(T1330-11-74) Novel LAAM Immediate Release Capsule for Treating Opioid Use Disorder

Purpose: Drug overdose deaths in the U.S. top 100,000 in 2022 according to CDC. Advancements in medication treatment for treating opioid use disorders (OUD) are greatly needed. Levo-alpha-acetylmethadol (LAAM) offers numerous behavioral and clinical advantages as an alternative to methadone, the major medication but requires daily visits. Superior to methadone, LAAM has a longer systemic half-life which reduces dosage frequency to 2-3 times per week and greatly improves patient compliance. Despite being approved for OUD treatment, LAAM solution ORLAAM® was withdrawn from market in 2003, not for a lack of effectiveness but economic benefit at the time. Reintroducing LAAM back into market will significantly improve OUD treatment outcomes. In this study, we aim to develop a novel oral immediate release capsule of LAAM, as alternatives to the approved solution formulation, to allow flexible dosing and maintain similar pharmacokinetic profiles. The optimal formulation will proceed to the clinical trial study.

Methods: LAAM solid dispersion-coated pellets were developed with VIVAPUR® MCC Spheres 700 as the core, and LAAM-carrier coating solution was sprayed on to the core pellets by bottom-spray coating method using a fluid bed coater. LAAM-carrier coating solution was optimized. Polymeric carriers including Soluplus, Kollicoat Protect, and Kollicoat IR were compared. Different LAAM concentrations varying from 2%-3% (w/w) were investigated as well as different polymer to drug ratios were compared. LAAM coated pellets were filled in size #1 clear gelatin capsules and packed in the blisters. (Figure 1.) Capsules with different dosage strengths (5mg, 10 mg, and 40mg) were prepared with 100 capsules per dosage strength. Capsule weight variation, content uniformity, and in vitro release tests were conducted for quality assessment. The storage stability of the LAAM capsules were evaluated under the accelerated condition and room temperature for 6 months. The weight gain, drug content, and dissolution profile were evaluated at months 1, 2, 3, and 6. Pharmacokinetic (PK) study was performed in rabbits. Blood samples were collected before dosing and at pre-determined time points following oral administration. The concentrations of LAAM and its active metabolites in plasma were determined by LC-MS/MS. Plasma concentration-time profiles were plotted and used to calculate pharmacokinetic parameters.

Results: Kollicoat IR was selected due to the high drug loading on the final products, fast release property and less coating time. The Kollicoat IR-to-LAAM ratio of 1:2 with 2% (w/w) LAAM was selected as the final coating solution formulation due to higher yield and less pellets aggregation during preparation. Capsules with different dosage strengths (5mg, 10 mg, and 40mg) were manufactured with 100 capsules per dosage strength in lab. Quality control tests were performed. There was no deviation outside ±10% with any weight of a finished capsule's contents and the weight of a finished capsule. All three dosage strengths passed the content uniformity test. The LAAM capsules showed the immediate release profile with 100% release in 10 minutes. Storage stability under accelerated and room temperature was evaluated. The weight gain of capsules stored in accelerated condition was higher than that in normal condition. The capsule weights between 1, 2, 3, and 6 months were steady. The results showed that drug contents and immediate release property were remained after 6 months of storage. PK analysis showed that capsules have longer t_max as well as higher C_max of LAAM compared with oral solution. Capsules have higher AUC of LAAM but lower AUC of norLAAM and dinorLAAM, the two active metabolites of LAAM.

Conclusion: LAAM immediate release capsules with different dosage strengths were manufactured. These capsules passed the quality control tests and remained stable under accelerated condition for 6 months. These capsules have different C_max but similar AUC of LAAM and its metabolites to oral solution. It has been demonstrated that the developed LAAM capsules have the desired properties for the subsequent clinical studies.

Acknowledgements: The authors would like to acknowledge the NIH/NIDA HEAL Initiative for financial support of this research (Grant Number: DA048768-01A1).

Figure 1. Scheme of LAAM immediate release capsule preparation and release profile