| Ketoprofen is an a-Arylpropionic non-steroidal anti-inflammatory drugs (NSAIDs). It has a similar anti-inflammatory and even stronger antipyretic analgesic effect compared with ibuprofen. The main mechanism of ketoprofen is reversible inhibition of cyclooxygenase and lipoxygenase. Thereby the biosynthesis of leukotrienes and prostaglandins will be inhibited. Then against chemical mediators(bradykinin) of inflammation and pain to possess analgesic, anti-inflammatory and antipyretic effects. Clinically, ketoprofen is mainly used for the treatment of neuropathic pain, muscle pain, headache, postoperative pain, rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and acute gout. Normal oral formulations of ketoprofen has short half-life (1.6-1.9h). The frequency of clinical application is 3 to 4 times per day. And it has the side effects such as irritation of the gastrointestinal tract, stomach discomfort, gastrointestinal ulcers and bleeding. As proton pump inhibitor, lansoprazole which is recommended for those who took NSAIDs GI protective agents by American College of Rheumatology treatment guidelines can relieve severe stomach ulcers and complications arising from taking NSAIDs. A sustained-release pellets contain ketoprofen and lansoprazole will be prepared in this article. According to Chinese chemical registration taxonomy, it belongs to the first class of new drugs. The research of this new sustained-release pellets has been applied for Chinese patent. Lansoprazole, combinated with ketoprofen, aim to reduce or eliminate oral ketoprofen-induced gastrointestinal side effects. Sustained-release pellets could delay the release of ketoprofen and lansoprazole thereby reduce the number of doses per day. According to the requirements in Chinese Drug Registration for the disclosure of information, the formulation and process, quality standards, stability and non-clinical pharmacokinetics of ketoprofen/lansoprazole sustained-release pellets were studied in this paper. The purpose is to accumulate data for documents of preclinical studies, clinical trials and drug registration application of ketoprofen/lansoprazole sustained-release pellets.The study in the first part was to prepare and optimize the novel ketoprofen/1 ansoprazole matrix sustained-release pellets, and to evaluate the release rate of the pellets in vitro. The pellets were prepared by extrusion-spheronization method and the release study in vitro was conducted through paddle method combined with HPLC. A carefully executed central composite design was applied to screen the optimal formulation of the pellets. The optimal formulation consisted of ethyl cellulose 49.6%, microcrystalline cellulose 24.7%, L-arginine 1.0%, ketoprofen 21.5%, lansoprazole 3.2%. The characteristics of drug release: the release time was over 12 h. The drug release behavior was consistent with first order kinetic equation. The process of drug release was drug diffusion with frame erosion. The ketoprofen/lansoprazole matrix sustained-release pellets with good effects of sustained-release properties in vitro had reasonable formulation and simple preparation technology.The main indicators of quality standards such as method for determining the content and related substances of ketoprofen/lansoprazole delayed-release pellets were studied in the second part. We established a HPLC method for simultaneous determination the content and related substances of ketoprofen/lansoprazole sustained pellets. Chromatographic conditions:stationary phase: Hypersil BDS C18(250mmx 4.6mm,5μm); mobile phase:Water-acetonitrile-triethylamine (65:32:3, V/V/V), 10% phosphoric acid to adjust pH= 7.0; The flow rate was 1mL · min-1; Detection wavelength on 285nm; Column temperature was 25℃. Results:Degradable substances and related substances after the destruction can be completely separated from the main peak; the concentrations at the range of 40-160μg · mL-1, ketoprofen had a good linear relationship. The recovery was 100.00% (n= 9), the limit of detection was 3.4ng, the limit of quantification was 20.0ng; the concentrations at the range of 6-24ug · mL-1, lansoprazole had a good linear relationship. The recovery was 99.91% (n= 9), the limit of detection was 6.7ng, the limit of quantification was 60.0ng. According to the established method of content and related substances determination, three batches of homemade ketoprofen/lansoprazole sustained-release pellets sample were detected.. In the results, the average content of ketoprofen was 100.82%, the average content of lansoprazole was 98.93%, related substances of the pellets were less than 0.3%. This method is simple, accurate, rapid and high sensitivity. It’s suitable for the determination of contents and related substances of ketoprofen/lansoprazole sustained-release pellets.In the third part, the stability of ketoprofen/lansoprazole sustained pellets. Three batches of Ketoprofen/lansoprazole sustained-release pellets were taken factors test, long-term test and accelerate experimental study. The glare and high temperature test of pellets showed that the content of the drug had a downward trend in light and high temperature test conditions. But these conditions did not affect the release rate of the pellets in vitro. In accelerated and long-term testing, the results showed good stability of the pellets. There were no significant changes in appearance, content, related substances and release in vitro of the pellets. The stability of pellets in long-term trials are continuing.Part four Pharmacokinetic study of ketoprofen/lansoprazole sustained-release pelletsin in SD rats. Using the same content specifications homemade ketoprofen/lansoprazole capsules as reference preparation, the pharmacokinetic characteristics of ketoprofen/lansoprazole sustained-release pellets were studied in SD rats. Kinetica software was used to calculate the pharmacokinetic parameters and relative bioavailability. The results showed that the test preparation and reference preparation of ketoprofen AUCo-24 were 39.11μg/mL · h and 36.91 μg/mL · h, Cmax were 2.80μg/mL and 4.62μg/mL respectively. The AUCo-24 of lansoprazole were 10.99μg/mL·h and 9.24μg/mL·h, Cmax were1.20μg/mL and 1.51μg/mL respectively. The relative bioavailability of ketoprofen/lansoprazole sustained-release pellets were 106.94% and 118.94% separately. Minimum effective blood concentration of ketoprofen is 1.Oμg·mL-1 Compared to ordinary capsules, ketoprofen and lansoprazole of sustained-release pellets in SD rats prolonged the duration of action to 24 hours. In experimental animals, the preparation with obviously sustained action achieved the desired purpose. |
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