Nonproprietary Names

USP:Albumin Solution
PhEur:Human Albumin Solution
USP:Albumin Human

Synonyms

Alba; Albuconn; Albuminar; albumin human solution; albumini humani solutio; Albumisol; Albuspan; Albutein; Buminate; human serum albumin; normal human serum albumin; Octalbin; Plasbumin; plasma albumin; Pro-Bumin; Proserum; Zenalb.

Chemical Name and CAS Registry Number

Serum albumin [9048-49-1]

Empirical Formula and Molecular Weight

Human serum albumin has a molecular weight of about 66500 and is a single polypeptide chain consisting of 585 amino acids. Characteristic features are a single tryptophan residue, a relatively low content of methionine (6 residues), and a large number of cysteine (17) and of charged amino acid residues of aspartic acid (36), glutamic acid (61), lysine (59), and arginine (23).

Structural Formula

Primary structure Human albumin is a single polypeptide chain of 585 amino acids and contains seven disulfide bridges. Secondary structure Human albumin is known to have a secondary structure that is about 55% a-helix. The remaining 45% is believed to be divided among turns, disordered, and b structures.(1) Albumin is the only major plasma protein that does not contain carbohydrate constituents. Assays of crystalline albumin show less than one sugar residue per molecule.

Functional Category

Stabilizing agent; therapeutic agent. Albumin 15

Applications in Pharmaceutical Formulation or Technology

Technology Albumin is primarily used as an excipient in parenteral pharmaceutical formulations, where it is used as a stabilizing agent for formulations containing proteins and enzymes.(2) Albumin has also been used to prepare microspheres and microcapsules for experimental drug-delivery systems.(3–6) As a stabilizing agent, albumin has been employed in protein formulations at concentrations as low as 0.003%, although concentrations of 1–5% are commonly used. Albumin has also been used as a cosolvent(7) for parenteral drugs, as a cryoprotectant during lyophilization,(8,9) and to prevent adsorption of other proteins to surfaces. Therapeutically, albumin solutions have been used parenterally for plasma volume replacement and to treat severe acute albumin loss. However, the benefits of using albumin in such applications in critically ill patients has been questioned.(10)

Description

The USP 32 describes albumin human as a sterile nonpyrogenic preparation of serum albumin obtained from healthy human donors; see Section 13. It is available as a solution containing 4, 5, 20, or 25g of serum albumin in 100mL of solution, with not less than 96% of the total protein content as albumin. The solution contains no added antimicrobial preservative but may contain sodium acetyltryptophanate with or without sodium caprylate as a stablizing agent. The PhEur 6.0 similarly describes albumin solution as an aqueous solution of protein obtained from human plasma; see Section 13. It is available as a concentrated solution containing 150–250g/L of total protein or as an isotonic solution containing 35–50g/L of total protein. Not less than 95% of the total protein content is albumin. A suitable stabilizer against the effects of heat, such as sodium caprylate (sodium octanoate) or N-acetyltryptophan or a combination of these two at a suitable concentration, may be added, but no antimicrobial preservative is added. Aqueous albumin solutions are slightly viscous and range in color from almost colorless to amber depending upon the protein concentration. In the solid state, albumin appears as brownish amorphous lumps, scales, or powder.

Pharmacopeial Specifications

See Table I. Table I: Pharmacopeial specifications for albumin. Test PhEur 6.0 USP 32 Identification Characters Production Protein composition Molecular size distribution Heat stability pH (10 g/L solution) Potassium þ þ þ þ þ— 6.7–7.3 40.05 mmol/g — — — — — þ þ— Sodium 4160 mmol/L 130–160 mEq/L Heme Aluminum þ4200 mg/L þ— Sterility Hepatitis B surface antigen Pyrogens Total protein þ — þ95–105% þ þ þ 596% for 4 g in 100 mL — 93.75–106.25% for 5 to 25 g in 100 mL — 94.0–106.0% Prekallikrein activator 435 IU/mL —

Typical Properties

Acidity/alkalinity pH = 6.7–7.3 for a 1% w/v solution, in 0.9% w/v sodium chloride solution, at 208C. NIR spectra see Figure 1. Osmolarity A 4–5% w/v aqueous solution is isoosmotic with serum. Solubility Freely soluble in dilute salt solutions and water. Aqueous solutions containing 40% w/v albumin can be readily prepared at pH 7.4. The high net charge of the peptide contributes to its solubility in aqueous media. The seven disulfide bridges contribute to its chemical and spatial conformation. At physiological pH, albumin has a net electrostatic charge of about –17. Aqueous albumin solutions are slightly viscous and range in color from almost colorless to amber depending on the protein concentration.

Stability and Storage Conditions

Albumin is a protein and is therefore susceptible to chemical degradation and denaturation by exposure to extremes of pH, high salt concentrations, heat, enzymes, organic solvents, and other chemical agents. Albumin solutions should be protected from light and stored at a temperature of 2–258C or as indicated on the label.

Incompatibilities

See Section 11.

Method of Manufacture

Albumin human (USP 32) Albumin human is a sterile nonpyrogenic preparation of serum albumin that is obtained by fractionating material (source blood, plasma, serum, or placentas) from healthy human donors. The source material is tested for the absence of hepatitis B surface antigen. It is made by a process that yields a product safe for intravenous use. Human albumin solution (PhEur 6.0) Human albumin solution is an aqueous solution of protein obtained from plasma. Separation of the albumin is carried out under controlled conditions so that the final product contains not less than 95% albumin. Human albumin solution is prepared as a concentrated solution containing 150–250g/L of total protein or as an isotonic solution containing 35–50g/L of total protein. A suitable stabilizer against the effects of heat such as sodium caprylate (sodium octanoate) or N-acetyltryptophan or a combination of these two at a suitable concentration, may be added, but no antimicrobial preservative is added at any stage during preparation. The solution is passed through a bacteriaretentive filter and distributed aseptically into sterile containers, 1100 1300 1500 1700 1900 2100 2300 2500 Wavelength/nm Figure 1: Near-infrared spectrum of albumin measured by reflectance. Albumin which are then closed so as to prevent contamination. The solution in its final container is heated to 60 1.08C and maintained at this temperature for not less than 10 hours. The containers are then incubated at 30–328C for not less than 14 days or at 20–258C for not less than 4 weeks and examined visually for evidence of microbial contamination.

Safety

Albumin occurs naturally in the body, comprising about 60% of all the plasma proteins. As an excipient, albumin is used primarily in parenteral formulations and is generally regarded as an essentially nontoxic and nonirritant material. Adverse reactions to albumin infusion rarely occur but include nausea, vomiting, increased salivation, chills, and febrile reactions. Urticaria and skin rash have been reported. Allergic reactions, including anaphylactic shock, can occur. Albumin infusions are contraindicated in patients with severe anemia or cardiac failure. Albumin solutions with aluminum content of less than 200mg/L should be used in dialysis patients and premature infants.(11) LD50 (monkey, IV): >12.5g/kg(12) LD50 (rat, IV): >12.5g/kg

Handling Precautions

Observe handling precautions appropriate for a biologically derived blood product. 16 Regulatory Acceptance Included in the FDA Inactive Ingredients Database (oral, tablets, film-coatings; IV injections, IV infusions and subcutaneous injectables). Included in parenteral products licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 17 Related Substances Albumins derived from animal sources are also commercially available, e.g. bovine serum albumin.

Comments

A 100mL aqueous solution of albumin containing 25g of serum albumin is osmotically equivalent to 500mL of normal human plasma. The EINECS number for albumin is 310-127-6. 19 Specific References 1 Bramanti E, Benedetti E. Determination of the secondary structure of isomeric forms of human serum albumin by a particular frequency deconvolution procedure applied to Fourier transform IR analysis. Biopolymers 1996; 38(5): 639–653. 2 Wang JUC, Hanson MA. Parenteral formulations of proteins and peptides: stability and stabilizers. J Parenter Sci Technol 1988; 42(S): S1–S26. 3 Arshady R. Albumin microspheres and microcapsules: methodology of manufacturing techniques. J Control Release 1990; 14: 111–131. 4 Callewaert M et al. Albumin-alginate-coated microsopheres: resistance to steam sterilization and to lyophilization. Int J Pharm 2007; 344(1–2): 161–164. 5 Dreis S et al. Preparation, characterisation and maintenance of drug efficacy of doxorubicin-loaded human serum albumin (HSA) nanoparticles. Int J Pharm 2007; 341(1–2): 207–214. 6 Mathew ST et al. Formulation and evaluation of ketorolac tromethamine-loaded albumin microspheres for potential intramuscular administration. AAPS Pharm Sci Tech 2007; 8(1): 14. 7 Olson WP, Faith MR. Human serum albumin as a cosolvent for parenteral drugs. J Parenter Sci Technol 1988; 42: 82–85. 8 Hawe A, Friess W. Physicochemical characterization of the freezing behavior of mannitol-human serum albumin formulations. AAPS Pharm Sci Tech 2006; 7(4): 94. 9 Hawe A, Friess W. Physico-chemical lyophilization behaviour of mannitol, human serum albumin formulations. Eur J Pharm Sci 2006; 28(3): 224–232. 10 Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Br Med J 1998; 317: 235–240. 11 Quagliaro DA et al. Aluminum in albumin for injection. J Parenter Sci Technol 1988; 42: 187–190. 12 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 1970.

General References

Chaubal MV. Human serum albumin as a pharmaceutical excipient. Drug Deliv Technol 2005; 5: 22–23. Kragh-Hansen U. Structure and ligand properties of human serum albumin. Danish Med Bull 1990; 37(1): 57–84. Putnam FW, ed. The Plasma Proteins, Structure, Function and Genetic Control. London: Academic Press, 1975.

Author

RT Guest.

Date of Revision

12 February 2009.