The demand for excipients is likely to exhibit a steady growth with the pharmaceutical excipient global market poised to grow at a mid-range single digit CAGR to reach $7.7 billion by 2022, according to a new study.
North America holds the largest share in the pharmaceutical excipient market due to rising demand for pharmaceutical and biopharmaceutical drugs and presence of a large number of excipient manufacturers in this region. Europe holds second major share followed by Asia-Pacific and Rest of the World.
Asia-Pacific is the fastest growing region for pharmaceutical excipients where emerging countries such as China and India are the major players due to low labour costs, increased outsourcing of inorganic & organic chemicals manufacturing and increasing governmental spending on health care.
According to Manoj Palrecha, managing director, Lake Chemicals,India accounts for 50 per cent of the production of these substance which are formulated alongside the active ingredients by companies. The remaining 50 per cent are sourced from China and Europe.
With regards to intermediates, 80 per cent of the intermediates are imported and these are largely from China. This indicates the level of dependence on this dragon land, said Palrecha.
The role of excipients
Excipients play a key role in any pharmaceutical formulations along with active pharmaceutical ingredient (API). In fact excipients act as inert ingredients as carriers for drug component in any formulation and also facilitate sophistication of dosage forms for specialised purpose like controlled release/ sustained release dosage forms imparting well-controlled physicochemical characteristics as required for the purpose.
Now excipients are included for the purpose of long-term stabilization, bulking up solid formulations. These are fillers, or diluents to enhance the therapeutic compliance. The excipients improve API stability including protection from degradation. It also ensures a robust and reproducible physical product. Some of the excipients are Diluents, like for instance lactose, microcrystalline cellulose. Then there are disintegrants like sodium starch glycolate, croscarmellose sodium. Binders are PVP, HPMC. The lubricants are magnesium stearate and Gl idants, are colloidal silicon dioxide.
The use of ‘Inert ingredients’ as carriers for drugs can be traced back to the preparation of the earliest medicines. The ancient Egyptians and ancient Greeks compounded rudimentary medicines and formulated creams and ointments and the father of formulation Science is generally held to be Galen (c.130- c.200 AD).
Traditionally, excipients have been defined as inert substances used as diluents or vehicles for drug formulations i.e. components of a formulated drug product other than the active ingredient.
IPEC (International pharmaceutical Excipients council) defines an excipient as any substance other than the active drug. Excipients are a natural or synthetic substances formulated alongside the active ingredients of a medication included in formulations for the purpose of long term stabilization, bulking up solid formulations containing potent active ingredients often referred as ‘bulking agents’, ‘fillers’ or ‘diluents’ or to confer a therapeutic enhancement on the active ingredient in the final dosage form of pharmaceutical formulations. These may be used for facilitating drug absorption reducing viscosity, or enhancing solubility.
Excipients can also be useful in the manufacturing process, facilitating powder flow ability or non-stick properties, prevention of de-naturation or aggregation over the expected shelf life and aiding to stability.
The excipients form the major part of any medicinal product and proportion of it when compared to API exceeds two to three fold in any pharmaceutical preparations. Hence, various characteristics such as functionality, regulatory status, sources, cost, consistency, bioavailability, physicochemical properties, stability, and pharmacokinetic parameters etc. play a major role in determining the suitability of a substance as an excipient.
A pharmaceutical excipient is a substance-either natural or synthetically formulated-that serves multiple purposes in a medicines and drugs. It is used as a bulking or stabilizing substance, as an agent to enhance the solubility of a drug, or as an ingredient that enhances the therapeutic effect of a drug.
There are also some excipients that may lend more value during the manufacturing or handling process of a drug or medicine. Excipients are also used in applications where the in-vitro integrity and stability of drugs need to be preserved. The type and volume of excipient added to a pharmaceutical formulation depends largely on whether the drug is to be administered orally or intravenously. Since certain excipients may effect an undesirable chemical reaction when used alongside an active ingredient or in a certain environment, the select ion of the excipient needs to be made carefully.
Although excipients are used in chemicals and food and beverage sector as well, their use is very closely regulated in the pharmaceutical sector. This puts considerable pressure on manufacturers of pharmaceutical excipients who have to follow numerous process-related and regulatory procedures to bring their products to the market. Besides this factor, a slight but steady decline in the investment inflow in pharmaceutical R&D projects could act against the growth of the global pharmaceutical excipients market.
Opportunities in the global pharmaceutical excipients market are primarily centred on the growing scientific understanding of functionality excipients.
Excipient types
If broadly classified according to type, the global market for pharmaceutical excipients can be segmented into organic and inorganic. Carbohydrates and petrochemicals are the two main classes of organic excipients. Inorganic excipients include such substances as metal oxides, calcium carbonates, calcium phosphates, and halites.
Excipients can be used in different types of drug formulation, including but not limited to: oral formulation such as capsules and tablets, parenteral drugs, topical application drugs, and advanced drug delivery systems. The use of excipients in oral drug administration has traditionally been the highest and continues to stay so. Topical drugs are infusing new growth into the global pharmaceutical excipients market. Based on functionality, pharmaceutical excipients serve as flavoring agents, binders, coatings, preservatives, viscosity agents, lubricants, and more.
Organizations such as the International Pharmaceutical Excipient Councils function on the global and regional level to promote the proper and safe usage of pharma excipients.
General categories
Excipients fall into two following general categories. These are excipients having monograph in the various Pharmacopoeias and excipients not having monograph. Excipients with pharmacopoeial status have generally been well accepted as formulation components by regulatory bodies. However, pharmacopoeial status takes no account of safety issues and there are no regulatory bodies in the US or Europe to examine the safety and quality of pharmaceutical excipients per se. In effect, there is no such thing as an officially approved pharmaceutical excipient.
Pharmaceutical regulations and standards require that all ingredients in drug formulations be identified and shown to be safe. Though excipients were at one time assumed to be ”inactive” ingredients, it is now understood that they can sometimes be “a key determinant of dosage form performance” i.e. effects of excipients on pharmaco-dynamics and pharmacokinetics although usually negligible. In more recent years other routes of administration such as the transdermal route have been developed which call for increased sophistication of dosage forms apart from traditional tablets and capsules. In recent years new excipients have been developed to keep pace with new developments in drug delivery technology where excipients influence the bioavailability and disposition of drugs.
The United States Pharmacopoeia / National formulary (USP/ NF) distinguishes an ‘official substance’ from a ‘dosage form‘. The former ‘contains no added substances’ (i.e. excipients) ‘except where specially permitted in the individual monograph’.
Furthermore the USP states that suitable substances such as bases, carriers, coatings, colours, flavours, preservatives, stabilisers, and vehicles may be added to a pharmacopoeial dosage form or finished device to enhance its stability, usefulness, elegance or to facilitate its preparation but that such substances are regarded as unsuitable and prohibited unless they are harmless in the amounts used in formulation, do not exceed the minimum quantity required to provide their intended effect, do not impair the bioavailability or the therapeutic efficacy or the safety of the dosage form, do not interfere with the assays and tests prescribed for determining compliance with the pharmacopoeial standards and do not affect stability of dosage form. Similar considerations apply in the British Pharmacopoeia. In certain cases the absence of an excipients may be detrimental to product performance or safety of the product as a whole.
Excipients improve efficacy of formulations
Excipients can influence the bioavailability of active ingredients in formulation and thus assist in improving the efficacy of the drug product as a whole. In modern drug delivery systems certain excipients have a well-defined function. The use of transdermal absorption enhancers such as surfactants or solvents such as propylene glycol is well established. Propylene Glycol (PG) has been demonstrated to aid the skin permeation of steroids and metronidazole .
It is possible that PG acts as a penetration enhancer by affecting the integrity of the skin barrier but it may just act as a solvent for drugs during their passage through the stratum corneum. The role of polymers such as the Eudragit series is well known in the design of enteric-coated or modified release oral dosage forms. Hence role of specialized excipients to achieve a certain bioavailability profile, site-specific delivery or therapeutic effect in modern pharmaceutical technology become important with advances in pharmaceutical science.
Safety issues of excipients
Excipients can optimise the efficacy of a drug in a given formulation but it is also essential that they should not add their own adverse reactions or otherwise compromise the safety of the product. But literature suggest that some commonly used excipients can elicit physiological responses in susceptible individuals. Example lactose which is commonly used excipient in various formulations. However, risk of adverse reactions to commonly used excipients is negligible.
Excipients used in the manufacture of pharmaceuticals products are not approved in their own right either in Europe or the US. They are generally reviewed as part of the overall regulatory evaluation of the safety of pharmaceutical products. Excipients are categorized as compendial or non-compendial materials. Compendial excipients have composition consistent with monographs published in compendia such as USP-NF. They are preferred for pharmaceutical formulations.
Excipients approval in US and Europe
In United States, government bodies have established acceptable levels of excipients in dosage forms on an indirect basis. FDA (US) generally uses information submitted in an NDA (New drug application) or Drug Master File (DMF) to determine whether an individual excipient is safe. Excipient used must be ‘generally recognized as safe’ (GRAS). The excipients already included in NF are acceptable by FDA for use in formulations.
In Europe similar considerations apply. However, EC directive 91/507/EEC has classified ‘starting materials’ (active ingredients and excipients) into ‘starting materials listed in pharmacopoeias’ and ‘starting materials not in pharmacopoeias’. The requirements for excipients will be set out in a new CPMP guidelines: ‘Excipients in the registration dossier of a medicinal product’ (III/3196/91). The suggestions were that excipients need to be declared qualitatively and quantitatively on the labels of parenteral and other products.