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Excipient Selection

Excipient Selection

Delivery

Excipient Selection

Today’s excipients go far beyond simply acting as inert fillers – new excipient functionalities include complex release mechanisms, and absorption and bioavailability enhancers.

By Jinghua Yuan at Eastman Chemical Company

Jinghua Yuan was appointed Principal Technical Service Representative for Eastman Chemical Company in 2002, with responsibility for pharmaceutical excipient products. She has more than 20 years’ experience in formulation development and systems. Prior to joining Eastman, she worked as a Research Associate at both the School of Engineering at Purdue University and the Department of Chemical Engineering at the University of Virginia. She was also a lecturer and researcher at the Department of Chemical Engineering at Tianjin University in China. Yuan received a BSc in 1983, an MSc in 1986 and a PhD in 1989, all in Chemical Engineering from Tianjin University.

Historically, excipients have been regarded as inert preferred for most orally administered additives contained in a finished pharmaceutical dosage pharmaceutical products. They help control precise form. With current advances in drug delivery technology dosage, are more easily manufactured and packaged, and and growing knowledge of excipient functionality in drug help increase patient compliance. When formulating a delivery systems this definition is changing. dosage form, such as tablets, the principal excipients The International Pharmaceutical Excipients Council include fillers, binders, lubricants, flowing agents, of the Americas (IPEC-America) now defines a colourants, flavourants and coatings: pharmaceutical excipient as any substance other than the active drug or prodrug which has been appropriately Fillers increase the size due to the potency evaluated for safety and is included in a drug delivery system and low dosage of most active . (Examples to: 1) aid processing of the system during manufacture; 2) include dibasic calcium phosphate, , protect, support or enhance stability, bioavailability or , microcrystalline (MCC), patient acceptability; 3) assist in product identification; or powdered cellulose, and ) 4) enhance any other attribute of the overall safety and Binders cause adhesion of the powdered active effectiveness of the drug product during storage or use (1). to other additives. (Examples include Virtually all dosage forms are combinations of active ethylcellulose, pregelatinised starch, , ingredients and excipients. An active needs to be formulated povidone and carboxymethylcellulose) in a delivery device in order to be effectively delivered to a Lubricants assist tablet processing target site. Designing a suitable dosage form is a major Flowing agents assist the flowability challenge facing most drug formulators. In addition to their of a formulated mixture traditional uses (colour, flavour, branding and so on), Disintegrants promote tablet break-up excipients must also perform functions that control dosage Colourants help distinguish the tablet release, increase a drug’s effectiveness and reduce dosing Flavourants and sweeteners affect taste frequency which helps ensure patient compliance. Coatings improve stability, control release rate, When formulating pharmaceutical products, an in- mask bitter tastes and/or enhance appearance depth knowledge of the physical and chemical properties of excipients is essential. Functionality including release and Formulation is a very important part of designing absorption enhancement properties, safe use, stability of the drug delivery systems. These include various release dosage form, excipient availability and ease of processing are mechanisms that provide desired end-effects, supplying all key factors in selecting the appropriate excipient for a the active(s) more effectively to a target site. The release drug formulation. mechanism can be divided into four categories:

EXCIPIENT FUNCTIONALITY Immediate Release The appropriate functionality of an excipient is vital to Orally disintegrating tablets are one example of an the development of any dosage form. Tablets are the immediate release delivery system. The tablet is

74 Innovations in Pharmaceutical Technology administrated without and absorbed almost developed by Alza. The system consists of a core tablet immediately in the patient’s mouth and further absorbed in surrounded by a semipermeable membrane coating with the patient’s intestine. MCC or MCC combined with an orifice drilled by a laser. The core is a bi-layer tablet, hydroxypropyl cellulose (L-HPC) are commonly used in one containing the active (pull layer) and the other the formulation. containing an osmotic agent (push layer). The bi-layer tablet is coated with a , with an optional sub-coat Sustained Release or topcoat. Among the most popular coating An active is delivered to a target site in the body within for this application are cellulose acetate (CA, grade: CA a period of time to provide prolonged pharmacological 398-10NF), and cellulose acetate butyrate (CAB, grade: action. This increases the effectiveness of the active, the CAB 171-15PG). The end-use properties of CA and safety of the medicine and also patient compliance – CAB are closely related to the type of substituents and allowing patients to take prescribed tablets or capsules the amount of acylation on the cellulose backbone. one or two times, as opposed to three or four times, daily. Understanding cellulosic ester film properties is very Additional examples of sustained release dosage forms important when designing an osmotic drug delivery system. include erosion tablets, coated tablets or beads, and In CA films, as the acetyl content increases, the CA film hydrogels. Recently, there has been an increased use of permeability decreases, solvent resistance increases and the cellulose acetate (CA) and cellulose acetate butyrate glass-transition temperature increases. For CAB films, as the (CAB) as a matrix material when formulating butyryl content increases, the hydrophobicity increases, the compression tablets in order to achieve sustained release. glass-transition temperature decreases and the solubility in selected organic solvent systems increases (2). Delayed Release This type of release mechanism delays the delivery of the EXCIPIENTS AS ABSORPTION ENHANCERS active until it has reached a designated target, such as the Many new drug candidates exhibit poor water solubility, intestine, where the increased pH triggers the release. permeability and bioavailability. Helping formulation Normally, delayed release can be achieved by a thin scientists address these challenges, excipients can serve as coating of non-enteric polymers, such as CA and CAB, solubility and bioavailability enhancers. Methods for or a thin coating of enteric polymers. Enteric polymers enhancing drug solubility include chemical modification are pH-sensitive; the polymers do not dissolve in an using the prodrug concept, physical modification of the environment with a pH of lower than 3.5, but do drug (size reduction and surface modification), pH-control dissolve in an environment with a pH higher than about using a buffer system, use of co-solvents, complexation and 5.0. This allows the active in the coated dosage form to use of surfactants as absorption enhancers. release when the dosage form passes into the intestine, Typical excipients for solubilisation are hydrophilic rather than in the stomach of a patient. solvents such as , and Available enteric polymers include cellulose acetate povidine; hydrophobic solvents such as vegetable oils, phthalate (C-A-P), cellulose acetate trimellitate (C-A-T), and diethyl phthalate; polymeric emulsifiers, hydroxypropylmethylcellulose phthalate (HPMCP), such as poloxamers, polysorbate 20, 40, 60 and 80, and hydroxypropylmethylcellulose acetate succinate TPGS; and monomeric emulsifiers such as bile (HPMCAS), polyvinyl acetate phthalate (PVAP), and salts, sodium caprate, and mono- and di-glycerides. copolymer of methacrylic acid and ethyl acrylate (available Recently, Vitamin E TPGS has generated a significant dispersions on the market are Eastacryl 30 D, Eudragit L amount of interest. The chemical name of is D-α- 30D, Kollicoat MAE 30D, Sureteric and Acryl-Eze). tocopheryl polyethylene glycol 1000 succinate (TPGS 1000) and it is a water-soluble derivative of natural Controlled Release source vitamin E. Vitamin E TPGS 1000 is amphipathic, This type of release mechanism allows for drug release to miscible with water, and forms a variety of liquid be precisely controlled for delivery to a target tissue or cell. crystalline phases in water. Biopharmaceutical studies As they are not affected by environmental factors such as suggest that it can be used as a safe, effective absorption pH and enzyme levels, controlled release delivery systems enhancer for poorly absorbed drugs such as cyclosporine are able to specify the release rate and duration of a drug. and protease inhibitors (3). Studies have shown that in One of the best examples of controlled release some instances, it improves the permeability of a drug technology is the osmotic pump drug delivery system. across cell membranes by inhibiting P-glycoprotein (P- The pioneer oral osmotic pump is the Oros system gp), thus enhancing absorption of the drug.

Innovations in Pharmaceutical Technology 75 With increasing knowledge and continuous R&D efforts, THE NEED FOR NEW EXCIPIENTS new functionality for existing excipients is being explored. Some drugs exhibit incompatibilities with many of the For example, C-A-P is a typical polymer. excipients currently available. In addition, as newly At the New York Blood Center, Dr A.R. Neurath developed drugs and drug delivery systems become more reported that a cream formulation with micronised complex, the need for new functional excipients will cellulose acetate phthalate (C-A-P NF) can inactivate increase. The development of a new excipient is affected HIV, several herpes viruses and the bacterial STD by three main factors: safety, patent life after approval pathogens (4). Additionally, the pharmaceutical and economic return on investment. Because the formulation laboratory at Eastman Chemical Company acceptance of a new excipient is even more complex than invented an application to formulate C-A-P in a liquid approval of a new drug product, the development cycle dosage form to achieve delayed, followed by sustained is very long – significantly reducing the patent life. release without coating processes (5). CONCLUSION SAFETY, STABILITY AND AVAILABILITY As advances are made in drug delivery technology, the The issue of safety testing is extremely important traditionally defined boundaries of excipient functionality because excipients are major components of a dosage continue to expand. Today, excipients are not just used in form. Safety evaluation requirements vary for different processing to identify brands or mask bitter tastes. New types of formulation – including oral, parenteral and excipient functionalities include complex release topical/transdermal. mechanisms, and absorption and bioavailability enhancers. Formulations for oral toxicity studies may vary from the With this in mind, a detailed understanding of marketed formulation. By contrast, formulations for excipient functionality, safe use, stability, availability and parenteral or topical toxicity studies are usually similar or ease-of-processing is important in choosing an the same as the marketed formulation. In addition, the appropriate excipient for a drug formulation. Advances in safety requirements for an excipient may differ from country the industry’s understanding of excipients can lead to to country, and also among the different national greater control and reduced variability, which will result pharmacopoeias, such as the United States Pharmacopoeia in better products and better delivery of drugs to patients. (USP), European Pharmacopoeia (EP) and Japanese Pharmacopoeia (JP). The author can be contacted at Drug product stability testing is also critical in [email protected] assuring product quality. When selecting excipients for a particular application, the compatibility of the References Note to readers excipients with the active(s) or other additives Eastman cellulose acetate (CA), should be tested. 1. Moreton RC (1995). Excipients to the Year 2000. Eastman cellulose acetate butyrate (CAB), Eastman To ensure excipient availability, some In DR Karsa (Ed), Excipient and Delivery Systems cellulose acetate phthalate (C- pharmaceutical companies prefer to have a domestic for Pharmaceutical Formulations. London: Royal A-P), Eastman cellulose acetate trimellitate (C-A-T), Eastman supplier while others may prefer to have a second Society of Chemistry. hydroxypropylmethylcellulose supplier designated. It is important to note that one 2. Eastman Chemical Company (2004). Eastman Cellulose phthalate (HPMCP), Eastman hydroxypropylmethylcellulose of the difficulties presented by the practice of using Esters for Pharmaceutical Drug Delivery. Eastman acetate succinate (HPMCAS), multiple suppliers is that the same excipient may Online Publications [On-line]. Eastman polyvinyl acetate phthalate (PVAP), Eastacryl differ depending on where the material is sourced 3. Wu SH and Hopkins W (1999, October). Characteristics 30D, Eastman CA 398-10NF, from. In addition, the three major pharmacopoeias of D-α-Tocopheryl PEG 1000 Succinate for Applications Eastman CAB 171-15PG, as Absorption Enhancers in Drug Delivery Systems. Eastman Vitamin E TPGS, – the USP, EP and JP – have different Eastman Vitamin E TPGS testing methods and specifications for the same Pharmaceutical Technology. 1000, and Eastman C-A-P NF 4. Neurath AR, et al. US Patents: 5,985,313 are trademarks of Eastman excipient material. Excipients with conflicting Chemical Company. pharmacopoeial standards are often eliminated from and 6,165,493. consideration, even though they may be perfectly 5. Yuan J, and Clipse N (2005, November). Preparation Eudragit L 30D is a trademark of Rohm and Haas GmbH. adequate in terms of functionality. This issue can be and Composition of a Liquid Dosage Form: New Kollicoat MAE 30D is a overcome by fixing supplier specifications at an early Application of C-A-P. Paper presented at the 2005 trademark of BASF Corporation. Sureteric is a trademark of stage in the development of a dosage form to help annual meeting and exposition of the American BPSI Holdings, Inc. Acryl-Eze ensure the proper performance of an excipient in the Association of Pharmaceutical Scientists (AAPS), is a trademark of Colorcon, Inc. finished product. Nashville, TN.

76 Innovations in Pharmaceutical Technology

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