U.S. patent application number 12/987009 was filed with the patent office on 2011-04-28 for methods of treating epiphora.
Invention is credited to Mitchell H. FRIEDLAENDER, Harun Takruri.
Application Number | 20110097425 12/987009 |
Document ID | / |
Family ID | 39468217 |
Filed Date | 2011-04-28 |
United States Patent
Application |
20110097425 |
Kind Code |
A1 |
FRIEDLAENDER; Mitchell H. ;
et al. |
April 28, 2011 |
Methods of Treating Epiphora
Abstract
The present invention is related to a method for treating
epiphora, the method comprising administering to a nasal area of a
subject in need thereof a composition comprising camphor,
eucalyptus oil, and menthol, wherein the composition is
substantially free of lipids other than the eucalyptus oil.
Inventors: |
FRIEDLAENDER; Mitchell H.;
(La Jola, CA) ; Takruri; Harun; (Newport Beach,
CA) |
Family ID: |
39468217 |
Appl. No.: |
12/987009 |
Filed: |
January 7, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11979355 |
Nov 1, 2007 |
7887859 |
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12987009 |
|
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60856007 |
Nov 2, 2006 |
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Current U.S.
Class: |
424/742 |
Current CPC
Class: |
A61K 36/00 20130101;
A61P 27/00 20180101; A61K 36/53 20130101; A61P 27/02 20180101 |
Class at
Publication: |
424/742 |
International
Class: |
A61K 36/61 20060101
A61K036/61; A61P 27/00 20060101 A61P027/00 |
Claims
1. A method for treating epiphora in a subject in need of such
treatment, the method comprising administering to a nasal area of
the subject a therapeutically effective amount of a composition
comprising camphor, eucalyptus oil, and menthol, wherein the
composition is substantially free of lipids other than the
eucalyptus oil.
2. The method of claim 1, wherein the composition is a gel, cream,
ointment, jelly, lotion, or viscous liquid.
3. The method of claim 1, wherein the composition further comprises
a viscosity modifying agent.
4. The method of claim 3, wherein the viscosity modifying agent is
selected from the group consisting of polyethylene glycol,
polyvinyl alcohol, gelatin, hyaluronic acid, carbomer, tragacanth,
soluble cellulose derivatives, colloidal magnesium aluminum
silicate, sodium alginate, and combinations thereof.
5. The method of claim 4, wherein the viscosity modifying agent is
polyethylene glycol.
6. The method of claim 4, wherein the viscosity modifying agent is
about 50% to about 95% (w/w) of the composition.
7. The method of claim 1, wherein the camphor is about 1% to about
10% (w/w) of the composition.
8. The method of claim 1, wherein the eucalyptus oil is about 0.5%
to about 5% (w/w) of the composition.
9. The method of claim 1, wherein the menthol is about 1% to about
10% (w/w) of the composition.
10. The method of claim 1, wherein the composition is water
soluble.
11. The method of claim 1, wherein the composition further
comprises an excipient.
12. (canceled)
13. The method of claim 12, wherein the excipient is about 0.05% to
about 5% (w/w) of the composition.
14. (canceled)
15. The method of claim 1, wherein the composition further
comprises a mucoadhesive.
16. The method of claim 15, wherein the mucoadhesive is selected
from the group consisting of hydroxypropyl cellulose, hydroxypropyl
methylcellulose, hydroxy ethylcellulose, ethylcellulose,
carboxymethyl cellulose, dextran, guar gum, polyvinyl pyrrolidone,
a pectin, a starch, gelatin, casein, an acrylic acid polymer, a
polymer of acrylic acid ester, an acrylic acid copolymer, a vinyl
polymer, a vinyl copolymer, a polymer of vinyl alcohol, an alkoxy
polymer, a polyethylene oxide polymer, a polyether, and
combinations thereof.
17. The method of claim 1, wherein said administering to a nasal
area comprises administering to a nasal cavity, external nare,
upper lip, philtrum, or combination thereof of the subject in need
of such treatment.
18. A method of treating epiphora in a subject in need of such
treatment, the method comprising administering to an ocular area of
the subject a therapeutically effective amount of a composition
comprising camphor, eucalyptus oil, and menthol, wherein the
composition is substantially free of lipids other than the
eucalyptus oil.
19. The method of claim 18, wherein the composition comprises (a)
about 0.004% to about 0.4% (w/v) camphor; (b) about 0.001% to about
0.5% (w/v) eucalyptus oil; and (c) about 0.001% to about 0.5% (w/w)
menthol.
20. (canceled)
21. The method of claim 1, wherein said composition comprises: (a)
about 1.0% to about 10% (w/w) camphor; (b) about 0.05% to about 5%
(w/w) eucalyptus oil; and (c) about 1.0% to about 10% (w/w)
menthol.
22. A composition comprising: (a) about 1.0% to about 10% (w/w)
camphor; (b) about 0.05% to about 5% (w/w) eucalyptus oil; (c)
about 1.0% to about 10% (w/w) menthol; and (d) about 75% to about
97.5% (w/w) polyethylene glycol, wherein the composition is
substantially free of lipids other than the eucalyptus oil.
23. (canceled)
24. (canceled)
25. (canceled)
26. The method of claim 1, wherein the epiphora is brought about or
exacerbated by irritation of the eye.
Description
[0001] This application claims the benefit of the filing date of
U.S. Appl. No. 60/856,007, filed Nov. 2, 2006, the entirety of
which is fully incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is related to methods of treating
epiphora, the methods comprising administering to a nasal area or
ocular area of a subject in need thereof a composition comprising
camphor, eucalyptus oil, and menthol, wherein the composition is
substantially free of lipids other than the eucalyptus oil.
[0004] 2. Background Art
[0005] Tears are continuously produced by the lacrimal and
accessory lacrimal glands, and bathe the eye with a complex fluid
consisting of aqueous, mucinous, and oily components. Tears drain
through the lacrimal puncta, small openings at the inner edge of
the upper and lower eyelids, through canals (the canaliculi), into
the nasolacrimal duct, and finally into the nose. Excessive
tearing, or watering of the eyes, is known as "epiphora." Epiphora
is a common condition, especially in some populations, e.g., senior
citizens, allergic individuals, and people with rosacea and/or
blepharitis. The most common causes of epiphora are nasal
congestion, laxity of the lower eyelid (ectropion), and turning out
of the tear drainage duct (punctal ectropion). These causes are
usually associated with inadequate, or misdirected, drainage of
naturally-produced tears. If there is blockage, or a narrowing, of
the tear drainage system, clearance of tears can be impaired, and
the tears can "back up," accumulate in the eyes, or run down the
face.
[0006] In some instances, epiphora is due to excessive production
of tears. Excessive production of tears can occur when the eyes are
irritated by chemical, mechanical, and biological stimuli (such as
allergens, and microbial agents). Excessive tearing can also be
caused by irritation of the eye from debris on the eyelids, or from
misdirected eye lashes.
[0007] When epiphora is caused by impaired drainage into the nose,
the condition can be improved or corrected by opening the nasal
passages, either pharmacologically or mechanically. Pharmacologic
opening can be accomplished with nasal sprays, such as
oxymetazoline hydrochloride, 0.05%, or oral decongestants, such as
pseudoephedrine hydrochloride. Improved drainage can also be
accomplished mechanically, by probing, dilating, and irrigating the
nasolacrimal system.
[0008] Other treatments for epiphora can include administration of
antibiotic eye drops or ointments, surgery to correct an eyelid
deformity, or removal a foreign body. In some severe cases, an
obstruction of the nasolacrimal duct can be treated by a procedure
called a "dacryocystorhinostomy" (DCR). During the DCR procedure,
the obstruction in the nasolacrimal duct is bypassed by creating a
new drainage pathway. A temporary tube is then left in place to
keep the new passage from scarring and closing.
[0009] A need exists in the art for additional methods of treating
epiphora. For example, a need exists for a method of treating
epiphora that is safe, easy, and effective, and which in some
instances does not require a visit to a medical professional.
BRIEF SUMMARY OF THE INVENTION
[0010] The present invention is directed to a method for treating
epiphora, the method comprising administering to a nasal area or
ocular area of a subject in need thereof a composition comprising
camphor, eucalyptus oil, and menthol, wherein the composition is
substantially free of lipids other than the eucalyptus oil.
[0011] In some embodiments, the composition is a gel, cream,
ointment, jelly, lotion, or viscous liquid. In some embodiments,
the composition further comprises a viscosity modifying agent. For
example, the viscosity modifying agent can be selected from the
group consisting of polyethylene glycol, polyvinyl alcohol,
gelatin, hyaluronic acid, carbomer, tragacanth, soluble cellulose
derivatives, colloidal magnesium aluminum silicate, sodium
alginate, and combinations thereof. In some embodiments, the
viscosity modifying agent is polyethylene glycol. For example, the
polyethylene glycol can be selected from the group consisting of
polyethylene glycol 200, polyethylene glycol 300, polyethylene
glycol 400, polyethylene glycol 600, polyethylene glycol 900,
polyethylene glycol 1000, polyethylene glycol 1450, polyethylene
glycol 3350, polyethylene glycol 4500, polyethylene glycol 8000,
and combinations thereof. In some embodiments, the viscosity
modifying agent is about 10% to about 99% (w/w) of the composition,
about 50% to about 95% (w/w) of the composition, or about 75% to
about 95% (w/w) of the composition.
[0012] In some embodiments, the camphor is about 1% to about 10%
(w/w) of the composition, or about 4% to about 6% (w/w) of the
composition.
[0013] In some embodiments, the eucalyptus oil is about 0.5% to
about 5% (w/w) of the composition, or about 1% to about 2% (w/w) of
the composition.
[0014] In some embodiments, the menthol is about 1% to about 10%
(w/w) of the composition, or about 2% to about 4% (w/w) of the
composition.
[0015] In some embodiments, the composition is water soluble.
[0016] In the present invention, in some embodiments, the
composition further comprises an excipient. In some embodiments,
the excipient is about 0.05% to about 20% (w/w) of the composition,
about 0.05% to about 5% (w/w) of the composition, or about 2% to
about 10% (w/w) of the composition.
[0017] In some embodiments, the composition further comprises a
mucoadhesive. For example, in some embodiments, the mucoadhesive is
selected from the group consisting of hydroxypropyl cellulose,
hydroxypropyl methylcellulose, hydroxy ethylcellulose,
ethylcellulose, carboxymethyl cellulose, dextran, guar gum,
polyvinyl pyrrolidone, a pectin, a starch, gelatin, casein, an
acrylic acid polymer, a polymer of acrylic acid ester, an acrylic
acid copolymer, a vinyl polymer, a vinyl copolymer, a polymer of
vinyl alcohol, an alkoxy polymer, a polyethylene oxide polymer, a
polyether, and combinations thereof.
[0018] In some embodiments, the method comprises administering the
composition of the invention to a nasal area wherein the
composition is applied to a nasal cavity, external nare, upper lip,
philtrum, or combination thereof of the subject in need
thereof.
[0019] In some embodiments, the method of the present invention
comprises administering to an ocular area of a subject in need
thereof a composition comprising camphor, eucalyptus oil, and
menthol, wherein the composition is substantially free of lipids
other than the eucalyptus oil. In some embodiments, the composition
comprises (a) about 0.004% to about 0.4% (w/v) camphor; (b) about
0.001% to about 0.5% (w/v) eucalyptus oil; and (c) about 0.001% to
about 0.5% (w/w) menthol. In some embodiments, the composition is a
liquid.
[0020] In some embodiments, the composition comprises: (a) about
1.0% to about 10% (w/w) camphor; (b) about 0.05% to about 5% (w/w)
eucalyptus oil; and (c) about 1.0% to about 10% (w/w) menthol. In
some embodiments, the composition comprises: (a) about 1.0% to
about 10% (w/w) camphor; (b) about 0.05% to about 5% (w/w)
eucalyptus oil; (c) about 1.0% to about 10% (w/w) menthol; and (d)
about 75% to about 97.5% (w/w) polyethylene glycol, wherein the
composition is substantially free of lipids other than the
eucalyptus oil.
[0021] In some embodiments, the composition comprises (a) about
4.8% (w/w) camphor; (b) about 1.2% (w/w) eucalyptus oil; (c) about
2.6% (w/w) menthol; (d) about 30% (w/w) polyethylene glycol 3350;
and (e) about 61.4% (w/w) polyethylene glycol 300, wherein the
composition is substantially free of lipids other than the
eucalyptus oil.
[0022] In some embodiments, the composition comprises (a) about
4.8% (w/w) camphor; (b) about 1.2% (w/w) eucalyptus oil; (c) about
2.6% (w/w) menthol; (d) about 40% (w/w) polyethylene glycol 3350;
(e) about 40% (w/w) polyethylene glycol 300; and (f) about 11.4%
(w/w) water, wherein the composition is substantially free of
lipids other than the eucalyptus oil.
[0023] In some embodiment, the present invention is directed to a
kit comprising: (a) a composition comprising camphor, eucalyptus
oil, and menthol, wherein the composition is substantially free of
lipids other than the eucalyptus oil; and (b) instructions for
using the composition of (a) for the treatment of epiphora.
[0024] In some embodiments, the present invention is directed to a
means for administering the composition.
[0025] In some embodiments, a kit comprises the composition of the
present invention, wherein the composition is individually packaged
for a single administration.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The present invention is directed to a method for treating
epiphora, the method comprising administering to a nasal area or
ocular area of a subject in need thereof a composition comprising
camphor, eucalyptus oil, and menthol, wherein the composition is
substantially free of lipids other than the eucalyptus oil.
[0027] It is to be noted that the term "a" or "an" refers to one or
more of that entity; for example, "a viscosity modifying agent," is
understood to represent one or more viscosity modifying agents. As
such, the terms "a" (or "an"), "one or more," and "at least one"
can be used interchangeably herein. As used herein, "about" refers
to plus or minus 10% of the indicated number. For example, "about
0.5%" indicates a range of 0.45% to 0.55%.
[0028] Epiphora is the medical term for excessive tearing of the
eye. "Watery eyes" is sometimes used as a synonym for epiphora. The
most common cause of epiphora is an overflow of tears, usually
caused by insufficient drainage of tears from the eye due to a
blockage of the nasolacrimal system. The nasolacrimal system
comprises the complete drainage system from the eyes to the nose,
including the lacrimal puncta, through the canaliculi, into the
nasolacrimal duct, and into the nasal cavity. Blockage of the
nasolacrimal system can be caused by acquired punctal stenosis,
canalicular stenosis or canaliculitis, dacryocystitis or lacrimal
sac tumors. Conditions that obstruct tear flow can also include
congenital (present at birth) malformation of the tear duct system,
foreign bodies, sinus or nasal infections, or inflammation of the
tear ducts. Conditions such as allergic conjunctivitis can also
cause blockage of the nasolacrimal system. Blockage can be caused
by inflammation, injury, or tumors of the nasolacrimal system.
Blockage can occur at any point in the nasolacrimal system from the
punctum to the nose.
[0029] Epiphora can also be associated with increased tear
production generally caused by irritation of the eye. Potential
irritants include foreign bodies or inward-growing eyelashes.
Additionally, eye infections or cancer of the eyelid can cause
epiphora.
[0030] Epiphora also can result from the inability of the eyelid to
blink correctly, which inhibits removal of tears from the surface
of the eyeball. Nerve damage, entropion (inward turning of the
eyelid), and ectropion (outward turning of the eyelid) are
conditions that can interfere with the blinking process. The
symptoms of epiphora can be exacerbated by environmental factors
such as excessive cold, wind, pollen or other airborne particulate
matter, sleep deprivation, eye strain, or emotional stress.
[0031] Symptoms of epiphora can include excessive tearing, matting
of the eyelashes, and mucous or pus-like discharge from the puncta.
Excess tearing can cause infection and, if left untreated, could be
detrimental to good vision. In subjects experiencing epiphora,
eyelid irritation is common because the area remains wet.
[0032] The term "epiphora" can include chronic epiphora and/or
acute epiphora. In some embodiments, it is within the scope of the
present invention to administer to patients who present with
complaints of "excessive tearing," even when this tearing is
typically not significant enough to constitute true epiphora. In
some embodiments, the present invention is directed to a method of
treating a subject presenting with complaints of excessive
tearing.
[0033] The current invention is directed to a method for treating
epiphora, wherein the method treats one or more of the causes or
symptoms of epiphora as described herein. However, one of skill in
the art will recognize that not all the causes or symptoms of
epiphora need to be treated by the method of the present
invention.
[0034] While not being bound by any particular theory, in some
embodiments the method of the invention is believed to treat
epiphora by widening the nasolacrimal passages. However, in some
embodiments, even subjects whose tearing was caused by excessive
tear production, rather than impaired tear drainage, can benefit
from the composition of the present invention, since a wider, more
efficient drainage system can carry away excessive amounts of
tears.
[0035] The composition of the present invention can be in any
physical state suitable for administration to a nasal area. In some
embodiments, the composition is a gel, cream, ointment, jelly,
lotion, or viscous liquid. In some embodiments, the composition can
be a liquid. In some embodiments, the composition is in a physical
form suitable for placement in an inhaler and/or a nasal spray. For
example, in some embodiments can be a solid, solution, suspension,
or emulsion.
[0036] The present invention comprises compositions substantially
free of lipids other than the eucalyptus oil. Although oleaginous
bases such as petrolatum and petrolatum-based pharmaceutical gels
are effective vehicles for camphor, eucalyptus oil and menthol,
they are not preferred embodiments since application near the nasal
area increases the possibility of lipids migrating into the
respiratory system and causing lipoidal pneumonia. Of particular
importance are compositions whose vehicles are lipid free, e.g.,
water-based or water-soluble gels, rather than lipid-based
gels.
[0037] Lipoidal pneumonia refers to a pulmonary condition marked by
inflammatory and fibrotic changes in the lungs due to the
inhalation of various lipid substances, e.g. petroleum. Due to the
possibility of lipoidal pneumonia, the product information sheet
for the topical petroleum-based analgesic Vick's VapoRub.RTM.
(Proctor and Gamble, Cincinnati, Ohio), which is a product that
contain camphor, eucalyptus oil, and menthol, specifically
instructs users to apply the product only to the chest and throat.
Application of a lipid-based composition to the chest or throat
reduces the likelihood that the lipid-based product will get into
the lungs.
[0038] Application to the chest and throat is sufficient when using
Vick's VapoRub.RTM. for its analagesic effect, since it is not
intended for the treatment of epiphora. However, for treatment of
epiphora, application of a composition comprising camphor,
eucalyptus oil and menthol closer to the nasolacrimal system is
desired. Thus, the present invention overcomes the problems
associated with traditional petroleum-based compositions by making
a composition wherein the camphor, eucalyptus oil, and menthol are
in vehicle substantially free of lipids other than the eucalyptus
oil.
[0039] The present compositions can be in any physical state
suitable to be administered to the nasal or ocular area, such as,
but not limited to, liquids (e.g., solutions or suspensions),
semi-solids (gels, creams, ointments, etc.), and the like. Each of
these physical states of the present compositions can be prepared
using techniques and processes which are conventional and well
known in the art. For a more detailed discussion of the preparation
and administration of ophthalmic formulations see Remington's
Pharmaceutical Sciences, 15 Ed., pgs. 1489 to 1504 (1975) which is
incorporated in its entirety herein by reference. In some
embodiments, the composition is administered in a liquid state. In
some embodiments, the composition is administered as a gel, cream
or ointment.
[0040] In some embodiments, the composition further comprises a
viscosity modifying agent. Any viscosity modifying agent suitable
for contact with a nasal area can be used. For example, the
viscosity modifying agent can be selected from the group consisting
of polyethylene glycol, polyvinyl alcohol, gelatin, hyaluronic
acid, carbomer, tragacanth, soluble cellulose derivatives,
colloidal magnesium aluminum silicate, sodium alginate, and
combinations thereof. In some embodiments, the composition does not
comprise a viscosity modifying agent.
[0041] In some embodiments, the viscosity modifying agent is
polyethylene glycol. Any mixture of solid and liquid polyethylene
glycols can be substituted in the above formulation to give the
desired consistency. In addition the liquid polyethylene glycol
component can be replaced partially or completely by suitable
amounts of glycerin, propylene glycol, or similar liquid polyols.
For example, the polyethylene glycol can be selected from the group
consisting of polyethylene glycol 200, polyethylene glycol 300,
polyethylene glycol 400, polyethylene glycol 600, polyethylene
glycol 900, polyethylene glycol 1000, polyethylene glycol 1450,
polyethylene glycol 3350, polyethylene glycol 4500, polyethylene
glycol 8000, and combinations thereof.
[0042] Various amounts of viscosity modifying agents can be used in
the present invention. In some embodiments, the viscosity modifying
agent is about 10% to about 99% (w/w) of the composition, about 50%
to about 95% (w/w) of the composition, or about 75% to about 95%
(w/w) of the composition.
[0043] In other embodiments of this invention, water, or other
water-based solvents, can be added to the viscosity agent to
provide the desired consistency of the composition. Various amounts
of water or water-based solvent can be used. In some embodiments,
the composition can comprise about 5% to about 50% (w/w) water,
about 10% to about 40% (w/w) water, or about 15% to about 30% (w/w)
water. By way of example, in some embodiments a vehicle consisting
of: 40% PEG 3350, 40% PEG 300 and 20% water can have the right
consistency and properties to serve as a vehicle for camphor,
eucalyptus oil, and menthol. For compositions of the present
invention that are in a liquid state, the compositions can comprise
about 50% to 99.9% (v/v) water, about 70% to 99% (v/v) water, or
about 80% to about 97% (v/v) water. In some embodiments, the
compositions can comprise about 98%, about 98.5%, about 99%, about
99.5%, about 99.8% or about 99.9% water.
[0044] In some embodiments, the composition comprises all three of
camphor, eucalyptus oil, and/or menthol. In some embodiments of the
present invention, the combination of two or three of camphor,
eucalyptus oil, and menthol is used to achieve the preferred
therapeutic result of treating epiphora. However, one of skill in
the art can appreciate that in some embodiments, only one of
camphor, eucalyptus oil, and menthol can be sufficient to achieve
the therapeutic result of treating epiphora. Thus, in some
embodiments of the present invention, the composition comprises one
or more of camphor, eucalyptus oil, and/or menthol. For example, in
some embodiments, the method of the present invention comprises
administering to a nasal area of a subject in need thereof a
composition comprising camphor, wherein the composition is
substantially free of lipids other than the eucalyptus oil. In some
embodiments, the method of the present invention comprises
administering to a nasal area of a subject in need thereof a
composition comprising menthol, wherein the composition is
substantially free of lipids other than the eucalyptus oil. In some
embodiments, the method of the present invention comprises
administering to a nasal area of a subject in need thereof a
composition comprising eucalyptus oil, wherein the composition is
substantially free of lipids other than the eucalyptus oil.
[0045] The term "camphor," also known as
1,7,7-trimethylbicyclo[2.2.1]heptan-2-one or 2-camphanone, refers
to a compound of Formula I or derivatives thereof:
##STR00001##
[0046] Various grades and purities of camphor may be used, as long
as they are suitable for use in the composition of the present
invention. Various amounts of camphor can be used in the present
invention. In some embodiments, the camphor is about 0.1% to about
20% (w/w) of the composition, about 1% to about 10% (w/w) of the
composition, or about 4% to about 6% (w/w) of the composition. In
some embodiments, the camphor is in a liquid composition, and the
camphor is about 0.001% to about 1.0% (w/v) of the composition,
about 0.004% to about 0.4% (w/v) of the composition, or about 0.01%
to about 0.1% (w/v) of the composition.
[0047] The term eucalyptus oil refers to oil derived from a
Eucalyptus tree. The components of oils extracted from Eucalyptus
trees can vary according to the species from which the oil was
harvested, as well as which part of the tree the oil was harvested
from (e.g., dry leaves, fresh leaves, buds, mature fruit, bark,
etc.). In general, the main chemical components of eucalyptus oil
are a-pinene, b-pinene, a-phellandrene, 1,8-cineole, limonene,
terpinen-4-ol, aromadendrene, epiglobulol, piperitone and globulol,
although one of skill in the art can appreciate that the
composition of eucalyptus oil does not require one or more of these
components. For example, the same compounds (e.g., 1,8-cineole)
exist in many of species, but some compounds can be found in only
one or a few species. In some embodiments, eucalyptus oil contains
greater than 10% (w/w) 1,8-cineole (eucalyptol), greater than 30%
(w/w) 1,8-cineole, greater than 50% (w/w) 1,8-cineole, 50% to 95%
(w/w) 1,8-cineole, 60% to 90% (w/w) 1,8-cineole, or 70% to 85%
(w/w) 1,8-cineole. In some embodiments, the oil from E. globulus or
E. polybractea is used in the present invention. In some
embodiments, the oils comprise a blend of oils from different
species of Eucalyptus. In some embodiments, the eucalyptus oil is
obtained by steam distillation from the fresh leaves of Eucalyptus
globulus Labillardiere and other species of Eucalyptus L'Heritier
(Fam. Myrtaceae). In some embodiments, the eucalyptus oil is a
commercially available oil, e.g., a eucalyptus oil supplied by
Spectrum Chemicals (Gardena, Calif.). In some embodiments, the
eucalyptus oil meets Food Chemical Code (FCC) specifications.
[0048] Various amounts of eucalyptus oil can be used in the
composition of the present invention. In some embodiments, the
eucalyptus oil is about 0.1% to about 10% (w/w), about 0.5% to
about 5% (w/w) of the composition, or about 1% to about 2% (w/w) of
the composition. In some embodiments, the eucalyptus oil is in a
liquid composition, and the eucalyptus oil is about 0.0005% to
about 1.0% (w/v) of the composition, about 0.001% to about 0.5%
(w/v) of the composition, or about 0.01% to about 0.1% (w/v) of the
composition.
[0049] The term "menthol" refers to a compound of Formula II, and
any stereoisomer or derivative thereof
##STR00002##
[0050] Various grades and purities of menthol can be used in the
present invention, as long as they are suitable for use in the
composition of the present invention. Various amounts of menthol
can be used in the composition of the present invention. In some
embodiments, the menthol is about 0.2% to about 20% (w/w) of the
composition, about 1% to about 10% (w/w) of the composition, or
about 2% to about 4% (w/w) of the composition. In some embodiments,
the menthol is in a liquid composition, and the menthol is about
0.0005% to about 1.0% (w/v) of the composition, about 0.001% to
about 0.5% (w/v) of the composition, or about 0.01% to about 0.1%
(w/v) of the composition.
[0051] In the present invention, the composition is substantially
free of lipids other than the eucalyptus oil. The term "lipid"
refers to hydrocarbon-based molecules of biological origin that are
predominantly nonpolar or hydrophobic. The basic classes of lipids
are: fatty acids (e.g., saturated or unsaturated fatty acids),
glycerides or glycerolipids (e.g., monoglycerides, diglycerides,
triglycerides (neutral fats), phosphoglycerides or
glycerophospholipids), nonglycerides (e.g. sphingolipids, sterol
lipids (includes cholesterol and steroid hormones)), prenol lipids
(includes terpenoids), waxes, polyketides, and complex lipid
derivatives (e.g., glycolipids, and protein-linked lipids). In some
embodiments, the term lipid refers to petrolaturn or petroleum. The
term "petrolatum" refers to a substance which is a complex
combination of semi-solid, saturated hydrocarbons, mainly of a
paraffinic nature, obtained from petroleum. Generally, petrolatum
comprises liquid hydrocarbons having carbon numbers predominately
greater than C.sub.25. As described previously, the absence of
lipids can be beneficial when placing the composition of the
present invention to the nasal area to avoid the occurrence of
lipoidal pneumonia.
[0052] In the present invention, the composition is substantially
free of lipids other than the eucalyptus oil, to avoid or reduce
the risk of lipoidal pneumonia. In some embodiments, the term
"substantially free of lipids" refers to a composition wherein
about 0% to 2% (w/w) of the composition is a lipid other than
eucalyptus oil, about 0% to 1% (w/w) of the composition is a lipid
other than eucalyptus oil, about 0% to 0.5% (w/w) of the
composition is a lipid other than eucalyptus oil, or about 0% to
0.2% (w/w) of the composition is a lipid other than eucalyptus oil,
or about 0% to 0.1% (w/w) of the composition is a lipid other than
eucalyptus oil. In some embodiments, the term "substantially free
of lipids" refers to compositions wherein less than 0.1% of the
composition is a lipid other than eucalyptus oil.
[0053] In some embodiments, the composition is water soluble. The
term "water soluble" refers the ability of the composition to
dissolve (i.e., form a solution) in water. One of skill in the art
will recognize that solubility will be dependent on the volume of
the solvent (i.e., water), the presence or absence of other
compounds (e.g., solubilizing agents), as well as the temperature
of the solvent. In some embodiments, the term "water soluble"
refers to the ability of at least 90% of a substance to dissolve
completely in water at room temperature in 1 hour, wherein the
substance is 10% the volume of the water.
[0054] In the present invention, in some embodiments the
composition further comprises an excipient. For example, in some
embodiments, the excipient is selected from the group consisting of
a moisturizer; acid, base or buffering agent; preservative agent;
and combinations thereof.
[0055] Various moisturizers can be used. In some embodiments, the
moisturizer can be selected from the group consisting of water,
urea, guanidine, glycolic acid, polyhydroxy alcohols such as
sorbitol, glycerin, hexanetriol, propylene glycol, hexylene glycol
and the like, polyethylene glycol, sugars and starches, sugar and
starch derivatives, D-panthenol, hyaluronic acid, lactamide
monoethanolamine, acetamide monoethanolamine, and mixtures
thereof.
[0056] The composition of the present invention can also include an
acid, base or buffering agent (buffers). Acids/bases/buffers can be
included to provide and/or maintain the composition at a pH in the
physiologically acceptable range, more preferably in a range of
about 3 to about 9, or about 4 to about 8.5, still more preferably
about 5 to about 8.5 or about 5.5 to about 8.0, and especially
about 6.0 to about 8.0 or about 6.5 to about 7.0. As one of skill
in the art will recognize, the pH can vary over time, depending on
various factors, e.g., stability of the composition, amount of
exposure to the atmosphere, strength of buffer, etc. Thus, as used
herein, when referring to compositions, kits or methods of the
present invention, any specified pH refers to the pH at any time
between the time of manufacturing and time of administering.
[0057] The term "buffer" or buffering agent refers to a
pharmaceutically acceptable compound or composition that is capable
of neutralizing both acids and bases and thereby maintaining the
original acidity or basicity of the composition. Buffers can
include, but are not limited to, phosphate buffers (e.g., sodium
and potassium phosphates), phosphates, bicarbonate, citrate,
borate, acetate buffers, citrate buffers, tromethamine buffers and
combinations thereof. Preferred buffers are selected from the group
consisting of citric acid, sodium citrate, boric acid, sodium
borate, one or more sodium salts of phosphoric acid, one or more
potassium salts of phosphoric acid, sodium bicarbonate, and
combinations thereof.
[0058] Acids useful in the present compositions can include boric
acid, hydrochloric acid, acetic acid, other acids which are
ophthalmically acceptable in the concentrations used, and the
like.
[0059] Bases which can be included in the present compositions
include, but are not limited to, sodium and/or potassium
hydroxides, other alkali and/or alkaline earth metal hydroxides,
organic bases, other bases which are ophthalmically acceptable in
the concentrations used, and the like.
[0060] In some embodiments, the excipient is a preservative.
Typical preservatives include the lower alkyl esters of
para-hydroxybenzoates (parabens), especially methylparaben,
propylparaben, isobutylparaben and mixtures thereof, benzyl
alcohol, phenyl ethyl alcohol, benzoic acid, EDTA, and benzalkonium
chloride.
[0061] In some embodiments, the excipient is about 0.05% to about
20% (w/w) of the composition, about 0.05% to about 5% (w/w) of the
composition, or about 2% to about 10% (w/w) of the composition.
[0062] In some embodiments of the present invention, the
composition further comprises a mucoadhesive. In some embodiments,
the mucoadhesive is selected from the group consisting of
hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxy
ethylcellulose, ethylcellulose, carboxymethyl cellulose, dextran,
guar gum, polyvinyl pyrrolidone, a pectin, a starch, gelatin,
casein, an acrylic acid polymer, a polymer of acrylic acid ester,
an acrylic acid copolymer, a vinyl polymer, a vinyl copolymer, a
polymer of vinyl alcohol, an alkoxy polymer, a polyethylene oxide
polymer, a polyether, and combinations thereof.
[0063] In some embodiments, the method of the present invention
comprises administering a composition to a nasal area. It is to be
appreciated that the term "administering" refers to the placement
of the composition in or in close proximity to the nasal area of
the subject being treated. Thus, the term administering would refer
to placement of the composition near a nasal area, whether or not
there was direct contact between the skin or mucosa of the subject
to which the composition is being administered. The term
"administering to a nasal area" also refers to placement of the
composition of the invention on an apparatus or other object, and
then placing the nasal area in close proximity to the composition.
For example, "administering to a nasal area" would include a
subject who sniffed or breathed in while placing his/her nasal area
in close proximity to the composition of the present invention
(e.g., sniffing a jar, tube, bottle, etc., filled with the
composition of the present invention). In some embodiments,
"administering to a nasal area" includes nasally applying the
composition of the invention, e.g., from an inhaler or a nasal
spray apparatus, optionally while sniffing or inhaling. In some
embodiments, the term "administering" refers to the direct
placement of the composition of the present invention onto the skin
or mucosa of the subject. For example, administering can comprise
smearing or spreading the composition on the skin or mucosa of the
subject. In some embodiments, administering to a nasal area
includes the application of the composition using a nasal swab or
other applicator. In some embodiments, the term "administering"
refers to the placement of a liquid composition of the present
invention to an ocular area (e.g., administering eye drops).
[0064] In some embodiments, the term "nasal area" refers to any
area on the head of the subject to which the composition is being
administered. In some embodiments, the nasal area refers to the
face of the subject to which the composition is being administered
(e.g., the area of the body between the top of the forehead and the
chin, or the area on the face between the two ears). In some
embodiments, the nasal area of the present invention comprises a
nasal cavity, external nare, upper lip, philtrum, or combination
thereof of the subject in need thereof.
[0065] In some embodiments of the present invention, the method of
treating epiphora comprises administering to an ocular area of a
subject in need thereof a composition comprising camphor,
eucalyptus oil, and menthol, wherein the composition is
substantially free of lipids other than the eucalyptus oil. The
term "ocular area" refers to an eye ball surface as well as the
external skin surrounding the eye ball, i.e., the eyelid and the
margin of the eyelid, and associated hair projecting therefrom,
i.e., eyelashes and eye brows. The ocular area can be present on
any animal having an eyelid.
[0066] The methods of the present invention are applicable to both
human use and veterinary use, preferably for human use. In some
embodiments, the methods are applicable for use on domesticated
animals such as companion animals (dogs and/or cats), livestock, or
other economically important animals (e.g., model or breeding
animals).
[0067] The composition of the present invention can be administered
a single time or multiple times throughout the day. For example,
the composition can be applied to the nasal mucosa each night,
during the day, or at both times. In some embodiments, the
composition is administered once daily, twice daily, three times
daily, or four times daily. In some embodiments, the composition is
administered hourly. In some embodiments, the composition can be
administered on an "as needed" or "as desired" basis, as determined
by a medical professional or the subject being administered to.
[0068] Various amounts of the composition can be administered. One
of skill in the art will understand that the amount to be
administered is dependent on various factors, e.g., the location of
administration, the concentration of the eucalyptus oil, menthol,
and camphor, the viscosity or physical state of the composition,
the frequency of administration, etc. For example, lower
concentrations of camphor, menthol and eucalyptus can be used if
the composition is administered to an ocular area compared to if
the composition was administered to the nasal cavity. In some
embodiments, the amount of the composition to be administered is
less than about 10 mL, about 0.1 mL to about 5 mL, about 0.2 mL to
about 3 mL, or about 0.5 mL to about 2 mL. In some embodiments, the
composition is a liquid, and the amount to be administered is about
1 to 30 drops, about 1 to 20 drops, about 2 to 10 drops, or about 3
to 5 drops.
[0069] The composition can comprise camphor, eucalyptus oil, and
menthol in various amounts. In some embodiments, the composition
comprises: (a) about 1.0% to about 10% (w/w) camphor; (b) about
0.05% to about 5% (w/w) eucalyptus oil; and (c) about 1.0% to about
10% (w/w) menthol. In some embodiments, the composition comprises:
(a) about 1.0% to about 10% (w/w) camphor; (b) about 0.05% to about
5% (w/w) eucalyptus oil; (c) about 1.0% to about 10% (w/w) menthol;
and (d) about 75% to about 97.5% (w/w) polyethylene glycol, wherein
the composition is substantially free of lipids other than the
eucalyptus oil. In some embodiments, the composition comprises (a)
about 4.8% (w/w) camphor; (b) about 1.2% (w/w) eucalyptus oil; (c)
about 2.6% (w/w) menthol; (d) about 30% (w/w) polyethylene glycol
3350; and (e) about 61.4% (w/w) polyethylene glycol 300, wherein
the composition is substantially free of lipids other than the
eucalyptus oil. In some embodiments, the composition comprises (a)
about 4.8% (w/w) camphor; (b) about 1.2% (w/w) eucalyptus oil; (c)
about 2.6% (w/w) menthol; (d) about 40% (w/w) polyethylene glycol
3350; (e) about 40% (w/w) polyethylene glycol 300; and (f) about
11.4% (w/w) water, wherein the composition is substantially free of
lipids other than the eucalyptus oil.
[0070] In some embodiments, the composition is in a liquid state
and comprises (a) about 0.004% to about 0.4% (w/v) camphor; (b)
about 0.001% to about 0.5% (w/v) eucalyptus oil; and (c) about
0.001% to about 0.5% (w/w) menthol.
[0071] In some embodiments, the compositions of the present
inventions are "pharmaceutically acceptable." The term
"pharmaceutically acceptable" refers to those compounds, materials,
compositions, and/or solutions which are, within the scope of sound
medical judgment, suitable specifically for contact with the skin,
lips, and nasal mucosal without excessive toxicity, irritation,
allergic response, or other problem complications commensurate with
a reasonable benefit/risk ratio.
[0072] In some embodiments, The compositions of the present
inventions are "ophthalmically acceptable." The term
"ophthalmically acceptable" refers to those compounds, materials,
compositions, and/or solutions which are, within the scope of sound
medical judgment, suitable specifically for contact with the
tissues of the eye, and the area surrounding the eye without
excessive toxicity, irritation, allergic response, or other problem
complications commensurate with a reasonable benefit/risk
ratio.
[0073] The composition of the present invention can be included in
a kit. In some embodiment, the present invention is directed to a
kit comprising: (a) a composition comprising camphor, eucalyptus
oil, and menthol, wherein the composition is substantially free of
lipids other than the eucalyptus oil; and (b) instructions for
using the composition of (a) for the treatment of epiphora.
[0074] The composition can be individually packaged for a single
administration, e.g., in a bottle, jar, ampoule, tube, syringe,
envelope, container, vial, medicated swab, single-use inhaler, or
single-use nasal spray. Alternatively, the composition can be
contained in a package that is capable of holding multiple units
for administration, e.g., in resealable glass or plastic packages,
multi-use nasal spray, or multi-use inhaler. In some kits, the
components of the composition are mixed together immediately
preceding their usage. For example, in some embodiments one or more
dry components of the composition of the kit are packaged in a
separate container, e.g., a plastic bottle, and then mixed with one
or more of the liquid components of the composition immediately
prior to use.
[0075] In some embodiments, the present invention is directed to a
means for administering the composition of the present invention.
The means for administering the composition to the subject can
include any apparatus suitable to physically place the composition
in close proximity to the nasal area or ocular area, e.g., a stick,
spatula, swab, adhesive patch, glove, etc. A means for
administering can also include an inhaler, which allows the
composition to be directed to a nasal cavity of a subject upon
inhalation. In some embodiments, a means for administering can also
include nasal spray apparatus, which is suitable for applying the
composition in a liquid, mist, or spray to a nasal cavity. Means
for administering can also include a nebulizer. In some
embodiments, a means for administering can include an
eyedropper.
[0076] Optionally, the kit can further comprise printed matter
containing instructions for using the composition of the present
invention. For example, such printed instructions can be in a form
prescribed by a governmental agency regulating the manufacture, use
or sale of pharmaceuticals or biological products, which reflects
approval by the agency of the manufacture, use or sale for human
application. In some embodiments, the kit further comprises printed
matter, which, e.g., provides information on the use of the
composition or a pre-recorded media device which, e.g., provides
information on the use of the method of the present invention.
"Printed matter" can be, for example, a book, booklet, brochure,
leaflet or the like. The printed matter can describe the use of the
composition of the present invention.
[0077] The kit can also include a container for storing the
components of the kit. The container can be, for example, a bag,
box, envelope or any other container that would be suitable for use
in the present invention. In some embodiments, the container is
large enough to accommodate each component of the present
invention. However, in some cases, it can be desirable to have a
smaller container which is large enough to carry only some of the
components of the present invention.
Example 1
[0078] The gel matrix of the present invention was produced by
mixing the ingredients of Table 1.
TABLE-US-00001 TABLE 1 Ingredient % w/w Camphor 4.8 Eucalyptus Oil
1.2 Menthol 2.6 Polyethylene Glycol 3350 30 Polyethylene Glycol 300
61.4
[0079] The polyethylene glycol (PEG) components were mixed, melted
and heated to give a homogeneous vehicle. The active ingredients
(camphor, eucalyptus oil, and menthol) were then added and mixed
into the homogeneous vehicle until dissolved. The solution was
cooled to room temperature while mixing to maintain
homogeneity.
Example 2
[0080] The composition of Example 1 was administered just inside
the external nares of 15 subjects who had bothersome tearing in one
or both eyes. The composition was administered one time/day for 14
days. After 14 days, six of the subjects had complete, or near
complete, elimination of epiphora, three had some improvement, and
six had no improvement. There were no adverse events.
[0081] It is to be appreciated that the Detailed Description
section, and not the Summary and Abstract sections, is intended to
be used to interpret the claims. These examples illustrate possible
compositions used in the present invention. While the invention has
been particularly shown and described with reference to some
embodiments thereof, it will be understood by those skilled in the
art that they have been presented by way of example only, and not
limitation, and various changes in form and details can be made
therein without departing from the spirit and scope of the
invention. Thus, the breadth and scope of the present invention
should not be limited by any of the above-described exemplary
embodiments, but should be defined only in accordance with the
following claims and their equivalents.
[0082] All documents cited herein, including journal articles or
abstracts, published or corresponding U.S. or foreign patent
applications, issued or foreign patents, or any other documents,
are each entirely incorporated by reference herein, including all
data, tables, figures, and text presented in the cited
documents.
* * * * *