MSD MANUAL

Veterinary Manual
The trusted provider of veterinary information since 1955

Routes of Administration and Dosage Forms

By Philip T. Reeves , BVSc (Hons), PhD, FANZCVS, Veterinary Medicines and Nanotechnology, Australian Pesticides and
Veterinary Medicines Authority;
Camille Roesch , PhD, Australian Pesticides and Veterinary Medicines Authority, Symonston, Australia;
Michelle Nic Raghnaill , PhD, National Academy of Science, Canberra, Australia
Last full review/revision Nov 2015 | Content last modified Nov 2015

A diverse range of dosage forms and delivery systems has been developed to provide 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 (pharmacokinetics, PK); concentration-effect relationships and drug-receptor interactions (pharmacodynamics,
PD); and treatment of the disease state (therapeutics). Formulation of a dosage form typically involves combining 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 PK/PD model that describes the drug response is the basis of dose optimization. The PK and PD phases are
linked by the premise that free drug in the systemic circulation is in equilibrium with the receptors. The PD phase generally
involves interaction of the drug with a receptor, which triggers post-receptor events and eventually leads 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 (see Chemical Residues in Food and Fiber), and the
level of 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 of administration is frequently used in both companion and food animals. In dogs and cats, tablets,
capsules, solutions, and suspensions are administered orally; 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 to the tongue, and granules are added to rations for ingestion. The oral route of administration is the most widely
used in cattle, pigs, and poultry. 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 possibilities 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 comprise 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 below.
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 susceptibility
to 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 is used in the formulation of oral solutions,
including buffers, flavors, antioxidants, and preservatives. Oral solutions provide a convenient means of drug
administration to neonates and young animals. Cookies
A suspension is a coarse dispersion of insoluble drug particles, generally with a diameter >1 μm, in a liquid (usually
aqueous) medium. Suspensions are useful to administer 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. The taste of
most drugs is less noticeable in suspension than in solution, because the drug is less soluble in suspension. Particle size is
an important determinant of the dissolution rate and bioavailability of drugs in suspension. In addition to the excipients
described above for solutions, suspensions include surfactants and thickening agents. Surfactants wet the solid particles,
thereby ensuring the particles disperse readily throughout the liquid. Thickening agents reduce the rate at which particles
settle to the bottom of the container. Some settling is acceptable, provided the sediment can be readily dispersed when
the container is shaken. Redispersion of the suspension may not be achievable 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 0.1–100 μm. The two phases of an emulsion are known as
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. Creaming, as occurs with milk, also occurs with
pharmaceutical emulsions. However, it is not a serious problem because a uniform dispersion returns upon shaking.
Creaming is, nonetheless, undesirable because it is associated with an increased likelihood of the droplets coalescing and
the emulsion “breaking.” Other additives include buffers, antioxidants, and preservatives. 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 allows, within limits, both water-soluble and alcohol-soluble medicinal substances to be
maintained in solution. The proportion of alcohol in elixirs varies widely, 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.
A paste is a two-component semisolid in which 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 μm. 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
xanthum gum or hydroxypropylmethyl cellulose. The degree 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 using a preservative. It is critical that pastes have a pleasant taste or are tasteless and are able to
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 and 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 of the need to pass into the intestine and then undergo disintegration and dissolution before absorption
across the gut wall, the low bioavailability of poorly water-soluble drugs or poorly absorbed drugs, and the local irritation
of the GI mucosa that some drugs may cause.
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
afford good drug release and absorption by the GI tract. Gelatin capsules are frequently more expensive than tablets but
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
Cookies
because disintegration is not an issue. This translates into faster absorption for those drugs characterized by dissolution
rate-limited absorption. 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/or 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. They are administered to poultry,
pigs, and ruminants. 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 to facilitate uniform mixing. 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, but unlike carriers, 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 caused by hygroscopic ingredients and is addressed by adding 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 reduced by including 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 a nutritional supplement, and is commonly packaged in a cardboard box to feed to
livestock. Ruminants typically have free access to the medicated block over several days, and variable consumption may be
problematic. This concern is addressed by ensuring the active ingredient is nontoxic, stable, palatable, and preferably of
low solubility. In addition, excipients in the formulation modulate consumption by altering the palatability and/or the
hardness of the medicated block. For example, molasses increases palatability, and sodium chloride decreases it.
Additionally, 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 impact the hardness of medicated blocks and is addressed by using appropriate packaging.

Oral Modified-release Delivery Systems for Ruminants

Several modified-release delivery systems have been developed that 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. They are
administered using a balling gun. Most of the commercially available intraruminal boluses are continuous-release devices
that rely on erosion, diffusion from a reservoir, dissolution of a dispersed matrix, or an osmotic “driver” to release the
active ingredient. The pay-out period for intraruminal boluses is commonly >100 days. Regurgitation during rumination is
prevented by the bolus having a density of ~3 g/cm3 or a variable geometry.
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 hr 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. The glass
boluses are retained in the rumen for up to 9 mo.
Intraruminal pellets containing selenium or cobalt are available for sheep. Selenium or cobalt is released throughout a
period of ~3 yr from the pellet matrix, which consists of compressed iron grit. When selenium or cobalt intraruminal
pellets are administered alone, a “grinder” 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
Cookies
particles progress to the abomasum, where some are trapped in the mucosal folds and release copper.
Parenteral Route of Administration and Dosage Forms
A drug given parenterally is one given by a route other than the mouth (topical dosage forms are considered separately).
The three main parenteral routes of drug administration are IV, IM, and SC, and in all cases administration is usually via a
hollow needle. Injectable preparations are usually sterile solutions or suspensions of 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, and for IM and SC injections is minutes. Depot injectable preparations achieve
prolonged release and maintain therapeutic concentrations of 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 drug. A number of recombinant proteins and peptides are orally inactive and
must be given by the parenteral route. 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 intra-articular injections, recombinant proteins and peptides, and
vaccines are discussed below. Also see the Drug Volume Calculator on this page to calculate the volume of a drug in ml 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, including
antioxidants, antimicrobial agents, buffers, chelating agents, inert gases, and substances to adjust tonicity. 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 oxidative degradation of drugs. Inert gases are used to displace the air in
solutions and enhance product integrity of oxygen-sensitive drugs. Isotonicity of the formulation is achieved by including 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 given IV in quantities >100 mL. Injectable
formulations must be sterile and free of pyrogens. Pyrogenic substances are primarily lipid polysaccharides derived from
microorganisms, with those produced by gram-negative bacilli generally being most potent. Injectable solutions are very
commonly used, and aqueous solutions given IM result in immediate drug absorption, provided 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 while
suspending agents modify the viscosity of the formulation. The ease of injection and the availability of the drug in depot
therapy 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 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 disintegration and dissolution of the suspended drug particles. 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. Parenteral emulsions are rare, because it is seldom necessary to achieve an emulsion for drug
administration. Untoward physiologic effects after IV administration may occur, including emboli in blood vessels if the
droplets are >1 μm in diameter. Formulation options for injectable emulsions are also severely restricted, because suitable
stabilizers and emulsifiers are very limited. Examples of parenteral emulsions include oil-in-water, sustained-release depot
preparations (given IM), and water-in-oil emulsions of allergenic extracts (given 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 driers. Rather, freeze-drying, or
lyophilization, is used to produce a porous powder that reconstitutes readily.
Intramammary infusion products to treat mastitis are available for lactating and nonlactating (dry) cows. Lactating cow
Cookies
intramammary infusions should demonstrate fast and even distribution of the drug and a low degree 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 degree 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, whereas 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 either the wings (CIDR device) or the entire device (sponges and
PRIDs) expanding. 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. Drug release from dispersed matrix systems involves dissolution of
the drug into the polymer, followed by diffusion of the drug through the polymer and partitioning 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 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 is available to enhance reproductive performance in breeding animals. These include ear implants containing
norgestomet dispersed in polyethylene methacrylate or silicone, a biocompatible tablet implant containing deslorelin (a
GnRH agonist) for use in mares that 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 are available to implant in the ears of
wethers at doses of 70–100 mg every 3 mo for the prevention of ulcerative posthitis.

Special Dosage Form Considerations with Intra-articular

Injections:
The dosage forms used in intra-articular administration are sterile aqueous solutions. In horses, the two most common
reasons for intra-articular 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, including glucocorticoids, pentosan
polysulfate sodium, and hyaluronic acid, are administered intra-articularly in inflammatory joint disease. The intra-articular
administration of glucocorticoids avoids the adverse effects associated with large systemic doses. In dogs, hyaluronate
sodium is administered by intra-articular injection for adjunctive treatment of synovitis.

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), increase feed conversion efficiency and produce leaner carcasses in pigs (porcine
growth hormone), for the chemical shearing of sheep (epidermal growth factor), to reduce 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. A range of strategies has 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: Cookies
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 additionally protected using stabilizers such as lactose
or other saccharides, skim milk, and serum.
Formulations used for inactivated and subunit vaccines consist of antigen(s), adjuvants, stabilizers, and preservatives (in
the case of multiple-dose products). Inactivating agents such as phenol, thiomersal, and formaldehyde are used to kill the
virus or 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, quil A, 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
using 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 principally
determined by the semisolid base 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 and 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. Numerous methods are used to apply parasiticides to farm animals (see
below). A special consideration relating to the use of topical dosage forms is the potential for residues in wool and mohair
to occur. 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.
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 below.
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, whereas powders containing particles that are <20 μm in all dimensions have a smooth
feel. Some dusting powders absorb moisture, which discourages 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 0.1–100 μm. Cream emulsions are most commonly oil-in-water but may be water-in-oil.
The former readily rub into the skin (hence the term “vanishing” cream) and 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 as a consequence of the water in the formulation evaporating.
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 a polymer imparting a continuous
structure 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 such as carbopol. Medicaments are generally well released from gels, which are easily washed off on account Cookies 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, antibiotics, 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 antibiotics,
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 μm). 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 μm 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 Ca2+ and/or
Mg2+ reacts with anionic surfactants in the emulsifiable concentrate formulation; this affects both spontaneity of
emulsification and stability. Zinc sulfate, used as a dip additive to minimize the spread of dermatophilosis in sheep, also
adversely affects emulsions.
A flank paint comprises an antifoaming agent such as a detergent or mineral oil and is used to prevent pasture bloating in
cattle. A flank paint is applied to the flanks of animals, from where it is licked off and ingested. Bloat, or ruminal tympany,
refers to 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 reduce the stability of the froth by lowering the viscosity of the fluid ingesta.
A tincture for topical application uses a vehicle containing 15%–80% alcohol, requiring the preparation to be tightly
stoppered and not exposed to high temperatures. In addition to alcohol, tinctures may contain cosolvents, stabilizers, and
solubilizers. Iodine tincture is a topical anti-infective that contains 44%–50% alcohol. The reddish brown color of iodine
tincture produces skin staining that delineates treated skin. Friar's balsam is compound benzoin tincture and is used to
protect and toughen ulcerated or fissured skin.

Specialized Topical Dosage Forms and Delivery Systems for

Transdermal Drug Delivery:
A transdermal delivery gel consists of a vehicle, most commonly pluronic lecithin organogel (PLO gel), which delivers
drug 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 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, thereby offering ease of administration, 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
Cookies
agonist, is delivered by transdermal patch in dogs, cats, and horses.
Specialized Topical Dosage Forms, Delivery Systems, and
Application Methods for Parasite Control:
The control of internal and external parasites of companion and food-producing animals has led to development of
specialized dosage forms, delivery systems, and application methods unique to veterinary medicine.
A spot-on formulation is a solution of active ingredient(s) 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 ingredient(s) are important determinants of topical or transdermal
behavior. Topical activity against ectoparasites depends to some extent on the active ingredient spreading, mixing with the
sebum coating the skin and hair, and forming 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 hr after shearing (ie, off-shears) or spray-on application (in short-wool sheep
with wool growth <6 wk, and in long-wool sheep with wool growth >6 wk). Their efficacy 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 that occurs 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 wk) is done to control lice, keds, mites, and sheep blowflies. The
pesticides used include rotenone, synthetic pyrethroids, organophosphates, insect growth regulators, and macrocyclic
lactones. Hand-jetting involves the use of a handpiece (or wand) 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 people 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 run-off 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 be active against external parasites that are not blood sucking. In addition, too rapid passage of drug through the skin
may result in unacceptable chemical residues in tissues or milk.
The 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 relate 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 loss from the dip wash occurring at a greater rate than water loss) 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, with the degree of filtration being primarily determined 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 ‘‘topping-up” is used. Reinforcement refers to the addition of undiluted chemical product to the
dip without the addition of water, whereas topping-up 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. This requires that the race leading to the vat is 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. Cookies
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, which means
the fleece seldom becomes saturated. Because of this, spray races should be used as an adjunct to shower or plunge
dipping of sheep.
Shower dips are less labor intensive than plunge dips and are cheaper to operate. 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: a conventional shower dip in which the sump volume is periodically
maintained by adding fresh dip wash, and a constant replenishment shower dip 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 above for plunge dipping. In addition, all equipment must be functioning properly for the fleece to
become saturated. Sheep should not be dipped (by either the plunge or shower method) until shearing wounds have
healed to avoid clostridial infections or caseous lymphadenitis caused by Corynebacterium pseudotuberculosis. Moreover,
the correct use of bacteriostats is recommended to prevent post-dipping lameness caused by 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 distributes 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 distributes as a liquid in the collar matrix and to the surface, where it is released. The animal’s activity
plus the dissolution of lipophilic insecticides in skin secretions are important factors 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 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 soaking thoroughly in oil-containing pesticide, typically a synthetic pyrethroid, an organophosphate, or a
combination of the two. The oil retards 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 Dosage Forms and Delivery Systems

Inhalational anesthetics are critical in management of anesthesia. Currently, enflurane, halothane, isoflurane,
methoxyflurane, and nitrous oxide are the most commonly used inhaled anesthetic agents. These agents are usually
delivered to animals in a carrier gas that includes oxygen, using an anesthetic machine fitted with one or more vaporizers
and a patient breathing circuit.
Inhalational therapy 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, either as
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, the onset of pharmacologic action of inhaled
agents is faster and the doses administered smaller, thereby reducing the potential incidence of adverse systemic effects.
The delivery systems used for inhalational therapy of airway disease in animals are nebulizers and metered-dose inhalers.
In the poultry industry, inhalation of aerosolized vaccines is a common way to immunize flocks of birds.

© 2020 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA)

Cookies