PLA-PCL microsphere formulation to deter abuse of prescription opioids by smoking.

Opioids are commonly prescribed across the United States (US) for pain relief, despite their highly addictive nature that often leads to abuse and overdose deaths. Abuse deterrent formulations (ADFs) for prescription opioids make the non-therapeutic use of these drugs more difficult and less satisfying. Although approximately one-third of surveyed abusers in the US reported smoking opioids, to our knowledge, no commercialized ADF effectively prevents opioid smoking. Here, we report a novel approach to deter smoking of a model prescription opioid drug, thebaine (THB), by using polymer blend microspheres (MS) comprising polylactic acid (PLA) and polycaprolactone (PCL). We utilized high-performance liquid chromatography (HPLC) and thermogravimetric analysis (TGA) to test the ability of PLA-PCL MS to limit the escape of vaporized THB. Additionally, we compared the abuse-deterrent potential of PLA-PCL MS to that of activated carbon (AC) and mesoporous silica (MPS), two materials with excellent drug-adsorbing properties. Our MS formulation was effective in reducing the amount of both active drug and thermal degradation products in the vapor generated upon heating of THB. These results support that PLA-PCL microspheres can be co-formulated in a tablet with common prescription opioids to deter their abuse via the smoking route.

Emerging Trends in Abuse-Deterrent Formulations: Technological Insights and Regulatory Considerations.

BACKGROUND: Opioid medications are an integral part of the management of acute and chronic severe pain. However, non-medical practice of these prescription drug products is emerging as a serious public health problem. To control this opioid epidemic, USFDA is encouraging pharmaceutical companies to develop Abuse Deterrent Formulations (ADFs). ADF's are much more difficult to manipulate and abuse when compared to their conventional formulations. This feature of ADFs is due to their ability to incumber extraction of active ingredients, to prevent administration through alternative routes, making abuse of altered product less rewarding. OBJECTIVE: The main objective of this review is to abridge different ADFs and various laboratory- based in vitro manipulation and extraction studies, demonstrating that these approved ADFs have the capabilities to deter abuse. METHODS: The method includes the collection of data from different search engines like PubMed, FDA guidance documents, ScienceDirect, Google Patents to get coverage of literature in order to get appropriate information regarding ADFs. RESULTS: Various in vitro studies demonstrate that ADFs are effective in minimizing opioid drug abuse, including opioid overdose. However, real impact of these ADFs on reducing the drug abuse can be concluded only after receiving the post marketing data. CONCLUSION: ADFs are embracing fundamentally different paradigms in the management of severe pain. We believe that the development of abuse deterrent technologies would shift the architype, deterring multipill abuse and can prove as a breakthrough strategy in controlling this opioid epidemic menace.

Development of Abuse-Deterrent Formulations Using Sucrose Acetate Isobutyrate.

The objective of the present investigation was to understand the effect of sucrose acetate isobutyrate (SAIB) on abuse-deterrent properties (ADPs) of abuse-deterrent formulations (ADFs) based on Polyox™. SAIB would enhance ADPs of Polyox™-based formulations due to its glassy liquid and hydrophobic properties. Formulations were prepared by granulation followed by compression and heat curing at 90°C. The formulations were evaluated for surface morphology, hardness, manipulation in coffee grinder, particle size distribution, drug (pseudoephedrine hydrochloride) extraction in water, alcohol, 0.1 N HCl, 0.1 N NaOH at room temperature and elevated temperature using microwave and oven, syringeability and injectability, and dissolution. The heat curing of formulations significantly increased the hardness (> 490 N). Addition of SAIB imparted elasticity to formulations and decreased brittleness as indicated by lower values of work done and gradient compared to control formulations. After grinding, about 7.7-25.6% of the powder remained on the sieve (1 mm pore opening), D90 was 53.1-136.7 µm more, and Q (fraction < 500 µm) was 17.8-40.7% less in SAIB-based formulations compared to control formulations. Drug extraction between control and test intact formulations was similar. However, drug extraction was 23.9-42.5% (water), 20.6-26.1% (0.1 N HCl), and 37.4-50.6% (0.1 N NaOH) less in SAIB-based powder cured and uncured formulations compared to control formulations. Dissolution varied from 65.6 ± 4.2 to 97.6 ± 4.0% in 9 h from the formulations. In conclusion, addition of SAIB to Polyox™-based ADFs has synergistic effect on ADPs. This would further decrease potential of drug abuse/misuse by various routes.

A cellulose-based therapeutic polymer to deter intravenous drug abuse.

Prescription opioids have widely been abused as an epidemic. In this research, we developed a drug composition based on the crosslinked carboxymethylcellulose (XCMC) and a drug model that can effectively deter abuse by injection via multiple mechanisms. The anionic nature of the XCMC is responsible for complexing the cationic opioids in aqueous solutions, minimizing the free drug amount accessible for extraction. The crosslinked nature of the polymer is responsible for its swelling and partial containment of the drug solution within the swollen polymer's network, thus minimizing the available volume for subsequent injection. We have shown that XCMC can efficiently interact with cationic drugs in the form of physical blends and chemical complexes in different aqueous solvents, forming abuse-deterrent complexes. The complexation efficiency was affected by the solution pH and ionic strength, as well as the drug to polymer ratio in the formulation. The in vitro dissolution studies were conducted in two stages, the stage I in 0.1 M HCl and the stage II in water and pH 7.5 phosphate buffer. These studies confirmed the proper drug release under the legitimate conditions of use. Therefore, the XCMC polymers have a great potential to be used as deterring agents in developing opioid medications with abuse-deterrent properties.

Mitigation of IV Abuse Through the Use of Abuse-Deterrent Opioid Formulations: An Overview of Current Technologies.

Providers who treat patients with chronic pain face a dual challenge: providing adequate access to opioid therapies for appropriate pain management while adopting strategies to minimize the risk for abuse. Commonly prescribed opioids have substantial abuse potential when administered intravenously, and extended-release (ER)/long-acting (LA) opioids may be targeted for IV abuse because of the higher per-dose medication level. The consequences of IV opioid abuse are severe and increase the risks for adverse outcomes, including mortality due to acute health events, serious infections, and deep vein thrombosis, to name a few. To reduce the potential for abuse of prescription opioids by both recreational and experienced drug abusers, abuse-deterrent formulations (ADFs) of opioid medications employ either physical/chemical barriers or agonist-antagonist combinations. Here we review the development and use of opioid ADFs as a harm-reduction strategy, and their potential for mitigating IV opioid abuse. The approved ER/LA opioids with ADF labeling in the United States include formulations of oxycodone, hydrocodone, and morphine. Findings from in vitro laboratory tests of abuse deterrence for opioid ADFs are described herein, as are data from human abuse potential studies for IV abuse of those ADF products, for which such studies are feasible (ie, abuse-deterrent agonist-antagonist formulations). The available ADF opioids may decrease both the attractiveness and the feasibility of IV abuse. The adoption of ADF opioids represents one tactic for providing access to needed medication for patients with chronic pain, while potentially reducing the risk for opioid abuse, in a comprehensive effort to combat the opioid epidemic.

Intranasal Pharmacokinetics of Morphine ARER, a Novel Abuse-Deterrent Formulation: Results from a Randomized, Double-Blind, Four-Way Crossover Study in Nondependent, Opioid-Experienced Subjects.

Objective: To investigate the pharmacokinetics (PK) of Morphine ARER, an extended-release (ER), abuse-deterrent formulation of morphine sulfate after oral and intranasal administration. Methods: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study assessed the PK of morphine and its active metabolite, M6G, from crushed intranasal Morphine ARER and intact oral Morphine ARER compared with crushed intranasal ER morphine following administration to nondependent, recreational opioid users. The correlation between morphine PK and the pharmacodynamic parameter of drug liking, a measure of abuse potential, was also evaluated. Results: Mean maximum observed plasma concentration (Cmax) for morphine was lower with crushed intranasal Morphine ARER (26.2 ng/mL) and intact oral Morphine ARER (18.6 ng/mL), compared with crushed intranasal ER morphine (49.5 ng/mL). The time to Cmax (Tmax) was the same for intact oral and crushed intranasal Morphine ARER (1.6 hours) and longer for crushed intranasal morphine ER (1.1 hours). Higher mean maximum morphine Cmax, Tmax, and abuse quotient (Cmax/Tmax) were positively correlated with maximum effect for drug liking (R2 ≥ 0.9795). Conclusion: These data suggest that Morphine ARER maintains its ER profile despite physical manipulation and intranasal administration, which may be predictive of a lower intranasal abuse potential compared with ER morphine.

Opioids: The Painful Public Health Reality.

The analgesic, sedative, antidepressant, euphoriant, intoxicating, and addictive properties of opium and its synthetic derivatives are well known and have been known for centuries. Hence, the current major public health problems due to excessive availability should be no surprise. What is unprecedented in the United States, and emerging elsewhere, is the extent of the profound consequences and complexity of addressing this public health crisis.

Abuse-Deterrent Opioid Formulations: A Key Ingredient in the Recipe to Prevent Opioid Disasters?

The US Food and Drug Administration (FDA) is encouraging the innovation of long-acting opioid formulations that are manipulation-resistant. The purpose of this commentary is to assess the benefits and limitations of abuse-deterrent opioid formulations (ADFs) and discuss their role in mitigating the current opioid epidemic. ADFs have been created with chemical properties that make it difficult for people who non-medically use prescription drugs to crush and dissolve opioid tablets, as well as by combining opioids with antagonists such as naloxone or naltrexone, which are released only when the dosage form has been manipulated or the drug is taken by a non-intended route. Despite these and other technologies, consensus regarding the effectiveness of these formulations in preventing non-medical use is lacking given the difficulty in obtaining post-marketing data. Researchers also question if the creation of abuse-deterrent drugs will have a positive effect on those struggling with a severe opioid-use disorder, fearing that current opioid users will simply find a new - perhaps more dangerous - drug of choice. Abuse-deterrent opioids are still opioids, and although they may make manipulation more difficult than non-ADF formulations, they are not "abuse proof." The introduction of ADFs could provide a false sense of security among prescribers and dispensers, and we fear that ADFs may have a minimal impact on non-medical use of prescription opioids. Further epidemiological studies will be required to determine the large-scale impact of abuse-deterrent opioids in preventing opioid use disorder and its downstream consequences.

Challenges Involved in the Development and Delivery of Abuse-deterrent Formulations of Opioid Analgesics.

PURPOSE: This commentary examines the development, regulatory, and reimbursement challenges facing abuse-deterrent formulation (ADF) products. METHODS: In January 2017, the Tufts Center for the Study of Drug Development convened a roundtable to explore clinical development, regulatory, and reimbursement challenges with respect to ADFs of opioid analgesics. Roundtable participants, who included a range of pharmaceutical industry and other experts, discussed multiple challenges. FINDINGS: First, several key clinical development challenges were identified and discussed. These challenges pertain to prodrug development and development of deterrents against oral abuse. Second, experts suggested that more clarity is needed from regulatory authorities regarding standards for proving ADF labeling claims and for being rewarded with 3-year data exclusivity. Similarly, given the substantial burdens associated with the development of postapproval evidence generation, experts raised the need for a consistent regulatory policy related to postapproval evidence generation for all ADFs (branded and generic). Third, despite the public health benefits of certain ADF products, current coverage and access policies impede patient access. Payer justification for restrictive policies appears to be based more on budget impact considerations than cost-effectiveness. Fourth, there remains a need to further expand the evidence base regarding clinical and cost-effectiveness as well as abuse deterrence in a real-world setting for all ADF products. IMPLICATIONS: Clinical development challenges need to be overcome with respect to novel ADF technologies, such as prodrugs and deterrents against oral abuse. More clarity is needed from regulatory authorities on labeling claims and data exclusivity eligibility with respect to ADFs. Ensuring prescriber training and awareness of various options for treating pain, including ADF products, is an important step, as is educating payers about the public health benefits of ADFs in appropriate subpopulations of pain patients. In addition, physicians may need to incorporate appropriate risk stratification methods. Finally, it is important to establish a level playing field between coverage of ADF and non-ADF products so that non-ADF products are not given preferred formulary placement.

Opioid addiction, diversion, and abuse in chronic and cancer pain.

PURPOSE OF REVIEW: The primary cause of overdose death in the United States is related to pharmaceutical opioids. A few particular populations that struggle with adverse outcomes related to opioid abuse are those in palliative care, those with chronic pain, and those receiving pain treatments secondary to cancer or chemotherapy. RECENT FINDINGS: There have been massive efforts to decrease the use of opioid abuse in patient care in a gestalt manner, but palliative care provides unique challenges in applying these reduction tactics used by other specialties. SUMMARY: We explore behavioral interventions, provider education, alternative pain management techniques, postmarketing surveillance, and abuse-deterrent formulas as emerging methods to counteract opioid abuse in these populations.

A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Intranasal Drug Liking Study on a Novel Abuse-Deterrent Formulation of Morphine-Morphine ARER.

OBJECTIVE: Misuse and abuse of prescription opioids remains a major healthcare concern despite considerable efforts to increase public awareness. Abuse-deterrent formulations of prescription opioids are designed to reduce intentional misuse, abuse, and prescription opioid-related death. A novel extended-release (ER) formulation of morphine (Morphine ARER; MorphaBond™) resists physical manipulation and retains the drug's ER characteristics, even if attempts are made to manipulate the formulation. DESIGN: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study investigated the abuse potential and safety of crushed intranasal and intact oral Morphine ARER compared with commercially available crushed intranasal ER morphine sulfate (ER morphine). OUTCOME MEASURES: Endpoints included maximum mean drug liking (E max ) as measured by subjects on a bipolar 100 mm visual analog scale (primary), a subject's desire to take the drug again, good effects of the drug, and drug high. RESULTS: Twenty-five subjects completed the treatment phase. There was a 40% reduction in E max for crushed intranasal Morphine ARER compared with crushed intranasal ER morphine ( P < .0001). There was no significant difference when comparing the E max for crushed intranasal vs intact Morphine ARER. When comparing crushed intranasal Morphine ARER with ER morphine, subjects reported lower mean scores for good effects of the drug, drug high, and overall drug liking, as well as a lower desire to use Morphine ARER again. Other than adverse events associated with intranasal administration of a drug, all adverse events were typical of those reported for opioid-containing drugs. CONCLUSIONS: Overall, these data suggest that Morphine ARER has a lower abuse potential via the intranasal route of administration when compared with ER morphine.

Human Abuse Potential of an Abuse-Deterrent (AD), Extended-Release (ER) Morphine Product Candidate (Morphine-ADER Injection-Molded Tablets) vs Extended-Release Morphine Administered Intranasally in Nondependent Recreational Opioid Users.

OBJECTIVE: To compare the relative human abuse potential after insufflation of manipulated morphine abuse-deterrent, extended-release injection-molded tablets (morphine-ADER-IMT) with that of marketed morphine ER tablets. METHODS: A randomized, double-blind, double-dummy, active- and placebo-controlled five-way crossover study was performed with adult volunteers who were experienced, nondependent, recreational opioid users. After intranasal (IN) administration of manipulated high-volume (HV) morphine-ADER-IMT (60 mg), participants were randomized (1:1:1:1) to receive IN manipulated low-volume (LV) morphine ER (60 mg), IN manipulated LV morphine-ADER-IMT, intact oral morphine-ADER-IMT (60 mg), and placebo in crossover fashion. Pharmacodynamic and pharmacokinetic assessments included peak effect of drug liking (E max ; primary endpoint) using drug liking visual analog scale (VAS) score, E max using overall drug liking, and take drug again (TDA) VASs scores, and mean abuse quotient (AQ), a pharmacokinetic parameter associated with drug liking. RESULTS: Forty-six participants completed the study. After insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT, drug liking E max was significantly lower ( P < 0.0001) compared with IN morphine ER. Overall drug liking and TDA E max values were significantly lower ( P < 0.0001) after insufflation of HV morphine-ADER-IMT and LV morphine-ADER-IMT compared with IN morphine ER. Mean AQ was lower after insufflation of HV (9.2) and LV (2.3) morphine-ADER-IMT or ingestion of oral morphine-ADER-IMT (5.5) compared with insufflation of LV morphine ER (37.2). CONCLUSIONS: All drug liking, take drug again, and abuse quotient endpoints support a significantly lower abuse potential with insufflation of manipulated morphine-ADER-IMT compared with manipulated and insufflated non-AD ER morphine.