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Factor viii formulations

Inactive Publication Date: 2010-07-01
UNIV OF CONNECTICUT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]FVIII compositions of the present disclosure are, in one embodiment, formulated such that NaCl is not present in the final formulation or is present in trace amounts, which allows for a concomitant reduction in the lyophilization cycle time and increased stability of the lyophilized FVIII.
[0023]Methods of preparing a stable, lyophilized FVIII are provided in the present disclosure. In one embodiment, a method of preparing a stable, lyophilized FVIIII is provided comprising the steps of (a) preparing an aforementioned formulation; and (b) lyophilizing the formulation of step (a). In still another embodiment, the aforementioned method is provided wherein stability of the lyophilized FVIII is higher compared to a FVIII formulation that is lyophilized in the presence of sodium chloride.

Problems solved by technology

FVIII is known to be relatively unstable in therapeutic preparations.
The albumin and vWF used in currently marketed FVIII preparations are derived from human blood plasma, however, and the use of such material has certain drawbacks.
Because a large molar excess of albumin compared to FVIII is generally added in order to increase the stability of the FVIII in such preparations, it is difficult to characterize the FVIII protein itself in these preparations.
The addition of human-derived albumin to FVIII is also perceived as being a disadvantage with respect to recombinantly-produced FVIII preparations.
Although there exists an extensive literature focused on formulation and process development issues with freeze dried products, studies of freeze dried FVIII are limited to a study of formulations based upon use of NaCl as a bulking agent
A major complication in formulation development is the presence of sodium chloride in the bulk drug substance, which is generally introduced by the purification process.
Uncrystallized sodium chloride lowers the collapse temperature and may leave the product incapable of being manufactured in anything resembling an elegant product.
Further, the amorphous sodium chloride may compromise stability of the product.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials and Methods

Materials

[0117]The excipients used are analytical reagent grade. D-mannitol, trehalose, raffinose, sorbitol and sucrose were purchased from Pfanstiehl Lab. Inc. Glycine was obtained form Chattem Chemicals. M-hydroxyethyl starch, arginine, and alanine were obtained from Ajinomoto Co., Inc. Sodium chloride, calcium chloride and Tris base were obtained from Mallinckrodt Inc. Hepes, L-histidine and Polysorbate-80 were obtained from E. M. Science, Tanabe, Co. Inc. and Spectrum Int. Inc., respectively. Reduced glutathione was obtained from Sigma.

Formulation Preparation

[0118]The formulations described hereto were prepared using bulk drug substance (BDS), supplied by Baxter Healthcare Ltd. The BDS was composed of 3130 IU / ml rAHF (i.e., rFVIII); 50 mM Tris base, 0.4M NaCl, 0.1% polysorbate-80 (surfactant), 4 mM CaCl2, pH 7. The CaCl2 and surfactant are present to stabilize native conformation and reduce processing losses, respectively, and pH 7 was selected for optimal s...

example 2

[0125]Since variation in the level of NaCl is generally not acceptable, particularly in a commercial product, and since crystallization of a component is generally facilitated by increased concentration of that component relative to the other components, it was decided to add NaCl to increase the level to a value above the highest level expected in the process and sufficiently high so that crystallization of NaCl during the freezing step would be possible. Modulated Differential Scanning Calorimeter (MDSC) was used to study the freezing of various concentrations of sodium chloride in a formulation that further contained 0.02% (w / v) Polysorbate-80, mM Tris, 4 mM calcium chloride, and 2% (w / v) sucrose. For this experiment, 200 mM sodium chloride was used. Other concentrations could be used, including, but not limited to those in the range of 1 mM to 10000 mM, or 10 mM to 1000 mM or 100 mM to 500 mM, or 150 mM to 300 mM to ensure that complete crystallization of the sodium chloride occ...

example 3

[0127]The effect different concentrations of rAHF have on the stability of rAHF when the rAHF is exposed to stresses in different stages of freeze-drying was examined. Two samples containing different concentrations of rAHF, 600 and 60 IU / mL (corresponding to 150 & 15 μg / ml) were used without any stabilizer. The formulation composition for these samples was: 8% mannitol (bulking agent), 10 mM Tris buffer, 200 mM NaCl, 4 mM CaCl2, 0.02% Polysorbate-80, pH 7.0. A third sample used a formulation that employed 2% sucrose as a stabilizer in addition to these components. The drying process used, described in Table 1, produces product temperatures of about −42° C., which is sufficiently low to prevent collapse in most formulations; though this process was not optimized.

TABLE 1Freezing and lyophilization procedure for preliminary rAHFstability studies.Process stepDescriptionFreezingCool to +5° C., hold for 10 minutesCool to −5° C. at 1° C. / minute, hold for 20 minutesCool to −20° C. at 1° C....

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Abstract

A Factor VIII (FVIII) composition formulated such that NaCl is not present in the final formulation or is present in trace amounts, which allows for a concomitant reduction in the lyophilization cycle time and increased stability of the lyophilized FVIII.

Description

FIELD OF THE INVENTION[0001]Generally, the invention relates to a Factor VIII composition formulated such that NaCl is not present in the final formulation or is present in trace amounts, which allows for a concomitant reduction in the lyophilization cycle time and increased stability of the lyophilized Factor VIII.BACKGROUND OF THE INVENTION[0002]Factor VIII (FVIII) is a protein found in blood plasma, which acts as a cofactor in the cascade of reactions leading to blood coagulation. A deficiency in the amount of FVIII activity in the blood results in the clotting disorder known as hemophilia A, an inherited condition primarily affecting males. Hemophilia A is currently treated with therapeutic preparations of FVIII derived from human plasma or manufactured using recombinant DNA technology. Such preparations are administered either in response to a bleeding episode (on-demand therapy) or at frequent, regular intervals to prevent uncontrolled bleeding (prophylaxis).[0003]FVIII is kno...

Claims

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Application Information

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IPC IPC(8): A61K38/37A61P7/00
CPCA61K9/0019A61K9/19A61K47/02A61K47/10A61K38/37A61K47/183A61K47/20A61K47/26A61K47/18A61P7/00A61P7/04A61K47/34
Inventor PIKAL, MICHAELTCHESSALOV, SERGUEIBJORNSON, ERIKJAMEEL, FEROZBESMAN, MARC
Owner UNIV OF CONNECTICUT
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