Epinephrine formulations

Although epinephrine autoinjectors are widely dispensed for first-aid treatment of anaphylaxis in some countries, they are neither available nor affordable in many others [33]. In these situations, physicians sometimes equip patients at risk for anaphylaxis in the community with an epinephrine ampule and a disposable 1-ml syringe. Some physicians also recommend this approach for infants, for whom, as noted previously, no appropriate epinephrine dose is available in an autoinjector formulation. 

Stablizers. Stabilizers are ingredients added to a formula to decrease the rate of decomposition of the active ingredients. Antioxidants are the principal stabilizers added to some ophthalmic solutions, primarily those containing epinephrine and other oxidizable drugs. Sodium bisulfite or metabisulfite are used in concentration up to 0.3% in epinephrine hydrochloride and bitartrate solutions. Epinephrine borate solutions have a pH range of 5.5 7.5 and offer a more difficult challenge to formulators who seek to prevent oxidation. Several patented antioxidant systems have been developed specifically for this compound. These consist of ascorbic acid and acetylcysteine, and sodium bisulfite and 8-hydroxyquinoline. Isoascorbic acid is also an effective antioxidant for this drug. Sodium thiosulfate is used with sodium sulfacetamide solutions. 

T. E. Peterson and D. Trowbridge, Quantitation of 1-epinephrine and determination of the d-/l-epinephrine enantiomer ratio in a pharmaceutical formulation by capillary electrophoresis, J. Chromatogr., 603 298 (1992). 

Direct injection of the gel into solid tumors and skin lesions provides high local concentrations of a dmg specifically where needed (Figure 4.15). The gel is injected intradermally in a fanning or tracking manner to disperse the gel formulation throughout the tumor. Dmg retention at the site of implantation is further enhanced by the addition of chemical modifiers such as the vasoconstrictor, epinephrine (adrenaline). This adjunct reduces blood flow and acts as a chemical tourniquet to hold the therapeutic agent in place. 

Chlorobutanol is primarily used in ophthalmic or parenteral dosage forms as an antimicrobial preservative at concentrations up to 0.5% w/v see Section 10. It is commonly used as an antibacterial agent for epinephrine solutions, posterior pituitary extract solutions, and ophthalmic preparations intended for the treatment of miosis. It is especially useful as an antibacterial agent in nonaqueous formulations. Chlorobutanol is also used as a preservative in cosmetics [see Section 16) as a plasticizer for cellulose esters and ethers and has been used therapeutically as a mild sedative and local analgesic. 

Local tissue reactions, including inflammation and necrosis, can occur, particularly if local anesthetic formulations containing epinephrine (adrenaline) have been administered. Allergic reactions can also occur and are most commonly associated with the esters (e.g. procaine, see Ch. 2). Neurotoxicity is rare but may occur when 200 ml or more of a local anesthetic is administered by infiltration in a short period. It is more likely that a horse will become ataxic, which can lead to selftrauma, after nerve blockade in the limbs, and severe hindlimb ataxia can follow the caudal... 

Drugs that contain two phenolic groups, such as adrenaline (epinephrine) and other catecholamines such as noradrenaline (norepinephrine) and isoprenaline are particularly susceptible to oxidation and have to be formulated at acidic pH. All of these compounds are white crystalline solids that darken on exposure to air. Adrenaline forms the red coloured compound adrenochrome on oxidation (Figure 8.10), which can further polymerise to give black compounds similar in structure to melanin, the natural skin pigment. Injections of adrenaline that develop a pink colour, or that contain crystals of black compound, should not be used for this reason. Adrenaline for injection is formulated as the acid tartrate... 

Sciarra JJ, Patel JM, Kapoor AL. Synthetics and formulation of several epinephrine salts as an aerosl dosage form. J Pharm Sci 61(2) 219-223, 1972. 

Solich, R, Polydorou, C. K., Koupparis, M. A., and Efstathion, C. E. Automated flow-injection spectrophotometric determination of catecholamines (epinephrine and isoproterenol) in pharmaceutical formulations based on ferrous complex formation. J. Pharm. Biomed. Anal. 22(5) 781-789,2000. 

Preformulation screening of the antioxidant efficiency in parenteral solutions containing epinephrine has been reported by Akers (1979), who concluded that screening was difficult on the basis of the redox potential, and was complicated by a complex formulation of many components. Indeed, the most recent study on the preformulation screening of antioxidants found that the ability of an antioxidant to consume the oxygen in the formulation was a superior indicator of suitability when compared to redox methods (Ugwu and Apte 1999). 

Sterile Epinephrine Ophthalmic Solution USP takes us out of the realm of sterile parenteral products into ophthalmics. The manner of presentation of ophthalmics (i.e., as drops or ointments) is likely to be quite familiar. For the most part (but not exclusively) they are in multidose presentations. As such, most formulations include some form of preservative to control proliferation of any microorganisms that may by chance contaminate the product on one or other of the occasions when it is open, or during the time when it is left standing on the bathroom shelf. The inclusion of preservatives in a multidose formulation of an ophthalmic (or parenteral) is not a primary part of the process of achieving sterility. It has quite a separate purpose. 

Because labetalol, an adrenoceptor-blocking agent structurally related to epinephrine, has two asymmetric centers, four diastereomers exist (Fig. 4.4). The formulation available for use as a mixed a- and (3-adrenoceptor blocker contains equal amounts of each diastereomer. The R,R isomer accounts for much of the (3-adrenoceptor blocking activity, whereas the S.R isomer has the greatest effect on a-adrenoceptors. The S,S isomer has some a-adrenoceptor blocking activity but no activity at [3-adrenoceptors. The R.S isomer is essentially devoid of activity at both a- and (3-adrenoceptors. 

The pressurized metered-dose inhaler (pMDI) for the delivery of antiasthma drugs originated in the U.S. cosmetic industry. George Maison, the president of Riker Laboratories, and Irvin Porash, who worked in Riker s pharmaceutical development laboratory, are credited with the development of the first pMDI (32). Experiments were conducted to formulate pressurized aerosols of isoproterenol and epinephrine, which had been dissolved in alcohol, using the freon propellants 12 and 114. 

Catecholamines (norepinephrine, epinephrine, dopamine) Injection formulations Cation exchange Nonsuppressed conductivity... 

---