GABA ANALOG PRODRUG SUSTAINED RELEASE ORAL DOSAGE FORMS
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 dosage form of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid, which
when administered to one or more fasted human patients at a dose of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from about 1100 mg to about 1300 mg provides a gabapentin plasma concentration profile characterized by a C max ranging from about 3 μg/mL to about 6 μg/mL, a T max ranging from about 4 hours to about 7 hours, and an AUC ranging from about 30 μg·hr/mL to about 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 about 1100 mg to about 1300 mg provides a gabapentin plasma concentration profile characterized by a C max ranging from about 5 μg/mL to about 8 μg/mL, a T max ranging from about 6 hours to about 11 hours, and an AUC ranging from about 60 μg·hr/mL to about 110 μg·hr/mL.
2 . A sustained release oral dosage form of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid, which
when administered to one or more fasted human patients at a dose of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from about 1100 mg to about 1300 mg provides a gabapentin plasma concentration profile bioequivalent to the profile shown in FIG. 1 ; 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 about 1100 mg to about 1300 mg provides a gabapentin plasma concentration profile bioequivalent to the profile shown in FIG. 2 .
3 . The dosage form of any one of claims 1 and 2 , comprising:
(a) about 10 wt % to about 80 wt % of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; and
(b) about 1 wt % to about 50 wt % of a release rate-modifying polymer;
wherein wt % is based on the total dry weight of the dosage form.
4 . The dosage form of claim 3 , wherein the dosage form comprises a tablet.
5 . The dosage form of claim 3 , wherein the 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranges from about 30 wt % to about 75 wt % and the release rate-modifying polymer ranges from about 1 wt % to about 50 wt %.
6 . The dosage form of claim 3 , wherein the 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranges from about 40 wt % to about 65 wt % and the release rate-modifying polymer ranges from about 1 wt % to about 50 wt %.
7 . The dosage form of claim 3 , wherein the 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranges from about 50 wt % to about 60 wt % and the release rate-modifying polymer ranges from about 20 wt % to about 50 wt %.
8 . The dosage form of claim 3 , wherein the release rate-modifying polymer is selected from a fatty compound and a methacrylic acid copolymer.
9 . The dosage form of claim 8 , wherein the fatty compound is a glyceryl ester.
10 . The dosage form of claim 9 , wherein the glyceryl ester is selected from glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, lauroyl macrogol glyceride, stearoyl macrogol glyceride, and a combination of any of the foregoing.
11 . The dosage form of claim 10 , wherein the glyceryl ester is glyceryl behenate.
12 . The dosage form of claim 8 , wherein the fatty compound is selected from lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, stearic acid, paraffin wax, beeswax, glycowax, castor wax, carnauba wax, and a combination of any of the foregoing.
13 . The dosage form of claim 8 , wherein the methacrylic acid copolymer is selected from an acrylic acid ester copolymer, a methacrylic acid ester copolymer, and a combination of any of the foregoing.
14 . The dosage form of claim 3 , comprising an amount of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from about 50 mg to about 800 mg.
15 . The dosage form of claim 3 , comprising an amount of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from about 100 mg to about 800 mg.
16 . The dosage form of claim 3 , comprising an amount of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from about 300 mg to about 700 mg.
17 . The dosage form of claim 3 , wherein the 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid is in a crystalline form.
18 . The dosage form of claim 3 , further comprising one or more pharmaceutically acceptable excipients selected from diluents, lubricants, anti-adherents, glidants, surfactants, disintegrants, and combinations of any of the foregoing.
19 . The dosage form of claim 18 , wherein the diluent is selected from dibasic calcium phosphate and microcrystalline cellulose.
20 . The dosage form of any one of claims 1 and 2 , wherein the dosage form is a tablet comprising about 600 mg of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid, and the dose comprises two of the tablets and about 1200 mg of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid.
21 . The dosage form of claim 3 , comprising a coating.
22 . The dosage form 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 about 1100 mg to about 1300 mg provides a gabapentin plasma concentration profile characterized by a C max ranging from about 3 μg/mL to about 6 μg/mL, a T max ranging from about 4 hours to about 7 hours, and an AUC ranging from about 30 μg·hr/mL to about 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 about 1100 mg to about 1300 mg provides a gabapentin plasma concentration profile characterized by a C max ranging from about 5 μg/mL to about 8 μg/mL, a T max ranging from about 6 hours to about 11 hours, and an AUC ranging from about 60 μg·hr/mL to about 110 μg·hr/mL.
23 . The dosage form 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 about 1100 mg to about 1300 mg provides a gabapentin plasma concentration profile characterized by a mean C max ranging from about 3 μg/mL to about 6 μg/mL, a mean T max ranging from about 4 hours to about 7 hours, and a mean AUC ranging from about 30 μg·hr/mL to about 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 about 1100 mg to about 1300 mg provides a gabapentin plasma concentration profile characterized by a mean C max ranging from about 5 μg/mL to about 8 μg/mL, a mean T max , ranging from about 6 hours to about 11 hours, and a mean AUC ranging from about 60 μg·hr/mL to about 110 μg·hr/mL.
24 . The dosage form of claim 2 , 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 about 1100 mg to about 1300 mg provides a gabapentin plasma concentration profile bioequivalent to the profile shown in FIG. 1 ; 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 about 1100 mg to about 1300 mg provides a gabapentin plasma concentration profile bioequivalent to the profile shown in FIG. 2 .
25 . The dosage form of any one of claims 1 and 2 , wherein:
the one or more fasted human patients do not eat any food from about 10 hours prior to administering the dose until about 4 hours after dosing, drink about 250 mL of water about 2 hours and about 1 hour prior to dosing and about 250 mL of water about 2 hours after dosing, eat a lunch about 4 hours after dosing, and eat a dinner about 10 hours after dosing; and
the one or more fed human patients begin eating a test meal about 30 minutes prior to administering the dose and complete eating the test meal about 5 minutes prior to administering the dose, eat a lunch about 4 hours after dosing, and eat a dinner about 10 hours after dosing, wherein the test meal comprises about 1000 total calories of which about 500 calories comprise fat calories.
26 . A method of treating a disease or condition selected from neuropathic pain, epilepsy, restless legs syndrome, hot flashes, urinary incontinence, premature ejaculation, and vulvodynia in a patient, comprising administering to a patient in need of such treatment the dosage form of any one of claims 1 and 2 .
27 . The method of claim 26 , wherein the pain comprises post-herpetic neuralgia.
28 . A sustained release oral dosage form of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid, which 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 about 20% of the 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid after about 2 hours, about 50% after about 5 hours, and about 80% after about 8 hours.
29 . The dosage form of claim 28 , comprising:
(a) about 10 wt % to about 80 wt % of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; and
(b) about 1 wt % to about 50 wt % of a release rate-modifying polymer;
wherein wt % is based on the total dry weight of the dosage form.
30 . The dosage form of claim 29 , comprising an amount of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from about 500 mg to about 700 mg.
31 . The dosage form of claim 29 , further comprising dibasic calcium phosphate.
32 . A sustained release oral dosage form of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid, which 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 about 30% of the 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid after about 5 hours, about 60% after about 10 hours, and about 80% after about 15 hours.
33 . The dosage form of claim 32 , comprising:
(a) about 10 wt % to about 80 wt % of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; and
(b) about 1 wt % to about 50 wt % of a release rate-modifying polymer;
wherein wt % is based on the total dry weight of the dosage form.
34 . The dosage form of claim 33 , comprising an amount of 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid ranging from about 500 mg to about 700 mg.
35 . The dosage form of claim 33 , further comprising microcrystalline cellulose.