Insulins combinations

• US 7,786,077 B2
• Filed: 10/29/2007
• Issued: 08/31/2010
• Est. Priority Date: 04/27/2005
• Status: Expired due to Fees

• Current Assignee: Jallal Messadek
• Original Assignee: Jallal Messadek
• Inventors: Messadek, Jallal
• Primary Examiner(s): Landsman; Robert
• Assistant Examiner(s): DANG, IAN D
• Application Number:
  US11/927,172
• Publication Number:
  US 20080214441A1
• Time in Patent Office: 1,037 Days
• Field of Search: None
• US Class Current: 514/1.1
• 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 31/205 Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

A pharmaceutical association or combination comprising a therapeutic effective amount of insulin or insulin analogue, and a therapeutic effective amount of a pharmaceutically acceptable betaine, in which the insulin and the betaine possibly form a chemical entity or complex, and in which the amount of betaine is adapted for controlling the degradation and/or for increasing the duration of action and/or for enhancing the therapeutically effect of the insulin or insulin analogue.

Claims

1. A pharmaceutical combination comprising (a) a therapeutic effective amount of an insulin compound selected from the group consisting of insulin, insulin analogues and mixtures thereof, and (b) a therapeutic effective amount of a pharmaceutically acceptable betaine of general formula (CH₃)₃N⁺—

(CH₂)n —

COO⁻

;

with n being an integer from 1 to 5, in which the insulin and the betaine form at least partly a structure selected from the group consisting of chemical entity, chemical complex, physico complex, insulin/betaine micelles, insulin/betaine microstructures, insulin/betaine nanostructures, and combinations thereof, and in which the weight ratio of therapeutic effective amount of the insulin compound/therapeutic effective amount of betaine is between 1;

400 and 1;

5.

2. The pharmaceutical combination of claim 1, in which the therapeutic effective amount of betaine is selected from the group consisting of therapeutic effective amount of betaine suitable for reducing the onset of action of the insulin compound after administration in a human, therapeutic effective amount of betaine suitable for extending the duration of action of the therapeutic effective amount of insulin compound after administration in a human, and therapeutic effective amount of betaine suitable for reducing the onset of action of the insulin compound and for extending the duration of action of the therapeutic effective amount of insulin compound after administration in a human, and in which the weight ratio of therapeutic effective amount of the insulin compound/therapeutic effective amount of betaine is between 1:

100 and 1;

5.

3. The pharmaceutical combination of claim 1, in which the therapeutic effective amount of betaine is suitable for increasing the duration of action of the therapeutic effective amount of insulin compound after administration in a human by at least 30% with respect to the duration of action of the same therapeutic effective amount of insulin compound after administration in a human without betaine.

4. The pharmaceutical combination of claim 1, which comprises a therapeutic effective amount of betaine for increasing the efficiency of the therapeutic effective amount of insulin compound at least for a period of 2 to 24 hours after administration in a human of the combination.

5. The pharmaceutical combination of claim 1, in which the in vivo total bioavailability of the therapeutic effective amount of insulin compound after human administration is increased by at least 20% with respect to the in vivo total bioavailability of said therapeutic effective amount of the insulin compound after administration in a human without betaine.

6. The pharmaceutical effective combination of claim 1, which comprises a daily therapeutic effective dose of the insulin compound corresponding to less than 80% of the daily therapeutic effective amount of said insulin compound administered in a human without betaine.

7. The pharmaceutical combination of claim 1, in which the insulin compound and the betaine form a structure selected from the group consisting of a complex in which the insulin compound is at least micro-dispersed in a betaine phase, a complex in which the insulin compound is at least nano-dispersed in a betaine phase, a complex in which the insulin compound is at least partly dissolved in a betaine phase, a complex comprising a core comprising insulin compound and an envelope comprising betaine surrounding at least partly said core, and combinations of said complexes.

8. The pharmaceutical combination of claim 1, in which at least 50% by weight of the insulin compound and the betaine present in the combination form a physico complex selected from the group consisting of co-precipitates of insulin compound and betaine, co-crystals of insulin compound and betaine, and mixtures of said co-precipitates and co-crystals.

9. The pharmaceutical combination of claim 1, in which the insulin compound and the betaine are at least partly entrapped as a mix in capsules selected from the group consisting of microcapsules, nanocapsules, and mixtures thereof.

10. The pharmaceutical combination of claim 1, in which at least 10% by weight of the insulin compound is entrapped in a betaine structure selected from the group consisting of betaine microcapsules, betaine nanocapsules, betaine meso structures, betaine micro structures, betaine nanostructures and mixtures thereof.

11. The pharmaceutical combination of claim 1, in which the insulin compound and the betaine are entrapped at least partly in a structure selected from the group consisting of liposomes, multiple liposomal formulations and combinations thereof.

12. The pharmaceutical combination of claim 1, which comprises beads or particles comprising pharmaceutically acceptable betaine and insulin compound, said beads or particles being provided with a water insoluble entero soluble polymer coating.

13. A pharmaceutical composition combining:

a form A comprising a pharmaceutically acceptable short-acting insulin compound selected from the group consisting of short-acting insulins and their analogues, said form being free of betaine of general formula (CH₃)₃N⁺—

(CH₂)n —

COO⁻

, and

a form B comprising a mixture of;

a. a pharmaceutically acceptable insulin compound selected from the group consisting of short acting insulins, intermediate-acting insulins, long-acting insulins, analogues thereof and their mixtures, and

b. a pharmaceutically acceptable betaine of general formula (CH₃)₃N₊—

(CH₂)n —

COO⁻

;

with n being an integer from 1 to 5.

14. The pharmaceutical composition of claim 13, in which the form B comprises short-acting insulin dispersed in a betaine containing phase.

15. The pharmaceutical composition of claim 13, which comprises an amount of form A and an amount of form B with a weight ratio of form A/form B of between 0.1 and 1.

16. The pharmaceutical composition of claim 13, which comprises an amount of form A and an amount of form B with a weight ratio of form B/form A of between 0.1 and 1.

17. The pharmaceutical composition of claim 13, in which the form B is separated from the form A by a controlled-release layer.

18. The pharmaceutical composition of claim 13, in which the form B comprises a co-crystal of the insulin compound and the betaine,

19. An isotonic aqueous composition comprising (a) a therapeutic effective amount of an insulin compound selected from the group consisting of insulin, insulin analogues and mixtures thereof, and (b) a therapeutic effective amount of a pharmaceutically acceptable betaine of general formula (CH₃)₃N⁺—

(CH₂)n —

COO⁻

;

with n being an integer from 1 to 5, in which the insulin and the betaine form at least partly a structure selected from the group consisting of chemical entity, chemical complex, physic complex, insulin/betaine micelles, insulin/betaine microstructures, insulin/betaine nanostrucures, and combinations thereof, and in which the weight ratio of therapeutic effective amount of the insulin compound/therapeutic effective amount of betaine is between 1;

100 and 1;

5.

20. The pharmaceutical combination of claim l, wherein said combination is in a dosage form suitable for an administration route selected from the group consisting of oral, dermal, transdermal, subcutaneous, parenteral, intraperitoneal, sublingual, nasal, pulmonary, rectal, and combinations thereof.