Enzyme delivery systems and methods of preparation and use

• US 9,415,014 B2
• Filed: 07/28/2011
• Issued: 08/16/2016
• Est. Priority Date: 04/13/2009
• Status: Active Grant

• Current Assignee: Curemark LLC
• Original Assignee: Curemark LLC
• Inventors: Fallon, Joan M., Heil, Matthew
• Primary Examiner(s): Kolker, Daniel E
• Assistant Examiner(s): Dutt, Aditi
• Application Number:
  US13/193,346
• Publication Number:
  US 20120027848A1
• Time in Patent Office: 1,846 Days
• Field of Search: None
• US Class Current: 1/1
• 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 coated free-flowing particulate digestive enzyme preparation, comprising particles that comprise:

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

(b) a coating comprising an emulsifiable lipid, wherein the coating coats the core and the emulsifiable lipid emulsifies upon exposure to a solvent;

wherein the digestive enzymes are present in an amount of from 77.5-82.5% by weight of the particles, and

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

2. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the coated free-flowing particulate digestive enzyme preparation provides a therapeutically effective amount of the digestive enzymes to treat a subject suffering from autism, Attention Deficit Disorder (ADD), or Attention Deficit Hyperactivity Disorder (ADHD).

3. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the core is from about 105 μ

m to about 425 μ

m.

4. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the core is sieved from about 40 mesh to about 140 mesh.

5. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the preparation is non-aerosolizable.

6. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the emulsifiable lipid is selected from the group consisting of hydrogenated soy oil, hydrogenated castor wax, and carnauba wax.

7. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein about 80% of the digestive enzymes are released by 30 minutes in a dissolution test performed at pH 6.0.

8. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the coating consists essentially of the emulsifiable lipid that is one or more monoglycerides.

9. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the emulsifiable lipid comprises monoglycerides.

10. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein at least 90% of the particles are sieved from about #40 to about #140 mesh in size.

11. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein less than 20%, or less than 15%, of the particles can be sieved through #100 mesh.

12. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the emulsifiable lipid comprises at least one hydrophilic group and at least one hydrophobic group.

13. The coated free-flowing particulate digestive enzyme preparation of claim 12, wherein the emulsifiable lipid is capable of forming a hydrophilic and hydrophobic interface.

14. The coated free-flowing particulate digestive enzyme preparation of claim 13, wherein the interface is a micelle interface.

15. The coated free-flowing particulate digestive enzyme preparation of claim 13, wherein the interface is a bilayer interface.

16. The coated free-flowing particulate digestive enzyme preparation of claim 12, wherein the emulsifiable lipid is obtained from animal or vegetable origins.

17. The coated free-flowing particulate digestive enzyme preparation of claim 16, wherein the emulsifiable lipid is selected from the group consisting of palm kernel oil, soybean oil, cottonseed oil, canola oil, poultry fat, hydrogenated soy oil, hydrogenated castor wax, and carnauba wax.

18. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the emulsifiable lipid is hydrogenated, saturated or partially saturated.

19. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the emulsifiable lipid consists of hydrogenated soy oil.

20. The coated free-flowing particulate digestive enzyme preparation 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 combinations thereof.

21. The coated free-flowing particulate digestive enzyme preparation of claim 20, 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.

22. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the emulsifiable lipid is a food grade emulsifiable lipid.

23. The coated free-flowing particulate digestive enzyme preparation of claim 22, wherein the food grade emulsifiable lipid comprises sorbitan monostearates, sorbitan tristearates, or calcium stearoyl lactylates.

24. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the core is processed by a technique selected from the group consisting of encapsulation, compression, extrusion and molding.

25. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein at least 75% of the particles are sieved from about #40 to about #80 mesh in size.

26. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the emulsifiable lipid comprises hydrogenated soy oil.

27. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the coating consists essentially of the emulsifiable lipid that is hydrogenated soy oil.

28. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the digestive enzymes have a protease activity of not less than 156 USP units/mg.

29. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein the core comprises the digestive enzymes present in an amount of 80% by weight of the particles.

30. The coated free-flowing particulate digestive enzyme of claim 1, wherein at least 90% of the particles are from about 105 to about 425 μ

m.

31. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein less than 20% of the particles can be sieved through about 150 μ

m mesh.

32. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein less than 15% of the particles can be sieved through about 150 μ

m mesh.

33. The coated free-flowing particulate digestive enzyme preparation of claim 1, wherein at least 75% of the particles are from about 180 to about 425 μ

m.

34. The coated free-flowing particulate digestive enzyme preparation of claim 1 or 27, wherein the digestive enzymes are a pancreatin composition.

35. A pharmaceutical composition comprising a therapeutically effective amount of a coated free-flowing particulate digestive enzyme preparation, wherein the preparation comprises particles that comprise:

a core comprising digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase and a lipase; and

,

a coating comprising an emulsifiable lipid, wherein the coating coats the core and the emulsifiable lipid emulsifies upon exposure to a solvent;

wherein the digestive enzymes are present in an amount of from 77.5-82.5% by weight of the particles, wherein the coating masks the taste and smell of the digestive enzymes and wherein the therapeutically effective amount of the coated free-flowing particulate digestive enzyme preparation is effective to treat a subject suffering from autism, Attention Deficit Disorder (ADD), or Attention Deficit Hyperactivity Disorder (ADHD).

36. The pharmaceutical composition of claim 35, provided in a sachet or a pouch.

37. The pharmaceutical composition of claim 35, wherein at least 80% of the digestive enzymes are released by 30 minutes in a dissolution test performed at pH 6.0.

38. The pharmaceutical composition of claim 35, wherein at least 90% of the particles are sieved from about #40 to about #140 mesh in size.

39. The pharmaceutical composition of claim 35, wherein less than 20% of the particles can be sieved through #100 mesh.

40. The pharmaceutical composition of claim 35, wherein at least 75% of the particles are sieved from about #40 to about #80 mesh in size.

41. The pharmaceutical composition of claim 35, wherein the emulsifiable lipid comprises hydrogenated soy oil.

42. The pharmaceutical composition of claim 35, wherein the coating consists essentially of the emulsifiable lipid that is hydrogenated soy oil.

43. The pharmaceutical composition of claim 35, wherein the digestive enzymes have a protease activity of not less than 156 USP units/mg.

44. The pharmaceutical composition of claim 35, wherein the core comprises the digestive enzymes present in an amount of 80% by weight of the particles.

45. The pharmaceutical composition of claim 35, wherein at least 90% of the particles are from about 105 to about 425 μ

m.

46. The pharmaceutical composition of claim 35, wherein less than 20% of the particles can be sieved through about 150 μ

m mesh.

47. The pharmaceutical composition of claim 35, wherein less than 15% of the particles can be sieved through about 150 μ

m mesh.

48. The pharmaceutical composition of claim 35, wherein at least 75% of the particles are from about 180 to about 425 μ

m.

49. The pharmaceutical composition of claim 35 or 42, wherein the digestive enzymes are a pancreatin composition.

50. A pharmaceutical composition comprising a dose of a coated free-flowing particulate digestive enzyme preparation, wherein the preparation comprises particles that comprise:

a core comprising digestive enzymes, wherein the digestive enzymes comprise a protease, an amylase and a lipase; and

a coating to provide for controlled release of the digestive enzymes, wherein the coating comprises an emulsifiable lipid, wherein the emulsifiable lipid is a soy lipid;

wherein the digestive enzymes are present in an amount of from 77.5-82.5% by weight of the particles, wherein the coating masks the taste and smell of the digestive enzymes, and wherein the digestive enzymes have a protease activity of not less than 156 USP units/mg.

51. The pharmaceutical composition of claim 50, wherein the digestive enzymes are present in an amount effective for treatment of a subject suffering from autism, ADD, or ADHD.

52. The pharmaceutical composition of claim 50, wherein the emulsifiable lipid is hydrogenated soy oil, hydrogenated castor wax, or carnauba wax.

53. The pharmaceutical composition of claim 50, wherein the dose is provided in a sachet or pouch.

54. The pharmaceutical composition of claim 50, wherein at least 90% of the particles are sieved from about #40 to about #140 mesh in size.

55. The pharmaceutical composition of claim 50, wherein less than 20% of the particles can be sieved through #100 mesh.

56. The pharmaceutical composition of claim 50, wherein at least 75% of the particles are sieved from #40 to about #80 mesh in size.

57. The pharmaceutical composition of claim 50, wherein the coating consists essentially of the emulsifiable lipid that is hydrogenated soy oil.

58. The pharmaceutical composition of claim 50, wherein the core comprises the digestive enzymes present in an amount of 80% by weight of the particles.

59. The pharmaceutical composition of claim 50, wherein at least 90% of the particles are from about 105 to about 425 μ

m.

60. The pharmaceutical composition of claim 50, wherein less than 20% of the particles can be sieved through about 150 μ

m mesh.

61. The pharmaceutical composition of claim 50, wherein less than 15% of the particles can be sieved through about 150 μ

m mesh.

62. The pharmaceutical composition of claim 50, wherein at least 75% of the particles are from about 180 to about 425 μ

m.

63. The pharmaceutical composition of claim 50 or 57, wherein the digestive enzymes are a pancreatin composition.

64. The pharmaceutical composition of claim 50, wherein the dose contains about 900 mg of the coated free-flowing particulate digestive enzyme preparation.

65. The pharmaceutical composition of claim 50, wherein the coating is generally uniform.