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Parenteral Dosage Forms and Delivery Systems |  |
| Parenteral dosage forms and delivery systems include injectables (ie, solutions, suspensions, emulsions, and dry powders for reconstitution), intramammary infusions, intravaginal delivery systems, and implants. |
| A solution for injection is a mixture of 2 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 for adjusting tonicity. Antioxidants maintain product stability by being preferentially oxidized over the shelf life of the product. Antimicrobial preservatives inhibit the growth of any microbes that are accidentally introduced while doses are being withdrawn from multiple-dose bottles and act as adjuncts in aseptic processing of products.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 following 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, which are given IM, and water-in-oil emulsions of allergenic extracts, which are given SC. |
| A dry powder for parenteral administration is reconstituted as a solution or as a suspension immediately prior to injection. The principal advantage of this dosage form is that it overcomes the problem of instability in solution. |
| Mastitis intramammary infusion products are available for lactating and nonlactating (dry) cows. Lactating cow 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. By comparison, 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 in reducing 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 in the formulations to prevent rancidity. Mastitis infusion products are often terminally sterilized by irradiation. |
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Intravaginal delivery systems include controlled internal drug release (CIDR) devices, progesterone-releasing intravaginal devices (PRID), 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 PRID into the vaginal cavities of cattle. A different type of applicator is used for inserting CIDR devices into the vaginal cavities of sheep, goats, and cattle. Retention in the vagina depends on either the entire device (sponges and PRID), or the wings (CIDR
device), expanding. With all 3 devices, gentle pressure exerted on the vaginal wall is responsible for retention of the device, which is >95%. |
| The majority of 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-producing 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 for implanting in the ears of wethers at doses of 70-100 mg every 3 mo for the prevention of ulcerative posthitis. |
