Granted Patent B2

US 9,012,469 · App. 13/823,953 · Granted Apr 21, 2015

Abstract

Claims (24)

1. A crystalline oxalate salt of mPEG 7 -O-naloxol.

2. A method of producing a naloxol-polyethylene glycol conjugate oxalate salt, wherein the salt comprises an ionic species of mPEG 7 -O-naloxol and oxalic acid having the formula:

the method comprising:

dissolving mPEG 7 -O-naloxol free base in 2 relative volumes of acetonitrile;

adding 3 equivalents of water to the dissolved mPEG 7 -O-naloxol solution;

adding oxalic acid in ethyl acetate to the dissolved mPEG 7 -O-naloxol over a period of at least 2 hours to produce a slurry; and

filtering the slurry to yield the naloxol-polyethylene glycol conjugate oxalate salt in solid form.

3. A method of producing a naloxol-polyethylene glycol conjugate oxalate salt, wherein the salt comprises an ionic species of mPEG 7 -O-naloxol and oxalic acid having the formula:

the method comprising:

dissolving mPEG 7 -O-naloxol free base in 2 relative volumes of ethanol;

adding 8 relative volumes of methyl t-butyl ether to the dissolved mPEG 7 -O-naloxol solution;

adding oxalic acid in methyl t-butyl ether to the dissolved mPEG 7 -O-naloxol over a period of at least 2 hours to produce a slurry; and

filtering the slurry to yield the naloxol-polyethylene glycol conjugate oxalate salt in solid form.

4. A naloxol-polyethylene glycol conjugate oxalate salt prepared according to the method of claim 2 .

5. A naloxol-polyethylene glycol conjugate oxalate salt, wherein the naloxol-polyethylene glycol conjugate has the formula:

6. The naloxol-polyethylene glycol conjugate oxalate salt of claim 5 , wherein the salt is in a substantially pure crystalline form.

7. The naloxol-polyethylene glycol conjugate oxalate salt of claim 6 wherein the crystalline form exhibits Form A X-ray powder diffraction pattern substantially as that shown in FIG. 2 .

8. The naloxol-polyethylene glycol conjugate oxalate salt of claim 6 wherein the crystalline form exhibits Form B X-ray powder diffraction peak d values (Å) comprising 13.2; 7.9; 7.0; 6.6; 6.0; 5.7; 5.2; 5.1; 4.44; 4.39; 3.95; 3.88; 3.63; and 3.43.

9. The naloxol-polyethylene glycol conjugate oxalate salt of claim 8 , wherein X-ray powder diffraction peak d values (Å) comprise 13.2; 12.0; 9.7; 9.4; 8.3; 8.2; 7.9; 7.4; 7.0; 6.6; 6.0; 5.7; 5.6; 5.4; 5.2; 5.1; 4.91; 4.86; 4.78; 4.71; 4.48; 4.44; 4.39; 4.17; 4.09; 3.95; 3.91; 3.88; 3.69; 3.63; 3.43; 3.29; 3.14; and 3.01.

10. The naloxol-polyethylene glycol conjugate oxalate salt of claim 6 wherein the crystalline form exhibits Form B X-ray powder diffraction 2θ angle peaks at (degrees): 6.72; 11.24; 12.65; 13.44; 14.72; 15.61; 17.01; 17.34; 19.98; 20.21; 22.50; 22.93; 24.53; and 25.99.

11. The naloxol-polyethylene glycol conjugate oxalate salt of claim 6 having a purity of at least about 90%.

12. The naloxol-polyethylene glycol conjugate oxalate salt of claim 6 , wherein the salt exhibits a single endothermal peak on differential scanning calorimetry between room temperature and about 150° C., wherein the single endothermal peak maximum occurs between about 91° C. to about 94° C.

13. A pharmaceutical composition comprising the naloxol-polyethylene glycol conjugate oxalate salt of claim 6 and a pharmaceutically acceptable excipient.

14. The pharmaceutical composition of claim 13 formulated for oral administration to a subject.

Assignments (12)