U.S. patent application number 12/350898 was filed with the patent office on 2009-05-07 for buccal, polar and non-polar spray or capsule.
Invention is credited to Harry A. Dugger, III.
Application Number | 20090118170 12/350898 |
Document ID | / |
Family ID | 22261809 |
Filed Date | 2009-05-07 |
United States Patent
Application |
20090118170 |
Kind Code |
A1 |
Dugger, III; Harry A. |
May 7, 2009 |
BUCCAL, POLAR AND NON-POLAR SPRAY OR CAPSULE
Abstract
Buccal aerosol sprays or capsule 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 comprises formulation I: polar solvent 37-98.58%, active
compound 0.005-55%, optionally containing flavoring agent
0.1-10%.
Inventors: |
Dugger, III; Harry A.;
(Flemington, NJ) |
Correspondence
Address: |
DICKSTEIN SHAPIRO LLP
1825 EYE STREET NW
Washington
DC
20006-5403
US
|
Family ID: |
22261809 |
Appl. No.: |
12/350898 |
Filed: |
January 8, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10663817 |
Sep 17, 2003 |
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12350898 |
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10100156 |
Mar 18, 2002 |
6676931 |
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10663817 |
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09537118 |
Mar 29, 2000 |
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10100156 |
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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 ;
514/220; 514/397 |
Current CPC
Class: |
A61K 9/0056 20130101;
A61K 31/137 20130101; A61K 31/197 20130101; A61K 31/7076 20130101;
A61K 38/13 20130101; A61K 31/138 20130101; A61K 47/44 20130101;
A61K 9/006 20130101; A61K 9/124 20130101; A61K 31/433 20130101;
A61K 31/085 20130101; A61K 31/27 20130101; A61K 31/4178 20130101;
A61K 47/06 20130101; A61K 47/14 20130101; A61P 1/08 20180101; A61K
31/421 20130101 |
Class at
Publication: |
514/11 ; 514/220;
514/397 |
International
Class: |
A61K 38/13 20060101
A61K038/13; A61K 31/551 20060101 A61K031/551; A61K 31/4178 20060101
A61K031/4178; A61P 1/08 20060101 A61P001/08 |
Claims
1-29. (canceled)
30. 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: a polar solvent in an amount
ranging from 30-99.69%; and an active compound in an amount ranging
from 0.005-55% by weight of the total composition; wherein the
active compound is selected from the group consisting of a central
nervous system active amine, a sulfonyl urea, an antibiotic, an
antiviral, a sleep inducer, an antiasthmatic, an antiemetic, a
histamine H-2 receptor antagonist, a barbiturate, a prostaglandin
or a bronchial dilator.
31. The method of claim 30, wherein the amount of the spray is
predetermined.
32. The method of claim 30, further comprising a flavoring agent in
an amount ranging from 0.1 to 10 percent by weight of the
composition.
33. The method of claim 32, wherein the polar solvent is present in
an amount ranging from 60.9-97.06 percent by weight of the
composition, the active compound is present in an amount ranging
from 0.01 to 40 percent by weight of the composition, and the
flavoring agent is present in an amount ranging from 0.75 to 7.5
percent by weight of the composition.
34. The method of claim 30, wherein the polar solvent comprises a
low molecular weight polyethylene glycol (PEG) having a molecular
weight ranging from 400 to 1,000, a C.sub.2 to C.sub.8 mono- and
polyalcohol, or an alcohol of C.sub.7 to C.sub.18 hydrocarbon of
linear or branched configuration.
35. The method of claim 30, wherein the solvent comprises aqueous
polyethylene alcohol.
36. The method of claim 30, wherein the solvent comprises aqueous
ethanol.
37. The method of claim 30, wherein the active compound is selected
from the group consisting of cyclosporine, clozapine, zidevudine,
ondansetron, carboprost, thromethamine or a pharmaceutically
acceptable salt thereof.
38. 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: propylene glycol in an amount of
about 60%; and ondansetron hydrochloride in an amount ranging from
2.5 to 15% by weight of the total composition; wherein a
therapeutically effective amount of the active compound is absorbed
through the oral mucosa to the systemic circulatory system of the
mammal.
Description
RELATED APPLICATIONS
[0001] This application is a continuation in part of applicant PCT
application PCT/US97/17899 filed Oct. 1, 1997.
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%, non-polar solvent 20-85%, active
compound 0.05-50%, suitably additionally comprising, by weight of
total composition a flavoring agent 0.01-10%. Preferably the
composition comprises: propellant 10-85%, non-polar solvent
25-89.9%, active compound 0.01-40%, flavoring agent 1-8%; most
suitably propellant 20-70%, non-polar solvent 30-74.75%, 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 comprise in weight % of
total composition: aqueous polar solvent 10-99%, 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: 3-5%; most
suitably polar solvent 25-97%, active compound 0.2-25%, flavoring
agent 0.1-2.5% and propellant: 3-4%.
[0006] The buccal pump spray composition of the present invention
for transmucosal administration of a pharmacologically active
compound where said active compound is soluble in a
pharmacologically acceptable non-polar solvent said composition
comprise 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, for transmucosal administration of a pharmacologically
active compound soluble in a pharmacologically acceptable polar
solvent comprising 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: non-polar
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 bite
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 0-40.degree. C. at a pressure range of 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, will 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 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, anti-virals, 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.
BRIEF DESCRIPTION OF THE DRAWING
[0023] The FIGURE is a schematic diagram showing routes of
absorption and processing of pharmacologically active substances in
a mammalian system.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0024] 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 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.
[0025] 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%.
[0026] 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.
[0027] 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.
[0028] 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. Therefore, the values
given herein are for the compositions as prepared, it being within
the scope of the invention that minor variations will occur.
[0029] The preferred flavoring agents are synthetic or natural oil
of pepper-mint, oil of spearmint, citrus oil, fruit flavors,
sweeteners (sugars, aspartame, saccharin, etc.), and combinations
thereof.
[0030] 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, 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] The invention is further defined by reference to the
following examples, which are intended to be illustrative and not
limiting.
[0036] The following are examples of each class (all values unless
otherwise specified are in weight percent):
EXAMPLE 1
Biologically Active Peptides Including Peptide Hormones
TABLE-US-00001 [0037] A. Cyclosporine lingual spray most preferred
Amounts preferred 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
TABLE-US-00002 B. Cyclosporine Non-Polar lingual spray most
preferred Amounts preferred amount amount Cyclosporine 1-50 3-40
5-30 Migylol 20 25 30-40 Polyoxyethylated 20 25 30-40 castor oil
Butane 25-80 30-70 33-50 flavors 0.1-5 1-4 2-3
TABLE-US-00003 C. Cyclosporine non-polar bite capsule most
preferred Amounts preferred 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
TABLE-US-00004 D. Cyclosporine bite capsule most preferred Amounts
preferred 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
TABLE-US-00005 E. Sermorelin (as the acetate) lingual spray Amounts
preferred amount most preferred sermorelin (as the .01-5 .1-3
.2-1.0 acetate) mannitol, 1-25 5-20 10-15 monobasic sodium 0.1-5
1-3 1.5-2.5 phosphate, dibasic sodium 0.01-5 .05-3 0.1-0.5
phosphate water ethanol 5-30 7.5-25 9.5-15 polyethylene glycol
20-60 30-45 35-40 propylene glycol 5-25 10-20 12-17 flavors 0.1-5
1-4 2-3
TABLE-US-00006 F. Octreotide acetate (Sandostatin*) lingual spray
most preferred Amounts preferred 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 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
TABLE-US-00007 G. Calcitonin-salmon lingual spray most preferred
Amounts preferred 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
TABLE-US-00008 H. insulin lispro, lingual spray most preferred
Amounts preferred 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 HCl or NaOH
EXAMPLE 2
CNS Active Amines and their Salts: Including but not Limited to
Tricyclic Amines, GABA Analogues, Thiazides, Phenothiazine
Derivatives, Serotonin Antagonists and Serotonin Reuptake
Inhibitors
TABLE-US-00009 [0038] A. Sumatriptan succinate lingual spray most
preferred Amounts preferred 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
TABLE-US-00010 B. Sumatriptan succinate bite capsule most preferred
Amounts preferred 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
TABLE-US-00011 C. Clozepine lingual spray most preferred Amounts
preferred 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
TABLE-US-00012 D. Clozepine Non-Polar lingual spray with propellant
most preferred Amounts preferred amount amount Clozepine 0.5-30
1-20 10-15 Migylol 20-85 25-70 30-40 Butane 15-80 30-75 60-70
flavors 0.1-5 1-4 2-3
TABLE-US-00013 E. Clozepine Non-Polar lingual spray without
propellant most preferred Amounts preferred amount amount Clozepine
0.5-30 1-20 10-15 Migylol 70-99.5 80-99 85-90 flavors 0.1-5 1-4
2-3
TABLE-US-00014 F. Cyclobenzaprine Non-polar lingual spray most
preferred Amounts preferred amount amount Cyclobenzaprine 0.5-30
1-20 10-15 (base) Migylol 20-85 25-70 30-40 Isobutane 15-80 30-75
60-70 flavors 0.1-5 1-4 2-3
TABLE-US-00015 G. dexfenfluramine hydrochloride lingual spray most
preferred Amounts preferred 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
TABLE-US-00016 [0039] A. Glyburide lingual spray most preferred
Amounts preferred 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
TABLE-US-00017 B. Glyburide non-polar bite capsule most preferred
Amounts preferred amount amount Glyburide 0.01-10 0.025-7.5 0.1-4
olive oil 30-60 35-55 30-50 polyoxyethylated 30-60 35-55 30-50
oleic glycerdes flavors 0.1-5 1-4 2-3
EXAMPLE 4
Antibiotics Anti-Fungals and Anti-Virals
TABLE-US-00018 [0040] A. zidovudine [formerly called azidothymidine
(AZT) (Retrovir) non-polar lingual spray most preferred Amounts
preferred 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
TABLE-US-00019 B. Erythromycin bite capsule bite capsule most
preferred Amounts preferred 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
TABLE-US-00020 C. Ciprofloxacin hydrochloride bite capsule most
preferred Amounts preferred amount amount Ciprofloxacin 25-65 35-55
40-50 hydrochloride glycerin 5-20 7.5-15 10-12.5 polyethylene
glycol 20-75 30-65 40-60 flavors 1-10 2-8 3-6
TABLE-US-00021 D. zidovudine [formerly called azidothymidine (AZT)
(Retrovir) lingual spray most preferred Amounts preferred amount
amount zidovudine 10-50 15-40 25-35 water 30-80 40-75 45-70 ethanol
5-20 7.5-15 9.5-12.5 polyethylene glycol 5-20 7.5-15 9.5-12.5
flavors 0.1-5 1-4 2-3
EXAMPLE 5
Anti-Emetics
TABLE-US-00022 [0041] A. Ondansetron hydrochloride lingual spray
most preferred Amounts preferred amount 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
TABLE-US-00023 B. Dimenhydrinate bite capsule most preferred
Amounts preferred amount amount Dimenhydrinate 0.5-30 2-25 3-15
glycerin 5-20 7.5-15 10-12.5 polyethylene glycol 45-95 50-90 55-85
flavors 1-10 2-8 3-6
TABLE-US-00024 C. Dimenhydrinate polar lingual spray most preferred
Amounts preferred amount amount Dimenhydrinate 3-50 4-40 5-35 water
5-90 10-80 15-75 ethanol 1-80 3-50 5-10 polyethylene 1-80 3-50 5-15
glycol 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 6
Histamine H-2 Receptor Antagonists
TABLE-US-00025 [0042] A. Cimetidine hydrochloride bite capsule most
preferred Amounts preferred amount amount Cimetidine Hcl 10-60
15-55 25-50 glycerin 5-20 7.5-15 10-12.5 polyethylene glycol 20-90
25-85 30-75 flavors 1-10 2-8 3-6
TABLE-US-00026 B. Famotidine lingual spray most preferred Amounts
preferred amount amount Famotidine 1-35 5-30 7-20 water 2.5-25 3-20
5-10 L-aspartic acid 0.1-20 1-15 5-10 polyethylene glycol 20-97
30-95 50-85 flavors 0.1-10 1-7.5 2-5
TABLE-US-00027 C. Famotidine non-polar lingual spray most preferred
Amounts preferred amount amount Famotidine 1-35 5-30 7-20 Soya oil
10-50 15-40 15-20 Butane 15-80 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-00028 [0043] A. Phenytoin sodium lingual spray most
preferred Amounts preferred amount amount Phenytoin sodium 10-60
15-55 20-40 water 2.5-25 3-20 5-10 ethanol 5-30 7.5-20 9.5-15
propylene glycol 5-30 7.5-20 9.5-15 polyethylene glycol 5-30 7.5-20
9.5-15 flavors 1-10 3-8 5-7.5
TABLE-US-00029 B. Phenytoin non-polar lingual spray most preferred
Amounts preferred amount amount Phenytoin 5-45 10-40 15-35 migylol
10-50 15-40 15-20 Butane 15-80 30-75 60-70 polyoxyethylated 10-50
15-40 15-20 oleic glycerides flavors 0.1-10 1-8 5-7.5
EXAMPLE 8
Prostaglandins
TABLE-US-00030 [0044] A. Carboprost thromethamine lingual spray
most preferred Amounts preferred amount 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 pH is adjusted with
sodium hydroxide and/or hydrochloric acid
TABLE-US-00031 B. Carboprost non-polar lingual spray most preferred
Amounts preferred amount amount Carboprost 0.05-5 0.1-3 0.25-2.5
migylol 25-50 30-45 35-40 Butane 5-60 10-50 20-35 polyoxyethylated
25-50 30-45 35-40 oleic glycerides flavors 0.1-10 1-8 5-7.5
EXAMPLE 9
TABLE-US-00032 [0045] A. Carnitine as bite capsule (contents are a
paste) 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
TABLE-US-00033 B. Valerian as lingual spray 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
TABLE-US-00034 B. Echinacea as bite capsule 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 0.005-0.5 .01-0.1
Soya fats 7.5-50 10-40 12.5-35 flavors 1-10 2-8 3-6
TABLE-US-00035 B. Mixtures of ingredients 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)
TABLE-US-00036 [0046] A. Diphenhydramine hydrochloride lingual
spray 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 1-80 3-50 5-15 glycol 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-00037 [0047] A. Isoproterenol Hydrochloride as polar
lingual spray most preferred Amounts preferred amount amount
Isoproterenol 0.1-10 0.2-7.5 0.5-6 Hydrochloride water 5-90 10-80
50-75 ethanol 1-80 3-50 5-10 polyethylene 1-80 3-50 5-15 glycol
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
TABLE-US-00038 B. Terbutaline sulfate as polar lingual spray most
preferred Amounts preferred amount amount Terbutaline 0.1-10
0.2-7.5 0.5-6 sulfate 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
TABLE-US-00039 C. Terbutaline as non-polar lingual spray 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
TABLE-US-00040 D. Theophylline polar bite capsule most preferred
Amounts preferred amount amount Theophylline 5-50 10-40 15-30
polyethylene 20-60 25-50 30-40 glycol glycerin 25-50 35-45 30-40
propylene glycol 25-50 35-45 30-40 flavors 0.1-5 1-4 2-3
TABLE-US-00041 E. Albuterol sulfate as polar lingual spray most
preferred Amounts preferred amount amount Albuterol sulfate 0.1-10
0.2-7.5 0.5-6 water 5-90 10-80 50-75 ethanol 1-10 2-8 2.5-5
Sorbitol 0.1-5 0.2-4 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1
flavors 0.1-5 1-4 2-3
EXAMPLE 12
Polar Solvent Formulations Using a Propellant
TABLE-US-00042 [0048] A. Sulfonylurea Most-Preferred Amount
Preferred Amount Amount Glyburide 0.1-25% 0.5-15% 0.6-10% Ethanol
40-99% 60-97% 70-97% Water 0.01-5% 0.1-4% 0.2-2% Flavors 0.05-10%
0.1-5% 0.1-2.5% Propellant 2-10% 3-5% 3-4%
TABLE-US-00043 B. Prostaglandin E.sub.1 (vasodilator)
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%
TABLE-US-00044 C. Promethazine (antiemetic, sleep inducer, and CNS
active amine) 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%
TABLE-US-00045 D. Meclizine 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%
* * * * *