The Studies On Quality Standard Of The Innovative Drug IMMH002

IMMH002, a selective S1P receptor agonist which is developed by a research group of Institute of Materia Medica of Chinese Academy of Medical Sciences, can selectively excite S1P1 receptor subtypes, while show a weak activity for exciting S1P3 receptor subtypes and less side effects on the heart; and its short half-life lead to more efficient and rapid reversible inhibition for lymphocytes exhibit transport. As a new structural and highly selective S1P1 receptor agonist, IMMH002 has applied for a domestic patent application and an international PCT patent. The clinical indications of IMMH002 was located treating psoriasis.Therefore, this paper carried out the systematic study of quality standard of the raw material for the new immunosuppressant drug IMMH002. Firstly, the characters of IMMH002 were studied in detail. According to the 2010 edition of the Pharmacopoeia of the People’s Republic of China, the appearance, solubility, melting point, hygroscopicity and absorption coefficient were detected. The results showed that, IMMH002 is a white powder; no wet primer; no rotation; it is sparingly soluble in methanol; slightly soluble in ethanol; very slightly soluble in water, 0.1mol/L HCl; insoluble or practically insoluble in methylene chloride, acetone, ethyl acetate, chloroform and 0.1mol/L NaOH; its melting point is 228℃～230℃; absorption coefficient is 865.6. According to the characteristics of IMMH002, chemical, spectroscopy and chromatography analysis by various principles were carried out to identify IMMH002.According to the production process, the IMMH002 related impurities checks were carried out. For inorganic impurities such as sulfates, residue on ignition, heavy metals, arsenic salts, were examined according to the 2010 edition of the the Pharmacopoeia of the People’s Republic of China. According to the production process of IMMH002, this product may exist residual solvent such as ethanol, methanol, dichloromethane and acetonitrile. We establish a GC method for the determination of residual solvent and method validation was carried out, the results showed, methanol, ethanol, acetonitrile and methylene chloride solvent residues did not exceed the limit in Pharmacopoeia. For related substances, gradient HPLC method was established, main components and related substances can be completely separated by the selecting and optimizing of the column, the column temperature, flow rate, mobile phase and mobile phase gradient, HPLC conditions were finalized:C8 column; column temperature was 40℃; the flow rate was 1.0mL/min; acetonitrile -0.2% sodium acetate buffer (pH3.6) as mobile phase; detection wavelength was 283nm. The results showed that, the total related substances of IMMH002 is less than 1.0%, the content of individual impurities is less than 0.4% respectively. The determination of the drug content also used high performance liquid chromatography(HPLC) based on the related substances’ analytical method and its methodology has been verified, the content of three batches of bulk drug were:99.0%, 99.5%,99.8%.The established quality standards can control the quality of IMMH002 well, and ensure the efficacy and safety of MMH002.