Considerations and recommendations on traditional and non-traditional uses of excipients in oral drug products
© The Author(s) 2016
Received: 16 February 2016
Accepted: 28 March 2016
Published: 10 May 2016
Excipients represent diverse classes of molecules, small molecules or macromolecules, with versatile structures within a given class and are from natural, semi-synthetic and synthetic sources. They are essential ingredients in drug products independently of the route of administration where both traditional and non-traditional uses are present. Beyond their traditional use as formulation and manufacturing aids, certain excipients exhibit biological effects and thus can be used either as atypical active pharmaceutical ingredients alone or synergistically with conventional active pharmaceutical ingredients to affect the overall pharmacokinetics/ pharmacodynamics and therapeutic effect(s) of the co-administered drug(s). In reference to oral drugs, biological effects of the excipients that contribute to improved drug absorption and pharmacokinetics include their ability to modulate drug dissolution, intestinal membrane permeability, gut wall metabolism and efflux pumps. These non-traditional uses of excipients are illustrated in representative case studies from published literature. From a drug development and regulatory perspective, it is apparent that an appropriate excipient classification system is considered which is applied to new uses of existing excipients as well as to the development of novel excipients and segregates biologically active excipients from the larger pool of excipients. This classification system should be a useful tool to pharmaceutical scientists and its successful implementation and broader acceptance requires input and ownership from all major stakeholders, that is, the excipient manufacturers, the end users, excipient forums and discussion groups such as the International Pharmaceutical Excipients Council (IPEC) and regulatory agencies.
KeywordsExcipients Traditional and non-traditional uses Oral drug products Biologically active excipients Drug transport Permeability Metabolism Pharmacodynamics Pharmacokinetics Atypical active pharmaceutical ingredient Excipient classification system
In order to harvest the maximum therapeutic activity of the drug molecules, appropriate dosage forms are designed using various additives called ‘Excipients’ (Rowe et al. 2009). It is due to the use of excipients that the drug can be delivered to the patients in a presentable form that meets the targeted dose requirements. Excipients represent diverse classes with versatile structures and are of natural or semi-synthetic origin, small molecules and macromolecules and represent all states of matter, that is, gases, liquids, semi-solid and solids. Examples of small molecule excipients include, mannitol and dextrose, sodium chloride, vitamins such as ascorbic acid (vitamin C) and α-tocopherol (vitamin E), calcium carbonate and calcium phosphates (Rowe et al. 2009), whereas macromolecular excipients include, polyethylene glycols, methacrylates, povidone, aluminosilicates and hydrocolloids, such as starches, cellulose esters, gums, gelatin, alginates, carrageenan and pectin (Rowe et al. 2009). Excipients are manufactured in large quantities often through continuous processing in dedicated plants and are available in several grades. Traditionally excipients are regarded as “inert carriers” (inactives). However, they may also exert biological activity as modulators of drug absorption and metabolism or as atypical active pharmaceutical ingredients.
Cremophor EL/RH40, Solutol-HS-15, TPGS, Tween 80
Stearylamine, cetyl phosphate
Lauroyl- and palmitoyl-carnitine chloride
Sodium lauryl sulfate
Dioctyl sodium sulfosuccinate
Oleic Acid, sodium caprylate, sodium caprate
Capmul MCM, Labrasol
Chitosan, polycarbophil, starch, carrageenan
Sodium salicylate, N-methylpiperazine
C8–C20 fatty acid glycerol and PEG esters: Cremophor EL and RH40, Solutol HS-15, Labrasol, Softigen 767, Aconnon E
Polysorbates : Tween 80, Tween 20
Sucrose esters : sucrose monolaurate
Tocol esters : TPGS
Pluronic block copolymer (Pluronic F68)
Amphiphilic diblock copolymers (Me-PEG-b-PCL)
Traditional Uses as Functional Excipients
Non-Traditional Uses as Atypical Active Pharmaceutical Ingredients
Kaolin, Montmorillonite (bentonite), Magnesium Aluminum Silicate, Talc (hydrated magnesium silicate), Precipitated Calcium Carbonate, Calcium sulfate, Dibasic Calcium Phosphate, Magnesium Carbonate, Colloidal Silicon Dioxide, Sodium Chloride
suspensions, gels, lotions, magmas and milks, adsorbents, fillers and diluents disintegrants, lubricants anti-adherents, glidants
gastric antacids, laxatives, anti-diarrhea agents, topical OTC medications, antimicrobial agents: antiviral, antibacterial antifungal, inhibitors of the absorption of dietary cholesterol
Non-traditional uses of excipients in oral drug products as well as in dietary supplements has been the subject of various conferences and workshops and more recently of a symposium at the 2014 AAPS Annual Meeting in San Diego with a theme Excipients as Atypical Actives in Nutraceuticals and Pharmaceuticals: Application and Development Considerations (Constantinides 2014). In this latter program talks included, dietary role of excipients, excipients as inhibitors of the absorption of dietary cholesterol, development challenges in the utilization of atypical actives in drug products and regulatory perspectives surrounding non-traditional uses of excipients.
In a regulatory note, Chen et al.; (Chen et al. 2013) reviewed and analyzed pharmacokinetic data on the use of osmotically active excipients, such as, sorbitol, mannitol, D-xylose and PEG400 on the bioavailability and bioequivalence of BCS III drugs that included, ranitidine, cimetidine and amoxicillin, and concluded that, “a better understanding of the dose–response relationship of an “active” excipient can facilitate its optimal use in formulations and further provide opportunities of biowaivers while ensuring product quality and performance”. It was pointed out by the authors that “from a regulatory viewpoint, the importance of recognizing the presence of an “active” excipient in the formulation cannot be overemphasized during the development for both generic and innovator companies”. They further suggested that additional mechanistic studies are needed in order to shed light into the effects of “active” excipients on drug absorption and bioavailability/bioequivalence (Chen et al. 2013). These findings are certainly relevant to the perspectives and recommendations presented in this commentary and regulatory agencies represent a key stakeholder on the qualification and classification of excipients as discussed below.
The effect of twenty commonly used excipients on the oral bioavailability of nalbuphine, a potent opioid analgesic, in rats and humans was investigated and reported (Wang et al. 2014). The excipients used included, surfactants (Tween 20/40/80, Cremophor EL/RH40, Solutol HS-15, Pluronic F68 and sodium lauryl sulfate), PEG 400 and PEG2000, as well as preservatives (methyl and propyl parabens, and sodium benzoate). Improvement in the oral bioavailability of nalbuphine was correlated to the ability of these excipients to inhibit the activity of UDP-glucoronosyltranferase 2B7 activity, the major metabolic enzyme for nalbuphine, with Tween 20 and PEG400 being the most active, alone and in combination (Wang et al. 2014).
It should also be pointed out that several biomaterials/excipients used in various drug carriers such as micro- and nanoparticles and administered by the oral, parenteral and other routes of administration, are reported to exhibit bioactivities in the body by modulating cellular and physiological processes, well beyond their primary role to modify the pharmacokinetics and biodistribution of the drug (Yeo et al. 2015). These pharmaceutical excipients include, chitosan and chitosan derivatives, hyaluronic acid, pluronics, polar lipids such as pegylated phospholipids and cationic lipids, cyclodextrins and N-(2-hydroxylpropyl) methacrylamide copolymers (Yeo et al. 2015). Reported bioactivities of these materials which are either known or newly discovered include, suppression of pro-inflammatory cytokine production and slight increase in tumor burdens (Yeo et al. 2015). As discussed by the authors, understanding the bioactivities of the drug-free and drug-incorporating carriers and their implications in drug product development is very important to optimize drug product safety and performance.
Though the above facts are well known, a system to classify excipients on the basis of their in vivo functionality and ability to significantly influence the therapeutic activity of co-formulated drugs or their use as atypical active pharmaceutical ingredients is still unavailable. This is particularly important for novel excipients and new uses of approved excipients. Driving forces behind a new use of an approved excipient, include, addressing unmet medical need(s), no product without the excipient, patent protection and revenues. Understanding excipient effects (in vitro/in vivo) and development timeline constraints including toxicity and safety requirements are critical to the new use of an approved excipient as well to the use of a novel excipient. The International Pharmaceutical Excipients Council (IPEC) has been a strong advocate of the qualification and uses of excipients and authored many publications and meeting proceedings that deal with excipient functionality, specifications, characterization, manufacturing and quality-by-design (QbD) aspects as well as toxicity and safety aspects especially with novel excipients (DeMerlis et al. 2009; Moreton 2010; IPEC Americas website http://www.ipecamericas.org). A classification which currently exists as indicated in the Handbook of Pharmaceutical Excipients (Rowe et al. 2009) depends on their role in the dosage form and manufacturing application like lubricants, glidants, emulsifiers, fillers, rate controlling agents, preservatives etc. However, this classification system (Rowe et al. 2009) is based on the function of the excipient in the formulation and dosage form and fails to address non-traditional uses of biologically “active” excipients as presented in this commentary. Therefore, it is recommended that a broad ‘Excipient Classification System’ (ECS) be considered and introduced to segregate the excipients used as formulation and manufacturing aids from those affecting the absorption, distribution, metabolism, and elimination (ADME) and PK/PD properties of the co-administered drugs. This would help both established and new researchers in the area to clearly understand the role of excipients, assist in their judicious selection and interpretation of the effect of formulation variables on the in vivo performance of the dosage forms. Furthermore, ECS would be instrumental for the regulatory bodies to set standards and introduce appropriate guidelines to control within required limits or allow minimum variation in use of such excipients in post approval cases and also recommend submitting of adequate information/data related to their use in new drug products. It should also facilitate the approval process for novel excipients. A suggested system may include for example, inactive/inert excipients used as formulation and manufacturing aids versus excipients exhibiting biological activity, where the latter can be further subdivided in excipients that modulate the PK/PD of the co-formulated drug versus excipients which are atypical active pharmaceutical ingredients. Properties such as membrane permeability modulation, gut wall metabolism and efflux pump inhibition can be considered for the excipients that affect the PK/PD of the co-formulated drug.
Input from all stakeholders, that is, the excipient manufacturers, end users in the biotech and pharmaceutical industry, the International Pharmaceutical Excipients Council (IPEC) and regulatory agencies such as the Inactive Ingredient Subcommittee (IIS) of the CDER of the FDA, is needed before a widely accepted ECS is implemented. Figure 2 illustrates the interplay between these stakeholders along with the proposed tentative three classes of excipients for oral drugs.
absorption, distribution, metabolism, elimination
active pharmaceutical ingredient
biopharmaceutics classification scheme
center for drug evaluation and research
Excipient Classification System
food and drug administration
Inactive Ingredient Subcommittee
International Pharmaceutical Excipients Council
α-tocopherol-polyethylene glycol 1000-succinate
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