Topical Dosage Forms and Delivery Systems - The Merck Veterinary Manual

Topical Dosage Forms and Delivery Systems

Specialized Topical Dosage Forms, Delivery Systems, and Application Methods for Parasite Control

The topical dosage forms available for treating animals include solids (dusting powders), semisolids (creams, ointments, and pastes), and liquids (solutions, suspension concentrates, suspoemulsions, and emulsifiable concentrates). Of special interest are transdermal delivery systems that elicit clinical responses by carrying medications across the skin barrier to the bloodstream. Examples of these are transdermal gels and patches that are used in companion animals. Also of interest are dosage forms that are unique to veterinary medicine, such as spot-on, pour-on, and backliner formulations developed for the control of parasites.

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, as 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 readily 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 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 2 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 due to their occlusive nature. Ointments 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. Pastes are also less occlusive than ointments. Pastes are indicated for ulcerated lesions.

A solution for topical use is a mixture of 2 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 normally 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 serve to 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.

Following dilution, an emulsifiable concentrate for topical use produces a 2-phase system involving 2 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, which is used as a dip additive to minimize the spread of dermatophilosis in sheep, also adversely affects emulsions.

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 for securing 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 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 that are unique to veterinary medicine.

A spot-on formulation is a solution of active ingredient(s), which typically contains a cosolvent and a spreading agent. The active ingredients in spot-on products for flea, GI parasite, and 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 or spray-on application (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 is facilitated by the increased secretion of wool grease that occurs after shearing.

The active ingredients in sheep blowfly products include insect growth regulators, synthetic pyrethroids, and organophosphates. Following their topical application, sheep blowfly larvicides form follicular depots at the time of application 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 or crutch, as well as the poll. The solution penetrates to the skin.

Some of the 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 prior to 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 (eg, cattle and sheep) in which the emulsifying properties of skin secretions and the large numbers of follicles and glands per unit surface area must be taken into account. 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. 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 draining 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 prior to 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 the 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 for animals to be held in a yard overnight prior to dipping, during which time they are offered water but no food.

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 that 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 an overhead rotating boom with nozzles and fixed nozzles near ground level. There are 2 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 continuously 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 physical activity of the animal. 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 the translocation of the insecticide from the collar to the animal.

Two types of insecticide-releasing ear tags for controlling 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 in the control of 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.