(M1130-02-11) Extended Release Abuse Deterrent Formulation of an Opioid Analgesic

Purpose: Morphine Sulfate is prescribed for severe pain management requiring long-term opioid treatment and for which alternative options are inadequate. In USA, there is a significant increase in deaths resulting from prescription opioid overdose¹. The abuse and misuse associated with opioids is a significant health concern. Hence, there is need and encouragement for development of Abuse Deterrent Formulation (ADF). The present works describes development of ADF as ER tablet based on physical/chemical barrier and prevents abuse by chewing, crushing, cutting, grinding, extraction and syringeability. The work evaluated role of polyethylene oxide (PEO) as a release controlling agent, in imparting abuse deterring properties & on PK parameters. The ADF formulation has great potential to address accidental misuse or abuse and meets most of the studies as required by FDA’s guidance for industry. The key Purposes were: 1. To develop Abuse Deterrent Extended Release formulation, 2. To study of effect of PEO Grade and level on dissolution and, 3. To develop dissolution method co-related to in-vivo pharmacokinetic parameters.

Methods: ER tablets were developed by using Polyethylene Oxide (PEO). Manufacturing process involved granulation of API followed by mixing with PEO & excipients to yield blend, compressed into ER tablets which were film coated and cured. Formulation/s were characterized for 1. In-vitro dissolution, 2. Crush resistance, 3. Syringeability, 4. Extractability using level 2 solvents and 5. PK parameters.

Results: The low viscosity PEO grades exhibited faster dissolution and higher than target profile. Addition of Na2CO3 slowed the drug release significantly. The crush resistance test indicated that 39% of PEO in formulation was insufficient, whereas, 60% or more imparted crush resistance based on a hardness of > 40kp. Based on PSD of crushed tablets, formulations containing Polyox N 80 and N 750 were difficult to crush as > 75% particles retained on mesh # 40 (425 μ). From syringeability test, the milled Test sample became gel like viscous mass and contents were unable to be withdrawn by a syringe with #18 needle. The milled Control sample remained fluid and contents could be withdrawn using # 25 needle. When 5 mL of water was added, the Control sample could be withdrawn using #27 needle whereas Test and Reference could not be withdrawn using a #23 needle. Solvent extraction studies were carried out using level-2 solvents per FDA guidelines at room temp. and elevated temp., data was found to be comparable between test and reference.

Conclusion: Multiple grades of PEO were evaluated and levels were identified to impart abuse deterrent properties. Either single or mixture of PEO grades can be used to obtain desired dissolution profile. Formulation F1 (containing ~ 82% of PEO consisting of WSR205 and N80 in 70:30) and Formulation F2 (containing ~ 78% of PEO consisting of WSR 205 and N80 in 53:47) were evaluated for in-vivo performance (Cmax and AUC) and a bio-relevant dissolution medium was identified as 0.1N HCl. Using this model, one can obtain desired dissolution & in-vivo performance. Bioequivalence studies were performed using reference as one of marketed abuse deterrent ER Tablets. The test formulation containing > 80% Polyox was tested for physical (mechanical) means of manipulation - crush resistance test, grinding; abuse by parenteral route and solvent extraction studies and was found to have abuse deterrent potential.

Acknowledgements: The work was supported by Teva Pharmaceuticals, Inc. USA (R&D)

Fig.1. Effect of PEO grade on Dissolution in pH 1.2, Basket, 50 rpm

Fig.2 a. PK Parameters b. Syringeability Test

Fig.3: Dissolution of two formulations from Bioequivalence Study