COMPOSITIONS FOR DELIVERING HYPNOTIC AGENTS ACROSS THE ORAL MUCOSA AND METHODS OF USE THEREOF

COMPOSITIONS PERMETTANT D'ADMINISTRER DES AGENTS HYPNOTIQUES DANS LA MUQUEUSE ORALE ET METHODES D'UTILISATION

English Abstract

The present invention provides novel compositions for the delivery of a
hypnotic agent across the oral mucosa. In particular, the buffer system in the
compositions of the present invention raises the pH of saliva to a pH greater
than about 7.8, thereby facilitating the substantially complete conversion of
the hypnotic agent from its ionized to its un-ionized form. As a result, the
dose of hypnotic agent is rapidly and efficiently absorbed by the oral mucosa
with surprisingly low inter-subject variability. Furthermore, delivery of the
hypnotic agent across the oral mucosa advantageously bypasses hepatic first
pass metabolism of the drug and avoids enzymatic degradation of the drug
within the gastrointestinal tract. Methods for using the compositions of the
present invention for treating sleep disorders such as insomnia are also
provided.

French Abstract

La présente invention concerne de nouvelles compositions permettant d'administrer un agent hypnotique dans la muqueuse orale. L'invention concerne, en particulier, le système tampon desdites compositions, qui permet d'augmenter le pH de la salive jusqu'à obtenir un pH supérieur à environ 7,8, facilitant ainsi la conversion sensiblement complète de l'agent hypnotique, de sa forme ionisée à sa forme non ionisée. La dose d'agent hypnotique est ainsi absorbée rapidement et efficacement par la muqueuse orale avec une faible variabilité inter-sujet. L'administration de l'agent hypnotique dans la muqueuse orale permet, de plus, de dériver de manière avantageuse le mécanisme de premier passage hépatique du médicament, et évite la dégradation enzymatique du médicament dans le tractus gastro-intestinal. L'invention concerne également des méthodes d'utilisation de la présente invention dans le traitement des troubles du sommeil tels que l'insomnie.

Claims

WHAT IS CLAIMED IS:
1. Use of a solid pharmaceutical composition comprising zolpidem or a
pharmaceutically acceptable salt thereof for treating insomnia, the
pharmaceutical
composition further comprising a buffer, wherein the buffer raises the pH of
saliva to a
of about 7.8 or greater, wherein zolpidem is absorbed across a permeable
membrane of the
subject's oral mucosa, and wherein at least 75% of the solid pharmaceutical
composition
dissolves within about 10 minutes or less within an oral cavity following
administration.
2. The use of claim 1, wherein the solid pharmaceutical composition further
comprises a binder and a disintegrating agent.
3. The use of claim 1 or 2, wherein the solid pharmaceutical composition
dissolves
within about 1-3 minutes within the oral cavity of the subject following
administration.
4. The use of any one of claims 1 to 3, wherein the solid pharmaceutical
composition
dissolves within about 2-3 minutes within the subject's oral cavity following
administration.
5. The use of any one of claims 1 to 4, wherein the solid pharmaceutical
composition
is in a form suitable for sublingual administration.
6. The use of any one of claims 1 to 5, wherein the oral mucosa is selected
from the
group consisting of sublingual mucosa, buccal mucosa, gingival mucosa, palatal
mucosa
and lining of the lips.
7. The use of any one of claims 1 to 6, wherein a mean peak plasma
concentration of
zolpidem between about 20 to about 100 ng/mL is produced within about 30
minutes.
8. The use of any one of claims 1 to 7, wherein a therapeutically effective
amount of
zolpidem enters the bloodstream within about 30 minutes.
9. The use of any one of claims 1 to 8, wherein the buffer comprises a
carbonate
buffer.
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10. The use of any one of claims 1 to 8, wherein the buffer comprises a
biocarbonate
buffer.
11. The use of any one of claims 1 to 8, wherein the buffer comprises a
carbonate
buffer and a bicarbonate buffer.
12. The use of claim 11, wherein the carbonate buffer and bicarbonate
buffer are
present in a carbonate:bicarbonate weight ratio of about 1:1 to about 1:10.
13. The use of any one of claims 1 to 12, wherein the solid pharmaceutical
composition
is a lozenge.
14. The use of any one of claims 1 to 12, wherein the solid pharmaceutical
composition
is a tablet.
15. The use of claim 11 or 12, wherein the carbonate buffer and bicarbonate
buffer are
present in a carbonate:bicarbonate weight ratio of about 1:1 to about 1:5.
16. The use of any one of claims 1 to 15, wherein an average plasma
concentration is
from about 20 to about 300 ng/ml.
17. The use of any one of claims 1 to 16, wherein the zolpidem or
pharmaceutically
acceptable salt is zolpidem tartrate.
18. The use of any one of claims 1 to 17, wherein the zolpidem or
pharmaceutically
acceptable salt thereof is in an amount from about 1 mg to about 5 mg.
19. The use of any one of claims 1 to 18, wherein the zolpidem or
pharmaceutically
acceptable salt thereof is in an amount from about 2 mg to about 5 mg.
20. Use of a solid pharmaceutical composition comprising zolpidem for
treating
insomnia in a subject, the composition comprising zolpidem in an amount from
about 1 mg
to about 5 mg and a buffer, wherein zolpidem is absorbed across the subject's
oral mucosa,
wherein the buffer raises the pH of saliva to a pH of about 7.8 or greater,
and wherein at
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least 75% of the solid pharmaceutical composition dissolves within about 10
minutes or
less within an oral cavity following the use.
21. The use of claim 20, wherein the solid pharmaceutical composition
further
comprises a binder and a disintegrating agent.
22. The use of claim 20 or 21, wherein the solid pharmaceutical composition
dissolves
within about 10 minutes or less within said oral cavity following use.
23. The use of any one of claims 20 to 22, wherein the solid pharmaceutical
composition dissolves within about 1-3 minutes within said oral cavity
following use.
24. The use of any one of claims 20 to 23, wherein the solid pharmaceutical
composition dissolves within about 2-3 minutes within said oral cavity
following use.
25. The use of any one of claims 20 to 24, wherein the solid pharmaceutical
composition is in a form for sublingual administration.
26. The use of any one of claims 20 to 25, wherein the oral mucosa is
selected from the
group consisting of sublingual mucosa, buccal mucosa, gingival mucosa, palatal
mucosa
and lining of the lips.
27. The use of any one of claims 20 to 26, wherein a mean peak plasma
concentration
of zolpidem between about 20 to about 100 ng/mL is produced within about 30
minutes.
28. The use of any one of claims 20 to 27, wherein a therapeutically
effective amount
of zolpidem enters the bloodstream within about 30 minutes.
29. The use of any one of claims 20 to 28, wherein the buffer comprises a
carbonate
buffer.
30. The use of any one of claims 20 to 28, wherein the buffer comprises a
bicarbonate
buffer.

31. The use of any one of claims 20 to 28, wherein the buffer comprises a
carbonate
buffer and a bicarbonate buffer.
32. The use of claim 31, wherein the carbonate buffer and bicarbonate
buffer are
present in a carbonate:bicarbonate weight ratio of about 1:1 to about 1:5.
33. The use of claim 31 or 32, wherein the carbonate buffer and bicarbonate
buffer are
present in a carbonate:bicarbonate weight ratio of about 1:1 to about 1:2.
34. The use of any one of claims 20 to 33, wherein the solid pharmaceutical
composition is a lozenge.
35. The use of any one of claims 20 to 33, wherein the solid pharmaceutical
composition is a tablet.
36. The use of any one of claims 20 to 35, wherein a therapeutically
effective amount
of zolpidem enters the bloodstream within about 20 minutes.
37. A pharmaceutical composition comprising about 1 mg to about 5 mg of
zolpidem
and a buffer, wherein the buffer raises the pH of saliva to about 7.8 or
greater following
administration, and wherein the solid pharmaceutical composition dissolves by
at least
75% within about 10 minutes or less within an oral cavity following
administration.
38. The pharmaceutical composition of claim 37, wherein the pharmaceutical
composition is a solid pharmaceutical composition.
39. The pharmaceutical composition of claim 37 or 38, wherein the buffer
comprises a
carbonate buffer.
40. The pharmaceutical composition of claim 37 or 38, wherein the buffer
comprises a
bicarbonate buffer.
41. The pharmaceutical composition of claim 37 or 38, wherein the buffer
comprises a
carbonate buffer and a bicarbonate buffer.
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42. The pharmaceutical composition of claim 41, wherein the carbonate
buffer and
bicarbonate buffer are present in a carbonate:bicarbonate weight ratio of
about 1:1 to about
1:5.
43. The pharmaceutical composition of any one of claim 41 or 42, wherein
the
carbonate buffer and bicarbonate buffer are present in a carbonate:bicarbonate
weight ratio
of about 1:1 to about 1:2.
44. The pharmaceutical composition of claim 39, 41, 42 or 43, wherein the
carbonate
buffer is selected from the group consisting of sodium carbonate, potassium
carbonate,
calcium carbonate, ammonium carbonate, and magnesium carbonate.
45. The pharmaceutical composition of any one of claims 40 to 43, wherein
the
bicarbonate buffer is selected from the group consisting of sodium
bicarbonate, potassium
bicarbonate, calcium bicarbonate, ammonium bicarbonate, and magnesium
bicarbonate.
46. The pharmaceutical composition of claim 40, 41, 42, 43 or 45, wherein
the
bicarbonate buffer is dessicant-coated sodium bicarbonate.
47. The pharmaceutical composition of any one of claims 37 to 46, further
comprising
a binder and a disintegrating agent.
48. The pharmaceutical composition of any one of claims 37 to 47, wherein
the solid
pharmaceutical composition is a lozenge.
49. The pharmaceutical composition of any one of claims 37 to 48, wherein
the solid
pharmaceutical composition is a tablet.
50. The pharmaceutical composition of any one of claims 37 to 49, wherein
the solid
pharmaceutical composition is adapted to deliver a therapeutically effective
amount of
zolpidem into the bloodstream within about 30 minutes.
51. The pharmaceutical composition of any of claims 37 to 49, wherein the
solid
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pharmaceutical composition is adapted to deliver a therapeutically effective
amount of
zolpidem into the bloodstream within about 20 minutes.

Description

CA 02556450 2011-11-23
COMPOSITIONS FOR DELIVERING HYPNOTIC AGENTS ACROSS
THE ORAL MUCOSA AND METHODS OF USE THEREOF
BACKGROUND OF THE INVENTION
[00021 Insomnia is a condition that affects a person's ability to fall asleep
or to maintain
sleep. It is the most common sleep disorder, affecting millions of Americans
each year.
Benzodiazepines, which are available as short, intermediate, or long-acting
hypnotic agents,
have proven useful in treating insomnia. These benzodiazepines are thought to
bind non-
selectively to benzodiazepine! (omega!) and benzodiazepine2 (omega2)
receptors. This non-
selective binding may be responsible for some of the potential problems
associated with the
use of benzodiazepine compounds as hypnotics. For example, some
benzodiazepines are
thought to interfere with memory, cognition, and psychomotor function. In
addition,
problems with altered sleep architecture, rebound insomnia, hangover effects,
and abuse
potential have been reported with benzodiazepine use.
[00031 Selective benzodiazepine1 receptor agonists have been developed and
studied. For
example, zolpidem. (Ambien ; Searle and Co.) and zaleplon (Sonata ; Wyeth-
Ayerst Co.) are
non-benzodiazepine sedative agents thought to selectively bind to
benzodiazepine (HZ!)
receptors. Zolpidem, an imidazopyridine, has been demonstrated to reduce sleep
latency,
increase sleep duration, and reduce nighttime awakenings. In addition,
zolpidem has been
found to preserve stage III and stage IV sleep, and to result in less
disruption of REM (Rapid
Eye Movement) sleep. Zaleplon is a pyrazolopyrimidine derivative, which has
also proven
useful as a hypnotic agent. However, zolpidem and zaleplon are both poorly
soluble in
aqueous media.
[0004] Typically, these hypnotic agents are delivered as oral dosages, which
are
formulated, for example, as tablets or capsules that are swallowed. Oral
administration,
however, has several disadvantages, such as drug losses during hepatic first
pass metabolism,
during enzymatic degradation within the GI tract, and during absorption. These
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not only increase the variability in drug response, but also often require
that the medicament
be given in greater initial doses. In addition, because the drug has to pass
through the
gastrointestinal system in order to enter the blood stream, the time to reach
a therapeutic
effect may be quite long, typically around forty-five minutes or longer.
those involving transport across the mucous membranes. Of the various mucous
membranes
(e.g., oral, rectal, vaginal, ocular, nasal, etc.), drug delivery via the
mucous membranes in the
oral cavity seems to be the most easily tolerated by patients. In addition to
avoiding the
problems with traditional oral administration, drug delivery via the mucous
membranes of the
[0006] In general, the mucous membranes of the oral cavity can be divided into
five main
regions: the floor of the mouth (sublingual), the cheeks (buccal), the gums
(gingival), the roof
[0007] In addition to the differences in permeability of the various mucous
membranes, the
extent of drug delivery is also affected by the properties of the drug to be
delivered. The
ability of a molecule to pass through any mucous membrane is dependent upon
its size, its
[0008] The extent to which a drug is ionized has further been investigated
with respect to
drug delivery across the mucous membranes. Ionization is dependent on the
dissociation
constant (pKa), and the pH of the molecule's surrounding environment. In its
un-ionized
form, a drug is sufficiently lipophilic to traverse a membrane via passive
diffusion. In fact,
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[0009] At equilibrium, the concentrations of the un-ionized form of the drug
are equal on
both sides of the membrane. As the concentration gradient drives passive
diffusion, an
increase in the percentage of the un-ionized form of a drug correspondingly
increases the
transmucosal absorption of the drag. Maximum absorption across the membrane is
thought
to occur when a drug is 100% in its un-ionized form. Similarly, absorption
across the
membrane decreases as the extent of ionization increases. Therefore, one may
influence the
extent of drug absorption across the mucous membranes of the oral cavity by
altering the
salivary pH.
[0010] Some of the known transmucosal dosage forms include the use of a single
buffering
agent in order to change the pH of the saliva and tissues surrounding the
buccal mucosa.
However, these single buffering agents typically react with an acid or a base
to create a final
pH that is dependent upon the initial pH of the saliva of the user. A
buffering agent used to
attain a final pH that is dependent upon the initial pH of the user results in
great variability.
The extent of ionization, and henCe the extent of absorption across the mucous
membranes
cannot be predicted with any sort of accuracy. This may pose significant
problems when
calculating precise doses, minimizing variability in patient response, and
proving consistency
in drug loading to the regulatory authorities. In addition, a single buffering
agent is typically
not capable of sustaining a given pH over a period of time for optimal
absorption. While
others in the art have disclosed the use of more than one buffering agent,
these
aforementioned problems are not easily cured by the nonchalant addition of an
extra
buffering agent, which may be unsafe and cause irreversible damage to the
mucous
membranes of the oral cavity. As such, a buffering system capable of achieving
and
sustaining a final pH independent of the initial pH in order to increase
transmucosal
absorption has not heretofore been demonstrated.
[0011] Similarly, a buffer system that facilitates substantially complete
conversion of the
ionized form of a drug to the un-ionized form in the shortest period of time,
which is critical
for producing rapid delivery of practically an entire drug dose across the
oral mucosa, has not
heretofore been demonstrated. Previous dosage forms resulted in great
variability in drug
delivery, due to the variability in the rates in which a drag was released
from its carrier. That
is, the rates of drug release in previously described chewing gums or lozenges
are largely
dependent upon the rate of chewing or sucking of the user. The variability in
these rates from
user to user further exacerbates the ability to predict the final amount of
drug that will enter
systemic circulation. In addition, the rate of drug release from the carrier
is further dependent
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upon the ability of the drug to be released therefrom. Often times, the
carrier (e.g., gum base)
strongly adheres to the drug, making portions of the drug unavailable for
absorption.
[0012] Accordingly, there is a need in the art for compositions for delivering
hypnotic
agents across the oral mucosa having buffer systems that facilitate absorption
of the agents in
a safe and stable manner. Similarly, there is a need in the art for
compositions for delivering
hypnotic agents across the oral mucosa having a buffer system that produces a
final pH,
independent of the initial pH, and sustains that final pH for a given period
of time. In
addition, there is a need in the art for compositions capable of rapidly
facilitating
substantially complete conversion of the hypnotic agent from its ionized to
its un-ionized
form. The present invention satisfies these and other needs.
BRIEF SUMMARY OF THE INVENTION
[0013] The present invention provides novel compositions for the delivery of a
hypnotic
agent across the oral mucosa. In particular, the buffer system in the
compositions of the
present invention raises the pH of saliva to a pH greater than about 7.8,
thereby facilitating
the substantially complete conversion of the hypnotic agent from its ionized
to its un-ionized
form. As a result, the dose of hypnotic agent is rapidly and efficiently
absorbed by the oral
mucosa with surprisingly low inter-subject variability (e.g., lower
variability than absorption
across the gut in the same patients). Furthermore, delivery of the hypnotic
agent across the
oral mucosa advantageously bypasses hepatic first pass metabolism of the drug
and avoids
enzymatic degradation of the drug within the gastrointestinal tract. Methods
for using the
compositions of the present invention for treating sleep disorders such as
insomnia are also
provided.
[0014] As such, in one aspect, the present invention provides a solid
composition for
delivery of a hypnotic agent across the oral mucosa, the composition
comprising:
(a) a hypnotic agent selected from the group consisting of an imidazopyridine,
a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable
salt thereof;
(b) a carrier that provides complete buccal or sublingual disintegration in
about 5
minutes or less following administration to the mouth; and
(c) a binary buffer system comprising a carbonate salt and a bicarbonate salt,
wherein the binary buffer system raises the pH of saliva to a pH greater than
about 7.8,
irrespective of the starting pH of saliva.
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[0015] In another aspect, the present invention provides a composition for
delivery of a
hypnotic agent across the oral mucosa, the composition comprising:
(a) a hypnotic agent selected from the group consisting of an imidazopyridine,
a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable
salt thereof;
(b) a carrier; and
(c) a binary buffer system comprising a carbonate salt and a bicarbonate salt,
wherein the binary buffer system raises the pH of saliva to a pH greater than
about 7.8,
irrespective of the starting pH of saliva.
[0016] In yet another aspect, the present invention provides a composition for
delivery of a
hypnotic agent across the oral mucosa, the composition comprising:
(a) a hypnotic agent selected from the group consisting of an imidazopyridine,
a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable
salt thereof;
(b) a carrier; and
(c) a binary buffer system comprising a carbonate salt or a bicarbonate salt
and a
second buffering agent,
wherein the binary buffer system raises the pH of saliva to a pH greater than
about 7.8,
irrespective of the starting pH of saliva.
[0017] In still yet another aspect, the present invention provides a
composition for delivery
of a hypnotic agent across the oral mucosa, the composition comprising:
(a) a hypnotic agent selected from the group consisting of an imidazopyridine,
a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable
salt thereof;
(b) a carrier; and
(c) a binary buffer system comprising a metal oxide and a citrate, phosphate,
or
borate salt,
wherein the binary buffer system raises the pH of saliva to a pH greater than
about 7.8,
irrespective of the starting pH of saliva.
[0018] In a further aspect, the present invention provides a composition for
delivery of a
hypnotic agent across the oral mucosa, the composition comprising:
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(a) a hypnotic agent selected from the group consisting of an
imidazopyridine,
a dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable salt thereof;
(b) a carrier; and
(c) a ternary buffer system comprising a carbonate salt, a bicarbonate
salt, and
a third buffering agent,
wherein the ternary buffer system raises the pH of saliva to a pH greater than
about 7. 8,
irrespective of the starting pH of saliva.
[0019] In another aspect, the present invention provides a composition for
delivery of a
hypnotic agent across the oral mucosa, the composition comprising:
(a) a hypnotic agent selected from the group consisting of an
imidazopyridine,
a dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable salt thereof;
(b) a carrier; and
(c) a buffer system comprising a carbonate salt or a bicarbonate salt and
two or
more buffering agents selected from the group consisting of a metal oxide, a
citrate salt, a phosphate salt, and a borate salt,
wherein the buffer system raises the pH of saliva to a pH greater than about
7.8,
irrespective of the starting pH of saliva.
[0020] In yet another aspect, the present invention provides a method for
treating a sleep
disorder in a subject in need thereof, the method comprising:
administering to the subject a composition comprising a therapeutically
effective
amount of a hypnotic agent selected from the group consisting of an
imidazopyridine, a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable salt
thereof; a carrier; and a binary buffer system comprising a carbonate salt and
a bicarbonate
salt, wherein the binary buffer system raises the pH of saliva to a pH greater
than about
7.8, irrespective of the starting pH of saliva.
In accordance with an aspect of the present invention, there is provided the
use of a
pharmaceutical composition comprising zolpidem to treat insomnia in a subject,
wherein the
pharmaceutical composition comprises zolpidem in an amount from about 1 mg to
about 5
mg, a carbonate buffer, and a bicarbonate buffer,
wherein the pharmaceutical composition provides delivery of zolpidem across
the
6

CA 02556450 2011-11-23
subject's oral mucosa, and
further wherein the carbonate buffer and bicarbonate buffer are present in a
carbonate: bicarbonate weight ratio of about 1:1 to about 1:10.
In accordance with another aspect of the present invention, there is provided
a
pharmaceutical composition comprising about 1 mg to about 5 mg of zolpidem, a
carbonate buffer, and a bicarbonate buffer,
wherein the carbonate buffer and bicarbonate buffer are present in a
carbonate:
bicarbonate weight ratio of about 1:1 to about 1:10.
In accordance with another aspect of the present invention, there is provided
use of a solid pharmaceutical composition comprising zolpidem or a
pharmaceutically
acceptable salt thereof for treating insomnia, the pharmaceutical composition
further
comprising a buffer, wherein the buffer raises the pH of saliva to a pH of
about 7.8 or
greater, wherein zolpidem is absorbed across a permeable membrane of the
subject's
oral mucosa, and wherein at least 75% of the solid pharmaceutical composition
dissolves within about 10 minutes or less within an oral cavity following
administration.
In accordance with another aspect of the present invention, there is provided
use of a solid pharmaceutical composition comprising zolpidem for treating
insomnia
in a subject, the composition comprising zolpidem in an amount from about 1 mg
to
about 5 mg, a carbonate buffer, and a bicarbonate buffer, wherein zolpidem is
absorbed across the subject's oral mucosa, wherein the carbonate buffer and
bicarbonate buffer are present in a carbonate:bicarbonate weight ratio of
about 1:1 to
about 1:10 and raise the pH of saliva to a pH of about 7.8 or greater, and
wherein at
least 75% of the solid pharmaceutical composition dissolves within about 10
minutes
or less within an oral cavity following the use.
In accordance with another aspect of the present invention, there is provided
a
pharmaceutical composition comprising: about 1 mg to about 5 mg of zolpidem; a
carbonate buffer; and a bicarbonate buffer, wherein the carbonate buffer and
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bicarbonate buffer are present in a carbonate:bicarbonate weight ratio of
about 1:1 to
about 1:10 and are adapted to raise the pH of saliva to about 7.8 or greater
following
administration, and wherein the solid pharmaceutical composition is adapted to
dissolve by at least 75% within about 10 minutes or less within an oral cavity
following administration.
In accordance with a further aspect of the present invention, there is
provided
a use of a solid pharmaceutical composition comprising zolpidem or a
pharmaceutically acceptable salt thereof for treating insomnia, the
pharmaceutical
composition further comprising a buffer, wherein the buffer raises the pH of
saliva to
a pH of about 7.8 or greater, wherein zolpidem is absorbed across a permeable
membrane of the subject's oral mucosa, and wherein at least 75% of the solid
pharmaceutical composition dissolves within about 10 minutes or less within an
oral
cavity following administration.
In accordance with a further aspect of the present invention, there is
provided
a use of a solid pharmaceutical composition comprising zolpidem for treating
insomnia in a subject, the composition comprising zolpidem in an amount from
about
1 mg to about 5 mg and a buffer, wherein zolpidem is absorbed across the
subject's
oral mucosa, wherein the buffer raises the pH of saliva to a pH of about 7.8
or greater,
and wherein at least 75% of the solid pharmaceutical composition dissolves
within
about 10 minutes or less within an oral cavity following the use.
In accordance with a further aspect of the present invention, there is
provided
a pharmaceutical composition comprising: about 1 mg to about 5 mg of zolpidem
and
a buffer, wherein the buffer raises the pH of saliva to about 7.8 or greater
following
administration, and wherein the solid pharmaceutical composition dissolves by
at
least 75% within about 10 minutes or less within an oral cavity following
administration.
[0021] Other objects, features, and advantages of the present invention will
be
apparent to one of skill in the art from the following detailed description
and figures.
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BRIEF DESCRIPTION OF THE DRAWINGS
[00221 Figure 1 is a bar chart illustrating the relationship between the pH
and
membrane permeation for zolpidem tartrate.
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[0023] Figure 2 shows the mean dissolution profiles for a zolpidem quick-
dissolving tablet
and zolpidem lozenge of the present invention.
[0024] Figure 3 shows the plasma concentration over time in each subject for
Formulation
A (zolpidem sublingual powdered tablet) at a 2 minute swallowing time.
A at a 5 minute swallowing time.
[0026] Figure 5 shows the plasma concentration over time in each subject for
Formulation
A at a 10 minute swallowing time.
[0027] Figure 6 shows the mean plasma concentration over time for Formulation
A at the 3
[0028] Figure 7 shows the mean plasma concentration over time for Formulation
A at
swallowing times of 2 and 5 minutes using the data from all subjects or
excluding the data
from subjects 3, 6, and 7.
[0030] Figure 9 shows a representative plasma concentration over time for
Formulation C
(SL Tablet) at swallowing times of 2 and 5 minutes and for Formulation B.
[0031] Figure 10 shows a representative plasma concentration over time for
Formulation D
(FS Tablet) at swallowing times of 2 and 5 minutes and for Formulation B.
20 DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0032]
As used herein, the following terms have the meanings ascribed to them unless
specified otherwise.
[0033] The term "sleep disorder" refers to a disruptive pattern of sleep
arising from many
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hypnotic-dependent sleep disorder, and stimulant-dependent sleep disorder;
disorders
associated with difficulties in staying awake such as sleep apnea, narcolepsy,
restless leg
syndrome, obstructive sleep apnea, central sleep apnea, idiopathic
hypersomnia, respiratory
muscle weakness-associated sleep disorder; disorders associated with
difficulties in adhering
including, without limitation, difficulty in falling asleep, difficulty in
staying asleep,
intermittent wakefulness, and/or waking up too early. The term also
encompasses daytime
symptoms such as sleepiness, anxiety, impaired concentration, impaired memory,
and
irritability. Types of insomnia suitable for treatment with the compositions
of the present
[0035] The terms "therapeutic agent" and "drug" are used interchangeably
herein to refer to
[0036] The term "therapeutically effective amount" refers to the amount of a
hypnotic agent
that is capable of achieving a therapeutic effect in a subject in need
thereof. For example, a
therapeutically effective amount of a hypnotic agent can be the amount that is
capable of
[0037] The term "bioavailability" refers to the rate and/or extent to which a
drug is
absorbed or becomes available to the treatment site in the body.
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[0038] The terms "disintegration" and "dissolution" are used interchangeably
herein to refer
to the reduction of a solid dosage form of the present invention to a liquid
form. More
particularly, a complete disintegration or dissolution of a solid dosage form
refers to less than
about 25% by weight of the solid dosage form remaining in the mouth following
an
appropriate time period, e.g., 5 minutes or less, after administration.
Suitable methods known
in the art for determining the disintegration profile of a solid dosage form
include, e.g., the
United States Pharmacopeia (USP) disintegration test. Suitable methods known
in the art for
determining the dissolution profile of a solid dosage form include, e.g., USP
dissolution tests
such as USP <711> Apparatus 1 or USP <711> Apparatus 2.
[0039] As used herein, the phrase "substantially complete conversion of the
hypnotic agent
from its ionized to its un-ionized form" refers to greater than about 50%
conversion of the
hypnotic agent from its ionized form into its un-ionized form. For example,
the buffer
system may favor at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,
95%, or
99% conversion of the hypnotic agent from its ionized form into its un-ionized
form. In
some embodiments, the conversion occurs within about 10 minutes following
administration.
[0040] The term "variability" refers to inter-subject variability in terms of
the percent of
relative standard deviation (RSD) for the maximum plasma concentration (Cmax)
and the time
to reach the maximum plasma concentration (Tmaõ). Notably, the compositions of
the present
invention have an RSD for Cmaõ of about 27% versus about 45% for commercial
oral tablets
such as Ambiee tablets. Further, the compositions of the present invention
have an RSD for
Tmax of about 50% versus about 100% for commercial oral tablets such as Ambiee
tablets.
[0041] The term "administering" refers to administration of the compositions
of the present
invention to the mucous membranes of the oral cavity (i.e., oral mucosa).
Examples of
suitable sites of administration within the oral mucosa include, without
limitation, the mucous
membranes of the floor of the mouth (sublingual mucosa), the cheeks (buccal
mucosa), the
gums (gingival mucosa), the roof of the mouth (palatal mucosa), the lining of
the lips, and
combinations thereof. Preferably, the compositions of the present invention
are administered
to the sublingual mucosa, buccal mucosa, or a combination thereof.
II. General
[0042] The present invention provides novel compositions for the delivery of a
hypnotic
agent across the oral mucosa. In particular, the buffer system in the
compositions of the
present invention raises the pH of saliva to a pH greater than about 7.8,
thereby facilitating
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the substantially complete conversion of the hypnotic agent from its ionized
to its un-ionized
form. As a result, the dose of hypnotic agent is rapidly and efficiently
absorbed by the oral
mucosa with surprisingly low inter-subject variability in terms of maximum
plasma
concentration (Cm) and the time to reach the maximum plasma concentration
(Tmaõ).
Furthermore, delivery of the hypnotic agent across the oral mucosa
advantageously bypasses
hepatic first pass metabolism of the drug and avoids enzymatic degradation of
the drug within
the gastrointestinal tract, resulting in increased bioavailability of the
hypnotic agent and
reduced time to onset of therapeutic activity as compared to traditional
dosage forms for oral
(e.g., tablet) administration. Methods for using the compositions of the
present invention for
treating sleep disorders such as various types of insomnia are also provided.
[0043] The present invention is based upon the surprising discovery that
sublingual
delivery of zolpidem compositions containing the buffer systems described
herein provides
both increased bioavailability of the therapeutic agent and reduced time to
onset of
therapeutic activity that far surpass those observed for commercial oral
tablets such as
Ambienn tablets and buccal tablets such as zolpidem FlashDose tablets
(Biovail
Technologies Ltd.; Chantilly, VA). In fact, it was counterintuitive to expect
that the rapidly
disintegrating zolpidem solid dosage forms described herein would provide the
rapid
absorption and marked increase in bioavailability of zolpidem that was
observed. As a result,
the zolpidem in the compositions of the present invention reaches the systemic
circulation in
a substantially shorter period of time and at a substantially higher
concentration than the
zolpidem in either of the commercial tablet compositions. Thus, the zolpidem
compositions
of the present invention are superior to the commercial tablet compositions in
reducing the
time to onset of therapeutic activity, maintaining sleep (e.g., total sleep
time, number of
awakenings), enhancing sleep quality, eliminating the effect of food, and
reducing any
morning-after residual effects.
III. Description of the Embodiments
[0044] In one aspect, the present invention provides a solid composition for
delivery of a
hypnotic agent across the oral mucosa, the composition comprising:
(a) a hypnotic agent selected from the group consisting of an imidazopyridine,
a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable
salt thereof;

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(b) a carrier that provides complete buccal or sublingual disintegration in
about 5
minutes or less following administration to the mouth; and
(c) a binary buffer system comprising a carbonate salt and a bicarbonate salt,
wherein the binary buffer system raises the pH of saliva to a pH greater than
about 7.8,
irrespective of the starting pH of saliva.
[0045] In certain instances, the binary buffer system raises the pH of saliva
to a pH greater
than about 8.5, irrespective of the starting pH of saliva. In certain other
instances, the binary
buffer system raises the pH of saliva to a pH greater than about 9 (e.g.,
about 9-11),
irrespective of the starting pH of saliva. In one embodiment, the
imidazopyridine hypnotic
agent is selected from the group consisting of zolpidem and alpidem.
Preferably, the
imidazopyridine hypnotic agent is zolpidem. Any form of zolpidem is suitable
for use in the
compositions described herein, e.g., a salt form of zolpidem (e.g., zolpidem
tartrate), a free
base form of zolpidem, or a mixture thereof. In another embodiment, the
dihydropyrrolopyrazine hypnotic agent is zopeclon. In yet another embodiment,
the
pyrazolopyrimidine hypnotic agent is selected from the group consisting of
zaleplon and
indiplon.
[0046] In certain instances, the carrier provides complete buccal or
sublingual
disintegration in about 2 minutes or less following administration. In certain
other instances,
the carrier comprises at least one binder and at least one disintegrating
agent in such relative
proportion to provide a buccal or sublingual disintegration time of about 5
minutes or less,
preferably about 2 minutes or less, following administration. Preferably, the
ratio of the
binder to the disintegrating agent is from about 0.1 to about 10.0, more
preferably from about
0.1 to about 1.0, and most preferably from about 0.26 to about 0.79. However,
one skilled in
the art will appreciate that the compositions of the present invention can be
made without any
binders, e.g., to produce a highly friable dosage form.
[0047] In another embodiment, the carbonate salt is selected from the group
consisting of
sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate,
and
magnesium carbonate. In yet another embodiment, the bicarbonate salt is
selected from the
group consisting of sodium bicarbonate, potassium bicarbonate, calcium
bicarbonate,
ammonium bicarbonate, and magnesium bicarbonate. In a preferred embodiment,
the binary
buffer system comprises sodium carbonate and sodium bicarbonate. In another
preferred
embodiment, the sodium bicarbonate is dessicant-coated sodium bicarbonate.
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[0048] In yet another embodiment, the compositions of the present invention
are in a
dosage form selected from the group consisting of a lozenge, a chewing gum, a
chewable
tablet, and a dissolving tablet such as a slow-dissolving tablet or a quick-
dissolving tablet.
Preferably, the composition is a lozenge or a dissolving tablet. A description
of lozenge,
chewing gum, chewable tablet, slow-dissolving tablet, and quick-dissolving
tablet
compositions containing a hypnotic agent is provided in the Examples below.
[0049] In a preferred embodiment, the hypnotic agent is delivered across an
oral mucosa
selected from the group consisting of the sublingual mucosa, the buccal
mucosa, and a
combination thereof. In a particularly preferred embodiment, the composition
is
administered sublingually so that the hypnotic agent is delivered across the
sublingual
mucosa.
[0050] In another embodiment, the carrier is selected from the group
consisting of a binder,
a gum base, and combinations thereof. Suitable binders for use in the
compositions of the
present invention include, without limitation, sugar alcohols such as
mannitol, sorbitol, and
xylitol; sugars such as lactose, dextrose, sucrose, glucose, and powdered
sugar; natural gums
such as acacia gum, xanthan gum, guar gum, tara gum, mesquite gum, fenugreek
gum, locust
bean gum, ghatti gum, and tragacanth gum; other substances such as inositol,
molasses,
maltodextrin, starch, cellulose, microcrystalline cellulose,
polyvinylpyrrolidone, alginate,
extract of Irish moss, panwar gum, mucilage of isapol husks, Veegum , larch
arabogalactan,
gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose,
hydroxypropylmethylcellulose, polyacrylic acid (e.g., Carbopol), calcium
silicate, calcium
phosphate, dicalcium phosphate, calcium sulfate, kaolin, sodium chloride,
polyethylene
glycol; and combinations thereof. Suitable gum bases for use in the
compositions of the
present invention include, for example, materials selected from among the many
water-
insoluble and saliva-insoluble gum base materials known in the art. In certain
instances, the
gum base comprises at least one hydrophobic polymer and at least one
hydrophilic polymer.
Non-limiting examples of suitable hydrophobic and hydrophilic polymers for gum
bases
include both natural and synthetic polymers such as elastomers, rubbers, and
combinations
thereof. Examples of suitable natural polymers include, without limitation,
substances of
plant origin such as chicle, jelutong, gutta percha, crown gum, and
combinations thereof.
Examples of suitable synthetic polymers include elastomers such as butadiene-
styrene
copolymers, isobutylene and isoprene copolymers (e.g., "butyl rubber"),
polyethylene,
polyisobutylene, polyvinylester (e.g., polyvinyl acetate and polyvinyl acetate
phthalate), and
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combinations thereof. In other instances, the gum base comprises a mixture of
butyl rubber
(i.e., isobutylene and isoprene copolymer), polyisobutylene, and optionally,
polyvinylacetate
(e.g., having a molecular weight of approximately 12,000).
[0051] In yet another embodiment, the compositions of the present invention
can further
comprise a sweetening agent, a flavoring agent, a protecting agent, a
plasticizer, a wax, an
elastomeric solvent, a filler material, a preservative, or combinations
thereof. In still yet
another embodiment, the compositions of the present invention can further
comprise a
lubricating agent, a wetting agent, an emulsifying agent, a solubilizing
agent, a suspending
agent, a coloring agent, a disintegrating agent, or combinations thereof. In a
preferred
embodiment, the average particle size of the drug in the compositions
described herein is
about 20 microns, as compared to a typical average drug particle size of from
about 75 to
about 100 microns. In another preferred embodiment, the average particle size
of the drug in
the compositions described herein is less than or equal to the average
particle size of the
carrier ingredients (e.g., gum base, binders, etc.).
[0052] In preferred embodiments of the present invention, the hypnotic agent
is zolpidem
and the binary buffer system comprises sodium carbonate and sodium
bicarbonate. Such
compositions are preferably formulated in the form of a lozenge, candy, or
dissolving tablet
(e.g., slow-dissolving tablet or quick-dissolving tablet) for sublingual
administration. As a
result, upon sublingual administration, zolpidem is delivered across the
sublingual mucosa.
In other preferred embodiments, the sodium bicarbonate is dessicant-coated
sodium
bicarbonate. A combined weight percent of sodium carbonate and sodium
bicarbonate that is
greater than or equal to the weight percent of zolpidem is also preferred.
[0053] In certain instances, the composition comprises from about 1.0 to about
5.5 weight
percent zolpidem; from about 6.0 to about 10.0 weight percent sodium
carbonate; and from
about 9.0 to about 13.0 weight percent dessicant-coated sodium bicarbonate. In
a preferred
embodiment, the composition comprises about 4.5 weight percent zolpidem; about
8.0 weight
percent sodium carbonate; and about 11.0 weight percent dessicant-coated
sodium
bicarbonate. Such compositions are preferably in the form of a lozenge or
candy with a mass
of from about 100 to about 300 mg, e.g., about 100, 110, 120, 130, 140, 150,
160, 170, 180,
190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, and 300 mg. The
lozenges or candies
dissolve in a subject's mouth at a very rapid rate, e.g., within about 2-3
minutes following
administration.
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[0054] In certain other instances, the composition comprises from about 1.0 to
about 5.0
weight percent zolpidem; from about 5.0 to about 9.0 weight percent sodium
carbonate; and
from about 7.0 to about 11.0 weight percent sodium bicarbonate. In a preferred
embodiment,
the composition comprises about 4.0 weight percent zolpidem; about 7.0 weight
percent
sodium carbonate; and about 9.0 weight percent sodium bicarbonate. Such
compositions are
preferably in the form of a dissolving tablet such as a slow-dissolving tablet
or a quick-
dissolving tablet of from about 100 to about 300 mg, e.g., about 100, 110,
120, 130, 140, 150,
160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, and 300
mg. The
quick-dissolving tablets dissolve in a subject's mouth at a rapid rate, e.g.,
within about 5
minutes following administration, and the slow-dissolving tablets dissolve in
a subject's
mouth at a slower rate, e.g., within about 10 minutes following
administration.
[0055] In another aspect, the present invention provides a composition for
delivery of a
hypnotic agent across the oral mucosa, the composition comprising:
(a) a hypnotic agent selected from the group consisting of an imidazopyridine,
a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable
salt thereof;
(b) a carrier; and
(c) a binary buffer system comprising a carbonate salt and a bicarbonate salt,
wherein the binary buffer system raises the pH of saliva to a pH greater than
about 7.8,
irrespective of the starting pH of saliva.
[0056] In certain instances, the binary buffer system raises the pH of saliva
to a pH greater
than about 8.5, irrespective of the starting pH of saliva. In certain other
instances, the binary
buffer system raises the pH of saliva to a pH greater than about 9 (e.g.,
about 9-11),
irrespective of the starting pH of saliva. Suitable imidazopyridine,
dihydropyrrolopyrazine,
and pyrazolopyrimidine hypnotic agents for use in the present invention are
described above.
Suitable carbonate salts and bicarbonate salts for use in the binary buffer
systems of the
present invention are also described above.
[0057] In another embodiment, the compositions of the present invention are in
any of the
dosage forms described above. Preferably, the hypnotic agent is delivered
across an oral
mucosa as described above. In yet another embodiment, the carrier is selected
from the
group consisting of a binder, a gum base, and combinations thereof. Suitable
binders and
gun bases for use in the compositions of the present invention are described
above. In
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certain instances, the carrier provides a buccal or sublingual disintegration
time of about 10
minutes or less, preferably about 5 minutes or less, and more preferably about
2 minutes or
less, following administration. In certain other instances, the carrier
comprises at least one
binder and at least one disintegrating agent in such relative proportion to
provide a buccal or
sublingual disintegration time of about 10 minutes or less, preferably about 5
minutes or less,
and more preferably about 2 minutes or less, following administration.
[0058] In yet another embodiment, the compositions of the present invention
can further
comprise one or more of the additional agents described above. In preferred
embodiments,
the average particle size of the drug in the compositions described herein is
about 20 microns
and/or is less than or equal to the average particle size of the carrier
ingredients (e.g., gum
base, binders, etc.).
[0059] In other preferred embodiments of the present invention, the hypnotic
agent is
zolpidem and the binary buffer system comprises sodium carbonate and sodium
bicarbonate.
Preferred amounts of each of these components is described above, along with
preferred
dosage forms and their preferred weight.
[0060] In yet another aspect, the present invention provides a composition for
delivery of a
hypnotic agent across the oral mucosa, the composition comprising:
(a) a hypnotic agent selected from the group consisting of an imidazopyridine,
a=
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable
salt thereof;
(b) a carrier; and
(c) a binary buffer system comprising a carbonate salt or a bicarbonate salt
and a
second buffering agent,
wherein the binary buffer system raises the pH of saliva to a pH greater than
about 7.8,
irrespective of the starting pH of saliva.
[0061] In certain instances, the binary buffer system raises the pH of saliva
to a pH greater
than about 8.5, irrespective of the starting pH of saliva. In certain other
instances, the binary
buffer system raises the pH of saliva to a pH greater than about 9 (e.g.,
about 9-11),
irrespective of the starting pH of saliva. Suitable imidazopyridine,
dihydropyrrolopyrazine,
and pyrazolopyrimidine hypnotic agents for use in the present invention are
described above.
Suitable carbonate salts and bicarbonate salts for use in the binary buffer
systems of the
present invention are also described above.

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-
[0062] In one embodiment, the second buffering agent is selected from the
group consisting
of a metal oxide, a citrate salt, a phosphate salt, a borate salt, an ascorb
ate salt, an acetate salt,
and alkaline starch. Suitable metal oxides include, without limitation,
magnesium oxide and
aluminum oxide. Preferably, the magnesium oxide is amorphous magnesium oxide.
Suitable
citrate, phosphate, and borate salts include, without limitation, any salt of
citric acid,
phosphoric acid, or boric acid known in the art. For example, in some
embodiments, the
citrate salt is selected from the group consisting of sodium citrate,
potassium citrate, calcium
citrate, magnesium citrate, and ammonium citrate. In other embodiments, the
phosphate salt
is selected from the group consisting of monobasic sodium phosphate, dibasic
sodium
phosphate, monobasic potassium phosphate, dibasic potassium phosphate,
monobasic
calcium phosphate, dibasic calcium phosphate, monobasic magnesium phosphate,
dibasic
magnesium phosphate, monobasic ammonium phosphate, and dibasic ammonium
phosphate.
In yet other embodiments, the borate salt is selected from the group
consisting of sodium
borate, potassium borate, calcium borate, magnesium borate, and ammonium
borate. In
certain instances, the binary buffer system comprises a carbonate salt and a
metal oxide, a
citrate salt, a phosphate salt, or a borate salt. In certain other instances,
the binary buffer
system comprises a bicarbonate salt and a metal oxide, a citrate salt, a
phosphate salt, or a
borate salt.
[0063] In another embodiment, the compositions of the present invention are in
any of the
dosage forms described above. Preferably, the hypnotic agent is delivered
across an oral
mucosa as described above. In yet another embodiment, the carrier is selected
from the
group consisting of a binder, a gum base, and combinations thereof. Suitable
binders and
gum bases for use in the compositions of the present invention are described
above. In
certain instances, the carrier provides a buccal or sublingual disintegration
time as described
above. In certain other instances, the carrier comprises at least one binder
and at least one
disintegrating agent as described above.
[0064] In yet another embodiment, the compositions of the present invention
can further
comprise one or more of the additional agents described above. In preferred
embodiments,
the average particle size of the drug in the compositions described herein is
about 20 microns
and/or is less than or equal to the average particle size of the carrier
ingredients (e.g., gum
base, binders, etc.).
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[0065] In preferred embodiments of the present invention, the hypnotic agent
is zolpidem
and the binary buffer system comprises sodium carbonate or sodium bicarbonate
and a
second buffering agent. Such compositions are preferably formulated in the
form of a
lozenge, candy, or dissolving tablet for sublingual administration.
[0066] In still yet another aspect, the present invention provides a
composition for delivery
of a hypnotic agent across the oral mucosa, the composition comprising:
(a) a hypnotic agent selected from the group consisting of an imidazopyridine,
a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable
salt thereof;
(b) a carrier; and
(c) a binary buffer system comprising a metal oxide and a citrate, phosphate,
or
borate salt,
wherein the binary buffer system raises the pH of saliva to a pH greater than
about 7.8,
irrespective of the starting pH of saliva.
[0067] In certain instances, the binary buffer system raises the pH of saliva
to a pH greater
than about 8.5, irrespective of the starting pH of saliva. In certain other
instances, the binary
buffer system raises the pH of saliva to a pH greater than about 9 (e.g.,
about 9-11),
irrespective of the starting pH of saliva. Suitable imidazopyridine,
dihydropyrrolopyrazine,
and pyrazolopyrimidine hypnotic agents for use in the present invention are
described above.
[0068] Suitable metal oxides include, without limitation, magnesium oxide and
aluminum
oxide. Suitable citrate, phosphate, and borate salts include, without
limitation, any salt of
citric acid, phosphoric acid, or boric acid known in the art such as those
described above. In
certain instances, the binary buffer system comprises a metal oxide and a
citrate salt. In
certain other instances, the binary buffer system comprises a metal oxide and
a phosphate
salt. In further instances, the binary buffer system comprises a metal oxide
and a borate salt.
[0069] In one embodiment, the compositions of the present invention are in any
of the
dosage forms described above. Preferably, the hypnotic agent is delivered
across an oral
mucosa as described above. In yet another embodiment, the carrier is selected
from the
group consisting of a binder, a gum base, and combinations thereof. Suitable
binders and
gum bases for use in the compositions of the present invention are described
above. In certain
instances, the carrier provides a buccal or sublingual disintegration time as
described above.
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In certain other instances, the carrier comprises at least one binder and at
least one
disintegrating agent as described above.
[0070] In another embodiment, the compositions of the present invention can
further
comprise one or more of the additional agents described above. In preferred
embodiments,
the average particle size of the drug in the compositions described herein is
about 20 microns
and/or is less than or equal to the average particle size of the carrier
ingredients (e.g., gum
base, binders, etc.).
[0071] In preferred embodiments of the present invention, the hypnotic agent
is zolpidem
and the binary buffer system comprises amorphous magnesium oxide and a
citrate,
phosphate, or borate salt. Such compositions are preferably formulated in the
form of a
lozenge, candy, or dissolving tablet for sublingual administration.
[0072] In a further aspect, the present invention provides a composition for
delivery of a
hypnotic agent across the oral mucosa, the composition comprising:
(a) a hypnotic agent selected from the group consisting of an imidazopyridine,
a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable
salt thereof;
(b) a carrier; and
(c) a ternary buffer system comprising a carbonate salt, a bicarbonate salt,
and a third
buffering agent,
wherein the ternary buffer system raises the pH of saliva to a pH greater than
about 7.8,
irrespective of the starting pH of saliva.
[0073] In certain instances, the binary buffer system raises the pH of saliva
to a pH greater
than about 8.5, irrespective of the starting pH of saliva. In certain other
instances, the binary
buffer system raises the pH of saliva to a pH greater than about 9 (e.g.,
about 9-11),
irrespective of the starting pH of saliva. Suitable imidazopyridine,
dihydropyrrolopyrazine,
and pyrazolopyrimidine hypnotic agents for use in the present invention are
described above.
Suitable carbonate salts and bicarbonate salts for use in the ternary buffer
systems of the
present invention are also described above.
[0074] In one embodiment, the third buffering agent is selected from the group
consisting
of a metal oxide, a citrate salt, a phosphate salt, a borate salt, an
ascorbate salt, an acetate salt,
and alkaline starch. Suitable metal oxides include, without limitation,
magnesium oxide and
aluminum oxide. Suitable citrate, phosphate, and borate salts include, without
limitation, any
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salt of citric acid, phosphoric acid, or boric acid known in the art such as
those described
above. In certain instances, the ternary buffer system comprises a carbonate
salt, a
bicarbonate salt, and a metal oxide. In certain other instances, the ternary
buffer system
comprises a carbonate salt, a bicarbonate salt, and a citrate, phosphate, or
borate salt.
[0075] In another embodiment, the compositions of the present invention are in
any of the
dosage forms described above. Preferably, the hypnotic agent is delivered
across an oral
mucosa as described above. In yet another embodiment, the carrier is selected
from the
group consisting of a binder, a gum base, and combinations thereof. Suitable
binders and
gum bases for use in the compositions of the present invention are described
above. In
certain instances, the carrier provides a buccal or sublingual disintegration
time as described
above. In certain other instances, the carrier comprises at least one binder
and at least one
disintegrating agent as described above.
[0076] In yet another embodiment, the compositions of the present invention
can further
comprise one or more of the additional agents described above. In preferred
embodiments,
the average particle size of the drug in the compositions described herein is
about 20 microns
and/or is less than or equal to the average particle size of the carrier
ingredients (e.g., gum
base, binders, etc.).
[0077] In preferred embodiments of the present invention, the hypnotic agent
is zolpidem
and the ternary buffer system comprises sodium carbonate, sodium bicarbonate,
and a third
buffering agent. Such compositions are preferably formulated in the form of a
lozenge,
candy, or dissolving tablet for sublingual administration. In instances where
the third
buffering agent is a metal oxide, a weight percent of the metal oxide that is
greater than the
combined weight percent of sodium carbonate and sodium bicarbonate is
preferred.
[0078] In another aspect, the present invention provides a composition for
delivery of a
hypnotic agent across the oral mucosa, the composition comprising:
(a) a hypnotic agent selected from the group consisting of an imidazopyridine,
a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable
salt thereof;
(b) a carrier; and
(c) a buffer system comprising a carbonate salt or a bicarbonate salt and two
or more
buffering agents selected from the group consisting of a metal oxide, a
citrate salt,
a phosphate salt, and a borate salt,
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wherein the buffer system raises the pH of saliva to a pH greater than about
7.8, irrespective
of the starting pH of saliva.
[0079] In certain instances, the binary buffer system raises the pH of saliva
to a pH greater
than about 8.5, irrespective of the starting pH of saliva. In certain other
instances, the binary
buffer system raises the pH of saliva to a pH greater than about 9 (e.g.,
about 9-11),
irrespective of the starting pH of saliva. Suitable imidazopyridine,
dihydropyrrolopyrazine,
and pyrazolopyrirnidine hypnotic agents for use in the present invention are
described above.
Suitable carbonate salts and bicarbonate salts for use in the buffer systems
of the present
invention are also described above.
[0080] Suitable metal oxides include, without limitation, magnesium oxide and
aluminum
oxide. Suitable citrate, phosphate, and borate salts include, without
limitation, any salt of
citric acid, phosphoric acid, or boric acid known in the art such as those
described above. In
certain instances, the buffer system comprises a carbonate salt or a
bicarbonate salt, a metal
oxide, and a citrate, phosphate, or borate salt. In certain other instances,
the buffer system
comprises a carbonate salt or a bicarbonate salt, a citrate salt, and a
phosphate salt. In certain
instances, the buffer system comprises a carbonate salt or a bicarbonate salt,
a citrate salt, and
a borate salt. In certain other instances, the buffer system comprises a
carbonate salt or a
bicarbonate salt, a phosphate salt, and a borate salt.
[0081] In one embodiment, the compositions of the present invention are in any
of the
dosage forms described above. Preferably, the hypnotic agent is delivered
across an oral
mucosa as described above. In yet another embodiment, the carrier is selected
from the
group consisting of a binder, a gum base, and combinations thereof. Suitable
binders and
gum bases for use in the compositions of the present invention are described
above. In
certain instances, the carrier provides a buccal or sublingual disintegration
time as described
above. In certain other instances, the carrier comprises at least one binder
and at least one
disintegrating agent as described above.
[0082] In another embodiment, the compositions of the present invention can
further
comprise one or more of the additional agents described above. In preferred
embodiments,
the average particle size of the drug in the compositions described herein is
about 20 microns
and/or is less than or equal to the average particle size of the carrier
ingredients (e.g., gum
base, binders, etc.).

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[0083] In preferred embodiments of the present invention, the hypnotic agent
is zolpidem
and the buffer system comprises sodium carbonate or sodium bicarbonate and two
or more
buffering agents selected from the group consisting of a metal oxide, a
citrate salt, a
phosphate salt, and a borate salt. Such compositions are preferably formulated
in the form of
a lozenge, candy, or dissolving tablet for sublingual administration.
[0084] In yet another aspect, the present invention provides a method for
treating a sleep
disorder in a subject in need thereof, the method comprising:
administering to the subject a composition comprising a therapeutically
effective
amount of a hypnotic agent selected from the group consisting of an
imidazopyridine, a
dihydropyrrolopyrazine, a pyrazolopyrimidine, and a pharmaceutically
acceptable salt
thereof; a carrier; and a binary buffer system comprising a carbonate salt and
a bicarbonate
salt, wherein the binary buffer system raises the pH of saliva to a pH greater
than about 7.8,
irrespective of the starting pH of saliva.
[0085] In a preferred embodiment, the composition delivers the hypnotic agent
across the
oral mucosa such as, for example, the sublingual mucosa, the buccal mucosa, or
a
combination thereof. In a particularly preferred embodiment, the composition
is
administered sublingually so that the hypnotic agent is delivered across the
sublingual
mucosa. Suitable sleep disorders that can be treated with the compositions of
the present
invention include, without limitation, insomnia such as transient insomnia,
short-term
insomnia, and chronic insomnia.
[0086] In certain instances, the binary buffer system raises the pH of saliva
to a pH greater
than about 8.5, irrespective of the starting pH of saliva. In certain other
instances, the binary
buffer system raises the pH of saliva to a pH greater than about 9 (e.g.,
about 9-11),
irrespective of the starting pH of saliva. Suitable imidazopyridine,
dihydropyrrolopyrazine,
and pyrazolopyrimidine hypnotic agents for use in the present invention are
described above.
Suitable carbonate salts and bicarbonate salts for use in the binary buffer
systems of the
present invention are also described above.
[0087] In addition to a binary buffer system comprising a carbonate salt and a
bicarbonate
salt, other buffer systems are suitable for use in the compositions of the
present invention.
For example, in an alternative embodiment, the binary buffer system comprises
a carbonate
salt or a bicarbonate salt and a second buffering agent such as a metal oxide,
a citrate salt, a
phosphate salt, a borate salt, an ascorbate salt, an acetate salt, and
alkaline starch. In another
21

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alternative embodiment, the binary buffer system comprises a metal oxide and a
citrate,
phosphate, or borate salt. In yet another alternative embodiment, the buffer
system is a
ternary buffer system comprising a carbonate salt, a bicarbonate salt, and a
third buffering
agent such as a metal oxide, a citrate salt, a phosphate salt, a borate salt,
an ascorb ate salt, an
acetate salt, and alkaline starch, hi still yet another alternative
embodiment, the buffer
system comprises a carbonate salt or a bicarbonate salt and two or more
buffering agents
selected from the group consisting of a metal oxide, a citrate salt, a
phosphate salt, and a
borate salt.
[0088] In one embodiment, the compositions of the present invention are in any
of the
=
dosage forms described above. Preferably, the hypnotic agent is delivered
across an oral
mucosa as described above. In yet another embodiment, the carrier is selected
from the
group consisting of a binder, a gum base, and combinations thereof. Suitable
binders and
gum bases for use in the compositions of the present invention are described
above. In
certain instances, the carrier provides a buccal or sublingual disintegration
time as described
above. In certain other instances, the carrier comprises at least one binder
and at least one
disintegrating agent as described above.
[0089] In another embodiment, the compositions of the present invention can
further
comprise one or more of the additional agents described above. In preferred
embodiments,
the average particle size of the drug in the compositions described herein is
about 20 microns
and/or is less than or equal to the average particle size of the carrier
ingredients (e.g., gum
base, binders, etc.).
[0090] In preferred embodiments of the present invention, the hypnotic agent
is zolpidem
and the binary buffer system comprises sodium carbonate and sodium
bicarbonate. Preferred
amounts of each of these components is described above, along with preferred
dosage forms
and their preferred weight.
A. Hypnotic Agents
[0091] The hypnotic agents of the present invention are preferably selected
from an
imidazopyridine compound such as zolpidem or alpidem; a dihydropyrrolopyrazine
compound such as zopeclon; a pyrazolopyrimidine compound such as zaleplon or
indiplon;
pharmaceutically acceptable salts thereof; and combinations thereof. More
preferably, the
hypnotic agent is zolpidem, in all suitable forms.
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[0092] In general, the hypnotic agents of the present invention are basic
compounds having
an ionized form and an un-ionized form. In certain instances, the hypnotic
agent is initially
present at least partly in an ionized form. In certain other instances, the
hypnotic agent is
initially present in an un-ionized form. As described in more detail below,
the buffer system
of the compositions described herein helps to convert substantially all of the
hypnotic agent
from its ionized form to its un-ionized form. Alternatively, the buffer system
helps ensure
that the hypnotic agent, initially in an un-ionized form, remains in an un-
ionized form.
[0093] As used herein, the term "hypnotic agent" includes all pharmaceutically
acceptable
forms of the hypnotic agent being described. For example, the hypnotic agent
can be in a
racemic or isomeric mixture, a solid complex bound to an ion exchange resin,
or the like. In
addition, the hypnotic agent can be in a solvated form. The term "hypnotic
agent" is also
intended to include all pharmaceutically acceptable salts, derivatives, and
analogs of the
hypnotic agent being described, as well as combinations thereof. For example,
the
pharmaceutically acceptable salts of the hypnotic agent include, without
limitation, the
tartrate, succinate, tartarate, bitartarate, dihydrochloiide, salicylate,
hemisuccinate, citrate,
maleate, hydrochloride, carbamate, sulfate, nitrate, and benzoate salt forms
thereof, as well as
combinations thereof and the like. Any form of the hypnotic agent is suitable
for use in the
compositions of the present invention, e.g., a pharmaceutically acceptable
salt of the hypnotic
agent (e.g., zolpidem tartrate), a free base of the hypnotic agent, or a
mixture thereof.
[0094] Conversion of the ionized form to the un-ionized form for the hypnotic
agent is
related to pH according to the formula: pH = pKa + Logic) (un-ionized
concentration/ionized
concentration). When the pH is the same as the pKa, equimolar concentrations
of the un-
ionized form and ionized form exist. For basic compounds such as the hypnotic
agents
described herein, when the pH is one unit higher than the pKa, the ratio of
the un-ionized
form to the ionized form is 91:9. Similarly, when the pH is two units higher
than the pKa, the
ratio of un-ionized form to the ionized form is 100:1. As noted above, the un-
ionized form is
lipophilic and, therefore, more capable of passing through mucous membranes
such as the
oral mucosa than the ionized form, which is lipophobic in nature. Accordingly,
increasing
the pH of the saliva favors conversion of the ionized form into the un-ionized
form for basic
compounds such as the hypnotic agents described herein, and the final pH can
be determined
by making use of the above formula.
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[0095] The hypnotic agents of the present invention are selected from the
class of
compounds in the imida7opyridine, dihydropyrrolopyrazine, or
pyrazolopyrimidine family
and are useful in the treatment of conditions such as sleep disorders.
Illustrative examples of
suitable imidazopyridine compounds for use in the present invention are
zolpidem, alpidem,
pharmaceutically acceptable salts thereof, analogs thereof, and derivatives
thereof. These
imidazopyridine compounds each have an imidazopyridine group, as shown below:
cH3
H3C
N'CH3
H3c
Zolpidem
II CI
0
=
H3c cH3
Alpidem
[0096] For the imidazopyridine compounds, the nitrogen in the imidazole
portion of the
bicyclic ring of the structure controls the extent of ionization and the
degree of lipophilicity
in any given medium. Typically the nitrogen in the imidazole portion imparts a
pKa of from
about 6.8 to about 7.5 to the molecule. Therefore, using the above formula, it
can be
demonstrated that about 90% conversion to an un-ionized form can be achieved
for these
compounds at a pH of from about 7.8 to about 8.5.
[0097] Illustrative examples of suitable dihydropyrrolopyrazine compounds for
use in the
present invention are zopeclon, pharmaceutically acceptable salts thereof,
analogs thereof,
and derivatives thereof. These dihydropyrrolopyrazines each have a
dihydropyrrolopyrazine
group, as shown below:
24

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0
N
0
\CH3
Zopeclon
[00981 Illustrative examples of suitable pyrazolopyrimidine compounds for use
in the
present invention are zaleplon, indiplon, pharmaceutically acceptable salts
thereof, analogs
thereof, and derivatives thereof. These pyrazolopyrimidines each have a
pyrazolopyrimidine
group, as shown below:
N
0 =
N
H3C
u
n3C
Zaleplon
TH3
=
0 \
Indiplon

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[0099] For the pyrazolopyrimidine compounds, the nitrogen in the pyrimidine
group
controls the extent of ionization and the degree of lipophilicity in any given
medium.
Typically, the nitrogen in the pyrimidine group imparts a pKa of from about 8
to about 9 to
the molecule. Therefore, using the above formula, it can be demonstrated that
about 90%
conversion to an un-ionized form can be achieved for these compounds at a pH
of from about
9 to about 10.
[0100] In general, the hypnotic agents of the present invention acts as
benzodiazepine
receptor agonists. Preferably, the hypnotic agents selectively bind to the
benzodiazepinei
receptor. Without being bound to any particular theory, the therapeutic
activity of the
hypnotic agents of the present invention in treating sleep disorders is
attributed to an
enhancement of the inhibitory action of gamma-aminobutyric acid (GABA) in the
central
nervous system.
B. Buffer Systems
[0101] The buffer systems of the compositions described herein are capable of
raising the
pH of saliva to a pH greater than about 7.8, irrespective of the starting p11
of saliva. In this
way, the buffer system helps convert substantially all of the hypnotic agent
from its ionized
form to its un-ionized form. Alternatively, the buffer system helps ensure
that the hypnotic
agent, initially in an un-ionized form, remains in an un-ionized form.
Although basic
buffering agents are typically used in the buffer systems of the present
invention, one skilled
in the art will appreciate that acidic agents can also be used to adjust the
pH of the buffer
system as long as the buffer system as a whole raises the pH of saliva to a pH
greater than
about 7.8.
[0102] In one embodiment, the present invention provides binary buffer systems
comprising a carbonate salt and a bicarbonate salt. The concentration of each
buffer system
component is tailored such that the final salivary pH is achieved and
sustained for a period of
time, e.g., for at least about 2 minutes, at least about 5 minutes, at least
about 10 minutes, at
least about 20 minutes, or at least about 60 minutes. This typically involves
a sensory and
safety trial and error type of procedure of adding various amounts of each
buffer system
component and then measuring the final pH over time. In this way, selection of
an
appropriate weight ratio for each buffer system component can be easily
determined in just a
few trials. For example, the weight ratio of carbonate salt to bicarbonate
salt can be from
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about 1:10 to about 10:1, preferably from about 1:5 to about 5:1, more
preferably from about
1:3 to about 3:1, and still more preferably from about 1:2 to about 2:1.
[0103] The carbonate salt is generally selected from sodium carbonate,
potassium
carbonate, calcium carbonate, ammonium carbonate, and magnesium carbonate.
Preferably,
the carbonate salt is sodium carbonate or potassium carbonate. Most
preferably, the
carbonate salt is sodium carbonate. Similarly, the bicarbonate salt is
generally selected from
sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium
bicarbonate,
and magnesium bicarbonate. Preferably, the bicarbonate salt is sodium
bicarbonate or
potassium bicarbonate. Most preferably, the bicarbonate salt is sodium
bicarbonate. In some
embodiments, a dessicant-coated sodium bicarbonate is preferred. The amount of
carbonate
salt and bicarbonate salt used in the binary buffer system is an amount that
is sufficient to
raise salivary pH to a pH of about 7.8 or more, preferably about 8.5 or more,
and more
preferably about 9 or more (e.g., about 9-11), irrespective of the starting
pH.
[0104] In certain instances, the amount of bicarbonate salt is greater than or
equal to the
amount of carbpnate salt, and the weight ratio of carbonate salt to
bicarbonate salt is from
about 1:1 to about 1:10, preferably from about 1:1 to about 1:5, and more
preferably from
about 1:1 to about 1:2, e.g., 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6,
1:1.7, 1:1.8, 1:1.9, or,
1:2. Alternatively, the amount of bicarbonate salt is less than or equal to
the amount of
carbonate salt, and the weight ratio of carbonate salt to bicarbonate salt is
from about 1:1 to
about 10:1, preferably from about 1:1 to about 5:1, and more preferably from
about 1:1 to
about 2:1, e.g., 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1,
1.9:1, or 2:1. In
certain other instances, the combined amount of carbonate salt and bicarbonate
salt is greater
than or equal to the amount of the hypnotic agent, and the weight ratio of
carbonate salt and
bicarbonate salt to hypnotic agent is preferably from about 1:1 to about 10:1,
e.g., 1:1, 2:1,
3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1. Alternatively, the combined amount
of carbonate salt
and bicarbonate salt is less than or equal to the amount of the hypnotic
agent, and the weight
ratio of carbonate salt and bicarbonate salt to hypnotic agent is preferably
from about 1:1 to
about 1:10, e.g., 1:1, 1:2,1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.
[0105]
In view of the above, the buffer systems of the present invention, in some of
the
most preferred embodiments, are binary buffer systems containing sodium
carbonate and
sodium bicarbonate.
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[0106] Alternatively, in another embodiment, the buffer systems of the present
invention
are binary buffer systems comprising a carbonate salt or a bicarbonate salt
and a second
buffering agent. The concentration of each buffer system component is tailored
such that the
final salivary pH is achieved and sustained for a period of time, e.g., for at
least about 2
minutes, at least about 5 minutes, at least about 10 minutes, at least about
20 minutes, or at
least about 60 minutes.
[0107] Suitable carbonate salts and bicarbonate salts are described
above. The amount of
carbonate salt or bicarbonate salt used in the binary buffer system is an
amount that is
sufficient, when used with the second buffering agent, to raise salivary pH to
a pH of about
7.8 or more, preferably about 8.5 or more, and more preferably about 9 or more
(e.g., about
9-11), irrespective of the starting pH. In certain instances, the amount of
the second buffering
agent in the binary buffer system is greater than or equal to the amount of
the carbonate salt
or bicarbonate salt. For example, the weight ratio of the second buffering
agent to the
carbonate salt or bicarbonate salt can be from about 1:1 to about 10:1,
preferably from about
1:1 to about 5:1, and more preferably from about 1:1 to about 3:1. In certain
other instances,
the amount of the second buffering agent in the binary buffer system is less
than or equal to
the amount of the carbonate salt or bicarbonate salt. For example, the weight
ratio of the
second buffering agent to the carbonate salt or bicarbonate salt can be from
about 1:1 to about
1:10, preferably from about 1:1 to about 1:5, and more preferably from about
1:1 to about
1:3.
[0108] The second buffering agent is generally selected from a metal oxide
such as
magnesium oxide or aluminum oxide; a citrate salt such as sodium citrate,
potassium citrate,
calcium citrate, magnesium citrate, and ammonium citrate; a phosphate salt
such as
monobasic sodium phosphate, dibasic sodium phosphate, monobasic potassium
phosphate,
dibasic potassium phosphate, monobasic calcium phosphate, dibasic calcium
phosphate,
monobasic magnesium phosphate, dibasic magnesium phosphate, monobasic ammonium
phosphate, and dibasic ammonium phosphate; a borate salt such as sodium
borate, potassium
borate, calcium borate, magnesium borate, and ammonium borate; an ascorbate
salt such as
potassium ascorbate or sodium ascorbate; an acetate salt such as potassium
acetate or sodium
acetate; and alkaline starch. However, one skilled in the art will appreciate
that any metal
oxide or salt of citric acid, phosphoric acid, boric acid, ascorbic acid, or
acetic acid is suitable
for use in the buffer systems of the present invention. The amount of the
second buffering
agent used in the binary buffer system is an amount that is sufficient, when
used with the
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carbonate salt or bicarbonate salt, to raise salivary pH to a pH of about 7.8
or more,
preferably about 8.5 or more, and more preferably about 9 or more (e.g., about
9-11),
irrespective of the starting pH. In some embodiments, a metal oxide such as
magnesium
oxide or aluminum oxide is the preferred second buffering agent. In a
particularly preferred
embodiment, the metal oxide is amorphous magnesium oxide.
[0109] Alternatively, in yet another embodiment, the buffer systems of the
present
invention are binary buffer systems comprising a metal oxide and a citrate,
phosphate, or
borate salt. The concentration of each buffer system component is tailored
such that the final
salivary pH is achieved and sustained for a period of time, e.g., for at least
about 2 minutes, at
least 5 about minutes, at least about 10 minutes, at least about 20 minutes,
or at least about 60
minutes.
[0110] Suitable metal oxides include, without limitation, magnesium oxide and
aluminum
oxide. Suitable citrate, phosphate, and borate salts include, without
limitation, essentially any
salt of citric acid, phosphoric acid, or boric acid known in the art such as
those described
above. In certain instances, the binary buffer system comprises a metal oxide
and a citrate
salt. In certain other instances, the binary buffer system comprises a metal
oxide and a
phosphate salt. In further instances, the binary buffer system comprises a
metal oxide and a
borate salt. The amount of the metal oxide used in the binary buffer system is
an amount that
is sufficient, when used with the citrate, phosphate, or borate salt, to raise
salivary pH to a pH
of about 7.8 or more, preferably about 8.5 or more, and more preferably about
9 or more
(e.g., about 9-11), irrespective of the starting pH. Similarly, the amount of
the citrate,
phosphate, or borate salt used in the binary buffer system is an amount that
is sufficient, when
used with the metal oxide, to raise salivary pH to a pH of about 7.8 or more,
preferably about
8.5 or more, and more preferably about 9 or more (e.g., about 9-11),
irrespective of the
starting pH.
[0111] In certain instances, the amount of the metal oxide in the binary
buffer system is
greater than or equal to the amount of the citrate, phosphate, or borate salt.
For example, the
weight ratio of the metal oxide to the citrate, phosphate, or borate salt can
be from about 1:1
to about 10:1, preferably from about 1:1 to about 5:1, and more preferably
from about 1:1 to
about 3:1. In certain other instances, the amount of the metal oxide in the
binary buffer
system is less than or equal to the amount of the citrate, phosphate, or
borate salt. For
example, the weight ratio of the metal oxide to the citrate, phosphate, or
borate salt can be
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from about 1:1 to about 1:10, preferably from about 1:1 to about 1:5, and more
preferably
from about 1:1 to about 1:3.
[0112] Alternatively, in still yet another embodiment, the buffer systems of
the present
invention are ternary buffer systems comprising a carbonate salt, a
bicarbonate salt, and a
third buffering agent. The concentration of each buffer system component is
tailored such
that the final salivary pH is achieved and sustained for a period of time,
e.g., for at least about
2 minutes, at least 5 about minutes, at least about 10 minutes, at least about
20 minutes, or at
least about 60 minutes. The procedure described above for determining an
appropriate
weight ratio for each buffer system component can also be applied to ternary
buffer systems.
[0113] Suitable carbonate salts and bicarbonate salts are described above. The
amount of
carbonate salt and bicarbonate salt used in the ternary buffer system is an
amount that is
sufficient, when used with the third buffering agent, to raise salivary pH to
a pH of about 7.8
or more, preferably about 8.5 or more, and more preferably about 9 or more
(e.g., about 9-
11), irrespective of the starting pH.
[0114] The third buffering agent is generally selected from a metal oxide, a
citrate salt, a
phosphate salt, a borate salt, an ascorbate salt such as potassium ascorbate
or sodium
ascorbate, an acetate salt such as potassium acetate or sodium acetate, and
alkaline starch.
Suitable metal oxides include, without limitation, magnesium oxide and
aluminum oxide.
Suitable citrate, phosphate, and borate salts include, without limitation, any
salt of citric acid,
phosphoric acid, or boric acid known in the art such as those described above.
The amount of
the third buffering agent used in the ternary buffer system is an amount that
is sufficient,
when used with the remaining components, to raise salivary pH to a pH of about
7.8 or more,
preferably about 8.5 or more, and more preferably about 9 or more (e.g., about
9-11),
irrespective of the starting pH. In some embodiments, a metal oxide such as
magnesium
oxide or aluminum oxide is the preferred third buffering agent. In a
particularly preferred
embodiment, the metal oxide is amorphous magnesium oxide.
[0115] In certain instances, the amount of the carbonate salt or bicarbonate
salt in the
ternary buffer system is greater than or equal to the amount of the third
buffering agent. For
example, the weight ratio of the carbonate salt or bicarbonate salt to the
third buffering agent
can be from about 1:1 to about 10:1, preferably from about 1:1 to about 5:1,
and more
preferably from about 1:1 to about 3:1. In certain other instances, the amount
of the
carbonate salt or bicarbonate salt in the ternary buffer system is less than
or equal to the

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amount of the third buffering agent. For example, the weight ratio of the
carbonate salt or
bicarbonate salt to the third buffering agent can be from about 1:1 to about
1:10, preferably
from about 1:1 to about 1:5, and more preferably from about 1:1 to about 1:3.
[0116] The ternary buffer systems of the present invention, in some of
the most preferred
embodiments, contain sodium carbonate, sodium bicarbonate, and amorphous
magnesium
oxide. In certain instances, the amount of sodium bicarbonate is greater than
or equal to the
amount of sodium carbonate. For example, the weight ratio of sodium
bicarbonate to sodium
carbonate can be from about 1:1 to about 10:1, preferably from about 1:1 to
about 5:1, and
more preferably from about 1:1 to about 3:1. In certain other instances, the
amount of
amorphous magnesium oxide is greater than or equal to the combined amount of
sodium
carbonate and sodium bicarbonate. For example, the weight ratio of amorphous
magnesium
oxide to sodium carbonate and sodium bicarbonate can be from about 1:1 to
about 10:1,
preferably from about 1:1 to about 5:1, and more preferably from about 1:1 to
about 3:1.
[0117] Alternatively, in a further embodiment, the buffer systems of the
present invention
are buffer systems comprising a carbonate salt or a bicarbonate salt and two
or more
buffering agents selected from the group consisting of a metal oxide, a
citrate salt, a
phosphate salt, and a borate salt. The concentration of each buffer system
component is
tailored such that the final salivary pH is achieved and sustained for a
period of time, e.g., for
at least about 2 minutes, at least 5 about minutes, at least about 10 minutes,
at least about 20
minutes, or at least about 60 minutes.
[0118] Suitable carbonate salts and bicarbonate salts are described above. The
amount of
carbonate salt or bicarbonate salt used in the buffer system is an amount that
is sufficient,
when used with the remaining components, to raise salivary pH to a pH of about
7.8 or more,
preferably about 8.5 or more, and more preferably about 9 or more (e.g., about
9-11), ,
irrespective of the starting pH.
[0119] The two or more buffering agents are generally selected from a metal
oxide, a
citrate salt, a phosphate salt, a borate salt, an ascorbate salt, an acetate
salt, and alkaline
starch. Suitable metal oxides include, without limitation, magnesium oxide and
aluminum
oxide. Suitable citrate, phosphate, borate, ascorbate, and acetate salts
include, without
limitation, essentially any salt of citric acid, phosphoric acid, boric acid,
ascorbic acid, or
acetic acid known in the art such as those described above. The amount of the
additional
buffering agents used in the buffer system is an amount that is sufficient,
when used with the
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carbonate salt or bicarbonate salt, to raise salivary pH to a pH of about 7.8
or more,
preferably about 8.5 or more, and more preferably about 9 or more (e.g., about
9-11),
irrespective of the starting pH.
[0120] In certain instances, the buffer system comprises a carbonate salt or a
bicarbonate
salt, a metal oxide, and a citrate, phosphate, or borate salt. In certain
other instances, the
buffer system comprises a carbonate salt or a bicarbonate salt, a citrate
salt, and a phosphate
salt. In certain instances, the buffer system comprises a carbonate salt or a
bicarbonate salt, a
citrate salt, and a borate salt. In certain other instances, the buffer system
comprises a
carbonate salt or a bicarbonate salt, a phosphate salt, and a borate salt.
Preferably, the metal
oxide is amorphous magnesium oxide.
[0121] In certain instances, the amount of the carbonate salt or bicarbonate
salt in the buffer
system is greater than or equal to the amount of the metal oxide or the
citrate, phosphate, or
borate salt. For example, the weight ratio of the carbonate salt or
bicarbonate salt to the
metal oxide or the citrate, phosphate, or borate salt can be from about 1:1 to
about 10:1,
preferably from about 1:1 to about 5:1, and more preferably from about 1:1 to
about 3:1. In
certain other instances, the amount of the carbonate salt or bicarbonate salt
in the buffer
system is less than or equal to the amount of the metal oxide or the citrate,
phosphate, or
borate salt. For example, the weight ratio of the carbonate salt or
bicarbonate salt to the
metal oxide or the citrate, phosphate, or borate salt can be from about 1:1 to
about 1:10,
preferably from about 1:1 to about 1:5, and more preferably from about 1:1 to
about 1:3.
[0122] While the foregoing discussion has focused on the ability of the buffer
system to
alter salivary pH to favor substantial conversion to the un-ionized form of a
therapeutic agent,
it is conceivable that the buffer system may also have subsidiary beneficial
effects on the
extent of absorption across the oral mucosa. For example, the buffer system
may create a
final salivary pH that in turn affects the molecular configuration of the
therapeutic agent in a
way in which absorption across the oral mucosa is increased. It is to be
understood that these
subsidiary beneficial effects of the buffer system are within the general
scope of the buffer
system and compositions herein described.
C. Dosage Forms
[0123] The compositions of the present invention may take the form of solid,
semi-solid,
lyophilized powder, or liquid dosage forms, such as, for example, tablets
(e.g., chewable,
slow-dissolving, quick-dissolving), pills, capsules, lozenges, gums, powders,
solutions,
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suspensions, emulsions, aerosols, or the like. Preferably, the dosage form is
a chewing gum,
dissolving tablet, chewable tablet, candy, or lozenge.
[0124] While each subject or patient possesses unique factors that may affect
the rate and
extent of absorption of the therapeutic agents described herein, dosage forms
such as chewing
gums, chewable tablets, dissolving tablets, or lozenges containing a buffer
system described
herein offer advantages over the traditional dosage forms for oral
administration (i.e.,
Ambien ). For example, each of these dosage forms avoids hepatic first pass
metabolism,
degradation within the gastrointestinal tract, and drug loss during
absorption. Consequently,
the amount of therapeutic agent required per dose is less than that which
would be required if
formulated, for example, in a pill or tablet for oral administration.
Similarly, the
bioavailability of the therapeutic agent is increased, thereby reducing the
time to onset of
therapeutic activity as compared to traditional dosage forms for oral
administration (see,
Example 5 below).
[0125] In addition, the preferred dosage forms of the present invention (e.g.,
chewing
gums, chewable tablets, dissolving tablets, lozenges) containing a buffer
system described
herein offer advantages over dosage forms for oral mucosal administration that
do not contain
the buffer system (i.e., zolpidem FlashDose' tablet). Importantly, because the
buffer system
in the dosage forms of the present invention helps convert substantially all
of the therapeutic
agent from its ionized form to its un-ionized form, the bioavailability of the
therapeutic agent
is increased, thereby reducing the time to onset of therapeutic activity as
compared to dosage
forms for oral mucosal administration that do not contain the buffer system.
For example,
U.S. Patent Publication No. 2003/0165566 discloses that the buccally
administered zolpidem
FlashDose tablet has a pharmacokinetic profile similar to that observed for
the orally
administered Ambien tablet. As such, the zolpidem compositions of the present
invention
surpass both commercial tablet compositions by providing an increase in the
bioavailability
of zolpidem and a reduction in the time to onset of therapeutic activity.
[0126] As used herein, the term "dosage form" refers to physically discrete
units suitable as
unitary dosages for human subjects and other mammals, each unit containing a
predetermined
quantity of therapeutic agent calculated to produce the desired onset,
tolerability, and
therapeutic effects, in association with one or more suitable pharmaceutical
excipients such
as carriers. Methods for preparing such dosage forms are known or will be
apparent to those
skilled in the art. For example, in some embodiments, a chewing gum dosage
form of the
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present invention can be prepared according to the procedures set forth in
U.S. Pat. No.
4,405,647. In other embodiments, a tablet, lozenge, or candy dosage form of
the present
invention can be prepared according to the procedures set forth, for example,
in Remington:
The Science and Practice of Pharmacy, 20th Ed., Lippincott, Williams & Wilkins
(2003);
Pharmaceutical Dosage Forms, Volume I: Tablets, 21id Ed., Marcel Dekker, Inc.,
New York,
N.Y. (1989); and similar publications. The dosage form to be administered
will, in any event,
contain a quantity of the therapeutic agent in a therapeutically effective
amount for relief of
the condition being treated when administered in accordance with the teachings
of this
invention.
[0127] As used herein, the term "carrier" refers to a typically inert
substance used as a
diluent or vehicle for a drug such as a therapeutic agent. The term also
encompasses a
typically inert substance that imparts cohesive qualities to the composition.
Suitable carriers
for use in the compositions of the present invention include, without
limitation, a binder, a
gum base, and combinations thereof. Non-limiting examples of binders include
mannitol,
sorbitol, xylitol, maltodextrin, lactose, dextrose, sucrose, glucose,
inositol, powdered sugar,
molasses, starch, cellulose, microcrystalline cellulose, polyvinylpyrrolidone,
acacia gum,
guar gum, tragacanth gum, alginate, extract of Irish moss, panwar gum, ghatti
gum, mucilage
of isapol husks, Veegumi", larch arabogalactan, gelatin, methylcellulose,
ethylcellulose,
carboxymethylcellulose, hydroxypropylmethylcellulose, polyacrylic acid (e.g.,
Carbopol),
calcium silicate, calcium phosphate, dicalcium phosphate, calcium sulfate,
kaolin, sodium
chloride, polyethylene glycol, and combinations thereof. These binders can be
pre-processed
to improve their flowability and taste by methods known in the art such as
freeze drying (see,
e.g., Fundamentals of Freeze-Drying, Pharm. Biotechnol., 14:281-360 (2002);
Lyophililization of Unit Dose Pharmaceutical Dosage Forms, Drug. Dev. Ind.
Pharm.,
29:595-602 (2003)); solid-solution preparation (see, e.g., U.S. Pat. No.
6,264,987); and
lubricant dusting and wet-granulation preparation with a suitable lubricating
agent (see, e.g.,
Remington: The Science and Practice of Pharmacy, supra). For example,
Mannogemil and
Sorbogem , sold by SPI Pharma Group (New Castle, DE), are freeze-dried
processed forms
of mannitol and sorbitol, respectively. Typically, the compositions of the
present invention
comprise from about 25% to about 90% by weight of the binder, and preferably
from about
50% to about 80%. However, one skilled in the art will appreciate that the
compositions of
the present invention can be made without any binders, e.g., to produce a
highly friable
dosage form.
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[0128] Non-limiting examples of gum bases include materials selected from
among the
many water-insoluble and saliva-insoluble gum base materials known in the art.
For
example, in some instances, the gum base comprises at least one hydrophobic
polymer and at
least one hydrophilic polymer. Non-limiting examples of suitable hydrophobic
and
hydrophilic polymers for gum bases include both natural and synthetic polymers
such as
elastomers, rubbers, and combinations thereof. Examples of suitable natural
polymers
include, without limitation, substances of plant origin such as chicle,
jelutong, gutta percha,
crown gum, and combinations thereof. Examples of suitable synthetic polymers
include
elastomers such as butadiene-styrene copolymers, isobutylene and isoprene
copolymers (e.g.,
"butyl rubber"), polyethylene, polyisobutylene, polyvinylester (e.g.,
polyvinyl acetate and
polyvinyl acetate phthalate), and combinations thereof. In other instances,
the gum base
comprises a mixture of butyl rubber (i.e., isobutylene and isoprene
copolymer),
polyisobutylene, and optionally, polyvinylacetate (e.g., having a molecular
weight of
approximately 12,000). Typically, the gum base comprises from about 25% to
about 75% by
weight of these polymers, and preferably from about 30% to about 60%.
[0129] The compositions of the present invention can additionally include
lubricating
agents; wetting agents; emulsifying agents; solubilizing agents; suspending
agents;
preserving agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates,
butylated
hydroxytoluene, and butylated hydroxyanisole; sweetening agents; flavoring
agents; coloring
agents; and disintegrating agents (i.e., dissolving agents) such as
crospovidone as well as
croscarmellose sodium and other cross-linked cellulose polymers.
[0130] Lubricating agents can be used to prevent adhesion of the dosage form
to the
surface of the dies and punches, and to reduce inter-particle friction.
Lubricating agents may
also facilitate ejection of the dosage form from the die cavity and improve
the rate of
granulation flow during processing. Examples of suitable lubricating agents
include, without
limitation, magnesium stearate, calcium stearate, zinc stearate, stearic acid,
simethicone,
silicon dioxide, talc, hydrogenated vegetable oil, polyethylene glycol,
mineral oil, and
combinations thereof. The compositions of the present invention can comprise
from about
0% to about 10% by weight of the lubricating agent, and preferably from about
1% to about
5%.
[0131] Sweetening agents can be used to improve the palatability of the
composition by
masking any unpleasant tastes it may have. Examples of suitable sweetening
agents include,

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without limitation, compounds selected from the saccharide family such as the
mono-, di-,
iii-, poly-, and oligosaccharides; sugars such as sucrose, glucose (corn
syrup), dextrose,
invert sugar, fructose, maltodextrin, and polydextrose; saccharin and salts
thereof such as
sodium and calcium salts; cyclamic acid and salts thereof; dipeptide
sweeteners; chlorinated
sugar derivatives such as sucralose and dihydrochalcone; sugar alcohols such
as sorbitol,
sorbitol syrup, mannitol, xylitol, hexa-resorcinol, and the like, and
combinations thereof.
Hydrogenated starch hydrolysate, and the potassium, calcium, and sodium salts
of 3,6-
dihydro-6-methy1-1-1,2,3-oxathiazin-4-one-2,2-dioxide may also be used. Of the
foregoing,
sorbitol, mannitol, and xylitol, either alone or in combination, are preferred
sweetening
agents. The compositions of the present invention can comprise from about 0%
to about 80%
by weight of the sweetening agent, preferably from about 5% to about 75%, and
more
preferably from about 25% to about 50%.
[0132] Flavoring agents can also be used to improve the palatability of the
composition.
Examples of suitable flavoring agents include, without limitation, natural
and/or synthetic
(i.e., artificial) compounds such as peppermint, spearmint, wintergreen,
cinnamon, menthol,
cherry, strawberry, watermelon, grape, banana, peach, pineapple, apricot,
pear, raspberry,
lemon, grapefruit, orange, plum, apple, fruit punch, passion fruit, chocolate
(e.g., white, milk,
dark), vanilla, caramel, coffee, hazelnut, combinations thereof; and the like.
Coloring agents
can be used to color code the composition, for example, to indicate the type
and dosage of the
therapeutic agent therein. Suitable coloring agents include, without
limitation, natural and/or
artificial compounds such as FD & C coloring agents, natural juice
concentrates, pigments
such as titanium oxide, silicon dioxide, and zinc oxide, combinations thereof,
and the like.
The compositions of the present invention can comprise from about 0% to about
10% by
weight of the flavoring and/or coloring agent, preferably from about 0.1% to
about 5%, and
more preferably from about 2% to about 3%.
1. Chewing Gums
[0133] When the dosage form is a chewing gum, the compositions of the present
invention
comprise a hypnotic agent or a pharmaceutically acceptable salt thereof; a
carrier such as a
gum base, a binary or ternary buffer system, and optionally a protecting
agent. The chewing
gum composition may further comprise lubricating agents, wetting agents,
emulsifying
agents, solubilizing agents; suspending agents, Preserving agents, sweetening
agents,
flavoring agents, and coloring agents. Typically, the chewing gum composition
comprises
from about 0.001% to about 10.0% by weight of the hypnotic agent (in whatever
chosen
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form, measured as per its free base form), more typically from about 0.01% to
about 5.0%,
and still more typically from about 0.1% to about 3.0%. One skilled in the art
understands
that the foregoing percentages will vary depending upon the particular source
of hypnotic
agent utilized, the amount of hypnotic agent desired in the final formulation,
as well as on the
[0134] The chewing gum composition may further comprise a protecting agent.
The
protecting agent coats at least part of the therapeutic agent, typically upon
the mixing of the
two agents. The protecting agent may be mixed with the therapeutic agent in a
ratio of from
about 0.1 to about 100 by weight, preferably in a ratio of from about 1 to
about 50, and more
[0135] The gum base may additionally include plasticizers such as softeners or
emulsifiers.
Such plasticizers may, for example, help reduce the viscosity of the gum base
to a desirable
consistency and improve its overall texture and bite. Plasticizers may also
facilitate the
release of the therapeutic agent upon mastication. Non-limiting examples of
plasticizers
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[0136] The gum base may further comprise waxes such as beeswax and
microcrystalline
wax, fats or oils such as soybean and cottonseed oil, and combinations
thereof. Typically, the
gum base comprises from about 0% to about 25% by weight of these waxes and
oils, and
more typically comprises from about 15% to about 20%.
[0137] In addition, the gum base may further comprise one or more elastomeric
solvents
such as rosins and resins. Non-limiting examples of such solvents include
methyl, glycerol,
and pentaerythritol esters of rosins, modified rosins such as hydrogenated,
dimerized or
polymerized rosins, or combinations thereof (e.g., pentaerythritol ester of
partially
hydrogenated wood rosin, pentaerythritol ester of wood rosin, glycerol ester
of wood rosin,
glycerol ester of partially climerized rosin, glycerol ester of polymerized
rosin, glycerol ester
of tall oil rosin, glycerol ester of wood rosin and partially hydrogenated
wood rosin and
partially hydrogenated methyl ester of rosin such as polymers of alpha-pinene
or beta-pinene,
terpene resins including polyterpene, and combinations thereof). Typically,
the gum base
comprises from about 0% to about 75% of the elastomeric solvent, and more
typically less
than about 10%.
[0138] The gum base may further comprise a filler material to enhance the
chewability of
the final chewing gum composition. Fillers that are substantially non-reactive
with other
components of the final chewing gum formulation are preferable. Examples of
suitable fillers
include, without limitation, calcium carbonate, magnesium silicate (i.e.,
talc), dicalcium
phosphate, metallic mineral salts (e.g., alumina, aluminum hydroxide, and
aluminum
silicates), and combinations thereof. Typically, the gum base comprises from
about 0% to
about 30% by weight of the filler, and more typically from about 10% to about
20%.
[0139] One skilled in the art will appreciate that the gum base need not be
prepared from its
individual components. For example, the gum base can be purchased with the
desired
ingredients contained therein, and can be modified to include additional
agents. Several
manufacturers produce gum bases suitable for use with the described chewing
gum
compositions. Examples of such gum bases include, without limitation,
PharmagumTM M, S,
or C (SPI Pharma Group; New Castle, DE). In general, PharrnagumTM comprises a
mixture of
gum base, sweetening agent, plasticizer, and sugar.
[0140] In certain instances, the chewing gum composition includes a
therapeutic agent
centerfill. A centerfill may be particularly suitable when immediate release
of the therapeutic
agent is preferred. In addition, encapsulating the therapeutic agent in a
centerfill may help to
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CA 02556450 2011-11-23
mask any undesirable taste that the therapeutic agent may have. In these
instances, the gum
base surrounds, at least in part, a centerfill. The centerfill comprises at
least one therapeutic
agent, and may be a liquid or semi-liquid material. The centerfill material
can be a synthetic
polymer, a semi-synthetic polymer, low-fat, or fat-free and contain one or
more sweetening
includes a binary or ternary buffer system as described herein. Methods for
preparing a
center-fill chewing gum are described, for example, in U.S. Pat. No.
3,806,290.
[0141] The chewing gum compositions can have any desired shape, size, and
texture. For
2. Tablets
[01421 When the dosage form is a tablet such as a dissolving tablet (i.e.,
disintegrating
tablet) or chewable tablet, the compositions of the present invention comprise
a hypnotic
agent or a pharmaceutically acceptable salt thereof, a carrier such as a
binder, and a binary or
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10143] In certain embodiments, the tablet is a dissolving tablet such as a
slow-dissolving or
quick-dissolving tablet that is dissolved by a subject's saliva, without the
need for chewing.
For example, a dissolving tablet placed on the subject's tongue can be used
for buccal
delivery of the therapeutic agent. Alternatively, a dissolving tablet placed
underneath the
subject's tongue can be used for sublingual delivery of the therapeutic agent.
This type of
dosage form may be particularly desirable for pediatric and geriatric
patients, since small
children and aged individuals often have difficulty chewing certain items.
Typically, the
dissolving tablet is formulated to dissolve within about 1 to about 15
minutes, preferably
within about 2 to about 10 minutes, e.g., within about 2, 3, 4, 5, 6, 7, 8, 9,
or 10 minutes,
following administration. One skilled in the art will understand that quick-
dissolving tablets
dissolve faster than slow-dissolving tablets, which are typically dissolved
gradually rather
than rapidly by a subject's saliva. In a preferred embodiment, the slow-
dissolving or quick-
dissolving tablet delivers the therapeutic agent across the sublingual mucosa.
[0144] In certain other embodiments, the tablet is a chewable tablet that is
chewed by a
subject and formulated to dissolve either rapidly or gradually. For example, a
chewable
tablet placed on the subject's tongue can be used for buccal delivery of the
therapeutic agent.
During chewing, the chewable tablet can be moved around within the mouth and
can
sometimes be parked between the gums and the cheeks or underneath the tongue.
As a result,
at least a portion of the therapeutic agent contained within a chewable tablet
may also be
delivered sublingually (i.e., across the sublingual mucosa). Typically, the
chewable tablet is
formulated to dissolve within about 1 to about 15 minutes, preferably within
about 2 to about
10 minutes, e.g., within about 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes,
following administration.
[0145] As described above, the dissolving and chewable tablets of the present
invention are
typically formulated to dissolve within about 1 to 15 minutes following
administration.
However, while these time frames are amenable to maximum exposure of the
therapeutic
agent to the oral mucosa (e.g., to the sublingual and/or buccal mucosa), they
are not always
amenable to user compliance (e.g., users may swallow too frequently and,
therefore, hinder
maximal transmucosal absorption). Consequently, in certain instances, it may
be desirable to
strike a balance between patient compliance and maximum exposure time of the
therapeutic
agent to the oral mucosa. This can be accomplished, for example, by reducing
the tablet size
(e.g., from about 700-800 mg to about 200-300 mg) without reducing the
concentration or
amount per unit dose of the buffer system or the therapeutic agent. In
addition, subtle
changes to the tablet formulation such as, for example, replacing one
flavoring agent for

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another (e.g., chocolate for spearmint) or replacing one binder or sweetening
agent for
another (e.g., lactose for mannitol or sorbitol) may be used to reduce
salivation.
[0146] The carrier present in the tablets of the present invention is
typically a binder that is
useful in keeping the tablet in a semi-solid state, and may be a solid or a
liquid, and may for
example be a high-melting point fat or waxy material. Materials suitable as
binders are
discussed in detail above and may be used alone or in combination in the
tablet compositions
of the present invention. In addition, binders such as mannitol, sorbitol,
lactose, sucrose, and
inositol can impart properties to the tablet that permit or enhance its
disintegration in the
mouth.
[0147] The tablet composition may further comprise a protecting agent. The
protecting
agent coats at least part of the therapeutic agent, typically upon the mixing
of the two agents.
The protecting agent may be mixed with the therapeutic agent in a ratio of
from about 0.1 to
about 100 by weight, preferably in a ratio of from about 1 to about 50, and
more preferably in
a ratio of about 1 to about 10. Without being bound to any particular theory,
the protecting
agent reduces the adhesion between the therapeutic agent and the binder so
that the
therapeutic agent may be more easily released from the binder. In this way,
the therapeutic
agent may be delivered across the mucous membranes of the oral cavity within
about 5 to
about 20 minutes, preferably within about 10 minutes. Materials suitable as
protecting agents
are discussed in detail above and may be used alone or in combination in the
tablet
compositions of the present invention.
[0148] The tablet composition may also comprise one or more elastomeric
solvents such as
rosins and resins. Non-limiting examples of such solvents are discussed in
detail above and
may be used alone or in combination in the tablet compositions of the present
invention. In
addition, the tablet composition may further comprise waxes such as beeswax
and
microcrystalline wax, fats or oils such as soybean and cottonseed oil, and
combinations
thereof. Moreover, the tablet composition may additionally include
plasticizers such as
softeners or emulsifiers. Such plasticizers may, for example, help reduce the
viscosity of the
salivary solution of the dissolved tablet to a desirable consistency and
improve its overall
texture and bite and help facilitate the release of the therapeutic agent. Non-
limiting
examples of such plasticizers are discussed in detail above and may be used
alone or in
combination in the tablet compositions of the present invention.
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[0149] In certain instances, the tablet composition includes a therapeutic
agent centerfill. A
centerfill may be particularly suitable when immediate release of the
therapeutic agent is
preferred. In addition, encapsulating the therapeutic agent in a centerfill
may help to mask
any undesirable taste that the therapeutic agent may have. In these instances,
the binder
surrounds, at least in part, a centerfill. The centerfill comprises at least
one therapeutic agent,
and may be a liquid or semi-liquid material. The centerfill material can be a
synthetic
polymer, a semi-synthetic polymer, low-fat, or fat-free and contain one or
more sweetening
agents, flavoring agents, coloring agents, and/or scenting agents. Preferably,
the centerfill
includes a binary or ternary buffer system as described herein.
[0150] In certain other instances, the tablet composition of the present
invention is
multilayered. In this way, the dissolving or chewable tablet can be designed
to provide more
than one therapeutic agent, e.g., two or more hypnotic agents or one or more
hypnotic agents
in combination with one or more non-hypnotic therapeutic agents. For example,
with a bi-
layered tablet, the first layer contains a hypnotic agent and the second layer
contains the same
or different hypnotic agent or a non-hypnotic therapeutic agent. Typically,
the first layer
comprises the dissolving or chewable portion of the tablet, and the second
(i.e., subsequent)
layer is coated by the first layer. This type of formulation may be
particularly suitable when
immediate release of the hypnotic agent, followed by gastrointestinal
absorption of a second
therapeutic agent, is desirable. Gastrointestinal absorption of the second
therapeutic agent
may be desirable, for example, in order to mitigate co-morbid symptoms or to
sustain the
therapeutic benefit of the hypnotic agent in the dissolving or the chewable
portion of the
tablet. Alternatively, the second layer is present as a layer lateral to the
first layer. The
second layer typically comprises at least one therapeutic agent, and can also
comprise one or
more sweetening agents, flavoring agents, coloring agents, and scenting agents
as described
above. In some instances, the second layer further includes a binary or
ternary buffer system
as described herein.
[0151] In still other instances, the combination of hypnotic agents with or
without non-
hypnotic therapeutic agents need not take the form of a multilayered tablet,
but instead
comprises a single homogenous tablet layer. This type of formulation may also
be used in
the case where gastrointestinal absorption of at least one therapeutic agent
is desirable. In
this case, the relative extent of ionization of the two or more therapeutic
agents determines
how they are to be absorbed. For example, those therapeutic agents that are un-
ionized are
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. _
absorbed through the oral mucosa, while the ionized agents are swallowed for
gastrointestinal
absorption.
[01521 The tablet compositions can have any desired shape, size, and texture.
For example,
the tablet can have the shape of a stick, tab, pellet, sphere, and the like.
Similarly, the tablet
can be any desirable color. For example, the tablet can be any shade of red,
blue, green,
orange, yellow, violet, indigo, and mixtures thereof, and can be color coded
to indicate the
type and dosage of the therapeutic agent therein. The tablets can be
individually wrapped or
grouped together in pieces for packaging by methods well known in the art.
3. Lozenges
[01531 When the dosage form is a lozenge or candy, the compositions of the
present
invention comprise a hypnotic agent or a pharmaceutically acceptable salt
thereof, a carrier
such as a binder, and a binary or ternary buffer system. The lozenge or candy
composition
may further comprise lubricating agents, wetting agents, emulsifying agents,
solubilizing
agents; suspending agents, preserving agents, sweetening agents, flavoring
agents, coloring
agents, and disintegrating agents. A general discussion of lozenges and
candies is provided,
e.g., in Pharmaceutical Dosage Forms, Volume 1: Tablets, 2nd Ed., Marcel
Dekker, Inc.,
New York, N.Y., pages 75-418 (1989). Typically, the lozenge compositions of
the present
invention comprise from about 0.001% to about 10.0% by weight of the hypnotic
agent (in
whatever chosen form, measured as per its free base form), and more typically
from about
1.0% to about 5.0%. In some embodiments, about 4.5% by weight of the hypnotic
agent is
used. One skilled in the art understands that the foregoing percentages will
vary depending
upon the particular source of hypnotic agent utilized, the amount of hypnotic
agent desired in
the final formulation, as well as on the particular release rate of hypnotic
agent desired. The
binary or ternary buffer system of the lozenge composition provides for a
final salivary pH in
excess of at least about 7.8, preferably at least about 8.5, and more
preferably at least about 9
(e.g., about 9-11).
[0154] In certain embodiments, the lozenge or candy is dissolved by a
subject's saliva,
without the need for chewing. For example, a lozenge placed on the subject's
tongue can be
used for buccal delivery of the therapeutic agent. Alternatively, a lozenge
placed underneath
the subject's tongue can be used for sublingual delivery of the therapeutic
agent. This type of
dosage form may be particularly desirable for pediatric and geriatric
patients, since small
children and aged individuals often have difficulty chewing certain items.
Typically, the
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lozenge is formulated to dissolve within about 1 to about 15 minutes,
preferably within about
2 to about 10 minutes, e.g., within about 2, 3, 4, 5, 6, 7, 8, 9, or 10
minutes, following
administration. In a preferred embodiment, the lozenge or candy delivers the
therapeutic
agent across the sublingual mucosa.
[0155] As described above, the lozenges the present invention are typically
formulated to
dissolve within about 1 to 15 minutes following administration. However, while
these time
frames are amenable to maximum exposure of the therapeutic agent to the oral
mucosa (e.g.,
to the sublingual and/or buccal mucosa), they are not always amenable to user
compliance
(e.g., users may swallow too frequently and, therefore, hinder maximal
transmucosal
absorption). Consequently, in certain instances, it may be desirable to strike
a balance
between patient compliance and maximum exposure time of the therapeutic agent
to the oral
mucosa. This can be accomplished, for example, by reducing the lozenge size
(e.g., from
about 700-800 mg to about 200-300 mg) without reducing the concentration or
amount per
unit dose of the buffer system or the therapeutic agent. In addition, subtle
changes to the
lozenge formulation such as, for example, replacing one flavoring agent for
another (e.g.,
chocolate for spearmint) or replacing one binder or sweetening agent for
another (e.g., lactose
for mannitol or sorbitol) may be used to reduce salivation.
[0156] The carrier present in the lozenges of the present invention is
typically a binder that
is useful in keeping the lozenge in a semi-solid state, and may be a solid or
a liquid, and may
for example be a high-melting point fat or waxy material. Materials suitable
as binders are
discussed in detail above and may be used alone or in combination in the
lozenge
compositions of the present invention. In addition, binders such as mannitol,
sorbitol,
lactose, sucrose, and inositol can impart properties to the lozenge that
permit or enhance its
disintegration in the mouth.
[0157] The lozenge composition may further comprise a protecting agent. The
protecting
agent coats at least part of the therapeutic agent, typically upon the mixing
of the two agents.
The protecting agent may be mixed with the therapeutic agent in a ratio of
from about 0.1 to
about 100 by weight, preferably in a ratio of from about 1 to about 50, and
more preferably in
a ratio of about 1 to about 10. Without being bound to any particular theory,
the protecting
agent reduces the adhesion between the therapeutic agent and the binder so
that the
therapeutic agent may be more easily released from the binder. In this way,
the therapeutic
agent may be delivered across the mucous membranes of the oral cavity within
about 5 to
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about 20 minutes, preferably within about 10 minutes. Materials suitable as
protecting agents
are discussed in detail above and may be used alone or in combination in the
lozenge
compositions of the present invention.
[0158] The lozenge composition may also comprise one or more elastomeric
solvents such
as rosins and resins. Non-limiting examples of such solvents are discussed in
detail above
and may be used alone or in combination in the tablet compositions of the
present invention.
In addition, the lozenge composition may further comprise waxes such as
beeswax and
microcrystalline wax, fats or oils such as soybean and cottonseed oil, and
combinations
thereof. Moreover, the lozenge composition may additionally include
plasticizers such as
softeners or emulsifiers. Such plasticizers may, for example, help reduce the
viscosity of the
salivary solution of the dissolved lozenge to a desirable consistency and
improve its overall
texture and bite and help facilitate the release of the therapeutic agent. Non-
limiting
examples of such plasticizers are discussed in detail above and may be used
alone or in
combination in the lozenge compositions of the present invention.
[0159] In certain instances, the lozenge composition includes a therapeutic
agent centerfill.
A centerfill may be particularly suitable when immediate release of the
therapeutic agent is
preferred. In addition, encapsulating the therapeutic agent in a centerfill
may help to mask
any undesirable taste that the therapeutic agent may have. In these instances,
the binder
surrounds, at least in part, a centerfill. The centerfill comprises at least
one therapeutic agent,
and may be a liquid or semi-liquid material. The centerfill material can be
low-fat or fat free
and contain one or more sweetening agents, flavoring agents, coloring agents,
and/or scenting
agents. Preferably, the centerfill includes a binary or ternary buffer system
as described
herein.
[0160] In certain other instances, the lozenge composition of the present
invention is
multilayered. In this way, the lozenge can be designed to provide more than
one therapeutic
agent, e.g., two or more hypnotic agents or one or more hypnotic agents in
combination with
one or more non-hypnotic therapeutic agents. For example, with a bi-layered
lozenge, the
first layer contains a hypnotic agent and the second layer contains the same
or different
hypnotic agent or a non-hypnotic therapeutic agent. Typically, the first layer
comprises the
dissolving portion of the lozenge, and the second (i.e., subsequent) layer is
coated by the first
layer. This type of formulation may be particularly suitable when immediate
release of the
hypnotic agent, followed by gastrointestinal absorption of a second
therapeutic agent, is

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desirable. Gastrointestinal absorption of the second therapeutic agent may be
desirable, for
example, in order to mitigate co-morbid symptoms or to sustain the therapeutic
benefit of the
hypnotic agent in the dissolving portion of the lozenge. Alternatively, the
second layer is
present as a layer lateral to the first layer. The second layer typically
comprises at least one
therapeutic agent, and can also comprise one or more sweetening agents,
flavoring agents,
coloring agents, and scenting agents as described above. In some instances,
the second layer
further includes a binary or ternary buffer system as described herein.
[0161] In still other instances, the combination of hypnotic agents with or
without non-
hypnotic therapeutic agents need not take the form of a multilayered lozenge,
but instead
comprises a single homogenous lozenge layer. This type of formulation may also
be used in
the case where gastrointestinal absorption of at least one therapeutic agent
is desirable. In
this case, the relative extent of ionization of the two or more therapeutic
agents determines
how they are to be absorbed. For example, those therapeutic agents that are un-
ionized are
absorbed through the oral mucosa, while the ionized agents are swallowed for
gastrointestinal
absorption.
[0162] The lozenge compositions can have any desired shape, size, and texture.
For
example, the lozenge can have the shape of a stick, tab, pellet, sphere, and
the like. Similarly,
the lozenge can be any desirable color. For example, the lozenge can be any
shade of red,
blue, green, orange, yellow, violet, indigo, and mixtures thereof, and can be
color coded to
indicate the type and dosage of the therapeutic agent therein. The lozenges
can be
individually wrapped or grouped together in pieces for packaging by methods
well known in
the art.
D. Methods of Administration
[0163] The compositions of the present invention are useful in therapeutic
applications,
e.g., for treating a sleep disorder. Importantly, the compositions of the
present invention
provide the rapid and predictable delivery of a hypnotic agent across the oral
mucosa with
surprisingly low inter-subject variability in terms of maximum plasma
concentration (Cm)
and the time to reach the maximum plasma concentration (T.) by raising the pH
of saliva to
a pH greater than about 7.8, irrespective of the starting pH of saliva. In
particular, the
delivery of the therapeutic agent across the oral mucosa avoids hepatic first
pass metabolism,
degradation within the gastrointestinal tract, and drug loss during
absorption. As a result, the
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therapeutic agent reaches the systemic circulation in a substantially shorter
period of time and
at a substantially higher concentration than with traditional oral (e.g.,
tablet) administration.
[01641 In addition, the compositions of the present invention offer advantages
over
compositions for oral mucosal administration that do not contain the buffer
system described
herein. In particular, because the buffer system in the compositions of the
present invention
helps convert substantially all of the therapeutic agent from its ionized form
to its un-ionized
form, the therapeutic agent reaches the systemic circulation in a
substantially shorter period
of time (e.g., reducing the time to onset of therapeutic activity) and at a
substantially higher
concentration than with compositions for oral mucosal administration that do
not contain the
buffer system.
[0165] The compositions of the present invention have particular utility in
the area of
human and veterinary therapeutics. Generally, administered dosages will be
effective to
deliver picomolar to micromolar concentrations of the hypnotic agent to the
appropriate site.
[0166] Administration of the compositions of the present invention is
preferably carried out
via any of the accepted modes of administration to the mucous membranes of the
oral cavity.
Examples of suitable sites of administration within the oral mucosa include,
without
limitation, the mucous membranes of the floor of the mouth (sublingual
mucosa), the cheeks
(buccal mucosa), the gums (gingival mucosa), the roof of the mouth (palatal
mucosa), the
lining of the lips, and combinations thereof. These regions differ from each
other with
respect to their anatomy, drug permeability, and physiological response to
drugs. Preferably,
the compositions of the present invention are administered to the sublingual
mucosa, buccal
mucosa, or a combination thereof.
[0167] The oral mucosa, possessing a rich blood supply and suitable drug
permeability, is
an especially attractive route of administration for systemic drug delivery.
Furthermore,
delivery of a therapeutic agent across the oral mucosa bypasses hepatic first
pass metabolism,
avoids enzymatic degradation within the gastrointestinal tract, and provides a
more suitable
enzymatic flora for drug absorption. As used herein, the term "sublingual
delivery" refers to
the administration of a therapeutic agent across the mucous membranes lining
the floor of the
mouth and/or the ventral tongue. The term "buccal delivery" as used herein
refers to the
administration of a therapeutic agent across the mucous membranes lining the
cheeks.
[0168] The oral mucosa is composed of an outermost layer of stratified
squamous
epithelium. Beneath this layer lies a basement membrane, i.e., the lamina
propria, followed
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by the submucosa as the innermost layer. The epithelium of the oral mucosa is
similar to the
stratified squamous epithelia found in the rest of the body in that it
contains a mitotically
active basal cell layer, advancing through a number of differentiating
intermediate layers to
the superficial layers, where cells are shed from the surface of the
epithelium (Gandhi et al.,
Ind. J. Pharm. Sci., 50:145-152 (1988)). For example, the epithelium of the
buccal mucosa is
about 40-50 cell layers thick, while that of the sublingual epithelium
contains somewhat
fewer cell layers. The epithelial cells increase in size and become flatter as
they travel from
the basal layers to the superficial layers.
[0169] The turnover time for buccal mucosal epithelium, estimated at 5-6 days,
is
representative of the turnover time for sublingual mucosal epithelium as well
as other
epithelia in the oral mucosa (Harris et aL, Pharm. Sci., 81:1-10 (1992)). The
thickness of
the oral mucosa varies depending on the site in the oral cavity. For example,
the buccal
mucosa measures at about 500-800 gm in thickness, while the hard and soft
palatal mucosa,
the sublingual mucosa, the ventral tongue, and the gingival mucosa measure at
about 100-200
p.m in thickness. The composition of the epithelium also varies depending on
the site in the
oral cavity. For example, the mucosae of areas subject to mechanical stress
(i.e., the gingivae
and hard palate) are keratinized similar to the epidermis. However, the
mucosae of the soft
palate, the sublingual region, and the buccal region are not keratinized
(Harris et al., supra).
The keratinized epithelia contain neutral lipids like ceramides and
acylceramides, which have
been associated with providing a barrier function. As a result, these
epithelia are relatively
impermeable to water. In contrast, non-keratinized epithelia, such as
sublingual and buccal
epithelia, do not contain acylceramides and have only small amounts of
cerarnide (Wertz et
al., Crit. Rev. Ther. Drug Carr. Sys., 8:237-269 (1991); Squier et al., .1
Invest. Dermat.,
96:123-126 (1991); Squier et al., in Oral Mucosal Drug Delivery, Ed. M. J.
Rathbone,
Marcel Dekker, Inc., New York, New York, 1-26 (1996)). Non-keratinized
epithelia also
contain small amounts of neutral but polar lipids, e.g., cholesterol sulfate
and glucosyl
ceramides. As such, these epithelia have been found to be considerably more
permeable to
water than keratinized epithelia (Harris et al., supra; Wertz et aL, supra;
Squier et al., supra,
1991).
[0170] In general, the oral mucosa is a somewhat leaky epithelia intermediate
between that
of the epidermis and intestinal mucosa. For example, the permeability of the
buccal mucosa
is estimated to be about 4-4000 times greater than that of skin (Galey et al.,
J Invest.
Dermat., 67:713-717 (1976)). The permeability of different regions of the oral
mucosa
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generally decrease in the order of sublingual mucosa greater than buccal
mucosa, and buccal
mucosa greater than palatal mucosa (Harris et al., supra). This permeability
is generally
based upon the relative thickness and degree of keratinization of these
membranes, with the
sublingual mucosa being relatively thin and non-keratinized, the buccal mucosa
being thicker
and non-keratinized, and the palatal mucosa being intermediate in thickness,
but keratinized.
[0171] The epithelial cells of the oral mucosa are surrounded by mucus
comprising
primarily complexes of proteins and carbohydrates that may or may not be
attached to certain
regions on the cell surface. The mucus may play a role in cell-cell adhesion,
as well as acting
as a lubricant, allowing cells to move relative to one another (Tabak et al.,
J. Oral Pathol.,
11:1-17 (1982)). In stratified squamous epithelia found elsewhere in the body,
mucus is
synthesized by specialized mucus secreting cells such as goblet cells;
however, in the oral
mucosa, mucus is secreted by the major and minor salivary glands as part of
saliva (Tabak et
al., supra; Rathbone et al., Adv. Drug Del. Rev., 13:1-22 (1994)). At
physiological pH, the
mucus network carries a negative charge due to the sialic acid and sulfate
residues present on
the carbohydrates. At this pH, mucus can form a strongly cohesive gel
structure that binds to
the epithelial cell surface as a gelatinous layer (Gandhi et al., supra).
Without being bound to
any particular theory, the buffer systems of the present invention neutralize
the sialic acid
residues present on the carbohydrates and prevent them from interacting with
the therapeutic
agent, thereby further enhancing drug permeation.
[0172] Another feature of the environment of the oral cavity is the presence
of saliva
produced by the salivary glands. Saliva is the protective fluid for all
tissues of the oral
cavity. Saliva is an aqueous fluid with about 1% organic and inorganic
materials. The major
determinant of the salivary composition is the flow rate, which in turn
depends upon factors
such as the time of day, the type of stimulus, and the degree of stimulation.
The salivary pH
typically ranges from about 5.5 to about 7.0, depending on the flow rate. For
example, at
high flow rates, the sodium and bicarbonate concentrations increase, leading
to an increase in
the pH. Because the daily salivary volume is between about 0.5 to about 2
liters, the oral
cavity provides an aqueous environment for the hydration and/or dissolution of
the oral
mucosal dosage forms of the present invention.
[0173] The sublingual mucosa is the most highly permeable region of the oral
cavity, and
provides rapid absorption and high bio availability of a drug in a convenient,
accessible, and
well-accepted route of administration (Harris et al., supra). Suitable
sublingual dosage forms
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include, without limitation, tablets (e.g., quick-dissolving, slow-
dissolving), lozenges, candy,
and soft gelatin capsules filled with liquid drug. Such systems create a very
high drug
concentration in the sublingual region before they are systemically absorbed
across the
sublingual mucosa. As a result, the sublingual mucosa is particularly well-
suited for
producing a rapid onset of action, and sublingual dosage forms can be used to
deliver drags
with shorter delivery period requirements and/or less frequent dosing
regimens. Although the
buccal mucosa is considerably less permeable than the sublingual area, rapid
absorption and
high bio availability of a drug can also be observed with buccal
administration. Suitable
buccal dosage forms include, without limitation, chewing gums, tablets (e.g.,
quick-
dissolving, slow-dissolving), lozenges, candy, and the like. Both the buccal
mucosa and the
sublingual mucosa are far superior to the gastrointestinal tract for providing
increased
absorption and bioavailability of a drug.
[0174] To increase the permeability of drugs through the oral mucosa,
penetration
enhancers can be included in the dosage forms of the present invention. The
penetration
enhancers may be of the type that alters the nature of the oral mucosa to
enhance penetration,
or of the type that alters the nature of the therapeutic agent to enhance
penetration through the
oral mucosa. Suitable penetration enhancers include, without limitation,
polyoxyethylene 23-
lauryl ether, aprotin, azone, benzalkonium chloride, cetylpyridinium chloride,
cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, lauric acid,
propylene
glycol, lysophosphatidylcholine, menthol, methoxysalicylate, methyloleate,
oleic acid,
phosphatidylcholine, polyoxyethylene, polysorbate 80, sodium
ethylenediaminetetraacetic
acid ("EDTA"), sodium deoxycholate, sodium glycocholate, sodium
glycodeoxycholate,
sodium lauryl suflate, sodium salicylate, sodium taurocholate, sodium
taurodeoxycholate, as
well as certain sulfoxides and glycosides, and combinations thereof.
IV. Examples
[0175] The following examples are offered to illustrate, but not to limit, the
claimed
invention.
Example 1. Zolpidem Membrane Assay.
[0176] This example illustrates the beneficial effects of pH adjustment on
membrane
penetration for a zolpidem dosage form.
[0177] The effect of pH adjustment on the extent of ionization, and hence, the
extent to
which a therapeutic agent will traverse the mucous membrane can be
demonstrated using a

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membrane assay; see, e.g., Kansy et al., J. Med. Chem., 41:1007-1010 (1998);
and Avdeef,
Cum Topics Med. Chem., 1:277-351 (2001). This assay uses a lipid-coated
membrane to
predict lipid mucosal membrane penetration. The membrane apparatus consists of
a
dodecane membrane sandwiched between a donor and acceptor cell. The lipid-
coated
membrane is less porous then the mucous membrane of the oral cavity. Thus, the
enhancement seen in the membrane assay is very likely to be magnified in vivo.
[0178] Membrane assays were performed using zolpidem tartrate solutions at a
pH of 5.8,
6.8, and 7.8. The alkaline pH values of 7.8 were adjusted using freshly
prepared 0.01 M
sodium bicarbonate/sodium carbonate buffer solution. The acidic pH of 5.8 was
achieved
using a 0.01 M acetate buffer solution (a mixture of sodium acetate and acetic
acid). The
neutral pH of 6.8 was achieved by adding 0.01 M acetate solution to the sodium
bicarbonate/sodium carbonate buffer solution. Permeation through the membrane
was
measured by determining the concentration of zolpidem in the acceptor cell and
is expressed
as Pe (effective permeability in centimeters per second). As shown in Table 1
below, the
effective permeability of zolpidem increased by more than 53% at a pH of 7.8
relative to a
pH of 6.8 and 129% relative to a pH of 5.8. Figure 1 shows a bar chart
illustrating the
relationship between pH and zolpidem membrane permeability.
Table 1: Effective permeability (Pe) of zolpidem in a membrane assay.
pH Pe (cm/0
5.8 19.8
6.8 29.6
7.8 45.3
Example 2. Zolpidem Gum Compositions.
[0179] This example illustrates the zolpidem chewing gum compositions of the
present
invention.
[0180] Zolpidem can be formulated as a chewing gum composition as described
above. In
these embodiments, the unit dose or serving of the chewing gum comprises from
about 0.1 to
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about 100 milligrams (mg) zolpidem (as measured in its tartrate salt form),
preferably from
about 1 to about 50 mg, and more preferably from about 2 to about 25 mg. In
other
embodiments, the unit dose comprises from about 2 to about 20 mg zolpidem,
preferably
from about 5 to about 15 mg. Extra zolpidem, for example, up to from about 10%
to about
25% by weight, can be added as "overage" or as the amount that may be expected
to be
"washed away" and not otherwise released or absorbed during mastication.
[0181] In another embodiment, the unit dose or serving of the chewing gum
comprises
from about 0.81 to about 42 mg zolpidem in its base form, and more preferably
from about
1.64 to about 20.5 mg. In other embodiments, the unit dose comprises from
about 1.64 to
about 16.4 mg zolpidem in its free base form, preferably from about 1.64 to
about 12.3 mg,
and more preferably from about 1.64 to about 8.2 mg, e.g., about 1.64, 2.46,
3.28, 4.1,4.92,
5.78, 6.56, 7.38, or 8.2 mg. In additional embodiments, the unit dose
comprises a mixture of
zolpidem in free base form and salt form (e.g., zolpidem tartrate).
[0182] Given in weight percentages, the zolpidem chewing gum composition
comprises
from about 0.001% to about 10.0% zolpidem (in whatever chosen form, measured
as per its
free base form), preferably from about 0.05% to about 2.0%, and more
preferably from about
0.1% to about 1.0%. In some embodiments, about 0.25% zolpidem is used. One
skilled in
the art understands that the foregoing percentages will vary depending upon
the particular
source of zolpidem utilized, the amount of zolpidem desired in the final
formulation, as well
as on the particular release rate of zolpidem desired. The buffer system of
the zolpidem
chewing gum composition provides for a final salivary pH in excess of at least
about 7.8,
preferably at least about 8.5, and more preferably at least about 9 (e.g.,
about 9-11).
[0183] A zolpidem chewing gum was made according to the following procedure.
Silicon
dioxide USP (0.35 kg) was passed through a #20 mesh screen, and then loaded
into a blender
containing 0.810 kg mannitol granular USP and 9.569 kg PharmagumTM C. The
material was
blended for 10 minutes. Zolpidem tartrate EP (0.034 kg) was ground with the
silicon dioxide
(0.02 kg) using a mortar and pestle. The remaining silicon dioxide, along with
0.228 kg
magnesium stearate, was added into the mortar while continuing to grind. The
ground
materials were transferred into a plastic bag, and the mortar was rinsed using
0.01 kg silicone
dioxide, and transferred into the bag. The contents of the bag were then
blended for five
minutes.
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[0184] Equal parts of the blended bag contents and the blended mannitol gum
base mixture
were blended for an additional five minutes. This process was repeated until
all the zolpidem
and gum base mixture had been blended together. Sodium carbonate (0.110 kg),
sodium
bicarbonate (0.570 kg), gum acacia (0.43 kg), xanthan gum (0.013 kg), and
aspartame (0.072
kg) were then loaded into the blender along with natural and artificial
flavors and blended for
ten minutes with 0.090 kg of silicon dioxide. The flavors used were as
follows: natural and
artificial grape flavor S.D. (0.215 kg), natural and artificial cherry flavor
(0.108 kg), natural
and artificial fruit punch flavor S.D. (0.180 kg), natural cherry WONF
DLTRAROME flavor
(0.215 kg), and natural passion fruit type DURAROMEn flavor (0.035 kg).
[0185] The blend was passed through a #12 mesh screen and then blended for an
additional
minutes. Magnesium stearate (0.114 kg) was passed through a #20 mesh screen
and
added to the blend and blended for five minutes. The blend was collected and
placed in
plastic bags. Two silica gel desiccant bags were placed around the plastic
bags to absorb
ambient moisture. The blend was then compressed into tablets. By using the
above-
15 described procedure, the average particle size of the drug (i.e.,
zolpidem) in the chewing gum
is about 20 microns, as compared to a typical average drug particle size of
from about 75 to
about 100 microns. In addition, the average particle size of the drug in the
chewing gum is
less than or equal to the average particle size of the carrier ingredients
(e.g., gum base,
binders, etc.).
[0186] The zolpidem chewing gum composition of the present invention can be
used, e.g.,
for treatment of insomnia; see, Holm et al., Drugs, 59:865-889 (2000). In
certain instances,
after the introduction of a serving size piece of the chewing gum composition
into the mouth,
the subject chews the chewing gum as is normally done with any non-medicated
type of
chewing gum for about 5 to about 20 minutes, at approximately an average rate
of about 10 to
about 45 chews per minute. The gum is then discarded.
[0187] A typical dosage form of the zolpidem chewing gum of the present
invention is
designed to produce an average plasma concentration of at least from about 20
to about 300
nanograms of zolpidem per milliliter of plasma. For example, a 5 mg zolpidem
chewing gum
can be designed to produce a mean peak plasma concentration within the range
of from about
20 to about 100 nanograms of zolpidem per milliliter of plasma within about 5
minutes to
about 2 hours. Similarly, a 10 mg zolpidem chewing gum can be designed to
produce a mean
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peak plasma concentration within the range of from about 100 to about 300
nanograms of
zolpidem per milliliter of plasma within about 5 minutes to about 2 hours.
[0188] The chewing gum compositions of the present invention provide a
convenient,
reliable, practical, and painless system for delivering zolpidem across the
oral mucosa.
carrier.
Example 3. Zolpidem Tablet Compositions.
[0189] This example illustrates the slow-dissolving, quick-dissolving, and
chewable
zolpidem tablet compositions of the present invention.
[0190] Zolpidem can be formulated as a tablet composition as described above.
In these
[0191] In another embodiment, the unit dose or serving of the tablet comprises
from about
0.81 to about 42 mg zolpidem in its base form, and more preferably from about
1.64 to about
zolpidem in its free base form, preferably from about 1.64 to about 12.3 mg,
and more
preferably from about 1.64 to about 8.2 mg, e.g., about 1.64, 2.46, 3.28, 4.1,
4.92, 5.78, 6.56,
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7.38, or 8.2 mg. In additional embodiments, the unit dose comprises a mixture
of zolpidem
in free base form and salt form (e.g., zolpidem tartrate).
[0192] Given in weight percentages, the zolpidem tablet composition comprises
from about
0.001% to about 10.0% zolpidem (in whatever chosen form, measured as per its
free base
form), preferably from about 0.1% to about 8.0%, more preferably from about
1.0% to about
7.0%, and still more preferably from about 1.0% to about 5.0%. In some
embodiments, about
4.0% zolpidem is used. One skilled in the art understands that the foregoing
percentages will
vary depending upon the particular source of zolpidem utilized, the amount of
zolpidem
desired in the final formulation, as well as on the particular release rate of
zolpidem desired.
The buffer system of the zolpidem tablet composition provides for a final
salivary pH in
excess of at least about 7.8, preferably at least about 8.5, and more
preferably at least about 9
(e.g., about 9-11).
Zolpidem slow-dissolving tablets:
[01931 A zolpidem slow-dissolving tablet was made according to the following
procedure.
Magnesium stearate USP (0.35 kg) was passed through a 420 mesh screen, and
then loaded
into a blender containing 0.810 kg mannitol granular USP and 9.569 kg
sorbitol. The
material was blended for 10 minutes. Zolpidem tartrate EP (0.034 kg) was
ground with the
magnesium stearate (0.02 kg) using a mortar and pestle. The remaining silicon
dioxide,
along with 0.228 kg magnesium stearate was added into the mortar while
continuing to grind.
The ground materials were transferred into a plastic bag, and the mortar was
rinsed using
0.01 kg silicone dioxide, and transferred into the bag. The contents of the
bag were then
blended for five minutes.
[01941 Equal parts of the blended bag contents and the blended mannitol
mixture were
blended for an additional five minutes. This process was repeated until all
the zolpidem and
mannitol mixture had been blended together. Sodium carbonate (0.110 kg),
sodium
bicarbonate (0.570 kg), gum acacia (0.43 kg), xanthan gum (0.013 kg), and
aspartame (0.072
kg) were then loaded into the blender with natural and artificial flavors and
blended for ten
minutes with 0.090 kg of silicon dioxide. The flavors used were as follows:
natural and
artificial grape flavor S.D. (0.215 kg), natural and artificial cherry flavor
(0.108 kg), natural
and artificial fruit punch flavor S.D. (0.180 kg), natural cherry WONF
DURAROME flavor
(0.215 kg), and natural passion fruit type DURAROME flavor (0.035 kg).

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[0195] The blend was passed through a #12 mesh screen and then blended for an
additional
15 minutes. Magnesium stearate (0.114 kg) was passed through a #20 mesh screen
and
added to the blend and blended for fiye minutes. The blend was collected and
placed in
plastic bags. Two silica gel desiccant bags were placed around the plastic
bags to absorb
ambient moisture. The blend was then compressed into tablets. By using this
procedure, the
average particle size of the drug (i.e., zolpidem) in the slow-dissolving
tablet is about 20
microns, as compared to a typical average drug particle size of from about 75
to about 100
microns. In addition, the average particle size of the drug in the slow-
dissolving tablet is less
than or equal to the average particle size of the carrier ingredients (e.g.,
gum base, binders,
etc.).
[0196] A second zolpidem slow-dissolving tablet was made according to the
formulation
shown in Table 2 and the following procedure. Three separate blends of silicon
dioxide with
zolpidem, sodium bicarbonate, and sodium carbonate; maimitol and sorbitol; and
spearmint
flavor, sucralose, stearic acid, and magnesium stearate were prepared. The
three blends were
screened separately and mixed to form a single blend. The single blend was
then compressed
into tablets after testing for content uniformity. By using this procedure,
the average particle
size of the drug (i.e., zolpidem) in the slow-dissolving tablet is about 20
microns, which is
less than or equal to the average particle size of the carrier ingredients
(e.g., gum base,
binders, etc.). The unit weight for each tablet was 250 mg. The pH of the
tablet was about
9.8 and remained stable. These tablets dissolve within about 10 minutes
following sublingual
administration.
Table 2. Zolpidem slow-dissolving tablet formulation.
Material Unit Quantity (mg) Batch Quantity (g)
Sodium Carbonate, NF 17.000 357.000
Sodium Bicarbonate USP 23.000 483.000
Zolpidem Tartrate, EP 10.000 210.000
Mannitol, USP 40.000 840.000
Sorbitol, NF 136.000 2856.000
Natural & Artificial Spearmint 6.500 136.500
Flavor
Sucralose, NF 1.000 21.000
Silicon Dioxide, USP 5.500 115.500
Stearic Acid, NF 3.500 73.500
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Magnesium Stearate, NF 7.500 157.500
The batch quantity formulation produces 21,000 unit doses.
Zolpidem quick-dissolving tablets:
[0197] A zolpidem quick-dissolving tablet was made according to the following
procedure.
Mannitol (3.633 kg) and sorbitol (0.469 kg) were blended for ten minutes.
Sodium carbonate
(0.330 kg), sodium bicarbonate (0.165 kg), natural peppermint flavor (0.125
kg), natural
menthol flavor (0.025 kg), and sucralose (0.020 kg) were blended separately
for ten minutes.
Magnesium stearate (0.075 kg), and zolpidem tartrate (0.034 kg) were blended
for ten
minutes and then passed through a #12 mesh screen. The blended mixtures were
then added
together and compressed into tablets. By using this procedure, the average
particle size of the
drug (i.e., zolpidem) in the quick-dissolving tablet is about 20 microns, as
compared to a
typical average drug particle size of from about 75 to about 100 microns. In
addition, the
average particle size of the drug in the quick-dissolving tablet is less than
or equal to the
average particle size of the carrier ingredients (e.g., gum base, binders,
etc.).
[0198] A second zolpidem quick-dissolving tablet was made according to the
formulation
shown in Table 3 and the following procedure. Three separate blends of silicon
dioxide with
zolpidem, sodium carbonate, and sodium bicarbonate; mannitol and sorbitol; and
polyethylene glycol, spearmint flavor, sucralose, magnesium stearate,
crospovidone, and
croscarmellose sodium were prepared. The three blends were screened separately
and mixed
to form a single blend. The single blend was then compressed into tablets
after testing for
content uniformity. By using this procedure, the average particle size of the
drug (i.e.,
zolpidem) in the quick-dissolving tablet is about 20 microns, which is less
than or equal to
the average particle size of the carrier ingredients (e.g., gum base, binders,
etc.). The unit
weight for each tablet was 250 mg. The pH of the tablet was about 9.8 and
remained stable.
These tablets dissolve within about 5 minutes following sublingual
administration.
Table 3. Zolpidem quick-dissolving tablet formulation.
Material Unit Quantity (mg) Batch Quantity (g)
Sodium Carbonate, NF 17.000 357.000
Sodium Bicarbonate USP 23.000 483.000
Zolpidem Tartrate, EP 10.000 210.000
Mannitol, USP 40.000 840.000
Sorbitol, NF 103.500 2173.500
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Crospovidone, NF 12.500 262.500
Croscarmellose Sodium, NF 12.500 262.500
Polyethylene Glycol 3350, NF 12.500 262.500
Natural & Artificial Spearmint 6.500 136.500
Flavor
Sucralose, NF 1.000 21.000
Silicon Dioxide, USP 8.500 178.500
Magnesium Stearate, NF 3.000 63.000
The batch quantity formulation produces 21,000 unit doses.
Zolpidem chewable tablets:
[0199] A zolpidem chewable tablet was made according to the following
procedure.
Magnesium stearate USP (0.35 kg) was passed through a #20 mesh screen, and
then loaded
into a blender containing 0.810 kg mannitol granular USP, 9.569 kg sorb itol,
and 0.020 kg
stearic acid. The material was blended for 10 minutes. Zolpidem tartrate EP
(0.034 kg) was
ground with the magnesium stearate (0.02 kg) using a mortar and pestle. The
remaining
silicon dioxide, along with 0.228 kg magnesium stearate was added into the
mortar while
continuing to grind. The ground materials were transferred into a plastic bag,
and the mortar
was rinsed using 0.01 kg silicone dioxide, and transferred into the bag. The
contents of the
bag were then blended for five minutes.
[0200] Equal parts of the blended bag contents and the blended mannitol
mixture were
blended for an additional five minutes. This process was repeated until all
the zolpidem and
mannitol mixture had been blended together. Sodium carbonate (0.110 kg),
sodium
bicarbonate (0.570 kg), gum acacia (0.43 kg), xanthan gum (0.013 kg), and
aspartame (0.072
kg) were then loaded into the blender with natural and artificial flavors and
blended for ten
minutes with 0.090 kg of silicon dioxide. The flavors used were as follows:
natural and
artificial grape flavor S.D. (0.215 kg), natural and artificial cherry flavor
(0.108 kg), natural
and artificial fruit punch flavor S.D. (0.180 kg), natural cherry WONF
DURAROME flavor
(0.215 kg), and natural passion fruit type DURAROME flavor (0.035 kg).
[0201] The blend was passed through a #12 mesh screen and then blended for an
additional
15 minutes. Magnesium stearate (0.114 kg) was passed through a #20 mesh screen
and
added to the blend and blended for five minutes. The blend was collected and
placed in
plastic bags. Two silica gel desiccant bags were placed around the plastic
bags to absorb
ambient moisture. The blend was then compressed into tablets. By using this
procedure, the
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average particle size of the drug (i.e., zolpidem) in the chewable tablet is
about 20 microns, as
compared to a typical average drug particle size of from about 75 to about 100
microns. In
addition, the average particle size of the drug in the chewable tablet is less
than or equal to
the average particle size of the carrier ingredients (e.g., gum base, binders,
etc.).
treatment of insomnia. In certain instances, after the introduction of a
chewable tablet into
the mouth, the subject chews the chewable tablet as is normally done with any
non-medicated
type of chewable tablet at approximately an average rate of about 10 to about
45 chews per
minute. In certain other instances, after the introduction of a dissolving
tablet into the mouth,
[0203] A typical dosage form of the zolpidem tablet of the present invention
is designed to
produce an average plasma concentration of at least from about 20 to about 300
nanograms of
zolpidem per milliliter of plasma. For example, a 5 mg zolpidem tablet can be
designed to
practical, and painless system for delivering zolpidem across the oral mucosa.
Notably, the
tablet compositions are capable of rapidly delivering zolpidem with low inter-
subject
variability in terms of maximum plasma concentration (C.) and the time to
reach the
maximum plasma concentration (T.) so that a therapeutically effective amount
of zolpidem
Example 4. Zolpidem Lozenge Compositions.
[0205] This example illustrates the zolpidem lozenge compositions of the
present
invention.
In these embodiments, the unit dose or serving of the lozenge comprises from
about 0.1 to
about 100 milligrams (mg) zolpidem (as measured in its tartrate salt form),
preferably from
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about 1 to about 50 mg, and more preferably from about 2 to about 25 mg. In
other
embodiments, the unit dose comprises from about 2 to about 20 mg zolpidem,
preferably
from about 2 to about 15 mg, and more preferably from about 2 to about 10 mg,
e.g., about 2,
3, 4, 5, 6, 7, 8, 9, or 10 mg. In particularly preferred embodiments, the unit
dose comprises a
dose of zolpidem that is less than the dose typically used in commercial oral
tablets, but
possesses comparable or greater bioavailability and onset of therapeutic
activity as well as
lower inter-subject variability of drug absorption. In such embodiments, unit
doses of from
about 2 to about 5 mg zolpidem are preferred, with unit doses of about 4 mg
zolpidem being
particularly preferred. Extra zolpidem, for example, up to from about 10% to
about 25% by
[0207] In another embodiment, the unit dose or serving of the lozenge
comprises from
about 0.81 to about 42 mg zolpidem in its base form, and more preferably from
about 1.64 to
about 20.5 mg. In other embodiments, the unit dose comprises from about 1.64
to about 16.4
[0208] Given in weight percentages, the zolpidem lozenge composition comprises
from
[0209] A zolpidem lozenge was made according to the formulation shown in Table
4 and
magnesium stearate, and croscarmellose sodium were prepared. The three blends
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screened separately and mixed to form a single blend. The single blend was
then compressed
into lozenges after testing for content uniformity. By using this procedure,
the average
particle size of the drug (i.e., zolpidem) in the lozenge is about 20 microns,
as compared to a
typical average drug particle size of from about 75 to about 100 microns. In
addition, the
average particle size of the drug in the lozenge is less than or equal to the
average particle
size of the carrier ingredients (e.g., gum base, binders, etc.). The unit
weight for each
lozenge was 210 mg. The pH of the lozenge was about 9.8 and remained stable.
These
lozenges dissolve within about 2-3 minutes following sublingual
administration.
Table 4. Zolpidem lozenge formulation.
Material Unit Quantity (mg) Batch Quantity (g)
Sodium Carbonate, NF 17.000 357.000
Sodium Bicarbonate (Effer 23.000 483.000
Soda)
Zolpidem Tartrate, EP 10.000 210.000
Pharmaburst B2 133.000 2793.000
Croscarmellose Sodium 10.000 210.000
Natural & Artificial Spearmint 6.500 136.500
Flavor
Sucralose, NF 1.500 31.500
Silicon Dioxide, USP 5.500 115.500
Magnesium Stearate, NF 3.500 73.500
The batch quantity formulation produces 21,000 unit doses.
[0210] The zolpidem lozenge composition of the present invention can be used,
e.g., for
treatment of insomnia. In certain instances, after the introduction of a
lozenge into the
mouth, the subject holds the lozenge underneath the tongue and either swallows
while the
lozenge is dissolving or swallows after the lozenge has dissolved. The
lozenges described
herein have a very rapid rate of dissolution, and are capable of dissolving
within about 2-3
minutes following sublingual administration.
[0211] A typical dosage form of the zolpidem lozenge of the present invention
is designed
to produce an average plasma concentration of at least from about 20 to about
300 nanograms
of zolpidem per milliliter of plasma. For example, a 5 mg zolpidem lozenge can
be designed
to produce a mean peak plasma concentration within the range of from about 20
to about 100
nanograms of zolpidem per milliliter of plasma within about 5 minutes to about
2 hours.
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Similarly, a 10 mg zolpidem lozenge can be designed to produce a mean peak
plasma
concentration within the range of from about 100 to about 300 nanograms of
zolpidem per
milliliter of plasma within about 5 minutes to about 2 hours.
[0212] The lozenge compositions of the present invention provide a convenient,
reliable,
practical, and painless system for delivering zolpidem across the oral mucosa.
Notably, the
lozenge compositions are capable of very rapidly delivering zolpidem with low
inter-subject
variability in terms of maximum plasma concentration (Cm.) and the time to
reach the
maximum plasma concentration (Tmaõ) so that a therapeutically effective amount
of zolpidem
enters the bloodstream within about 30 minutes, 20 minutes, 15 minutes, 10
minutes, 5
minutes, or even within about 1-2 minutes after zolpidem is released from the
carrier.
Example 5. Dissolution Profiles for Zolpidem Tablet and Lozenge Compositions.
[0213] This example illustrates the mean dissolution profiles for a zolpidem
quick-
dissolving tablet made according to Table 3 and a zolpidem lozenge made
according to Table
4.
[0214] The compositions tested were as follows:
1. Zolpidem quick-dissolving tablet (typically dissolves sublingually in about
5
minutes).
2. Zolpidem lozenge (typically dissolves sublingually in about 2-3 minutes).
[0215] The experimental conditions were as follows:
Method = USP
Apparatus = USP Apparatus II
Medium = Phosphate Buffer pH 6.8
=
Volume of the Medium = 500 ml
Spindle Speed =25 rpm
= =
Temperature = 37 C
[0216] Table 5 below shows the dissolution data and Figure 2 shows the mean
dissolution
profiles for a zolpidem quick-dissolving tablet and zolpidem lozenge of the
present invention
at 5, 10, 15, 20, and 30 minutes in phosphate buffered medium (pH 6.8).
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Table 5. Dissolution data for the zolpidem quick-dissolving tablet and
zolpidem lozenge.
Time Quick-Dissolving Tablet Lozenge
(Min.) (% Dissolved, RSD1) (% Dissolved, RSD1)
5 14.3, 17.7 32.4, 16.2
10 32.8, 14.8 61.7, 8.6
15 50.1, 14.6 75.7,4.9
20 63, 15.9 82.1,4.6
30 85.2, 7.9 88.6, 2.8
iRsD = Relative Standard Deviation
Example 6. Zolpidem Pharmacokinetic Studies.
[02171 This example provides two studies illustrating the pharmacokinetic
profile of the
zolpidem tablets of the present invention as compared to a dose equivalent
commercial oral
tablet.
Zolpidem Sublingual Powdered Tablet vs. Ambien Oral Tablet:
[02181 To evaluate the pharmacokinetic profile of a sublingually administered
zolpidem
formulation, a 10 mg zolpidem powdered tablet buffered at a pH of 9.8 with 23
mg sodium
bicarbonate and 17 mg sodium carbonate (Formulation A) was determined in eight
healthy
subjects (5 male, 3 female). Formulation A was administered under the
subject's tongue and
had a very rapid dissolution rate, i.e., within about 1 to about 3 minutes.
The study
performed was a fixed-sequence, open-label pharmacokinetic study in which
subjects
swallowed saliva at a rate of every 2, 5, or 10 minutes over a 10 minute
period of time
("swallowing time"). For example, a 2 minute swallowing time refers to
swallowing saliva
every 2 minutes over a 10 minute period (i.e., 5 blocks of 2 minutes each); a
5 minute
swallowing time refers to swallowing saliva every 5 minutes over a 10 minute
period (i.e., 2
blocks of 5 minutes each); and a 10 minute swallowing time refers to
swallowing saliva every
10 minutes over a 10 minute period (i.e., 1 block of 10 minutes). Serum blood
samples were
collected over an 8 hour period and the plasma was assayed for zolpidem
levels, e.g., using
high pressure liquid chromatography (HPLC)-tandem mass spectrometry (MS).
[0219] Figures 3-5 show the plasma concentration over time in each subject for
Formulation A at swallowing times of 2, 5, and 10 minutes, respectively.
Tables 6-8 below
show the values for the pharmacokinetic parameters determined in each subject
for
Formulation A at swallowing times of 2, 5, and 10 minutes, respectively.
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Table 6. Phannacokinetic parameters for Formulation A at a 2 minute swallowing
time.
Subject Tmax (min.) Cmax (mg/ml)
AUC0.8 (ng.hr/mI)
1 30 142 317
2 25 231 1096
3 180 211 776
4 90 141 430
50 182 645
6 90 128 441
7 90 142 663
8 25 96 363
Median (Range) 70
(25-180)
Mean (CV%) 159 592
(28%) (44%)
Table 7. Pharmacokinetic parameters for Formulation A at a 5 minute swallowing
time.
Subject Tin. (min.) C.., (mg/ml)
AUC0.8 (ng.hr/m1)
1 30 134 350
2 25 252 1201
3 90 168 906
4 50 172 517
5 25 191 520
6 90 146 490
7 120 185 805
8 40 77 464
Median (Range) 45
(25-120)
Mean (CV%) 165 656
(30%) (44%)
5
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Table 8. Pharmacokinetic parameters for Formulation A at a 10 minute
swallowing time.
Subject Tmax (min.) Cmax (ng/ml) AUC0_8
(ng.hr/m1)
1 390 137 364
2 25 241 913
3 120 183 824
=
4 90 120 508
50 196 728
6 50 208 587
7 50 131 708
8 60 158 826
Median (Range) 55
(25-120)
Mean (CV%) 172 682
(28%) (27%)
[02201 The pharmacokinetic results obtained for Formulation A were then
compared to
pharmacokinetic data obtained from the package insert and the literature for a
dose equivalent
5 Arnbiee
oral tablet formulation (Formulation B). Figure 6 shows the mean plasma
concentration over time for Formulation A (zolpidem sublingual powdered
tablet) at the 3
different swallowing times and for Formulation B (peroral (PO) Ambiene), which
was
obtained from the literature (Greenblatt et al., Clin. Pharmaeol. Ther.,
64:553-561(1998);
Greenblatt et aL, Gun. Pharmaeol. Ther., 64:661-671 (1998)). Table 9 below
shows the
Table 9. Phannacoldnetic parameters for Formulation A and Formulation B.
Formulation Tmax (min.) Cmax (ng/ml) AUC (ng.hr/m1)
Formulation A 70 159 592
(2 min. swallowing time) (25-180) (28%) (44%)
Formulation A 45 165 656
(5 min. swallowing time) (25-120) (30%) (44%)
Formulation A 55 172 682
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Formulation A 55 166 644
(Cumulative) (25-180) (25%) (37%)
Formulation B 102 125 408
(84-120) (12%) (12%)
Values represent the mean. The numbers in parentheses for T,, represent
represent the minimum and maximum
values, respectively. The numbers in parentheses for C and AUC represent the
coefficient of variation
percent (CV%).
[0221] This study demonstrates that delivery of zolpidem across the oral
mucosa produced
swallowing times of 2 and 5 minutes using the data from all 8 subjects and the
mean plasma
concentration over time for Formulation A at swallowing times of 2 and 5
minutes excluding
the data from subjects 3, 6, and 7, who apparently swallowed earlier than
their scheduled
swallowing time. Table 10 below shows the mean values for the pharmacokinetic
parameters
who swallowed early.
Swallowing Time Tmax (min.) C. (ng/ml) AUC (ng.hr/m1)
2 minutes 70 159 592
(all subjects) (25-180) (28%) (44%)
2 minutes 30 159 570
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(excluding subjects 3, 6, (25-90) (31%) (44%)
and 7)
5 minutes 45 165 656
(all subjects) (25-120) (30%) (56%)
5 minutes 30 165 609
(excluding subjects 3, 6, (25-50) (40%) (55%)
and 7)
Values represent the mean. The numbers in parentheses for Tmaõ represent the
minimum and maximum
values, respectively. The numbers in parentheses for C,õ.õ and AUC represent
the coefficient of variation
percent (CV%).
[0223] Figure 8 is an expanded view of the first 90 minutes shown in Figure 6.
In
particular, Figure 8 illustrates the estimated time for the onset of sleep in
subjects taking
Formulation A (left dotted line) compared to the time for the onset of sleep
in subjects taking
Formulation B (right dotted line). The mean plasma zolpidem concentration
effective for
inducing sleep onset is shown by the horizontal line in Figure 8. Table 11
below shows the
reported time for the onset of sleep during the daytime in each subject taking
Formulation A
at the 3 different swallowing times.
Table 11. Reported daytime sleep onset times for Formulation A.
Subject 2 min. swallowing
5 min. swallowing 10 min. swallowing
time (min.) time (min.) time (min.)
1 10 16 18
2 12 9 14
3 7 7 18
4 49 19 8
5 5 19 24
6 30 19 18
7 25 23 15
8 13 24 14
Median 12.5 19 16.5
[0224] This study demonstrates that the onset of sleep for subjects taking the
zolpidem
powdered sublingual tablet is substantially faster than that achieved with the
commercial oral
tablet. In fact, the onset of sleep for subjects taking the sublingual tablets
of the present
invention can be as early as within about 12.5 minutes following
administration, which is
more than 3 times faster than the onset of sleep for subjects taking the
commercial oral tablet.
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One skilled in the art will appreciate that the onset of sleep observed during
the daytime
corresponds to the onset of sleep at night.
[02251 Furthermore, the pharmacokinetic profiles for sublingually administered
zolpidem
provide a softer and longer-lasting peak of zolpidem (see, Figure 6), and thus
resemble a
pharmacokinetic profile for intravenously administered zolpidem. As a result,
this infusion-
like
profile is equivalent to or even superior to the commercial oral tablet in
reducing the time to onset of therapeutic activity, maintaining sleep (e.g.,
total sleep time,
number of awakenings), enhancing sleep quality, eliminating the effect of
food, and reducing
any morning-after residual effects.
Zolpidem Slow-Dissolving and Quick-Dissolving Sublingual Tablets vs.
Ambien Oral Tablet:
= [0226] To further evaluate the pharmacokinetic profile of a sublingually
administered
zolpidem formulation, a 10 mg zolpidem slow-dissolving tablet made according
to Table 2
(Formulation C) and a 10 mg zolpidem quick-dissolving tablet made according to
Table 3
(Formulation D) was compared to a dose equivalent Ambien oral tablet
formulation
(Formulation B) in eight healthy subjects. Formulation C (SL Tablet) was
administered
under the subject's tongue and had a slow dissolution rate, i.e., within about
10 minutes.
Formulation D (FS Tablet) was administered under the subject's tongue and had
a fast
dissolution rate, i.e., within about 5 minutes. Formulation B (PO Ambien) was
administered
perorally with 180 ml of water. The study performed was a three-way crossover,
fixed-
sequence pharmacokinetic study in which subjects swallowed saliva at a rate of
every 2 or 5
minutes over a 10 minute period of time ("swallowing time") for Formulations C
and D.
Serum blood samples were collected over a 12 hour period and the plasma was
assayed for
zolpidem levels, e.g., using high pressure liquid chromatography (HPLC)-tandem
mass
spectrometry (MS).
[02271 Figure 9 shows the mean plasma concentration over time for Formulation
C (SL
Tablet) at swallowing times of 2 and 5 minutes and for Formulation B (PO
Ambien).
Likewise, Figure 10 shows the mean plasma concentration over time for
Formulation D (FS
Tablet) at swallowing times of 2 and 5 minutes and for Formulation B (PO
Ambien). This
study demonstrates that delivery of zolpidem across the oral mucosa produced
peak plasma
zolpidem concentrations at a substantially earlier period in time and at a
substantially higher
level following sublingual administration than observed for the commercial
oral tablet
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administration. As such, the present study shows that zolpidem from both
dissolving tablets
is rapidly absorbed and has substantially better bioavailability than the
commercial oral
tablet. Furthermore, the onset of sleep for subjects taking either zolpidem
dissolving tablet is
substantially faster than that achieved with the commercial oral tablet. The
present study also
shows that the improvement in bioavailability is independent of the swallowing
time and the
formulation of the dissolving tablet.
[02281 Although the foregoing invention has been described in some detail by
way of illustration and
example for purposes of clarity of understanding, it will be readily apparent
to those of ordinary skill in
the art in light of the teachings of this invention that certain changes and
modifications may
be made thereto without departing from the scope of the appended claims.
69