Enzyme delivery systems and methods of preparation and use

• US 9,687,452 B2
• Filed: 04/22/2015
• Issued: 06/27/2017
• Est. Priority Date: 04/13/2009
• Status: Active Grant

• Current Assignee: Curemark LLC
• Original Assignee: Curemark LLC
• Inventors: Heil, Matthew, Fallon, Joan M.
• Primary Examiner(s): Kolker, Daniel E
• Assistant Examiner(s): Dutt, Aditi
• Application Number:
  US14/693,711
• Publication Number:
  US 20150335589A1
• Time in Patent Office: 797 Days
• Field of Search: None
• CPC Class Codes: A23L 33/17 Amino acids, peptides or proteins
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A61J 15/00 Feeding-tubes for therapeutic purposes
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/465 acting on ester bonds (3.1), e.g. lipases, ribonucleases
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 38/48 acting on peptide bonds (3.4)
• CPC Class Codes: A61K 38/4826 Trypsin (3.4.21.4) Chymotrypsin (3.4.21.1)
• CPC Class Codes: A61K 38/54 Mixtures of enzymes or proenzymes covered by more than a single one of groups A61K38/44 - A61K38/46 or A61K38/51 - A61K38/53
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/009 Sachets, pouches characterised by the material or function of the envelope with gastric retention A61K9/0065; sachets which are not administered but function merely as a container are classified according to the content, e.g. sachets comprising powder for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/1682 Processes
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5063 Compounds of unknown constitution, e.g. material from plants or animals oils, fats, waxes, shellac A61K9/5015
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Y 301/01003 : Triacylglycerol lipase (3.1.1.3)
• CPC Class Codes: C12Y 302/01 : Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
• CPC Class Codes: C12Y 304/21001 : Chymotrypsin (3.4.21.1)
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention relates to coated digestive enzyme preparations and enzyme delivery systems and pharmaceutical compositions comprising the preparations. This invention further relates to methods of preparation and use of the systems, pharmaceutical compositions and preparations to treat persons having ADD, ADHD, autism, cystic fibrosis and other behavioral and neurological disorders.

Claims

1. A method of treating a subject having an Attention Deficit Disorder (ADD), comprising administering to the subject a pharmaceutical composition that comprises a coated digestive enzyme preparation, wherein the coated digestive enzyme preparation comprises coated particles that comprise:

(a) a core that comprises digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase and a lipase; and

(b) a coating that comprises an emulsifiable lipid, wherein the coating coats the core,

wherein the digestive enzymes are present in the coated particles in an amount of from about 75% to about 85% by weight, and

wherein the coating masks the taste and smell of the digestive enzymes.

2. The method of claim 1, wherein the emulsifiable lipid is a hydrogenated soy oil.

3. The method of claim 1, wherein the coating consists essentially of one or more monoglycerides.

4. The method of claim 1, wherein the coating comprises monoglycerides.

5. The method of claim 1, wherein the emulsifiable lipid is selected from the group consisting of monoglycerides, diglycerides, fatty acids, esters of fatty acids, phospholipids, salts thereof, and a combination thereof.

6. The method of claim 5, comprising the esters of fatty acids, wherein the esters of fatty acids are selected from the group consisting of acetic acid esters of mono- and diglycerides, citric acid esters of mono- and diglycerides, lactic acid esters of mono- and diglycerides, polyglycerol esters of fatty acids, propylene glycol esters of fatty acids, and diacetyl tartaric acid esters of mono- and diglycerides.

7. The method of claim 1, wherein the emulsifiable lipid is a food grade emulsifiable lipid.

8. The method of claim 7, wherein the food grade emulsifiable lipid comprises a sorbitan monostearate, a sorbitan tristearate, or a calcium stearoyl lactylate.

9. The method of claim 1, wherein the emulsifiable lipid is a hydrogenated castor wax or a carnauba wax.

10. The method of claim 1, wherein the digestive enzymes have a protease activity of not less than 156 United States Pharmacopeia (U.S.P.) units/mg.

11. The method of claim 1, wherein the digestive enzymes are provided as pancreatin.

12. The method of claim 1, wherein the core is from about 105 μ

m to about 425 μ

m.

13. The method of claim 1, wherein the core is sieved from about 40 mesh to about 140 mesh.

14. The method of claim 1, wherein the coated particles are non-aerosolizable.

15. The method of claim 1, wherein about 80% of the digestive enzymes are released by 30 minutes in a dissolution test performed at pH 6.0.

16. The method of claim 1, wherein at least 90% of the coated particles are sieved from about #40 to about #140 mesh in size.

17. The method of claim 1, wherein less than 20% of the coated particles are capable of being sieved through #100 mesh.

18. The method of claim 1, wherein less than 15%, of the coated particles are capable of being sieved through #100 mesh.

19. The method of claim 1, wherein the emulsifiable lipid comprises at least one hydrophilic group and at least one hydrophobic group.

20. The method of claim 19, wherein the emulsifiable lipid is an animal emulsifiable lipid or a vegetable emulsifiable lipid.

21. The method of claim 20, wherein the animal emulsifiable lipid or the vegetable emulsifiable lipid is selected from the group consisting of a palm kernel oil, a soybean oil, a cottonseed oil, a canola oil and a poultry fat.

22. The method of claim 19, wherein the emulsifiable lipid is capable of forming a hydrophilic and hydrophobic interface.

23. The method of claim 22, wherein the hydrophilic and hydrophobic interface is a micelle interface.

24. The method of claim 22, wherein the hydrophilic and hydrophobic interface is a bilayer interface.

25. The method of claim 1, wherein the emulsifiable lipid is hydrogenated, saturated or partially saturated.

26. The method of claim 1, wherein the core is processed by a technique selected from the group consisting of encapsulation, compression, extrusion and molding.

27. The method of claim 1, wherein at least 75% of the coated particles are sieved from about #40 to about #80 mesh in size.

28. The method of claim 1, wherein the emulsifiable lipid comprises a hydrogenated soy oil.

29. The method of claim 1, wherein the coating consists essentially of the emulsifiable lipid that is a hydrogenated soy oil.

30. The method of claim 1, wherein the digestive enzymes are present in the coated particles in an amount of 75% by weight.

31. The method of claim 1, wherein the digestive enzymes are present in the coated particles in an amount of 77.5% by weight.

32. The method of claim 1, wherein the digestive enzymes are present in the coated particles in an amount of 80% by weight.

33. The method of claim 1, wherein the digestive enzymes are present in the coated particles in an amount of 82.5% by weight.

34. The method of claim 1, wherein the digestive enzymes are present in the coated particles in an amount of 85% by weight.

35. The method of claim 1, wherein at least 90% of the coated particles are from about 105 to about 425 μ

m.

36. The method of claim 1, wherein less than 20% of the coated particles are capable of being sieved through about 150 μ

m mesh.

37. The method of claim 1, wherein less than 15% of the coated particles are capable of being sieved through about 150 μ

m mesh.

38. The method of claim 1, wherein at least 75% of the coated particles are from about 180 to about 425 μ

m.

39. The method of claim 1, wherein a therapeutically effective amount of the pharmaceutical composition is a dose that contains about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050mg, about 1100 mg, or about 1150 mg of the coated digestive enzyme preparation.

40. A method of treating a subject having an Attention Deficit Hyperactive Disorder (ADHD), comprising administering to the subject a pharmaceutical composition that comprises a coated digestive enzyme preparation, wherein the coated digestive enzyme preparation comprises coated particles that comprise:

(a) a core that comprises digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase and a lipase; and

(b) a coating that comprises an emulsifiable lipid, wherein the coating coats the core,

wherein the digestive enzymes are present in the coated particles in an amount of from about 75% to about 85% by weight, and

wherein the coating masks the taste and smell of the digestive enzymes.

41. The method of claim 40, wherein the emulsifiable lipid is a hydrogenated soy oil.

42. The method of claim 40, wherein the coating consists essentially of one or more monoglycerides.

43. The method of claim 40, wherein the coating comprises monoglycerides.

44. The method of claim 40, wherein the emulsifiable lipid is selected from the group consisting of monoglycerides, diglycerides, fatty acids, esters of fatty acids, phospholipids, salts thereof, and a combination thereof.

45. The method of claim 44, comprising the esters of fatty acids, wherein the esters of fatty acids are selected from the group consisting of acetic acid esters of mono- and diglycerides, citric acid esters of mono- and diglycerides, lactic acid esters of mono- and diglycerides, polyglycerol esters of fatty acids, propylene glycol esters of fatty acids, and diacetyl tartaric acid esters of mono- and diglycerides.

46. The method of claim 40, wherein the emulsifiable lipid is a food grade emulsifiable lipid.

47. The method of claim 46, wherein the food grade emulsifiable lipid comprises a sorbitan monostearate, a sorbitan tristearate, or a calcium stearoyl lactylate.

48. The method of claim 40, wherein the emulsifiable lipid is a hydrogenated castor wax or a carnauba wax.

49. The method of claim 40, wherein the digestive enzymes have a protease activity of not less than 156 U.S.P. units/mg.

50. The method of claim 40, wherein the digestive enzymes are provided as pancreatin.

51. The method of claim 40, wherein the core is from about 105 μ

m to about 425 μ

m.

52. The method of claim 40, wherein the core is sieved from about 40 mesh to about 140 mesh.

53. The method of claim 40, wherein the coated particles are non-aerosolizable.

54. The method of claim 40, wherein about 80% of the digestive enzymes are released by 30 minutes in a dissolution test performed at pH 6.0.

55. The method of claim 40, wherein at least 90% of the coated particles are sieved from about #40 to about #140 mesh in size.

56. The method of claim 40, wherein less than 20% of the coated particles are capable of being sieved through #100 mesh.

57. The method of claim 40, wherein less than 15%, of the coated particles are capable of being sieved through #100 mesh.

58. The method of claim 40, wherein the emulsifiable lipid comprises at least one hydrophilic group and at least one hydrophobic group.

59. The method of claim 58, wherein the emulsifiable lipid is an animal emulsifiable lipid or a vegetable emulsifiable lipid.

60. The method of claim 59, wherein the animal emulsifiable lipid or the vegetable emulsifiable lipid is selected from the group consisting of a palm kernel oil, a soybean oil, a cottonseed oil, a canola oil and a poultry fat.

61. The method of claim 58, wherein the emulsifiable lipid is capable of forming a hydrophilic and hydrophobic interface.

62. The method of claim 61, wherein the hydrophilic and hydrophobic interface is a micelle interface.

63. The method of claim 61, wherein the hydrophilic and hydrophobic interface is a bilayer interface.

64. The method of claim 40, wherein the emulsifiable lipid is hydrogenated, saturated or partially saturated.

65. The method of claim 40, wherein the core is processed by a technique selected from the group consisting of encapsulation, compression, extrusion and molding.

66. The method of claim 40, wherein at least 75% of the coated particles are sieved from about #40 to about #80 mesh in size.

67. The method of claim 40, wherein the emulsifiable lipid comprises a hydrogenated soy oil.

68. The method of claim 40, wherein the coating consists essentially of the emulsifiable lipid that is a hydrogenated soy oil.

69. The method of claim 40, wherein the digestive enzymes are present in the coated particles in an amount of 75% by weight.

70. The method of claim 40, wherein the digestive enzymes are present in the coated particles in an amount of 77.5% by weight.

71. The method of claim 40, wherein the digestive enzymes are present in the coated particles in an amount of 80% by weight.

72. The method of claim 40, wherein the digestive enzymes are present in the coated particles in an amount of 82.5% by weight.

73. The method of claim 40, wherein the digestive enzymes are present in the coated particles in an amount of 85% by weight.

74. The method of claim 40, wherein at least 90% of the coated particles are from about 105 to about 425 μ

m.

75. The method of claim 40, wherein less than 20% of the coated particles are capable of being sieved through about 150 μ

m mesh.

76. The method of claim 40, wherein less than 15% of the coated particles are capable of being sieved through about 150 μ

m mesh.

77. The method of claim 40, wherein at least 75% of the coated particles are from about 180 to about 425 μ

m.

78. The method of claim 40, wherein a therapeutically effective amount of the pharmaceutical composition is a dose that contains about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050mg, about 1100 mg, or about 1150 mg of the coated digestive enzyme preparation.