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Full Project – THE USE OF QUALITY CONTROL PARAMETERS IN THE EVALUATION OF VEGETABLE CRUDE DRUGS

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CHAPTER ONE

INTRODUCTION

BACKGROUND OF THE STUDY

The universal role of plants in the treatment of disease is exemplified by their employment in all the major systems of medicine irrespective of the underlying philosophical premise. How and when such medicinal plants were first used ,is, in many cases, lost in pre-history, indeed animals other than man , appear to have their own materia medica.(Prajapati, et al., 2003). Nevertheless, it can be said with certainty that vegetable kingdom already existed when man made his appearance on earth. As man began to acquire closure acquaintance with his environment,he began to know more about plants, as these were the only curative agents he had. As he progressed and evolved, he was not only able to sort out which plants could be eaten, but also began to associate curative characteristics with certain plants.

The World Health Organization (WHO, 1978) estimated that 4 billion people(80%) of the world population presently use herbal medicine for one form of primary health or another. Early human recognised their dependence on nature for a healthy life and since that time, humanity has depended on the diversity of plant resources for food, clothing, shelter, and medicines to cure myriads of ailments. However, man did not require the modern methods of investigation to collect for himself a materia medica of plants which he often used in conjunction with magical and other ritual practices. It is interesting to reflect that such collection of herbal medicines compiled over centuries by trial and error, and presumably using the patient as the experimental animal throughout, must surely contain some materials worthy of further investigation and should not be too readily discarded.

Medicinal plants are of great value in the field of treatment and cure of disease. Over the years, scientific research has expanded our knowledge of the chemical effects and composition of the active constituents which determine the medicinal properties of plants. It has now been a universally accepted fact that the plant drugs and remedies are far more safe than synthetic medicines for curing complex diseases. Large numbers of alkaloids, glycosides, and antibiotics have been isolated, identified and used as curative agents. In the western world, as people are becoming aware of the potency and side effects of synthetic drugs, there is an increasing interest in the plant based remedies with a basic approach towards the nature. The future development of Pharmacognosy as well as herbal drug industry would be largely dependent upon the reliable methodologies for identification of marker compounds of the extracts, and also upon the standardization and quality control of these extracts.

Little more needs to be said about the present day importance of medicinal plants for it will be apparent to know that the plant themselves either in the form of crude drugs or even more important for the medicinally active materials isolated from them have been and always will be an important aid to physician in the treatment of disease.

1.2 HERBAL MEDICINE

An herb is a plant or part of a plant valued for its medicinal, aromatic, or savoury qualities. Herbs can be viewed as biosynthetic chemical laboratories, producing a number of chemical compounds. Herbal remedies or medicines consist of portions of plants or unpurified plant extracts containing several constituents, which often work together synergistically. As per WHO definition, there are three kinds of herbal medicines: raw plant material, processed plant material and medicinal herbal products. Herbal drugs are finished labelled products that contain active ingredients such as aerial or underground parts of plant or other plant material or combination thereof, whether in the crude state or as plant preparations. Herbal medicine or herbalism is the use of herbs or herbal products for their therapeutic or medicinal value. They may come from any part of the plant but are most commonly made from leaves, roots, bark seeds, and flowers. They are eaten, swallowed, drunk, inhaled, or applied topically to the skin. Herbal products often contain a variety of naturally-occurring biochemicals from plants, many of which contribute to the plant’s medicinal benefits. Chemicals known to have medicinal benefits are referred to as “active ingredients” or “active principles” and their presence depends on a number of factors including the plant species, the time and season of harvest, the type of soil, the way the herb is prepared. Herbal medicines may contain excipients in addition to the active ingredients.

Medicines containing plant material combined with chemically defined active substances, including chemically defined, isolated constituents of plants are not considered to be herbal medicines. Exceptionally, in some countries herbal medicines may also contain, by tradition, natural organic or inorganic active ingredients which are not of plant origin”. (Copper, et al., 1986).

The use of herbal medicines has increased remarkably in line with the global trend of people returning to natural therapies. Herbal medicine products are dietary supplements that people take to improve their health and are sold as tablets, capsules, powders, teas, extracts and fresh or dried plants. Herbals are traditionally considered harmless and increasingly being consumed by people without prescription. However, some can cause health problems, some are not effective and some may interact with other drugs. To avoid confusion with culinary herbs, herbs and plant extracts that have some association with medicinal uses are called “Herbal Medicinal Products”.

In the past, the cure of disease and the use of medicinal plants has been much influenced by religious practice and the exercise of magical rites. From a pharmacognostical viewpoint, the study of herbal medicines differs little from that for the allopathic medicinal plants. In practice, many herbal remedies have not been as extensively studied either pharmacologically or phytochemically, a situation which must change for over- the-counter products as stricter licensing controls are implemented.

During the past decade, there has been increasing public interest and acceptance of natural therapies in both developing and developed countries. Due to poverty and limited access to modern medicine, about 80% of the world’s population, especially in the developing countries uses herbal medicine as their source of primary healthcare (Bodeker et al., 2005; Mukherjee, 2002; Farnsworth et al., 1985; Bisset, 1994). In these communities, traditional medical practice is often viewed as an integral part of their culture. In the West, people are attracted to herbal therapies for many reasons, the most important reason being that, like our ancestors, it is believed they will help us live healthier lives. Herbal medicines are often viewed as a balanced and moderate approach to healing. Individuals who use them as home remedies and over-the-counter drugs spend billions of dollars on herbal products. As such, they represent a substantial proportion of the global drug market (WHO, 2005, 2002a, Blumenthal et al., 1998; Roberts and Tyler, 1997; Farnsworth et al., 1985).

Herbal Medicinal Products ( HMPs) form the largest part of what is sometimes called Complementary and Alternative Medicine (CAM), and are at one end of a continuum from “healthy foods” through “nutraceuticals” to “herbal medicinal products”, which are products that have mainly a use in treating or preventing disease. However, it should not be forgotten that these advances in medicine and therapy are easily available to only a minority in the world as a whole. In many places, mainly in developing countries, but also in pockets, in every affluent society, herbal products are the major, if not only, source of medication, for economic or geographical reasons. This is in contrast to the more affluent areas of the globe where they are used as a matter of choice rather than necessity. Serious different reasons have been put forward for the resurgence of interest in the use of HMPs. This include a reaction against the serious side-effects sometimes observed when orthodox drugs are used, especially the more potent ones; the inability of western medicines to treat some diseases satisfactorily, especially chronic conditions and the generally mistaken idea that “natural” must be better or safe.

To achieve the desired benefit from herbal preparations, an individual must take the required dose over a certain length of time. Although it is generally believed that most herbal preparations are safe for consumption, some herbs like most biologically active substances could be toxic with undesirable side effects (Bisset, 1994).

Herbal treatment is usually directed towards restoring a state of homeostasis or a normal physiological balance of the body, rather than directly attacking the symptoms of the disease. The extracts of the plants prescribed will contain a wide range of plant metabolites, of which some will be therapeutically active. This admixture, containing a spectrum of the constituents of the plants cell may give rise to fewer side-effects than a single isolated principle. A number of constituents, which on their own may appear pharmacologically inactive, combine synergistically to produce therapeutic effects.

In most countries, herbal products are launched into the market without proper scientific evaluation, and without any mandatory safety and toxicological studies. There is no effective machinery to regulate manufacturing practices and quality standards. Consumers can buy herbal products without a prescription and might not recognize the potential hazards in an inferior product. A well-defined and constant composition of the drug is therefore, one of the most important prerequisites for the production of a quality drug. Given the nature of products of plant origin, which are not usually constant and are dependent on and influenced by many factors, ensuring consistent quality of products is vital for the survival and success of the industry (Bauer, 1998).

Standardization of herbal formulations is essential in order to assess the quality of drugs, based on the concentration of their active principles. Quality evaluation of herbal preparation is a fundamental requirement of industry and other organization dealing with ayurvedic and herbal products. The growing use of botanicals (drug and other products derived from plants) by the public is forcing moves to assess the health claims of these agents and to develop standards of quality and manufacture. It is evident that the herbal industry needs to follow strict guidelines and such regulations are necessary.

1.3 STANDARDIZATION OF BOTANICAL HERBS AND QUALITY OF BOTANICAL PREPARATIONS:

Plants contain several hundred constituents and some of them are present at very low concentrations. In spite of the modern chemical analytical procedures available, only rarely do phytochemical investigations succeed in isolating and characterizing all secondary metabolites present in the plant extract. Apart from this, plant constituents vary considerably depending on several factors that impair the quality control of phytotherapeutic agents. (Jablonski, 2004). Quality control and standardization of herbal medicines involve several steps. However, the source and quality of raw materials play a pivotal role in guaranteeing the quality and stability of herbal preparations. Other factors such as the use of fresh plants, temperature, light exposure, water availability, nutrients, period and time of collection, method of collecting, drying, packing, storage and transportation of raw material, age and part of the plant collected, etc., can greatly affect the quality and consequently the therapeutic value of herbal medicines. Some plant constituents are heat labile and the plants containing them need to be dried at low temperatures. Also, other active principles are destroyed by enzymatic processes that continue for long periods of time after plant collection. This explains why frequently the composition of herbal based drugs is quite variable. As pointed out before, apart from these variable factors, others such as the method of extraction and contamination with microorganisms, heavy metals, pesticides, etc., can also interfere with the quality, safety and efficacy of herbal drugs. For these reasons, pharmaceutical companies prefer using cultivated plants instead of wild-harvested plants because they show smaller variation in their constituents. Furthermore and certainly more relevant, when medicinal plants are produced by cultivation, the main secondary metabolites can be monitored and this permits definition of the best period for harvesting. (Koo, et al., 2004).

Quality control of herbal medicines is a critical and essential issue to be considered in assuring the therapeutic efficacy, safety and to rationalize the use of herbal medicinal products (HMPs) in healthcare. Definition and characterization of the material is necessary prior to the assessment of the relevance of available efficacy and safety data. It is also important that the material used and available commercially should be consistent with the evaluated material because any significant change in quality would trigger the need for re-evaluation of the relevance of the safety and efficacy data (Mukherjee, 2002). Adulterants, and more often, the incorrect identification of the herbs, are the causes of low quality in herbals.

Standardization is a system that ensures a predefined amount of quantity, quality & therapeutic effect of ingredients in each dose. Herbal product cannot be considered scientifically valid if the drug tested has not been authenticated and characterized in order to ensure reproducibility in the manufacturing of the product. Moreover, many dangerous and lethal side effects have recently been reported, including direct toxic effects, allergic reactions, effects from contaminants, and interactions with herbal drugs. Therapeutic activity of an herbal formulation depends on its phytochemical constituents. The development of authentic analytical methods which can reliably profile the phytochemical composition, including quantitative analyses of marker/bioactive compounds and other major constituents, is a major challenge to scientists. Standardization is an important step for the establishment of a consistent biological activity, a consistent chemical profile, or simply a quality assurance program for production and manufacturing of an herbal drug. The authentication of herbal drugs and identification of adulterants from genuine medicinal herbs are essential for both pharmaceutical companies as well as public health and to ensure reproducible quality of herbal medicine. (Choudhary and Sekhon, 2011).

It is very important that a system of standardization is established for every plant medicines in the market because the scope for variation in different batches of medicine is enormous. Plant materials may vary in its therapeutic effect according to different places of collection, with different times in a year for collection, with collection at the same time and place but in different years, and with different environmental factors surrounding the cultivation of a particular medicinal plant. Adding to this variability is the fact that in herbal medicine, several plants may be used together in the same preparation. These means that there should be a quality control test for the entire preparation to ensure quality of the preparation (Prajapati, et al., 2003).

1.4 CONVENTIONAL METHOD FOR STANDARDIZATION OF HERBAL FORMULATION

Standardization of herbal raw drugs include passport data of raw plant drugs, botanical authentication, microscopic and molecular examination, identification of chemical composition by various chromatographic techniques and biological activity of the whole plant. Macroscopic and microscopic evaluation and chemical profiling of the herbal materials for quality control and standardization have been reported by various workers. Macroscopic identity of medicinal plant materials is based on sensory evaluation parameters like shape, size, colour, texture, odour and taste while microscopy involves comparative microscopic inspection of powdered herbal drug. Further, advances in microscope technology have increased the accuracy and capabilities of microscopy as a mean of herbal crude material identification due to the implication of light and scanning electron microscopes (SEM) in herbal drug standardization. Furthermore, various advanced methods such as chromatographic, spectrophotometric and combination of these methods, electrophoresis, polarography, and the use of molecular biomarkers in fingerprints are currently employed in standardization of herbal drugs ( Choudhary and Sekhon, 2011).

1.5 CURRENT REGULATIONS FOR STANDARDIZATION OF CRUDE DRUGS

Internationally, several pharmacopoeias have provided monographs stating parameters and standard of many herbs and some products made out of these herbs. Several pharmacopoeias like:

Pharmacopoeia committee

Chinese Herbal Pharmacopoeia

United States Herbal Pharmacopoeia

British Herbal Pharmacopoeia

British Herbal Compendium

Japanese Standards for Herbal Medicine

The Ayurvedic Pharmacopoeia of India

Lay down monograph for herbs and herbal products to maintain their quality in their respective nations (Agarwal, 2005).

1.6 STANDARDIZATION AND QUALITY CONTROL PARAMETERS FOR EVALUATION OF HERBAL CRUDE DRUGS

According to WHO (1996a and b), standardization and quality control of herbals is the process involved in the physicochemical evaluation of crude drug covering aspects, such as selection and handling of crude material, safety, efficacy and stability assessment of finished product, documentation of safety and risk based on experience, provision of product information to consumer and product promotion. Attention is normally paid to such quality indices such as:

Macroscopic Examination: In case of whole drugs, the macroscopic and secondary characters are sufficient for identification of right variety and search of adulterants.

Microscopic Examination: These are valuable both for powders and ungrounded drugs for identification of right variety and search of adulterants.

Foreign organic matter: This involves removal of matter other than source plant to get the drug in pure form.

Ash values: These are criteria to judge the identity and purity of crude drug such as: Total ash, sulphated ash, water soluble ash and acid insoluble ash etc.

Moisture content: Checking moisture content helps reduce errors in the estimation of the actual weight of drug material. Low moisture suggests better stability against degradation of product.

Extractive values: These are indicative weights of the extractable chemical constituents of crude drug under different solvents environment.

Crude fibre: This helps to determine the woody material component, and it is a criterion for judging purity.

Qualitative chemical evaluation: This covers identification and characterization of crude drug with respect to phytochemical constituent. It employs different analytical technique to detect and isolate the active constituents. Phytochemical screening techniques involve botanical identification, extraction with suitable solvents, purification, and characterization of the active constituents of pharmaceutical importance.

Chromatographic examination: Include identification of crude drug based on the use of major chemical constituents as markers.

Quantitative chemical evaluation: To estimate the amount of the major classes of constituents.

Solubility: The solubility, especially exceptional behaviour towards solvent, is useful in examination of many oils and oleo-resins.

Physical Constituents: Physical constituents such as specific gravity, optical rotation, viscosity, and refractive index are especially valuable for the evaluation of fats, oleo-resins, balsams and similar substances.

Swelling Index: It measures the swelling property of the medicinal plants.

Volatile Oils: It covers the measurement of the volatile content of the plant.

Bitterness Value: The bitter properties of the plant materials are determined by comparing the threshold bitter concentration of an extract of the materials with that of a dilute soluble of guanine hydrochloride.

Hemolytic Activity: The hemolytic activity of a plant materials, or a preparation containing saponins, is determined by comparison with that of a reference material, saponin.

Foaming Index: The foaming ability of an aqueous decoction of plant materials and their extracts is measured in terms of a foaming index.

Pesticide Residue: It measures the pesticide residues in the plant.

Arsenic and Heavy Metals: Contamination of medicinal plant materials with arsenic and heavy metals can be attributed to many causes including environmental pollution and traces of pesticides.

Microorganisms: Current practices of harvesting, handling and production may cause additional contamination and microbial growth.

Aflatoxins: Minute presence in crude drug can be toxic and hence their presence is being tested.

DNA Fingerprinting: Technique is useful for identification of phytochemically indistinguishable genuine drugs from substituted or adulterated drugs.

Chemical Fingerprinting: To allow the detection of all the components in the extracts.

Biological Profiling: It identifies the biologically active plants allowing highly sophisticated standardization and quality control.

Radioactive Contamination: A certain amount of exposure to ionizing radiation cannot be avoided since they are many sources including radionuclides occuring naturally in the ground and atmosphere.

Toxicological Studies: To help determine pesticide residue, potentially toxic elements, safety studies in animals like LD50 and microbial count approach to ascertain their presence or absence.

1.7 PURITY DETERMINATION

Purity is closely linked with the safe use of drugs and deals with factors such ash values, contaminants (e.g. foreign matter in the form of other herbs), and heavy metals. However, due to the application of improved analytical methods, modern purity evaluation also includes microbial contamination, aflatoxins, radioactivity, and pesticide residues. Analytical methods such as photometric analysis, thin layer chromatography (TLC), high performance liquid chromatography (HPLC), and gas chromatography (GC) can be employed in order to establish the constant composition of herbal preparations(Kunle, et al . , 2012).

High Performance thin layer chromatography (HPTLC) is valuable quality assessment tool for the evaluation of botanical materials. It allows for analysis of a broad number of compounds both efficiently and cost effectively. With HPTLC, the same analysis can be viewed using different wavelengths of light thereby providing a more complete profile of the plant than is typically observed with more specific type of analyses (Chakravarth, 1993).

1.8 W.H.O GUIDELINES FOR QUALITY STANDARDIZED HERBAL FORMULATIONS

WHO has evolved guidelines to support the member states in their efforts to formulate national policies on traditional medicine and to study their potential usefulness including evaluation, safety, and efficacy. Standardization and quality control parameter for herbal formulations are based on the following fundamental parameters:

Quality control of crude drugs material, plant preparations and finished products.

Stability assessment and shelf life.

Safety assessment; documentation of safety based on experience or toxicological studies.

Assessment of efficacy by ethno medical information and biological activity evaluations.

1.9 QUALITY CONTROL OF CRUDE MATERIALS

Quality can be defined as the status of a drug that is determined by identity, purity, content, and other chemical, physical, or biological properties, or by the manufacturing processes. Quality control is a term that refers to processes involved in maintaining the quality and validity of a manufactured product.

The quality of herbal medicine that is. the profile of the constituents in the final product has implication in efficacy and safety. Quality controls of synthetic drug offer no problems with very well defined parameters of analysis. In contrast, herbal products represent a number of unique problems when quality aspects are considered. These are because of the nature of the herbal ingredients present therein, which are complex mixtures of different secondary metabolites that can vary considerably depending on environmental and generic factors. Furthermore, the constituents responsible for the claimed therapeutic effects are frequently unknown or only partly explained. These complex positions of quality aspects of herbal drugs are further complicated by the use of combination of herbal ingredients as are being used in traditional practice. It is not uncommon to have as many as five different herbal ingredients in one product. Thus batch to batch variation starts from the collection of raw material itself in the absence of any reference standard for identification. These variations multiply during storage and further processing.

The task of lying down standards for quality control of herbal crude and their formulation involves biological evaluation for a particular disease area, chemical profiling of the material and lying down specification for the finished product. Therefore, in case of herbal drugs and product, the word “Standardization” should encompass entire field of study from cultivation of medicinal plant to its clinical application (Wani, 2007).

To ensure safety and quality of the medicinal plants it is necessary to focus on all aspects of medicinal plant research from ethno – pharmacology, utilization, isolation and identification of active constituents to efficacy evaluation, safety, formulation and clinical evaluation. Quality control of the medicinal plants starts right at the source of the plant material. The phytochemical composition of the plant material and the resulting quality can vary due to several factors including a number of environmental factors such as geographical location, soil quality, temperature and rainfall etc. taxonomy, the time of collection, method of collection, cultivation, harvesting, drying and storage conditions, preparation and processing methods can also affect composition. Contamination by microbes, chemical agents such as pesticides and heavy metals as well as by insects and animals during any of these stages can also lead to poor quality of the finished products. Standardization of all these factors is necessary to meet the current standards of quality, safety and efficacy (Brijesh et al., 2006).

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