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Liquid, aqueous, pharmaceutical compositions of factor VII polypeptides

A technology of composition, aqueous liquid, applied in the field of aqueous liquid pharmaceutical composition

Inactive Publication Date: 2006-05-31
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there are currently no commercially available ready-to-use liquid or concentrated Factor VII products

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0270] Preparation of the composition of the present invention

[0271] The present invention also provides, in another aspect, a process for the preparation of the aqueous liquid pharmaceutical composition of the present invention.

[0272] Accordingly, in one embodiment, a method of preparing an aqueous liquid pharmaceutical composition of a Factor VII polypeptide comprises the step of: providing the Factor VII polypeptide (i) in a solution comprising a compound suitable for maintaining the pH between about 5.0 and about 9.0 in the range of buffer (ii); while ensuring that in the final composition, uncoordinated calcium ions (Ca 2+ ) to a factor VII polypeptide molar ratio of less than 0.5.

[0273] Accordingly, in another embodiment, a method of preparing an aqueous liquid pharmaceutical composition of a Factor VII polypeptide comprises the step of providing the Factor VII polypeptide (i) in a solution comprising: - buffering agent (ii) in the range of about 9.0; at least...

Embodiment 1

[0345] Effect of Calcium Content in Example 1-rFVIIa Aqueous Solution on Heavy Chain Degradation (Autocatalytic Cracking)

[0346] In order to study the effect of calcium ions on rFVIIa, the following operations were performed:

[0347] rFVIIa (Mw-50,000) was transferred by desalting with a PD-10 column (Amersham Biosciences) into the following solution:

[0348] Product 1-1:

[0349] rFVIIa 1.0mg / mL

[0350] PIPES-di-Na 17.32mg / mL (50mM)

[0351] Add 1M NaOH or 1M HCl to pH 6.5

[0352] Ca 2+ / FVII ratio 0

[0353] Products 1-2:

[0354] rFVIIa 1.0mg / mL

[0355] Calcium chloride 2H 2 O 1.47mg / mL (10mM)

[0356] Sodium chloride 2.92mg / mL (50mM)

[0357] Glycylglycine 1.32mg / mL (10mM)

[0358] Sodium acetate 0.82mg / mL (10mM)

[0359] Histidine 1.55mg / mL (10mM)

[0360] 1M NaOH or 1M HCl added to pH 6.5

[0361] Ca 2+ / FVII ratio 500

[0362] The preparations were stored at 5°C or 25°C, respectively, and analyzed at the times indicated in Table 1.

[0363] ...

Embodiment 2

[0368] Effect of Calcium and Divalent Metal Ion Content on Heavy Chain Degradation in Example 2-rFVIIa Aqueous Solution (Autocatalytic Cracking)

[0369] In order to study the influence of calcium ions and divalent metal ions on rFVIIa, the following operations were performed:

[0370] rFVIIa was transferred by desalting with a PD-10 column (Amersham Biosciences) into the following solutions:

[0371] All products (2-1-2-8) included

[0372] rFVIIa 1.0mg / mL

[0373] Calcium chloride 2H 2 O 1.47mg / mL (10mM)

[0374] Sodium chloride 2.92mg / mL (50mM)

[0375] Glycylglycine 1.32mg / mL (10mM)

[0376] Histidine 1.55mg / mL (10mM)

[0377] Add 1M NaOH or 1M HCl to pH 6.5

[0378] Which further includes benzamidine and EDTA as shown in Table 2

[0379] Product number

Benzamidine

(mM)

EDTA

(mM)

uncomplexed calcium

Ions (mM)

Ca 2+ / rFVII

Ratio

2-1

10

0

about 10

500

2-2

10

9.9

...

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Abstract

The present invention relates to an aqueous liquid pharmaceutical composition comprising a factor VII polypeptide (eg human factor VIIa) and a buffer; wherein the molar concentration ratio of uncomplexed calcium ions (Ca2+) to factor VII polypeptide is less than 0.5. The composition may further include stabilizers (such as copper or magnesium ions, benzamidine or guanidine), nonionic surfactants, tonicity regulators, antioxidants and preservatives. The composition is useful in the treatment of factor VII-responsive syndromes, such as bleeding disorders, including: those disorders resulting from deficiencies of clotting factors (e.g., hemophilia A, hemophilia B, factor XI deficiency, factor VII deficiency), thrombocytopenia or Willebrand disease or bleeding disorders due to clotting factor inhibitors; and intracerebral hemorrhage or excessive bleeding from any cause. These formulations may also be administered to patients in conjunction with surgery or other trauma therapy or to patients receiving anticoagulant therapy.

Description

field of invention [0001] The present invention relates to aqueous liquid pharmaceutical compositions containing Factor VII polypeptides and methods of making and using such compositions, as well as containers containing such compositions and the use of such compositions in the treatment of Factor VII-responsive syndrome . More specifically, the present invention relates to liquid compositions stabilized against chemical and / or physical degradation. Background of the invention [0002] Various factors have been identified that are involved in the coagulation process, including Factor VII (FVII), a plasma glycoprotein. Coagulation is initiated by the formation of a complex between tissue factor (TF), which is exposed to the blood circulation after injury to the vessel wall, and FVIIa, which is present in the circulation in an amount equivalent to about 1% by mass of the total FVII protein. FVII exists mainly in plasma as a single-chain zymogen, which can be cleaved by Fxa i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/36A61J1/06A61K38/00A61P7/04C12N9/64
CPCA61K38/00A61P7/04C12N9/6424C12N9/64
Inventor M·B·詹森B·L·汉森T·科恩费尔特K·K·雅克布森J·科拉鲁普E·佩尔松A·K·佩特森A·N·鲍勒
Owner NOVO NORDISK AS
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