Abstract
To explore the mechanism of drug release and depot formation of in situ forming implants (ISFIs), osthole-loaded ISFIs were prepared by dissolving polylactide, poly(lactide-co-glycolide), polycaprolactone, or poly(trimethylene carbonate) in different organic solvents, including N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), and triacetin (TA). Drug release, polymer degradation, solvent removal rate and depot microstructure were examined. The burst release effect could be reduced by using solvents exhibit slow forming phase inversion and less permeable polymers. Both the drug burst release and polymer depot microstructure were closely related to the removal rate of organic solvent. Polymers with higher permeability often displayed faster drug and solvent diffusion rates. Due to high polymer-solvent affinity, some of the organic solvent remained in the depot even after the implant was completely formed. The residual of organic solvent could be predicted by solubility parameters. The ISFI showed a lower initial release in vivo than that in vitro. In summary, the effects of different polymers and solvents on drug release and depot formation in ISFI systems were extensively investigated and discussed in this article. The two main factors, polymer permeability and solvent removal rate, were involved in different stages of drug release and depot formation in ISFI systems.
Highlights
Implants received additional significance as typical controlled release systems in the last decades
The drug release from in situ forming implants (ISFIs) can be separated into three steps: The initial burst release, a long period of constant release mainly caused by matrix diffusion and the last stage of release due to the erosion of the polymer
The slowest initial drug release was found in the PLGA based ISFI with TA as the organic solvent, which released 38.92% of Ost on the first day
Summary
Implants received additional significance as typical controlled release systems in the last decades. The marketed ISFIs, such as Atridox®, showed a significant improvement in patient compliance and therapeutic effect to periodontal disease, and Eligard® for the treatment of prostate cancer [3,4,5,6] This injectable implant system consists of water-insoluble polymers and organic solvents that are fully or partially water miscible. The drug release from ISFI can be separated into three steps: The initial burst release, a long period of constant release mainly caused by matrix diffusion and the last stage of release due to the erosion of the polymer It is not uncommon for the initial burst release of the drug to be seen from solvent removal precipitation-based ISFIs. The initial large bonus of drug can result in tissue irritation and even systemic toxicity, reduced the effective lifetime of implants. A true solution to reduce drug burst release has not yet been found
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