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Advanced Drug Delivery Reviews 54 (2002) 805–824
www.elsevier.com/locate/drugdeliv
A pplying the Biopharmaceutics Classification System to
veterinary pharmaceutical products
Part I: Biopharmaceutics and formulation considerations
a, b c
*
Marilyn Martinez , Larry Augsburger , Thomas Johnston ,
a
Wendelyn Warren Jones
a
Office of New Animal Drug Evaluation
,
Food and Drug Administration
,
Rockville
,
MD
20855,
USA
b
University of Maryland
,
Baltimore
,
MD
21201,
USA
c
University of Missouri
,
Kansas City
,
MO
64110,
USA
Abstract
The complexity of multiple species approvals continues throughout the life of a product as post-approval manufacturing
changes, as well as all generic versions of approved products, are evaluated for each of the approved target animal species.
In comparing product bioavailability across animal species, it is not unusual to observe marked interspecies differences. For
many compounds, these differences reflect species-specific presystemic metabolism. However, a host of other variables must
also be considered, including in vivo drug solubility, gastric transit time, intestinal permeability, diet, and species-by-
formulation interactions. To predict potential species-by-formulation interactions, one must consider the solubility and
intestinal permeability of the drug entity, the type of formulation, nature of the excipients, and the physiological
characteristics of the animal recipient. In this paper, we examine manufacturing and formulation variables that can affect
drug bioavailability, and the potential for species-specific differences in the responses to these formulations.
2002 Elsevier Science B.V. All rights reserved.
Keywords
:
Veterinary oral dosage forms; Biopharmaceutics Classification System; Solubility; Dissolution; In vivo/in vitro correlation
Contents
1 . Bioequivalence and the regulatory process ................................................................................................................................ 806
1 .1. Parameters affecting bioequivalence.................................................................................................................................. 808
1 .2. The Biopharmaceutics Classification System (BCS) ........................................................................................................... 808
2 . Characterizing drug solubility and permeability......................................................................................................................... 809
2 .1. Solubility......................................................................................................................................................................... 809
2 .2. Permeability .................................................................................................................................................................... 810
3 . Formulation effects.................................................................................................................................................................. 811
3 .1. Excipients and tableting processes in oral formulations ....................................................................................................... 811
*
Corresponding author. Tel.: 11-301-827-7577; fax: 11-301-
594-2298.
E-mail address
:
mmartin1@cvm.fda.gov (M. Martinez).
0169-409X/02/$ – see front matter 2002 Elsevier Science B.V. All rights reserved.
PII: S0169-409X(02)00070-4
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3 .2. Particle size ..................................................................................................................................................................... 812
3 .3. Noyes-Whitney equation................................................................................................................................................... 813
3 .4. Minor and major types of changes in formulation ............................................................................................................... 814
4 . In vitro predictions of product dissolution ................................................................................................................................. 815
5 . Oral formulations used in veterinary medicine........................................................................................................................... 816
6 . Potential interspecies differences in excipient response .............................................................................................................. 818
7 . Predicting species-specific differences in oral bioavailability ...................................................................................................... 820
8 . Concluding thoughts: forming a bridge between veterinary and human medicine ......................................................................... 821
9 . Uncited reference .................................................................................................................................................................... 821
References .................................................................................................................................................................................. 821
1 . Bioequivalence and the regulatory process of an establishment not covered by the approval
that is in effect)
When a drug product is approved for veterinary
use, effectiveness and safety must be confirmed for Examples of pre-approval and post-approval sup-
each animal species included on the product label plements received by the CVM include a switch
[1]. The complexity of multiple species approvals from swallow tablets to chewable dosage forms,
continues throughout the life of a product as the changes in flavorants to increase product palatability,
potential impact of any post-approval change in formulation and manufacturing changes to increase
product manufacture and formulation must be con- ease of use, changes in active bulk substance, and
sidered for each of these target animal species [2]. formulation or process changes proposed to increase
Moreover, since generic products are required to the efficiency of product manufacture. These re-
have the same indication as the pioneer, product evaluations can be based on the demonstration of
bioequivalence must be confirmed independently for comparable bioavailability of the original and revised
each of the labeled veterinary species [1]. Therefore, formulations [4]. As with human pharmaceuticals, a
the ability to predict potential species-by-formulation demonstration of product bioequivalence is also the
interactions is of great importance to the FDA’s basis for assessing the safety and effectiveness of
Center for Veterinary Medicine (CVM). generic drug product applications [5].
Changes in veterinary drug products that will The impact of requiring that product (formulation)
necessitate a re-evaluation of product safety or bioequivalence be considered in multiple animal
effectiveness include [3]: species is best appreciated from the perspective of
the number of marketed products approved for use in
• A change in the active ingredient concentration or more than one target animal species. In 1999, 31% of
composition of the final product all oral dosage forms were approved for use in two
• A change in quality, purity, strength, and identity or more target animal species (this does not include
specifications of the active or inactive ingredients oral solutions for which waiver would be granted).
• A revised method of synthesis or fermentation of For parenteral formulations, 45% of all intramuscular
the new drug substance (i.m.) and subcutaneous (s.c.) products were ap-
• A change in the manufacturing process of the new proved for use in two or more target animal species.
drug substance and/or final dosage form (other Of these, | 25% were approved for use in three or
than a change in equipment that does not alter the more target animal species.
method of manufacture of a new animal drug, or a Without a reliable alternative to in vivo drug
change from one commercial batch size to another absorption data, multiple in vivo bioequivalence/
without any change in manufacturing procedure), relative bioavailability studies are necessary. Such a
or a change in the methods, facilities, or controls requirement poses several critical problems:
used for the manufacture, processing, packaging,
or holding of the new animal drug (other than use 1. Due to the relatively small profit margin associ-
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ated with veterinary pharmaceuticals, the need between treatment means and a 15% residual
to perform multiple bioequivalence studies may error, there is a 20% risk of failing to submit an
be economically prohibitive for all but the must approvable bioequivalence application when the
lucrative of animal health products. Should pioneer product is approved for use in two
sponsors consequently elect to forego pursuing target animal species. For more variable drugs
these applications or formulation changes, this (20% CV), this risk increases to 56%, even if
could have deleterious effects on the availability the test and reference means are identical.
of cost effective and optimally formulated ani-
mal health products. Given the potential for species-by-formulation
2. When the number of studies is increased with- interactions with both oral [6] and parenteral [7,8]
out adjusting the corresponding approval products, the pivotal question is whether or not we
criteria, we increase the risk of Type 1 errors. can predict those drugs and drug products for which
For example, Fig. 1 provides a simulated esti- the demonstration of product bioequivalence can be
mate of the risk of failing to demonstrate extrapolated across target animal species. Recently,
product bioequivalence when studies are re- the FDA’s Center for Drug Evaluation and Research
quired for two target animal species and when (CDER) published guidance on the use of the
both studies must meet a 620% confidence Biopharmaceutics Classification System (BCS) and
interval criterion for both the rate (C ) and in vitro dissolution data to support bioequivalence
MAX
extent (AUC) of absorption. For these simula- evaluations [9]. Accordingly, CVM would like to
tions, the residual error was varied between 10 consider the feasibility of using in vitro dissolution
and 20% relative to the overall treatment means, data to support bioequivalence determinations and
and the ratio of treatment means (for AUC and cross-species bioequivalence extrapolations when
C ) ranged between 0.95 and 1.0. The appropriate.
MAX
degrees of freedom for these confidence interval Working in collaboration with experts from the
calculations was 22, which translates to either a University of Missouri (Drs Lane Clarke, Thomas
24 subject cross-over study or a 48 subject Johnston, and Ashim Mitra) and Drs Gordon Amidon
parallel study (for the purposes of this example, (University of Michigan), Larry Augsburger (Uni-
we did not distinguish between estimates of versity of Maryland) and Jim Riviere (North
within or between subject variability). From Carolina State University), CVM recently investi-
these results, we see that with a 5% difference gated current scientific thinking on in vivo/in vitro
Fig. 1. Risk of failure to demonstrate product bioequivalence based on C and AUC at three different confidence intervals, 610%,
MAX
615%, and 620%.
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relationships and potential causes for cross-species • Surface area:
differences in product bioavailability. Drs Aug- i Particle size and wettability
sburger, Amidon, Riviere, Mitra, Johnston and ii Wettability
Clarke were invited to CVM as part of the Office of iiiSurfactants in gastric juice
New Animal Drug Evaluation and Research iv Bile salts
(ONADE) Visiting Scientists program. • Diffusivity:
The overall approach to this problem was to i Molecular size
consider product bioavailability from three perspec- ii Viscosity of lumenal contents
tives: • Boundary layer thickness
i Gastrointestinal motility pattern
1. Drug entity: The BCS was used to determine if ii Fluid flow rate
we could identify drug candidates suited for • Solubility
cross-species extrapolations of product bio- i Hydrophilicity
equivalence. In this regard, we explored how ii Crystalline structure,
the physico-chemical characteristics of a com- iiiGastrointestinal pH and buffering capacity
pound could impact its oral absorption prop- iv Bile
erties. v Food components
2. Formulation: We examined those changes in • Maintenance of sink conditions
formulation and manufacturing processing that i Gastrointestinal fluid flow
are expected to have the greatest impact on drug ii Drug permeability
absorption. These changes were related to the • Volume of solvent available
BCS classification of drug. i Secretions
3. Interspecies differences: We considered how ii Co-administered fluids
interspecies differences in GI physiology might
result in differences in the absorption charac- The impact of these factors must be considered
teristics of various compounds. We also consid- when developing in vitro methods for predicting
ered how interspecies differences in diet and GI product quality and in vivo performance. However,
physiology might lead to species-by-formulation in some cases, it is not drug solubility or product
interactions. dissolution that limits bioavailability but rather it is
the ability of the drug to cross the gastrointestinal
Part I of this two-part manuscript focuses on (GI) mucosa. Depending upon what constitutes the
points 1 and 2 while Part II focuses on point 3 [6]. rate-liming step in the drug absorption process,
physiological differences, whether due to species
1 .1.
Parameters affecting bioequivalence differences in GI transit time, GI fluid composition,
site of absorption, disease, etc., can markedly impact
Bioequivalence is defined as two or more products in vivo dissolution and thus drug bioavailability.
that exhibit comparable rates and extent of drug Therefore, a pivotal question is whether or not it is
absorption [10]. Recently, CDER has modified this possible to identify those compounds and in vitro test
definition in accordance with drug exposure con- conditions that can assure product bioequivalence
cepts, defining equivalence as two or more products across a range of physiological states.
exhibiting comparable rates and extent of exposure
[11]. Regardless of which definition is used, to be
1 .2.
The Biopharmaceutics Classification System
bioavailable, an oral dosage form must go into
(
BCS
)
solution prior to being absorbed. Thus, ensuring
optimal dissolution characteristics is one of the One of the most significant prognostic tools
fundamental concerns of the formulation chemist. developed in recent years has been the BCS [13]. By
Dressman et al. [12] list the following physico- knowing a compound’s solubility and intestinal
chemical and physiological parameters as important permeability characteristics, drugs are classified into
determinants of in vivo drug dissolution: one of four categories:
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• Class I: High solubility, high permeability. These to identify the dissolution conditions that best corre-
compounds are generally very well absorbed. late with the in vivo physiology of the animal species
Examples include propranol and metoprolol. For in question.
those Class I compounds formulated as immediate
release products, dissolution rate generally ex-
ceeds gastric emptying. Therefore, nearly 100%
2 . Characterizing drug solubility and
absorption can be expected if at least 85% of a
permeability
product dissolves within 30 min of in vitro
dissolution testing across a range of pH values
2 .1.
Solubility
[9,11]. Accordingly, in vivo bioequivalence data
are not necessary to assure product comparability.
From a biopharmaceutics perspective, the term
• Class II: Low solubility, high permeability. The
solubility pertains to the amount of a particular
bioavailability of products containing these com-
solute that can dissolve within a specified volume of
pounds is likely to be dissolution-rate limited. For
liquid. A compound’s aqueous solubility is a func-
this reason, a correlation between in vivo bioavail-
tion of its ability to form hydrogen bonds with water
ability and in vitro dissolution rate (an IVIVC)
molecules. Generally, aqueous solubility is directly
may be observed. Examples include piroxicam
proportion to the number of hydrogen bonds that can
and naproxen.
be formed with water, and ionized compounds
• Class III: High solubility, low permeability: Ab-
exhibit greater aqueous solubility than do the union-
sorption is permeability-rate limited but dissolu-
ized counterparts. Consequently, the rate of solute
tion will most likely occur very rapidly. For this
dissolution can be markedly affected by the pH of
reason, there has been some suggestion that as
the aqueous solvent. The effect of pH on drug
long as the test and reference formulations do not
ionization can be described by the Henderson-Has-
contain agents that can modify drug permeability
selbach equation [14]:
or GI transit time, waiver criteria similar to those
associated with Class I compounds may be appro-
pH5 pK 1 log([ionized]/[unionized]) (1)
a
priate. Examples include ranitidine and
cimetidine.
• Class IV: Low solubility, low permeability: very Weak bases dissolve more slowly at higher pH
poor oral bioavailability. These compounds are values (since above its pK , more drug exists in its
a
not only difficult to dissolve but once dissolved, unionized form), whereas weak acids dissolve faster
often exhibit limited permeability across the GI at a higher pH (since above its pK , more drug exists
a
mucosa. These drugs tend to be very difficult to in its ionized form).
formulate and can exhibit very large intersubject Solubility, as defined for human BCS-based waiv-
and intrasubject variability. Examples of these ers, is determined on the basis of the highest
compounds include furosemide and hydrochlo- manufactured strength [9]. The pH–solubility profile
rothiazide. of the test drug substance is determined at 3761 8C
in aqueous media with a pH in the range of 1–7.5
Upon combining this information with an under- using the standard buffer solutions described in the
standing of the interrelationship between pH, product USP. The solubility class is determined by calculat-
dissolution and GI transit time, conditions can be ing the volume of an aqueous medium sufficient to
defined such that in vitro dissolution data can be dissolve the highest dose strength in the pH range of
used as a surrogate for in vivo bioequivalence 1–7.5. A drug substance should be classified as
information. However, if scientists are to consider highly soluble when the highest dose strength is
using in vitro dissolution data to support veterinary soluble in equal to or less than 250 ml of aqueous
bioequivalence determinations or cross-species bio- media over the pH range of 1–7.5. This definition
equivalence extrapolations, it is essential that one differs from a traditional thermodynamic approach
first determine if a compound’s BCS classification is where solubility is defined with regard to fixed ratios
constant across target animal species. We also need of solute to solvent [15]:
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• Very soluble: less than 1 part solvent needed to ‘Rule of 5’ states that poor permeation, absorption
dissolve 1 part solute and bioavailability are more likely to occur when:
• Freely soluble: from 1 to 10 parts solvent
needed to dissolve 1 part solute
1. There are more than five H-bond donors (ex-
• Soluble: from 10 to 30 parts solvent needed to
pressed as the sum of OH’s and NH’s).
dissolve 1 part solute
2. The molecular weight is greater than 500.
• Sparingly soluble: from 30 to 100 parts solvent
3. The log P value is greater than 5. Generally,
needed to dissolve 1 part solute
compounds with log P values less than 1.5 tend
• Slightly soluble: from 100 to 1000 parts solvent
to exhibit minimal distribution into lipid mem-
needed to dissolve 1 part solute
branes while compounds ranging between 2 to 4
• Very slightly soluble: from 1000 to 10,000 parts
tend to exhibit excellent partitioning into mem-
solvent needed to dissolve 1 part solute
branes [17].
• Practically insoluble: more than 10,000 parts
4. There are more than ten H-bond acceptors
solvent needed to dissolve 1 part solute
(expressed as the sum of N’s and O’s).
5. Compound classes that are substrates for bio-
Considering the current BCS definitions of solu-
logical transporters are exceptions to this rule.
bility, a BCS class may not be universal across
mammalian species. Reasons for this include:
Orally administered drug classes that are know to
violate the ‘Rule of 5’ are antibiotics, antifungals,
1. Differences in tablet strength: Veterinary dosage
vitamins and cardiac glycosides. It is suggested that
forms are generally administered on a mg/kg
the members of these drug classes violate this rule
basis. Due to wide variations in body weights
because they possess structure features that enable
across breeds, gender and age, a multifold range
them to act as substrates for naturally occurring
of tablet strengths may be needed within a line
transporters.
of products. However, it is uncertain as to
More recently, multivariate methods have been
whether or not gastric volume within a species
used to predict high versus low permeability com-
varies in proportion to body size.
pounds [18]. Through the use of pattern recognition
2. Differences in pH: As discussed in Part II [6],
statistics, lipophilicity and polar surface area were
gastric and intestinal pH values may not be
found to be the primary variables determining drug
comparable across target animal species, there-
permeability. Given these two variables, molecular
by raising a question of whether or not scientists
weight was found to be redundant. The relationship
are justified in using the same pH range for
between lipophilicity and polar surface area was
classifying drug solubility across target animal
plotted for high permeability and low permeability
species.
compounds. These plots showed a non-linear rela-
tionship whereby the upper limit of lipophilicity was
2 .2.
Permeability dependent upon the magnitude of the polar surface
area. Generally, the limits of polar surface area for
˚
Effective permeability (P ) is generally described high permeability compounds were | 130–140 A.
eff
in terms of units of molecular movement distance per Initially, for highly permeable compounds, the limits
24
unit time (e.g. 10 cm/s). High permeability drugs for lipophilicity increased as polar surface increased.
are those with an extent of absorption greater than or However, further increases in polar surface area were
equal to 90% and are not associated with any associated with a decrease in drug lipophilicity.
documented instability in the gastrointestinal tract When considering the area within the 95% confi-
[9,13]. dence ellipse for the relationship between polar
Although exceptions do exist, initial predictions surface area versus lipophilicity, it was noted that
regarding a compound’s permeability characteristics this area accounted for | 90% of the highly perme-
can be made based upon the ‘Rule of 5’ [16]. The able drugs included in the study (over 400 com-
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pounds were considered). In contrast, this area in the monolayers maybe attributable to its smaller
included only 21% of those drugs classified as low surface area [6].
permeable compounds. The use of in vitro systems for classifying human
Numerous in vitro and in situ methods are current- drug permeability characteristics implies that we
ly available for assessing drug permeability in would not expect to see interspecies differences in
humans. For example, chromatographic methods that drug permeability across a wide range of com-
model intestinal permeability have been developed pounds. While for many molecules this assumption is
where the permeability is related to the retention correct, as discussed in Part II [6], in some cases,
time of the drug on a stationary phase [19,20]. High interspecies differences do exist.
throughput screening methods using 96-well microti-
ter filter plates impregnated with phospholipids and
organic solvent allow the in vitro study of passive 3 . Formulation effects
transmembrane movement [21].
Tissue-based in vitro methods, including the Us-
3 .1.
Excipients and tableting processes in oral
sing chamber and Caco-2 cells, are being used to formulations
predict both active and passive transport mechanisms
[22]. Ussing chambers were initially used for study- Prior to considering potential interspecies differ-
ing the active transport of sodium as a potential ences in formulation effects, it may be helpful to
source of the electric current in the short-circuited review the types of excipients that might be included
isolated frog skin [23]. However, since then, it has in an oral dosage form and their function. A brief
been used extensively for the study of transport overview is provided in Table 1.
mechanisms across the intestinal regions of a variety It should be noted that lubricants and glidants
of animal species [24]. must be added in very small quantities and should be
Caco-2 cell monolayers mimic the intestinal ab- subjected to minimal blending times. These hydro-
sorptive epithelium and represent a very useful tool phobic compounds can impede drug dissolution by
for studying transepithelial transport. However, the coating drug particles, thereby decreasing the area of
literature on Caco-2 cells is controversial regarding drug–solvent interface and reducing particle wet-
the ability of this monolayer to accurately mimic in tability [28]. Additionally, certain compounds that
vivo transepithelial resistance and the human intesti- are administered in small quantities, such as cardiac
nal permeability of several marker compounds [25]. glycosides, alkaloids, synthetic estrogens and ster-
Although human in vivo permeability of passively oids, can be adsorbed to the surface of some diluents
transported compounds can be predicted with this and disintegrants, thereby lowering their bioavail-
model, this cell line is not suitable for studying drug ability [29].
transport in the presence of bile salt preparations The selection of tableting process is another
[26]. Moreover, the accuracy of in vivo predictions critical variable in the optimization of drug product
appears to be a function of drug permeability. While bioavailability. The three most common methods
the permeability estimates obtained with human include [28,29]:
perfusion studies and Caco-2 data were approximate-
ly equal [27], estimates for low permeability com- 1. Wet granulation: improves the dissolution rates
pounds were, on average, 50 times lower in the of poorly soluble drugs by imparting hydro-
Caco-2 monolayers as compared to that observed philic properties to the surface of the granules.
with the human gut [9]. This finding is in accordance 2. Dry granulation: used when the drug is sensitive
with the hypothesis that lipophilic compounds are to moisture or heat.
absorbed at the villus tip. Therefore no differences 3. Direct compression: the most cost effective of
exist in the absorptive surface area of the flat the three manufacturing methods, it can be used
monolayer and the folded human jejunum. However, when the drug and excipients are free flowing,
since hydrophilic compounds tend to be absorbed cohesive and do not degrade under the heat and
across the length of the villus, the lower permeability pressure associated with the tableting process.
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Table 1
Excipients and their functions (an update of Ref. [28])
Excipient Role
Filler A filler (diluent) is often needed to increase the bulk of a formulation when the amount of drug substance
is insufficient to produce a tablet of practical size. Examples include lactose, dicalcium phosphate and
pregelatinized starch.
Disintegrant A substance routinely included in tablet formulations (and many hard shell capsule formulations) to promote
moisture penetration and dispersion of the matrix of the dosage form in dissolution fluids to expose primary
drug particles. Through swelling or other mechanisms, disintegrants overcome the cohesive strength introduced
into the mass by compression and by any binder present. Examples include starch, sodium starch glycolate,
croscarmellose, sodium, and crospovidone.
Lubricants Lubricants are substances that (1) act to reduce friction at the die wall during tablet compression and ejection
(antiadherents, (the ‘true lubricant’ role), (2) reduce adhesion to punch faces (the ‘antiadherent’ role, and (3) promote powder
true flow by reducing interparticle friction and cohesion (the ‘glidant’ role). Lubricants generally are not equally
lubricants, efficient at all three roles. For example, colloidal silicon dioxide, often considered an ‘excellent’ glidant, can
and provide ‘good’ antiadherency, but it is not effective in reducing friction at the die wall. Magnesium and calcium
glidants) stearates are considered ‘excellent’ true lubricants and ‘good’ antiadherents, but are less effective as glidants.
Binder Binders are adhesives added to wet-granulate powders. Whether added as a binder solution or dry-
blended with the powders followed by wetting with a solvent, the binder serves as a ‘glue’ that facilitates
the agglomeration and adhesion of the particles into granules. When dried and sized, granules flow better than
the original powder. When the granules are compressed into a tablet, the binder helps hold the tablet together.
Examples include polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), and pregelatinized starch.
Filler-binder These special fillers make tableting of many low-to-moderate dose drugs by direct compression practical.
They may be selected physical forms of conventional fillers that flow and/or compact well (e.g. microcrystalline
cellulose, unmilled dicalcium phosphate dihydrate) or fillers that have been physically modified to give
them these qualities (e.g. spray processed lactose).
Surfactant A surfactant may be included in a formulation to increase the wetting of a powder mass or tablet matrix
and enhance dissolution of the drug. Examples include sodium lauryl sulfate and sodium docusate.
Antioxidant Antioxidants such as ascorbyl palmitate may be included in a formulation to provide chemical stability by
inhibiting oxidation.
Coating agent Commonly, polymer-based films are applied to modern tablets for multiple reasons, such as to provide
protection from atmosphere, improve aesthetics, or modify drug release (sustained/controlled release or
delayed release). Enteric coatings can protect sensitive drugs from inactivation in gastric fluid by delaying
release until the dosage passes to the intestine. Examples include HPMC, ethyl cellulose latexes, HPMC
phthalate (enteric), and polymers and esters of methacrylic acid (enteric and sustained release functions).
Table 2
3 .2.
Particle size
Impact of particle size on product characteristics
Low solubility High solubility
Augsburger [30] has suggested that a grid similar
(BCS definition) (BCS definition)
to that associated with the BCS be used to identify
those conditions when particle size may be a critical Low dose Dissolution Content uniformity
Content uniformity
formulation variable. Grid parameters include drug
solubility and relative dose amount. Using this grid,
High dose Dissolution Not important
one can predict those situations where particle size
will have a significant impact on product dissolution on the rate of particle transit from the stomach. Since
or content uniformity (Table 2). this relationship exhibits marked difference across
However, as discussed in Part II [6], in addition to animal species, this point must be considered when
dissolution characteristics, one must also consider developing oral veterinary formulations. Moreover,
the relationship between particle size and its effect both size and density can modify in vivo particle
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dispersion, with greater dispersion resulting in im- drug at the upper intestine (pH | 5.5) where the drug
proved dissolution of poorly soluble and slowly is absorbed [34]. This release system was shown to
dissolving drugs [31]. This consideration may be produce superior bioavailability and to reduce inter-
particularly important when formulating Class II subject variability when evaluating the absorption of
compounds or sustained release preparations. Since a highly lipophilic compound in dogs.
hydrophilic polymers can facilitate particle disper- While ionic complexes are readily broken, co-
sion via increasing fluid viscosity, both viscosity and valent complexes require chemical or enzymatic
particle characteristics (e.g. shapes, size and density) modification to release the active ingredient. An
may be critical formulation variables impacting example of this is the addition of ester groups to
cross-species differences in product bioavailability reduce drug degradation in the small intestine.
[31]. However, as discussed in Part II [6], mucosal
The crystalline form of the drug [29] can also esterase activity varies both between sites in the
markedly affect its solubility. About one third of all intestine and across target animal species [33].
organic drug substances are polymorphic, including Therefore, formulators must ensure that the prodrug
crystalline versus non-crystalline (amorphous) forms. is adequately dissolved in the upper small intestine,
Each polymorph usually exhibits its own distinct where enzymatic activity is greatest, and avoid using
physicochemical properties, including melting point this formulation technique in species with relative
and aqueous solubility. In fact, amorphous powders low esterase activity, such as the pig [6].
are almost always the more water-soluble of the
crystalline forms since they require less energy for
3 .3.
Noyes-Whitney equation
dissolution. This in turn can affect bioavailability.
For example, crystalline particles such as chloram-
Drug absorption depends upon delivery of the
phenicol palmitate and ultralente insulin demonstrate
dissolved particles to its site of absorption. The
little or very slow absorption from the GI tract.
Noyes-Whitney equation describes the variables that
However, their amorphous counterparts demonstrate
can affect drug dissolution [29,35]:
substantially more complete and rapid absorption
dmDS
[32].
]]
5 (C 2 C ) (2)
st
dth
Formulators often face a double-edged sword
where: dm/dt is the dissolution rate, expressed as the
when attempting to improve product bioavailability.
change in the amount of drug dissolved (m) per unit
On the one hand, the drug must possess sufficient
time (t); D the the diffusion coefficient; S is the
lipophilicity to ensure its permeability across bio-
surface area; h is the thickness of the diffusion film
logical membranes. On the other hand, the drug must
adjacent to the dissolving surface; C is the satura-
have sufficient hydrophilicity to enable it to dissolve
s
tion solubility of the drug molecule; and C is the
in GI fluids. One method of addressing this issue is
t
concentration of the dissolved solute.
through the use of excipients that either promote
Pharmaceutical formulators can use this equation
dissolution of highly lipophilic compounds (e.g. the
to identify those variables that serve as rate-limiting
inclusion of surfactants) or penetration enhancers
factors in drug dissolution. Generally, these are the
that increase the membrane permeability of hydro-
saturation solubility of the drug molecule, the avail-
philic molecules. Another option is the modification
able surface area for dissolution, and the thickness of
of the active ingredient by the use of covalently
the diffusion film. Methods for improving drug
linked complexes, such as ionic or inclusion com-
dissolution for each of these variables include [36]:
plexes [33].
Inclusion compounds include matrix-forming sub-
stances such as cyclodextrins [3]. These compounds 1. Increasing surface area: micronization
trap the lipophilic drug in a cage-like meshwork, 2. Increasing drug solubility:
thereby enhancing its solubility and bioavailability. • Use of a salt form of a weak acid that acts as a
In fact, inclusion complexes can be formulated such buffer to increase the pH of the microenviron-
that they behave as pH-sensitive particles, releasing ment.
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• Induce an increase in the pH of the microen- expected for the following minor changes in product
vironment for weak acids via the use of formulation:
buffering excipients.
3. Decrease the thickness of the diffusion layer, e.g.
• Filler #5% change
create an effervescent dosage form.
• Disintegrant
Starch #3% change
Since surface area increases with decreasing par-
Other #1% change
ticle size, we generally expect that dissolution rate
• Binders #0.5% change
will increase proportionally to an increase in surface
• Lubricants
area. However, it is the effective surface area that is
Ca/Mg stearates #0.25% change
important (i.e. the surface area available to the
Other #1% change
dissolution fluid) rather than the actual particle size.
• Glidants
Consequently, if the drug is hydrophobic and if the
Talc #1% change
dissolution medium has poor wetting properties, a
Other #0.1% change
decrease in particle size may retard dissolution rate
• Film coat #1% change
[37]. Drugs such as aspirin and phenobarbital have
• Drug/excipient ratio #5% change
hydrophobic surfaces that adsorb air at their surface,
thereby inhibiting their wettability. Often, such prob-
Changes outside of these ratios are considered
lems can be overcome by the addition of surfactants
major changes and require some form of docu-
to the formulation [29,37].
mentation of product comparability.
To increase the bioavailability of Class II com-
From AAPS/FDA Workshop [1 [41] on formula-
pounds (poorly soluble, highly permeable), pharma-
tion changes, the following other types of changes
ceutical scientists may rely upon particle microniza-
were considered to be major:
tion, the inclusion of surfactants, complexing agents
such as cyclodextrins, and emulsion or microemul-
sion formulation. In contrast, for Class III com- • Change in drug particle size, surface area of
pounds, the problem to be addressed is poor per- immediate dosage release:
meability. To enhance the bioavailability of products (i) The change in drug particle size is considered
containing these compounds, formulators may at- to be major when the aqueous solubility of the
tempt to manipulate the transcellular flux of drugs, drug is ,5 mg/ml and if the change in drug
increase paracellular fluxes by the opening of tight particle size exceeds 10%.
junctions, promote carrier-mediated transport, inhibit (ii) The change in drug particle size is considered
degradative enzyme systems, or inhibit excretory- to be major if the aqueous solubility of the
mediated efflux systems [38]. drug exceeds 5 mg/ml and if the change in
drug particle size exceeds 25%.
3 .4.
Minor and major types of changes in • Fillers (such as lactose, phosphates and cellulose):
formulation When the change in the particles size of the filler
exceeds 20% or if there is a change in the
Since drug sponsors are often confronted with the physicochemical type of filler used in the formula-
need to introduce small changes in product formula- tion, the formulation change is considered to be
tion and manufacturing process, CDER has written a major.
guide to define what constitutes minor versus major • Disintegrating agents: The change is considered
changes and the corresponding data requirements to major if the particle size of the disintegrating
support each type of change [39]. These guidance agent is altered by a factor of more than 25% or if
documents were largely based upon collaborative there is a change in the type of disintegrating
research efforts between CDER and the University of agent used in the formulation.
Maryland [40]. • Wet binders: The modification is considered major
No impact on product performance or stability is if there is more than a 10% change in the
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815
concentration of the granulating solution or more Level A: Point-to-point relationship between in
than a 20% change in volume of the solution. vitro dissolution and the in vivo input rate of the
• Lubricants: The following revisions are consid- dosage form (i.e. in vivo dissolution). This is
ered to potentially impact product quality and the highest category of correlation where in
performance: vitro data can be used to represent the complete
(i) Greater than a 20% change in water content. plasma level curve.
(ii) More than a 15% change in particle size. Level B: Mean in vitro dissolution time com-
(iii)Greater than a 10% change in bulk density. pared to either the mean residence time or the
(iv) A change in the morphology or the supplier of mean in vivo dissolution time. This does not
the lubricant. reflect the actual in vivo plasma level curve,
since several curves may produce the same
mean residence time values.
Similar definitions of major and minor formula-
Level C: One dissolution time point (e.g. t ,
tions are being applied by CVM [42,43].
50%
t , etc.) is related to one pharmacokinetic
90%
parameter (e.g. AUC, C , T , etc.).
MAX MAX
4 . In vitro predictions of product dissolution
For immediate release products, it is uncertain as
to whether or not a true IVIVC can be obtained.
In vitro dissolution testing can serve one of several
Nevertheless, in vitro dissolution data can confirm
functions [12]:
that rapidly dissolving, highly soluble drugs (Class I
and III compounds) will present as oral solutions
• Act as a guide for formulation design and de-
upon reaching the small intestine. In this regard, it
velopment.
may be worthwhile to consider granting waivers,
• Provide a measure of manufacturing process
regardless of animal species, in cases where .85%
consistency.
dissolution occurs within 15 min across a range of
• Establish a relationship with in vivo performance.
pH values. We may also wish to consider the use of
• Provide a regulatory approval criterion.
in vitro dissolution data to support bioequivalence
determinations for those Class II compounds that
In a research contract between CDER and the dissolve rapidly upon exposure to intestinal pH (e.g.
University of Maryland [40], the relationship be- weak acids such as naproxen [49]). In each of these
tween product formulation, in vitro dissolution and cases, the premise for granting biowaivers would be
product bioavailability was compared. Covering that when products dissolve completely prior to
compounds in Classes I (metoprolol and proprano- gastric emptying (or dissolve within minutes at pH
lol), II (piroxicam) and III (ranitidine), scientists at values comparable to that in the duodenum), in vitro
the University of Maryland observed few in vitro/in dissolution data can provide a reliable surrogate for
vivo correlations (IVIVC’s). Rather, they noted that in vivo dissolution. Accordingly, excluding cases
the bioavailability of immediate release dosage forms where formulators include excipients that exert their
is frequently unaffected by apparently major changes own direct physiological effect, such as permeability
in formulation and in vitro dissolution characteristics enhancers, in vitro dissolution data could provide a
[44–47]. When considering product comparability in reliable surrogate for confirming product bioequival-
different animal species, the question remains as to ence, both for human and veterinary species.
whether or not product bioequivalence will continue For Class II compounds or modified release
to prevail in spite of differences in GI physiology. dosage forms, drug bioavailability is dissolution-rate
Clearly, what is needed is a method for assessing the limited. For highly lipophilic compounds, dissolution
relative impact of formulation as a function of in aqueous media will be poor. Therefore, in vitro
species-specific physiological variables. methods need to be developed that adequately simu-
IVIVC’s can be classified as one of three types of late the conditions of the GI tract of the species in
correlations [48]: question. This includes fluid composition, volume
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and hydrodynamics [50]. With this in mind, it is Matching a target animal species to an oral dosage
possible that for sustained release preparations or for form requires consideration of drug physico-chemi-
products containing Class II compounds (excluding cal characteristics, animal behavioral and husbandry
those described in the previous paragraph), in vitro practices. For example, oral suspensions, pastes, and
test conditions will need to be tailored to the specific syrups can be used for drug delivery across all target
target animal species to obtain biologically meaning- animal species including dogs, cats, swine, horses,
ful results. For these complex situations, it may be and cattle. In contrast, pellets and granules are
difficult to extrapolate product bioequivalence across generally placed in feed to treat horses and cattle.
target animal species or to use in vitro dissolution Less frequently, medicated pellets and granules are
data to confirm product bioequivalence, unless a used for drug administration in the feed of swine,
species-specific IVIVC has been established for that dogs and cats. The majority of cat and canine
drug or for that modified release preparation. medications are formulated as either suspensions,
tablets or capsules. Rarely are solid oral dosage
forms such as tablets and capsules intended for use
5 . Oral formulations used in veterinary in horses, cattle, or swine. With swine, the majority
medicine of oral medications are formulated for delivery in
water and feed. Similar drug delivery methods are
Many of the oral dosage forms used in veterinary used in the treatment of chickens and turkeys. For
medicine are identical to those used in human these reasons, when two target animal species are
medicine. However, there are some dosage forms included on the approved oral product label, the pairs
that are unique to veterinary drugs. Types of vet- most frequently observed are swine and poultry,
erinary drug products include [51]: horses and cattle (oral suspensions or use in feed),
and dogs and cats (tablets, capsules and suspension).
• Tablets: non-chewable (swallowed whole) and Occasionally, other approval pairs may occur, such
chewable. In some cases, chewable tablets are as dogs and horses for mebendazole, or pyrantel
formulated as soft, gummy materials. tartrate pellets mixed in the food of horses and
• Capsules. swine.
• Oral suspensions and gels. An important point often ignored in veterinary
• Syrups. medicine is the impact of chewing behavior on
• Boluses: these are tablet or caplet-like products product bioavailability. Inter-animal differences in
that are formulated with very large quantities of pellet crushing (e.g. that observed in horses) can
drug to be administered once daily. For example, introduce substantial variability in the in vivo bio-
furosemide oral bolus is formulated as a 2-g tablet availability profiles and can be particularly proble-
that is to be administered once daily. Haloxan oral matic when administering sustained release dosage
bolus is formulated to provide 10 g of drug and is forms [52]. Therefore, the appropriateness of de-
administered once to cattle. Boluses are most veloping certain modified release oral formulations
frequently marketed for use in larger animals such for veterinary species must factor the likelihood of
as horses and cattle. product mastication, particularly if the formulation is
• Medicated blocks: these are blocks of nutritional to be administered with food. Chewing can also
substances such as minerals and proteins or affect particle size, the impact of which is discussed
molasses that are formulated to deliver drug while in detail in Part II [6].
being licked by the animal. Companion animals are particularly sensitive to
• Granules and pellets: these are formulated to be taste [53], resulting in the need for taste masking.
mixed either in feed or in water. Many of the flavorants include organic-based materi-
• Drenches: these are liquid formulations (water als (e.g. beef derivatives) that could potentially
soluble powders or suspensions) that are intended influence product dissolution. Other improvements
to be delivered to the back of the tongue, forcing include the use of ion-exchange resins for taste
the animal to swallow the medication. masking. Since taste masking is rarely as simple as
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the inclusion of water soluble flavorants, there exists Maryland has resulted in the development of novel
a risk of altered product dissolution which, par- methods for dissolution testing of oral boluses, using
ticularly in the case of Class II compounds, could not only the traditional USP Apparatus 2, but also
lead to reduced bioavailability. The rate of release of 900 ml dissolution medium [57–59].
drugs from resins and microencapsulated products Currently, only a handful of veterinary products
has been shown to be highly sensitive to changes in are manufactured as oral sustained release formula-
pH and the presence of cations [54,55]. Since a large tions. Nevertheless, as the emerging technologies
number of these oral dosage forms are intended for associated with human pharmaceuticals make their
use in both dogs and cats, we need to consider how way into veterinary drug development, new dosage
the differences in GI pH, GI fluid composition, and forms are expected to evolve. This is particularly
dietary components may affect in vivo drug release. true in companion animal medicine where the medi-
Moreover, since cellulose derivatives are often used cal conditions being treated are becoming increasing-
for suspension stability, taste protection and im- ly similar to those of human medicine (for more
proved bioavailability [56], we might expect that information in this regard, visit the AHI website at
these formulations (e.g. if administered as an oral www.AHI.org). For example, gastric retention de-
suspension or gel) would behave differently in vices may be an invaluable option for effecting
ruminant (e.g. cattle) than monogastric species or prolonged drug release, particularly in species with
horses. rapid GI transit. However, the ability of each of these
A dosage form unique to ruminants is the use of devices to be retained within the stomach depends
rumen retention devices [53]. These are devices that upon the physiological characteristics of the animal
remain in the reticulorumen for prolonged periods species, such as particle size retention, gastric fluid
due to their density or geometry (e.g. morantel composition, and system swelling time versus the
tartrate). These devices are formulated for zero rate of gastric emptying [60,61]. Accordingly, cau-
buoyancy (often accomplished through the use of tion must be exercised as oral controlled release
stainless steel) and its resultant lodging in the preparations are developed, since each must accom-
reticulum prevents regurgitation. As a result, the modate potential differences in GI transit time across
device allows for drug delivery over weeks or even species. Again, a synopsis of many of these inter-
years. Such devices are generally used to treat or species relationships are expanded upon in Part II
control mineral deficiencies, bloat and parasitic [6].
infestation. Sustained release mechanisms used in In addition to these oral dosage forms, there are a
these devices include matrix disintegration, dif- large number of drugs that are approved for use in
fusion-controlled systems, osmotic pumps, and animal feeds. Species generally impacted by feed
erosion-controlled devices. Due to the complexity of formulations include poultry, swine, horses and cattle
these systems, clearly nothing short of an in vivo (i.e. farm animals). There are several categories of
demonstration of product comparability can be used medicated articles [51]. These include:
to support the approval of new or revised product
formulations or manufacturing procedures. • Type A: these medicated articles are intended
Another uniquely veterinary dosage form is the solely for use in the manufacture of another Type
oral bolus where large quantities of drug (e.g. 12.5-g A, or a Type B or C medicated feed. Type A
sulfadimethoxine oral bolus) are contained within a articles are considered new animal drugs, and may
single solid oral dosage form. These products are be manufactured with or without carriers (e.g.
traditionally developed for use in large animals such calcium carbonate, rice hull, and core), and may
as cattle and horses. Until recently, there was no or may not contain inactive ingredients.
established discriminatory dissolution method. In • Type B: these articles are intended solely for the
part, this problem was attributable to the large manufacture of another Type B or a Type C
volume of aqueous medium required to maintain sink medicated feed, and contain a substantial quantity
conditions. However, a recent collaborative effort of nutrients (not less than 25% nutritional content,
between the CVM scientists and the University of w/w). Type B medicated articles are manufac-
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tured by diluting a Type A article or another Type single animal species, we must carefully consider
B article. The maximum concentration of drug(s) any potential mechanism for extrapolating these
in a Type B medicated feed is 200 times the equivalence conclusions for products associated with
continuous use level for drugs not requiring a multiple species approvals.
withdrawal time, and 100 times the highest con- Finally, it is essential that oral dosage form release
tinuous use level of disease control and prevention characteristics be matched to the GI transit time of
for those compounds associated with a withdrawal the animal species in question. By examining in-
time. formation across a wide range of investigations,
• Type C: these articles are intended to be used as Sabnis [33] developed a table to predict the relation-
the complete animal feed or may be added on the ship between GI transit time versus drug and dosage
top of the usual ration (i.e. used as a top dress). form bioavailability. This table provides an excellent
summary of the potential correlations between these
All Type A articles require approval as an ap- variables and product bioavailability. Keeping within
proved medicated feed application. Only under cer- a framework of the BCS, a modified version of this
tain conditions are Type B or C medicated feeds table is provided in Table 3.
required to be approved as a medicated feed. These
conditions are defined in 21 CFR 558. If the medi-
cated feed is manufactured as a pellet or granule, it is 6 . Potential interspecies differences in excipient
regulated as an oral dosage form. response
Pre and postapproval formulation and manufactur-
ing changes in medicated articles provide a different Within the pharmaceutical industry, there has been
set of challenges. Firstly, there is the question as to a surge of interest in the use and safety of excipients
whether a change in an excipient will have nearly the [62–64]. Preclinical evaluation of excipients is im-
impact as that associated with normal fluctuations in portant, as these components are not inert and can
the composition and nutrient quality of feed materi- themselves result in both adverse reactions as well as
als. Secondly, it is unclear as to how to conduct in altered bioavailability. In several instances, these
vitro dissolution testing on a medicated article, or excipient effects appear to be species-specific. For
even an oral dosage form that contains animal feed example:
(e.g. granules and pellets). Unlike the in vivo con-
dition where the food materials are digested, the • Methanol exhibits a sensitization reaction in
formulation never completely dissolves in vitro, guinea pigs, although very infrequent allergic
potentially trapping drug and leading to inappropriate reactions are noted in humans [65]
conclusions of incomplete in vivo dissolution. Final- • Polyethylene glycol (low molecular weight) is
ly, we must consider whether or not it is appropriate associated with teratogenic effects in mice, but is
to extrapolate the impact of a change in a Type A not teratogenic in humans. These adverse effects
medicated articles across animal species, given the are not considered to be relevant to human use
very marked differences that may exist in the [66].
corresponding Type B or C medicated articles for the • Propylene glycol toxicosis in llamas results from
respective animal species. Clearly, with differences administration of propylene glycol gels formu-
in meal composition, this may be an even greater lated and labeled for use in cattle. The resulting
opportunity for species-by-formulation interactions. ketosis in the llama reflects the toxic nature of the
However, bioequivalence testing on medicated feeds excipient on the stomach gut flora of the llama
is extremely complex, both because of variability in [67].
animal intake (which will magnify normal phar- • Chlorofluorocarbons induce cardiac arrythmias in
macokinetic variation) and because of the need to dogs, but appear to have a wide margin of safety
consider palatability in these bioequivalence tests. in humans [68].
Given the difficulty in meeting traditional bioequiv- • Diethyl phthalate produces slight to moderate
alence criteria when testing medicated feeds in a dermal irritation in rabbits, rats, and guinea pigs,
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Table 3
Relationship between dosage form and transit time relative to the BCS characteristics of the active ingredient (based upon table by S. Sabnis
[33])
Dosage form Drug character Probable effect on drug absorption
Immediate Faster gastric Delay gastric Faster intestine Delay intestine
a
release emptying transit transit transit
b d
Liquid Class I NC F, NC F, possible ↓FNCF
d
Solid Class II, soluble ↓F possible ↑F possible ↓FNCF
at gastric pH
Solid Class II, soluble NC F NC F ↓F possible ↑F
at intestine pH
Sustained Class I NC F NC F ↓FNCF
c
release
c
Enteric coat NC F Possible ↓F Possible ↓FNCF
NC, no change. F, relative bioavailability.
a
Assumes no lumenal degradation.
b
It is difficult to predict the effect of changes in intestinal transit time on Class III compounds because it will depend largely upon the
drug-specific absorption characteristics.
c
Assumes that the drug is readily absorbed throughout the small intestine and absorption problems are due solely to inadequate time for
product dissolution.
d
Although the bioavailability of highly permeable compounds are generally believed to be unaffected by a decrease in intestinal transit
time, the potential for large changes in transit time to affect the bioavailability of Class I or II compounds (e.g., due to high concentrations of
osmotically active agents) still needs to be considered [9].
but there is no evidence of similar irritation in [72,73]. Other excipients shown to hasten small
humans [69]. intestinal transit (and therefore decrease the bioavail-
ability of low permeability compounds) include
A number of excipients under development for use sodium acid pyrophospate [73,74], sorbitol [75], and
in controlled release formulations have been found to xylitol [76,77]. These effects are known to occur at
be safe based upon studies conducted in traditional concentrations relevant to pharmaceutical formula-
rats, rabbits, mice and dogs [64]. These include: tions. Conversely, sucrose is without effect on GI
transit time [73].
• Chitosan (controlled release tablets, microspheres) In other cases, chemical characteristics of the
[70] excipient may result in species-related differences in
• Aquateric aqueous enteric coating (film coating its effect on oral bioavailability. For example, we can
for tablets and capsules) [71] predict that the in vivo dissolution of cellulose-
• Ethylene glycols containing formulations would be affected by the
• Phospholipid-based excipients (liposomes) presence of fermenting bacteria present in ruminants.
• Glycolic and lactic acid polymers (PGLA; used in With chitosan, although to these authors’ knowledge,
controlled release formulations) no data have been published to confirm or refute the
• Erythritol (sugar substitute) potential impact on species-by-formulation interac-
tion, such an effect may be worthy of consideration.
Certain excipients may alter in vivo dissolution Sustained release granules formed from chitosan and
without affecting in vitro dissolution due to their indomethacin were found to release drug faster at pH
effect on GI transit time. For example, owing to its 7.5 after exposure to acid pH as compared to
osmotic activity, certain sugar alcohols (such as granules not previously exposed to the low pH [78].
mannitol) decrease GI transit time, resulting in more This leads to the question of whether or not inter-
rapid dosage form transit through the intestine species differences in gastric pH may alter drug
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release from these granules. Moreover, there is the themselves demonstrate site-specific effects. For
suggestion that the presence of bacterial enzymes can example, nitric oxide donors significantly enhance
degrade chitosan [70]. Accordingly, chitosan may the absorption of hydrophilic compounds, and this
not be a product suitable for use in ruminant species. effect is significantly greater in the colon as com-
Although Cremophor EL appears to have little oral pared to the jejunum [90]. Similarly, when compar-
bioavailability [79], it is recognized to significantly ing the permeability of insulin across jejunum or
inhibit in vitro P-gp activity [80]. Similarly, sodium colonic rat intestine strips (Ussing chamber), sig-
caprate has been shown to demonstrate P-gp inhib- nificantly larger improvement in colonic as compared
itory activity [81]. Accordingly, we cannot be as- to jejunal insulin absorption was observed with
sured that if included in an oral formulation, Cre- permeability enhancers, such as EDTA, sodium
mophor EL would not impact the absorption charac- deoxycholate, n-lauryl-b-D-maltopyranoside, sodium
teristics of compounds subject to an intestinal P-gp- caprate and EDTA. Conversely, effectively no site-
induced efflux mechanism. As would be the case specific differences were observed in the degree of
with any compound acting as an inhibitor of pre- permeability enhancement associated with either
systemic metabolism or drug efflux proteins, phar- sodium glycocholate or sodium taurocholate [91].
maceutical scientists need to consider the effect that EDTA itself has been linked to altered metabolic
species differences in the site and activity of these rates resulting in improved feed efficiency in food
activities may have on the impact of product formu- animals [92].
lation. Finally, one might predict differences in the
Surfactants are well known for potential side- handling of certain excipients based solely on species
effects. For example, polysorbate 80 is known to physiology, such as expected differences in the
result in toxic effects in a variety of neonatal species, performance of cellulose-based formulations in
including humans [82,83]. It has also been associated ruminants versus monogastric species.
with histamine release and hypotension in a variety
of species, although the concentration associated
with this response appears to vary across species
7 . Predicting species-specific differences in oral
[84]. Cremophor EL produces an acute and fatal
bioavailability
anaphylactic reaction in dogs, and a lesser response
in cats. Although previously considered to be with-
Lobenberg and Amidon [93] have summarized the
out effect in man, rat, pig and rabbit [85], Cre-
relationships between dose, dissolution characteris-
mophor EL is now recognized to mediate severe
tics, drug solubility, and drug absorption properties
anaphylactic reactions, as well a host of other toxic
as follows:
effects, in many species including humans [80].
Absorption number (An)5 (P /R)*kTsil (3)
eff
Surfactants can also exert a direct effect on the
integrity of the GI tract [86]. As discussed in Part II
where: R is the gut radius and kTsil is the residence
[6], species specific enzymatic deficiencies are
time of the drug within the intestine.
known to exist. Therefore, an excipient such as
2
Dissolution number (Dn)5 (3D/r )*(C /
r
)*kTsil
propylene glycol, which may be safely used in other
s
animal species, is not generally recognized as safe in
(4)
cats [87] and therefore should be avoided due to its
where: D is the diffusivity of the dissolved drug,
r
is
potential toxicity.
the density of the dissolved drug, C is the drug
Permeability enhancers can facility drug absorp-
s
solubility; and r is the initial radius of the drug
tion through several mechanisms including an in-
particle.
crease in membrane fluidity, increase in pore diam-
eter, solubilization of the mucous membrane, in-
Ratio of dose to dissolved drug (D )5 M*V /C (5)
00s
crease in water flux, and reduced viscosity of the
mucous layer [88,89]. Similar to the compounds they where: M is the dose of the drug and V is the
0
are intended to affect, permeability enhancers may volume of fluid consumed with the dose.
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For Class I compounds (where Dn.1), the frac- quate product dissolution within the poorly hydrated
tion absorbed (F) can be expressed as: colonic environment [94]. Animal models have been
invaluable in that regard.
In addition to considerations we have focused on
F 5 12 exp(22An) (6)
in this review, it may be worthwhile to consider that
the impact of some of these normal physiological
differences across animal species may not be unlike
As An increases, the fraction of drug absorbed
the changes in product bioavailability that may occur
increases, with 90% absorption (highly permeable
in human pathologies. If we can improve our ability
compounds) occurring when An51.15. Referring
to predict species-by-formulation interactions in vet-
back to Eq. (3), we see that F can be affected by a
erinary species, we would also significantly improve
change in the compound’s membrane permeability,
our ability to adjust dosages and dosage forms to
intestinal surface area or the intestinal transit time.
better suit particular patient populations. This point
Each of these factors can vary across animal species.
is explored further in Part II [6].
For Class II drugs (high permeability, low solu-
bility), Dn,1. In these cases, the relationship be-
tween D and Dn is critical in determining the
0
fraction of drug absorbed, and the rate of drug
R eferences
dissolution tends to be the rate-limiting step. Accord-
ingly, anything that increases the rate and extent of
[1] The Food, Drug and Cosmetic Act, Section 512.
in vivo dissolution will also increase the bioavail-
[2] 21 CFR 514.8, April 2002.
[3] 21 CFR 514.106, April 2002.
ability of that compound. Therefore, interspecies
[4] CVM Draft Guidance For Industry: Development of Supple-
differences in the absorption of Class II compounds
mental Applications For Approved New Animal Drugs,
can be related to the volume and composition of GI
Issued 1/00 (http://www.fda.gov/cvm/guidance/
secretions (including bile salts), GI motility patterns
dguide82.pdf).
and dietary constituents.
[5] CVM Guidance For Industry: Bioequivalence Guidance,
Revised 10/00 (http://www.fda.gov/cvm/guidance/
bioeqapril1996.html).
[6] M. Martinez, G. Amidon, L. Clarke, W.W. Jones, A. Mitra, J.
Riviere, Applying the biopharmaceutics classification system
8 . Concluding thoughts: forming a bridge
to veterinary pharmaceutical products, Part II: Physiological
between veterinary and human medicine
considerations
this issue
Whether or not animal models can be used to
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