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Objective: To explore glass in vivo injectable sustained release Submicrospheres in preparation for the prevention and treatment of proliferative vitreoretinopathy. Proliferative vitreoretinopathy (proliferative vitreoretinopathy, PVR) is a refractory blinding eye disease, its occurrence to the complexity of the development process, very difficult, to the prevention and treatment of PVR common clinical treatment is surgical reduction , but still about 1/3 of the cases of recurrence. Studies have shown that the intravitreal infusion or injection has a significant inhibitory effect of matrine on the genesis and development of the PVR. But because the the free drug biological half-life is short, such as to maintain effective blood concentration required frequent injections; the ideal dosing is of matrine administered long-acting release intravitreal implant system, both lowering drug in the eye toxicity, also extend the treatment time. In this paper, as a model drug to matrine biodegradable material polylactic acid (Poly-L-lactide, PLLA) as the carrier, made the Matrine polylactic acid Submicrospheres can intravitreal injection to improve drug bioavailability, reduce drug side effects, and laid a theoretical foundation for its further clinical application. Methods: on the basis of the literature and preliminary experiments to determine PLLA carrier, using the organic phase dispersed - the solvent diffusion method matrine the polylactic acid Submicrospheres. Of the preparation process, prescriptions and other single factor, determine the basic process of preparation and use the Star Dot Design - response surface methodology to optimize. Drug loading, encapsulation efficiency, particle size and polydispersity index for the evaluation of indicators to determine the preparation matrine polylactic acid Submicrospheres optimum conditions, and to predict the results. To examine the nature of the optimized formulation was obtained matrine polylactic acid sub-microspheres. In the dry state using the scanning electron microscope Submicrospheres appearance thermostat oscillometric method; determination of the particle size and its distribution of Submicrospheres particle analyzer; differential scanning calorimetry (DSC), verify whether Submicrospheres formed; test the Chaya microspheres in vitro release by classic release model fitting, fitting result and the vitro Submicrospheres of degradation experiments to explore the Submicrospheres drug release mechanism; examine the high temperature, high humidity, and bright light factors Submicrospheres stability; 60% relative humidity at 25 ± 2 ℃, sealed for six months, to test the long-term stability of the Chaya microspheres. The visits 60Co radiation sterilization method whether the nature of the Submicrospheres. Using rabbits as experimental animals were randomly divided into two groups, respectively, to the the rabbit eye single dose of intravitreal injection of matrine solution and matrine Asia microsphere suspension, timing stripping eye separation of the vitreous, iris, sclera, retina, and choroid matrine concentration using HPLC with organizations in Matrine the polylactic acid Submicrospheres intraocular organize distribution and pharmacokinetic studies. Using non-compartmental model analysis methods the matrine maximum concentration (CBmax) and peak time (TBmax), take the measured value, calculated using the trapezoidal method drug area under the curve (AUC0-∞), and calculate the mean residence time (MRT ) and relative bioavailability. Results: theoretical drug loading and Foreign Minister gelatin concentration on the single factor and star point design experiments, screening out of matrine the polylactic acid Submicrospheres best preparation and prescription, the influencing factors within the phase PLLA concentration each index Submicrospheres have the most significant impact. Matrine of the optimized prescription and prepared poly the lactic Submicrospheres cylindrical spherical surface is smooth, uniform size dispersed in good condition. Prepared three batches Submicrospheres investigation, the results show that the stability of the preparation process, good reproducibility, its drug loading, encapsulation efficiency, the average particle size and PD were 6.526%, 50.2%, 699.2nm and 0.005, The deviation is small, with the predicted values, indicating that the model predictive. DSC analysis showed that the drug is based on a non-crystalline form dispersed in a carrier material, Submicrospheres form; vitro release experiment table Minya micro the ball 30d cumulative release rate of 80.66%, and further release of drugs to meet the requirements of the long-acting release; release Mechanism: Matrine the polylactic acid Submicrospheres vitro release profile of the Higuchi model, the drug through the the skeleton pore diffusion release. Preliminary stability test: Factors Affecting the experimental results found in the 40 ℃ and bright light the 4500 ± 500lx conditions under, Submicrospheres traits, drug content and release there was no significant change; relative humidity 90% ± 5% 75% ± 5%, moisture weight gain greater than 5%; 25 ± 2 ℃ / RH60% for 6 months, sampling investigated traits, drug content and release of long-term trial, the results were no significant changes in . The sterilization experiments show that a dose of 12kGy gamma ray irradiation, before and after sterilization traits, drug content and release there was no significant change. Rabbit eye tissue distribution and pharmacokinetic study: Matrine solution group, higher peak concentration of the drug in various tissues, maintaining a short time. Time to peak in the intravitreal 1h, 12h below the detection limit, similar to the situation in other organizations, matrine drug metabolism faster in the eye, the biological half-life is short, and the higher concentration of the drug peak easily cause retinal toxicity; Asia microspheres group, the concentration of the drug in various tissues were lower, but maintain a longer time. Drug peak in the glass body of 1d, 25d still be able to detect, the situation is similar in other tissues, the tissue within the eye, described the matrine polylactic acid Submicrospheres long residence time. Conclusion: The above in vitro and in vivo experiments prove the polylactic acid Submicrospheres preparations significantly extended matrine intravitreal residence time, significantly improved bioavailability and The preparation is simple, quality controlled, so to show a good The ocular application prospects.
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