(T1130-12-78) Particle Engineering of Large Surface Area, Low Bulk Density, High Drug Load Particles of Poorly Water-Soluble Drugs for Depot Delivery at the Site of Disease

Purpose: The delivery of poorly soluble drugs in a controlled release formulation can be difficult when the amount of drug administered is constrained by the presence of excipients and limited by the delivery method. This problem frequently occurs with inhaled dry powders, intratumoral injections, intramuscular injections and subcutaneous injections. A novel formulation technology, supercritical precipitation (SCP), that produces micron size particles with a large surface area (created both inside and outside the particles) with no added excipients was used to engineer particles of poorly water soluble drugs.

Methods: SCP involves drug precipitated from an organic solvent using a flowing stream of supercritical carbon dioxide (scCO₂) as the antisolvent. Turbulent mixing is provided by sonic energy at the point of injection of the drug loaded organic solvent. The precipitating particles collide and fuse during the particle formation process creating large surface area, open structure particles with low bulk density. SCP particles are created and collected in a continuous process using alternating sintered stainless steel harvesting filters (1). SCP particles are tested for particle size distribution (Malvern Mastersizer, wet dispersion), BET specific surface area (USP < 846 >), scanning electron microscopy (FEI Quanta), X-ray powder diffraction (Siemens) and bulk density (USP < 616 >) plus additional testing which is more specific to the particular drug or route of delivery. Dissolution testing is performed using the Apparatus 2 (USP < 711 >).

Results: The SCP technology is not compatible with all drugs. Compatible drugs must be insoluble in scCO₂ and soluble in an organic solvent that is highly soluble in scCO2. More than 300 drugs have been processed using SCP. Optimizing the processing variables (solvent, flow rate of the drug solution, flow rate of scCO2, sonic energy intensity, nozzle, pressure and temperature), yields consistent and predictable particle characteristics. Every drug represents a new challenge and requires a different set of processing variables to obtain optimally engineered particles. The SCP particle manufacturing process is continuous and fully cGMP compliant with a typical production rate of 1 to 2 Kg per day. Most SCP particles produced are crystalline. A few compounds can form stable amorphous particles. In some cases, different polymorphs can be produced by varying the solvent and other processing variables. Particles generally have a mean particle size (D_v50) between 0.5 and 7 microns. The typical specific surface area (SSA) is at least 10m²/gm and bulk density is typically less than 0.15gm/cm³. Example SEM photomicrographs of SCP processed and unprocessed micronized paclitaxel are shown in Image 1. The mean particle size (D_v50) was about the same (2.97µm vs 2.51µm). The SSA increased from 7.11m² to 20.26m²/gm and the bulk density dropped from 0.209gm/cm³ to 0.075gm/cm³. No excipients were added to form the SCP paclitaxel particles. An inhaled pharmacokinetic study was conducted in rats (2) with SCP paclitaxel in a nebulized suspension. Results are shown in Image 2. High lung tissue concentrations and long lung residence times were achieved. The systemic exposure from the inhaled particles was much lower than the blood levels found for the IV dose of paclitaxel. SCP paclitaxel fits into a category of large porous inhaled dry powder where the low bulk density results in the aerodynamic particle size being smaller than the actual physical particle size. The large physical particle size facilitates avoidance of phagocytosis (3-6) allowing the particles to remain in the lung for a longer time. The intraperitoneal injection of SCP paclitaxel for the treatment of ovarian cancer (7), inhaled treatment of NSCLC (8) and intratumoral injections into solid tumors using ultrasound guided endoscopy (9) have been presented in previous publications. SCP particles of the kinase inhibitor sorafenib (Image 3a) and the PARP inhibitor niraparib (Image 3b) were also evaluated. Both drugs processed very well using SCP. The mean particle size (D_v50) for SCP sorafenib was 1.76µm. The SSA was 9.97m²/gm and the bulk density was 0.076gm/cm³. For SCP niraparib, the mean particle size (D_v50) was 4.66µm. The SSA was 11.96m²/gm and the bulk density was 0.077gm/cm³. Comparisons of the dissolution of SCP sorafenib and SCP niraparib versus their corresponding unprocessed drugs at neutral pH were conducted. The dissolution of both drugs was substantially enhanced. No excipients were added to form either of the SCP sorafenib or SCP niraparib particles.

Conclusion: SCP has been shown to be an effective technology for engineering particles of poorly soluble drugs for pulmonary delivery or for creating micron size depot injectable formulations. The large surface area of the SCP particles is similar to submicron particles but the larger physical size allows for easier handling. The larger size also contributes to much improved residence times at the site of disease. Higher drug concentrations for longer periods of time have been observed in the lungs and in tumors with much lower concentrations of drug in systemic circulation thereby reducing negative side effects.

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