ORAL INSULIN THERAPIES & PROTOCOL

• US 20090253614A1
• Filed: 06/16/2009
• Published: 10/08/2009
• Est. Priority Date: 08/22/2003
• Status: Active Grant

• Current Assignee: NOVO Nordisk North America Operations A/S (Novo Nordisk A/S)
• Original Assignee: Ehud Arbit, Michael Goldberg, Shingai Majuru
• Inventors: MAJURU, Shingai, ARBIT, Ehud, GOLDBERG, Michael
• Granted Patent: US 8,729,016 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

Methods for treating impaired glucose tolerance and early and late stage diabetes in mammals, for prophylactically sparing β-cell function, aiding in preventing β-cell death, preventing the onset of overt diabetes in a mammal with type 2 diabetes, treating the current level of glycemic control dysfunction of a mammal with impaired glucose tolerance or diabetes, comprising orally administering insulin and a delivery agent that facilitates insulin absorption from the gastrointestinal tract at the time of or shortly before mealtime, e.g., within about 10 minutes prior to ingestion of a meal, on a chronic basis. The methods also comprise, in addition to administering a rapid-acting insulin to provide a first insulin peak, administering a slow acting insulin to provide a second insulin peak occurring at a later time but of a longer duration. These methods achieve improved glycemic control without the risks of hypoglycemia, hyperinsulinemia and weight gain and the need for frequent blood glucose monitoring that are normally associated with insulin therapy.

Claims

1. A method of treating a human diabetic patient, comprising:

orally administering to said diabetic patient, at a time from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of a meal, a dose of a therapeutically effective amount of insulin with from about 20 to about 600 mg of a pharmaceutically acceptable delivery agent that facilitates absorption of said insulin from the gastrointestinal tract, said delivery agent of the formula or a pharmaceutically acceptable salt thereof,

2. The method of claim 1, further comprising administering said dose such that said patient obtains a first peak plasma insulin concentration substantially from said administered dose and a second phase insulin response to said meal substantially from endogenous insulin release.

3. The method of claim 1, wherein said patient is a patient with type I diabetes or late stage type II diabetes, said method further comprising:

said step of orally administering to said patient comprising administering, at the time of or shortly prior to ingestion of a meal, a first unit dose of from about 10 Units to about 600 Units of insulin with said delivery agent, and

at the same time or shortly thereafter, administering to said patient a second, separate dose of insulin in an effective amount to replace a second phase insulin response to a meal which occurs in a non-diabetic subject substantially from endogenous insulin release.

4. The method of claim 3, further comprising orally administering said first dose of insulin with said delivery agent such that said patient obtains a first peak plasma insulin concentration substantially from said administered dose and administering said second, separate dose such that said patient obtains a second phase insulin response to said meal substantially from said administered separate dose.

5. The method of claim 3, further comprising, instead of the step of administering to said patient a separate dose of insulin, the step of administering to said patient an effective amount of an agent that causes the patient to secrete sufficient insulin to provide a second phase insulin response similar to a second phase insulin response to a meal which occurs in a non-diabetic subject substantially from endogenous insulin release.

6. The method of claim 5, further comprising orally administering said dose such that said patient obtains a first peak plasma insulin concentration substantially from said administered dose and administering said separate dose such that said patient obtains a second phase insulin response to said meal substantially from endogenous insulin release.

7. The method of claim 3, wherein administration to said patient of said first dose of insulin with said delivery agent takes place from about 30 minutes prior to ingestion of one meal daily to concurrently with ingestion of one meal daily.

8. The method of claim 3, wherein administration to said patient of said first dose of insulin with said delivery agent takes place at bedtime or in the morning, and preprandial to one meal from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.

9. The method of claim 3 wherein administration to said patient is for at least two consecutive weeks.

35. The method of claim 3 wherein the second pharmaceutical formulation is administered at least once orally.

36. The method of claim 3 wherein the second pharmaceutical formulation is administered at least once subcutaneously.

45. The method of claim 1, wherein said delivery agent is 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid.

46. The method of claim 45, wherein X is a halogen, or wherein R═

C3, or both.

47. The method of claim 46, wherein said halogen is chlorine.

48. The method of claim 3, wherein said delivery agent is 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid.

49. The method of claim 48, wherein X is a halogen, or wherein R═

C3, or both.

50. The method of claim 49, wherein said halogen is chlorine.

51. The method of claim 1, wherein said insulin is unmodified.

52. The method of claim 1, wherein said dosage form is a tablet.

10. A method of treating pre-diabetic patients, early stage type 2 patients and/or late stage type 2 diabetic patients comprising:

orally administering to a mammal on a chronic basis a pharmaceutical formulation comprising a therapeutically effective dose of insulin and a delivery agent that facilitates absorption of insulin from the gastrointestinal tract, said delivery agent of the formula or a pharmaceutically acceptable salt thereof,

11. The method of claim 10 wherein said improved effect is improved glucose tolerance as demonstrated by better endogenous capacity of the mammal to handle sugar load as measured by blood glucose concentration, following a sugar load, that is reduced by a statistically significant amount as compared with baseline blood glucose concentration, following a glucose load, prior to said chronic administration.

12. The method of claim 11 wherein said amount of reduction in blood glucose concentration is a mean of about 15%.

13. The method of claim 10 wherein said improved effect is improved glycemic control as measured by fasting blood glucose concentration that is reduced by a statistically significant amount as compared with baseline fasting blood glucose concentration prior to treatment.

14. The method of claim 13 wherein said amount of reduction in fasting blood glucose concentration is a mean of about 19%.

15. The method of claim 10 wherein said improved effect is improved glucose tolerance, further comprising the step of achieving said improved glucose tolerance without any statistically significant weight gain by said patient over said period of chronic administration.

16. The method of claim 15 wherein said improved effect is improved glucose tolerance, further comprising the step of achieving said improved glucose tolerance without any statistically significant risk of hypoglycemia in said mammal over said period of chronic administration.

17. The method of claim 10 wherein said improved effect is improved glucose tolerance, further comprising the step of achieving said improved glucose tolerance without any statistically significant risk of hyperinsulinemia in said mammal over said period of chronic administration.

18. The method of claim 10 wherein said improved effect is improved glucose tolerance, further comprising the step of achieving said improved glucose tolerance without the need for monitoring said patient'"'"'s blood glucose concentrations or HbA1c levels over said period of chronic administration.

19. The method of claim 10 wherein said improved effect is improved glycemic control as measured by serum fructosamine level that is reduced by a statistically significant amount as compared with baseline serum fructosamine level prior to treatment.

20. The method of claim 19 wherein said amount of reduction in serum fructosamine level is a mean of about 9%.

21. The method of claim 10 wherein said improved effect is improved HbA₁c levels as measured by an HbA₁c concentration that is reduced by a statistically significant amount as compared with baseline HbA₁c concentration prior to treatment.

22. The method of claim 10 wherein said improved effect is improved glycemic control, further comprising the step of achieving said improved glycemic control without any statistically significant weight gain by said patient over said period of chronic administration.

23. The method of claim 10 wherein said improved effect is improved glycemic control, further comprising the step of achieving said improved glycemic control without any statistically significant risk of hypoglycemia in said mammal over said period of chronic administration.

24. The method of claim 10 wherein said improved effect is improved glycemic control, further comprising the step of achieving said improved glycemic control without any statistically significant risk of hyperinsulinemia in said mammal over said period of chronic administration.

25. The method of claim 10 wherein said improved effect is improved glycemic control, further comprising the step of achieving said improved glycemic control without the need for monitoring said patient'"'"'s blood glucose concentrations or HbA1c levels over said period of chronic administration.

26. The method of claim 10 wherein said improved effect is improved insulin utilization and insulin sensitivity as measured by HOMA (Homeostasis Model Assessment) that is reduced by a statistically significant amount as compared with baseline HOMA (Homeostasis Model Assessment) prior to treatment.

27. The method of claim 10 wherein said improved effect is improved insulin secretion capacity as measured by a Stumvoll first-phase insulin secretion capacity index as compared with a baseline Stumvoll first-phase insulin secretion capacity index prior to treatment.

28. The method of claim 10 wherein administration to said patient takes place from about 30 minutes prior to ingestion of one meal daily to concurrently with ingestion of one meal daily.

29. The method of claim 10 wherein administration to said patient takes place at least once daily at a time point chosen from among the group consisting of at bedtime, in the morning and preprandial to one meal from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.

30. The method of claim 10 wherein administration to said patient takes place at least twice daily at time points chosen from among the group consisting of at bedtime, in the morning and preprandial to at least one meal at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.

31. The method of claim 10 wherein administration to said patient takes place at least three times daily at time points chosen from among the group consisting of at bedtime, in the morning and preprandial to at least one meal at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.

32. The method of claim 10 wherein administration to said patient takes place at least four times daily at time points chosen from among the group consisting of at bedtime, in the morning and preprandial to at least two meals at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.

33. The method of claim 10 wherein administration to said patient takes place at bedtime and preprandial to three meals at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.

34. The method of claim 10 wherein chronic administration to said patient is for at least two consecutive weeks.

37. The method of claim 10, wherein said method achieves a therapeutically effective reduction in blood glucose after treatment of said patient, and provides a ratio of portal vein to peripheral blood insulin concentration from about 2:

1 to about 6;

1.

38. The method of claim 10, wherein administration of said oral dose provides a maximum blood glucose concentration reduction caused by said dose of insulin after about 30 minutes after oral administration.

39. The method of claim 10, wherein the amount of insulin contained in said dose is from about 10 Units to about 600 Units.

40. The method of claim 10, wherein the amount of insulin contained in said dose is from about 100 Units to about 450 Units.

41. The method of claim 10, wherein the amount of insulin contained in said dose is from about 200 Units to about 350 Units.

42. The method of claim 10, wherein said delivery agent is 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid.

43. The method of claim 42, wherein X is a halogen, or wherein R═

C3, or both.

44. The method of claim 43, wherein said halogen is chlorine.

53. The method of claim 10, wherein said insulin is unmodified.

54. A method for treating a human diabetic patient in accordance with the patient'"'"'s stage of development of diabetes mellitus, comprising:

(a) identifying a patient'"'"'s stage of diabetes along a continuum of development of diabetes as one of prediabetic stage, early stage type 2 diabetes, late stage type 2 diabetes and type 1 diabetes; and

(b) recommending a treatment to said patient that includes an oral insulin treatment appropriate to said patient'"'"'s stage along the continuum of development of diabetes.

55. The method of claim 54 wherein said patient is at the prediabetic stage along said continuum of development of diabetes, and said treatment is administration to said patient on a chronic basis a pharmaceutical formulation comprising a therapeutically effective dose of insulin and a the delivery agent 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid that facilitates absorption of insulin from the gastrointestinal tract, at least once daily at a time point chosen from among the group consisting of at bedtime, in the morning and preprandial to one meal from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.

56. The method of claim 55 wherein administration to said patient is at bedtime.

57. The method of claim 54 wherein said patient is at the early stage type 2 diabetes stage along said continuum of development of diabetes, and said treatment is administration to said patient on a chronic basis a pharmaceutical formulation comprising a therapeutically effective dose of insulin and a the delivery agent 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid that facilitates absorption of insulin from the gastrointestinal tract, at least twice daily at time points chosen from among the group consisting of at bedtime and preprandial to at least one meal at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.

58. The method of claim 57 wherein administration to said patient is at bedtime.

59. The method of claim 57 wherein administration to said patient is at bedtime and preprandial all meals.

60. The method of claim 54 wherein said patient is at the late stage type 2 diabetes stage along said continuum of development of diabetes, and said treatment is administration to said patient on a chronic basis a pharmaceutical formulation comprising a therapeutically effective dose of insulin and the delivery agent 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid that facilitates absorption of insulin from the gastrointestinal tract, at least three times daily at time points chosen from among the group consisting of at bedtime and preprandial to at least one meal at from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of the meal.

61. The method of claim 60 wherein administration to said patient is at bedtime and preprandial all meals.

62. The method of claim 60 further comprising administering to the mammal on a chronic basis a therapeutically effective dose of a second pharmaceutical formulation comprising an intermediate-acting insulin or a long-acting insulin or both.

63. The method of claim 62 wherein the second pharmaceutical formulation is administered at least once a day orally.

64. The method of claim 62 wherein the second pharmaceutical formulation is administered at least once a day subcutaneously.

65. The method of claim 62 wherein the pharmaceutical formulation and the second pharmaceutical formulation provide two different activity rates in order to simulate the endogenous biphasic release of insulin to an ingested meal in a non-diabetic subject.