Parenteral formulations injection volume

Insulin preparations that are commercially available differ in their relative onset of action, maximal activity, and duration of action. Conjugation of the insulin molecule with either zinc or protamine, or both, will convert the normally rapidly absorbed parenterally administered insulin to a preparation with a more prolonged duration of action. The various formulations of insulin are usually classified as short acting (0.5 to 14 h), intermediate acting (1 to 28 h), and long acting (4 to 36 h). The duration of action can vary, however, depending on injection volume, injection site, and blood flow at the site of administration. 

The use of cosolvents in small-volume parenteral preparations is often critical due to the limited volume of solution that can be administered by a single injection. Thus, the required dose of drug must often be incorporated in 1 or 2mL of solution. Table 6 lists parenteral products containing cosolvents. The cosolvents most often used include ethanol, propylene glycol, glycerin, PEG 400, and, sometimes, dimethylacetamide. Other cosolvents, such as DMSO, have been used as solvents for parenteral formulations of experimental anticancer agents however, their use is restricted due to toxicity and potential incompatibilities with plastic administration devices. ... 

Polymers are widely used in various pharmaceutical formulations, such as traditional oral formulations (tablets and capsule) and complex parenteral formulations (such as microspheres, nanoparticles, implants, and in situ forming gels). Dissolution testing is used in formulation development, quality control for batch release of product, and in vitro-in vivo correlations. FDA has a database listing dissolution methods for around 1000 formulations such as tablets, capsules, granules, and injectable suspensions. These methods provide information about the standardized USP apparatus used, testing speed, type and volume of release medium, and the recommended sampling points. For detailed informadon abont the seven standardized dissolution apparatuses, method development, and validation of compendial methods, the reader is referred to USP Chapters 711,... 

Many drugs are administered as parenterals for speed of action because the patient is unable to take oral medication or because the drug is a macromolecule such as a protein that is unable to be orally absorbed intact due to stability and permeability issues. The U.S. Pharmacopoeia defines parenteral articles as preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal. They include intravenous, intramuscular, or subcutaneous injections. Intravenous injections are classified as small volume (<100 mL per container) or large volume (>100 mL per container) injections. The majority of parenteral dosage forms are supplied as ready-to-use solutions or reconstituted into solutions prior to administration. Suspension formulations may also be used,101 although their use is more limited to a subcutaneous (i.e., Novolin Penfill NOVO Nordisk) or intramuscular (i.e., Sandostatin LAR Depot Novartis) injection. Intravenous use of disperse systems is possible but limited (i.e., Doxil Injection Ortho Biotec). 

It has been also observed that hypertonic and hypotonic salt solutions tend to irritate sensitive tissue and cause pain when applied to mucous membranes of the eye, ear, and nose, etc., whereas isotonic solution causes no tissue irritation when it comes in contact with the tissue. Obviously, the tonicity of formulations that come in to direct contact with blood, muscle, eye, nose, and delicate tissues is critical. Therefore, the issue of tonicity is important in small- and large-volume injectables, ophthalmic products, and products intended for tissue irrigation. The degree of tissue irritation or hemolysis or crenation observed depends on the degree of deviation from isotonicity, the volume injected, the speed of injection, the concentration of the solutes in the injection, and the nature of the membrane. The parenteral and ophthalmic formulations are therefore adjusted to isotonicity if possible. 

Homogeneous solutions are the preferred formulation systems for parenteral administration because they can be easily visually inspected for the absence of particulate matter. For this reason, cosolvent solubilization is the first choice for parenteral products once purely aqueous systems provide insufficient solvency. The compositions of three commercial, injectable products are given in Table 39.5. The first product (1) has a low percentage of cosolvent in the separate solvent ampoule. The drug substance is provided as a dry powder because of its limited stability in solution. The second one (2) is solubiUzed with two cosolvents amounting to 50% of the total volume, whereas in the third product the drug dose is dissolved in a water-free mixture of cosolvents. This draws the attention to a further point to consider when cosolvents are employed in formulations. The formulation has to be devised such that the effect of dilution of... 

The formulation of parenteral products involves careful consideration of the proposed route of administration and the volume of the injection. Injections are administered to the body by many routes into various layers of the skin, the subcutaneous and muscle tissue, into arteries or veins, into or around the spinal cord, or directly into various organs (e.g., the heart or the eye). The volume to be injected can range from microliters, typically diagnostic agents administered intradermally or insulin administered subcutaneously, to several liters administered intravenously as infusions. The route of administration and the volume to be injected affect the composition of the formulation. 

Parenteral suspensions and oil-based parenterals must be administered either subcutaneously or intramuscularly (see Sect. 13.5.3). The volume of subcutaneous injection typically amounts to 1 mL. To increase the applicable volume at the subcutaneous application site, hyaluronidase can be added to the formulation [1]. The volume of intramuscular injection is also small, usually 1-3 mL or up to 10 mL in divided doses. In practice the pharmacist also may dispense special injections (see Sect. 13.5.15). 

---