GABA analog prodrug sustained release oral dosage forms
View Patent ↗Sustained release oral dosage forms of a gabapentin prodrug, 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid, are disclosed. The dosage forms are useful for treating or preventing diseases and disorders for which gabapentin is therapeutically effective.
1. A sustained release oral tablet comprising:
(a) 40 wt % to 65 wt % of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;
(b) 1 wt % to 30 wt % of glyceryl behenate; and
(c) 30 wt % to 50 wt % of dibasic calcium phosphate;
wherein wt % is based on the total dry weight of the dosage form, which tablet:
when administered to one or more fasted human patients at a dose of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from 1100 mg to 1300 mg provides a gabapentin plasma concentration profile characterized by a C max ranging from 3 μg/mL to 6 μg/mL, a T max ranging from 4 hours to 7 hours, and an AUC ranging from 30 μg·hr/mL to 70 μg·hr/mL; or
when administered to one or more fed human patients at a dose of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from 1100 mg to 1300 mg provides a gabapentin plasma concentration profile characterized by a C max ranging from 5 μg/mL to 8 μg/mL, a T max ranging from 6 hours to 11 hours, and an AUC ranging from 60 μg·hr/mL to 110 μg·hr/mL.
2. The tablet of claim 1 , which is compressed to a hardness of at least 15 kiloponds.
3. The tablet of claim 1 , comprising an amount of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from 300 mg to 700 mg.
4. The tablet of claim 1 , wherein the 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid is in a crystalline form.
5. The tablet of claim 1 , comprising one or more pharmaceutically acceptable excipients selected from diluents, lubricants, anti-adherents, glidants, surfactants, disintegrants, and combinations of any of the foregoing.
6. The tablet of claim 5 , wherein the diluent is microcrystalline cellulose.
7. The tablet of claim 1 , wherein the tablet comprises 600 mg of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid, and the dose comprises two of the tablets.
8. The tablet of claim 1 , comprising a coating.
9. The tablet of claim 1 , which
when administered to the one or more fasted human patients at a dose of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from 1100 mg to 1300 mg provides a gabapentin plasma concentration profile characterized by a C max ranging from 3 μg/mL to 6 μg/mL, a T max ranging from 4 hours to 7 hours, and an AUC ranging from 30 μg·hr/mL to 70 μg·hr/mL; and
when administered to the one or more fed human patients at a dose of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from 1100 mg to 1300 mg provides a gabapentin plasma concentration profile characterized by a C max ranging from 5 μg/mL to 8 μg/mL, a T max ranging from 6 hours to 11 hours, and an AUC ranging from 60 μg·hr/mL to 110 μg·hr/mL.
10. The tablet of claim 1 , which
when administered to a population of said fasted human patients at a dose of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from a 1100 mg to 1300 mg provides a gabapentin plasma concentration profile characterized by a mean C max ranging from 3 μg/mL to 6 μg/mL, a mean T max ranging from 4 hours to 7 hours, and a mean AUC ranging from 30 μg·hr/mL to 70 μg·hr/mL; and
when administered to a population of said fed human patients at a dose of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from 1100 mg to 1300 mg provides a gabapentin plasma concentration profile characterized by a mean C max ranging from 5 μg/mL to 8 μg/mL, a mean T max ranging from 6 hours to 11 hours, and a mean AUC ranging from 60 μg·hr/mL to 110 μg·hr/mL.
11. The tablet of claim 1 , wherein:
the one or more fasted human patients do not eat any food from 10 hours prior to administering the dose until 4 hours after dosing, drink 250 mL of water 2 hours and 1 hour prior to dosing and 250 mL of water a 2 hours after dosing, eat a lunch 4 hours after dosing, and eat a dinner 10 hours after dosing; and
the one or more fed human patients begin eating a test meal 30 minutes prior to administering the dose and complete eating the test meal 5 minutes prior to administering the dose, eat a lunch 4 hours after dosing, and eat a dinner 10 hours after dosing, wherein the test meal comprises 1000 total calories of which 500 calories comprise fat calories.
12. A sustained release oral tablet comprising:
(a) 40 wt % to 65 wt % of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;
(b) 1 wt % to 30 wt % of glyceryl behenate; and
(c) 30 wt % to 50 wt % of dibasic calcium phosphate;
wherein wt % is based on the total dry weight of the tablet, which tablet when placed in 10 mM monobasic potassium phosphate buffer and 1% (wt/volume) sodium lauryl sulfate at pH 7.4 and 37° C. agitated at 50 rpm (USP, Type II), releases 20% of the 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid after 2 hours, 50% after 5 hours, and 80% after 8 hours.
13. The tablet of claim 12 , comprising an amount of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from 500 mg to 700 mg.
14. The sustained release oral tablet according to claim 1 , further comprising: 5 wt % to 20 wt % of microcrystalline cellulose.
15. The tablet of claim 14 , comprising an amount of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from 500 mg to 700 mg.
16. A sustained release oral tablet, comprising:
45.8 wt % 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;
39.56 wt % dibasic calcium phosphate;
4.58 wt % glyceryl behenate;
6.11 wt % talc;
0.41 wt % colloidal silicon dioxide;
1.84 wt % sodium lauryl sulfate; and
1.69 wt % magnesium stearate;
which tablet is optionally coated.
17. The tablet of claim 16 , comprising 300 mg to 700 mg 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid.
18. A method of treating restless legs syndrome, comprising administering a tablet according to one of claims 1 , 12 , or 16 , to a patient in need of such treatment.
19. A method of treating post-herpetic neuralgia, comprising administering a tablet according to one of claims 1 , 12 , or 16 , to a patient in need of such treatment.