Figure1. Export of some herbal drugs from Macedonia in a period from 1993-1999.
A lot of medicinal plants have been collected for a long time in Macedonia and used in healing of various diseases or in disease protecting. Nowadays, the usage of medicinal herb is based on scientific foundations. Much more attention is paid on quality of herbal drugs and their products. In this paper some important aspects of Macedonian medicinal and aromatic plants such as collecting, cultivating, manufacturing and quality control have been discussed. Collecting of medicinal plants from natural resources is the main approach of providing herbal drugs. Cultivating of medicinal plants does not represent remarkable commercial branch in the state, with an exception of cultivation of Papaver somniferum. Business orientation of enterprises that trade herbal drugs is export. Manufacturing of medicinal plants means mainly production of teas for every day use and medicinal teas, and secondary other products on herbal basis. Import of teas and phytopharmacetucals is relatively on low level. Low regulation in the state defines all products on herbal basis as adjuvant medicinal products. Their therapeutical efficiency should not be scientifically proved but their quality has to be controlled.
The usage of medicinal plants in Macedonia has its origins far in the past, although there are no sure written documents about it. After the Ottoman conquest of Macedonia, people were deprived of any medicinal help. During that period, too long for Macedonia, one of the most important things was the influence of the churches and monasteries, where many Arabic medicinal books could be found, translated into Macedonian. These books contain many formulations for home made remedies, usually prepared from medicinal plants. Those experiences are preserved even today and the development of technology, pharmacology and medicine increased the number of ways for usage of medicinal plants. Today we can speak about use of medicinal plants based on scientific foundation. In this review regarding medicinal and aromatic plants in Republic of Macedonia, special attention will be paid to some important aspects such as collecting, cultivating, manufacturing and quality control of herbal drugs and their products.
Collecting of plants
Climate condition, specific geographical position and relief, influent presence of a great number of medicinal plants in Macedonian flora. The species of Lamiaceae and Asteraceae, then Apiaceae, Poaceae, Ranunculaceae, Scrofulariaceae, etc, are very characteristic. They dominate with their occurrence and spreading in the hills and mountain meadows. The presence of some Ericaceae and Rosaceae species makes the flora even more interesting from the aspect of possibility of collecting forest fruits. The traditional way of collecting medicinal plants is the most important way of providing herbal raw materials in Macedonia. Organized collecting from natural resources is present for a long time and the skills of persons who are engaged in collecting are very important for the success and quality of this work. Organized collecting of medicinal plants means providing of many other factors - planning and rational use of natural resources, providing of buildings for drying, packing and storing of the raw materials, providing money for repurchasing of the raw materials and many other factors. Regarding these factors it can be said that there are only few companies in Republic of Macedonia which fulfill those conditions and are regarded as serious and important in this business.
The most important pharmaceutical company which repurchase medicinal and aromatic plants in Macedonia is "Alkaloid" from Skopje, separated Profit Center named as "Botanicals". The list of herbal drugs repurchased by this Profit Center includes about 100 different medicinal plants. Most of them are herbs (20%), than leaves (25%) and flowers (12%) and smaller percentages of other kinds of drugs. According to the chemical composition of the main active components the most important are aromatic plants which constitute 30% from the whole amount of drugs then glycoside containing plant materials, especially drugs which contain flavonoids and kumarins and less those with antrahinones and amara glycosides, which constitute about 17% in total; about 9% are herbal drugs containing saponins; about 9% are tannins drugs; a great percentage goes to the vitamin herbal drugs which include the forest fruits (12% in total); mucilaginous drugs 6% and alkaloid containing drugs only 3%.
The repurchasing of raw plant materials by Alkaloid Profit Center Botanicals takes place in the 8 cities in the state: Skopje, Kičevo, Bitola, Struga, Veles, Kočani, Berovo and Kumanovo. The network of purchase units organized by this company for local collection of the herbal row materials is the link that provide "a continued life cycle" of the herbs collected within the indispensable requirements of modern civilization. In this field, it is very important to emphasize that Alkaloid from Skopje won the Certificate for management with the natural environment ISO 14001. Preparations and winning of this certificate have been lasting for a long time and they included education by foreign lecturers of the special services for introduction of the standard and management education of the workers, direction of relevant life aspect following of the latter analyzing, making program for ruling of the natural environment and putting that Standard into use.
Since 1998 Profit Center Botanicals possesses Certificate for system of quality production ISO 9001. Obtaining of ISO 14001 shows the orientation of this very important pharmaceutical company in Macedonia for contemporary internationally accepted way of work turned into use. This pharmaceutical company is the first and unique possessor of the Certificate for organic origin and organic production not only in Republic of Macedonia, but widely at the region. The Certificate is given by the International organization for control methods of organic production and officially registered organization. This Organization is Dutch part of IFOAM (International Foundation for Organic Agriculture Manufacture). The certificates are issued following an international audit conducted in accordance with the European Union directives. Winning of the Certificate for management with the natural environment depends on 3 kinds of control: production, products and areas where the herbal drugs are collected. Herbal drugs from Macedonian origin are considered as organic i.e. ecological products with a green ECO mark, which denotes that those materials were collected from soil untreated with herbicides, pesticides, fertilizers and other artificial agents. The list of the certificated medicinal plants includes 40 different herbal drugs such as: Chamomillae flos, Herniariae herba, Hyperici herba, Equiseti herba, Juniperi fructus, Lichen quercus, Milefolii herba, Verbasci flos, etc.
The repurchasing and trade of medicinal plants take place in more than hundred other smaller or bigger manufactures in the state also. The capacities of these manufactures are very different and much smaller. The work orientation also differs. Some of them pay much into the work force and the high level of professionality in the work but most of them are insufficient in appropriate educated professionals. It must be mentioned that the specific economic and social situation in Macedonia made possible appearance of many smaller enterprises, which count on easy profit by trade of plants. It is not rare that these enterprises trade with only one plant, which is very good, paid on the market at the moment and sometimes that is a cause for extinction of the natural populations. The problem is very serious because the collected material is not qualitative, the natural resources are destroyed and the possibility of the bigger companies for planned and organized collecting these plants is lowered. All these problems make the general situation of collecting medicinal plants sometimes very difficult.
Cultivation and drug production
Cultivating of medical plants does not represent a remarkable commercial branch in Republic of Macedonia. Actually, organized and planned cultivation on big areas does not exist. Some efforts have been done in scene of introducing medicinal or aromatic plants into culture. The results show complicated way of doing that. According to specialists in this field, climate and pedological conditions for cultivation are very good almost excellent. In spite of this, in the past, on the plantations in East Macedonia, only few plants were cultivated such as: Coriandrum sativum, Foeniculum vulgare, Mentha piperita, Malva silvestris, Melissa officinalis, Thymus vulgaris, Salvia officinalis, Satureja hortensis, Chamomilla recucita and Ocimum baslicum. Today cultivation of all these plants in Macedonia is past. Plantations in East Macedonia were abandoned and production of medicinal plants is evaluated as unsuccessful. It was considered, cultivation conditions exist, but lack of specialists in this field and lack of financial support for prolonging drugs production are factor number one for a bad situation. Very simply, organized cultivating of medicinal plants is evaluated as very expensive investment, from all points of view. Therefore as simpler, faster and cheaper is accepted obtaining of raw material by traditional approach by collecting from nature. Shortage in supply of some herbal drugs is provided by import.
In 80's production of Papaver bractetum, perennial poppy with big amounts of tebain started. The plan was this plant to be the main biological resource of tebain supplying, basic substance for morphine and codeine production. The results did not approve expectations.
The most important cultivated plant in Macedonia is opium poppy (Papaversomniferum), which is being planted for over 100 years. Numbers of varieties are being planted in addition to own developed types. The planting is being followed by compulsory takeover of the complete crop what is managed by pharmaceutical industry, actually Alkaloid from Skopje. In accordance to the regulations poppy is being planted for the purpose of extraction of morphine and other opium alkaloids and is being used exclusively for poppy straw or dry capsule. Production of opium is forbidden. The poppy seed as a secondary product is obtaining and is being exported in large quantities.
Today, beside big pharmaceutical companies some smaller enterprises appear, organized through the contracts with individual farmers. They supply them with saw material and seeds and are obligated to buy all their herbal production. This kind of cultivation is just being born and in this way some quantities of mint, chamomile, balm and other drugs are supplied. There is a big interesting in cultivating of St. John's wort, valerian, lavender, and there are some preparations for starting.
Export and import of herbal drugs
Business orientation of big pharmaceutical companies and smaller manufactures is drug export. Macedonia successfully export herbal drugs in Germany (50% of all export), in France, Belgium, Italy, Switzerland, Spain, Austria etc., and partly in USA. The most important herbal drugs for export are Matricariae flos, Tiliae flos, Althaeae radix, Gentianae radix and Lichen Quercus. The export of these herbal drugs is presented in Fig.1. On the other hand, Macedonia imports large amounts of Menthae piperitae folium and Glycyrrhizae radix. Variably, Macedonia imports Capita papaveris, fulfilling the lack of this drug if self-production show low recovery.
Manufacturing of medicinal plants
The largest pharmaceutical industry for manufacturing medicinal herbs in the Republic of Macedonia is the Profit Center "Botanicals", within the framework of "Alkaloid" from Skopje. As it was previously mentioned, the production in this center has been certified by ISO 9001/96. The Center deals with gross sale of herbal drugs and their processing into individual raw materials, single-component and multi-component teas for every-day use, and medicinal teas. The sale of herbal drugs and the production of teas are at the same time the most substantial activities of the Center. The center also deals with production of certain adjuvant medicinals.
Regarding drugs manufacturing and production of teas in this Profit Center, more than 100 drugs are packed as individual herbal drugs and are distributed on the market via specialized pharmacies for selling herbal drugs. The assortment of teas for every-day use is wide indeed and consists of approximately 20 different kinds, including refreshment teas also. Medicinal teas are mixtures of a number of drugs prepared according to a certain prescription intended for treatment of various indications. The Center produces 24 such mixtures. These are tea mixtures for respiratory infection treatment, for blood circulation improvement, lowering the high blood pressure, upgrading of the kidney function, uroantiseptic tea, sedative tea, etc. Overall, the Profit Center Botanicals manufacture about 50 different teas.
Apart from Alkaloid, there are other smaller enterprises for tea production, but their products are solely meant for wide and every-day consumption like the teas of mint, linden, chamomile, etc.
The enterprises that deal with production of adjuvant medicinal products on herbal basis are Alkaloid from Skopje and three other (Galafarm, Fitofarm, and Gradski Apteki, all from Skopje). The palette of products is modest including about 30 products. Ten of them are tinctures, and the rest are syrups, extracts, creams and gels, and powders. It is interesting that some of the products are comprised by the production program of a few producers, so nearly all of them produce Primulae sirupus compositus, Olem Hyperici, T-ra Valerinae, etc. Hence, the variety of products of domestic origin reduces to about 15 really different products.
Since 1990 a lot of adjuvant medical products (different phytopharmaceuticals) are importing chiefly from Slovenia, less from Yugoslavia, and only a few products from Germany and other countries. Nowadays in Macedonia there have been about 60 adjuvant medicinal products registered, both from domestic origin and from import. If the medicinal teas are included as well, it makes a total of about 85 adjuvant medicinal products. However, it is not a rare case that certain imported products are parallels to the ones produced at home or almost identical products to be imported by a number of enterprises. A typical example is Primulae sirupus compositus, which is imported under various trade names but with only insignificant changes in the formulation, which means in fact the same product, and for the same purpose.
In general, the products are in various pharmaceutical dosage forms. According to the indications, the product are meant chiefly for the treatment of diseases of the respiratory system, cardiovascular system and central nervous system and less as holagoga, laxatives, diuretic products or for external use (Fig.2).
Quality control
Macedonian legislation defines adjuvant medicinal products as products with week action and usage in traditional medicine. Their therapeutucal efficiency is not necessary to be scientifically proved. They are for oral or external usage and are produced from substances of plant, animal or mineral origin. This group consists of: teas, mixtures of teas, powders, extracts, tinctures, ointments and creams, solutions for contact lenses etc. The quality of those products has to be controlled in the authorized laboratory for drug quality control.
The quality of adjuvant medicinal products is controlled by laboratory physico-chemical and microbiological tests, performed in accordance with the standards of the modern drug analysis and rules of Good Laboratory Practice (GLP). The trend of contemporary analysis is to reduce the differences between the control of drugs and adjuvant medicinal products. The choice of parameters that are going to be investigated for quality control depends on pharmaceutical dosage form. One of the most important parameter that is investigated for all phytopharmaceuticals for oral and external usage is microbiological purity that is investigated by the same criteria as those for medicines.
As usual, the quality control of teas includes control of row materials and control of final products. The control comprises: organoleptic investigation, identification (macroscopic, microscopic, and chemical), tests for pureness, investigation of the presence of chemical contamination (heavy metals, pesticides, micotoxines and radioactivity), microbiological contamination, and the assay of active component.
No medicinal product or adjuvant medicinal product may be placed on the market of the Republic of Macedonia unless the competent authorities in accordance with the legislation have issued a marketing authorization. The request for registration for commercial usage of adjuvant medicinal products represent the type of abridged applications and could be submitted by domestic or foreign producer. This request includes data about the producer and the product (administrative data), report from the authorized laboratory for quality control consisted of the physico-chemical and microbiological results, evaluation of chemical, pharmaceutical and biological documentation and also estimation for the pharmaceutical quality of the product. Pharmacological and toxicological investigation is replaced by issuing pharmaco-toxicological estimation for the products issued by the authorized institution.
The request from the foreign producers also includes certificate for the Good Manufacture Practice of the producer, and list of countries in which this product is already in use.
Marketing
In the Republic of Macedonia the adjuvant medicinal products can be advertised but only using information for their influence from the official instructions for usage. This instruction is placed in the packing of the products.
Teas are the most important form of usage of medicinal plants in the Republic of Macedonia. Teas and other adjuvant products of this type can be purchased in pharmacies, as a form of self-medication or by the advice of the pharmacist, so their consumption except for teas is very modest. In the Republic of Macedonia no physician will advise adjuvant medicinal products, except Primulae sirupus compositus, which is a classic expectorant, especially for children. For abdominal pains mint tea could also be advised, or valerian for neurosis. Everything else depends on the level of information of the people and their personal wish to be cured by adjuvant medicinal products. The readiness of the pharmacists to advise this medicine for certain indication is also important.
Scientific research and development programs
The Institute for Pharmacognosy at the Faculty of Pharmacy in Skopje is the most important institution in the state that conducts research of the medical plants by various research studies. The main orientation is towards domestic resources, having in mind that natural resources are the most important source for herbal drugs. The Government financially supported many scientific projects. Today, the close co-operation with pharmaceutical industry is important, in the sector for development as well as in the sector of scientific research.
The European Pharmacopoeia 3rd edition (1997) Council of Europe, Strasbourg.
Rapport from the National Institute for Statistics (2000).
Botanicals, Catalog of product, Alkaloid - Joint Stock Company Pharmaceutical Chemical Industry.
Zakon za lekovite, pomošni lekoviti sredstva i medicinski pomagala (1998), Služben vesnik na R. Makedonia, br. 21/98.