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

• US 20090202608A1
• Filed: 02/12/2009
• Published: 08/13/2009
• Est. Priority Date: 02/13/2008
• Status: Active Grant

• Current Assignee: Intarcia Therapeutics, Inc.
• Original Assignee: Intarcia Therapeutics, Inc.
• Inventors: Leung, Karling Alice, Negulescu, Cristina G., Alessi, Thomas R., Rohloff, Catherine M., Yang, Bing, Mercer, Ryan D.
• Granted Patent: US 8,343,140 B2
• Time in Patent Office: Days
• US Class Current: 424/424
• 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 chamber containing two or more beneficial agents, comprising

a beneficial agent formulation comprising a viscous vehicle and the two or more beneficial agents, wherein the formulation is selected from the group consisting of:

(i) two or more beneficial agents dispersed directly in the vehicle;

(ii) one or more beneficial agent dispersed directly in the vehicle and one or more beneficial agent formulated into a particle formulation that is suspended in the vehicle;

(iii) two or more beneficial agents combined in one particle formulation and the particle formulation suspended in the vehicle; and

(iv) two or more beneficial agents formulated individually into different particle formulations and the different particle formulations suspended together in the vehicle.

2. The device of claim 1, wherein at least two beneficial agents are polypeptides.

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

4. The device of claim 2, 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.

5. The device of claim 3, wherein the first polypeptide is exendin-4, and the second polypeptide is oxyntomodulin or PYY.

6. The device of claim 4, wherein the first polypeptide is exendin-4, and the second polypeptide is oxyntomodulin or PYY.

15. 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 the osmotic delivery device delivers a therapeutically effective amount of two or more beneficial agents to treat the disease or condition.

16. The method of claim 15, wherein the disease or condition is type II diabetes.

17. The method of claim 16, wherein (i) at least two beneficial agents are polypeptides;

(ii) the first polypeptide is exendin-4, and the second polypeptide is oxyntomodulin or PYY; and

(iii) 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.

18. The method of claim 15, wherein the disease or condition is being overweight or obesity.

19. The method of claim 18, wherein (i) at least two beneficial agents are polypeptides;

(ii) the first polypeptide is exendin-4, and the second polypeptide is oxyntomodulin or PYY; and

(iii) 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.

20. A method of treating two or more diseases or conditions in a subject in need of treatment, comprising

providing the osmotic delivery device of claim 1 to the subject, wherein the osmotic delivery device delivers a therapeutically effective amount of (i) one or more beneficial agent to treat a first disease or condition, and (ii) one or more beneficial agent to treat a second disease or condition.

7. A dual osmotic delivery device, comprising

a first osmotic delivery device contained within a second osmotic delivery device, wherein each osmotic delivery device comprises an impermeable reservoir that defines a lumen and two ends, the diameter of the lumen of the second device is greater than the diameter of the lumen of the first device, the ends of the first and the second device are substantially coincident and each end of the first osmotic delivery device is substantially concentric in relationship to a corresponding end of the second delivery device;

the first osmotic delivery device, comprising

the first impermeable reservoir having an inner and an outer surface,

a first piston that divides the first reservoir into a first, and a second₁ chamber and isolates the first₁ chamber from the second₁ chamber,

a first osmotic agent formulation in the first₁ chamber,

a first beneficial agent formulation in the second₁ chamber,

a first semi-permeable membrane in sealing relationship with the open end of the first₁ chamber, and

a first diffusion moderator in mating relationship with the open end of the second₁ chamber, wherein the diffusion moderator defines an orifice through which the first beneficial agent is capable of exiting the first device, and the first diffusion moderator effectively isolates the first beneficial agent formulation within the second₁ chamber from the environment of use; and

the second osmotic delivery device, comprising

the second impermeable reservoir having an inner and an outer surface,

a second piston that divides the second reservoir into a first₂ and a second₂ chamber, wherein the second piston (i) contacts the inner surface of the second reservoir in sealing relationship, and (ii) defines an internal opening that contacts the outer surface of the first reservoir in sealing relationship, thus isolating the first₂ chamber from the second₂ chamber,

a second osmotic agent formulation in the first₂ chamber,

a second beneficial agent formulation in the second₂ chamber,

a second semi-permeable membrane in sealing relationship with the open end of the second₂ chamber, wherein the second semi-permeable membrane contacts the outer surface of the first reservoir in sealing relationship, and

a second diffusion moderator in mating relationship with the open end of the second₂ chamber, wherein (i) the second diffusion moderator (a) defines an orifice through which the second beneficial agent is capable of exiting the device, and (b) contacts the outer surface of the first reservoir in sealing relationship, and (ii) the second diffusion moderator effectively isolates the second beneficial agent formulation within the second₂ chamber from the environment of use.

8. A dual osmotic delivery device, comprising

an impermeable reservoir having outer and inner surfaces and first and second ends, wherein the reservoir (i) defines a lumen between the first and second ends, and at least one opening between the inner and outer surface, and (ii) the opening is located approximately half-way between the first and second ends;

a first osmotic delivery device, comprising

a first reservoir portion extending from the first end of the reservoir to adjacent the opening,

a first piston that divides the first reservoir portion into a first₁ and a second₁ chamber, and isolates the first₁ chamber from the second₁ chamber, wherein the first₁ chamber is adjacent the opening,

a first osmotic agent formulation in the first₁ chamber,

a first beneficial agent formulation in the second₁ chamber,

a first semi-permeable membrane in sealing relationship with the open end of the first₁ chamber, wherein the first semi-permeable membrane is adjacent the opening and isolates the first₁ chamber from the opening, and

a first diffusion moderator in mating relationship with the open end of the second₁ chamber, wherein (i) the diffusion moderator defines an orifice through which the first beneficial agent is capable of exiting the second₁ chamber, and (ii) the first diffusion moderator effectively isolates the first beneficial agent formulation within the second₁ chamber from the environment of use;

a second osmotic delivery device, comprising

a second reservoir portion extending from the second end of the reservoir to adjacent the opening,

a second piston that divides the second reservoir portion into a first₂ and a second₂ chamber, and isolates the first₂ chamber from the second₂ chamber, wherein the first₂ chamber is adjacent the opening,

a second osmotic agent formulation in the first₂ chamber,

a second beneficial agent formulation in the second₂ chamber,

a second semi-permeable membrane in sealing relationship with the open end of the first₂ chamber, wherein the second semi-permeable membrane is adjacent the opening and isolates the first₂ chamber from the opening, and

a second diffusion moderator in mating relationship with the open end of the second₂ chamber, wherein (i) the diffusion moderator defines an orifice through which the second beneficial agent is capable of exiting the second₂ chamber, and (ii) the second diffusion moderator effectively isolates the second beneficial agent formulation within the second₂ chamber from the environment of use; and

wherein the first semi-permeable membrane and the second semi-permeable membrane define a fluid imbibition chamber that includes a portion of the reservoir that defines the opening.

9. A dual osmotic delivery device, comprising

an impermeable reservoir having outer and inner surfaces and first and second ends, wherein the reservoir (i) defines a lumen between the first and second ends, (ii) defines at least two openings between the inner and outer surface, and (iii) the openings are located approximately half-way between the first and second ends;

a first osmotic delivery device, comprising

a first reservoir portion extending from the first end of the reservoir to adjacent the openings,

a first piston that divides the first reservoir portion into a first, and a second₁ chamber, wherein the piston isolates the first₁ chamber from the second₁ chamber, and the second₁ chamber is adjacent the openings,

a first osmotic agent formulation in the first₁ chamber,

a first beneficial agent formulation in the second₁ chamber,

a first semi-permeable membrane in sealing relationship with the open end of the first₁ chamber, and

a first diffusion moderator in mating relationship with the open end of the second₁ chamber, wherein the diffusion moderator defines an orifice through which the first beneficial agent is capable of exiting the second₁ chamber, the orifice is aligned with one of the openings in the reservoir, and the first diffusion moderator effectively isolates the first beneficial agent formulation within the second₁ chamber from the environment of use; and

a second osmotic delivery device, comprising

a second reservoir portion extending from the second end of the reservoir to adjacent the openings,

a second piston that divides the second reservoir portion into a first₂ and a second₂ chamber, wherein the piston isolates the first₂ chamber from the second₂ chamber, and the second₂ chamber is adjacent the openings,

a second osmotic agent formulation in the first₂ chamber,

a second beneficial agent formulation in the second₂ chamber,

a second semi-permeable membrane in sealing relationship with the open end of the first₂ chamber, and

a second diffusion moderator in mating relationship with the open end of the second₂ chamber, wherein the diffusion moderator defines an orifice through which the second beneficial agent is capable of exiting the second₂ chamber, the orifice is aligned with the second opening in the reservoir, and the diffusion moderator effectively isolates the second beneficial agent formulation within the second₂ chamber from the environment of use.

10. A dual osmotic delivery device, comprising

a first osmotic delivery device, comprising

a first impermeable reservoir having a first open end and a second open end,

a first piston that divides the first reservoir into a first, and a second₁ chamber, wherein the piston isolates the first₁ chamber from the second₁ chamber,

a first osmotic agent formulation in the first₁ chamber,

a first beneficial agent formulation in the second₁ chamber,

a first semi-permeable membrane in sealing relationship with the open end of the first₁ chamber, and

a diffusion moderator in mating relationship with the open end of the second₁ chamber, wherein the diffusion moderator defines a first orifice through which the first beneficial agent is capable of exiting the second₁ chamber, and the diffusion moderator effectively isolates the first beneficial agent formulation within the second₁ chamber from the environment of use;

and

a second osmotic delivery device, comprising

a second impermeable reservoir having a first open end and a second open end,

a second piston that divides the second reservoir portion into a first₂ and a second₂ chamber, wherein the piston isolates the first₂ chamber from the second₂ chamber,

a second osmotic agent formulation in the first₂ chamber,

a second beneficial agent formulation in the second₂ chamber,

a second semi-permeable membrane in sealing relationship with the open end of the first₂ chamber, and

the diffusion moderator in mating relationship with the open end of the second₂ chamber, wherein the diffusion moderator defines a second orifice through which the second beneficial agent is capable of exiting the second₂ chamber, and the diffusion moderator effectively isolates the second beneficial agent formulation within the second₂ chamber from the environment of use.

11. A dual osmotic delivery device, comprising

an impermeable reservoir having outer and inner surfaces and first and second ends, wherein the reservoir defines a first chamber adjacent the first end of the reservoir in fluid communication with second and third essentially columnar chambers that extend to the second end of the reservoir each of the second and third chambers defining an open end, wherein each set of the first chamber and second chamber, and the first chamber and the third chamber defines a flow path through the reservoir;

a first piston and a second piston located in the second and third chambers, respectively, wherein the pistons isolate the first chamber from the second and third chambers,

an osmotic agent formulation in the first chamber,

a semi-permeable membrane in sealing relationship with the open end of the first chamber, and

a first beneficial agent formulation in the second chamber,

a second beneficial agent formulation in the third chamber, and

a diffusion moderator in mating relationship with the end of the reservoir, wherein the diffusion moderator defines a first orifice through which the first beneficial agent is capable of exiting the second chamber, and a second orifice through which the second beneficial agent is capable of exiting the third chamber, and the diffusion moderator effectively isolates the first and second beneficial agent formulations, within, respectively, the second and third chambers, from the environment of use.

12. A multiple osmotic delivery device with three or more beneficial agent chambers, comprising

an impermeable reservoir having first and second ends, wherein the reservoir defines at least first, second and third essentially columnar hollow tubes that extend from the first end of the reservoir to the second end of the reservoir, each of the first, second and third essentially columnar hollow tube defining a first open end and a second open end;

a first osmotic delivery device, comprising

a first piston that divides the first columnar tube into a first, and a second₁ chamber, wherein the piston isolates the first, and second₁ chambers,

a first osmotic agent formulation in the first₁ chamber,

a first beneficial agent formulation in the second₁ chamber,

a first semi-permeable membrane in sealing relationship with the first open end of the first₁ chamber, and

a diffusion moderator in mating relationship with the second open end of the second₁ chamber, wherein the diffusion moderator defines an orifice through which the first beneficial agent is capable of exiting the second₁ chamber, and the diffusion moderator effectively isolates the first beneficial agent formulation within the second₁ chamber from the environment of use;

a second osmotic delivery device, comprising

a second piston that divides the second columnar tube into a first₂ and a second₂ chamber, wherein the piston isolates the first₂ and second₂ chambers,

a second osmotic agent formulation in the first₂ chamber,

a second beneficial agent formulation in the second₂ chamber,

a second semi-permeable membrane in sealing relationship with the first open end of the first₂ chamber, and

a diffusion moderator in mating relationship with the second open end of the second₂ chamber, wherein the diffusion moderator defines an orifice through which the second beneficial agent is capable of exiting the second₂ chamber, and the diffusion moderator effectively isolates the second beneficial agent formulation within the second₂ chamber from the environment of use; and

a third osmotic delivery device, comprising

a third piston that divides the third columnar tube into a first₃ and a second₃ chamber, wherein the piston isolates the first₃ and second₃ chambers,

a third osmotic agent formulation in the first₃ chamber,

a third beneficial agent formulation in the second₃ chamber,

a third semi-permeable membrane in sealing relationship with the first open end of the first₃ chamber, and

a diffusion moderator in mating relationship with the second open end of the second₃ chamber, wherein the diffusion moderator defines an orifice through which the third beneficial agent is capable of exiting the second₃ chamber, and the diffusion moderator effectively isolates the third beneficial agent formulation within the second₃ chamber from the environment of use.

13. The osmotic delivery device of claim 12, wherein at least one beneficial agent chamber contains a beneficial agent formulation comprising two or more beneficial agents and a viscous vehicle.

14. The osmotic delivery device of claim 13, wherein the beneficial agent formulation comprising two or more beneficial agents and a viscous vehicle is selected from the group consisting of:

(i) two or more beneficial agents dispersed directly in the vehicle;

(ii) one or more beneficial agent dispersed directly in the vehicle and one or more beneficial agent formulated into a particle formulation that is suspended in the vehicle;

(iii) two or more beneficial agents combined in one particle formulation and the particle formulation suspended in the vehicle; and

(iv) two or more beneficial agents formulated individually into different particle formulations and the different particle formulations suspended together in the vehicle.