Devices, formulations, and methods for delivery of multiple beneficial agents

• US 8,926,595 B2
• Filed: 11/29/2012
• Issued: 01/06/2015
• Est. Priority Date: 02/13/2008
• Status: Active Grant

• Current Assignee: Intarcia Therapeutics, Inc.
• Original Assignee: Intarcia Therapeutics, Inc.
• Inventors: Alessi, Thomas R., Leung, Karling Alice, Mercer, Ryan D., Negulescu, Cristina G., Rohloff, Catherine M., Yang, Bing
• Primary Examiner(s): FLICK, JASON E
• Application Number:
  US13/689,410
• Publication Number:
  US 20130090287A1
• Time in Patent Office: 768 Days
• Field of Search: 604/19
• US Class Current: 604/892.1
• 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 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/2264 Obesity-gene products, e.g. leptin
• CPC Class Codes: A61K 38/2278 Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention relates to osmotic delivery devices, formulations, and methods for delivery of two or more beneficial agents. In one aspect, the present invention provides osmotic delivery devices useful for substantially concurrent administration of two or more beneficial agents. In another aspect, the present invention provides beneficial agent formulations for use in the osmotic delivery devices. The formulations include formulations wherein beneficial agents are soluble in the vehicle, suspension formulations comprising particle formulations of one or more beneficial agent, and combinations thereof. Further, methods for treatment of a variety of diseases or conditions using two or more beneficial agents are disclosed, wherein the methods are preferably practiced using the osmotic delivery devices and/or formulations of the invention.

Claims

1. An osmotic delivery device comprising:

a beneficial agent formulation comprising (i) a non-aqueous, viscous vehicle comprising a solvent and a polymer, the vehicle having a viscosity of between about 12,000 to about 18,000 poise at 33°

C., and (ii) a particle formulation comprising two or more polypeptides, wherein the two or more polypeptides are selected from the group consisting of GLP-1, exendin-4, PYY, and oxyntomodulin;

wherein the particle formulation is suspended in the non-aqueous, viscous vehicle.

2. The device of claim 1, wherein the two or more polypeptides are formulated into one particle formulation that is suspended in the vehicle.

3. The device of claim 2, wherein (i) the solvent is benzyl benzoate and the polymer is polyvinylpyrrolidone, and the vehicle comprises about 25 wt % to about 80 wt % polyvinylpyrrolidone and about 75 wt % to about 20 wt % benzyl benzoate, and (ii) the polypeptides are exendin-4 and oxyntomodulin, and the particle formulation further comprises sucrose, methionine, and citrate buffer.

4. The device of claim 2, wherein (i) the solvent is benzyl benzoate and the polymer is polyvinylpyrrolidone, and the vehicle comprises about 25 wt % to about 80 wt % polyvinylpyrrolidone and about 75 wt % to about 20 wt % benzyl benzoate, and (ii) the polypeptides are exendin-4 and PYY, and the particle formulation further comprises sucrose, methionine, and citrate buffer.

5. The device of claim 2, wherein (i) the solvent is benzyl benzoate and the polymer is polyvinylpyrrolidone, and the vehicle comprises about 25 wt % to about 80 wt % polyvinylpyrrolidone and about 75 wt % to about 20 wt % benzyl benzoate, and (ii) the polypeptides are GLP-1 and oxyntomodulin, and the particle formulation further comprises sucrose, methionine, and citrate buffer.

6. The device of claim 2, wherein (i) the solvent is benzyl benzoate and the polymer is polyvinylpyrrolidone, and the vehicle comprises about 25 wt % to about 80 wt % polyvinylpyrrolidone and about 75 wt % to about 20 wt % benzyl benzoate, and (ii) the polypeptides are GLP-1 and oxyntomodulin, and the particle formulation further comprises sucrose, methionine, and citrate buffer.

7. The device of claim 1, wherein a first polypeptide is formulated into a first particle formulation and a second polypeptide is formulated into a second particle formulation, and the first and second particle formulations are suspended in the vehicle.

8. The device of claim 7, wherein (i) the solvent is benzyl benzoate and the polymer is polyvinylpyrrolidone, and the vehicle comprises about 25 wt % to about 80 wt % polyvinylpyrrolidone and about 75 wt % to about 20 wt % benzyl benzoate, (ii) the first polypeptide is exendin-4 and the first particle formulation further comprises sucrose, methionine, and citrate buffer, and (iii) the second polypeptide is oxyntomodulin and the second particle formulation further comprises sucrose, methionine, and citrate buffer.

9. The device of claim 7, wherein (i) the solvent is benzyl benzoate and the polymer is polyvinylpyrrolidone, and the vehicle comprises about 25 wt % to about 80 wt % polyvinylpyrrolidone and about 75 wt % to about 20 wt % benzyl benzoate, (ii) the first polypeptide is exendin-4 and the first particle formulation further comprises sucrose, methionine, and citrate buffer, and (iii) the second polypeptide is PYY and the second particle formulation further comprises sucrose, methionine, and citrate buffer.

10. The device of claim 7, wherein (i) the solvent is benzyl benzoate and the polymer is polyvinylpyrrolidone, and the vehicle comprises about 25 wt % to about 80 wt % polyvinylpyrrolidone and about 75 wt % to about 20 wt % benzyl benzoate, (ii) the first polypeptide is GLP-1 and the first particle formulation further comprises sucrose, methionine, and citrate buffer, and (iii) the second polypeptide is oxyntomodulin and the second particle formulation further comprises sucrose, methionine, and citrate buffer.

11. The device of claim 7, wherein (i) the solvent is benzyl benzoate and the polymer is polyvinylpyrrolidone, and the vehicle comprises about 25 wt % to about 80 wt % polyvinylpyrrolidone and about 75 wt % to about 20 wt % benzyl benzoate, (ii) the first polypeptide is GLP-1 and the first particle formulation further comprises sucrose, methionine, and citrate buffer, and (iii) the second polypeptide is PYY and the second particle formulation further comprises sucrose, methionine, and citrate buffer.

12. The device of claim 1, wherein first polypeptide is exendin-4 and a second polypeptide is oxyntomodulin.

13. The device of claim 1, wherein a first polypeptide is exendin-4 and a second polypeptide is PYY.

14. A method of treating a disease or condition in a subject in need of treatment, comprising:

providing the osmotic delivery device of claim 1 to the subject, wherein (i) the osmotic delivery device delivers a therapeutically effective amount of two or more polypeptides to treat the disease or condition, and (ii) the disease or condition is selected from the group consisting of type II diabetes, overweight, and obesity.

15. The method of claim 14, wherein (i) a first polypeptide is exendin-4, and a second polypeptide is oxyntomodulin or PYY;

and (ii) the two polypeptides are formulated into one particle formulation that is suspended in the vehicle or the first polypeptide is formulated into a first particle formulation and the second polypeptide is formulated into a second particle formulation and the first and second particle formulations are suspended in the vehicle.

16. The method of claim 14, wherein (i) a first polypeptide is GLP-1, and a second polypeptide is oxyntomodulin or PYY;

and (ii) the two polypeptides are formulated into one particle formulation that is suspended in the vehicle or the first polypeptide is formulated into a first particle formulation and the second polypeptide is formulated into a second particle formulation and the first and second particle formulations are suspended in the vehicle.

17. The device of claim 1, wherein a first polypeptide is PYY, and a second polypeptide is oxyntomodulin.

18. The device of claim 1, wherein a first polypeptide is exendin-4, a second polypeptide is oxyntomodulin, and a third polypeptide is PYY.

19. The device of claim 1, wherein a first polypeptide is GLP-1, a second polypeptide is oxyntomodulin, and a third polypeptide is PYY.

20. The device of claim 1, wherein the solvent is selected from the group consisting of lauryl lactate, lauryl alcohol, and benzyl benzoate.

21. The device of claim 20, wherein the polymer is polyvinylpyrrolidone.

22. The device of claim 1, wherein the polymer is polyvinylpyrrolidone.

23. The device of claim 1, wherein the solvent is benzyl benzoate and the polymer is polyvinylpyrrolidone.

24. The device of claim 1, wherein the vehicle comprises about 25 wt % to about 80 wt % polymer and about 75 wt % to about 20 wt % solvent.

25. The device of claim 1, wherein the particle formulation comprises a carbohydrate, an antioxidant, and a buffer.

26. The device of claim 25, wherein the carbohydrate is a non-reducing sugar, the antioxidant is an amino acid, and the buffer is an organic buffer.

27. The device of claim 26, wherein the non-reducing sugar is selected from the group consisting of sucrose, trehalose, and raffinose.

28. The device of claim 26, wherein the amino acid is selected from the group consisting of cysteine, methionine, and tryptophan.

29. The device of claim 26, wherein the organic buffer is selected from the group consisting of citrate, histidine, succinate, and tris.

30. The device of claim 1, wherein a first polypeptide is GLP-1 and a second polypeptide is oxyntomodulin.

31. The device of claim 1, wherein a first polypeptide is GLP-1 and a second polypeptide is PYY.