(W0930-01-04) Fabrication and Characterization of Amlodipine Besylate Based Sub-cutaneous Implants: Fabricated with the Help of Hot Melt Extrusion

Purpose: Hypertension (HTN) can lead to heart attack, cardiac arrest, or coronary heart disease, and eventually death without proper treatment. Amlodipine Besylate (AMB) was approved by, US Food and Drug Administration in 1987, as a monotherapy for the management of HTN [1]. AMB is commercially available in tablet (2.5, 5, and 10 mg) and solution (1mg/mL) dosage forms. However, adherence to the properly prescribed dosage form is critical and difficult for patients with chronic diseases such as HTN to prevent illness progression and death. Implantable drug delivery systems provide a simple and effective way to deliver the drug for an extended period [2]. Amalgamation of implantable drug delivery and hot melt extrusion would help in overcoming the challenges associated with hypertension in patients. This study aimed to develop AMB-loaded subcutaneous implants to reduce the frequency of administration, thus improving patient compliance during HTN management.

Methods: Drug Loaded Implants were prepared by dissolving the AMB, PCL, and PLGA in chloroform for solvent evaporation in predetermined ratios. The implants were physically characterized for their fracturability and evaluated with a texture analyzer. Thermal Characteristics were evaluated with Differential Scanning Chromatography (DSC), and Drug-Excipient incompatibilities were further evaluated with Fourier Transform Infrared (FTIR). The surface Morphology of Implants was characterized with Scanning Electron Microscopy (SEM). The stability of implants in accelerated conditions was evaluated in the Stability Chamber. The extruded filaments had 2 mm (diameter) and 7.5 cm (length). Further, the implants were in a phosphate buffer for 15 days to study the release profile of the implants.

Results: Thermal Characteristics of successfully prepared drug-loaded implants are depicted in Figure 1. The drug was in a crystalline state after extrusion and was stable during the 15 days. Figure 2 depicts the fracturability of the formulations which was least for F8 while F9 depicted the highest tensile strength. F6 and F9 formulations depicted a smooth surface in SEM which is depicted in Figure 2 (a) while F8 showed a rough surface. Drug Content was equal to 102.2±2.18. FTIR depicted that all the above peaks mentioned were present in all the formulations. Hence, there was no interaction between AMB and polymers (PCL, PLGA). Drug Release Profile for F6, F8, and F9 are depicted in Figure 3, F6 formulation released ~1.56 mg of the drug over 15 days while F8 released ~2.47 mg of the drug. F9 formulation showed a controlled release of ~2.25mg over 15 days. F9 formulation was selected as a lead formulation because it showed good strength, smooth surface, stability during the accelerated conditions, and a good release profile.

Conclusion: The implants were successfully fabricated with hot melt extrusion using PCL, and PLGA for controlling the release. The lead formulation was stable in thermal characteristics, drug-polymer compatibility, fracturability, and release profile. The filament produced can be further explored for fixed-dose combination and animal studies. The study showed an approach of delivering the medication for a long period for the management of hypertension.

References: 1. Tripathi, K.D. Essentials of Medical Pharmacology; JP Medical Ltd, 2013;
2. Dash, A.; Cudworth, G. Therapeutic Applications of Implantable Drug Delivery Systems. Journal of Pharmacological and Toxicological Methods 1998, 40, 1–12, doi:10.1016/S1056-8719(98)00027-6.
3. Kleiner, L.W.; Wright, J.C.; Wang, Y. Evolution of Implantable and Insertable Drug Delivery Systems. Journal of Controlled Release 2014, 181, 1–10, doi:10.1016/j.jconrel.2014.02.006.

Figure 2. (a) SEM of (A) AMB, (B) F6 at 30x, (C) F8 at 30x, (D) F8 at 50x, (E) F9 at 30x, (F) F9 at 50x and (b) Texture Analysis of AMB, PCL, F6, F8, and F9

Figure 3. Per day AMB release of F6, F8, and F9 formulations over 15-day period

Figure 1. DSC of AMB, PCL, PLGA, F6, F8, F9, F6 Stability, F8 Stability, F9 Stability