(W1130-04-22) Preparation and Evaluation of Choline Alfoscerate Sustained Release Coated Soft Capsule Using the Controlled Osmotic Pump System

Purpose: In the case of poorly soluble drugs, the form of preparations is often limited due to the characteristics of the drug, and as a representative example, the drug is taken in the form of a soft capsule in a solution state. Choline alfoscerate (CA), one of the drugs taken in soft capsules, is used for the improvement of cognitive dysfunction in patients with dementia of neurodegenerative and vascular origin. CA is used in the soft capsule because of its stability and CA soft capsule has a frequent dosing regimen. Sustained release is required to reduce the dose frequency and increase medication compliance. This study aims to achieve sustained release through a single membrane of coating by using a Controlled Porosity Osmotic Pump (CPOP) system to the soft capsule.

Methods: The sustained-release coating was applied for the conventional soft capsule product, choline max® (COMAX PHRMA, Republic of Korea). The composition of the coating solution consists of a film-forming agent, sustained-release agent, pore-forming agent, plasticizer, and an anti-adherent. The CPOP coated CA soft capsule (CA-CPOP) was prepared by pan coater (1AT2012-CT0. 12-10, HANA ADD TECH, Republic of Korea). The surface of the coating membrane was observed through the Scanning electron microscopy (SEM) image, and the rupture strength was evaluated by texture analysis. Dissolution tests were performed with pH 6.8 medium 50 rpm, USP apparatus II methods. In addition, release studies of optimized formulations in various osmotic pressure dissolution media were conducted to confirm the drug release mechanism. The release kinetics were evaluated according to zero-order kinetics.

Results: The Dissolution tests were performed with different coating amounts (10, 15, 20, and 30%) of the CF2 formulation. After 24 hours of dissolution test, the coating percent weight gain of 10, 15, 20, and 30% formulations of CF2 was released at 100, 98.09, 96.03, and 92.04%, respectively, and the lag times were 1.4, 2.3, 3.6, and 6.8 hours, respectively (Figure 1 (A)). It was confirmed that the release rate of CA decreased as the coating weight increased. To confirm the sustained-release effect of sustained-release agent to film-forming ratio on drug release, CF1, CF2, CF3, and CF4 (1.9, 2.3, 2.8, 4.1, respectively) formulations were compared. After the final dissolution test, the CF1, CF2, CF3, and CF4 formulations at coating percent weight gain of 15% released 97.74, 98.09, 95.80, and 14.57%, respectively, with lag times of 1.4, 2.3, 5.2, and 20 hours, respectively (Figure 1 (B)). In addition, drug release occurs equally regardless of the agitational intensity (paddle rpm), demonstrating that it is not affected by the hydrodynamic conditions in the human body (Figure 2(A)). To confirm the effect of osmotic pressure, the CF7 formulation was tested for dissolution in a pH 6.8 medium with different osmotic pressures, and the osmotic pressure was adjusted to 3.01, 8.32, and 16.59 atm, respectively. After 24 hours of dissolution test, 96.99, 90.85, and 61.46% were released at osmotic pressure 3.01, 8.32, and 16.59 atm medium, respectively, and the lag time was 5.1, 6.5, and 6.6 hours, respectively (Figure 2(B)). This indicates that the release of choline alfoscerate from CA-CPOP is dependent on external osmotic pressure. Consequently, The CA-CPOP capsule release profile was well fitted to the zero-order kinetic model. The surface morphology of CA-CPOP before and after the dissolution was observed by SEM (Figure 3). CF1 of the same formulation confirmed that pores were formed after the dissolution test. That is, it shows that the leaching of the pore former from the membrane formed a pore, and drug release occurs through it. The coating membrane was maintained without rupture for more than 16 hours in Simulated Intestinal Fluid and the rupture strength decreased with increasing exposure time to the dissolution medium.

Conclusion: The physicochemical evaluation and dissolution results of CA-CPOP were suitable for sustained-release formulations and could provide a solution for a frequent dosing regimen.

Acknowledgments: This study was supported by the National Research Foundation of Korea grants provided by the Korean government (NRF-2021R1A2C4002746 and 2017R1A5A2015541). This study was also supported by the Regional Innovation Strategy (RIS) through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (MOE).

Figure 1. In vitro release profile showing (A) the effect of coating percent weight gain and (B) the effect of PVAD/HPMC changes of the coating layer on CA release from CA-CPOP.



Figure 2. In-vitro release profile showing (A) the effect of agitational intensity and (B) the effect of external osmotic pressure on CA release from CA-CPOP (CF7-15%)



Figure 3. SEM images of the surface of CA-CPOP at (a) initial and (b) after dissolution test