Oral delivery of medications to companion animals_palatability considerations

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Advanced Drug Delivery Reviews 56 (2004) 1399–1413

Oral delivery of medications to companion animals:

palatability considerations

Avinash G. Thombre*

Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA

Received 20 June 2003; accepted 18 February 2004

Available online 10 May 2004

Abstract

There is an increased need for highly palatable solid oral dosage forms for companion animals, which are voluntarily

accepted by the dog or cat, either from a feeding bowl or from the outstretched hand of the pet owner. Such dosage forms

represent an emerging trend in companion animal formulations with major impact on medical needs such as convenience and

compliance, particularly for chronically administered medications, and on marketing needs such as product differentiation. This

review focuses on the science of taste, food and flavor preferences of dogs and cats, and palatability testing, in the context of

applying these principles to the development of an oral palatable tablet for companion animals.

D 2004 Elsevier B.V. All rights reserved.

Keywords: Palatability; Companion animals; Dogs; Cats; Food; Flavors

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1400

2. Flavor fundamentals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1400

3. Food and flavor preferences of dogs and cats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1403

4. Palatability and palatability testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1404

4.1. Acceptance test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1405

4.2. Preference test. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1405

5. Formulation considerations for a palatable oral tablet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1406

5.1. Taste masking the active . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1406

5.2. Adding food based products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1406

5.3. Flavors added to tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1406

6. Palatability tests for companion animal medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1408

7. Palatable oral controlled release formulations for companion animals . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411

8. Current needs and future directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1412

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1412

0169-409X/$ - see front matter D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.addr.2004.02.012

* Tel.: +1-860-441-8734; fax: +1-860-715-7668.

E-mail address: [email protected] (A.G. Thombre).

A.G. Thombre / Advanced Drug Delivery Reviews 56 (2004) 1399–14131400

1. Introduction
This review focuses on the state-of-the-art in the
The pet owner generally administers oral tablets

and capsules to companion animals such as dogs and

cats in one of two different ways. The so called ‘‘poke

down’’ method refers to placing the medication at the

base (far back) of the tongue and then closing the pet’s

mouth, returning the head and neck to a normal

position, and massaging the throat, or otherwise dis-

tracting the animal, until the medication is swallowed.

Often, this is easier said than done, particularly in the

case of dosing cats, as they are more independent and

less accustomed to being restrained. The second

method involves hiding the tablet in a highly palatable

food, such as cheese, peanut butter or meat. This

method also has some limitations, because some

medications have to be administered in the fasted

state and, in some cases, the active drug may be too

unpleasant/bitter in taste to mask successfully. Anec-

dotal evidence suggests that sometimes the animal

will eat the food around the medicament and leave the

tablet unconsumed. Crushing the tablet and sprinkling

it over food (crush and sprinkle) and crushing the

tablet and dissolving it in water (crush and dissolve)

are also options, both with potential taste masking

issues. In the case of cats, medication is sometimes

smeared onto fur (e.g., back of front paw) for inges-

tion during self-grooming. While all these methods

are acceptable under certain conditions, they all share

two major issues: taste and compliance.

Thus, there is a need for palatable oral pharmaceu-

tical formulations for companion animals, which are

voluntarily accepted by the dog or cat. In other words,

when the owner/caregiver places the tablet in the

feeding bowl or in an outstretched hand, the pet

willingly and by free choice accepts and consumes

the medication. This is particularly an advantage in

the case of chronically administered drug formula-

tions. It is possible that in some cases, because of a

loss of appetite due to illness or because the animal

may be too sick or may have an unusual aversion to

medications, the tablet will not be accepted in this

manner. In these cases, it is desirable that the tablet be

of such shape and size that it could also be dosed in

the conventional poke-down fashion.

Several book chapters have broadly addressed the

development of veterinary drug dosage forms; includ-

ing oral formulations for companion animals [1,2].

development of palatable oral formulations for com-

panion animals. Palatability considerations have been

somewhat limited to the pet food industry and the

primary focus has been on nutrition. However, as the

market for companion animal health products has

expanded, so has the need to provide premium

pharmaceutical products with greater appeal to the

animal as well as to its human companion.

2. Flavor fundamentals

The flavor of a substance generally refers to its

attributes of taste (gustation), odor (olfaction) and

other qualities such as ‘‘mouth feel’’. There is a large

body of literature on taste and olfaction, including

anatomical, physiological, chemical, genetic and be-

havioral aspects for many animal species, including

cats and dogs [3–5]. Taste refers to the sensation

(perception) arising from the stimulation of taste

buds, which are onion-like clusters embedded on

specialized structures located on the surface of the

tongue, called papillae. At the tip of a taste bud is a

pore, formed by the bundling of taste cells. Extend-

ing through this pore into the oral cavity are finger-

like protrusions or the microvilli, which bear the

actual chemoreceptors. Fig. 1a shows the anatomical

basis of gustation including the tongue, fungiform

and foliate papillae. Fig. 1b shows a cross-section of

the taste bud with taste receptor cells [6]. The spatial

heterogeneity (front and rear of tongue) with respect

to monovalent chloride salts and sweet tastants has

been studied in dogs [7]. Fungiform papillae and

taste buds on the cat’s tongue have also been studied

[8].

When presented with taste stimuli, the stimulus

molecules adsorb onto the receptor surface [9], and

the taste receptor cell undergoes a change in mem-

brane polarization, which initiates nerve impulses in

the nerve fibers supplying those receptors. These

nerves, in turn, transmit these impulses to other nerve

cells and fibers, which convey the taste impulses to

the brain. The taste impulses can be recorded using

electrophysiological techniques [10,11] (Fig. 2). Un-

derstanding the mechanisms of receptor activation and

the subsequent transduction process at the biochemi-

cal level is important because this ultimately leads to

Fig. 1. Canine anatomy showing the tongue, papillae, and longtitudinal of a taste bud [6]. Reproduced with permission from ref. [6]. (Source:

Miller’s Anatomy of the dog, 3rd Edition.)

A.G. Thombre / Advanced Drug Delivery Reviews 56 (2004) 1399–1413 1401

the behavioral aspects of a particular food or flavor

being palatable to the animal.

The taste qualities or major taste receptor types are:

sweet (sugars) sour (acids), salty (NaCl, LiCl), bitter

(e.g., alkaloids, peptides) and umami, which is a

unique savory flavor induced by substances such as

monosodium glutamate (MSG) and disodium guany-

late (GMP) [12]. It is present in many food substan-

ces, including vegetables (tomato, potato, cabbage,

mushroom, carrot, soybean), seafood (fish, seaweed,

oyster, prawn, crab), meats (beef, pork, chicken) and

cheese. The receptor and transduction processes for

the umami taste have been reviewed [13,14] including

differentiation between umami and salt components

[15], and it has been shown that there is synergism

between MSG and 5V-nucleotides in the taste nerve

responses in dogs [16]. Umami taste has also been

shown to affect pancreatic secretion in dogs [17].

There are important differences between the dog

and cat, particularly in the spectra of compounds to

which each taste group responds [18]. The sensory

effect of a wide variety of chemical substances was

studied in cats by recording single unit pulse signals

from neurons on the fungiform papillae of the cat’s

Fig. 2. Block diagram of the recording and stimulation equipment together with a diagrammatic illustration of a summated single fiber recording

[68]. Reproduced with permission from ref. [68].


tongue. The stimulating substances (e.g., amino

acids, nucleotides, inorganic ions, etc.) are common

constituents of meats [19]. It has been shown that

nitrogeneous compounds such as amino acids that

are neurophysiologically active in cats are also

behaviorally active in terms of preference and avoid-

ance [20].

The sweet taste of sugar or artificial sweeteners in

dogs and cats has been studied extensively [21–24]. It

has been shown that although cats prefer the taste of

sucrose, they reject the taste of nonnutritive sweet-

eners such as saccharin [25]. Some studies have

shown that the cat exhibits no preference for sucrose

over water, except when the concentration of sucrose

is high. In contrast, cats are highly responsive to

amino acids [26]. Adaptation (decreased response to

constant stimulus) has been studied in cats by record-

ing the chorda tympani nerve responses to HCl, NaCl

and quinine HCl [27]. The enhancing effect of salt on

sugar responses was studied in dogs [28].

It was shown that sodium-replete adult cats

exhibited no preference for salt solutions over tap

water, except when the salt concentration was 0.1 M

for which cats showed a slight preference [29].

Studies in kittens have shown that they do not possess

an innate appetite for sodium and that a sodium

appetite was not induced in sodium-depleted kittens

[30]. However, salts have been shown to enhance

canine taste responses to amino acids [31] and to

umami substances [32].

Bitter and hot flavors, such as capsaicin, capsicum

and horseradish extract, are considered taste repellants

in dogs [33]. Cats were found to be averse to medium

chain triglycerides and caprylic acid [34].

The effect of temperature on the gustatory nerve

response was studied and it was found that the


maximum response to fructose, sucrose, acetic acid

and GMP was obtained when the temperature was at

about 30 jC, or at the temperature of the tongue

[35,36]. In small concentrations, menthol was shown

to enhance the taste response to various taste stimuli;

however, in larger concentrations or after extended

exposure, it depressed the response [37]. When salt

and acid solutions were tested in pairs, it was ob-

served in cats that the first exposure usually depressed

the response to the following one [38].

Characterizing natural flavors is complex because

of the numerous compounds present in a natural

flavor. Furthermore, many aroma chemicals are vola-

tile and will disappear if the flavor is not stored

properly. Several studies have attempted to break-

down flavors into their components through flavor

fingerprinting. There has also been some effort to

produce an ‘‘artificial tongue’’, with only moderate

success because typically, flavors consist of hundreds

of individual compounds.

Fig. 3. Normal canine and feline dentition [69]. Reproduced with

permission from ref. [69].

3. Food and flavor preferences of dogs and cats

In general, treats and premium canned food prod-

ucts are considered to be highly palatable. Treats are

relatively large in size and have interesting or attrac-

tive shapes and textures. Moist and semi-moist canned

food preparations are more palatable than dry pet food

rations.

The taste preferences of dogs and cats are well

established and it is known that cats prefer fish and

commercial cat food to rats. Dogs prefer beef, pork

and lamb to chicken, liver and horsemeat, and strong-

ly prefer meat to cereal diets [39]. Canned meat is

preferred to fresh meat, ground meat to cubed meat

and cooked meat to raw meat. Canned or semi-moist

preparations are preferred to dry ones [40]. The role of

olfaction in canine food preferences has been studied

[41].

The taste preferences of dogs versus cats can be

understood in the context that cats belong to the

order Carnivora and are strict carnivores with a

strong preference for food derived from animal

tissue. In contrast, dogs can be classified as omni-

vores and can eat food of both animal and vegetable

origin. The teeth of dogs and cats are functionally

adapted to their dietary needs [42]. Cats have sharp,

pointy teeth (canines) (Fig. 3a) designed for captur-

ing prey and rendering it into small portions whereas

the dog also has molars, which have a flat surface

for grinding (Fig. 3b). It is important to note that in

the case of companion animals, the pet owners

provide most of the food ingested by the animals.

Thus, the likes and dislikes of the pet owners also


play an important role in the taste preferences of

companion animals.

Flavors that are generally considered to be highly

palatable in companion animals include animal pro-

tein digests and hydrolysates, animal proteins, emul-

sified meats, amino acids, animal fats, sugars (dogs)

and acids (cats). In contrast, flavors that are consid-

ered to negatively affect palatability include vegetable

protein meals, fibers, vegetable oils, vitamins, miner-

als and bitter-tasting drugs. In addition, dogs also like

the following: meat, liver, sweet, sulfur (garlic), baked

flavors, yeast and moisture. Cats like fish, liver, meat,

sour/acidic flavors (pH range of 4.5–5.5 is optimum

in increasing salivation), Brewers yeast, yeast extract,

dairy (milk and cream) and moisture. Although it is

widely believed that ethylene glycol-based antifreeze

is an attractive tastant to dogs, studies have shown that

this is not the case [43].

Artificial versus natural flavors: Natural and artifi-

cial flavors are defined in the U.S. Code of Federal

Regulations [44]. A natural flavor is ‘‘the essential oil,

oleoresin, essence or extractive, protein hydrolysate,

distillate or any product of roasting, heating or enzy-

molysis, which contains the flavoring constituents

derived from a spice, fruit or fruit juice, vegetable

or vegetable juice, edible yeast, bark, bud, root, leaf or

similar plant material, meat, seafood, poultry, eggs,

dairy products or fermentation products thereof,

whose significant function in food is flavoring rather

than nutritional’’. An artificial flavor is one that does

not meet these criteria [45].

In addition to flavor, which incorporates taste and

aroma, mouth feel, which incorporates texture, shape,

and size is considered more important in cats as they

tend to nibble food rather than chew and eat the food

quickly like dogs. Interestingly, the ‘‘cheerio’’ shape

or a ‘‘star’’ shape is more preferred than a ‘‘fish’’

shape. The product’s tackiness or stickiness may also

contribute to mouth-feel. The role of visual appeal,

such as the product’s presentation and color, has not

been systematically studied.

It is also known that, in addition to the ingre-

dients present in a given formulation, the manufac-

turing processes can also have an impact on

palatability. An extrusion process is used to manu-

facture many pet foods, and flavor precursors are

added to the core formulation prior to extrusion, or,

palatability or flavor enhancers are added to the

extruded core as a coating. The nutritive and palat-

ability values of soybeans were improved by extru-

sion [46]. It has been speculated that non-enzymatic

browning reaction of flavor precursors during the

extrusion process can lead to Maillard-type savory

flavors present in the final product, which enhances

palatability.

There is a pronounced acceleration in the heart rate

at the beginning of eating of the most attractive food,

which subsequently returns to baseline. However, this

cannot be taken as the unique index of hedonistic

sensations because of the complicating factor of

hunger [47].

Overall, it can be concluded that the natural pref-

erence of dogs and cats is towards meat-based flavors

and complex mixtures of flavors.

4. Palatability and palatability testing

There is no standard, widely accepted definition of

palatability. For the purpose of this review, the fol-

lowing definition is offered: The term ‘‘palatability’’

refers to the voluntary (free choice) acceptance or

ingestion of a pharmaceutical composition by com-

panion animals, as measured by a standard palatability

test, such as an acceptance, preference or consumption

test. ‘‘Acceptance’’ or ‘‘voluntary acceptance’’ means

that the dosage form is voluntarily taken into the

mouth of the animal and consumed. Sometimes, the

speed with which the animal accepts the product and

the degree of interest or enthusiasm shown by the

animal are considered measures of palatability. How-

ever, in connection with pharmaceutical products,

consumption or compliance should be considered as

the measure of primary importance.

The major developments in the area of palatability

testing, identifying food preferences of dogs and

cats, and developing and testing flavors for compan-

ion animals were done in support of the pet-food

industry, which focused on studies conducted to

assess the palatability of pet food and pet treats

[48]. Determining palatability in dogs and cats is

complicated because of the subjective nature of the

animal’s response. Attention has been drawn to the

gap between basic research on the mechanism of

taste and olfaction, and the biochemical processes

that lead to neuronal stimulation of receptors and the


hedonistic tests that are used in the development of

pet food and treats [49]. In general, the objective of

palatability tests is to quantify the ‘‘hedonic value’’

of a food or treat. Two types of palatability tests are

commonly used: the acceptance test and the prefer-

ence test [50].

4.1. Acceptance test

The acceptance test is a one-pan intake test in

which the formulations are generally crossed-over

with a control formulation. The test is designed to

answer the question: ‘‘Will the animal consume the

tablet when offered?’’. The disadvantages of the

acceptance test are (a) interference due to appetite

considerations (appetite increases as a function of time

between offerings and decreases as a function of the

quantity offered), and (b) the inherent noise in the test

because it is difficult to control the numerous varia-

bles that can influence the outcome of the test. For

example, there could be day-to-day differences and

influences due to the attractiveness of the test sample.

The advantage of the acceptance test in the case of

pharmaceuticals is obvious: it tests consumption of

the medication and therefore is a direct measure of the

compliance.

4.2. Preference test

The preference test is a two-pan free choice test

designed to answer the question: ‘‘Does the animal

prefer one option to another?’’. One of the formula-

tions is generally the control and the other is the test

formulation. Because the animals can exercise their

choice, this test is more sensitive than the acceptance

test. Also, appetite is a less critical variable in

preference tests. In the pet industry, this test is

generally used to compare the preference for two

different treats. There are several complicating fac-

tors in the interpretation of the results from a

preference test: individual variation, the attractive-

ness of the treat, previous diet, quantity of water

added to the formulation, lateral bias, or preference

for the left- or right-hand bowl regardless of its

contents and the owner–pet interaction, which

occurs in a home situation but not in a laboratory

situation. Some of the potential sources of bias have

been discussed [51,52].

In acceptance tests, the data are binary (was the

treatment accepted, yes or no) whereas the data from

preference tests are generally expressed in the form A/

(A +B) or A/B (A and B being the weight of the two

treatments or rations consumed by the animal) and

analyzed by standard statistical methods. For both

tests, a design of experiment (DOE) technique could

be used, particularly if there are many variables to be

studied or if it is desired to determine the incremental

influence of a particular flavor ingredient in the

formulation and/or processing factors.

Palatability tests in cats are similar to those in dogs,

however, cats are considered particularly ‘‘fussy’’ and

are more likely to refuse rations or go off feed for

unknown reasons [53]. Cats undoubtedly use smell in

the detection and selection of food. It has been

reported that cats will exclusively consume a food

that they find more attractive without tasting the less

attractive food on offer [54]. Cats also lose interest

very quickly. Furthermore, cats cannot generally chew

on very hard items (they chew side to side) consistent

with their dentition.

Prior to palatability tests, the animals must be

acclimatized to the test and testing conditions, prefer-

ably several days prior to the actual test. This is

particularly important in the case of laboratory dogs

with artificial eating patterns—they are used to re-

ceiving only their daily rations and not used to being

given treats. Thus, palatability results obtained with

strictly laboratory dogs may not correlate well with

the actual situation of pets in homes.

The major overall difficulties in interpreting the

results of palatability tests are as follows:

(a) Lab animal versus home pet differences. This also

includes breed or species differences. The food

preferences of dogs housed in testing kennels and

consumer homes have been studied [55] as well as

species differences [56]. There are anecdotal

reports that beagles are poor choice for preference

tests. This could be because of inadequate

acclimatization. The major difference between a

laboratory and in-home setting is the lack of

owner-pet interaction in the laboratory setting. It is

possible that cultural differences (i.e., what the pet

owners generally give their pets for treats based on

local traditions in a particular country) might

outweigh any breed differences. Thus, it is highly


recommended that the definitive assessment of

palatability be done in the consumers home.

(b) Novelty effect. In contrast to a primary effect, the

novelty effect refers to a companion animal’s

preference for a novel diet [57]. It has been

observed that dogs and cats show a preference for

a new ration or treat after being offered the same

treatment for a few days. Also, it is known that

they can show a change in food preference after a

period of time. Taste fatigue or rejection of a

formulation that was initially well accepted is less

well studied and can have important repercussions

in the delivery of pharmaceutical products to

companion animals.

(c) Because of the individualistic nature of companion

animals (some animals will consistently deny

everything that is offered to them whereas some

will accept almost everything), selection of

animals for palatability testing can be very

important.

5. Formulation considerations for a palatable oral

tablet

The primary attributes of a successful pharmaceu-

tical product for companion animals remain safety

and efficacy of the active ingredient. Palatability is a

desired attribute because it affects convenience and

compliance. This is particularly important if the

medication has to be administered chronically, e.g.,

every day. Also, if the animal is too sick to accept

the medication by free choice, it should be of such

size and shape that it could be given in the conven-

tional poke-down fashion. In addition to palatability,

other requirements for pharmaceutical products are

stability of the active ingredient and adequate shelf

life. Dry pet foods have shelf life of 6 months to a

year; semi-moist foods stay fresh for 9 months; a

canned pet food will stay fresh for several years [58].

Pharmaceutical products generally target at least a 2-

year shelf life.

Some commercially available palatable pharma-

ceutical products for companion animals are given

in Table 1. Additionally, there are several vitamin

and nutritional supplements that are available in

palatable chewable dosage forms. Some examples

are listed in Table 2. The palatability approaches

used in these products are summarized below. In

some cases, a combination approach may be re-

quired. For example, a highly bitter active may first

have to be taste masked (e.g., by microencapsula-

tion) and then mixed with flavors and compressed

into a tablet.

5.1. Taste masking the active

In human health, taste-masking bitter drugs using

flavors is well known and dates back several

centuries. Thus, several approaches and technolo-

gies are available for taste-masking drugs used in

companion animal pharmaceuticals including: mi-

cro-encapsulation, ion exchange, using a poorly

soluble salt form of the drug, chemical masking

or taste blocking. The large body of literature on

taste-masking and odor-masking drugs is considered

outside of the scope of this review.

5.2. Adding food based products

A natural food product such as fish-meal or

desiccated liver could be added to the blend prior

to the manufacture of tablets. One example where

this is used is PetTabsR (which has close to 100%

acceptability). HeartgardR Chewables (ivermectin)

and Heartgard PlusR (ivermectin/pyrantel) are

beef-based chewable once-a-month products for

heartworm disease and for the treatment and control

of certain gastrointestinal parasites in dogs and cats.

In general, because they are meat based, these

products are highly palatable and are designed to

be readily accepted by dogs when proferred to

them, thus obviating the needs to insert the medi-

cation into the dog’s mouth [59]. Thus, they are

widely regarded as a benchmark in the industry.

5.3. Flavors added to tablets

Flavors that are used as ingredients in pet foods

and treats could be incorporated [60] into blends prior

to manufacturing conventional pharmaceutical tablets.

Some examples of palatable products that contain

flavor ingredients are: InterceptorR Flavor Tabs,

SentinelR Flavor Tabs and ProgramR Flavor Tabs.

Many of these flavors are available as commodity

items from flavor houses that specialize in flavors for

Table 1

Some commercially available palatable pharmaceutical formulations for companion animals

Product Company Active(s) Palatability notes (from manufacturer’s package insert)

RimadylR Chewable Pfizer Carprofen Rimadyl chewable tablets are palatable and willingly consumed by

most dogs when offered by the owner. Therefore, they may be fed by

hand or placed on food.

A controlled palatability study was conducted which demonstrated

that Rimadyl chewable tablets were readily accepted and consumed

on first offering by a majority of dogs.

InterceptorR Flavor TabsR Novartis Milbemycin oxime Interceptor Flavor Tabs are palatable and most dogs will consume the

tablet willingly when offered by the owner.

Palatability trials conducted in 244 dogs from 10 different U.S.

veterinary practices demonstrate that INTERCEPTOR Flavor Tabs

were willingly accepted from the owner by over 95% of dogs. The

trial was comprised of dogs representing 60 different breeds and both

sexes, with weights ranging from 2.1 to 143.3 lb and ages ranging

from 8 weeks to 15 years [67].

SentinelR Flavor TabsR Novartis Milbemycin oxime,

lufenuron

As an alternative to direct dosing, the tablets can be hidden in food.

ProgramR Flavor TabsR Novartis Lufenuron As an alternative to direct dosing, tablets may be offered in food.

HeartgardR Chewables Merial Ivermectin Because most dogs find Heartgard palatable, the product can be

offered to the dog by hand. Alternately, it may be added intact to a

small amount of dog food.

Acceptability: In acceptability and field trials, Heartgard Chewables

were shown to be an acceptable oral dosage that was consumed at the

first offering by the majority of dogs.

HeartgardR Plus Chewables Merial Ivermectin, pyrantel Because most dogs find Heartgard Plus palatable, the product can be

offered to the dog by hand. Alternately, it may be added intact to a

small amount of dog food.

Acceptability: In acceptability and field trials, Heartgard Plus

Chewables were shown to be an acceptable oral dosage that was

consumed at the first offering by the majority of dogs.


cats and dogs, and their level of use in formulations is

available from their manufacturers. Table 3 lists some

of the flavors with their suppliers, description and

recommended use levels.

Typical flavor selection criteria for pharmaceutical

products are as follows:

(a) Acceptability and preference in dogs and cats

(b) Regulatory acceptance worldwide

(c) Stability and shelf life

(d) Cost and availability

(e) Ease of manufacture

Based on the earlier discussion on the flavor

preferences of dogs versus cats, cultural differences

in the type of food flavors given to pets, species

and breed differences, and the complexity of flavor

fatigue, it seems unlikely that one flavor could be

universally acceptable to both dogs and cats. A

more realistic goal could be to identify a flavor

system that is acceptable to most animals and then

to provide the pharmaceutical product in several

flavors formulations. Custom flavors may have the

advantage that they could provide product differen-

tiation in a competitive market.

Meat based flavors could be problematic in

many countries. There is a growing concern over

the possibility of BSE transfer in meat-based prod-

ucts and many countries do not allow the import

of meat or other animal parts from countries

without proper certification. The Regulatory pro-

cesses of approval of pharmaceutical products have

also become more complex. Manufacturing may

also become more complex because of cleaning

between batches and possibility of microbiological

contamination.

Natural products present in the pharmaceutical

formulation lead to more complicated analytical meth-

Table 2

Some additional palatable formulations (source: VPB 2001/2002, 12th Edition)

Product Company Active ingredient(s) Palatability notes from manufacturer

ArthriCarekChewable Tablets

V.P.L. Buffered

microencapsulated

aspirin

Blended in a roast beef and liver flavor

containing base

Canine Aspirin Chewable

Tablets for Dogs

Pala-Tech Microencapsulated

buffered aspirin

Buffered aspirin in a proprietary highly

palatable roast beef and liver flavor base to

ensure dogs readily consume the tablet

Canine F.A./Plus Chewable

Tablets For Dogs

Pala-Tech Omega fatty acids,

vitamins and minerals

Formulated with a proprietary, highly palatable

roast beef and liver flavor base to ensure dogs

readily consume the tablet. Administer free

choice orally to the dog as a treat or crumble

over the dog’s food at mealtime.

Feline F.A./Plus Chewable

Tablets

Pala-Tech Omega fatty acids,

vitamins and minerals

Formulated with a proprietary, highly palatable

roast beef and liver flavor base to ensure cats

readily consume the tablet. Administer free

choice orally to the cat as a treat or crumble

over the cat’s food at mealtime.

Nutrivedk Chewable

Vitamins

Vedco Vitamins and

combinations

Administer free choice just prior to feeding, or

crumble and mix with food. (liver meal and

roast beef flavor)

K-ZymeR Chewable Dog

Tablets

BioZyme Vitamins A highly palatable (roast beef and liver flavor)

digestive enhancer fortified with vitamins and

minerals

D-Wormk Dog Wormer

Chewable Tablets for

Dogs

Farnam Pyrantel pamoate Offer the proper dosage by hand or in the dog’s

food container with or without food.

HartzR Health MeasureskEveryday Chewable

Vitamins

Hartz Mountain Vitamins and minerals A highly palatable liver flavored vitamin and

mineral supplement. It can be hand fed as a

treat, just prior to feeding or crumbled and

mixed with food.

Canine Thyroid Chewable

Tablets

Pala-Tech Levothyroxine sodium It may be given orally to dogs as a treat or

crumbled over their food. If crumbled over

food, consumption should be monitored.


ods—identification of degradation products of natural

flavors can be complex. They may also have signif-

icant batch-to-batch variability. Also, the palatability

of the product at the end of its shelf life may be

important to assess. From the perspective of analytical

characterization, a synthetic flavor and a simple, one-

component system that is compatible with the active

drug is most preferred.

Assuming that the quantity of palatability en-

hancing flavor that is incorporated into the tablet is

a small percentage of the total tablet weight, no

special manufacturing considerations above and

beyond those normally applied to the manufacture

of compressed tablets may be necessary. If the

active agent is extremely bitter, it may have to be

taste-masked by encapsulation, which would in-

volve additional manufacturing steps resulting in

greater manufacturing costs and complexity. The

ideal flavor for a pharmaceutical tablet will provide

palatability when present in low amounts in the

tablet and will have good flow and compression

characteristics that are important in the manufacture

of tablets.

6. Palatability tests for companion animal

medications

As mentioned earlier, there is no standard, broadly

accepted method for testing the palatability of phar-

maceutical formulations in companion animals. Fur-

thermore, there are very few reports in the scientific

Table 3

Examples of commercially available flavors for dogs and cats

Product Manufacturer/supplier Description Listed ingredients

Cheese Plus Cheese Product International Ingredient, Blend of white and yellow Dried cheese product

St. Louis, MO cheese product powders and

cheese rind

Protein 34%, fat 20%, fiber 1%, moisture

9%, lysine 3%, ash 6%

Sirius Stuff Dirigo, Boston, MA Heavenly blend of natural

flavorings and spices

A blend of yeast, garlic, salt, herbs, kelp,

fermented soy

Art. Chicken Flavor Bush Boake Allen

Americas, Chicago, IL

Mixture of GRAS flavors (GRAS=

generally accepted as safe)

BrewTech Dried

Brewers Yeast

International Ingredient,

St. Louis, MO

100% Saccharomyces cerevisiae

from the brewing industry

Crude protein 43%, crude fat 1.5%, crude

fiber 1%, ash 5.5%, moisture 6%

Vegetarian Beef

Type Flavor

Geneva Ingredients,

Waunakee, WI

Savory full-bodied beef flavor

from natural ingredients

Maltodextrin, autolyzed yeast extract,

natural flavors, partially hydrogenated

vegetable oil (soybean and/or cottonseed),

onion powder and silicon dioxide

(to prevent caking)

Vegetarian Bacon Geneva Ingredients,

Waunakee, WI

Full bodied bacon type flavor

with rich fatty notes from

natural ingredients

Maltodextrin, natural flavors,a natural

smoke flavor and silicon dioxide (to prevent

caking)

Artificial Powdered Beef Pharma Chemie,

Syracuse, NE

Blend of vegetable and natural

proteins and oils

Hydrolyzed vegetable protein, natural

flavor, and hydrogenated vegetable oils

Trusil Artificial Peanut

Butter Flavor

Bush Boake Allen




Roast Garlic Flavor Geneva Ingredients,

Waunakee, WI

Natural roast garlic flavor

enhanced with natural flavors

Salt, maltodextrin, autolyzed yeast extract,

natural flavors, partially hydrogenated

vegetable oil (cottonseed or soybean) and

silicon dioxide (to prevent caking)

Trusil Artificial Ham Flavor Bush Boake Allen




Sugar Food By-Product International Ingredient,

St. Louis, MO

(Produced from by-products of dry

packaged drink mixes, dried gelatin mixes,

hard candy and similar specialty food

products that have a high sugar content; also

contains citric acid) total sugars 80%, crude

protein 1.5%, crude fat 1%, crude fiber

0.5%, moisture 4.5%, ash 0.5%

All Dairy Blend International Ingredient,

St. Louis, MO

Nonfat dried milk (dried skim), whey

protein concentrate, casein, dried whey,

dried milk products

Dog Bone Marinade Dirigo, Boston, MA Blend of all natural spices and

flavorings

EggsAct Dried Egg

Replacer

International Ingredient,

St. Louis, MO

Blend of animal proteins and

fat formulated to replace

whole eggs

Animal protein products, animal fat and/

vegetable oil

Crude protein 50%, crude fat 32%, crude

fiber 0%, ash 3%, moisture 4.5%, lysine 2%

Note: does not contain ruminant protein

a Contains peanut oil as flavor carrier.


literature on palatability studies conducted using

pharmaceutical products for companion animals. Pal-

atability is however mentioned in several instances

during product introductions and on product labels.

For example, when Janssen AH-Cilag introduced a

new formulation of flubendazole, Flubenol EasyR in

France, it was reported that the palatability of the final

tablets was studied in 6 different experiments and

Table 4

Canine acceptability of 300 mg flavored lactose (placebo) tablets

Small screen 1 flavors Tasted Consumed Not consumed Time (s) Rank

Artificial chicken 38 33 7 36 4

Artificial powdered beef 36 29 11 62 8

Artificial peanut 39 30 10 55 7

Eggsact 39 38 + 1 + 22 1

Roast garlic 38 35 5 34 2

Sirius stuff 40 34 6 44 3

Sugar food product 39 33 7 47 5

Trusil ham flavor 39 33 7 49 5


90% of the 476 dogs spontaneously accepted the

product [61].

The free choice acceptance in dogs for a bland,

bitter and odorous drug without any flavor added to

the tablet formulation were shown to be f 60%,

40% and 20%, respectively [62]. In another study,

the free choice acceptance rate of unflavored place-

bo tablets in dogs was shown to be only about 68%

and those that contained Bitrex (denatonium benzo-

ate, a known bitter agent) was only about 44% [63].

With the addition of 1%, 5% and 10% Artificial

Beef Flavor (from PharmaChemie) to lactose-based

placebo tablets, the free choice acceptance increased

to 92%, 96% and 96%, respectively. Brewer’s yeast

flavor was found to have a significant positive

effect on the palatability of lactose-based placebo

tablets.

The methodology used to test palatability of

products from the pet food industry has been mod-

ified appropriately and adapted for testing drug

products [64] in dogs and cats. The modifications

allowed rapid screening of flavors using an accep-

tance test, in which the lapsed time from offering the

tablet to the time of consumption or rejection was

noted in addition to whether the tablet was accepted

or not. Visual observations of the animal behavior

Table 5

Responses to flavor choices by 30 dogs

Flavor % dogs with Consumable tablet summ

100% consumedConsumed

Brewers yeast 90 97.5

Vegetable beef 83 96.0

Cheese and cheese 83 95.7

Vegetable bacon 83 94.2

Sirius stuff 83 92.7

Artificial chicken 80 93.2

(e.g., degree of enthusiasm or level of interest dis-

played for a particular flavor) were also recorded.

The set of flavors narrowed down by the acceptance

test were then progressed to a modified version of

the preference test. The scoring for the preference

test was based on the order in which tablets were

picked up by the animals and the order in which they

were consumed by the animal (excellent correlation

was found between these two factors). Typical

results obtained from an acceptance test are shown

in Table 4 and those from a preference test are

shown in Table 5.

The following conclusions were drawn from the

study. Most dogs voluntarily consumed tablets of all

the flavors studied (80%). Those dogs with more

exacting preferences were few (20%) and varied in

their preference. Because of the variability (some

dogs ‘‘hate everything’’), the analysis of the data

presented a statistical challenge. The acceptance

screen could be used to eliminate least attractive

flavors. The preference study, giving the animal a

choice, allowed discrimination between attractive

flavors and the frequency of first choice was a good

measure of the palatability of the flavor. However, it

is recognized that multiple tests are needed to assess

flavors.

ary (%) % Consumption order (%)

Rejecteddropped

1sts 2nds

2.5 0.8 58 39

4.0 2.5 49 45

4.3 3.9 50 46

5.8 4.7 38 52

7.3 4.7 51 42

6.8 5.3 45 48


7. Palatable oral controlled release formulations

for companion animals

Oral controlled release dosage forms for compan-

ion animals, e.g., dogs and cats are not as common as

those developed and marketed for humans. However,

there is a growing interest in controlled release for-

mulations in the veterinary medicine [65]. The ratio-

nale for these formulations in companion animals is

similar to that in humans, e.g., reduced dosing fre-

quency, better toleration, increased efficacy, cost sav-

ings and convenience/compliance with respect to the

pet as well as the pet owner.

Often, the hydrophilic matrix tablet technology is

employed in oral controlled release formulations.

When exposed to water, the polymer present in the

tablet swells to form an external gel layer, which

increases in thickness and eventually erodes/dis-

solves. The release rate is controlled by diffusion

of drug through the gel layer and erosion of the

polymer. The drug release rate is dependent on the

type of polymer (MW, viscosity, degree of substitu-

tion, etc.) and its amount in the tablet. The release is

dependent on the surface area of the tablet available

for diffusion of the drug.

A palatable controlled release matrix tablet, made

by simply incorporating a flavor in the tablet formu-

lation, may not provide the desired in vivo perfor-

mance. This is because dogs generally chew the

flavored tablets prior to swallowing. It was observed

that in all instances of the dogs accepting the

flavored tablet and consuming it, they chewed the

tablets before swallowing. It was estimated that the

dogs chewed the tablets more than two times and, in

some cases, it was estimated that the dogs chewed

the tablets to a powder prior to consumption [66].

Thus, alternate approaches based on multiparticulates

need to be considered, as these may be more

resistant to chewing.

8. Current needs and future directions

The growth in veterinary pharmaceuticals has been

largely in the field of companion animal medicine

and, increasingly, pharmaceutical companies are fo-

cusing on this sector. Traditionally, pharmaceutical

companies have concentrated more on the disease

state and the drug substance being developed. Com-

pliance/convenience aspects and product differentia-

tion were previously largely ignored but are now

receiving more attention. Thus, additional work needs

to be done to quantify the value added by the

introduction of palatable oral dosage forms with a

high acceptance rate (e.g., greater than 90%).

Collaborations between pharmaceutical companies

and flavor manufacturers could be helpful in identi-

fying one or more ‘‘standard’’ flavors for pharmaceu-

tical products. The goal of achieving palatability using

a simple, single, synthetic molecule, which is accept-

able world-wide, is a difficult one, but it has the

potential of reducing the burden on analytical chem-

ists involved in the physicochemical characterization

of tablet ingredients, following the degradation prod-

ucts and estimating product shelf life.

Because of the greater difficulty in dosing cats,

palatable cat products represent a stiffer challenge to

the dosage form designer. It may be possible to

develop custom flavors for cats (as well as dogs)

using the expertise that resides with the manufacturers

of cat and dog foods and treats (e.g., Hill’s Mars,

Heinz and Purina). The concept of a medicament that

is given as a treat has the potential of making a

substantial impact in the marketplace.

There is also a need to standardize palatability-

testing protocols and study designs so that the work

done in this area by different researchers can be

compared to each other. This also has impact on the

regulatory issues such has labeling pharmaceutical

products with respect to palatability and the palatabil-

ity testing done by generic companies to compare

their product to the innovator’s.

Clearly, the challenge associated with bitter tasting

drugs is much greater than neutral tasting drugs and

may require utilization of taste-masking and odor-

masking technology. This will add to the dosage form

complexity, processing, as well as costs. In order to

reduce costs, a simple blend and compress process is

preferred. Extrusion in order to develop palatability is

common in dog and cat kibbles, but may present a

problem in pharmaceutical dosage forms because of

potential stability issues.

Flavored tablets represent only one type of palat-

able oral formulations for companion animals. Other

dosage forms include: medicated treats, biscuits, med-

icated chow, medications added to drinking fluids,


palatable buccal films and palatable oral gels. Obvi-

ously, the manufacturing considerations will be dif-

ferent depending on the dosage form chosen.

Finally, licensing and intellectual property issues

will likely remain important in palatable oral medi-

cations for companion animals.

We may have just scratched the surface in identi-

fying palatable oral formulations as a means to en-

hance (a) convenience and compliance, and (b) animal

and owner acceptability, while maintaining the con-

straints of acceptable cost of goods and pharmaceuti-

cally acceptable processing. Development of palatable

oral formulations for companion animal goes beyond

the convenience and compliance issues. The needs of

the pet owner in terms of the human-animal bond are

also important, underscoring the need for premium

formulations for companion animals.

Acknowledgements

The author would like to acknowledge his co-

workers and collaborators, I. Ahmed, K. Kasrarian,

R.J. Lloyd and E.F. Illyes.

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