Solids

The primary solid dosage forms for veterinary medicine include tablets, capsules, and feed additives.

Tablets

Because animals cannot self-administer, tablets as a single-unit dosage form are used less often in veterinary medicine compared with human medicine. However, they are still a prevalent dosage form. Tablets are used in a wide variety of indications, with several species, are available in a large size range, and are manufactured by several different processes. The primary species treated with tablets are dogs and cats; however, for some indications, cattle and sheep may receive a large tablet (often referred to as a bolus).

The major indications for tablets in dogs and cats would be those diseases that mirror those seen in humans. These would include the therapeutic areas of anticonvulsants, anti-inflammatories, antimicrobials, antitussives (there is a treatment for coughing dogs), antispasmodics (there is a treatment for cats with upset stomachs/ diarrhea), behavior modification (e.g., separation anxiety in dogs), cardiovascular, diuretics, thyroid hormone replacement, laxatives, muscle relaxants, nutraceuticals (e.g., antioxidants, glucosamine/chondroitin), sedatives, vitamin and mineral supplements (e.g., multivitamins, calcium), and parasiticides.

In general, the manufacturing process used for the majority of these tablets are the same as those used for humans and are discussed elsewhere (chap. 13, vol. 1). Direct compression and granulation (wet, dry) are both used. Chewable tablets can also be made by these methods or sometimes are molded via excursion and cut into appropriate sizes. The terms "chewable tablets" and "treats" are sometimes confusing. One way to classify is to state that chewable tablets that are made by direct or granulation processes are then called tablets. This would be similar to the mannitol-based chewable tablets prevalent for humans. The term treat is used for the more soft tablets that are produced via extrusion or cast molding.

Tablets can be coated to differentiate the product by color, to help mitigate offensive-tasting compounds, or to prevent dusting in the bottle (which minimizes handler safety issues). Again, the same coating techniques used for human products are utilized.

The relative size of the tablets for companion animals are somewhat similar to those used for humans. Tablets are manufactured large enough for pet owners to handle but small enough to "push" down the throat or hide in foods. Sizes from 80-mg weight up to 1- to 2-g weight are appropriate for use in animals. The tablet sizes for cattle, sheep, and horses are larger to incorporate the larger amount of active and facilitate administration. These tablets are typically called boluses and are often oblong for easier administration. Approximate weights are several grams to 8 g. To minimize the number of product presentations (i.e., tablet strengths), scoring of tablets can be used. Product presentations also include the bottle counts or blister cards and both can be used for animal health products. Child-resistant packaging is frequently considered for products used for cats and dogs.

Tablets are mainly formulated as immediate release types with once- to twice-daily dosing for the course of therapy depending on the disease being treated. Because of the faster gastrointestinal tract motility in dogs and cats, it is fairly difficult to achieve once-daily dosing unless the pharmacokinetic properties of the drug (i.e., a drug with a longer half-life) allow it. Thus, an important area of current research is that of achieving once-daily dosing through retention of the dosage form in the stomach. The use of fast-dissolving tablets (in the mouth) to minimize degradation in the gastrointestinal tract and facilitate ease of use is also of interest. Schering-Plough markets a rapidly disintegrating tablet (Zubrin®) for osteoarthritic dogs and, according to the label, the tablet is placed in the mouth and which is kept shut for approximately four seconds to aid tablet dispersion.

The following examples of anti-inflammatory agents illustrate some tablet products that are used in animal health: Amtech® Phenylbutazone Tablets; Aspirin Bolus; Canine Aspirin Chewable Tablets for Large Dogs; EtoGesic® (etodolac); Deramaxx® Chewable Tablets (deracoxib); Rimadyl® Caplets and Chewable Tablets (carprofen); Medrol® (prednisone); and Zubrin (tepoxalin).

Capsules

Like tablets, capsules are mainly used for dogs and cats, but there are some vitamin and mineral supplement capsules formulated for cattle. There are three main treatment areas using capsules as the dosage form: nutraceuticals, vitamins and minerals, and antimicrobials.

While the typical gelatin capsules used for humans can be used for veterinary medicine if the doses are small (e.g., sizes no. 000, no. 00), there are very large veterinary capsules that range in sizes from no. 13 (2-3 g) to no. 7 (14-24 g). Interestingly,

Capsuline manufactures DOGCaps and CATCaps , which are capsules containing beef, chicken, or bacon flavoring in the shells to entice dogs and cats to consume the products. These may be good capsules to hide small tablets that a finicky pet will not consume.

There are fewer capsule animal health products on the market when compared with the human health care market. This is somewhat surprising since capsules are often thought to take less time to develop (blending and flow are the important steps compared with tablets where blending, flow, compression, and sometimes coating are needed). Since time to develop the formulation is often the rate-limiting step for product approval, one may have thought that more capsules would have been developed for the veterinary market. One possible reason for there not being more animal health capsule formulations is that the eating action of cats and dogs would result in capsules being split and spill their contents. If the drug contained in the capsule is associated with a bad taste, then the cat or dog will be more careful to accept that product on a subsequent occasion.

Formulation development of capsule products involves the key areas of (i) blending active with bulking excipients, (»') forming a free-flowing granulation, which results in good content uniformity, and (ill) ensuring drug stability in the capsule.

While the majority of the capsule products are hard shell gelatin products, two soft elastic capsules are marketed that contain fish oils/omega-3 and vitamin K,. Some products on the market include vitamin K, Oral Capsules, 3V CAPS® series of products by DVM, which contain fish and cod liver oils, BioStart™ Capsules for Adult Cattle (contains vitamins; minerals; rumen and intestinal bacteria, yeast, enzymes), Vita Charge® Gel Cap (a 21-g capsule for cattle containing a mixture of Aspergillus oryzae, vitamins, and minerals), Aller G-3™ Capsules (omega-3), Cosequin® (glucosamine, chondroitin capsules that can be opened and flavored granules sprinkled on food), and Antirobe® Capsules (clindamycin hydrochloride).

Feed Additives

Feed additives are useful dosage forms for treating large numbers of animals simultaneously. Cattle, poultry, and swine are the main species to receive feed additives. The dosage forms include solid powders, which are mixed with feeds and liquids that are mixed in the feeds. Products that can be placed into the drinking systems could also be classified as feed additives. They would usually be a solution but could be a soluble powder that is reconstituted before being added to the drinking system.

People typically associate feed additives with solid powders (containing the actives) that are placed into the feed. It is important to understand the designation of type A, B, or C feed additives. Medicated type A feeds are the products containing one or more animal drugs that are sold to feed mills or producers and are intended to be mixed into feeds. Medicated type B feeds are feeds that contain type A or another type B plus a substantial quantity of nutrients (not less than 25% of the total weight) and are intended to be mixed with feeds and additional nutrients to make the feed that the animals consume. The important point is that medicated type B feeds are not to be fed directly to the animals. Type C is the final diluted feed that is fed to animals. This medicated type C feed can be offered directly to the animal or top dressed on to the animal's normal daily rations.

Challenges with developing feed additives reside in blend homogeneity and stability. The type A medicated feeds may contain concentrations of 1% or less

(sometimes down to 0.05%). With concentrations of 0.05% achieving homogeneous products is important. These type A medicated feeds are usually formulated with a "carrier" such as rice hulls or calcium carbonate. Ideally the active will be milled or micronized to a similar particle size as the carrier to help insure blend uniformity. These carriers then help facilitate the blending of the type A with type B and C feeds by providing a greater surface area. Because type B and C feeds will consist of ground grains, the particle sizes will be large but obtaining content uniformity is necessary to ensure proper dosing. Often dilution down to several parts per million is required. In addition, a robust formulation is required as the blending equipment and capabilities of feed mills will vary.

A second major challenge is to ensure adequate stability. While maintaining stability in the type A medicated feed (sometimes called Premix) may not be difficult, when blending in to type B and C, stability must be ensured. Because these feeds may include numerous metals (like copper that catalyzes oxidation) and contain grains with high moisture content, accelerated potency loss is possible. Additionally, type B medicated feeds may be stored for several months while they are being used on a daily basis to mix the final feeds. Storage can be in hot, moist grain bins or sometimes in the open where the sun and rain can further cause problems.

Finally, there are other challenges like minimizing dust. Most often mineral oil is added to feed additives to prevent the type A feed from being lost in to the air, which cannot only reduce potency but also potentially be a safety issue for the feed operators. A solid feed additive is definitely a challenging dosage form to develop.

For feed additives that are soluble powders, the key challenge is designing a powder that will readily go into solution and be stable when blended with the feed. Whether a soluble powder or a ready-to-use solution that is mixed with feeds, obtaining a homogenous blend is again important. For those solutions that are added to water systems, ensuring that no complexation occurs with minerals in the water or adsorption to pipes is important. These can happen because the drug may be in concentrations of parts per million or less. A dose-metering device is hooked into the water system to continuously add the drug solution at a prescribed rate.

The major uses for feed additives are as vitamin/mineral supplements, electrolyte replacements, and antimicrobials/progestins (for increased rate of weight gain and improved feed efficiency in livestock). The vitamin/mineral supplements are numerous and include cobalt, cooper, iodine, manganese, multiple vitamins/minerals, vitamin A, vitamin K, vitamin E, selenium, and zinc. Electrolyte replacements include Calf Quencher and Bluelite®Swine Formula, while products for weight gain include MGA®200 Premix and MGA500 Liquid Premix.

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