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Excipients in drug delivery: trends in excipient selection for sustained release formulations.

INNOVATOR COMPANIES CONSIDER sustained release oral dosage forms as a means to maximize drug efficacy, minimize the potential for adverse events, address clinical considerations such as dosing frequency, and respond to patient preference for simplified medication regimens for chronic disease. Key growth drivers in the rapidly expanding sector of controlled and sustained release oral drug delivery include enabling technologies, trends in patient preference, and increasing physician comfort with the ability of prolonged drug release to deliver reliable blood levels. According to GBI Research, the entire drug delivery market is forecast to grow to $199 billion in 2016 from $101 billion in 2009 while the prediction of controlled and sustained release drug release is expected to reach $92 billion by 2016 from the present value of $49 billion (1).

Recent studies show an increasing number of licensing and signed partnership deals for the development of sustained release drug forms in concentrated therapeutic areas like eNS, Oncology, and Oral Vaccines. The competitive landscape has resulted in number of sustained release technologies in injectable forms (MacroMed, OligosphRecent studies show an increasing number of licensing and signed partnership deals for the development of sustained release drug forms in concentrated therapeutic areas like CNS, Oncology, and Oral Vaccines. The competitive landscape has resulted in number of sustained ere; Alkermes, Prolease, Medisorb), Oral (MacroMed, SQ2Gei; Altus Biologics, Crystalized proteins; Alkermes, PLG microspheres; Spherics, sticky spheres; DepoMed, GR System), Ocular (InSite Vision, Durasite polymer eye drops), and Pulmonary areas too (Acusphere, microspheres; Alkermes, AIR microparticles) (2).


Designing polymer-based sustained release dosage formulations poses a number of challenges to formulators that include but are not limited to excipient selection, an understanding of the drug release mechanism, manufacturing process considerations, and an understanding of the API characteristics that may contribute to physical and chemical challenges.

Drug-Design Considerations

Excipients are employed in pharmaceutical dosage forms for numerous reasons to support not only physical and chemical dosage form robustness but also to alter the drug release in the body. Broadly, excipients in the body are classified for inclusion in dosage forms as either functional or non-functional. Functional excipients are delivery-specific and utilized for the purpose of delivering drug at a specific desired rate or to a targeted location in a manner designed to improve drug efficacy. Non-functional excipients are included to make the manufacturing process robust and to improve chemical stability.

Excipient Evaluation & Selection

During the evaluation process, all formulators have access to a vast bank of information on available excipients. The Handbook of Pharmaceutical Excipients references hundreds of excipients with pharmacopeial specifications from British Pharmacopoeia, European Pharmacopeia, Japanese Pharmacopeia, and the United States Pharmacopeia/ National Formulary. Of course, the European Pharmacopeia is family of many countries whereas USP and NF are combined as a single reference (3).

Once a suitable excipient has been selected, formulators search the U.S. Food and Drug Administration (FDA) Inactive Ingredient Search for Approved Drug Products website to determine the maximum concentration already employed in an approved drug product (4).

Excipient selection is often heavily influenced by past experience and knowledge that the excipient has been used in a previously approved product. Though the number and variety of available excipients has significantly expanded over the past decade, formulators often hesitate to be the first to utilize a novel excipient. But there cannot be compromise to the grade choice since the excipient selection early in the formulation development process is based on the API characteristics.

Manufacturing Process Considerations

Matrix system polymers, such as Methocel (TM) for direct compression technology, are broadly available and, unlike patented delivery systems, do not require licensing agreements for sustained release formulations. This translates to a lower cost for a polymer that meets requirements for U.S., Japanese, and European Pharmacopeia, Food Chemicals Codex, and the International Codex Alimentarius. Further, selection of this cellulose derivative carries low risk since it has been used as a key ingredient in pharmaceutical formulations for more than 50 years and formulators have a good understanding of the techniques and equipment for formulation development. Another preferred option would be to stay with matrix tablet approach by employing Polyox (TM) Poly resin, which is ideal for use in water granulation, as it can be easily granulated in a high shear unit. Another alternative would be to employ a plastic material such as polyvinyl acetate, which is inert to drug substance due to absence of ionic groups. This excipient has excellent compressibility and endows tablets with enormous hardness and low friability (5).

Another choice can be to employ an organosoluble polymer, such as Ethocel (TM), as an alternative in film or and bead coating technologies. A choice available with ethyl cellulose as a component is Surelease[R], which is an easy-to-use aqueous coating system with a unique combination of film-forming polymer, plasticizer, and stabilizer. By simply increasing or decreasing the quantity of Surelease applied, the rate of drug release is modified and provides uniform drug release independent of pH. Surelease[R] NG is latest system addition, offering enhanced stability over time, improved reproducibility, and extended 24 months shelf life.

The application of lipids in sustained release formulations is a growing area of interest. This excipient, such as Compritol[R] 888 ATO, delivers drug by creating an insoluble matrix structure from which diffusion is the principal drug release mechanism. It not only forms a water-insoluble matrix, but provides pH-inde-pendent release, non-digestible, highly resistant to physiological conditions, and does not result in alcohol-related dose dumping. Because there is no need to have solvent disperse the lipid, there is no drying step, no organic vapors handling, and no risk of API hydrolysis. Application of lipids can be used in direct compression formulations as it results in excellent mixing, flow and compressibility properties and provides an alternative to bypass patent issues (6).

Considerations for Granulation Technology

Granulation technology is required to improve product flowability, increase material density, improve powder compressibility during the tableting sequence, eliminate dust and improve drug content uniformity. Excipient selection in this context can be challenging. Formulator bias and company culture tend to dictate a preference for dry, high-shear or fluid-bed granulation approach. When extended drug-release times are required, polymer concentrations must be increased or higher molecular weight polymers must be chosen to achieve the desired release profiles. This situation occasionally results in powders that though compressible, demonstrate unacceptable flow characteristics, especially to tablet on highspeed production equipment. Because wet granulation can be a labor-intensive operation and high molecular weight cellulose ethers sometimes impose manufacturing difficulties, roller compaction can be an ideal choice to consider as "dry" process. Roller compaction also avoids rapid polymer swelling in water.

Whatever the method of dry granulation, choosing powder over granular grades can be an effective excipient selection strategy. Granular grades are efficient in extending the drug release, but unfortunately not free flowing. Finding the right combination of powder and granular grades enables processing versatility and achievement of the required drug release profile. Employing a part intra-granularly and part extra-granularly in the formula is an additional strategy to overcome processing challenges.

Recently, formulators have shown that hot melt extrusion is a viable option to prepare a solid dispersion of the drug, provided the processing temperature is maintained below the polymer glass transition temperature.

Consideration must be given to presence of quaternary ammonium groups because the swell ability and the permeability of the films in aqueous media are determined by percentage of Eudragit[R] RL in the formula. This option can produce dosage forms with more permeable films thereby resulting in very little delaying action. Choice to consider in early clinical development to later stages is, if a neutral methacrylic polymer is employed without a plasticizer, then the developed soft matrix structure of coated particles can be converted to a multiparticulate tablet dosage form (7).

In situ Gel Systems

The development of in situ gel systems has received considerable attention over the past few years. This interest has been sparked by the advantages shown by in situ forming polymeric delivery systems that forms gel depending on factors like temperature modulation, pH change, presence of ions, and ultra violet irradiation. Various biodegradable polymers used for the formulation of in situ gels include gellan gum, alginic acid, xyloglu-can, pectin, chitosan, poly (DL-lactic acid), poly (DL-lactide-co-glycolide), and poly-caprolactone. This type of delivery system's formulation development requires additional evaluation and characterization in sol-gel transition temperature, gelling time, gel strength, and in vitro drug release studies (8).

Predicting Human Bioavailability

Selection of functional excipients is the first step in identification of a 'lead' prototype formulation to take forward into a human clinical PK study. It is important to note that despite the variety of excipients discussed, interspecies physiological differences in absorption and metabolism make it difficult to predict human bioavailability from earlier animal study data. Unfortunately, there is still lack of predictability between animal and human bioavailability.

Post-Production Challenges

Once a sustained release dosage form is formulated, the next question is whether a postproduction tablet treatment step is required. It is a question that needs to be addressed, depending on the choice of excipient and periodic dissolution testing of tablets placed in normal ICH stability condition (25[degrees]C/60% RH). It is a good idea to compare cured versus uncured dosage forms. A rule of thumb followed in the industry is this: if the time needed to obtain at the stable drug release profile corresponding to the dissolution of the cured tablet is several weeks/months, then curing is the viable solution. Another challenge worth mentioning is the risk of alcohol induced dose dumping. FDA recommends evaluation on this effect in hydro-ethanolic media. There is a likely-hood of increase in dissolution profile due to enhancement of drug solubility in ethanolic media. Hopefully, the increase remains within the created dissolution profile specification.

Final Considerations

Though formulators are successful in formulating and manufacturing products that can deliver the drugs by in vitro method, it remains a challenge to deliver a uniform dose under the variable conditions of patient physiology and therapy. The ideal design should have an even drug release rate in the gastrointestinal tract by zero-order kinetics, but in most cases the final dosage form ends up demonstrating first-order kinetics. Along with drug-design considerations, effective excipient selection and manufacturing process considerations, a final and important aspect to consider is the potential for increase in initial drug release, since time-release preparations have no rationale for drugs with a long biologic half-life in the body. To overcome time lag following administration before the drug reaches steady-state concentration in the body, some sustained release products are formulated with an instant release in the outer coating.

In summary, the formulators are challenged with a number of available polymers to employ in coatings, tablets, microspheres, nanoparticles, gels, and more. The belief is that each pharmaceutical compound brings a variation of challenges for designing a polymer-based sustained release dosage form. How many of the described concepts are considered is dependent on formulators' familiarity and formulation development company's culture.


(1.) PRLog. (2011). GBI: Oral Drug Delivery Market - Controlled and Sustained Release to be Major Revenue Generators. Retrieved April 04, 2011, from

(2.) Brunner, S. C. (2004). Challenges and Opportunities in Emerging Drug Delivery Technologies. Product Genesis. Retrieved April 04, 2011, from

(3.) Rowe, C. R., Sheskey, J. P., & Quinn, E. M. (2009). Handbook of Pharmaceutical Excipients (6th ed.). London: Pharmaceutical Press.

(4.) FDA. (2011). Inactive Ingredient Search for Approved Drug Products. Retrieved May 5, 2011, from

(5.) Colorcon. (2011). Extended/Controlled Release. Retrieved May 5,201 1, from

(6.) Gattefosse. (201 1). Sustained Release. Retrieved May 5, 2011, from

(7.) Evonik. (201 1). Eudragit. Retrieved May 5, 2011, from

(8.) Nirmal, H.B, Bakliwal, S. R., & Pawar, S. P. (2010). "In-Situ gel: New Trends in Controlled and Sustained Drug Delivery System. Intl. Jour. Of PharmTech Res, 2 (2), 1398-1408.

By BalajsV. Kadri Xcelience

Balaji V. Kadri, M. Pharm., M.Sc, MBA, is manager of preformulation and formulation development, for Xcelience, LLC, a Tampa, FL-based formulation development contract research organization. He can be reached at
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Author:Kadri, Balaji V.
Publication:Contract Pharma
Date:Jun 1, 2011
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