Veterinary

• Many changes and challenges are occurring in the veterinary market
• Some of these issues include

  • A curtailing of R&D on antibiotics because of antibiotic resistance that some attribute to the overuse in veterinary medicine
  • The appearance of less product line extensions via drug delivery as a consequence of less overall R&D dollars
  • A higher risk in developing certain new medicines because of a consolidation of farms resulting for certain species (e.g., Swine, chickens) in the profitable U.S. Market being controlled by only a few companies
• Chemical stability


  • Neither farm sheds nor farm vehicles (typical storage places for purchased veterinary pharmaceuticals) have cold storage facilities or even air conditioning, therefore assuming that a product can be stored below 20°C or in the fridge for the duration of its lifetime prior to administration is an unreasonable assumption
  • Dosage forms must therefore be stable to elevated heat conditions and hot/cold heat fluctuations
• Moisture protection


  • Formulation scientist's responsibility to determine and demonstrate if moisture protection needs to be addressed through relevant packaging, but this can add cost to the final product
• Physical stability


  • Farmers do not have the time to premix individual doses of suspensions, nor constantly "shake the bottle" between administrations to some several hundred individual cows of their herd
  • For suspensions, the final product physical characteristics are often a balance between retardation of sedimentation and ease of flow to draw up into the syringe
• Farmer priorities


  • Farmers are less interested in what the product looks like compared with its efficacy profile, ease of use, ease of administration, ease of removal, tissue residue profile, and time it takes to herd, administer, and release his animals back into the paddock
• Veterinary formulation scientists may therefore trade off pharmaceutical elegance to improve other features, provided the efficacy and safety profile is acceptable and not altered during storage
• The challenge is that these products must also be inherently safe for children when they pet their dog, or, for example, to the other cattle that may lick the hides of their field mates
• Tablets for companion animals

  • The relative size of the tablets for companion animals are somewhat similar to those used for humans
  • Tablets are manufactured large enough for pet owners to handle but small enough to "push" down the throat or hide in foods
  • Sizes from 80-mg weight up to 1- to 2-g weight are appropriate for use in animals
• Tablets for cattle, sheep, and horses

  • The tablet sizes for cattle, sheep, and horses are larger to incorporate the larger amount of active and facilitate administration
  • These tablets are typically called boluses and are often oblong for easier administration
  • Approximate weights are several grams to 8 g
• Tablet presentations


  • To minimize the number of product presentations (i.e., tablet strengths), scoring of tablets can be used
  • Product presentations also include the bottle counts or blister cards and both can be used for animal health products
• Child-resistant packaging


  • Child-resistant packaging is frequently considered for products used for cats and dogs
• Capsules for veterinary use

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


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


  • Capsuline manufactures DOGCapsTM and CATCaps TM, which are capsules containing beef, chicken, or bacon flavoring in the shells to entice dogs and cats to consume the products
• Eating action of cats and dogs would result in capsules being split and spill their contents
• If the drug contained in the capsule is associated with a bad taste, then the cat or dog will be more careful to accept that product on a subsequent occasion
• Challenges with developing feed additives

  • Blend homogeneity and stability
  • Medicated feeds may contain concentrations of 1% or less (sometimes down to 0.05%)
  • Medicated feeds may be stored for several months while they are being used on a daily basis to mix the final feeds
  • Storage can be in hot, moist grain bins or sometimes in the open where the sun and rain can further cause problems
• Minimizing dust in feed additives

  • Most often mineral oil is added to feed additives to prevent the feed from being lost in to the air, which cannot only reduce potency but also potentially be a safety issue for the feed operators
• Soluble powder feed additives


  • The key challenge is designing a powder that will readily go into solution and be stable when blended with the feed
  • Obtaining a homogenous blend is again important
• Reasons to develop long-acting veterinary preparations

  • Reduction of stress to the animal, reduced herding, and reduced labour costs
• Differences between human and veterinary long-acting preparations

  • Human long-acting preparations are designed for 12 to 24 hours, perhaps days, whereas veterinary preparations are designed to last for weeks or months
• Mechanism of long-acting veterinary preparations

  • The half-life of the drug combined with its formulation into a nonaqueous vehicle (which allows for the creation of a depot at the site of injection) prolongs the action of the drug for over a month
• Challenges with tetracycline suspensions

  • Tetracyclines were well known to also be insoluble, as well as irritating, upon injection
  • To alleviate this problem, formulators identified 2-pyrrolidone as a solubilizer and developed methods of chelating the oxytetracycline with magnesium ion to reduce the irritation upon injection
  • The theory was to prepare a solution of drug that was close to saturation so that upon injection the drug would slowly deposit a fine precipitate creating, in effect, a drug suspension depot at the injection site
  • This depot formulation would reduce the irritation and provided release of drug over two to three days
• Approach to minimising tissue residues with Pfizer's ceftiofur product


  • This one-time administered oil-based suspension is injected into the middle section of the ear
  • During slaughter the ears of cattle are not put into the food chain
• Implants


  • Implants are cylindrical rod-shaped delivery systems that contain drugs incorporated into lactose, cholesterol, polyethylene, or silicone rubber delivery matrices
  • Lactose-based implants are shorter acting (~40 days) compared with cholesterol-based implants (~80 days)
  • Silicone rubber matrices provide the longest duration of release for estrogen (~200-400 days)
  • The actual duration is very dependent on the physicochemical drug characteristics, especially solubility
  • The amount of drug released from these delivery systems is greatest initially and slowly decreases with time, and release kinetics are typically described by first-order kinetics
• Microspheres


  • The production of the microspheres is affected by multiple factors such as the type of polymer and solvent being used, and the drug being encapsulated
  • High yields, lower residual solvent content, and better control of microsphere size distributions are all extremely important in large-scale commercial production
  • Sterility and pyrogenicity and the need to use sterile water for injection in the manufacturing process are extremely important
  • Any products using steroids, especially estrogen, also add significant regulatory and environmental concerns as does the large amount of nearly pure wastewater generated, which can disrupts ecosystem
• Intravaginal delivery systems


  • Applicator design
  • Retention rate
  • Retention mechanism
  • Dimensions
  • Removal
  • Damage to vaginal mucosa and cervix
  • Environmental considerations
  • Release characteristics
  • Geometry
• An intravaginal delivery system is usually designed and optimized for a given species; therefore its design features that provide retention, safety, etc. may not be as effective in a second species
• Normally animals cannot self-medicate (exceptions are feed additives, insect dusters) and innovative solutions must be devised by the veterinary formulation scientists to assure that their final products can be administered safely, quickly, and easily by the end user
• Applicators


  • The means of administration must be carefully considered and be part of the product development process
  • Applicators vary considerably between route of administration and volume/capacity for delivery and are available for intravaginal, intraruminal and for subcutaneous implants
• Crossover from human to animal health


  • Injectable products are generally good dosage forms for (almost) direct transition to use in animals
  • Immediate-release tablets appear attractive candidates, but might prove difficult, particularly if there are palatability issues with the product
  • The shorter gastrointestinal tract transit time for dogs and cats could result in inadequate absorption
  • There may be different extents of drug metabolism or different drug absorption mechanisms in animals compared with that in humans
  • Other dosage forms like topical delivery systems, ocular formulations, oral films, and oral controlled-release tablets need to be studied carefully if a switch from use in humans to animals is desired