(M1330-03-20) Development of Various Formulation Strategies/Approaches for an Extended Release of a Non-opioid Narcotic for the Treatment of Acute/Chronic Pain

Purpose: Extended/delayed release (ER/DR) formulations are frequently used to decrease the number of doses needed to maintain the desired therapeutic effect for a longer period. Numerous non-opioid narcotic formulations are designed for immediate release, with maximum drug absorption achieved by consuming several evenly spaced doses throughout the day. However, it is advantageous to develop ER/DR formulations for treatment of acute/chronic pain to increase consumer compliance and better dosing effect. A non-opioid narcotic used in this study is a hydrochloride salt of a weak base. It is a fast-acting, non-opioid analgesic for the treatment of acute pain. The usual oral dose range is 30 mg to 90 mg three times daily; the recommended initial dose is 60 mg. Currently it is available only as an immediate release formulation. Based on the IR dosing from prior clinical evaluations (30 mg), a preliminary target dose that was established was 90 mg – 120 mg QD, with an early onset characteristic 20–30 mg of the dose could be considered as part of the early onset dose to ensure immediate relief and then an extended dose lasting 10–12 h. Thus, the purpose of this study was to develop a formulation with a combination of IR/ER formulations that can be administered once a day.

Methods: Three different formulation approaches were evaluated for development of a non-opioid narcotic extended-release formulations were 1.Bilayer tablets: It consisted of immediate-release (IR) layer and an ER layer compressed into one tablet. A high viscosity grade of HPMC, Methocel K100M was used to achieve sustained release for the ER layer. Different polymer concentration was evaluated to achieve the desired ER profile. The final IR and ER blends were compressed using a Bilayer tablet press. The compression parameters were optimized to get desired weight of 400 mg and hardness of 25 kp. The compressed tablets were color coated using 8" O’Hara Coating machine. 2. IR and ER Minitabs in capsules: It consisted of two populations of minitabs, IR minitabs, and matrix ER minitabs in capsule. The minitabs were manufactured by blending/compression. The matrix minitabs were manufactured with a high viscosity grade of HPMC to achieve the extended release. The final IR and ER blend was compressed using Synthesis 300 tablet press using multi-tip tooling. 3. IR/ DR minitabs in capsule: The IR and DR minitabs approach consists of IR minitabs and DR minitabs within one capsule. The minitabs were manufactured by direct blending/compression. The DR minitabs were manufactured by coating the IR minitabs with a delayed-release polymer such as Eudragit S100. Dissolution of the bi-layered tablets and IR/ER minitabs in capsules was performed using 900 mL of pH 6.8 phosphate buffer at 37.0ºC, using Apparatus II (Paddle), and Apparatus I (Basket) respectively at 50 rpm. Dissolution of the IR/DR minitabs in capsules was performed using 900 mL of 0.1 N HCl (2 hours) / pH 7.4 phosphate buffer at 37.0ºC, Apparatus II (Paddle), 50 rpm.

Results: For Bilayer tablet approach, Methocel K100M was evaluated at two levels, 15% (Batch # 58) and 20% w/w (Batch# 48). Based on the dissolution profile, batch with higher polymer concentration (20%) was selected as the optimized concentration in the ER layer. As shown by the dissolution data in Fig. 1, the IR dose (~40%) releases immediately within 30 minutes and the ER dose releases over 14 h. For IR/ER matrix minitabs, the IR minitabs were designed to contain 40% dose and the ER minitabs were designed to contain 60% dose. Methocel K200M was evaluated at 50% w/w of the ER Minitab for Batch41. As sown in Fig 2.,75% drug was released in 2 h, and complete drug release was observed by end of 8 h. For IR/DR minitabs in capsule approach the DR core minitabs were further processed by coating the IR minitabs with enteric coating to 15% weight gain (w.g). Triethyl citrate was utilized as a plasticizer at two levels – 10% of polymer, Eudragit S100 (batch # 24) and 15% of Eudragit S100 (batch #38). The DR coated minitabs of Batch 24 disintegrated quickly in acid on visual appearance check. The DR coating was optimized to increase the plasticizer level to 15% TEC in Batch 38. As shown in Fig. 3., the delayed release characteristics could be maintained in the acid phase for this batch. This approach provided desirable dissolution profile for the formulation with 15% plasticizer.

Conclusion: Several formulations were developed for a non-opioid narcotic with the immediate release component releasing about 40% of the dose rapidly within 30 minutes and the extended/delayed release component releasing the remaining 60% of the dose gradually over an extended period.

In-vitro dissolution studies of a Bilayer tablet in 900 mL of pH 6.8 phosphate buffer at 37.0ºC, using Apparatus II (Paddle).

In-vitro dissolution studies of Minitab's in a capsule a) IR/ER matrix Minitab's b) IR/DR Minitab's in capsule