(W0930-06-35) Formulation and Development of Haloperidol Implants for Patients with Schizophrenia

Purpose: Schizophrenia is a severe and chronic mental disorder that affects approximately 1% of the global population. The disease is characterized by a range of symptoms, including hallucinations, delusions, disordered thinking, and abnormal behaviors, which can significantly impair a person's ability to function in their daily life. Antipsychotic medications are the primary treatment for schizophrenia, but their efficacy can be limited by poor patient adherence. Subcutaneous implants are a promising solution to this problem, providing sustained and controlled drug delivery, reducing the need for frequent medication dosing, and improving patient adherence. This study aimed to evaluate the potential of HME for the manufacturing of subcutaneous implants for the treatment of schizophrenia. The study utilized a combination of Haloperidol (HLP) as an antipsychotic drug, Polycaprolactone (PCL) as a biodegradable and biocompatible polymer, and Kolliphor P 188 as a solubilizing excipient to develop the implant. The study evaluated the physical and chemical properties of the implant, including its drug release profile, stability, and performance, to assess the applicability of HME in the manufacturing process. The ultimate goal of this research was to improve the efficacy and patient outcomes of subcutaneous implants by advancing their manufacturing processes. The results showed that the implant had a uniform drug distribution, achieved targeted drug release, and had good stability.

Methods: The solvent evaporation method was used to formulate cake, which was further introduced into the HME. A minilab twin screw extruder was utilized to extrude the filaments (10 gm for each batch). Table 1 and 2 shows the drug loadings of filaments extruded at a temperature of 80C.  The filaments were cut into desired weight (30 mg) of implants irrespective of the loading. The diameter of the filament was 2.25 mm and 50 mm in length (F3). The in-vitro drug release studies were conducted for developed implants in a horizontal water bath at 37°C at 100 rpm for 24 hours. Phosphate buffer pH 7.4 was used as a releasing media, and studies were conducted for 30 days. The concentration of haloperidol released in media was determined using UV spectrophotometry at a maximum wavelength of 248 nm. Per day drug release profile was evaluated.

Results: Formulation F1 to F7 was successfully extruded using hot melt extrusion at a temperature of 80°C. The solvent evaporation technique was used to formulate F3 to F7 using chloroform. The uniformity of drug content for solvent cakes was evaluated and found within limits. The filaments were further characterized for uniformity of drug content, and for F1 and F2 it was found 26% and 60%, respectively (Table 4). Formulations F3 to F7 (Figure 4) showed uniformity of content in the range of 97% to 100%. Further, surface morphology (Figure 1) was performed and found that the surface of the implant was smooth. FTIR and DSC studies revealed that there was no chemical interaction between polymers and drug and drug was completely dispersed into the polymer (Figure 2). In-vitro drug release studies were conducted for F3 to F7 implants shown in Figure 3. Stability studies were performed at 45°C/ 75RH, and it was found to be stable for 30 days.

Conclusion: Haloperidol-loaded subcutaneous implant using solvent evaporation followed by Hot-Melt Extrusion was formulated successfully. Different formulations were prepared, with F1 and F2 not meeting the required content uniformity and drug content. Formulation F3 showed constant drug release over 30 days, while F4-F7 did not show constant release and caused fluctuations due to saturation. The implant remained stable during 30-day stability testing at 40°C and 75% relative humidity, with 98-101% HLP content present. The use of a surfactant and solubilizer improved drug release, with the Minilab II twin screw extruder enhancing the release of haloperidol. DSC, FTIR, SEM, and in-vitro drug release analysis characterized the implant's structure and properties. Overall, the study provides valuable insights into the fabrication and characterization of subcutaneous implants, which have the potential to improve treatment outcomes.

References: Chitnis, K., Narala, N., Vemula, S.K. et al. Formulation, Development, and Characterization of AMB-Based Subcutaneous Implants using PCL and PLGA via Hot-Melt Extrusion. AAPS PharmSciTech 26, 16 (2025). https://doi.org/10.1208/s12249-024-03004-4


Composition (%w/w) of Haloperidol loaded Filament


Scanning and Electron Microscopy and a) Thermograms of haloperidol, PCL, Kolliphor P188 and formulations F3, F4, F5, F6, and F7; b) FTIR spectra of all formulations.


Drug release from PCL/Kolliphor P188 over the period of 30 days a) Per day drug release; b) Cumulative percent drug release