Regulatory Toxicology and Pharmacology 32, 210 ²218 (2000)
`doi:10.1006/rtph.2000.1421, available online at http://www.idealibrary.com on
`
`I D Oft
`
`Pharmaceutical Excipient Development:
`The Need for Preclinical Guidance
`
`Paul Baldrick
`
`Covance Laboratories Ltd., Harrogate, England, United Kingdom
`
`Received July 6, 2000
`
`Pharmaceutical excipients have a vital role in drug
`formulations, a role that has tended to be neglected as
`evidenced by the lack of mechanisms to assess excip-
`ient safety outside a new drug application process.
`Currently, it is assumed that an excipient is «ap-
`proved» when the new drug formulation, of which it is
`a constituent, receives regulatory acceptance. Exist-
`ing regulations and guidelines indicate that new
`(novel) excipients should be treated as new chemical
`entities with full toxicological evaluation. No guid-
`ance is available for potentially useful materials (es-
`sentially new excipients) available from other indus-
`tries, e.g., food additives or for established excipients
`with a new application, e.g., dose route change. How-
`ever, despite this situation, drug companies are ac-
`tively evaluating new materials or applying new uses
`to established excipients. Recently developed excipi-
`ents (e.g., materials giving «sugar-free» status to med-
`ical preparations, the cyclodextrins, and the hydroflu-
`oroalkane inhalation propellants) and excipients
`undergoing development (e.g., chitosan, various en-
`teric coating substances, liposomes, polymers derived
`from glycolic and lactic acids, and vaccine adjuvants)
`are all discussed. In light of many other areas of drug
`development having recently benefited from new or
`updated regulatory guidance, specific guidance to as-
`sist companies in the development of their excipients
`is urgently needed. Also, an excipient testing strategy
`would be an excellent topic for inclusion for Interna-
`tional Conference on Harmonisation (ICH) consider-
`ation. Such guidance/discussion would complement
`the current advances in pharmacopoeial standardiza-
`tion of excipient quality. As a consequence, it may be
`possible to have excipients reviewed by a committee of
`an international pharmacopoeia with the safety data
`assessed by elected experts and published.
`ž 2000
`Academic Press
`
`INTRODUCTION
`
`Excipients are materials used in the formulation of
`pharmacologically active drugs; currently over 1000
`
`such materials are used in marketed pharmaceuticals.
`They have a variety of roles including diluents/fillers/
`bulking agents, binders/adhesives, propellants, disin-
`tegrants, lubricants/glidants, colors, flavors, coating
`agents, polishing agents,
`fragrances,
`sweetening
`agents, polymers, and waxes; vaccine adjuvants also
`represent an excipient form. Excipients can be broadly
`divided into three categories: established («approved»),
`new (novel), and essentially new excipients. Estab-
`lished excipients are well-known materials with long
`use in pharmaceutical preparations. Indeed, the 12
`most common excipients in U.S. regulatory submis-
`sions from 1964 to 1984 were water, magnesium stear-
`ate, starch, lactose, microcrystalline cellulose, stearic
`acid, sucrose, talc, silicon dioxide, gelatin, acacia, and
`dibasic calcium phosphate of which six were being used
`in 1904 and the majority by 1949 (Shangraw, 1986). A
`recent publication has indicated that most common
`excipients in UK-licensed medicines are water, magne-
`sium stearate, povidone, sodium chloride, stearic acid,
`and dextrose (Robertson, 1999). Recent additions to the
`ranks of established excipients include materials giv-
`ing «sugar-free» status to medical preparations, the
`cyclodextrins, and the hydrofluoroalkane (HFA) inha-
`lation propellants. A novel excipient is a compound
`which has not been previously used or permitted for
`use in a pharmaceutical preparation. Essentially new
`excipients form an intermediate category and include
`substances resulting from a structural modification of
`an «approved» excipient, a recognized food additive (or
`cosmetic ingredient), a structurally modified food ad-
`ditive, or a constituent of an over the counter (OTC)
`medicine.
`Within industry there has been a recent surge of
`interest in the use and safety of established and new
`excipients in drug development and has resulted in
`numerous recent publications (e.g., Steinberg
`et aL,
`1996; de Jong, 1999; Baldrick, 2000). This interest has
`followed a period of neglect. Crucial aspects of excipi-
`ent development are chemical and manufacturing
`(quality) and preclinical (safety) data. The former as-
`pects are often addressed in national and international
`
`0273-2300/00 $35.00
`Copyright ž 2000 by Academic Press
`All rights of reproduction in any form reserved.
`
`210
`
`MYLAN EXHIBIT - 1043
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd. - IPR2022-00722
`
`

`

`PHARMACEUTICAL EXCIPIENT DEVELOPMENT
`
`211
`
`pharmacopeial monographs. However, a current issue
`is that these product specifications often differ in their
`quality requirements for identical excipients although
`global standardized monographs are appearing for
`some materials (e.g., lactose). Preclinical assessment
`has been hampered by:
`
`! A lack of a concerted international guideline di-
`rectly relating to the safety evaluation of pharmaceu-
`tical excipients;
`! Limited help to address the question of registra-
`tion of an excipient as a separate entity;
`! There is no such thing as an approved excipient;
`and
`! Difficulty for industry to develop strategies for pre-
`clinical assessment of completely novel and established
`excipients as well as potentially useful materials avail-
`able in the food and cosmetic industries.
`
`This paper describes why preclinical evaluation is
`necessary for excipients, what various companies have
`done and are doing from a testing perspective, and
`what is in the future.
`
`CURRENT REGULATORY SITUATION
`
`In Europe, the testing of excipients is included in the
`regulatory framework in that novel excipients need to
`be evaluated as new chemical entities (e.g., Notice to
`Applicants, 1998) and information on excipients is ex-
`pected
`in marketing
`authorization applications
`(MAAs) for new drugs (CPMP/DGIII, 1992). Thus, es-
`tablished excipients are included in MAAs with the
`assumption that their presence and characterization in
`pharmacopoeias will not raise an issue with the Euro-
`pean regulators.
`In the United States, the guideline relating to pre-
`clinical data for a new drug application (NDA) does not
`mention excipients (CDER, 1987), but as in Europe, it
`is assumed that the use of an «approved» excipient
`ensures its acceptance in the new drug formulation.
`NDA submissions should cross-reference to a drug
`master file (DMF) containing all relevant information
`on excipients. The Food and Drug Administration
`(FDA) favors the use of commercially established ex-
`cipients as well as established food additives and «gen-
`erally recognized as safe» (GRAS) substances. Pub-
`lished literature guidance is very limited. A paper on
`the testing of new inhalation excipients in the United
`States recommends that a complete toxicological eval-
`uation of the excipient alone and bridging studies in
`animals with the new complete formulation are gener-
`ally sufficient for regulatory approval for a new excip-
`ient with unknown inhalation toxicology potential (De
`et al.,
`1997).
`George
`In Japan, although excipients are not mentioned in
`the guidelines (Japanese Technical Requirements,
`1997), their assessment has recently been clarified
`
`(Uchiyama, 1999). Under the Japanese Ministry of
`Health and Welfare (JMHW) evaluation system, drugs
`containing excipients with prior use in Japan are eval-
`uated at the Pharmaceuticals and Medical Devices
`Evaluation Center (PMDE) while products which con-
`tain an excipient with no prior use in Japan are eval-
`uated by the Subcommittee on Pharmaceutical Excipi-
`ents of the Central Pharmaceutical Affairs Council
`(CPAC). Information concerning the reasons for inclu-
`sion of the excipient and precedents of use as well as
`quality, stability, and safety data are all needed. Ma-
`terials will be considered new excipients if there has
`been no prior use in Japan (even if it has been used in
`a pharmaceutical product in other countries) and when
`the route of administration differs or when the dose
`level exceeds that of prior use (even if already approved
`in the Japanese market).
`Overall, there is an expectation for relevant quality
`and preclinical data for excipients together with evi-
`dence of no excipient-induced adverse effects in the
`final formulated clinical drug substance. The expecta-
`tion to develop an excipient as a new chemical entity
`can result in an expensive and potentially time delay-
`ing process which in the past has led pharmaceutical
`manufacturers to reformulate rather than incur regis-
`tration delays. The lack of specific regulatory guidance
`helped lead to the creation of IPEC (International
`Pharmaceutical Excipients Council) in the early 1990s,
`an industry association with European, United States,
`and Japanese membership. This group has published
`safety evaluation guidelines for excipients (Steinberg
`et al.,
`1996), although they have had no regulatory
`comment. Recommended toxicity studies on excipients
`for longer term use in humans comprise single-dose
`studies, genotoxicity and ADME studies, subacute and
`chronic studies, plus reproduction and carcinogenicity
`studies. Overall, these guidelines are useful as a basis
`for the development of a new excipient but the testing
`program is not dissimilar to the strategy used for an
`active drug. Safety evaluation requirements for new
`excipients in Japan comprise acute, subacute, and
`chronic toxicity; mutagenicity; effects on reproduction;
`dependency; antigenicity; carcinogenicity; and local ir-
`ritation (human patch test) studies (Uchiyama, 1999).
`With the exception of the local irritation test, non-
`Japanese data are acceptable for these studies.
`Another aid to excipient development is published
`data of materials known to the regulators. In the
`United States, the «Inactive Ingredients Guide» which
`is published by the FDA, lists excipients contained in
`approval drug formulations with dosage route and, in
`many cases, the range of levels used (FDA, 1996). A
`similar situation occurs for Japan, with data available
`from an Excipients Directory controlled by JMHW
`(JPEC, 1996). In Europe, some information can be ob-
`tained by direct contact with the regulatory agencies.
`Further information on excipients in marketed drugs
`
`

`

`212
`
`PAUL BALDRICK
`
`can be obtained through various drug directories (e.g.,
`Medical Economics, 1996; ABPI, 1998).
`
`cology data are available for many well-known mate-
`rials.
`
`WHY PRECLINICAL EVALUATION IS NECESSARY
`
`RECENTLY DEVELOPED EXCIPIENTS
`
`Preclinical evaluation of excipients is not only nec-
`essary because of regulatory expectation but because
`excipients are not inert (as traditionally viewed) and
`can show adverse toxicological findings by themselves
`or in drug formulations. Drug delivery can be affected
`by excipients through altered release of drug, bioavail-
`ability, and increased solubility, stability, and dissolu-
`tion rates leading to improved therapeutic activity and
`even a decrease of unwanted side effects. The role of
`excipients in drug delivery systems and sustained re-
`lease formulations is discussed later. Regulators are
`fully aware that a number of clinically manifested ad-
`verse reactions are caused by established excipients,
`although they are of low occurrence and uncommon
`when compared to the overall prevalence of adverse
`drug reactions. Such reactions are commonly of a hy-
`persensitivity, allergic, or anaphylactic nature and the
`area is well covered in the literature (e.g., Golightly
`et
`1988; Barband, 1995; AAP, 1997; Pharmaceutical
`al.,
`Press, 1999).
`From a safety perspective, the following situations
`will raise questions about a known excipient from reg-
`ulatory authorities unless specifically addressed:
`
`! Published data suggest that there may be poten-
`tial toxicity issues (see Table 1);
`! An excipient approved for one dose route may be
`changed to another administration route where sys-
`temic exposure/target site may be greatly different;
`! Level of excipient in the new drug formulation
`exceeds that already known to the regulatory agency
`for prior instances of use; and
`! More recently, is the excipient derived from an
`animal source, e.g., issues surrounding the use of gel-
`atin and transmissible spongiform encephalopathies?
`
`As mentioned, various food additives have applica-
`tions as essentially new excipients and safety stan-
`dards such as an acceptable daily intake (ADI) or
`GRAS status, established using animal data, may al-
`low use of these materials without the need for exten-
`sive preclinical testing. However, some of the situa-
`tions above also apply to these materials along with the
`fact that data will relate to oral administration, which
`is of little use for nonoral products, and the level of the
`food additive to be used as a proposed new excipient
`may be higher than the ADI value.
`Overall, the process of evaluation is becoming easier
`for toxicologists as more data on established excipients
`become available through published literature. Some
`general safety data can be found in various publica-
`tions (e.g., Richardson and Gangolli, 1992; Kibbe,
`2000). However, it is surprising how little useful toxi-
`
`As a result of concerns related to the use of sugar in
`various health areas, notably dental care, obesity, and
`diabetes, a number of new excipients have appeared in
`sugar-free medical preparations over the past 15 years
`(Herbert, 1998). These materials comprise intense
`sweeteners such as aspartame, saccharin, and cycla-
`mate plus bulk sweeteners such as the polyols sorbitol,
`mannitol, xylitol, and lactitol and represent naturally
`occurring or synthesized materials of which some are
`approved for food use. Literature reviews show an ar-
`ray of preclinical studies for these excipients, including
`carcinogenicity bioassays. As well as assessing safety,
`some of these studies relate to specific toxicological
`concerns such as bladder tumor formation with saccha-
`rin and adrenal/testes proliferation with polyols (see
`Table 1).
`Cyclodextrins (CDs) are enzymatically modified
`starches with many favorable properties as excipients
`including the ability to form inclusion complexes with a
`variety of drug molecules allowing increased bioavail-
`ability. The use of CDs in food products in the late
`1970s and 1980s, together with extensive preclinical
`-CD,
`testing, has resulted in these materials (as
`a
`o
`13
`-CD, or HP3- -CD) appearing in pharmaceutical for-
`mulations licensed in Europe, the United States, and
`Japan (Thompson, 1997; Mosher and Thompson,
`2000). Preclinical assessment has included a range of
`metabolism studies, short- to long-term toxicity studies
`in the rodent and nonrodent, and reproduction toxicol-
`ogy studies plus genotoxicity and carcinogenicity as-
`says. Specific parenteral studies have investigated the
`fact that CDs can show a toxic effect on the kidneys
`when given by this dose route; it is argued that this
`finding is related to an adaptive response due to the
`excretion of osmotic agents at extremely high concen-
`trations (Mosher and Thompson, 2000).
`Although not viewed as a typical excipient, HFAs
`have been raised to prominence both in the United
`States and in Europe in recent years as inhalation
`propellants. This prominence has arisen from the need
`to replace chlorofluorocarbonates (CFCs) in metered-
`dose inhalers (MDIs) used by asthmatics, due to con-
`cerns over ozone layer depletion and greenhouse gas
`effects and defined in the Montreal protocol (Wolff and
`Dorato, 1993). The various forms include HFA 134a
`(tetrafluoroethane), HFA 152a (difluoroethane), and
`HFA 227 (heptafluoropropane) and gradual regulatory
`approval for these materials is appearing; HFA 152a is
`accepted by the FDA for use as a topical aerosol pro-
`pellant (Kibbe, 2000). HFAs underwent extensive pre-
`clinical testing programs in the early to mid-1990s
`with studies including a comprehensive range of inves-
`
`

`

`PHARMACEUTICAL EXCIPIENT DEVELOPMENT
`
`213
`
`TABLE 1
`Toxicological Effects with Well-Known Excipients
`
`Excipient
`
`Toxicological finding
`
`Explanation
`
`Reference
`
`Lactose and polyols
`
`Saccharin
`
`Polyvinylpyrrolidone
`(PVP)
`
`Menthol
`
`Limonene
`
`Adrenal medullary proliferative
`changes/tumors and
`hyperplastic/neoplastic testes
`changes in rats
`Proliferative changes in male
`rat bladder epithelium
`
`Accumulation in the
`reticuloendothelial system in
`rodents with the occurrence
`of «foam cells»
`
`Limited sensitization reaction
`in guinea pigs
`
`Hyaline droplet formation in
`male rat kidney
`
`Talc
`
`(i) Lung tumors in female rats
`
`Polyethylene glycol (PEG)
`(low molecular weight)
`
`Maltodextrin
`
`Mannitol
`
`CFCs
`
`Aluminum salts
`
`Thimersol
`
`(ii) Adrenal gland neoplasms
`(pheochromocytomas) in rats
`Teratogenic in the mouse with
`increased fetal loss,
`decreased body weight, and
`malformations
`Minimal reversible laryngeal
`irritation (squamous
`metaplasia) with 4%
`maltoxdextrin in chronic rat
`inhalation study
`Induced acute renal and
`cardiac injury and apoptosis
`in kidney and heart
`Cardiac arrhythmias notably in
`the dog
`
`Local tissue reaction at dose
`site in guinea pig and rat
`
`Hypersensitivity found in the
`guinea pig
`
`Considered to be rat specific and related
`to altered calcium homeostatis due to
`high-dose levels given and not relevant
`to man
`Considered to be species specific with
`large doses used. Mechanism of action
`may involve urinary proteins not
`normally found in humans
`Toxicological significance is unclear from
`the literature, but findings may be
`related to high-dose regimens used. No
`adverse effects from long-term storage
`in humans
`Toxicological significance is not clear from
`the literature, although very infrequent
`human allergy reactions are reported in
`the presence of menthol
`Considered to be male rat specific and
`related to the presence/accumulation of
`2-microglobulin
`a
`
`(i) Related to high-dose level and
`resulting chronic toxicity
`(ii) Review of data indicates that tumors
`were not treatment-related
`Not teratogenic in the rat. Not considered
`to be relevant to human use
`
`Baldrick and Bamford
`(1997); BaÉr (1988,
`1992); Roe (1989);
`et al.
`(1996)
`Lynch
`et al.
`Golightly
`(1988);
`Wysner and Williams
`(1996); Cohen (1998)
`
`Robinson
`
`et al.
`(1990)
`
`Sharp (1978)
`
`Alden (1986); Lehman-
`et al.
`McKeeman
`(1989); Flamm and
`Lehman-McKeeman
`(1991)
`Goodman (1995)
`
`Vannier
`Gupta
`
`et al.
`(1989);
`et al.
`(1996)
`
`Considered to be a background finding of
`no consequence to man
`
`Baldrick (2000)
`
`May be related to osmolality in the
`specific model used (old male
`spontaneously hypertensive rats)
`Relatively good safety margins and long/
`wide use of CFC propellants in MDIs
`have shown these compounds to be safe
`Local injection site reaction, skin nodules,
`and granulomas have all been related
`to aluminum adjuvants
`Increased incidence of hypersensitivity
`reported, particularly with vaccines
`
`Zhang
`
`et al.
`
`(1999)
`
`Wolff and Dorato (1993)
`
`Vogel and Powell (1995);
`Martindale (1999)
`
`Kibbe (2000)
`
`tigations in mice, rats, and dogs (Alexander and Li-
`bretto, 1995). The change from established CFC-con-
`taining drug formulations to those with HFA has also
`required toxicity bridging studies; these studies can
`vary from 1 month to lifetime in duration. Human data
`show that the new HFA 134a and 227 excipients are as
`safe as the CFCs they are replacing (e.g., Harrison
`et
`et al.,
`1996; Blumenthal
`1998).
`
`EXCIPIENTS UNDERGOING DEVELOPMENT
`Despite the lack of regulatory guidance, the develop-
`ment of new or improvement of existing excipients has
`
`been expanding in recent years. In addition, the «acti-
`vating» of old drug formulations by inclusion of new
`excipients for a range of pharmaceutical classes is be-
`ing investigated (Kalinkova, 1999). Development pro-
`grams range from assessment of new formulations
`in vitro
`with an active role for the excipient using
`pharmaceutical systems to establish release patterns
`in vivo
`efficacy models to a full preclinical package
`and
`of studies and/or clinical evaluation. Some examples of
`preclinical testing studies are given in Table 2.
`Various applications are being investigated for the
`polysaccharide chitosan which is an approved food ad-
`
`

`

`214
`
`PAUL BALDRICK
`
`TABLE 2
`Assessment Programs for Various Excipients under Development
`
`Excipient
`
`Use
`
`Study type
`
`Remarks
`
`Reference
`
`Chitosan
`
`Controlled-release tablets,
`microsphere use in
`transmucosal transport,
`wound healing
`
`Aquateric aqueous
`enteric coating
`
`Film coating for tablets and
`capsules
`
`Aquacoat ECD
`
`Coating for tablets and
`capsules
`
`Ethylene glycols
`
`Formulation aid for nasal
`delivery of benzodiazepines
`
`Phospholipid-based
`excipient
`(liposome)
`
`Glycolic and lactic
`acid polymers
`(PLGAs)
`Adjuvants
`
`Delivery system for antiviral
`drug
`
`Delivery system for growth
`factor
`Controlled-release delivery of
`humanized monoclonal
`antibody
`Vaccine delivery
`
`Erythritol
`
`Sugar substitute
`
`Negligible toxicity
`reported
`
`Illum (1998)
`
`A lack of toxicity and
`no genotoxicity
`reported
`
`Kotkoskie
`et al.
`(1999); Batt and
`Kotkoskie (1999)
`
`No toxicologically
`significant findings
`reported
`
`Palmier
`(2000)
`
`et al.
`
`Only mild local
`toxicity was noted
`
`Hjortkjaer
`(1999)
`
`et al.
`
`No adverse effects
`reported for
`liposome
`
`Cheng
`
`(2000)
`et al.
`
`Katre
`
`et al
`
`(1998)
`
`No adverse effects
`seen
`
`Mordenti
`(1999)
`
`et al.
`
`Many of the new
`adjuvants under
`development show
`no notable adverse
`effects
`
`Vogel and Powell
`(1995)
`
`Well tolerated with no
`toxicological issues
`
`Munro
`et al.
`(1998)
`
`! Assessment of cilia beat (guinea
`pig), mucociliary clearance rate
`(frog palate), immunogenicity
`(mouse), nasal histology (rat and
`human volunteers), membrane
`transport (rat)
`! Single-dose toxicity studies
`! Up to 2-week rabbit toxicity
`studies
`! 90-day dietary rat toxicity study
`! Embryofetal rat dietary study
`! Genotoxicity battery (Ames,
`mouse lymphoma, and mouse
`micronucleus tests)
`! 90-day oral gavage rat toxicity
`study
`! Developmental rat oral gavage
`study
`! Single-dose rabbit toxicity study
`14-day rabbit toxicity study
`4-week rabbit toxicity study
`evaluation
`In vitro
`!
`! Intravitreal toxicology rabbit
`study
`human plasma study
`In vitro
`!
`! Subcutaneous rat study
`! Combined pharmacokinetic and
`toxicity rabbit study over 56 days
`using intravitreal administration
`model
`! A wide variety of
`in vivo
`systems to assess
`immunomodulatory role of
`adjuvant with/without candidate
`vaccine
`! Local tolerance and limited
`toxicity studies
`! Various clinical studies
`! Metabolism and deposition rat
`intravenous and oral gavage
`studies
`! Single-dose rat and dog studies
`(various routes)
`! Repeat dose studies ranging from
`4 to 78 weeks in mice, rat, and
`dog (various routes, notably
`dietary)
`! Reproduction toxicology package
`(intravenous and oral route)
`! Carcinogenicity feeding rat study
`! Genotoxicity studies
`! Single- and repeat-dose oral
`human studies
`
`ditive. These include use in controlled-release matrix
`tablets, as microspheres/microcapsules (e.g., for hor-
`mone release) in transmucosal drug transport of pep-
`tides and proteins, and in wound healing. Preclinical
`evaluation to date has shown no adverse toxicity (Il-
`lum, 1999). Aquateric aqueous enteric coating, which
`has pharmaceutical applications as an enteric film
`
`coating in solid dosage forms, has recently undergone
`subchronic and developmental toxicity studies based
`on IPEC recommendations with no adverse effects or
`genotoxicity found (Kotkoskie
`1999; Batt and
`et al.,
`Kotkoskie, 1999). This material represents a good ex-
`ample to show that all relevant preclinical data need to
`be taken into consideration when making a safety eval-
`
`

`

`PHARMACEUTICAL EXCIPIENT DEVELOPMENT
`
`215
`
`uation of a material. Thus, data on the major compo-
`nent of Aquateric aqueous enteric coating, cellulose
`acetate phthalate, are also relevant. Various studies on
`this material, performed in the 1970s and comprising
`14-day oral gavage studies in the rat and dog and
`teratogenicity studies in the mouse and rat (Kotkoskie
`1999), confirmed the expected lack of toxicity of
`et al.,
`the newer excipient. Interestingly, cellulose acetate
`phthalate itself, traditionally viewed as being «inert,»
`has recently been shown to have antiviral activity and
`maybe a role in the prevention of sexually transmitted
`diseases (Neurath
`1999). IPEC recommended
`et al.,
`studies on another material, Aquacoat ECD, which is
`GRAS listed as a coating for tablets and capsules, have
`shown no toxicologically significant findings.
`Polyethylene glycols (PEGs) have a well-established
`role as safe pharmaceutical excipients by a variety of
`dose routes. The safety of these materials as enhancers
`of nasal delivery of benzodiazepines has been assessed
`in various toxicity studies with only mild local toxicity
`noted (Hjortkjaer
`1999). PEG 400 caused no
`et al.,
`adverse effects on the morphology and integrity of the
`nasal mucosa when tested as an enhancer of calcium
`entry blocker bioavailability in a study in the rat (Rah-
`man and Lau-Cam, 1999).
`An array of published data exist for the use of either
`liposomes (phospholipid-based vesicles) or micro-/
`nanoparticles containing excipients to promote the de-
`livery of candidate drugs. Liposomes have a role in
`reducing the toxicity and improving the stability of
`drugs as well as prolonging the duration of action and
`have a role in specific site delivery. No adverse effects
`have been reported for liposomes. Thus, the toxicology
`of liposomes containing a novel antiviral has been as-
`sessed following intravitreal administration in the rab-
`bit with no obvious liposome-related effects (Cheng
`et
`2000). Rat studies with insulin-like growth factor-1
`al.,
`administrated in liposomes (DepoFoam) has shown no
`adverse effects with the liposomes (Katre
`1998).
`et al.,
`PEG-containing liposomes have been shown to have a
`possible role in localization of the infected site as as-
`-infected rat lung tis-
`sessed in
`Klebsiella pneumoniae
`sue (Schiffelers
`1999). Tumor-bearing mice have
`et al.,
`been used to show a potential role for these liposomes
`as intracellular targeting carriers for tumor therapy
`(Ishida and Maruyama, 1998). PEGylated liposomes
`with target-specific surface antibodies (immunolipo-
`somes) are also under evaluation (Torchilin, 1994).
`Various animal studies have indicated a role for poly-
`vinylpyrrolidone²iodine (PVP-I) liposomes in ocular
`medicine and wound healing (Reimer
`1997).
`et al.,
`Polymers derived from glycolic and lactic acids
`(PLGAs) and formulated as micro-/nanospheres are
`currently being evaluated for a variety of controlled-
`release drug delivery applications. A combined phar-
`macokinetic and toxicological study in the rabbit with
`humanized monoclonal antibody given intravitreally in
`
`PLGA micospheres showed no adverse effects with the
`excipient (Mordenti
`1999). A system using
`et al.,
`stealth poly(lactic acid)²polyethylene glycol
`(PLA-
`PEG) nanoparticles as protein carriers through the
`nasal mucosa has been investigated in the rat using
`tetanus toxoid as a marker (Tobio
`1998). The
`et al.,
`success with the use of these materials as excipients
`has led to the regulatory approval of at least three
`medicinal products, Lupron Depot, Decapeptyl, and
`Zoladex, all of which are luteinizing hormone-releasing
`hormone analogues in a PLA or PLGA matrix (Nema
`et
`2000). Although not directly cited, there has been
`al.,
`no reported toxicity issues with the PLA or PLGA
`components of these carrier systems.
`Although aluminum-based mineral salts are the only
`«approved» adjuvants for vaccine delivery, an array of
`new materials are under investigation as immuno-
`modulators and/or for controlled release. Various
`in
`efficacy models have been investigated for these
`vivo
`materials in the presence and absence of the candidate
`vaccine(s) with some adjuvants being tested in various
`local tolerance and limited toxicology studies and in
`the clinic (Vogel and Powell, 1995). Interestingly, some
`of the systems under evaluation are vaccines contained
`in liposomes and PLGA or PLA microspheres. A recent
`study in mice and guinea pigs using the latter material
`showed minimal local tissue reaction 1 year after in-
`jection compared to local granulomas with aluminum
`adjuvant (Gupta
`1997). Poly(lactic/glycolic acid)
`et al.,
`microspheres containing antigen (ovalbumin) showed
`efficacy and safety following repeated injections in the
`guinea pig (Takagi
`1992).
`et al.,
`As well as the established excipients in sugar-free
`medical preparations mentioned in the previous sec-
`tion, other materials are also in development as sugar
`substitutes. The polyol erythritol has undergone com-
`prehensive metabolic and toxicological assessment in
`mice, rats, and dogs as well as administration to hu-
`mans and has been shown to be well tolerated with no
`toxicological issues (Munro
`1998).
`et al.,
`
`THE FUTURE
`
`The lack of regulatory guidance to assess excipient
`safety has slowed the development of these vital com-
`ponents of drug formulations. Drug companies have
`had to assess carefully the benefits of using the new
`substance in light of extra workload, cost, and possible
`regulatory delays/rejection. Furthermore, excipients
`are neither inert nor inactive substance and may affect
`drug bioavailability and cause adverse reactions and so
`need consideration when formulating new drugs. The
`newer excipients quoted in this paper have all encoun-
`tered problems, e.g., some of the sugar substitute ma-
`terials have produced species-specific toxicology issues
`with no relevance to humans but these findings have
`taken time, effort, and cost to resolve; the routine use
`
`

`

`216
`
`PAUL BALDRICK
`
`of CDs in formulations is still questioned due to uncer-
`tain regulatory acceptance of a formulation containing
`a «nonstandard»
`inactive ingredient
`(Mosher and
`Thompson, 2000) and even with government pressure
`to change a formulation, considerable time, effort, and
`cost have occurred in the development of the HFAs.
`As a consequence, well-known excipients which are
`listed in international pharmacopoeias and for which
`there are robust published safety data have tended to
`have been used.
`However, despite this situation, companies are ac-
`tively evaluating new materials or applying new uses
`to established excipients. Various approaches to pre-
`clinical evaluation have been followed in the examples
`of materials undergoing development described in this
`paper although many of these materials are at an early
`stage and so published data on the full development
`strategy are not yet available. Evaluation can comprise
`a testing package as given by IPEC; these recommen-
`dations are helpful as guidance, although they still
`have had no official regulatory agency comment and
`are not dissimilar to the full preclinical program that is
`necessary for a new chemical entity. However, they are
`probably appropriate for the development of a stand-
`alone excipient. A minimal preclinical program for a
`new excipient to be added to a drug formulation may be
`sufficient and could take the following form:
`! Ames studyÑto assess genotoxicity potential;
`! Single-dose toxicity studyÑto assess adverse ef-
`fects at high doses;
`! Investigative mass/balance/whole body autora-
`diography studyÑto provide information on absorp-
`tion, distribution, metabolism, and excretion;
`metabolism study (e.g., hepatocytes)Ñto
`In vitro
`assess species differences; and
`! One-month toxicity study (plus toxicokinetic satel-
`lite animals)Ñto establish if higher doses are causing
`toxicity or metabolic overload.
`The findings from these studies could then be dis-
`cussed with relevant regulatory bodies and advice
`sought as to whether further testing is recommended
`in conjunction with typical toxicology investigations
`needed for a new drug substance. A common problem
`in the safety evaluation of many new excipients is
`measurement of systemic exposure. Routine drug de-
`velopment allows pharmacokinetic radiolabeling (or
`cold assay) of the component drug and to follow its
`metabolism in the presence and absence of the new
`excipient. However, in many cases there is a difficulty
`in labeling the excipient material, e.g., PEG, PVP, or
`PLA, as they are quickly metabolized into normal com-
`ponents of the cellular system. This problem has been
`successfully overcome by some workers, e.g., absorp-
`tion of PEGs can be followed by urinary excretion using
`HPLC (Donovan
`1990).
`et al.,
`Overall, the current regulatory situation of having to
`
`!
`
`wait to see if an excipient is «approved» by virtue of
`regulatory acceptance of the new drug formulation in
`which it is a constituent is not helpful or acceptable.
`Nor is the view that new excipients should be treated
`as new chemical entitie