Solvent/polymer solutions as suspension vehicles

• US 9,095,553 B2
• Filed: 10/09/2012
• Issued: 08/04/2015
• 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:
  US13/647,873
• Publication Number:
  US 20130034210A1
• Time in Patent Office: 1,029 Days
• Field of Search: 378/62
• 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 method for detecting at least one air bubble in at least one component of an implantable osmotic drug delivery device, wherein the implantable osmotic drug delivery device comprises a suspension formulation, a semipermeable membrane, an osmotic engine, a piston, a diffusion moderator, and a reservoir, the reservoir comprising titanium, the method comprising:

X-raying the implantable osmotic drug delivery device under conditions sufficient to detect the at least one air bubble if present, so as to determine or verify prior to implantation of the implantable osmotic drug delivery device, during a period of implantation of the implantable osmotic drug delivery device, or after explantation of the implantable osmotic drug delivery device at least one of;

stability of the suspension formulation; and

integrity of the implantable osmotic delivery device.

2. The method of claim 1, wherein the at least one component of the implantable osmotic drug delivery device comprises the suspension formulation.

3. The method of claim 1, wherein the at least one component of the implantable osmotic drug delivery device comprises the osmotic engine.

4. The method of claim 1, wherein the at least one component of the implantable osmotic drug delivery device comprises the diffusion moderator.

5. The method of claim 1, wherein the at least one component of the implantable osmotic drug delivery device comprises the reservoir.

6. The method of claim 1, wherein the integrity of the implantable osmotic delivery device is indicative of whether the implantable osmotic delivery device will deliver or has delivered the suspension formulation at a controlled rate without blocking or occluding the implantable osmotic delivery device.

7. The method of claim 1, wherein the stability of the suspension formulation is indicative of whether the suspension formulation will maintain or has maintained stability over an extended period of time.

8. A method for detecting a position of a piston in an implantable osmotic drug delivery device relative to the implantable osmotic drug delivery device, the implantable osmotic drug delivery device comprising a suspension formulation, a semipermeable membrane, an osmotic engine, a piston, a diffusion moderator, and a reservoir, the reservoir comprising titanium, the method comprising:

X-raying the implantable osmotic drug delivery device under conditions sufficient to detect the position of the piston relative to the implantable osmotic drug delivery device, so as to determine or verify integrity of the implantable osmotic delivery device prior to implantation of the implantable osmotic drug delivery device, during a period of implantation of the implantable osmotic drug delivery device, or after explantation of the implantable osmotic drug delivery device.

9. The method of claim 8, wherein the position of the piston is detected after the device is explanted from an animal.

10. The method of claim 9, wherein the animal is a human.

11. A method for imaging one or more contents of an implantable osmotic drug delivery device, the implantable osmotic drug delivery device comprising a suspension formulation, a semipermeable membrane, an osmotic engine, a piston, a diffusion moderator, and a reservoir, the reservoir comprising titanium, the method comprising:

N-raying the implantable osmotic drug delivery device under conditions sufficient to image the one or more contents of the implantable osmotic drug delivery device, so as to determine or verify prior to implantation of the implantable osmotic drug delivery device, during a period of implantation of the implantable osmotic drug delivery device, or after explantation of the implantable osmotic drug delivery device at least one of;

stability of the suspension formulation; and

integrity of the implantable osmotic drug delivery device.

12. The method of claim 11, wherein the integrity of the implantable osmotic delivery device is indicative of whether the implantable osmotic delivery device will deliver or has delivered the suspension formulation at a controlled rate without blocking or occluding the implantable osmotic delivery device.

13. The method of claim 11, wherein the stability of the suspension formulation is indicative of whether the suspension formulation will maintain or has maintained stability over an extended period of time.

14. The method of claim 11, wherein the determining or the verifying the integrity of the implantable osmotic delivery device comprises determining or verifying whether the semipermeable membrane is intact.

15. The method of claim 11, wherein the determining or the verifying of the integrity of the implantable osmotic delivery device comprises detecting a position of the piston in the implantable osmotic drug delivery device relative to the implantable osmotic drug delivery device.

16. The method of claim 11, further comprising detecting at least one of:

an air bubble in at least one component of the implantable osmotic drug delivery device by N-ray; and

detecting a position of the piston in the implantable osmotic drug delivery device relative to the implantable osmotic drug delivery device.

17. A method for characterizing stability or integrity of at least one component of an implantable osmotic drug delivery device, wherein the implantable osmotic drug delivery device comprises a suspension formulation, a semipermeable membrane, an osmotic engine, a piston, a diffusion moderator, and a reservoir, the reservoir comprising titanium, the method comprising:

X-raying the implantable osmotic drug delivery device under conditions sufficient to detect at least one of;

at least one air bubble in the at least one component of the implantable osmotic drug delivery device; and

a position of the at least one component of the implantable osmotic drug delivery device relative to the implantable osmotic drug delivery device, so as to determine or verify prior to implantation of the implantable osmotic drug delivery device, during a period of implantation of the implantable osmotic drug delivery device, or after explantation of the implantable osmotic drug delivery device at least one of;

stability of the suspension formulation; and

integrity of the at least one component of the implantable osmotic delivery device.