Benzodiazepine formulation in a polyorthoester carrier

• US 8,940,315 B2
• Filed: 04/17/2009
• Issued: 01/27/2015
• Est. Priority Date: 04/18/2008
• Status: Active Grant

• Current Assignee: Companion Spine LLC
• Original Assignee: Medtronic Incorporated (Medtronic Plc)
• Inventors: Hobot, Christopher M., Benz, Michael E., Hildebrand, Keith R., Pudil, Bryant J.
• Primary Examiner(s): Heyer, Dennis
• Assistant Examiner(s): PODGORSKI, DANIEL MICHAEL
• Application Number:
  US12/426,031
• Publication Number:
  US 20090202604A1
• Time in Patent Office: 2,111 Days
• Field of Search: None
• US Class Current: 424/422
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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

Abstract

Effective treatments of pain for extended periods of time are provided. The treatments include the administration of one or more drug depots intraspinally wherein the drug depots include an effective amount of a benzodiazepine, such as midazolam, formulated within a polyorthoester. By administration of one or more drug depots, one can relieve pain caused by diverse sources, including but not limited to chronic pelvic pain syndromes, spinal disc herniation (i.e. sciatica), spondilothesis, stenosis, discongenic back pain and joint pain, as well as pain that is incidental to surgery. In some embodiments, the relief can be for at least twenty-five days, at least fifty days, at least one hundred days or at least one hundred and thirty-five days.

Claims

1. An implantable drug depot useful for reducing or treating pain in a patient in need of such treatment, the drug depot comprising a polyorthoester in an amount of about 95 to 99 wt % based on the total weight of the drug depot, and mPEG, the drug depot comprising a gel and having a viscosity of about 500 to 10,000 centipoises and a benzodiazepine in an amount of about 1 to 5 wt. % based on the total weight of the drug depot and having a particle size of between about 5 μ

m to 50 μ

m the drug depot adapted to be administered intraspinally in the patient to reduce or treat pain, wherein the drug depot is capable of releasing benzodiazepine for a period of at least 30 days after administration.

2. An implantable drug depot according to claim 1, wherein the benzodiazepine is midazolam.

3. An implantable drug depot according to claim 1, wherein the benzodiazepine is capable of being released for a period of 30 to 135 days after administration.

4. An implantable drug depot according to claim 1, wherein the depot further comprises a radiographic marker.

5. An implantable drug depot according to claim 1, further comprising one or more of polyaspirin, polyphosphazene, polyanhydride polyketal, collagen starch, pre-gelatinized starch, hyaluronic acid, chitosan , gelatin, alginate, albumin, fibrin, vitamin E analog, d-alpha tocopheryl succinate, poly-epsilon caprolactone, dextran, polyvinylpyrrolidone, polyvinyl alcohol PEGT-PBT copolymer, PEO-PPO-PEO, sucrose acetate isobutyrate, a different polyorthoester or a combination thereof.

6. An implantable drug depot according to claim 1, wherein the benzodiazepine is in the form of a hydrochloride salt or a mixture of hydrochloride salt and free base.

7. An implantable drug depot according to claim 1 , wherein the drug depot is in the form of a ribbon.

8. An implantable drug depot according to claim 1, wherein the drug depot has a modulus of elasticity in the range of about 2×

10⁴ to about 5×

10⁵ dynes/cm².

9. An implantable drug depot according to claim 1, wherein the drug depot releases about 0.25 mg to about 10 mg of the benzodiazepine over a period of 30 days.

10. A method for treating pain, wherein the method comprises implanting a drug depot of claim 1 intraspinally in an organism to reduce or treat pain.

11. A method according to claim 10, wherein the benzodiazepine is midazolam.

12. A method according to claim 10, wherein the midazolam is released in an amount between 0.25 and 10 mg per day for a period of 30 to 135 days.

13. A method according to claim 10, wherein the drug depot is a ribbon.

14. A method according to claim 10, wherein the polyorthoester comprises at least 70 wt. % of the drug depot.

15. A method according to claim 10, wherein the depot is in the form of microspheres having an average diameter from about 1 micron to about 500 microns.

16. A method according to claim 10, wherein the benzodiazepine is present in the depot in the form of particles, wherein at least 75% of the particles have a size from about 5 microns to about 50 microns in diameter.

17. A method according to claim 10, wherein the drug depot further comprises a radiographic marker.

18. A method of making an implantable drug depot of claim 1, the method comprising combining a polyorthoester and a benzodiazepine and forming the implantable drug depot from the combination.