| Objective:Rectal cancer is one of the most common malignancies in the digestive tract.In recent years,with the continuous improvement of people's living standards,changes in living habits and dietary structure,and aging of the population,the incidence and mortality of rectal cancer in China are on the rise.It is one of the malignant tumors that seriously endanger people's health.Thermosensitive gel refers to a formulation in which a macromolecule material responds to an external temperature after being administered in a solution state and undergoes a phase transition from a liquid state to a non-chemically crosslinked semi-solid gel.Thermosensitive gel materials can undergo certain phase changes with changes in the ambient temperature.They arecontrolled-release,sustained-release,and targeted.They can reduce toxicity in the human body.They can be used for injection implantation and long-term drug release.They are widely used in ophthalmic,nasal,rectal and injection administration.The thermosensitive gel materials play an important role in the pharmaceutical field and have become a research hotspot in recent years.This study uses 5-fluorouracil as a model drug to prepare a thermosensitive gel with a suitable phase transition temperature,and investigates the drug release profile in vitro and the stability of the drug-containing gel.It is expected to lay a foundation for the research and development of new preparations for rectal administration.Methods:1.Study on Preparation and Formulation of 5-Fu Thermosensitive Gel.The related physicochemical properties of 5-Fu were studied to investigate the solubility of 5-Fu in different pH phosphate buffers and the apparent oil/water partition coefficient in n-octanol buffer.Poloxamer(P407)was the main gel matrix,and the gelation temperature was taken as the index.The“gel stirrer method”was used to determine the gelation temperature of the thermosensitive gel.The single-factor study was used to preliminarily determine the components and dosages of the formulation.Then,the dosages of P407,SA,and PEG 4000 were taken as the investigation factors,and formulation prescriptions were optimized through orthogonal experiments.2.Study on Determination Method of 5-Fu Thermosensitive Gel Content.The RP-HPLC method was used to determine the content of 5-Fu thermosensitive gel and the method validation was performed.The content of5-Fu thermosensitive gel sample prepared by the“cold method”was determined.3.Study on in vitro Release of 5-Fu Thermosensitive Gel.According to the relevant provisions of the“Chinese Pharmacopoeia”and the literature,the“dialysis bag-paddle method”was established to measure the release of thermosensitive gels in vitro.Thenthe release of 5-Fu thermosensitive gels and common gels in vitro were compared.The model fitting of release curves was performed and the release mechanism and characteristics of 5-Fu thermosensitive gels were explored.4.Stability study.In order to investigate the stability of the 5-Fu thermosensitive gel,the influence factor experiment and long-term experiment were studied,taking the appearance of the preparation and the change of content of 5-Fuas indicators.Results:1.The results showed that the solubility of 5-Fu in phosphate buffer gradually increased with the increase of pH,while the apparent oil/water partition coefficient decreased with the increase of pH.The formulation of5-Fu thermosensitive gel formulation,was determined by orthogonal experiment optimization:P407(18%),SA(0.5%),PEG 4000(0.4%).Under the above prescription,the gelation temperature of the formulation was approximately 35°C,with condensation time 10s~20s.2.A RP-HPLC method for the determination of 5-Fu thermosensitive gel was established.The chromatographic conditions were as follows:column was C18-ODS,mobile phase was water-methanol(95:5,v/v),detection wavelength was 266nm,flow rate was 1 m L/min.with column temperature30°C;injection volume 10?L;5-FU concentration linear range 3.17~19.01?g/mL;intraday precision RSD<2%,daytime accuracy RSD<3%,the RSD of content determination1.35%.The presented method is rapid,accurate,and reproducible,which is accurate and precise for quality control of formulations.3.The“dialysis bag-paddle method”was used to measure the the release of thermosensitive gels in vitro.Compared with common gels,5-Fu thermosensitive gels have a longer duration of drug efficacy,stable drug release,and a certain sustained-release effect.The first-order release process was more reasonable(r~2=0.9916).The drug release mechanism study showed that the release of the drug in the temperature-sensitive gel was well fitted by the Ritger-Peppas model(r~2=0.9459).The experiment initially suggested that the drug release mechanism of 5-Fu thermosensitive gel is a synergistic effect of diffusion and dissolution.4.The results show that light and high temperature have a great influence on the stability of the preparation.Under the light conditions of 4500Lx±200Lx,the content of 5-Fu thermosensitive gel is slightly reduced,while the gel denatured and precipitation occurred under the experimental conditions of 60°C.Itindicated that the preparation should be stored without light and and under low temperature;And there was a certain stratification phenomenon if the preparation was placed for 6 months,but it could be re-dispersed uniformly.the stable drug content before and after centrifugation suggests that the long-term placement would not change the drug content.Conclusion:According to the"Chinese Pharmacopoeia"and related literature,the study applied the modern methods of preparation,took the gelation temperature as an inspection index,optimized the of formulation prescriptions by orthogonal experiment,and developed a 5-Fu thermosensitive gel.A rapid,accurate and reproducible RP-HPLC method was established to determine the content of 5-Fu thermosensitive gel.Through the investigation of the release in vitro and the fitting test of drug release model,it showed that the temperature-sensitive gel has a longer duration and more stable drug release than the common gel,and its drug release mechanism is a synergistic effect of diffusion and dissolution.For the stability study,the thermosensitive gel is suitable and its temperature is uniform.The 5-Fu thermosensitive gel developed in this project provides a certain experimental basis and scientific basis for the development of drugs used in rectum and new dosage forms of antitumor drugs. |
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