Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-28
2004-08-10
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S144000, C514S148000, C514S475000, C514S720000, C514S723000
Reexamination Certificate
active
06774123
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to methods and compositions for inactivating viruses in biological compositions.
Transmission of viral diseases (e.g., hepatitis A, B, and C, acquired immunodeficiency syndrome, cytomegalovirus infections) by blood or blood products is a significant problem in medicine. The screening of donor blood for viral markers can help reduce the transmission of viruses to recipients, but many screening methods are directed to only a few discrete viruses and are therefore incomplete or less than 100% sensitive. Furthermore, other biological compositions, such as mammalian and hybridoma cell lines, products of cell lines, milk, colostrum, and sperm, can contain infectious viruses as well.
It is therefore important to inactivate viruses contained in donor blood, blood products, or other biological compositions. At the same time, it is desirable to leave the structure and function of valuable constituents, such as red blood cells, platelets, leukocytes, proteins, and polysaccharides, relatively unchanged.
A number of virus inactivating agents have been developed empirically. For example, formalin, beta-propiolactone, and gamma radiation have been used to inactivate viruses. In addition, ethyleneimine monomer has been used to inactivate foot-and-mouth disease virus and binary ethyleneimine (i.e., ethyleneimine monomer generated by a combination of two reagents) has been used to inactivate feline enteric coronavirus.
Many of these agents modify viruses nonspecifically; methods using these agents can therefore be difficult to standardize and apply reproducibly. Furthermore, many of these agents inactivate only some of the viruses present in a given biological composition.
SUMMARY OF THE INVENTION
The invention features a method of inactivating a virus in a biological composition; the method includes the steps of (a) contacting the composition with an organic solvent under viral inactivating conditions, where the organic solvent is selected from the group consisting of (i) trialkylphosphates of the formula PO(OR
1
)(OR
2
)(OR
3
), where each of R
1
, R
2
, and R
3
is, independently, C
1-10
alkyl, (ii) ethers of the formula R
4
—O—R
5
, where each of R
4
and R
5
is, independently, a C
1
to C
18
alkyl or alkenyl radical which can contain an oxygen or sulfur atom, and (iii) alcohols of the formula R
6
—OH, where R
6
is a C
1
to C
18
alkyl or alkenyl radical which can contain 1 to 4 oxygen or sulfur atoms, inclusive, in the chain, and which can be substituted by 1 to 4 hydroxy groups, inclusive, and (b) contacting the composition with an ethyleneimine oligomer inactivating agent under viral inactivating conditions, where steps (a) and (b) are performed less than 24 hours apart. Preferably, the inactivating agent is ethyleneimine dimer or ethyleneimine trimer.
A preferred method further includes the step of (c) contacting the composition with a nonionic detergent, such as polyoxyethylene sorbitan monooleate, under viral inactivating conditions, where steps (a), (b), and (c) are performed less than 24 hours apart. Preferred solvents include tri-n-butyl phosphate, ethers of the formula R
4
—O—R
5
, where each of R
4
and R
5
is, independently, a C
1
to C
8
alkyl radical, and alcohols of the formula R
6
—OH, where R
6
is a C
1
to C
8
alkyl radical; a preferred detergent is polyoxyethylene sorbitan monooleate.
Preferably, steps (a), (b), and (c) are performed substantially simultaneously.
The invention also features a composition containing an organic solvent as described above, a non-ionic detergent, and an ethyleneimine oligomer inactivating agent.
The invention further features a method of inactivating a virus in a biological composition; the method includes the steps of (a) contacting the composition with an organic solvent under viral inactivating conditions, where the organic solvent is selected from the group consisting of (i) trialkylphosphates of the formula PO(OR
1
)(OR
2
)(OR
3
), where each of R
1
, R
2
, and R
3
is, independently, C
1-10
alkyl, (ii) ethers of the formula R
4
—O—R
5
, where each of R
4
and R
5
is, independently, a C
1
to C
18
alkyl or alkenyl radical which can contain an oxygen or sulfur atom, and (iii) alcohols of the formula R
6
—OH, where R
6
is a C
1
to C
18
alkyl or alkenyl radical which can contain 1 to 4 oxygen or sulfur atoms, inclusive, in the chain, and which can be substituted by 1 to 4 hydroxy groups, inclusive, and (b) contacting the composition with an inactivating agent under viral inactivating conditions, where the inactivating agent has the formula:
where each of R
1
, R
2
, R
3
, R
4
, R
6
, R
7
, and R
8
is, independently, H or a monovalent hydrocarbon moiety containing between 1 and 4 carbon atoms, inclusive, provided that R
1
, R
2
, R
3
, R
4
, R
6
, R
7
, and R
8
cannot all be H; R
5
is a divalent hydrocarbon moiety containing between 2 and 4 carbon atoms, inclusive; X is a pharmaceutically acceptable counter-ion; and n is an integer between 1 and 10, inclusive, where steps (a) and (b) are performed less than 24 hours apart.
A preferred method further includes the step of (c) contacting the composition with a nonionic detergent under viral inactivating conditions, where steps (a), (b), and (c) are performed less than 24 hours apart. In another preferred method, steps (a), (b), and (c) are performed substantially simultaneously.
The invention also features a composition including an organic solvent as described above, a non-ionic detergent, and an inactivating agent, where the inactivating agent has the formula:
where each of R
1
, R
2
, R
3
, R
4
, R
6
, R
7
, and R
8
is, independently, H or a monovalent hydrocarbon moiety containing between 1 and 4 carbon atoms, inclusive, provided that R
1
, R
2
, R
3
, R
4
, R
6
, R
7
, and R
8
cannot all be H; R
5
is a divalent hydrocarbon moiety containing between 2 and 4 carbon atoms, inclusive; X is a pharmaceutically acceptable counter-ion; and n is an integer between 1 and 10, inclusive.
The invention also features a method of inactivating a virus in a biological composition; the method includes the steps of (a) contacting the composition with an organic solvent under viral inactivating conditions, where the organic solvent is selected from the group consisting of (i) trialkylphosphates of the formula PO(OR
1
)(OR
2
)(OR
3
), where each of R
1
, R
2
, and R
3
is, independently, C
1-10
alkyl, (ii) ethers of the formula R
4
—O—R
5
, where each of R
4
and R
5
is, independently, a C
1
to C
18
alkyl or alkenyl radical which can contain an oxygen or sulfur atom, and (iii) alcohols of the formula R
6
—OH, where R
6
is a C
1
to C
18
alkyl or alkenyl radical which can contain 1 to 4 oxygen or sulfur atoms, inclusive, in the chain, and which can be substituted by 1 to 4 hydroxy groups, inclusive, and (b) contacting the composition with an inactivating agent under viral inactivating conditions, where the inactivating agent has the formula
&ohgr;-X
1
—[R
1
—N
+
(R
2
, R
3
)—]
n
R
4
.(X
2
−
)
n
where X
1
is Cl or Br; R
1
is a divalent hydrocarbon moiety containing between 2 and 4 carbon atoms, inclusive; each of R
2
, R
3
, and R
4
is, independently, H or a monovalent hydrocarbon moiety containing between 1 and 4 carbon atoms, inclusive; X
2
is a pharmaceutically acceptable counter-ion; and n is an integer between 2 and 10, inclusive, where steps (a) and (b) are performed less than 24 hours apart. Preferably, R
1
is ethylene; R
2
, R
3
, and R
4
are H; and n is 3 or 4.
A preferred method further includes the step of (c) contacting the composition with a nonionic detergent under viral inactivating conditions, where steps (a), (b), and (c) are performed less than 24 hours apart. In another preferred method, steps (a), (b), and (c) are performed substantially simultaneously.
The invention further features a composition including an organic solvent as described above, a non-ionic detergent, and an inactivating agent, where the inactivating agent has the formula:
&ohgr;-X
1
—[R
1
—N
+
(R
2
, R
3
)—&r
Ackerman Samuel K.
Budowsky Edward I.
Edson Clark M.
Purmal Andrei A.
Williams Martin D.
Travers Russell
V.I. Technologies, Inc.
Wolf Greenfield & Sacks P.C.
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