NIFARMA'98 SA - COMPANY PROFILE



The Shareholder Association NIFARMA΄98 was established in the early 1998 by a group of specialists, who had worked for many years in the field of the pharmaceutical science and pharmaceutical technology, as heads of the main departments in the Chemical Pharmaceutical Research Institute (NIHFI) – Sofia, part of the former Pharmachim structure.

NIFARMA employs leading specialists in the field of:

• bioavailability studies;

• quality control of drug substances and final products;

• development of technologies and technological and chemical pharmaceutical documentation for manufacture and registration of dosage forms;

• GMP;

• standardization and registration of drug substances and final products;

• synthesis of active substances, isolation and purification of natural products;

Main activities of the company:

• Preparation of DMFs and registration of dosage forms and substances in the country and abroad;

• Development of technologies and technological documentation for manufacture of drug substances and dosage forms and introducing the above technologies in production of the ordering or purchasing company;

• Development of validated methods of quality control of drug substances and final products;

• Quantitation of drug substances in biological liquids for evaluation of bioavailability/bioequivalence;

• Training pharmaceutical companies’ staff in the requirements of GMP of WHO and EC.

This activity includes also performance of GMP audits, as well as consultant services in the introduction of GMP rules in the pharmaceutical manufacturing companies.

For its nine years existing in NIFARMA are developed for Bulgarian and foreign companies manufacture technologies for more than ten generic and several new dosage forms.

There are prepared and submitted for registration in Bulgaria more than 25 DMFs including these for foreign companies. For all of the submitted documentations, drugs approvals for manufacture and sale are already obtained.

There are prepared more than 20 DMFs for registration in other countries for Bulgarian and foreign companies and most of them are already approved.

More than 60 bioequivalence studies on dosage forms owned by Bulgarian and foreign companies are performed. There are no objections received till now from Bulgaria or another country concerning the studies carried out.

The company possesses:

• Laboratory for dosage forms

The laboratory has available all necessary equipment for development, characterization and creation of dosage forms – tablets, sustained release tablets and coated tablets, and checking the technologies in pilot plant scale.

Head of the laboratory is Prof. Mag. Pharm. Evtimia Velikova

• Bioavailability/bioequivalence Testing Laboratory

The laboratory is accredited to perform testing of finished pharmaceutical products for bioavailability/ bioequivalence by quantitative determination of drugs concentration in biological liquids according to BDS EN ISO/IEC 17025:2006

Head of the laboratory is Assoc. Prof. Dr. Nadezhda Tyutyulkova Medical Dr.

• Laboratory for analysis of drug substances and dosage forms

The laboratory possesses up-date equipment for analysis of drug substances and dosage forms and has contracts with many Bulgarian pharmaceutical companies for analytical control on their final production.

Head of the laboratory and QA is Assoc. Prof. Dr. Eng. Rumen Vodenicharov

• Bureau for preparation of technological documentation and DMFs for registration in the country and abroad

Head of the bureau is Res. Fellow Eng. Kina Konstantinava

The company works in laboratories on the territory of Bulgarian Academy of Sciences (BAN).

Chairman of the Board and Executive Director of The Shareholder Association NIFARMA΄98 is Assoc. Prof. Dr. Eng. Kiril Ninov

For correspondence and contacts:

1113 Sofia, Akad. G. Bonchev str., Bl.108, Complex BAN, BULGARIA

Tel: +359 2 870 5213; +359 2 870 4132; Tel/Fax +359 2 870 3501

E-mail: nifarma98sa@mbox.contact.bg

A NEW DRUG WITH HIGH POTENCY FOR TREATMENT OF TYPICAL AND ATYPICAL (IN IMMUNOCOMPROMISED PATIENTS), SENSITIVE AND MULTIDRUG RESISTANT TUBERCULOSIS.

3-(4-cinnamyl-1-piperazinyl)-imino-methyl rifamycin SV, Sodium salt - (T-11, Rifalong)

1. Chemical structure

The new product named Rifalong is member of the group of derivatives of 3-formyl-rifamicine SV.

Chemical Structure:

Chemical name: 3-(4-cinnamyl-1-piperazinyl)-imino-methyl rifamycin SV, Sodium salt

CAS [277001-57-0]

2. Patent protection

The new chemical entity is patent protected in USA, Europe (all countries member of EC), Russia, India and Brazil.

3. Investigation made till now:

- Anti-mycobacterium activity in vitro and in vivo.

- Antibacterial activity in vitro (aerobe and anaerobe bacteria)

- Patho-morphological study on generalized tuberculosis in rats and guinea pigs with and without treatment by T11.

- Pharmacokinetics of T11 in experimental animals.

-Toxicological studies – acute toxicity (LD 50), chronic toxicity on 3-(4-cinnamyl-1-iminomethyl ) piperazinyl rifamycin SV.

- Influence of 3-(4-cinnamyl-1-iminomethyl) piperazinyl rifamycin SV on drug metabolizing enzyme systems (DMES) in rats.

- Experimental study on the anti-inflammatory action of 3-(4-cinnamyl-1-iminomethyl) piperazinyl rifamycin SV

- Neuro-pharmacological study of 3-(4-cinnamyl-1-iminomethyl ) piperazinyl rifamycin SV

- Antimicrobial activities against mycobacterium tuberculosis and mycobacterium avium complex

- Pharmacokinetics of cinnamyl rifamicin derivative in mice

- Pharmacokinetics of cinnamyl rifamicin derivative in rat and rabbits

- Clinical study “Open examination of effectiveness and tolerability of Rifacinna capsules 150 mg and 300 mg, in treatment of pulmonary tuberculosis”, (Phase II)

- DMF of a new drug substance is prepared.

4. The main characteristics of the drug:

- Extremely high in vitro activity against clinical isolated strains of gram-positive and gram-negative (aerobic and anaerobic) pathogens and tuberculosis mycobacterium including MAC and Mycobacterium Leprae.

- High in vitro and high intraphagocytic activity against MAC strains.

- Higher and more rapid therapeutic efficacy in vivo in generalized experimental tuberculosis in mice and guinea pigs.

- Lower hepato-toxicity of T-11 compared to Rifampicin;

- Lower immunosuppressive effect than Rifampicin.

- Higher activity against intracellular developing infections (Listeria monocytogenes and Mycobacterium Avium), higher than Rifampicin and Rifapentine and equal with than of Rifabutin.

- No teratogenetic and embryo toxic effect in experimental animals.

- Excellent pharmacokinetic profile – rapid and complete absorption after oral administration, high and most prolonged serum concentrations following single oral dose of 10 mg/kg (with Tmax 6-8 h, Cmax 7-8 (g/ml, and plasma T1/2 31 h) compare other Rifamycin antituberculous agents like Rifampicin, Rifapentine, Rifabutin.

- Bactericidal activity against MDR-strains of Mycobacterium TBCc (t. humans and MAC-strains isolated from AIDS patients) comparable to activity of Rifampicin and Rifabutin.

- Prominent anti-inphlammatory effect and absence of ulcerogenic activity.

- Lower activation (5 times) of the liver drug-metabolising enzyme systems compared to Rifampicin.

- EXCELLENT CLINICAL EFFICACY OF RIFACINNA® IN TUBERCULOUS PATIENTS WITH PULMONARY TUBERCULOSIS CAUSED EITHER SENSITIVE OR MDR STRAINS OF MYCOBACTERIA.

- Excellent tolerability and safety profile of RIFACINNA® in tuberculous patients treated with 10 mg/kg daily dose tree time weekly.

- Most convenient dosage regiment of RIFACINNA® compare Rifampicin and Rifabutin-

- BEST COST EFFECTIVE COURSE OF TREATMENT.

- Additionally – excellent anti-Lepra activity (Prof. A.Dople)

5. The data of efficacy of T-11, resp. Rifacinna® was established in:

- Mycobacterium Department of Illinois University, Chicago, USA; (Prof. Gandgaharam, Assoc. Prof. V. Dimova).

- Microbiological and Immunological Institute, Shimane Medical University-Japan (Prof. Haruaki Tomioka, Assoc. Prof. V.Dimova)

- Chemical Pharmaceutical Research Institute- Sofia, Bulgaria (Assoc. Prof. V.Dimova)

- Medical University- Institute of Pulmology and Tuberculosis- Sofia, Bulgaria (Prof. Radanov, Prof. Dobrev, Assoc. Prof. V.Dimova)

- National Centre of Infectious and Parasitic Diseases- Sofia, Bulgaria (Prof. G. Gencheva, Assoc. Prof. E. Sapundjieva, Assoc. Prof. T. Kantardjiev, Assoc. Prof. V.Dimova)

- Technical University – Melburn, Florida, USA (Prof. A. Dople, Assoc. Prof. V.Dimova)

- Department of Microbiology and Immunology, Haruaki Tomioka and Katsumasa Sato, Shimane University School of Medicine, Izumo, Shimane 693-8501, Japan

- Academy of Medical Sciences of Ukraine, Institute for phtisiatry and pulmonology “ F. G. Yanovski” of the AMSc of Ukraina (IFP)( Academic Feshchenko, Prof. Dr. L. O. Yashina, Assoc. Prof. A. M. Tumanov)

6. Medicinal product formulations:

RIFACINNA® – Capsules 150mg and 300mg.

RIFACINNA® Capsule 150mg - contains 150 mg Rifalong (Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-imino-methyl rifamycin SV)

RIFACINNA® Capsule 300 mg - contains 300 mg Rifalong (Sodium salt of 3-(4-cinnamyl-1-piperazinyl)-imino-methyl rifamycin SV)

7. To finalize the investigation and to prepare the documentation necessary for registration we have to do:

- Bioavailability study in healthy volunteers (Phase I)

- Clinical study of the new medicinal product

8. What we are looking for:

We are looking for financial support to finalize the Rifalong investigations:

First step will be the bioavailability study of the product in healthy volunteers (Phase I).

If we do such a study in Bulgaria we will save money, as the bioavailability studies here are cheaper than abroad. For this purpose we need about 100 000 euro.

Next step will be the clinical examination (in Bulgaria too, by the same reason) in treatment of pulmonary tuberculosis, (Phase II).

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