U.S. patent application number 10/809221 was filed with the patent office on 2004-09-16 for aqueous solvent for corticosteroids.
Invention is credited to Hanna, Calvin.
Application Number | 20040180870 10/809221 |
Document ID | / |
Family ID | 23366112 |
Filed Date | 2004-09-16 |
United States Patent
Application |
20040180870 |
Kind Code |
A1 |
Hanna, Calvin |
September 16, 2004 |
Aqueous solvent for corticosteroids
Abstract
A solvent comprising a combination of water and organic
solvent(s) capable of dissolving a therapeutically effective amount
of medicament(s) not readily soluble in aqueous solvents, said
organic solvents including alcohol and glycol, and said medicaments
including hydrocortisone.
Inventors: |
Hanna, Calvin; (Little Rock,
AR) |
Correspondence
Address: |
Clark G. Sullivan, Esq.
KING & SPALDING LLP
45th Floor
191 Peachtree Street, N.E.
Atlanta
GA
30303
US
|
Family ID: |
23366112 |
Appl. No.: |
10/809221 |
Filed: |
March 25, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10809221 |
Mar 25, 2004 |
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10279340 |
Oct 24, 2002 |
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10809221 |
Mar 25, 2004 |
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09347974 |
Jul 6, 1999 |
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6723714 |
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Current U.S.
Class: |
514/179 |
Current CPC
Class: |
Y10S 514/975 20130101;
Y10S 514/952 20130101; A61K 47/10 20130101; Y10S 514/97 20130101;
A61K 47/44 20130101; A61K 47/14 20130101; A61K 9/0014 20130101;
A61K 31/56 20130101; Y10S 514/973 20130101 |
Class at
Publication: |
514/179 |
International
Class: |
A61K 031/573 |
Claims
What is claimed is:
1) A clear stable one phase solution that is non-irritating and
resistant to freezing comprising: a) between about 30% and about
50% water; b) propylene glycol; c) 2-propanol or ethanol; and d)
hydrocortisone in an amount of from about 0.5% to about 2.0% (w/v),
wherein said hydrocortisone is solubilized in said water.
2) The solution of claim 1 wherein said water is present in an
amount sufficient to expand an ear wick a therapeutically effective
amount when from 1 to 7 drops of the solution are administered to
the ear canal.
3) The solution of claim 1 further comprising chloroxylenol in an
amount of between about 0.1% (w/v) and about 0.4% (w/v).
4) The solution of claim 1 further comprising chloroxylenol in an
amount of about 0.1% (w/v).
5) The solution of claim 1 further comprising pramoxine in an
amount of between about 0.5% (w/v) and about 2.0% (w/v).
6) The solution of claim 1 further comprising pramoxine in an
amount of about 1.0% (w/v).
7) The solution of claim 1 further comprising chloroxylenol in an
amount of between about 0.1% (w/v) and about 0.4% (w/v) and
pramoxine in an amount of between about 0.5% (w/v) and about 2.0%
(w/v).
8) The solution of claim 1 wherein said propylene glycol is present
in an amount of between about 35% (v/v) and about 65% (v/v).
9) The solution of claim 1 wherein said ethanol or 2-propanol is
present in an amount of between about 10% (v/v) and about 80%
(v/v).
10) The solution of claim 2 wherein: a) said 2-propanol or ethanol
is present in an amount of between about 10% (v/v) and about 80%
(v/v), b) said propylene glycol is present in an amount of between
about 35% (v/v) and about 65% (v/v), and c) said water is present
in an amount of between about 30% (v/v) and about 50% (v/v).
11) The solution of claim 1 further comprising propylene glycol
diacetate in an amount of between about 0.01% (w/v) and about 0.5%
(w/v).
12) The solution of claim 1 further comprising propylene glycol
diacetate in an amount of about 0.01% (w/v).
13) The solution of claim 1 further comprising mineral oil.
14) A clear stable one phase solution that is non-irritating and
resistant to freezing comprising: a) greater than about 33% water;
b) propylene glycol; c) 2-propanol or ethanol; and d)
hydrocortisone in an amount of from about 0.5% to about 2.0% (w/v),
wherein said hydrocortisone is solubilized in said water.
15) The solution of claim 14 further comprising chloroxylenol in an
amount of between about 0.1% (w/v) and about 0.4% (w/v).
16) The solution of claim 14 further comprising chloroxylenol in an
amount of about 0.1% (w/v).
17) The solution of claim 14 further comprising pramoxine in an
amount of between about 0.5% (w/v) and about 2.0% (w/v).
18) The solution of claim 14 further comprising pramoxine in an
amount of about 1.0% (w/v).
19) The solution of claim 14 further comprising chloroxylenol in an
amount of between about 0.1% (w/v) and about 0.4% (w/v) and
pramoxine in an amount of between about 0.5% (w/v) and about 2.0%
(w/v).
20) The solution of claim 14 wherein said propylene glycol is
present in an amount of between about 35% (v/v) and about 65%
(v/v).
21) The solution of claim 14 wherein said ethanol or 2-propanol is
present in an amount of between about 10% (v/v) and about 80%
(v/v).
22) The solution of claim 14 further comprising propylene glycol
diacetate in an amount of between about 0.01% (w/v) and about 0.5%
(w/v).
23) The solution of claim 14 further comprising propylene glycol
diacetate in an amount of about 0.01% (w/v).
24) The solution of claim 14 further comprising mineral oil.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/347,974, filed Jul. 6, 1999, and U.S.
patent application Ser. No. 10/279,340, both entitled "Aqueous
Solvent For Corticosteroids," both currently allowed, the
disclosure of both being hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The invention disclosed herein generally relates to the
field of solvents capable of dissolving medicaments. More
particularly, it relates to the field of water-containing solvents
capable of dissolving medicaments not regularly soluble in aqueous
solutions, such as steroids (especially corticosteroids) and
antimicrobial phenols (especially chloroxylenol). The present
invention is especially suited for dissolving hydrocortisone into a
clear solution for topical application.
[0003] One application of the present invention is in the field of
treatment of ear aches and similar maladies of the ear. One problem
to which the present invention is directed is the relative
inability of water to dissolve medicaments commonly used to treat
such ear maladies, and the relative inability or undesirability of
organic solvent solutions for delivery of medicaments for topical
applications using certain methods.
[0004] The auricle of the ear is covered with a layer of skin that
extends part way into the external ear canal. The inner part of the
ear canal, including the external surface of the ear drum, is
covered with a thin layer of epithelial cells. The outer part of
the external ear canal has ceruminous glands which produces a waxy
material composed of free fatty acids, other organic compounds,
salts and water. This area also contains hair which prevents debris
in the immediate environment from entering the ear canal. The
epithelial cells of the canal slough off and combine with the waxy
organic materials, water, cells, debris and hair to form cerumin,
commonly known as ear wax. No bland organic agent or water will
dissolve all of the ear wax particles. However, water and organic
solvents (and combinations) will loosen and swell the wax.
[0005] Excessive water in the ear canal will swell the ear wax,
leading to a plugging of the canal, which may thereby become
infected. This condition is sometimes called swimmer's ear, or
otitis externa. Ear drops containing antimicrobial agents are
commonly applied to the external ear canal to abate the infection;
other medicaments within the ear drops, such as hydrocortisone, may
reduce inflammation, while local anesthetics (such as, for example,
pramoxine) reduce pain. Substances such as glycerol, for example,
also aid in the removal of excess ear wax.
[0006] Ear plugs or wicks made of cloth, plastic or cellulose
(collectively "wicks") may be inserted into the ear canal after the
ear drop medicaments are applied to the ear canal. These wicks
expand and retain the ear drops within the ear canal. For ear drops
to expand the wick within several minutes, the ear drops must
contain 33% or more water.
[0007] Hydrocortisone is approved as 1.+-.0.2% concentration for
ear drop pharmaceutical products. Hydrocortisone is nearly
insoluble in water (0.028% on a weight volume basis) and glycerol.
However, it is soluble to at least 1% in several organic solvents
such as propylene glycol, polypropylene glycol diacetate, hexenyl
glycol, 2-propanol, ethanol and in pure (glacial) acetic acid. It
is also solubalized in non-ionic surfactants (micells and
colloids).
[0008] Many solutions of hydrocortisone have a relatively short
"shelf life," losing efficacy if not used fairly promptly after
mixing. The stability of hydrocortisone in solution is relative,
since there is a gradual loss of this chemical over time; in many
such solutions, hydrocortisone becomes oxidized or otherwise
rendered less active (or completely inactive) after a period of
days or months in storage at room temperature.
[0009] Monder, Endocrinology 82(2), 318 (1968), reported that
aqueous solutions of hydrocortisone were rapidly oxidized and lost.
Short, et al., J. Pharm. Pharmacology 61(11), 17825 (1972) studied
the cause of the-loss of hydrocortisone in-solution and Bansal, et
al., J. Pharm. Sci. 72(9) 1079 (1983) slowed this loss by adding
0.1% fructose. Barry, et al., J. Pharm. Pharmacology 28(3), 210
(1976) and Hajratwala, et al., J. Pharm. Pharmacology 28(3), 934
(1976) reported on surfactants to produce micells of hydrocortisone
in water. Lovgren, et al., J. Pharm. Sci. 67(10), 1419 (1978),
Hagen, et al., J. Pharm. Sci. 72(4), 409 (1983), Gupta, Drug
Development and Industrial Pharmacy 11(12),2083097 (1985) reported
on the use of surfactants and the loss of hydrocortisone in these
solutions.
[0010] Due to the low solubility of hydrocortisone in many
solvents, such as glycerol and water, the preparation of clear
solutions of 1%-2% concentrations of the drug solution is
difficult. Co-solvents such as lower molecular weight alcohols,
i.e., ethanol, 2-propanol and glycols (propylene glycol, hexenyl
glycol) may be added to increase the water content of the
solutions. Also, surfactants may be added to form micells in
water.
[0011] Jacobson, U.S. Pat. No. 2,779,707 disclosed the use of 20%
water and 80% hexenyl glycol to prepare 0.8% hydrocortisone acetate
to be used for intravenous administration.
[0012] U.S. Pat. No. 2,880,130 issued to Johnson in 1959 described
the possible use of polyoxyethylene sorbitan monooleate (Tween 80)
in amounts of 2-25% for the vehicle to obtain micells in water of
0.2% hydrocortisone. This was to be applied to the eye, ear, nose
and throat.
[0013] Two Italian patents Rom RO 65,112 and 84,025 reported on the
formulation of hydrocortisone and antibiotics in oil for the
treatment of olitis externa.
[0014] U.S. Pat. No. 3,422,186 issued to Sasmor in 1969 discloses
aqueous, viscous solutions of 0.05-0.5% hydrocortisone using (10%)
water, propylene glycol, glycerol or polyoxyethylene glycol. These
were to be used to dissolve ear wax and to treat ear disease in the
human and animal.
[0015] A stable, sprayable 0.5% hydrocortisone preparation is
disclosed in U.S. Pat. No. 4,213,979 issued to Levine in 1980. Said
compound employs
polyoxypropylene-(12)-polyoxyethylene-(50)-lanolin, 15% ethanol,
25% propylene glycol to form a film. Moreover, it contains a
relatively high ethanol content, limiting its usefulness for
topical application (especially to the ear, near the eye).
[0016] U.S. Pat. No. 4,289,764 issued to Yarrow et al. in 1981
describes formulations containing 0.025 to 0.4% hydrocortisone in
an aqueous propylene glycol (15-50%) solution with citric acid; it
discloses dissolving more than 0.1% hydrocortisone in 50:50 v/v
water: propylene glycol solution exceed known physical solubility
values of hydrocortisone.
[0017] U.S. Pat. No. 4,305,936 issued to Klein in 1981 provides for
a 0.005 to 2.5% hydrocortisone clear cream formulation containing 1
to 4% by weight of a glycerol ester of fatty acids having 6-22
carbon atoms, 1-3% by weight of the hydrocortisone of a betaine
surfactant, and 10-50% of an alkanol co-solvent, preferably
ethanol; solutions having such surfactants generally have stability
problems, and are not recommended for topical application to the
ear. Furthermore, it contains a relatively high ethanol content,
limiting its usefulness for topical application (especially to the
ear, near the eye).
[0018] U.S. Pat. No. 5,728,690 issued to Chen in 1998 discloses a
clear non-alcoholic 1-2% hydrocortisone preparation using 15-30%
polyethylene glycol, 15-30% propylene glycol, 5-20% glycerol,
3-12.4% sodium diactyl sulfosuccinate, and as much as 20% water to
make a liquid or gel product for application to the skin.
[0019] U.S. Pat. No. 5,744,166 describes a hydrocortisone
composition with aminopolysaccharides; such as, chitosan and
chitosan derivatives and polycationic polymers that forms a film
when applied dermally.
[0020] Purwar et al., WO 9,639,146 describes an aqueous solution of
the antimicrobial ciprofloxacin for the treatment of otitis externa
and media. Hydrocortisone is mentioned as a possible ingredient in
the ciprofloxacin preparation.
[0021] One primary object of the present invention is to provide a
clear aqueous solution capable of delivering the optimal allowable
amount of medicament(s) for topical application, especially to the
ear canal of humans or animals.
[0022] Another object of the present invention is to provide a
clear aqueous solution containing the optimal amount of
hydrocortisone, anti-microbial and anesthetic agents for
application as ear drops.
[0023] Another object is to provide a solvent capable of dissolving
an optimal amount of medicaments not readily soluble in water, yet
containing sufficient water to expand a wick.
[0024] Another object is to provide a method of making said
solution that is easy and relatively inexpensive.
[0025] Another object is to provide a stable solution, and one that
has a long shelf life.
[0026] Another object is to provide a method of using said solution
that facilitates delivery of the optimal amount of medicament to
the ear.
[0027] Other objects will be apparent from a reading of the written
description disclosed herein, together with the claims.
SUMMARY OF THE INVENTION
[0028] Generally, the solvent and solution disclosed herein (and
the methods of making and using same) relate to the formation of
solutions using both organic solvents and water. Optimally, said
solution will be a clear, aqueous solution capable of delivering a
therapeutically effective amount of medicament(s) for topical
application, especially to the ear canal; in particular, a
preferred embodiment of the solvent and solution disclosed herein
will both dissolve a therapeutically effective amount of
medicament(s) and have sufficient water content to also promptly
swell a wick within the ear canal a sufficient amount to facilitate
contact with the ear canal and to thereby facilitate the reduction
of ear wax, inflammation, infection and pain.
[0029] This invention yields stable, aqueous solutions of
hydrocortisone using a bland combination of propylene glycol,
water, ethanol or 2-propanol, together with mineral oil and/or
propylene glycol diacetate, for the treatment of otitis externa,
ear infections, inflammation and/or itching in or around the
external ear canal. In addition, medicaments such as an anesthetic
(pramoxine, for example) and an anti-microbial (such as
chloroxylenol) can be included in the solution. These formulations
for external ear treatment are stable in solution; they also have a
shelf life exceeding nine months. The ear drop formulations of 1.0%
hydrocortisone USP, with at least 33% water, can be used to expand
the cellulose, cloth or plastic wick to retain the medication in
the ear canal, and to maintain contact between the medicament and
the ear canal. This enhances the ceruminolytic efficacy of the
solution; the ear wax is broken down, facilitating ease of
removal.
DETAILED DESCRIPTION OF THE INVENTION
[0030] In most general terms, one primary aspect of the invention
disclosed herein is a solvent comprising a combination of water and
organic solvent(s) capable of dissolving a therapeutically
effective amount of medicament(s) not readily soluble in aqueous
solvents. Preferably said water is included in the range of between
about 30% (v/v) and about 50% (v/v), to facilitate the
wick-expanding facets of the invention. More specifically, said
water is included in the range of at least about 33% (v/v).
[0031] For the sake of simplicity and to give the claims of this
patent application the broadest interpretation and construction
possible, the following definitions will apply:
[0032] 1. The term "alcohol" primarily means alcohols of alkanes
having a low molecular weight, such as (for example) the alkanols
2-propanol and ethanol; not usually included are alcohols such as
glycol and glycerol.
[0033] 2. The term "bland" or any similar word means evoking
essentially no material adverse reaction after topical
application.
[0034] 3. The term "glycol" primarily means alcohols having at
least two alcohol groups, such as (for example) glycol and
glycerol.
[0035] 4. The term "medicaments" means an agent that promotes
recovery from an ailment or symptom(s) thereof; such agents may be
groups of related substances or compounds (or functional
derivatives or equivalents) such as, for example: (a)
anti-inflammatory agents like steroids such as hydrocortisone or
hydrocortisone derivatives (for example, hydrocortisone
hemisuccinate, hydrocortisone sodium phosphate, and hydrocortisone
sodium succinate); (b) anti-microbial agents like chloroxylenol,
cresyl acetate and phenol; and (c) anesthetic agents like pramoxine
and members of the benzoesters or amides group of anesthetics
(benzocaine, lidocaine and tetracaine, for example).
[0036] 5. The phrase "therapeutically effective amount" or similar
phrase means the amount necessary to reduce or prevent the symptom
or malady stated, implied or inherent in the context of usage.
[0037] 6. The term "% (v/v)" or a similar phrase means the
volume-per-volume percentage concentration of a liquid substance,
usually expressed as the number of milliliters (mL) of dissolved in
100 milliliters (mL) of solution.
[0038] 7. The term "% (w/v)" or a similar phrase means the
weight-per-volume percentage, concentration of a solid substance,
usually expressed as the number of grams of solute dissolved in 100
milliliters of solution.
[0039] 8. The term "water" may include isotonic saline, and
combinations of same with water.
[0040] Also for the sake of simplicity, the conjunctive "and" may
also be taken to include the disjunctive "or," and vice versa,
whenever necessary to give the claims of this patent application
the broadest interpretation and construction possible. Likewise,
when the plural form is used, it may be taken to include the
singular form, and vice versa.
[0041] The invention disclosed herein is not limited by
construction materials to the extent that such materials satisfy
the structural or functional requirements; for example, any
materials may be used to make the solvent so long as the solvent
allows for the dissolution of a therapeutic amount of medicament
while containing sufficient water content for absorption and
expansion of a wick. For this reason, the various components of
each solvent and solute may include members of specified groups of
substances, plus functional derivatives or equivalent
substances.
[0042] The organic solvent portion of the present invention may be
comprised of one or more glycol, especially glycol(s) selected from
the group consisting of propylene glycol, glycerol, propylene
glycol diacetate, and hexylene glycol, and functional derivatives
(or equivalents) and combinations thereof. One of the important
characteristics common to each of said members in said group,
supporting the inclusion of each member in said particular group,
is that glycols (especially propylene glycol) are known to fairly
readily dissolve hydrocortisone in sufficient amounts for topical
application. Another such common characteristic is that they are
bland (i.e., non-irritative) when applied to tissue. Preferably,
said glycol may include propylene glycol, and in the range of
between about 35% (v/v) and about 65% (v/v). Ideally, the
concentration of propylene glycol will not exceed 65%, because it
has less solvent properties when cooled, especially to freezing.
More particularly, one preferred formulation of the invention
provides that said propylene glycol may be included in the range of
about 50% (v/v); another preferred formulation of the invention
provides that said propylene glycol may be included in the range of
about 40% (v/v).
[0043] The organic solvent portion of the present invention may be
comprised of alcohol, especially the alcohol selected from the
group consisting of 2-propanol and ethanol, and functional
derivatives (or equivalents) and combinations thereof. One of the
important characteristics common to each of said members in said
group, supporting the inclusion of each member in said particular
group, is that is that low molecular weight alcohol are known to
readily dissolve hydrocortisone in sufficient amounts (1%) for
topical application. Another such common characteristic is that in
the event that the hydrocortisone-alcohol solution is cooled to
0.degree. C., said hydrocortisone will remain in said solution.
(Hydrocortisone will come out of solution if dissolve in a solution
comprised predominantly of glycol.) Preferably, said alcohol may
include 2-propanol, and in the range of between about 10% (v/v) and
about 80% (v/v). More particularly, one preferred formulation of
the invention provides that said 2-propanol may be included in the
range of about 16% (v/v); another preferred formulation of the
invention provides that said 2-propanol may be included in the
range of about 15% (v/v).
[0044] It is believed that at least 10% alcohol must be included in
the solution containing at least 33% water, to facilitate both the
dissolution of hydrocortisone and the expansion of the wick.
Assuming the solution contains at least 33% water, ideally the
solution should have a minimum concentration in the neighborhood of
10% alcohol, and a maximum concentration of about 55% glycol;
similarly, as the concentration of alcohol increases to a maximum
in the neighborhood of 30%, the concentration of glycol should
decrease to the neighborhood of about 35%. Ideally, the solution
should have no more than a total and glycol with alcohol comprising
at least 10%, because of its ability to dissolve hydrocortisone
when combined with a high enough concentration of water to
facilitate expansion of the wick. Moreover, to decrease the danger
and discomfort posed by possible contact between the solution and
the eye, the concentration of ethanol and/or 2-propanol should not
exceed around 30%.
[0045] The organic solvent may be comprised of combinations of both
alcohol and glycol. For example, a solvent may include 2-propanol
in the range of between about 10% (v/v) and about 80% (v/v), and
with said glycol including propylene glycol in the range of between
about 35% (v/v) and about 65% (v/v). More particularly, in one
formulation, said alcohol includes 2-propanol in the range of about
16% (v/v), and said glycol includes propylene glycol in the range
of about 50% (v/v); in another formulation, said alcohol includes
2-propanol in the range of about 15% (v/v), and said glycol
includes propylene glycol in the range of about 40% (v/v).
[0046] The organic solvent may also include propylene glycol
acetate, and in the range of between about 0.01% to about 3.0%. As
an alternative or additional solvent, mineral oil may be included,
and in trace amounts.
[0047] The present invention also includes a method of making
solvent described above. Said method includes the steps of mixing:
(1) glycol selected from the group consisting of propylene glycol,
glycerol, propylene glycol diacetate and hexylene glycol, and
functional derivatives (or equivalents) and combinations thereof;
(2) alcohol selected from the group consisting of 2-propanol and
ethanol, and functional derivatives (or equivalents) and
combinations thereof; (3) shelf life extender selected from the
group consisting of propylene glycol diacetate, mineral oil and
vitamin E, and functional derivatives (or equivalents) and
combinations thereof; and (4) eventually mixing water (after solute
is added to the mixture or (1) through (3) above) in the amount
necessary to bring the final solution up to 100%, at least 33% of
which is water. In one preferred formulation, said propylene glycol
is included in the range of about 50%; said 2-propanol is included
in the range of about 16%; and said propylene glycol diacetate is
included in the range of about 0.01%. In another preferred
formulation, said propylene glycol is included in the range of
about 40%; said 2-propanol is included in the range of about 15%;
and said mineral oil is included in about trace amounts; this
version may also include propylene glycol diacetate in the range
specified herein.
[0048] Aside from the aforementioned solvents, the present
invention may also include a solution of medicament(s) dissolved in
solvent, comprising a combination of water and organic solvent(s)
capable of dissolving a therapeutically effective amount of
medicament(s) not readily soluble in aqueous solvents. An example
of the type of medicaments includes anti-inflamatory medicament
selected from the group consisting of hydrocortisone,
hydrocortisone hemisuccinate, hydrocortisone sodium phosphate,
hydrocortisone sodium succinate or other hydrocortisone
derivatives, and functional derivatives (or equivalents) and
combinations thereof. One of the important characteristics common
to each of said members in said group, supporting the inclusion of
each member in said particular group, is that they are known or
believed to have anti-inflammatory effects; hydrocortisone is also
approved for topical application in ears in amounts soluble in the
invented solvent. Another such common characteristic is that they
are relatively stable in the solvent disclosed herein. Preferably,
said medicament includes hydrocortisone, and in the range of
between about 0.5% to about 2.0%. More particularly, said
medicament includes hydrocortisone in the range of about 1.2%.
[0049] Another example of said medicament includes anti-microbial
medicament selected from the group consisting of chloroxylenol,
cresyl acetate and phenol, and functional derivatives (or
equivalents) and combinations thereof. One of the important
characteristics common to each of said members in said group,
supporting the inclusion of each member in said particular group,
is that they are known or believed to be anti-bacterial and
anti-fungal, approved for topical application in ears in amounts
soluble in the invented solvent. Preferably, said medicament
includes chloroxylenol, and in the range of between about 0.1% to
about 0.4%. More particularly, said medicament includes
chloroxylenol in the range of about 0.1%.
[0050] Another example of said medicament is topical anesthetic
medicament selected from the group consisting of pramoxine,
benzocaine (and members of the benzocaine-ester group), lidocaine
(and members of the lidocaine-amide group), tetracaine, and
functional derivatives (or equivalents) and combinations thereof.
One of the important characteristics common to each of said members
in said group, supporting the inclusion of each member in said
particular group, is that they are known or believed to have
anesthetic effects, and they are approved for topical application
in ears in amounts soluble in the invented solvent. Preferably,
said medicament includes pramoxine, and in the range of between
about 0.5% to about 2.0%. More particularly, said medicament
includes pramoxine in the range of about 1.0%.
[0051] Another example of said medicament is shelf life extender
selected from the group consisting of propylene glycol diacetate,
mineral oil and vitamin E, and functional derivatives (or
equivalents) and combinations thereof. One of the important
characteristics common to each of said members in said group,
supporting the inclusion of each member in said particular group,
is that they are known or believed to extend the shelf life of
solutions, thereby extending the efficacy of such solutions.
Another such common characteristic is that they help keep
hydrocortisone in solution at freezing temperatures. Preferably,
said medicament includes propylene glycol diacetate, and in the
range of between about 0.01% to about 3.0%. More particularly said
medicament includes propylene glycol diacetate in the range of
about 0.01%. As an alternative or substitute shelf life extender
said medicament may include mineral oil in the range of its
solubility, that is, about trace amounts.
[0052] One preferred formulation provides for a solution of
medicaments dissolved in solvent, comprising the combination of (1)
solvent comprising propylene glycol in the range of about 50%
(v/v), 2-propanol in the range of about 16% (v/v), propylene glycol
diacetate in the range of about 0.01% (v/v), and water in the
amount necessary to bring the final solution up to 100%; and (2)
hydrocortisone in the range of about 1.2% (w/v); and (3) pramoxine
hydrochloride in the range of between about 1.0% (w/v); and (4)
chloroxylenol in the range of between about 0.1% (w/v). The present
invention also includes a method of making a solution described
above. Said method includes the steps of:
[0053] (a) mixing said non-aqueous solvent components and warming
same to about 50.degree. C.;
[0054] (b) adding said hydrocortisone and stirring until
dissolved;
[0055] (c) adding said pramoxine hydrochloride and chloroxylenol,
and cooling to about 25.degree. C.; and
[0056] (d) adding said water to bring the solution to 100%
(v/v).
[0057] Another preferred formulation provides for a solution of
medicaments dissolved in solvent, comprising the combination of:
(1) solvent comprising propylene glycol in the range of about 40%
(v/v), 2-propanol in the range of about 15% (v/v), mineral oil in
about trace amounts, and water in the amount necessary to bring the
final solution up to 100%; and (2) hydrocortisone in the range of
about 1.2% (w/v); (3) pramoxine hydrochloride in the range of about
1.0% (w/v); and (4) chloroxylenol in the range of about 0.1% (w/v)
and/or (5) benzalkonium chloride in the range of about 0.001%
(w/v). The present invention also includes a method of making a
solution described above. Said method includes the steps of:
[0058] (a) mixing said non-aqueous solvent components and warming
same to about 50.degree. C.;
[0059] (b) adding said hydrocortisone and stirring until
dissolved;
[0060] (c) adding said pramoxine hydrochloride, and adding said
chloroxylenol and/or said benzalkonium chloride, and cooling to
about 25.degree. C.; and
[0061] (d) adding said water to bring the solution to 100%
(v/v).
[0062] The present invention also includes a method of using
medicament solution described herein. Said method may include the
steps of: dispensing a therapeutic amount of said solution into an
external ear canal; positioning an expandable wick in the external
ear canal; and contacting said wick with said solution, in
sufficient amount to facilitate expansion of said wick within said
canal. In one version of this method of use, said solution is one
of the two preferred formulations disclosed above, and said
therapeutic amount of said solution is in the range of between
about 1 drop and 7 drops.
[0063] The following examples are included to illustrate the
various formulations useful in this invention and the processes for
their preparations.
EXAMPLE 1
[0064]
1 Raw Material % v/v Propylene glycol diacetate, USP 0.01 Propylene
glycol, USP 50 2-Propanol, USP 16 Raw Material % w/v
Hydrocortisone, USP 1.2 Pramoxine Hydrochloride, USP 1.0
Chloroxylenol, USP 0.1 Water, USP q.s. to 100%
[0065] Place the propylene glycol diacetate, propylene glycol and
2-propanol in a suitable mixing container equipped with a mixer.
Warm the solution to around 50.degree. C. Add hydrocortisone with
stirring and when dissolved, add pramoxine hydrochloride and
chloroxylenol. Cool to room temperature and bring the solution to
100% with water or isotonic saline.
[0066] The solution formulated in Example I remained clear when
stored at room temperature for two years. Stability studies on said
solution revealed the following: hydrocortisone initially 96.1%;
and 94.3% at 90 day shelf life. (Hydrocortisone, USP contains at
least 95% hydrocortisone.)
2 Raw Material % v/v Mineral Oil, USP Trace Propylene glycol, USP
40 2-Propanol, USP 15 Raw Material % w/v Hydrocortisone, USP 1.2
Pramoxine Hydrochloride, USP 1.0 Chloroxylenol, USP 0.1
Benzalkonium chloride, USP Isotonic saline, USP q.s. to 100%
volume
[0067] Prepare as in Example I
[0068] The, compressed ear plug, Pope Ear Wick Merocel.TM. is used
as an example for hydration and expansion of an ear plug. This wick
will expand to maximum size in water at room temperature in less
than 0.25 minute; in 80% 2-propanol: 20% water v/v, it will expaned
to maximum size in one (1) minute; and in propylene glycol, there
is no noticeable expansion. Using the solution formulated in
Example I or II, the wick will expand to maximum size in two (2)
minutes at room temperature. Also, as the temperature is increased
to body temperature, the expansion time is decreased to 30 seconds
or less.
[0069] Time to Maximum Expansion of Merocel.RTM. Pope Ear Wick on
Immersion in Example II Solution.
[0070] Initial wick size of 2.times.3.times.9 mm; maximum wick size
of 10.times.11.times.20 mm. Temperature of external ear canal
33.degree. C. [91.degree. F.]; body temperature of 37.degree. C.
[98.6.degree. F.].
3 Time (minutes) 2.25 1.5 0.5 0.125 Temp. (.degree. C. [.degree.
F.]) 20 [68] 26 [79] 31 [88] 34 [93]
[0071] 7 drop of Example II solution applied to the ears of ten
subjects, then 15 seconds elapsed before insertion of ear wick.
Removal of ear wick after 30 seconds. Wide expansion sufficient to
occlude external ear canal. Expansion of ear wick in room
temperature water to maximum in about 15 seconds.
[0072] Those skilled in the art who have the benefit of this
disclosure will appreciate that it may be used as the creative
basis for designing devices or methods similar to those disclosed
herein, or to design improvements to the invention disclosed
herein; such new or improved creations should be recognized as
dependant upon the invention disclosed herein, to the extent of
such reliance upon this disclosure.
* * * * *