U.S. patent application number 16/508217 was filed with the patent office on 2019-10-31 for magnesium chloride composition for dermatological use.
This patent application is currently assigned to BioPharmX, Inc.. The applicant listed for this patent is BioPharmX, Inc.. Invention is credited to Kin F. CHAN.
Application Number | 20190328775 16/508217 |
Document ID | / |
Family ID | 64014360 |
Filed Date | 2019-10-31 |
United States Patent
Application |
20190328775 |
Kind Code |
A1 |
CHAN; Kin F. |
October 31, 2019 |
MAGNESIUM CHLORIDE COMPOSITION FOR DERMATOLOGICAL USE
Abstract
Provided herein is a topical composition and related methods for
making and using the composition. In a first aspect, the topical
composition comprises a magnesium salt (e.g. magnesium chloride)
dissolved in an anhydrous or non-aqueous solvent. Exemplary
solvents comprise a monohydric aliphatic alcohol, and a polyol.
Inventors: |
CHAN; Kin F.; (Los Gatos,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BioPharmX, Inc. |
San Jose |
CA |
US |
|
|
Assignee: |
BioPharmX, Inc.
|
Family ID: |
64014360 |
Appl. No.: |
16/508217 |
Filed: |
July 10, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15970683 |
May 3, 2018 |
10391121 |
|
|
16508217 |
|
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|
|
62501078 |
May 3, 2017 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/02 20130101;
A61K 47/44 20130101; A61P 17/10 20180101; A61K 9/0014 20130101;
A61K 33/06 20130101; A61K 47/38 20130101; A61K 47/08 20130101; A61K
47/10 20130101 |
International
Class: |
A61K 33/06 20060101
A61K033/06; A61P 17/10 20060101 A61P017/10; A61K 47/10 20060101
A61K047/10; A61K 9/00 20060101 A61K009/00; A61K 47/38 20060101
A61K047/38; A61K 47/02 20060101 A61K047/02 |
Claims
1. A topical composition, comprising: a magnesium salt and a
non-aqueous solvent system comprised of a monohydric aliphatic
alcohol and a polyol, wherein the composition does not comprise a
tetracycline-class drug, wherein the monohydric aliphatic alcohol
and the polyol are in a ratio of from about 1:1 to 99:1.
2. The composition of claim 1, wherein the monohydric aliphatic
alcohol is present in the composition at a greater percent by
weight than the polyol.
3. The composition of claim 1, wherein the monohydric aliphatic
alcohol to polyol ratio is between about 2:1 to 10:1.
4. The composition of claim 1, wherein the monohydric aliphatic
alcohol is selected from the group consisting of ethanol,
isopropanol, propyl alcohol, tert-butyl alcohol, and combinations
thereof.
5. The composition of claim 1, wherein the monohydric aliphatic
alcohol is a liquid at room temperature, the polyol is a liquid at
room temperature, or both the monohydric aliphatic alcohol and the
polyol are liquids at room temperature.
6. The composition of claim 1, wherein the polyol is a C3-C8 diol
or triol.
7. The composition of claim 1, wherein the polyol is propylene
glycol.
8. The composition of claim 1, wherein the magnesium salt is
selected from the group consisting of magnesium chloride, magnesium
sulfate, magnesium salicylate, and combinations thereof.
9. The composition of claim 1, wherein the magnesium salt is
selected from the group consisting of the anhydrous magnesium
chloride, anhydrous magnesium sulfate, anhydrous magnesium
salicylate, and combinations thereof.
10. The composition claim 1, comprising between about 0.1% to about
10% by weight magnesium salt.
11. The composition of claim 10, wherein the magnesium salt is
magnesium chloride.
12. The composition of claim 1, further comprising an essential
oil.
13. The composition of claim 13, wherein the essential oil is
1,8-cineole.
14. The composition of claim 13, comprising between about 0.01 to 5
weight percent of 1,8-cineole.
15. The composition of claim 1, further comprising a thickening
agent.
16. The composition of claim 15, wherein the thickening agent is
hydroxypropyl cellulose.
17. The composition of claim 1, wherein the magnesium salt is
dissolved in the composition.
18. The composition of claim 1, wherein the composition comprises
less than about 3 weight percent water.
19. A method for treating a dermatological condition or disease,
comprising: topically applying to an exterior epithelial surface of
a human body a composition according to claim 1 at least once daily
for a period of at least one week.
20. A method for treating acne in a human subject, comprising
topically applying to a local skin region affected by acne a
composition according to claim 1 at least once daily for a period
of at least one week.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Non-Provisional
application Ser. No. 15/970,683, filed May 3, 2018, which claims
priority to U.S. Provisional Application No. 62/501,078, filed May
3, 2017, each of which are incorporated herein by reference in
their entirety.
TECHNICAL FIELD
[0002] This disclosure relates generally to compositions and
methods for preparing such compositions, as well as to related
uses. Uses include, for example, the treatment of various
dermatological conditions and diseases, among other things. More
particularly, this disclosure is directed to compositions
comprising a magnesium salt, a monohydric aliphatic alcohol, and a
polyol, and to related methods for making and using such
compositions.
BACKGROUND
[0003] Epsom salts (magnesium sulfate) have been used to treat a
variety of skin conditions when mixed with water. There is a need
for a topically-applied composition that delivers magnesium
chloride to the skin in quantities sufficient to inhibit growth of
Propionibacterium acnes (P. acnes) bacteria on the skin surface and
to actively draw water out of the skin.
BRIEF SUMMARY
[0004] The present disclosure overcomes one or more limitations
associated with current magnesium-salt containing topical
compositions. Provided herein is a topical composition comprising a
magnesium salt (e.g. magnesium chloride or magnesium sulfate) and a
non-aqueous solvent system comprised of a monohydric aliphatic
alcohol and a polyol, wherein the composition does not comprise a
tetracycline-class drug, and wherein the monohydric aliphatic
alcohol and polyol comprise 30-99.9% of the weight of the
composition. In some related embodiments, the ratio of monohydric
aliphatic alcohol to polyol is in a range of 1:1 to 99:1 by
weight.
[0005] In yet one or more further embodiments, the composition
comprises a greater percent by weight of the monohydric aliphatic
alcohol than the polyol. For example, in one or more related
embodiments, the w/w ratio of monohydric aliphatic alcohol to
polyol is in a range of about 2:1 to 10:1 by weight.
[0006] In yet one or more further embodiments, the magnesium salt
is dissolved in the non-aqueous solvent. In other embodiments, the
magnesium salt is dissolved in the composition. In another
embodiment, the magnesium salt is dissolved in the composition upon
its application to skin and subsequent to its application on skin.
In another embodiment, the magnesium salt is dissolved in the
composition upon its application to skin, whereupon the monohydric
aliphatic alcohol evaporates from the composition to form a
residual composition, and the magnesium salt is dissolved in the
residual composition.
[0007] In some further embodiments, the monohydric aliphatic
alcohol is selected from the group consisting of ethanol,
isopropanol, propyl alcohol, tert-butyl alcohol, or combinations
thereof. In some particular embodiments, the monohydric aliphatic
alcohol is ethanol.
[0008] In yet some additional embodiments, the topical composition
comprises from about 0.1% to about 10% by weight magnesium
chloride.
[0009] In yet some additional embodiments, the topical composition
comprises from about 0.5% to about 2% by weight magnesium
chloride.
[0010] In yet some additional embodiments, the topical composition
comprises about 1.2% by weight magnesium chloride.
[0011] In yet one or more further embodiments, the polyol is a
C3-C8 diol or a triol. In some embodiments, the polyol is propylene
glycol.
[0012] In some further embodiments, the topical composition
comprises from about 0.005% to about 3.0% by weight of a sulfite
compound. In one or more particular embodiments, the sulfite is
selected from the group consisting of sodium sulfite, sodium
bisulfite, and sodium meta-bisulfite.
[0013] In yet some additional embodiments, the topical composition
comprises less than about 3 weight percent water. In yet some
further embodiments, the topical composition comprises less than
about 2 weight percent water.
[0014] In some further embodiments, the topical composition further
comprises an essential oil. In one or more related embodiments, the
essential oil is 1,8-cineole. In some embodiments, the topical
composition comprises from about 0.01 to 5 weight percent of
1,8-cineole.
[0015] In some further embodiments, the topical composition
comprises a thickening agent. In one or more related embodiments,
the thickening agent is hydroxypropyl cellulose.
[0016] In some further embodiments, the topical composition has an
effective pH of 3.5-8.0 when mixed with water in a ratio of 1:9 by
weight. In some embodiments, the topical composition has an
effective pH of about 5.0 to about 7.5 when mixed with water in a
ratio of 1:9 by weight.
[0017] In yet one or more additional embodiments, the composition
is non-irritating when applied to rats daily over a period of 28
days. For instance, a non-irritating composition will generally not
irritate the skin or cause an allergic reaction.
[0018] In one or more embodiments of the composition, the
monohydric aliphatic alcohol is a liquid at room temperature. In
one or more further embodiments, the monohydric aliphatic alcohol
is selected from the group consisting of ethanol, isopropanol,
propyl alcohol, tert-butyl alcohol, and combinations thereof.
[0019] In yet some further embodiments, the monohydric aliphatic
alcohol is a volatile monohydric aliphatic alcohol.
[0020] In yet some additional embodiments related to the polyol
component, the polyol is a liquid at room temperature. In one or
more particular embodiments, the polyol is a C3-C8 diol or triol.
In yet some more particular embodiments, the polyol is propylene
glycol.
[0021] In yet some additional embodiments directed to the polyol,
the polyol is not glycerol or glycerin.
[0022] In some particular embodiments of the composition, the
magnesium salt is selected from the group consisting of magnesium
chloride, magnesium sulfate, magnesium salicylate, and combinations
thereof.
[0023] In some particular embodiments of the composition, the
magnesium salt is selected from the group consisting of anhydrous
magnesium chloride, anhydrous magnesium sulfate, anhydrous
magnesium salicylate, and combinations thereof.
[0024] In one or more further embodiments, the composition further
comprises a thickening agent. In some particular embodiments, the
thickening agent is hydroxypropyl cellulose.
[0025] In some further embodiments of the composition, the
composition possesses a viscosity in a range of about 75 centipoise
to about 10,000 centipoise at 25.degree. C. In some further
embodiments of the second aspect, the composition comprises one or
more additional additives, such as, for example, an antioxidant, a
thickener, a colorant, or other suitable additive.
[0026] In some further embodiments, the topical composition is not
an emulsion.
[0027] In some further embodiments, the composition is not an
emulsion and/or does not comprise nanoparticles or
microparticles.
[0028] In some further embodiments, the composition does not
comprise an antibiotic. In some further embodiments, the
composition does not comprise a tetracycline-class drug. In some
further embodiments, the composition does not comprise
minocycline.
[0029] In some further embodiments, the composition does not
comprise a retinoid.
[0030] In some further embodiments, the composition does not
comprise an active pharmaceutical ingredient (API).
[0031] In some further embodiments, the composition does not
comprise added water. In one embodiment, the composition does not
comprise exogenous or exogenously added water.
[0032] In some further embodiments, the composition does not
comprise polyethylene glycol.
[0033] In some further embodiments, the composition does not
comprise an oil.
[0034] In some further embodiments, the composition does not
comprise an oil other than 1,8-cineole.
[0035] In some further embodiments, the composition does not
comprise more than 5% of a calcium salt by weight. In some further
embodiments, the composition does not comprise more than 1% of a
calcium salt by weight. In some further embodiments, the
composition does not comprise a calcium salt. In some further
embodiments, the composition does not comprise calcium.
[0036] In some further embodiments, the composition is not
occlusive.
[0037] In some additional embodiments, the topical composition does
not comprise nanoparticles or microparticles.
[0038] In certain embodiments, the topical composition is
non-aqueous. In alternative embodiments, the topical composition is
anhydrous. In certain embodiments, the composition comprises less
than 10% water as measured by Karl Fisher. In certain embodiments,
the composition comprises less than 5% water as measured by Karl
Fisher. In certain embodiments, the composition comprises less than
2% water as measured by Karl Fisher.
[0039] In some embodiments, the concentration of the magnesium
chloride in the topical composition exceeds the minimum inhibitory
concentration (MIC) of magnesium chloride for a target bacteria in
a target tissue or target body fluid. In one or more related
embodiments, the target bacteria is P. acnes.
[0040] In yet some further embodiments, the composition dries in
less than 60 seconds when applied to a region of skin in vivo.
[0041] In yet some additional embodiments in which the composition
comprises a polyol and 1,8-cineole, the combination of the polyol
and the 1,8-cineole is effective to prevent the skin from scaling
and from extreme drying due to extended use for two weeks or more
when applied at least 3 times per week.
[0042] Also provided herein is a method of treating acne in a human
subject comprising topically applying an effective amount of a
composition as provided herein to an exterior epithelial body
surface of the human. In one embodiment, the composition is
topically applied to an affected area of the epithelial body
surface.
[0043] Also provided herein is a method of treating rosacea in a
human subject comprising topically applying an effective amount of
a composition as provided herein to an exterior epithelial body
surface of the human. In one embodiment, the composition is
topically applied to an affected area of the epithelial body
surface.
[0044] In yet a further aspect, provided is a method for treating a
condition or disease responsive to treatment with magnesium
chloride in a human, where the method comprises topically applying
a composition as provided herein to an exterior epithelial surface
of a human body at least daily for a period of at least 1 week. In
one or more related embodiments, the condition or disease is a
dermatological condition or disease, and the applying step
comprises applying the topical composition to the skin once or
twice daily for a period of from about 6 to about 52 weeks.
[0045] In one or more additional embodiments, the dermatological
condition or disease is acne or rosacea. In one or more particular
embodiments, the acne is acne vulgaris. In yet or more alternative
embodiments, the acne is acne fulminans.
[0046] In another aspect, a method for treating a subject having
acne is provided. The method comprises topically applying a
composition as described herein to a local skin region affected by
acne. The method is effective to reduce the inflammatory lesion
count by at least 25% or at least 50% when applied daily for a
period of from about 6 to about 52 weeks. In one or more
embodiments, the method is effective to result in at least a
2-point reduction in acne intensity score according to the
Investigator's Global Assessment (IGA) scale ("Guidance for
Industry: Acne Vulgaris: Developing Drugs for Treatment", U.S.
Department of Health and Human Services, Food and Drug
Administration, September 2005) when the composition is topically
applied daily for 6-52 weeks to a human with an initial acne
intensity score of in the range of 3 to 4, or in the range of 2 to
4.
[0047] In one embodiment, the Investigator's Global Assessment
(IGA) for acne or rosacea for the human subject is reduced from
moderate or severe to clear or almost clear following 12 weeks of
daily application of the topical formulation.
[0048] In another embodiment, the acne lesion count or rosacea
lesion count for the human subject reduced by more than 10 lesions
following 12 weeks of daily application of the topical
formulation.
[0049] In another aspect, a method for improving or alleviating a
symptom associated with a dermatological disease or condition is
provided. The method comprises topically applying a composition as
described herein to a local skin region presenting a symptom of the
disease or condition. In one embodiment, the composition is applied
to an external skin surface from one to three times daily for a
period of from about 2 weeks to at least about 6 weeks or until a
visible improvement in the symptom of the dermatological condition
or disease is observed.
[0050] In yet one or more further embodiments, provided is a
composition as described herein accompanied by instructions for
topical use for treatment of a dermatological condition or disease
of the skin. In one or more related embodiments, the instructions
comprise instructions for applying the composition to an external
skin surface from one to three times daily for a period of from
about 2 weeks to at least about 6 weeks or until a visible
improvement in the dermatological condition or disease is
observed.
[0051] In yet an additional aspect, provided herein is a method for
making a composition, e.g., one suitable for treating acne or
rosacea in a human, preferably a topical composition, the method
comprising (i) combining a magnesium salt, a volatile monohydric
aliphatic alcohol, and a polyol to form a mixture, and (ii)
agitating the mixture from (i) to form a solution in which the
magnesium salt is dissolved.
[0052] In yet another aspect, provided is a method for making a
composition, the method comprising (i) combining a magnesium salt
and a non-aqueous solvent to form a mixture, and (ii) agitating the
mixture from (i) to form a solution in which the magnesium salt is
dissolved.
[0053] Each of the foregoing aspects and embodiments is meant to
apply to each and every other aspect and embodiment. Additional
embodiments of the composition, related methods, components of the
composition, and the like will be apparent from the following
description, examples and claims. These and other objects and
features of the disclosure will become more fully apparent when
read in conjunction with the following detailed description.
DETAILED DESCRIPTION
[0054] The present invention will be described more fully
hereinafter. This invention may, however, be embodied in many
different forms and should not be construed as limited to the
embodiments set forth herein; rather, these embodiments are
provided so that this disclosure will be thorough and complete, and
will fully convey the scope of the invention to those skilled in
the art. As can be appreciated from the foregoing and following
description, each and every feature described herein, and each and
every combination of two or more of such features, is included
within the scope of the present disclosure provided that the
features included in that such combinations are not inconsistent.
In addition, any feature or combination of features may be
specifically excluded from any embodiment of the present invention.
Additional aspects and advantages of the present invention are set
forth in the following description and claims, particularly when
considered in conjunction with the accompanying examples and
drawings.
[0055] All publications, patents and patent applications cited
herein are hereby incorporated by reference in their entirety,
unless otherwise indicated. In an instance in which the same term
is defined both in a publication, patent, or patent application
incorporated herein by reference and in the present disclosure, the
definition in the present disclosure represents the controlling
definition. For publications, patents, and patent applications
referenced for their description of a particular type of compound,
chemistry, etc., portions pertaining to such compounds, chemistry,
etc. are those portions of the document that are incorporated
herein by reference.
Definitions
[0056] It must be noted that, as used in this specification, the
singular forms "a," "an," and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to an "active ingredient" includes a single ingredient as
well as two or more different ingredients, reference to a "solvent"
refers to a single solvent as well as to two or more different
solvents or a complex mixture of solvents, reference to a
"magnesium salt" includes a single magnesium salt as well as two or
more different magnesium salts, and the like.
[0057] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions described below.
[0058] The term "topical composition" refers to a material that
comprises pharmaceutically acceptable ingredients, including an
active ingredient, and is intended for administration to an animal
or human subject and is applied to the surface of the skin, in
contrast to materials that are taken orally or via intravenous
(subdermal) injection. A topical composition is generally intended
to have its intended effect at the site of application and does not
result in significant concentrations of active ingredient in the
bloodstream or other tissues (as is the case with, for example,
transdermal compositions). Topical compositions as provided herein
are typically administered for the purpose of alleviation of
symptoms associated with a dermatological disease or condition,
treatment of a dermatological disease or condition, or prevention
of a dermatological disease or condition.
[0059] The term "solvent" refers to a substance in which one or
more solid ingredients are dissolved to some extent. For example,
ethanol, isopropanol, and propylene glycol, to name a few, are
considered as solvents for magnesium chloride and other magnesium
salts.
[0060] The term "tetracycline-class drug" refers to tetracycline
and tetracycline derivatives such as, for example, minocycline,
doxycycline, oxytetracycline, and their corresponding
pharmaceutically acceptable salt forms, as well as solvates and
hydrates thereof, including various crystalline forms, polymorphs,
amorphous materials, etc. A tetracycline antibiotic generally
contains a four ring octahydrotetracene-2-carboxamide skeleton,
while the actual substituents on the skeleton may vary.
[0061] The term "monohydric aliphatic alcohol" refers to a
monofunctional organic compound that contains a single hydroxyl
group, in which the hydroxyl functional group is covalently
attached to a saturated carbon atom forming part of a branched or
linear alkyl chain, and which does not contain an aromatic-ring
configuration of atoms. Generally, a monohydric aliphatic alcohol
for use in the compositions provided herein conforms to the formula
R--OH, where R is a C.sub.1-C.sub.4 alkyl. Suitable R groups
include ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and
tert-butyl.
[0062] The term "polyol" refers to a pharmaceutically acceptable
alcohol containing two or more hydroxyl groups, and possessing from
3-8 carbon atoms. Polyols suitable for use in the instant
compositions may but do not necessarily contain functional groups
in addition to the hydroxyl groups, such as e.g., an ether bond. As
used herein, polyethylene glycol shall not be considered to be a
polyol. Illustrative polyols include diols such as propylene glycol
(PG) and dipropylene glycol, triols such as glycerol, 1,2,6
hexanetriol, trimethylolpropane, and higher alcohols (i.e.,
containing more than 3 hydroxyl groups) such as sorbitol and
pentaerythritol. Polyols also include butylene glycol, hexylene
glycol, 1,6 hexanediol, mannitol, and xylitol. It is recognized
that some of these solvents are solids that may be undesirable, but
when combined in appropriate mixtures, they may be suitable for use
in a topical composition as described herein.
[0063] The term "cineole" refers to 1,8-cineole.
[0064] The term "cosmetic" refers to an item that is an "article
intended to be rubbed, poured, sprinkled, or sprayed on, introduced
into, or otherwise applied to the human body for cleansing,
beautifying, promoting attractiveness, or altering the appearance"
(from U.S. FD&C Act, section 201(i)). The U.S. Food and Drug
Administration classifies various items as cosmetics or drugs. This
definition is intended to follow the U.S. FDA classifications. U.S.
FDA further clarifies on its web site that "Among the products
included in this definition are skin moisturizers, perfumes,
lipsticks, fingernail polishes, eye and facial makeup preparations,
cleansing shampoos, permanent waves, hair colors, and deodorants,
as well as any substance intended for use as a component of a
cosmetic product."
[0065] The term "topical", in reference to administration of an
active ingredient or composition, refers to application of such
active ingredient or composition to an exterior epithelial surface
of the body, including the skin or cornea. For purposes of this
application, applications inside a bodily orifice, such as the
mouth, nose, or ear shall not be considered to be topical
applications.
[0066] A solvent (or solvents) is said to "dissolve" a magnesium
salt (or conversely, the salt is said to be soluble in a solvent)
if the solubility of that salt at 25.degree. C. is at least 0.1%
(w/w). For emulsions and the like, the salt is only considered to
"dissolve" in the solvent if the salt is in direct interaction with
the solvent such that the salt is incorporated into the solvent to
form a solution. So, for example, a salt that is coated to limit
interaction with a solvent would not be considered dissolved in
that solvent if it remained in particulate form. A salt may
separate into ionic components with solvent dissolving the ionic
components. In such cases, the solvent is said to dissolve the
salt.
[0067] A solvent or composition is said to be "anhydrous" or to
have "no added water" if there is no added water in the solvent or
composition. That is to say, as used herein, an anhydrous
composition is one in which water has not been added as a
component. For clarity, a solution or composition can be considered
to be anhydrous even if it contains water arising from a
composition component, such as through the addition of magnesium
chloride hexahydrate, as long as no free water is added to the
composition. Many of the solvents described herein are hydroscopic
to a greater or lesser extent and such solvents may be part of an
anhydrous composition without regards to the water that is
naturally absorbed by such materials.
[0068] A solvent or composition is said to be "non-aqueous" if
there is less than 5% by weight water content in the solvent or
composition, respectively, as measured by Karl Fischer titration or
other suitable method.
[0069] A solvent or composition is said to be "volatile" if it has
a boiling point of less than 100.degree. C. at atmospheric
pressure. Volatile solvents or compositions typically evaporate
readily at room temperature and atmospheric pressure. Examples of
volatile solvents include isopropanol, ethanol, and t-butyl
alcohol. Examples of non-volatile solvents include water, white
petrolatum, and olive oil.
[0070] "Room temperature" refers to a temperature in a range of
about 20-25 degrees Centigrade (20-25.degree. C.). In reference to
a measurement or other feature requiring a precise indication of
room temperature, room temperature is taken as 25 degrees
centigrade.
[0071] "MIC" or minimum inhibitory concentration is defined as the
lowest concentration of an antimicrobial compound that will inhibit
the visible growth of a microorganism after 48 hours of
incubation.
[0072] The abbreviation "(w/w)" indicates that relative
concentrations of components in a composition are presented on a
"weight for weight" basis (i.e. percentages refer to a percentage
of the total weight), rather than on the basis of volume or some
other basis.
[0073] The term "viscosity" refers to the measurement of a
substance using a viscometer, such as a Brookfield LVF viscometer
(Brookfield Engineering Laboratories, Inc., Middleboro, Mass.) or
equivalent, with spindle and speed combinations suitable for the
testing of applicable viscosity level.
[0074] As used herein, "dermatological condition" refers to
cosmetic and pathological disorders of the skin. Dermatological
conditions include topical inflammatory skin conditions such as
eczema, seborrhoeic dermatitis, bullous dermatoses, cutaneous
sarcoidosis, Kaposi's sarcoma, neutrophilic dermatoses, contact
dermatitis, rosacea, psoriasis and acne including acne rosacea, and
infections such as Impetigo, cellulitis, erysipelas, folliculitis,
furuncles, carbuncles, Lyme disease, and other skin infections.
[0075] As used herein, "acne" is a disorder of the skin
characterized by papules, pustules, cysts, nodules, comedones, and
other blemishes or skin lesions. These blemishes and lesions are
often accompanied by inflammation of the skin glands and
pilosebaceous follicles, as well as, microbial, especially
bacterial, infection. As used herein, acne includes all known types
of acne. Some types of acne include, for example, acne vulgaris,
cystic acne, acne atrophica, bromide acne, chlorine acne, acne
conglobata, acne cosmetica, acne detergicans, epidemic acne, acne
estivalis, acne fulminans, halogen acne, acne indurata, iodide
acne, acne keloid, acne mechanica, acne papulosa, pomade acne,
premenstral acne, acne pustulosa, acne scorbutica, acne
scrofulosorum, acne urticata, acne varioliformis, acne venenata,
propionic acne, acne excoriee, gram negative acne, steroid acne,
nodulocystic acne and acne rosacea. Acne rosacea is characterized
by inflammatory lesions (erythema) and telangiectasia.
Telangiectasia is abnormally and permanently dilated blood vessels
associated with a number of diseases. For example, facial
telangiectasia is associated with age, acne rosacea, sun exposure,
and alcohol use.
[0076] The term "pharmaceutically acceptable" in reference to an
entity or ingredient is one that may be included in the
compositions provided herein and that causes no significant adverse
toxicological effects in the patient at specified levels, or if
levels are not specified, in levels known to be acceptable by those
skilled in the art. All ingredients in the compositions described
herein are provided at levels that are pharmaceutically acceptable.
For clarity, active ingredients may cause one or more side effects
and inclusion of the ingredients with a side effect profile that is
acceptable from a regulatory perspective for such ingredients will
be deemed to be "pharmaceutically acceptable" levels of those
ingredients.
[0077] "Pharmaceutically acceptable salt" denotes a salt form of a
drug or active ingredient having at least one group suitable for
salt formation that causes no significant adverse toxicological
effects to the patient. Reference to an active ingredient as
provided herein is meant to encompass its pharmaceutically
acceptable salts. Pharmaceutically acceptable salts include salts
prepared by reaction with an inorganic acid, an organic acid, a
basic amino acid, or an acidic amino acid, depending upon the
nature of the functional group(s) in the drug. Suitable
pharmaceutically acceptable salts include acid addition salts which
may, for example, be formed by mixing a solution of a basic drug
with a solution of an acid capable of forming a pharmaceutically
acceptable salt form of the basic drug, such as hydrochloric acid,
iodic acid, fumaric acid, maleic acid, succinic acid, acetic acid,
citric acid, tartaric acid, carbonic acid, phosphoric acid,
sulfuric acid and the like. Typical anions for basic drugs, when in
protonated form, include chloride, sulfate, bromide, mesylate,
maleate, citrate, phosphate, and the like. Suitable
pharmaceutically acceptable salt forms and methods for identifying
such salts are found in, e.g., Handbook of Pharmaceutical Salts:
Properties, Selection and Use, Weinheim/Zurich:Wiley-VCH/VHCA,
2008; P. H. Stahl and C. G. Wermuth, Eds.
[0078] "Non-irritating" in reference to a topical formulation as
provided herein refers to a formulation having an average score of
less than 0.50 on the modified Draize scale for a test of 5 or more
Sprague-Dawley rats. The modified Draize test is an acute
irritation test carried out as follows. A Sprague-Dawley rat is
shaved in an application area, and the application area allowed to
rest for approximately 24 hours and then rinsed with non-irritating
soap. A test composition is applied evenly, without significant
rubbing, to a 10 cm.sup.2 area of the rat's skin in a volume of 2.5
mg/cm.sup.2. The sample is allowed to sit uncovered for 24 hours.
After 24 hours, the application area is washed gently with 1.times.
phosphate buffered saline (lx PBS) and non-irritating soap to
facilitate observation of the application area. The application
area is then scored according to the following scale: 0=no evidence
of irritation; 1=minimal erythema, barely perceptible; 2=definite
erythema, readily visible, minimal edema or minimal popular
response; 3=erythema and papules; 4=definite edema; 5=erythema,
edema, and papules; 6=vesicular eruption; 7=strong reaction
spreading beyond test site.
[0079] "Therapeutically effective amount" is used herein to mean
the amount of a preparation, or amount of an active ingredient in
the preparation, that is needed to provide a desired level of
active ingredient in a target tissue or at a target site. The
precise amount will depend upon numerous factors, e.g., the
particular active ingredient, the components and physical
characteristics of the preparation, intended patient population,
patient considerations, and the like, and can readily be determined
by one skilled in the art, based upon the information provided
herein and available in the relevant literature.
[0080] The term "patient" refers to a living organism suffering
from or prone to a condition that can be prevented or treated by
administration of a composition as provided herein, and includes
both humans and animals. Preferred animals are mammals.
[0081] "Optional" or "optionally" means that the subsequently
described circumstance may or may not occur, so that the
description includes instances where the circumstance occurs and
instances where it does not.
[0082] In many cases, the patent application describes ranges of
values. Such ranges shall be construed to include the endpoints of
the range unless doing so would be inconsistent with the text or
otherwise noted.
Topical Composition
[0083] In a first aspect, a composition that treats certain
dermatological conditions is provided. The composition comprises a
magnesium salt (e.g. magnesium chloride or magnesium sulfate) and a
non-aqueous solvent comprising a monohydric aliphatic alcohol and a
polyol. The composition does not comprise a tetracycline-class
drug, in one embodiment. In another embodiment, the monohydric
aliphatic alcohol and polyol comprise 50-99.9% of the weight of the
composition. In one embodiment, magnesium chloride is a preferred
magnesium salt due to its low skin irritation and its low skin
toxicity.
[0084] Anhydrous or non-aqueous compositions and solvents (e.g.
anhydrous or non-aqueous monohydric aliphatic alcohol) are
desirable because it is beneficial for the magnesium salt to
dehydrate the skin surface. Dehydrating the skin surface limits the
water that is available to bacteria on the skin surface which
reduces the survival rate for potentially harmful or detrimental
bacteria. Use of anhydrous or non-aqueous compositions and solvents
thus promotes the reduction of the bacterial concentration on the
skin surface and supports the treatment or prophylaxis of
dermatological conditions and diseases. Furthermore, using
anhydrous forms of magnesium salts, rather than their hydrates
(e.g. magnesium chloride anhydrous instead of magnesium chloride
hexahydrate) further promotes these beneficial effects by allowing
the magnesium salts to attract water and thus promote the drying of
the skin surface.
[0085] The present application provides a topical composition and
related methods for preparing the topical composition. In one
aspect, the topical composition comprises a magnesium salt in a
non-aqueous solvent, where details regarding the magnesium salt and
the non-aqueous solvent are provided above and in the sections
which follow.
[0086] In another aspect, provided herein is a topical composition
comprising a magnesium salt, a monohydric aliphatic alcohol, and a
polyol, wherein the magnesium salt is dissolved within the topical
composition. In some exemplary embodiments, the monohydric
aliphatic alcohol is ethanol, isopropanol, or tert-butyl alcohol
(i.e., t-butyl alcohol). In one or more additional exemplary
embodiments, the polyol is a C3-C8 aliphatic, saturated diol or
triol. In one or more further embodiments, the polyol is a
1,2-diol, a 1,3-diol or a triol. Illustrative polyols include
propylene glycol, dipropylene glycol, and glycerol. Further details
of the composition and related methods are provided herein.
[0087] Materials can be sourced, for example, from the following
providers: ethanol (anhydrous) (Spectrum Chemicals, Gardena,
Calif.), propylene glycol (Spectrum Chemicals, Gardena, Calif.),
1,8-cineole (Penta International Company, Livingston, N.J.),
hydroxypropyl cellulose (Ashland, Inc., Covington, Ky.), sodium
meta-bisulfite (Spectrum Chemicals, Gardena, Calif.), and magnesium
chloride (anhydrous) (Sigma-Aldrich Corp., St. Louis, Mo.).
[0088] In some embodiments, the composition is used for the
treatment of a dermatological condition or disease. Non-limiting
examples of dermatological conditions or diseases for which the
composition may be used include but are not limited to acne,
rosacea, seborrhoeic dermatitis, psoriasis, and superficial skin
infections such as impetigo, as well as in wound management.
[0089] Accordingly, in one aspect, the topical composition
comprises a magnesium salt in a non-aqueous or anhydrous solvent.
In another aspect, the composition comprises a magnesium salt, a
monohydric aliphatic alcohol, and a polyol. Composition components
and features will now be described in greater detail.
[0090] The amount of magnesium salt in the topical composition
(e.g., magnesium chloride or magnesium sulfate) typically ranges
from about 0.01% to about 10% by weight, or from about 0.1% to
about 5% by weight. In one embodiment, the magnesium salt is
present in the composition from about 0.1% to about 4% by weight,
or from about 0.2% to about 3% by weight or from about 0.2% to
about 1.5% by weight. In another embodiment, the topical
formulation may comprise any one of the following weight
percentages of magnesium salt: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%,
0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%,
1.8%, 1.9%, 1.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5% and so forth.
[0091] Illustrative magnesium salts include but are not limited to
magnesium bromide, magnesium chloride, magnesium fluoride,
magnesium iodide, magnesium sulfate, magnesium salicylate, and
magnesium phosphate. In preferred embodiments, the magnesium salt
is anhydrous.
[0092] The topical composition generally additionally comprises, as
part of its non-aqueous or anhydrous solvent system, a monohydric
aliphatic alcohol, preferably a volatile alcohol. Generally, a
monohydric aliphatic alcohol for use in the compositions provided
herein conforms to the formula R--OH, where R is a C.sub.1-C.sub.4
alkyl group. Suitable R groups include methyl, ethyl, propyl,
isopropyl, butyl, sec-butyl, isobutyl and tert-butyl. Preferably,
the monohydric aliphatic alcohol is a primary alcohol such as ethyl
alcohol, propyl alcohol or butyl alcohol. One particularly
preferred monohydric aliphatic alcohol is ethanol. In some
embodiments, the monohydric aliphatic alcohol is one having a
solubility in water of 5 percent or greater at room temperature.
Methanol, ethanol, 1- and 2-propanol, and t-butyl alcohol, for
example, are miscible with water, while 1-butanol has a solubility
of about 9% in water and 2-butaol has a solubility in water of 7.7%
at room temperature. Preferred alcohols are hydrophilic.
[0093] Yet a further component of the topical composition (i.e.,
forming part of its solvent system) is a polyol containing two or
more hydroxyl groups, and possessing from 3-8 carbon atoms.
Typically, the polyol is an aliphatic compound; exemplary polyols
for use in the instant composition include diols such as propylene
glycol (PG, propane-1,2-diol), hexylene glycol
(2-methylpentane-2,4-diol), 1,3-butylene glycol (1,3-butane diol),
and dipropylene glycol, triols such as glycerol and
trimethylolpropane, and higher alcohols (meaning containing more
than 3 hydroxyl groups) such as sorbitol and pentaerythritol.
Preferred polyols are C3-C8 diols and triols. The diol or triol
will typically have a molecular weight less than about 250 Daltons,
or even less than about 200 Daltons. In some instances, the polyol
will have a molecular weight less than about 125 Daltons. The
polyol, may, in some instances, be hygroscopic, such as in the case
of propylene glycol. In some embodiments, the polyol is a triol
other than glycerol or glycerin.
[0094] Many monohydric aliphatic alcohols, such as ethanol, can
provide a stable solvent for magnesium salts. Since ethanol is a
volatile solvent, much of the solvent evaporates quickly when
applied to the skin where the surface temperature is typically
between about 33.5-36.9.degree. C. For example, in one embodiment,
the solvent evaporates and/or penetrates into the skin when applied
to the skin in less than about 3 minutes, 2 minutes, 1.5 minutes or
1 minute. This evaporation and/or penetration increase the
concentration of the magnesium salt in the composition remaining on
the surface of the skin and can lead to formation of solid deposits
on the skin surface or in the upper layers of the skin. Formation
of solid deposits is less favorable than maintaining the magnesium
salt in solution because the dissolved form provides better
chemical interaction between the magnesium salt and the skin
bacteria and the water within the skin and at the skin surface. The
compositions provided herein are aimed, at least in part, in
overcoming the shortcomings noted above. For example, consider a
composition comprising 1.2% (w/w) magnesium chloride, 78.8% (w/w)
ethanol, and 20% (w/w) propylene glycol. The ethanol is more
volatile than the propylene glycol, such that even if all of the
ethanol evaporates from the skin and/or penetrates into the skin,
the concentration of the magnesium chloride in the residual
composition following evaporation of ethanol would be approximately
5.6%. Magnesium chloride is soluble at room temperature and/or at
skin surface temperature in propylene glycol at levels above this
concentration, which means that in the foregoing example, the
magnesium chloride will desirably remain in solution (i.e., in a
dissolved state), especially at the elevated temperature of the
skin. Moreover, the concentration of magnesium chloride in the
residual composition would be less than that described in this
calculation, as some of the ethanol would transport magnesium
chloride into the skin rather than evaporating.
[0095] For the exemplary compositions provided herein, the
monohydric aliphatic alcohol and the polyol in combination comprise
about 30% to about 99.9% by weight of the composition. In other
exemplary compositions, the monohydric aliphatic alcohol and the
polyol in combination comprise about 60% to about 99% by weight of
the composition. Further representative ranges for the weight
percent for the combination of the aliphatic alcohol and the polyol
are about 30-40%, about 40-50%, about 50-60%, about 60-70%, about
70-80%, about 80-85%, about 5-90%, about 90-95%, about 95-98%,
about 95-99%, about 0-75%, and about 50-90%.
[0096] Exemplary compositions as provided herein will generally
comprise a greater percent by weight of the monohydric aliphatic
alcohol in comparison to the polyol. For example, advantageous
compositions as described herein may comprise from about 50% (w/w)
to about 95% (w/w) monohydric aliphatic alcohol, from about 5%
(w/w) to about 40% (w/w) polyol, and from about 0.1% (w/w) to about
10% (w/w) magnesium salt. Some preferred compositions as described
herein may comprise from about 60% (w/w) to about 90% (w/w)
monohydric aliphatic alcohol, from about 5% (w/w) to about 35%
(w/w) polyol, and from about 0.2% (w/w) to about 5% (w/w) magnesium
salt.
[0097] Illustrative liquid compositions may contain, for example,
any one or more of the following weight-weight percentages of
monohydric aliphatic alcohol, including ranges between each of the
following values: 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or
95% alcohol, where preferably, the weight percent alcohol is
greater than the weight percent polyol. Further representative
ranges for the alcohol component, which may be combined with w/w
amounts or ranges for the magnesium salt and other formulation
components as provided herein are from: 50-55% w/w, 50-60% w/w,
50-65% w/w, 50-70% w/w, 50-75% w/w, 50-80% w/w, 50-85% w/w, 50-90%
w/w, 50-55% w/w, 55-60% w/w, 55-65% w/w, 55-70% w/w, 55-75% w/w,
55-80% w/w, 55-85% w/w, 55-90% w/w, 55-95% w/w, 60-65% w/w, 60-70%
w/w, 60-75% w/w, 60-80% w/w, 60-85% w/w; 60-90% w/w, 60-95% w/w,
65-70% w/w, 65-75% w/w, 65-80% w/w, 65-85% w/w; 65-90% w/w, 65-95%
w/w, 70-75% w/w, 70-80% w/w, 70-85% w/w, 70-90% w/w, 70-95% w/w,
75-80% w/w, 75-85% w/w, 75-90% w/w, 75-95% w/w, 80-85% w/w, 80-95%
w/w, 80-95% w/w, 85-90% w/w, 85-95% w/w, 90-95% w/w.
[0098] Representative amounts of a polyol component, include, any
one or more of the following: 5%, 10%, 15%, 20%, 25% 30%, 35% or
40% (w/w), including ranges between each of the foregoing, such as,
for example: 5%-10% w/w, 5-15% w/w, 5-20% w/w, 5-30% w/w, 5-35%
w/w, 5-40% w/w, 10-15% w/w, 10-20% w/w, 10-25% w/w, 10-30% w/w,
10-35% w/w, 10-40% w/w, 15-20% w/w, 15-25% w/w, 15-30% w/w, 15-35%
w/w, 15-40% w/w, 20-25% w/w, 20-30% w/w, 20-35% w/w, 20-40% w/w;
25-30% w/w, 25-35% w/w, 25-40% w/w, 30-35% w/w, 30-40% w/w, or
35-40% w/w.
[0099] Generally, the ratio between the monohydric aliphatic
alcohol and the polyol is in a range of 1:1 to 99:1 by weight. As
set forth above, the composition will generally comprise a greater
percent by weight of the monohydric aliphatic alcohol in comparison
to the polyol. Exemplary w/w ratios of alcohol to polyol include,
for example, about 1:1, 1.5:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1,
9:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1,
60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, and 95:1. The composition
may comprise a w/w ratio between the monohydric aliphatic alcohol
and the polyol between about 1:1 to 20:1, or from about 1:1 to
about 15:1, or from about 1:1 to about 10:1, or from about 2:1 to
about 20:1, or from about 2:1 to about 10:1, or from about 2:1 to
about 7:1.
[0100] In one embodiment, the greater percent by weight of the
monohydric aliphatic alcohol in comparison to the polyol provides a
composition that transitions from a wet, liquid composition to a
dry formulation when applied to the skin in less than about 3
minutes, less than about 2.5 minutes, less than about 2 minutes,
less than about 1.5 minutes, or less than about 1 minute. The
monohydric aliphatic alcohol is, in one embodiment, one that
evaporates when applied to the skin, where the surface temperature
is between about 33.5-36.9.degree. C., in less than about 3
minutes, less than about 2.5 minutes, less than about 2 minutes,
less than about 1.5 minutes or less than about 1 minute.
Evaporation of the monohydric aliphatic alcohol leaves on the skin
surface a residual composition comprised of the polyol and the
magnesium salt dissolved in the polyol, along with any other
composition ingredients that are non-volatile at skin surface
temperature.
[0101] The instant compositions may also contain relatively small
amounts, e.g., less than about 10% (w/w) of one or more auxiliary
excipients suitable for topical use including but not limited to pH
modifying agents, preservatives, thickening agents, gel-forming
agents, emulsifying agents, antioxidants, scent agents, and the
like. Compounds suitable for incorporation may be found, e.g., in
R. C. Rowe, et al., Handbook of Pharmaceutical Excipients (4.sup.th
Ed.), Pharmaceutical Press, London, 2003.
[0102] Gelling agents which may be used in the topical compositions
include conventional gelling agents well known for their gelling
properties, such as, for example, cellulose ethers such as
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
carboxymethyl cellulose, sodium carboxymethyl cellulose,
hydroxyethyl cellulose, and the like; vinyl alcohols; vinyl
pyrrolidones; natural gums such as karaya gum, locust bean gum,
guar gum, gelan gum, xanthan gum, gum arabic, tragacanth gum,
carrageenan, pectin, agar, alginic acid, sodium alginate and the
like, and methacrylates such as those available under the tradename
Eudragit.RTM. from Rohm Pharma. Other gelling agents include
polyoxyethylene-polyoxypropylene copolymers (poloxamers) such as
those available under the tradename "Lutrol.RTM.", and the like.
Preferred gelling agents are those absent free carboxyl groups such
as, for instance, hydroxypropylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose,
methylcellulose, organo/cold water soluble cellulose,
hydroxyethylmethylcellulose, ethylcellulose,
ethyl(hydroxyethyl)cellulose. For substituted celluloses, a
moderate to high degree of substitution is preferred in order to
increase the solubility of the gelling agent in a selected solvent
system. The preferred degree of substitution is at least 1.0, or
preferably in the range of 1.2 to 6.0, or more preferably in the
range of 2.5 to 4.5.
[0103] The composition may also contain an antioxidant. The amount
of antioxidant, if present, will typically range from about 0.005%
to about 3.0% by weight of the composition. Illustrative ranges
include from about 0.01% to about 2.5% by weight antioxidant, from
about 0.05% to about 2% by weight antioxidant, and from about 0.1%
to about 1.5% by weight anti-oxidant. Illustrative amounts of
antioxidant include 0.01%, 0.025%, 0.05%, 0.075%, 0.1%, 0.2%, 0.3%,
0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% and 1% by weight. In one
embodiment, the amount of antioxidant comprised within the
composition is 0.01% by weight. In another embodiment, the amount
of antioxidant comprised within the formulation is 0.2% by weight.
Suitable antioxidants include, for example, butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tertiary
butyl hydroquinone, propyl gallate, .alpha.-tocopherol, sodium
metabisulfite, and the like. One preferred class of antioxidants
are sulfur-containing antioxidants such as sodium metabisulfite,
glutathione, N-acetylcysteine, thioproline, and taurine. Additional
preferred compositions comprise an antioxidant selected from the
list consisting of a sulfite compound, BHT, sodium selenite,
DL-alpha tocopherol, a combination of dithioerythreitol and
DL-alpha tocopherol, and sodium erythorbate. Sulfurous acid salts
and organic esters (referred to collectively as "sulfites") are
also preferred, such as bisulfites, pyrosulfites, metabisulfites,
and sulfites.
[0104] In one or more embodiments, the topical composition
comprises a suitable amount (e.g., about 0.005% to about 3.0% by
weight) of a sulfite compound, e.g., a sulfite, metabisulfite or
bisulfite salt, where the sulfite is accompanied by a suitable
counterion.
[0105] The composition may further contain one or more
preservatives in an amount typically ranging from about 0.01% to
about 2.0% by weight of the composition. Illustrative preservatives
include, for example, phenoxyethanol, methyl paraben, propyl
paraben, butyl paraben, benzyl alcohol, and the like.
[0106] The topical composition may also comprise a small amount,
such as 0.1% to 10% by weight, of one or more compounds effective
to introduce a favorable scent or aroma, such as a natural oil or
other suitable agent. Suitable essential oils include, for example,
plant essential oils from eucalyptus, frankincense, patchouli,
peppermint, lemon, lavender, orange, rosehip, rosemary, tea tree,
jasmine, and the like. For example, in one or more embodiments, the
composition comprises a small amount, such as 0.1% to 5% by weight,
of 1,8-cineole, or some other essential oil.
[0107] The combination of polyol and 1,8-cineole can be
particularly effective in preventing the skin from scaling and
extreme dryness, especially when administration is for an extended
period of time, e.g., for 2 weeks or more. Signs of dry skin which
can be prevented include both scaling and itching.
[0108] The topical composition may be in a number of different
forms, including, for example, a solution, liquid, spray, foam,
lotion, gel and the like. Preferably, the composition is a liquid,
adheres to the skin, and has a smooth feel. Generally, preferred
compositions are absent nanoparticles and/or microparticles,
although in some instances, the composition may comprise
nanoparticles and/or microparticles. For additional information
regarding suitable formulations, see, for example, "Remington: The
Science and Practice of Pharmacology," 22nd edition,
(Pharmaceutical Press, 2013).
[0109] A wide variety of methods may be used for preparing the
compositions described herein. Broadly speaking, the compositions
may be prepared by combining together the components of the
compositions, as described herein, at a temperature and for a time
sufficient to provide a pharmaceutically effective and desirable
composition. The term "combining together", as used herein, means
that all of the components of the compositions are combined and
mixed together at about the same time, or that various components
are combined in one or more sequences or orders of addition to
provide the desired product. The composition can be prepared on a
weight/weight (w/w) or a weight/volume (w/v) basis. The composition
will generally be readily spreadable, e.g., on a surface of the
skin, and preferably will not be runny.
[0110] The composition may be prepared by, e.g., admixture of the
ingredients typically through the use of vigorous agitation such as
high shear mixing. Mixing can also be accomplished by any suitable
method using any suitable manual or automated means. Optional
additional steps include those which result in the addition of one
or more of the optional auxiliary ingredients as set forth above.
Methods for preparing a pharmaceutical formulation are well known
in the art and are described, for example, in Landbook of
Pharmaceutical Formulations: Liquid Products, Vol 3, S. Niazi., CRC
Press, 2004.
[0111] The composition may be topically applied directly to the
affected areas of the skin, for example, using the fingertips, a
sponge applicator, a cotton applicator, by spraying,
aerosolization, or any other suitable method. The compositions
provided herein are useful for treating any condition that is
susceptible to treatment with a magnesium salt. The compositions
provided herein may be used, for example, for treating conditions
such as acne, impetigo, cellulitis, erysipelas, folliculitis,
furuncles, carbuncles, Lyme disease and other skin infections,
rosacea, seborrheic dermatitis, bullous dermatoses, cutaneous
sarcoidosis, Kaposi's sarcoma, and neutrophilic dermatoses, and
inflammation associated therewith. Types of acne include, example,
acne vulgaris, acne rosacea, acne conglobata, acne fulminans,
gram-negative folliculitis, and pyoderma faciale, among others. For
example, the composition may be used for treating moderate to
severe acne, and the acne may be nodular or cystic.
[0112] In one or more embodiments, the method comprises the step of
administering a topical composition as provided herein to an
accessible body surface of a human or an animal in need of such
treatment. Generally, the composition is applied in a conventional
amount from once to several times weekly or daily on the affected
areas of the skin, until the acne or condition being treated has
visibly diminished or disappeared. For example, the topical
composition may be applied topically at least once daily for a
period of at least 1 month, or may be applied to the skin once or
twice daily for a period of from 6 to 52 weeks or even longer. The
number of applications and course of treatment will vary with the
severity of the condition being treated, patient considerations,
and the like. Thus, the composition may, in certain instances by
applied one daily, twice daily, once every other day, from one to
three times weekly, from 1 to 4 times weekly, every 3 days,
etc.
[0113] A conventional amount is an amount that is sufficient to
spread, e.g., thinly spread, over the affected area. If desired,
the efficacy of treatment may be quantified by using a grading
system such as the Leeds system (O'Brien, S C., et al., J. Dermatol
Treat 1998; 9:215-220), the Comprehensive Acne Severity Scale (Tan,
J K, et al., Cutan Med Surg 2007 November; 11(6):211-6), or the
Global Acne Grading System (Doshi, A., et al., Int. J. Dermatol
1997 June 36(6); 416-8). In one or more embodiments, the efficacy
of treatment is assessed by a visual examination of the affected
area. In some cases, prophylactic treatment may be continued even
if the condition has visibly diminished or disappeared, as a
preventative measure. In some embodiments, the efficacy of
treatment is assessed by an evaluation of a reduction in total
lesion count, where application of a topical composition as
described herein is effective to result in a reduction in total
lesion count as measured from the commencement of treatment.
[0114] Turning now to consideration of the Examples, various
exemplary embodiments of the topical compositions are described.
Example 1 describes the preparation of ten exemplary compositions,
identified in Table 1 by composition numbers 1-10. Magnesium
chloride (anhydrous) was used in the compositions in an amount
between 0.3 wt % to 4.6 wt %. The solvent system was comprised of
ethanol and propylene glycol. The ratio of ethanol to propylene
glycol ranged from 2.0 (composition #10) to 3.9 (composition #1, 2,
3, and 7). Other than composition #8, the compositions were
thickened using between about 0.2-0.6 wt % of a thickening agent.
Sodium metabisulfite was included at 0.2 wt % in all of the
exemplary compositions other than composition #7. The essential oil
cineole was included at between 1-5 wt % in several of the
compositions.
[0115] An in vivo study of an exemplary topical composition was
conducted using minipigs, as described in Example 2. The test
animals were randomized into a 7-day treatment group and a 20-day
treatment group. An exemplary formulation, identified in Table 2 of
Example 2 and referred to as MG06, was prepared. The MG06
formulation was comprised of, inter alia, 0.6 wt % magnesium
chloride (anhydrous), 77.6% ethanol, and 20.0 wt % (propylene
glycol ethanol/propylene glycol ratio of 3.9). The formulation was
applied topically to the animals each day until the end of the 6
day (Group 1) or 20 day (Group 2) test period. The dosing site on
each animal was inspected daily for erythema or edema. The absence
of erythema and edema from the dosing site in both the test groups
demonstrate that the compositions are non-irritating to the skin.
Accordingly, in one embodiment, a method for treatment is
contemplated, where a composition comprised of a magnesium salt in
an anhydrous solvent system of a monohydric alcohol and a polyol is
applied to the skin, the composition lacking a pharmaceutically or
therapeutically active ingredient (other than the magnesium salt).
The composition when applied to a local application site on the
skin at least once daily for a period of 6 days, 7 days, 10 days or
20 days does not cause irritation as evidenced by lack of erythema
and edema at the local application site.
[0116] Examples 3 and 4 describe further studies using a
composition comprising a magnesium salt in a solvent system
comprising ethanol and propylene glycol (e.g., from 50-99.9 w/w %).
The water content for the composition, as measured by Karl Fischer
titration, was less than 5%, less than 2%, less than 1.0%, and less
than 0.5%. The specific composition used in the studies was
identified as MG06-2. The MG06-2 formulation was comprised of,
inter alia, 0.6 wt % magnesium chloride (anhydrous), 77.6% ethanol,
and 20.0 wt % propylene glycol (ethanol/propylene glycol ratio of
3.9; Table 4 in Example 3). In Example 3, the formulation was
applied to a shaved skin area on rats. The application site was
inspected at defined intervals for up to 24 hours after application
to evaluate the skin for erythema, redness, irritation, and/or
edema using a modified Draize score. The study results demonstrated
that the composition when applied to a local application site on
the skin does not cause irritation as evidenced by lack of erythema
and edema at the local application site. In Example 4, using an in
vitro eye irritation model the eye irritation effects of MG06-2
were evaluated. This evaluation provided a cell viability target
for compositions, where in one embodiment, cell viability measured
using a methylthiazoly diphenyl tetrazolium bromide (MTT) assay is
greater than 60% after exposure to the composition relative to the
initial value for MTT cell viability when tested with the MATTEK
EPIOCULAR model according to the MATTEK EPIOCULAR Eye Irritation
Test Protocol.
[0117] Example 5 describes a study in human patients where the
topical composition identified as MG06-2 was evaluated for the
treatment of acne. The subjects had moderate to severe
inflammatory, non-nodular acne vulgaris. Each subject was treated
with the topical composition by applying to the area affected by
acne an amount of the composition each day for a period of 12
weeks. At regular two-week intervals the subjects were evaluated by
an investigator and the acne lesions were scored. In the treated
population, a reduction of 11.3 inflammatory lesions was observed
at the 12-week time point relative to baseline. Also, using the
Investigator's Global Assessment (IGA), the proportion of subjects
in the population with at least a two-grade reduction in IGA to
clear ("0") or almost clear ("1") was 17.1%. Accordingly, the
compositions described herein are effective in the treatment of
certain dermatological skin conditions and in the reducing of
symptoms associated with dermatological diseases or conditions,
such as non-nodular acne vulgaris. In one embodiment, the
composition is effective to provide at least a two grade reducing
in acne severity based on the IGA scale in at least 10%, 15%, or
20% of the subjects by daily treatment for 12 weeks.
[0118] Example 6 describes a study in four human patients where the
topical composition identified as MG06-2 was evaluated for the
treatment of rosacea. The subjects had moderate rosacea. Each
subject was treated with the topical composition by applying to the
area affected by acne an amount of the composition each day for a
period of 4 weeks. At regular two-week intervals the subjects were
evaluated by an investigator and the rosacea lesions were scored.
In the treated population, a reduction of 13.3 lesions was observed
at the 4-week time point relative to baseline. This represented a
60% reduction in lesion count at the 4-week time point relative to
baseline. Also, using the Investigator's Global Assessment (IGA),
the proportion of subjects in the population with at least a
two-grade reduction in IGA to clear ("0") or almost clear ("1") was
75%. Accordingly, the compositions described herein are effective
in the treatment of certain dermatological skin conditions and in
the reducing of symptoms associated with dermatological diseases or
conditions, such as rosacea. In one embodiment, the composition is
effective to provide at least a two-grade reducing in acne severity
based on the IGA scale in at least about 10%, 15%, 20%, or 50% of
the subjects by daily treatment for 4 or 12 weeks.
[0119] Additional advantages and features of the instant
compositions are described throughout the instant document.
[0120] Thus, several advantageous properties are associated with
the compositions and topical treatment methods described herein.
The topical compositions are effective to deliver a magnesium salt
(e.g. magnesium chloride) to the skin. Moreover, the compositions
described herein are easy to apply, not sticky, and do not occlude
the skin. The compositions are effective for treatment of acne. The
compositions demonstrate no or minimal irritation potential.
EXAMPLES
[0121] The following examples are put forth to provide those of
ordinary skill in the art with a complete disclosure and
description of how the composition, its components, active
ingredients, solvents, and the like, are prepared and evaluated,
along with related methods, and are intended to be purely
exemplary. Thus, the examples are in no way intended to limit the
scope of what the inventors regard as their invention. There are
numerous variations and combinations, e. g., component
concentrations, desired solvents, solvent mixtures, antioxidants,
and other mixture parameters and conditions that may be employed to
optimize composition characteristics such as purity, yield,
stability, odor, color, viscosity, penetration, and the like. Such
are considered as well within the scope of the present
disclosure.
Example 1
Topical Compositions
[0122] Table 1 provides additional illustrative topical
compositions. The compositions are prepared by mixing the various
components as previously described. Each column lists the
percentage by weight of the component listed at the left side of
each row in the composition. Each column adds to a total of
100%.
TABLE-US-00001 TABLE 1 EXEMPLARY COMPOSITIONS EXEMPLARY COMPOSITION
# 1 2 3 4 5 6 7 8 9 10 Magnesium source Magnesium 0.3 0.6 1.2 2.3
4.6 1.2 1.2 4.6 4.6 4.6 chloride anhydrous Monohydric aliphatic
alcohol Ethanol 78.9 78.6 78.0 71.9 64.6 77.0 77.2 65.2 65.0 60.0
Polyol Propylene glycol 20 20 20 25 30 20 20 30 30 30 Other
components Sodium meta- 0.2 0.2 0.2 0.2 0.2 0.2 -- 0.2 0.2 0.2
bisulfite Hydroxypropyl 0.6 0.6 0.6 0.6 0.6 0.6 0.6 -- 0.2 0.2
cellulose HF (HPC HF) Cineole -- -- -- -- -- 1 1 -- -- 5
Example 2
In Vivo Minipig 7- and 20-Day Repeat Dose Patch Study
[0123] A minipig topical application study was conducted over a
period of either 7 days or 20 days to evaluate the dermal toxicity
associated with repeat dose applications of the test article shown
in Table 2. The study was performed using four non naive,
antibiotic free female minipigs, weighing between 20 and 30 kg and
of 12-18 months age.
TABLE-US-00002 TABLE 2 MG06 FORMULATION % (w/w) Hydroxypropyl
cellulose 0.6% (KLUCEL .RTM. HF) Magnesium Chloride, 0.6% anhydrous
Ethanol, anhydrous 77.59% Propylene Glycol 20.0% Eucalyptol 1.0%
Sodium Metabisulfite 0.2% Quinoline Yellow 0.01%
[0124] On Day 0, the animals were weighed and anesthetized. The
right and left flank area were carefully clipped and shaved, and
application sites of 3 cm.times.3 cm each or approximately about 10
cm.sup.2 were marked. Test articles were applied topically using a
positive displacement pipette and spreading in the marked test area
using metal spatula in the amounts described in Table 3. Dosing
continued daily until Day 6 (Group 1) and Day 20 (Group 2). Animals
151 and 152 were in Group 1. Animals 251 and 252 were in Group 2.
Prior to daily dosing, treatment sites were gently wiped once with
soap followed by a gentle wash with phosphate buffer saline (PBS).
Body weights were measured once weekly.
TABLE-US-00003 TABLE 3 SUMMARY OF DOSING SITES TREATMENT Do-
Animals 151/251 Animals 152/252 sing Test Dose/ Volume Test Dose/
Volume Site Article Formulation (.mu.L) Article Formulation (.mu.L)
L1 MG06 0.6% 25 MG06 0.6% 125 magnesium magnesium chloride
chloride
[0125] Dosing sites was evaluated daily for erythema and edema
using a modified Draize scoring system. Photographs were taken
prior to dose administration on Day 0 and daily thereafter. Skin
pigmentation was visually noted daily. Additionally, UV lamp photos
of the dosing sites were taken on Day 0 and at the end of the
dosing (Day 7 for Group 1 and Day 20 for Group 2). At the end of
the study, animals were sacrificed and skin tissues were collected
from the dosing sites, along with one untreated site.
[0126] No abnormal weight changes were observed. No skin irritation
was noted throughout the treatment period as indicated by a lack of
erythema and edema.
Example 3
In Vivo Rat Single Dose Study Skin Irritation and Histology
[0127] A skin irritation study was conducted in rats using a
composition comprised of a magnesium salt in a solvent system
comprising ethanol and propylene glycol. The composition is set
forth in Table 4.
TABLE-US-00004 TABLE 4 Composition of Topical Formulation MG06-2
Ingredient wt % Hydroxypropyl cellulose 0.6% Magnesium chloride
(anhydrous) 0.6% Ethanol (anhydrous) 77.59% Propylene Glycol 20.0%
1,8-Cineole 1.0% Sodium meta-bisulfite 0.2% D&C Yellow #10
0.01% Measured pH for composition 4.86 Measured water content for
composition 0.39%
[0128] The day before treatment, a 15 cm.sup.2 area was shaved on
the dorsal area in the region of the shoulders and back of each of
six male Sprague-Dawley rats and a 10 cm.sup.2 area was marked as
the application test site. The rats were randomly divided evenly
into 2 groups, a treatment group and a no-treatment group. Each rat
in the treatment group received application of 2.5 mg/cm.sup.2 of
the composition listed in Table 4 (MG06-2). The composition was
applied uniformly to the application test site on each rat at time
T=0. No topical was applied to the rats in the no-treatment
group.
[0129] Skin irritation was evaluated using the modified Draize
scoring system. Evaluations were performed prior to and immediately
after application and at the following time points: 30 minutes, 1
hour, 3 hours, 6 hours, and 24 hours after application. No
measurable erythema, redness, irritation, and/or edema were
observed. The modified Draize score was 0 for each of the time
points and each of the rats in the study. This indicates that each
of the compositions tested was non-irritating.
[0130] No abnormal weight changes were observed in any treatment
group.
[0131] The rats were euthanized shortly after the 24-hour time
point. Biopsies were taken from the skin of the rats and frozen or
fixed in 10% formalin to allow further histological analysis,
including staining with hematoxylin and eosin. No significant
changes were observed in any of the skin sections when the
treatment group was compared to those in the no treatment
group.
Example 4
In Vitro Eye Irritation Test in Epiocular EIT Model
[0132] The eye irritation effects for one composition comprising a
magnesium salt in a solvent system comprising ethanol and propylene
glycol was evaluated. This was compared to positive and negative
controls, described below.
[0133] The United Nations publishes the "Globally Harmonized System
of Classification and Labelling of Chemicals (GHS)" for
classification of eye effects (Globally Harmonized System of
Classification and Labelling of Chemicals (GHS); Chapter 3: Serious
Eye Damage/Irritation--Second Revised Edition, United Nations; No.
ST/SG/AC. 10/30, Rev 2, 2007). Tested chemicals and compositions
are classified into one of 3 categories: no eye damage (i.e., GHS
category "No Category"), irreversible eye damage (i.e., GHS
category 1), or reversible eye irritation (i.e., GHS category
2).
[0134] In this study, the eye irritation effects were evaluated by
following the procedure described in the MATTEK EPIOCULAR Eye
Irritation Test (EIT) Protocol (EpiOcular.TM. Eye Irritation
(OCL-200-EIT) for the Prediction of Acute Ocular Irritation of
Chemicals, Reference No. MK-24-007-0055, MatTek Corporation,
Ashland, Mass.). The MATTEK EPIOCULAR model is a commercially
available 3-dimensional model of the human corneal epithelium
derived from normal human epidermal keratinocytes. The endpoint of
the test is an estimation of cell viability by MTT assay
(methylthiazolyldiphenyltetrazolium bromide). Since the region of
the eye that is most commonly damaged by a composition would be the
outer surface of the cornea and this model emulates the outer
portion of the cornea, this model is commonly used to evaluate the
eye irritation potential for chemicals. The use of the EPIOCULAR
EIT protocol is specified in OECD Test Guideline No. 492. This test
thus provided an indication of the level of eye irritation or
damage that would be observed in an in vivo test.
[0135] Compositions were classified as having no eye damage (i.e.,
GHS category "Not Classified") if the MTT cell viability was
greater than 60% relative to control samples of ultrapure water.
Ethyl acetate was used as a positive control and ultrapure water
was used as a negative control. Cell viability was measured via
optical density as measured by a MULTISKAN SPECTRUM plate reader
(Thermo Fisher Scientific Oy, Vantaa, Finland). MTT cell viability
for MATTEK EPIOCULAR models were tested following an exposure to a
composition (or a control) in a humidified incubator maintained at
37.degree. C. in a 5% CO2 atmosphere for 30 minutes. The cell
viability scale was measured relative to the post-exposure cell
viability for the negative control (ultrapure water). The mean cell
viability for the negative control was used to set the value that
corresponded to 100% cell viability. The composition was classified
as having eye irritation or damage (i.e., GHS category 1 or 2) if
the post-exposure cell viability was less than or equal to 60% of
the corresponding mean cell viability for the negative control
sample. The composition MG06-2 as described in Table 4 of Example 3
was assessed.
[0136] The results of the study showed that the mean post-exposure
MTT cell viability relative to the negative control was 48% for
composition MG06-2. Thus, it was determined that compositions
MG06-2 was eye irritating or damaging (UN GHS category 1 or 2).
[0137] Thus, some compositions according to the invention have a
MTT cell viability after exposure to the composition relative to
the initial value for MTT cell viability of greater than 60% when
tested with the MATTEK EPIOCULAR model according to the MATTEK
EPIOCULAR EIT Protocol.
Example 5
Method of Treating Acne
[0138] A clinical trial was conducted with composition MG06-2 of
Example 3 (Table 4). The multi-center trial evaluated the
composition in 74 subjects, aged 9 to 40, with moderate-to-severe
inflammatory, non-nodular acne vulgaris. Subjects applied
composition MG06-2 to their faces daily for a continuous period of
12 weeks. Subjects visited investigating sites at baseline, 2
weeks, 4 weeks, 8 weeks, and 12 weeks. At each visit, investigators
observed the subjects and asked subjects about any adverse events
that they had experienced since their last visit.
[0139] The results of the study were that in the intent-to-treat
(ITT) population, a reduction of 11.3 inflammatory lesions was
observed at the 12-week time point relative to baseline.
[0140] The trial also measured reduction in Investigator's Global
Assessment (IGA). The proportion of subjects in the ITT population
with at least a two-grade reduction in IGA to clear ("0") or almost
clear ("1") was 17.1%.
[0141] No treatment related serious adverse events were reported in
the clinical trial.
[0142] These trial results demonstrate that the compositions
described herein, particularly MG06-2, are effective in the
treatment of certain dermatological skin conditions, such as
non-nodular acne vulgaris.
Example 6
Method of Treating Rosacea
[0143] A clinical trial was conducted with composition MG06-2 of
Example 3 (Table 4). The single-center trial evaluated the
composition in four subjects with moderate rosacea. Subjects
applied composition MG06-2 to their faces daily for a continuous
period of four weeks. Subjects visited investigating site at
baseline and four weeks. At each visit, investigators observed the
subjects and asked subjects about any adverse events that they had
experienced since their last visit.
[0144] The results of the study were that a reduction of 13.3
inflammatory lesions was observed at the 4-week time point relative
to baseline, reducing from an average of 25.3 lesions to an average
of 8.8 lesions. This represented a 60% reduction in lesion count at
the 4-week time point relative to baseline.
[0145] The trial also measured reduction in Investigator's Global
Assessment (IGA). The proportion of subjects in the ITT population
with at least a two-grade reduction in IGA to clear ("0") or almost
clear ("1") was 75%.
[0146] No treatment related serious adverse events were reported in
the clinical trial.
[0147] These trial results demonstrate that the compositions
described herein, particularly MG06-2, are effective in the
treatment of certain dermatological skin conditions, such as
rosacea.
* * * * *