Methods of production and use of liquid formulations of plasma proteins

Inactive Publication Date: 2004-02-17
THE COALITION FOR HEMOPHILIA B +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

A third advantage of the present invention is the ability to store the plasma protein without the additional cost and restriction of refrigeration. While the present invention demonstrates as an example extended storage of Factor IX under refrigeration, 4.degree. C., for over one year without loss of activity, it also demonstrates storage at body temperature, 37.degree. C., for over one month. For situations where refrigeration is not possible, the present invention permits the storage of ready-to-inject plasma proteins at room temperature, for use either prophylactically or in emergency situations.
A fourth advantage of the present invention is the ability to prophylactically treat congenital or acquired plasma protein deficiency in a manner that provides a continuous level of the plasma protein that more closely resembles the level found in normal plasma and achieves normal hemostasis. It is the uninterrupted condition of normal hemostasis that prevents the progressive, cumulative, unrepairable tissue damage that permanently debilitates patients. The elimination of the risk of bleeding episodes and their consequent damage also significantly enhances the quality of life for the patients and their families, enabling younger patients to more fully parti

Problems solved by technology

Repeated bleeding into joints results in hemarthroses, causing painful crippling anthropathy that often necessitates joint replacement.
Hematomas in soft tissues can result in pseudo tumors composed of necrotic coagulated blood; they can obstruct, compress, or rupture into adjacent organs and can lead to infection.
Once formed the hematomas are difficult to treat, even with surgery.
Recovery of nerves after compression is poor, resulting in palsy.
Those bleeding episodes that involve the gastrointestinal

Method used

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  • Methods of production and use of liquid formulations of plasma proteins
  • Methods of production and use of liquid formulations of plasma proteins
  • Methods of production and use of liquid formulations of plasma proteins

Examples

Experimental program
Comparison scheme
Effect test

Example

EXAMPLE 1

Effect of Buffer, Divalent Cations, and Other Excipients on the Stability of Coagulation Factor IX

CFIX-M (JHL) / DEAE was dialyzed into 0.01 M histidine, 0.1 M NaCl, pH 6.8 (histidine-saline) or was left in 0.02 M sodium citrate (NaCit), 0.11 NaCl, pH 6.8 (citrate-saline). An aliquot of the solution was mixed with an equal volume of 2X additive, prepared at twice the desired final concentration in the appropriate buffer (histidine-saline or citrate-silane). The formulated solutions were sterile filtered, aseptically dispensed into sterilized tubes, incubated at 37.degree. C. or 4.degree. C. for the designated length of time, and frozen until the end of the study, when the samples were thawed and assayed.

Factor IX coagulation assays were performed by a one-stage method using Kontakt brand APTT (Pacific Haemostasis) and congenital Factor IX-deficient plasma (George King or Universal Reagents). The standard was a lyophilized CFIX-SD concentrate. Working dilutions of Factor IX we...

Example

EXAMPLE 2

Effect of Various Excipients on Stability of Coagulation Factor IX in Histidine-saline

CFIX-M (JHL) in citrate-saline was diluted 1:10 in 0.01 M histidine, 0.1 M NaCl, pH 6.8 (histidine-saline) to give a final composition of 0.009 M histidine, 0.002 M citrate, 0.1 M NaCl, pH 6.8 (Buffer A) or was dialyzed against histidine-saline (Buffer B). Thereafter, the samples were treated as in Example 1, above, with the following changes:

(1) Samples were incubated at 37.degree. C., as indicated on the table below.

(2) Factor IX coagulation assays were performed on a Lancer Coagulyzer II.

Results

The stability of samples is shown in Table 2, below:

TABLE 2 In Vitro Half-life (T.sub.1 / 2 in Days) of Clotting Activity of Factor IX-M at 37.degree. C. NUMBER FORMULATION T.sub.1 / 2 (DAYS) 1 0.009M Histidine, 0.002M citrate, 0.1M NaCl, 2.2 pH 6.0 2 0.009M Histidine, 0.002M citrate, 0.1M NaCl, 4.2 pH 8.0 3 0.009M Histidine, 0.002M citrate, 0.1M NaCl, 5.0 pH 6.8 (Buffer A) 4 0.05M Glycine in Buffer ...

Example

EXAMPLE 3

Effect of pH, Purity and Excipients on Stability of Coagulation Factor IX

Factor IX-M (JHL) with or without DEAE polishing, CFIX-SD, and ine in ARC formulation (ARC / A9) were treated as in Example 2 above.

Results

The stability of samples is shown in Table 3, below:

TABLE 3 In Vitro Half-life (T.sub.1 / 2 in Days) of Clotting Activity of Factor IX at 37.degree. C. T.sub.1 / 2 NO. FORMULATION pH FIX 37.degree. C. 1 0.01M Hist / 0.1M NaCl + 10 mM CaCl.sub.2 6.8 DEAE 49 2 0.01M Hist / 0.1M NaCl 6.8 DEAE 12 3 Hist / NaCl + 20% Sucrose + 10 mM 6.8 DEAE 42 CaCl.sub.2 4 Hist / NaCl + 0.5M Glycine + 20% 6.8 DEAE 37 Sucrose + 10 mM CaCl.sub.2 5 Hist / NaCl + 10 mM CaCl 6.8 CFIX-SD 18* 6 Hist / NaCl 6.9 CFIX-SD 7 7 Hist / NaCl + 10 mM CaCl.sub.2 6.8 ARC / A9 17 8 Hist / NaCl 6.9 ARC / A9 2.5 9 Hist / NaCl + 10 mM CaCl.sub.2 6.0 DEAE 43 10 Hist / NaCl + 10 mM CaCl.sub.2 6.8 DEAE 43 11 Hist / NaCl + 10 mM CaCl.sub.2 7.4 DEAE 35 12 Hist / NaCl + 10 mM CaCl.sub.2 8.0 DEAE 16 13 Hist / NaCl + 0.5M Lysine + 10 mM 6.8 DEAE 6 CaC...

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Abstract

The present invention relates to the preparation and use of liquid formulations of plasma proteins, particularly blood coagulation factors. More specifically, the present invention relates to stable liquid formulations of Factor VIII and Factor IX that can be administered by injection or infusion to provide a constant level of the coagulation factor in the blood.

Description

FIELD OF THE INVENTIONThe present invention relates to the preparation and use of liquid formulations of plasma proteins, particularly blood coagulation factors. More specifically, the present invention relates to stable liquid formulations of Factor VIII and Factor IX and to the treatment of congenital or acquired deficiencies of plasma proteins by continuous injection or infusion of these formulations to provide a constant level of the coagulation factor in the blood.BACKGROUND OF THE INVENTIONCoagulationCoagulation of blood occurs by either the "intrinsic pathway" or the "extrinsic pathway", whereby certain blood proteins interact in a cascade of proteolytic activations to ultimately convert soluble fibrinogen to insoluble fibrin. These threads of fibrin are cross-linked to form the scaffolding of a clot; without fibrin formation, coagulation cannot occur.The intrinsic pathway consists of seven steps: (1) the proteolytic activation of Factor XII; (2) activated Factor XII cleaves ...

Claims

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Application Information

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IPC IPC(8): A61K38/43A61K38/36A61K38/37A61K38/48A61K47/02A61K47/16A61K47/10A61K47/18
CPCA61K38/37A61K38/4846A61K47/02A61K47/10A61K47/183
Inventor MIEKKA, SHIRLEY I.DROHAN, WILLIAM N.JAMESON, THOMAS R.TAYLOR, JR., JOHN R.SINGH, MANISH P.MACPHEE, MARTIN J.
Owner THE COALITION FOR HEMOPHILIA B
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