any significant correlation with MSsNT dose, age, or sex. Of 4 participants with the highest naltrexone concentrations, none had COWS scores consistent with moderate opioid withdrawal symptoms. Only 5 participants had COWS scores consistent with moderate opioid withdrawal; all 5 had not taken MS-sNT as directed. Limitations: Study populations may not be fully representative of patients receiving opioid therapy for the management of chronic, moderate-to-severe pain and of opioid abusers. Conclusions: When MS-sNT capsules are crushed, all of the sequestered naltrexone (relative to oral NS) is released and immediately available to mitigate morphine-induced effects. When MSsNT was crushed, the naltrexone released abated drug liking and euphoria relative to that from an equal dose of immediate-release morphine from MSS administration in a majority of participants. Naltrexone concentrations were low over a period of 12 months without evidence of accumulation, and there were no observable opioid withdrawal symptoms when MS-sNT was taken as directed. Key words: Chronic pain, drug liking, euphoria, extended-release opioids, morphine, naltrexone, opioid withdrawal, pharmacodynamics, pharmacokinetics

Preparation and characterization of tri-block poly(lactide)–poly(ethylene glycol)–poly(lactide) nanogels for controlled release of naltrexone

Tri-block poly(lactide)–poly(ethylene glycol)–poly(lactide) (PLA–PEG–PLA) copolymers and related acrylated derivative were synthesized and used to prepare micelles and nanogels for controlled release of naltrexone. The resulting copolymers, micelles and nanogels were characterized by various techniques such as proton nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, gel permeation chromatography, fluorescence spectrometry, differential scanning calorimetry, photon correlation spectroscopy and scanning electron microscopy. The nanogels exhibited high encapsulation efficiency around 60% and excellent stability for long periods of time. The drug release profiles of micelles and nanogels were compared and it was found that the naltrexone loaded nanogels offered a steady and long-term release pattern for different periods of time up to 35 days, depending on the crosslinker concentration, compared to the micelles. The size of nanogels could be manipulated easily in the range of 128–200 nm by variations in polymer concentration used in the nanogels preparation step. From the results obtained it can be concluded that PLA–PEG–PLA nanogels can be considered as a promising carrier for drug delivery purpose.

In situ gelling hexagonal phases for sustained release of an anti-addiction drug

In this study, fluid precursor formulations for subcutaneous injection and in situ formation of hexagonal phase gels upon water absorption were developed as a strategy to sustain the release of naltrexone, a drug used for treatment of drug addiction. Precursor formulations were obtained by combining BRIJ 97 with propylene glycol (PG, 5-70%, w/w). To study the phase behavior of these formulations, water was added at 10-90% (w/w), and the resulting systems were characterized by polarized light microscopy. Two precursor formulations containing BRIJ:PG at 95:5 (w/w, referred to as BRIJ-95) and at 80:20 (w/w, referred to as BRIJ-80) were chosen. Naltrexone was dissolved at 1% or suspended at 5% (w/w). Precursor formulations were transformed into hexagonal phases when water content exceeded 20%. Water uptake followed second-order kinetics, and after 2-4h all precursor formulations were transformed into hexagonal phases. Drug release was prolonged by the precursor formulations (compared to a drug solution in PBS), and followed pseudo-first order kinetics regardless of naltrexone concentration. The release from BRIJ-80 was significantly higher than that from BRIJ-95 after 48 h. The relative safety of the precursor formulations was assessed in cultured fibroblasts. Even though BRIJ-95 was more cytotoxic than BRIJ-80, both precursor formulations were significantly less cytotoxic than sodium lauryl sulfate (considered moderate-to-severe irritant) at the same concentration (up to 50 μg/mL). These results suggest the potential of BRIJ-based precursor formulations for sustained naltrexone release.