Microencapsulation of hydrophilic drug substances using biodegradable polyesters. Part II: Implants allowing controlled drug release--a feasibility study using bisphosphonates.

The prolonged delivery of hydrophilic drug salts from hydrophobic polymer carriers at high drug loading is an ambitious goal. Pamidronate disodium salt (APD) containing implants prepared from spray-dried microparticles were investigated using a laboratory ram extruder. An APD-containing polymer matrix consisting of an APD-chitosan implant embedded in the biodegradable polymer D,L-poly(lactide-co-glycolide acid-glucose) (PLG-GLU) was compared with a matrix system with the micronized drug distributed in the PLG-GLU. The APD-chitosan matrix system showed a triphasic release behaviour at loading levels of 6.86 and 15.54% (w/w) over 36 days under in-vitro conditions. At higher loading (31.92%), a drug burst was observed within 6 days due to the formation of pores and channels in the polymeric matrix. In contrast, implants containing the micronized drug showed a more continuous release profile over 48 days up to a loading of 31.78% (w/w). At a drug loading of 46.17% (w/w), a drug burst was observed. Using micronized drug salts and reducing the surface area available for diffusion, parenteral delivery systems for highly water-soluble drug candidates were shown to be technically feasible at high drug loadings.

Microencapsulation of hydrophilic drug substances using biodegradable polyesters. Part I: evaluation of different techniques for the encapsulation of pamidronate di-sodium salt.

The preparation of microparticles (MP) with a high loading of hydrophilic, low molecular weight drugs is an ambitious goal. This study investigated the microencapsulation of a bisphosphonate salt (BP) into a biodegradable star branched terpolymer Poly(D,L-lactide-co-glycolide-D-glucose) (PLG-GLU). Two aqueous solvent evaporation microencapsulation-techniques were studied, namely the water-in-oil-in-water-technique (WOW) and the solid-in-oil-in-water-technique (SOW) as well as a non-aqueous microencapsulation method based on suspension of the drug in organic solvents (SOO). The aqueous microencapsulation techniques showed several disadvantages, which rendered it difficult to prepare MP with high drug loading (approximately 30% w/w). A modified SOO-technique allowed the preparation of highly loaded MP up to 28% (w/w). A micronized drug substance and a polymer solvent system consisting of equal volumes of acetonitrile (ACN) and dichloromethane (DCM) were essential features of the SOO-process. A morphologic examination of the internal structure by confocal laser scanning microscopy demonstrated that these MP contain many vacuoles and pores, leading to an unfavourable initial burst release of APD. This process needs further optimization with respect to drug release and may then be of general interest for the preparation of highly-loaded MP with other drug salts and hydrophilic macromolecules.