Adding that “spoonful of sugar”—and more

The reason that different medicines—and even many of the same kind—can show up in thousands of dissimilar forms lies not in the active ingredients themselves, but in the hundreds of different inactive ingredients, or excipients, that are used in the delivery of each therapeutic product. Excipients package active ingredients into discrete amounts that are easy to handle, give medications a specific look and color for branding purposes, or imbue unpleasant-tasting medication with an agreeable flavor to help with patient compliance, among hundreds of other uses.

Although these ingredients are chosen to be biologically inert and nonreactive with the active ingredients, recent studies have shown that patients can and do display different responses to the same drug, depending on the excipients with which it is made. This can lead to problems in prescribing generic medications, in which the same active ingredient can be packaged in different ways. In addition, some patients experience allergic reactions to many common excipients, making it impossible for them to take some commercially available medications.

A long history of inactivity
From a “spoonful of sugar” to the most complicated drug delivery system currently in the works, almost every drug needs a few inactive ingredients to help the medicine go down.

“The first excipient was probably a piece of parchment in which someone put some magic ingredient, folded it over, and said, ‘Look, take this back home, and take the powder and drink it,’” said Louis Blecher, a retired excipients expert who currently works as a consultant for the International Pharmaceutical Excipients Council (IPEC). IPEC is an international trade association for excipient manufacturers, with headquarters in the United States, Europe, and Japan.

As time passed and drug delivery methods became more complicated, says Blecher, more excipients were added to serve different purposes—for example, a binder to hold ingredients together so they won’t fall apart too fast in the digestive tract; lubricants to help remove tablets from machines, where they’re manufactured in bulk; and dyes and printing inks to color-code different brands of medication so they’re easy to tell apart. For oral drugs, these ingredients must all be easily digestible and physiologically inert or inactive. All excipients, no matter what form of medication they’re in, must be safe and cannot harm the efficacy of the active drug.

When pharmacists looked for ingredients to fill their individual needs, they found virtually all of them in chemicals that already existed. “Almost all of the excipients in common usage were invented for something else, and somebody found out they were useful in pharmacy,” says Blecher. “Most of them were foods, originally.”

A chicken-and-egg ordeal
The U.S. FDA has approved at least 773 additives for use in prescription and over-the-counter drugs. Almost 400 of these additives are in the National Formulary (NF), a comprehensive manual that details standards for the description, identification, allowed impurity level, and strength of materials allowed in pharmaceuticals. The NF is compiled by the U.S. Pharmacopeia (USP), a private organization established to set standards to ensure the quality of medicines for human and veterinary use.

Each excipient cataloged by the USP fits into one of 40 categories, which include binders, disintegrants, fillers, lubricants, and sweeteners. Excipients listed for each category range from compounds as well known as water and alcohol, both used as solvents, to those as curious as microcrystalline cellulose (otherwise known as ground-up wood pulp), a bulking agent.

According to Irwin Silverstein, COO for International Pharmaceutical Excipients Auditing, Inc., a subsidiary of IPEC that monitors excipient manufacturers for good manufacturing processes, very few new excipients have been approved for pharmaceutical use in the past several decades. The reason? For a product to appear in the NF, it must either be on the GRAS sheet—“generally recognized as safe” by the FDA—or have been used in a pharmaceutical approved by the FDA. However, for a new excipient to be approved for pharmaceutical use, it must already be in the NF, or risk being rejected by the FDA—a rather chicken-and-egg ordeal.

“The problem with going the latter route is that a pharmaceutical company is going to bet hundreds of millions of dollars it takes to develop a new drug on a chemical to be used as an excipient that the FDA could turn around and say shouldn’t be there. If the FDA could refuse that drug application or disagrees that this material can be used as an excipient, then you have to start all over again,” said Silverstein. “Unless you have no alternative, you’re not going to risk your application on a new entity.”

Generic nonequivalents
But even having a product listed in the NF doesn’t guarantee its safety for everyone. Many patients are sensitive to common drug additives that can appear in name brand, generic, and over-the-counter drugs. The problem is especially pronounced for users of generic drugs, who may experience completely different reactions when switched to a generic medication from the name brand version. While generics are required to contain the same active ingredient, they sometimes include entirely different excipients than their name brand “equivalents”.

In a recent study presented at the Canadian Cardiovascular Congress 2001 in Halifax, Nova Scotia, researchers showed that some patients experienced pulmonary difficulties and abnormal ratios of drug metabolite concentrations after switching from Cordarone, a name brand drug used to correct irregular heartbeats, to its generic version, amiodarone. When the patients were placed back on Cordarone, their problems subsided in a period of several days to a few months.

In another example involving different responses to a generic drug versus a name brand, a letter appearing in The Lancet expressed concern about the use of docusate sodium and magnesium stearate as fillers in generic co-trimoxazole DS tablets (Lancet 1996, 347, 9001). Co-trimoxazole DS is often used to treat Pneumocystis carinii pneumonia, a life-threatening form of pneumonia contracted by patients infected with HIV. However, docusate sodium and magnesium stearate are known to cause laxative effects. In the doses that AIDS patients must take, the letter says, these fillers might exacerbate the chronic diarrhea, nausea, and vomiting that often accompany this disease.

Researchers and physicians have recognized many instances in which generics cannot be substituted for name brand medication; 14 categories of unsuitable substitutions are listed in The Merck Manual of Medical Information: Home Edition, a medical reference for prescription drugs. These categories include drugs that were on the market before the 1938 amendments to the Food, Drug, and Cosmetic Act and several different drugs that possess a “narrow therapeutic index”, or NTI. Drugs with an NTI can cause toxic side effects or loss of disease control if they are absorbed or released at even the slightest changes in dosage, whether too high or too low.

The Center for Drug Evaluation and Research gave some examples of NTI drugs in a 1995 report. These include conjugated estrogen (Premarin), a hormone replacement; phenytoin (Dilantin) and carbamazepine (Tegretol), both anticonvulsants; and cyclosporine (Sadimmune or Neoral), an organ transplant antirejection drug.

Additive allergies
Some patients have the bad luck of being allergic to additives that appear commonly in many medications, including those sold over the counter. Ironically, sometimes the medications that patients take to ease symptoms of their allergic reactions actually contain excipients that cause the reactions themselves.

For example, sulfites, which are used to maintain the stability and potency of many anti-asthma drugs, can cause bronchioconstriction in some asthma sufferers. In addition, a small minority of those allergic to aspirin are also allergic to tartrazine, also known as FD&C Yellow No. 5. This dye is present in some nonaspirin pain medications taken to ease the swelling of an allergic reaction.

Perhaps one of the most paradoxical examples of medications taken to stem allergic reactions they inadvertently cause is the case of lactose-intolerant individuals, who are sometimes prescribed dozens of drugs containing lactose to quiet their gastric distress. Lactose, also known as milk sugar, is often used as a filler in tablets and capsules or as an anticaking agent in chewable medications, or it is sprayed onto a pill to produce a hard, shiny coating. Most pills containing this excipient have no more than 12.5 to 25 mg of lactose, compared with the 12,000 mg found in the average glass of milk. However, an individual chewing dozens of antacids containing lactose during the day may find his or her symptoms getting worse instead of better.

Compounding is helpful when a patient needs a strength of medication that isn’t commercially available or when a medication’s instability makes it preferable to prepare small amounts to be used more frequently. However, it is an ideal practice for patients who want to be able to take an active ingredient but still avoid a specific excipient. By using preparations that are missing the offending ingredient, a patient who is allergic can still consume a drug’s active ingredients without suffering an allergic reaction.

“This is a different setup, for sure,” said L. D. King, the executive director of the Inter national Academy of Compounding Pharmacists (IACP). “These pharmacists have a lab with an analytical balance, capsule-making equipment, the whole nine yards.”

King explained that a compounding pharmacist buys the active ingredient, such as ibuprofen, and whatever excipients he or she needs to deliver the product to the body.

“They can buy lactose, but in this case, if the patient is allergic to lactose, they can buy a different kind of excipient, like corn starch. Then they prepare the tablet, capsule, suspension, solution, suppository, or whatever, in whatever dosage forms they need. It’s really endless,” he said.

However, although all pharmacists are licensed to practice compounding, only a few are still trained to do so. A small number of schools still offer a wet lab to teach compounding, and some pharmacy organizations present continuing education courses for pharmacists interested in learning. IACP represents more than 1300 pharmacists in the United States and Canada and promotes a referral service through its toll-free phone number (800-927-4227) and website (www.iacprx.org/referral_service/index.html).

Even with the aid of compounding, adds Blecher, it’s impossible to avoid excipients entirely. “There’s no way you’re going to put an active drug on the market without the help of a lot of excipients.” Because that spoonful of sugar—and its ilk—still helps the medicine go down.

Suggested reading

• International Pharmaceutical Excipients Council; www.ipec.org.
• U.S. Pharmacopeia; www.usp.org.
• Allergy Guide for Food and Drug Allergies; http://allergies.about.com/cs/additives/.

Christen L. Brownlee is an associate editor of Modern Drug Discovery. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.