Stable pharmaceutical composition containing viii factor

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a novel stable ready formulation of pharmaceutical composition containing VIII factor and can be used in treatment of hemophilia. Invention relates to a solid pharmaceutical composition prepared by lyophilization of an amino acid-free solution and comprising the following components: (a) VIII factor in the concentration 50-10000 IU/ml for human VIII factor or human recombinant VIII factor, or 50-10000 U/ml for swine VIII factor or swine recombinant VIII factor; (b) surfactant in the concentration above critical micellar concentration up to 1% (vol./vol.); (c) calcium chloride; (d) sucrose; (e) sodium chloride; (f) trisodium citrate, and (g) amino acids-free buffer in the concentration 1-50 mM with pH 6-8 before lyophilization and after dissolving in water for injection. Also, invention relates to a liquid pharmaceutical composition prepared after dissolving indicated stable solid pharmaceutical composition in sterile water optionally containing sodium chloride. Invention provides preparing a stable ready formulation of pharmaceutical composition of VIII factor wherein albumin is replaced with other stabilizing agents.

EFFECT: improved and valuable properties of pharmaceutical composition.

25 cl, 3 tbl, 3 ex

 

This invention relates to new stable pharmaceutical composition containing factor VIII.

Factor VIII is a well-known plasma protein, which is necessary for normal blood clotting and therefore, is applicable in the treatment of hemophilia.

For the treatment of hemophilia used or proposed to use several forms of factor VIII as an existing active substances for the treatment of hemophilia. They include the human factor VIII (such as active ingredients Humate® P, Monoclate® P, Immunate® or Hemofil® M), recombinant human factor VIII (such as rVIII SQ, which is described in WO 91/09122 (the active ingredient ReFacto®), or active ingredients Kogenate® or Recombinate®), porcine factor VIII (which is the active beginning of the product Hyate:C®sold Ipsen, Inc., USA) or recombinant porcine factor VIII (e.g., modified does not contain In-domain form of porcine factor VIII, such as those described in WO 01/68109 and identified as "POL1212", or the protein of SEQ ID NO:38 of the same patent application).

Stability of the finished shape has always been a problem for the pharmaceutical industry, dealing with the pharmaceutical compositions of factor VIII.

To stabilize these ready-made forms often used albumin. However, despite his interest stabilizer the abuser action albumin has the disadvantage that namely, that it is expensive and represents a danger, namely, that he can carry infectious particles such as prions. For these reasons, the pharmaceutical industry in recent years, seeking to replace albumin other stabilizing agents in the pharmaceutical compositions of factor VIII.

Several stable pharmaceutical compositions that do not contain albumin, already known to specialists with expertise in this area. For example:

- U.S. patent No. 5565427 describes stable does not contain albumin solution with the activity of factor VIII:C, containing the factor VIII:C, amino acid or one of its salts or homologues and detergent (such as Polysorbate 80 or tween® 80) or an organic polymer (such as polyethylene glycol).

- U.S. patent No. 5605884 describes a stable composition of factor VIII containing factor VIII and the environment of high ionic strength, which preferably consists of an aqueous solution containing a mixture of sodium chloride, calcium chloride and histidine as a buffer ion.

- U.S. patent numbers 5763401 and 5874408, both describe the stable does not contain albumin composition of recombinant factor VIII, recombinant factor VIII, glycine, histidine, sucrose, sodium chloride and calcium chloride.

- Patent No. 5962650 describes stable not contain asuu albumin composition of recombinant factor VIII which consists of an aqueous solution with a low concentration of oxygen containing recombinant factor VIII, calcium salt such as calcium chloride, and preferably an antioxidant, a nonionic surfactant (surfactant), sodium chloride or potassium, amino and mono - or disaccharide.

- U.S. patent No. 5972885 relates to pharmaceutical finished form for subcutaneous, intramuscular or intradermal injection, which contains a highly concentrated (at least 1000 IU/ml) of recombinant factor VIII and, preferably, one or more components selected from the group consisting (in particular) of sodium chloride or potassium, of calcium chloride, nonionic surfactant (e.g., poloxamer), mono - or disaccharide (preferably sucrose) and antioxidants (e.g., citric acid).

- PCT patent application WO 89/09784 describes a method of obtaining a stable concentrate of factor VIII, which includes the gel-filtration buffer solution containing the factor VIII and Tris(hydroxymethyl)methylamine, trinatriytsitrat, sodium chloride, sucrose and sodium chloride, followed by lyophilization of the resulting concentrate. Thus prepared, the factor VIII capable of withstanding temperatures up to 80aboutC for up to 72 hours.

- WO 94/07510 describes the composition of factor VIII, which is th stabilized by nonionic surfactant (for example, poloxamers, such as Polysorbate 80). This composition may also contain one or more elements selected from the group consisting (in particular) of sodium chloride or potassium, chloride, calcium, amino, mono - or disaccharide, such as sucrose.

Unexpectedly it was found that the solid pharmaceutical composition obtained by lyophilization of a solution that does not contain amino acids, containing the following components:

(a) factor VIII;

(b) surfactant (surfactant);

(C) calcium chloride;

(d) sucrose;

(e) sodium chloride;

(f) trinatriytsitrat and

(g) a buffer that does not contain amino acids;

moreover, the mentioned pharmaceutical composition has a pH of 6-8 before lyophilization and after recovery in water for injection, also detects stability over time.

Under the factor VIII in this application mean factor VIII, human, recombinant human factor VIII, porcine factor VIII, recombinant porcine factor VIII, or more generally any other recombinant factor VIII, which can be used to replace them.

Preferably, the factor VIII contained in the compositions according to this invention, is selected from porcine factor VIII or recombinant porcine factor VIII. Even more preferably, the factor VIII contained in the compositions according to Yes the resultant invention, is a recombinant porcine factor VIII, in particular not containing In-domain form of porcine factor VIII, such as the form described in the patent application WO 01/68109, i.e. modified porcine factor VIII with amino acid sequence SEQ ID NO:1 below:

SEQ ID NO:1:

Preferably, the surfactant is nonionic surfactant. Nonionic surfactants include, in particular, Polysorbate and block copolymers, such as poloxamer (i.e. copolymers of polyethylene and propylene glycol). According to a preferred variant of the present invention, the surfactant is a Polysorbate. More preferably, Polysorbate included in the composition in accordance with this invention will have an average degree of polymerization of from 20 to 100 Monomeric elementary parts (preferably about 80) and may be, for example, Polysorbate 80. Preferably also, the Polysorbate must be obtained from plants.

Preferably, the buffer does not contain amino acid is Tris(hydroxymethyl)methylamine (hereinafter abbreviated as "Tris").

Preferably also, the pH of this pharmaceutical composition prior to lyophilization and after Rast is orenia in water for injection will be 6.5-7.5 and more preferably approximately 7,0.

Preferably, the solid composition in accordance with this invention will be such that it can be obtained by lyophilization of a solution that does not contain amino acids that has:

(a) the concentration of factor VIII in the range of 50-10000 international units per ml for factor VIII human or recombinant human factor VIII or 50-10000 swine units per ml for porcine factor VIII or recombinant porcine factor VIII;

(b) the concentration of surfactant (surfactant) in the range of concentrations above the critical micellar concentration to 1% (vol./vol.);

(C) the concentration of calcium chloride in the range of 0.5-10 mm;

(d) the concentration of sucrose in the range of 5-50 mm;

(e) the concentration of sodium chloride in the range of 0.15-0.5 M;

(f) the concentration of triacrylate in the range of 1-50 mm and

(g) the concentration of the buffer does not contain amino acids, in the range of 1-50 mm.

To assess activity in international units of factor VIII product should be analyzed in comparison with the concentrate standard, such as standard NIBSC 95/608 the United Kingdom (UK) (NIBSC stands for national Institute for Biological Standards and Control).

Under the swine unit of factor VIII mean national standard unit of the United Kingdom, used NIBSC) in the UK. To assess activity in common is Zach porcine factor VIII test product analyzed in comparison with the national pork standard NIBSC 86/514 UK. As for recombinant porcine factor VIII, it should be clear that 1 unit of activity of recombinant porcine factor VIII equivalent to 1 unit of activity of porcine factor VIII.

More preferably, the solid composition in accordance with this invention will be such that it can be obtained by lyophilization of a solution that does not contain amino acids that has at least one of the following characteristics:

the concentration of factor VIII in the range of 100-5000 international units per ml for factor VIII human or recombinant human factor VIII or from 100-5000 swine units per ml for porcine factor VIII or recombinant porcine factor VIII;

the concentration of surfactant (surfactant) in the range of 0.002%-0,04% (vol./vol.);

the concentration of calcium chloride in the range of 1-5 mm;

the concentration of sucrose in the range of 5-25 mm;

the concentration of sodium chloride in the range of 0.2-0.4 M;

the concentration of triacrylate in the range of 1-20 mm, or

the concentration of the buffer does not contain amino acids, in the range of 1-20 mm.

Even more preferably, the solid composition in accordance with this invention will be such that it can be obtained by lyophilization of a solution that does not contain amino acids that has at least one of the following characteristics:

the concentration of factor VIII in dia is the azone 200-2000 international units per ml (and in particular, approximately 1000 international units/ml) for factor VIII human or recombinant human factor VIII or 200-2000 swine units per ml (and, in particular, approximately 1000 swine units per ml) for porcine factor VIII or recombinant porcine factor VIII;

the concentration of surfactant (surfactant) in the range of 0.002%to-0.02%(vol./about.) (and, in particular, about 0.01% vol./vol.);

the concentration of calcium chloride in the range of 1-3 mm (and, in particular, approximately 2 mm);

the concentration of sucrose in the range of 5-15 mm and, in particular, approximately 11.7 mm);

the concentration of sodium chloride in the range of 0.25-0.35 M (and, in particular, approximately 0.3 M);

the concentration of triacrylate in the range of 1-20 mm and, in particular, approximately 10 mm) or

the concentration of the buffer does not contain amino acids, in the range of 5-15 mm and, in particular, approximately 10 mm).

Solid compositions of factor VIII according to this invention, can be obtained by lyophilization of a solution containing appropriate amounts identified above components, such as (a), (b), (c), (d), (e), (f) and (g), in accordance with the standard procedures of preparation (sterile conditions and so on).

The stability of the composition over a given period of time may be determined, for example, the method described here, in part, zaglav the military "Analytical methods", or any other means found suitable way, a specialist with expertise in this field.

The composition of this invention is stable for a certain period of time, if 70-130% (and preferably 80-120%) of the original activity of factor VIII, measured using the method described in the part entitled "Analytical methods", below, is maintained during the specified period of time.

Preferably, the solid compositions of this invention are stable for at least 6 or 12 months when stored at 2-8 °C. More preferably, they will be stable for at least 6 or 12 months when stored at a temperature of 30-32°C.

Solid compositions of factor VIII of the present invention may be diluted with sterile water, optionally containing sodium chloride, and then the resulting liquid pharmaceutical composition may inetservices directly to the patient in need. The liquid pharmaceutical composition, and liquid pharmaceutical composition obtained by dilution of the solid compositions of factor VIII, in accordance with this invention, the sterile water containing sodium chloride, are also part of this invention.

Treatment of hemophilia, predusmatriva the matter of introduction of the liquid composition of the present invention to the patient, needy, are also within the scope of this invention. By way of introduction of the liquid compositions of the present invention is preferably intravenous. Dose compositions of the present invention, which shall be administered will be determined by the attending physician or veterinarian, taking into account the severity of the disease for each patient.

The term "approximately" refers to the interval about the considered values. In the application for this patent application, "approximately X" means the interval from X minus 10% of X to X plus 10% of X, preferably the interval from X minus 5% of X to X plus 5% of X.

If not indicated otherwise, all technical and scientific terms used herein have the same meaning, what is usually understood by a specialist with average skills in the field to which this invention. Similarly, all publications, patent applications, all patents and other references mentioned herein incorporated by reference.

The following examples are presented to illustrate the above description and in any case should not be construed as limiting the scope of the invention.

EXAMPLES

Example 1

Prepare a solution in 0.5 ml of sterile water containing the following components:

Modified porcine factor VIII after which outermost SEQ ID NO:1 800 swine units/ml
Derived from plants Polysorbate 800,01% vol./about.
Calcium chloride2 mm
Sucrose11.7 mm
Sodium chloride0.3 M
Trinatriytsitrat10 mm
Tris-buffer10 mm
PH7,0

This mixture lyophilizer in a sterilized vial, which is then sealed. The obtained solid composition felt, and it was shown that it is stable at a temperature of 2-8°C for at least 18 months and at 30-32°C for at least six months when tested on the activity of factor VIII. No indications for the formation of high-molecular component, as defined distribution gel-exclusion VIH (SEC HPLC), or fragments, as determined by electrophoresis in LTO-PAG.

The obtained freeze-dried mixture usually recover in the form of a solution using 1.0 ml of sterile water before injection into the patient.

Example 2

Prepare a solution in 1.0 ml of sterile water containing the following components:

Modified porcine factor VIII sequence SEQ ID NO:1400 swine units/ml/td>
Derived from plants Polysorbate 800,002% vol./about.
Calcium chloride2 mm
Sucrose11.7 mm
Sodium chloride0.3 M
Trinatriytsitrat10 mm
Tris-buffer10 mm
pH7,0

This mixture lyophilizer in a sterilized vial, which is then sealed.

The obtained freeze-dried mixture is usually dissolved using 2.0 ml of sterile water before injection into the patient.

Example 3

Prepare a solution in 0.5 ml of sterile water containing the following components:

Obtained from plasma porcine factor VIII100 swine units/ml
Derived from plants Polysorbate 800,01% vol./about.
Calcium chloride2 mm
Sucrose11.7 mm
Sodium chloride0.3 M

This mixture lyophilizer in a sterilized vial, which is then sealed.

The obtained freeze-dried mixture usually recover in the form of a solution using 1.0 ml of sterile water before injection into the patient.

Analytical methods

Chromogenic analysis

The activity of factor VIII define a modified chromogenic assay (Technochrom FVIII:C Reagent Kit, Technoclone). The formation of activated factor X by factor IX stimulating factor VIII, which acts in this reaction as a cofactor. The release of p-nitroaniline from this chromogenic substrate to catalyze activated factor X. the Number of p-nitroaniline released, measured photometrically at nm, and this analysis gives a linear correlation between the amount of p-nitroaniline and content of factor VIII (FVIII).

SEC HPLC

Soluble macromolecular components and fragments was determined by gel filtration performed on a HPLC instrument (VGH) using a pre-Packed column 0,78×30 cm TosoHaas TSK G3000 SWXL with a fluorescence detector (Waters LC Module 1 plus). The wavelength of excitation 280 nm and the wavelength of emission of 340 nm. The evaluation of the results was performed by integration of peak areas.

Analysis using electrophoresis in LTO-PAG

Electrophoresis in LTO-SDS page (polyacrylamide gel electrophoresis using electrophoresis with the use of plates (Multiphor II, LKB) and preformed 7.5% gels (EXCELGEL SDS, Pharmacia) was used to determine any degradation products of the FVIII molecule. Protein bands were visualized by staining Kumasi blue.

Analysis of the stable is a major

The stability can be analyzed by performing the above analyses at different time points on the sample of the same composition, maintained at the desired temperature (which may be a temperature of about +4°or +31°). After the activity of factor VIII falls more than 30%, believe that the song has lost its stability.

1. Solid pharmaceutical composition obtained by lyophilization of a solution of free amino acids containing

(a) factor VIII in a concentration of from 50 to 10,000 international units/ml of factor VIII human or recombinant human factor VIII, or from 50 to 10,000 units/ml porcine factor VIII or recombinant porcine factor VIII;

(b) a surfactant at a concentration above the critical micellar concentration up to 1% vol./vol.;

(c) calcium chloride in a concentration of from 0.5 to 10 mm;

(d) sucrose at a concentration of from 5 to 50 mm;

(e) sodium chloride at a concentration of from 0.15 to 0.5 M;

(f) trinatriytsitrat in a concentration of from 1 to 50 mm and

(g) a buffer free of amino acids in a concentration of from 1 to 50 mm;

having a pH value of from 6 to 8 before lyophilization and after reconstitution in water for injection.

2. Solid pharmaceutical composition according to claim 1, wherein the factor VIII selected from porcine factor VIII or recombine the aqueous porcine factor VIII.

3. Solid pharmaceutical composition according to claim 2, wherein the factor VIII is recombinant porcine factor VIII.

4. Solid pharmaceutical composition according to claim 2, characterized in that the recombinant porcine factor VIII has the amino acid sequence SEQIDNO:1.

5. Solid pharmaceutical composition according to any one of claims 1 to 4, characterized in that the surfactant is a Polysorbate.

6. Solid pharmaceutical composition according to claim 5, characterized in that the surfactant is Polysorbate 80.

7. Solid pharmaceutical composition according to claim 1, characterized in that the buffer does not contain amino acid is Tris(hydroxymethyl)methylamine.

8. Solid pharmaceutical composition according to claim 1, which, prior to lyophilization and after reconstitution in water for injection has a pH of 6.5 to 7.5.

9. Liquid pharmaceutical composition obtained after dissolution of the solid pharmaceutical composition according to claim 1 sterile water, optionally containing sodium chloride.

10. Solid pharmaceutical composition according to claim 2, characterized in that the buffer is free from amino acid is Tris(hydroxymethyl)methylamine.

11. Solid pharmaceutical composition according to claim 3, characterized in that the buffer is free from amino acid is Tris(hydroxymethyl)methylamine.

12. Solid pharmaceutical composition according to claim 4, the tives such as those that the buffer is free from amino acid is Tris(hydroxymethyl)methylamine.

13. Solid pharmaceutical composition according to claim 5, characterized in that the buffer is free from amino acid is Tris(hydroxymethyl)methylamine.

14. Solid pharmaceutical composition according to claim 6, characterized in that the buffer is free from amino acid is Tris(hydroxymethyl)methylamine.

15. Solid pharmaceutical composition according to claim 2, which before lyophilization and after reconstitution in water for injection has a pH of 6.5 to 7.5.

16. Solid pharmaceutical composition according to claim 3, which before lyophilization and after reconstitution in water for injection has a pH of 6.5 to 7.5.

17. Solid pharmaceutical composition according to claim 4, which before lyophilization and after reconstitution in water for injection has a pH of 6.5 to 7.5.

18. Solid pharmaceutical composition according to claim 5, which before lyophilization and after reconstitution in water for injection has a pH of 6.5 to 7.5.

19. Solid pharmaceutical composition according to claim 6, which before lyophilization and after reconstitution in water for injection has a pH of 6.5 to 7.5.

20. Solid pharmaceutical composition according to claim 7, which before lyophilization and after reconstitution in water for injection has a pH of 6.5 to 7.5.

21. Solid pharmaceutical composition according to claim 4, which can be obtained by lyophilization of a solution, make the tion from amino acids, with

(a) the concentration of factor VIII in the range from 50 to 10,000 international units/ml of factor VIII human or recombinant human factor VIII, or from 50 to 10,000 units/ml porcine factor VIII or recombinant porcine factor VIII;

(b) the concentration of surfactant in the range of concentrations above the critical micellar concentration up to 1% vol./vol.;

(c) the concentration of calcium chloride in the range from 0.5 to 10 mm;

(d) the concentration of sucrose in the range from 5 to 50 mm;

(e) the concentration of sodium chloride in the range from 0.15 to 0.5 M;

(f) the concentration of triacrylate in the range from 1 to 50 mm and the concentration of buffer in the range from 1 to 50 mm.

22. Solid pharmaceutical composition according to claim 5, which can be obtained by lyophilization of a solution, free amino acids, having

(a) the concentration of factor VIII in the range from 50 to 10,000 international units/ml of factor VIII human or recombinant human factor VIII, or from 50 to 10,000 units/ml porcine factor VIII or recombinant porcine factor VIII;

(b) the concentration of surfactant in the range of concentrations above the critical micellar concentration up to 1% vol./about;

(c) the concentration of calcium chloride in the range from 0.5 to 10 mm;

(d) the concentration of sucrose in the range from 5 to 50 mm;

(e) concentration is the situation of sodium chloride in the range from 0.15 to 0.5 M;

(f) the concentration of triacrylate in the range from 1 to 50 mm and the concentration of buffer in the range from 1 to 50 mm.

23. Solid pharmaceutical composition according to claim 6, which can be obtained by lyophilization of a solution, free amino acids, having

(a) the concentration of factor VIII in the range from 50 to 10,000 international units/ml of factor VIII human or recombinant human factor VIII, or from 50 to 10,000 units/ml porcine factor VIII or recombinant porcine factor VIII;

(b) the concentration of surfactant in the range of concentrations above the critical micellar concentration up to 1% vol./vol.;

(c) the concentration of calcium chloride in the range from 0.5 to 10 mm;

(d) the concentration of sucrose in the range from 5 to 50 mm;

(e) the concentration of sodium chloride in the range from 0.15 to 0.5 M;

(f) the concentration of triacrylate in the range from 1 to 50 mm and the concentration of buffer in the range from 1 to 50 mm.

24. Solid pharmaceutical composition according to claim 7, which can be obtained by lyophilization of a solution, free amino acids, having

(a) the concentration of factor VIII in the range from 50 to 10,000 international units/ml of factor VIII human or recombinant human factor VIII, or from 50 to 10,000 units/ml porcine factor VIII or recombinant porcine factor VIII;

(b) concentric the Yu surfactant in the range of concentrations above the critical micellar concentration up to 1% vol./vol.;

(c) the concentration of calcium chloride in the range from 0.5 to 10 mm;

(d) the concentration of sucrose in the range from 5 to 50 mm;

(e) the concentration of sodium chloride in the range from 0.15 to 0.5 M;

(f) the concentration of triacrylate in the range from 1 to 50 mm and the concentration of buffer in the range from 1 to 50 mm.

25. Solid pharmaceutical composition of claim 8, which can be obtained by lyophilization of a solution, free amino acids, having

(a) the concentration of factor VIII in the range from 50 to 10,000 international units/ml of factor VIII human or recombinant human factor VIII, or from 50 to 10,000 units/ml porcine factor VIII or recombinant porcine factor VIII;

(b) the concentration of surfactant in the range of concentrations above the critical micellar concentration up to 1% vol./vol.;

(c) the concentration of calcium chloride in the range from 0.5 to 10 mm;

(d) the concentration of sucrose in the range from 5 to 50 mm;

(e) the concentration of sodium chloride in the range from 0.15 to 0.5 M;

(f) the concentration of triacrylate in the range from 1 to 50 mm and the concentration of buffer in the range from 1 to 50 mm.



 

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10 cl, 15 ex, 6 tbl

FIELD: medicine.

SUBSTANCE: preparation comprises echinocandine substance of formula I or its pharmaceutically permissible salt, pharmaceutically permissible micelle-forming surface-active agent and non-toxic aqueous solvent and stabilizing agent.

EFFECT: improved stability and bioaccessibility properties.

48 cl, 4 tbl

FIELD: medicine, pharmaceuticals.

SUBSTANCE: invention relates to pharmaceutical agent containing factor VII or factor VII-related polypeptide and factor VIII or factor VIII-related polypeptide. Disclosed are application of factor VII or factor VII-related polypeptide and factor VIII or factor VIII-related polypeptide in production of drug, kit for episodic bleeding treatment, as well as methods for prophylaxis and treatment of episodic bleeding in subject.

EFFECT: accelerated coagulation of FVIII-deficit plasma.

43 cl, 1 tbl, 2 dwg, 6 ex

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