Process for embolization using swellable and deformable microspheres
First Claim
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1. A method for embolization in a mammal comprising administering into the vasculature of said mammal microspheres prepared by a process comprising:
- a) forming a first solution comprising;
(i) water;
(ii) at least one water miscible monomer selected from the group consisting of acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, salts of styrene-sulfonic acid, 2-hydroxyethyl acrylate, and 2-hydroxyethyl methacrylate, provided that;
(A) if said monomer is acrylamide, methacrylamide, N-substituted acrylamides, 2-hydroxyethyl acrylate, or 2-hydroxyethyl methacrylate, said monomer is used in combination with at least one other monomer selected from subgroup 1 consisting of;
acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid;
(B) if said first solution contains at least one monomer from subgroup 2 consisting of acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 2-hydroxyethyl acrylate, and 2-hydroxyethyl methacrylate, but does not contain a monomer selected from subgroup 3 consisting of 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid, then the pH of the first solution is at least about 3;
(C) if said first solution contains at least one monomer from subgroup 3 consisting of 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid, then the pH of the first solution is less than about 3;
(iii) a crosslinking agent that is miscible in the first solution in less than or equal to about 5 Mol %, relative to total moles of monomer and crosslinking agent, said crosslinking agent being selected from the group consisting of N,N′
-methylene-bis-acrylamide, N,N′
-methylene-bis-methacrylamide, N-methylolacrylamide, N-methylolmethacrylamide, glycidyl acrylate, glycidyl methacrylate, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, polyvalent metal salts of acrylic acid and methacrylic acid, divinyl benzene phosphoacrylates, divinylbenzene, divinylphenylphosphine, divinyl sulfone, 1,3-divinyltetramethyldisiloxane, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5,5]undecane, phosphomethacrylates, ethylene glycol diglycidyl ether, glycerin triglycidyl ether, glycerin diglycidyl ether, and polyethylene glycol diglycidyl ether;
(iv) a water soluble protecting colloid;
(v) an emulsifier; and
(vi) a low temperature aqueous soluble azo initiator;
b) forming a second solution comprising at least one substantially chlorinated hydrocarbon of less than 6 carbon units, provided that the chlorinated hydrocarbon is not a halogenated aromatic hydrocarbon, and an organic soluble protecting colloid;
c) forming a first suspension with agitation comprising the first and second solutions at a temperature below the initiation temperature of the azo initiator of (a);
d) increasing the temperature of the agitating first suspension to a temperature at which the low temperature aqueous soluble azo initiator is activated;
e) agitating the first suspension until it forms a second suspension comprising a gelatinous precipitate suspended in an organic liquid phase, wherein microspheres are formed;
f) allowing the second suspension to cool to a temperature that is at or below about 30°
C. while agitating the second suspension;
g) washing the second suspension at least once with a dehydrating solvent wherein water is removed from the microspheres forming a microsphere preparation;
h) recovering the microsphere preparation; and
i) drying the microsphere preparation to form a free-flowing microsphere powder.
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Abstract
A method for embolization treatment was developed in which microspheres with novel properties are administered in a mammal. The microspheres are made using a novel process that results in microspheres with new combined properties of high density, low fracture, high swell capacity, rapid swell, and deformability following swell. These microspheres form occlusions with high durability, withstanding over 100 mm Hg (13.3 kPa) of pressure.
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Citations
29 Claims
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1. A method for embolization in a mammal comprising administering into the vasculature of said mammal microspheres prepared by a process comprising:
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a) forming a first solution comprising;
(i) water;
(ii) at least one water miscible monomer selected from the group consisting of acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, salts of styrene-sulfonic acid, 2-hydroxyethyl acrylate, and 2-hydroxyethyl methacrylate, provided that;
(A) if said monomer is acrylamide, methacrylamide, N-substituted acrylamides, 2-hydroxyethyl acrylate, or 2-hydroxyethyl methacrylate, said monomer is used in combination with at least one other monomer selected from subgroup 1 consisting of;
acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid;
(B) if said first solution contains at least one monomer from subgroup 2 consisting of acrylic acid, methacrylic acid, salts of acrylic acid and methacylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 2-hydroxyethyl acrylate, and 2-hydroxyethyl methacrylate, but does not contain a monomer selected from subgroup 3 consisting of 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid, then the pH of the first solution is at least about 3;
(C) if said first solution contains at least one monomer from subgroup 3 consisting of 2-acryloylethane-sulfonic acid, 2-methacryloylethane-sulfonic acid, salts of 2-acryloylethane-sulfonic acid and 2-methacryloylethane-sulfonic acid, styrene-sulfonic acid, and salts of styrene-sulfonic acid, then the pH of the first solution is less than about 3;
(iii) a crosslinking agent that is miscible in the first solution in less than or equal to about 5 Mol %, relative to total moles of monomer and crosslinking agent, said crosslinking agent being selected from the group consisting of N,N′
-methylene-bis-acrylamide, N,N′
-methylene-bis-methacrylamide, N-methylolacrylamide, N-methylolmethacrylamide, glycidyl acrylate, glycidyl methacrylate, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, polyvalent metal salts of acrylic acid and methacrylic acid, divinyl benzene phosphoacrylates, divinylbenzene, divinylphenylphosphine, divinyl sulfone, 1,3-divinyltetramethyldisiloxane, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5,5]undecane, phosphomethacrylates, ethylene glycol diglycidyl ether, glycerin triglycidyl ether, glycerin diglycidyl ether, and polyethylene glycol diglycidyl ether;
(iv) a water soluble protecting colloid;
(v) an emulsifier; and
(vi) a low temperature aqueous soluble azo initiator;
b) forming a second solution comprising at least one substantially chlorinated hydrocarbon of less than 6 carbon units, provided that the chlorinated hydrocarbon is not a halogenated aromatic hydrocarbon, and an organic soluble protecting colloid;
c) forming a first suspension with agitation comprising the first and second solutions at a temperature below the initiation temperature of the azo initiator of (a);
d) increasing the temperature of the agitating first suspension to a temperature at which the low temperature aqueous soluble azo initiator is activated;
e) agitating the first suspension until it forms a second suspension comprising a gelatinous precipitate suspended in an organic liquid phase, wherein microspheres are formed;
f) allowing the second suspension to cool to a temperature that is at or below about 30°
C. while agitating the second suspension;
g) washing the second suspension at least once with a dehydrating solvent wherein water is removed from the microspheres forming a microsphere preparation;
h) recovering the microsphere preparation; and
i) drying the microsphere preparation to form a free-flowing microsphere powder. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27)
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28. A method for embolization in a mammal comprising administering to said mammal microspheres prepared by a process comprising:
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a) forming a first solution having a pH of between about 5 and about 9 comprising;
(i) water;
(ii) a combination comprising acrylic acid and at least one monomer selected from the group consisting of sodium acrylate, acrylamide, 2-hydroxyethyl methacrylate, and 2-hydroxyethyl acrylate;
(iii) N,N′
-methylenebisacrylamide crosslinking agent in about 0.08 Mol % to about 2.3 Mol %, relative to total moles of monomer and crosslinking agent;
(iv) methyl cellulose protecting colloid;
(v) an alkylaryl polyether alcohol preparation as emulsifier, and (vi) 2,2′
-azobis(2-[2-imidazolin-2-yl])propane dihydrochloride azo initiator;
b) forming a second solution comprising a combination of methylene chloride and chloroform, or methylene chloride and a mixture of 30 vol % ethyl heptanoate;
70 vol % phenethyl acetate;
in a volume ratio that is between about 1;
5 and 5;
1, and ethyl cellulose as an organic soluble protecting colloid;
c) forming a first suspension with agitation comprising the first and second solutions at a temperature of about 25°
C.;
d) increasing the temperature of the agitating first suspension to a temperature of about 51°
C. to 52°
C. wherein the 2,2′
-azobis(2-[2-imidazolin-2-yl])propane dihydrochloride azo initiator is activated;
e) agitating the first suspension until it forms a second suspension comprising a gelatinous precipitate suspended in an organic liquid phase, wherein microspheres are formed;
f) allowing the second suspension containing microspheres to cool to a temperature of about 25°
C. while agitating the second suspension;
g) washing the second suspension twice with methanol, followed by once with ethanol wherein water is removed from the microspheres forming a microsphere preparation;
h) recovering the microsphere preparation; and
i) drying the microsphere preparation to form a free-flowing microsphere powder.
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29. A method for embolization in a mammal comprising administering to said mammal microspheres prepared by a process comprising:
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a) forming a first solution having a pH of less than about 3 comprising;
(i) water;
(ii) styrene sulfonic acid or a combination comprising styrene sulfonic acid and styrene sulfonic acid sodium salt;
(iii) N,N′
-methylenebisacrylamide crosslinking agent in about 0.08 Mol % to about 2.3 Mol %, relative to total moles of monomer and crosslinking agent;
(iv) methyl cellulose protecting colloid;
(v) an alkylaryl polyether alcohol preparation as emulsifier, and (vi) 2,2′
-azobis(2-[2-imidazolin-2-yl])propane dihydrochloride azo initiator;
b) forming a second solution comprising a combination of methylene chloride and chloroform, or methylene chloride and a mixture of 30 vol % ethyl heptanoate;
70 vol % phenethyl acetate;
in a volume ratio that is between about 1;
5 and 5;
1, and ethyl cellulose as an organic soluble protecting colloid;
c) forming a first suspension with agitation comprising the first and second solutions at a temperature of about 25°
C.;
d) increasing the temperature of the agitating first suspension to a temperature of about 51°
C. to 52°
C. wherein the 2,2′
-azobis(2-[2-imidazolin-2-yl])propane dihydrochloride azo initiator is activated;
e) agitating the first suspension until it forms a second suspension comprising a gelatinous precipitate suspended in an organic liquid phase, wherein microspheres are formed;
f) allowing the second suspension containing microspheres to cool to a temperature of about 25°
C. while agitating the second suspension;
g) washing the second suspension twice with methanol, followed by once with ethanol wherein water is removed from the microspheres forming a microsphere preparation;
h) recovering the microsphere preparation; and
i) drying the microsphere preparation to form a free-flowing microsphere powder.
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Specification