Introduction
Pharmaceutical excipients are defined in United States Pharmacopoeia (USP) 33 as “substances other than the active pharmaceutical ingredient (API) that have been appropriately evaluated for safety and are intentionally included in a drug delivery system”. Excipients are essential components to enable the delivery, manufacturability and stabilization of the API in a formulation. As compounds become more challenging to formulate, new excipients are needed to enable the delivery, manufacture and development of these compounds [1]. However, there is ambiguity on how new excipients are defined. There is also no independent regulatory approval process for new excipients. Thus, this leads to challenges associated with the implementation of new excipients. Nevertheless, use of several new excipients has been implemented successfully and some examples will be described here.
Challenges with the Use of New Excipients
According to the 2005 FDA “Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients” [2], new excipients are defined as “any inactive ingredients that are intentionally added to therapeutic and diagnostic products, but that: (1) are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g., enhance absorption or control release of the drug substance); and (2) are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration.” The regulatory approval and implementation process of new excipients with case studies are further described in our recent review [3].
Classes of new excipients are described by Moreton [4] to include: (1) new chemical material; (2) co-processing of existing material; (3) new semi-synthetic derivatives or new chemistry (e.g. degree of substitution) of existing materials; (4) excipients used in food (e.g. GRAS materials) and animals, now proposed for pharmaceuticals; (5) excipients for new route of administration; (6) new botanical source or manufacturing process for existing materials; (7) new physical grades.
Figure 1 illustrates the development timeline for new excipients, which can compare similarly to NDA products. Although new excipients can be launched and made available to the market sooner, there is an additional duration required for consumer acceptance of new excipients. This shortens the economic benefit and market exclusivity for excipients innovators.
Figure 1: Development times for new excipients in comparison to NDA products. Adapted from references [5, 6]
The hurdles to getting customer acceptance to use new excipients are attributed to the development and regulatory risks of using new excipients. Limited safety data on the new excipients require additional groups of subjects to be added during clinical testing to receive the new excipients as placebo for safety assessment. Usually, it is not known if the new excipient will be approvable until submission and approval of the new drug product application. It should be noted from the definition of new excipients, according to the 2005 FDA guidance, that existing excipients used at higher levels may also be considered new. Thus, generally, pharmaceutical manufacturers prefer to use excipients at the levels and routes of administration listed in the FDA Inactive Ingredients Guide (IIG) database [http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm]. Only excipients that have been used in an FDA approved product along with information on the route of administration and level, are listed in the IIG. A similar process applies to new excipients used in new drug products approved in Europe and Japan. However, as far as we know, there is no equivalent IIG database from Europe or Japan’s approved products.
New excipients cost more at higher bulk prices since they are proprietary and available only from a single manufacturer - the innovator company. For example, β-cyclodextrin costs approximately US$ 5/kg, whereas the newer hydroxypropyl β-cyclodextrin costs about US$ 300/kg. Thus, formulators need to provide justification for use of the more costly new excipients. Besides, upon launch of the new excipient, it really depends on the excipient manufacturer to create awareness of the new functionalities offered by the excipient to potential customers. Otherwise, formulators with a need for the excipient may not know the existence of the new excipient to apply it. This is because information on the new excipients can be proprietary and formulators may have limited access to the new excipients developed by the innovators. Pharmaceutical manufacturers that choose to use new excipients will have to accept realities such as a single supplier source and unknowns of excipient variability, since there is limited manufacturing experience (i.e. quality by design (QbD)-type studies will be limited).
Advances in Formulations and Drug Delivery Systems
Discussions on the advances in formulations and drug delivery systems in this review are classified into (A) improvements to immediate and controlled release dosage forms; (B) nanotechnology and specialized delivery systems; (C) biologics. The advances and examples of new excipients used in these classes are described below and summarized in Table 1.
Table 1 - Advances in formulations and drug delivery systems and examples of new excipients
Improvements to Conventional Immediate and Controlled Release Dosage Forms
New excipients are continuously developed to increase the efficiency of drug product manufacturing of conventional dosage forms and enhance stability to achieve longer product shelf lives. In addition, challenging new molecules in the pipeline require greater solubilization and bioavailability enhancement when formulated as conventional dosage forms.
Co-processed excipients or blends of existing excipients are developed predominantly to improve performance and increase manufacturing efficiency. Co-processed excipients are usually multi-functional or considered “high functionality”. These excipients can consist of combinations of excipients from many functional classes. For example, they are combinations of filler-binders e.g. microcrystalline cellulose or lactose (80-95%), binders e.g. hydroxypropyl methyl cellulose (HPMC) or povidone (2-5%) and disintegrant e.g. crospovidone (5- 10%). Thus, they can be used to replace multiple excipients for a given formulation. Formulations then become simplified, being made up of drug, co-processed excipient and a lubricant. In 2009, the USP Excipient Monographs 2 Expert Committee published a stimuli article on coprocessed excipients to solicit public input [7]. The article summarized the Expert Committee’s thoughts regarding co-processed excipients, and presented some suggested criteria for acceptance of such monograph proposals into NF. The case studies of co-processed excipients provided in the stimuli article include Silicified Microcrystalline Cellulose and Polyvinyl Acetate Dispersion. The proposed monographs for these co-processed excipients, which met the acceptance criteria, were published in the Pharmacopeial Forum in 2008.
New excipient grades, with better performance or tighter controls are also developed for pharmaceutical use. Hydroxypropyl methylcellulose (HPMC) is a commonly used hydrophilic polymer to achieve matrixbased controlled release. However, direct compression of HPMC-based formulations is challenging because HPMC may impart poor flow properties to the formulation, causing problems during high-speed tablet manufacturing [8]. Thus, granulation of HPMC-based formulations is usually required. Granulation process variables can exert a significant impact on the dissolution characteristics of HPMC-based tablets. Huang et al found that when HPMC K15M matrix tablets were prepared by wet-granulation, tablet hardness, distribution of HPMC within the tablet (intergranular and intragranular), and the amount of water added in the wet granulation step all have a significant impact on dissolution and release profiles of the drug from the tablets [9]. Recently, new grades of HPMC K4M and K100M DC have been designed to possess properties such as larger particle sizes and better flow properties to facilitate direct compression, thus avoiding the need for granulation. Tableting trials with the new HPMC DC grades showed lower tablet weight variability with similar release using model drugs compared to the CR grades [10].
New excipient grades with tighter specifications are designed for pharmaceuticals. Wu et al profiled reactive impurities such as aldehydes, reducing sugars, peroxides, nitrites, nitrates and metals in some common excipients and have also identified potential reactions between drug candidates and the reactive impurities in the excipients [11]. Crospovidone is used in many formulations as a superdisintegrant to facilitate tablet disintegration. Peroxide is the main impurity found in crospovidone, and may adversely affect stability of some susceptible drug molecules. To address the need for pharmaceuticals requiring tighter peroxide controls, new crospovidone grades have been launched and are available on a commercial scale since November 2010 [12]. These contain almost 10-fold lower peroxide specification, compared to the typical 400 ppm peroxide specification allowed by global compendial monographs for crospovidone. The lower levels of peroxides in these ultra-pure grades of crospovidone are achieved by manufacturing, drying, packing, and sealing the product under inert conditions (i.e., nitrogen) to limit peroxide formation.
Nanotechnology and Specialized Delivery Systems
Nanotechnology is broadly defined as “the understanding and control of matter at dimensions of roughly 1 to 100 nanometers, where unique phenomena enable novel applications” [13, 14]. Koo et al published a well cited review on the role of nanotechnology in targeted drug delivery and imaging [14]. In the review, biophysical attributes of the drug delivery and imaging platforms as well as the biological aspects that enable targeting of these platforms to injured and diseased tissues and cells, were discussed. Nanoscale systems for drug delivery and imaging can be classified into: liposomes, micelles, nanoemulsions, nanoparticulates and nanocrystals, dendrimers and nanogels. There are also sub-classifications of these systems depending on the materials that are used to form these systems. For example, nanoparticulates can be further divided into polymer-based nanoparticles, lipid-based nanoparticles, albumin particles and ceramic particles etc. Out of these classes of nanoscale systems, the most advanced include liposomes, albumin nanoparticles and nanocrystals. Marketed products that are formulated into these systems include AmBisome®, Doxil®, DaunoXome®, Abraxane® and Rapamune®.
Recent advances in nanotechnology for drug delivery are divided into 4 areas. Firstly, advances to improve manufacturability and robustness of existing technologies (e.g. liposomes, nanoparticles and nanocrystals). Secondly, strategies to improve stability of the nanoscale systems in vivo and in vitro are researched. For example, PEGylation and alternatives to PEGylation to improve in vivo stability and reduce immunogenicity are explored. Short shelf-life due to chemical instability is a major limitation of some nanotechnology systems, like the phospholipid-based systems. Thus, freeze-drying of these systems is studied as a potential way to improve the chemical stability. Koo et al published one of the first studies to investigate the properties of camptothecin-loaded PEGylated phospholipid micelles before and after freeze-drying [15]. There was no significant change in solubilized camptothecin concentration, micelle diameter, drug localization within the micelle and phospholipid concentration before and after freeze-drying and reconstitution. This can be attributed to the stabilization of the polyethylene glycol (PEG) chains to the system during the freeze-drying process. Further studies using other polymers, besides PEG, to achieve the same stabilization effect will be interesting. Thirdly, new materials are designed to obtain improved properties, such as derivatization of existing polymers like poloxamer to optimize drug solubilization or customized drug release at targeted sites or rates have been conducted. Fourthly, numerous new targeting functionalities have been designed by many to improve specificity to target organs.
As more drug candidates are either poorly water soluble or challenging to deliver, there is a need for new solubilizers and specialized drug delivery systems to enable solubilization and bioavailability. Polyoxyl 15 Hydroxystearate is an example of a new solubilizer that also exhibits good tolerability over traditional solubilizers like polysorbate 80. It is also the first new excipient to be evaluated under the new IPEC Novel Excipient Safety Evaluation Procedure, established in 2007 [16]. Cyclodextrins are also used to achieve drug solubilization by complexation. To date, cyclodextrins have been used in the formulations of 34 marketed products [17]. Recent advances in cyclodextrins research are focused on designing new derivatives with “customized” substitutions, substitutions to increase solubility and lower toxicity, and scale-up of the inclusion complexes manufacturing.
Solid dispersions are also a hot research field because they have shown much promise to improve the dissolution and bioavailability of poorly water soluble drugs. The introduction of new polymeric carriers such as hypromellose acetate succinate (HPMCAS), copolymers based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, poly(vinylpyrrolidone-vinyl acetate) (PVP-VA), lauroyl macrogolglycerides (polyoxylglycerides) have further advanced this field. These excipients provide thermoplastic and thermal stability to solid dispersions and have also improved manufacturability. Furthermore, polymers such as HPMCAS and PVP-VA also inhibit drug precipitation from the supersaturated state. They provide the capacity for API-polymer hydrogen bonding to stabilize drug amorphous forms. Recently, a new small-scale screening method has been developed to investigate the ability of 7 chemically diverse polymers to inhibit the crystallization of 8 readily crystallizable model compounds [18]. Excipients with lower melting temperatures like lauroyl macrogolglycerides (polyoxylglycerides) have been used to enable molten filling of solid dispersions into hard gelatin capsules and eliminate the milling and blending steps [19].
Taste masking is important in the development of pediatric formulations and dosage forms like rapidly disintegrating tablets containing bitter drugs. One mechanism of taste masking is to prevent dissolution of the drug in the mouth and contacting the taste buds, and only releasing drug in the stomach or beyond in the gastrointestinal tract. A newly available methyl methacrylate diethylaminoethyl methacrylate (6:4) copolymer dispersion with macrogol cetostearylether and sodium lauryl sulfate included as stabilizers in the formulation, works according to this principle. The co-polymer being pH-sensitive, effectively prevents drug dissolution under neutral conditions in the saliva, with immediate release under acidic conditions of the stomach [20]. Another example is the application of copolymers based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate for taste masking by interacting complementary ionic groups. The taste masked product is formed by either interacting a cationic drug with an anionic methacrylate polymer or interacting an anionic drug with a cationic methacrylate polymer. Randale et al demonstrated this in the preparation of rapidly disintegrating tablets containing taste masked metoclopramide [21]. Metoclopramide HCl was complexed with aminoalkyl methacrylate copolymer in different ratios by the extrusion–precipitation. Drug–polymer complexes were tested for drug content, in vitro taste in simulated salivary fluid (SSF) of pH 6.8 and taste evaluation in oral cavity and molecular property. In that study, the complex having drug–polymer ratio of 1:2 showed significant taste masking, confirmed by both drug release in SSF and in-vivo taste evaluation by a human volunteer panel. The drug-polymer complexes exhibited considerable taste masking with the degree of bitterness below threshold value (0.5) within 10 s, whereas, metoclopramide HCl alone was rated intensely bitter with a score of +3 for 10 s.
Biologics
Recent advances in biologics are focused primarily on parenteral routes of administration. Materials have been investigated for greater stabilization (in vitro and in vivo), reduced frequency of administration, achievement of high doses and improved manufacturability of biologic formulations such as maintaining protein activity on scale-up. Major classes of delivery systems used in biologics formulation include microspheres (PLGA-based, chitosan-based), liposomes (PEGylated lipids) and hydrogels (modified dextran and starch-based).
An emerging class of materials to be considered for biologics is the dendrimer-based polymers. Dendrimers are highly monodisperse, unlike the polydispersity of traditional polymers. Commercial dendrimers can achieve polydispersities of Mw/Mn ≤ 1.005 [21]. Dendrimers are highly stable structures since they are covalently fixed 3D structures. Furthermore, they have properties that make them amenable for targeting. For example, dendrimers are polyvalent, and they have surface groups that can be engineered to undergo pH- or polarity-related changes in conformations. These properties have been leavaged to use dendrimers for DNA delivery [21]. Furthermore, hyperbranched dendrimers (low generation (G) or partially degraded high G) can form more compact complexes with DNA than linear polymers. Amino-terminated PAMAM dendrimers also exhibit lower toxicity than more flexible amino-functionalized linear polymers. This is attributed to the lower adherence of the rigid globular dendrimers to cellular surfaces.
In the area of siRNA delivery systems for systemic administration, three major groups of systems based on material are used [22]. The first are the lipid systems, including neutral liposomes composed of dioleyl-glycerophosphatidylcholine (DOPC) and cationic liposomes composed of 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP). The second are the systems that use polymers, such as natural polymers (e.g. atelocollagen and cyclodextrins) and synthetic polymers (e.g. polyethyleneimine (PEI). Lastly, peptides and proteins, like antibody-protamine fusion proteins are also used to formulate siRNA.
Conclusions
In conclusion, there are many considerations when developing and using new excipients in formulations of drug products. Firstly, manufacturing and commercialization considerations, such as the added cost of using new excipients, robustness of the new excipient scale-up process to enable large quantities to be available. Also, supply chain considerations in using a new excipient can be critical, since it will come from a single source/excipient manufacturer. Secondly, regulatory issues need to be considered when using a new excipient. The testing that is needed to establish the in vivo performance of the new excipient including assessment whether it is non-toxic/non-immunogenic, biodegradable or not, and pharmacokinetic data such as rate of excretion/elimination. The generation of this data may require close collaboration between the excipient manufacturer and the pharmaceutical manufacturer. Thirdly, new excipients may have more restrictions in use, in terms of allowable concentration range due to limited safety data and route of administration. Fourthly, environmental and safety considerations of using new excipients can be important, especially if the new excipient is a new material. Materials such as carbon nanotubes, which have been investigated extensively in nanotechnology, require strict environment, health and handling controls. Finally, the stability considerations of using a new excipient may require shelf life studies and customized packaging.
Disclaimer
Examples used in this article are not meant to be endorsements of any product or technology from the author.
Acknowledgment
The author would like to thank S. Varia (BMS) for reviewing this article.
References
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Author Biography
Otilia Koo, Ph.D. is currently Senior Research Investigator at Bristol-Myers Squibb Company, Drug Product Science and Technology, in New Brunswick, New Jersey. Otilia is also adjunct assistant professor at the department of Biopharmaceutical Sciences, University of Illinois at Chicago. Otilia is the newly elected Secretary/Treasurer of the FDD section within AAPS for 2011. Otilia has been an active member of the steering committee of the Excipients Focus Group within AAPS since 2006. Otilia was also the 2008-2009 Chair of the Excipients Focus Group. Currently, Otilia serves as the guest lead editor for a special AAPS PharmSciTech theme issue on excipients.
Otilia’s current position involves pharmaceutical development of commercial oral solid dosage formulations. Her research interests are in excipients characterization and the role of excipients behavior in influencing formulation performance and choice of unit operation processes. Her doctoral dissertation was to develop novel targeted nano-sized lipid-based carriers for drug delivery in cancer and arthritis. She has authored close to 20 research papers and oral/poster presentation proceedings in these areas. She is also inventor in 4 patents. Otilia was recipient of the Graduate Student Symposium in Drug Delivery and Pharmaceutical Technologies Award in 2005. Otilia received her Ph.D. in Pharmaceutics (2005) from the University of Illinois at Chicago (UIC). Prior to this, Dr. Koo received her Bachelor (Hons) in Pharmacy (1997) and Masters in Pharmaceutics (2000) from the National University of Singapore.