Propofol formulations with non-reactive container closures

DC CAFC

US 8,476,010 B2
Filed: 07/10/2003
Issued: 07/02/2013
Est. Priority Date: 07/10/2003
Status: Active Grant

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First Claim

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1. A sterile pharmaceutical composition of propofol in a container, comprising:

a container which includes a closure and a composition in the container, andthe composition in the container comprising from 0.5% to 10% by weight propofol and from about 0 to about 10% by weight solvent for propofol,where when the composition in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 93% of the starting concentration (w/v) of the propofol;

where the closure is selected from the group consisting of siliconized bromobutyl rubber, metal, and siliconized chlorobutyl rubber.

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Abstract

A sterile pharmaceutical composition for parenteral administration of propofol, said composition comprising propofol, optionally albumin, and less than about 10% by weight solvent for propofol, wherein said composition is stored in a container having a closure wherein said closure is inert to propofol.

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70 Claims

1. A sterile pharmaceutical composition of propofol in a container, comprising:
- a container which includes a closure and a composition in the container, andthe composition in the container comprising from 0.5% to 10% by weight propofol and from about 0 to about 10% by weight solvent for propofol,where when the composition in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 93% of the starting concentration (w/v) of the propofol;
  
  where the closure is selected from the group consisting of siliconized bromobutyl rubber, metal, and siliconized chlorobutyl rubber.
- 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, 28, 29, 30, 31, 32)
- - 2. The sterile pharmaceutical composition in a container according to claim 1, the composition further comprising an aqueous phase and protein.
  - 3. The sterile pharmaceutical composition in a container according to claim 2, wherein the protein is albumin.
  - 4. The sterile pharmaceutical composition in a container according to claim 3, wherein the albumin is present in an amount of from about 0.01% to about 5% by weight of the composition.
  - 5. The sterile pharmaceutical composition in a container according to claim 3, wherein the pH modifier is sodium hydroxide.
  - 6. The sterile pharmaceutical composition in a container according to claim 2, wherein the aqueous phase comprises water for injection and a pH modifier.
  - 7. The sterile pharmaceutical composition in a container according to claim 2, wherein the composition comprises a tonicity agent.
  - 8. The sterile pharmaceutical composition in a container according to claim 7, wherein the tonicity agent is glycerin.
  - 9. The sterile pharmaceutical composition in a container according to claim 2, wherein the composition further comprises a surfactant.
  - 10. The sterile pharmaceutical composition in a container according to claim 9, wherein the surfactant is selected from the group consisting of phosphatides, synthetic phospholipids, natural phospholipids, lecithins, ethoxylated ethers and esters, tocopherol polyethylene glycol stearate, polypropylene-polyethylene block co-polymers, polyvinyl pyrrolidone, and polyvinylalcohol and combinations thereof.
  - 11. The sterile pharmaceutical composition in a container according to claim 10, wherein the surfactant is selected from the group consisting of egg phosphatides, soya phosphatides, egg lecithins, soya lecithins, and combinations thereof.
  - 12. The sterile pharmaceutical composition in a container according to claim 11, wherein the surfactant is egg lecithin.
  - 13. The sterile pharmaceutical composition in a container according to claim 1 wherein the solvent is a water-immiscible solvent.
  - 14. The sterile pharmaceutical composition in a container according to claim 13, wherein the water-immiscible solvent is selected from the group consisting of soybean, safflower, cottonseed, corn, coconut, sunflower, arachis, castor sesame, orange, limonene or olive oil, an ester of a medium or long-chain fatty acid, a chemically modified or manufactured palmitate, glyceral ester or polyoxyl, hydrogenated castor oil, a marine oil, fractionated oils, and mixtures thereof.
  - 15. The sterile pharmaceutical composition in a container according to claim 14, wherein the water-immiscible solvent is soybean oil.
  - 16. The sterile pharmaceutical composition in a container according to claim 1, wherein the solvent is selected from the group consisting of chloroform, methylene chloride, ethyl acetate, ethanol, tetrahydrofuran, dioxane, acetonitrile, acetone, dimethyl sulfoxide, dimethyl formamide, methyl pyrrolidinone, C1-C20 alcohols, C2-C20 esters, C3-C20 ketones, polyethylene glycols, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons and combinations thereof.
  - 17. The sterile pharmaceutical composition in a container according to claim 1, wherein the closure is coated with a material inert to propofol.
  - 18. The sterile pharmaceutical composition in a container according to claim 1, wherein the closure consists essentially of a material that is itself inert to propofol.
  - 19. The sterile pharmaceutical composition in a container according to claim 18, wherein the closure material is metal.
  - 20. The sterile pharmaceutical composition in a container according to claim 1, wherein the closure comprises siliconized bromobutyl rubber.
  - 21. The sterile pharmaceutical composition in a container according to claim 1, wherein the closure comprises metal.
  - 22. The sterile pharmaceutical composition in a container according to claim 1, wherein the closure comprises siliconized chlorobutyl rubber.
  - 23. The sterile pharmaceutical composition in a container according to claim 1, wherein the composition comprises soybean oil in an amount of from about 0.5% to about 6% by weight of the composition, egg lecithin in an amount of from about 0.1% to about 5% by weight of the composition and human serum albumin in an amount of from about 0.1% to about 5% of the composition.
  - 24. The sterile pharmaceutical composition in a container according to claim 1, wherein when the composition is stored in the container sealed with the closure for at least two months, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least about 95% of the starting concentration (w/v) of the propofol.
  - 25. The sterile pharmaceutical composition in a container according to claim 24, wherein the composition is stored in the container sealed with the closure in a controlled environment of about 40°
    - C. and about 75% relative humidity for at least two months.
  - 26. The sterile pharmaceutical composition in a container according to claim 1, where when the composition in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 95% of the starting concentration (w/v) of the propofol.
  - 27. The sterile pharmaceutical composition in a container according to claim 1, where when the composition in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 97% of the starting concentration (w/v) of the propofol.
  - 28. The sterile pharmaceutical composition in a container according to claim 1, where when the composition in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 99% of the starting concentration (w/v) of the propofol.
  - 29. The sterile pharmaceutical composition in a container according to claim 1, the composition comprising less than about 0.5% by weight solvent for propofol.
  - 30. The sterile pharmaceutical composition in a container according to claim 1, the composition comprising from about 0.5% to about 6% by weight solvent for propofol.
  - 31. The sterile pharmaceutical composition in a container according to claim 30, the composition comprising from about 3% to about 6% by weight solvent for propofol.
  - 32. The sterile pharmaceutical composition in a container according to claim 31, the solvent comprising soybean oil.

33. A sterile pharmaceutical composition of propofol in a container, comprising:
- a container which includes a closure and an oil-in-water emulsion for parenteral administration of propofol in the container,the emulsion comprising an oil phase comprising propofol and a solvent for propofol, and an aqueous phase comprising water for injection,the emulsion comprising from about 0 to about 10% by weight of the solvent,the emulsion further comprising a stabilizing layer for the oil phase, the stabilizing layer comprising a surfactant and a protein;
  
  where when the emulsion in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the emulsion maintains a propofol concentration (w/v) measured by HPLC that is at least 93% of the starting concentration (w/v) of the propofol;
  
  where the closure is selected from the group consisting of siliconized bromobutyl rubber, metal, and siliconized chlorobutyl rubber.
- View Dependent Claims (34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56)
- - 34. The sterile pharmaceutical composition in a container according to claim 33, wherein the protein is selected from the group consisting of albumins, globulins, immunoglobulins, lipoproteins, caseins, insulins, hemoglobins, lysozymes, alpha-2-macroglobulin, fibronectins, vitronectins, fibrinogens, lipases, peptides, enzymes, antibodies and combinations thereof.
  - 35. The sterile pharmaceutical composition in a container according to claim 33, wherein the surfactant is selected from the group consisting of phosphatides, synthetic phospholipids, natural phospholipids, lecithins, ethoxylated ethers and esters, tocopherol polyethylene glycol stearate, polypropylene-polyethylene block co-polymers, polyvinyl pyrrolidone, and polyvinylalcohol.
  - 36. The sterile pharmaceutical composition in a container according to claim 35, comprising:
    - a) about 1% to 2% by weight of propofol,b) 3-6% by weight of soybean oil,c) 0.2-1.0% by weight of egg lecithin,d) about 2.25% by weight of glycerin,e) sodium hydroxide,f) water to 100%, andg) pH between 5.0-8.5.
  - 37. The sterile pharmaceutical composition in a container according to claim 33, wherein the oil phase is propofol neat.
  - 38. The sterile pharmaceutical composition in a container according to claim 33, wherein the surfactant is lecithin and the protein is albumin.
  - 39. The sterile pharmaceutical composition in a container according to claim 38, wherein the egg lecithin is present in the emulsion in an amount of from about 0.1% to about 5% by weight of the emulsion and the albumin is present in the emulsion in an amount of from about 0.01% to about 5% by weight of the emulsion.
  - 40. The sterile pharmaceutical composition in a container according to claim 39, wherein the oil phase includes soybean oil.
  - 41. The sterile pharmaceutical composition in a container according to claim 40, wherein the soybean oil is present in an amount of from about 0.5% to about 6% by weight of the emulsion.
  - 42. The sterile pharmaceutical composition in a container according to claim 40, wherein the soybean oil is present in the emulsion in an amount of from about 0.5% to about 3% by weight of the emulsion.
  - 43. The sterile pharmaceutical composition in a container according to claim 33, wherein the oil phase includes a solvent, and wherein the solvent is selected from the group consisting of soybean, safflower, cottonseed, corn, coconut, sunflower, arachis, castor sesame, orange, limonene or olive oil, an ester of a medium or long-chain fatty acid, a chemically modified or manufactured palmitate, glyceral ester or polyoxyl, hydrogenated castor oil, a marine oil, fractionated oils, and mixtures thereof, chloroform, methylene chloride, ethyl acetate, ethanol, tetrahydrofuran, dioxane, acetonitrile, acetone, dimethyl sulfoxide, dimethyl formamide, methyl pyrrolidinone, C1-C20 alcohols, C2-C20 esters, C3-C20 ketones, polyethylene glycols, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons and combinations thereof.
  - 44. The sterile pharmaceutical composition in a container according to claim 43, wherein the solvent is soybean oil.
  - 45. The sterile pharmaceutical composition in a container according to claim 44, wherein the soybean oil is present in an amount of from about 0.5% to about 6% by weight of the emulsion.
  - 46. The sterile pharmaceutical composition in a container according to claim 33, wherein the closure is treated with a material inert to propofol.
  - 47. The sterile pharmaceutical composition in a container according to claim 33, wherein the closure consists essentially of a material that is itself inert to propofol.
  - 48. The sterile pharmaceutical composition in a container according to claim 47, wherein the closure material is metal.
  - 49. The sterile pharmaceutical composition in a container according to claim 33, wherein the closure comprises siliconized bromobutyl rubber.
  - 50. The sterile pharmaceutical composition in a container according to claim 33, wherein the closure comprises metal.
  - 51. The sterile pharmaceutical composition in a container according to claim 33, wherein the closure comprises siliconized chlorobutyl rubber.
  - 52. The sterile pharmaceutical composition in a container according to claim 33, where when the emulsion in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the emulsion maintains a propofol concentration (w/v) measured by HPLC that is at least 95% of the starting concentration (w/v) of the propofol.
  - 53. The sterile pharmaceutical composition in a container according to claim 33, where when the emulsion in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the emulsion maintains a propofol concentration (w/v) measured by HPLC that is at least 97% of the starting concentration (w/v) of the propofol.
  - 54. The sterile pharmaceutical composition in a container according to claim 33, where when the emulsion in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the emulsion maintains a propofol concentration (w/v) measured by HPLC that is at least 99% of the starting concentration (w/v) of the propofol.
  - 55. The sterile pharmaceutical composition in a container according to claim 33, where when the emulsion is stored in the container sealed with the closure for at least two months, the emulsion maintains a propofol concentration (w/v) measured by HPLC that is at least 95% of the starting concentration (w/v) of the propofol.
  - 56. The sterile pharmaceutical composition in a container according to claim 33, where when the emulsion is stored in the container sealed with the closure in a controlled environment of about 40°
    - C. and about 75% relative humidity for at least two months, the emulsion maintains a propofol concentration (w/v) measured by HPLC that is at least 95% of the starting concentration (w/v) of the propofol.

57. A sterile, injectable pharmaceutical composition in a container, comprising:
- a container which includes a closure and a composition in the container, the composition comprisinga) microdroplets having a mean size of from about 20 nanometers to about 1000 nanometers, the microdroplets comprising a sphere of propofol surrounded by a stabilizing layer comprising a phospholipid and devoid of oils capable of supporting bacterial growth; and
  
  b) a pharmaceutically acceptable injectable carrier;
  
  where when the composition in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 93% of the starting concentration (w/v) of the propofol;
  
  where the closure is selected from the group consisting of siliconized bromobutyl rubber, metal, and siliconized chlorobutyl rubber.
- View Dependent Claims (58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70)
- - 58. The sterile, injectable pharmaceutical composition in a container according to claim 57, wherein the composition further comprises albumin.
  - 59. The sterile, injectable pharmaceutical composition in a container according to claim 57, wherein the stabilizing layer includes albumin.
  - 60. The sterile, injectable pharmaceutical composition in a container according to claim 57, wherein the closure is coated with a material inert to propofol.
  - 61. The sterile, injectable pharmaceutical composition in a container according to claim 57, wherein the closure consists essentially of a material that is itself inert to propofol.
  - 62. The sterile, injectable pharmaceutical composition in a container according to claim 61, wherein the closure material is metal.
  - 63. The sterile, injectable pharmaceutical composition in a container according to claim 57, wherein the closure comprises siliconized bromobutyl rubber.
  - 64. The sterile, injectable pharmaceutical composition in a container according to claim 57, wherein the closure comprises metal.
  - 65. The sterile, injectable pharmaceutical composition in a container according to claim 57, wherein the closure comprises siliconized chlorobutyl rubber.
  - 66. The sterile, injectable pharmaceutical composition in a container according to claim 57, where when the composition in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 95% of the starting concentration (w/v) of the propofol.
  - 67. The sterile, injectable pharmaceutical composition in a container according to claim 57, where when the composition in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 97% of the starting concentration (w/v) of the propofol.
  - 68. The sterile, injectable pharmaceutical composition in a container according to claim 57, where when the composition in the container sealed with the closure is agitated at a frequency of 300-400 cycles/minute for 16 hours at room temperature, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 99% of the starting concentration (w/v) of the propofol.
  - 69. The sterile, injectable pharmaceutical composition in a container according to claim 57, where when the composition is stored in the container sealed with the closure for at least two months, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 95% of the starting concentration (w/v) of the propofol.
  - 70. The sterile, injectable pharmaceutical composition in a container according to claim 57, where when the composition is stored in the container sealed with the closure in a controlled environment of about 40°
    - C. and about 75% relative humidity for at least two months, the composition maintains a propofol concentration (w/v) measured by HPLC that is at least 95% of the starting concentration (w/v) of the propofol.

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Current Assignee
Fresenius KABI USA LLC (Fresenius SE & Co. KGaA)
Original Assignee
APP Pharmaceuticals LLC (Fresenius SE & Co. KGaA)
Inventors
Desai, Neil P., Yang, Andrew, Ci, Sherry Xiaopei
Primary Examiner(s)
Weber, Jon P
Assistant Examiner(s)
TELLER, ROY R

Application Number

US10/616,709
Publication Number

US 20050009731A1
Time in Patent Office

3,645 Days
Field of Search

None
US Class Current

435/6
CPC Class Codes

A61J 1/00   Containers specially adapte...

A61J 1/05   for collecting, storing or ...

A61J 1/06   Ampoules or carpules syring...

A61J 1/1412   Containers with closing mea...

A61J 1/1468   Containers characterised by...

A61K 31/05   Phenols cannabinoids A61K31...

A61K 47/10   Alcohols; Phenols; Salts th...

A61K 47/24   containing atoms other than...

A61K 47/44   Oils, fats or waxes accordi...

A61K 9/0019   Injectable compositions; In...

A61K 9/0075   for inhalation via a dry po...

A61K 9/107   Emulsions ; Emulsion precon...

A61K 9/1075   Microemulsions or submicron...

Propofol formulations with non-reactive container closures

First Claim

14 Assignments

Litigations

2 Petitions

Accused Products

Abstract

36 Citations

70 Claims

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Propofol formulations with non-reactive container closures

First Claim

14 Assignments

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Litigations

2 Petitions

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Accused Products

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Abstract

36 Citations

70 Claims

Specification

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Solutions

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