Solid dispersions of opioid antagonists
View Patent ↗Solid dispersions of stable, amorphous opioid antagonists, particularly [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid, with improved water solubility and bioavailability are disclosed. Also disclosed are methods of preventing or treating a side effect associated with an opioid. In addition, methods of treating or preventing pain, ileus, and opioid bowel dysfunction are disclosed.
1. A solid dispersion, which is at least a two-phase solid system of which one phase consists of finely divided solid particles distributed throughout a bulk solid substance, comprising:
at least one pharmaceutically-acceptable excipient selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone homopolymer (PVP), polyvinylpyrrolidone copolymer, and mixtures thereof; and
the compound of formula II:
wherein said compound is in a solid amorphous form; and
wherein said amorphous form is stable.
2. A solid dispersion according to claim 1 ,
wherein said pharmaceutically-acceptable excipient is a polyvinylpyrrolidone copolymer.
3. A solid dispersion according to claim 2 ,
wherein said polyvinylpyrrolidone copolymer is poly(vinylpyrrolidone/vinyl acetate) (PVP/VAc).
4. A solid dispersion according to claim 1 ,
wherein said compound of formula II is a solid dispersion in a matrix formed by said pharmaceutically-acceptable excipient.
5. A solid dispersion according to claim 1 ,
wherein the weight ratio of said compound of formula II to said pharmaceutically-acceptable excipient is about 5:95 to about 75:25.
6. A solid dispersion according to claim 5 ,
wherein the weight ratio of said compound of formula II to said pharmaceutically-acceptable excipient is at least about 10:90.
7. A solid dispersion according to claim 6 ,
wherein the weight ratio of said compound of formula II to said pharmaceutically-acceptable excipient is at least about 15:85.
8. A solid dispersion according to claim 7 ,
wherein the weight ratio of said compound of formula II to said pharmaceutically-acceptable excipient is at least about 20:80.
9. A solid dispersion according to claim 8 ,
wherein the weight ratio of said compound of formula II to said pharmaceutically-acceptable excipient is at least about 25:75.
10. A solid dispersion according to claim 9 ,
wherein the weight ratio of said compound of formula II to said pharmaceutically-acceptable excipient is at least about 30:70.
11. A solid dispersion according to claim 1 , further comprising at least one opioid.
12. A solid dispersion according to claim 11 ,
wherein said opioid is selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, and tramadol.
13. A dosage form, comprising:
a solid dispersion according to claim 1 .
14. A dosage form according to claim 13 ,
wherein said dosage form is a tablet, capsule, or lozenge.
15. A method of preventing or treating a side effect associated with an opioid in a patient, comprising the step of:
administering to said patient an effective amount of the solid dispersion of claim 1 .
16. A method according to claim 15 ,
wherein said side effect is ileus, opioid bowel dysfunction, constipation, nausea, vomiting, or a combination thereof.
17. A method according to claim 16 ,
wherein said side effect is postoperative ileus, postoperative nausea, or postoperative vomiting.
18. A method of treating pain in a patient, comprising the step of:
administering to said patient in need thereof an effective amount of the solid dispersion of claim 1 .
19. A method according to claim 18 , further comprising:
administering to said patient in need thereof an effective amount of at least one opioid.
20. A method of treating ileus in a patient, comprising the step of:
administering to said patient in need thereof an effective amount of the solid dispersion of claim 1 .
21. A method of treating opioid bowel dysfunction in a patient, comprising the step of:
administering to said patient in need thereof an effective amount of the solid dispersion of claim 1 .
22. A solid dispersion according to claim 1 ,
wherein said pharmaceutically-acceptable excipient is hydroxypropyl methylcellulose.