A diverse range of drug dosage forms and delivery systems have been developed for the care and welfare of animals. The development of dosage forms draws on the discipline of biopharmaceutics, which integrates an understanding of formulations, dissolution, stability, and controlled release (pharmaceutics); absorption, distribution, metabolism, and excretion (ADME; pharmacokinetics, or PK); concentration-effect relationships and drug-receptor interactions (pharmacodynamics, or PD); and treatment of the disease state (therapeutics).
Typically, dosage forms are formulated by combination of an active ingredient and one or more excipients. The resultant dosage form determines the route of administration and the clinical efficacy and safety of the drug.
Optimization of drug doses is also critical to achieving clinical efficacy and safety. Increasingly, a pharmacokinetic-pharmacodynamic model that describes the drug response is the basis of dose optimization. Pharmacokinetics and pharmacodynamics are linked by the premise that free drug in the systemic circulation is in equilibrium with the drug's receptors. Pharmacodynamics describes how a drug interacts with a receptor, triggering postreceptor events and eventually leading to a drug effect (see Drug Concentration and Effect).
Drug delivery strategies for veterinary formulations are complicated by the diversity of species and breeds treated, the wide range in body sizes, different husbandry practices, seasonal variations, cost constraints associated with the value of the animal being treated, the persistence of residues in food and fiber, and convenience, among other factors. Innovative solutions have been developed to meet many of these challenges (eg, the convenient dosing option offered by topical spot-on formulations to treat external and internal parasites on dogs and cats, the microencapsulation of NSAIDs as a way to mask taste when these agents are added to the rations of horses).
The anatomy of the GI tract of ruminants presents unique opportunities for controlled-release drug delivery systems, and many such systems are on the market. For example, controlled-release boluses have been developed to deliver antimicrobials, anthelmintics, production enhancers, nutritional supplements, and other drugs.
Oral Route of Administration and Dosage Forms
The oral route is frequently used to administer drugs to both companion and food animals.
In dogs and cats, tablets, capsules, solutions, and suspensions are administered PO; pastes are also applied to the forelimbs of cats, from which they are licked and ingested.
In horses, solutions and suspensions are administered by nasogastric tubes, pastes are applied in the back of the mouth with oral dosing syringes, and granules are added to rations for ingestion.
In cattle, pigs, and poultry, the oral route of administration is the most widely used. Formulations range from premixes and drinking-water additives to licks, pastes, drenches, tablets, capsules, and boluses.
Oral dosage forms are usually intended for systemic effects resulting from drug absorption from the GI tract. However, some oral suspensions (eg, kaolin) are intended to produce local effects, and these are not absorbed.
Disadvantages of the oral route of administration include the relatively slow onset of action, the possibility of irregular absorption, the destruction of acid-labile drugs in the stomach, and the unsuitability of this route for many high–molecular-weight drugs. Oral dosage forms require careful pharmaceutical formulation.
Oral dosage forms include liquids (solutions, suspensions, emulsions, elixirs, and syrups), semisolids (pastes), and solids (tablets, capsules, powders, granules, premixes, and medicated blocks). These dosage forms, together with examples of modified-release delivery systems for ruminants, are discussed here.
A solution is a mixture of two or more components that form a single phase that is homogeneous down to the molecular level. Solutions offer several advantages over other dosage forms. Compared with solid dosage forms, solutions are absorbed faster and generally cause less irritation of the GI mucosa. Moreover, phase separation on storage is not a concern with solutions, as it may be for suspensions and emulsions. The disadvantages of solutions include potential for microbial contamination and the hydrolysis in aqueous solution of susceptible active ingredients. In addition, the taste of some drugs is more unpleasant when in solution. A range of additives are used in the formulation of oral solutions, including buffers, flavors, antioxidants, and preservatives. Oral solutions provide a convenient means of administering drugs to neonates and young animals.
A suspension is a coarse dispersion of insoluble drug particles, generally with a diameter > 1 mcm, in a liquid (usually aqueous) medium. Particle size is an important determinant of the dissolution rate and bioavailability of drugs in suspension. The taste of most drugs is less noticeable in suspension than in solution because the drug is less soluble in suspension.
Suspensions are useful for administering insoluble or poorly soluble drugs or when the presence of a finely divided form of the material in the GI tract is required. An example of the latter is the treatment of frothy bloat with dimethyl polysiloxanes, which relies on a dispersion of finely divided silica in the forestomach of ruminants.
In addition to the excipients described for solutions, suspensions include surfactants and thickening agents. Surfactants wet the solid particles, thereby ensuring that the particles disperse readily throughout the liquid. Thickening agents decrease the rate at which particles settle to the bottom of the container.
Some settling is acceptable, as long as the sediment can be readily dispersed when the container is shaken. It may not be possible to redisperse the suspension if the sediment has packed closely to form a hard mass—a process known as "caking."
An emulsion is a system consisting of two immiscible liquid phases, one of which is dispersed throughout the other in the form of fine droplets; droplet diameter generally ranges from 0.1 to 100 mcm. The two phases of an emulsion are the dispersed phase and the continuous phase.
Emulsions are inherently unstable and are stabilized through the use of an emulsifying agent, which prevents coalescence of the dispersed droplets. Other additives include buffers, antioxidants, and preservatives.
Creaming (the rise of dispersed particles to the top of the emulsion), as occurs with milk, also occurs with pharmaceutical emulsions. It is not a serious problem with pharmaceutical emulsions, however, because shaking restores a uniform dispersion. Nonetheless, creaming is undesirable because it is associated with an increased likelihood of the droplets coalescing and the emulsion “breaking.”
Emulsions for oral administration are usually oil (the active ingredient) in water, and they facilitate the administration of oily substances such as castor oil or liquid paraffin in a more palatable form.
An elixir is a sweetened, usually hydroalcoholic solution of a bitter or nauseous drug intended for oral administration. The hydroalcoholic character of elixirs enables, within limits, both water-soluble and ethanol-soluble medicinal substances to be maintained in solution. The proportion of ethanol in elixirs, which varies widely, is a characteristic used to advantage to solubilize medicinal agents. If the active ingredient is sensitive to moisture, it may be formulated as a flavored powder or granulation and reconstituted in water immediately before oral administration. Nonmedicated elixirs are used as the vehicles for pharmaceutical formulations.
A syrup is a concentrated aqueous solution of sugar or a sugar substitute with or without flavoring agents and a water-soluble drug. Sucrose is the most frequently used sugar, and syrups usually contain 60%–80%. Syrups may also contain cosolvents, solubilizing agents, thickeners, or stabilizers. Nonmedicated syrups are used as vehicles for water-soluble drugs. Molasses is a commonly used syrup that makes medications more palatable for horses.
A paste is a two-component semisolid in which a drug is dispersed as a powder in an aqueous or fatty base. The particle size of the active ingredient in pastes can be as large as 100 mcm.
The vehicle containing the drug may be water; a polyhydroxy liquid such as glycerin, propylene glycol, or polyethylene glycol; a vegetable oil; or a mineral oil. Other formulation excipients include thickening agents, cosolvents, adsorbents, humectants, and preservatives. The thickening agent may be a naturally occurring material such as acacia or tragacanth, or a synthetic or chemically modified derivative such as xanthan gum or hydroxypropyl methylcellulose. The extent of cohesiveness, plasticity, and syringeability of pastes is attributed to the thickening agent. It may be necessary to include a cosolvent to increase the solubility of the drug.
Syneresis of pastes is a form of instability in which the solid and liquid components of the formulation separate over time; it is prevented by including an adsorbent such as microcrystalline cellulose. A humectant (eg, glycerin or propylene glycol) is used to prevent the paste that collects at the nozzle of the dispenser from forming a hard crust. Microbial growth in the formulation is inhibited by use of a preservative.
It is critical that pastes have a pleasant taste or are tasteless and can be used throughout a wide temperature range. Pastes are a popular dosage form to treat cats and horses and can be easily and safely administered by owners.
A tablet consists of one or more active ingredients and numerous excipients. It may be a conventional tablet that is swallowed whole, a chewable tablet, or a modified-release tablet (these are commonly referred to as "modified-release boluses" when the unit size is large). Conventional and chewable tablets are used to administer drugs to dogs and cats, whereas modified-release boluses are administered to cattle, sheep, and goats.
The physical and chemical stability of tablets is generally better than that of liquid dosage forms. The main disadvantages of tablets are a relatively slow onset of action because they need to pass into the intestine and then disintegrate and dissolve before being absorbed across the gut wall, the bioavailability of poorly water-soluble drugs or poorly absorbed drugs is low, and some drugs may cause local irritation of the GI mucosa.
A capsule is an oral dosage form usually made from gelatin and filled with an active ingredient and excipients. Two common capsule types are available: hard gelatin capsules for solid-fill formulations, and soft gelatin capsules for liquid-fill or semisolid-fill formulations. Soft gelatin capsules are suitable to formulate poorly water-soluble drugs because they allow good drug release and absorption by the GI tract. Gelatin capsules are frequently more expensive than tablets, but they have some advantages. For example, particle size is rarely altered during capsule manufacture, and capsules mask the taste and odor of the active ingredient and protect photolabile ingredients.
A powder is a formulation in which a drug powder is mixed with other powdered excipients to produce a final product for oral administration. Powders have better chemical stability than liquids and dissolve faster than tablets or capsules because disintegration is not an issue. Therefore, if absorption is limited by the drug's dissolution rate, the drug is absorbed more quickly.
Unpleasant tastes can be more pronounced with powders than with other dosage forms and can be a particular concern with in-feed powders, leading to variable ingestion of the desired dose. Moreover, sick animals often eat less and are therefore not amenable to treatment with in-feed powder formulations.
Drug powders are principally used prophylactically in feed or formulated as a soluble powder for addition to drinking water or milk replacer. Powders have also been formulated with emulsifying agents to facilitate their administration as liquid drenches.
A granule is a dosage form consisting of powder particles that have been aggregated to form a larger mass, usually 2–4 mm in diameter. Granulation overcomes segregation of the different particle sizes during storage and dose administration, the latter being a potential source of inaccurate dosing. Granules and powders generally behave similarly; however, granules must deaggregate before dissolution and absorption.
A premix is a solid dosage form in which an active ingredient, such as a coccidiostat, production enhancer, or nutritional supplement, is formulated with excipients. Premix products are mixed homogeneously with feed at rates (when expressed on an active ingredient basis) that range from a few milligrams to ~200 g/ton of feed.
These products are administered to poultry, pigs, and ruminants. To facilitate uniform mixing, the density, particle size, and geometry of the premix particles should match as closely as possible those of the feed in which the premix will be incorporated. Issues such as instability, electrostatic charge, and hygroscopicity must also be addressed.
The excipients present in premix formulations include carriers, liquid binders, diluents, anticaking agents, and antidust agents.
Carriers, such as wheat middlings, soybean mill run, and rice hulls, bind active ingredients to their surfaces and are important in attaining uniform mixing of the active ingredient. A liquid binding agent, such as a vegetable oil, should be included in the formulation whenever a carrier is used.
Diluents increase the bulk of premix formulations; unlike carriers, however, they do not bind the active ingredients. Examples of diluents include ground limestone, dicalcium phosphate, dextrose, and kaolin.
Caking in a premix formulation may be due to hygroscopic ingredients and is addressed by the addition of small amounts of anticaking agents such as calcium silicate, silicon dioxide, and hydrophobic starch.
The dust associated with powdered premix formulations can have serious implications for both operator safety and economic losses and is decreased by the inclusion of a vegetable oil or light mineral oil in the formulation. An alternative approach to overcoming dust is to granulate the premix formulation.
A medicated block is a compressed feed material that contains an active ingredient such as a drug, anthelmintic, surfactant (for bloat prevention), or nutritional supplement and is commonly packaged in a cardboard box to feed to production animals.
Ruminants typically have free access to the medicated block over several days, and variable consumption may be problematic. To address this concern, the active ingredient is nontoxic, stable, palatable, and preferably of low solubility.
Excipients in the formulation modulate consumption by altering the palatability or the hardness of the medicated block. For example, molasses increases palatability, and sodium chloride decreases it. In addition, the incorporation of a binder such as lignin sulfonate in blocks manufactured by compression, or magnesium oxide in blocks manufactured by chemical reaction, increases hardness. The hygroscopic nature of molasses in a formulation may also affect the hardness of medicated blocks and is addressed by the use of appropriate packaging.
Oral Modified-release Delivery Systems for Ruminants
Several modified-release delivery systems take advantage of the unique anatomy of the ruminant forestomach. Prominent among these systems are intraruminal boluses, which contain a range of active ingredients, including parasiticides, nutritional supplements, antibloat agents, and production enhancers. Intraruminal boluses are administered via a balling gun.
Most commercially available boluses are continuous-release preparations that rely on erosion, diffusion from a reservoir, dissolution of a dispersed matrix, or an osmotic driver to release the active ingredient. The payout period for intraruminal boluses is commonly > 100 days. Having either a density of ~3 g/cm3 or a variable geometry prevents the bolus from being regurgitated during rumination.
Other types of oral modified-release delivery systems are also available for ruminants. For example, sustained-release boluses that deliver sulfonamides throughout a period of ~72 hours are available to treat cattle. In addition, sustained-release boluses containing methoprene or diflubenzuron are approved for the control of manure-breeding flies in cattle.
The intraruminal devices to supplement ruminants with selenium, cobalt, or copper include soluble-glass boluses and intraruminal pellets. Boluses of soluble glass containing selenium, cobalt, and copper are available for cattle and sheep. Because glass is susceptible to sudden changes in temperature, glass boluses should be at least 15°–20°C at the time of administration to avoid fracturing, which in turn may lead to regurgitation. Glass boluses are designed to dissolve in ruminal fluids, thereby releasing the incorporated elements. The composition of the glass determines the solubility of the bolus, with an increase in the ratio of monovalent to divalent cations resulting in an increase in solubility. Glass boluses are retained in the rumen for up to 9 months.
Intraruminal pellets containing selenium or cobalt are available for sheep. Selenium or cobalt is released throughout a period of ~3 years from the pellet matrix, which consists of compressed iron grit. When selenium or cobalt intraruminal pellets are administered alone, a metal grinder, which provides an abrasive action, is usually coadministered to prevent the formation of calcium phosphate coatings on the surface of the pellets.
Copper capsules, which contain oxidized copper-wire particles encapsulated in gelatin, are available for adult sheep and goats. After oral administration, the gelatin capsule dissolves in the rumen and releases the particles of copper oxide. The particles progress to the abomasum, where some are trapped in the mucosal folds and release copper.
Parenteral Route of Administration and Dosage Forms
Any route of drug administration other than oral is a parenteral route (topical dosage forms are considered separately). The four main parenteral routes of drug administration are intravenous (IV), intramuscular (IM), subcutaneous (SC), and intra-articular (IA), and in all cases the drug is usually administered via a hollow needle.
Injectable preparations are usually sterile solutions or suspensions of a drug in water or other suitable physiologically acceptable vehicles. Volumes delivered can range from milliliter to liter quantities.
The time of onset of action for IV administration is seconds; for IM, SC, and IA injections, minutes. Depot-injectable preparations achieve prolonged release and maintain therapeutic concentrations of a drug throughout 2–5 days.
The bioavailability of a drug, particularly from prolonged-release formulations, can be influenced by the location of the IM injection site. SC implants and pellets also achieve prolonged release of a drug.
A number of recombinant proteins and peptides are orally inactive and must be administered parenterally. Specialized dosage forms, usually for parenteral administration, are required for vaccines. In food animals, intramammary infusions and intravaginal devices are administered by the parenteral route.
Parenteral dosage forms and delivery systems include injectables (ie, solutions, suspensions, emulsions, and dry powders for reconstitution), intramammary infusions, intravaginal delivery systems, and implants. These dosage forms and delivery systems, as well as the special considerations relating to IA injections, recombinant proteins and peptides, and vaccines, are discussed here. Also see the Constant Rate Infusions Calculator to calculate the volume of drug, in milliliters, to administer.
A solution for injection is a mixture of two or more components that form a single phase that is homogeneous down to the molecular level.
“Water for injection” is the most widely used solvent for parenteral formulations. However, a nonaqueous solvent or a mixed aqueous/nonaqueous solvent system may be necessary to stabilize drugs that are readily hydrolyzed by water or to improve solubility.
A range of excipients may be included in parenteral solutions:
Antioxidants maintain product stability by being preferentially oxidized over the shelf life of the product.
Antimicrobial preservatives inhibit the growth of any microbes accidentally introduced when doses are being withdrawn from multiple-dose bottles, and they act as adjuncts in aseptic processing of products.
Buffers are necessary to maintain both solubility of the active ingredient and stability of the product.
Chelating agents are added to complex and thereby inactivate metals, including copper, iron, and zinc, which generally catalyze the oxidative degradation of drugs.
Inert gases are used to displace the air in solutions and enhance the product integrity of oxygen-sensitive drugs.
Isotonicity of the formulation is achieved by the inclusion of a tonicity-adjusting agent. Failing to adjust the tonicity of the solution can result in the hemolysis or crenation of erythrocytes when hypotonic or hypertonic solutions, respectively, are administered IV.
Injectable formulations must be sterile and free of pyrogens. Pyrogenic substances are primarily lipid polysaccharides derived from microorganisms; those produced by gram-negative bacilli generally are the most potent.
Injectable solutions are very commonly used, and aqueous solutions administered IM result in immediate drug absorption, provided that precipitation at the injection site does not occur.
A suspension for injection consists of insoluble solid particles dispersed in a liquid medium, with the solid particles accounting for 0.5%–30% of the suspension. The vehicle may be aqueous, oil, or both.
Caking of injectable suspensions is minimized through the production of flocculated systems, comprising clusters of particles (flocs) held together in a loose, open structure.
Excipients in injectable suspensions include antimicrobial preservatives, surfactants, dispersing or suspending agents, and buffers.
Surfactants wet the suspended powders and provide acceptable syringeability.
Suspending agents modify the viscosity of the formulation. The ease of injection and the availability of the drug in depot form are affected by the viscosity of the suspension and the particle size of the suspended drug. These systems afford enhanced stability to active ingredients that are prone to hydrolysis in aqueous solutions.
Injectable suspensions (eg, procaine penicillin G) are commonly used. Compared with that of injectable solutions, the rate of drug absorption of injectable suspensions is prolonged because additional time is required for the suspended drug particles to disintegrate and dissolve. The slower release of drug from an oily suspension compared with that of an aqueous suspension is attributed to the additional time taken by drug particles suspended in an oil depot to reach the oil-water boundary and become wetted before dissolving in tissue fluids.
An emulsion for injection is a heterogeneous dispersion of one immiscible liquid in another. It relies on an emulsifying agent for stability. Formulation options for injectable emulsions are severely restricted because suitable stabilizers and emulsifiers are very limited.
Parenteral emulsions are rare, because achieving an emulsion is seldom necessary for drug administration; however, the popular anesthetic propofol is formulated as an emulsion. Although not observed for propofol, adverse physiologic effects after IV administration may occur with emulsions, including emboli in blood vessels if the droplets are > 1 mcm in diameter. It is especially critical to obtain emulsions from reputable sources to avoid adverse effects.
Other examples of parenteral emulsions include oil-in-water, sustained-release depot preparations (administered IM), and water-in-oil emulsions of allergenic extracts (administered SC).
A dry powder for parenteral administration is reconstituted as a solution or as a suspension immediately before injection. The principal advantage of this dosage form is that it overcomes the problem of instability in solution. Proteins and other materials that are extremely heat sensitive cannot be dried in pharmaceutical dryers. Rather, freeze-drying, or lyophilization, is used to produce a porous powder that reconstitutes readily. Vaccines are commonly supplied in this manner.
Intramammary infusion products to treat mastitis are available for lactating and nonlactating (dry) cows.
Lactating cow intramammary infusions should demonstrate fast and even distribution of the drug and a low amount of binding to udder tissue. These properties result in lower concentrations of drug residues in the milk.
In contrast, it is desirable for nonlactating cow formulations to demonstrate prolonged drug release and a high amount of binding to mammary secretions and udder tissues.
Particle size is particularly important, because it affects both the rate of release of the active ingredient and irritancy to the udder tissue. Drug particle size in nonlactating intramammary formulations is usually smaller than in those for lactating cows, which is critical to reduce irritancy during prolonged retention in the udder.
Thickening agents are added to modify the rate of release of the suspended particles from oil formulations, and antioxidants are commonly incorporated to prevent rancidity. Mastitis infusion products are often terminally sterilized by irradiation.
Intravaginal delivery systems include controlled internal drug-release (CIDR) devices, progesterone-releasing intravaginal devices (PRIDs), and vaginal sponges. These systems are used for estrus synchronization in sheep, goats, and cattle.
Silicone is used in the manufacture of the T-shaped CIDR device and the coil-shaped PRID; intravaginal sponges are made from polyurethane. The active ingredients in these systems are synthetic or natural hormones such as progesterone, methylacetoxy progesterone, fluorogestone acetate, or estradiol benzoate.
An applicator consisting of a speculum and a separate plunger is used to insert sponges into the vaginal cavities of sheep and goats, and PRIDs into the vaginal cavities of cattle. A different type of applicator is used to insert CIDR devices into the vaginal cavities of sheep, goats, and cattle.
Retention in the vagina depends on expansion of either the wings (CIDR device) or the entire device (sponges and PRIDs). With all three devices, gentle pressure is exerted on the vaginal wall. Retention of the device is > 95%.
Most implants used in veterinary medicine are compressed tablets or dispersed matrix systems in which the drug is uniformly dispersed within a nondegradable polymer. To be released from dispersed matrix systems, drugs are dissolved into the polymer. They then diffuse through the polymer and are partitioned from the surface of the polymer into the surrounding aqueous environment.
Implants are available to increase weight gain and feed conversion efficiency in food animals. These implants are typically prepared in a manner similar to the preparation of tablets. One controlled-release implant consists of a cylindrical core of silicone, surrounded by an outer layer of estradiol-loaded silicone.
A range of implants are available to enhance reproductive performance in breeding animals. These include ear implants containing norgestomet dispersed in polyethylene methacrylate or silicone, a biocompatible tablet implant for mares that contains deslorelin (a GnRH agonist) and does not require removal, and a sustained-release pellet of melatonin, which is implanted in the ear of ewes to enhance breeding performance. Testosterone pellets can be implanted in the ears of wethers (70–100 mg, every 3 months) for the prevention of ulcerative posthitis; however, available products in the US are approved for use in cattle only. Extralabel use of a drug for the purposes of growth promotion is not legal in the US.
Special Dosage Form Considerations With Intra-articular Injections of Drugs
The dosage forms used for intra-articular (IA) administration are sterile aqueous solutions. In horses, the two most common reasons for IA injections are to anesthetize or block a joint during a lameness examination and to treat noninfectious inflammatory joint diseases such as synovitis and capsulitis.
Drugs such as glucocorticoids, pentosan polysulfate sodium, and hyaluronic acid are administered IA in inflammatory joint disease. The IA administration of glucocorticoids minimizes the adverse effects associated with large systemic doses.
In dogs, hyaluronate sodium is administered by IA injection for adjunctive treatment of synovitis. Regenerative treatments involving stem cells, platelet-rich plasma (PRP), or interleukin-1 receptor antagonist protein (IRAP) have also been developed and are injected IA in horses to slow the progression of osteoarthritis.
Special Dosage Form Considerations With Recombinant Proteins and Peptides
Recombinant proteins and peptides are used in some countries to increase feed conversion efficiency and milk production in cattle (bovine growth hormone), to increase feed conversion efficiency and produce leaner carcasses in pigs (porcine growth hormone), to manage the chemical shearing of sheep (epidermal growth factor), to decrease the incidence of skeletal weaknesses leading to leg injuries in horses (equine growth hormone), and for other uses.
Recombinant proteins and peptides have been formulated as solutions, lyophilized powders, implants, and microparticles. The chemical and physical instability of recombinant proteins and peptides is a special consideration during formulation development. The major causes of chemical instability are proteolysis, deamidation, oxidation, and racemization. Causes of physical instability are aggregation, precipitation, denaturation, and adsorption to surfaces.
Various strategies have been reported to stabilize formulations containing recombinant proteins and peptides, including the choice of carrier vehicle (eg, oleaginous vehicles), the use of lyophilization excipients, the use of stabilizers such as sugars and detergents, chemical modification of the proteins and peptides, and the use of site-directed mutagenesis to synthesize more stable proteins.
Special Dosage Form Considerations With Live Vaccines, Inactivated and Subunit Vaccines, and DNA Vaccines
The organisms in live vaccines are subjected to freeze-drying and, less commonly, to deep freezing at or below −70°C. To maintain the viability of organisms under these conditions, formulations include complex mixtures of proteins, peptides or amino acids, sugars, and mineral salts. The viability of organisms is further protected through the use of stabilizers such as lactose or other saccharides, skim milk, and serum.
Formulations used for inactivated and subunit vaccines consist of antigens, adjuvants, stabilizers, and preservatives (in the case of multiple-dose products). Inactivating agents such as phenol, thiomersal, and formaldehyde are used to inactivate virus or kill bacteria without destroying the critical integrity of the antigens necessary to induce a protective immune response.
Adjuvants enhance the immunogenicity of antigens by stimulating the immune system and prolonging antigen release. In this respect, aluminum hydroxide, aluminum phosphate, and oil emulsions are generally preferred to confer antibody-mediated immunity, whereas saponin, quillaia A adjuvant, and immunity-stimulating complexes are preferred to confer cell-mediated immunity.
Plasmid DNA vectors have been used to express antigens in vivo to generate immune responses. Two delivery systems for DNA vaccines have been reported. In one system, the segment of DNA is coated with gold and administered to the patient via a gene gun. The other delivery system uses a viral vector or plasmid to carry the DNA segment into the patient.
Topical Route of Administration and Dosage Forms
The topical route of administration is used for local treatment of skin, control of external and internal parasites, and transdermal delivery of therapeutic agents.
Drugs applied to the skin for local effect include antiseptics, antifungals, anti-inflammatory agents, and skin emollients. The rate of drug release from ointments, creams, and pastes is determined principally by the semisolid base that is used.
In dogs and cats, an extensive range of topical formulations is used in the control of fleas, lice, mites, and ticks. These include insecticidal and acaracidal soaps, foams, shampoos, sprays, and rinses. Also available are topical delivery systems such as spot-on formulations, as well as flea and tick collars and medallions.
In food animals, a diverse range of topical dosage forms and delivery systems are used to control external parasites. For example, most pour-on formulations, plunge and shower dip concentrates, and jetting fluids are suspension concentrates or emulsifiable concentrates. In addition, many pour-on formulations display endectocidal activity in cattle. The efficacious systemic concentrations attained with these preparations result from the animal's licking behavior and, to a lesser extent, percutaneous absorption of the active ingredient.
A special consideration relating to the use of topical dosage forms is the potential for residues to exist in wool and mohair. The topical route of administration is also used to deliver therapeutic agents systemically. Transdermal patches, for instance, are used to deliver analgesics to the systemic circulation, and a pour-on preparation of flunixin meglumine is now available for treating pain and fever in cattle.
The topical dosage forms available to treat animals include solids (dusting powders), semisolids (creams, ointments, pastes, and gels), and liquids (solutions, suspension concentrates, suspoemulsions, emulsifiable concentrates, paints, and tinctures). These dosage forms, as well as the specialized topical dosage forms and delivery systems for transdermal drug delivery and parasite control, are discussed here.
A dusting powder is a finely divided insoluble powder containing ingredients such as talc, zinc oxide, or starch. Coarse powders often have a gritty feel; powders containing particles < 20 mcm in all dimensions have a smooth feel. Some dusting powders absorb moisture, thereby discouraging bacterial growth. Others are used for their lubricant properties. The use of dusting powders is indicated on skin folds and contraindicated on wet surfaces because caking is likely to result.
A cream is a semisolid emulsion formulated for application to the skin or mucous membranes. Droplet diameter in topical emulsions generally ranges from 0.1 to 100 mcm. Cream emulsions are usually oil in water, but they may be water in oil. Oil-in-water emulsions readily rub into the skin (hence the term “vanishing” cream), and they are removed by licking and washing. By comparison, water-in-oil emulsions are emollient and cleansing. Water-in-oil emulsions are also less greasy and spread more readily than ointments, and they soothe inflamed skin because the water in the formulation evaporates.
An ointment is a greasy, semisolid preparation that contains dissolved or dispersed drug. A range of ointment bases is used, including hydrocarbons, vegetable oils, silicones, absorption bases consisting of a mixture of hydrocarbons and lanolin, emulsifying bases consisting of a mixture of hydrocarbons and an emulsifying agent, and water-soluble bases. Ointment bases influence topical drug bioavailability via two mechanisms. First, their occlusive properties are responsible for hydrating the stratum corneum, which enhances the flux of drug across the skin. Second, they affect drug dissolution within the ointment and drug partitioning from the ointment into the skin. Ointments are effective emollients because of their occlusive nature. They are indicated for chronic, dry lesions and contraindicated in exudative lesions.
A paste for topical use is a stiff preparation containing a high proportion of finely powdered solids such as starch, zinc oxide, calcium carbonate, and talc. Pastes are less greasy than ointments because much of the fluid hydrocarbon fraction is absorbed onto the solid particles; they are also less occlusive than ointments. Pastes are indicated for ulcerated lesions.
A gel is a nongreasy, semisolid, aqueous solution. The semisolid properties are due to the continuous structure that a polymer imparts to the hydrophilic liquid. The polymers used include natural gums such as tragacanth, pectin, and agar; semisynthetic materials such as methylcellulose, hydroxymethylcellulose, and carboxymethylcellulose; and synthetic polymers. Medicaments are generally well released from gels, which are easily washed off because of their water miscibility.
A solution for topical use is a mixture of two or more components that form a single phase down to the molecular level. Topical solutions include eye drops, ear drops, and lotions.
Eye drops are sterile liquids that contain a range of drugs, including local anesthetics, antimicrobials, anti-inflammatory agents, and drugs acting on the autonomic nervous system of the eye. They are instilled onto the eyeball or within the conjunctival sac.
Ear drops are solutions of drugs such as antimicrobials, insecticides, or anti-inflammatory agents. The vehicle may be water, glycerol, propylene glycol, or alcohol-water mixtures. They are applied to the external auditory canal.
A lotion is usually an aqueous solution (or suspension) for application to inflamed, ulcerated skin. Lotions cool the skin by evaporation of solvents, leaving a film of dry powder. Lotions are suitable for use on hairy areas and for lesions with minor exudation and ulceration.
A suspension concentrate for topical use is a mixture of insoluble, solid active ingredients, which are typically at high concentrations, in water or oil. Suspension concentrate formulations are generally water based; the water-insoluble active ingredients and inert ingredients are of very small particle size (0.1–5 mcm).
Other formulation additives include suspending agents, surfactants, and other excipients to ensure the production of a shelf-stable, pourable product. Surfactants wet, disperse, and stabilize the solid particles in the continuous phase, prevent flocculation, and prevent changes in particle size. Thickening agents are included to increase the viscosity of the formulation, thereby overcoming sedimentation of the suspended particles and affording good longterm stability.
Suspension concentrates are used topically as pour-ons, plunge and shower dip concentrates, and jetting fluids.
A suspoemulsion combines the elements of an emulsion and a suspension, allowing active ingredients with widely varying physical properties to be formulated in a single product. Typically, a suspoemulsion contains one or more solvent-soluble active ingredients in an emulsion phase, combined with one or more low-solubility active ingredients in a continuous aqueous suspension phase.
After dilution, an emulsifiable concentrate for topical use produces a two-phase system involving two immiscible liquids: a dispersed phase, consisting of fine oil droplets ranging in size from 0.5 mcm to several hundred microns; and a continuous phase. Addition of an emulsifiable concentrate formulation to water results in the formation of an emulsion, which relies on surface-active agents concentrating at the oil-water interface. Active ingredients that are soluble in water-immiscible organic solvents are frequently formulated as emulsifiable concentrates. The flocculation of oil droplets in emulsifiable concentrate formulations leads to a layer of cream that can be readily dispersed by mild agitation, whereas the coalescence of droplets leads to the inversion, or “breaking,” of the emulsion. Water with a high content of calcium or magnesium ions reacts with anionic surfactants in the emulsifiable concentrate formulation; this reaction affects both spontaneity of emulsification and stability. Zinc sulfate, used as a dip additive to minimize the transmission of dermatophilosis in sheep, also adversely affects emulsions.
Flank paints comprise an antifoaming agent such as a detergent or mineral oil and are used to prevent pasture bloating in cattle. Flank paints are applied to the flanks of animals, from where they are licked off and ingested. Bloat, or ruminal tympany, is excessive accumulation of gas in the rumen. Frothy bloat commonly develops in cattle on pasture, particularly those grazing lush, leguminous pastures. Frothing of rumen ingesta occurs when the viscosity of the fluid is increased. Froth obstructs the cardia of the stomach, preventing the eructation of excessive gas produced in the rumen. Antifoaming agents decrease the stability of the froth by lowering the viscosity of the fluid ingesta.
Tinctures for topical application use a vehicle containing 15%–80% ethanol, requiring the preparation to be tightly stoppered and not exposed to high temperatures. In addition to ethanol, tinctures may contain cosolvents, stabilizers, and solubilizers. Iodine tincture is a topical anti-infective that contains 44%–50% ethanol. The reddish brown color of iodine tincture produces skin staining that delineates treated skin. Friar's balsam, a compound benzoin tincture, is used to protect and toughen ulcerated or fissured skin.
Specialized Topical Dosage Forms and Transdermal Delivery Systems of Drugs
A transdermal delivery gel consists of a vehicle, most commonly pluronic lecithin organogel (PLO gel), which delivers drugs via the transdermal route to the bloodstream. The micellar composition of PLO gel enhances skin penetration of the pharmaceutical agent present in the formulation. PLO gel is generally well tolerated and is nontoxic if ingested. However, not all drugs are suitable for transdermal application, and there are relatively few studies of the bioavailability of drugs from compounded transdermal gels.
Transdermal gels are used to deliver drugs (eg, methimazole) to treat several diseases in dogs and cats, including undesirable behavior, cardiac disease, and hyperthyroidism. The dose is applied to the inner surface of the pinnae, making it easy to administer, especially in cats.
A transdermal delivery patch typically consists of a drug incorporated into a reservoir, a protective backing layer, a rate-limiting release membrane, and an adhesive layer to secure the patch to the skin. The physicochemical properties of a drug suitable for transdermal delivery ideally include low molecular weight (< 500 daltons), high potency, water solubility (to facilitate movement of the drug out of the reservoir and to allow passage through the epidermal and dermal layers of the skin), and lipid solubility (to permit penetration of the stratum corneum of the skin). Fentanyl, a synthetic opioid agonist, is delivered by transdermal patch in dogs, cats, and horses.
Specialized Topical Dosage Forms, Delivery Systems, and Application Methods of Drugs for Parasite Control
The control of internal and external parasites of companion and food-producing animals has led to the development of specialized dosage forms, delivery systems, and application methods unique to veterinary medicine.
A spot-on formulation is a solution of active ingredients that typically contains a cosolvent and a spreading agent. The active ingredients in spot-on products for flea, GI parasite, or heartworm control in dogs and cats include fipronil, imidacloprid, selamectin, pyriproxyfen, ivermectin, and moxidectin. Spot-on formulations are also available to control lice in cattle.
The physicochemical properties of the active ingredients are important determinants of topical or transdermal behavior. For topical activity against ectoparasites to work, the active ingredient must spread, mix with the sebum coating the skin and hair, and form depots in the pilosebaceous units. The mechanism of percutaneous drug absorption varies between species and is not completely understood. However, low molecular weight and a high lipid-water partition coefficient tend to favor passage of the drug through the skin.
Backliner products for sheep consist of pour-on and spray-on formulations for the control of lice and sheep blowflies. Sheep lousicides include synthetic pyrethroids, organophosphates, and insect growth regulators. These products are formulated for pour-on application within 24 hours after shearing (ie, off-shears) or spray-on application (in short-wool sheep with wool growth < 6 weeks, and in long-wool sheep with wool growth > 6 weeks). The efficacy of backliner products against lice depends on topical activity and not on percutaneous absorption of the active ingredient into the bloodstream. Translocation of the pesticide from the application site to remote sites at concentrations lethal to lice is critical to the efficacy of these products and, in the case of pour-on applications, is facilitated by the increased secretion of wool grease at shearing.
The active ingredients in sheep blowfly products include insect growth regulators, synthetic pyrethroids, and organophosphates. After their topical application, sheep blowfly larvicides form follicular depots and subsequently translocate as a coating on new wool growing out of the follicles.
Hand jetting of long-wool sheep (wool growth > 6 weeks) is done to control lice, keds, mites, and sheep blowflies. The pesticides used include rotenone, synthetic pyrethroids, organophosphates, insect growth regulators, and macrocyclic lactones. A handpiece (or wand) is used to rake a pesticide solution into the wool along the dorsal midline and sometimes into the breech, crutch, and poll. The solution is applied under pressure and penetrates to the skin.
Some pour-on products on the market are formulated to deliver an active ingredient percutaneously. The macrocyclic lactones ivermectin, moxidectin, doramectin, and eprinomectin are formulated as pour-on preparations for application to cattle. These formulations are usually solutions or emulsifiable concentrates for dilution with water before use. The principal route of percutaneous absorption for most drugs in humans is the intercellular pathway, making the intercellular lipid matrix the primary barrier to absorption. However, this may not be the case in species in which the emulsifying properties of skin secretions and the large numbers of follicles and glands per unit surface area must be considered (eg, cattle and sheep). Ionized solutes, for example, are reported to cross the skin of animals via shunt pathways (sweat ducts, follicles).
Pour-on products are formulated to spread without runoff when applied to the skin, and to be resistant to rain. The formulation also facilitates the partitioning of the drug out of the vehicle and into the skin and transport of the drug across the skin. The control of these processes is critical because some drug is required to remain at the skin if the drug is to act against external parasites that are not bloodsucking. In addition, too-rapid passage of drug through the skin may result in unacceptable chemical residues in tissues or milk.
Plunge dipping of sheep and cattle for external parasites requires a dipping vat, which may be a portable unit or a permanent in-ground structure shielded from direct sunlight by roofing. A draining pen located at the exit of the vat allows dip wash that drains off treated animals to return to the vat.
Dip chemicals are usually formulated as aqueous solutions, emulsifiable concentrates, or suspension concentrates, all of which are diluted with water before use. The high costs associated with plunge dipping are due principally to the costs of chemicals for charging large vats, labor, and the disposal of the hazardous wastes. Plunge dips must be managed properly, and the pesticide maintained at the concentration recommended by the manufacturer.
Dipping of sheep and cattle is associated with stripping of the active ingredient from the dip wash (eg, pesticide being lost from the dip wash at a greater rate than water is lost) and is categorized as mechanical or chemical. In the case of sheep, mechanical stripping results from the fleece acting as a sieve toward the active ingredient, and the extent of filtration is determined primarily by particle size. Chemical stripping is due to the preferential absorption of pesticide by the fleece. To counteract stripping, a complex dip management regimen that involves reinforcement and replenishment (or “topping-up”) is used. "Reinforcement" refers to the addition of undiluted chemical product to the dip without the addition of water; "replenishment" refers to the addition of water and undiluted chemical product to the dip vat to return the volume to the starting level.
Proper dip management also minimizes contamination of the dip with organic matter. Minimizing contamination requires that the race leading to the vat be constructed of concrete or slats to remove dirt from the animals’ feet and that animals be held in a yard overnight before dipping, during which time they are offered water but no feed.
Hand spraying generally results in uneven coverage of animals and is considered an inefficient method of application. By comparison, recirculating and nonrecirculating spray races facilitate whole-body spraying and wet cattle to the skin. The situation with sheep is different: the very short contact time in a spray race limits the uptake of insecticide, so the fleece seldom becomes saturated. For this reason, spray races should be used as an adjunct to shower or plunge dipping of sheep.
Shower dipping is less labor intensive and less costly than plunge dipping. A typical shower dip consists of a sump containing the dip wash, a pump, and a showering pen constructed with a concrete floor and fitted with rotating and fixed nozzles.
There are two types of shower dips: conventional shower dips, in which the sump volume is periodically maintained by the addition of fresh dip wash, and constant-replenishment shower dips, in which a small-volume sump is continually filled from a large-volume supply tank to maintain dip levels.
Proper dip management requires attention to the factors described for plunge dipping. In addition, all equipment must be functioning properly for the fleece to become saturated. To avoid clostridial infections or caseous lymphadenitis due to Corynebacterium pseudotuberculosis, sheep should not be dipped (by either the plunge or the shower method) until shearing wounds have healed. Moreover, the correct use of bacteriostats is recommended to prevent postdipping lameness due to Erysipelothrix insidiosa.
Insecticidal collars are plasticized polymer resins impregnated with an active ingredient. Collars for the control of ticks and fleas on dogs and cats release the active ingredient as a vapor, a dust, or a liquid, depending on the physicochemical properties of the chemical. Volatile liquid insecticides such as dichlorvos or naled are used in vapor-release collars. The insecticide is distributed through the collar matrix as a vapor before being released. Powdered insecticides such as phosmet, stirofos, carbaryl, and propoxur are used in dust-release collars. Translocation of the active ingredient within the collar matrix leads to deposits forming at the surface; distribution of the insecticide to the animal depends on the animal's physical activity. Nonvolatile liquid insecticides such as chlorfenvinphos or diazinon are used in liquid-release collars. The active ingredient is distributed as a liquid in the collar matrix and to the surface, where it is released. The animal’s activity, along with the dissolution of lipophilic insecticides in skin secretions, is an important factor in translocation of the insecticide from the collar to the animal.
Two types of insecticide-releasing ear tags to control flies on cattle are available. One is constructed from a polymer that provides structural support and acts as a release rate–controlling matrix. The other is a membrane-based ear tag that consists of an insecticidal reservoir with a relatively impermeable backing on one side and a release rate–controlling membrane on the other. Both types rely on the animal’s ear and head movements and grooming to transfer insecticide from the surface of the ear tag to the animal’s skin or to other animals.
Back rubbers typically consist of burlap supported across lanes, gateways, or areas where cattle congregate. Back rubbers are charged by being soaked thoroughly in oil-containing pesticide, typically a synthetic pyrethroid, an organophosphate, or a combination of the two. The oil delays evaporation of the insecticide and enhances adherence to the animal’s coat.
Dust bags facilitate the self-treatment of cattle to control flies and lice. They are constructed of an inner porous bag containing the active ingredient, which is commonly a synthetic pyrethroid or an organophosphate, and an outer weatherproof skirt. Dust bags are hung in lanes or gateways so that passing cattle brush against them and receive a topical application of pesticide.
Inhaled Delivery Systems and Dosage Forms
Inhalation anesthetics are critical to the management of anesthesia. Halothane, isoflurane, desflurane, and sevoflurane are the most commonly used inhalation anesthetic agents. These agents are usually delivered to animals in a carrier gas that includes oxygen, by means of an anesthetic machine fitted with one or more vaporizers and a patient breathing circuit.
Inhalation treatment of airway disease is used to deliver high concentrations of drugs to the lungs while avoiding or minimizing systemic adverse effects.
To be delivered into the airways, a drug must be presented as an aerosol, as either solid particles or liquid droplets in air. Particle or droplet size largely determines the extent to which the drug penetrates the alveoli. Particles too small or too large for optimal delivery into alveolar sacs are either exhaled or deposited on larger bronchial airways.
Compared with delivery by the oral or parenteral routes, inhalation facilitates an earlier onset of pharmacological action of the inhaled agents, and the doses administered are smaller, thereby decreasing the potential incidence of adverse systemic effects.
The delivery systems used for the inhalation treatment of airway disease in animals are nebulizers and metered-dose inhalers.
The delivery of ciclesonide has been approved by the FDA for the treatment of asthma in horses. In the poultry industry, inhalation of aerosolized vaccines is a common way to immunize flocks of birds.
