Oral delivery of medications to companion animals_palatability considerations by Salah EL MOUSTAGHFIR

Advanced Drug Delivery Reviews 56 (2004) 1399 â&#x20AC;&#x201C; 1413 www.elsevier.com/locate/addr

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. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . Flavor fundamentals . . . . . . . . . . . . . . . . . . Food and flavor preferences of dogs and cats . . . . . . . Palatability and palatability testing . . . . . . . . . . . . 4.1. Acceptance test . . . . . . . . . . . . . . . . . 4.2. Preference test. . . . . . . . . . . . . . . . . . 5. Formulation considerations for a palatable oral tablet . . . 5.1. Taste masking the active . . . . . . . . . . . . . 5.2. Adding food based products . . . . . . . . . . . 5.3. Flavors added to tablets . . . . . . . . . . . . . 6. Palatability tests for companion animal medications . . . . 7. Palatable oral controlled release formulations for companion 8. Current needs and future directions. . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .

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* Tel.: +1-860-441-8734; fax: +1-860-715-7668. E-mail address: Avinash_G_Thombre@groton.pfizer.com (A.G. Thombre). 0169-409X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2004.02.012

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1. Introduction 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 distracting 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. Anecdotal 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 ingestion 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 pharmaceutical 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 formulations. 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; including oral formulations for companion animals [1,2].

This review focuses on the state-of-the-art in the development of palatable oral formulations for companion 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 behavioral 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. Extending through this pore into the oral cavity are fingerlike 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 membrane 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). Understanding the mechanisms of receptor activation and the subsequent transduction process at the biochemical level is important because this ultimately leads to

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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.)

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 guanylate (GMP) [12]. It is present in many food substances, 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

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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 avoidance [20]. The sweet taste of sugar or artificial sweeteners in dogs and cats has been studied extensively [21 â&#x20AC;&#x201C;24]. It has been shown that although cats prefer the taste of sucrose, they reject the taste of nonnutritive sweeteners 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 recording 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

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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 observed 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 volatile and will disappear if the flavor is not stored properly. Several studies have attempted to breakdown 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.

3. Food and flavor preferences of dogs and cats In general, treats and premium canned food products are considered to be highly palatable. Treats are relatively large in size and have interesting or attractive 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 strongly 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 omnivores 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,

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

pointy teeth (canines) (Fig. 3a) designed for capturing 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

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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 protein digests and hydrolysates, animal proteins, emulsified meats, amino acids, animal fats, sugars (dogs) and acids (cats). In contrast, flavors that are considered to negatively affect palatability include vegetable protein meals, fibers, vegetable oils, vitamins, minerals 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 artificial 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 enzymolysis, 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 ingredients present in a given formulation, the manufacturing processes can also have an impact on palatability. An extrusion process is used to manufacture 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 palatability values of soybeans were improved by extrusion [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 preference 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 following definition is offered: The term ‘‘palatability’’ refers to the voluntary (free choice) acceptance or ingestion of a pharmaceutical composition by companion 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. However, 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 companion 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

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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 preference 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 variables 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 formulations 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 factors in the interpretation of the results from a preference test: individual variation, the attractiveness 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].

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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, preferably 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 receiving 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

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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 animalâ&#x20AC;&#x2122;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.

used in these products are summarized below. In some cases, a combination approach may be required. For example, a highly bitter active may first have to be taste masked (e.g., by microencapsulation) 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 technologies are available for taste-masking drugs used in companion animal pharmaceuticals including: micro-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

5. Formulation considerations for a palatable oral tablet The primary attributes of a successful pharmaceutical 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 conventional 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 2year shelf life. Some commercially available palatable pharmaceutical 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

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 medication into the dogâ&#x20AC;&#x2122;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

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Table 1 Some commercially available palatable pharmaceutical formulations for companion animals Product

Company

Active(s)

Palatability notes (from manufacturerâ&#x20AC;&#x2122;s package insert)

RimadylR Chewable

Pfizer

Carprofen

InterceptorR Flavor TabsR

Novartis

Milbemycin oxime

SentinelR Flavor TabsR

Novartis

ProgramR Flavor TabsR HeartgardR Chewables

Novartis Merial

Milbemycin oxime, lufenuron Lufenuron Ivermectin

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

HeartgardR Plus Chewables

Merial

Ivermectin, pyrantel

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) (b) (c) (d) (e)

Acceptability and preference in dogs and cats Regulatory acceptance worldwide Stability and shelf life Cost and availability 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

As an alternative to direct dosing, tablets may be offered in food. 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. 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.

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 differentiation 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 products and many countries do not allow the import of meat or other animal parts from countries without proper certification. The Regulatory processes 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-

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Table 2 Some additional palatable formulations (source: VPB 2001/2002, 12th Edition) Product

Company

Active ingredient(s)

Palatability notes from manufacturer

ArthriCarek Chewable Tablets

V.P.L.

Blended in a roast beef and liver flavor containing base

Canine Aspirin Chewable Tablets for Dogs

Pala-Tech

Buffered microencapsulated aspirin Microencapsulated buffered aspirin

Canine F.A./Plus Chewable Tablets For Dogs

Pala-Tech

Omega fatty acids, vitamins and minerals

Feline F.A./Plus Chewable Tablets

Pala-Tech

Omega fatty acids, vitamins and minerals

Nutrivedk Chewable Vitamins

Vedco

Vitamins and combinations

K-ZymeR Chewable Dog Tablets

BioZyme

Vitamins

D-Wormk Dog Wormer Chewable Tablets for Dogs HartzR Health Measuresk Everyday Chewable Vitamins

Farnam

Pyrantel pamoate

Hartz Mountain

Vitamins and minerals

Pala-Tech

Levothyroxine sodium

Canine Thyroid Chewable Tablets

ods—identification of degradation products of natural flavors can be complex. They may also have significant 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, onecomponent system that is compatible with the active drug is most preferred. Assuming that the quantity of palatability enhancing 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-

Buffered aspirin in a proprietary highly palatable roast beef and liver flavor base to ensure dogs readily consume the tablet 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. 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. Administer free choice just prior to feeding, or crumble and mix with food. (liver meal and roast beef flavor) A highly palatable (roast beef and liver flavor) digestive enhancer fortified with vitamins and minerals Offer the proper dosage by hand or in the dog’s food container with or without food. 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. It may be given orally to dogs as a treat or crumbled over their food. If crumbled over food, consumption should be monitored.

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 pharmaceutical formulations in companion animals. Furthermore, there are very few reports in the scientific

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Table 3 Examples of commercially available flavors for dogs and cats Product

Manufacturer/supplier

Description

Listed ingredients

Cheese Plus Cheese Product

International Ingredient, St. Louis, MO

Sirius Stuff

Dirigo, Boston, MA

Blend of white and yellow cheese product powders and cheese rind Heavenly blend of natural flavorings and spices

Art. Chicken Flavor

Bush Boake Allen Americas, Chicago, IL International Ingredient, St. Louis, MO Geneva Ingredients, Waunakee, WI

Dried cheese product Protein 34%, fat 20%, fiber 1%, moisture 9%, lysine 3%, ash 6% A blend of yeast, garlic, salt, herbs, kelp, fermented soy Mixture of GRAS flavors (GRAS = generally accepted as safe) Crude protein 43%, crude fat 1.5%, crude fiber 1%, ash 5.5%, moisture 6% Maltodextrin, autolyzed yeast extract, natural flavors, partially hydrogenated vegetable oil (soybean and/or cottonseed), onion powder and silicon dioxide (to prevent caking) Maltodextrin, natural flavors,a natural smoke flavor and silicon dioxide (to prevent caking) Hydrolyzed vegetable protein, natural flavor, and hydrogenated vegetable oils Mixture of GRAS flavors (GRAS = generally accepted as safe) Salt, maltodextrin, autolyzed yeast extract, natural flavors, partially hydrogenated vegetable oil (cottonseed or soybean) and silicon dioxide (to prevent caking) Mixture of GRAS flavors (GRAS = generally accepted as safe) (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% Nonfat dried milk (dried skim), whey protein concentrate, casein, dried whey, dried milk products

BrewTech Dried Brewers Yeast Vegetarian Beef Type Flavor

Vegetarian Bacon

Geneva Ingredients, Waunakee, WI

Artificial Powdered Beef

Pharma Chemie, Syracuse, NE Bush Boake Allen Americas, Chicago, IL Geneva Ingredients, Waunakee, WI

Trusil Artificial Peanut Butter Flavor Roast Garlic Flavor

Trusil Artificial Ham Flavor Sugar Food By-Product

100% Saccharomyces cerevisiae from the brewing industry Savory full-bodied beef flavor from natural ingredients

Full bodied bacon type flavor with rich fatty notes from natural ingredients Blend of vegetable and natural proteins and oils

Natural roast garlic flavor enhanced with natural flavors

Bush Boake Allen Americas, Chicago, IL International Ingredient, St. Louis, MO

All Dairy Blend

International Ingredient, St. Louis, MO

Dog Bone Marinade

Dirigo, Boston, MA

EggsAct Dried Egg Replacer

International Ingredient, St. Louis, MO

Blend of all natural spices and flavorings 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

Contains peanut oil as flavor carrier.

literature on palatability studies conducted using pharmaceutical products for companion animals. Palatability 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

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

Table 4 Canine acceptability of 300 mg flavored lactose (placebo) tablets Small screen 1 flavors

Tasted

Consumed

Not consumed

Time (s)

Rank

Artificial chicken Artificial powdered beef Artificial peanut Eggsact Roast garlic Sirius stuff Sugar food product Trusil ham flavor

38 36 39 39 38 40 39 39

33 29 30 38 + 35 34 33 33

7 11 10 1+ 5 6 7 7

36 62 55 22 34 44 47 49

4 8 7 1 2 3 5 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 placebo tablets in dogs was shown to be only about 68% and those that contained Bitrex (denatonium benzoate, 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 modified appropriately and adapted for testing drug products [64] in dogs and cats. The modifications allowed rapid screening of flavors using an acceptance 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

(e.g., degree of enthusiasm or level of interest displayed 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.

Table 5 Responses to flavor choices by 30 dogs Flavor

Brewers yeast Vegetable beef Cheese and cheese Vegetable bacon Sirius stuff Artificial chicken

% dogs with 100% consumed

Consumable tablet summary (%) Consumed

Rejected

90 83 83 83 83 80

97.5 96.0 95.7 94.2 92.7 93.2

2.5 4.0 4.3 5.8 7.3 6.8

% dropped

Consumption order (%) 1sts

2nds

0.8 2.5 3.9 4.7 4.7 5.3

58 49 50 38 51 45

39 45 46 52 42 48

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

7. Palatable oral controlled release formulations for companion animals Oral controlled release dosage forms for companion 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 formulations in the veterinary medicine [65]. The rationale for these formulations in companion animals is similar to that in humans, e.g., reduced dosing frequency, better toleration, increased efficacy, cost savings 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/dissolves. 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 substitution, 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 formulation, may not provide the desired in vivo performance. 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 focusing on this sector. Traditionally, pharmaceutical companies have concentrated more on the disease

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state and the drug substance being developed. Compliance/convenience aspects and product differentiation 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 identifying one or more ‘‘standard’’ flavors for pharmaceutical products. The goal of achieving palatability using a simple, single, synthetic molecule, which is acceptable world-wide, is a difficult one, but it has the potential of reducing the burden on analytical chemists involved in the physicochemical characterization of tablet ingredients, following the degradation products 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 palatabilitytesting 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 palatability 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 odormasking 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 palatable oral formulations for companion animals. Other dosage forms include: medicated treats, biscuits, medicated chow, medications added to drinking fluids,

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palatable buccal films and palatable oral gels. Obviously, the manufacturing considerations will be different depending on the dosage form chosen. Finally, licensing and intellectual property issues will likely remain important in palatable oral medications for companion animals. We may have just scratched the surface in identifying palatable oral formulations as a means to enhance (a) convenience and compliance, and (b) animal and owner acceptability, while maintaining the constraints of acceptable cost of goods and pharmaceutically 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 coworkers and collaborators, I. Ahmed, K. Kasrarian, R.J. Lloyd and E.F. Illyes.

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