The Development And Quality Research On Ketorolac Tromethamine Nasal Spray

Objectives:To prepare a nasal spray of ketorolac tromethamine based nonsteroidal anti-inflammatory drugs,and preliminary research study on its quality standard and stability.Methods:Firstly,the method to detect the amount of ketorolac tromethamine by High Performance Liquid Chromatography(HPLC)was established.The oil-water partition coefficient of ketorolac tromethamine was measured.The stability of ketorolac tromethamine against high temperature and powerful light was examined by varying influential factors.Proper absorption enhancer was screened by investigating different absorption enhancers'effect on the medicine adsorption of nasal mucosa,which was accomplished by in situ rat nasal perfusion.Secondly,with reference to the innovator drug SPRIX(?),we chose ketorolac tromethamine as the active ingredient(API),sodium hydroxide(NaOH),edetate disodium(EDTA)and monobasic potassium phosphate as excipients.Conducted compatibility test between API and excipients.pH was the key factor for formulation investigation.The formulation was preliminarily screened by selecting one with a pH value approximate to the one in SPRIX(?),among prescriptions with NaOH and potassium dihydrogen phosphate buffers of different pH values.Thirdly,the quality standards of ketorolac tromethamine nasal spray including appearance,pH,the related substances,the content,each spray content,the total spray,the spray angle,the particle size distribution were studied.These standards provided the foundation for the drug's safety and effectiveness and further study of its toxicity and pharmacokinetics.Lastly,referring to 2015 version of "Pharmacopoeia of people's republic of China",Guidelines for Stability Testing of APIs and Preparations,the stability of pharmaceutical preparations against high temperature and powerful light was examined.Results:(1)The determination method of in vitro analysis of ketorolac tromethamine was stable and reliable.The result of oil-water partition coefficient test showed that the logarithm of oil-water partition coefficient was-0.81,indicating that the API has excellent hydrophilicity and may be mainly absorbed through the nasal water channel.The preliminary stability test showed that ketorolac tromethamine was more unstable when exposed in strong light than in high temperature conditions,so it should be protected from light.(2)Perfusion test results showed that the formulation with 0.006%disodium EDTA is superior to the one with 5%HP-?-CD in adsorption,and the former exhibited as a chelating agent.(3)Monobasic potassium phosphate and sodium hydroxide were used as pH adjusters.When the buffer consists of monobasic potassium phosphate and sodium hydroxide(25:33),the pH value of the spray is similar to that of the innovator drug.(4)The prepared spray are in line with the provision of the 2015 version of "Pharmacopoeia of people's republic of China"-general rules 0106 and 0112 regarding the nasal preparations and sprays,including appearance,pH,the related substances,the content,each spray content,the total spray,the spray angle,the particle size distribution,etc.(5)Analysis of influencing factors on the stability of high temperature(40?)and low temperature(-20 ?)was conducted.The results showed that the spray of appearance,pH,the related substances,the content and each spray content were matched the requirements,but it were more stable in the weak light and low temperature environment.Conclusion:Successfully prepared the ketorolac tromethamine nasal spray.The formulation composition and related quality indicators are similar to those of the innovator drug SPRIX(?).And the stability of the spray is good,the conditions of weak light and low temperature are good for transportation and storage.