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Figure 4 Ovuplant, a small white implant (2x3 mm ) packaged in its applicator.

Compudose is a silicone implant composed of a drug-free silicone cylinder coated with a layer of silicone containing 20% dispersion estradiol (Fig. 3). It has a surface area of 4.84 cm2 and has been shown to release drug by a square-root-of-time mechanism. Different release durations are achieved by manufacturing the product with coatings of different thickness. It has been coated with oxytetracycle to minimize reactions at the injection site and enhance implant retention. The Crestar implant (Fig. 3) is an ear implant that also uses silicone as the polymeric matrix, but in this case it contains 3 mg norgestomet homogeneously distributed throughout the entire cylinder.

Ovuplant (Fig. 4) is a cylindrical subcutaneous implant containing the synthetic GnRH analog Deslorelin [6-D-tryptophan-9-(Af-ethyl-L-prolinamide)-10-desglycinamide]. The implant is 2.3 mm in diameter and 3.6 mm in length and contains 2.1 mg of Deslorelin acetate in an inert matrix. The implant is biocompatible and becomes absorbed overtime and therefore does not need removal after administration.

Syncro-Mate-B comprises a norgestomet/Hydron implant (Fig. 3). It measures 3 x 18 mm2, contains 6-mg norgestomet, and weighs approximately 0.125 g. During manufacture the implants are encased within a protective plastic sheath and packaged in individually sealed foil packaging. A specially designed applicator is then used to administer them under the skin of the outer surface of the ear of cattle.

Although implants are a useful dosage form for administering drugs to farmed animals, they are not so well accepted in the small animal field as they can be felt through the skin, a feature that pet owners do not like.

In situ forming gels An in situ forming gel system based on sucrose acetate isobutyrate (SAIB) has been investigated for veterinary applications. SAIB is a fully esterified sucrose molecule. It is a low molecular weight material that has many properties associated with polymeric materials; however, it is a nonpolymer, and dilution with only small amounts of solvents such as alcohol results in an easily injectable solution. Formulations are manufactured by a simple process of weighing and mixing SAIB, diluting solvent, and adding drug and mixing. The resultant formulation is a hydrophobic, low-viscosity liquid that rapidly increases in viscosity after intramuscular injection as the solvent diffuses away leaving behind a SAIB-drug matrix, which releases drug by diffusion through the highly viscous SAIB, accompanied by degradation of SAIB to sucrose and the aliphatic acids from which the sucrose ester was prepared.

Microspheres Intramuscular injections comprising a microsphere formulation manufactured from poly(DL-lactide) have been described for veterinary applications. Microspheres have been formulated to deliver progesterone (1.25 g) and estradiol (100 mg) continuously for a duration of 12 to 14 days. Other microsphere products have been developed, which contain various active ingredients including ivermectin, estradiol, moxidectin, and vitamin Bi2.

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 of such. Also, extremely important in the production of microspheres is sterility and pyrogenicity and the need to use sterile water for injection in the manufacturing process. Lastly, any products using steroids, especially estrogens, also add significant regulatory and environmental concerns as does the large amount of nearly pure wastewater generated. Several microsphere products have been commercialized for use in animal health (Fig. 5). These include Proheart®6, a 180-day moxidectin in microspheres for heartworm in dogs (Fort Dodge Animal Health, Wyeth, Madison, New Jersey, U.S.); SMART Shot®, a 150-day vitamin B12 PLGA microsphere product for cattle (Stockguard, New Zealand); and Celerin®, a 150 day EB PLGA microsphere product for cattle (PR Pharmaceuticals, Colorado, U.S.).

Intraruminal Bolus Formulations

Intraluminal drug delivery systems are products administered to, and retained in, the rumen of ruminant animals (e.g., cattle, sheep) and formulated to deliver drugs over extended periods (months). Many controlled-release intraruminal drug delivery systems have been developed over the last few decades, and for extensive reviews on intraruminal drug delivery the reader is referred to Refs. 11, 13, and 14.

Microspheres Product Drugs

Figure 5 Proheart®6, SMART Shot®, and Celerin® microsphere products used in veterinary animal health.

Cardinal has outlined several key design features that are required of a controlled-release intraruminal drug delivery system (13). These include the inherent need to (i) design the delivery system around a balling gun (an administration device for discharging a rumen bolus down the throat of an animal) to allow for oral administration, (»') design the delivery system with a shape compatible with passage down the esophagus, (iii) design the device with some mechanism that allows for long-term retention in the rumen of the animal (i.e., prevents regurgitation), and (iv) incorporate some form of controlled-release technology that allows for the long-term delivery of the drug (up to 180 days).

Intraruminal boluses are cylindrical or elongated capsule-shaped devices that are typically 7- to 16-cm long and 1 to 3 cm in diameter, dependant on the species for which they are intended. They must be designed to provide some mechanism for long-term

Figure 6 Rumbul Bullet (left) and Rumetrace Magnesium Capsule (right) heavy density products.

retention in the rumen of the animal. Two methods are commonly employed to retain devices in the rumen. The first involves the incorporation of components that provide an overall device density of greater than 2 g/cm3. This condition ensures that the device will remain at the bottom of the reticulo-rumen cavity and will not be regurgitated. The TimeCapsule bolus (Fig. 1), which contains high amounts of the active ingredient zinc oxide, is an example of this approach. Zinc oxide is a dense powder, and this property affords sufficient density to the product to retain in it the rumen. Other examples of heavy density products include the Rumbul Bullet and Rumetrace Magnesium Capsule (Fig. 6), which erode to completion following administration. In the case where the product does not erode, incorporation of a density element such as iron or sintered iron block in the product allows for prolonged retention in the rumen. The Ivomec SR bolus is an example of this approach (Fig. 7).

Alternatively, device retention can be achieved by using a design that leads to a significant expansion of the device in at least one dimension following its introduction into the reticulo-rumen cavity. The Captec device (Auckland, New Zealand) is an example of a technology that uses this method for retention (Fig. 8). The Captec device incorporates polymeric "wings" that are constrained by a water-soluble tape during administration. Upon passage into the rumen, the tape dissolves allowing the wings to expand, thereby preventing regurgitation. This "winged-cylinder" design has also been utilized for the Rumensin ABC and the Monensin RDD (Fig. 8) devices. As an alternate to the opening wings, a device in the form of a large trilaminate sheet, approximately 21 x 10 cm2 (Paratect Flex), serves as another example of the change in shape approach. The sheet is rolled into a cylinder and constrained with a water-soluble adhesive tape, which following administration dissolves to allow the device to unroll. The unrolled device has dimensions that are greater than those of the esophageal channel, thereby preventing device regurgitation. Interestingly the tape was composed of multiple layers, special water-soluble adhesives, and was also perforated to enhance the rate of water penetration once the device reaches the rumen. It was found that it was critical that the tape released

Figure 7 Ivomec SR bolus.
Rumensin Bolus
Figure 8 Captec device (left) and Monensin RDD (right) products that utilize a change in geometry (plastic wings) to impel retention to the rumen delivery system.

and permitted the device to unroll within the first hour or two following administration to ensure that the device was not regurgitated. For these reasons, the design of the tape was as difficult as the design of the controlled-release matrix. This serves as an example of the range of issues, sometimes unusual, the veterinary formulation scientist will encounter, and must solve, when developing a product for animal health.

Intravaginal

The processes of designing, developing, optimizing, and assessing a long-acting intravaginal veterinary drug delivery system has been discussed by Rathbone et al.

Table 2 Factors Affecting Design of an Intravaginal Veterinary Drug Delivery System

Factor affecting design

Factor influences

Factor influenced by

Applicator design

Retention rate

Retention mechanism Dimensions

Geometry

Irritation (mucopurulent discharge production)

Dimensions and geometry of delivery system Ease of use Animal comfort End-user acceptance Overall efficacy of delivery system

Ease of use Retention rate Release rate Ease of use Animal comfort End-user acceptance Release rate Ease of use Animal comfort End-user acceptance End-user acceptance Release rate

Removal

Damage to vaginal mucosa and cervix

Environmental considerations

Release characteristics

Ease of use End-user acceptance Animal comfort Applicator design Removal mechanism Retention mechanism End-user acceptance Environment Regulatory acceptance Optimal drug load Efficacy of delivery system

Size and shape of vaginal cavity Dimensions and geometry of delivery system

Retention mechanism Dimensions and geometry of delivery system

Dimensions and geometry of delivery system

Size and shape of vaginal cavity Applicator design Desired release rate

Size and shape of vaginal cavity Applicator design Desired release rate

Dimensions and geometry of delivery system

Polymer used to manufacture delivery system

Drug incorporated into delivery system

Presence or absence of additives Retention mechanism Dimensions and geometry of delivery system

Dimensions and geometry of delivery system

Polymer

Method of disposal Drug load Residue

Polymer used to manufacture delivery system

Drug incorporated into delivery system

Presence or absence of additives Manufacturing process

(13,20,21). Several factors affect the design and development of an intravaginal veterinary drug delivery system. These are listed in Table 2 (13).

The drugs used in intravaginal veterinary delivery systems are synthetic and natural hormones used to control the estrous cycle (progesterone, methyl acetoxy progesterone, fluorogestone acetate, and EB). Other drugs (melatonin, prostaglandin F2ot, and a variety of other synthetic progestagens) have been shown to be systemically absorbed from the

Figure 9 Intravaginal inserts (CIDR 1380 Insert, CueMate, PCL Intravaginal Insert, PRID, sponge, CIDR Pig Insert, and CIDR-G).

vagina of farmed animals. Polymers utilized in intravaginal veterinary delivery systems have included polyurethane, silicone, and polycaprolactone.

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. This may be for several reasons including differences in vaginal size and structure as well as different dosage requirements.

Several drug delivery systems of intravaginal veterinary delivery systems are commercially available (Fig. 9), and include

• The PRID (progesterone-releasing intravaginal device), which consists of a stainless steel spiral covered with a silicone elastomer, with micronized progesterone (1.55 or 2.25 g) uniformly dispersed throughout.

• The CIDR 1380 Cattle Insert, which is a T-shaped delivery system comprising a nylon spine that gives form to the device, over which a layer of silicone is cured, and 1.38 g (10%w/w) of USP grade micronized progesterone is dispersed homogeneously throughout it.

• Several sponge delivery systems made from polyurethane and impregnated with a potent progestagen. They are cylindrical in shape with a string (tail) fitted to aid removal at the end of treatment period.

• The CIDR-G (Controlled Internal Drug Release-Goat), which is a T-shaped intravaginal device with a body, wings, and tail for use in sheep and goats, comprises a preformed nylon spine that has a filament of flexible nylon molded to it (tail). The body and wings of the preformed spine are coated with silicone, which is impregnated with 0.3 g (9% w/w) of USP grade micronized progesterone.

• The CueMate, which is a wishboned-shaped delivery system comprising a polyester spine that gives form to the device onto which progesterone impregnated silicone pods can be attached. These pods are manufactured by injection molding at high temperatures.

• The Pig CIDR, which contains 2 g of progesterone that is homogeneously dispersed throughout a silicone matrix cured at low temperatures (below 120°C) over a polyester spine.

• The PCL Intravaginal Insert, which is a T-shaped delivery system comprising a single-mold polycaprolactone polymeric insert impregnated with progesterone that is manufactured by injection molding at very low molding temperatures (around 80°C).

Collars and Spot-Ons

Collar technologies for animals such as dogs and cats have been formulated for the prolonged topical control of ectoparasites. The collar is worn by the animal and the active ingredient is slowly delivered from the device, permeates the fur of the animal, and kills the ectoparasites. Collars offer the advantages of ease of use and an extended duration of action, which can be up to six months after only one application.

These collar technologies can be divided into (i) matrix devices, (»') reservoir devices, and (ii'i) mechanical devices. Matrix devices in which the active agent is blended directly into the polymer itself represent the most commonly used technology. The vinyl collar is an example of a matrix collar. Others include elastomeric and wax-based devices. In some cases the devices contain additives, which increase the overall percentage of active agent delivered. A reservoir technology comprises dispersed or dissolved active in a vehicle that is encapsulated in a solid or mesh-like casing. Mechanical systems including ultrasonic devices, which emit sound waves, designed to disrupt the flea life cycle; topical pumps, which deliver small quantities of a dissolved active agent; and chambered devices designed to physically entrap the flea inside the collar have also been formulated.

More recently spot-on products have been developed, which have a long action due to the inherent properties of the active ingredient. Commercially available topical liquids include Ex-spot® (permethrin), Advantage® (imidacloprid), and Frontline (fipronil). These products are very easy to use and, because of the potency of the active ingredient, require only a few drops per treatment to be administered on the back of the animal. These products are mainly used for dogs and cats and have a duration as long as one month.

Excellent overviews on the collar and spot-on technologies have been published by Witchey-Laskmanan (15).

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