Discovery and development of drugs from natural sources

E. NJAU

Tanzania Pharmaceutical Industries Ltd
P. O. Box 7063 Arusha, Tanzania

Introduction

Half a century ago, there were relatively few useful drugs available. However, today there are nearly 1400 drugs in use which are derived from both natural and synthetic resources. Most countries, especially those in the tropics, are endowed with a wealth of natural (often herbal) products as well as inorganic materials which have been explored, and to a lesser extent exploited through the years. During the 19th Century, systematic evaluation of herbal remedies involved the establishment of active substances within these drugs, identification of the properties responsible for their actions, and subsequent synthesis of drugs which were more effective. During this period only as little as 5% or less, of all new molecules isolated were found to be of use as therapeutic agents. Seeking to establish the relationship between structure and activity, eminent scientists of the 19th and 20th centuries including Pasteur, Koch, Lister, Ehrlich, Domagk, Dale, Fleming and others made outstanding contributions to the advancement of knowledge in chemical and biological sciences, which have had remarkable influence on public health.

It is a popularly held opinion that most of these herbal products should be put into use in developing countries to reduce the much needed foreign currency now incurred on imported pharmaceutical products. If this opinion finds general acceptance, one does not see why anyone should go into trouble and expense to discover and develop new drugs. The major reasons for the development of new drugs today include the desire to satisfy intellectual curiosity; the need to improve on the efficacy of existing substances; an effort to control new diseases, e.g. AIDS; and the need to fight drug resistance (mostly antibiotics).

The search for products from natural sources has to go a long way towards meeting such objective goals.

The importance of products from natural sources

Naturally occurring substances form a significant base of raw materials for the chemical and pharmaceutical industry as well as for the cosmetic and food industry. They are a starting point for a series of pharmaceutical products with specific therapeutic efforts, various volatile oils and other products used in cosmetics and skin care products. Aromatic plants are often processed into various extracts used in the alcoholic and soft drink industry and in production of consumer goods such as tea (simple or compound products), spices, syrups, tablets and dry extracts. In countries with developed chemical and pharmaceutical industries, the production of products of natural origin is gaining more and more importance year after year.

Discovery and development

Cardiac glycosides from some Digitalis species are almost certainly the only major discovery of the 18th Century, followed later by morphine from Papaver somniferum, quinine from Cinchona species, atropine from Belladonnae species, papaverine from the family Papaveraceae and cocaine from the Coca plant, Erythroxylon coca, which were isolated from crude drugs (Serturner, 1805 and 1817, Pelletier, et al, 1833, Merck, 1848, Wohler, 1860 and Bowman, 1979). By the end of the 19th Century there were only about 20 useful drugs listed in the first few editions of the British Pharmacopoeia (Bowman, 1979). Indeed most of the molecules isolated were found to be of little or no use as therapeutic agents, and this aroused interest in scientists to look for the relationship between structure and activity. The work of eminent scientists such as Pasteur, Koch, Lister, Ehrlich, Domagk, Dale, Fleming and others during the 19th and 20th centuries resulted in advances which had an impact on public health (Weatherall, 1986).

It is quite obvious that the most important drugs in use today have been developed from natural sources. While we continue with the search and introduction of more drugs from plant sources today, the systematic appraisal of herbal remedies was epitomised by the 19th Century pharmacologist, Rudolph Bucheim, who wrote: "The mission of pharmacology is to establish the active substances within these drugs, to find the properties responsible for their action and to prepare synthetically drugs which are more effective (Bucheim, 1876)." Today we are just as far away from achieving this goal as we were in the last century.

The design of modern drugs has, today, reached a state of sophistication where some of the physical parameters can be predicted by use of computer graphics. However, this has not so far permitted prediction of biological activity of a drug from its chemical structure. So most drugs, whether derived from natural sources, or prepared synthetically, are developed the same way.

Figure 1 shows some of the important scientific operations involved in drug discovery and development. The important stage here is that of identification of "lead compounds", i.e. those with biological activities which are interesting. Essentially, random screening of large numbers of herbs and chemicals is time consuming, expensive and rather wasteful although often there are no short cuts to arrive at a "lead compound".

Constraints of new product development

(i) Approximately 10,000 candidate compounds have to be screened to afford one new chemical entity marketable as a therapeutic agent. This takes about ten years for the work to be completed.

(ii) Financial investment for such a task is of the order of 100 - 200 million US dollars for research and development only.

(iii) The commercial risk involved here is that a new product enters a competitive market and has the task of having to establish an adequate earnings level.

(iv) Development of a new product stands the risk of being affected at any time by regulatory intervention or by parent life erosion.

These constraints do apply to the development and introduction of traditional medicinal products although, I would say, the financial risk is not of the same order of magnitude.

Figure 1: Programme of drug discovery and development

Patent protection of pharmaceutical products

The maximum duration possible for a patent is laid down by the laws of each country, and lies between 10 years (e.g. Peru and Venezuela) and 20 years (e.g. Belgium and France). The differences between countries are also increased in that the duration of the patent sometimes begins with the filing date (Germany and Switzerland); sometimes with the laying open to public inspection (Japan and Yugoslavia); sometimes with the granting date (USA and Canada), and also in that many places the duration of protection begins later than the duration of the patent. Extension of duration may be obtained on request in certain circumstances, e.g., in the U.K. and Australia.

Yearly fees have to be paid to maintain the patents in force (except in USA and Canada) and the amounts vary from about 20 to 1000 US dollars.

Pharmaceutical products have special patent regulations in many countries. The motives, therefore, are frequently felt to be justified by national expediency and/or social conditions. These can go so far that pharmaceutical products and even processes for the production thereof are denied patent protection, e.g. in Italy. Another means for the erosion of patent protection in this sector is the too great use made of compulsory licenses, for which often an application without any supporting ground is simply insufficient. Great Britain and countries having similar laws and practice, such as Canada, India, etc. are to be noted for this. The granting of a license is at the "discretion" of the competent authority. Opposition to the granting of such licenses, however, at most only delays the granting of a license and is generally never able to prevent it.

In most countries no patent can be obtained for the protection of the pharmaceutical use of a substance because the application of medicaments to the human body is not a technical procedure, i.e., it is not a "new invention which can be put to commercial use" (in the sense of Art. 1 of the patent law), but it is a procedure of medical art. Such patents are granted in principle in some countries such as the USA and France.

The protection of natural products or products of nature can be quite difficult. Only when you have definite controlled processes for arriving at the end products, as is apparent in genetic engineering, can such products withstand scrutiny with respect to novelty, technical progress, and also unobviousness. Where the products are achieved as a result of established extraction procedures the protection of the substances per se, or of the process, may be difficult. Our chances of protection of our traditional medicinal products with existing legislation, seem rather remote.

References

Bowman, W.C. (1979). Scot. Med., 24: 131.

Bucheim, R. (1876). Arch. Expl. Pathol. Pharmakol., 5: 261.

Geiger, P. L. and Hesse, O. (1833). Ann. Chim., 5: 43 and 1833: Ann. Chim., 6: 44 and 7: 269.

Merck, G. (1848). Ann. Chim, 66: 125.

Pelletier, J., and Caventou, E. (1820). Ann. Chim. Phys, (2) 15: 291 and 337.

Poitent, P. J. (1967). The role of industrial Property in the Economic Development of States, Zurich.

Serturner, F. W. A. (1805). J. Pharm. Arzte, 13: 29 Ann. Phys. 55: 36.

Weatherall, M. (1986). Pharmaceut. J., 237: 634.

Wohler, F. (1860). Ann. Chim. 114: 213.