U.S. patent application number 10/230059 was filed with the patent office on 2003-10-02 for buccal, polar and non-polar spray or capsule containing drugs for treating pain.
Invention is credited to Dugger, Harry A. III.
Application Number | 20030185761 10/230059 |
Document ID | / |
Family ID | 32312002 |
Filed Date | 2003-10-02 |
United States Patent
Application |
20030185761 |
Kind Code |
A1 |
Dugger, Harry A. III |
October 2, 2003 |
Buccal, polar and non-polar spray or capsule containing drugs for
treating pain
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, Harry A. III;
(Flemington, NJ) |
Correspondence
Address: |
PENNIE & EDMONDS LLP
1667 K STREET NW
SUITE 1000
WASHINGTON
DC
20006
|
Family ID: |
32312002 |
Appl. No.: |
10/230059 |
Filed: |
August 29, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10230059 |
Aug 29, 2002 |
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09537118 |
Mar 29, 2000 |
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09537118 |
Mar 29, 2000 |
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PCT/US97/17899 |
Oct 1, 1997 |
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Current U.S.
Class: |
424/43 |
Current CPC
Class: |
A61K 31/138 20130101;
A61P 23/02 20180101; A61K 31/085 20130101; A61K 38/13 20130101;
A61K 31/4178 20130101; A61P 25/36 20180101; A61K 31/137 20130101;
A61P 33/00 20180101; A61K 31/27 20130101; A61K 31/7076 20130101;
A61K 9/0056 20130101; A61P 35/00 20180101; A61K 31/433 20130101;
A61P 25/06 20180101; A61K 31/197 20130101; A61P 29/00 20180101;
A61K 31/421 20130101; A61P 31/00 20180101; A61K 9/006 20130101;
A61P 25/04 20180101 |
Class at
Publication: |
424/43 |
International
Class: |
A61K 009/00; A61L
009/04 |
Claims
What is claimed is:
1. A propellant free buccal spray composition for transmucosal
administration of a pharmacologically active compound comprising:
an active compound in an amount of between 0.001 and 60 percent by
weight of the total composition selected from the group consisting
of anti-opioid agents, anti-migraine agents, pain control agents,
anesthetics, and mixtures thereof; and a polar solvent in an amount
between 30 and 99 percent by weight of the total composition.
2. The composition of claim 1, further comprising a flavoring agent
in an amount of between 0.1 and 10 percent by weight of the total
composition.
3. The composition of claim 2, wherein the polar solvent is present
in an amount between 37 and 98 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.
4. The composition of claim 3, wherein the polar solvent is present
in an amount between 60 and 97 percent by weight 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.
5. The composition of claim 1, wherein the polar solvent is
selected from the group consisting of polyethylene glycols having a
molecular weight between 400 and 1000, C.sub.2 to C.sub.8 mono- and
poly-alcohols, and C.sub.7 to C.sub.18, alcohols of linear or
branched configuration.
6. The composition of claim 1, wherein the polar solvent comprises
aqueous polyethylene glycol.
7. The composition of claim 1, wherein the polar solvent comprises
aqueous ethanol.
8. The composition of claim 1, wherein the active compound is an
anti-opioid agent selected from the group consisting of naloxone,
nalmefene, naltrexone, cholecystokinin, nociceptin, neuropeptide
FF, oxytocin, vasopressin, and mixtures thereof.
9. The composition of claim 1, wherein the active compound is an
anti-migraine agent selected from the group consisting of
frovatriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan,
naratriptan, almotriptan, ergotamine, diethylergotamine,
sumatriptan, and mixtures thereof.
10. The composition of claim 1, wherein the active compound is a
pain control agent selected from the group consisting of
non-steroidal anti-inflammatory drugs, alfentanil, butorphanol,
codeine, dezocine, fentanyl, hydrocodone, hydromorphone,
levorphanol, meperidine, methadone, morphine, nalbuphine,
oxycodone, oxymorphone, propoxyphene, pentazocine, sufentanil,
tramadol, and mixtures thereof.
11. The composition of claim 1, wherein the active compound is an
anesthetic selected from the group consisting of benzonatate,
bupivacaine, desflurane, enflurane, isoflurane, levobupivacaine,
lidocaine, mepivacaine, prilocaine, propofol, rapacuronium bromide,
ropivacaine, sevoflurane, ketamine, and mixtures thereof.
12. The composition of claim 2, wherein the flavoring agent is
selected from the group consisting of synthetic or natural oil of
peppermint, oil of spearmint, citrus oil, fruit flavors,
sweeteners, and mixtures thereof.
13. A method of administering a pharmacologically active compound
to a mammal comprising spraying the oral mucosa of the mammal with
the composition of claim 1.
14. The method of claim 13, wherein the amount of the spray is
predetermined.
15. A buccal spray composition for transmucosal administration of a
pharmacologically active compound comprising: an active compound in
an amount of between 0.1 and 25 percent by weight of the total
composition selected from the group consisting of anti-opioid
agents, anti-migraine agents, pain control agents, anesthetics, and
mixtures thereof; a polar solvent in an amount between 10 and 97
percent by weight of the total composition; and a propellant in an
amount between 2 and 10 percent by weight of the total composition,
wherein said propellant is a C.sub.3 to C.sub.8 hydrocarbon of
linear or branched configuration.
16. The composition of claim 15, further comprising a flavoring
agent in an amount between 0.05 and 10 percent by weight of the
total composition.
17. The composition of claim 16, wherein the polar solvent is
present in an amount between 20 and 97 percent by weight of the
total composition, the active compound is present in an amount
between 0.1 and 15 percent by weight of the total composition, the
propellant is present in an amount between 2 and 5 percent by
weight of the composition, and the flavoring agent is present in an
amount between 0.1 and 5 percent by weight of the total
composition.
18. The composition of claim 17, wherein the polar solvent is
present in an amount between 25 and 97 percent by weight of the
total composition, the active compound is present in an amount
between 0.2 and 25 percent by weight of the total composition, the
propellant is present in an amount between 2 and 4 percent by
weight of the composition, and flavoring agent is present in an
amount between 0.1 and 2.5 percent by weight of the total
composition.
19. The composition of claim 15, wherein the polar solvent is
selected from the group consisting of polyethyleneglycols having a
molecular weight between 400 and 1000, C.sub.2 to C.sub.8 mono- and
poly-alcohols, and C.sub.7 to C.sub.18 alcohols of linear or
branched configuration.
20. The composition of claim 19, wherein the polar solvent
comprises aqueous polyethylene glycol.
21. The composition of claim 19, wherein the polar solvent
comprises aqueous ethanol.
22. The composition of claim 15, wherein the active compound is an
anti-opioid agent selected from the group consisting of naloxone,
nalmefene, naltrexone, cholecystokinin, nociceptin, neuropeptide
FF, oxytocin, vasopressin, and mixtures thereof.
23. The composition of claim 15, wherein the active compound is an
anti-migraine agent selected from the group consisting of
frovatriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan,
naratriptan, almotriptan, ergotamine, diethylergotamine,
sumatriptan, and mixtures thereof.
24. The composition of claim 15, wherein the active compound is a
pain control agent selected from the group consisting of
non-steroidal anti-inflammatory drugs, alfentanil, butorphanol,
codeine, dezocine, fentanyl, hydrocodone, hydromorphone,
levorphanol, meperidine, methadone, morphine, nalbuphine,
oxycodone, oxymorphone, propoxyphene, pentazocine, sufentanil,
tramadol, and mixtures thereof.
25. The composition of claim 15, wherein the active compound is an
anesthetic selected from the group consisting of benzonatate,
bupivacaine, desflurane, enflurane, isoflurane, levobupivacaine,
lidocaine, mepivacaine, prilocaine, propofol, rapacuronium bromide,
ropivacaine, sevoflurane, ketamine, and mixtures thereof.
26. The composition of claim 16, wherein the flavoring agent is
selected from the group consisting of synthetic or natural oil of
peppermint, oil of spearmint, citrus oil, fruit flavors,
sweeteners, and mixtures thereof.
27. The composition of claim 15, wherein the propellant is selected
from the group consisting of propane, N-butane, iso-butane,
N-pentane, iso-pentane, neo-pentane, and mixtures thereof.
28. A method of administering a pharmacologically active compound
to a mammal comprising spraying the oral mucosa of the mammal with
the composition of claim 15.
29. The method of claim 28, wherein the amount of the spray is
predetermined.
30. A propellant free buccal spray composition for transmucosal
administration of a pharmacologically active compound comprising:
an active compound in an amount between 0.005 and 55 percent by
weight of the total composition selected from the group consisting
of anti-opioid agents, anti-migraine agents, pain control agents,
anesthetics, and mixtures thereof; and a non-polar solvent in an
amount between 30 and 99 percent by weight of the total
composition.
31. The composition of claim 30, further comprising a flavoring
agent in an amount between 0.1 and 10 percent by weight of the
total composition.
32. The composition of claim 30, wherein the active compound is an
anti-opioid agent selected from the group consisting of naloxone,
nalmefene, naltrexone, cholecystokinin, nociceptin, neuropeptide
FF, oxytocin, vasopressin, and mixtures thereof.
33. The composition of claim 30, wherein the active compound is an
anti-migraine agent selected from the group consisting of
frovatriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan,
naratriptan, almotriptan, ergotamine, diethylergotamine,
sumatriptan, and mixtures thereof.
34. The composition of claim 30, wherein the active compound is a
pain control agent selected from the group consisting of
non-steroidal anti-inflammatory drugs, alfentanil, butorphanol,
codeine, dezocine, fentanyl, hydrocodone, hydromorphone,
levorphanol, meperidine, methadone, morphine, nalbuphine,
oxycodone, oxymorphone, propoxyphene, pentazocine, sufentanil,
tramadol, and mixtures thereof.
35. The composition of claim 30, wherein the active compound is an
anesthetic selected from the group consisting of benzonatate,
bupivacaine, desflurane, enflurane, isoflurane, levobupivacaine,
lidocaine, mepivacaine, prilocaine, propofol, rapacuronium bromide,
ropivacaine, sevoflurane, ketamine, and mixtures thereof.
36. The composition of claim 31, wherein the flavoring agent is
selected from the group consisting of synthetic or natural oil of
peppermint, oil of spearmint, citrus oil, fruit flavors,
sweeteners, and mixtures thereof.
37. The composition of claim 30, wherein the solvent is selected
from the group consisting of (C.sub.2-C.sub.24) fatty acid
(C.sub.2-C.sub.6) esters, C.sub.7-C.sub.18 hydrocarbons of linear
or branched configuration, C.sub.2-C.sub.6 alkanoyl esters, and
triglycerides of C.sub.2-C.sub.6 carboxylic acids.
38. The composition of claim 37, wherein the solvent is
miglyol.
39. A method of administering a pharmacologically active compound
to a mammal comprising spraying the oral mucosa of the mammal with
the composition of claim 30.
40. The method of claim 39, wherein the amount of the spray is
predetermined.
41. A buccal spray composition for transmucosal administration of a
pharmacologically active compound comprising: an active compound in
an amount between 0.05 and 50 percent by weight of the total
composition selected from the group consisting of anti-opioid
agents, anti-migraine agents, pain control agents, anesthetics, and
mixtures thereof; and a non-polar solvent in an amount between 19
and 85 percent by weight of the total composition; and a propellant
in an amount between 5 and 80 percent by weight of the total
composition, wherein said propellant is a C.sub.3 to C.sub.8
hydrocarbon of linear or brancehed configuration.
42. The composition of claim 41, further comprising a flavoring
agent in an amount of between 0.1 and 10 percent by weight of the
total composition.
43. The composition of claim 42, wherein the flavoring agent is
selected from the group consisting of synthetic or natural oil of
peppermint, oil of spearmint, citrus oil, fruit flavors,
sweeteners, and mixtures thereof.
44. A buccal spray composition for transmucosal administration of a
pharmacologically active compound comprising: an active compound in
an amount between 0.01 and 40 percent by weight of the total
composition selected from the group consisting of anti-opioid
agents, anti-migraine agents, pain control agents, anesthetics, and
mixtures thereof; and a non-polar solvent in an amount between 25
and 89 percent by weight of the total composition; a propellant in
an amount between 10 and 70 percent by weight of the total
composition, wherein said propellant is a C.sub.3 to C.sub.8
hydrocarbon of linear or brancehed configuration; and A flavoring
agent is present in an amount between 1 and 8 percent by weight of
the total composition.
45. The composition of claim 44, wherein the propellant is present
in an amount between 20 and 70 percent by weight of the total
composition, the non-polar solvent is present in an amount between
25 and 75 percent by weight of the total composition, the active
compound is present in an amount from between 0.25 and 35 percent
by weight of the total composition, and the flavoring agent is
present in an amount between 2 and 7.5 percent by weight of the
total composition.
46. The composition of claim 42, wherein the propellant is selected
from the group consisting of propane, n-butane, iso-butane,
n-pantane, iso-pentane, neo-pentane, and mixtures thereof.
47. The composition of claim 46, wherein the propellant is n-butane
or iso-butane and has a water content of not more than 0.2 percent
and a concentration of oxidizing agents, reducing agents, Lewis
acids, and Lewis bases of less than 0.1 percent.
48. The composition of claim 41, wherein the solvent is selected
from the group consisting of (C.sub.2-C.sub.24) fatty acid
(C.sub.2-C.sub.6) esters, C.sub.7-C.sub.18 hydrocarbons of linear
or branched configuration, C.sub.2-C.sub.6 alkanoyl esters, and
triglycerides of C.sub.2-C.sub.6 carboxylic acids.
49. The composition of claim 48, wherein the solvent is
miglyol.
50. The composition of claim 41, wherein the active compound is an
anti-opioid agent selected from the group consisting of naloxone,
nalmefene, naltrexone, cholecystokinin, nociceptin, neuropeptide
FF, oxytocin, vasopressin, and mixtures thereof.
51. The composition of claim 41, wherein the active compound is an
anti-migraine agent selected from the group consisting of
frovatriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan,
naratriptan, almotriptan, ergotamine, diethylergotamine,
sumatriptan, and mixtures thereof.
52. The composition of claim 41, wherein the active compound is a
pain control agent selected from the group consisting of
non-steroidal anti-inflammatory drugs, alfentanil, butorphanol,
codeine, dezocine, fentanyl, hydrocodone, hydromorphone,
levorphanol, meperidine, methadone, morphine, nalbuphine,
oxycodone, oxymorphone, propoxyphene, pentazocine, sufentanil,
tramadol, and mixtures thereof.
53. The composition of claim 41, wherein the active compound is an
anesthetic selected from the group consisting of benzonatate,
bupivacaine, desflurane, enflurane, isoflurane, levobupivacaine,
lidocaine, mepivacaine, prilocaine, propofol, rapacuronium bromide,
ropivacaine, sevoflurane, ketamine, and mixtures thereof.
54. A method of administering a pharmacologically active compound
to a mammal comprising spraying the oral mucosa of the mammal with
the composition of claim 41.
55. The method of claim 54, wherein the amount of the spray is
predetermined.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of application
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.
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%. 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%.
[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 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%.
[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 0.01-65%, 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%.
[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 nerve impulse
inhibitors, anti-opioid agents, anti-migraine agents, anti-muscle
spasm agents, pain control agents, anesthetics, anti-inflammatory
drugs, or mixtures 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 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%.
[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 may be 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,
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.
[0033] In another embodiment, the active compound is a nerve
impulse inhibitor, anti-opioid agent, anti-migraine agent,
anti-muscle spasm agent, pain control agent, anesthetic,
anti-inflammatory drug, or a mixture thereof.
[0034] 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,
doxacurium, mivacurium, pancuronium, vecuronium, pipecuronium,
rocuronium, and mixtures thereof.
[0035] In one embodiment the active compound is an anti-opioid
agent. Suitable anti-opioid agents for use in the buccal sprays of
the invention include, but are not limited to, naloxone, nalmefene,
naltrexone, cholecystokinin, nociceptin, neuropeptide FF, oxytocin,
vasopressin, and mixtures thereof.
[0036] In one embodiment the active compound is an anti-migraine
agent. Suitable anti-migraine agents for use in the buccal sprays
of the invention include, but are not limited to, frovatriptan,
zolmitriptan, rizatriptan, almotriptan, eletriptan, naratriptan,
almotriptan, ergotamine, diethylergotamine, sumatriptan, and
mixtures thereof.
[0037] In one embodiment the active compound is an anti-muscle
spasm agent. Suitable anti-muscle spasm agents for use in the
buccal sprays of the invention include, but are not limited to,
baclofen, botulinum toxin, carisoprodol, chlorphenesin,
chlorzoxazone, cyclobenzaprine, dantrolene, diazepam, metaxalone,
methocarbamol, orphenadrine, tizanidine, and mixtures thereof.
[0038] In one embodiment the active compound is a pain control
agent. Suitable pain control agents for use in the buccal sprays of
the invention include, but are not limited to, non-steroidal
anti-inflammatory drugs, alfentanil, butorphanol, codeine,
dezocine, fentanyl, hydrocodone, hydromorphone, levorphanol,
meperidine, methadone, morphine, nalbuphine, oxycodone,
oxymorphone, propoxyphene, pentazocine, sufentanil, tramadol, and
mixtures thereof.
[0039] In one embodiment the active compound is an anesthetic.
Suitable anesthetics for use in the buccal sprays of the invention
include, but are not limited to, benzonatate, bupivacaine,
desflurane, enflurane, isoflurane, levobupivacaine, lidocaine,
mepivacaine, prilocaine, propofol, rapacuronium bromide,
ropivacaine, sevoflurane, ketamine, and mixtures thereof.
[0040] In one embodiment the active compound is an
anti-inflammatory drug. Suitable anti-inflammatory drugs for use in
the buccal sprays of the invention include, but are not limited to,
alosetron, anakinra, beclomethasone, betamethasone, budesonide,
clobetasol, celecoxib, cromolyn, desoximetasone, dexamethasone,
epinastic, etanercept, etoricoxib, flunisolide, fluocinonide,
fluticasone, formoterol, hydrocortisone, hydroxychloroquine,
ibudilast, ketotifen, meloxicam, mesalamine, methotrexate,
methylprednisolone, mometasone, montelukast, nedocromil,
olsalazine, prednisone, ramatroban, rofecoxib, salsalate,
terbutaline, triamcinolone, valdecoxib, zafirlukast, and mixtures
thereof.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] The invention is further defined by reference to the
following examples, which are intended to be illustrative and not
limiting.
[0046] 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
[0047] A. Cyclosporine Lingual Spray
1 preferred most preferred Amounts amount 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 glycol 20-60 30-45 35-40 flavors 0.1-5 1-4 2-3
[0048] B. Cyclosporine Non-Polar Lingual Spray
2 preferred most preferred Amounts amount amount 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
[0049] C. Cyclosporine Non-polar Bite Caosule
3 preferred most preferred Amounts amount 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
[0050] D. Cyclosporine Bite Capsule
4 preferred most preferred Amounts amount amount 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
[0051] E. Sermorelin (as the Acetate) Lingual Spray
5 preferred Amounts amount most preferred sermorelin (as the
acetate) .01-5 .1-3 .2-1.0 mannitol 1-25 5-20 10-15 monobasic
sodium phosphate, 0.1-5 1-3.1 .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
[0052] F. Octreotide Acetate (Sandostatin) Lingual Spray
6 preferred most preferred Amounts amount 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 .sup. .5-25.sup. 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
[0053] G. Calcitonin-salmon Lingual Spray
7 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 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
[0054] H. Insulin Lispro, Lingual Spray
8 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 1-15 2.5-10 4-8
phosphate 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
CNS Active Amines and their Salts: Including but not Limited to
Tricyclic Amines, GABA Analogues, Thiazides, Phenothiazine
Derivatives, Serotonin Antagonists and Serotonin Reuptake
Inhibitors
[0055] A. Sumatriptan Succinate Lingual Spray
9 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
[0056] B. Sumatriptan Succinate Bite Capsule
10 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
[0057] C. Clozepine Lingual Spray
11 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
[0058] D. Clozepine Non-polar Lingual Spray with Propellant
12 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
[0059] E. Clozepine Non-polar Lingual Spray without Propellant
13 preferred most preferred Amounts amount amount clozepine 0.5-30
1-20 10-15 Migylol .sup. 70-99.5 80-99 85-90 flavors 0.1-5 1-4
2-3
[0060] F. Cyclobenzaprine Non-polar Lingual Spray
14 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
[0061] G. Dexfenfluramine Hydrochloride Lingual Spray
15 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
[0062] A. Glyburide Lingual Spray
16 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
[0063] B. Glyburide Non-polar Bite Capsule
17 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
[0064] A. Zidovudine [Formerly Called Azidothymidine (AZT)
(Retrovir)] Non-polar Lingual Spray
18 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
[0065] B. Erythromycin Bite Capsule Bite Capsule
19 preferred most preferred Amounts amount amount 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
[0066] C. Ciprofloxacin Hydrochloride Bite Capsule
20 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
[0067] D. zidovudine [Formerly Called Azidothymidine (AZT)
(Retrovir)] Lingual Spray
21 most Amounts preferred amount preferred 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
[0068] A. Ondansetron Hydrochloride Lingual Spray
22 most Amounts preferred amount preferred amount ondansetron 1-25
2-20 2.5-15 hydrochloride citric acid 1-10 2-8 2.5-5 monohydrate
sodium citrate 0.5-5 1-4 1.25-2.5 dihydrate 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
[0069] B. Dimenhydrinate Bite Capsule
23 most Amounts preferred amount preferred 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
[0070] C. Dimenhydrinate Polar Lingual Spray
24 most Amounts preferred amount preferred 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
[0071] A. Cimetidine Hydrochloride Bite Capsule
25 most Amounts preferred amount preferred 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
[0072] B. Famotidine Lingual Spray
26 most Amounts preferred amount preferred 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
[0073] C. Famotidine Non-polar Lingual Spray
27 most Amounts preferred amount preferred 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
[0074] A. Phenytoin Sodium Lingual Spray
28 most Amounts preferred amount preferred 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
[0075] B. Phenytoin Non-polar Lingual Spray
29 most Amounts preferred amount preferred 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
[0076] A. Carboprost Thromethamine Lingual Spray
30 most Amounts preferred amount preferred amount carboprost 0.05-5
0.1-3 0.25-2.5 thromethamine 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
[0077] pH is Adjusted with Sodium Hydroxide and/or Hydrochloric
Acid
[0078] B. Carboprost Non-polar Lingual Spray
31 Amounts preferred amount most preferred 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
[0079] A. Carnitine as Bite Capsule (Contents are a Paste)
32 most preferred Amounts preferred 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
[0080] B. Valerian as Lingual Spray
33 most preferred Amounts preferred 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
[0081] C. Echinacea as Bite Capsule
34 most preferred Amounts preferred 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.sup. 0.005-0.5 .01-0.1 Soya fats 7.5-50 10-40 12.5-35
flavors 1-10 2-8 3-6
[0082] D. Mixtures of Ingredients
35 most preferred Amounts preferred 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)
[0083] A. Diphenhydramine Hydrochloride Lingual Spray
36 most preferred Amounts preferred 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
[0084] A. Isoproterenol Hydrochloride as Polar Lingual Spray
37 most preferred Amounts preferred amount amount 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 .sup. 0.01-0.5.sup. 0.02-0.4 0.04-0.1
flavors 0.1-5 1-4 2-3
[0085] B. Terbutaline Sulfate as Polar Lingual Spray
38 most preferred Amounts preferred amount 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 .sup.
0.01-0.5.sup. 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3
[0086] C. Terbutaline as Non-polar Lingual Spray
39 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
[0087] D. Theophylline Polar Bite Capsule
40 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
[0088] E. Albuterol Sulfate as Polar Lingual Spray
41 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 .sup. 0.01-0.5.sup. 0.02-0.4
0.04-0.1 flavors 0.1-5 1-4 2-3
Example 12
Polar Solvent Formulations Using a Propellant
[0089] A. Sulfonylurea
42 Amount Preferred Amount Most-Preferred 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%
[0090] B. Prostaglandin E (Vasodilator)
43 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%
[0091] C. Promethazine (Antiemetic, Sleep Inducer, and CNS Active
Amine)
44 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%
[0092] D. Meclizine
45 Most-Preferred Amount Preferred Amount Amount meclizine 1-25%
3-15% 5-12% Ethanol 1-15% 2-10% 3-6 .sup. 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%
* * * * *