PharmaDiall

Results of work

Since the beginning of 2008, we have been developing an innovative anticoagulant drug at our own expense. In the process of this activity, we have achieved the following results:

  • New, patent-pure classes of chemical compounds, direct inhibitors of the factor Xa have been developed.
  • About 30 synthesized compounds were tested in vitro for biological activity against factor Xa. Activity of some synthesized compounds have proved to be at the level of the best known world analogues.
  • The most important indicator of hemostasis, the concentration of compound DD217, which doubles the prothrombin time on human plasma, is 100 nM, which is the best result among known inhibitors according to available literature data.
  • The project of manufacturer’s pharmacopoeial monograph, an experimental industrial procedure for production of DD217 substance was developed. The substance stability was studied.
  • Tablets containing DD217 in dosage of 10 mg, were developed in the amount necessary for conduction of the 1st phase clinical trials.
  • Trials on DD217 genetic toxicology were conducted in three tests and reports on them were received.
  • Trials on DD217 acute toxicity were conducted on mice and rats, two routes of administration, males and females separately, and reports on them were received. We have produced MPD, LD16, LD50, LD84. The Lim cumulation was studied.
  • Metabolism of DD217 on human liver microsomes in vitro was studied.
  • Cell permeability of the DD217 substance on the Caco-2 model was studied.
  • As a result of testing of 9 variants of tablets containing DD217 on animals (rats, rabbits, primates), the FDF (Finisched Dosage Form)composition was selected for further trials according to several parameters.
  • The experimental-industrial regulations for the dosage form being developed were written, the stability was studied.
  • Pharmacodynamic activity of the DD217 substance and the FDF containing the DD217 substance was studied, which has shown through the example of rats and monkeys and using rat, monkey and human blood plasma, the effectiveness of the DD217 substance and the DD217 substance FDF for prevention of thrombus formation, and the estimated therapeutic dose for conducting of clinical trials was determined.
  • Chronic toxicity of DD217 substance was studied (3 doses of the substance daily for 6 months, orally, rats and rabbits, males and females separately), as a result of which it was shown that the administration of DD217 substance in a double therapeutic dose did not cause physiological and functional changes in the body of female and male rats and rabbits with multiple administration of the substance being tested.
  • Immunotoxicity of the DD217 substance was studied. As a result of the immunotoxicity study, it was found that intragastric administration of the drug being studied to rats in doses of 10 mg/kg and 100 mg/kg did not lead to an increase in inflammatory reaction development by stimulating the cellular element of the immune response. The reaction index of the test groups did not differ significantly from control values.
  • Allergenicity of the DD217 substance was studied. It was found that the administration of the drug being studied in doses of 3.0 mg/kg and 15 mg/kg to male guinea pigs did not cause a significant increase in sensitivity of the organism (sensitization) with the course (30-day) intragastric administration of the drug.
  • Generative (reproductive) toxicity of the DD217 substance was studied. It was shown that intragastric administration of the drug in doses of 3.5 mg/kg and 35 mg/kg did not have a negative effect on the reproductive function of female and male rats. It was also shown that the DD217 substance did not have a significant negative effect on parameters of the physiological development of the offspring of experimental groups within 40 days after birth.
  • Pharmacokinetics of the DD217 substance was studied. The study of pharmacokinetics was carried out in rats - after single intragastric administration of DD217 in several doses, rabbits after single intravenous administration and intragastric administration, rabbits after repeated daily intragastric administration of the substance and monkeys after a single intravenous administration of the substance in dosage of 3 mg/kg and oral administration of FDF (Finisched Dosage Form) (tablets containing DD217) in doses of 3 and 6 mg/kg of active substance.
  • The tissue distribution of DD217 substance was studied, as a result of which it was found that DD217 substances after single intragastric administration to rats in dosage of 30 mg/kg are distributed over practically all organs and tissues.
  • A protocol for carrying out of the 1st phase of clinical trials (CT) was developed.
  • The permission (No.843 dated December 7, 2016) of regulatory bodies of the Russian Federation for conducting of the 1st phase of the CT was obtained.
  • The 1st phase of CT was started on healthy volunteers (the first dosing was performed in the end of January 2017).
  • An interim report of the Chief investigator on results of CT in the 1st and 2nd group of healthy volunteers was received.