Source: http://www.google.com/patents/US7790852?dq=5,832,511
Timestamp: 2017-11-21 04:06:51
Document Index: 368491866

Matched Legal Cases: ['art. 0', 'art. 0', 'art. 0', 'art. 0', 'art 2', 'art1', 'art 4', 'art 2', 'art 2', 'art 1', 'art 2']

Patent US7790852 - Liquid composition of factor VII polypeptides - Google Patents
The invention concerns a liquid aqueous composition comprising (i) a factor VII polypeptide, (ii) an agent suitable for keeping pH in the range of from about 4.0 to about 9.0; (iii) an agent selected from the group consisting of: a calcium salt, a magnesium salt, or a mixture thereof; wherein the concentration...http://www.google.com/patents/US7790852?utm_source=gb-gplus-sharePatent US7790852 - Liquid composition of factor VII polypeptides
Publication number US7790852 B2
Application number US 12/154,088
Also published as EP1641487A1, EP1641487B1, US20060183683, US20080227715, WO2004112828A1
Publication number 12154088, 154088, US 7790852 B2, US 7790852B2, US-B2-7790852, US7790852 B2, US7790852B2
Inventors Birthe Lykkegaard Hansen, Michael Bech Jensen, Troels Kornfelt
Patent Citations (86), Non-Patent Citations (79), Referenced by (6), Classifications (13), Legal Events (2)
US 7790852 B2
21. A composition as defined in claim 1, which is stable for at least 6 months at 2-80° C.
The present inventors have now found that factor VII or analogues thereof (i) (“factor VII polypeptides”), when formulated in aqueous solution at an ionic strength of at least 200 mM are stable in the pH range from about 4 to about 9.
FIG. 1 shows the content of FVII aggregates and FVII fragments in FVII preparations after 3 months of storage at 2-8° C.
The compositions according to the present invention are useful as stable and preferably ready-to-use compositions of factor VII polypeptides. Furthermore, it is believed that the principles, guidelines and specific embodiments given herein are equally applicable for bulk storage of Factor VII polypeptides, mutatis mutandis. The compositions are stable for at least six months, and preferably up to 36 months; when stored at temperatures ranging from 2° to 8° C. The compositions are chemically and/or physically stable, in particular chemically stable, when stored for at least 6 months at from 2° to 8° C.
The term “storage-stable” or interchangeable “stable” encompasses a product that is stabilised upon storage at temperatures between 2° C.-8° C. and remains within pre-selected product specifications for a suitable time period—often several months.
The term “stable” is intended to encompass a composition that, after storage for 6 months at 2 to 8° C., retains at least 50% of its initial biological activity as measured by a one-stage clot assay, for example essentially as described in Assay 4 of the present specification. Preferably, the stable composition retains at least 70%, such as 75% or 80% of its initial activity after storage for 6 months at 2 to 8° C.
Furthermore, the term “stable” encompasses a composition that, after storage for at least 6 months at 2 to 8° C., contains less (in %) of at least one of the following degradation products: (i) enzymatic degradation products, (ii) aggregates (dimers, oligomers, polymers), (iii) oxidized forms, or (iv) deamidated forms relative to the amount of corresponding degradation product(s) contained in a solution of reconstituted NovoSeven® product which has been stored under similar conditions for a similar period of time.
The term “chemical stability” is intended to relate to the formation of any chemical change in the Factor VII polypeptides upon storage in solution at accelerated conditions. By example are hydrolysis, deamidation and oxidation as well as enzymatic degradation resulting in formation of fragments of factor VII polypeptides (such as heavy chain degradation), In particular, the sulphur-containing amino acids are prone to oxidation with the formation of the corresponding sulphoxides.
In interesting embodiments of the invention, suitable compositions have a limited increase in the content of enzymatic degradation forms upon storage for at least 6 months at 2-8° C. Interesting embodiments relate to compositions that are stable such that not more than about 25% w/w, such as 20%, 15%, 10%, or not more than about 5% of the initial content of Factor VII polypeptide is converted to enzymatic degradation forms heavy chain fragments upon storage of said composition at 2-8° C. for 6 months.
The terms “human factor VII” or “FVII” denote human factor VII produced by methods including natural source extraction and purification, and by recombinant cell culture systems. Its sequence and characteristics are set forth, for example, in U.S. Pat. No. 4,784,950. The terms likewise cover biologically active human factor VII equivalents, e.g., differing in one or more amino acid(s) in the overall sequence. Furthermore, the terms used in this application are intended to cover substitution, deletion and insertion amino acid variants of factor VII or posttranslational modifications. As used herein, “Factor VII polypeptide” encompasses, without limitation, Factor VII, as well as Factor VII-related polypeptides. Factor VII-related polypeptides include, without limitation, Factor VII polypeptides that have either been chemically modified relative to human Factor VII and/or contain one or more amino acid sequence alterations relative to human Factor VII (i.e., Factor VII variants), and/or contain truncated amino acid sequences relative to human Factor VII (i.e., Factor VII fragments). Such factor VII-related polypeptide s may exhibit different properties relative to human Factor VII, including stability, phospholipid binding, altered specific activity, and the like.
As used herein, “Factor VII-related polypeptides” encompasses, without limitation, polypeptides exhibiting substantially the same or improved biological activity relative to wild-type human Factor VII. These polypeptides include, without limitation, Factor VII or Factor VIIa that has been chemically modified and Factor VII variants into which specific amino acid sequence alterations have been introduced that modify or disrupt the bioactivity of the polypeptide.
In different embodiments, the factor VII polypeptide is human factor VIIa; recombinant human factor VIIa; a factor VII-related polypeptide; a factor VII sequence variant; or a factor VII polypeptide wherein the activity of the factor VII polypeptide and the activity of native human Factor VIIa (wild-type FVIIa) is at least about 1.25, preferably at least about 2.0, or 4.0, most preferred at least about 8.0, when tested in the “In Vitro Proteolysis Assay” as described in the present specification. In one embodiment, the factor VII polypeptide has a glycosylation different from wild-type human factor VII. In different embodiments, the factor VII polypeptide is present in a concentration of from about 0.1 mg/ml to about 15 mg/ml; from about 0.5 mg/ml to about 10.0 mg/ml; from about 0.5 mg/ml to about 5.0 mg/ml; from about 0.6 mg/ml to about 4.0 mg/ml; from about 1.0 mg/ml to about 4.0 mg/ml; from about 0.1 mg/ml to about 5 mg/ml; from about 0.1 mg/ml to about 4.0 mg/ml; from about 0.1 mg/ml to about 2 mg/ml; or from about 0.1 mg/ml to about 1.5 mg/ml.
The term “buffering agent” encompasses those agents or combinations of agents which maintain the solution pH in an acceptable range from about 4.0 to about 9.0. These may include, but are not limited to, acids and salt of: MES, PIPES, ACES, BES, TES, HEPES, TRIS, histidine (e.g. L-histidine), imidazole, glycine, glycylglycine, glycinamide, phosphoric acid (e.g. sodium or potassium phosphate), acetic acid (e.g. ammonium, sodium or calcium acetate), lactic acid, glutaric acid, citric acid (e.g. sodium or potassium citrate), tartaric acid, malic acid, maleic acid, and succinic acid. It should be understood that the buffering agent may comprise a mixture of two or more components, wherein the mixture is able to provide a pH value in the specified range. As examples can be mentioned acetic acid and sodium acetate, or acetic acid and histidine, etc.
As used herein, the term “ionic strength modifying agent” includes agents, which contribute to the ionic strength of the solution. The agents include, but are not limited to, neutral salts, e.g., sodium chloride or potassium chloride; amino acids; small peptides (e.g., having from 2 to 5 amino acid residues such as, e.g., glycylglycine), or a mixture of at least two of said modifying agents. The “ionic strength modifying agent” may also be a mixture of two or more such agents that in combination are able to modify the ionic strength to a level as defined in the present invention. Preferred agents are sodium chloride or a mixture of sodium chloride with one or more small peptides or amino acids. The ionic strength modifying agent(s) is/are present in a concentration sufficient to elevate the ionic strength of the solution to at least 200 mM (calculated on the basis of millimolar concentrations of agents). The ionic strength modifying agents may, e.g., without limitation, each be present in a concentration of at least about 5 mM, 10 mM, 20 mM, 50 mM, 100 mM, 200 mM, 400 mM, 800 mM, 1000 mM, 1200 mM, 1500 mM, 1800 mM, 2000 mM, or at least 2200 mM.
The term “ionic strength” is the ionic strength of the solution (μ) which, in the present context, is defined by the equation: μ=½ΣCi(Zi 2), where μ is the ionic strength, Ci is the molar concentration of an ion, and Zi is the charge (+ or −) of that ion (see, for example, Solomon, Journal of Chemical Education, 78(12):1691-92, 2001; James Fritz and George Schenk: Quantitative Analytical Chemistry, 1979).
By “neutral salt” is meant a salt that is neither an acid nor a base when dissolved in aqueous solution. Examples include sodium chloride or potassium chloride.
As used herein, the term “tonicity modifier” includes agents, which contribute to the osmolality of the solution. Tonicity modifiers include, but are not limited to, amino acids; small peptides (e.g., having from 2 to 5 amino acid residues); neutral salts; mono- or disaccharides; polysaccharides; sugar alcohols, or a mixture of at least two of said modifiers. Examples of tonicity modifiers include, but are not limited to, sodium chloride, potassium chloride, sodium citrate, sucrose, glucose, glycylglycine, trehalose, and mannitol. Normally, the modifiers are present at a concentration of from about 1 to about 500 mM; from about 1 to about 300 mM; from about 10 to about 200 mM; or from about 20 to about 150 mM, depending on the other ingredients present. Neutral salts such as, e.g., sodium chloride or potassium chloride may be used.
Optionally, the compositions may also contain a surfactant or detergent (vi). “Surfactants” or “detergents” generally include those agents which protect the protein from air/solution interface induced stresses and solution/surface induced stresses (e.g., resulting in protein aggregation). The detergent is preferably a non-ionic detergent including, without limitation, polysorbates (e.g. Tween®), such as polysorbate 20 or 80; polyoxyethylene alkyl ethers or poloxamers, such as poloxamer 188 or 407, (e.g., Pluronic® polyols) and other ethylene/polypropylene block polymers, or polyethyleneglycol (PEG) such as PEG8000. The amount of surfactant present ranges from about 0.005 to about 2.0%.
A preservative (viii) may also be included in the composition to retard microbial growth and thereby allow “multiple use” packaging of the FVII polypeptides. Preservatives include phenol, benzyl alcohol, orto-cresol, meta-cresol, para-cresol, methyl paraben, propyl paraben, benzalconium chloride, and benzethonium chloride. The preservative is normally included at a concentration of 0.1 to 20 mg/ml depending on pH range and type of preservative.
In one embodiment, the composition is isotonic; in another, it is hypertonic. In one embodiment, the composition is formulated for pharmaceutical administration. In one embodiment, the composition is stable for storage for at least 6 months at 2-8° C.
Measuring the physical binding of Factor VIIa or a Factor VII-related polypeptide to TF using an instrument based on surface plasmon resonance (Persson, FEBS Letts. 413:359-363, 1997);
Measuring hydrolysis of a synthetic substrate by Factor VIIa and/or a Factor VII-related polypeptide (“In Vitro Hydrolysis Assay”, see below);
EXAMPLES Example 1 Analytical Methods Used in Determining Stability Indicating Parameters:
HPLC Column: 4.5×250 mm column packed with butylbonded silica with a particle size of 5 μm and pore size 300 Å. Column temperature: 70° C. Eluent A: water 99.9% v/v and trifluoracetic acid 0.1% v/v. Eluent B: acetonitrile 80% v/v. trifluoracetic acid 0.09% v/v and water 19.91% v/v. The column was eluted with a linear gradient from X % B to (X+13) % B in 30 minutes. Flow rate: 1.0 ml/min. Detection: 214 nm.
GP-HPLC was run on a Waters Protein Pak 300 SW column. 7.5×300 mm. using 0.2 M ammoniumsulfat pH 7.0 containing 50% isopropanol as the mobile phase. Flow rate: 0.5 ml/min and detection: 215 nm.
(I) Vials of the rFVIIa aqueous composition containing 1.4 mg rFVIIa/mL, 50 mM Sodium chloride, 10 mM Calcium chloride and a mixture of 10 mM glycylglycine, acetate and histidine adjusted to pH 3, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, and 9.0 were incubated at either a temperature of 2-8° C., or at elevated storage temperatures of 30° C., and then removed at various time points and assayed for changes in pH and the chemical stability was determined by RP-HPLC and GP-HPLC.
After storage at 2-8° C. for up to three months the aqueous compositions showed insignificant changes in pH. Non-denaturing size exclusion HPLC performed on samples stored for up to three months at 2-8° C. showed no significant aggregation of the drug product at pH values 5.5 (FIG. 1). RP-HPLC performed on these samples showed no significant increase in the fragmentation or oxidation of the protein in the pH range 4.5-5.5. FIG. 1 shows data after 3 months of storage at 2-8° C. The initial content of aggregates was approximately 0.5% and the initial content of fragments was approximately 9%.
(II) Vials of the rFVIIa aqueous composition containing 1.4 mg rFVIIa/mL, 200 mM Sodium chloride, 10 mM Calcium chloride and a mixture of 10 mM glycylglycine, acetate and histidine adjusted to pH 3, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, and 9.0 are incubated at either a temperature of 2-8° C., or at elevated storage temperatures of 30° C., and then removed at various time points and assayed for changes in pH; the chemical stability is determined by RP-HPLC and GP-HPLC.
After storage at 2-8° C. for up to three months, it is contemplated that the aqueous compositions will show insignificant changes in pH. It is further contemplated that non-denaturing size exclusion HPLC performed on samples stored for up to three months at 2-8° C. will show no significant aggregation of the drug product at pH values 5.5. It is further contemplated that RP-HPLC performed on these samples will show no significant increase in the fragmentation or oxidation of the protein in the pH range 4.5-5.5.
Example 4 Physical Stability of Aqueous Compositions Containing Various Detergents
CaCl2, 2H2O 1.47 mg/ml
Conc. Appearance Absorbance (400 nm)
Tween ® 80 0.1 Very few part. Clear, few part. 0.0044 0.0036 −0.0008
Poloxamer 188 1.0 Very few part. Clear, few part. 0.0063 0.0027 −0.0036
Polyethylenglycol 0.1 Very few part. Turbid 0.0076 1.5708 1.5632
Polyethylenglycol 0.5 Few part. Very turbid 0.0108 1.6624 1.6516
Brij ® 35 0.1 Very few part. Clear, few part. 0.0028 0.0015 −0.0013
LPCM 0.1 Very few part. Clear, few part. 0.0026 0.0012 −0.0014
The results show that the reference (without addition of any detergent/solubiliser) becomes visually turbid when shaken and a significant increase is observed in the absorbance at 400 nm. Addition of Tween® 20 (=polysorbate 20), Tween® 80 (=polysorbate 80), Poloxamer 188, Pluronic® F127 (=poloxamer 407), Brij® 35 (=polyoxyl 23 lauryl ether), and LPCM (=α-lysophasphatidylcholine myristoyl) almost completely prevented increase in turbidy and absorbance, while a slighter increase in turbidity (as compared to the reference) was observed for Myrj® 59 (=polyoxyl 100 stearate) and Myrj® 52 (=polyoxyl 40 stearate).
Example 5 Chemical Stability of Aqueous Compositions Containing Methionine as Antioxidant
The compositions were prepared from a liquid bulk solution of rFVIIa. The methionine was dissolved in buffers containing NaCl, CaCl2, 2H2O, and glycylglycine in the concentrations stated above. The rFVIIa bulk and the methionine solutions were mixed, and the pH in the solutions was adjusted to 6.5. The compositions were filtered (0.2 μm) and filled in vials (1 ml solution per vial). The vials were stored at 5° C., 25° C. and 40° C. Samples were withdrawn and analysed for content of oxidized forms (by RP-HPLC) at the time point stated in the table below. The table shows the content of oxidised forms (in %).
25° C. 40° C. 25° C. 40° C. 5° C.
Methionine Time 14 14 28 28 90
(mg/ml) zero days days days days days
NaCl 11.68 mg/ml (200 mM)
The compositions are prepared from a liquid bulk solution of rFVIIa. The methionine is dissolved in buffers containing NaCl, CaCl2, 2H2O, and glycylglycine to obtain the concentrations stated above. The rFVIIa bulk and the methionine solutions are mixed, and the pH in the solutions is adjusted to 6.5. The compositions are filtered (0.2 μm) and filled in vials (1 ml solution per vial). The vials are stored at 5° C., 25° C. and 40° C. Samples are withdrawn and analysed for content of oxidized forms (in %) (by RP-HPLC) at the time point stated in the table above.
NaCl 2.92 mg/ml (50 mM; Composition 1)
11.68 mg/ml (200 mM; Composition 2)
23.36 mg/ml (400 mM; Composition 3)
46.42 mg/ml (800 mM; Composition 4)
58.4 mg/ml (1000 mM; Composition 5)
CaCl2, 2H2O 1.47 mg/ml (10 mM)
The compositions are prepared from a liquid bulk solution of rFVIIa. Calcium chloride is dissolved in buffers containing NaCl and glycylglycine to give the concentrations stated above after mixing with rFVIIa bulk. After mixing, the pH in the solutions are adjusted to 7.0. The compositions are filtered (0.2 μm) and filled in vials (1 ml solution per vial). The vials are stored at 5° C.
For each formulation the activity of factor VII (IU/ml) are determined by clot assay at 0 months (measuring IU/ml) and after 3 months of storage at 5° C. (measuring IU/ml). It is contemplated that the clot assays will show that the compositions containing at least 200 mM of sodium chloride (Compositions 2-5) have a higher clotting activity after 3 months of storage (higher IU/ml) compared to Composition 1.
For each formulation the formation of heavy chain fragments are measured by RP-HPLC as described in example 1. The results (as % fragments) are measured at 0 months as well as during storage at 5° C. and 30° C., respectively; The contents of heavy chain fragments (as % fragments) are measured at 1, 2, 3, and 6 months.
Example 7 Chemical Stability of Aqueous Compositions Containing Sodium Chloride
NaCl 0 mg/ml (0 mM; Composition 1)
29.2 mg/ml (500 mM; Composition 2)
43.8 mg/ml (750 mM; Composition 3)
58.4 mg/ml (1000 mM; Composition 4)
PIPES-di-Na 17.3 mg/ml (50 mM)
The compositions were prepared from a liquid bulk solution of rFVIIa. The liquid bulk solution was desalted into the desired compositions using PD-10 columns from Pharmacia. After desalting, the pH in the solutions were adjusted to 6.5. The compositions were filtered (0.22 μm) and filled in cartridges. The cartridges were stored at 5° C. For each formulation the content of heavy chain fragments (%) were measured by RP-HPLC (example 1) at various time points, data are listed in the table below.
Composition 0 ½ 1 2 3
1 11.6 15.6 19.0 24.1 27.8
2 12.2 13.2 15.3 16.7 18.9
3 12.2 13.2 14.6 16.0 18.1
4 12.2 13.0 14.4 15.3 17.1
5° C. (months)
Composition 0 3 11
1 100% 85% 67%*
4 100% 88% 82%
Example 8 Effect of Ionic Strength on Chemical Stability
B 58.4 1.47
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US9186323 * Apr 30, 2008 Nov 17, 2015 Novo Nordisk Healthcare Ag High concentration factor VII polypeptide formulations comprising an aromatic preservative and an antioxidant
US20100294677 * Apr 30, 2008 Nov 25, 2010 Novo Nordisk Health Care Ag High Concentration Factor VII Polypeptide Formulations Comprising an Aromatic Preservative and an Antioxidant
US20110104142 * May 22, 2009 May 5, 2011 Novo Nordisk Health Care Ag Formulations of peg-functionalised serine proteases with high concentrations of an aromatic preservative
US20110112029 * May 22, 2009 May 12, 2011 Novo Nordisk Health Care Ag Low viscosity compositions comprising a pegylated gla-domain containing protein
U.S. Classification 530/384
International Classification A61K47/02, A61K47/26, A61K47/18, A61K38/48
Cooperative Classification A61K47/183, A61K47/02, A61K31/19, A61K9/0019
European Classification A61K47/02, A61K31/19, A61K9/00M5, A61K47/18B