Plant-Based Medicines Formulation and Manufacture PDF

# Formulation and Manufacture of Plant-Based Medicines ## Active Constituent Considerations ### Purity of Active Constituent(s) - Production and formulation of plant-based medicines lead to technology and stability problems far greater than those for single, natural isolated chemicals or synthetic...

# Formulation and Manufacture of Plant-Based Medicines ## Active Constituent Considerations ### Purity of Active Constituent(s) - Production and formulation of plant-based medicines lead to technology and stability problems far greater than those for single, natural isolated chemicals or synthetic compounds. - One major cause of the problem is the inclusion of compounds which are either pharmacologically inactive, or are active but possess additive, synergistic, or even opposite or dissimilar activities. - Ideally, these constituents should have been removed during primary production, but this is often unrealistic because of constraints of cost, lack of knowledge of their identities, and technical inability to remove them. - Formulation with plant extracts requires complete knowledge of the composition of the extract so that the formulator can choose the most suitable excipients and formulations. - Ideally, only one plant extract should be included in any formulation, but there are many examples where there are more than one. - This may cause formulation problems due to interaction of components of one extract with the components of the other extract(s) causing instability. ### Variability of Crude Drug Material - The supply of raw material is a major problem, owing to wide-scale variations in composition. - Published surveys show that there can be a distinct difference in constituent levels even between batches from the same supplier. - Adulteration (deliberate or accidental substitution of inferior material) has long been a problem with herbal remedies. - Traditional quality control procedures have been adopted to detect this situation, with a number of parameters specifically designed to identify the problem of adulteration with inferior material. - With the increased use of herbal remedies, the causes may be more sophisticated, for example, attempts to improve the characteristics of the extracts with material not detected by standard assays. - Bilberry extracts have been found adulterated with the food dye amaranth added specifically to make their colour appear more intense. ## Finished-Product Considerations - A wide range of typical formulations are widely used for plant extracts, which include most of the types used for conventional pharmaceuticals. - Most conventional dosage forms can be produced from plant liquid or dried extracts by conventional techniques. - As with conventional pharmaceuticals, solid dosage forms are the preferred type of formulation, whilst liquids such as syrups are losing favour because of lack of patient acceptability and poor stability during storage. - Controlled-release solid dosage forms of plant-based material can also be manufactured. ## Preparation of Solid Dosage Forms - Approximately 75% of European herbal medicines are constituted from dry extracts. - These dry extracts are invariably hygroscopic. - A high-porosity excipient, such as microcrystalline cellulose is usually added to the formulation, together with a cellulose derivative binder. - As is the case with conventional tablets, these extra excipients are responsible for improved physical characteristics of the tablets, notably hardness, friability and disintegration when used in the correct proportions for a particular plant extract. ## Preparation of Liquid Dosage Forms - Nearly all types of extracts can be used in formulating liquid dosage forms. - If dry extracts are used, the material must be redissolved, which may result in precipitation of components or at least the presence of turbidity. - To avoid these issues, it is advisable to redissolve the material at precisely the same concentration in the solvent as that which was used to prepare the extract. - On some occasions the downstream processing of the initial extract may modify the composition of the extract so that dissolution does not occur, in which case cosolvents or surfactants may need to be added. - The solubility and stability of some extracts can be increased by pH manipulation, particularly, when reduction favors salt formation for the active constituent, such as in the case of an alkaloid. - The stability of these dosage forms is adversely affected by fermentation which is prone to occur in extracts containing nutritive plant constituents, but this can be reduced by regulation of the alcohol content or by use of traditional preservatives such as p-hydroxybenzoic acid esters. ## Newer Delivery Systems - Herbal medicines are now being formulated and administered via the most up-to-date delivery technologies available. - Methods used to manufacture liposomes, nanoparticles, phytosomes, emulsions and microsphere formulations of numerous plant extracts are regularly reported in the scientific literature. - Liposomes have been produced for markedly different products, including paclitaxel, curcumin, garlic and quercetin. - Transferosomes and ethosomes are being used for a range of topical applications. - A range of herbal entities have also been formulated into microspheres as small as 6 µm, which can be ingested or injected and targeted to specific organs of the body. ## Excipients ### Antimicrobial Preservatives - The p-hydroxybenzoic acid esters, such as the methyl and propyl esters (parabens), are widely used. - However, in a number of formulations, such as herbal cosmetics and external medicaments, bronopol is also widely used. - The possibility of manufacturing 'organic products' without addition of preservatives has been commercially exploited in a number of herbal products. This strategy normally results in products having a reduced shelf life. ### Antioxidants - The use of antioxidants to limit oxidation in pharmaceuticals and foods is widespread; ascorbate is widely used for this purpose. ### Colouring Materials - As concerns about the dangers of artificial colours continue worldwide, plant-derived colours are increasingly being used because their use obviates the use of synthetic dyes. - An example is turmeric from the roots of Curcuma longa, which contains curcuminoids that have a yellow or orange colour. - ẞ-Carotene is another example and is orange-yellow. - Commercial ẞ-carotene is derived from algae or is synthesized and is oil soluble, but it can also be made into a water-dispersible emulsion. - These natural yellow to orange colours are an alternative to synthetic yellow dyes. - Other plant-based colours include anthocyanins and tomato extract, which can produce a range of red colours in place of synthetic red dyes. ### Flavours - Plant extracts are often bitter or astringent and such characteristics are usually masked with sweeteners or flavours. - Flavours are invariably included in liquid oral formulations to mask these bitter or unpleasant tastes, to improve patient adherence. - Apart from volatile oils, which are selectively used for flavouring formulations designed for different patient groups, a wide range of soft fruit flavours, such as banana and strawberry, either natural or synthetic, are also used for flavouring. ## Quality of Finished Products ### Quality of Formulated Herbal Products - Unlike medicinal products, there are few agreed standards for formulated herbal remedies. - A survey of a large number of herbal products from a range of manufacturers found incorrect/inadequate labelling and products with wide-ranging content claims, wide-ranging recommended daily dosage, a range of different plant parts used, and from a number of claimed sources of botanical origins. - Wide-ranging values for active constituent content have been reported for parthenolide in feverfew and for the active constituent(s) in, for example, ginseng, gingko, echinacea, and St John's wort. - This demonstrates the possible risk to patients and the urgent need for appropriate standards. ### Shelf Life of Formulated Products - Labelling of products with the shelf life or expiry date is presently not mandatory for all formulated plant products. - Scientific knowledge of degradation and acceptable shelf life is obviously necessary for these complex products. - Improved packaging designs are now being used to limit degradation, but control of storage conditions from the warehouse to the point of sale is of major importance. - There are a number of difficulties in conducting shelf-life determinations with complex products, and often simplistic parameters are used, such as the colour and consistency of the formulation in addition to chemical evaluation. - Further, detailed real-time and accelerated testing may be performed at specific temperature and humidities, as for conventional pharmaceuticals. - These techniques are particularly useful to speed up data collection and for determining suitable formulations. ### Bioequivalence of Different Formulations - The issue of bioequivalence of different formulations of conventional pharmaceuticals is well understood. - Data from studies of different formulations of a limited number of single-component herbal medicines show variable plasma concentrations. - Major complications occur when an herbal medicine's activity is derived from a range of components. - In this instance, plasma concentrations are often insufficient to determine the levels of activity and therefore assays for effects on biomarkers are required to show comparative activities of different formulations. - Further problems are clearly evident when the active constituents of a plant-based product are unknown, which is often the case.