Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
2000-04-07
2004-02-24
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Lymphokine
C514S008100, C514S021800
Reexamination Certificate
active
06696056
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides aqueous pharmaceutical formulations of erythropoietin that are free of human serum blood products, stabilized with a quantity of an amino acid and a sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivative. The present invention also provides aqueous stable, preserved pharmaceutical formulations of erythropoietin that contain an antimicrobial quantity of cresol and a quantity of an amino acid.
BACKGROUND OF THE INVENTION
Erythropoietin (EPO) is a glycoprotein hormone secreted by the kidneys in response to tissue hypoxia, which stimulates red blood cell production in the bone marrow (1). The gene for EPO has been cloned and expressed in Chinese hamster ovary cells (2,3). This recombinant human erythropoietin (epoetin alfa, rhEPO) has an amino acid sequence identical to that of human urinary erythropoietin, and the two are indistinguishable on the basis of functional and immunological assays, although differences exist regarding protein glycosylation, affecting in vivo efficacy (4,5).
In clinical trials to date, rhEPO has been evaluated in normal subjects as well as in patients with various anemic conditions (6,7). EPO induces a brisk hematologic response in normal human volunteers, provided that adequate supplies of iron are available to support increased hemoglobin synthesis (8). The majority of trials have investigated the safety and effectiveness of rhEPO in the treatment of chronic renal failure maintained on dialysis and in those not yet on maintenance dialysis. Other indications approved in the US include anemia secondary to chemotherapy treatment in cancer and anemia associated with zidovudine treatment of human immunodeficiency virus infection. Worldwide, EPO has been used to treat anemia associated with rheumatoid arthritis, prematurity, myelofibrosis, sickle cell anemia, bone marrow transplantation, thermal injury, &bgr;-thalassemia, as a facilitator of presurgical autologous blood donation, and use as a presurgical adjuvant (6,7).
Although rhEPO is generally well tolerated, occasional skin rashes and urticaria have been observed suggesting allergic hypersensitivity to some components of the Epoetin alfa formulation, likely human serum albumin. Further, despite blood screening, there exists a risk of infection with a transmissible agent when a pharmaceutical agent is formulated using human blood products. Therefore pharmaceutical formulations of rhEPO that are stable and are free of human blood products, such as albumin are needed.
U.S. Pat. No. 4,992,419 describes lyophilized formulations of erythropoietin containing 5 to 50 g/L urea, 1 to 50 g/L amino acids, 0.05 to 5 g/L surfactants, and without human serum albumin. Aqueous formulations are described, but show a limited stability compared to formulations containing human serum albumin, and thus are not practical commercially. Hence the end user, either a physician or patient, must reconstitute the formulation immediately prior to administration. Lyophilized formulations are not preferred in a clinical formulation of erythropoietin because the reconstitution process is time consuming, poses risks of improper handling of the protein formulation, or may be reconstituted improperly and certain additives such as stabilizers are usually required to retain sufficient activity of the drug. Hence aqueous formulations of erythropoietin are generally preferred.
U.S. Pat. No. 5,376,632 describes aqueous, lyophilized, or spray-dried formulations or erythropoietin containing &bgr; or &ggr; cyclodextrins and not containing other additional stabilizers such as human serum albumin, bovine serum albumin, lecithin, methyl cellulose, polyethylene glycol, sulfur containing reducing agents, urea, amino acids, and surfactants (col 4 lines 51-54).
U.S. Pat. No. 5,661,125 describes aqueous formulations of erythropoietin containing antimicrobial preservatives such as benzyl alcohol, parabens, phenols, and mixtures thereof. Formulations free of human serum albumin were prepared and examined for stability relative to corresponding human serum albumin containing formulations. The results indicated significant precipitation of erythropoietin in HSA-free cresol (0.5%) and chlorocresol (0.3%) formulations, even at 0° C. (col 8. lines 1-29), thus rendering these formulations clinically impractical. Further, EPO formulations containing cresol used in the range of 0.2-0.5% are described as having poor accelerated stability and a more rapid decay of EPO (col 6, lines 21-25). Current commercially available preserved multidose formulations contain 1- % benzyl alcohol.
Commercially available rhEPO formulations are prepared in citrate buffer in strengths of 1000 IU/0.5 mL, 2000 IU/mL, 5000 IU/mL, and 10,000 IU/mL (10K) for both intravenous (iv) and subcutaneous (sc) injection. These formulations are clinically documented to commonly cause patient discomfort associated with s.c. administration of the citrate-buffered formulations (9,10). As the predominant clinical use of rhEPO was switched from i.v. to s.c., it soon became evident that the local tolerance of the present formulation was not optimal. Neither adapting the drug to room temperature before injection nor avoiding volumes in excess of 1 ml were sufficient to prevent pain at the injection site. As neither human albumin, which is used as a stabilizer of the formulation, nor low osmolality of the solution were found to be pain inducers, the citrate buffer of rhEPO was a suggested candidate. A 40,000 IU/ml, single dose, preservative free formulation is commercially available that contains sodium phosphate, rather than citrate buffer. There is a need for stable, smaller dose formulations that contain phosphate buffer instead of the less preferable citrate buffer.
SUMMARY OF THE INVENTION
The present invention provides pharmaceutical formulations of erythropoietin comprising: (a) a pH buffering agent; (b) a stabilizing amount of a sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) derivative; (c) a stabilizing amount of an amino acid; and (d) a pharmaceutical quantity of erythropoietin; wherein the formulation does not contain urea or a human blood product. Preferred formulations comprise combinations of polysorbate 80 and glycine as stabilizing agents. Particularly preferred formulations comprise combinations of polysorbate 80 and glycine as stabilizing agents in a phosphate buffer system.
The present invention also provides pharmaceutical formulations of erythropoietin comprising: (a) a pH buffering agent; (b) a stabilizing amount of human serum albumin; (c) a stabilizing amount of an amino acid; (d) a antimicrobial quantity of cresol; and (e) a pharmaceutical quantity of erythropoietin. Preferred formulations comprise combinations of human albumin and glycine as stabilizing agents. Particularly preferred formulations comprise combinations of human serum albumin and glycine as stabilizing agents in a phosphate buffer system with m-cresol used at a concentration of about 0.3%.
Formulations of the present invention display pharmacokinetic properties similar to the current pharmaceutical products, such as absorption, disposition and serum concentration levels similar to currently marketed pharmaceutical formulations of recombinant human erythropoietin. Further, formulations of the present invention present less intense discomfort to the patient upon administration and exhibit much shorter duration of discomfort at the injection site. Hence the present invention provides human serum albumin free or preserved pharmaceutical formulations of erythropoietin that can be used for erythropoietin and may be formulated to reduce patient discomfort.
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patent:
Begum Selima
Cheung Wing K.
Natarajan Jaya
Sanders Marilyn
Sharma Basant
Ortho -McNeil Pharmaceutical, Inc.
Russel Jeffrey E.
Woodcock & Washburn LLP
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