Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Free from infectious agents
Reexamination Certificate
2000-05-03
2002-11-26
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Free from infectious agents
C424S177100, C530S390100, C530S390500, C530S416000, C530S421000
Reexamination Certificate
active
06485725
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to an immunoglobulin preparation for intravenous injection, more specifically, a room temperature storable immunoglobulin liquid preparation for intravenous injection.
2. Description of the Related Art
Among &ggr;-globulins which are plasma protein components, an immunoglobulin preparation comprising IgG has been used for preventing and treating various infectious diseases. The immunoglobulin is unstable in the form of a solution. It is known that as a result of the aggregation of immunoglobulin, in other words, as a result of the denaturation of the immunoglobulin during the fractionating operation resulting in the formation of a polymer or dimer of immunoglobulin, the immunoglobulin shows a marked increase in the complement-fixing property which is called anticomplementary activity, leading to a) lowering the serum complement concentration upon intravenous administration to a human body or b) serious side effects such as anaphylactic shock. Accordingly, immunoglobulin has been formulated not as a liquid preparation but as a dry preparation, particularly, in a lyophilized form. However, the dry preparation is accompanied with the problem that it cannot be administered easily because of the necessity of dissolving it in distilled water for injection or the like upon use.
On the other hand, the liquid preparation does not require any dissolving operation in distilled water for injection or the like and can be administered easily compared with the dry preparation. As described above, however, it is accompanied with such drawbacks as inferiority in the stability of immunoglobulin. Accordingly, there has conventionally been an attempt to develop a liquid composition of immunoglobulin for intravenous injection having stability even in the form of a solution.
For example, JP-A-63-192724 (the term “JP-A” as used herein means an “unexamined published Japanese patent application” (U.S. Pat. No. 4,876,088, EP 278422)) discloses a liquid immunoglobulin composition for intravenous injection having stability even in the form of a solution, said composition having a low conductivity and pH of 5.5±0.2 and containing sorbitol as a stabilizer.
JP-A-58-43914 (U.S. Pat. Nos. 4,396,608 and 4,499,073, EP 73371) discloses that in order to obtain an immunoglobulin composition which is substantially free of an aggregate of immunoglobulin and has a monomer content of immune serum globulin exceeding about 90%, a solution of the immune serum globulin is adjusted to have an ionic strength less than about 0.001 and a pH of 3.5 to 5.0.
JP-A-9-124507 (EP 764447) discloses a step of lowering ionic strength at pH 3.5 to 5.0 in order to lower anticomplementary activity after a virus inactivation step by tri-(n-butyl) phosphate (TNBP) treatment of immunoglobulin.
JP-A-7-238036 (EP 702960) discloses that for the improvement of stability, the aggregation of immunoglobulin, in other words, an increase of not only a polymer of immunoglobulin but also a dimer of immunoglobulin is suppressed by acid treatment or storage at room temperature.
JP-W-59-501546 (the term “JP-W” as used herein means an “unexamined published Japanese international patent application”, WO 84-891) discloses ultrafiltration treatment of an immunoglobulin preparation at pH 5 to 5.6 in the presence of 0.05 to 2 w/v% polyethyleneglycol (PEG).
However, even considering the effects of the steps of the above disclosure, still there is room for improving storage stability of an immunoglobulin preparation, especially, storage stability of an immunoglobulin preparation in the form of a solution.
JP-A-63-8340 (U.S. Pat. Nos. 4,762,714 and 4,948,877, EP 240856) discloses a process for preparing immune serum globulin substantially free of an acquired virus, which comprises obtaining immune serum globulin from the human plasma source by the cold ethanol fractionating method at a pH of about 5.4 or lower and storing the immune serum globulin at a pH of about 4.25 or lower for at least about three days or storing it at a pH of about 6.8 or lower and a temperature of at least 45° C. so as not to contain an infectious retrovirus substantially. However, the above-described invention aims at the inactivation of a retrovirus. It has not been reported that the immunoglobulin preparation thus obtained shows an improvement in the aggregation-wise problem of immunoglobulin.
WO 95-3826 discloses the immunoglobulin preparation comprising 0.1 g/L or less of non-ionic surfactant as stabilizer for maintaining solution state, and being substantially free of albumin. However, the contaminated albumin cannot be detected in accordance with WO 95-3826 when it is in an amount of 1% or less as a relative ratio because of the sensitivity of the measuring method disclosed in said patent.
JP-A-63-183539 (U.S. Pat. No. 5,132,406, EP 246579) discloses a method for the production of immunoglobulin preparations for intravenous injection, which comprises a combination of a heat treatment step, a supernatant fraction recovering step by a fractionation treatment with 4 to 10% PEG and a precipitation fraction recovering step by a 10 to 15% PEG fractionation treatment.
SUMMARY OF THE INVENTION
As described above, immunoglobulin is essentially an unstable protein so that the stability thereof upon preparation of a liquid composition is one of the great concerns.
An object of the present invention is to overcome the above-described problem and hence to provide an immunoglobulin preparation having good storage stability even in the form of a solution.
This and other objects of the present invention have been accomplished by:
(1) a method for producing an immunoglobulin preparation for intravenous injection, which comprises the steps of:
fractionating an immunoglobulin-containing aqueous solution with 4 to 10 w/v% of polyethylene glycol having a molecular weight of from 1,000 to 10,000, at a pH value of from 4.5 to 6.5 at an ionic strength of from 0.0001 to 0.1 M and a temperature of from 0 to 4° C. to recover an immunoglobulin-containing supernatant fraction; and
concentrating the supernatant fraction at a pH of from 3.5 to 5.0;
(2) a method for producing the immunoglobulin preparation for intravenous injection according to the above (1) further comprises at least one, preferably all, of the steps of carrying out a virus inactivation treatment, recovering an unabsorbed fraction by an anion exchange treatment, carrying out a filtration treatment with a porous membrane having an average pore size of from 1 to 100 nm, and recovering an unabsorbed fraction by a contact treatment using colloidal silica; and
(3) an immunoglobulin preparation for intravenous injection which is prepared by the above-described production method (1) or (2), particularly an immunoglobulin liquid preparation for intravenous injection which is an immunoglobulin preparation for intravenous injection that contains a chemically unmodified (chemical modification-free) complete molecule type immunoglobulin and has a pH of from 5 to 6 and an electric conductivity of 1 mmho or less (calculated at 8° C.), wherein the preparation can be stored at room temperature for at least 1 year after the production and can maintain an anticomplementary activity at 20 units or less and a dimer content of the immunoglobulin at 7% or less constantly during the storage.
DETAILED DESCRIPTION OF THE INVENTION
(1) Starting Material
A fraction containing immunogubulin is used as a starting material. This fraction is not particularly limited in so far as it originates from human serum and contains an immunoglobulin fraction. Specific examples of such as immunoglobulin-containing fraction include Fraction II+III and Fraction II obtainable by ethanol fractionation of Cohn (E. J. Cohn et al.,
J. Am. Chem. Soc.,
68, 459 (1946)), and pastes of immunoglobulin-containing fractions equivalent thereto. The starting material may contain impurities, such as human blood-group antibodies, kallikrein, prekallikrein, IgM, IgG polymers, etc.
(2) Process
(a) Polyethylene Glycol (
Hashimoto Motonori
Hirao Yutaka
Kitamura Tae
Uemura Yahiro
Saunders David
Sughrue & Mion, PLLC
Welfide Corporation
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