|More than just the sugar in the pill
Excipients are the chemicals that carry the medicine in powders, potions, pills, and poultices.
Not many think of the drug market in terms of large-scale chemical production, but along with some of the medicines produced in bulk like aspirin, for example, some 600,000 tons of pharmaceutical excipients are produced annually. Often referred to as inert ingredients, excipients are the fillers that allow the proper delivery of the active therapeutic compounds contained in nearly all over-the-counter and prescription drugs. They also serve critical functions in facilitating the industrial production of medicines.
The excipient products themselves range from simple sugars to various polymers, complex carbohydrates, and even, in more recent times, recombinant human and animal gelatins. Although all excipients are rigorously tested and most are recognized as safe in food production, theyrather than the drug itselfcan sometimes cause side effects in patients. These side effects from excipients in medications are one proposed reason for the variation in patient response sometimes seen in generic versus brand-name versions of drugs with the same active ingredients.
The International Pharmaceutical Excipients Council (IPEC) consists of three independent organizations, IPEC-Americas, IPEC-Europe, and IPEC-Japan. IPEC-Americas is the chief organization for excipient producers in the United States and fulfills a major educational and advisory role, especially with regard to excipient regulations and safety concerns. Its sister organizations perform similar functions in Europe and Japan.
Excipient manufacturers range from the chemical giants such as Dow Chemical Co. and Union Carbide Corp. to niche producers such as CHR Hansen and Shire Laboratories, Inc. The excipient market yearly ranges between $1 and 2 billion. Significantly, no player offers a full range of excipient chemistries or commands more than a 5% market share for either volume or value for the total global market, according to a report entitled The Global Excipients Market (Part 1) by IPEC-Europe in their November 2000 IPEC Europe Newsletter (available in PDF form at www.ipec.org/europe.htm).
According to IPEC, these inert ingredients are classified by the functions they perform in a pharmaceutical dosage form. The principal classifications, including a brief definition of their characteristics and some examples of each, follows below.
Binders are used to cement the active and inert components of tablets together to maintain cohesive and discrete portions. These are especially important in the production of time-release products. Binders provide the matrix from which the drug is gradually secreted. Typical binders include the cellulosics and starch.
Disintegrants help the tablets break up within the gastrointestinal track to ensure full release of the pharmaceutically active material. Microcrystalline cellulose is one such disintegrant.
Fillers (diluents) are perhaps the earliest and most obvious form of excipients. They are used not only to increase the volume of the material to accommodate easier processing of the drug (especially accurate dilutions) but also to make it a suitable size for patient consumption (1 µg of a drug or nutrient supplement such as a vitamin would hardly be a reasonably sized product to handle or take). Typical fillers include calcium phosphate (also an added source of both minerals), lactose, and soy oil (for oil-soluble drugs).
Lubricants ease the release of stamped tablets from their dies, improving the efficiency of manufacturing. Magnesium stearate is one example.
Glidants (flow enhancers) are added to powdered materials used in pill production to aid their movement through tabletting machinery. Silicon dioxide is one such.
Compression aids help to make pills hold their shape upon compression and improve compressibility properties in general.
Colors include a wide variety of dyes and coloring agents from among the more than 100 approved by the FDA for pharmaceutical use. Allergic reactions to these compounds have been shown to be a potential problem for some patients. These hypersensitive responses include contact dermatitis, abdominal pain and vomiting, and even anaphylaxis. The azo dyes (FD&C Yellow 5, Yellow 6, Red 36, and Red 17) and the triphenylmethane dyes (FD&C Blue 1, Blue 2, and Green 3) have been associated with these hypersensitive reactions. Other chemical dye categories include the quinolines (Yellow 10 and Yellow 11) and the xanthene dyes (Red 3 and Red 22).
Sweeteners are extremely common in oral medications. In a survey reported in Pediatrics in 1993 by Kumar et al., more than 90% of products evaluated contained these excipients. Aspartame, fructose, saccharin, sorbitol, and sucrose are the most commonly used sweeteners in the United States. Sweeteners are especially important for medicines directed at children; in typical oral formulations, sweeteners can make up to 3050% w/v, and in antibiotics and cough or cold medicines, its as high as 80%. The sugar-free sweeteners are especially important for chronic medication to prevent dental caries and, of course, are necessary for diabetic patients.
Preservatives are chemicals that are added to drug products to prolong shelf life and maintain sterility. The antimicrobials include chlorobutanol, benzyl alcohol, sodium benzoate, sorbic acid, and phenol. The antioxidizing agents include butylated hydroxytolune, hydroxyanisole, propyl gallate, and sulfites. However, the necessary addition of preservatives for both safety and economy sometimes has been associated with significant adverse effects in certain patient populations as pointed out in Pediatric Pharmacotherapy (see Suggested Reading). For example, benzyl alcohol was found associated with neonatal cardiovascular collapse, the gasping baby syndrome, in 1982. Subsequently, both FDA and the American Academy of Pediatrics recommended discontinuing its use for infants wherever possible.
Suspensing/dispersing agents are used to prevent aggregation of the active drug in solid or liquid form, allowing uniform concentrations to be maintained for accurate dosing.
Film formers/coatings are used to protect against premature physical breakup and to prevent unwanted environmental interactions. They can mask bad taste and allow pills to be swallowed easily. Typical pill coatings include zein, shellac, or sugars.
Flavors are both natural and synthetic amendments to improve drug palatability. This is especially necessary for children and for chronic illnesses in which medication compliance is critical. Flavors can be complex mixtures of compounds and often fall under the rubric of trade secrets, thus remaining unspecified on labels (up to 35% of products evaluated in the Kumar survey did not break down the list of flavorings). Such nondisclosure can cause difficulties in identifying often-used potential allergens such as menthol, lemon oil, and peppermint oil.
Printing inks are biologically safe dyes used for printing information or company logos on the surface of tablets or capsules.
Some materials, such as microcrystalline cellulose, can act simultaneously as a filler, binder, and disintegrant. Other multifunctional excipients include vegetable stearin (used in time-release binding and also as a lubricant) and lactose, which although primarily a diluent or filler can also have a sweetening effect.
Regulation and Production
In the United States, excipients are regulated by the FDA and must be qualified under one or more of three FDA mechanisms outlined for components used in food and/or drug usage. As outlined by IPEC, these three mechanisms are
- determination by FDA that the substance is GRAS, or generally recognized as safe, according to Title 21, U.S. Code of Federal Regulations, Part 182, 184, or 186 (21 CFR);
- approval of a food additive petition as set forth in 21 CFR 171; or
- inclusion of the excipient as part of an approved new drug application (NDA) for a particular function in that specific drug product.
Standards for excipient quality and analysis are set by the U.S. Pharmacopeial Convention, Inc., the independent body that publishes and maintains the U.S. Pharmacopeia and the National Formulary (USP-NF). Since 1980, these have been published under the same cover as the USP-NF and contain the all-important USP Reference Standards. The excipient standards (which are, in reality, monographs concerning the product) are published in the NF portion of the document and are recognized as official and enforceable by U.S. and state agencies.
Tragic Echoes in Haiti
|A major impetus to the passage of the U.S. Food, Drug, and Cosmetic Act in 1938 was the murderous action of a particular excipient used for the laudable purpose of solubilizing a particular drug. Elixir of sulfanilamide contained diethylene glycol, a highly toxic component of some modern antifreezes, in combination with the active sulfa drug. More than 100 children died.
In 1995, Haiti experienced a terrible echo of this tragedy when 80 children died from diethylene glycol-contaminated glycerine used in the manufacture of a childrens cough medicine. The convoluted trail of where the glycerine came from points out the need for international standards. According to a report by David R. Schoneker, vice chair for Science and Regulatory Policy at IPEC-Americas, the glycerine was obtained from a European distributor that represented itself as a manufacturer but was really only a repackager that had obtained the material through a series of intermediaries. The original glycerine had been produced in China, at whose border the trail turned cold because of the investigators inability to gain access to the communist country. The material was ultimately sold to the Haitian pharmaceutical company as USP-grade glycerine complete with a certificate of analysis indicating that it had been tested to meet USP specifications. The user trusted the analysis rather than perform appropriate identification testing upon receipt of the glycerine as would be required by cGMPs.
A continuing debate exists on the issue of worldwide regulatory standards, and IPEC-Americas has developed various guidelines for standardizing the format and content of Certificates of Analysis for bulk pharmaceutical excipients based on Good Manufacturing Practices standards.
Although excipients must conform with USP standards in the United States, and in the European Union by European Pharmacopeia (PhEur) monographs when available independently of USP guidance, the IPEC has developed programs and guidelines for the makers, distributors, and users of excipients internationally to help ensure appropriate quality control for their use in pharmaceutical manufacture. This is because, according to IPEC-Americas, the regulatory framework for excipients is not as well specified in most countries as it is for bulk active drug substances. One particular tragedy in Haiti prompted a more severe look at the situation (see box, Tragic Echoes in Haiti).
According to IPEC and other analysts, industrial research into totally new excipients is rare. This is due to the simple fact that the economic margin on excipients is vastly below that of actual drug compounds. Because excipients are part and parcel of drugs consumed, any new excipient compound would have to be assessed in almost the same extensive, and expensive, manner as a new pharmaceutical. This assessment could include potential clinical trials for it to be approved in countries with strong regulatory controls such as the United States. The so-called chilling effect on developing new delivery systems of the difficulties of qualifying a new excipient for pharmaceutical use is given as one of the chief reasons for the formation of IPEC in 1991.
Because of the aforementioned difficulties, the bulk of research into future development of excipients exists in the form of modification or new combinations of the already used chemicals to improve or expand their functionality. This can be done by adding side chains or by changing manufacturing processes to create new physical forms of polymeric compoundsthat is, to change inner pore sizes or overall hardness, thereby changing delivery properties for releasing the associated drug molecules. Cyclodextrins and N-vinyl-2-pyrrolidone polymers are some examples of materials amenable to such manipulations.
Still, functional excipients may not really be a new issue for debate, even in the industry itself. As pointed out above, almost all of these so-called inert ingredients have traditionally performed necessary or desirable functions in enhancing drug delivery, not just manufacturing. So some researchers in the field bridle at the label functional excipients, abjuring it as a new concept. They claim the term is either oxymoronic or misleading. But as drugs become more complex, participation of the excipients in efficacy and delivery becomes more and more important, treading a fine line between filler and cotherapeutic agent. Excipients can enhance solubility, participate in transport across membranes in the body, and enhance powdering and dispersion of drugs used in inhalants (such as used by asthma sufferers).
Many hope that these enhanced and altered excipients may help to reinvigorate a scientifically and economically mature field, improving both the economic picture for manufacturers and the health potential of patients.
Ultimately, the chemical industry, as a whole, and individual consumers have even more reason to be interested in the production and fate of these so-called inert ingredients. Increasingly, excipients will be involved in enhancing drug delivery and activity as partners in the pharmaceutical economy and the health revolution that genomics, bioinformatics, combinatorial chemistry, and high-throughput screening continually promise. Certainly, they are far more than just the sugar in the pill.
A Guide to Pharmaceutical Excipients. Pediatric Pharmacotherapy: A Monthly Review for Health Care Professionals at the Childrens Medical Center, Vol. 2, Sept 1996, http://avery.med.virginia.edu/medicine/clinical/pediatrics/CMC/pedpharm/v2n9.htm (accessed Dec 2000).
Flickinger, B. Functional ExcipientsGetting Creative with the Chemistry. Pharmaceutical Formulation and Quality Magazine, Dec 10, 1999, http://pharmaquality.com/excipien.html (accessed Dec 2000).
International Pharmaceutical Excipients Council, www.ipec.org (accessed Dec 2000).
The Encyclopedia of Controlled Drug Delivery; Mathiowitz, E., Ed.; Wiley & Sons: New York, 1999.
Rogers, R. S. Cinderellas of the Drug Industry. Chem. Eng. News 1999, 77 (47), 35-41.
Mark S. Lesney is a senior editor of Todays Chemist at Work.
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