U.S. patent application number 12/351275 was filed with the patent office on 2009-07-23 for buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system.
Invention is credited to Harry A. Dugger, III.
Application Number | 20090186099 12/351275 |
Document ID | / |
Family ID | 32106355 |
Filed Date | 2009-07-23 |
United States Patent
Application |
20090186099 |
Kind Code |
A1 |
Dugger, III; Harry A. |
July 23, 2009 |
BUCCAL, POLAR AND NON-POLAR SPRAY OR CAPSULE CONTAINING DRUGS FOR
TREATING DISORDERS OF THE CENTRAL NERVOUS SYSTEM
Abstract
Buccal aerosol sprays or capsules using polar and non-polar
solvent have now been developed which provide biologically active
compounds 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, active
compound, and optional flavoring agent; formulation II: aqueous
polar solvent, active compound, optionally flavoring agent, and
propellant; formulation III: non-polar solvent, active compound,
and optional flavoring agent; and formulation IV: non-polar
solvent, active compound, optional flavoring agent, and
propellant.
Inventors: |
Dugger, III; Harry A.;
(Flemington, NJ) |
Correspondence
Address: |
DICKSTEIN SHAPIRO LLP
1825 EYE STREET NW
Washington
DC
20006-5403
US
|
Family ID: |
32106355 |
Appl. No.: |
12/351275 |
Filed: |
January 9, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10230060 |
Aug 29, 2002 |
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12351275 |
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09537118 |
Mar 29, 2000 |
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10230060 |
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PCT/US97/17899 |
Oct 1, 1997 |
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09537118 |
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Current U.S.
Class: |
514/1.1 ;
424/733; 424/737; 514/220; 514/253.06; 514/255.04; 514/263.3;
514/29; 514/370; 514/398; 514/400; 514/411; 514/415; 514/50;
514/557; 514/654 |
Current CPC
Class: |
A61P 31/04 20180101;
A61K 31/4178 20130101; A61K 38/13 20130101; A61K 31/137 20130101;
A61P 43/00 20180101; A61K 9/0056 20130101; A61K 31/433 20130101;
A61P 5/00 20180101; A61P 31/00 20180101; A61P 25/00 20180101; A61K
9/006 20130101; A61P 25/18 20180101; A61P 35/00 20180101; A61P 3/02
20180101; A61P 25/28 20180101; A61K 31/138 20130101; A61P 25/16
20180101; A61P 11/06 20180101; A61P 31/10 20180101; A61P 25/08
20180101; A61P 25/20 20180101; A61K 31/421 20130101; A61P 33/00
20180101; A61K 31/7076 20130101; A61P 25/22 20180101; A61P 31/12
20180101; A61K 31/00 20130101; A61K 31/197 20130101; A61P 1/12
20180101; A61P 11/08 20180101; A61K 31/27 20130101; A61K 9/12
20130101; A61K 31/437 20130101; A61P 37/08 20180101; A61K 31/085
20130101 |
Class at
Publication: |
424/692 ; 514/11;
514/2; 514/9; 514/12; 514/3; 514/415; 514/220; 514/654; 514/50;
514/29; 514/253.06; 514/411; 514/263.3; 514/400; 514/370; 514/398;
514/557; 424/733; 424/737; 514/255.04 |
International
Class: |
A61K 33/08 20060101
A61K033/08; A61K 38/13 20060101 A61K038/13; A61K 38/02 20060101
A61K038/02; A61K 38/12 20060101 A61K038/12; A61K 38/16 20060101
A61K038/16; A61K 38/28 20060101 A61K038/28; A61K 31/404 20060101
A61K031/404; A61K 31/551 20060101 A61K031/551; A61K 31/135 20060101
A61K031/135; A61K 31/7072 20060101 A61K031/7072; A61K 31/7048
20060101 A61K031/7048; A61K 31/496 20060101 A61K031/496; A61K
31/403 20060101 A61K031/403; A61K 31/522 20060101 A61K031/522; A61K
31/4164 20060101 A61K031/4164; A61K 31/426 20060101 A61K031/426;
A61K 31/19 20060101 A61K031/19; A61K 36/84 20060101 A61K036/84;
A61K 36/28 20060101 A61K036/28; A61K 31/495 20060101 A61K031/495;
A61P 25/00 20060101 A61P025/00 |
Claims
1-134. (canceled)
135. A method for administering an effective amount of a
pharmacologically active compound to a mammal to provide
transmucosal absorption of a therapeutically effective amount of
the active compound through the oral mucosa of the mammal to the
systemic circulatory system of the mammal, comprising: spraying the
oral mucosa of the mammal with a propellant free buccal spray
composition, containing a pharmacologically active compound
dissolved in a pharmacologically acceptable solvent, comprising in
weight percent of the composition: an active compound in an amount
between 0.001 and 60 percent by weight of the total composition
comprising an acetylcholinesterase inhibitor, a nerve impulse
inhibitor, an anti-cholinergic, an anti-convulsant, an
anti-psychotic, an anxiolytic agent, a dopamine metabolism
inhibitor, an agent for treating post stroke sequelae, a
neuroprotectant, an agent treating Alzheimer's disease, a
neurotransmitter, a neurotransmitter agonist, a sedative, an agent
for treating attention deficit disorder, an agent for treating
narcolepsy, a central adregenic antagonist, an anti-depression
agent, an agent for treating Parkinson's disease, a benzodiazepine
antagonist, a stimulant, a neurotransmitter antagonist, a
tranquilizer or a mixture thereof; and a polar solvent in an amount
between 30 and 99.69 percent by weight of the total
composition.
136. The method of claim 135, wherein the active compound is an
acetylcholinesterase inhibitor comprising galantamine, neostigmine,
physostigmine, edrophonium or a mixture thereof.
137. The method of claim 135, wherein the active compound is a
nerve impulse inhibitor comprising levobupivacaine, lidocaine,
prilocaine, mepivacaine, propofol, rapacuronium bromide,
ropivacaine, tubocurarine, atracurium, doxaurium, mivacuium,
pancuronium, vercuronium, pipecuronium, rocurronium or a mixture
thereof.
138. The method of claim 135, wherein the active compound is an
anti-cholinergic comprising amantadine, ipratropium, oxitropium,
dicycloverine or a mixture thereof.
139. The method of claim 135, wherein the active compound is an
anti-convulsant comprising acetazolamide, carbamazepine,
clonazepam, diazepam, divalproex, ethosuximide, lamotrignine acid,
levetriacetam, oxcarbazepine, Phenobarbital, phenyloin, pregabalin,
primidone, remacemide, trimethadione, topiramate, vigabatrin,
zonisamide or a mixture thereof.
140. The method of claim 135, wherein the active compound is an
anti-psychotic comprising amisulpride, aripiprazole bifemelane,
bromperidol, clozapine, chlorpromazine, haloperidol, iloperidone
loperidone, olanzapine, quetiapine, fluphenazine, esperidone,
thiothixene, thioridazine, sulpride, ziprasidone or a mixture
thereof.
141. The method of claim 135, wherein the active compound is an
anxiolytic agent comprising amitryptiline, atracurium, buspirone,
chlorzoxazone, clorazepate, cisatracurium, cyclobenzaprine,
eperisone, esopiclone, hydroxyzine, mirtazapine, mivacurium,
pagoclone, superide, zaleplon, zopiclone or a mixture thereof.
142. The method of claim 135, wherein the active compound is a
dopamine metabolism inhibitor comprising entacapone, lazebemide,
selegiline, tolcapone or a mixture thereof.
143. The method of claim 135, wherein the active compound is an
agent for treating post stroke sequelae comprising glatiramer,
estradiol, progesterone or a mixture thereof.
144. The method of claim 135, wherein the active compound is a
neuroprotectant comprising donepezil, memanine, nimodipine,
riluzole, rivastigmine, tacrine, xaliproden or a mixture
thereof.
145. The method of claim 135, wherein the active compound is a
agent for treating Alzheimer's disease comprising carbidopa,
levodopa, tacrine, donezepil, rivastigmine, galantamine or a
mixture thereof.
146. The method of claim 135, wherein the active compound is a
neurotransmitter comprising acetylcholine, serotonin,
5-hydroxytryptamine (5-HT), GABA, glutamate, aspartate, glycine,
histamine, epinephrine, norpinephrine, dopamine, adenosine, ATP
nitric oxide or a mixture thereof.
147. The method of claim 135, wherein the active compound is a
neurotransmitter agonist comprising almotriptan, aniracetam,
atomoxetine, benserazide, bromocriptine, bupropion, cabergoline,
citalopram, clomipramine, desipramine, diazepam, dihydroergotmine,
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,
zolmitriptan or a mixture thereof.
148. The method of claim 135, wherein the active compound is a
sedative comprising dexmedetomidine, eszopiclone, indiplon,
zolpidem, zaleplon or a mixture thereof.
149. The method of claim 135, wherein the active compound is an
agent for treating attention deficit disorder comprising
amphetamine, dextroamphetamine, methylphenidate, pemoline or a
mixture thereof.
150. The method of claim 135, wherein the active compound is an
agent for treating narcolepsy comprising modafinil, mazindol or a
mixture thereof.
151. The method of claim 135, wherein the active compound is an
anti-depression agent comprising amitriptyline, amoxapine,
bupropion, clomipramine, clorgyline, despipramine, doxepin,
fluoxetine, imipramine, isocarboxazid, maprotiline, mirtazapine,
nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline,
sertraline, tranylcypromine, trazodone, venlafaxine or a mixture
thereof.
152. The method of claim 135, wherein the active compound is an
agent for treating Parkinson's disease comprising amantadine,
bromocriptine, carvidopa, levodopa, pergolide, selegiline or a
mixture thereof.
153. The method of claim 135, wherein the active compound comprises
flumazenil.
154. The method of claim 135, wherein the active compound comprises
deramciclane.
155. The method of claim 135, wherein the active compound is a
stimulant comprising amphetamine, dextroamphetamine, dinoprostone,
methylphenidate, methylphenidate, modafinil, pemoline or a mixture
thereof.
156. The method of claim 135, wherein the active compound comprises
mesoridazine.
157. The method of claim 135, wherein the amount of the spray is
predetermined.
158. The method of claim 135, further comprising a flavoring agent
in an amount between 0.1 and 10 percent by weight of the total
composition.
159. The method of claim 158, wherein the flavoring agent comprises
a synthetic or natural oil of peppermint, oil of spearmint, citrus
oil, fruit flavor, sweetener or a mixture thereof.
160. The method of claim 158, wherein the polar solvent is present
in an amount between 37 and 98.58 percent by weight of the total
composition, the active compound is present in an amount between
0.005 and 55 percent by weight of the total composition, and the
flavoring agent is present in an amount between 0.5 and 8 percent
by weight of the total composition.
161. The method of claim 160, wherein the polar solvent is present
in an amount between 60.9 and 97.06 percent by eight of the total
composition, the active compound is present in an amount between
0.01 and 40 percent by weight of the total composition, and the
flavoring agent is present in an amount between 0.75 and 7.5
percent by weight of the total composition.
162. The method of claim 135, wherein the polar solvent comprises a
polyethylene glycol having a molecular weight between 400 and 1000,
a C.sub.2 to C.sub.8 mono- and polyalcohol, or a C.sub.7 to
C.sub.18 alcohol of linear or branched configuration.
163. The method of claim 135, wherein the polar solvent comprises
aqueous polyethylene glycol.
164. The method of claim 135, wherein the polar solvent comprises
aqueous ethanol.
165. A method for administering an effective amount of a
pharmacologically active compound to a mammal to provide
transmucosal absorption of a therapeutically effective amount of
the active compound through the oral mucosa of the mammal to the
systemic circulatory system of the mammal, comprising: spraying the
oral mucosa of the mammal with a propellant free buccal spray
composition, containing a pharmacologically active compound
dissolved in a pharmacologically acceptable solvent, comprising in
weight percent of the composition: an active compound in an amount
between 0.005 and 55 percent by weight of the total composition
comprising an acetylcholinesterase inhibitor, a nerve impulse
inhibitor, an anti-cholinergic, an anti-convulsant, an
anti-psychotic, an anxiolytic agent, a dopamine metabolism
inhibitor, an agent for treating post stroke sequelae, a
neuroprotectant, an agent treating Alzheimer's disease, a
neurotransmitter, a neurotransmitter agonist, a sedative, an agent
for treating attention deficit disorder, an agent for treating
narcolepsy, a central adregenic antagonist, an anti-depression
agent, an agent for treating Parkinson's disease, a benzodiazepine
antagonist, a stimulant, a neurotransmitter antagonist, a
tranquilizer or a mixture thereof; and a non-polar solvent in an
amount between 30 and 99.69 percent by weight of the total
composition.
166. The method of claim 165, further comprising a flavoring agent
in an amount between 0.1 and 10 percent by weight of the total
composition.
167. The method of claim 165, wherein the active compound is an
acetylcholinesterase inhibitor comprising galantamine, neostigmine,
physostigmine, and edrophonium or a mixture thereof.
168. The method of claim 165, wherein the active compound is a
nerve impulse inhibitor comprising levobapivacaine, lidocaine,
prilocaine, mepivacaine, propofol, rapacuronium bromide,
ropivacaine, tubocurarine, atracurium, doxaurium, mivacuium,
pancuronium, vercuronium, pipecuronium, rocuronium or a mixture
thereof.
169. The method of claim 165, wherein the active compound is an
anti-cholinergic comprising amantadine, ipretropium, oxitropium,
dicycloverine or a mixture thereof.
170. The method of claim 165, wherein the active compound is an
anti-convulsant comprising acetazloamide, earbamazepine,
clonazepatn, diazepam, divalproex, ethosuximide, lamotrignine acid,
levetriacetam, oxcarbazepine, phenobarbital, phenyloin, pregabalin,
primidone, remacemide, trimethadione, topiramate, vigabatrin,
zonisamide or a mixture thereof.
171. The method of claim 165, wherein the active compound is an
anti-psychotic comprising amisulpride, aripiprazole bifemelane,
bromperidol, clozapine, chlorpromazine, haloperidol, iloperidone
loperidone, olanzapine, quetiapine, fluphenazine, risperidone,
thiothixene, thioridazine, sulpride, ziprasidone or a mixture
thereof.
172. The method of claim 165, wherein the active compound is an
anxiolytic agent comprising amitryptiline, atracurium, buspirone,
chlorzoxazone, clorazepate, cisatracurium, cyclobenzaprine,
eperisone, esopiclone, hydroxyzine, mirtazapine, mivacurium,
pagoclone, sulperide, zaleplon, zopiclone or a mixture thereof.
173. The method of claim 165, wherein the active compound is a
dopamine metabolism inhibitor comprising entacapone, lazebemide,
selegiline, tolcapone or a mixture thereof.
174. The method of claim 165, wherein the active compound is an
agent for treating post stroke sequelae comprising glatiramer,
estradiol, progesterone or a mixture thereof.
175. The method of claim 165, wherein the active compound is a
neuroprotectant comprising donepezil, memanine, nimodipine,
riluzole, rivastigmine, tacrine, xaliproden or a mixture
thereof.
176. The method of claim 165, wherein the active compound is an
agent for treating Alzheimer's disease comprising carbidopa,
lelvodopa, tacrine, donezepil, rivastigmine, galantamine or a
mixture thereof.
177. The method of claim 165, wherein the active compound is a
neurotransmitter comprising acetylcholine, serotonin,
5-hydroxytryptamine (5-HT), GABA, glutamate, aspartate, glycine,
histamine, epinephrine, norpinephrine, dopamine, adenosine, ATP,
nitric oxide or a mixture thereof.
178. The method of claim 165, wherein the active compound is a
neurotransmitter agonist comprising almotriptan, aniracetam,
atomoxetine, benserazide, bromociptine, 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,
zolmitriptan or a mixture thereof.
179. The method of claim 165, wherein the active compound is a
sedative comprising dexmedetomidine, eszopiclone, indiplon,
zolpidem, zaleplon or a mixture thereof.
180. The method of claim 165, wherein the active compound is an
agent for treating attention deficit disorder comprising
amphetamine, dextroamphetamine, methylphenidate, pemoline or a
mixture thereof.
181. The method of claim 165, wherein the active compound is an
agent for treating narcolepsy comprising modafinil, mazindol or a
mixture thereof.
182. The method of claim 165, wherein the active compound is an
anti-depression agent comprising amitriptyline, amoxapine,
bupropion, clomipramine, clomipramine, clorgyline, despipramine,
doxepin, fluoxetine, imipramine, isocarboxazid, maprotiline,
mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine,
protriptyline, sentraline, tranylcyporomine, trazodone, venlafaxine
or a mixture thereof.
183. The method of claim 165, wherein the active compound is an
agent for treating Parkinson's disease comprising amantadine,
bromocriptine, carvidopa, levodopa, pergolide, selegiline or a
mixture thereof.
184. The method of claim 165, wherein the active compound comprises
flumazenil.
185. The method of claim 165, wherein the active compound comprises
deramciclane.
186. The method of claim 165, wherein the active compound is a
stimulant comprising amphetamine, dextroamphetamine, dinoprostone,
methylphenidate, methylphenidate, modafinil, pemoline or a mixture
thereof.
187. The method of claim 165, wherein the active compound comprises
mesoridazine.
188. The method of claim 165, wherein the amount of the spray is
predetermined.
189. The method of claim 165, further comprising a flavoring agent
which comprises a synthetic or natural oil of peppermint, oil of
spearmint, citrus oil, fruit flavor, sweetener or a mixture
thereof.
190. The method of claim 165, wherein the solvent comprises a
(C.sub.2-C.sub.24) fatty acid (C.sub.2-C.sub.6) ester, a
C.sub.7-C.sub.18 hydrocarbon of linear or branched configuration, a
C.sub.2-C.sub.6 alkanoyl ester, or a triglyceride of
C.sub.2-C.sub.6 carboxylic acid.
191. The method of claim 190, wherein the solvent comprises one or
more fatty acid esters.
192. A method for administering an effective amount of a
pharmacologically active sedative to a mammal to provide
transmucosal absorption of a therapeutically effective amount of
the sedative through the oral mucosa of the mammal to the systemic
circulatory system of the mammal, comprising: spraying the oral
mucosa of the mammal with a propellant free buccal spray
composition, containing a pharmacologically active sedative
dissolved in a pharmacologically acceptable solvent, comprising in
weight percent of the composition: zolpidem in an amount between
0.001 and 60 percent by weight of the total composition; and
propylene glycol in an amount between 30 and 99.69 percent by
weight of the total composition; wherein a therapeutically
effective amount of zolpidem is absorbed through the oral mucosa to
the systemic circulatory system to the mammal.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application 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/US97/17399 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 anticoronary 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 trough the
membranes to which they are administered.
SUMMARY OF THE INVENTION
[0003] 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.
[0004] 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%.
[0005] 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 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%.
[0006] 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%.
[0007] 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%. Preferrably 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%.
[0008] 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 soil 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%.
[0009] 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 0.01-45%, provided
that si 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%.
[0010] It is an object of the invention to coat the mucosal
membranes either with extremely fine droplets of spray containing
the active compounds or a solution or paste thereof from bite
capsules.
[0011] 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.
[0012] 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.
[0013] As the propellant evaporates after activation of the aerosol
valve, a mist of fine droplets is formed which contains solvent and
active compound.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] 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.
[0018] 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.)
[0019] 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.
[0020] 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%.
[0021] 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 H-2
receptor antagonists, barbiturates, prostaglandins and
neutraceuticals.
[0022] 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.
[0023] 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, tranquilizer, or a mixture
thereof.
BRIEF DESCRIPTION OF THE DRAWING
[0024] 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
[0025] 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.
[0026] 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 isobutane, 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 an 0.1%, except that water may be
as high as 0.2%.
[0027] 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 maybe used instead of the above low molecular weight
solvents. These include soya oil, corn oil, other vegetable
oils.
[0028] 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.
[0029] 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.
[0030] Therefore, the values given herein are for the compositions
as prepared, it being within the scope of the invention that minor
variations will occur.
[0031] 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.
[0032] The active substances include the active compounds selected
from the group consisting of cyclosporine, sermorelin, octreotide
acetate, calcitonin-salmon, insulin lispro, sumatriptan succinate,
elozepine; cyclobenzaprine, dexfenfluramine hydrochloride,
glyburide, zidovudine, erythromycin, ciprofloxacin ondansetron
hydrochloride, dimenhydrinate, cimetidine hydrochloride,
famotidine, phenyloin sodium, phenyloin, 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.
[0033] 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, anixiolytic 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-expression agent, agent for treating Parkinson's disease,
benzodiazepine antagonist, stimulant, neurotransmitter antagonist,
tranquilizer, or a mixture thereof.
[0034] 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.
[0035] 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.
[0036] 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,
doxaurim, mivacurium, pancuronium, vercuronium, pipecuronium, and
rocuronium.
[0037] 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.
[0038] 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, phenyloin, pregabalin, primidone, remacemide,
trimethadione, topiramate, vigabatrin, and zonisamide.
[0039] 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,
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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,
nortyptiline, paroxetine, pergolide, pramipexole, rizatriptan,
ropinirole, sertraline, sibutramine, sumatriptan, tiagabine,
trazodone, venlafaxine, and zolmitriptan.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] 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-dimethylaminoethanol, 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.
[0059] 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.
[0060] 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.
[0061] The invention is further defined by reference to the
following examples, which are intended to be illustrative and not
limiting.
[0062] 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
TABLE-US-00001 [0063] Amounts preferred amount most preferred
amount A. Cyclosporine lingual spray 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
glycol 20-60 30-45 35-40 flavors 0.1-5 1-4 2-3 B. Cyclosporine
Non-Polar lingual spray cyclosporine 1-50 3-40 5-30 Migylol 20 25
30-40 Polyoxyethylated castor oil 20 25 30-40 Butane 25-80 30-70
33-50 flavors 0.1-5 1-4 2-3 C. Cyclosporine non-polar bite caosule
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 D. Cyclosporine bite capsule cyclosporine 5-50 10-35 15-25
polyethylene glycol 20-60 30-45 35-40 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 E.
Sermorelin (as the acetate) lingual spray sermorelin (as the
acetate) .01-5 .1-3 .2-1.0 mannitol 1-25 5-20 10-15 monobasic
sodium phosphate, 0.1-5 1-31 .5-2.5 dibasic sodium phosphate water
0.01-5 .05-3 0.1-0.5 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 F. Octreotide acetate (Sandostatin) lingual spray
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 G. Calcitonin-salmon
lingual spray 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 glycol 2-15 3-10
7-9.5 sodium chloride 2.5-20 5-15 10-12.5 flavors 0.1-5 1-4 2-3 H.
Insulin lispro, lingual spray 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 amounts
trace amounts trace 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 HCI or NaOH
Example 2
[0064] CNS active amines and their salts: including but not limited
to tricyclic amines, GABA analogues, thiazides, phenothiazine
derivatives, serotonin antagonists and serotonin reuptake
inhibitors
TABLE-US-00002 most Amounts preferred amount preferred amount A.
Sumatriptan succinate lingual spray 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 B. Sumatriptan succinate bite capsule
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 C. Clozepine lingual spray 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 D. Clozepine non-polar lingual spray with
propellant 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 E. Clozepine
non-polar lingual spray without propellant clozepine 0.5-30 1-20
10-15 Migylol 70-99.5 80-99 85-90 flavors 0.1-5 1-4 2-3 F.
Cyclobenzaprine non-polar lingual spray 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 G. Dexfenfluramine hydrochloride
lingual spray 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
TABLE-US-00003 [0065] most Amounts preferred amount preferred
amount A. Glyburide lingual spray 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 B. Glyburide non-polar bite capsule 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
TABLE-US-00004 [0066] preferred most Amounts amount preferred
amount A. Zidovudine [formerly called azidothymidine (AZT)
(Retrovir)] non-polar lingual spray 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 B. Erythromycin bite capsule bite capsule erythromycin
25-65 30-50 35-45 polyoxyethylene glycol 5-70 30-60 45-55 glycerin
5-20 7.5-15 10-12.5 flavors 1-10 2-8 3-6 C. Ciprofloxacin
hydrochloride bite capsule 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 D. zidovudine [formerly called
azidothymidine (AZT) (Retrovir)] lingual spray 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
TABLE-US-00005 [0067] preferred most Amounts amount preferred
amount A. Ondansetron hydrochloride lingual spray 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 9.5-1 flavors 1-10 3-8 5-7.5
B. Dimenhydrinate bite capsule 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 C. Dimenhydrinate polar lingual spray
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
TABLE-US-00006 [0068] Amounts preferred amount most preferred
amount A. Cimetidine hydrochloride bite capsule cimetidine HCl
10-60 15-55 25-50 glycerin 5-20 7.5-15 10-12.5 polyethylene 20-90
25-85 30-75 glycol flavors 1-10 2-8 3-6 B. Famotidine lingual spray
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 20-97 30-95 50-85 glycol flavors
0.1-10 1-7.5 2-5 C. Famotidine non-polar lingual spray famotidine
1-35 5-30 7-20 Soya oil 10-50 15-40 15-20 Butane1 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
TABLE-US-00007 [0069] Amounts preferred amount most preferred
amount A. Phenytoin sodium lingual spray 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 5-30 7.5-20 9.5-15
glycol flavors 1-10 3-8 5-7.5 B. Phenytoin non-polar lingual spray
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
TABLE-US-00008 [0070] preferred most Amounts amount preferred
amount A. Carboprost thromethamine lingual spray 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 B. Carboprost
non-polar lingual spray 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 pH is
adjusted with sodium hydroxide and/or hydrochloric acid
Example 9
Neutraceuticals
TABLE-US-00009 [0071] most Amounts preferred amount preferred
amount A. Carnitine as bite capsule (contents are a paste)
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 B. Valerian as lingual spray 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 C. Echinacea as bite capsule 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 D. Mixtures of ingredients 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)
TABLE-US-00010 [0072] A. Diphenhydramine hydrochloride lingual
spray preferred most Amounts amount preferred 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
TABLE-US-00011 [0073] preferred most Amounts amount preferred
amount A. Isoproterenol Hydrochloride as polar lingual spray
isoproterenol Hydrochloride 0.1-10 0.2-7.5 0.5-6 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 B. Terbutaline sulfate as polar lingual spray
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 C. Terbutaline as
non-polar lingual spray 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 D.
Theophylline polar bite capsule 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 E.
Albuterol sulfate as polar lingual spray 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
TABLE-US-00012 [0074] Most-Preferred Amount Preferred Amount Amount
A. Sulfonylurea 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% B. Prostaglandin E
(vasodilator) 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% C. Promethazine (antiemetic, sleep inducer, and CNS
active amine) 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%
D. Meclizine 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%
* * * * *