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Sonal Sekhar M*, Jiny Varghese K, Aneesh T P, Deepa T Vasudaven, Revikumar KG *Lecturer (Pharmacy Practice), Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham University, AIMS Healthcare Campus, Elamakkara (P.O.), Kochi, Kerala, India: 682026, E-mail: ask4sonal@yahoo.co.in Fax: 0484-2802141, Phone: 0484-2802140 / 2802141 / 2801234 / 28018275

Emerging Role of Excipients in the Pharmaceutical Industry

Novel drug delivery systems are developed to address the challenges of drug development such as bioavailability, permeability, and poor solubility. These demand changes in the conventional use of excipients. The growth of the biotechnology industry, including stem cell therapy, vaccines, and genetic products, also necessitates different drug delivery requirements. Global excipient markets are expected to grow rapidly with the emerging trends in the pharmaceutical industry. The pharmaceutical industry is marketing refinement in the physical structure of active pharmaceutical ingredients (APIs). The need of a parallel refinement in the excipient sector is very much obvious. www.pharmabioworld.com

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he emergence of novel drug delivery platforms can rearrange markets and propel the demand for excipient compounds that cater to the specific needs of the system. There is a strong need and necessity to increase awareness about new excipient developments among pharmacy professionals and other technocrats. Excipients (additives) are compounds other than the active ingredients that are intentionally incorporated into pharmaceutical dosage forms. They play specific functional roles in the formulation of dosage forms. The symbiotic relationship between the pharmaceutical and the excipient industries shows that both of them have the same fluctuations in the drug usage trend. In the case of most dosage forms, the quantity of one or more excipients is greater than the quantity of the active pharmaceutical ingredients (APIs) present in them. The importance of an excipient was recognized after the occurrence of phenytoin toxicity in Australia in 1968. The pharmaceutical firm, which was marketing Dilantin Sodium Capsules, was using calcium sulphate as an inert diluent. When stocks of calcium sulphate got exhausted, and there was a delay in getting a new stock of it, the manufacturing chemist substituted it with lactose with the permission of the company authorities. They did not think that such a minor change in diluents would affect the formulation. But with the reformulated batch of the capsules, the plasma concentration of phenytoin increased drastically and reached around 30 mg/ml leading to its toxicity. The higher plasma levels of phenytoin were due to the wetting properties of lactose. The easy wetting of lactose resulted in faster dissolution with quicker absorption. This consequently led to higher plasma concentration and resultant toxicity. Again, in 1971, it was demonstrated that for the same technical reasons, different digoxin formulations yielded different blood levels of the drug.1,2 Like APIs, excipients are also derived from natural sources, synthesized chemically, or

prepared semi-synthetically starting from natural sourced materials. They range from simple, usually well-characterized, organic or inorganic molecules to highly complex materials that are difficult to fully characterize. The British Chambers of Commerce (BCC) Researchers reports titled Excipients in pharmaceuticals, published in June 2007, foresees the trends propelling chemical suppliers to the global $ 3.5 billion excipient market. In response, the suppliers have begun to reposition excipient chemicals into two distinct categories commodity chemicals with solid performance reputation and high value specialty chemicals with multifunctioning. 3 Classification of excipients is based on their role in the pharmaceutical formulation, their interactions influencing drug delivery,

drug development such as poor solubility, permeability, and bioavilability. The growth of the biotechnology industry, including gene and cell therapy products, necessitates different drug delivery requirements compared to traditional small molecule pharmaceuticals. 4 Chemical compounds used as excipients The pharmaceutical industry had recognized long back certain chemical compounds as necessary and integral components of a formulation and their ability to enhance the efficacy of the therapeutic agent. Such recognition helped to generate continued interest in the viable global excipients in pharmaceutical markets. The market size for organic chemical excipients exceeds that of the inorganic and the United States Pharmacopoeia (USP) water

or their chemical and physico-chemical properties. The main classes include antioxidants, coating materials, emulgents, taste and smell improvers, ointment bases, conserving agents, consistency-improvers, and disintegrating materials. Some of the excipients serve multiple purposes. For example, methylcellulose is a coating material that is applied in the preparation of suspensions to increase viscosity or as a disintegrating agent or binder in tablets. More than 800 excipients are currently used in the marketed pharmaceutical products in the US. This number is expected to grow rapidly as new drug delivery technologies are developed to address the challenges of

categories. USP water is the largest single chemical moiety used as an excipient. Its dominance skews the market volume, and is expected to achieve a demand to the time of 11.0 billion in 2011, and sets the stage for the projected 5.1% compound average annual growth rate (CAGR). 3,5 Functional uses of excipients Excipients play a wide variety of functional roles in pharmaceutical dosage forms that include: Modulating solubility and bioavailability of active pharmaceutical ingredients. Increasing the stability of active ingredients in the dosage forms.

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Helping active ingredients to maintain preferred polymorphic forms. Maintaining the pH and/or osmolarity of liquid formulations. Acting as antioxidants, emulsifying agents, aerosol propellants, tablet binders, and disintegrants. Preventing aggregation or dissociation. Modulating immunogenic responses of active ingredients. Global excipients for the pharmaceuticals market are adapting to refinement that the pharmaceutical industry is making in the physical structure of APIs. Corresponding changes should occur in the functional categories for excipient chemical compounds. In some cases, the refinements will mean that fewer excipients may be needed. In other cases, they will usher some functional categories into more prominent roles while creating a downward shift for other categories. Vehicles, with an estimated 2011 market volume of 9.6 billion, hold the leading position in the functional categories. Their position rests solidly on the large amounts of USP water consumed, especially in injections. Fillers (Binders) follow with an estimated 849 million and emollients at 136 million. In terms of market value, the situation is revised. Fillers come out on the top, with an estimated 2011 market value of $1.2 billion. Vehicles drop to third place with $ 781 million, just below emollients at $ 816 million. 3,5 Selection and use of excipients An excipient is selected and used because it contributes one or more functional attributes to the product characteristics. The excipient, in certain cases, interacts with the active ingredient in the final formulated dosage form or may provide a matrix that affects the critical quality attributes of the active ingredients like stability and bioavailability. It follows logically that the quality of an excipient and its function play critical roles in the effectiveness, safety, potency, purity, and product, or in a novel drug delivery system such as an inhalation product.6 Excipients also influence the safety and effectiveness of drugs depending on the route of administration. The qualitative and quantitative understanding of the excipients composition is critically important to understand the bioavailability and bioequivalance of the dosage forms. In the case of orally administered dosage forms, excipients can affect safety and effectiveness outcomes by promoting or delaying gastrointestinal release. This is also the case in certain injections, where excipients can modify the release patterns in a way that they do for orally administered dosage forms. For locally acting products like topical applications, products for oral inhalations, nasal drops, otic products, and ophthalmic dosage forms, excipients often modify their effectiveness outcome by influencing the pharmacodynamic properties of the active principles. Excipients used in the protein and conjugate vaccines play a very critical role in the immunological characteristics of vaccines.7 Because excipients can affect the safety and effectiveness of dosage forms, manufacturers should understand the functional contributions of the excipients, that is, their processability. Manufacturers should have a good understanding of the processability of the excipients used

quality of a product. It is always necessary to understand the functions of excipients in order to fully characterize, understand, and control the process as well as the product quality, particularly in the new era of quality by design. The lack of understanding of the functions of excipients may lead to a situation in which process control and thereby product quality may be compromised. This is more so in cases where the impact of normal variations of the excipients quality on process control has not been established. The need for complete characterization of an excipient and understanding its functional role in the formulated product is greater when the excipient is used in a more complex product like a monoclonal antibody, vaccine, or gene therapy/cell therapy

Figure 1: excipients in delivery systems

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available. The excipient usage pattern may not be affected much by such changes. However, there is a strong need for additional information and guidelines regarding the development, characterization, and quality of new excipients and new applications of the current excipients. The pharmacopoeias and international councils have spearheaded some efforts to develop and harmonize the standards as well as to provide guidelines on good manufacturing and distribution practices for excipients.7 However, additional efforts are necessary to develop comprehensive and authoritative standards to promote innovation in the area of excipients in order to improve the understanding of the importance of excipients in the global market. References 1. U n i t e d S t a t e s P h a r m a c o p e i a l Convention. USP 29-NF 24.Rockville MD: United States Pharmacopeial Convention, Inc.; 2006 2. w w w. r o c w. r a i f o u n d a t i o n . o r g / biotechnology/MScBioinformatics/ drugdelivery/lecture-notes/lecture19.pdf. Accessed January 19, 2008. 3. w w w . b c c r e s e a r c h . c o m / pharmaceuticals. Accessed February19, 2008. 4. http://cat.inist.fr/? aModele=afficheN &cpsidt=18017534/. Accessed April 19, 2008. 5. Hussain A S. Engineering a proactive decision system for pharmaceutical quality: integrating science of design, process analytical technology, and quality system. www.fda.gov/cder/OPS/ hussain_1_2005.pdf. Accessed March 09, 2008. 6. Bhattacharyya L, et al. The value of USP public standards for therapeutic products.Pharm.Res.2004; 21:17251731 7. International Pharmaceutical Excipient Council. www.ipec.org. Accessed January 09, 2008. 8. Evert Izeboud. Excipients are Crucial for the Future of Medicine. Pharma & Bioingredients.2007; 4(2)

in their products; otherwise, they will not be able to reliably demonstrate pharmaceutical equivalence among the products synthesized or formulated differently at different manufacturing sites, using various excipients obtained from different suppliers or vendors. Excipients are manufactured by different processes using various starting materials. Their properties may vary from those referenced in the original New Drug Application (NDA). Thus, it is likely that the quality of the excipients used by different product manufacturers or at different manufacturing sites of the same manufacturer may be different; particularly, if the manufacturer engages in multi-sourcing. In the latter case, interchangeability cannot be ruled out. Such aspects, together with the potential variation in equipment, processing operations, and personnel who may have different backgrounds, training, and levels of expertise, may present a complex multivariate situation, which can often make control of the product quality difficult. The variation could range from being a minor to a significant one depending upon the function of the excipient used in the product, the excipient interaction with the actives, and the characteristics of the product, including its route of administration amongst other factors.8 The delivery system and the finished product for excipients

Consumption of excipient chemical compounds is often dictated by the specific delivery system into which drug actives are formulated. In terms of market value, oral products are the top dosage forms (53.1%), with topical products being about half that amount (28.3%). Injections (3.0%) and advanced delivery systems (15.6%) make up the rest of the market; however, in case of market volume, injections come out on the top (61.2%), which is followed by oral products (21.4%), topical products (12.1%) and advanced products (5.3%), (see figure 1). The emergence of novel delivery platforms can, within a short period of time, transform how drugs are delivered. The platforms can rearrange the markets and propel the demand for excipient chemical compounds that cater to the specific needs of the delivery systems. The advent of buccal tablets and thin strips, which dissolve in the mouth without the need for water, demonstrate the revolutionizing effect of medicine delivery and excipient usage. Formulators will continue to use excipients to give their final products the necessary or desired functional use properties. Conclusion The constant drive for new drug candidates in the pharmaceutical industry will result in a growing number of finished products entering the market. Many of them can displace products that are now

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