COMPOSITIONS AND METHODS FOR TREATING DISORDERS AMELIORATED BY MUSCARINIC RECEPTOR ACTIVATION
Provided herein is an oral pharmaceutical composition, comprising a plurality of xanomeline beads having a core comprising xanomeline or a salt thereof; and a plurality of trospium beads having a core comprising a salt of trospium.
1 . An oral pharmaceutical composition, comprising:
a plurality of xanomeline beads comprising xanomeline or a salt thereof; and
a plurality of trospium beads comprising a salt of trospium.
2 . The oral pharmaceutical composition of claim 1 , wherein the plurality of xanomeline beads have a core comprising the xanomeline or a salt thereof.
3 . The oral pharmaceutical composition of claim 1 or 2 , wherein the plurality of trospium beads have a core comprising the salt of trospium.
4 . The oral pharmaceutical composition of any of claims 1 to 3 , wherein the size of the xanomeline beads is between 0.425 mm and 1.18 mm.
5 . The oral pharmaceutical composition of claim 4 , wherein the size of the xanomeline beads is between 0.6 mm and 0.85 mm.
6 . The oral pharmaceutical composition of any of claims 1 to 5 , wherein the size of the trospium beads is between 0.425 mm and 1.18 mm.
7 . The oral pharmaceutical composition of claim 6 , wherein the size of the trospium beads is between 0.6 mm and 0.85 mm.
8 . The oral pharmaceutical composition of any of claims 1 to 7 , wherein the xanomeline beads contain about 2.5 times as much xanomeline as the trospium beads contain trospium salt.
9 . The oral pharmaceutical composition of any of claims 1 to 8 , the plurality of xanomeline and the plurality of trospium beads having a dissolution rate of more than about 95% within about the first 45 minutes following entry of the dosage form into an aqueous solution.
10 . The oral pharmaceutical composition of claim 9 , having a dissolution rate of more than about 95% within about the first 20 minutes following entry of the dosage form into an aqueous solution.
11 . The oral pharmaceutical composition of any of claims 1 to 10 , when administered to a patient for at least 7 days at 20 mg trospium twice daily, providing a mean C max of trospium at 7850±3360 μg/mL.
12 . The oral pharmaceutical composition of any of claims 1 to 11 , when administered to a patient for at least 7 days at 20 mg trospium twice daily, providing a mean AUC 0-12 of 41900±15500 hr·pg/mL.
13 . The oral pharmaceutical composition of any of claims 1 to 12 , wherein the xanomeline is xanomeline tartrate.
14 . The oral pharmaceutical composition of claim 13 , wherein the xanomeline beads comprise between 30 wt. % and 80 wt. % xanomeline tartrate.
15 . The oral pharmaceutical composition of claim 14 , wherein the xanomeline beads comprise 66 wt. % xanomeline tartrate.
16 . The oral pharmaceutical composition of any of claims 1 to 15 , wherein the xanomeline beads comprise between 15 wt. % and 65 wt. % microcrystalline cellulose.
17 . The oral pharmaceutical composition of claim 14 , wherein the xanomeline beads comprise 33.5 wt. % microcrystalline cellulose.
18 . The oral pharmaceutical composition of any of claims 1 to 17 , wherein the xanomeline beads comprise between 0 wt. % and 2 wt. % talc.
19 . The oral pharmaceutical composition of claim 18 , wherein the xanomeline beads comprise 0.5 wt. % talc.
20 . The oral pharmaceutical composition of any of claims 1 to 12 , wherein the xanomeline beads comprise between 30 wt. % and 80 wt. % xanomeline tartrate, between 15 wt. % and 65 wt. % microcrystalline cellulose, and between 0 wt. % and 2 wt. % talc.
21 . The oral pharmaceutical composition of claim 20 , wherein the xanomeline beads comprise 66 wt. % xanomeline tartrate, 33.5 wt. % microcrystalline cellulose, and 0.5 wt. % talc.
22 . The oral pharmaceutical composition of any of claims 1 to 21 , wherein the trospium salt is trospium chloride.
23 . The oral pharmaceutical composition of claim 22 , wherein the trospium beads comprise between 8 wt. % and 35 wt. % trospium chloride.
24 . The oral pharmaceutical composition of claim 23 , wherein the trospium beads comprise 17.7 wt. % trospium chloride.
25 . The oral pharmaceutical composition of any of claims 1 to 24 , wherein the trospium beads comprise between 25 wt. % and 80 wt. % microcrystalline cellulose.
26 . The oral pharmaceutical composition of claim 25 , wherein the trospium beads comprise 46.8 wt. % microcrystalline cellulose.
27 . The oral pharmaceutical composition of any of claim 1 or 26 , wherein the trospium beads comprise between 15 wt. % and 70 wt. % lactose monohydrate.
28 . The oral pharmaceutical composition of claim 27 , wherein the trospium beads comprise 35 wt. % lactose monohydrate.
29 . The oral pharmaceutical composition of any of claims 1 to 28 , wherein the trospium beads comprise between 0 wt. % and 2 wt. % talc.
30 . The oral pharmaceutical composition of claim 29 , wherein the trospium beads comprise 0.5 wt. % talc.
31 . The oral pharmaceutical composition of claims 1 to 21 , wherein the trospium beads comprise between 8 wt. % and 35 wt. % trospium chloride, between 25 wt. % and 80 wt. % microcrystalline cellulose, between 15 wt. % and 70 wt. % lactose monohydrate, and between 0 wt. % and 2 wt. % talc.
32 . The oral pharmaceutical composition of claim 31 , wherein the trospium beads comprise 17.7 wt. % trospium chloride, 46.8 wt. % microcrystalline cellulose, 35 wt. % lactose monohydrate, and 0.5 wt. % talc.
33 . The oral pharmaceutical composition of any of claims 1 to 32 , further comprising a capsule containing the plurality of xanomeline beads and the plurality of trospium beads.
34 . An oral pharmaceutical composition, comprising:
a plurality of xanomeline beads having a size between 0.425 mm and 1.18 mm, and core comprising between 30 wt. % and 80 wt. % xanomeline tartrate, between 15 wt. % and 65 wt. % microcrystalline cellulose, and between 0 wt. % and 2 wt. % talc; and
a plurality of trospium beads having a size between 0.425 mm and 1.18 mm, and a core comprising between 8 wt. % and 35 wt. % trospium chloride, between 25 wt. % and 80 wt. % microcrystalline cellulose, between 15 wt. % and 70 wt. % lactose monohydrate, and between 0 wt. % and 2 wt. % talc;
the plurality of xanomeline and the plurality of trospium beads having a dissolution rate of more than about 95% within about the first 45 minutes following entry of the dosage form into an aqueous solution; and wherein, when administered to a patient for at least 7 days at 20 mg trospium twice daily, providing a mean C max of trospium at 7850±3360 μg/mL and a mean AUC 0-12 of 41900±15500 hr·pg/mL.
35 . The oral pharmaceutical composition of claim 34 , wherein the size of the xanomeline beads is between 0.6 mm and 0.85 mm.
36 . The oral pharmaceutical composition of claim 34 or 35 , wherein the size of the trospium beads is between 0.6 mm and 0.85 mm.
37 . The oral pharmaceutical composition of any of claims 34 to 36 , wherein the xanomeline beads contain about 2.5 times as much xanomeline as the trospium beads contain trospium chloride.
38 . The oral pharmaceutical composition of any of claims 34 to 37 , having a dissolution rate of the xanomeline and the trospium of more than about 95% within about the first 20 minutes following entry of the dosage form into an aqueous solution.
39 . The oral pharmaceutical composition of any of claims 34 to 38 , wherein the xanomeline beads comprise 66 wt. % xanomeline tartrate, 33.5 wt. % microcrystalline cellulose, and 0.5 wt. % talc.
40 . The oral pharmaceutical composition of any of claims 34 to 39 , wherein the trospium beads comprise 17.7 wt. % trospium chloride, 46.8 wt. % microcrystalline cellulose, 35 wt. % lactose monohydrate, and 0.5 wt. % talc.
41 . The oral pharmaceutical composition of any of claims 34 to 40 , further comprising a capsule containing the plurality of xanomeline beads and the plurality of trospium beads.
42 . An oral pharmaceutical composition, comprising:
a capsule containing a plurality of xanomeline beads and a plurality of trospium beads;
the plurality of xanomeline beads having a size between 0.6 mm and 0.85 mm, and core comprising between 66 wt. % xanomeline tartrate, 33.5 wt. % microcrystalline cellulose, and 0.5 wt. % talc; and
the plurality of trospium beads having a size between 0.6 mm and 0.85 mm, and a core comprising 17.7 wt. % trospium chloride, 46.8 wt. % microcrystalline cellulose, 35 wt. % lactose monohydrate, and 0.5 wt. % talc;
the plurality of xanomeline and the plurality of trospium beads having a dissolution rate of more than about 95% within about the first 20 minutes following entry of the dosage form into an aqueous solution; and
wherein, when administered to a patient for at least 7 days at 20 mg trospium twice daily, providing a mean C max of trospium at 7850±3360 μg/mL and a mean AUC 0-12 of 41900±15500 hr·pg/mL.
43 . The oral pharmaceutical composition of any of claims 1 to 42 , wherein the capsule has a dosage strength of 25 mg xanomeline free base and 10 mg trospium chloride.
44 . The oral pharmaceutical composition of any of claims 1 to 42 , wherein the capsule has a dosage strength of 50 mg xanomeline free base and 20 mg trospium chloride.
45 . The oral pharmaceutical composition of claims 1 to 42 , wherein the capsule has a dosage strength of 50 mg xanomeline free base and 10 mg trospium chloride.
46 . The oral pharmaceutical composition of claims 1 to 42 , wherein the capsule has a dosage strength of 75 mg xanomeline free base and 10 mg trospium chloride.
47 . The oral pharmaceutical composition of claims 1 to 42 , wherein the capsule has a dosage strength of 75 mg xanomeline free base and 20 mg trospium chloride.
48 . The oral pharmaceutical composition of claims 1 to 42 , wherein the capsule has a dosage strength of 125 mg xanomeline free base and 20 mg trospium chloride.
49 . The oral pharmaceutical composition of claims 1 to 42 , wherein the capsule has a dosage strength of 125 mg xanomeline free base and 30 mg trospium chloride.
50 . The oral pharmaceutical composition of claims 1 to 42 , wherein the capsule has a dosage strength of 125 mg xanomeline free base and 40 mg trospium chloride.
51 . The oral pharmaceutical composition of any one of the preceding claims , wherein the xanomeline beads comprise less than 0.5 wt. % 3-[(4-hexyloxy)-1,2,5-thiadizaol-3-yl]-5-hydroyl-1-methylpyridin-1-ium.
52 . An oral pharmaceutical composition, comprising xanomeline and/or a salt thereof and trospium chloride for treating a muscarinic disorder in a patient in need thereof, wherein when administered to the patient in need thereof, is sufficient to provide an in-vivo plasma profile comprising a median T max for xanomeline of 2 hours and a median T max for trospium of 1 hour.
53 . The oral pharmaceutical composition of claim 52 , wherein the in-vivo plasma profile further comprises a mean dose-normalized C max of between 48.5 and 121.3 pg/mL/mg and a mean dose-normalized C max of trospium of between 156 and 375 μg/mL/mg.
54 . The oral pharmaceutical composition of claim 52 or 53 , wherein the in-vivo plasma profile further comprises a mean dose-normalized AUC 0-12 of xanomeline of between 263 and 577 hr·pg/mL/mg and a mean dose-normalized AUC 0-12 of trospium of between 881 and 2024 hr·pg/mL/mg.
55 . A method of activating muscarinic receptors in a biological sample comprising contacting the biological sample with the oral pharmaceutical composition of any of claims 1 to 54 .
56 . A method for treating a disorder ameliorated by activating muscarinic receptors in a subject in need thereof, comprising administering to a patient in need thereof an oral pharmaceutical composition of any of claims 1 to 54 .
57 . A method of treating a disorder ameliorated by activating muscarinic receptors in a subject in need thereof, comprising the sequential or co-administration of an oral pharmaceutical composition of any of claims 1 to 54 ; and a second therapeutic agent.
58 . The method of any of claims 55 to 57 , wherein the subject is a human.
59 . The method of any of claims 55 to 57 , wherein the disorder is selected from schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, pain, drug addiction, tauopathy, and synucleinopathy.
60 . The method of any of claims 55 to 57 , wherein the disorder is a neurodegenerative disease.
61 . The method of any of claims 55 to 57 , wherein the disorder is a central nervous system disease.
62 . The compound 3-[(4-hexyloxy)-1,2,5-thiadizaol-3-yl]-5-hydroyl-1-methylpyridin-1-ium.
63 . An oral pharmaceutical composition, comprising xanomeline and/or a salt thereof and less than 0.5 wt. % 3-[(4-hexyloxy)-1,2,5-thiadizaol-3-yl]-5-hydroyl-1-methylpyridin-1-ium.
64 . A method for preparing an oral pharmaceutical composition of any one of claims 1 to 55 , comprising admixing beads comprising a plurality of xanomeline beads comprising xanomeline or a pharmaceutically acceptable salt thereof with a plurality of trospium beads comprising a salt of trospium.
65 . The method of claim 64 , wherein the plurality of beads comprising xanomeline or a pharmaceutically acceptable salt thereof comprises an antioxidant.
66 . The method of claim 64 or 65 , further comprising formulating the admixed beads into capsules.
67 . The method of any one of claims 64 to 66 , further comprising storing the oral pharmaceutical composition at a temperature of between about 2° C. and about 8° C. prior to dispensing the oral pharmaceutical composition to the subject.
68 . The method of claim 67 , wherein after the oral pharmaceutical composition is dispensed to the subject, the method further comprises storing the oral pharmaceutical composition at a temperature of between about 20° C. and about 25° C.