Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ether doai
Reissue Patent
1999-11-19
2001-07-17
Shippen, Michael L. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ether doai
Reissue Patent
active
RE037285
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a preparation of polyoxypropylene/polyoxyethylene copolymer which has an improved toxicity and efficacy profile. The present invention also includes polyoxypropylene/polyoxyethylene block copolymers with a polydispersity value of less than approximately 1.05.
BACKGROUND OF THE INVENTION
Certain polyoxypropylene/polyoxyethylene copolymers have been found to have beneficial biological effects when administered to a human or animal. These beneficial biological effects are summarized as follows:
Polyoxypropylene/polyoxyethylene Copolymers as Rheologic Agents
The copolymers can be used for treating circulatory diseases either alone or in combination with other compounds, including but not limited to, fibrinolytic enzymes, anticoagulants, free radical scavengers, antiinflammatory agents, antibiotics, membrane stabilizers and/or perfusion media. These activities have been described in U.S. Pat. Nos. 4,801,452, 4,873,083, 4,879,109, 4,837,014, 4,897,263, 5,064,643; 5,028,599; 5,047,236; 5,089,260; 5,017,370; 5,078,995; 5,032,394; 5,041,288; 5,071,649; 5,039,520; 5,030,448; 4,997,644; 4,937,070; 5,080,894; and 4,937,070, all of which are incorporated herein by reference.
The polyoxypropylene/polyoxyethylene copolymers have been shown to have quite extraordinary therapeutic activities. The surface-active copolymers are useful for treating pathologic hydrophobic interactions in blood and other biological fluids of humans and animals. This includes the use of a surface-active copolymer for treatment of diseases and conditions in which resistance to blood flow is pathologically increased by injury due to the presence of adhesive hydrophobic proteins or damaged membranes. This adhesion is produced by pathological hydrophobic interactions and does not require the interaction of specific ligands with their receptors. Such proteins and/or damaged membranes increase resistance in the microvasculature by increasing friction and reducing the effective radius of the blood vessel. It is believed that the most important of these proteins is soluble fibrin.
Pathologic hydrophobic interactions can be treated by administering to the animal or human suffering from a condition caused by a pathological hydrophobic interaction an effective amount of a surface-active copolymer. The surface-active copolymer may be administered as a solution by itself or it may be administered with another agent, including, but not limited to, a fibrinolytic enzyme, an anticoagulant, or an oxygen radical scavenger.
The method described in the foregoing patents comprises administering to an animal or human an effective amount of a surface-active copolymer with the following general formula:
HO(C
2
H
4
O)
b
(C
3
H
6
O)
a
(C
2
H
4
O)
b
H
wherein a is an integer such that the hydrophobe represented by (C
3
H
6
O) has a molecular weight of approximately 950 to 4000 daltons, preferably about 1200 to 3500 daltons, and b is an integer such that the hydrophile portion represented by (C
2
H
4
O) constitutes approximately 50% to 95% by weight of the compound.
A preferred surface-active copolymer is a copolymer having the following formula:
HO(CH
2
H
4
O)
b
(C
3
H
6
O)
a
(C
2
H
4
O)
b
H
wherein the molecular weight of the hydrophobe (C
3
H
6
O) is approximately 1750 daltons and the total molecular weight of the compound is approximately 8400 daltons.
The surface-active copolymer is effective in any condition where there is a pathological hydrophobic interaction between cells and/or molecules. These interactions are believed to be caused by 1) a higher than normal concentration of fibrinogen, 2) generation of intravasculasr or local soluble fibrin, especially high molecular weight fibrin, 3) increased friction in the microvasculature, or 4) mechanical or chemical trauma to blood components. All of these conditions cause an increase in pathological hydrophobic interactions of blood components such as cells and molecules.
It is believed that fibrin, especially soluble fibrin, increases adhesion of cells to one another, markedly increases friction in small blood vessels and increases viscosity of the blood, especially at low shear rates. The effects of the surface-active copolymer are believed to be essentially lubrication effects because they reduce the friction caused by the adhesion.
Although not wanting to be bound by the following hypothesis, it is believed that the surface-active copolymer acts according to the following mechanism: Hydrophobic interactions are crucial determinants of biological structure. They hold the phospholipids together in membranes and protein molecules in their native configurations. As understanding of the biology of the surface-active copolymer is necessary to appreciate the biologic activities of the compound. Water is a strongly hydrogen bonding liquid which, in its fluid state, forms bonds in all directions with surrounding molecules. Exposure of a hydrophobic surface, defined as any surface which forms insufficient bonds with water, produces a surface tension or lack of balance in the hydrogen bonding of water molecules. This force can be exceedingly strong. The surface tension of pure water is approximately 82 dynes/cm. This translates into a force of several hundred thousand pounds per square inch on the surface molecules.
As two molecules or particles with hydrophobic surfaces approach, they adhere avidly. This adhesion is driven by the reduction in free energy which occurs when water molecules transfer from the stressed non-hydrogen bonding hydrophobic surface to the non-stressed bulk liquid phase. The energy holding such surfaces together, the work of adhesion, is a direct function of the surface tension of the particles:
1
W
AB=&ggr;A+&ggr;B−&ggr;AB
where W
AB=
work of adhesion or the energy necessary to separate one square centimeter of particle interface AB into two separate particles,
&ggr;A
and
&ggr;B
are the surface tensions of particle A and particle B,
&ggr;AB
the interfacial tension between them.
Consequently, any particles or molecules in the circulation which develop significant surface tensions will adhere to one another spontaneously. Such adhesion within membranes and macromolecles is necessary to maintain their integrity. We use the term “normal hydrophobic interaction” to describe such forces. Under normal circumstances, all cells and molecules in the circulation have hydrophilic non-adhesive surfaces. Receptors and ligands which modulate cell and molecular interactions are generally located on the most hydrophilic exposed surfaces of cells and molecules where they are free to move about in the aqueous media and to interact with one another. Special carrier molecules are necessary to transport lipids and other hydrophobic substances in the circulation. In body fluids such as blood, nonspecific adhesive forces between mobile elements are extremely undesirable. These forces are defined as “pathologic hydrophobic interactions” because they restrict movement of normally mobile elements and promote inappropriate adhesion of cells and molecules.
In damaged tissue, hydrophobic domains normally located on the interior of cells and molecules may become exposed and produce pathologic adhesive surfaces whose interaction compounds the damage. Fibrin deposited along vessel walls also provide an adhesive surface. Such adhesive surfaces appear to be characteristic of damaged tissue. It is believed that the ability of the surface-active copolymer to bind to adhesive hydrophobic surfaces and covert them to non-adhesive hydrated surfaces closely resembling those of normal tissue underlies its potential therapeutic activities in diverse disease conditions.
Adhesion due to surface tension described above is different from the adhesion commonly studied in biology. The commonly studied adhesion is due to specific receptor ligand interactions. In particular, it is different from the receptor-mediated adhesion of the fibrinogen—von Willibrands factor family of proteins.
2
Both the hydrophilic and hydrophobic chains of the su
Culbreth Paula H.
Emanuele R. Martin
Hunter Robert L.
Arismendi, Jr. A. M. (Andy)
Cytrx Corporation
Shippen Michael L.
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