INTRODUCTION:

The quality of formulation depends on active pharmaceutical ingredient (API), production processes and the excipients used. These excipients contribute in a great way to the performance of the API and maintain the safety, efficacy of the product (1). The term excipient was derived from latin word, excipiens, which means to receive, to gather, to take out. The definition of excipient has changed from time to time with the change in their function. 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 (2). Safety has always been the most important requirement and the most studied when dealing with pharmaceutical drugs.Less attention has been devoted to the safety o excipients, because their intertia and innocuity were taken for granted.

The importance of an excipient was recognized after the occurrence of phenytoin toxicity in Australia in 1968. Calcium sulphate which was used as inert diluents was substituted with lactose (as calcium sulphate was exhausted). However with the reformulated batch of capsules, the concentration of Phenytoin increased drastically and reached around 30 mg/ml leading to its toxicity. This was due to easy wetting of lactose. Again in 1971, it was seen that for same technical reasons, different digoxin formulations yielded different blood levels of the drug (3). The lack of regulatory guidance led the IPEC to publish safety evaluation guidance for these materials. Because excipients can affect the safety and efficacy of dosage forms, manufacturers should understand the functional contributions of the excipients (4 – 6). Quality by design (QbD) initiative by Food and Drug Administration (FDA) has made the formulator/ manufacturer consider excipients in drug development process (7).

Why Natural excipients:

India is rich in biodiversity and biological niches. The flora and fauna of India have been studied and recorded from early times in folk traditions and later by researchers following more formal scientific approaches (8). Herbs are staging a comeback and herbal renaissance is happening all over the globe. The herbal products today symbolise safety in contrast to the synthetics that are regarded as unsafe to human and environment. Over three quarters of the world population relies mainly on plants and plants extracts for health care. It is estimated that world market for plant derived drugs may account for about 200000 crores and Indian contribution is less than 2000 crores. India is one of world’s 12 biodiversity centres with presence of 16 different agro – climatic zones, 10 vegetarian zones, 25 biotic province and 426 biomes (habitats of specific species) (9).

In recent years, plant derived polymers have evoked tremendous interest due to their diverse pharmaceutical applications such as diluents, binder, disintegrant in tablets, thickeners in oral liquids, protective colloids in suspensions, gelling agents in gels and bases in suppository. A majority of the investigations on natural excipients in drug delivery systems have centrered on proteins and polysaccharides, due to their ability to produce a wide range of materials and properties according to molecular structural alterations (10). India, due to its geographical and environmental positioning has traditionally been a good source for such products among the Asian countries (11).

Regulatory status of new excipients:

Good Manufacturing Practice (GMP) is a requirement for nearly every component of a drug – from the packaging to the active pharmaceutical ingredient. However, a global regulatory standard does not exist for excipients. The path to accredited certification for excipients began in 2008, when the US Food and Drug Administration stated that excipient GMP conformance certification could benefit the excipient and pharmaceutical industry beyond the existing International Pharmaceutical Excipient Auditing (IPEA) program. By August 2009, IPEA and ANSI had developed an accreditation plan and process.

Under the current paradigm, even though excipient innovators are able to adapt to new procedures and are willing to invest in development and safety-evaluation costs, novel excipients are not finding their way into drug products. Understandably, drug-product manufacturers are risk-averse because of the large investments required for drug development. Despite these challenges, the expanding FDA Inactive Ingredient Database (IID) suggests that the demand for new excipients is strong. The IID lists excipients used in approved drug products, their route of administration, and their maximum dosage (i.e., maximum potency per dosage unit). A regulatory system with a strong, predictable excipient safety and efficacy evaluation could potentially lead to an explosion of new choices for drug formulators. Under current drug approval processes, novel excipients are not independently evaluated; they are only reviewed in the context of the first drug application containing the excipient. There is no regulatory approval process specifically for a new excipient as a unique molecule. Globally, the International Conference on Harmonization (ICH) does not have specific excipient safety evaluation guidelines, but FDA guidance on excipient safety evaluation cites several ICH safety-testing guidelines (e.g., ICH S1A, S2B, S3A, S5A, S7A and M3) as reference materials for the conduct of safety tests.

According to FDA and ICH definitions, an excipient is considered “novel” if it is used for the first time in a human drug product. Although FDA maintains the IID, none of the US nor ICH standards distinguish between new chemical entities and minor modifications of approved excipients, coprocessed mixtures of existing excipients, approved excipients proposed for a new route of administration, or excipients approved for use in foods or cosmetics. Some of these excipients may not require the full battery of tests listed in the FDA guidance on excipient safety evaluation. In these cases, excipient and pharmaceutical manufacturers must predict what the reviewing agency will require upon review of the drug application. If the manufactuer is wrong, the consequence could be significant delays in drug approvals or rejection of the drug application. Most drug manufacturers are wary of this process and therefore rely on excipients already used in approved drug products for their formulation needs. In 2007, the IPEC–Americas Safety Committee proposed and developed the IPEC Novel Excipient Safety Evaluation Procedure, which is an independent excipient review procedure. This process was anticipated to reduce the cost and uncertainty related to the use of novel excipients in pharmaceutical formulations, thereby encouraging their use in drug-development programs and providing a needed boost to drug formulation innovation (13).

Efficient pharmaceutical development:

For lifecycle management, improved formulations replace or are marketed with already available products. By setting up an excipient formulary, which includes a sufficient number of carefully selected excipients and links to various unit processes, efforts can be geared toward a better understanding of excipients, functionality-test development, vendor relationships and second-vendor identification and qualification. The establishment of an excipient formulary can lead to more efficient use of available assets, decreased development times, harmonized specifications, worldwide formulation acceptance, and economy in product manufacturing.

Excipient selection in the drug product–development phase focuses on the desirable characteristics (e.g., functionality, material consistency, regulatory acceptance, cost, availability, and sources). Ingredients derived from natural animal sources (e.g., gelatin, starch) have raised concerns of transmissible spongiform encephalopathy/bovine spongiform encephalopathy/genetically modified organism (TSE/BSE/GMO). A verification letter from a vendor of these natural materials is sufficient to support non-GMO or TSE/BSE implication for consumer protection. Inattention to excipients, excipient suppliers, and regulations may lead to product development failure. Quality-by-design concepts, which have recently been initiated by FDA, emphasize the need for characterizing material properties (e.g., micromeritic, chemical, thermal, rheological, and mechanical properties) and elucidate their vital role in formulation and manufacturing processes (14 – 16)

Global Market and Future of Natural Excipients:

The global excipients market is expected to grow a moderate pace through 2016 in line with overall pharmaceutical industry growth. The global pharmaceutical market is expected to reach $1trillion by 2014, according to IMS Institute for Healthcare Informatics. The global excipient market was valued at $4.6 billion in 2010 and reached $4.9 billion in 2011 (17). Figure 1 shows the estimated volumes and revenues of Sugar and other excipients market during 2010 – 18 in tons and USD millions respectively.

© Transparency Market Research

Fig 1: Sugar and other excipients market volumes and revenues, 2010 – 18 (Tons) (USD millions)

India is becoming a major force in the world market for pharmaceutical ingredients. The excipient market is expected to grow almost two times faster than the global excipients market growth. The experts expect a growth rate of Indian excipients market at around 15 – 18% annum as against the global growth rate (18).

The key driving force for growth in excipient market is greater use of functional excipients. It is expected that US demands for excipients will advance from 3.9% annually to $1.87 billion in 2015 according to Freedonia. In 2015, polymers will be largest excipient category by value capturing 43% of total market followed by alcohols such as propylene glycol with 20% sugar will have market share by value at a little over 3% but will remain an important high volume category based on the processing advantage of lactose as tablet filler (19).

However growth in excipients will lag that of finished pharmaceutical products because a large proportion of the market remains commoditised with limited pricing flexibility. The hectic and time consuming process of establishment of toxicity and approval from regulatory authorities poses a problem with synthetic excipients. The synthetic polymers have certain disadvantages such as high cost, toxicity, environmental pollution during synthesis, ono renewable sources, side effects, and poor patient compliance. This has grown the interest of researchers towards natural excipient/ polymers.

CONCLUSION:

Natural excipient development is gaining a lot of attention these days. This being cheap, safe, acceptable to patients adds to its advantage. National and International excipient market is developing day by day. This suggests a need to look at natural excipient development not only in terms of safety and acceptability but also the economics involved with it.

REFERENCE:

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3. http://aims.amrita.edu/school-of-pharmacy/pdfs/article-Excipients.pdf.

4. International Pharmaceutical Excipients Council (IPEC). The proposed guidelines for the safety evaluation of new excipients. The IPEC Edurope Safety Committe. Eur. Pharm. Rev.

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8. www.http//en.wikipedia.org/wiki/Fauna_of_Inida

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13. FDA, Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (Rockville, MD, 2005).

14. CDER, Quality Systems Approach to Pharmaceutical Good Manufacturing Practices, Draft Guidance (Rockville, MD, 2004).

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17. Arnum PV. Sizing up the global market for excipients. Pharmaceutical Technology, 35 (10) 2011. 62 – 68

18. http://www.gnaipr.com/article/gireesh%20babu.pdf

19. www.inpharm.com/news/158438/functional-excipients-driving-US-market-growth.

Received on 27.12.2013 Accepted on 20.02.2014

Asian J. Pharm. Res. 4(1): Jan.-Mar. 2014; Page 12-15

*Corresponding Author E-mail: