U.S. patent application number 16/130860 was filed with the patent office on 2019-03-21 for buccal, polar and non-polar spray containing zolipidem.
The applicant listed for this patent is Magna Pharmaceuticals, Inc.. Invention is credited to Harry A. Dugger, III, Mohammed Abd El-Shafy.
Application Number | 20190083471 16/130860 |
Document ID | / |
Family ID | 34422010 |
Filed Date | 2019-03-21 |
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United States Patent
Application |
20190083471 |
Kind Code |
A1 |
Dugger, III; Harry A. ; et
al. |
March 21, 2019 |
BUCCAL, POLAR AND NON-POLAR SPRAY CONTAINING ZOLIPIDEM
Abstract
Buccal aerosol sprays or capsules using polar and non-polar
solvents have now been developed which provide zolpidem for rapid
absorption through the oral mucosa, resulting in fast onset of
effect. The buccal polar compositions of the invention comprise
formulation I: aqueous polar solvent, zolpidem, and optional
flavoring agent; formulation II: aqueous polar solvent, zolpidem,
optionally flavoring agent, and propellant; formulation III:
non-polar solvent, zolpidem, and optional flavoring agent;
formulation IV: non-polar solvent, zolpidem, optional flavoring
agent, and propellant; formulation V: a mixture of a polar solvent
and a non-polar solvent, zolpidem, and optional flavoring agent;
formulation VI: a mixture of a polar solvent and a non-polar
solvent, zolpidem, optional flavoring agent, and propellant.
Inventors: |
Dugger, III; Harry A.;
(Flemington, NJ) ; El-Shafy; Mohammed Abd;
(Hauppauge, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Magna Pharmaceuticals, Inc. |
Louisville |
KY |
US |
|
|
Family ID: |
34422010 |
Appl. No.: |
16/130860 |
Filed: |
September 13, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13208429 |
Aug 12, 2011 |
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16130860 |
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12576457 |
Oct 9, 2009 |
8236285 |
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13208429 |
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11384444 |
Mar 21, 2006 |
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12576457 |
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10671715 |
Sep 29, 2003 |
7632517 |
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11384444 |
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10230060 |
Aug 29, 2002 |
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10671715 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0056 20130101;
A61K 31/437 20130101; A61K 9/4866 20130101; Y10S 514/923 20130101;
A61P 25/20 20180101; A61K 9/12 20130101; A61K 31/4745 20130101;
A61K 9/006 20130101 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61K 9/00 20060101 A61K009/00; A61K 9/12 20060101
A61K009/12; A61K 9/48 20060101 A61K009/48; A61K 31/4745 20060101
A61K031/4745 |
Claims
1-62. (canceled)
63. An oral spray composition comprising zolpidem tartarate in an
amount of about 4-5% by weight of the total composition, propylene
glycol in an amount about 30-40% by weight of the total
composition, and a flavoring agent at in an amount about 0.1-0.3%
by weight of the total composition.
64. The composition of claim 63, wherein the Zolpidem tartarate is
present in an amount of about 4.66%, propylene glycol is present in
an amount about 35%, and the flavoring agent is present at about
0.26%.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of application
Ser. No. 10/230,060, filed Aug. 29, 2002, pending, which is a
continuation-in-part of application Ser. No. 09/537,118, filed Mar.
29, 2000 which is a continuation-in-part of the U.S. national phase
designation of PCT/US97/17899 filed Oct. 1, 1997, the disclosures
of which are incorporated by reference herein in their
entirety.
BACKGROUND OF THE INVENTION
[0002] It is known that certain biologically active compounds are
better absorbed through the oral mucosa than through other routes
of administration, such as through the stomach or intestine.
However, formulations suitable for such administration by these
latter routes present their own problems. For example, the
biologically active compound must be compatible with the other
components of the composition such as propellants, solvents, etc.
Many such formulations have been proposed. For example, U.S. Pat.
No. 4,689,233, Dvorsky et al., describes a soft gelatin capsule for
the administration of the anti-coronary drug nifedipine dissolved
in a mixture of polyether alcohols. U.S. Pat. No. 4,755,389, Jones
et al., describes a hard gelatin chewable capsule containing
nifedipine. A chewable gelatin capsule containing a solution or
dispersion of a drug is described in U.S. Pat. No. 4,935,243,
Borkan et al. U.S. Pat. No. 4,919,919, Aouda et al, and U.S. Pat.
No. 5,370,862, Klokkers-Bethke, describe a nitroglycerin spray for
administration to the oral mucosa comprising nitroglycerin,
ethanol, and other components. An orally administered pump spray is
described by Cholcha in U.S. Pat. No. 5,186,925. Aerosol
compositions containing a hydrocarbon propellant and a drug for
administration to a mucosal surface are described in U.K.
2,082,457, Su, U.S. Pat. No. 3,155,574, Silson et al., U.S. Pat.
No. 5,011,678, Wang et al., and by Parnell in U.S. Pat. No.
5,128,132. It should be noted that these references discuss
bioavailability of solutions by inhalation rather than through the
membranes to which they are administered.
[0003] Zolpidem is a imidazopyridine having the structure shown
below:
##STR00001##
[0004] The chemical name for zolpidem is N, N,
6-trimethyl-2-p-tolyl-imidazo[1, 2-a]pyridine-3-acetamide
[0005] Zolpidem is a non-benzodiazepine sedative-hypnotic and is
used to treat insomnia. To treat insomnia, zolpidem is typically
administered orally at a dose of between 10 and 25 mg. Typically
zolpidem is administered as the tartrate salt, i.e., N, N,
6-trimethyl-2-p-tolyl-imidazo[1, 2-a]pyridine-3-acetamide
L-(+)-tartrate (2:1). Following discontinuation of zolpidem the
beneficial effects on sleep can last for up to a week. Tolerance
and physical dependence is only rarely observed with zolpidem.
(Goodman and Gilman's The Pharmacological Basis of Therapeutics,
9.sup.th ed., pp. 471-472).
SUMMARY OF THE INVENTION
[0006] A buccal aerosol spray or soft bite gelatin capsule using a
polar or non-polar solvent has now been developed which provides
biologically active compounds for rapid absorption through the oral
mucosa, resulting in fast onset of effect.
[0007] The buccal aerosol spray compositions of the present
invention, for transmucosal administration of a pharmacologically
active compound soluble in a pharmacologically acceptable non-polar
solvent comprise in weight % of total composition: pharmaceutically
acceptable propellant 5-80%, nonpolar solvent 19-85%, active
compound 0.05-50%, suitably additionally comprising, by weight of
total composition a flavoring agent 0.01-10%. Preferably the
composition comprises: propellant 10-70%, non-polar solvent
25-89.9%, active compound 0.01-40%, flavoring agent 1-8%; most
suitably propellant 20-70%, non-polar solvent 25-74.75%, active
compound 0.25-35%, flavoring agent 2-7.5%.
[0008] The buccal polar aerosol spray compositions of the present
invention, for transmucosal administration of a pharmacologically
active compound soluble in a pharmacologically acceptable polar
solvent are also administrable in aerosol form driven by 353577.1 a
propellant. In this case, the composition comprises in weight % of
total composition: aqueous polar solvent 10-97%, active compound
0.1-25%, suitably additionally comprising, by weight of total
composition a flavoring agent 0.05-10% and propellant: 2-10%.
Preferably the composition comprises: polar solvent 20-97%, active
compound 0.1-15%, flavoring agent 0.1-5% and propellant 2-5%; most
suitably polar solvent 25-97%, active compound 0.2-25%, flavoring
agent 0.1-2.5% and propellant 2-4%.
[0009] In another embodiment, the buccal polar aerosol spray
compositions of the present invention for transmucosal
administration of a pharmacologically active compound (i.e., those
administrable in aerosol form driven by a propellant) comprises a
mixture of a polar solvent and a non-polar solvent comprising in
weight % of total composition: solvent 10-97%, active compound
0.05-50%, propellant 5-80%, and optionally a taste mask and/or
flavoring agent 0.01-10%. Preferably the composition comprises:
solvent 20-97%, active compound 0.1-40%, propellant 10-70%, and
taste mask and/or flavoring agent 1-8%; most suitably solvent
25-97%, active compound 0.25-35%, propellant 20-70%, and taste mask
and/or flavoring agent 2-7.5%. The ratio of the polar solvent to
the non-polar solvent can range from about 1:99 to about 99:1,
preferable from about 60:40 to about 40:60, and more preferably
about 50:50.
[0010] The buccal pump spray composition of the present invention,
i.e., the propellant free composition, for transmucosal
administration of a pharmacologically active compound wherein said
active compound is soluble in a pharmacologically acceptable
non-polar solvent comprises in weight % of total composition:
non-polar solvent 30-99.69%, active compound 0.005-55%, and
suitably additionally, flavoring agent 0.1-10%.
[0011] The buccal polar pump spray compositions of the present
invention, i.e., the propellant free composition, for transmucosal
administration of a pharmacologically active compound soluble in a
pharmacologically acceptable polar solvent comprises in weight % of
total composition: aqueous polar solvent 30-99.69%, active compound
0.001-60%, suitably additionally comprising, by weight of total
composition a flavoring agent 0.1-10%. Preferably the composition
comprises: polar solvent 37-98.58%, active compound 0.005-55%,
flavoring agent 0.5-8%; most suitably polar solvent 60.9-97.06%,
active compound 0.01-40%, flavoring agent 0.75-7.5%.
[0012] In another embodiment, the buccal pump spray composition
(i.e., the propellant free composition) for transmucosal
administration of a pharmacologically active compound comprises a
mixture of a polar solvent and a non-polar solvent comprising in
weight % of total composition solvent 30-99.69%, active compound
0.001-60%, and optionally a taste mask and/or flavoring agent
0.1-10%. Preferably the composition comprises: solvent 37-98.58%,
active compound 0.005-55%, taste mask and/or flavoring agent
0.5-8%; more preferably the composition comprises solvent
60.9-97.06%, active compound 0.01-40%, and taste mask and/or
flavoring agent 0.75-7.5%. The ratio of the polar solvent to the
non-polar solvent can range from about 1:99 to about 99:1,
preferable about 60:40 to about 40:60, and more preferably about
50:50.
[0013] The soft bite gelatin capsules of the present invention for
transmucosal administration of a pharmacologically active compound,
at least partially soluble in a pharmacologically acceptable
non-polar solvent, having charged thereto a fill composition
comprise in weight % of total composition: non-polar solvent
4-99.99%, emulsifier 0-20%, active compound 0.01-80%, provided that
said fill composition contains less than 10% of water, suitably
additionally comprising, by weight of the composition: flavoring
agent 0.01-10%. Preferably, the soft bite gelatin capsule
comprises: non-polar solvent 21.5-99.975%, emulsifier 0-15%, active
compound 0.025-70%, flavoring agent 1-8%; most suitably: nonpolar
solvent 28.5-97.9%, emulsifier 0-10%, active compound 0.1-65.0%,
flavoring agent 2-6%.
[0014] The soft bite polar gelatin capsules of the present
invention for transmucosal administration of a pharmacologically
active compound, at least partially soluble in a pharmacologically
acceptable polar solvent, having charged thereto a composition
comprising in weight % of total composition: polar solvent
25-99.89%, emulsifier 0-20%, active compound 0.01-65%, provided
that said composition contains less than 10% of water, suitably
additionally comprising, by weight of the composition: flavoring
agent 01-10%. Preferably, the soft bite gelatin capsule comprises:
polar solvent 37-99.95%, emulsifier 0-15%, active compound
0.025-55%, flavoring agent 1-8%; most suitably: polar solvent
44-96.925%, emulsifier 0-10%, active compound 0.075-50%, flavoring
agent 2-6%.
[0015] It is an object of the invention to coat the mucosal
membranes either with fine droplets of spray containing the active
compounds or a solution or paste thereof from bite capsules.
[0016] It is also an object of the invention to administer to the
oral mucosa of a mammalian in need of same, preferably man, by
spray or bite capsule, a predetermined amount of a biologically
active compound by this method or from a soft gelatin capsule.
[0017] A further object is a sealed aerosol spray container
containing a composition of the non polar or polar aerosol spray
formulation, and a metered valve suitable for releasing from said
container a predetermined amount of said composition.
[0018] As the propellant evaporates after activation of the aerosol
valve, a mist of fine droplets is formed which contains solvent and
active compound.
[0019] The propellant is a non-Freon material, preferably a
C.sub.3-8 hydrocarbon of a linear or branched configuration. The
propellant should be substantially non-aqueous. The propellant
produces a pressure in the aerosol container such that under
expected normal usage it will produce sufficient pressure to expel
the solvent from the container when the valve is activated but not
excessive pressure such as to damage the container or valve
seals.
[0020] The non-polar solvent is a non-polar hydrocarbon, preferably
a C.sub.7-18 hydrocarbon of a linear or branched configuration,
fatty acid esters, and triglycerides such as miglyol. The solvent
must dissolve the active compound and be miscible with the
propellant, i.e., solvent and propellant must form a single phase
at a temperature of 0-40.degree. C. a pressure range of between 1-3
atm.
[0021] The polar and non-polar aerosol spray compositions of the
invention are intended to be administered from a sealed,
pressurized container. Unlike a pump spray, which allows the entry
of air into the container after every activation, the aerosol
container of the invention is sealed at the time of manufacture.
The contents of the container are released by activation of a
metered valve, which does not allow entry of atmospheric gasses
with each activation. Such containers are commercially
available.
[0022] A further object is a pump spray container containing a
composition of the pump spray formulation, and a metered valve
suitable for releasing from said container a predetermined amount
of said composition.
[0023] A further object is a soft gelatin bite capsule containing a
composition of as set forth above. The formulation may be in the
form of a viscous solution or paste containing the active
compounds. Although solutions are preferred, paste fills may also
be used where the active compound is not soluble or only partially
soluble in the solvent of choice. Where water is used to form part
of the paste composition, it should not exceed 10% thereof. (All
percentages herein are by weight unless otherwise indicated.)
[0024] The polar or non-polar solvent is chosen such that it is
compatible with the gelatin shell and the active compound. The
solvent preferably dissolves the active compound. However, other
components wherein the active compound is not soluble or only
slightly soluble may be used and will form a paste fill.
[0025] Soft gelatin capsules are well known in the art. See, for
example, U.S. Pat. No. 4,935,243, Borkan et al., for its teaching
of such capsules. The capsules of the present invention are
intended to be bitten into to release the low viscosity solution or
paste therein, which will then coat the buccal mucosa with the
active compounds. Typical capsules, which are swallowed whole or
bitten and then swallowed, deliver the active compounds to the
stomach, which results in significant lag time before maximum blood
levels can be achieved or subject the compound to a large first
pass effect. Because of the enhanced absorption of the compounds
through the oral mucosa and no chance of a first pass effect, use
of the bite capsules of the invention will eliminate much of the
lag time, resulting in hastened onset of biological effect. The
shell of a soft gelatin capsule of the invention may comprise, for
example: gelatin: 50-75%, glycerin 20-30%, colorants 0.5-1.5%,
water 5-10%, and sorbitol 2-10%.
[0026] The active compound may include, biologically active
peptides, central nervous system active amines, sulfonyl ureas,
antibiotics, antifungals, antivirals, sleep inducers,
antiasthmatics, bronchial dilators, antiemetics, histamine H2
receptor antagonists, barbiturates, prostaglandins and
neutraceuticals.
[0027] The active compounds may also include antihistamines,
alkaloids, hormones, benzodiazepines and narcotic analgesics. While
not limited thereto, these active compounds are particularly
suitable for non-polar pump spray formulation and application.
[0028] The active compounds may also include p-FOX (fatty acid
oxidation) inhibitors, acetylcholinesterase inhibitors, nerve
impulse inhibitors, anti-cholinergics, anti-convulsants,
anti-psychotics, anxiolytic agents, dopamine metabolism inhibitors,
agents to treat post stroke sequelae, neuroprotectants, agents to
treat Alzheimer's disease, neurotransmitters, neurotransmitter
agonists, sedatives, agents for treating attention deficit
disorder, agents for treating narcolepsy, central adregenic
antagonists, anti-depression agents, agents for treating
Parkinson's disease, benzodiazepine antagonists, stimulants,
neurotransmitter antagonists, tranquilizers, or a mixture
thereof.
[0029] In one embodiment, the active compound is zolpidem or a
pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWING
[0030] FIG. 1. is a schematic diagram showing routes of absorption
and processing of pharmacologically active substances in a
mammalian system.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0031] The preferred active compounds of the present invention are
in an ionized, salt form or as the free base of the
pharmaceutically acceptable salts thereof (provided, for the
aerosol or pump spray compositions, they are soluble in the spray
solvent). These compounds are soluble in the non-polar solvents of
the invention at useful concentrations or can be prepared as pastes
at useful concentrations. These concentrations may be less than the
standard accepted dose for these compounds since there is enhanced
absorption of the compounds through the oral mucosa. This aspect of
the invention is especially important when there is a large
(40-99.99%) first pass effect.
[0032] As propellants for the non polar sprays, propane, N-butane,
iso-butane, N-pentane, iso-pentane, and neo-pentane, and mixtures
thereof may be used. N-butane and iso-butane, as single gases, are
the preferred propellants. It is permissible for the propellant to
have a water content of no more than 0.2%, typically 0.1-0.2%. All
percentages herein are by weight unless otherwise indicated. It is
also preferable that the propellant be synthetically produced to
minimize the presence of contaminants which are harmful to the
active compounds. These contaminants include oxidizing agents,
reducing agents, Lewis acids or bases, and water. The concentration
of each of these should be less than 0.1%, except that water may be
as high as 0.2%.
[0033] Suitable non-polar solvents for the capsules and the
non-polar sprays include (C.sub.2-C.sub.24) fatty acid
(C.sub.2-C.sub.6) esters, C.sub.7-C.sub.18 hydrocarbon,
C.sub.2-C.sub.6 alkanoyl esters, and the triglycerides of the
corresponding acids. When the capsule fill is a paste, other liquid
components may be used instead of the above low molecular weight
solvents. These include soya oil, corn oil, other vegetable
oils.
[0034] As solvents for the polar capsules or sprays there may be
used low molecular weight polyethyleneglycols (PEG) of 400-1000 Mw
(preferably 400-600), low molecular weight (C.sub.2-C.sub.8) mono
and polyols and alcohols of C.sub.7-C.sub.18 linear or branch chain
hydrocarbons, glycerin may also be present and water may also be
used in the sprays, but only in limited amount in the capsules.
[0035] It is expected that some glycerin and water used to make the
gelatin shell will migrate from the shell to the fill during the
curing of the shell. Likewise, there may be some migration of
components from the fill to the shell during curing and even
throughout the shelf-life of the capsule.
[0036] Therefore, the values given herein are for the compositions
as prepared, it being within the scope of the invention that minor
variations will occur.
[0037] The preferred flavoring agents are synthetic or natural oil
of peppermint, oil of spearmint, citrus oil, fruit flavors,
sweeteners (sugars, aspartame, saccharin, etc.), and combinations
thereof.
[0038] The compositions may further include a taste mask. The term
"taste mask" as used herein means an agent that can hide or
minimize an undesirable flavor such as a bitter or sour flavor. A
representative taste mask is a combination of vanillin, ethyl
vanillin, maltol, iso-amyl acetate, ethyl oxyhydrate, anisic
aldehyde, and propylene glycol (commercially available as "PFC 9885
Bitter Mask" from Pharmaceutical Flavor Clinic of Camden, N.J.). A
taste mask in combination with a flavoring agent is particularly
advantageous when the active compound is an alkaloid since
alkaloids often have a bitter taste.
[0039] The active substances include the active compounds selected
from the group consisting of cyclosporine, sermorelin, octreotide
acetate, calcitonin-salmon, insulin lispro, sumatriptan succinate,
clozepine, cyclobenzaprine, dexfenfluramine hydrochloride,
glyburide, zidovudine, erythromycin, ciprofloxacin, ondansetron
hydrochloride, dimenhydrinate, cimetidine hydrochloride,
famotidine, phenytoin sodium, phenytoin, carboprost thromethamine,
carboprost, diphenhydramine hydrochloride, isoproterenol
hydrochloride, terbutaline sulfate, terbutaline, theophylline,
albuterol sulfate and neutraceuticals, that is to say nutrients
with pharmacological action such as but not limited to carnitine,
valerian, echinacea, and the like.
[0040] In another embodiment, the active compound is a p-FOX (fatty
acid oxidation) inhibitor, acetylcholinesterase inhibitor, nerve
impulse inhibitor, anti-cholinergic, anti-convulsant,
anti-psychotic, anxiolytic agent, dopamine metabolism inhibitor,
agent to treat post stroke sequelae, neuroprotectant, agent to
treat Alzheimer's disease, neurotransmitter, neurotransmitter
agonist, sedative, agent for treating attention deficit disorder,
agent for treating narcolepsy, central adregenic antagonist,
anti-depression agent, agent for treating Parkinson's disease,
benzodiazepine antagonist, stimulant, neurotransmitter antagonist,
tranquilizer, or a mixture thereof.
[0041] In one embodiment the active compound is a p-FOX inhibitor.
A suitable p-FOX inhibitor for use in the buccal sprays of the
invention includes, but is not limited to, ranolazine.
[0042] In one embodiment the active compound is an
acetylcholinesterase inhibitor. Suitable acetylcholinesterase
inhibitors for use in the buccal sprays of the invention include,
but are not limited to, galantamine, neostigmine, physostigmine,
and edrophonium.
[0043] In one embodiment the active compound is a nerve impulse
inhibitor. Suitable nerve impulse inhibitors for use in the buccal
sprays of the invention include, but are not limited to,
levobupivacaine, lidocaine, prilocaine, mepivacaine, propofol,
rapacuronium bromide, ropivacaine, tubocurarine, atracurium,
doxaurium, mivacurium, pancuronium, vercuronium, pipecuronium, and
rocuronium.
[0044] In one embodiment the active compound is an
anti-cholinergic. Suitable anti-cholinergics for use in the buccal
sprays of the invention include, but are not limited to,
amantadine, ipratropium, oxitropium, and dicycloverine.
[0045] In one embodiment the active compound is an anti-convulsant.
Suitable anti-convulsants for use in the buccal sprays of the
invention include, but are not limited to, acetazolamide,
carbamazepine, clonazepam, diazepam, divalproex (valproic acid),
ethosuximide, lamotrignine acid, levetriacetam, oxcarbazepine,
phenobarbital, phenytoin, pregabalin, primidone, remacemide,
trimethadione, topiramate, vigabatrin, and zonisamide.
[0046] In one embodiment the active compound is an anti-psychotic.
Suitable anti-psychotics for use in the buccal sprays of the
invention include, but are not limited to, amisulpride,
aripiprazole bifemelane, bromperidol, clozapine, chlorpromazine,
haloperidol, iloperidone loperidone, olanzapine, quetiapine,
fluphenazine, fumarate, risperidone, thiothixene, thioridazine,
sulpride, and ziprasidone,
[0047] In one embodiment the active compound is an anxiolytic
agent. Suitable anxiolytic agents for use in the buccal sprays of
the invention include, but are not limited to, amitryptiline,
atracurium, buspirone, chlorzoxazone, clorazepate, cisatracurium,
cyclobenzaprine, eperisone, esopiclone, hydroxyzine, mirtazapine,
mivacurium, pagoclone, sulperide, zaleplon, and zopiclone.
[0048] In one embodiment the active compound is a dopamine
metabolism inhibitor. Suitable dopamine metabolism inhibitors for
use in the buccal sprays of the invention include, but are not
limited to, entacapone, lazebemide, selegiline, and tolcapone.
[0049] In one embodiment the active compound is an agent to treat
post stroke sequelae. Suitable agents to treat post stroke sequelae
for use in the buccal sprays of the invention include, but are not
limited to, glatiramer, interferon beta 1A, interferon beta 1B,
estradiol, and progesterone.
[0050] In one embodiment the active compound is a neuroprotectant.
Suitable neuroprotectants for use in the buccal sprays of the
invention include, but are not limited to, donepezil, memanine,
nimodipine, riluzole, rivastigmine, tacrine, TAK147, and
xaliproden.
[0051] In one embodiment the active compound is an agent to treat
Alzheimer's disease. Suitable agents to treat Alzheimer's disease
for use in the buccal sprays of the invention include, but are not
limited to, carbidopa, levodopa, tacrine, donezepil, rivastigmine,
and galantamine.
[0052] In one embodiment the active compound is a neurotransmitter.
Suitable neurotransmitters for use in the buccal sprays of the
invention include, but are not limited to, acetylcholine,
serotonin, 5-hydroxytryptamine (5-HT), GABA, glutamate, aspartate,
glycine, histamine, epinephrine, norpinephrine, dopamine,
adenosine, ATP, and nitric oxide.
[0053] In one embodiment the active compound is a neurotransmitter
agonist. Suitable neurotransmitter agonists for use in the buccal
sprays of the invention include, but are not limited to,
almotriptan, aniracetam, atomoxetine, benserazide, bromocriptine,
bupropion, cabergoline, citalopram, clomipramine, desipramine,
diazepam, dihydroergotamine, doxepin duloxetine, eletriptan,
escitalopram, fluvoxamine, gabapentin, imipramine, moclobemide,
naratriptan, nefazodone, nefiracetam acamprosate, nicergoline,
nortryptiline, paroxetine, pergolide, pramipexole, rizatriptan,
ropinirole, sertraline, sibutramine, sumatriptan, tiagabine,
trazodone, venlafaxine, and zolmitriptan.
[0054] In one embodiment the active compound is a sedative.
Suitable sedatives for use in the buccal sprays of the invention
include, but are not limited to, dexmedetomidine, eszopiclone,
indiplon, zolpidem, and zaleplon.
[0055] In one embodiment the active compound is an agent for
treating attention deficit disorder. Suitable agents for treating
attention deficit disorder for use in the buccal sprays of the
invention include, but are not limited to, amphetamine,
dextroamphetamine, methylphenidate, and pemoline.
[0056] In one embodiment the active compound is an agent for
treating narcolepsy. Suitable agents for treating narcolepsy for
use in the buccal sprays of the invention include, but are not
limited to, modafinil and mazindol.
[0057] In one embodiment the active compound is a central adregenic
antagonists. A suitable central adregenic antagonists for use in
the buccal sprays of the invention includes, but is not limited to,
mesoridazine.
[0058] In one embodiment the active compound is an anti-depression
agent. Suitable anti-depression agents for use in the buccal sprays
of the invention include, but are not limited to, amitriptyline,
amoxapine, bupropion, clomipramine, clomipramine, clorgyline,
desipramine, doxepin, fluoxetine, imipramine, isocarboxazid,
maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine,
phenelzine, protriptyline, sertraline, tranylcypromine, trazodone,
and venlafaxine.
[0059] In one embodiment the active compound is an agent for
treating Parkinson's disease. Suitable agents for treating
Parkinson's disease for use in the buccal sprays of the invention
include, but are not limited to, amantadine, bromocriptine,
carvidopa, levodopa, pergolide, and selegiline.
[0060] In one embodiment the active compound is a benzodiazepine
antagonist. A suitable benzodiazepine antagonist for use in the
buccal sprays of the invention includes, but is not limited to,
flumazenil.
[0061] In one embodiment the active compound is a neurotransmitter
antagonist. A suitable neurotransmitter antagonist for use in the
buccal sprays of the invention includes, but is not limited, to
deramciclane.
[0062] In one embodiment the active compound is a stimulant.
Suitable stimulants for use in the buccal sprays of the invention
include, but are not limited to, amphetamine, dextroamphetamine,
dinoprostone, methylphenidate, methylphenidate, modafinil, and
pemoline.
[0063] In one embodiment the active compound is a tranquilizer. A
suitable tranquilizer for use in the buccal sprays of the invention
includes, but is not limited to, mesoridazine.
[0064] In a another embodiment, the active compound is zolpidem or
a pharmaceutically acceptable salt thereof. In one embodiment, the
active compound is zolpidem tartrate.
[0065] Typically, when zolpidem or a pharmaceutically acceptable
salt thereof is the active compound the buccal spray contains from
about 0.01 to 20 weight/weight (w/w) percent zolpidem, more
preferably 0.1 to 15 w/w percent zolpidem, and most preferably 0.2
to 10 w/w percent zolpidem.
[0066] The invention further relates to a method of treating
insomnia in a patient by spraying the oral mucosa of the patient
with a therapeutically effective amount of a buccal spray
comprising zolpidem or a pharmaceutically acceptable salt
thereof.
[0067] The formulations of the present invention comprise an active
compound or a pharmaceutically acceptable salt thereof. The term
"pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic acids or bases including
organic and inorganic acids or bases.
[0068] When an active compound of the present invention is acidic,
salts may be prepared from pharmaceutically acceptable non-toxic
bases. Salts derived from all stable forms of inorganic bases
include aluminum, ammonium, calcium, copper, iron, lithium,
magnesium, manganese, potassium, sodium, zinc, etc. Particularly
preferred are the ammonium, calcium, magnesium, potassium, and
sodium salts. Salts derived from pharmaceutically acceptable
organic non-toxic bases include salts of primary, secondary, and
tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines and basic ion-exchange resins
such as arginine, betaine, caffeine, choline, N,N
dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,
2-dimethyl-aminoethanol, ethanolamine, ethylenediamine,
N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, isopropylamine, lysine, methyl-glucosamine, morpholine,
piperazine, piperidine, polyamine resins, procaine, purine,
theobromine, triethylamine, trimethylamine, tripropylamine,
etc.
[0069] When an active compound of the present invention is basic,
salts may be prepared from pharmaceutically acceptable non-toxic
acids. Such acids include acetic, benzenesulfonic, benzoic,
camphorsulfonic, citric, ethane-sulfonic, fumaric, gluconic,
glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic,
mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,
phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, etc.
Particularly preferred are citric, hydrobromic, maleic, phosphoric,
sulfuric, and tartaric acids.
[0070] In the discussion of methods of treatment herein, reference
to the active compounds is meant to also include the
pharmaceutically acceptable salts thereof. While certain
formulations are set forth herein, the actual amounts to be
administered to the mammal or man in need of same are to be
determined by the treating physician.
[0071] The invention is further defined by reference to the
following examples, which are intended to be illustrative and not
limiting.
[0072] The following are examples of certain classes. All values
unless otherwise specified are in weight percent.
EXAMPLES
Example 1
Biologically Active Peptides Including Peptide Hormones
[0073] A. Cyclosporine Lingual Spray
TABLE-US-00001 Amounts preferred amount most preferred amount
cyclosporine 5-50 10-35 15-25 water 5-20 7.5-50 9.5-12 ethanol 5-60
7.5-50 10-20 polyethylene 20-60 30-45 35-40 glycol flavors 0.1-5
1-4 2-3
[0074] B. Cyclosporine Non-Polar Lingual Spray
TABLE-US-00002 Amounts preferred amount most preferred amount
cyclosporine 1-50 3-40 5-30 Migylol 20 25 30-40 Polyoxyethylated 20
25 30-40 castor oil Butane 25-80 30-70 33-50 flavors 0.1-5 1-4
2-3
[0075] C. Cyclosporine Non-Polar Bite Capsule
TABLE-US-00003 Amounts preferred amount most preferred amount
cyclosporine 1-35 5-25 10-20 olive oil 25-60 35-55 30-45
polyoxyethylated 25-60 35-55 30-45 oleic glycerides flavors 0.1-5
1-4 2-3
[0076] D. Cyclosporine Bite Capsule
TABLE-US-00004 Amounts preferred amount most preferred amount
cyclosporine 5-50 10-35 15-25 polyethylene 20-60 30-45 35-40 glycol
glycerin 5-30 7.5-25 10-20 propylene glycol 5-30 7.5-25 10-20
flavors 0.1-10 1-8 3-6
[0077] E. Sermorelin (as the Acetate) Lingual Spray
TABLE-US-00005 Amounts preferred amount most preferred sermorelin
(as the acetate) .01-5 .1-3 .2-1.0 mannitol 1-25 5-20 10-15
monobasic sodium 0.1-5 1-3 1 .5-2.5 phosphate, dibasic sodium
0.01-5 .05-3 0.1-0.5 phosphate water ethanol 5-30 7.5-25 9.5-15
polyethylene glycol 20-60 30-45 35-40 propylene glycol 5-25 10-20
12-17 flavors 0.1-5 1-4 2-3
[0078] F. Octreotide Acetate (Sandostatin) Lingual Spray
TABLE-US-00006 Amounts preferred amount most preferred amount
octreotide acetate 0.001-0.5 0.005-0.250 0.01-0.10 acetic acid 1-10
2-8 4-6 sodium acetate 1-10 2-8 4-6 sodium chloride 3-30 .5-25
15-20 flavors 0.1-5 0.5-.4 2-3 ethanol 5-30 7.5-20 9.5-15 water
15-95 35-90 65-85 flavors 0.1-5 1-4 2-3
[0079] G. Calcitonin-Salmon Lingual Spray
TABLE-US-00007 preferred most preferred Amounts amount amount
calcitonin-salmon 0.001-5 0.005-2 01-1.5 ethanol 2-15 3-10 7-9.5
water 30-95 50-90 60-80 polyethylene 2-15 3-10 7-9.5 glycol sodium
chloride 2.5-20 5-15 10-12.5 flavors 0.1-5 1-4 2-3
[0080] H. Insulin Lispro, Lingual Spray
TABLE-US-00008 preferred most preferred Amounts amount amount
insulin 20-60 4-55 5-50 glycerin 0.1-10 0.25-5 0.1-1.5 dibasic
sodium phosphate 1-15 2.5-10 4-8 m-cresol, 1-25 5-25 7.5-12.5 zinc
oxide 0.01-0.25 .05-0.15 0.075-0.10 m-cresol 0.1-1 0.2-0.8 0.4-0.6
phenol trace trace trace amounts amounts amounts ethanol 5-20
7.5-15 9-12 water 30-90 40-80 50-75 propylene glycol 5-20 7.5-15
9-12 flavors 0.1-5 0.5-3 0.75-2 adjust pH to 7.0-7.8 with HCl or
NaOH
Example 2
CNS Active Amines and their Salts: Including but not Limited to
Tricyclic Amines, GABA Analogues, Thiazides, Phenothiazine
Derivatives, Serotonin Antagonists and Serotonin Reuptake
Inhibitors
[0081] A. Sumatriptan Succinate Lingual Spray
TABLE-US-00009 preferred most preferred Amounts amount amount
sumatriptan succinate 0.5-30 1-20 10-15 ethanol 5-60 7.5-50 10-20
propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45
35-40 water 5-30 7.5-20 10-15 flavors 0.1-5 1-4 2-3
[0082] B. Sumatriptan Succinate Bite Capsule
TABLE-US-00010 preferred most preferred Amounts amount amount
sumatriptan succinate 0.01-5 0.05-3.5 0.075-1.75 polyethylene
glycol 25-70 30-60 35-50 glycerin 25-70 30-60 35-50 flavors 0.1-10
1-8 3-6
[0083] C. Clozepine Lingual Spray
TABLE-US-00011 preferred most preferred Amounts amount amount
clozepine 0.5-30 1-20 10-15 ethanol 5-60 7.5-50 10-20 propylene
glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45 35-40 water
5-30 7.5-20 10-15 flavors 0.1-5 1-4 2-3
[0084] D. Clozepine Non-Polar Lingual Spray with Propellant
TABLE-US-00012 preferred most preferred Amounts amount amount
clozepine 0.5-30 1-20 10-15 Migylol 20-85 25-70 30-40 Butanol 5-80
30-75 60-70 flavors 0.1-5 1-4 2-3
[0085] E. Clozepine Non Polar Lingual Spray without Propellant
TABLE-US-00013 preferred most preferred Amounts amount amount
clozepine 0.5-30 1-20 10-15 Migylol 70-99.5 80-99 85-90 flavors
0.1-5 1-4 2-3
[0086] F. Cyclobenzaprine Non-Polar Lingual Spray
TABLE-US-00014 preferred most preferred Amounts amount amount
cyclobenzaprine (base) 0.5-30 1-20 10-15 Migylol 20-85 25-70 30-40
Iso-butane 15-80 30-75 60-70 flavors 0.1-5 1-4 2-3
[0087] G. Dexfenfluramine Hydrochloride Lingual Spray
TABLE-US-00015 preferred most preferred Amounts amount amount
dexfenfluramine Hcl 5-30 7.5-20 10-15 ethanol 5-60 7.5-50 10-20
propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45
35-40 water 5-30 7.5-20 10-15 flavors 0.1-5 1-4 2-3
Example 3
Sulfonylureas
[0088] A. Glyburide Lingual Spray
TABLE-US-00016 preferred most preferred Amounts amount amount
glyburide 0.25-25 0.5-20 0.75-15 ethanol 5-60 -7.5-50 10-20
propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45
35-40 water 2.5-30 5-20 6-15 flavors 0.1-5 1-4 2-3
[0089] B. Glyburide Non-Polar Bite Capsule
TABLE-US-00017 preferred most preferred Amounts amount amount
glyburide 0.01-10 0.025-7.5 0.1-4 olive oil 30-60 35-55 30-50
polyoxyethylated oleic 30-60 35-55 30-50 glycerides flavors 0.1-5
1-4 2-3
Example 4
Antibiotics Anti-Fungals and Anti-Virals
[0090] A. Zidovudine [Formerly Called Azidothymidine (AZT)
(Retrovir)] Non-Polar Lingual Spray
TABLE-US-00018 preferred most preferred Amounts amount amount
zidovudine 10-50 15-40 25-35 Soya oil 20-85 25-70 30-40 Butane
15-80 30-75 60-70 flavors 0.1-5 1-4 2-3
[0091] B. Erythromycin Bite Capsule Bite Capsule
TABLE-US-00019 preferred most preferred Amounts amount amount
erythromycin 25-65 30-50 35-45 polyoxyethylene 5-70 30-60 45-55
glycol glycerin 5-20 7.5-15 10-12.5 flavors 1-10 2-8 3-6
[0092] C. Ciprofloxacin Hydrochloride Bite Capsule
TABLE-US-00020 preferred most preferred Amounts amount amount
ciprofloxacin hydrochloride 25-65 35-55 40-50 glycerin 5-20 7.5-15
10-12.5 polyethylene glycol 120-75 30-65 40-60 flavors 1-10 2-8
3-6
[0093] D. Zidovudine [Formerly Called Azidothymidine (AZT)
(Retrovir)] Lingual Spray
TABLE-US-00021 preferred most preferred Amounts amount amount
zidovudine 10-50 15-40 25-35 water 30-80 40-75 45-70 ethanol 5-20
7.5-15 9.5-12.5 polyethylene glycol 5-20 7.5-15 9.5-12.5 flavors
0.1-5 1-4 2-3
Example 5
Anti-Emetics
[0094] A. Ondansetron Hydrochloride Lingual Spray
TABLE-US-00022 preferred most preferred Amounts amount amount
ondansetron hydrochloride 1-25 2-20 2.5-15 citric acid monohydrate
1-10 2-8 2.5-5 sodium citrate dihydrate 0.5-5 1-4 1.25-2.5 water
1-90 5-85 10-75 ethanol 5-30 7.5-20 9.5-15 propylene glycol 5-30
7.5-20 9.5-15 polyethylene glycol 5-30 7.5-20 9.5-15 flavors 1-10
3-8 5-7.5
[0095] B. Dimenhydrinate Bite Capsule
TABLE-US-00023 preferred most preferred Amounts amount amount
dimenhydrinate 0.5-30 2-25 3-15 glycerin 5-20 7.5-15 10-12.5
polyethylene glycol 45-95 50-90 55-85 flavors 1-10 2-8 3-6
[0096] C. Dimenhydrinate Polar Lingual Spray
TABLE-US-00024 preferred most preferred Amounts amount amount
dimenhydrinate 3-50 4-40 5-35 water 5-90 10-80 15-75 ethanol 1-80
3-50 5-10 polyethylene glycol 1-80 3-50 5-15 sorbitol 0.1-5 0.2-40
0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4
2-3
Example 6
Histamine H-2 Receptor Antagonists
[0097] A. Cimetidine Hydrochloride Bite Capsule
TABLE-US-00025 preferred most preferred Amounts amount amount
cimetidine HCl 10-60 15-55 25-50 glycerin 5-20 7.5-15 10-12.5
polyethylene glycol 20-90 25-85 30-75 flavors 1-10 2-8 3-6
[0098] B. Famotidine Lingual Spray
TABLE-US-00026 preferred most preferred Amounts amount amount
famotidine 1-35 5-30 7-20 water 2.5-25 3-20 5-10 L-aspartic acid
0.1-20 1-15 5-10 polyethylene glycol 20-97 30-95 50-85 flavors
0.1-10 1-7.5 2-5
[0099] C. Famotidine Nonpolar Lingual Spray
TABLE-US-00027 preferred most preferred Amounts amount amount
famotidine 1-35 5-30 7-20 Soya oil 10-50 15-40 15-20 Butanel 5-80
30-75 45-70 polyoxyethylated 10-50 15-40 15-20 oleic glycerides
flavors 0.1-5 1-4 2-3
Example 7
Barbiturates
[0100] A. Phenytoin Sodium Lingual Spray
TABLE-US-00028 preferred most preferred Amounts amount amount
phenytoin sodium 10-60 15-55 20-40 water 2.5-25 3-20 5-10 ethanol
5-30 7.5-20 9.5-15 propylene glycol 5-30 7.5-20 9.5-15 polyethylene
glycol 5-30 7.5-20 9.5-15 flavors 1-10 3-8 5-7.5
[0101] B. Phenytoin Non-Polar Lingual Spray
TABLE-US-00029 preferred most preferred Amounts amount amount
phenytoin 5-45 10-40 15-35 migylol 10-50 15-40 15-20 Butane 15-80
30-75 60-70 polyoxyethylated 10-50 15-40 15-20 oleic glycerides
flavors 0.1-10 1-8 5-7.5
Example 8
Prostaglandins
[0102] A. Carboprost Thromethamine Lingual Spray
TABLE-US-00030 preferred most preferred Amounts amount amount
carboprost thromethamine 0.05-5 0.1-3 0.25-2.5 water 50-95 60-80
65-75 ethanol 5-20 7.5-15 9.5-12.5 polyethylene glycol 5-20 7.5-15
9.5-12.5 sodium chloride 1-20 3-15 4-8 flavors 0.1-5 1-4 2-3
[0103] pH is adjusted with sodium hydroxide and/or hydrochloric
acid
[0104] B. Carboprost Non-Polar Lingual Spray
TABLE-US-00031 preferred most preferred Amounts amount amount
carboprost 0.05-5 0.1-3 0.25-2.5 migylol 25-50 30-45 35-40 Butane
5-60 10-50 20-35 polyoxyethylated 25-50 30-45 35-40 oleic
glycerides flavors 0.1-10 1-8 5-7.5
Example 9
Neutraceuticals
[0105] A. Carnitine as Bite Capsule (Contents are a Paste)
TABLE-US-00032 preferred most preferred Amounts amount amount
carnitine fumarate 6-80 30-70 45-65 soya oil 7.5-50 10-40 12.5-35
soya lecithin 0.001-1.0 0.005-0.5 .01-0.1 Soya fats 7.5-50 10-40
12.5-35 flavors 1-10 2-8 3-6
[0106] B. Valerian as Lingual Spray
TABLE-US-00033 preferred most preferred Amounts amount amount
valerian extract 0.1-10 0.2-7 0.25-5 water 50-95 60-80 65-75
ethanol 5-20 7.5-15 9.5-12.5 polyethylene glycol 5-20 7.5-15
9.5-12.5 flavors 1-10 2-8 3-6
[0107] C. Echinacea as Bite Capsule
TABLE-US-00034 preferred most preferred Amounts amount amount
echinacea extract 30-85 40-75 45-55 soya oil 7.5-50 10-40 12.5-35
soya lecithin 0.001-1.0 0.005-0.5 .01-0.1 Soya fats 7.5-50 10-40
12.5-35 flavors 1-10 2-8 3-6
[0108] D. Mixtures of Ingredients
TABLE-US-00035 preferred most preferred Amounts amount amount
magnesium oxide 15-40 20-35 25-30 chromium picolinate 0.01-1.0
0.02-0.5 .025-0.75 folic acid .025-3.0 0.05-2.0 0.25-0.5 vitamin
B-12 0.01-1.0 0.02-0.5 .025-0.75 vitamin E 15-40 20-35 25-30 Soya
oil 10-40 12.5-35 15-20 soya lecithin 0.1-5 0.2-4 0.5-1.5 soya fat
10-40 15-35 17.5-20
Example 10
Sleep Inducers (Also CNS Active Amine)
[0109] A. Diphenhydramine Hydrochloride Lingual Spray
TABLE-US-00036 preferred most preferred Amounts amount amount
diphenhydramine 3-50. 4-40 5-35 HCl water 5-90 10-80 50-75 ethanol
1-80 3-50 5-10 polyethylene glycol 1-80 3-50 5-15 Sorbitol 0.1-5
0.2-4 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5
1-4 2-3
Example 11
Anti-Asthmatics-Bronchodilators
[0110] A. Isoproterenol Hydrochloride as Polar Lingual Spray
TABLE-US-00037 preferred most Amounts amount preferred amount
isoproterenol 0.1-10 0.2-7.5 0.5-6 Hydrochloride water 5-90 10-80
50-75 ethanol 1-80 3-50 5-10 polyethylene glycol 1-80 3-50 5-15
Sorbitol 0.1-5 0.2-4 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1
flavors 0.1-5 1-4 2-3
[0111] B. Terbutaline Sulfate as Polar Lingual Spray
TABLE-US-00038 Amounts preferred amount most preferred amount
terbutaline sulfate 0.1-10 0.2-7.5 0.5-6 water 5-90 10-80 50-75
ethanol 1-10 2-8 2.5-5 Sorbitol 0.1-5 0.2-4 0.4-1.0 aspartame
0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3
[0112] C. Terbutaline as Non-Polar Lingual Spray
TABLE-US-00039 most preferred Amounts preferred amount amount
terbutaline 0.1-10 0.2-7.5 0.5-6 migylol 25-50 30-45 35-40
isobutane 5-60 10-50 20-35 polyoxyethylated 25-50 30-45 35-40 oleic
glycerides flavors 0.1-10 1-8 5-7.5
[0113] D. Theophylline Polar Bite Capsule
TABLE-US-00040 most preferred Amounts preferred amount amount
theophylline 5-50 10-40 15-30 polyethylene glycol 20-60 25-50 30-40
glycerin 25-50 35-45 30-40 propylene glycol 25-50 35-45 30-40
flavors 0.1-5 1-4 2-3
[0114] E. Albuterol Sulfate as Polar Lingual Spray
TABLE-US-00041 Amounts preferred amount most preferred amount
albuterol sulfate 0.1-10 0.2-7.5 0.5-6 water 5-90 10-80 50-75
ethanol 1-10 2-8 2.5-5 Sorbitol 0.1-5 0.2-4 0.4-1.0 aspartame
0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3
Example 12
Polar Solvent Formulations Using a Propellant
[0115] A. Sulfonylurea
TABLE-US-00042 Preferred Most-Preferred Amount Amount Amount
glyburide 0.1-25% 0.5-15% 0.6-10% Ethanol 40-99% 60-97% 70-97%
Water 0.01-5% 0.1-4% 0.2-2% Flavors 0.05-10% 0.1-5% 0.1-2.5%
Propellant 2-10% 3-5% 3-4%
[0116] B. Prostaglandin E (Vasodilator)
TABLE-US-00043 Most-Preferred Amount Preferred Amount Amount
prostaglandin E.sub.1 0.01-10% 0.1-5% 0.2-3% Ethanol 10-90% 20-75%
25-50% Propylene glycol 1-90% 5-80% 10-75% Water 0.01-5% 0.1-4%
0.2-2% Flavors 0.05-10% 0.1-5% 0.1-2.5% Propellant 2-10% 3-5%
3-4%
[0117] C. Promethazine (Antiemetic, Sleep Inducer, and CNS Active
Amine)
TABLE-US-00044 Most-Preferred Amount Preferred Amount Amount
promethazine 1-25% 3-15% 5-12% Ethanol 10-90% 20-75% 25-50%
Propylene glycol 1-90% 5-80% 10-75% Water 0.01-5% 0.1-4% 0.2-2%
Flavors 0.05-10% 0.1-5% 0.1-2.5% Propellant 2-10% 3-5% 3-4%
[0118] D. Meclizine
TABLE-US-00045 Most-Preferred Amount Preferred Amount Amount
meclizine 1-25% 3-15% 5-12% Ethanol 1-15% 2-10% 3-6 Propylene
glycol 20-98% 5-90% 10-85% Water 0.01-5% 0.1-4% 0.2-2% Flavors
0.05-10% 0.1-5% 0.1-2.5% Propellant 2-10% 3-5% 3-4%
Example 13
Zolpidem Formulations
[0119] A. A Propellant Free Zolpidem Formulation Containing a Polar
Solvent has the Following Formula:
TABLE-US-00046 Component Percent (w/w) Zolpidem tartrate 2.5
Propylene glycol 15 Glycerol 10 Bitter mask 0.2 Benzalkonium
chloride 0.1 Citrate buffer (1N, pH 6) 8 Ethanol QS 100 mL
[0120] B. A Zolpidem Formulation in a Polar Solvent with a
Propellant has the Following Formula:
TABLE-US-00047 Component Percent (w/w) Zolpidem tartrate 2.5
Ethanol 35 Glycerol 10 Bitter mask 0.2 Butane QS 100
[0121] C. A Propellant Free Zolpidem Formulation in a Mixture of a
Polar and a Non-Polar Solvent has the Following Formula:
TABLE-US-00048 Component Percent (w/w) Zolpidem tartrate 0.5
Miglyol 15 Lemon oil 10 Ethanol QS to 100 mL
[0122] D. A Zolpidem Formulation in a Mixture of a Polar Solvent
and a Non-Polar Solvent with a Propellant can be Made According to
the Following Formula:
TABLE-US-00049 Component Percent (w/w) Zolpidem tartrate 0.5 Liquid
paraffin 15 Lemon oil 10 Ethanol 40 Butane QS 100
[0123] E. A Propellant Free Zolpidem Formulation in a Non-Polar
Solvent can be Made According to the Following Formula:
TABLE-US-00050 Component Percent (w/w) Zolpidem Tartrate 0.2 Lemon
oil 0.1 Miglyol Qs to 100
[0124] F. A zolpidem formulation in a non-polar solvent with a
propellant can be made according to the following formula:
TABLE-US-00051 Component Percent (w/w) Zolpidem Tartrate 0.2 Lemon
oil 0.1 Miglyol 50 Butane Qs to 100
* * * * *