| Osteoarthritis(OA) is one of the most common clinical arthritis, Non steroidal anti-inflammatory drugs(NSAIDs) are widely used in the field of OA therapy. ML3000, a balanced inhibitor of cyclooxygenase(COX) and 5-lipoxygenase(5-LOX), covalently bounds to one NO-donating moiety to produce ML4000, the model drug in this paper.ML4000 has satisfactory anti-inflammatory activity,significant NO releasing activity, gastrointestinal tolerability and has no cardiovascular complications.ML4000's physical and chemical properties were studied before formulation screening. It included appearance properties, melting point, crystalline, solubility, and moisture absorption.The raw material was a pale yellow powder, Tm=106.3~107.3 ?.The powder X-ray diffraction and differential scanning calorimetry curves showed that ML4000 was a crystalline compound. ML4000 was solublable in acetonitrile, DMF, chloroform, acetone and dichloromethane, slightly solublable in ether, minimal solublable in methanol and ethanol, and was insoluble in water. It was almost insoluble in different pH buffer solutions and almost had no hygroscopicity.ML4000 suffers from a drawback of poor aqueous solubility.Solid dispersion technique is often used to improve the solubility of poorly soluble drugs.In the study, ML4000 solid dispersion(SD) and the tablets were prepared aiming at improving dissolution in vitro and the bioavailability in vivo.High performance liquid chromatography method(HPLC) was established for determing the content and dissolution of solid dispersion and the tablets. The HPLC method was proved to be accurate,reliable and easy to operate. The stability of ML4000 SD and the tablets were preliminary evaluated through influential factors test.ML4000 SDs were prepared with water soluble materials poloxamer 188, polyethylene glycol4000(PEG4000), polyethylene glycol 6000(PEG6000), PVP K30, PVP K90, Co-PVP and SOLUPLUS?,by appropriate preparation method such as melting method,solvent melting method or solvent evaporation method. We chose dissolution in vitro as the evaluation index to analyse the formulation and preparation process of SD.It was found SD made by all carriers above, in a certain extent, can improve the drug dissolution rate and extent. SDs made by the carriers of poloxamer 188, PEG4000 and PEG6000 were prepared respectively by three kinds of methods, but the solubilization effect was not obvious. Dissolution effect of solvent evaporation method was obviously superior to the other two methods. During the preparation process, PVP K90 and SOLUPLUS? were so viscous that it was hard to scrape the prepared SDs from the flask. Ratio of ML4000 and Co-PVP was 1:5, the amount of Co-PVP needed was far more than PVP K30(1:2). The optimal prescription was ML4000-PVP K30(1:2), with dichloromethane as the solvent(1g ML4000 to 40 ml dichloromethane) and the preparation process was solvent evaporation method.Differential scanning calorimetry(DSC) and Fourier transform infrared spectroscopy(FT-IR)were used to study the existing status of ML4000 in SD and the interreaction between ML4000 and carriers.DSC curves showed that ML4000 had a significant endothermic peak. In the physical mixture, drug crystallization peak decreased, but was still significant. In SD(1:2), the drug crystallization peak disappeared, and ML4000 existed in SD was in amorphous state. From the FT-IR curves, we speculated that ML4000 and PVP K30 were associated with hydrogen bonds. The mass fraction of drug in SD and dissolution reproducibility met the requirements.The results showed that dissolution and the mass fraction of SD had no obvious change and ML4000 solid dispersion was stable under high temperature(60?) and the condition of illumination(45001x±5001x) for ten days. However, SD had a significant moistureabsorption, so it was necessary to keep the samples under airtight and dry condition.Long term experiment showed that SD was stable in 3 months, which proved that it could be made into tablets.With powder's fluidity, appearance and their dissolution propertes as the main indexes,studies about the formulation composition and preparation process of ML4000 SD tablets were carried out in this text. By single factor analysis we selected crosslinked polyvininylpolyrrolidone as disintegrating agent and magnesium stearate as a lubricant, then ued L9(34) orthogonal experimental design to optimize proportion of disintegrating agent and lubricant and the type of filler. Finally, the optimized formulation and preparation process of the tablets were determined and then we producted three batch samples. The uniformity and reproducibility of three batches were all qualified.The preliminary investigation showed that the quality and stability of the samples met relevented requirements. The samples were stable in the condition of illumination(45001x±5001x), high temperature(60?) and high humidity(75%±5%) for 10 days and also no index of the tablets had got significant change in the accelerated test for 1 month. |
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