Liquids

The previously discussed dosage forms had a solid physical appearance. This section will explore those that are classified as liquids. The three main liquid dosage forms are those administered via the mouth, injected, or placed on the skin.

Oral Liquids

Oral liquids would typically be aqueous, nonaqueous, or blends to create a solution. In some cases they may be a suspension if it is difficult to find a vehicle that completely solubilizes the active or yields chemical stability. The liquid may be used directly "as is" from the container or, if sold in a concentrated form, is diluted before administration. Oral liquids may be given directly to the animal or, if administering to many animals, placed in drinking water or even dispersed among feed.

Oral liquids are probably one of the easier dosage forms to develop. The main challenges are finding a vehicle that results in adequate chemical stability while achieving a solution. Many prefer to develop a solution instead of a suspension because of the added requirement with the latter of insuring physical stability, namely the ease of resuspendability. The first vehicle choice will be water. A good understanding of the pH and temperature effects on solubility are needed to ensure no precipitation of the marketed product when exposed to abrupt changes in temperature or pH. Having a twofold or above cushion with solubility will help avoid crystallization during product storage. Use of a buffering agent may be appropriate for an oral liquid if the solubility-pH curve is very sharp and slight changes in pH have a dramatic effect on solubility.

If water does not solubilize the drug, a cosolvent system is next explored. Vehicles to consider include ethanol, propylene glycol, polyethylene glycol (low molecular weight), glycerin, and triacetin as examples. These can be used alone or in combination to give a truly nonaqueous system. In some cases cosolvents with oleaginous vehicles may be utilized to solubilize the drug.

If a solution is not achieved, a suspension may be developed. The main challenge is to achieve a product that uniformly and easily resuspends. This needs to happen at room temperature and for livestock products even at very low temperatures. Whether developing a suspension for oral or parenteral use, the issue of resupendability is equally important. The key is achieving appropriate particle-to-particle interaction to yield a flocculated system. With the appropriate surface charges of the particles, interaction will occur resulting in floes that settle in the vehicle but do not compact in the bottom of the bottle. This might result in sedimentation volumes of 30% to 70%, which then, with little energy (e.g., shaking), will resuspend. Besides achieving floe formation, using a vehicle of appropriate viscosity to allow uniform dosing is also important. For aqueous systems, this could mean using a cellulose (such as carboxymethylcellulose) to enhance viscosity so that after shaking the product stays uniform for sufficient time to allow dosing.

An oral liquid product for animals is quite often a multiple-use product. If the container is going to be opened and closed several times with storage time between uses, then a preservative should be used. These should be soluble in the vehicle and result in the formulation meeting the Preservative Efficacy Test as outlined in the pharmacopoeias (USP, EP, BP, JP). Examples of preservatives for oral liquids include benzoic acid, sodium or potassium benzoate, and sorbic acid. The vehicles ethanol, glycerin, and propylene glycol can also be good preservatives themselves. If treating companion animals, a flavoring agent may also be required.

As mentioned above, liquid dosage forms are one of the easier products to develop especially solutions. It is also fairly easy to manufacture requiring a tank, mixer, and bottle-filling line. The main challenge with a suspension is ensuring homogeneity throughout the filling process. This can be done by mixing the product throughout filling; however, careful study of suspension uniformity when product levels drop below the mixing blades is required.

The uses of oral liquids is quite varied and in some cases rather unique in veterinary medicine. For example, propylene glycol is marketed to treat ketosis in dairy cows where it is mixed with the solid feeds or given as a drench. A formulation consisting of vegetable oil, polyethylene glycol, and other ingredients is sold as Bloat Drench™ to be given as a drench (a large oral dose of liquid medicine) in cattle to treat bloating. Oral liquid products are available as antacids, anticoccidials, anti-inflammatories, antimicrobials, and antitussives. They are used in dental care, as diuretics, for electrolyte replacement, growth promotants in cattle, as laxatives, and as vitamin/mineral supplements. All species are treated with oral liquid products.

Parenteral Liquids

The uses of parenteral products for animals and the development process of these are nearly identical to those products used for humans. The sterile dosage form types include solutions, suspensions, emulsions, and lyophilized powders. Any dosage form must be chemically, physically, and microbiologically stable, sterile, easy to inject, cause minimal pain and irritation upon injection, and packaged in appropriate vial sizes. Multiple-use vials are more common in animal health to treat herds/flocks).

One somewhat different, but critical, parameter in animal health sterile products compared with human health care products is the irritation and residue at the injection site. For companion animals, the pain upon injection should be minimal, and any lasting reactions that cause either pain or visual lumps to a pet will not be tolerated by many owners. For food-producing animals such as cattle, pigs, and poultry, the added challenge is that of ensuring the residue levels at the injection site have been depleted adequately by the time the animal is harvested. The formulation scientist thus may need to carefully observe the viscosity and polarity of the vehicle as they can affect residue times. Volumes injected and the route can also have an impact. Oftentimes subcutaneous administration is used instead of intramuscular administration to minimize residues in the tissue and potential damage to meat (i.e., muscle).

Parenteral liquids are used as analgesics, general and local anesthetics, antihistamines, anti-inflammatories (steroidal and nonsteriodal), antimicrobial agents, antiprotozoal, antitussives, andrenergics, anticholinergics, antiparasiticides, blood substitutes, diuretics, euthanasia agents, electrolyte replacements, hematinics, hormone replacements (e.g., insulin, gonadotropins), milk production enhancer, immunostimulants, muscle relaxants, respiratory stimulants, sedatives, and vitamins/mineral supplements. All species are treated with injectable liquids, including off-label exotic animal uses.

Representative dosage forms that are sterile solutions include the many vitamin/ mineral supplements such as multiple vitamins (Vta-15™ injection for horses, Mineral

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Max for cattle), antibiotics like oxytetratcyclines (Oxybiotic -200) or florfenicol (Nuflor® Injectable Solution), anti-inflammatories (Ketoprofen Sterile Solution), and unique products like an artificial blood substitute for dogs, called Oxyglobin® Solution. Sterile suspensions include antibiotics like Excenel® RTU or Sterile Suspension (ceftiofur hydrochloride). Freeze-dried products for reconstitution prior to administration include Solu-Delta-Cortef® (prednisolone sodium succinate) in a unique Act-O-Vial system (Fig. 2), where the sterile water is pushed through an orifice into the sterile powder chamber. Other freeze-dried products are Naxcel® (ceftiofur sodium) and many of the vaccines (which are not discussed in this chapter). Some powders may be dry filled and then reconstituted to form a sterile liquid for injection [Polyflex® (ampicillin)]. There are even available a few sterile emulsions like BO-SE® containing selenium and vitamin E as the oleaginous component with water and vitamin E plus vitamin AD that has vitamins E, A, and D3 in an aqueous emulsion.

DermaUTransdermal Liquids

Probably the first thought for liquids for dermal and transdermal application is in animals used to treat ticks, fleas, and mites in dogs, cats, and cattle. But, there are other

Figure 2 Act-O-Vial system that allows sterile water to be pushed through an orifice into a chamber containing sterile powder.

applications such as antifungals, anti-inflammatories, antimicrobials, antiseptics, antipruritics, teat dips/udder washes, otic/ocular preparations, and miscellaneous items like egg dips and wart removers. The last two refer to Gentadip, a gentamicin sulfate solution for dipping turkey eggs before hatching to reduce or eliminate organisms such as salmonella or mycoplasma, and Wartsoff® to remove warts from cow teats.

Dermal/transdermal liquids are normally solution dosage forms. The viscosities can vary and may often increase to the point of being called gels, ointments, or creams. With the less viscous liquids for dermal/transdermal use, designing the delivery device may be one of the greater challenges during development. The spot-ons (e.g., tubes), sprays (e.g., pump/pressurized containers), or even impregnated collars to deliver antiparasiticides to cats and dogs would be good examples of challenging-to-develop dosage forms. Designing the delivery system to provide adequate coverage of the fur/skin, for example, with a spray can be difficult. Then, obtaining long enough activity can be critical because frequent administration is not wanted. The fipronil active in Frontline® is a good example. It is thought that the ability of fipronil to diffuse slowly out of the hair follicles and sebaceous oils gives flea and tick prevention for at least one month. A good understanding of how the active and formulation contributes to the duration of efficacy is important for topical products. Other issues to consider with these special packaged products include egress/ingress of solvents (including water) from plastic tubes and diffusion of active from collars during storage.

The liquid products used to treat parasites topically are typically called pour-ons. Example products include ivermectin (Ivomec® Pour-on for Cattle; Top Line™) that can treat gastrointestinal roundworms, lungworms, cattle grubs, mites, lice, and horn flies. These are administered with special squeeze bottles that have dose-metering cups or application guns and are applied in a narrow line from the withers to the tail head in cattle.

Antifungal liquid dermal products include Clotrimazole Solution USP and Micazole Lotion or Spray 1%, which are used in cats and dogs. Topical antibiotics include Gentamicin Spray. The antiseptics are isopropyl alcohol based and contain hydrogen peroxide, chlorhexidine, iodine, or benzalkonium chloride. Teat dips and udder washes to prevent bacterial contamination during milking generally contain iodine or chlorhexidine.

Intramammary Drug Delivery

The intramammary route for drug delivery is primarily used for the treatment of mastitis in cows and can be classified according to two main areas: for the treatment of animals lactating and dry (nonlactating). A once-only administration is beneficial to both these areas since it reduces handling of the animal. Each approach offers specific challenges to the delivery of an active agent. For example, the requirements for drug delivery to lactating cattle requires that the active ingredient be removed from the mammary gland or milk as soon as possible after the treatment period has elapsed so that there is no issue with regard to the presence of drug in the milk. In contrast, intramammary delivery in dry cows would allow for the formulation to be developed so that the drug persists for a longer period after the treatment period has elapsed. Dry cow applications, therefore, lend themselves more readily to controlled drug delivery applications since the prolonged exposure of the infected site to drug improves the efficacy of treatment, and the concerns for drug residues in milk are not an issue.

Various formulation types have been explored for the intramammary route and include water- and ointment-based systems, oil-based systems, encapsulated systems, polymeric aqueous systems, and vaccines and recombinant therapies.

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