Solvent/polymer solutions as suspension vehicles

• US 9,526,763 B2
• Filed: 06/24/2015
• Issued: 12/27/2016
• Est. Priority Date: 02/03/2005
• Status: Active Grant

• Current Assignee: Intarcia Therapeutics, Inc.
• Original Assignee: Intarcia Therapeutics, Inc.
• Inventors: Rohloff, Catherine M., Chen, Guohua, Luk, Andrew S., Ayer, Rupal A., Houston, Paul R., Desjardin, Michael A., Zamora, Pauline, Lam, Stan
• Primary Examiner(s): Fubara, Blessing M
• Application Number:
  US14/749,178
• Publication Number:
  US 20150290291A1
• Time in Patent Office: 552 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/043 Kallidins; Bradykinins; Related peptides
• CPC Class Codes: A61K 38/085 Angiotensins
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 38/095 Oxytocins; Vasopressins; Related peptides
• CPC Class Codes: A61K 38/105 Bombesin; Related peptides
• CPC Class Codes: A61K 38/1808 Epidermal growth factor [EGF] urogastrone
• CPC Class Codes: A61K 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: A61K 38/191 Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/2242 Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
• CPC Class Codes: A61K 38/225 Calcitonin gene related peptide
• CPC Class Codes: A61K 38/24 Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/31 Somatostatins
• CPC Class Codes: A61K 38/35 Corticotropin [ACTH]
• CPC Class Codes: A61K 38/36 Blood coagulation or fibrinolysis factors
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 : Carboxylic acids; Salts or anhydrides thereof
• 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 47/20 : containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/26 : Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• 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 9/10 : Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61P 1/16 : for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 : of the kidneys
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: Y10T 29/494 : Fluidic or fluid actuated device making
• CPC Class Codes: Y10T 29/49826 : Assembling or joining

Abstract

A nonaqueous, single-phase vehicle that is capable of suspending an active agent. The nonaqueous, single-phase vehicle includes at least one solvent and at least one polymer and is formulated to exhibit phase separation upon contact with an aqueous environment. The at least one solvent may be selected from the group consisting of benzyl benzoate, decanol, ethyl hexyl lactate, and mixtures thereof and the at least one polymer may be selected from the group consisting of a polyester, pyrrolidone, ester of an unsaturated alcohol, ether of an unsaturated alcohol, polyoxyethylenepolyoxypropylene block copolymer, and mixtures thereof. In one embodiment, the at least one solvent is benzyl benzoate and the at least one polymer is polyvinylpyrrolidone. A stable, nonaqueous suspension formulation that includes the nonaqueous, single-phase vehicle and an active agent, and a method of forming the same, are also disclosed.

Claims

1. A stable, nonaqueous suspension formulation, comprising:

a particle formulation comprising an active agent and at least one excipient, wherein;

the active agent comprises at least one of a peptide, a polypeptide, and a protein; and

the at least one excipient comprises methionine; and

a nonaqueous, single-phase vehicle consisting essentially of about 10% (w/w) to about 90% (w/w) polymer and about 90% (w/w) to about 10% (w/w) solvent, wherein;

the polymer is at least one of a polyester, a pyrrolidone, an ester of an unsaturated alcohol, an ether of an unsaturated alcohol, and a polyoxyethylenepolyoxypropylene block copolymer;

the solvent is at least one of lauryl alcohol, lauryl lactate, benzyl benzoate, benzyl alcohol, decanol, and ethyl hexyl lactate; and

the vehicle has a viscosity of about 1,000 poise to about 100,000 poise.

2. The suspension formulation of claim 1, wherein the at least one excipient further comprises at least one of a buffer and a sugar.

3. The suspension formulation of claim 2, wherein the at least one excipient comprises the sugar, wherein the sugar is at least one of sucrose and dextran.

4. The suspension formulation of claim 2, wherein the at least one excipient comprises the buffer, wherein the buffer is at least one of citrate, phosphate, histidine, and succinate.

5. The suspension formulation of claim 2, wherein the at least one excipient further comprises citrate and sucrose.

6. The suspension formulation of claim 1, wherein the particle formulation is formed by at least one of lyophilization, spray-drying, and freeze-drying.

7. The suspension formulation of claim 1, wherein the particle formulation is present in the suspension formulation in a range from about 0.1% (w/w) to about 50% (w/w).

8. The suspension formulation of claim 1, wherein the particle formulation is present in the suspension formulation in a range from about 3% (w/w) to about 12% (w/w).

9. The suspension formulation of claim 1, wherein the polymer is the pyrrolidone, and the pyrrolidone is polyvinylpyrrolidone (PVP).

10. The suspension formulation of claim 1, wherein the nonaqueous, single-phase vehicle consists essentially of about 25% (w/w) to about 75% (w/w) polymer and about 75% (w/w) to about 25% (w/w) solvent.

11. The suspension formulation of claim 1, wherein the nonaqueous, single-phase vehicle consists essentially of about 40% (w/w) to about 60% (w/w) polymer and about 60% (w/w) to about 40% (w/w) solvent.

12. The suspension formulation of claim 1, wherein the nonaqueous, single-phase vehicle consists essentially of about 50% (w/w) polymer and about 50% (w/w) solvent.

13. The suspension formulation of claim 1, wherein the nonaqueous, single-phase vehicle exhibits phase separation upon contact with an aqueous environment having less than about 10% water.

14. The suspension formulation of claim 1, wherein the viscosity is about 5,000 poise to about 50,000 poise.

15. The suspension formulation of claim 1, wherein the viscosity is about 10,000 poise to about 20,000 poise.

16. The suspension formulation of claim 1, wherein the viscosity is measured at 37°

C.

17. An implantable osmotic drug delivery device, comprising:

a reservoir containing a stable, nonaqueous suspension formulation, the suspension formulation comprising;

a particle formulation comprising an active agent and at least one excipient, wherein;

the active agent comprises at least one of a peptide, a polypeptide, and a protein; and

the at least one excipient comprises methionine; and

a nonaqueous, single-phase vehicle consisting essentially of about 10% (w/w) to about 90% (w/w) polymer and about 90% (w/w) to about 10% (w/w) solvent, wherein;

the polymer is at least one of a polyester, a pyrrolidone, an ester of an unsaturated alcohol, an ether of an unsaturated alcohol, and a polyoxyethylenepolyoxypropylene block copolymer;

the solvent is at least one of lauryl alcohol, lauryl lactate, benzyl alcohol, benzyl benzoate, decanol, and ethyl hexyl lactate; and

the vehicle has a viscosity of about 1,000 poise to about 100,000 poise; and

an orifice through which at least the active agent is delivered.

18. A method of making a stable, nonaqueous suspension formulation, the method comprising:

combining a polymer and a solvent under dry conditions to form a nonaqueous, single-phase vehicle consisting essentially of about 10% (w/w) to about 90% (w/w) polymer and about 90% (w/w) to about 10% (w/w) solvent, wherein;

the polymer is at least one of a polyester, a pyrrolidone, an ester of an unsaturated alcohol, an ether of an unsaturated alcohol, and a polyoxyethylenepolyoxypropylene block copolymer;

the solvent is at least one of lauryl alcohol, lauryl lactate, benzyl alcohol, benzyl benzoate, decanol, and ethyl hexyl lactate; and

the vehicle has a viscosity of about 1,000 poise to about 100,000 poise; and

adding a particle formulation comprising an active agent and at least one excipient to the vehicle to form the suspension formulation, wherein;

the active agent comprises at least one of a peptide, a polypeptide, and a protein; and

the at least one excipient comprises methionine.

19. The method of claim 18, wherein a vacuum is applied during the combining to remove air bubbles from the vehicle, wherein the vacuum is about −

5 Hg to about −

30 Hg.

20. The method of claim 18, wherein the polymer and the solvent are combined at an elevated temperature, wherein the elevated temperature is about 40°

C. to about 70°

C.