(M0930-01-04) Development of a Sustained Release Softgel Dosage Form Based on Polyethylene Oxide Polymer

Purpose: The objective of this research project was to develop a sustained release softgel dosage form utilizing polyethylene oxide polymer (PEO). Polyethylene oxide polymer (Polyox™) was incorporated into softgel capsules as the release rate controlling matrix. The effects of polymer content and the molecular weight on drug release rate were assessed.

Methods: A 2x3 full factorial design of experiment (Table 1) with duplicates was utilized for the design of six (6) formulations (Molecular weight: low, medium and high; Polymer content: 20 and 40%). Each of the formulations was prepared twice to assess the drug release profiles. Diphenhydramine HCl was used as the model drug. Three batches of softgel capsules were manufactured. Dissolution tests were conducted to assess the resulting formulations using USP Apparatus II with paddle (50 and 100 RPM paddle speeds) equipped with fiber optic probes. The experiment data was analyzed statistically using Minitab software utilizing General Linear Model to investigate the main effects of polymer concentration and molecular weight and their interaction at the significance level of p < 0.05.

Results: The results indicate that there was an interaction between the molecular weight and polymer concentration (p < 0.02). The higher the molecular weight and the higher the resin concentration, the slower the drug releases. Figures 1 shows the dissolution profiles for the six (6) formulations. Formulations 5 and 6 were prepared using PEO polymer with 100,000 Da molecular weight exhibited immediate release profiles. Formulation 1 containing 40% polymer with 5,000,000 Da molecular weight showed slowest drug release. The other four formulations showed variable drug release profiles depending on the polymer concentration and molecular weight. Additionally, the dissolution profiles were similar at 50 and 100 RPM paddle speeds for the same formula, indicating that the drug release mechanism was mainly by diffusion. The softgel capsules had regular appearance and robust physical property indicated by higher seam and burst strength. When subjected to dissolution tests, the softgels demonstrated sustained release profiles up to 12 hours. The drug release rate was the fastest using PEO with 900,000 Da molecular weight (Batch 18MC-30). The drug release rate was similar and significantly slower when PEO polymers with higher molecular weights were used (5,000,000 Da for Batch 18MC-31, and 7,000,000 Da for Batch 18-MC-32).

Conclusion: Sustained release softgel formulations based on polyethylene oxide resins were developed per design of experiment. Effects of PEO concentration and molecular weight on drug release rate were studied. The drug release rate was significantly affected by both the molecular weight and PEO polymer concentration. The higher the molecular weight and the polymer concentration were, the slower the drug release rates were. The dissolution profiles were similar for the same formulation with either 50 RPM or 100 RPM paddle speed, indicating that the drug release mechanism is mainly due to diffusion through the polymer matrix. This sustained release softgel dosage form could be used for control release delivery of certain drug products requiring long acting or constant plasma concentration.

Figure 1. Dissolution Profiles of DOE Formulations

Table 1. Design of Experiment