When we think of any wonder drug ,we immediately think of the active pharmaceutical ingredient (API). But no one bothers about the modest excipient. This is because these are considered to be "inert" rather than "active," mere fillers that allow the finished formulation to be formed and carried within the patient's body.
The International Pharmaceutical Excipients Council (IPEC) defines an excipient as any substance other than the active drug or prodrug that is included in the manufacturing process or is contained in a finished pharmaceutical dosage form.
Although listed as inactive ingredients by FDA, excipients generally have well-defined functions in a drug product. The excipients may be small molecule or complex and may vary in terms of degree of characterization. They may be chemically synthesized or may be either natural source or biotechnology-derived (recombinant). In contrast to active ingredients, minor components of an excipient may have significant impact on its pharmaceutical performance. One interesting fact is that an excipient in a drug product may be an active ingredient in another formulation, depending on its intended use.
Currently, control of excipient manufacturing and distribution is not the priority for regulatory authorities or pharmaceutical manufacturers, perhaps due to the fact that most of these excipients originated from the food industry and have generally recognised as safe (GRAS) status. However, with the emergence of novel excipients and delivery systems, better control of these materials becomes increasingly important.Now -a - days, regulatory bodies and manufacturing facilities are paying a whole lot more attention to excipient issues, as these supporting actors play a crucial role in the final drug formulation and in ensuring patient safety. The wrong excipient can interact with an active ingredient, hurting patients, while a contaminated or fake one can lead to adverse patient responses, or worse. Consider natural products, starch processed from corn grown during a dry season may bear little resemblance, when its physical properties are measured, to starch made from corn grown from a rainy season. Lactose made from the milk of cows who have been fed on winter silage will differ dramatically from that made from the milk of cows fed on grass. But still, in both cases, the materials are considered to be similar when formulating.
It started in the 1980s when physicians began to explore the excipients' role in adverse patient responses. An article,published in 1994, in the Canadian Medical Association Journal, turned the phrase "out of sight, out of mind" on its head. It opined for complete disclosure of all ingredients, active and inactive in any drug formulation, something that we now take for granted.
Each and every component of prescription drug formulations - excipients, additives and active ingredients - should be listed on the label, where they can be read by physicians, nurses, pharmacists and patients. Without easy access to this information one cannot recognize and appropriately treat adverse reactions, and the safety and efficacy of any drug formulation cannot be established. It is unacceptable that health care professionals or patients must query a third party (the manufacturer) to determine the ingredients in a drug formulation.
Adverse drug reactions (ADRs) were studied extensively from the 1960s through the early 1980s, primarily in hospitals. The problem of ADRs was found to be widespread and serious enough that in 1968 the World Health Organization (WHO) started ADR surveillance program, which continues till today.
Canada was one of the 10 countries that founded the program. ADRs are a widespread and serious problem, but what portion of the problem is due to excipients is not known, but it is much larger than generally thought. Very rarely is a patient given a pure chemical or "active ingredient" as a therapeutic agent. Each formulation may contain 1 to about 30 excipients or additives. Just to name a few, the excipients include fluorotrichloromethane (Freon 11), dichlorodifluoromethane (Freon 12), phenol, benzyl alcohol, formaldehyde, sorbic acid, thimerosal, tartrazine and other dyes, gluten, ethanol, aspartame, lactose, propylene glycol, talc, povidone, polyethylene glycol, perfumes, lanolin, polyethoxylated castor oil and sulfites.
Poisoning caused by excipients
A huge number of serious ADRs are caused by excipients. Geiling and Cannon reported 76 deaths from acidosis and renal failure following the use of elixir of sulfanilamide; for this, the excipient diethylene glycol was found to be the cause. There were later reports of more than 100 deaths. The toxic nature of diethylene glycol was noticed again some 50 years later by Cantarell and collaborators. They described oliguria and acidosis in patients with burns who were treated with topical antibacterials containing diethylene glycol.
One could easily assume that adverse reactions to diethylene glycol had continued during the intervening 50 years; failure to diagnose these reactions may have resulted from diverse factors, including the belief that excipients were safe and ignorance about which excipients were found in drug formulations. Dilantin, a brand of phenytoin, had been sold for many years in Australia and New Zealand when the manufacturer decided to change the formulation to the one used in the United States.
Consequently, 51 patients whose epilepsy was stable with the use of the old formulation had severe and serious adverse reactions, including coma, with the new product. The reformulation involved replacement of calcium sulfate dehydrate with lactose, a seemingly innocuous change. However, it appeared that the calcium salt slowed absorption of the phenytoin, whereas lactose speeded it up. It was in 1982 when benzyl alcohol was implicated in the "gasping" syndrome as well as the deaths of premature infants who received the medication containing this excipient. Benzyl alcohol was also the involved in the exacerbation of asthma following intravenous administration of a hydrocortisone formulation.
The great words "out of sight, out of mind" hold true in the attribution of an adverse reaction to an unknown or undisclosed excipient in a drug formulation.
In a number of investigations of an ADR, when the patient showed a positive sign of a challenge with the suspected drug formulation, investigators concluded that the cause of the reaction was the active ingredient because it was the only constituent known; the rest of the formulation was considered inert. Luckily, a few sceptics in the medical community investigated not only the drug formulation but also each substance in it and combinations of ingredients.
In 1984, advice was taken for the management of a recurrent upper respiratory tract infection in a child. The infection tended to be refractory because the patient was hypersensitive to penicillin and its derivatives. A liquid oral erythromycin preparation (125 mg/mL) was prescribed. Just after the first dose, the patient suffered severe abdominal pain, nausea and vomiting. It was doubted that the child had an allergy to erythromycin, and so the physician prescribed another formulation of erythromycin (250 mg/mL). With this formulation the child suffered no adverse reaction; but; some time later, a local pharmacist disregarded the physician's "no substitution" order and substituted the 125 mg/mL formulation. The child again experienced the pain, nausea and vomiting.
When informed about the consequences, the pharmacist said, "The active ingredient is the same; the colouring and flavour don't matter." Actually, the child had reacted to the tincture of orange used as a colouring and flavouring agent in the 125 mg/mL formulation. The 250 mg/mL preparation did not contain tincture of orange, although the products were manufactured by the same company.
Don't ignore excipients !
In the world of today, Commercially available excipients provide a variety of required functions, from processing aids that increase lubricity, enhance flowability, and improve compressibility and compatibility to agents that impart a specific functional property to the final product. The US Pharmacopeia-National Formulary (USP-NF) categorizes excipients as binders, disintegrants, diluents, lubricants, glidants, emulsifying-solubilizing agents, sweetening agents, coating agents, antimicrobial preservatives, and so forth.
Additionally, excipients should be chemically stable, non-reactivee with the drug and other excipients, inert in the human body, have low equipment and process sensitivity, have pleasing organoleptic properties, and should be well characterized and well accepted by the industry and regulatory agencies. A limited choice of excipients with all of these attributes and presently available in the market can make formulation design and excipient selection challenging.
Although practitioners know the active ingredient in a drug formulation, they are unaware about the unlisted excipients. Inpatients in the study by Borda and associates were taking more than seven medications on average, meaning that each patient was exposed to some 8 to 100 substances. Some of these substances may have been in several of the formulations, which would increase the risk of a toxic reaction in a sensitive patient.
All said and done, the formulations should be simplified as much as possible, so as to reduce the number of excipients to those strictly necessary to fulfil the required functions of the medicinal product. In the same way as for the active principles, the risk/benefit ratio of an excipient should be evaluated on the basis not only of its performance, but also of its safety.
Now it's the right time to take a new look at some fundamental safety aspects from the pharmaceutical and the toxicological points of view.
The author is Process Excellence Group,Tata Consultancy Services, Uttar Pradesh