Track: Formulation and Delivery - Chemical - Formulation - Oral - Modified Release
Category: Poster Abstract
Controlled Release of an OTC Cough Suppressant in a Soft Gelatin Based Dosage Form
Purpose: The purpose of the present study was to design a controlled release drug delivery system for a model cough suppressant drug within a soft gel based dosage form. Two approaches were explored using a proprietary controlled technology (Versatrol®) release technology to achieve the objective: hydrophilic carrier-polymer based matrix and lipophilic carrier-high melting wax matrix. Several polymers and waxes were explored in combination with hydrophilic and hydrophobic vehicles to achieve extended release of the drug. Methods: Preliminary solubility studies for the model drug were conducted in various pharmaceutical excipients to choose appropriate bulk liquid carriers for both approaches. The formulation components were selected based on physicochemical characterization of the active pharmaceutical ingredient. Several polymeric excipients were suspended in the bulk carrier to yield binary and ternary mixtures. API was added at the last step and mixed to form a homogenous mixture. For the lipophilic based approach, the high melting lipids were dissolved in the carrier and cooled prior to suspending the active. Homogenization was employed to achieve a final uniform fill mixture. For preliminary evaluations, fill was dispensed into two-piece capsules for dissolution performance evaluation. Formulations were characterized for sedimentation rate, flowability and viscosity. Studies on the fills manufactured with two different approaches were also conducted to evaluate the impact of hold time on physical properties and encapsulation. The lead candidates from both approaches were encapsulated into soft gelatin capsules and evaluated for dissolution in simulated gastric fluid (SGF) at pH 1.2. Apparatus II method at 50-100 rpm was employed for the dissolution experiments. Capsules were bottled into HDPE bottles with the use of child resistant closures and induction sealed for ICH stability studies. Results: Dissolution in simulated gastric fluid (SGF) showed controlled release of the drug up to 12 hour for both approaches. Polymers such as hydroxypropyl methylcellulose (HPMC), polyethylene Oxide (PEO) were used with the hydrophilic vehicles. Use of hydrophilic vehicles (HLB > 14) which had solubilizing capacity for the active, resulted in an initial burst effect. High variability was noted for the HPMC based matrices compared to the PEO based matrix. In both instances, a diffusion-based release mechanism was noted. When the high HLB (hydrophilic-lipophilic balance) vehicle was switched with excipients in an HLB range of 9-12, the burst effect was mitigated. Compared to the PEO based matrix, a higher concentration of HPMC had to be used to achieve the 12-hour release profile. Faster rate of sedimentation was noted for the hydrophilic HPMC/PEO based systems compared to the lipidic systems. With the use of lipophilic based systems, the burst effect was eliminated which can be attributed to limited API solubility in the lipophilic vehicles and the use of high melting lipid (HML) excipients such as Compritol (glyceryl dibehenate), Precirol (glyceryl distearate). API:HML ratio was a critical factor in influencing the release rate of the drug from the lipophilic vehicle-based matrix. An erosion-based drug release was seen for the wax based lipophilic systems. It was also noted that the drug release for the lipid-based matrices was more variable compared to the hydrophilic HPMC/PEO based systems. From a softgel encapsulation standpoint, for the lipid based approach, encapsulation had to be performed at a temperature range of 37-42 °C, whereas the hydrophilic polymer-based formulations could be encapsulated at 25-30 °C. In addition, for the lipid based systems, the bulk fill could be held at least up to 72 hours under continuous mixing prior to encapsulation with minimal impact to the physical attributes. For the hydrophilic systems, the bulk fill could be held only up to 24 hours under continuous mixing prior to encapsulation. After 24 hours, hydration of the polymers occurred which resulted in non-flowable mixtures which could not be encapsulated. The lead candidates explored as part of this research were stable at 40°C-75% RH for 3 months. Conclusion: For antitussive agents with a short half-life, the approaches discussed in this work can yield sustained release dosage forms to avoid repeated administrations and increase patient compliance. The controlled release formulations presented in this research could potentially be deployed for OTC and prescription molecules across a wide range of therapeutic areas. In addition, the hydrophilic vehicle-based formulations which displayed the burst effect could be explored for combination drugs that need immediate and controlled release delivery.