As the new drug discovery is gaining momentum in the country, the Central Drug Research Institute (CDRI), Lucknow, with a host of new endeavours and world class facility, is realising its leadership position in the sector to give the right direction to the industry and other research organizations.
The CDRI, while continuing its efforts in the drug development studies, is also taking steps to create a world class drug research institute at a total cost of Rs 200 crore to cope up with the growth and expectations from the industry. The proposal for the research institute is in advanced stages of discussions with a series of meetings with the Central Government being held in time.
The new state-of-the-art drug research institute has been envisaged with a vision to discover and develop new chemical entities in disease areas of national priority and life-style and ageing related disorders. It would be located at the new premises and would have research and development laboratories conforming to the current and emerging international standards, apart from a flexible organisational structure comprising of only three major divisions - biological sciences, chemical sciences and pre-clinical sciences. Leadership positions at all levels will be merit based with an in-build stringent mechanism for assessment and monitoring of projects.
The new research facility would be used for conducting innovative research for discovery of new drugs and their mechanism of action. Dedicated to develop new drugs for controlling major diseases of national relevance and systematically explore the Indian flora and fauna for therapeutic potential, this proposed research institute would also develop human resource for future requirements of the pharmaceutical industry and R&D institutions.
With overall improvement in research quality and generating useful data on new leads and products under development, CDRI enjoyed yet another productive season in 2006-07. In the business development output area, the institute continued its open door policy by encouraging business cooperation with public and private players. CDRI has already signed several agreements.
"CDRI's timely efforts to consolidate its scientific and innovative capacities in the past few years have visibly improved the research quality and innovation capacity. While research quality is marked by increasing number of articles published in the prominent journals, large number of patents in India and abroad are indicative of CDRI's increased innovative strength. Improvement in innovation capacity has culminated into an impressive pipeline of products in development in not only those therapeutic areas, which CDRI is conventionally known for, but also new disease area like osteoporosis. The institute is also engaged in the development of various products, including anti-hyperglycemics, antidiabetics and antimalarials," said, Dr C M Gupta, director, CDRI.
"The industry has been particularly interested in CDRI's new leads and candidate drugs under development, including CDR-134F194, CDR-267F018, NP-1, S-002-853, S-002-857 and compound 99-411. The year witnessed cooperation with Ranbaxy, IPCA, Indigene Pharmaceutical and Satsanga Rasaishana Mandir. The institute outsourced facilities existing in a company for mechanism of action study of one of its products under development,'' he added. During the year, the institute attracted funding of Rs 1300 lakh and hence funding was never became a problem.
In the clinical studies area, the licensee firm Hindustan Latex conducted a product acceptability study on contraceptive cream at Chennai and Cochin and found that the product was acceptable and convenient.
"There is an ardent need to promote professionalism at all levels and quickly build up cohesive project teams by building trust and awarding those who make this effort. At CDRI, we have had one or more of these management related problems and aim to handle them far more effectively in the near future. Another front that we have failed is our ability to achieve quality certification for the major regulatory facilities, which is long overdue. Also, CDRI is seriously lagging behind in business development front. The current business activity principally relies on those approaching us instead of ourselves aggressively selling the projects, capacities and products in pipeline (or those ready on shelf) to potential national and international customers," said, Gupta.
He further added that though CDRI have had growing net-work projects within CSIR, under CDRI industry and others funded by national agencies, the national pharma companies need to be reaped in for larger collaborations. CDRI's existing projects with the industry include DST/DRF project on anticancer compound development and DST/IPCA project on new antimalarial compounds development. The existing opportunities in international collaboration through joint projects, such as those funded by various international agencies, need to be exploited,'' he added.
The drugs already developed and licensed by CDRI for marketing are Centchroman (a non-steroidal oral conceptive marketed by Hindustan Latex under the trade name of Saheli) and Centron by Torrent Pharmaceuticals. Also, Centbucridine, a local anaesthetic marketed by Themis Chemicals as Centoblock, Arteether, a blood schizontocidal antimalarial marketed by Themis Chemicals under the trade name of E-Mal, Bulaguin, an antirelapse anti-malarial marketed by Nicholas Piramal under the brand name of Aablaquin and Gugulipid, a hypolipidaemic, marketed by Cipla under the name of Guglip are other successful drugs developed by CDRI.
Out of the 12 drugs developed by the institute, 6 are in the markets, while six others could not be commercialized, though some private companies purchased them for marketing. It has so far filed for over 500 patents.
Apart, CDRI continued its multicentric efficacy studies on antimalarial drug Arteether in Dibrugarh, Rourkela, Jabalpur, Jodhpur and Guwahati, so far completing 234 cases and it has commenced compilation of data significant achievements. Capsules of the other antimalarial drug, compound 80/53, were sent to Thailand for safety evaluation in G6-PD deficient cases suffering from malaria. The findings reported by Thai researchers confirm efficacy and safety of compound 80/53. Besides, CDRI has initiated phase III multicentric clinical trials on compound 80/574 (hypolipidemic) at SGPGI and KGMU, Lucknow PGI, Chandigarh and Seth G.S. Medical College, Mumbai. These trials, besides pharmacokinetic studies are in progress.
Clinical studies to evaluate efficacy of Picroliv (hepatoprotective) in alcoholic cirrhosis and in tuberculosis patients on MDT have been carried out at three centres (Seth G.S Medical College, T.N. Medical College and KG.S Medical University). Exploratory double blind clinical trials, which were carried out on CT-1 (anti-diabetic) in a total of 55 patients, at KGMU, Lucknow, have been concluded. The findings reveal statistically significant reduction in total serum proteins, SGOT, SGPT in CT-1 treated patients.
Among other products under clinical studies, CDR-134D123 (antihyperglycemic) has completed phase I single dose double blind studies in healthy volunteers, apart from developing protocols for phase I studies on compound 97/78 (antimalarial), as per GCP guidelines.
Regulatory toxicity studies were carried out on in house products and outside products, besides some basic and applied toxicity studies. CDRI products 99/411, 97/78, herbal medicament, CDR-267F018, CDR-134F194 were evaluated for generating their safety profiles. Industry sponsored products were evaluated under contract research.
Experimental studies carried out by CDRI comprise of hepatotoxic effects of isoniazid with special reference to oxidative stress and apoptosis using hepatoma cell line (Hep-G2), nephrotoxic effects of cisplatin, amphotericin B and gentamycin by using renal cortical slices, primary cell cultures and renal cell lines. And teratogenicity potential of cyclophosphamide and synthetic compounds were carried out by measuring biochemical changes in an in vitro system.
CDRI also carried out pharmacokinetic evaluations (PK) on three candidate drugs - 97/78 (antimalarial), S-002-853 (antidiabetic) and 99-373 (anti-osteoporotic). Multiple dose PK studies on compound 97/78 and its metabolite in rhesus monkeys revealed insignificant plasma accumulation. Further, metabolite stability and CYP profile suggest involvement of CYP3A4 in its metabolism. Tissue distribution profile of compound 99/373 and its two major metabolites in rat liver, lung, spleen and kidney has been established.
Its urinary excretion studies have revealed excretion of the compound and its metabolite in conjugated form. Plasma pharmacokinetic studies of antidiabetic compound S-002-853 are in progress. Active S-isomer of this compound showed good systemic exposure with long elimination half-life.
Efforts have been made to develop appropriate technologies - chemical, fermentation and pharmaceutical - for institute. Candidate drugs, sponsored products and several other products have been produced in required quantities in order to allow further studies. An improved process of simvastatin with lesser number of steps, which also allows reactant recovery and recycling, has been developed at bench scale. A 5-step improved process for the synthesis of sertraline hydrochloride developed at bench scale avoids the use of hazardous titanium tetrachloride.
CDRI is also engaged in quality control and stability studies on several candidate drugs, besides using HPLC methods for proper resolution of starting materials and for separation of chiral preparation. Efforts for the development of novel delivery systems have led to progress on several fronts: preparation of nanometer emulsion for albendazole, studies on new formulation of inhalable biodegradable microparticles containing antitubercular drugs and surfactant vesicles containing cyclosporin.
During the year, CDRI has collected and documented 21 new terrestrial plants and 12 new marine flora and fauna samples. The institute also prepared 1749 new synthetic molecules. The compounds and extracts were evaluated for various primary and follow up biological screenings under different disease oriented research programs.