Process and apparatuses for preparing nanoparticle compositions with amphiphilic copolymers and their use

• US 20040091546A1
• Filed: 10/23/2003
• Published: 05/13/2004
• Est. Priority Date: 03/29/2002
• Status: Active Grant

• Current Assignee: The Trustees of Princeton University (Princeton University)
• Original Assignee: The Trustees of Princeton University (Princeton University)
• Inventors: PrudʼHomme, Robert K, Johnson, Brian K
• Granted Patent: US 8,137,699 B2
• Time in Patent Office: Days
• US Class Current: 424/501
• CPC Class Codes: A01N 2300/00 Combinations or mixtures of active ingredients covered by classes A01N27/00 - A01N65/48 with other active or formulation relevant ingredients, e.g. specific carrier materials or surfactants, covered by classes A01N25/00 - A01N65/48
• CPC Class Codes: A01N 25/04 Dispersions, emulsions, suspoemulsions, suspension concentrates or gels foams A01N25/16
• CPC Class Codes: A01N 43/70 Diamino—1,3,5—triazines with only one oxygen, sulfur or halogen atom or only one cyano, thiocyano (—SCN), cyanato (—OCN) or azido (—N3) group directly attached to a ring carbon atom
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: B01F 21/00 Dissolving separating by dissolving B01D; dissolving to effect cooling F25D5/00
• CPC Class Codes: B01F 27/91 with propellers
• CPC Class Codes: B01F 35/20 Measuring; Control or regulation
• CPC Class Codes: B01F 35/2211 Amount of delivered fluid during a period
• CPC Class Codes: B01F 35/2213 Pressure
• CPC Class Codes: B01F 35/22142 Speed of the mixing device during the operation
• CPC Class Codes: B01F 35/2215 Temperature
• CPC Class Codes: B01J 13/0021 containing a solid organic phase

Abstract

This invention discloses a process for making nanopanticles of amphiphilic copolymers by flash precipitation. Nanoparnicles may be of amphiphilic copolymer alone or may contain an additive target molecule, preferably an organic active. The inclusion of additive target molecules in amphiphilic copolymer nanoparticles can alter their water solubility characteristics, fluid dynamics, and/or stability. Changing an additive target molecule'"'"'s solubility and stability in an nanoparticle can make a water insoluble compound suitable for pharmaceutical administration as well as specifically target the molecule to a specific area of a patient'"'"'s body. The process affords the production of nanoparticles at high absolute active content, at high yield, high productivity, and high processing rates while using unusually low amounts of amphiphilic copolymers. Furthermore, the resulting particles exhibit sufficient stability for post processing as desired. The invention also discloses two apparatuses for the production of nanoparticles of amphiphilic copolymers by flash precipitation.

Claims

1. A process for preparing nanoparticles by flash precipitation comprising:

dissolving at least one amphiphilic copolymer in a process solvent;

mixing the process solvent comprising the amphiphilic copolymer with at least one non-process solvent; and

flash precipitating at least one amphiphilic copolymer to form nanoparticles in a product solvent, wherein the particle size of the resulting nanoparticles is a fimction of the temperature, the hydrophobic and hydrophilic character of at least one amphiphilic copolymer, and the mixing velocity of the process.

2. The process of claim 1, wherein at least one amphiphilic copolymer comprises a block, graft or random copolymer.

3. The process of claim 1, wherein at least one amphiphilic copolymer has both hydrophobic and hydrophilic blocks.

4. The process of claim 3, wherein the hydrophobic and hydrophilic blocks are comprised of sub-units wherein each block contains at least two sub-units.

5. The process of claim 4, wherein at least one amphiphilic copolymer has a diblock or triblock formation.

6. The process of claim 4, wherein at least one amphiphilic copolymer is comprised of blocks with a minimum contour length equal to the length of at least 5 ethylene units.

7. The process of claim 4, wherein at least one amphiphilic copolymer is comprised of blocks with a molecular weight of at least 300 g/mole.

8. The process of claim 4, wherein at least one sub-unit forming the hydrophobic blocks of at least one amphiphilic copolymer comprises acrylates, methacrylates, vinyls, aminoalkyls, styrenes, or lactic acids.

9. The process of claim 4, wherein at least one sub-unit forming the hydrophobic blocks of at least one amphiphilic copolymer is selected from the group consisting of acrylates, methacrylates, vinyls, aminoalkyls, styrenes, and lactic acids.

10. The process of claim 4, wherein at least one sub-unit forming the hydrophilic blocks of at least one amphiphilic copolymer comprises carboxylic, polyoxyethylenes, unsaturated ethylenic monocarboxylic acids, or unsaturated ethylenic dicarboxylic acids.

11. The process of claim 4, wherein at least one sub-unit forming the hydrophilic blocks of at least one amphiphilic copolymer is selected from the group consisting of carboxylic, polyoxyethylenes, unsaturated ethylenic monocarboxylic acids, and unsaturated ethylenic dicarboxylic acids.

12. The process of claim 1, wherein at least one amphiphilic copolymer comprise blocks of a polystyrene, polyethylene oxide, polybutylacrylate, polyacrylic acid, polybutylnethacrylate, or polyethyleneoxide.

13. The process of claim 1, wherein at least one amphiphilic copolymer comprise blocks selected from the group consisting of a polystyrene block, a polyethylene oxide block, a polybutylacrylate, a polyacrylic acid, polybutylmethacrylate block, and a polyethyleneoxide block.

14. The process of claim 1, wherein at least one amphiphilic copolymer contains a grafted moiety.

15. The process of claim 14, where the grafted moiety is at least 300 g/mole.

16. The process of claim 14, wherein the grafted moiety is an alkyl chain.

17. The process of claim 16, wherein the alkyl chains are 4 to 18 carbons in length or are equal to 2 to 9 ethylene units in length.

18. The process of claim 1, wherein at least one amphiphilic copolymer has a total molecular weight between about 1000 to about 50,000 g/mole.

19. The process of claim 1, wherein at least one amphiphilic copolymer has a total molecular weight of at least 2000 g/mole.

20. The process of claim 1, wherein at least one amphiphilic copolymer reduces the surface tension of water at least 50 dynes/cm at a concentration of 0.1 weight percent (“

wt%”

) at 25°

C.

21. The process of claim 1, wherein at least one amphiphilic copolymer includes polystyreneblock-polyethyleneoxide.

22. The process of claim 1, wherein at least one amphiphilic copolymer includes polybutylacrylate-b-polyacrylicacid.

23. The process of claim 1, wherein at least one amphiphilic copolymer includes polybutylmethacrylate-b-polyethyleneoxide.

24. The process of claim 1, wherein the process solvent is capable of dissolving at least 0.1% of at least one amphiphilic copolymer by weight.

25. The process of claim 1, wherein the process solvent is an ether or an alcohol.

26. The process of claim 1, wherein the process solvent includes tetrahydrofuran.

27. The process of claim 1, wherein the process solvent includes water.

28. The process of claim 1, wherein the process solvent includes methanol.

29. The process of claim 1, wherein the concentration of at least one amphiphilic copolymer in the process solvent is at least 0.1 wt%.

30. The process of claim 1, wherein the concentration of at least one amphiphilic copolymer in the process solvent is between about 0.3 wt% to about 10.0 wt%.

31. The process of claim 1, wherein the concentration of at least one amphiphilic copolymer in the product solvent is at least 0.05 wt%.

32. The process of claim 1, wherein the non-process solvent is capable of locally precipitating the hydrophilic or hydrophobic regions of at least one amphiphilic copolymer.

33. The process of claim 1, wherein the non-process solvent is an aqueous solution comprising a buffer, salt, inert molecule or a colloid dispersant.

34. The process of claim 1, wherein the non-process solvent includes water.

35. The process claim of claim 1, wherein the non-process solvent includes an organic solvent.

36. The process of claim 1, wherein the temperature of the process solvent and the non-process solvent is maintained between about 20°

C. to about 50°

C.

37. The process of claim 1, wherein the temperature of the process solvent and the non-process solvent is maintained at 35°

C.

38. The process of claim 1, wherein the mixing velocity of the process and non-process solvents is at least 0.1 m/sec.

39. The process of claim 1, wherein the pressure during mixing is controlled.

40. The process of claim 1, wherein the pressure during mixing is maintained above 8 psig.

41. The process of claim 1, wherein the nanoparticles are produced continuously.

42. The process of claim 1, wherein the process solvent is a liquefied gas.

43. The process of claim 1, wherein the non-process solvent is a liquefied gas.

44. The process of claim 1, wherein the average size of the resulting nanoparticles is less than about 150 nm.

45. The process of claim 1, further comprising the step of removing the solvent from the product solvent containing the nanoparticles.

46. The process of claim 45, wherein the product solvent is removed by a process selected from the group consisting of filtration, distillation, evaporation, expansion,lyophilization, and extraction.

47. The process of claim 1, further comprising the step of dissolving at least one additive target molecule in the process solvent or the non-process solvent prior to mixing.

48. The process of claim 47, wherein at least one amphiphilic copolymer and at least one additive target molecule are in a ratio between about 1:

20 to about 20;

1 by weight.

49. The process of claim 47, wherein at least one additive target molecule make up at least 0.2% by weight of the mixture based on initial charges to the mixer.

50. The process of claim 47, wherein at least one additive target molecule is selected from the group consisting of pharmaceutical organic actives and pharmaceutical organic precursor compounds.

51. The process of claim 47, wherein at least one additive target molecule is selected from the group consisting of cyclosporins, immunoactive agents, analgesics, anti-inflammatory agents, antheimintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives , astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immuriological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, xanthines, anti-oxidants, preservatives, vitamins, and nutrients.

52. The process of claim 47, wherein at least one additive target molecule is a proteins.

53. The process of claim 47, wherein at least one additive target molecule is an antioxidant.

54. The process of claim 47, wherein at least one additive target molecule is a water insoluble vitamin.

55. The process of claim 47, wherein at least one additive target molecule is selected from the group consisting of agricultural organic compounds, biocides, pesticides, herbicides, fimgicides, and insecticides.

56. The process of claim 47, wherein at least one additive target molecule is selected from the group consisting of cosmetic products, dyes, reagents, salts, biological markers, magnetic particle precursors, and radiopaque materials.

57. The process of claim 47, wherein at least one additive target molecule is β

-carotene.

58. The process of claim 47, wherein at least 85% of the resulting nanopartcles are <

1060 nm in diameter.

59. The process of claim 47, wherein at least one additive target molecule is incorporated into the nanoparticle.

60. The process of claim 47, wherein at least one additive target molecule is selected from the group consisting of a crystalline phase drug and an amorphous phase drug.

61. The process of claim 1, further comprising the step of adding at least one supplemental additive to the process solvent or non-process solvent before mixing or to the product solvent after mixing.

62. The process of claim 61, wherein at least one supplemental additive is selected from the group consisting of surfactants, gelatin, phospholipid, and pluronics.

63. The process of claim 47, further comprising the step of adding at least one supplemental additive to the process solvent or non-process solvent before mixing or to the product solvent after mixing.

64. The process of claim 61, wherein at least one supplemental additive is selected from the group consisting of surfactants, gelatins, phospholipids, and pluronics.

65. The process of claim 61, wherein at least one supplemental additive is selected from the group consisting of inert diluents, solubilizing agents, emulsifiers, suspending agents, adjuvants, wetting agents, colloidal dispersants, cellulose, dicalcium phosphate, dodecyl trimethyl ammonium bromide, glycerol, glycerol monostearate, glucose, pisononylphenoxypolt-(glycidol), glucamides, lecithin(phosphatides), maltosides, magnesium stearate, magnesium aluminum silicate, oils, starch, polyethylene glycols, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, poloxamers, polaxanines, silicic acid, sodium citrate, sodium dodecyl sulfate, sodium lauryl sulfate, steric acid, sucrose, tapioca starch, talc, thioglucosides, tragacanth, triethanolamine, and Triton X-200®

.

66. The process of claim 61, wherein at least one supplemental additive is added at a concentration by weight of up to 2:

1 of supplemental additive to additive target molecule.

67. The process of claim 61, wherein at least one supplemental additive is sodium dodecyl sulfate.

68. The process of claim 61, wherein at least one supplemental additive is selected from the group consisting of a salt, a functional surface modifier, a protein, a sugar, a fatty acid, an organic pharmaceutical excipient, an inorganic pharmaceutical excipient, a pharmaceutically acceptable carrier, and a low molecular weight oligomer.

69. The process of claim 1, wherein the mixing step and flash precipitation step are performed in a centripetal mixer.

70. The process of claim 1, wherein the mixing step and flash precipitation step are performed in a continuous flash mixer.

71. The process of claim 1, wherein the mixing step and flash precipitation step are performed in a batch flash mixer.

72. The composition of nanoparticles prepared according to the process of claim 1.

73. The composition of nanoparticles prepared according to the process claim 47.

74. The composition of nanoparticles prepared according to the process of claim 61.

75. The composition of nanoparticles prepared according to the process of claim 63.

76. An apparatus for malking nanoparticles from at least one amphiphilic copolymer by flash precipitation comprising:

a mixing vessel having at least two inlet tubes for the introduction of at least two solvent streams into the mixing vessel;

a pressure controller;

a fluid velocity controller;

a temperature controller for the solvent streams entering the mixing vessel;

a temperature controller for the solution in the mixing vessel; and

an outlet for continuous flow from the mixing vessel.

77. The apparatus of claim 76, wherein the at least two inlet tubes are positioned so that the solvent streams are directed at one another within the mixing vessel.

78. The apparatus of claim 76, wherein the distance between the inlet tubes for the solvent streams within the mixing vessel is less than 40 times the diameter of the inlet tubes.

79. The apparatus of claim 76, wherein the at least two inlet tubes have different diameters.

80. The apparatus of claim 76, wherein the inlet tubes protrude into the interior of the mixing vessel.

81. The apparatus of claim 76, wherein the inlet tubes have a diameter between about 0.5 mm to about 1.5 mm.

82. The apparatus of claim 76, wherein the inlet tubes have a diameter between about 0.25 mm to about 6 mm.

83. The apparatus of claim 76, wherein the position of the inlet tubes can be varied to alter the direction of the solvent streams entering the mixing vessel.

84. The apparatus of claim 76, wherein the diameter of the mixing vessel is between about 2.4 mm to about 4.8 mm.

85. The apparatus of claim 76, wherein the mixing vessel is cylindrical.

86. The apparatus of claim 76, wherein the mixing vessel has a domed top.

87. The apparatus of claim 76, wherein a velocity of the incoming solvent stream is between 0.02 to about 12.0 meters per second.

88. The apparatus of claim 76, further comprising a pump to force at least one solvent stream through at least one inlet tube.

89. The apparatus of claim 76, wherein the outlet has a conical shape leading from the mixing vessel.

90. The apparatus of claim 76, wherein the outlet has a square shape leading from the mixing vessel.

91. The apparatus of claim 76, wherein the outlet has a mixed configuration leading from the mixing vessel.

92. The apparatus of claim 76, wherein the diameter of the outlet is between about 0.5 mm to about 2.5 mm.

93. The apparatus of claim 76, wherein the mixing vessel is confined.

94. The apparatus of claim 76, further comprising a syringe pump to force the solvent streams through the inlet tubes.

95. The apparatus of claim 94, wherein the syringe pump is a Harvard Apparatus model number 7023.

96. An apparatus for making nanoparticles from at least one amphiphilic copolymer by flash precipitation comprising:

a mixing vessel;

a means for controlling the pressure in the mixing vessel;

a means for introducing at least two solvents into the mixing vessel at a controlled velocity;

a means for controlling the temperature of the liquids entering the mixing vessel;

a means for controlling the temperature in the mixing chamber; and

a means for providing a continuous flow rate out of the mixing vessel after mixing.

97. An apparatus for makiing nanoparticles from at least one amphiphilic copolymer by flash precipitation comprising:

a mixing vessel having at least one inlet tube for the introduction of at least one solvent stream into the mixing vessel;

a pressure controller;

is a fluid velocity controller;

a temperature controller for the solvent stream entering the mixing vessel;

a mechanical agitator;

a temperature controller for the solution in the mixing vessel; and

an outlet for remove of the product solvent from the mixing vessel.

98. The apparatus of claim 97, further comprising a pump to force at least one solvent stream through at least one inlet tube.

99. The apparatus of claim 97, wherein the mechanical agitator is a marine agitator having a single baffle.

100. The apparatus of claim 97, wherein the distance between a discharge point of the inlet tube is within 15% of the diameter of the sweep width of the mechanical agitator.

101. The apparatus of claim 97, wherein the velocity of the fluid exiting the inlet tube is between about 0.02 to about 12.0 meters per second.

102. The apparatus of claim 97, wherein the mechanical agitator can achieve a velocity in the surrounding fluid of between about 0.02 to about 8.5 meters per second.

103. An apparatus for maling nanoparticles from at least one amphiphilic copolymer by flash precipitation comprising:

a mixing vessel;

a means for controlling the pressure in the mixing vessel;

a means for introducing at least one solvent stream into the mixing vessel at a controlled velocity;

a means for controlling the temperature of the liquids entering the mixing vessel;

a means for controlling the temperature in the mixing vessel;

a means for mechanically agitating the fluid in the mixing vessel; and

a means for removing the product from the mixing vessel after mixing.

104. A process to finctionalize pre-existing particles by precipitation with at least one amphiphilic copolymer comprising:

dispersing the pre-existing particles into a first solvent at a controlled temperature and pressure;

dissolving at least one amphiphilic copolymer in a second solvent capable of mixing with the first solvent; and

mixing the first and second solvents together at a mixing velocity sufficient to produce a surface fimctionalization of the pre-existing particles by selective precipitation of at least one amphilyte portion of at least one amphiphilic copolymer while at least one amphilyte portion of the same copolymer remains soluble.

105. The process of claim 104, wherein the pre-existing particles are nanoparticles or microparticles.

106. The process of claim 104, wherein the pre-existing particles and at least one amphiphilic copolymer are mixed in at least a 1:

1 ratio by weight.

107. The process of claim 104, wherein the average size of the pre-existing particles after functionalization is within 30% of the initial size.

108. The process of claim 104, wherein the average initial size of the pre-existing particles is at least 2380 nm.

109. The process of claim 104, wherein the average size of the pre-existing particles is less than 50 μ

m.

110. The process of claim 104, wherein the pre-existing particles are comprised from molecules selected from the group consisting of biologically active compounds, organic active compounds, pharmaceutical organic actives, pharmaceutical precursors, antiinflammatories, anti-depressants, anti-oxidants, proteins, and water insoluble vitamins.

111. The process of claim 104, wherein the pre-existing particles are selected from the group consisting a ceramic, a latex, a glass, and a metal.

112. The process of claim 104, wherein the pre-existing particles are selected from the group consisting an organic active compound, an agricultural active, an agricultural active precursor, a biocide, an herbicide, a pesticide, a flngicide, and an insecticide.

113. The process of claim 104, wherein at least one amphiphilic copolymer has a total molecular weight of between about 1000 and 50,000 g/mole.

114. The process of claim 104, wherein at least one amphiphilic copolymer exhibits a surface tension in water by no more than 50 dynes/cm at a concentration of 0.1 wt%.

115. The process of claim 104, wherein at least one amphiphllic copolymer comprises a block, graft or random copolymer.

116. A method of treating a patient in need with a nanoparticle composition comprising and organic drug, wherein said method comprises:

administering to a mammal in need a therapeutically effective amount of nanoparticles produced by flash precipitation and having an effective average particles size of less than about 1000 nm;

a therapeutically effective organic drug; and

at least one amphiphilic copolymer on the surface of the drug wherein at least one amphiphilic copolymer increases the water soluble characteristics of the organic drug.