The basic drug substances, often known as Active Pharmaceutical Substances (APIs) are rarely used as such. They are converted into suitable dosage forms (or drug delivery systems) using pharmaceutical techniques so that the drug is made available in a stable, convenient, effective and economic way. Another important aspect of dosage form design is that they should be capable of large-scale manufacture with consistent product quality.
The pharmaceutical scientists or professionals use a variety of other substances to develop these dosage forms. These other substances are known as excipients. Without the use of excipients the development of dosage form is impossible. The word excipients is derived from the Latin word 'excipiens' which means to receive, to gather, to take out.
The excipients function widely. They aid in processing of drug delivery system during its manufacture; protect, support or enhance stability, bioavailability or patient acceptability; assist in product identification and enhance any other attribute of the overall safety and effectiveness of the drug during storage or use.
Though initially by definition, the excipients are pharmacologically inert substances, it no longer holds good. Like active drug, they too have their own activity leading to drug degradation to causing toxic effects on users. As the drug products are required to be safe and effective, so as the other ingredients (excipients) too needs to be safe and effective in terms of their function (not pharmacologically).
While the safety and efficacy both were of equal concern for the drug from the beginning, the importance of safety of excipients is painfully recognised very late only in 1938 following diethylene glycol tragedies in USA. In this incident, more than 100 children died of diethylene glycol poisoning where this was used as solvent to make sulphanilamide elixir. Sulphanilamide was not soluble in other common solvents of the day. This has resulted the enactment of Federal Food, Drug and Cosmetics Act 1938 and creation of Food and Drugs Administration (FDA) to administer the Act. This was not the only diethylene glycol poisoning case, there are many other instances around the globe like deaths of 80 children during 1995 and 1996 following ingestion of cough and cold syrup containing glycerol contaminated with diethylene glycol. Similar reports of deaths on use of paracetamol liquid product also appeared in India.
There was another important incident where change of excipient (diluent) in phenytoin capsule formulation from calcium compound to lactose resulted in outbreak of neurological disorder in epileptics in Australian cities in 1968. This was due to increased phenytoin concentration in patients because of change in diluent. Osmotic diarrhoea caused by ingested mannitol, hypersensitive reactions from lanolin, cardiotoxicity induced by propylene glycol, benzyl alcohol induced toxicity in neonates, aspartame induced headache and seizures, cross sensitivity reactions to saccharin in children with sulphonamide allergy and dye induced reactions in patients with aspirin sensitivity are just few more examples of toxicities associated with excipients used in dosage form design.
Like drugs, excipients too are obtained from animal, plant, mineral and synthetic sources. They have substantial impact on the manufacture and quality, safety and efficacy of drug substances in a dosage form. Impurities present in the excipients are carried over to the finished dosage form. The inclusion of D-manitol and macrogol 400 (Poly Ethelene Glycol 400) in vancomycin intravenous infusion have shown to have protective effect against nephrotoxicity of vancomycin.
These clearly demonstrate that the excipients are not inert as they are generally believed to be. Some of the scientists continue to argue that there are no things like pharmaceutical active substances and other substances in the formulation have no activity or functions. Like drugs, the excipients too require attention from manufacturers of excipients, manufacturers of dosage forms and the regulatory authorities.
The World Health Organization (WHO) has realised the importance of quality of excipients and accordingly designed Good Manufacturing Practice (GMP) guidelines for the manufacture of excipients. The manufacturers of excipients should identify the impurities. This should be based on appropriate toxicological data or limits as described in official compendia.
The manufacturers of formulations need to be more careful as they have primary responsibility of ensuring safety and efficacy of their products. They need to use only the approved excipients.
Since the first incidence of tragedy associated with pharmaceutical excipients, the regulatory bodies have been more careful ensuring the safety of pharmaceutical products. In order to ensure the safety and quality of excipients to be used in pharmaceutical products, the various pharmacopoeias of the globe have monographs of approved excipients.
The USFDA has guidance document "Non Clinical Studies for Development of Pharmaceutical Excipients". This was released to foster and expedite the development of new but safer excipients. The document provides guidance concerning development of safety profiles to support use of new excipients as components of drug or biological products. This guidance describes the types of toxicity data that the agency uses in determining whether a potential new excipient is safe for use in human pharmaceuticals. It discusses recommended safety evaluations for excipients proposed for use in OTC and generic drug products and describes testing strategies for pharmaceuticals proposed for short-term, intermediate and long-term use. It also describes recommended excipient toxicity testing for pulmonary, injectable and topical pharmaceuticals.
Similarly other regulatory bodies too have their own mechanisms: European Union requires evaluation of novel excipients as new chemical entities; Japan has a separate evaluation process for novel excipients. There are others who do not have clear guidelines for introduction of new excipients. They still rely on the basis of approval in other countries or existing safety data from their long standing use.
The lack of international regulatory guidelines on the excipients approval has led to the formation of international Pharmaceutical Excipients Council (IPEC) in 1991. This council has developed the safety evaluation of new excipients for pharmaceutical use. The regulatory bodies may use this for assessing the safety and approval.
As the focus of research on new drug discovery becomes extremely risky and more attention is now towards developing newer and more sophisticated delivery systems, there would be increasing demand for new and innovative excipients too. The newer strategies become a necessity for all concerned to ensuring the safety of such materials so that the tragedies may not happen again. At the same time it is also necessary to develop mechanism to name excipients in internationally acceptable nomenclature to avoid mislabelling and misunderstanding.
The regulatory authority should also make it mandatory for the formulation manufacturer to mention the name of the excipients on the label of the product or package. The provision of non-medicinal ingredients information on packing, patient information leaflets and prescribing information would help preventing excipient related toxicity.
The authors are with the Dept of Pharmacy, Annamalai University