Structure formation and characterization of injectable drug loaded biodegradable devices: in situ implants versus in situ microparticles.
The objective of the study was to investigate key formulation variables affecting the release of bupivacaine hydrochloride, a local anesthetic, from different in situ forming biodegradable drug delivery devices. The formulations included ISM systems [in situ microparticles, a poly(lactide)-solvent phase dispersed into an external oil phase] and poly(lactide) solutions (in situ implant systems). The solubility of the biodegradable polymer poly(d,l-lactide) (PLA) in various organic solvents was determined using the Hansen multicomponent solubility parameter concept. The solvent release from ISM and polymer solutions into phosphate buffer which influences the polymer precipitation rate was investigated as a function of the type of solvent, polymer concentration and polymer:oil phase ratio by using a HPLC assay. Scanning electron microscopy (SEM) was performed in order to relate the drug release to the surface properties of the precipitated implants or microparticles. Suitable solvents for the preparation of the in situ forming drug delivery systems, such as N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO) and 2-pyrrolidone were found using the Hansen multicomponent solubility parameter concept. The injection of the polymer solutions (in situ implants) into the aqueous medium led to a rapid solvent/non-solvent exchange. The resulting in situ implants were porous, thus explaining the rapid initial drug release. Upon contact with the release medium, the internal polymer phase of the ISM system solidified and formed microparticles as shown by SEM measurements. Due to the presence of an external oil phase the solvent release into the buffer medium from ISM was significantly slower compared to the polymer solutions. The solvent release of the ISM systems into the phosphate buffer decreased with increasing polymer concentration and decreasing polymer:oil phase ratio. The type of solvent used also affected the solvent release. A slower solvent release into the aqueous medium resulted in less porous microparticles, thus explaining the reduced initial drug release from ISM systems compared to the polymer solutions.
Kranz
H
H
College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany. Heiko.Kranz@bayerhealthcare.com
Bodmeier
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R
D020341:Absorbable Implants; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000737:chemistry; D002045:Bupivacaine / Q000008:administration & dosage / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D005079:Excipients; D019344:Lactic Acid; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D012995:Solubility; D012997:Solvents; D014783:Viscosity
D000779:Anesthetics, Local; D005079:Excipients; D004364:Pharmaceutical Preparations; D011108:Polymers; D012997:Solvents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D002045:Bupivacaine