Process for preparation of swellable and degradable microspheres

• US 20090041850A1
• Filed: 08/04/2008
• Published: 02/12/2009
• Est. Priority Date: 08/07/2007
• Status: Active Grant

• Current Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.)
• Original Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.)
• Inventors: Figuly, Garret D.
• Granted Patent: US 7,887,846 B2
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

A process for producing microspheres was developed that provides microspheres that are swellable and degradable. The process is reliable and high yielding, and makes use of a low temperature azo initiator, a small molecule chlorinated solvent as the organic phase, and a heat treatment step, and is carried out in absence of a crosslinking agent. The microsphere preparation made using the process is particularly useful as a degradable embolic material.

Claims

1. A process for making a swellable and degradable microsphere preparation comprising the steps of:

a) forming a first solution having a pH of at least about 3 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 methacrylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 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, and salts of acrylic acid and methacrylic acid;

(iii) a water soluble protecting colloid;

(iv) an emulsifier; and

(v) a water soluble azo initiator having a low activation temperature;

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 activation temperature of the azo initiator of (a);

d) increasing the temperature of the first suspension to a temperature at which the water 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, producing a microsphere slurry comprising washed microspheres;

h) recovering the washed microspheres from the microsphere slurry; and

i) heating the washed microspheres to a temperature above 25°

C. for a time sufficient to substantially dry the washed microspheres to form the swellable and degradable microsphere preparation;

wherein the process is carried out in absence of a crosslinking agent.

2. A process according to claim 1 wherein the second solution comprises a mixture of methylene chloride and chloroform.

3. A process according to claim 1 wherein the second solution comprises a combination of methylene chloride and a solvent or solvent mixture having a sum of differences in Hansen solubility parameters relative to the Hansen solubility parameters of chloroform of less than about 0.21.

4. A process according to claim 3 wherein the solvent mixture is selected from the group consisting of:

20 vol % methyl oleate;

80 vol % phenethyl acetate, 30 vol % ethyl heptanoate;

70 vol % phenethyl acetate, 30 vol % methyl octanoate;

70 vol % phenethyl acetate, 40 vol % diethyl carbonate;

60 vol % methylphenyl acetate, 20 vol % phenylpropyl methyl ether;

80 vol % phenyl propyl ether, 70 vol % ethyl phenyl ether;

30 vol % phenylpropyl methyl ether, 20 vol % diethylene glycol butyl ether;

80 vol % phenylpropyl methyl ether, 20 vol % ethyl propionate;

80 vol % phenylpropyl acetate, 80 vol % phenylpropyl acetate;

20 vol % tripropylamine, 90 vol % phenyl propyl ether;

10 vol % toluene, 30 vol % methyl hexanoate;

70 vol % phenylpropyl acetate, and 20 vol % isopropyl palmitate;

80 vol % phenethyl acetate.

5. A process according to claim 1 wherein the first solution further comprises a barium monomer salt.

6. A process according to claim 1 wherein the azo initiator of (a) has an activation temperature that is less than about 55°

C.

7. A process according to claim 6 wherein the azo initiator is 2,2′

-azobis(2-[2-imidazolin-2-yl])propane dihydrochloride.

8. A process according to claim 1 wherein the protecting colloid of (a) is a water soluble cellulose ester or ether.

9. A process according to claim 8 wherein the protecting colloid is methyl cellulose.

10. A process according to claim 1 wherein the protecting colloid of (b) is an organic soluble cellulose ester or ether.

11. A process according to claim 10 wherein the protecting colloid is ethyl cellulose.

12. A process according to claim 1 wherein the emulsifier of (a) is a nonionic surfactant.

13. A process according to claim 12 wherein the emulsifier is an alkylaryl polyether alcohol preparation.

14. A process according to claim 1 wherein the first suspension of (c) is formed at a temperature below about 30°

C.

15. A process according to claim 1 wherein the temperature in (d) is between about 50°

C. and 55°

C.

16. A process according to claim 1 wherein the monomer is a combination comprising acrylic acid and sodium acrylate.

17. A process according to claim 1 wherein the heating of step (i) is at a temperature above about 50°

C.

18. A process according to claim 1 wherein the heating of step (i) is at a temperature of about 50°

C. to about 150°

C.

19. A swellable and degradable microsphere preparation made by a process comprising the steps of:

a) forming a first solution having a pH of at least about 3 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 methacrylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 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, and salts of acrylic acid and methacrylic acid;

(iii) a water soluble protecting colloid;

(iv) an emulsifier; and

(v) a water soluble azo initiator having a low activation temperature;

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 activation temperature of the azo initiator of (a);

d) increasing the temperature of the first suspension to a temperature at which the water 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, producing a microsphere slurry comprising washed microspheres;

h) recovering the washed microspheres from the microsphere slurry; and

i) heating the washed microspheres to a temperature above 25°

C. for a time sufficient to substantially dry the washed microspheres to form the swellable and degradable microsphere preparation;

wherein the process is carried out in absence of a crosslinking agent.

20. A swellable and degradable microsphere preparation according to claim 19 wherein the second solution of (b) comprises a mixture of chloroform and methylene chloride.

21. A swellable and degradable microsphere preparation according to claim 19 wherein the second solution comprises a combination of methylene chloride and a solvent or solvent mixture having a sum of the differences in Hansen solubility parameters relative to the Hansen solubility parameters of chloroform of less than about 0.21.

22. A swellable and degradable microsphere preparation according to claim 21 wherein the solvent mixture is selected from the group consisting of:

20 vol % methyl oleate;

80 vol % phenethyl acetate, 30 vol % ethyl heptanoate;

70 vol % phenethyl acetate, 30 vol % methyl octanoate;

70 vol % phenethyl acetate, 40 vol % diethyl carbonate;

60 vol % methylphenyl acetate, 20 vol % phenylpropyl methyl ether;

80 vol % phenyl propyl ether, 70 vol % ethyl phenyl ether;

30 vol % phenylpropyl methyl ether, 20 vol % diethylene glycol butyl ether;

80 vol % phenylpropyl methyl ether, 20 vol % ethyl propionate;

80 vol % phenylpropyl acetate, 80 vol % phenylpropyl acetate;

20 vol % tripropylamine, 90 vol % phenyl propyl ether;

10 vol % toluene, 30 vol % methyl hexanoate;

70 vol % phenylpropyl acetate, and 20 vol % isopropyl palmitate;

80 vol % phenethyl acetate.

23. A swellable and degradable microsphere preparation according to claim 19 wherein the first solution further comprises a barium monomer salt.

24. A swellable and degradable microsphere preparation according to claim 19 wherein the azo initiator of (a) has an activation temperature that is less than about 55°

C.

25. A swellable and degradable microsphere preparation according to claim 24 wherein the azo initiator is 2,2′

-azobis(2-[2-imidazolin-2-yl])propane dihydrochloride.

26. A swellable and degradable microsphere preparation according to claim 19 wherein the protecting colloid of (a) is a water soluble cellulose ester or ether.

27. A swellable and degradable microsphere preparation according to claim 26 wherein the protecting colloid is methyl cellulose.

28. A swellable and degradable microsphere preparation according to claim 19 wherein the protecting colloid of (b) is an organic soluble cellulose ester or ether.

29. A swellable and degradable microsphere preparation according to claim 28 wherein the protecting colloid is ethyl cellulose.

30. A swellable and degradable microsphere preparation according to claim 19 wherein the emulsifier of (a) is a nonionic surfactant.

31. A swellable and degradable microsphere preparation according to claim 30 wherein the emulsifier is an alkylaryl polyether alcohol preparation.

32. A swellable and degradable microsphere preparation according to claim 19 wherein the first suspension of (c) is formed at a temperature below about 30°

C.

33. A swellable and degradable microsphere preparation according to claim 19 wherein the temperature in (d) is between about 50°

C. and 55°

C.

34. A swellable and degradable microsphere preparation according to claim 19 wherein the monomer is a combination comprising acrylic acid and sodium acrylate.

35. A swellable and degradable microsphere preparation according to claim 19 wherein the heating of step (i) is at a temperature above about 50°

C.

36. A swellable and degradable microsphere preparation according to claim 19 wherein the heating of step (i) is at a temperature of about 50°

C. to about 150°

C.

37. A swellable and degradable microsphere preparation according to claim 19 wherein the process further comprises separating microspheres of the microsphere preparation into microsphere samples having a predominant size that is between about 30 microns and about 600 microns in diameter and including microspheres in a size range that is within about 30% of the median for about 90% of the sample.

38. A method for embolization in a mammal comprising administering into the vasculature of said mammal, swellable and degradable microspheres prepared by a process comprising the steps of:

a) forming a first solution having a pH of at least about 3 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 methacrylic acid, acrylamide, methacrylamide, N-substituted acrylamides, N-substituted methacrylamides, 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, and salts of acrylic acid and methacrylic acid;

(iii) a water soluble protecting colloid;

(iv) an emulsifier; and

(v) a water soluble azo initiator having a low activation temperature;

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 activation temperature of the azo initiator of (a);

d) increasing the temperature of the first suspension to a temperature at which the water 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, producing a microsphere slurry comprising washed microspheres;

h) recovering the washed microspheres from the microsphere slurry; and

i) heating the washed microspheres to a temperature above 25°

C. for a time sufficient to substantially dry the washed microspheres to form the swellable and degradable microsphere preparation;

wherein the process is carried out in absence of a crosslinking agent.