Abuse-resistant pharmaceutical composition for the treatment of opioid dependence

• US 9,439,900 B2
• Filed: 12/19/2014
• Issued: 09/13/2016
• Est. Priority Date: 09/19/2011
• Status: Active Grant

• Current Assignee: Orexo AB
• Original Assignee: Orexo AB
• Inventors: Fischer, Andreas
• Primary Examiner(s): Schnizer, Richard
• Assistant Examiner(s): Peebles, Katherine
• Application Number:
  US14/577,823
• Publication Number:
  US 20150297583A1
• Time in Patent Office: 634 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4748 forming part of bridged ring systems strychnine A61K31/475; morphinan derivatives A61K31/485
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

There is provided pharmaceutical compositions for the treatment of e.g. opioid dependency comprising microparticles of a pharmacologically-effective amount of buprenorphine, or a pharmaceutically-acceptable salt thereof, in associative admixture with particles comprising a weak acid, or particles comprising weakly-acidic buffer forming materials. The composition may further comprise a disintegrant and/or particles of a pharmacologically-effective amount of naloxone, or a pharmaceutically-acceptable salt thereof. The compositions are useful in the treatment of opioid dependency/addiction and/or pain.

Claims

1. A pharmaceutical composition in the form of a tablet suitable for sublingual administration comprising:

buprenorphine, or a pharmaceutically acceptable salt thereof, provided in the form of microparticles,

a weak acid, provided in the form of particles, which particles are separate from the microparticles of buprenorphine, or a pharmaceutically acceptable salt thereof,

a disintegrant, and

naloxone or a pharmaceutically acceptable salt thereof,

wherein the per tablet dosage of buprenorphine (calculated as the free base) is 11.4 mg, 8.6 mg, 5.7 mg, 2.9 mg, or 1.4 mg; and

wherein the per tablet dosage ratio of buprenorphine;

naloxone dose (calculated as free bases) is about 4;

1.

2. The composition as claimed in claim 1 wherein the disintegrant is selected from the group of croscarmellose sodium, sodium starch glycolate, crosslinked polyvinylpyrrolidone and mixtures thereof.

3. The composition as claimed in claim 1, wherein the disintegrant is in particulate form, having a weight based mean diameter of between about 0.1 μ

m and about 100 μ

m.

4. The composition as claimed in claim 1, wherein the naloxone or pharmaceutically acceptable salt thereof is provided in the form of particles.

5. The composition as claimed in claim 4, wherein the microparticles of buprenorphine or salt thereof and the particles of naloxone or salt thereof each have a weight based mean diameter of between about 0.5 μ

m and about 15 μ

m.

6. The composition as claimed in claim 1, wherein the weak acid is selected from the group consisting of citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, succinic acid, lactic acid, acetic acid, oxalic acid, maleic acid, ammonium chloride, and a combination of such acids.

7. The composition as claimed in claim 1 further comprising an alkaline salt of a weak acid, provided in the form of particles.

8. The composition as claimed in claim 7, wherein the alkaline salt of the weak acid comprises an alkaline salt of citric acid, malic acid, tartaric acid, fumaric acid, adipic acid, succinic acid, lactic acid, acetic acid, oxalic acid, or maleic acid.

9. The composition as claimed in claim 1 further comprising water-soluble carrier particles.

10. The composition as claimed in claim 9, wherein the water-soluble carrier particles are of a size, based on a weight based mean diameter, of about 100 μ

m to about 800 μ

m.

11. The composition as claimed in claim 9, wherein the water-soluble carrier particles comprise a sugar or sugar alcohol.

12. The composition as claimed in claim 9, wherein the water-soluble carrier particles comprise mannitol.

13. The composition as claimed in claim 9, wherein the microparticles of buprenorphine are presented upon the surfaces of the water-soluble carrier particles.

14. The composition as claimed in claim 9, wherein the particles of the weak acid are presented upon the surfaces of, and/or between, the water-soluble carrier particles.

15. The composition as claimed in claim 1, wherein the tablet has a crushing strength in the range of about 10N to about 100N.

16. The composition as claimed in claim 1, wherein the microparticles of buprenorphine or salt thereof are in associative admixture with the particles of weak acid.

17. The composition as claimed in claim 1, wherein the microparticles of buprenorphine or salt thereof are in contact with the particles of weak acid.

18. The composition as claimed in claim 1, wherein the weak acid is citric acid, the disintegrant is croscarmellose sodium, and the composition further comprises mannitol, sodium citrate and microcrystalline cellulose.