Study On D008 Sustained Release Microsphere

The drug D008 is a synthetic in vivo polypeptide protein analogue,its biological activity is 100 times higher than that of natural polypeptide protein.Compared with the natural polypeptide protein,D008 has a longer half-life and is cleared slowly in the blood plasma.At present,the domestic production commonly of D008 injection has the characteristics of fast metabolism,low dosege and once a day.It will be used for a long time,when D008 was used the treatment of cancer,and bring greater pain and psychological effects to patients.The microsphere preparation has the effect of long term sustained release,which can greatly improve the convenience and compliance,and has the advantage in clinical and is a kind of potential dosage forms.In addition,there is a large market value,the microspheres preparation has become a hot spot of drug research and development in recent years.D008 made into sustained-release microspheres can be injected once a month or three months,and can be greatly increasing the compliance of patients.In this research system,import listed preparations for the reference preparation and lactic acid glycolic acid?PLGA?as the carrier,biodegradable PLGA microspheres for injection was prepared.In this paper,the method of measuring the content of D008 microspheres and in vitro release was established,and the methodology was researched.The established method is simple,specific,accurate and reproducible.The particle size,drug loading,encapsulation efficiency,burst release and release curve were used to evaluate the quality of microspheres.In the in vitro accelerated release,surfactant,pH value,ethanol concentration,ionic strength,temperature and shaking frequency,preservatives concentration and different kinds of release medium were studied,the D008 microspheres in vitro accelerated release method was established afther optimizing of release conditions,The results showed that different surfactants had different release rate of microspheres,Twain 80 concentration on the release rate of microspheres had no significant effects;with the ionic strength of the release medium increased,the drug release decreased;when the pH value of the medium was reduced,it can increase the drug release;ethanol solution can significantly increase the drug release;a certain concentration of benzalkonium chloride can not only effectively inhibit the growth of bacteria and blocking drug degradation,but also prevent the aggregation of microspheres,thereby promoting drug release;while the increase of temperature release increased,considering the stability of the drug and choose to release temperature of the water bath is 55?;with increased the frequency of shaking release increased,to achieve complete release and higher speed 200 rpm as the release frequency of shaking.The in vivo release of triptorelin acetate microspheres was measured by residual method in rats.Based on the evaluation of the in vitro release rate and the in vivo release rate of microspheres,the accelerated release method was determined.The release medium of triptorelin acetate microspheres was 15%ethanol solution?containing 0.06%tween 80 and 0.01%benzalkonium chloride amine?,the release rate was 87.35%at the temperature of 55?and rate of 200 rpm for 30 h.Accelerated release had a good correlation with in vivo release?y=0.884x+12.45,R²=0.9938?.The optimal formulation and technology were screened by single factor,such as drug loading,PLGA concentration,ultrasonic power,ultrasonic time and stirring rate,and then repeated preparation of three batches,the final optimization of the formulation and technology was the theoretical loading of 4%,PLGA concentration of200 mg/mL,ultrasonic power 400 w,ultrasonic time 3 min,and stirring speed 1200rpm.The microspheres had a burst release of about 20%,an average particle size of about 60?m,and a release period of 1 month.The optimal prescription process was 5times,10 times and 20 times respectively.After amplification,the results were similar to those of the reference preparation,which indicated that the prescription was reliable and the production was in accordance with the requirements.Finally,the influence factors test,accelerated test,long-term test and ⁶⁰Co irradiation test were studied.The results showed that the microspheres were stable under strong light;the microspheres were adhered at high temperature of 40?,therefore the preparation is kept at room temperature or low temperature.The microspheres were placed at 30?for 6 months and room temperature of 25?for 12months,results showed that the microspheres were stable in 3 months of accelerated test and long-term test.In study on microspheres ⁶⁰Co irradiation,results showed that raw materials,drug loaded microspheres and preparation were degraded in low dose?1 million rad?,middle dose?2 million rad?and high dose?3 million rad?irradiation,indicating that ⁶⁰Co irradiation is not suitable for terminal sterilization of D008 microspheres.