| With the continue improvement of modern medical, the diagnosis and treatment of prostate cancer has been made more progress. The development and metastasis mechanism of prostate cancer are not yet clear, but the influence of androgen receptors on prostate cancer is unanimous. And the androgen receptor antagonists become important research direction in the treatment of prostate cancer.GT0918, a novel androgen receptor antagonist, is a new chemical entity for the treatment of prostate cancer. The results show that, compared of the currently approved drugs, GT0918has a higher activity of the androgen receptor.During the exploitation process of new drug, comprehensive and systematic understanding of the physical and chemical properties of the drug is the first step. Preformulation studied the physical and chemical properties of the drug such as Appearance, crystalline, solubility, permeability and drug-excipient compatibility. This drug is a pale yellow powder. The powder X-ray diffractometry (XRPD), differential scanning calorimetry (DSC), thermal gravimetric analysis (DSC) study results showed that the drug was a single polymorph. High performance liquid chromatography method was established, and the solubility of the drug in different solvents and solutions of different pH are studied. The results showed maximum solubility in hydrochloric acid solution,717μg/mL, in the solution of pH2.5～10.0and the solubility was3.08～8.89μ/mL, solubility in pH5.0solution was minimum; Drug was easily dissolved in a solvent such as methanol, acetonitrile, ethanol and poorly dissolved in water. Application of the parallel artificial membrane permeability assay solution of pH3.0,5.0,6.2,7.4, drug showed high permeability. For tablet formulation, selected the different categories of excipients, such as fillers, binders, disintegrants, lubricants, and the tablet and mixed powder are selected to study the drug-excipient compatibility. The results displayed starch, HPMC (E6), L-HPC, talc have better compatibility with drug, and preferably as the initial prescription.On the basis of the initial prescription, the prescription and technology factors to be screened and prepared into tablets. Prescription factors such as the amount of fillers, the disintegrats dosage, adhesives concentration and lubricant categories for drug dissolution were investigated. The results showed the amount of fillers and lubricants had no significant influence on drug dissolution; adhesives concentration was inversely proportional to the rate of drug dissolution, and had a greater impact on the wet granulation process. When the adhesives concentration was4%, the particle had good hardness and ideal proportion of dry material particles.Prescription proportion of4%disintegrating agent, had a fastest dissolution. For the lubricant such as magnesium stearate, talc, aerosil, magnesium stearate was selected. The process factors such as particle size of the drug, mode of tablet, the adding way of disintegrating agent and drying temperature were investigated.The results showed that the adding way of disintegrating agent has influence on drug dissolution. Taking into account the L-HPC having a certain degree of hygroscopicity, and inside and outside the prepared film dissolution was no significant difference, choose the disintegrating agent inside. Selecting drying temperature of60℃, the drying rate was fast, and improved production efficiency. On the drying process, drug was maintaining stable. The dissolution conditions were investigated SDS solution of different concentrations and different pH solution for the drug dissolution, selected O.lmol/mL solution of hydrochloric acid as the dissolution medium. According to the the best prescription process conditions selected above, GT0918tablets was prepared, specifications for25mg,100mg.The GT0918tablet quality research in terms of appearance, identification, content uniformity, weight variation, dissolution, related substances, conten and et al.were inspected. Batches of samples were light yellow film-coated tablets, remove the coating, the tablet cores appeared significantly brown. By UV spectrophotometry to identify each batch of samples, the results showed that each batch of samples had maximum absorption peak at228nm,268nm. The small size of the sample containing dosage is25mg, uniformity of content is needed to check with reference to Appendix X E of the2010edition of "Chinese Pharmacopoeia".the results showed that each batch of samples to meet the requirements. With reference to the "Chinese Pharmacopoeia"2010edition Appendix I A relevant provisions, respectively, checked the weight difference of all samples, large and small size of each batch of samples results were in line with the requirements. Studying GT0918tablet dissolution, the results of each batch of samples showed GT0918dissolution behavior uniformity. Each batch of samples0.5h could be completely dissolved, but the smaller size showed fast dissolution rate of the large-sized tablet.Establish the method of GT0918Related Compounds, and each batch of samples were detected, no impurities was detected in batches of samples.Guided from market and clinical needs, preformulation research, screening prescription and technology, preparation, quality of GT0918carried out the accumulation of data and technology.It is expected to become a tool for the treatment of prostate cancer, and bring new hope for patients with prostate cancer. |
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