Compositions and methods of treating middle-of-the night insomnia
The present invention provides compositions and methods for treating middle-of-the-night insomnia without residual sedative effects upon awakening by administering low doses (about 5 mg or less) of zolpidem or a salt thereof.
1 . A solid unit dosage composition for the treatment of MOTN insomnia, said composition comprising an effective amount of zolpidem or a salt thereof, formulated for delivery of zolpidem across a subject's oral mucosa, wherein said effective amount is an amount of less than 1.30×10 −5 moles of zolpidem, and is an amount sufficient to produce a plasma concentration between about 25 ng/ml and about 50 ng/ml within 20 minutes of administration, when evaluated in an appropriate patient population.
2 . A solid unit dosage composition of claim 1 , which further provides 50% of the maximum plasma concentration (C max ) of zolpidem in 10 minutes or less.
3 . A solid unit dosage composition of claim 2 , which further provides blood levels of zolpidem that are less than 20 ng/ml at a time 4 hours after dosing.
4 . A solid unit dosage composition of claim 1 , further comprising at least one pH-adjusting agent selected from the group consisting of a carbonate salt and a bicarbonate salt.
5 . A solid unit dosage composition of claim 1 , further comprising a binary buffer system that raises the pH of said subject's saliva to a pH greater than about 8.5, irrespective of the starting pH of saliva.
6 . A solid unit dosage composition of claim 5 , wherein the binary buffer system consists of sodium carbonate and sodium bicarbonate.
7 . A solid unit dosage composition of claim 6 , in the form of a quick-dissolving tablet or lozenge.
8 . A solid unit dosage composition of claim 5 , containing from 0.5 to 4.75 mg of zolpidem hemitartrate.
9 . A solid unit dosage composition of claim 5 , containing from 1.5 to 2.5 mg of zolpidem hemitartrate.
10 . A solid unit dosage composition of claim 5 , containing from 3.0 to 3.75 mg of zolpidem hemitartrate.
11 . A solid unit dosage composition of claim 1 , wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.
12 . A solid unit dosage composition for the treatment of MOTN insomnia, said composition comprising an amount of zolpidem or a salt thereof effective to produce sleep within 30 minutes of dosing a subject, but does not produce residual sedative effects when said subject is awakened at a time 4 hours after dosing, when the composition is evaluated in an appropriate patient population.
13 . A solid unit dosage composition of claim 12 , further comprising at least one pH-adjusting agent.
14 . A solid unit dosage composition of claim 12 , further comprising a binary buffer system.
15 . A solid unit dosage composition of claim 14 , wherein said binary buffer system consists of a carbonate salt and a bicarbonate salt.
16 . A solid unit dosage composition of claim 14 , in a dosage form for delivery of zolpidem across the subject's oral mucosa, wherein said binary buffer system raises the pH of said subject's saliva to a pH greater than about 8.5, irrespective of the starting pH of saliva.
17 . A solid unit dosage composition of claim 16 , containing less than 5 mg of zolpidem hemitartrate.
18 . A solid unit dosage composition of claim 17 , containing from 1.5 to 2.5 mg of zolpidem hemitartrate.
19 . A solid unit dosage composition of claim 17 , containing from 3.0 to 3.75 mg of zolpidem hemitartrate.
20 . A solid unit dosage composition of claim 16 , in the form of a quick-dissolving lozenge or tablet.
21 . A solid unit dosage composition of claim 16 , which provides buccal and/or sublingual dissolution in about 5 minutes or less following administration.
22 . A method of treating insomnia in a subject, said method comprising:
administering a solid pharmaceutical composition comprising zolpidem in an amount less than 5 mg, to a subject who awakens from sleep and desires to resume sleep for less than 5 hours,
wherein the solid pharmaceutical composition provides delivery of zolpidem across the subject's oral mucosa, and wherein a blood level of zolpidem is achieved in the subject of between about 25 ng/ml and about 50 ng/ml within about 20 minutes of administration.
23 . A method in accordance with claim 22 , wherein the blood level of zolpidem in the subject is less than about 20 ng/ml within about 4 hours of administration.
24 . A method in accordance with claim 22 , wherein the solid pharmaceutical composition dissolves or disintegrates in the subject's mouth in about 2 minutes or less.
25 . A method in accordance with claim 22 , wherein the solid pharmaceutical composition dissolves or disintegrates in the subject's mouth in about 3 to about 6 minutes.
26 . A method in accordance with claim 22 , wherein the solid pharmaceutical composition further comprises a binary buffer.
27 . A method in accordance with claim 26 , wherein the binary buffer comprises a carbonate buffer and a bicarbonate buffer.
28 . A method in accordance with claim 22 , wherein the solid pharmaceutical composition comprises a buffer which raises the pH of saliva in the subject's mouth to a pH greater than about 9.0.
29 . A method in accordance with claim 28 , wherein the pH of the saliva is raised above 9.0 for at least about 2 minutes.
30 . A method in accordance with claim 22 , wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.
31 . A method of treating insomnia, said method comprising:
administering a solid pharmaceutical composition comprising zolpidem in an amount less than 5 mg, to a subject who awakens from sleep and desires to resume sleep for less than 5 hours,
wherein the solid pharmaceutical composition provides delivery of zolpidem across the subject's oral mucosa, wherein the solid pharmaceutical composition dissolves or disintegrates in about 2 minutes or less in the subject's mouth.
32 . A method in accordance with claim 31 , wherein said solid pharmaceutical composition further comprises a binary buffer, and the binary buffer raises the pH of saliva in the subject's mouth to a pH greater than about 9.0 for at least about 2 minutes.
33 . A method in accordance with claim 32 , wherein the binary buffer comprises a carbonate buffer and a bicarbonate buffer.
34 . A method in accordance with claim 31 , wherein a blood level of zolpidem in the subject is between about 25 ng/ml and about 50 ng/ml within about 20 minutes of administration.
35 . A method in accordance with claim 31 , wherein the blood level of zolpidem in the subject is less than about 20 ng/ml at about 4 hours after administration.
36 . A method in accordance with claim 31 , wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.
37 . A method of treating insomnia, said method comprising the steps of:
providing a solid pharmaceutical composition comprising zolpidem in an amount less than 5 mg to a patient who awakens from sleep and desires to resume sleep for less than 5 hours; and
administering the solid pharmaceutical composition to the patient for delivery of the zolpidem across the patient's oral mucosa,
wherein a blood level of zolpidem in the patient is between about 25 ng/ml and about 50 ng/ml within about 20 minutes of administration.
38 . A method in accordance with claim 37 , wherein the blood level of zolpidem in the patient is less than about 20 ng/ml at about 4 hours after administration.
39 . A method in accordance with claim 37 , wherein the solid pharmaceutical composition dissolves or disintegrates in the patient's mouth in about 2 minutes or less.
40 . A method in accordance with claim 37 , wherein the solid pharmaceutical composition dissolves or disintegrates in the patient's mouth in about 3 to about 6 minutes.
41 . A method in accordance with claim 37 , wherein the pharmaceutical composition further comprises a binary buffer.
42 . A method in accordance with claim 41 , wherein the binary buffer comprises a carbonate buffer and a bicarbonate buffer.
43 . A method in accordance with claim 41 , wherein the binary buffer raises the pH of saliva in the patient's mouth to a pH greater than about 9.0.
44 . A method in accordance with claim 43 , wherein the pH of the saliva is raised above 9.0 for at least about 2 minutes.
45 . A method in accordance with claim 37 , wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.
46 . A method of treating MOTN insomnia, said method comprising the steps of:
providing a solid pharmaceutical composition comprising zolpidem in an amount less than 5 mg to a patient who awakens from sleep and desires to resume sleep for less than 5 hours; and
administering the solid pharmaceutical composition to the patient for delivery of the zolpidem across the patient's oral mucosa,
wherein the solid pharmaceutical composition dissolves or disintegrates in about 2 minutes or less in the patient's mouth.
47 . A method in accordance with claim 46 , wherein the solid pharmaceutical composition further comprises a buffer that raises the pH of saliva in the patient's mouth to a pH greater than about 9.0 for at least about 2 minutes.
48 . A method in accordance with claim 46 , wherein the buffer is a binary buffer and comprises a carbonate buffer and a bicarbonate buffer.
49 . A method in accordance with claim 46 , wherein a blood level of zolpidem in the patient is between about 25 ng/ml and about 50 ng/ml within about 20 minutes of administration.
50 . A method in accordance with claim 46 , wherein the blood level of zolpidem in the patient is less than about 20 ng/ml at about 4 hours after administration.
51 . A method in accordance with claim 46 , wherein the zolpidem is delivered across at least one of the sublingual or buccal mucosa.