The use of medicinal plants is old as the existence of mankind. According to World Health Organization (WHO) data, about 80% of world population are using products based on medicinal herbs. Physiotherapy is based on the use of herbal drugs and medicinal products for the purpose of prevention and treatment. Rational phytotherapy is a modern concept of herbal medicines using, which are made of standardized herbal extracts. The quality of each final product is guaranteed by the use of raw materials of a standard quality, defined process of production, and validated equipment. Quality control of herbal drugs and herbal isolates (tinctures, extracts, and essential oils) is done according to the requirements of Pharmacopoeia and other relevant regulations. The scope of phytopreparation quality control depends on its pharmaceutical form. The formulation of a new phytopreparation is a process that has strictly defined phases: from analysis of literature and market, through defining recipes, validation of the production process, quality control of a final product to the preparation of technological and registration documents. The aim of this chapter is to present the process of herbal preparations production from selecting plant raw materials to herbal remedies (on the examples of making tea, tea mixture, drops, gels, and capsules).
Since ancient times, medical plants and simpler herbal remedies have been used in all parts of the world for the treatment and alleviation of various ailments. Although the use of medicinal plants is as old as mankind itself, their controlled application, the isolation and characterization of active substances, started only in the early nineteenth century. It is a known fact that the extractive plant isolates and isolated active substances played a major role in the development of modern pharmacotherapy. Many of the isolated compounds are still used today, or they have served as a model for the synthesis of a large number of drugs
The use of plants as medicines has a long history in the treatment of various diseases. Plants especially those with ethnopharmacological uses have been the primary sources of medicine for early drug discovery.
Herbal remedies, from simple to complex forms, should be made of the raw materials required for quality, because only then they could be safe and effective for use. The Pharmacopoeia monographs, Monographs European Medicinal Evaluation Agency (EMEA), which encompasses monographs World Health Organization (WHO), European Scientific Cooperative on Physiotherapy (ESCOP), and Commission E (The German Commission E is a scientific advisory board of the “Bundesinstitut für Arzneimittel und Nonproductive” formed in 1978. The commission gives scientific expertise for the approval of substances and products previously used in traditional, folk, and herbal medicine) national regulations, precisely defined parameters of control quality.
The process of drafting a new herbal remedies is very complex and strictly defined phase. Each step in the process is important, from the initial idea, market analysis, selecting high-quality plant material and ancillary pharmaceutical raw materials, recipe formulation, production preparation, quality control of product, preparation of documentation, protection of intellectual property rights, to the introduction of herbal drug in regular production. The drafting process must be validated and secure documentation.
In modern pharmacotherapy, despite the widespread use of drugs obtained by chemical synthesis, the importance of herbal medicines in the treatment and prophylaxis is still large. According to the latest WHO researches, 11% of the 252 basic medicines are in fact herbal preparations .
2. Development and manufacturing of herbal preparations
2.1. Use of medicinal plants through history
The use of medicinal plants in the prevention and treatment of various diseases is known since ancient times. Documents of exquisite value show that herbs were extensively used by human population throughout the history. Since ancient times, people have sought safety and relief for their health problems in medicines from nature. Prehistoric men have dared to use particular medicinal plants, based on careful observation of the behavior of animals who have been using them . Over time, the use of herbal medicines and other natural products has developed on the basis of both positive and negative experiences. The collected rich experiences have gradually developed into folk medicine, such as traditional European medicine, traditional Chinese medicine, Indian Ayurveda, Japanese Kampo, or traditional Arabic and Islamic medicine. They consist, not only of herbal remedies but also of other types of drugs, for example, from minerals or animals, or physical procedures.
Material evidence on the use of medicinal plants in the distant past is kept by many ethnographic and archaeological sources. The oldest of these sources are clay tables, discovered in Mesopotamia (2600 BC), which in addition to the description showed also therapeutic application and galenical form in which the plants were to be used. In those ancient times, medical plants mentioned were castor oil, grapes, coffee, oils of cedar and cypress, licorice, myrrh, and poppy juice . The ancient Egyptian papyrus, Ebers Papyrus (1550 BC), represented some kind of first Pharmacopoeia. Egyptians were known for their skill of embalming, distilling scented water, and making perfume of aromatic plants, and for those they were using many medicinal plants that are still in use today (aloe, peppermint, plantain, poppy seeds, and coriander) . The first written records about the use of medical herbs in Chinese traditional medicine date from the third millennium BC. Emperor Shen Nung made a collection of wild medicinal plants. He is credited with the discovery of tea and many of which are used nowadays: cinnamon, ephedra, rhubarb, camphor, and great yellow gentian . The Indian holy books provide many examples of the treatments using medical plants, widespread in that country. A large number of aromatic herbs and spices that are still in use nowadays throughout the world, such as pepper, cloves, nutmeg, originate from India. According to data from the Bible and the holy Jewish book, the Talmud, during various rituals accompanying a treatment, aromatic plants were utilized such as myrtle and incense
With comprehensive development of science in ancient Greece, the pharmacy also receives a special place. The most famous doctor of ancient Greece, which is considered to be the “father of medicine,” is Hippocrates (460–377 BC). He was the first to systematize overall medical and pharmaceutical experience and publish them in the capital work Corpus Hippocratic. The most ancient botanist Theosophists (371–286 BC) together with his students founded the first botanical garden in Athens. He described more than 500 most important medicinal plants. Among others, he referred to cinnamon, iris rhizome, false hellebore, mint, pomegranate, cardamom, fragrant hellebore, monkshood, and so on. In the description of the plant, its toxic action was also stated. The founder of the European pharmacognosy, a Roman doctor of Greek origin, Dioscorides, who lived in the first century BC., described medicinal plants which were used in the ancient world, in his capital work De Materia Medica. Dioscorides’ most appreciated domestic plants were as follows: willow, camomile, garlic, onion, marsh mallow, ivy, nettle, sage, common century, coriander, parsley, sea onion, and false hellebore. The strong influence of Hippocrates and Dioscorides was notable in the school of Alexandria, where some of the major breakthroughs in medicine were made. Unfortunately, a great fire has destroyed the vast library with approximately two million books, and at the same time all the knowledge of medicinal plants of that er. By the Roman conquest of Greece, Romans took over all the medical and pharmaceutical knowledge and certainly the most important mind in this area was the Roman statesman and military leader Pliny, the Elder (23–79). He is the writer of the capital work Historia naturalis. The most famous Roman doctor and a pharmacist is well-known Eugenius-Galen, who lived from 131 to 201 and is considered to be the father of galenic pharmacy. In his writings on the development of complex preparations or galenic preparations, he described 304 drugs of plant origin
The Arabs preserved a large amount of the Greece-Roman knowledge during the Dark and Middle ages (i.e., fifth to twelfth centuries), and complemented it with their own medicinal expertise, and with herbs from Chinese and Indian traditional medicines The treatments during the Middle Ages were conducted in the restricted environment of monasteries. Skills of cultivation and collection of herbal medicines, as well as making simple herbal remedies, were reserved for doctors-monks. They used the different herbs: mint, sage, tansy, anise, fenugreek, savory, and so on
At the time of Charles V, the famous medical school of Salerno was founded and started its rise by introducing and applying experiences of Arab medicine and pharmacy. Benedictine monks played an important role in the preservation of the Greece-Roman tradition. Their legacy was large botanical gardens where mainly medicinal plants were grown . The Arab world has promoted many sciences including medicine and pharmacy. Certainly, the most famous Arabic doctor was Abu Ali Ibn Sina (Avicenna) and his famous book, The Canon of Medical Science, has been translated into Latin and other languages, and has been used in Europe for many years.
In medieval Europe, the level of medical knowledge was quite low. Arab medicine, starting from the twelfth century, began to penetrate into Europe, through Spain and Sicily. The Arabic books were translated into Latin medicine, and in this sense also the Arabic translations of ancient Greek and Roman books. Paracelsus (during the late Middle Ages) argued that the salubrity of plant originates from chemical compounds that are represented in it . In the eighteenth century, Swedish botanist Carl Von Linné (1707–1778) created the Latin nomenclature for each plant (the name of the genus and species), and a botanical system for determining the species, which due to its transparency and convenience is used even nowadays. Scientific pharmacy began only after the French Revolution, and with it the development of the science of medicinal plants. In this area, the most distinguished pharmacists became Lavoisier in France, Scheele in Sweden, Priestley in England, and so on. . The turning point in the approach and the use of herbal medicines is considered to be the beginning of the nineteenth century, when a German pharmacist Sertürner managed to isolate the alkaloid of morphine in its pure form, from poppy (1806). In the period from 1817 to 1820, French scientists isolated a whole series of alkaloids: caffeine, emetine, quinine, cinchonine, and strychnine. Improvements of instrumental analytical methods have allowed further detection of other groups and complexes of active substances, such as hetero-sides, saponosides, tannins, vitamins, and so on
In the twentieth century, a large number of synthetic drugs were created and it represented the beginning of commercial production of a large number of allopathic medicines, which significantly led to neglect the use of herbs in pharmacotherapy.
2.2. Plants are valuable sources of drug discovery
As already mentioned, herbal medicines have been an extremely important source for the discovery of many drugs. Morphine, which was the first purely natural product to be isolated, was introduced in pharmacotherapy in 1826 (Merck). The first semi-synthetic pure substance of aspirin, salicylic acid-based, was isolated from the bark of Salix alba willow and was produced in 1899 (Bayer). This was followed by the isolation of active compounds from old herbal drugs, such as digitoxin, codeine, pilocarpine, quinine, and many others, some of which are still in use today. Many herbal remedies, emerged after extensive scientific tests of “old and well-known” medicinal plants, were introduced in the therapy. Silymarin, extracted from the seeds of Silibum marianum, is used as a hepatoprotective, Paclitaxel from the bark of Taxus brevifolia in the treatment of lung, ovarian, and breast cancer, and Artemisinin from Artemisia annua herb to combat multiple-resistant malaria
In recent years, many herbal medicines have found their way into the official medicine. Some of them are Dronabinol and Cannabidiol isolated from Cannabis sativa, Tiotropium derivative of atropine from Atropa belladonna for combating obstructive and chronic bronchitis, Galantamine, alkaloid from Galanthus nivalis which is used to relieve symptoms of Alzheimer’s disease, and Apomorphine, which is a semi synthetic compound based on morphine from Papaver somniferum and is intended for people suffering from Parkinson’s disease . We can certainly say that a large number of medicinal plants, which in the past, were used and represent an important raw material for the production of herbal medicines, or have served as a model for similar synthesis of new molecules.
Given that man is an integral part of nature, the human body is compatible with medicines coming from nature. Nature, much like a flawless, perfect complex of laboratories, has created a variety of sophisticated active compounds contained in herbal medicines, which have a huge range of remedial action. Perhaps, this fact will speed up serious research of old manuscripts related to herbal medicines and brings out the “old drugs” of pure historical curiosity
2.3. Basic terms related to herbal medicines
Physiotherapy, as a complementary part of pharmacotherapy, has an important place in many areas of modern medicine. It represents a system of treatments based on the use of natural medicinal resources (drugs) and herbal remedies (herbal remedies) in the purposes of prevention and treatment.
Herbal drug is the whole or grained, dried part of a plant, algae, fungi, or lichen, which is used for its medicinal properties. In addition to the plant organs (above-ground part of the blooming plant as flower, leaf, root, bark, fruit, and seed), plant exudates can also be considered as a drug (resins, balsams, and rubber). Herbal medicines, herbal remedies, or herbal medicinal products (HMPs) contain as active ingredients exclusively herbal drugs or herbal drug preparations. Herbal drug preparations are obtained from drugs, with the procedures of distillation, extraction, filtration, and so on. This concept does not include powdered forms of drugs, essential oils, fatty oils, tinctures, and extracts
Rational phytotherapy is a modern concept of use of herbal medicines, which was designed in Germany at the end of the last century and soon widely accepted in other European countries. It was created from the need to improve phytotherapy, in order for herbal preparations to be more efficient, safer, and their use based on the results of clinical trials. Herbal medicines, which are used in rational phytotherapy, are prepared from standardized herbal extracts, the chemical nature of their active principles is known, they exhibit dose-dependent therapeutic effect, their adverse effects and contraindications are known, and their pharmaceutical quality is well defined and standardized
Herbal medicines are used preventive, in the treatment of milder forms of a disease, or as adjunctive therapy for the treatment of chronic diseases. Most commonly, they are applied with the dysfunction of the respiratory, digestive, urogenital tract, mild, and medium forms of anxiety and depression, as well as of different lesions of the skin and mucous membranes. Their healing effects accrue gradually, so that the maximum effect manifested 2–3 weeks after the application.
According to the WHO, preparations based on medicinal herbs are used by 80% of the world population. Medical use of medicinal plants has a long tradition in Europe, while in some parts of the world (e.g., China and India), herbal remedies still represent a central link in the chain of health services .
Extractive isolates of herbal medicines and herbal preparations are extremely complex multi-component mixtures, as opposed to synthetic drugs that are most commonly a single pure compound. In the production of herbal remedies, certain actions and procedures are needed to be undertaken (collecting medicinal plants from spontaneous flora and plantation cultivation, obtaining extractive isolates, and their characterization), which do not precede the production of synthetic drugs. Fortunately, the procedures of making herbal medicines are largely modernized and defined in all segments. There are a number of guidelines that prescribe standards in all aspects of making herbal medicines: The European Medicines Agency guidelines for the quality of herbal medicines, the WHO guidelines provide standards and guidelines for good agricultural practices, good laboratory practices, and so on. The development of new, sophisticated analytical, and technological methods and procedures within the development and characterization of extractive isolate has greatly improved the quality of the final plant products. On the other hand, the process of harmonization of the quality system for the production and herbal drugs control is present in many countries. But globally speaking, more effort is yet to be made in order to revive the prescribed guidelines and regulations in practice The main goal of the Committee for herbal products (Herbal Medicinal Product Committee—HPMC) is to prepare a detailed list of monographs and processed herbal substances and preparations, which are in medical use for long enough time that their use is safe under normal conditions. The monograph contains the professional opinion of the Committee on a particular plant products based on scientific data or traditional use within the European Union (EU). For each plant, the substances are stated indications, speed, usage, and other relevant data concerning its safe use or composition that contains it. List and versions of monographs are available for public consultation . In Europe, companies can apply for three different types of market authorization of an herbal medicinal products (HMPs):
- Full implementation. Manufacturer of a herbal drug must provide documentation proving its efficiency and safety, and studies are identical to those submitted for the registration of a synthetic drug.
- Well-established use. Manufacturer of a herbal drug may be permitted to register, on the basis of the submitted detailed scientific literature, stating that the herbal medicinal preparation is in use for medical purposes not less than 10 years in Europe and has recognized efficiency and an acceptable level of safety.
- Traditional use. Efficiency and safety of a herbal drug can be accepted on the basis of long experience. Herbal remedies can be registered, if the documents prove their use in mitigating certain ailments, not less than 30 years, with at least 15 years in Europe.
The registration procedure for herbal medicines, at all levels of the European Union (EU), is done according to European Directive 2004/24/EC, which introduces simplified, but strictly defined procedures and affects the harmonization of existing national legislative regulations. Regarding the registration in the non-EU countries, despite the efforts made within the framework of national legislation and harmonization in larger systems, a limited number of herbal medicines have been registered. Therefore, the identification of problems and discrepancies and the systematic plan for overcoming them represent a major challenge for the presence of these herbal drugs on the market of EU countries
In Republic of Serbia, legislation on plant products is harmonized with recommendations of The European Directive 2004/24/EC. Law on medicines and medical devices (Official Gazette of the Republic of Serbia No. 30/2010), Regulation on health safety of dietary products (Official Gazette of RS No. 45/2010), Guidelines of Good Manufacturing Practice, Annex 7- Manufacture of herbal medicines, are all in effect. According to the Law on medicines and medical devices, Herbal medicine, is each drug whose active ingredients are exclusively one or more substances of vegetable origin or one or more herbal preparations, or one or more substances of vegetable origin in combination with one or more herbal preparations. Traditional herbal medicine may be based on scientific principles and is the result of tradition or other traditional therapeutic approaches. The active components of a herbal medicine/traditional herbal medicine are herbal drugs and herbal preparations and their combinations, and this is widely accepted in all European and national documents. In the context of food supplements (dietary supplements), a new the Regulation defines the notion of herbal dietary supplements. These are supplements that contain medicinal plants, their parts or preparations and their quantity in a daily dose of the product should not be less than 15% and greater than 65% compared to a known therapeutic dose of these plant materials or preparations.
2.5. Parameters of quality and quality control
The quality of each final product is ensured by the standard quality of raw materials, the application of validated production processes and procedures on validated equipment. It is similar with herbal remedies, which are made of high-quality herbal raw materials, extractive preparations (extracts and tinctures) and isolates (essential oil and fatty oil). The latest European Pharmacopoeia Ph Eur 8 comprises 270 Monographs on herbal drugs and herbal drug preparations Monographs define parameters of quality control.
2.5.1. Quality control of herbal drugs
The basis of high-quality herbal remedies is the plant material of a standard quality. Many factors affect the quality of plant material. Regardless of whether the medicinal plants are grown or collected from the wild, bio genetic factors are certainly important (species, variety, chemo type, and sorta). The following are the conditions in which a plant grows as air, climate, land, then ago-technical measures that are applied during the large-scale production (proper sowing, irrigation, fertilization, control against weed and pests), and then collection from the wild or harvest of the plantation, transport, proper storage, drying, and grinding. It is very important to educate people how to deal with the collection of herbal raw materials from spontaneous flora, as well as those who grow the plants, whether they are doing so in the conventional conditions or organic conditions of medicinal plants production. Quality control of herbal raw materials is strictly defined and traceable. First, the identification of plant raw materials is approached. Responsible and expert persons in laboratories for the pharmaceutical control or in other relevant institutions, conduct identification, and categorization under a certain number.