Pharmaceutical compositions comprising fluorinated co-polymers

Details Pharmaceutical compositions comprising fluorinated co-polymers Pharmaceutical compositions comprising fluorinated co-polymers

1999-08-05

2001-11-13

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic nonactive ingredient containing other...

C514S785000, C514S788000, C514S937000, C514S941000, C514S975000, C525S056000, C525S326900, C525S327100, C525S329400, C525S403000, C525S408000, C525S409000, C525S410000, C525S411000, C525S417000, C527S310000, C527S313000, C527S315000, C528S401000, C528S402000, C536S123100, C560S158000, C560S179000, C560S180000, C560S182000, C560S184000, C564S159000, C568S615000, C544S148000, C544S149000, C544S159000, C548S266200, C548S266600, C548S267400, C548S519000, C548S523000, C548S524000, C546S255000, C546S256000

Reexamination Certificate

active

06316505

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention pertains to block copolymer of the formula:
R
1
—L
1
—{R
2
—L
2
—M}
w
—L
4
—R
4
—L
3
—R
3
  IA.
in which:
either (i) R
1
is a monovalent fluorinated hydrocarbon of 2 to 50 carbon atoms and R
2
is a divalent hydrocarbon of 2 to 50 carbon atoms or (ii) R
1
is a monovalent hydrocarbon of 2 to 50 carbon atoms and R
2
is a divalent fluorinated hydrocarbon of 2 to 50 carbon atoms;
R
3
is (i) hydrogen, (ii) a monovalent fluorinated hydrocarbon of 2 to 50 carbon atoms, or (iii) a monovalent hydrocarbon of 2 to 50 carbon atoms;
R
4
is (i) a bond if R
3
is hydrogen; (ii) a divalent hydrocarbon of 2 to 50 carbon atoms if R
3
is a fluorinated hydrocarbon, or (iii) a divalent fluorinated hydrocarbon of 2 to 50 carbon atoms if R
3
is a hydrocarbon;
each of L
1
and L
2
, independently of the other, is a linking group;
L
3
and L
4
taken together with R
4
, is a bond if R
3
is hydrogen or if R
3
is other than hydrogen each of L
3
and L
4
, taken independently is a linking group;
M is a hydrophilic homopolymer or copolymer comprising at least three monomeric units each having the same or different pendant group containing at least atom selected from the group consisting of oxygen and nitrogen; and
w has a value of from 1 to 100.
The present invention also pertains to improved formulations for the administration of a pharmaceutical agent containing at least one block copolymer of Formula I.
These block copolymers can have profound effects on the therapeutic profile of the drug. They can, for example, produce an improvement in the therapeutic index of the drug; i.e., either or both of a decrease in side effects and an increase in therapeutic activity. While the mechanism is not know with certainty, it appears the block copolymers result in one or more of an enhancement of transport into cells and biological barriers such as histohematic barriers which separate the target cells from the perfusing blood; a decrease in sequestration of drug in organs of reticuloendothelial system; a decrease drug metabolism; and an increase drug circulation time in the body.
Moreover with antineoplastic agents, an increase in transport of the drug to solid tumors and a reverse multiple drug resistance often can be observed.
The hydrophilic homopolymer or copolymer M will contain at least three monomeric units, each of which unit will have the same or different pendant group. Each pendant group will contain at least one atom selected from the group consisting of oxygen and nitrogen. Representative hydrophilic homopolymers or copolymers include polyethylene oxides, copolymers of ethylene oxide and propylene oxide, polysaccharides, polyacrylamides, polygycerols, polyvinylalcohols, polyvinylpyrrolidones, polyvinylpyridine N-oxides, copolymers of vinylpyridine N-oxide and vinylpyridine, polyoxazolines, and polyacryloylmorpholine.
Preferably M is
in which each of m and j has a value of from 3 to 5000.
One preferred subgroup includes block copolymers of the formula:
R
1
—L
1
—R
2
—L
2
—(C
2
H
4
O)
n
—L
4
—R
4
—L
3
—R
3
  IB.
in which:
(i) R
1
is a monovalent fluorinated hydrocarbon of 2 to 50 carbon atoms and R
2
is a divalent hydrocarbon of 2 to 50 carbon atoms or (ii) R
1
is a monovalent hydrocarbon of 2 to 50 carbon atoms and R
2
is a divalent fluorinated hydrocarbon of 2 to 50 carbon atoms;
n has a value of from 3 to 50 or higher; i.e. 3 to about 200;
R
3
is (i) hydrogen, (ii) a monovalent fluorinated hydrocarbon of 2 to 50 carbon atoms, or (iii) a monovalent hydrocarbon of 2 to 50 carbon atoms;
R
4
is (i) a bond if R
3
is hydrogen; (ii) a divalent hydrocarbon of 2 to 50 carbon atoms if R
3
is a fluorinated hydrocarbon, or (iii) a divalent fluorinated hydrocarbon of 2 to 50 carbon atoms if R
3
is a hydrocarbon;
each of L
1
and L
2
, independently of the other, is a linking group; and
L
3
and L
4
taken together with R
4
, is a bond if R
3
is hydrogen or if R
3
is other than hydrogen each of L
3
and L
4
, taken independently is a linking group.
Within this subgroup, particularly preferred block copolymers are those of the formula:
R
1
—L
1
—{R
2
—L
2
—M}
w
—L
4
—R
4
—L
3
—R
3
  IC.
in which:
either R
1
is a monovalent hydrocarbon of 2 to 50 carbon atoms;
R
2
is a divalent fluorinated hydrocarbon of 2 to 50 carbon atoms;
(i) R
3
is hydrogen, R
4
, L
3
, and L
4
taken together are a bond or
(ii) R
3
is a monovalent hydrocarbon of 2 to 50 carbon atoms, R
4
is a divalent fluorinated hydrocarbon of 2 to 50 carbon atoms, and each of L
1
and L
2
, independently of the other, is a linking group;
M is a hydrophilic homopolymer or copolymer comprising at least three monomeric units each having the same or different pendant group containing at least atom selected from the group consisting of oxygen and nitrogen; and
w has a value of from 1 to 100.
These block copolymers can be viewed as compose of at least three units: a fluorocarbon block, a hydrocarbon block, and a polyoxyethylene block. In a first embodiment, in which R
3
is hydrogen and L
3
and L
4
taken together with R
4
are a bond, the polyoxyethylene block constitutes one terminus of the copolymer with one of either the fluorocarbon block or the hydrocarbon block constituting the other terminus (R
1
) and the other (R
2
) positioned between. This first embodiment may be viewed as encompassing compounds of the formula:
C
x
F
y
H
z
—L
1
—C
q
H
2q
—L
2
—(C
2
H
4
O)
n
—H  IIA.
in which x has a value of from 2 to 50; y has a value of from 1 to 2x+1, preferably x to 2x+1; z has a value of 2x−y+1; q has a value of from 2 to 50; n has a value of from 3 to 200; and each of L
1
and L
2
, independently of the other, is a linking group, and compounds of the formula:
C
q
H
2q+1
L
1
—C
x
F
z
—L
2
—(C
2
H
4
O)
n
—H  IIB.
in which x, q, n, L
1
, and L
2
are as just defined; y has a value of from x to 2x; and z has a value of 2x−y.
In a second embodiment, two fluorocarbon blocks or two hydrocarbon blocks constitute the termini (R
1
and R
3
) while the other bracket the central the polyoxyethylene block. This second embodiment may be viewed as encompassing compounds of the formula:
C
x
F
y
H
z
—L
1
—C
q
H
2q
—L
2
—(C
2
H
4
O)
n
—L
4
—C
q
H
2q
—L
3
—C
x
F
y
H
z
  IIIA.
in which x has a value of from 2 to 50; y has a value of from 1 to 2x+1, preferably from x to 2x+1; z has a value of 2x−y+1; q has a value of from 2 to 50; n has a value of from 3 to 200; and each of L
1
, L
2
, L
3
, and L
4
, independently of the other, is a linking group, and compounds of the formula:
C
q
H
2q+1
—L
1
—C
x
F
y
H
z
—L
2
—(C
2
H
4
O)
n
—L
4
—C
x
F
y
H
z
—L
3
—C
q
H
2q+1
  IIB
in which x, q, n, L
1
, L
2
, L
3
, and L
4
are as just defined; y has a value of from x to 2x; and z has a value of 2x−y.
In the fluorocarbon group C
x
F
y
H
z
—, x has a value of from 2 to 50; i.e., there can be from 2 to 50 carbon atoms. The fluorocarbon group will have at least as many fluorine atoms; i.e., there will be at least x fluorine atoms. If not perfluorinated, the remaining valence bonds of the fluorocarbon group will be satisfied with hydrogen atoms.
Differences in properties can be observed depending upon the nature of R
1
and R
2
. Block copolymers of Formulas IA, IIA and IIIA in which R
1
is a monovalent fluorinated hydrocarbon and R
2
is a divalent hydrocarbon tend to be very hydrophobic and interaction with cell membranes and tissues is reduced. These copolymers produce very stable micellar forms of drugs which do not interact with non-target tissues in the body, making them useful as micellar microcontainers for delivery of the drug with decreased drug metabolism and liver uptake. In the block copolymers of Formulas IA, IIA and IIIA, q preferably has a value of 6 or more.
Block copolymers of Formulas IB, IIB and IIIB in which R
1
is a monovalent hydrocarbon and R
2
is a divalent fluorinated hydrocarbon are membranetropic, leading to their activity in MDR cells, wh

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