In situ forming oral controlled release drug delivery formulations (ISFOF).

摘要

Novel oral drug delivery technologies have emerged and expanded into different drug delivery systems with different drug release mechanisms in the last few decades. Sophisticated instrumentation, modern mathematical models and computational power have revolutionized the entire process of formulation and development of drug delivery systems, and advanced the concept of drug delivery from a simple pill to a programmable, time controlled smart system. In situ forming oral controlled release formulation is a new technology in the field of oral controlled release delivery systems.; The concept of in situ forming devices (ISFD) entered the pharmaceutical field in the early 1980s as parenteral controlled release dosage forms. In last decade, this technology has grown significantly due to their potential advantages compared to the traditional parenteral controlled release dosage forms. However, a review of literature revealed that there are not many publications describing the usage of this technology for oral controlled release formulations. Therefore, the objective of this study was to develop novel in situ forming oral controlled release formulations that can control the drug release up to 24 hours.; In this project, preliminary studies were performed to ascertain the physical compatibility of different solvents with hard gelatin capsules. In addition, a combination of appropriate polymers and solvents were selected such that they could form a drug-loaded gel at the process temperature of 60-70°C, and the gel could convert into a rigid mass upon exposure to dissolution fluid at body temperature. The drug release mechanism from this rigid mass was controlled by different formulation factors such as different polymer grades, polymer concentrations, hydrophobicity or hydrophilicity of solvents, different drug loadings, and physicochemical properties of additional excipients. After evaluating different formulation factors, Ethocel RTM 10 FP and triethyl citrate (TEC) were selected for further studies using propranolol hydrochloride as a model drug. A polynomial correlation between viscosity of the blank gels and drug release profiles was also obtained. The drug release mechanism was investigated by performing solvent leaching studies.; The drug release profiles were optimized using different grades of polyethylene glycols (PEGs). Phase diagrams of ternary mixtures of ethylcellulose, PEG and TEC were obtained and used for optimization of drug release. The phase diagrams showed that addition of higher molecular weight of PEGs increased the phase separation and caused precipitation of ethylcellulose from the ternary mixtures. The effect of different grades and concentrations of PEGs in novel oral controlled release gel formulations were also investigated. In conclusion, the in situ forming oral controlled release formulations were successfully developed and the formulations were able to control the release of propranolol hydrochloride up to 24 hours.