U.S. patent application number 17/037070 was filed with the patent office on 2021-01-21 for compositions, gels and foams with rheology modulators and uses thereof.
The applicant listed for this patent is Foamix Pharmaceuticals Ltd.. Invention is credited to Elana Gazal, Yohan Hazot, Irakliy Papiashvili, David Schuz, Dov Tamarkin.
Application Number | 20210015928 17/037070 |
Document ID | / |
Family ID | 1000005123529 |
Filed Date | 2021-01-21 |
United States Patent
Application |
20210015928 |
Kind Code |
A1 |
Tamarkin; Dov ; et
al. |
January 21, 2021 |
COMPOSITIONS, GELS AND FOAMS WITH RHEOLOGY MODULATORS AND USES
THEREOF
Abstract
The present disclosure relates generally to compositions for
cosmetic or pharmaceutical application. The compositions include a
carrier and rheology modulators.
Inventors: |
Tamarkin; Dov; (Maccabim,
IL) ; Gazal; Elana; (Rehovot, IL) ; Hazot;
Yohan; (Rehovot, IL) ; Schuz; David; (Gimzu,
IL) ; Papiashvili; Irakliy; (Ashkelon, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Foamix Pharmaceuticals Ltd. |
Rehovot |
|
IL |
|
|
Family ID: |
1000005123529 |
Appl. No.: |
17/037070 |
Filed: |
September 29, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16280921 |
Feb 20, 2019 |
10821187 |
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17037070 |
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14078746 |
Nov 13, 2013 |
10265404 |
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16280921 |
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13100724 |
May 4, 2011 |
8618081 |
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14078746 |
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PCT/IB2010/002612 |
Oct 1, 2010 |
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13100724 |
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PCT/IB2010/002617 |
Oct 1, 2010 |
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13100724 |
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PCT/IB2010/002613 |
Oct 1, 2010 |
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13100724 |
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61248144 |
Oct 2, 2009 |
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61349911 |
May 31, 2010 |
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61385385 |
Sep 22, 2010 |
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61331126 |
May 4, 2010 |
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61388884 |
Oct 1, 2010 |
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61380568 |
Sep 7, 2010 |
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61248144 |
Oct 2, 2009 |
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61322148 |
Apr 8, 2010 |
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61349911 |
May 31, 2010 |
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61331126 |
May 4, 2010 |
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61388884 |
Oct 1, 2010 |
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61380568 |
Sep 7, 2010 |
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61248144 |
Oct 2, 2009 |
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61322148 |
Apr 8, 2010 |
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61349911 |
May 31, 2010 |
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61385385 |
Sep 22, 2010 |
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61331126 |
May 4, 2010 |
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61388884 |
Oct 1, 2010 |
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61380568 |
Sep 7, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/192 20130101;
A61K 47/24 20130101; A61K 9/0014 20130101; A61K 9/0048 20130101;
A61K 31/4164 20130101; A61K 47/44 20130101; A61K 45/06 20130101;
A61K 47/10 20130101; A61K 8/361 20130101; A61Q 19/00 20130101; A61Q
17/04 20130101; A61K 47/12 20130101; A61K 31/573 20130101; A61K
9/12 20130101; A61K 31/65 20130101; A61K 2800/31 20130101; A61K
8/31 20130101; A61K 9/122 20130101; A61K 31/137 20130101; A61K
47/06 20130101; A61K 31/57 20130101; A61K 47/02 20130101; A61K
8/342 20130101; A61K 9/124 20130101; A61K 31/593 20130101; A61Q
19/10 20130101; A61K 2800/33 20130101 |
International
Class: |
A61K 47/44 20060101
A61K047/44; A61K 47/06 20060101 A61K047/06; A61K 9/00 20060101
A61K009/00; A61K 9/12 20060101 A61K009/12; A61K 8/31 20060101
A61K008/31; A61Q 17/04 20060101 A61Q017/04; A61Q 19/00 20060101
A61Q019/00; A61Q 19/10 20060101 A61Q019/10; A61K 31/137 20060101
A61K031/137; A61K 31/192 20060101 A61K031/192; A61K 31/4164
20060101 A61K031/4164; A61K 31/57 20060101 A61K031/57; A61K 31/573
20060101 A61K031/573; A61K 31/593 20060101 A61K031/593; A61K 31/65
20060101 A61K031/65; A61K 8/34 20060101 A61K008/34; A61K 8/36
20060101 A61K008/36; A61K 47/10 20060101 A61K047/10; A61K 47/12
20060101 A61K047/12; A61K 45/06 20060101 A61K045/06; A61K 47/02
20060101 A61K047/02; A61K 47/24 20060101 A61K047/24 |
Claims
1. (canceled)
2. A method of treating rosacea, comprising administrating a foam
composition comprising: a) a combination of at least one fatty
alcohol and at least one wax; or a combination of at least one
fatty alcohol, at least one fatty acid, and at least one wax; b) at
least one hydrophobic solvent; and c) a minocycline at a
concentration between about 0.2% and about 20% by weight of the
composition; wherein the composition is free of surfactant; wherein
the composition has a water activity (Aw) value of less than about
0.9; and wherein the ratio of (1) fatty alcohol to wax or (2) fatty
alcohol and fatty acid to wax is between about 1:3 and about
3:1.
3. The method of claim 2, wherein the minocycline is present in a
free base form, a hydrate form, a salt form, or a complex form.
4. The method of claim 2, wherein the foam composition further
comprises a doxycycline.
5. The method of claim 2, wherein the concentration of the
minocycline is between about 1% and about 4% by weight of the
composition.
6. The method of claim 2, wherein the concentration of the
minocycline is about 1.5% by weight of the composition.
7. The method of claim 2, wherein the at least one fatty alcohol
comprises 14 carbon atoms in its backbone.
8. The method of claim 2, wherein the fatty alcohol comprises
stearyl alcohol, cetostearyl alcohol, behenyl alcohol, and/or
myristyl alcohol.
9. The method of claim 2, wherein the at least one fatty alcohol is
present at a concentration from about 0.1% to about 20% by weight
of the composition.
10. The method of claim 2, wherein the at least one wax and/or the
at least one fatty acid is present at a concentration from about
0.1% to about 20% by weight of the composition.
11. The method of claim 2, wherein the hydrophobic solvent
comprises soybean oil, coconut oil, cyclomethicone, and/or mineral
oil.
12. The method of claim 2, wherein the hydrophobic solvent is
present at a concentration from about 60% to about 95% by weight of
the composition.
13. The method of claim 2, wherein the foam composition further
comprises a silicon dioxide.
14. The method of claim 2, wherein the wax comprises beeswax and/or
hydrogenated castor oil.
15. The method of claim 2, wherein the wax comprises beeswax and
hydrogenated castor oil.
16. The method of claim 15, wherein the beeswax and hydrogenated
castor oil are at a ratio of about 5:1 to about 1:1.
17. The method of claim 15, wherein the beeswax and hydrogenated
castor oil are at a ratio of about 2:1 to about 1:1.
18. The method of claim 15, wherein the beeswax and hydrogenated
castor oil are at a ratio of about 4:3.
19. The method of claim 15, wherein the beeswax and hydrogenated
castor oil are at a ratio of about 1:1.
20. The method of claim 2, wherein the composition has an Aw value
of less than about 0.5.
21. A method of treating rosacea, comprising administrating a foam
composition comprising: a) a combination of at least one fatty
alcohol and at least one wax; or a combination of at least one
fatty alcohol, at least one fatty acid, and at least one wax; b) at
least one hydrophobic solvent; and c) a minocycline at a
concentration between about 0.2% and about 20% by weight of the
composition; wherein the composition is free of surfactant; wherein
the composition is essentially waterless; and wherein the ratio of
(1) fatty alcohol to wax or (2) fatty alcohol and fatty acid to wax
is between about 1:3 and about 3:1.
22. The method of claim 21, wherein the minocycline is present in a
free base form, a hydrate form, a salt form, or a complex form.
23. The method of claim 21, wherein the foam composition further
comprises a doxycycline.
24. The method of claim 21, wherein the concentration of the
minocycline is between about 1% and about 4% by weight of the
composition.
25. The method of claim 21, wherein the concentration of the
minocycline is about 1.5% by weight of the composition.
26. The method of claim 21, wherein the at least one fatty alcohol
comprises 14 carbon atoms in its backbone.
27. The method of claim 21, wherein the fatty alcohol comprises
stearyl alcohol, cetostearyl alcohol, behenyl alcohol, and/or
myristyl alcohol.
28. The method of claim 21, wherein the at least one fatty alcohol
is present at a concentration from about 0.1% to about 20% by
weight of the composition.
29. The method of claim 21, wherein the at least one wax and/or the
at least one fatty acid is present at a concentration from about
0.1% to about 20% by weight of the composition.
30. The method of claim 21, wherein the hydrophobic solvent
comprises soybean oil, coconut oil, cyclomethicone, and/or mineral
oil.
31. The method of claim 21, wherein the hydrophobic solvent is
present at a concentration from about 60% to about 95% by weight of
the composition.
32. The method of claim 21, wherein the foam composition further
comprises a silicon dioxide.
33. The method of claim 21, wherein the wax comprises a mixture of
beeswax and/or hydrogenated castor oil.
34. The method of claim 21, wherein the wax comprises beeswax and
hydrogenated castor oil.
35. The method of claim 34, wherein the beeswax and hydrogenated
castor oil are at a ratio of about 5:1 to about 1:1.
36. The method of claim 34, wherein the beeswax and hydrogenated
castor oil are at a ratio of about 2:1 to about 1:1.
37. The method of claim 34, wherein the beeswax and hydrogenated
castor oil are at a ratio of about 4:3.
38. The method of claim 34, wherein the beeswax and hydrogenated
castor oil are at a ratio of about 1:1.
39. The method of claim 21, wherein the composition has an Aw value
of less than about 0.5.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 13/100,724, filed May 4, 2011.
[0002] U.S. application Ser. No. 13/100,724, filed May 4, 2011, is
a continuation-in-part application of International Application No.
PCT/IB2010/002612, filed Oct. 1, 2010, and entitled
"Surfactant-Free Water-Free Foamable Compositions, Breakable Foams
and Gels, and Their Uses," which claims the benefit of priority to
U.S. Provisional Application No. 61/248,144, filed Oct. 2, 2009,
and entitled "Surfactant-Free Water-Free Foamable Compositions,
Breakable Foams and Their Uses;" U.S. Provisional Application No.
61/322,148, filed Apr. 8, 2010, and entitled "Surfactant-Free
Water-Free Foamable Compositions, Breakable Foams and Their Uses;"
U.S. Provisional Application No. 61/349,911, filed May 31, 2010,
and entitled "Surfactant-Free Water-Free Foamable Compositions,
Breakable Foams and Their Uses;" U.S. Provisional Application No.
61/385,385, filed Sep. 22, 2010, and entitled "Surfactant-Free
Water-Free Foamable Compositions, Breakable Foams and Gels and
Their Uses;" U.S. Provisional Application No. 61/331,126, filed May
4, 2010, and entitled "Compositions, Gels and Foams with Rheology
Modulators and Uses Thereof;" U.S. Provisional Application No.
61/388,884, filed Oct. 1, 2010, and entitled "Compositions, Gels
and Foams With Rheology Modulators and Uses Thereof"; and U.S.
Provisional Application No. 61/380,568, filed Sep. 7, 2010, and
entitled "Surfactant-Free Water-Free Foamable Compositions and
Breakable Foams and Their Uses; all of which are herein
incorporated in their entirety by reference.
[0003] U.S. application Ser. No. 13/100,724, filed May 4, 2011, is
a continuation-in-part application of International Application No.
PCT/IB2010/002617, filed Oct. 1, 2010, and entitled "Topical
Tetracycline Compositions" which claims the benefit of priority to
U.S. Provisional Application No. 61/248,144, filed Oct. 2, 2009,
and entitled "Surfactant-Free Water-Free Foamable Compositions,
Breakable Foams and Their Uses;" U.S. Provisional Application No.
61/322,148, filed Apr. 8, 2010, and entitled "Surfactant-Free
Water-Free Foamable Compositions, Breakable Foams and Their Uses;"
U.S. Provisional Application No. 61/349,911, filed May 31, 2010,
and entitled "Surfactant-Free Water-Free Foamable Compositions,
Breakable Foams and Their Uses;" U.S. Provisional Application No.
61/385,385, filed Sep. 22, 2010, and entitled "Surfactant-Free
Water-Free Foamable Compositions, Breakable Foams and Gels and
Their Uses;" U.S. Provisional Application No. 61/331,126, filed May
4, 2010, and entitled "Compositions, Gels and Foams with Rheology
Modulators and Uses Thereof;" U.S. Provisional Application No.
61/388,884, filed Oct. 1, 2010, and entitled "Compositions, Gels
and Foams With Rheology Modulators and Uses Thereof"; and U.S.
Provisional Application No. 61/380,568, filed Sep. 7, 2010, and
entitled "Surfactant-Free Water-Free Foamable Compositions and
Breakable Foams and Their Uses; all of which are herein
incorporated in their entirety by reference.
[0004] U.S. application Ser. No. 13/100,724, filed May 4, 2011, is
a continuation-in-part application of International Application No.
PCT/IB2010/002613, filed Oct. 1, 2010, and entitled
"Surfactant-Free Water-Free Foamable Compositions, Breakable Foams
and Their Uses" which claims the benefit of priority to U.S.
Provisional Application No. 61/248,144, filed Oct. 2, 2009, and
entitled "Surfactant-Free Water-Free Foamable Compositions,
Breakable Foams and Their Uses; U.S. Provisional Application No.
61/322,148, filed Apr. 8, 2010, and entitled "Surfactant-Free
Water-Free Foamable Compositions, Breakable Foams and Their Uses;
U.S. Provisional Application No. 61/349,911, filed May 31, 2010,
and entitled "Surfactant-Free Water-Free Foamable Compositions,
Breakable Foams and Their Uses; U.S. Provisional Application No.
61/385,385, filed Sep. 22, 2010, and entitled "Surfactant-Free
Water-Free Foamable Compositions, Breakable Foams and Gels and
Their Uses; U.S. Provisional Application No. 61/331,126, filed May
4, 2010, and entitled "Compositions, Gels and Foams with Rheology
Modulators and Uses Thereof; U.S. Provisional Application No.
61/388,884, filed Oct. 1, 2010, and entitled "Compositions, Gels
and Foams With Rheology Modulators and Uses Thereof"; and U.S.
Provisional Application No. 61/380,568, filed Sep. 7, 2010, and
entitled "Surfactant-Free Water-Free Foamable Compositions and
Breakable Foams and Their Uses; all of which are herein
incorporated in their entirety by reference.
BACKGROUND
[0005] The term rheology, describes the flow dynamics of liquids
and the deformation of solids. Rheological properties of
heterogeneous dispersions are complex and cannot be expressed in a
single parameter. Manufacturers of medicinal and cosmetic gels,
creams, pastes, lotions and foams must be capable of producing
products with acceptable consistency and smoothness and reproducing
these qualities each time a new batch is prepared including its
look, feel, body, and consistency.
[0006] Rheology is involved in the mixing and flow of materials,
their packaging into containers, and their dispensing prior to use,
whether this is achieved by pouring from a bottle, extrusion from a
tube, passage through a syringe needle, or extrusion through a
valve. The rheology of a particular product, which can range in
consistency from fluid to semisolid to solid, can affect its
patient acceptability, physical stability, and even biologic
availability. For example, viscosity which is a rheological
property has been shown to affect absorption rates of drugs.
[0007] Pharmaceutical areas, in which rheology is significant
include product design and processing are fluids, quasi-solids,
solids, and processing. Rheology of fluids is pertinent in respect
of: (a) mixing fluids; (b) reduction of systems with shear; (c)
passage through orifices, including pouring, packaging in bottles,
passage through hypodermic needles and passage through valves; (d)
fluid transfer, including pumping and flow through pipes; and (e)
physical stability of disperse systems. Rheology of quasi-solids or
semi-solids is pertinent including in respect of: (a) spreading and
adherence on the skin; (b) removal from jars or extrusion from
tubes; (c) capacity of solids to mix with miscible liquids; and (d)
release of the drug from the base.
[0008] When classifying materials according to types of flow and
deformation, it is customary to place them in one of two
categories: Newtonian or non-Newtonian systems. The choice depends
on whether or not their flow properties are in accord with Newton's
law of flow. Newton recognized that the higher the viscosity of a
liquid, the greater is the force per unit area (shearing stress)
required to produce a certain rate of shear. Many fluid
pharmaceutical products behave as Non-Newtonian systems.
[0009] Rheological properties such as tackiness or stickiness,
"body," "slip," and "spreadability" are difficult to measure by
means of conventional apparatus and, in fact, do not have precise
meanings. Whereas, viscosity, yield value, thixotropy, and the
other properties that contribute to the total consistency of
non-Newtonian pharmaceuticals can be analyzed.
[0010] Viscosity is a measure of the internal resistance of a fluid
to flow which is being deformed by either shear stress or tensile
stress; the higher the viscosity, the greater is the resistance.
Simple liquids can be described in terms of absolute viscosity. In
everyday terms (and for fluids only), viscosity is "thickness" and
may be thought of as an indication of fluid friction. Shear
viscosity, describes the reaction to applied shear stress; in other
words, it is the ratio between the pressure exerted on the surface
of a fluid, in the lateral or horizontal direction, to velocity
gradient.
[0011] Gels are jelly-like material that can have properties
ranging from soft and fluid to hard and tough. Gels may be in
liquid, semi-liquid or solid state. Solid gels are defined as a
substantially diluted crosslinked system, which exhibits no flow
when in the steady-state. By weight, gels are mostly liquid, yet
they behave like semi-solids due to a three-dimensional crosslinked
network of a solidifying, gelling or thickening agent within the
liquid. It is the crosslinks within the fluid that give a gel its
structure (hardness) and contribute to stickiness (tack). Depending
on the amounts of gelling agents in a formulation the gel may be
semi solid with some limited flowability, such that when the
semi-solid gel is placed in a tube and is inclined horizontally
from a vertical position it will slowly flow from the vertical
towards the horizontal or it may be a liquid gel where the amount
of gelling agents or gelling effect is lower such that the gel
structure or connections are weaker or loose so that when placed in
a tube and tilted from a vertical position to the horizontal the
gel readily flows and adapts to the horizontal position. The
rheological properties of gels at different surface temperatures
can influence the release and bioabsorption of drugs therefrom.
[0012] It is a desirable property for composition for topical use
to have controllable viscosity. High viscosity is required to avoid
drips and runs for ease of application and improve suspending
properties in order to avoid rapid sedimentation of non-dissolved
active ingredients. Whereas, low viscosity is desirable to enable
spreadability and good flow properties. The less viscous something
is, the greater its ease of movement (fluidity). A delicate balance
between these two attributes is sought out in accordance with the
intended use of the compositions. This balance is difficult to
attain as viscosity of a composition is influenced by different
factors such as reaction or interaction between different
components under different temperature and pressure conditions.
[0013] Thickening or solidifying agent or solidifying complexes are
materials added to a composition which increase viscosity and
retard sedimentation. The use of waxes, fatty alcohols, fatty acids
and 12 hydroxy stearic acid, in solidifying oils is known.
Pharmaceutical compositions having a netted framework, comprising
an oil and beeswax as a gelling agent that form a film after
application on a body surface are also known. Netted frameworks
and/or films can be in certain circumstances be a disadvantage.
[0014] The addition of a fatty alcohol, or a fatty acid, or both to
a liquid oil also gives rise to thixotropic properties (e.g., being
semi-solid at rest and liquid upon application of shear forces
thereto). This property enables application of a thixotropic
mixture as a semi-solid state to a body surface, which subsequently
becomes substantially liquid and therefore more spreadable and
penetrable when rubbed onto the body surface. Thus, they are
semi-solid at rest and that they liquefy upon application of shear
forces thereto. Semi-solid hydrophobic formulations are important
not only for the pharmaceutical market but also for cosmetic
products, such as carriers of sunscreen compounds, oil-soluble
plant extracts, materials for scrubbing purposes and other active
and non-active cosmetic ingredients.
[0015] Foams and, in particular, single-phase oleaginous foams are
complicated systems which do not form under all circumstances.
Slight shifts in foam composition, such as by the addition of
active agents or the removal of any of the essential ingredients,
may destabilize the foam. The prior art teaches that oleaginous
foam compositions require significant amounts of surface active
agents to form a foam. These compositions require various standard
surfactants, as essential components.
[0016] Surfactants are known as essential ingredients in foam
compositions; and specifically in oleaginous foams. However, many
surfactants are known to be irritating when left on the skin can
also react with unstable active agents and lead to their rapid
degradation.
[0017] Gels and foams are not pharmaceutically equivalent, unless
their composition upon administration is similar.
SUMMARY
[0018] The present application relates to compositions comprising a
carrier and a first and second rheology modulator or modulator
(used interchangeably). The application also relates to
compositions or foamable compositions and foam without surfactants
and/or without polymeric agents comprising an oleaginous carrier, a
first rheology modulator which is a suspended pharmaceutical or
cosmetic active agent (referred as "active agent") and second
rheology modulator consisting of at least one fatty alcohol, at
least one fatty acid, at least one wax and mixtures of two or more
thereof. Solid fatty alcohols and/or fatty acids and/or waxes were
carefully selected through experimentation as suitable thickening
agents, which can be compatible with unstable active agents.
[0019] It was surprisingly discovered that the addition of a very
low concentration of a suspended active agent into a composition or
formulation comprising a hydrophobic solvent, together with a
second rheology modulator, which may be at least one fatty alcohol
or at least one fatty acid, and/or at least one wax and mixtures of
two or more thereof dramatically modulates the rheological
properties of the composition and in particular can synergistically
increase the viscosity of a composition, thereby providing improved
usability of the composition.
[0020] It was further surprisingly discovered in the present
invention, that certain compositions comprising a hydrophobic
solvent, together with a second rheology modulator, which may be at
least one fatty alcohol or at least one fatty acid, and/or at least
one wax and mixtures of two or more thereof; and a suspended active
agent without any surface active agents resulted, upon packaging in
an aerosol container and adding a propellant, in a shakable and
homogenous foamable composition, which released a breakable foam
with good to excellent quality (as defined herein).
[0021] The resulting foam is pharmaceutically equivalent to the
respective gel (prior to adding the propellant), since immediately
upon dispensing of the foam the propellant evaporates and the
composition upon administration is similar to that of the gel. This
is an important pragmatic advantage, because many drug development
activities, including expensive and lengthy clinical trials on
thousands of patients, can be saved by conducting such studies once
for both the gel and foam instead of twice.
[0022] In one or more embodiments there is provided a composition
for cosmetic or pharmaceutical application comprising: [0023] a) a
first rheology modulator comprising a suspended pharmaceutical
active agent or a suspended cosmetic active agent; [0024] b) a
second rheology modulator comprising at least one fatty alcohol, at
least one fatty acid, at least one wax and mixtures thereof and
[0025] c) a hydrophobic carrier comprising at least one hydrophobic
solvent; [0026] wherein the viscosity of the composition is at
least about 30% higher than the viscosity of a first partial
composition comprising the second rheology modulator agent and the
hydrophobic carrier without the first rheology modulator; and is
higher than the viscosity of a second partial composition
comprising the first rheology modulator and the hydrophobic carrier
without the second rheology modulator; and
[0027] In certain embodiments, the viscosity of the first partial
composition is less than about 25,000 cPs at room temperature.
[0028] According to an another embodiment the composition further
comprises about 1% to about 25% by weight of a polar solvent or a
penetration enhancer.
[0029] In one or more embodiments the first rheology modulator
comprises at least one tetracycline. In one or more embodiments the
tetracycline is compatible with the carrier and with the second
rheology modulator.
[0030] In one or more embodiments the amount of first rheology
modulator is a therapeutically effective amount. In one or more
embodiments the first rheology modulator is a suspended active
agent.
[0031] In one or more embodiments the active agent is a
tetracycline. In one or more embodiments the tetracycline is
tetracycline, oxytetracycline, demeclocycline, doxycycline,
lymecycline, meclocycline, methacycline, minocycline,
rolitetracycline, chlorotetracycline or tigecycline. In one or more
embodiments the tetracycline is tetracycline, minocycline or
doxycycline or a salt thereof. In one or more embodiments the
tetracycline is a mixture of two or more tetracyclines. In one or
more embodiments the tetracycline is a hydrophobic tetracycline,
selected from minocycline and doxycycline. In one or more
embodiments it is a mixture of both. In one or more embodiments the
tetracycline is present in a free base form, a hydrate form, a salt
form or a complex form. In one or more embodiments at least part of
the tetracycline is not soluble and is suspended in the
composition. A tetracycline that is suitable as a first rheology
modulator according to the present invention is one that is not
soluble or is partially soluble and all or part thereof is
suspended in the composition.
[0032] In one or more embodiments the better rheology includes one
or more of a reduction in composition flow, an increase in
composition viscosity, an increase in hardness, or an increase in
adhesion, and/or thixotropy, or any two or more thereof.
[0033] Viscosity is raised significantly when a formulation
comprising beeswax in combination with another wax or a fatty acid
or fatty alcohol in a hydrophobic carrier is challenged with a
first rheology active agent (minocycline).
[0034] In one or more embodiments there is provided a composition
wherein the viscosity of the composition changes with time whilst
the composition is flowing. In certain embodiments the change is an
increase. In certain other embodiments the change is a decrease. In
some embodiments the composition is not flowing.
[0035] In one or more embodiments upon addition of the first
rheology modulator to a composition comprising a second rheology
modulator the composition becomes more viscous. An example is where
a tetracycline antibiotic is added to a fatty alcohol in an oil
carrier [see Examples 4 and 5].
[0036] In one or more embodiments there is provided a composition
in which the first and second rheology modulators act
synergistically. In one or more embodiments the first and second
modulators act synergistically to increase the viscosity of the
composition.
[0037] In one or more embodiments there is provided a composition
in which the viscosity of the composition after addition of the
first rheology modulator and second rheology modulator to the
carrier is higher than the viscosity of the composition with the
second modulator agent to the carrier, without the first modulator;
and is higher than the viscosity of the composition with the first
modulator to the carrier without the second modulator.
[0038] In an embodiment or more embodiments there is provided a
composition as a vehicle or carrier wherein by adding an active
agent to a composition comprising a second rheology modulator one
or more rheological properties of the composition are modulated
such as the viscosity of the composition is changed (e.g.,
increased substantially).
[0039] In one or more embodiments, there is provided an oleaginous
formulation comprising a hydrophobic solvent, such as mineral
oil(s) and at least one suspended active agent which is a
tetracycline in synergistic combination with a second rheology
modulator comprising a fatty alcohol and/or a fatty acid and/or a
wax.
[0040] A composition comprising the second rheology modulator and
the hydrophobic carrier without the first rheology modulator is
designated a first partial composition and a composition comprising
the first rheology modulator and the hydrophobic carrier without
the second rheology modulator is designated a second partial
composition. In one or more embodiments the viscosity of the
composition is at least about 50% more than the viscosity of the
first partial composition without the first rheology modulator. In
one or more embodiments the increase in viscosity of the
composition is at least about 100% more than the viscosity of the
first partial composition without the first rheology modulator. In
one or more embodiments the increase in viscosity of the
composition is at least about 100% and viscosity of the first
partial composition without the first rheology modulator is less
than about 12,000 cPs; or less than about 8,000 cPs; or less than
about 2,000 cPs. In one or more embodiments the viscosity of the
first partial composition without the first rheology modulator is
more than about 1,000 cPs; or more than about 1,300 cPs; or more
than about 1,500 cPs. or more than about 1,800 cPs or more than
about 2000 cPs.
[0041] In certain embodiments the increase in viscosity is a
synergistic increase such that the combined viscosity of the first
partial composition and the viscosity of the second partial
composition is less than the viscosity of the composition.
[0042] In one or more embodiments the change in viscosity is at
least about 20% or more than 20%. In one or more embodiments the
change in viscosity is at least about 30% or more than 30%. In one
or more embodiments the change in viscosity is at least about 40%
or more than 40%. In one or more embodiments the change in
viscosity is at least about 50% or more than 50%. In one or more
embodiments the change in viscosity is at least about 100% or more
than 100%. In one or more embodiments the change in viscosity is at
least about 150% or more than 150%. In one or more embodiments the
change in viscosity is at least about 200% or more than 200%. In
one or more embodiments the change in viscosity is at least about
250% or more than 250%. In one or more embodiments the change in
viscosity is at least about 300% or more than 300%. In one or more
embodiments the change in viscosity is at least about 350% or more
than 350%. In one or more embodiments the change in viscosity is at
least about 400% or more than 400%. In one or more embodiments the
change in viscosity is at least 450% or at least more than 450%. In
one or more embodiments the change in viscosity is at least about
500% or more than 500%. In one or more embodiments the change in
viscosity is at least about 1000% or more than 1000%. In one or
more embodiments the change in viscosity is at least about 1500% or
more than 1500%. %. In one or more embodiments the change in
viscosity is at least about 2000% or more than 2000%. In one or
more embodiments the change in viscosity is at least about 2500% or
more than 2500%. In one or more embodiments the change in viscosity
is at least about 20% or more than 20%. In one or more embodiments
the change in viscosity is at least about 30% or more than 30%. In
one or more embodiments the change in viscosity is at least about
40% or more than 40%. In one or more embodiments the change in
viscosity is between about 50% and about 100%. In one or more
embodiments the change in viscosity is between about 100% and about
500%. In one or more embodiments the change in viscosity is between
about 500% and about 1000%. In one or more embodiments the change
in viscosity is between about 1000% and about 1500%. In one or more
embodiments the change in viscosity is between about 1500% and
about 2000%. In one or more embodiments the change in viscosity is
between about 2000% and about 2500%. In one or more embodiments the
change in viscosity is between about 50% and about 3000%. In one or
more embodiments the change in viscosity is in a range between
about 150% and about 1000%. In one or more embodiments the change
in viscosity is in a range between about 1000% and about 2500% In
one or more embodiments the change in viscosity is between about
100% and about 2500%; about 100% and about 2000%; about 100% and
about 1500%; or about 100% and about 1000%.
[0043] In one or more embodiments the viscosity of the carrier and
the composition prior to the addition of the first rheology
modulator (namely the first partial composition) is less than about
30,000 cPs. In one or more embodiments the viscosity of the carrier
and the composition prior to the addition of the first rheology
modulator is less than about 25,000 cPs. In one or more embodiments
the viscosity of the carrier and the composition prior to the
addition of the first rheology modulator is less than about 20,000
cPs. In one or more embodiments the viscosity of the carrier and
the composition prior to the addition of the first rheology
modulator is less than about 15,000 cPs. In one or more embodiments
the viscosity of the carrier and the composition prior to the
addition of the first rheology modulator is less than about 12,000
cPs. In one or more embodiments the viscosity of the carrier is
less than about 10,000 cPs. In one or more embodiments the
viscosity of the carrier and the composition prior to the addition
of the first rheology modulator is less than about 8,000 cPs. In
one or more embodiments the viscosity of the carrier and the
composition prior to the addition of the first rheology modulator
is less than about 6,000 cPs. In one or more embodiments the
viscosity of the carrier and the composition prior to the addition
of the first rheology modulator is less than about 5,000 cPs. In
one or more embodiments the viscosity of the carrier and the
composition prior to the addition of the first rheology modulator
is less than about 4,000 cPs. In one or more embodiments the
viscosity of the carrier and the composition prior to the addition
of the first rheology modulator is less than about 3,000 cPs. In
one or more embodiments the viscosity of the carrier and the
composition prior to the addition of the first rheology modulator
is less than about 2,000 cPs. In one or more embodiments the
viscosity of the carrier and the composition prior to the addition
of the first rheology modulator is less than about 1,000 cPs. In
one or more embodiments the viscosity of the carrier and the
composition prior to the addition of the first rheology modulator
is less than about 500 cPs. In one or more embodiments the
viscosity of the carrier and composition prior to the addition of
the first rheology modulator is less than about 30,000 cPs; is less
than about 25,000 cPs; is less than about 20,000 cPs; is less than
about 15,000 cPs; is less than about 12,000 cPs; is less than about
10,000 cPs; is less than about 8,000 cPs; is less than about 6,000
cPs; is less than about 5,000 cPs; is less than about 4,000 cPs; is
less than about 3,000 cPs; is less than about 2,000 cPs; is less
than about 1,000 cPs; or is less than about 500 cPs. In one or more
embodiments the viscosity of the carrier and the composition prior
to the addition of the first rheology modulator is less than about
30,000 cPs; is less than about 25,000 cPs; is less than about
20,000 cPs; is less than about 15,000 cPs; is less than about
12,000 cPs; is less than about 10,000 cPs; is less than about 8,000
cPs; is less than about 6,000 cPs; is less than about 5,000 cPs; is
less than about 4,000 cPs; is less than about 3,000 cPs; is less
than about 2,000 cPs; is less than about 1,000 cPs; or is less than
about 500 cPs. In one or more embodiments the viscosity range of
the carrier or the composition prior to the addition of the first
rheology modulator or the carrier and the composition prior to the
addition of the first rheology modulator includes about 30,000 cPs
to about 1,000 cPs; about 25,000 cPs to about 1,000 cPs; about
20,000 cPs to about 1,000 cPs; about 12,000 cPs to about 1,000 cPs;
about 10,000 cPs to about 1,000 cPs; about 8,000 cPs to about 1,000
cPs; about 6,000 cPs to about 1,000 cPs; about 5,000 cPs to about
1,000 cPs; about 4,000 cPs to about 1,000 cPs; about 2,000 cPs to
about 1,000 cPs; or about 2,000 cPs to about 500 cPs; about 25,000
cPs to about 500 cPs; about 20,000 cPs to about 500 cPs; about
12,000 cPs to about 500 cPs; about 10,000 cPs to about 500 cPs;
about 8,000 cPs to about 500 cPs; about 6,000 cPs to about 500 cPs;
about 6,000 cPs to about 150 cPs; about 4,000 cPs to about 150 cPs;
about 2,000 cPs to about 150 cPs; or about 1,000 cPs to about 150
cPs;
[0044] In one or more embodiments there is provided a composition
in which the active agent is in an amount that is capable of
altering the viscosity of the composition to a level higher than
the viscosity of the composition prior to the addition of the
active agent and wherein the second rheology modulator is capable
of altering the viscosity of the composition before, upon or
following the addition of the first modulator.
[0045] In one or more embodiments the composition is substantially
waterless.
[0046] In one or more embodiments the composition is a liquid or
freely flowable. In one or more embodiments the composition is a
semi solid. In one or more embodiments the composition is a thick
gel.
[0047] In one or more embodiments the composition is essentially
free of one or more of the following: [0048] a) Water; [0049] b)
Polymeric agent; [0050] c) Surfactant; [0051] d) Short chain
alcohol; [0052] e) Polyol;
[0053] In one or more embodiments the composition is essentially
free of two or more of water; polymeric agent; surfactant; short
chain alcohol; or polyol. In one or more embodiments the
composition is essentially free of three or more of water;
polymeric agent; surfactant; short chain alcohol; or polyol. In one
or more embodiments the composition is essentially free of four or
more of water; polymeric agent; surfactant; short chain alcohol; or
polyol. In one or more embodiments the composition is essentially
free of water; polymeric agents; surfactants; short chain alcohols;
and polyols.
[0054] For example, in one or more embodiments the composition is
essentially free of water, polymeric agents, surfactants, short
chain alcohol and polyols. In one or more embodiments the
composition is essentially free of polymeric agents, surfactants,
short chain alcohol and polyols. In one or more embodiments the
composition is essentially free of water, surfactants, short chain
alcohols and polyols. In one or more embodiments the composition is
essentially free of water, polymeric agents, short chain alcohols
and polyols. In one or more embodiments the composition is
essentially free of water, polymeric agents, surfactants and
polyols. In one or more embodiments the composition is essentially
free of water, polymeric agents, surfactants and short chain
alcohols.
[0055] In one or more embodiments there is provided a composition
in which the composition has one two or three the following
characteristics: [0056] a) Provides for chemical stability of the
active agent in the composition; [0057] b) Provides for physical
stability of the composition; [0058] c) Provides a therapeutic
effect;
[0059] In one or more embodiments there is provided a composition
in which the active agent is stable at room temperature for at
least 1 month, or at least 2 months, or at least 3 months, or at
least 4 months, or at least 5 months, or at least 6 months, or at
least 12 months, or at least 18 months. In one or more embodiments
there is provided a composition in which the active is stable at
40.degree. C. for at least 1 month, or at least 2 months, or at
least 3 months, or at least 4 months, or at least 5 months, or at
least 6 months.
[0060] In one or more embodiments there is provided a composition
in which the active agent forms a complex with one or more
excipients.
[0061] In one or more embodiments there is provided a composition
in which the active agent is chemically stable in the presence of
the second rheology modulator and/or the carrier.
[0062] In one or more embodiments there is provided a composition
in which the suspended active agent is selected from a list
comprising a tetracycline, mometasone furoate, doxycycline hyclate,
salicylic acid, diclofenac, urea, terbinafine, permethrin,
metronidazole, pimecrolimus and benzoyl peroxide.
[0063] In one or more embodiments certain active agent, which are
fully soluble in the composition including cholesterol and vitamin
E also demonstrate a synergistic viscosity increase.
[0064] In one or more embodiments there is provided a composition
in which the rheology modulator is selected from the group
comprising a fatty alcohol, a fatty acid, beeswax, beeswax extract,
a paraffin wax and hydrogenated castor oil and mixture thereof.
[0065] In one or more embodiments there is provided a composition
in which the second rheology modulator comprises at least one fatty
alcohol, or at least one fatty acid or least one wax or mixtures of
two or more thereof.
[0066] In one or more embodiments there is provided a composition
in which the second rheology modulator comprises a combination of
(i) at least one fatty alcohol, (ii) at least one fatty acid; and
(iii) at least one wax.
[0067] In one or more embodiments there is provided a composition
in which the second rheology modulator comprises a compound,
selected from the groups consisting of at least one fatty alcohol,
at least one fatty acid, at least one wax and mixtures of two or
more thereof. At least one fatty alcohol is selected from the group
consisting of (a) a fatty alcohol having 14 or more carbons in
their carbon chain, myristyl alcohol, cetyl alcohol, stearyl
alcohol, erucyl alcohol, arachidyl alcohol, behenyl alcohol,
tetracosanol, hexacosanol, octacosanol, triacontanol,
tetratriacontanol, 1-triacontanol and a fatty alcohol, having a
carbon chain between C30 and C50, (b) a fatty alcohol mixture,
derived from beeswax, (c) a therapeutically-active fatty alcohol.
At least one fatty acid is selected from the group consisting of a
hydroxy fatty acid, a fatty acid having 12 or more carbons in its
carbon chain, dodecanoic acid, myristic acid, hexadecanoic acid,
heptadecanoic acid, stearic acid, arachidic acid, behenic acid,
tetracosanoic acid, hexacosanoic acid, heptacosanoic acid,
octacosanoic acid, triacontanoic acid, dotriacontanoic acid,
tritriacontanoic acid, tetratriacontanoic acid and
pentatriacontanoic acid and a fatty acid, having a carbon chain
between C30 and C50. At least one wax is selected from the group
consisting of: a wax, having the properties of (i) plastic behavior
at ambient temperatures, (ii) a melting point above approximately
45.degree. C., (iii) a relatively low viscosity when melted; and
(iv) hydrophobic nature;
[0068] In one or more embodiments the composition further comprises
a liquefied or compressed gas propellant wherein the composition is
a foamable composition; [0069] wherein the second rheology
modulator is about 0.1% to about 20% by weight of the composition;
wherein the hydrophobic carrier is about 60% to about 95% by weight
of the composition and wherein the ratio of composition other than
propellant to propellant is from about 100:1 to about 100:30; and
wherein upon dispensing the foamable carrier composition forms a
breakable foam that breaks easily upon application of shear force.
In an embodiment the formulation is short term stable.
[0070] In one or more embodiments, the formulation is a gel that is
capable of forming a foamable composition when packaged into an
aerosol canister, equipped with a valve and pressurized with a
liquid or pressurized gas propellant and is capable of releasing a
foam of quality that is breakable upon application of shear force
but is not thermolabile at about or close to body temperature
(about 36.degree. C.).
[0071] In one or more embodiments, upon addition of between about
4% to about 8%; or about 8% to about 12% propellant, the
formulations provide a foam of good or excellent quality that had a
collapse time in excess of 3 minutes.
[0072] In an embodiment the wax is selected from the group
consisting of vegetable wax, beeswax, chinese wax, cotton wax,
bayberry wax, candelilla wax, carnauba wax, castor wax, cuban palm
wax, esparto wax, fir wax, flax wax, flower wax, fat wax, japan
wax, sandy wax, lanolin wax, ouricury wax, palm waxes, rice bran
wax, rice-oil wax, shellac wax, soy wax, sugar cane wax, ucuhuba
wax, a hydrogenated oil, hydrogenated castor oil, hydrogenated
cottonseed oil, or hydrogenated jojoba oil, mink wax, montan wax,
ozokerite, PEG-6 beeswax, rezo wax, spent grain wax, stearyl
dimethicone, a paraffin wax, paraffin 58-62.degree. C. wax,
paraffin 51-53.degree. C. wax, paraffin 42-44.degree. C. wax,
synthetic mineral wax, fischer-tropsch wax, duroxon wax, or
polymekon wax, synthetic waxes, albacer wax, atlasene wax, BASF
waxes, cardis waxes, ceramid, glyco waxes, flexo wax, or oxazoline
waxes, as well as other waxes, as described in "The Complete
Technology Book on Wax and Polishes, Publisher: Asia Pacific
Business Press Inc., 2006".
[0073] In one or more embodiments the wax is a mixture of two or
more waxes. In certain embodiments the mixture of waxes comprises
hydrogenated caster oil and beeswax.
[0074] In one or more embodiments the ratio of fatty alcohol to wax
or fatty acid to wax or fatty alcohol and fatty acid to wax can be
between about 1:10 to about 10:1. In one or more embodiments the
ratio of fatty alcohol to wax or fatty acid to wax or fatty alcohol
and fatty acid to wax can be between about 1:5 to about 5:1. In one
or more embodiments the ratio of fatty alcohol to wax or fatty acid
to wax or fatty alcohol and fatty acid to wax can be between about
1:3 to about 3:1. In one or more embodiments the ratio of fatty
alcohol to wax or fatty acid to wax or fatty alcohol and fatty acid
to wax can be between about 1:2 to about 2:1. In one or more
embodiments the ratio of fatty alcohol to wax or fatty acid to wax
or fatty alcohol and fatty acid to wax can be about 1:1.
[0075] In one or more embodiments there is provided a composition
in which cholesterol has a rheology effect, wherein it acts as a
viscosity booster.
[0076] In one or more embodiments there is provided a composition
in which the concentration of the first rheology modulator in the
composition is from about 0.01% to about 25% by weight.
[0077] The composition comprises at least one hydrophobic
solvent
[0078] In one or more embodiments the hydrophobic solvent is
selected from the group consisting of a diglyceride, a therapeutic
oil, acetylated lanolin alcohol, alexandria laurel tree oil, alkyl
benzoate, alkyl octanoate, almond oil, an essential oil, an
unsaturated or polyunsaturated oil, apricot stone oil, arachidyl
behenate, arachidyl propionate, avocado oil, barley oil, basil oil,
beeswax, benzyl laurate, benzyl myristate, benzyl palmitate, bis
(octyldodecyl stearoyl) dimer dilinoleate, borage seed oil, butyl
myristate, butyl stearate, C12-C15 alkyl benzoate, C12-C15 alkyl
octanoate, calendula oil, camphor oil, canelle nut tree oil, canola
oil, capric/caprylic triglycerides, caprylic/capric triglyceride
castor oil, caprylyl methicone, cardamom oil, carrot oil, castor
oil, cetearyl ethylhexanoate, cetearyl isononanoate, cetearyl
octanoate, cetyl acetate, cetyl dimethicone, cetyl ethylhexanoate,
cetyl lactate, cetyl myristate, cetyl octanoate, cetyl palmitate,
cetyl ricinoleate, citronella oil, clary sage oil, clove oil,
cocoglycerides, coconut oil, cod-liver oil, corn oil, cotton oil,
cottonseed oil, cyclohexasiloxane, cyclomethicone, Cyclomethicone
5-NF (cyclopentasiloxane), cyclotetrasiloxane, cypress oil, decyl
oleate, diethyleneglycol diethylhexanoate, diethyleneglycol
diisononanoate, diethyleneglycol dioctanoate, diethylhexanoate,
diethylhexyl adipate, diethylhexyl malate, diethylhexyl succinate,
diisopropyl adipate, diisopropyl dimerate, diisopropyl sebacate,
diisosteary dimer dilinoleate, diisostearyl fumerate, dimethicone,
dimethyl polysiloxane, dioctyl malate, dioctyl sebacate, disopropyl
adipate, dodecyl oleate, Dow Corning 244 Fluid
(cyclotetrasiloxane), Dow corning 246 Fluid (d6+d5)
(cyclohexasiloxane & cyclopentasiloxane), epoxy-modified
silicone oil, essential oils, ester derivatives of lanolic acid,
ester oils, ethylhexyl cocoate, ethylhexyl ethylhexanoate,
ethylhexyl hydroxystarate, ethylhexyl isononanoate, ethylhexyl
palmitate, ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexyl
stearate, evening primrose oil, fatty acid-modified silicone oil,
flaxseed oil, fluoro group-modified silicone oil, frankincense oil,
gelled mineral oil, ginger oil, glycereth triacetate, glycerol
triheptanoate, glyceryl oleate, glyceryl trioctanoate, glyceryl
triundecanoate, grape seed oil, grapefruit oil, groundnut oil, hard
fat, hazelnut oil, heavy mineral oil, hempseed oil, herring oil,
hexadecyl stearate, hexyl laurate, hydrocarbon oils, hydrogenated
castor oil, hyssop oil, isoamyl laurate, isocetearyl octanoate,
isocetyl isocetyl behenate, isocetyl lanolate, isocetyl palmitate,
isocetyl salicylate, isocetyl stearate, isocetyl stearoyl stearate,
isodecyl ethylhexanoate, isodecyl isononanoate, isodecyl oleate,
isododecane, isohexadecane isododecane, isohexadecanol, isohexyl
decanoate, isononyl isononanoate, isononyl octanoate, isoparaffin,
isopropyl isostearate, isopropyl lanolate, isopropyl laurate,
isopropyl myristate, isopropyl palmitate, isopropyl stearate,
isosteary citrate, isosteary salicylate, isosteary tartarate,
isostearyl behenate, isostearyl erucate, isostearyl glycolate,
isostearyl isononanoate, isostearyl isostearate, isostearyl
lactate, isostearyl linoleate, isostearyl linolenate, isostearyl
malate, isostearyl neopentanoate, isostearyl palmitate, isotridecyl
isononanoate, jasmine oil, jojoba oil, lauryl lactate, lavender
oil, lemon oil, light mineral oil, liquid paraffin, liquid
triglycerides, lucerne oil, maize germ oil, maleated soybean oil,
mandarin oil, manuka oil, marjoram oil, marrow oil, MCT oil,
methylphenylpolysiloxane, millet oil, mineral oil, myristyl
lactate, myristyl myristate, myristyl neopentanoate, myristyl
propionate, myrrh oil, neopentylglycol dicaprate, neopentylglycol
dicaprylate/dicaprate, neroli oil, nutmeg oil, octyl palmitate,
octyl stearate, octyldodecanol, octyldodecyl behenate, octyldodecyl
hydroxystearate, octyldodecyl myristate, octyldodecyl stearoyl
stearate, oils from animal origin, oils of plant origin, oleyl
erucate, oleyl lactate, oleyl oleate, olive oil, or dimethiconol,
palm oil, passionflower oil, peanut oil, PEG/PPG 18/18 dimethicone,
pentaerythrityl tetrastearate, petitgrain oil, petrolatum, phenyl
trimethicone, phenyltrimethicone,
poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer, polyalkyl
siloxane, polyalkylaryl siloxane, polyalphaolefin, polyaryl
siloxane, polyaryl siloxanes, polyether group-modified silicone oil
cyclomethicone, polyether siloxane copolymer, polyether siloxane
copolymers, polyisobutylene, polyolefin, poppy oil, PPG alkyl
ethers, PPG-10 cetyl ether, PPG-10 oleyl ether, PPG-11 stearyl
ether, PPG-12 butyl ether, PPG-14 butyl ether, PPG-15 butyl ether,
PPG-15 stearyl ether, PPG-16 butyl ether, PPG-17 butyl ether,
PPG-18 butyl ether, PPG-2 butyl ether, PPG-2 methyl ether, PPG-20
butyl ether, PPG-20 oleyl ether, PPG-22 butyl ether, PPG-23 oleyl
ether, PPG-24 butyl ether, PPG-26 butyl ether, PPG-28 cetyl ether,
PPG-3 methyl ether, PPG-3 myristyl ether, PPG-30 butyl ether,
PPG-30 cetyl ether, PPG-30 isocetyl ether, PPG-30 oleyl ether,
PPG-33 butyl ether, PPG-37 oleyl ether, PPG-4 butyl ether, PPG-4
lauryl ether, PPG-4 myristyl ether, PPG-40 butyl ether, PPG-5 butyl
ether, PPG-50 cetyl ether, PPG-50 oleyl ether, PPG-52 butyl ether,
PPG-53 butyl ether, PPG-7 lauryl ether, PPG-9 butyl ether, PPG-9-13
butyl ether, propyl myristate, propylene glycol dicaprate,
propylene glycol dicaprylate, propylene glycol myristyl ether
acetate, propylene glycol ricinoleate, rapeseed oil, rosehip oil,
rye oil, safflower oil, sage oil, salmon oil, sesame oil, silicone
oil, soya oil, soybean oil, stearyl caprate, stearyl dimethicone,
stearyl heptanoate, stearyl propionate, sunflower oil, sweet almond
oil, synthetic isoalkane, sysymbrium oil, syzigium aromaticum oil,
tangerine oil, tea tree oil, therapeutic oils, tocopheryl acetate,
tocopheryl linoleate, tridecyl ethylhexanoate, tridecyl
isononanoate, triisocetyl citrate, unsaturated or polyunsaturated
oils, vanilla oil, verbena oil, walnut oil, wheat germ glycerides,
wheat germ oil, white petrolatum and mixtures thereof.
[0079] In one or more embodiments there is provided a composition
comprising a petrolatum or a paraffin.
[0080] In one or more embodiments there is provided a composition
in which the fatty alcohol has 14 or more carbons in their carbon
chain; the fatty acid has 16 or more carbons in their carbon chain;
the beeswax extract includes a mixture of fatty alcohols, a
majority of which has at least 20 carbon atoms in their carbon
chain, a fatty acid substituted with a hydroxyl group, cetyl
alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol,
1-triacontanol, hexadecanoic acid, stearic acid, arachidic acid,
behenic acid; octacosanoic acid, 12-hydroxy stearic acid and/or
mixtures thereof.
[0081] In one or more embodiments there is provided a composition
in which the viscosity modifier and the active agent act
synergistically to increase the viscosity.
[0082] In one or more embodiments there is provided a composition
which is a foamable composition and the carrier comprises: [0083]
a) about 60% to about 95% by weight of a hydrophobic solvent;
[0084] b) an oleaginous foamer complex comprising: [0085] (1) about
0.1% to about 20% by weight of a fatty alcohol; and [0086] (2)
about 0.1% to about 20% by weight of a fatty acid and/or a wax;
[0087] c) a liquefied or compressed gas propellant; wherein the
percent by weight is based on weight foamable composition; wherein
the ratio of composition other than propellant to propellant is
from about 100:1 to about 100:30; and wherein upon dispensing the
foamable carrier composition forms a breakable foam that is stable,
yet breaks easily upon application of shear force.
[0088] In one or more embodiments there is provided a foamable
composition in which the foam produced from the foamable
composition has an average bubble size of less than about 300
microns of less, or less than about 200 microns, or less than about
150 microns.
[0089] In one or more embodiments there is provided a composition
in which the composition further comprises at least one additional
therapeutic agent selected from the group consisting of an
antibiotic agent, a steroidal anti-inflammatory agent, an
immunosuppressive agent, an immunomodulator, an immunoregulating
agent, a hormonal agent, an androgen, an estrogen, a prostaglandin,
an antiandrogen agent, a testosterone inhibitor, a
dihydrotestosterone inhibitor, antibacterial agent, an antifungal
agent, an antiviral agent, an antiparasitic agent, antimicrobial, a
retinoid, vitamin A, a vitamin A derivative, vitamin B, a vitamin B
derivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin
D derivative, vitamin E, a vitamin E derivative, vitamin F, a
vitamin F derivative, vitamin K, a vitamin K derivative, a wound
healing agent, a disinfectant, an anesthetic, an antiallergic
agent, a keratolytic agent, urea, a urea derivative, an alpha
hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a
protein, a peptide, a neuropeptide, an allergen, an immunogenic
substance, a haptene, an oxidizing agent, an antioxidant, a
dicarboxylic acid, azelaic acid, sebacic acid, adipic acid, fumaric
acid, a retinoid, an antiproliferative agent, an anticancer agent,
a photodynamic therapy agent, benzoyl chloride, calcium
hypochlorite, magnesium hypochlorite, an anti-wrinkle agent, a
radical scavenger, a metal, silver, a metal oxide, titanium
dioxide, zinc oxide, zirconium oxide, iron oxide, silicone oxide,
an organo-metallic compound, and organo-boron compound, an
organo-berrilium compound, an tellurium compound, talc, carbon, an
anti wrinkle agent, a skin whitening agent, a skin protective
agent, a masking agent, an anti-wart agent, a refatting agent, a
lubricating agent and mixtures thereof.
[0090] In one or more embodiments there is provided a composition
further comprising a surfactant.
[0091] In one or more embodiments there is provided a composition
further comprising about 1% to about 25% by weight of a polar
solvent or a penetration enhancer.
[0092] In one or more embodiments there is provided a composition
in which the polar solvent is selected from polyols, glycerol
(glycerin), propylene glycol, hexylene glycol, diethylene glycol,
propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes,
terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene
glycol, other glycols, sulfoxides, dimethylsulfoxide (DMSO),
dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide,
monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxide
units), azone (1-dodecylazacycloheptan-2-one),
2-(n-nonyl)-1,3-dioxolane, esters, isopropyl myristate/palmitate,
ethyl acetate, butyl acetate, methyl proprionate, capric/caprylic
triglycerides, octylmyristate, dodecyl-myristate, myristyl alcohol,
lauryl alcohol, lauric acid, lauryl lactate ketones, amides,
acetamide oleates, triolein; various alkanoic acids, caprylic acid,
lactam compounds, azone; alkanols, dialkylamino acetates, and
admixtures thereof; or from polyethylene glycol (PEG), PEG200 (MW
(molecular weight) about 190-210 kD), PEG300 (MW about 285-315 kD),
PEG400 (MW about 380-420 kD), PEG600 (MW about 570-630 kD), PEG
4000, PEG 6000, PEG 10000 and mixtures thereof.
[0093] In one or more embodiments there is provided a composition
in which the penetration enhancer is selected from the group
consisting of propylene glycol, butylene glycol, hexylene glycol,
glycerol, pentaerythritol, sorbitol, mannitol, oligosaccharides,
dimethyl isosorbide, monooleate of ethoxylated glycerides having
about 8 to 10 ethylene oxide units, polyethylene glycol 200-600,
transcutol, glycofurol and a cyclodextrin.
[0094] In one or more embodiments there is provided a composition
in which the active agent is benzoyl peroxide.
[0095] In one or more embodiments there is provided a method for
controlling formulation viscosity by selecting appropriate
concentrations of a wax or fatty alcohol or fatty acid or a
combination thereof and an active agent where the viscosity of the
formulation can be increased, or stabilized by the addition of the
active agent
[0096] In one or more embodiments there is provided a method of
preventing or treating or alleviating a disease or disorder, the
method comprising administering any of the preceding compositions
topically to a subject having or anticipated to have a disease or a
disorder in need of treatment.
[0097] In one or more embodiments there is provided a method for
intradermal delivery of the active agent into the skin with minimal
or negligible transdermal delivery. In one or more alternative
embodiments a formulation is provided to achieve intra mucosal
delivery. In certain embodiments the composition provides for
transdermal delivery. In one or more embodiments the composition
can be used for prevention of a disease or disorder. The
composition or foam is applied to a target surface or area in or on
which prevention is sought. In other embodiments the composition or
foam is used to treat or ameliorate a disease or disorder. In still
further embodiments it may be used to provide a period of remission
from the disease or disorder.
[0098] In one or more embodiments the composition is used for
treating eye infections. In one or more embodiments the drug
carrier is formulated for use on sensitive target areas such as
sensitive or damaged skin areas, wounds, burns, mucosal membranes,
body cavities and the eye. In one or more embodiments the
composition is intended for use in treatment or prevention of eye
infections. For sensitive use, hydrophobic solvents that are
suitable for ophthalmic targets or for use in wounds or burns and
are compatible with the active pharmaceutical ingredients are
identified.
BRIEF DESCRIPTION OF THE DRAWINGS
[0099] The following figures are provided for the purpose of
illustration only and are not intended to be limiting.
[0100] FIG. 1 is a graph of the percentage of change in formulation
viscosity by addition of 0.1% Minocycline HCl as a function of
placebo viscosity.
[0101] FIG. 2 is photographs of vials in horizontal and vertical
position containing formulation 016 without active ingredient (left
vial) and with 0.1% Minocycline HCl (right vial).
DETAILED DESCRIPTION
[0102] The gist of the present invention is based on the striking
discovery that the addition of a low concentration of an suspended
active agent into a composition or formulation comprising a
oleaginous carrier comprising a hydrophobic solvent together with a
second rheology modulator which may be a fatty acid and/or a fatty
alcohol and/or a wax dramatically modulates the rheological
properties of the composition and in particular can synergistically
change the level of viscosity of a composition.
[0103] In one or more embodiments there is provided a composition
or formulation for use as a vehicle or carrier comprising, a first
rheology modulator comprising an suspended active agent in an
amount necessary to modify controllably different rheological
properties of the composition, a second rheology modulator
comprising a second rheology modulator in an amount necessary to
modify controllably the different rheological properties of the
composition and a carrier.
[0104] In one or more embodiments there is provided a composition
or formulation for use as a vehicle or carrier comprising a first
rheology modulator comprising an suspended active agent in an
amount necessary to modify controllably the different rheological
properties of the composition, a second rheology modulator in an
amount necessary to modify controllably the different rheological
properties of the composition and an oleaginous carrier wherein
adding a first modulator to an oleaginous carrier results in no
significant or substantial change to the rheology as reflected in
the viscosity of the composition; however further adding a second
modulator to the composition unexpectedly results in a synergistic
effect on the rheology as reflected in the viscosity of the
composition. Alternatively first adding a second modulator to an
oleaginous carrier results in an expected increase in the viscosity
of the composition, however then further adding a first modulator
to the composition surprisingly results in an unexpected
synergistic effect on the viscosity of the composition. However,
such synergistic affect is observed wherein the viscosity of the
carrier or composition is less than about 25,000 centipoises (cPs)
at room temperature prior to the addition of the first rheology
modulator.
[0105] In one or more embodiments there is provided a composition
as a carrier or vehicle in which a therapeutic rheology modulator
or complex thereof is incorporated therein and in which the
therapeutic agent is chemically stable and the formulation is
physically stable and the therapeutic properties of the agent are
sustained or substantially so.
[0106] In one or more embodiments there is provided a composition
as a vehicle or carrier in which a therapeutic rheology modulator
or complex thereof is incorporated therein and which further
includes a surfactant and in which the active pharmaceutical agent
is chemically stable and the formulation is physically stable and
the therapeutic properties of the agent are sustained or
substantially so.
[0107] In one or more embodiments there is provided a composition
as a vehicle or carrier in which a therapeutic rheology modulator
or complex thereof is incorporated therein which further includes
one or more other therapeutic agents and in which the active
pharmaceutical agent is chemically stable and the formulation is
physically stable and the therapeutic properties of the agent are
sustained or substantially so.
[0108] In one or more embodiments there is provided a composition
as a vehicle or carrier comprising a therapeutic rheology modulator
or complex thereof in a waterless or non aqueous environment and in
which the active pharmaceutical agent is chemically stable and the
formulation is physically stable and the therapeutic properties of
the agent are sustained or substantially so.
[0109] In one or more embodiments there is provided a composition
as a vehicle or carrier comprising a therapeutic rheology modulator
or complex thereof in a substantially waterless or non aqueous
environment and in which the active pharmaceutical agent is
chemically stable and the formulation is physically stable and the
therapeutic properties of the agent are sustained or substantially
so.
[0110] In an embodiment or more embodiments there is provided a
composition as a vehicle or carrier comprising a therapeutic
rheology modulator or complex thereof in a substantially waterless
or non aqueous environment, where the therapeutic agent has low or
minimal susceptibility to water and can withstand up to about 10%
water and more preferably up to about 5% water and in which the
active pharmaceutical agent is chemically stable and the
formulation is physically stable and the therapeutic properties of
the agent are sustained or substantially so.
[0111] In an embodiment or more embodiments there is provided a
composition as a vehicle or carrier comprising a therapeutic
rheology modulator or complex thereof, where addition of low
concentrations of the active agent has a strong and sometimes
synergistic impact on the rheology of the composition and in which
the active pharmaceutical agent is chemically stable and the
formulation is physically stable and the therapeutic properties of
the agent are sustained or substantially so.
[0112] In an embodiment or more embodiments there is provided a
composition as a vehicle or carrier comprising a therapeutic
rheology modulator or complex thereof, where addition of low
concentrations of said therapeutic agent has a synergistic and
dramatic impact on rheological properties of the composition for
example the viscosity of the composition and in which the active
pharmaceutical agent is chemically stable and the formulation is
physically stable and the therapeutic properties of the agent are
sustained or substantially so.
[0113] In an embodiment or more embodiments the therapeutic
rheology modulator or the therapeutic agent has a low concentration
of less than about 1%; or less than about 0.5%; or less than about
0.1%; or less than about 0.01%. In one or more other embodiments
the therapeutic rheology modulator or the therapeutic agent has a
medium concentration of less than about 10%; or less than about 5%;
or less than about 3%; or less than about 2%. In one or more other
embodiments the therapeutic rheology modulator or the therapeutic
agent has a high concentration of less than about 30%; or less than
about 25%; or less than about 20%; or less than about 15%. In one
or more embodiments the concentration range of therapeutic rheology
modulator or the therapeutic agent is between about 0.001% and
about 0.1%; or is between about 0.01% and about 1%; or is between
about 1% and about 10%; or is between about 10% and about 30%; or
is between any two ranges, such as, between about 0.01% and about
30%.
[0114] In an embodiment or more embodiments there is provided a
composition as a vehicle or carrier wherein the active agent is
selected from a list comprising an antibiotic agent, a steroidal
anti-inflammatory agent, an immunosuppressive agent, an
immunomodulator, an immunoregulating agent, a hormonal agent, an
androgen, an estrogen, a prostaglandin, an antiandrogen agent, a
testosterone inhibitor, a dihydrotestosterone inhibitor,
antibacterial agent, an antifungal agent, an antiviral agent, an
antiparasitic agent, an antimicrobial agent a retinoid, vitamin A,
a vitamin A derivative, vitamin B, a vitamin B derivative, vitamin
C, a vitamin C derivative, vitamin D, a vitamin D derivative,
vitamin E, a vitamin E derivative, vitamin F, a vitamin F
derivative, vitamin K, a vitamin K derivative, a wound healing
agent, a disinfectant, an anesthetic, an antiallergic agent, a
keratolytic agent, urea, a urea derivative, an alpha hydroxyl acid,
lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a
peptide, a neuropeptide, an allergen, an immunogenic substance, a
haptene, an oxidizing agent, an antioxidant, a dicarboxylic acid,
azelaic acid, sebacic acid, adipic acid, fumaric acid, a retinoid,
an antiproliferative agent, an anticancer agent, a photodynamic
therapy agent, benzoyl chloride, calcium hypochlorite, magnesium
hypochlorite, an anti-wrinkle agent, a radical scavenger, a metal,
silver, a metal oxide, titanium dioxide, zinc oxide, zirconium
oxide, iron oxide, silicone oxide, an organo-metallic compound, and
organo-boron compound, an organo-beryllium compound, a tellurium
compound, talc, carbon, an anti wrinkle agent, a skin whitening
agent, a skin protective agent, a masking agent, an anti-wart
agent, a refatting agent, a lubricating agent and mixtures
thereof.
[0115] In an embodiment or more embodiments there is provided a
composition as a vehicle or carrier wherein active agent is a
tetracycline.
[0116] In an embodiment or more embodiments there is provided a
composition as a vehicle or carrier wherein the tetracycline is
minocycline or doxycycline.
[0117] In an embodiment or more embodiments there is provided a
composition as a vehicle or carrier wherein active agent is
selected from a list comprising a cholesterol, mometasone furoate,
doxycycline hyclate, salicylic acid, vitamin E, diclofenac, urea,
terbinafine, permethrin, metronidazole, pimecrolimus benzoyl
peroxide or salt thereof.
[0118] In one or more embodiments there is provided a composition
as a vehicle or carrier wherein second rheology modulator is a
fatty alcohol and/or a fatty acid and/or a wax.
[0119] In one or more embodiments there is provided a solid or
semi-solid composition or gel. In one or more embodiments the
composition or gel is a liquid. Examples of a liquid gel include
where a propellant is added to the formulation (which prior to
adding the propellant is a gel) or where the gel is loose or such
that when subjected to gravity will pour or become liquid. In one
or more embodiments the composition is thixotropic. In one or more
embodiments when poured it displays flow but over time it reverts
to being more viscous or gel like. In one or more embodiments when
shear force is applied it displays flow but over time reverts to
being more viscous or gel like. In one or more embodiments a solid
gel becomes flowable and later with time becomes solid or semi
solid. In one or more embodiments a semi-solid gel becomes flowable
and later with time becomes solid or semi solid. In one or more
embodiments a liquid gel is flowable and later with time becomes
solid or semi solid.
[0120] In one or more embodiments there is provided a composition
as a vehicle or carrier wherein second rheology modulator is a
solid or semi-solid or a liquid.
[0121] In one or more embodiments there is provided a foamable
composition for use as a vehicle or carrier in which therapeutic
rheology modulator is stable or stabilized within foamable
composition.
[0122] In one or more embodiments there is provided a method of
preventing or treating or alleviating a disease or disorder, the
method comprising administering the composition topically to a
subject having or anticipated to having a disease or a disorder in
need of treatment. In one or more embodiments the method of
achieves a period of remission of the disease or disorder.
[0123] According to one or more embodiments, it is possible to make
excellent lotions, creams, ointments, gels and foams from waterless
or substantially waterless compositions. Such compositions
containing first and second rheology modulators as described herein
are also ideal carriers for active pharmaceutical agents that are
soluble in polar solvents and which may be potentially unstable in
an aqueous environment, for example, following a change in pH, or
the introduction a metal catalyst or in the presence of an
ionization or oxidation agent.
[0124] It has surprisingly been discovered that combinations of
different types and concentrations of active agents with different
second rheology modulators may result in modulations to the
rheology of formulations in which the active pharmaceutical or
cosmetic agent is chemically stable and furthermore, the
formulation is physically stable as demonstrated herein in the
Examples.
[0125] In one or more embodiments, the change in the formulation
viscosity is related to the concentration of the active agent.
[0126] In one or more embodiments, the viscosity of the formulation
is proportional to the concentration of the active agent: for
example, the higher the concentration of the active agent, the
higher the formulation viscosity. In one or more embodiments the
relationship is exponential.
[0127] In one or more embodiments, the viscosity increasing effect
of the active agent reaches a plateau when the concentration of the
active agent is increased. In certain other embodiments the
viscosity decreasing effect of the active agent likewise reaches a
plateau when the concentration of the active agent is
increased.
[0128] In one or more embodiments, the viscosity of the formulation
containing the active agent is more than about twice the viscosity
of the sample formulation is without the active agent, wherein the
active agent is present at a concentration of less than about 10%,
less than about 5%, less than about 1%, less than about 0.5%, less
than about 0.1%, less than about 0.05%, or less than about
0.01%.
[0129] In one or more embodiments skin penetration of the active
agent is improved. In one or more embodiments the penetration is
primarily intradermal. In one or more embodiments there is little
or no transdermal penetration. In one or more embodiments the
active agent is concentrated in the statum corneum. In one or more
embodiments the active agent is concentrated in the live skin
layer. In one or more embodiments the active agent is distributed
throughout the skin.
[0130] Active agents had practically no effect on the viscosity of
a composition which did not comprise second rheology modulators. As
shown in formulations of Example 2, mixtures of mineral oils or
soybean oil or petrolatum and C12-C15 alkyl benzoate had a low
viscosity. After the addition of a tetracycline such as
Minocyclineminocycline HCl, the viscosity of the formulation
remained practically unchanged and active agents sediment.
[0131] Similarly, as shown in formulations of Example 3, it appears
that in formulations based on high amounts of semi-solid
hydrophobic solvents, such as petrolatum or coconut oil, alone or
in combination with fatty alcohols and/or fatty acids, the
viscosity of the formulation remained unchanged after the addition
of 0.1% Minocyclineminocycline HCl.
[0132] It was therefore surprisingly observed that addition of low
concentrations of an active agent had a synergistic and dramatic
impact on the oleaginous composition viscosity as for example shown
in Example 4a. The addition of Minocyclineminocycline HCl to
mineral oil-based formulations led to a very substantial increase
in viscosity, despite the very low amount of Minocycline HCL used,
namely 0.1%. These totally unexpected results show that the
combination of a tetracycline, even at very low concentrations,
with fatty alcohols, or fatty acids and/or waxes (e.g. hydrogenated
castor oil, with or without beeswax) had a strong synergistic
effect on oleaginous formulation viscosity. This effect was
observed in compositions containing certain fatty alcohols such as
myristyl alcohol or cetyl alcohol or stearyl alcohol.
[0133] It was found that adding a first modulator to an oleaginous
carrier resulted in no significant or substantial change to the
rheology as reflected in the viscosity of the composition; however
further adding a second modulator to the composition unexpectedly
resulted in a synergistic effect on the rheology as reflected in
the viscosity of the composition. Alternatively first adding a
second modulator to an oleaginous carrier resulted in an expected
increase in the viscosity of the composition, however then further
adding a first modulator to the composition surprisingly resulted
in an unexpected synergistic effect on the viscosity of the
composition. However such synergistic affect is observed wherein
the viscosity of the carrier or composition is less than about
25,000 centipoises (cPs), less than about 12,000 cPs, less than
about cPs 8,000 cPs, or less than about 2,000 cPs at room
temperature prior to the addition of the first rheology
modulator.
[0134] Very surprisingly, as described in Example 4c it was
discovered that the addition of minocycline HCl to mineral
oil-based formulations, containing as low as 5% of a fatty alcohol,
or a fatty acid or a wax or a combination of a fatty alcohol and a
wax, led to a very substantial increase in viscosity, where the
increase in viscosity is dependent on the concentration of the
active agent. It was noticed that formulations having a higher
concentration of active agent had a higher viscosity. So there is a
relationship between the amount of the active agent and resultant
viscosity over a specific range of concentration typical for each
active ingredient.
[0135] It was further observed that the combination of a
tetracycline with a mixture of mineral oils, fatty alcohols, fatty
acids and waxes had a strong synergistic effect and increased the
formulation viscosity as shown in Example 4c. The viscosity of a
formulation containing 0.50% minocycline HCl was about three times
higher than the viscosity of the placebo formulation. It was also
evident that the effect on the formulation viscosity was directly
related to the concentration of the tetracycline: the higher the
tetracycline concentration, the higher the viscosity of the
formulation.
[0136] It was further discovered that in formulations based on
petrolatum and various amounts of mineral oil, the influence of the
combination of a tetracycline with fatty alcohols on formulation
having initial high viscosity was minor. As shown in Example 5 when
the viscosity of the placebo formulation is high, and the
concentration of minocyline is low (e.g. 0.1%) no significant
increase in viscosity was noticed. Formulations which contained low
amounts of mineral oil exhibited a minor increase in viscosity upon
the addition of 0.1% minocycline HCl (which with higher amounts of
minocycline could have been more substantial). However, very
surprisingly, it was observed that the addition of a very low
amount of minocycline HCl greatly increased formulation viscosity,
when the viscosity of the placebo formulation was low, which
contained high amounts of mineral oil.
[0137] As shown in FIG. 1, the percentage of change in viscosity by
the addition of minocycline HCl appears to be exponentially related
to the viscosity of the formulation placebo. As shown in FIG. 2,
the addition of minocycline HCl to the oleaginous formulation based
on mineral oil changes the physical state of the formulation from a
liquid to a semi-solid.
[0138] In one or more embodiments, the lower the viscosity of the
placebo formulation, the greater the increase in formulation
viscosity after addition of the active agent.
[0139] It was unexpectedly discovered that the combination of a
tetracycline with a mixture of vegetable oils, fatty alcohols,
fatty acids and waxes had a strong synergistic effect and increased
the formulation viscosity. The viscosity of a formulation
containing about 1% minocycline HCl was about twice as high as the
viscosity of the placebo formulation. Moreover, the effect on the
formulation viscosity was directly related to the concentration of
the tetracycline: the higher the tetracycline concentration, the
higher the viscosity of the formulation.
[0140] In one or more embodiments, there is provided an oleaginous
formulation containing vegetable oils and a tetracycline in
synergistic combination with a fatty alcohol, a fatty acid and a
wax, wherein the viscosity of the formulation is increased by the
addition of the active ingredient by more than about 20%, or by
more than about 50%, or by more than about 100%, or by more than
about 200%, or by more than about 300%, or by more than about
500%.
[0141] Tetracycline antibiotics are known to be very unstable
active agents that are degraded by a wide range of commonly used
pharmaceutical excipients. For example, it has been found that
minocycline is degraded in a few days by different hydrophilic
solvents (such as water, glycerin, sodium PCA, propylene glycol and
polyethylene glycols), by water dispersed polymers (such as xanthan
gum, poloxamers, carbomers, methocel, sodium
carboxymethylcellulose) and by surfactants (such as polysorbates,
sorbitan esters, polyoxyalkyl esters and lanolin-based
surfactants). Thus, the achievement of a long term stable
formulation of tetracycline antibiotics provided a major
challenge.
[0142] Surprisingly, and despite the known instability of
tetracycline antibiotics, the accelerated stability results of the
formulation at 6 months at 40.degree. C. showed minimal degradation
of the active agent in the formulations. The formulations showed an
extended accelerated stability for the tetracycline antibiotic
active agent and an outstanding physical stability, wherein the
viscosity of the formulation is substantially increased by the
addition of the active agent.
[0143] In another experiment, a sample of formulation was stored
during 6 months at 40.degree. C. and tested for active agent
content uniformity and physical stability. It was found that
minocycline HCl was homogeneously dispersed into formulation even
after prolonged incubation at 40.degree. C. Furthermore, it was
found that the formulation remained as a homogeneous gel after 6
months of incubation at 40.degree. C.
[0144] In one or more embodiments, there is provided a formulation
wherein the active agent is homogeneously dispersed in the
formulation and remains homogeneously dispersed after 3 weeks of
incubation at 40.degree. C., or at one month, or at two months, or
at three months, or at four months, or at five months, or at six
months incubation at 40.degree. C.
[0145] It was further discovered that the increase in viscosity was
demonstrated in different mineral oil based formulations comprising
a fatty alcohol and other active ingredients. To a lesser extent,
an increase in formulation viscosity was observed with cholesterol
which is also a 4-ring compound and with benzoyl peroxide. It can
be noted that the strongest effect was observed with tetracycline
compounds, such as minocycline HCl and tetracycline HCl (which is
another compound of the tetracycline class). Even at concentrations
as low as 0.05%, the addition of minocycline HCl to the
formulations more than doubled the viscosity. Micronized
preparations appear to have a more pronounced effect.
[0146] It was also unexpectedly discovered that viscosity increased
dramatically after the addition of a wide range of different active
ingredients to a mineral oil based formulation containing a
hydrogenated castor oil instead of fatty alcohol or fatty acid [See
Example 8]. The hydrogenated castor oil had a very strong
synergistic effect with different active ingredients for example
0.1% Minocyclineminocycline HCl non micronized, mometasone furoate,
terbinafine, metronidazole pimecrolimus. The viscosity of a
formulation containing 0.1% non-micronized minocycline HCl was more
than about 5 times as high as the viscosity of the formulation
containing 0.1% micronized minocycline HCl. This is in contrast to
the results with fatty alcohol where higher viscosity was observed
with micronized minocycline HCL.
[0147] It was unexpectedly found that the addition of minocycline
HCl to mineral oil-based formulations containing different
concentrations of beeswax alone led to changes in viscosity
depending on the amount of beeswax, at low concentration of
Minocycline HCL used. Without being bound to any theory, one
possibility may be that the addition of beeswax to oils can build a
some sort of netted framework. It may further be assumed that when
about 5% of beeswax is included in the composition, the netted
framework is relatively weak and is broken or destabilized by the
addition of Minocycline HCl, which may explain the decrease in
formulation viscosity. However, it may be assumed that when 10%
beeswax is included in the composition the netted framework is
stronger and the addition of low amounts of Minocycline HCl further
strengthens said netted framework leading to an increase in
formulation viscosity.
[0148] Thus according to one or more embodiments there is provided
a method for controlling formulation viscosity by selecting
appropriate concentrations of a wax or fatty alcohol or fatty acid
or a combination thereof and an active ingredient where the
viscosity of the formulation can be increased, or stabilized by the
addition of the active ingredient.
[0149] It was further discovered that tetracyclines like
minocycline are incompatible with many surfactants, many
hydrophilic solvents, an oil, a liquid branched fatty alcohol; a
metal oxide and water. A detailed list of compatible substances and
incompatible substances appears in Example 10.
Rheological Properties of Semisolids
[0150] Manufacturers of pharmaceutical gels, ointments and cosmetic
creams have recognized the desirability of controlling their
consistency. It must spread evenly and smoothly in various climates
yet adhere well to the affected area without being tacky or
difficult to remove.
Rheology of Gel Compositions and Gel Properties
[0151] Rigidity and viscosity are two separate rheological
parameters used to characterize the mechanical properties of gels.
Gel compositions should preferably posses the following properties.
[0152] 1. Uniformity: The composition should be formulated so that
it is and can remain uniform without separation or precipitation
over time. This property is of high importance when the product is
intended to be a pharmaceutical product. [0153] 2. Flowability: The
composition, when placed in a tube or container and expelled under
shear force should be flowable. [0154] 3. Quality: Upon release
from the tube or container, the composition should generate a
homogeneous gel. In one embodiment the gel is thixotropic. [0155]
4. Stability/Breakability: The fine balance between stability and
breakability of the gel coming out of the tube or container is very
delicate: on the one hand the gel should preferably not be very
runny upon release from the tube or container and not lose its
thixotropy property as a result of exposure to skin temperature;
and on the other hand, it should be "breakable", i.e., it should
spread easily, break down and absorb into the skin or membrane upon
application of mild shear force. [0156] 5. Skin Feeling: To ensure
patient compliance the skin feeling after application should be
pleasant, and greasy or waxy residues should be minimal. [0157] 6.
Non-irritating: The above requirements should be achieved with the
awareness that formulation excipients, especially surfactants, can
be irritating, and should preferably be eliminated from the
composition or reduced as much as possible. [0158] 7. Delivery: The
composition should also be designed to ensure efficient delivery of
a therapeutic agent into the target site of treatment. [0159] 8.
Compatibility: Finally, the first rheology modulating agent, which
is a pharmaceutical or cosmetic active agent should be chemically
compatible with the second viscosity modulating agent and with the
whole list of ingredients in the composition.
Foamable Composition and Foam Properties
[0160] The ability to achieve quality foam with a substantial
concentration of hydrophobic solvent without a surfactant is
described in U.S. Provisional Application No. 61/248,144 filed Oct.
2, 2009 and titled "Surfactant-Free Water-Free Foamable
Compositions, Breakable Foams And Their Uses," and in U.S.
Provisional Application No. 61/322,148 filed Apr. 8, 2010 and
titled "Surfactant-Free Water-Free Foamable Compositions, Breakable
Foams And Gels And Their Uses." This is surprising, because
usually, such solvents are not prone to creating a foam. The
challenge is not just to achieve a quality foam but also to attain
a formulation that will satisfy a plurality of two, three, four,
five, six or more of the following property specifications
simultaneously.
[0161] Notably, the pressurized composition is flowable and
releases a foam freely, even though it might be expected that such
concentrations of a fatty alcohol and fatty acid would make the
hydrophobic solvent `gel` or `semi-solid. [0162] 1. Uniformity: The
composition should be formulated so that it is uniform and can
remain uniform without phase separation or precipitation over time.
This property is of high importance when the product is intended to
be a pharmaceutical product. [0163] 2. Flowability: The
composition, when placed in an aerosol container and pressurized
should be flowable such that it can be expelled through the
canister valve. It should preferably also be shakable inside the
container. These requirements create a formulation challenge,
because low or non-viscous flowable and shakable compositions are
prone to undergo phase separation or precipitation. [0164] 3.
Quality: Upon release from the can, the composition should generate
a foam of good or excellent quality having low density and small
bubble size. [0165] 4. Stability/Breakability: The fine balance
between stability and breakability of the foam coming out of the
container is very delicate: on one hand the foam should preferable
not be "quick breaking", i.e., it should be at least short term
stable upon release from the pressurized container and not break as
a result of exposure to skin temperature; and on the other hand, it
should be "breakable", i.e., it should spread easily, break down
and absorb into the skin or membrane upon application of mild shear
force. [0166] 5. Skin Feeling: To ensure patient compliance the
skin feeling after application should be pleasant, and greasy or
waxy residues should be minimal. [0167] 6. Non-irritating: The
above requirements should be achieved with the awareness that
formulation excipients, especially surfactants, can be irritating,
and should preferably be eliminated from the composition or reduced
as much as possible. [0168] 7. Delivery: Finally, the composition
should also be designed to ensure efficient delivery of a
therapeutic agent into the target site of treatment.
[0169] Based on extensive investigations and trial and error
experiments, it has been found that such properties can be achieved
for formulations as disclosed in U.S. Provisional Application No.
61/248,144 filed Oct. 2, 2009 and titled "Surfactant-Free
Water-Free Foamable Compositions, Breakable Foams And Their Uses,"
and in U.S. Provisional Application No. 61/322,148 filed Apr. 8,
2010 and titled "Surfactant-Free Water-Free Foamable Compositions,
Breakable Foams And Gels And Their Uses," and which are further
advantageous because of the ability of hydrophobic solvents to
dissolve or suspend certain active agents while providing an
environment for the active agent which assists in preventing their
degradation.
Compositions
[0170] All % values are provided on a weight (w/w) basis.
[0171] In one or more embodiments where ever a phrase is used to
refer to a concentration of above X % or below X % it can also
include X % or of above about X % or below about X % it can also
include about X %.
[0172] In one or more embodiments the term "about" has its usual
meaning in the context of pharmaceutical and cosmetic formulations
to allow for reasonable variations in amounts that can achieve the
same effect. In one or more embodiments about can encompass a range
of plus and minus 20%. In one or more embodiments about can
encompass a range of plus and minus 10%.
[0173] In one or more embodiments there is provided a composition
for cosmetic or pharmaceutical application comprising: [0174] a) a
first rheology modulator comprising a suspended active agent [0175]
b) a second rheology modulator selected from the list of (i) at
least one at least one fatty alcohol, (ii) at least one fatty acid,
(iii) at least one wax; and mixtures thereof; and [0176] c) a
carrier, [0177] wherein the suspended active agent is a
pharmaceutical or cosmetic suspended active agent; [0178] wherein
the rheology of the composition after addition of the first
modulator and second modulator to the carrier is better than the
rheology of the composition after the addition of the second
modulator to the carrier without the first modulator and is better
than the rheology of the composition after the addition of the
first modulator to the carrier without the second modulator.
[0179] In certain embodiments, the viscosity of the carrier or
composition without the addition of the first rheology modulator is
less than about 25,000 centipoises (cPs) at room temperature.
[0180] In one or more embodiments the composition forms a gel. The
gel may be a liquid gel, a semi-solid gel or a solid gel. The gel
may further be an air gel, hydro gel or an oleaginous (organo)
gel.
[0181] In one or more embodiments a liquefied or compressed gas
propellant is added to the composition according to the different
embodiments mentioned above thereby transforming the gel into a
foamable composition. Upon release from an aerosol container, the
foamable composition forms an expanded foam suitable for topical
administration. In one or more embodiments the foamable composition
is either a breakable or quickly breaking foam. In one or more
embodiments the foamable composition is substantially surfactant
free. In one or more other embodiments it is essentially free of
any surfactants.
[0182] In one or more embodiments oily emollients are added to the
composition to provide or improve a pleasant skin feeling, and/or
lubricating effect with reduced friction. In one or more
embodiments volatile silicones are added to reduce greasy feeling.
In one or more embodiments waxes are added to improve rheology or
stabilize the composition's gels or structure.
[0183] In an embodiment, the wax can be a liquid wax, a solid wax,
an animal wax, a vegetable wax, a mineral wax, a natural wax or a
synthetic wax. In an embodiment the wax is selected from a list
comprising paraffin wax, beeswax, hydrogenated castor oil or
mixtures thereof. In an embodiment the wax is a polyolefin. In one
or more embodiments there is provided a composition comprising a
paraffin wax. In one or more embodiments the paraffin wax can have
a melting point form about 37.degree. C. In one or more embodiments
the paraffin wax comprises of alkane chains of between about
C.sub.20H.sub.42 to C.sub.40H.sub.82. In one or more embodiments
the chains are substantially straight chain. In some embodiments
branched or unsaturated molecules can be present. Branched chains
are sometimes referred to as isoparaffins. In one or more
embodiments the paraffin wax can be selected from the group
consisting of paraffin wax 58-62.degree. C., paraffin wax
51-53.degree. C., and paraffin wax 42-44.degree. C., or mixtures
thereof. In one or more other embodiments other melting point
ranges can be selected such as 125.degree. F. to 135.degree. F.;
127.degree. F. to 130.degree. F.; 130.degree. F. to 135.degree. F.;
135.degree. F. to 145.degree. F.; 140.degree. F. to 145.degree. F.;
150.degree. F. to 155.degree. F.; 150.degree. F. to 165.degree. F.;
160.degree. F. to 165.degree. F.; or such as 43-46.degree. C.;
46-53.degree. C.; 48-50.degree. C.; 52-54.degree. C.; 53-55.degree.
C.; 54-57.degree. C.; 54-58.degree. C.; 58-60.degree. C.;
59-61.degree. C.; 60-62.degree. C.; 62-66.degree. C.; 65-68.degree.
C.; or any other similar or relative range(s) or mixtures thereof.
In an embodiment the wax is fully refined. In an embodiment it is
suitable for cosmetic use. In an embodiment it is suitable for
pharmaceutical use. In an embodiment the paraffin wax is soft.
[0184] In one or more embodiments antioxidants can be used to
prevent degradation/oxidation, for example, butylated
hydroxytoluene, which is a fat soluble antioxidant.
[0185] According to one or more embodiments, the composition
further comprises one or more other cosmetic active agents or a
pharmaceutical active agents (severally and interchangeably termed
herein "active agent") which may or may not have a rheology
modulating effect.
[0186] Surfactants play a role in foam formation and induce foam
stability. In one or more embodiments the formulation is
substantially free of surfactants. In one or more other embodiments
it is essentially free of any surfactants. In one or more
alternative embodiments a small amount of surfactant may be added
preferably less than 1%. In one or more embodiments foam adjuvants
(e.g. fatty alcohols and fatty acids) and additives (such as SiO2
which acts as a thickener and can provide thixotropy) are added to
improve rheology or stabilize foam structure or as a protective
agent.
[0187] In one or more embodiments the composition is a foamable
composition and comprises propellant. Upon release from an aerosol
container, the foamable composition forms an expanded breakable
foam suitable for topical administration.
[0188] The composition is suitable for administration to various
body areas, including, but not limited to the skin, a body surface,
a body cavity, a mucosal surface, e.g., the mucosa of the nose,
mouth and eye, the ear, the respiratory system, the vagina or the
rectum (severally and interchangeably termed herein "target
site").
[0189] In one or more embodiments, the composition is waterless. By
waterless is meant that the composition contains no or
substantially no, free or unassociated or absorbed water. It will
be understood by a person of the art that to the extent the
waterless solvents and substances miscible with them of the present
disclosure are hydrophilic, they can contain water in an associated
or unfree or absorbed form and may absorb water from the
atmosphere.
[0190] In one or more embodiments the carrier comprises an active
pharmaceutical or cosmetic agent which degrades in the presence of
water, and in such cases the presence of water in the composition
is clearly not desirable. Thus, in certain preferred embodiments,
the composition is waterless. In other embodiments the active agent
may tolerate the presence of a small amount of water and the
waterless composition is substantially non-aqueous. The term
"substantially non-aqueous" is intended to indicate that the
waterless composition has water content preferably below about 2%,
such as, below about 1.5%, below about 1%; or below about 0.5%.
[0191] In one or more embodiments, at least a portion of the
therapeutic agent is suspended or dissolved evenly throughout the
entire composition. In one or more other embodiments the first
rheology modulator is a soluble active agent. For example when
hydrogenated caster oil in mineral oil is challenged with
cholesterol the viscosity increases by about 200%. In certain
embodiments two or more first rheology modulators may be used in
combination. Such combinations can be of two or more solid agents,
or of one or more solid agents (insoluble or partially soluble) and
one or more soluble agents or two or more soluble agents.
[0192] It has been discovered that formulations containing high
amount of a hydrophobic solvents (such as mineral oil) are not
prone to high viscosity or foaming. Surprisingly, it has been
discovered that the combination of a rheology modulating active
agent and/or a fatty alcohol and/or fatty acid and/or a wax has
viscosity and foam boosting properties and provides gels and foams
of good quality. It has been discovered that when rheology
modulating active agents are added to fatty alcohols and/or fatty
acids, for example, with a saturated carbon chain of between 14 to
22 carbons it can cause a rheology effect, such as, a synergistic
viscosity effect resulting in composition having outstanding
viscosity properties Furthermore, the formulations of the present
invention can provide foams of good quality in the presence of
various active ingredients with or without surfactants.
[0193] In one or more embodiments, the active agent is vitamin D or
a derivative or analog thereof.
[0194] In one or more embodiments, the active agent is
calcipotriol.
[0195] In one or more embodiments, the active agent is
calcitriol.
[0196] In one or more embodiments, the active agent is selected
from a list comprising a tetracycline, cholesterol, mometasone
furoate, doxycycline hyclate, salicylic acid, vitamin E,
diclofenac, urea, terbinafine, permethrin, metronidazole,
pimecrolimus, benzoyl peroxide or salt thereof.
[0197] In one or more embodiments, the tetracycline is minocycline
or doxycycline or tetracycline.
[0198] In one or more embodiments, the composition is essentially
free of polyols.
[0199] In one or more embodiments there is provided a surfactant
free composition that is also free of short chain alcohols and/or
polyol free and/or polymeric free.
[0200] In one or more embodiments, composition is capable of
providing intradermal delivery of the active agent into the skin
with minimal or negligible transdermal delivery.
[0201] In one or more embodiments, the composition has some
preservative efficacy.
[0202] In one or more embodiments, the composition is for use in
eye infections.
[0203] In one or more embodiments, the composition is physically
and chemically stable for at least two months.
[0204] In one or more embodiments, the composition is physically
and chemically stable for at least three months.
[0205] In one or more embodiments, the composition is physically
and chemically stable for at least six months.
Hydrophobic Solvent
[0206] In an embodiment, the composition of the present invention
comprises at least one hydrophobic organic solvent. A "hydrophobic
organic solvent" (also termed "hydrophobic solvent") as used herein
refers to a material having solubility in distilled water at
ambient temperature of less than about 1 gm per 100 mL, more
preferably less than about 0.5 gm per 100 mL, and most preferably
less than about 0.1 gm per 100 mL. It is liquid at ambient
temperature. The identification of a "hydrophobic solvent", as used
herein, is not intended to characterize the solubilization
capabilities of the solvent for any specific active agent or any
other component of the foamable composition. Rather, such term is
provided to aid in the identification of materials suitable for use
as a hydrophobic solvent in the compositions described herein.
[0207] In one or more embodiments the hydrophobic solvent is
present at a concentration of about 60% to about 95% or about 65%
to about 90%; or about 70% to about 90% or about 75% to about
85%.
[0208] In one or more embodiments, the composition of the present
invention comprises at least one hydrophobic solvent, selected from
the group consisting of a mineral oil, a hydrocarbon oil, an ester
oil, a triglyceride oil, an oil of plant origin, an oil from animal
origin, an unsaturated or polyunsaturated oil, a diglyceride, a PPG
alkyl ether and a silicone oil.
[0209] As exemplified herein, members of each of the above listed
groups of hydrophobic solvents have been found to be compatible
with hydrophobic tetracyclines, such as minocycline and
doxycycline.
[0210] Non-limiting examples of hydrocarbon oils include mineral
oil, liquid paraffin, an isoparaffin, a polyalphaolefin, a
polyolefin, polyisobutylene, a synthetic isoalkane, isohexadecane
and isododecane.
[0211] Non-limiting examples of ester oils include alkyl benzoate,
alkyl octanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate,
arachidyl behenate, arachidyl propionate, benzyl laurate, benzyl
myristate, benzyl palmitate, bis (octyldodecyl stearoyl) dimer
dilinoleate, butyl myristate, butyl stearate, cetearyl
ethylhexanoate, cetearyl isononanoate, cetyl acetate, cetyl
ethylhexanoate, cetyl lactate, cetyl myristate, cetyl octanoate,
cetyl palmitate, cetyl ricinoleate, decyl oleate, diethyleneglycol
diethylhexanoate, diethyleneglycol dioctanoate, diethyleneglycol
diisononanoate, diethyleneglycol diisononanoate, diethylhexanoate,
diethylhexyl adipate, diethylhexyl malate, diethylhexyl succinate,
diisopropyl adipate, diisopropyl dimerate, diisopropyl sebacate,
diisosteary dimer dilinoleate, diisostearyl fumerate, dioctyl
malate, dioctyl sebacate, dodecyl oleate, ethylhexyl palmitate,
ester derivatives of lanolic acid, ethylhexyl cocoate, ethylhexyl
ethylhexanoate, ethylhexyl hydroxystarate, ethylhexyl isononanoate,
ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexyl stearate,
hexadecyl stearate, hexyl laurate, isoamyl laurate, isocetyl
isocetyl behenate, isocetyl lanolate, isocetyl palmitate, isocetyl
stearate, isocetyl salicylate, isocetyl stearate, isocetyl stearoyl
stearate, isocetearyl octanoate, isodecyl ethylhexanoate, isodecyl
isononanoate, isodecyl oleate, isononyl isononanoate, isodecyl
oleate, isohexyl decanoate, isononyl octanoate, isopropyl
isostearate, isopropyl lanolate, isopropyl laurate, isopropyl
myristate, isopropyl palmitate, isopropyl stearate, isostearyl
behenate, isosteary citrate, isostearyl erucate, isostearyl
glycolate, isostearyl isononanoate, isostearyl isostearate,
isostearyl lactate, isostearyl linoleate, isostearyl linolenate,
isostearyl malate, isostearyl neopentanoate, isostearyl palmitate,
isosteary salicylate, isosteary tartarate, isotridecyl
isononanoate, isotridecyl isononanoate, lauryl lactate, myristyl
lactate, myristyl myristate, myristyl neopentanoate, myristyl
propionate, octyldodecyl myristate, neopentylglycol dicaprate,
octyl dodecanol, octyl stearate, octyl palmitate, octyldodecyl
behenate, octyldodecyl hydroxystearate, octyldodecyl myristate,
octyldodecyl stearoyl stearate, oleyl erucate, oleyl lactate, oleyl
oleate, propyl myristate, propylene glycol myristyl ether acetate,
propylene glycol dicaprate, propylene glycol dicaprylate, propylene
glycol dicaprylate, maleated soybean oil, stearyl caprate, stearyl
heptanoate, stearyl propionate, tocopheryl acetate, tocopheryl
linoleate, glyceryl oleate, tridecyl ethylhexanoate, tridecyl
isononanoate and triisocetyl citrate.
[0212] Non-limiting examples of triglycerides and oils of plant
origin include alexandria laurel tree oil, avocado oil, apricot
stone oil, barley oil, borage seed oil, calendula oil, canelle nut
tree oil, canola oil, caprylic/capric triglyceride castor oil,
coconut oil, corn oil, cotton oil, cottonseed oil, evening primrose
oil, flaxseed oil, groundnut oil, hazelnut oil, glycereth
triacetate, glycerol triheptanoate, glyceryl trioctanoate, glyceryl
triundecanoate, hempseed oil, jojoba oil, lucerne oil, maize germ
oil, marrow oil, millet oil, neopentylglycol dicaprylate/dicaprate,
olive oil, palm oil, passionflower oil, pentaerythrityl
tetrastearate, poppy oil, propylene glycol ricinoleate, rapeseed
oil, rye oil, safflower oil, sesame oil, shea butter, soya oil,
soybean oil, sweet almond oil, sunflower oil, sysymbrium oil,
syzigium aromaticum oil, tea tree oil, walnut oil, wheat germ
glycerides and wheat germ oil.
[0213] Non-limiting examples of PPG alkyl ethers include PPG-2
butyl ether, PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl
ether, PPG-12 butyl ether, PPG-14 butyl ether, PPG-15 butyl ether,
PPG-15 stearyl ether, PPG-16 butyl ether, PPG-17 butyl ether,
PPG-18 butyl ether, PPG-20 butyl ether, PPG-22 butyl ether, PPG-24
butyl ether, PPG-26 butyl ether, PPG-30 butyl ether, PPG-33 butyl
ether, PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether,
PPG-10 cetyl ether, PPG-28 cetyl ether, PPG-30 cetyl ether, PPG-50
cetyl ether, PPG-30 isocetyl ether, PPG-4 lauryl ether, PPG-7
lauryl ether, PPG-2 methyl ether, PPG-3 methyl ether, PPG-3
myristyl ether, PPG-4 myristyl ether, PPG-10 oleyl ether, PPG-20
oleyl ether, PPG-23 oleyl ether, PPG-30 oleyl ether, PPG-37 oleyl
ether, PPG-40 butyl ether, PPG-50 oleyl ether and PPG-11 stearyl
ether. Preferred PPG alkyl ethers according to the present
invention include PPG-15 stearyl ether, PPG-2 butyl ether and
PPG-9-13 butyl ether.
[0214] Non-limiting examples of oils from animal origin include
herring oil, cod-liver oil and salmon oil.
[0215] The hydrophobic solvent may be an emollient, i.e., a
hydrophobic liquid having a softening or soothing effect especially
to the skin. In some embodiments the liquid oil may contain a solid
or semi solid hydrophobic matter at room temperature.
[0216] Essential oil, which is usually a concentrated, hydrophobic
liquid containing volatile aroma compounds from plants usually
conveying characteristic fragrances. Non limiting examples include
lavender, peppermint, and eucalyptus. A therapeutic oil is a
hydrophobic liquid which is said to have a therapeutic effect or to
have associated with it certain healing properties. Therapeutic
oils contain active biologically occurring molecules and, upon
topical application, exert a therapeutic effect. Non limiting
examples include manuka oil, rosehip oil, which contains retinoids
and is known to reduce acne and post-acne scars, and tea tree oil,
which possesses anti-microbial activity including antibacterial,
antifungal and antiviral properties as well as any other
therapeutically beneficial oil known in the art of herbal
medication. Many essential oils, are considered "therapeutic oils."
Other non limiting examples of essential oils are basil, camphor,
cardamom, carrot, citronella, clary sage, clove, cypress,
frankincense, ginger, grapefruit, hyssop, jasmine, lavender, lemon,
mandarin, marjoram, myrrh, neroli, nutmeg, petitgrain, sage,
tangerine, vanilla and verbena,
[0217] Some embodiments include silicone oils. Non-limiting
examples of silicone oils include a cyclomethicone, a dimethicone,
a polyalkyl siloxane, a polyaryl siloxane, a polyalkylaryl
siloxane, a polyether siloxane copolymer, a
poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer, a dimethyl
polysiloxane, an epoxy-modified silicone oil, a fatty acid-modified
silicone oil, a fluoro group-modified silicone oil, a
methylphenylpolysiloxane, phenyl trimethicone and a polyether
group-modified silicone oil. In some embodiments, the silicone oil
is cyclomethicone, cyclotetrasiloxane, cyclohexasiloxane,
phyenyltrimethicone, Dow corning 246 Fluid (d6+d5)
(cyclohexasiloxane & cyclopentasiloxane), Dow Corning 244 Fluid
(cyclotetrasiloxane), Cyclomethicone 5-NF (cyclopentasiloxane),
stearyl dimethicone, phenyltrimethicone, cetyl dimethicone,
caprylyl methicone, PEG/PPG 18/18 dimethicone, or dimethiconol.
[0218] In one or more embodiments, the hydrophobic solvent may be
selected from cyclomethicone; isopropyl myristate, PPG-15 stearyl
ether; octyldodecanol; isohexadecanol, diisopropyl adipate;
cetearyl octanoate; hydrogenated castor oil; MCT oil; heavy mineral
oil; light mineral oil; coconut oil and soybean oil, castor oil,
cocoglycerides, disopropyl adipate, beeswax, isododecane, gelled
mineral oil, white petrolatum, petrolatum, paraffin 51-53,
calendula oil, shea butter, grape seed oil, almond oil, jojoba oil,
avocado oil, peanut oil, and hard fat and combination thereof.
[0219] Mixtures of two or more hydrophobic solvents in the same
composition is contemplated. Furthermore, in certain embodiments,
the use of mixtures of two or more hydrophobic solvents is
preferred.
[0220] Yet, in certain embodiments, the hydrophobic solvent is a
mixture of one or more liquid hydrophobic solvents, as listed
above, which an additional hydrophobic substance, which is not
liquid (such as petrolatum), provided that the mixture of all
hydrophobic substances (excluding the oleaginous foamer complexes),
is liquid at ambient temperature. In an embodiment the resultant
mixture upon including propellant is liquid at ambient temperature.
For example petrolatum may be added to provide a degree of
occlusivity so that the formulation when applied to a skin surface
can operate to increase skin moisture and/or reduced transdermal
water loss. In certain other embodiments fluidity of the
composition can be achieved by utilizing liquidizing solvents (e.g.
C12 C15 Alkyl benzoate) and/or liquefied propellants and/or
optionally liquid adjuvants. Inclusion of higher amounts of
propellant was found useful in order to improve flowability of the
formulation from the canister or by using propellants having a
higher vapor pressure.
Composition Components
[0221] The composition components comprise: a carrier, a first
rheology modulator and a second rheology modifier. The carrier can
comprise, for example a hydrophobic solvent. In one or more
embodiments the carrier can comprise about 60% to about 95% by
weight of the composition. The first rheology modulator is a
therapeutic rheology modulator. In one or more embodiments it can
comprise about 0.001% to about 30% by weight of the composition.
The second rheology modulator comprises a fatty alcohol; a fatty
acid; a wax and mixtures thereof. In one or more embodiments it can
comprising about 0.1% to about 20% by weight of a fatty alcohol;
and/or about 0.1% to about 20% by weight of a fatty acid; and/or a
wax and a third member which is a active agent. In one or more
embodiments the carrier is present at a concentration of about 60%
to about 95% or about 65% to about 90%; or about 70% to about 90%
or about 75% to about 85%. In certain embodiments the amount of the
second rheology modulator comprises about 0.4% to about 18% by
weight. In certain embodiments the amount of the second modulator
comprises about 0.6% to about 12% by weight. In certain embodiments
the amount of the second modulator comprises about 0.8% to about
10% by weight. In certain embodiments the amount of the second
modulator comprises about 2% to about 7% by weight. In certain
other embodiments, the concentration of the second modulator can be
within any one of the following ranges (i) between about 0.1% and
about 1%, (ii) between about 1% and about 5%, (iii) between about
5% and about 10%, or (iv) between about 10% and about 20%. In one
or more embodiments, each member is at a concentration at about 5%
to about 10% by weight. In one or more embodiments the amount of
the first modulator is present at a concentration of less than
about 1%, or less than about 0.5%, or less than about 0.1%, or less
than about 0.01%
Second Rheology Modulators
[0222] The second rheology modulator (waxes, fatty alcohols and
fatty acids) may be solids semi-solids or liquids. Unlike aqueous
liquids, which are rather easy to solidify due to their hydrogen
bond forming ability, oils are difficult to solidify.
Fatty Alcohol
[0223] In an embodiment, the second rheology modulator includes a
fatty alcohol. The fatty alcohol which acts as an adjuvant is
included in the gel and foamable compositions as a main
constituent, to evolve the solidifying effect of the gel and/or the
foaming property of the composition and/or to stabilize the foam.
In one or more embodiments, the fatty alcohol is selected from the
group consisting of fatty alcohols having 15 or more carbons in
their carbon chain, such as cetyl alcohol and stearyl alcohol (or
mixtures thereof). In one or more embodiments, the fatty alcohol is
selected from the group consisting of fatty alcohols having 14 or
more carbons in their carbon chain, such as myristyl alcohol (with
14 carbons). Other examples of fatty alcohols are arachidyl alcohol
(C20), behenyl alcohol (C22), tetracosanol, hexacosanol,
octacosanol, triacontanol, tetratriacontanol, 1-triacontanol (C30),
as well as alcohols with longer carbon chains (up to C50). In one
or more preferred embodiments, the fatty alcohol is myristyl
alcohol, cetyl alcohol, stearyl alcohol and combinations thereof.
Fatty alcohols, derived from beeswax and including a mixture of
alcohols, a majority of which has at least 20 carbon atoms in their
carbon chain, are suitable as fatty alcohols in the context herein.
In certain embodiments the amount of the fatty alcohol required to
support the foam system can be approximately inversely related to
the length of its carbon chains. In one or more other embodiments,
the fatty alcohol is selected from the group consisting of fatty
alcohols having 14 or less carbons in their carbon chain, such as
myristyl alcohol or lauryl alcohol. In an embodiment the fatty
alcohol is a solid at room temperature. Fatty alcohols are also
useful in facilitating improved spreadability and absorption of the
composition.
[0224] Fatty alcohols are amphiphatic, however unlike customary
surfactants, they do not usually function as stand-alone
surfactants, because of their very weak emulsifying capacity. They
are occasionally used as non-ionic co-emulsifiers, i.e., and are
commonly used as thickeners (Surfactants in personal care products
and decorative cosmetics By Linda D. Rhein, Mitchell Schlossman,
Anthony O'Lenick, P., Third Edition, 2006, p. 247). Fatty alcohols
are generally regarded as safe and they are not considered as
irritants.
[0225] An important property of the fatty alcohols used in context
of the composition disclosed herein is related to their therapeutic
properties per se. Long chain saturated and mono unsaturated fatty
alcohols, e.g., stearyl alcohol, erucyl alcohol, arachidyl alcohol
and behenyl alcohol (docosanol) have been reported to possess
antiviral, anti-infective, antiproliferative and anti-inflammatory
properties. Longer chain fatty alcohols, e.g., tetracosanol,
hexacosanol, heptacosanol, octacosanol, triacontanol, etc., are
also known for their metabolism modifying properties and tissue
energizing properties.
Fatty Acid
[0226] In an embodiment, the second rheology modulator further
includes a fatty acid. The fatty acid which acts as an adjuvant is
included in the gel and foamable compositions to evolve solidifying
effect of the gel and/or the foaming property of the composition
and/or to stabilize the foam. In one or more embodiments the fatty
acid can have 16 or more carbons in its carbon chain, such as
hexadecanoic acid (C16), heptadecanoic acid, stearic acid (C18),
arachidic acid (C20), behenic acid (C22), tetracosanoic acid (C24),
hexacosanoic acid (C26, heptacosanoic acid (C27), octacosanoic acid
(C28), triacontanoic acid, dotriacontanoic acid, tritriacontanoic
acid, tetratriacontanoic acid and pentatriacontanoic acid as well
as fatty acids with longer carbon chains (up to C50), or mixtures
thereof. In one or more other embodiments, the fatty acid is
selected from the group consisting of fatty acids having 14 or less
carbons in their carbon chain, such as dodecanoic acid, myristic
acid, myristoleic acid, and lauric acid.
[0227] In certain embodiments, the carbon atom chain of the fatty
acid may have at least one double bond; alternatively, the fatty
acid can be a branched fatty acid. The carbon chain of the fatty
acid also can be substituted with a hydroxyl group, such as
12-hydroxy stearic acid. In an embodiment the fatty alcohol is a
solid at room temperature. In one or more preferred embodiments,
the fatty acid is stearic acid.
Waxes
[0228] In certain embodiments the oleaginous second rheology
modulator may include a wax. The wax which acts as an adjuvant in a
gel and is included in the gel or foamable compositions to evolve
solidifying effect of the gel and/or the foaming property of the
composition and/or to stabilize the foam. Wax refers to beeswax or
another substance with similar properties. The term wax refers to a
class of substances with properties similar to beeswax, in respect
of (i) plastic behavior at normal ambient temperatures, a melting
point above approximately 45.degree. C., (iii) a relatively low
viscosity when melted (unlike many plastics); and (iv) hydrophobic
nature. Suitable exemplary waxes which can be incorporated into the
formulation include animal, vegetable, mineral or silicone based
waxes which may be natural or synthetic such as, for example:
beeswax, chinese wax, lanolin (wool wax), shellac wax, bayberry
wax, candelilla wax, carnauba wax, castor wax, esparto wax, japan
wax, ouricury wax, rice bran wax, soy wax, hydrogenated oil such
ashydrogenated castor oil, hydrogenated cottonseed oil, or
hydrogenated jojoba oil, mink wax, motan wax, ouricury wax,
ozokerite, PEG-6 beeswax, rezowax, spent grain wax, stearyl
dimethicone, paraffin waxes, such as paraffin 58-62.degree. C.,
paraffin 51-53.degree. C. wax, paraffin 42-44.degree. C. wax, and
the like and mixtures thereof. In certain embodiments the term wax
can extend to hydrogenated oils. In one or more embodiments the wax
is selected from a list comprising of a solid wax, an animal wax, a
vegetable wax, a mineral wax, a natural wax or a synthetic wax. In
certain embodiments the term wax can extend to hydrogenated oils.
In an embodiment wax includes polyolefins. In one or more preferred
embodiments, the wax is a beeswax or hydrogenated castor oil.
[0229] In one or more embodiments, the wax is a polyolefin such as
polyethylene, polypropylene, polymethylpentene, polybutene, a
polyolefin elastomer, polyisobutylene, ethylene propylene rubber,
ethylene propylene diene Monomer (M-class) rubber, polyethylene
terephthalate, polydicyclopentadiene, linear polyolefins, branched
polyolefins, cyclic polyolefins, low density polyolefins, high
density polyolefins, polyolefins with a low molecular weight,
polyolefins with a high molecular weight, halogenated polyolefins
and the like and mixture thereof.
Combination of a Fatty Alcohol or a Fatty Acid and/or a Wax
Together with a Therapeutic Active Agent
[0230] Example 2 describes formulations where adding an active
agent to oleaginous hydrophobic solvents does not affect viscosity
of the formulation. When, however, the same formulation contains a
fatty alcohol (or a mixture of fatty alcohols) or a fatty acid (or
a mixture of fatty acids) or a wax (or a mixture of waxes), or a
combination of a fatty alcohol with a wax or a fatty acid with a
wax the therapeutic active agent can, surprisingly, act
synergistically to produce enhanced viscosity (Example 4). These
successful combinations of an active agent and a fatty alcohol or a
fatty acid or a wax or alternatively an active agent and a fatty
alcohol and/or a wax or a fatty acid and/or wax are referred to
herein as "viscosity inducing complexes".
[0231] In one or more embodiments, the viscosity inducing complex
is a synergistic combination of an active agent and a fatty alcohol
(or a mixture of fatty alcohols) or a fatty acid (or a mixture of
fatty acids) or a wax or alternatively an active agent and a fatty
alcohol (or a mixture of fatty alcohols) and/or a wax (or a mixture
of waxes) or alternatively an active agent and a fatty acid (or a
mixture of fatty acids) and/or a wax (or a mixture of waxes).
[0232] In one or more embodiments, the viscosity inducing complex
is a synergistic combination of a fatty alcohol (or a mixture of
fatty alcohols) and a wax (or a mixture of waxes).
[0233] In one or more embodiments, the viscosity inducing complex
is a synergistic combination of a fatty acid (or a mixture of fatty
acids) and a wax (or a mixture of waxes).
[0234] In one or more embodiments the range of ratio of fatty
alcohol to wax or fatty acid to wax can be about 100:1 to about
1:100; or about 90:1 to about 1:45; or about 80:1 to about 1:40; or
about 70:1 to about 1:35; or about 60:1 to about 1:30; or about
50:1 to about 1:25; or about 40:1 to about 1:20; or about 30:1 to
about 1:15; or about 20:1 to about 1:10; or about 15:1 to about
1:5; or about 10:1 to about 1:1; or any ranges in between such as
1:20 to 20:1, or preferably from 1:10 to 10:1.
[0235] In one or more embodiments the range of ratio of therapeutic
soluble active agent to second rheology modulator can be about
1:50000 to about 250:1; or about 1:25000 to about 1:150; or about
1:10000 to about 100:1; or about 1:5000 to about 50:1; or about
1:2500 to about 1:25; or about 1:1000 to about 10:1; or about 1:100
to about 1:1; or about 1:10 to about 10:1 or any ranges in
between.
Propellant
[0236] Certain compositions comprising a hydrophobic solvent,
together with a first rheology modulator (a suspended active agent)
and a second rheology modulator without any surface active agents
result, upon packaging in an aerosol container and adding a
propellant, a shakable and homogenous foamable composition, which
releases a breakable foam with good to excellent quality (as
defined herein).
[0237] Suitable propellants include volatile hydrocarbons such as
butane, propane, isobutene or mixtures thereof. In one or more
embodiments a hydrocarbon mixture AP-70 is used. In one or more
other embodiments a lower pressure hydrocarbon mixture AP-46 is
used. Both contain butane, propane, isobutene although in different
proportions. AP-70 is composed of about 50% w/w of propane, about
20% w/w of isobutane and about 30% w/w of propane. AP-46 is
composed of about 16% w/w of propane, about 82% w/w of isobutane
and about 2% w/w of propane Hydrofluorocarbon (HFC) propellants are
also suitable as propellants in the context disclosed herein.
Exemplary HFC propellants include 1,1,1,2 tetrafluorethane (Dymel
134), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227). Dimethyl
ether is also useful. In one or more embodiments use of compressed
gases (e.g., air, carbon dioxide, nitrous oxide, and nitrogen) is
also possible.
[0238] In one or more embodiments a combination of at least two
propellants, selected from HFC, hydrocarbon propellants, dimethyl
ether and compressed gases is contemplated.
[0239] Yet, in additional embodiments, the propellant is a
self-foaming propellant, i.e., a volatile liquid having a boiling
point of less than the temperature of the target treatment site
(such as the skin). An example of a post-foaming propellant is
isopentane (bp=26.degree. C.)
[0240] Any concentration of the propellant, which affords an
acceptable foam is useful in accordance with the present invention.
In certain embodiments the propellant makes up between about 1% and
about 30% of the foamable composition, or about 3% and 25%,
preferably between about 5% and about 16% of the composition. In
other certain embodiments, the concentration of the propellant is
about 7% to about 17%; or about 10% to about 14% by weight of the
total composition. The percent by weight is based on weight
foamable composition. In preparing the formulations the ingredients
other than propellant are combined to 100% and the propellant is
added thereafter so that the ratio of formulation other than
propellant to propellant can range from 100:1 to 100:30 or from
about 100:3 to about 100:25; or from about 100:4 to about 100:24;
or from about 100:7 to about 100:17; or from about 100:10 to about
100:14 or preferably 100:5 to 100:16. Yet, in additional
embodiments, the ratio of composition other than propellant to
propellant is between about 100:20 and about 100:50.
[0241] In one or more embodiments the propellant can also be used
to expel formulation using a bag in can system or a can in can
system as will be appreciated by someone skilled in the art. In
certain embodiments the part of the propellant system is in the
formulation and part separate from the formulation. In this way it
is possible to reduce the amount of surfactant in the formulation
but still provide good expulsion from the canister, where the
foamable formulation is expelled quickly but without jetting or
noise.
[0242] In one or more embodiments a foam formulation is expelled
from a standard pressurized canister where the propellant is part
of formulation. Formulations can be expelled or helped to be
expelled by using propellant which is separate from the formulation
using a bag in can or can in can system. Although, these systems
can be used with compressed air the pressure may not be sufficient
to expel the formulation through the device and higher pressure
propellant such as AP70 should be selected. In one or more
embodiments, the formulation is packaged in bag in can systems or
in can in can system. In one or more embodiments, the formulation
is expelled from the canister using the pressure provided by the
propellant mixed with the formulation. In one or more embodiments,
the formulation is expelled from the canister using the pressure
provided by the propellant stored in a compartment surrounding the
formulation. According to other embodiments part of the propellant
system is in the formulation and part of the propellant system is
separate from the formulation, which is used to expel said
formulation using a bag or can in can system. In this way it is
possible to reduce the amount of propellant within the formulation
and avoid unwanted gaseous effects, for example in vaginal
applications, but still provide good expulsion from the canister,
where the foamable formulation is expelled sufficiently quickly but
without jetting or noise. So by way of example, between about 1% to
3%; or between about 2% to 4%; between about 3% to 5% propellant
(ratio of formulation to propellant of 100:1 to 3; 100:2 to 4;
100:3 to 5; respectively) is part of the formulation and a further
amount of propellant is separate form the formulation and helps
expel the formulation. In one or more embodiments a similar amount
of propellant is in the formulation and a pump or other mechanical
means is used to provide the additional expulsion force.
[0243] In one or more embodiments there is provided a composition
comprising a propellant having a vapor pressure between about 10
psi and about 130 psi. In one or more embodiments there is provided
a composition comprising a propellant which is hydrocarbon
propellant or a hydrofluorocarbon or another environmentally
acceptable propellant.
[0244] In an embodiment foam quality may be improved by increasing
the propellant, by say aliqots of 2% or 4%, for example, from 8% to
about 12%. The actual amount of propellant increase that is
suitable should be titrated from formulation to formulation.
Stability Modulating Agent
[0245] In one or more embodiments a stability modulating agent is
used in a waterless or substantially waterless composition. The
term stability modulating agent is used to describe an agent which
can improve the stability of, or stabilize a carrier or a foamable
composition and/or an active agent by modulating the effect of a
substance or residue present in the carrier or composition. The
substance or residue may, for example, be acidic or basic or buffer
system (or combinations thereof) and potentially alter an
artificial pH in a waterless or substantially non-aqueous
environment, such as, by acting to modulate the ionic or polar
characteristics and any pH balance of a waterless or substantially
non-aqueous carrier, composition, gel, foamable carrier or foamable
composition or resultant foam or it may be a chelating or
sequestering or complexing agent or it may be one or more metal
ions which may act as a potential catalyst in a waterless or
substantially non-aqueous environment or it may be an ionization
agent or it may be an oxidizing agent.
Dermatologic Excipients
[0246] In one or more embodiments the formulation may comprise
excipients that are suitable for dermatologic use. In one or more
embodiments, the hydrophobic carrier composition further contains
an anti-infective agent, selected from the group of an antibiotic
agent, an antibacterial agent, an antifungal agent, an agent that
controls yeast, an antiviral agent and an antiparasitic agent. In a
preferred embodiment the anti infective agent comprises a
tetracycline antibiotic. As has been previously shown in U.S.
Provisional Application No. 61/248,144 filed Oct. 2, 2009 and
titled "Surfactant-Free Water-Free Foamable Compositions, Breakable
Foams And Their Uses," and in U.S. Provisional Application No.
61/322,148 filed Apr. 8, 2010 and titled "Surfactant-Free
Water-Free Foamable Compositions, Breakable Foams And Gels And
Their Uses," which are incorporated herein in their entirety by
reference, combining the anti-infective effect of a hydrophobic
carrier composition, with an anti-infective agent can result in a
synergistic effect increasing the anti-infective effect and
consequently higher success rate of the treatment is attained.
According to the present application it has surprisingly been shown
that combination of an active agent with second rheology modulator
achieves a viscous formulation in which the active pharmaceutical
ingredient is chemically stable and the formulation is physically
stable as demonstrated herein in the Examples. Moreover the use of
hydrophobic based water free formulation has been previously shown
in said provisional application to maximize the antimicrobial
potential of the formulations. Storage in sealed, light and
airtight canisters can assist in preserving the formulations.
Ophthalmic Excipients
[0247] In one or more embodiments the formulation may comprise
excipients that are suitable for ophthalmic use. By virtue of their
suitability for ophthalmic use they may in certain embodiments be
applicable on other sensitive targets such as for use internal
and/or external wounds or burns or in body cavities. Excipients
selected as part of a drug carrier that can be used with the active
pharmaceutical ingredients are identified by compatibility studies
with active ingredients to ascertain which are compatible for use
with the active pharmaceutical agents, for example, by examining
which do not react with and/or promote break down of the active
pharmaceutical ingredients. Oleaginous ointments are viscous
preparations, which remain viscous when applied to the skin or
other body surfaces; and they require extensive rubbing. Because of
their viscosity, eye ointments cause blurred vision and consequent
low tolerability, especially for long term treatment. Because of
their high viscosity, drugs are trapped in the vehicle and cannot
migrate through to their target site of action, for example, the
skin or the eye.
[0248] Liquid, non viscous oleaginous medications are also
disadvantageous, as they spill easily and thus, are very
inconvenient to use. In eye treatment, liquid drops are difficult
to apply and they require lying on the back at rest for accurate
administration. Furthermore, because of their low viscosity, liquid
oil vehicles cannot carry suspended drugs, which tend to
precipitate and if the viscosity is not high enough, thereby
impairing the uniformity of the therapeutic product.
[0249] In one or more embodiments the formulations are not highly
viscous; and they may be flowable. In one or more embodiments the
formulations are thixotropic so that on application of shear force
their viscosity decreases and they become more flowable. In one or
more embodiments the formulations are foams which are breakable on
shear force. In one or more embodiments the foams are based on gel
formulations, which are thixotropic so that on application of shear
force their viscosity decreases and they become more flowable. In
one or more embodiments the viscosity of the formulation prior to
addition of propellant is more than about 1000 cPs and less than
about 25,000 cPs.
Additional Components
[0250] In an embodiment, a composition disclosed herein includes
one or more additional components. Such additional components
include but are not limited to anti perspirants, anti-static
agents, bulking agents, cleansers, colorants, skin conditioners,
deodorants, diluents, dyes, fragrances, hair conditioners, herbal
extracts, humectants, keratolytic agents, modulating agents,
pearlescent aids, perfuming agents, pH modifying or stabilizing
agents, skin penetration or permeation enhancers, softeners,
solubilizers, sunscreens, sun blocking agents, sunless tanning
agents, viscosity modifiers, flavanoids and vitamins. As is known
to one skilled in the art, in some instances a specific additional
component may have more than one activity, function or effect.
[0251] In certain embodiments, the additional component is an oil
soluble preservative, or an oil soluble antioxidant, or an oil
soluble radical scavenger, or an oil soluble complexing agent, or
an oil soluble pigment or dye.
Definitions
[0252] All % values are provided on a weight (w/w) basis.
[0253] By the term "about" herein it is meant as indicated above
and that a figure or range of figures can vary in an embodiments
plus or minus up to 30%. So in this embodiment if a figure of
"about 1" is provided then the amount can be up to 1.3 or from
0.70. In other embodiments it can reflect a variation of plus or
minus 20%. In still further embodiments it can describe a variation
of plus or minus 10%. In still further embodiments it can describe
a variation of plus or minus 5%. As will be appreciated by one of
the art there is some reasonable flexibility in formulating
compositions such that where one or more ingredients are varied
successful formulations may still be made even if an amount falls
slightly outside the range. Therefore, to allow for this
possibility amounts are qualified by about. In one or more other
embodiments the figures may be read without the prefix about.
[0254] The term "thixotropic," as used herein, means that the
formulation shows a significant decrease in viscosity upon
application of shear force.
[0255] The term "waterless," as used herein, means that the
composition contains no, or substantially no, free or unassociated
or absorbed water. Similarly, "waterless" or "substantially
waterless" carriers contain at most incidental and trace amounts of
water.
[0256] By the term "single phase" herein it is meant that the
liquid components of the composition or carrier are fully miscible,
and the solid components if any, are either dissolved or suspended
in the composition. By substantially a single phase is meant that
the composition or carrier is primarily or essentially a single
phase as explained above, but may also have present a small amount
of material which is capable of forming or may form a separate
phase amounting to less than about 5% of the composition or
carrier, preferably less than about 3%, and more preferably less
than about 1%. By the term "single phase" or "substantially a
single phase" in the context of a foamable composition the above
meaning applies even after addition of propellant to the
composition or carrier.
[0257] The term "unstable active agent" as used herein, means an
active agent which is oxidized and/or degraded within less than a
day, and in some cases, in less than an hour upon exposure to air,
light, skin or water under ambient conditions.
[0258] The term "co-surfactant" as used herein, means a molecule
which on its own is not able to form and stabilize satisfactorily
an oil in water emulsion but when used in combination with a
surfactant the co-surfactant has properties, which can allow it to
help surfactants to create an emulsion and can boost the
stabilizing power or effect of the surfactant and can include, for
example, a fatty alcohol, such as cetyl alcohol or a fatty acid
such as stearic acid. Cetyl alcohol is a waxy hydrophobic substance
that can be emulsified with water using a surfactant. Some
substances may have more than one function and for example, fatty
alcohols can in some formulations act as a co-solvent. In certain
circumstances a co-surfactant can itself be converted in to a
surfactant or soap by, for example, adding a base, such as,
triethanolamine to a fatty acid like stearic acid.
[0259] The identification of a "polyol", as used herein, is an
organic substance that contains at least two hydroxy groups in its
molecular structure.
[0260] In one or more embodiments, the polyol is a diol (a compound
that contains two hydroxy groups in its molecular structure).
Examples of diols include propylene glycol (e.g., 1,2-propylene
glycol and 1,3-propylene glycol), butanediol (e.g., 1,2-butanediol,
1,3-butanediol, 2,3-butanediol and 1,4-butanediol), butanediol
(e.g., 1,3-butanediol and 1,4-butenediol), butynediol, pentanediol
(e.g., pentane-1,2-diol, pentane-1,3-diol, pentane-1,4-diol,
pentane-1,5-diol, pentane-2,3-diol and pentane-2,4-diol),
hexanediol (e.g., hexane-1,6-diol hexane-2,3-diol and
hexane-2,56-diol), octanediol (e.g., 1,8-octanediol), neopentyl
glycol, 2-methyl-1,3-propanediol, diethylene glycol, triethylene
glycol, tetraethylene glycol, dipropylene glycol and dibutylene
glycol.
[0261] In one or more embodiments, the polyol is a triol (a
compound that contains three hydroxy groups in its molecular
structure), such as glycerin, butane-1,2,3-triol,
butane-1,2,4-triol and hexane-1,2,6-triol.
[0262] In one or more embodiments, the polyol is a saccharide.
Exemplary saccharides include, but are not limited to
monosaccharide, disaccharides, oligosaccharides and sugar
alcohols.
[0263] A monosaccharide is a simple sugar that cannot be hydrolysed
to smaller units. Empirical formula is (CH2O)n and range in size
from trioses (n=3) to heptoses (n=7). Exemplary monosaccharide
compounds are ribose, glucose, fructose and galactose.
[0264] Disaccharides are made up of two monosaccharides joined
together, such as sucrose, maltose and lactose.
[0265] In one or more embodiments, the polyol is a sugar alcohol
(also known as a polyol, polyhydric alcohol, or polyalcohol) is a
hydrogenated form of saccharide, whose carbonyl group (aldehyde or
ketone, reducing sugar) has been reduced to a primary or secondary
hydroxyl group. They are commonly used for replacing sucrose in
foodstuffs, often in combination with high intensity artificial
sweeteners to counter the low sweetness. Some exemplary sugar
alcohols, which are suitable for use according to the present
application are mannitol, sorbitol, xylitol, maltitol, lactitol.
(Maltitol and lactitol are not completely hydrogenated
compounds--they are a monosaccharide combined with a polyhydric
alcohol.) Mixtures of polyols, including (1) at least one polyol
selected from a diol and a triol; and (2) a saccharide are
contemplated within the scope of the present disclosure.
[0266] According to some embodiments, the composition is polyol
free i.e., free of polyols. In other embodiments, the composition
is substantially free and comprises less than about 5% final
concentration of polyols, preferably less than 2%, more preferably
less than 1%. Where a formulation includes insignificant amounts of
polyols it is considered to be essentially free of them.
[0267] In an embodiment, the polyol is linked to a hydrophobic
moiety. In the context of the present disclosure, a polyol linked
to a hydrophobic moiety is still defined as a "polyol" as long as
it still contains two or more free hydroxyl groups.
[0268] In an embodiment, the polyol is linked to a hydrophilic
moiety. In the context of the present disclosure, a polyol linked
to a hydrophilic moiety is still defined "polyol" as long as it
still contains two or more free hydroxyl groups.
[0269] The term "water activity" as used herein, activity
represents the hydroscopic nature of a substance; or the tendency
of a substance that absorbs water from its surroundings.
Microorganisms require water to grow and reproduce, and such water
requirements are best defined in terms of water activity of the
substrate. The water activity of a solution is expressed as
Aw=P/Po, where P is the water vapor pressure of the solution and Po
is the vapor pressure of pure water at the same temperature. Every
microorganism has a limiting Aw, below which it will not grow;
e.g., for Streptococci, Klebsiella spp, Escherichia coli,
Clostridium perfringens, and Pseudomonas spp, the Aw value is 0.95.
Staphylococcus aureus is most resistant and can proliferate with an
Aw as low as 0.86, and fungi can survive at Aw of at least 0.7. In
one or more embodiments, the concentration of the hydrophobic
solvent, and/or second rheology modulator in the composition is
selected to provide an Aw value selected from the ranges of (1)
about 0.8 and about 0.9; (2) about 0.7 and about 0.8; and (3) less
than about 0.7. By delivering the formulation in a pressurized
package does not allow for humidity to be absorbed by the
preparation, and therefore, the water free character of the
composition cannot be damaged.
[0270] In an embodiment no preservative is added because the
formulation is a waterless hydrophobic solvent or oil-based
formulation having an Aw (Water Activity) value of less than 0.9,
less, or less than about 0.8, or less than about 0.7 or less than
about 0.6 and preferably less than about 0.5 which is below the
level of microbial proliferation.
[0271] The identification of a "solvent," as used herein, is not
intended to characterize the solubilization capabilities of the
solvent for any specific active agent or any other component of the
composition. Rather, such information is provided to aid in the
identification of materials suitable for use as a part in the
carriers described herein.
Substantially Alcohol Free
[0272] Lower or short chain alcohols, having up to 5 carbon atoms
in their carbon chain skeleton, such as ethanol, propanol,
isopropanol, butanol, iso-butanol, t-butanol and pentanol are
considered less desirable solvents or co-solvents due to their
skin-irritating effect. Thus, according to some embodiments, the
composition is substantially alcohol-free i.e., free of short chain
alcohols. In other embodiments, the composition comprises less than
about 5% final concentration of lower alcohols, preferably less
than 2%, more preferably less than 1%. Where a formulation contains
insignificant amounts of short chain alcohols it is considered to
be essentially free of them.
Substantially Standard Surfactant Free
[0273] Surfactants have been categorized in to various sub classes
depending on there ionic characteristics, namely non-ionic
surfactants, anionic, cationic, zwitterionic, amphoteric and
amphiphilic surfactants. The term surfactant has been often loosely
used in the art to include substances which do not function
effectively as stand alone surfactants to reduce surface tension
between two substances or phases. Reduction of surface tension can
be significant in foam technology in relation to the ability to
create small stable bubbles. For example fatty alcohols, fatty
acids and certain waxes are amphiphatic, are essentially
hydrophobic with a minor hydrophilic region and for the purposes of
forming an emulsion unlike standard or customary surfactants, are
not effective as stand-alone surfactants in foamable emulsion
compositions, because of their very weak emulsifying capacity on
their own. They are occasionally used in a supporting role as
co-emulsifiers, i.e., in combination with a standard surfactant but
are commonly used as thickeners and have successfully been used as
foam adjuvants to assist customary surfactants to boost foam
quality and stability. For clarification in the context herein
whilst the term "standard surfactant" or "customary surfactant"
refers herein to customary non-ionic, anionic, cationic,
zwitterionic, amphoteric and amphiphilic surfactants a fatty
alcohol or a fatty acid and certain waxes are not regarded as a
standard surfactant. However, in contrast, an ether or an ester
formed from such fatty alcohols or fatty acids can be regarded as a
customary surfactant. Many standard surfactants are, derivatives of
fatty alcohols or fatty acids, such as an ethers or an esters
formed from such fatty alcohols or fatty acids with hydrophilic
moieties, such as polyethyleneglycol (PEG) can be regarded as a
customary surfactant. However, a native, (non derivatized) fatty
alcohols or a fatty acids, or as well as waxes are not regarded as
a standard surfactant.
[0274] Generally, surfactants are known to possess irritation
potential. One way that is used to try and reduce potential
irritation and drying of the skin or mucosa due to surfactants and
their repeated use especially when formulations are to be left on
the skin or mucosa rather than being washed off is to use
essentially or primarily non ionic surfactants at preferably low
concentrations below 5%. The current breakthrough of identifying
formulations which produce quality breakable foam yet omitting
customary surfactants from a composition may contribute to improved
tolerability of such a composition and can be an important
advantage. This is especially so when a formulation is to be
applied to a very sensitive target site, and particularly so on a
repeated basis.
[0275] Non-limiting examples of classes of customary non-ionic
surfactants include: (i) polyoxyethylene sorbitan esters
(polysorbates), such as polysorbate 20, polysorbate 40, polysorbate
60 and polysorbate 80; (ii) sorbitan esters, such as sorbitan
monostearate sorbitan monolaurate and sorbitan monooleate; (iii)
polyoxyethylene fatty acid esters, such as PEG-8 stearate, PEG-20
stearate, PEG-40 stearate, PEG-100 stearate, PEG-8 laurate, PEG-10
laurate, PEG-12 laurate, PEG-20 laurate, PEG-8 oleate, PEG-9
oleate, PEG-10 oleate, PEG-12 oleate, PEG-15 oleate and PEG-20
oleate; (iv) PEG-fatty acid diesters, such as PEG-150 distearate;
(v) polyethylene glycol (PEG) ethers of fatty alcohols; (vi)
glycerol esters, such as glyceryl monostearate, glyceryl
monolaurate, glyceryl monopalmitate and glyceryl monooleate; (vii)
PEG-fatty acid mono- and di-ester mixtures; (viii) polyethylene
glycol glycerol fatty acid esters; (ix) propylene glycol fatty acid
esters; (x) mono- and diglycerides; (xi) sugar esters (mono-, di-
and tri-esters of sucrose with fatty acids) and (xii) polyethylene
glycol alkyl phenols.
[0276] In certain embodiments, the composition is free of customary
surfactants, or "surfactant-free" and in certain embodiments the
foamable composition is substantially free of customary
surfactants, or "substantially surfactant-free". In certain
alternative embodiments, the composition comprises a
surfactant.
[0277] In the context herein, the term "substantially
surfactant-free composition" relates to a composition that contains
a total of less than about 0.4% of a surfactant selected from the
group consisting of customary non-ionic, anionic, cationic,
zwitterionic, amphoteric and ampholytic surfactants. Preferably,
the composition comprises less than about 0.2% by weight of a
standard surfactant and more preferably less than about 0.1%. Where
a formulation includes insignificant amounts of surfactants it is
considered to be essentially free of them. Non-surfactant or
surfactant-free compositions will comprise no or negligible levels
of surface active agents.
[0278] In additional embodiments, the term "substantially
surfactant-free" relates to a composition wherein the ratio between
the foamer complex and the surfactant is between 10:1 or 5:1; or
between 20:1 and 10:1 or between 100:1 and 20:1.
[0279] In certain embodiments, the composition is free or
substantially free of an ionic surfactant. In certain embodiments,
the composition is free or substantially free of a non-ionic
surfactant.
Substantially Polymer Free
[0280] By the term polymeric agent it is intended to mean a
compound having multiple repeated units such as cellulose polymers,
acrylic polymers, block polymers and copolymers. In one or more
certain embodiments the polymeric agent has a molecular weight of
in excess of a 1000 Daltons. Unexpectedly, it has been discovered
that quality oleaginous formulations and foams can be achieved
without the presence of significant amounts of standard polymeric
agents known in the art (e.g. gelling agents). Thus, in one or more
embodiments, there is provided a substantially surfactant free and
substantially polymeric agent free oleaginous formulation or foam.
In one or more preferred embodiments the oleaginous formulations
and foams are free of surface active agents and polymers.
Unexpectedly, it has further been discovered that quality
oleaginous formulations and foams can be achieved without the
presence of significant amounts of standard surfactants, foam
adjuvants and polymeric agents known in the art. Thus, in one or
more embodiments, there is provided a substantially surfactant free
and substantially polymeric agent free oleaginous formulation or
foam. In one or more preferred embodiments the oleaginous
formulations and foams are free of surface active agents and
polymeric agents.
[0281] By the term polymeric agent it is intended to mean a
compound having multiple repeated units such as cellulose polymers,
acrylic polymers, block polymers and copolymers. In one or more
embodiments the number of multiple or repeating units is at least
4. In one or more embodiments the oleagonious formulations are
substantially polymer free. In one or more embodiments the
oleagonious formulations are substantially polymer free of a
polymeric agent selected from the group consisting of a bioadhesive
agent, a gelling agent, a film forming agent and a phase change
agent, being locust bean gum, sodium alginate, sodium caseinate,
egg albumin, gelatin agar, carrageenin gum, sodium alginate,
xanthan gum, quince seed extract, tragacanth gum, guar gum,
cationic guars, hydroxypropyl guar gum, starch, amine-bearing
polymers such as chitosan; acidic polymers obtainable from natural
sources, such as alginic acid and hyaluronic acid; chemically
modified starches and the like, carboxyvinyl polymers,
polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers,
polymethacrylic acid polymers, polyvinyl acetate polymers,
polyvinyl chloride polymers, polyvinylidene chloride polymers,
semi-synthetic polymeric materials such as cellulose ethers, such
as methylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl
cellulose, methylhydroxyethylcellulose,
methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose,
carboxymethyl cellulose, carboxymethylcellulose
carboxymethylhydroxyethylcellulose, and cationic celluloses,
carbomer (homopolymer of acrylic acid is crosslinked with an allyl
ether pentaerythritol, an allyl ether of sucrose, or an allyl ether
of propylene); poloxamers (synthetic block copolymer of ethylene
oxide and propylene); polyethylene glycol having molecular weight
of 1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG
10,000) and which could function as a hydro alcoholic foam booster.
By substantially polymer free it is intended to mean less than
about 5%, preferably less than about 2%. By essentially polymer
free it is intended to mean less than about 1%, preferably less
than about 0.5%. In further embodiments they are essentially
polymer free and in still further embodiments they are free of
polymeric agents. In alternative embodiments the oleaginous
formulations may comprise a polymeric agent in such case the
polymeric agents are oil soluble polymeric agents. Non limiting
examples of oil-soluble polymeric agents are: Ethyl cellulose,
alkylated guar gum, trimethylsiloxysilicate, alkyl-modified
silicone, polyamide-modified silicone, homopolymers and copolymers
of alkyl methacrylates, alkyl acrylates, and alkyl styrenes,
polyisobutene, polybutyl metacrylate, polycyclohexylstyrene.
[0282] According to one or more embodiments, the composition
comprises less than about 0.1% by weight of a polymeric agent and
more preferably less than about 0.05%. Polymer free compositions
will comprise no or negligible levels of polymeric agents.
[0283] In the art, the term polymeric agent can be used loosely to
refer to any polymer. However, in some embodiments polymers that do
not have a gel building role but may act in other ways are not
excluded from the compositions. In one or more embodiments a
polyether siloxane copolymer and a
poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer and the like,
which can provide a good feeling to the composition are not
excluded.
Physical Characteristics of the Gels and Foamable Composition and
Foam
[0284] A composition manufactured according to one or more
embodiments herein is very easy to use. When applied onto the
afflicted body surface of mammals, i.e., humans or animals, it is
in a gel or foam state, allowing free application without spillage.
Upon further application of a mechanical force, e.g., by rubbing
the composition onto the body surface, it freely spreads on the
surface and is rapidly absorbed.
[0285] In one or more embodiments the composition is a single phase
solution. In one or more embodiments the composition is
substantially a single phase solution. In certain circumstances,
where the active agent is insoluble and is presented as a
homogenous suspension, the formulation is turbid or cloudy.
[0286] In one or more embodiments the composition has an acceptable
shelf-life of at least one year, or at least two years at ambient
temperature. A feature of a product for cosmetic or medical use is
long term stability. Propellants, which are a mixture of low
molecular weight hydrocarbons, tend to impair the stability. The
foamable compositions herein are surprisingly stable, even in the
absence of customary surfactants. Following accelerated stability
studies, they demonstrate desirable texture; they form fine bubble
structures that do not break immediately upon contact with a
surface, spread easily on the treated area and absorb quickly.
[0287] In certain embodiments the composition should also be free
flowing, to allow it to flow through the aperture of the container,
e.g., gel tube or an aerosol container, and provide an acceptable
gel or foam. Compositions containing a substantial amount of
semi-solid hydrophobic solvents, e.g., white petrolatum, as the
main ingredients of the oil phase of the emulsion, will likely
exhibit high viscosity and poor flowability and can be
inappropriate candidates for a foamable composition. Thus in one or
more embodiments semi-solid hydrophobic solvents are a subsidiary
component in the composition, for example being present at less
than about 25%, less than about 20%, less than about 15%, less than
about 10%, or less than about 5% by weight of the foamable
composition. In other embodiments they can be present in higher
amounts due to the solvent effect e.g of a liquid solvent or of the
propellant diluting the formulation and enabling flowability or
where the formulation is presented as a gel or ointment.
Foam Quality
[0288] Foam quality can be graded as follows:
[0289] Grade E (excellent): very rich and creamy in appearance,
does not show any bubble structure or shows a very fine (small)
bubble structure; does not rapidly become dull; upon spreading on
the skin, the foam retains the creaminess property and does not
appear watery.
[0290] Grade G (good): rich and creamy in appearance, very small
bubble size, "dulls" more rapidly than an excellent foam, retains
creaminess upon spreading on the skin, and does not become
watery.
[0291] Grade FG (fairly good): a moderate amount of creaminess
noticeable, bubble structure is noticeable; upon spreading on the
skin the product dulls rapidly and becomes somewhat lower in
apparent viscosity.
[0292] Grade F (fair): very little creaminess noticeable, larger
bubble structure than a "fairly good" foam, upon spreading on the
skin it becomes thin in appearance and watery.
[0293] Grade P (poor): no creaminess noticeable, large bubble
structure, and when spread on the skin it becomes very thin and
watery in appearance.
[0294] Grade VP (very poor): dry foam, large very dull bubbles,
difficult to spread on the skin.
[0295] Topically administrable foams are typically of quality grade
E or G, when released from the aerosol container. Smaller bubbles
are indicative of a more stable foam, which does not collapse
spontaneously immediately upon discharge from the container. The
finer foam structure looks and feels smoother, thus increasing its
usability and appeal.
Foam Density
[0296] Another property of the foam is specific gravity or density,
as measured upon release from the aerosol can. Typically, foams
have specific gravity of less than 0.50 g/mL or less than 0.12
g/mL, depending on their composition and on the propellant
concentration. In one or more embodiments the foam density is about
less than 0.3 g/mL.
Shakability
[0297] `Shakability` means that the composition contains some or
sufficient flow to allow the composition to be mixed or remixed on
shaking. That is, it has fluid or semi fluid properties.
Shakability is described further in the section on Tests. In one or
more certain limited embodiments the formulation is poorly shakable
but is nevertheless flowable.
Breakability/Collapse Time
[0298] A further optional aspect of the gel or foam is
breakability. The balance between stability and breakability of the
gel or foam coming out of the container is very delicate: on one
hand the gel or foam may not be "quick breaking", i.e., it should
be stable upon release from the pressurized container and not break
as a result of exposure to skin temperature; and on the other hand,
it should be "breakable", i.e., it should spread easily, break down
and absorb into the skin or membrane upon application of mild shear
force. The breakable gel or foam is thermally stable, yet breaks
under shear force. Shear-force breakability of the gel or foam is
clearly advantageous over thermally-induced breakability. Thermally
sensitive gels or foams start to collapse immediately upon exposure
to skin temperature and, therefore, cannot be applied on the hand
and afterwards delivered to the afflicted area.
[0299] The collapse time of a gel or foam represents its tendency
to be temperature-sensitive and its ability to be at least stable
in the short term so as to allow a user sufficient time to
comfortably handle and apply the gel or foam to a target area
without being rushed and/or concerned that it may rapidly collapse,
liquefy and/or disappear. Collapse time, as an indicator of thermal
sensitivity, is examined by dispensing a given quantity of gel or
foam and photographing sequentially its appearance with time during
incubation at 36.degree. C. Simple collapse time can be measured by
applying a gel or foam sample on a body surface like the fingers at
normal body temperature of about 37.degree. C.
[0300] Oils may cause foam to be thermolabile and "quick breaking."
However, in certain embodiments herein, despite the presence of
high oil content, quite unexpectedly the foam is substantially
thermally stable. By "substantially thermally stable" it is meant
that the foam upon application onto a warm skin or body surface at
about 35-37.degree. C. does not collapse within about 30 seconds.
Thus, in one or more embodiments the simple collapse time of the
foam is more than about 30 seconds or more than about one minute or
more than about two minutes. In one or more limited embodiments
simple collapse time can be a little shorter than 30 seconds, but
not less than about 20 seconds. In one or further or alternative
embodiments the collapse time is measured by introducing a sample
of foam into an incubator at 36.degree. C. and the collapse time of
the foam is more than 30 seconds or more than about one minute or
more than about two minutes.
[0301] There are many applications for a gel or foam of the present
invention. Below is a non-limiting list of applications which are
provided to demonstrate the versatility of such a composition and
method for modulating an oleogenous formulation viscosity. While
many of such applications are in the healthcare and cosmetic area,
adding a rheology modulator to waxes in olegeneous compositions can
be extended to applications outside the pharmaceutical and cosmetic
fields, including for example mechanics, electronics, food
industry, safety, sanitation etc.
Pharmaceutical Composition
[0302] The oleaginous composition of the present invention can be
used by itself as a topical treatment of a body surface, as many
hydrophobic solvents such as emollients, unsaturated oils,
essential oils or therapeutic oils that possess cosmetic or medical
beneficial effects. Furthermore, it is an ideal vehicle for active
pharmaceutical ingredients and active cosmetic ingredients. In the
context active pharmaceutical ingredients and active cosmetic
ingredients are collectively termed "active agent" or "active
agents". The absence of surfactants in the composition is
especially advantageous, since no surfactant-related adverse
reactions are expected from such a composition. Some surfactants
may act to facilitate gelling of the pre-foam formulation. In one
or more embodiments the active agent is soluble in the composition
of a phase thereof. In one or more other embodiments it is
partially soluble or insoluble. When partially soluble or insoluble
the active agent is presented as a suspension or it can be
encapsulated in a carrier. In one or more embodiments the active
agent is a rheology modifying active agent. In one or more
embodiments the active agent is a non rheology modifying active
agent. In one or more embodiments a rheology modifying active agent
and a non rheology modifying active agent can be used in
combination.
[0303] Suitable active agents include but are not limited to an
active herbal extract, an acaricides, an age spot and keratose
removing agent, an allergen, an alpha hydroxyl acid, an analgesic
agent, an androgen, an antiacne agent, an antiallergic agent, an
antiaging agent, an antibacterial agent, an antibiotic, an antiburn
agent, an anticancer agent, an antidandruff agent, an
antidepressant, an antidermatitis agent, an antiedemic anent, an
antifungal agent, an antihistamine, an antihelminth agent, an
anti-hyperkeratosis agent, an anti-infective agent, an
antiinflammatory agent, an antiirritant, an antilipemic agent, an
antimicrobial agent, an antimycotic agent, an antioxidant, an
antiparasitic agent, an antiproliferative agent, an antipruritic
agent, an antipsoriatic agent, an antirosacea agent, an
antiseborrheic agent, an antiseptic agent, an antiswelling agent,
an antiviral agent, an anti-wart agent, an anti-wrinkle agent, an
anti-yeast agent, an astringent, a beta-hydroxy acid, benzoyl
peroxide, a cardiovascular agent, a chemotherapeutic agent, a
corticosteroid, an immunogenic substance, a dicarboxylic acid, a
disinfectant, an estrogen, a fungicide, a hair growth regulator, a
haptene, a hormone, a hydroxy acid, an immunosuppressant, an
immunoregulating agent, an immunomodulator, an immunostimulant, an
insecticide, an insect repellent, a keratolytic agent, a lactam, a
local anesthetic agent, a lubricating agent, a masking agent, a
metal, a metal oxide, a mitocide, a neuropeptide, a non-steroidal
anti-inflammatory agent, an oxidizing agent, a pediculicide, a
peptide, a pesticide, a progesterone, a protein, a photodynamic
therapy agent, a radical scavenger, a refatting agent, a retinoid,
a sedative agent, a scabicide, a self tanning agent, a skin
protective agent, a skin whitening agent, a steroid, a steroid
hormone, a vasoactive agent, a vasoconstrictor, a vasodilator, a
vitamin, a vitamin A, a vitamin A derivative, a vitamin B, a
vitamin B derivative, a vitamin C, a vitamin C derivative, a
vitamin D, a vitamin D derivative, a vitamin D analog, a vitamin F,
a vitamin F derivative, a vitamin K, a vitamin K derivative, a
wound healing agent and a wart remover. According to a further
embodiment the active agent is a tetracycline antibiotic. In
certain embodiments the tetracycline is minocycline. In certain
embodiments the tetracycline is doxycycline. In certain embodiments
the agent is selected from a group consisting of calcitriol,
mometasone fuorate, calcitriol and lidocaine. As is known to one
skilled in the art, in some instances a specific active agent may
have more than one activity, function or effect. According to a
further embodiment the active agent is chemically stable for at
least two months and where the active agent is compatible with the
other ingredients. According to a further embodiment the active
agent is chemically stable for at least six months; or for at least
nine months for at least twelve months; or for at least fifteen
months; or for at least eighteen months; or for at least twenty one
months; or for at least twenty four months.
Encapsulation of an Active Agent
[0304] In one or more embodiments, the active agent is encapsulated
in particles, microparticles, nanoparticles, microcapsules,
microspheres, nanocapsules, nanospheres, liposomes, niosomes,
polymer matrix, silica-gel, graphite, nanocrystals or microsponges.
Such particles can have various functions, such as (1) protection
of the drug from degradation; (2) modification of the drug release
rate from the composition; (3) control of skin penetration profile;
and (4) mitigation of adverse effects, due to the controlled
release of the active agent from the encapsulation particles.
Solubility of an Active Agent
[0305] Solubility of the steroid is an important factor in the
development of a stable composition according to the present
invention.
[0306] For definition purposes, in the context of the present
invention, the descriptive terminology for solubility according to
the US Pharmacopoeia (USP 23, 1995, p. 10), the European
Pharmacopoeia (EP, 5.sup.th Edition (2004), page 7) and several
other textbooks used in the art of pharmaceutical sciences (see for
example, Martindale, The Extra Pharmacopoeia, 30.sup.th Edition
(1993), page xiv of the Preface; and Remington's Pharmaceutical
Sciences, 18.sup.th Edition (1990), page 208) is adapted:
TABLE-US-00001 Parts of Solvent Required Descriptive Term for 1
Part of Solute Very soluble Less than 1 Freely soluble From 1 to 10
Soluble From 10 to 30 Sparingly soluble From 30 to 100 Slightly
soluble From 100 to 1,000 Very slightly soluble From 1,000 to
10,000 Practically insoluble or Insoluble 10,000 and over
[0307] In preferred embodiments of the present invention, the
active agent, which constitutes the first rheology modulator is not
soluble or is partially soluble and all or part thereof, is
suspended in the composition. Thus, in one or more embodiments, the
active agent is present in the composition in a concentration which
is higher than prescribed in the above table for such an active
agent.
[0308] Yet, in one or more embodiments, the active agent is
insoluble i.e., "requires 10,000 parts or more of a solvent to be
solubilized", in the composition.
[0309] In certain embodiments it is desirable that the active agent
is maximally soluble in the composition, because solubility of the
active agents is expected to increase its bioavailability.
[0310] Yet, in additional embodiments it is desirable that the
active agent is insoluble in the composition, because its
degradation is enhanced when it is dissolved. In such cases, the
hydrophobic solvent is selected by (1) testing the solubility of
said active agent in various hydrophobic solvents, followed by (2)
inclusion in the composition of such solvents that do not
solubilize the active agent. In one or more embodiments the active
agent is presented as a suspension. In one or more further
embodiments the active agent is micronized, which can assist in
delivery into the skin, mucosal membrane and body cavity surfaces
and also aid homogenous distribution within the formulation. In
effect, part of the active agent is presented to a target in
soluble form and part is presented in insoluble form. As the
soluble part is absorbed it may help to form a gradient in which
insoluble agent replaces absorbed agent. In one or more embodiments
insoluble agent is suspended. In one or more embodiments the
suspension is homogenous. In certain embodiments the formulation is
readily resuspended and homogenous on shaking. In certain
embodiments the agent is soluble.
Exemplary Groups of Active Agents
[0311] Active agents, which constitute the first viscosity
modulators are not soluble or are partially soluble and all or part
thereof is suspended in the composition. It is known that every
chemical compound has different solubility in different solvents or
compositions, and therefore it is not possible to provide a general
list compounds that fulfill such a distinction. However, an active
agent, as exemplified in the lists below, is suitable as a first
viscosity modulator according to the present invention if it is not
soluble or is partially soluble or is suspended in the oleaginous
composition.
Antibiotics
[0312] In the context of the present disclosure, an antibiotic
agent is a substance, that has the capacity to inhibit the growth
of or to destroy bacteria and other microorganisms.
[0313] In one or more embodiments, the antibiotic agent is selected
from the classes consisting beta-lactam antibiotics,
aminoglycosides, ansa-type antibiotics, anthraquinones, antibiotic
azoles, antibiotic glycopeptides, macrolides, antibiotic
nucleosides, antibiotic peptides, antibiotic polyenes, antibiotic
polyethers, quinolones, antibiotic steroides, sulfonamides,
tetracycline, dicarboxylic acids, antibiotic metals including
antibiotic metal ions, oxidizing agents, a periodate, a
hypochlorite, a permanganate, substances that release free radicals
and/or active oxygen, cationic antimicrobial agents, quaternary
ammonium compounds, biguanides, triguanides, bisbiguanides and
analogs and polymers thereof, naturally occurring antibiotic
compounds, including antibiotic plant oils and antibiotic plant
extracts and any one of the following antibiotic compounds
including non classified antibiotic compound analogs, derivatives,
salts, ions, complexes and mixtures thereof
Tetracyclines
[0314] According to some embodiments, the antibiotic agent is a
tetracycline. The tetracyclines (also referred to herein as
"tetracycline antibiotics") are a group of antibacterials,
originally derived from certain Streptomyces spp., having the same
tetracyclic nucleus, naphthacene, and similar properties. They are
usually bacteriostatic but act by interfering with protein
synthesis in susceptible organisms. Tetracycline antibiotics are
susceptible to degradation by oxidation.
[0315] Tetracyclines include, but are not limited to,
dihydrosteffimycin, demethyltetracycline, aclacinomycin,
akrobomycin, baumycin, bromotetracycline, cetocyclin,
chlortetracycline, clomocycline, daunorubicin, demeclocycline,
doxorubicin, doxorubicin hydrochloride, doxycycline, lymecyclin,
marcellomycin, meclocycline, meclocycline sulfosalicylate,
methacycline, minocycline, minocycline hydrochloride, musettamycin,
oxytetracycline, rhodirubin, rolitetracycline, rubomycin,
serirubicin, steffimycin, tetracycline and analogs, salts and
derivatives thereof.
[0316] Chlortetracycline, oxytetracycline, tetracycline,
demeclocycline are all natural products that have been isolated
from Streptomyces spp. The more recent tetracyclines, namely
methacycline, doxycycline, and minocycline, are semisynthetic
derivatives. Methacycline, like demeclocycline, has a longer
half-life than tetracycline.
[0317] Tetracyclines are typically insoluble or partially soluble
in many hydrophobic solvents.
Minocycline
[0318] Minocycline is active against some tetracycline-resistant
bacteria, including strains of staphylococci. Both doxycycline and
minocycline are more lipid-soluble than the other tetracyclines and
they penetrate well into tissues. They are thus more suitable for
incorporating into oily or emollient containing formulations.
However, they have a place in the treatment of chlamydial
infections, rickettsial infections such as typhus and the spotted
fevers, mycoplasmal infections such as atypical pneumonia, pelvic
inflammatory disease, Lyme disease, brucellosis, tularaemia,
plague, cholera, periodontal disease, and acne. The tetracyclines
have also been useful in the treatment of penicillin-allergic
patients suffering from venereal diseases, actinomycosis,
bronchitis, and leptospirosis. Minocycline may sometimes be used in
multidrug regimens for leprosy. Doxycycline may be used for the
treatment and prophylaxis of malaria; it is also used in the
management of anthrax.
[0319] In an embodiment the active ingredient may be any one of the
following non limiting examples chlortetracycline, demeclocycline,
doxycycline, lymecycline, meclocycline, methacycline, minocycline,
oxytetracycline, rolitetracycline, tetracycline. In a preferred
embodiment they are doxycyline or minocycline.
[0320] Tetracycline antibiotics can be incorporated into the
formulations of the present invention to treat, ameliorate or
prevent a multitude of disorders responsive to tetracycline
antibiotics. The formulations can be applied topically to the skin
or to the genitals or to mucosal membranes and on and around the
eye, sub-gingival and can be applied into a wide range of body
cavities, including aural, digestive, oral, nasal, urethra, penal,
endocervical, rectum, respiratory, and vaginal and tooth pocket.
Non limiting examples of applications include eye infections,
blepharitis, dry eye, inclusion conjunctivitis, glaucoma,
inflammatory ocular conditions where bacterial infection or a risk
of bacterial ocular infection exists, neuropathic atrophy (in
diabetes), abrasions, injuries, wounds, burns, ulcers, pyoderma,
furunculosis, granuloma inguinale, periodontitis, rosacea,
post-operation infections and tissue reconstruction, trachoma,
lymphogranuloma venereum, granuloma inquinale, acne, inflammation,
sinusitis, neuro-protection, washing out, disinfectation, and
stabilization of body cavities, at on around or in the site of an
operation, which for example can provide multiple therapeutic
effects, such as, inhibition of post operation adhesions, anti
infection, neuro-protection.
[0321] Whether delivered as a foam, gel, ointment or suspension the
active pharmaceutical tetracycline can be present by weight in the
range of about 0.01% to about 20%, about 0.2% to about 20%, or at
about 0.01%, at about 0.1%, at about 0.2%, at about 0.3%, at about
0.4%, at about 0.5%, at about 0.6%, at about 0.7%, at about 0.8%,
at about 0.9%, at about 1%, at about 1.5%, at about 2%, at about
2.5%, at about 3%, at about 3.5% at about 4%, at about 4.5%, at
about 5%, at about 6%, at about 7%, at about 8%, at about 9%, at
about 10%, at about 12%, or at about 14%, at about 16%, at about
18%, or at about 20%.
Tetracyclines and Skin Infections
[0322] Tetracyclines have been used in ophthalmic ointments for the
prevention or treatment of infections of the eye caused by
susceptible bacteria. Although minor skin infections and wounds
usually heal without treatment, some minor skin wounds do not heal
without therapy and it is impossible to determine at the time of
injury which wounds will be self-healing. Therefore, some experts
believe that, by reducing the number of superficial bacteria,
topical anti-infectives are useful for preventing infection in
minor skin injuries (e.g., cuts, scrapes, burns).
[0323] Tetracycline hydrochloride may be used topically in the
prevention or treatment of inflammatory acne vulgaris.
Tetracyclines are usually bacteriostatic in action, but may be
bactericidal in high concentrations or against highly susceptible
organisms.
[0324] Tetracyclines appear to inhibit protein synthesis in
susceptible organisms primarily by reversibly binding to 30S
ribosomal subunits, thereby inhibiting binding of aminoacyl
transfer-RNA to those ribosomes. In addition, tetracyclines appear
to reversibly bind to 50S ribosomal subunits. There is preliminary
evidence that tetracyclines also alter cytoplasmic membranes of
susceptible organisms resulting in leakage of nucleotides and other
intracellular components from the cell. At high concentrations,
tetracyclines also inhibit mammalian protein synthesis.
[0325] The exact mechanisms by which tetracyclines reduce lesions
of acne vulgaris have not been fully elucidated; however, the
effect appears to be partly the result of the antibacterial
activity of the drugs. Following topical application to the skin of
a 0.22% solution of tetracycline hydrochloride in a vehicle
containing n-decyl methyl sulfoxide (Topicycline.RTM.; no longer
commercially available in the US), the drug inhibits the growth of
susceptible organisms (principally Propionibacterium acnes) on the
surface of the skin and reduces the concentration of free fatty
acids in sebum. The reduction in free fatty acids in sebum may be
an indirect result of the inhibition of lipase-producing organisms
which convert triglycerides into free fatty acids or may be a
direct result of interference with lipase production in these
organisms. Free fatty acids are comedogenic and are believed to be
a possible cause of the inflammatory lesions (e.g., papules,
pustules, nodules, cysts) of acne. However, other mechanisms also
appear to be involved because clinical improvement of acne vulgaris
with topical tetracyclines does not necessarily correspond with a
reduction in the bacterial flora of the skin or a decrease in the
free fatty acid content of sebum. (Martindale Electronic Version
2007).
Tetracyclines, Solubility and Stability
[0326] Tetracyclines are known to be unstable in the presence of
water, as well as numerous types of formulation excipients, such as
protic solvents, various surfactants and certain oils. It was
surprisingly discovered in U.S. Provisional Application No.
61/248,144 filed Oct. 2, 2009 and titled "Surfactant-Free
Water-Free Foamable Compositions, Breakable Foams And Their Uses,"
and to U.S. Provisional Application No. 61/322,148 filed Apr. 8,
2010 and titled "Surfactant-Free Water-Free Foamable Compositions,
Breakable Foams And Gels And Their Uses," that the inclusion of
tetracyclines in a composition comprising a hydrophobic solvent and
a foamer complex described therein results in a stable product,
with extended stability of the tetracycline. In an embodiment a
hydrophobic solvent is selected by (1) testing the solubility of
said active agent in various hydrophobic solvents, (2) identifying
those that do not solubilize the active agent followed by (3)
inclusion in the composition of such solvents that do not
solubilize the active agent. In preferred embodiments the
tetracycline is insoluble in the composition.
Doxycyline
[0327] According to some embodiments, the tetracycline is
doxycycline. Doxycycline is a tetracycline antibiotic and also has
anti-inflammatory and immunomodulatory effects. Doxycycline is a
semisynthetic tetracycline antibiotic derived from oxytetracycline.
In addition to antimicrobial activity, the drug has
anti-inflammatory and immunomodulatory effects. It is available as
Doxycycline calcium, doxycycline hyclate and doxycycline
monohydrate. Doxycycline hyclate and doxycycline monohydrate occur
as yellow, crystalline powders. The hyclate is soluble in water and
slightly soluble in alcohol; the monohydrate is very slightly
soluble in water and sparingly soluble in alcohol. Doxycycline
calcium is formed in situ during the manufacturing process.
Following reconstitution of doxycycline hyclate powder for IV
administration with sterile water for injection, solutions have a
pH of 1.8-3.3.
[0328] The mechanism(s) by which doxycycline reduces inflammatory
lesions (papules and pustules) in patients has not been elucidated,
but these effects may result at least in part from the
anti-inflammatory actions of the drug; other mechanisms may be
involved
[0329] Doxycycline is used for the treatment of rosacea treatment
or prophylaxis of anthrax (including inhalational anthrax
[postexposure]), treatment of presumed or confirmed rickettsial
infections, including Rocky Mountain spotted fever (RMSF), fever,
ehrlichiosis, and anaplasmosis, and for the treatment of Bartonella
infections, for the treatment of brucellosis, for the treatment of
Burkholderia Infections, Chlamydial Infections, Lymphogranuloma
venereum Psittacosis, Ehrlichiosis and Anaplasmosis, Gonorrhea and
Associated Infections, Epididymitis, Proctitis, Granuloma Inguinale
(Donovanosis), Legionella Infections, Leptospirosis, Lyme Disease,
Prophylaxis of Lyme Disease, Erythema Migrans, Early Neurologic
Lyme Disease, Lyme Carditis, or Borrelial Lymphocytoma, Lyme
Arthritis, Malaria, and prevention, Mycobacterial Infections,
Mycobacterium marinum Infections, Pelvic Inflammatory Disease,
Parenteral Regimens, Plague, pleural Effusion, Rickettsial
Infections, Q Fever, Syphilis, Tularemia, Treatment, Postexposure
Prophylaxis
[0330] When reconstituted and diluted with 0.9% sodium chloride or
5% dextrose, doxycycline hyclate IV solutions containing 0.1-1 mg
of doxycycline per mL are stable for 48 hours at 25.degree. C.;
when reconstituted and diluted with Ringer's, 10% invert sugar,
Normosol-M.RTM. in D5W, Normosol-R.RTM. in D5W, Plasma-Lyte.RTM. 56
in 5% dextrose, or Plasma-Lyte.RTM. 148 in 5% dextrose, doxycycline
hyclate IV solutions containing 0.1-1 mg/mL are stable for 12 hours
at room temperature. The manufacturer states that doxycycline
hyclate solutions prepared with any of these infusion solutions are
stable for 72 hours at 2-8.degree. C. when protected from direct
sunlight and artificial light; however, after storage in this
manner, infusion of these solutions must be completed within 12
hours Doxycycline hyclate IV solutions diluted to a concentration
of 0.1-1 mg/mL with lactated Ringer's injection or 5% dextrose in
lactated Ringer's injection must be infused within 6 hours to
ensure stability. During infusion, all doxycycline hyclate IV
solutions must be protected from direct sunlight. (Martindale 2007
Electronic Version). Thus it can be seen that Doxycycline is not
stable for more than short periods of a matter of hours.
[0331] Preparations of doxycycline hyclate have an acid pH and
incompatibility may reasonably be expected with alkaline
preparations or with drugs unstable at low pH.
[0332] Doxycycline is more active than tetracycline against many
bacterial species including Streptococcus pyogenes, enterococci,
Nocardia spp., and various anaerobes. Cross-resistance is common
although some tetracycline-resistant Staphylococcus aureus respond
to doxycycline. Doxycycline is also more active against protozoa,
particularly Plasmodium spp.
[0333] Doxycycline is a tetracycline derivative with uses similar
to those of tetracycline. It may sometimes be preferred to other
tetracyclines in the prevention or treatment of susceptible
infections because of its fairly reliable absorption and its long
half-life that permits less frequent (often once daily) dosing. It
also has the advantage that it can be given (with care) to patients
with renal impairment. However, relatively high doses may need to
be given for urinary-tract infections because of its low renal
excretion.
[0334] For relapsing fever and louse-borne typhus, for the
prophylaxis of leptospirosis, for periodontiti, for Lymphatic
filariasis, for Musculoskeletal and joint disorders and for the
treatment of acne.
Minocycline
[0335] According to some embodiments, the tetracycline is
minocycline. Minocycline hydrochloride is a semisynthetic
tetracycline antibiotic derived from tetracycline. The drug is
usually bacteriostatic in action; it exerts its antimicrobial
activity by inhibiting protein synthesis. It is a yellow
crystalline powder that is sparingly soluble in water; slightly
soluble in alcohol; practically insoluble in chloroform and in
ether; soluble in solutions of alkali hydroxides and carbonates. pH
of a solution in water containing the equivalent of minocycline 1%
is between 3.5 and 4.5. Preparations of minocycline hydrochloride
have an acid pH and incompatibility may reasonably be expected with
alkaline preparations or with drugs unstable at low pH.
[0336] Minocycle is highly sensitive and should be stored in
airtight containers and protected from light to prevent
degradation. Therefore use in foamable formulations stored in
airtight sealed containers under pressure with propellant may
contribute to preserving stability subject to selection of
compatible canisters and accessories.
[0337] Photosensitivity, manifested as an exaggerated sunburn
reaction on areas of the body exposed to direct sunlight or
ultraviolet light, has occurred with tetracyclines and Minocycline
has been associated with pigmentation of the skin and other
tissues.
[0338] Minocycline has a spectrum of activity and mode of action
similar to that of tetracycline but it is more active against many
species including Staphylococcus aureus, streptococci, Neisseria
meningitidis, various enterobacteria, Acinetobacter, Bacteroides,
Haemophilus, Nocardia, and some mycobacteria, including M. leprae.
Partial cross-resistance exists between minocycline and other
tetracyclines but some strains resistant to other drugs of the
group remain sensitive to minocycline, perhaps because of better
cell-wall penetration. Minocycline is a tetracycline derivative
with uses similar to those of tetracycline. It is also a component
of multidrug regimens for the treatment of leprosy and has been
used in the prophylaxis of meningococcal infection to eliminate the
carrier state, but the high incidence of vestibular disturbances
means that it is not the drug of choice for the latter. It has
neuroprotective properties. It is being investigated for motor
neurone disease, for the management of Huntington's chorea. It is
used in the treatment of rheumatoid arthritis and in the prevention
or treatment of various skin disorders, including acne.
Steroids
[0339] In an embodiment, the active agent is a steroid. In certain
embodiments the steroid is a corticosteroid, including but not
limited to, hydrocortisone, hydroxyltriamcinolone, alpha-methyl
dexamethasone, dexamethasone-phosphate, beclomethsone dipropionate,
clobetasol valemate, desonide, desoxymethasone,
desoxycorticosterone acetate, dexamethasone, dichlorisone,
diflorasone diacetate, diflucortolone valerate, fluadrenolone,
fluclorolone acetonide, fludrocortisone, flumethasone pivalate,
fluosinolone acetonide, fluocinonide, flucortine butylester,
fluocortolone, fluprednidene (fluprednylidene) acetate,
flurandrenolone, halcinonide, hydrocortisone acetate,
hydrocortisone butyrate, methylprednisolone, triamcinolone
acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,
difluorosone diacetate, fluradrenolone acetonide, medrysone,
amcinafel, amcinafide, betamethasone and the balance of its esters,
chloroprednisone, chlorprednisone acetate, clocortelone,
clescinolone, dichlorisone, difluprednate, flucloronide,
flunisolide, fluoromethalone, fluperolone, fluprednisolone,
hydrocortisone valerate, hydrocortisone cyclopentylpropionate,
hydrocortmate, mepreddisone, paramethasone, prednisolone,
prednisone, beclomethasone dipropionate, triamcinolone, as well as
analogs, derivatives, salts, ions and complexes thereof.
[0340] Many steroids are typically insoluble or partially soluble
in various hydrophobic solvents.
[0341] In certain embodiments, the steroid is a hormone or a
vitamin or an anti-infective agent, as exemplified by pregnane,
cholestane, ergostane, aldosterone, androsterone, calcidiol,
calciol, calcitriol, calcipotriol, clomegestone, cholesterol,
corticosterone, cortisol, cortisone, dihydrotestosterone,
ergosterol, estradiol, estriol, estrone, ethinylestradiol, fusidic
acid, lanosterol, prednisolone, prednisone, progesterone,
spironolactone, timobesone and testosterone, as well as analogs,
derivatives, salts, ions and complexes thereof. For substances like
calcitriol, very low amounts such as about 0.0001% to about 0.005%
by weight of foam formulation or gel or ointment or suspension, or
about 0.0001%, about 0.0002%, about 0.0003%, about 0.0004%, about
0.0005%, about 0.0006%, about 0.0007%, about 0.0008%, about
0.0009%, about 0.001%, about 0.0011%, about 0.0012%, about 0.0013%,
about 0.0014%, about 0.0015%, about 0.0016%, about 0.0017%, about
0.0018%, about 0.0019%, about 0.002%, about 0.003%, about 0.004%,
about 0.005% by weight are effective. In some embodiments the
active pharmaceutical agent is delivered by more than one route,
for example, topically and body cavity.
[0342] In an embodiment, the steroid is mometasone furoate. In
certain embodiments it can be used topically to treat psoriasis and
dermatitis. In certain other embodiments it can be applied in nasal
administration to treat disorders, such as, allergic rhinitis and
asthma.
NSAID
[0343] In an embodiment, the active agent is a non-steroidal
anti-inflammatory agent. In the context a nonsteroidal
antiinflammatory agent (also termed herein "NSAID") is a
pharmaceutically active compound, other than a corticosteroid,
which affects the immune system in a fashion that results in a
reduction, inhibition, prevention, amelioration or prevention of an
inflammatory process and/or the symptoms of inflammation and/or the
production pro-inflammatory cytokines and other pro-inflammatory
mediators, thereby treating or preventing a disease that involves
inflammation.
[0344] In one or more embodiments, the NSAID is an inhibitor of the
cyclooxygenase (COX) enzyme. Two forms of cyclooxygenase are known
today: the constitutive cyclooxygenase (COX-1); and the inducible
cyclooxygenase (COX-2), which is pro-inflammatory. Thus, in one or
more embodiments, the NSAID is selected from the group consisting
of a COX-1 inhibitor, a COX-2 inhibitor or a non-selective NSAID,
which simultaneously inhibits both COX-1 and COX-2.
[0345] In one or more embodiments, the NSAID is salicylic acid a
salicylic acid derivatives. Exemplary salicylic acid derivative
include, in a non limiting fashion, aspirin, sodium salicylate,
choline magnesium trislicylate, salsalate, diflunisal,
salicylsalicylic acid, sulfasalazine, olsalazine, esters of
salicylic acid with a carboxylic acid, esters of salicylic acid
with a dicarboxylic acid, esters of salicylic acid with a fatty
acid, esters of salicylic acid with a hydroxyl fatty acid, esters
of salicylic acid with an essential fatty acid, esters of salicylic
acid with a polycarboxylic acid, and any compound wherein salicylic
acid is linked to an organic moiety through a covalent bond.
[0346] In one or more embodiments, the NSAID is para-aminophenol
(e.g., acetaminophen) and salts and derivatives thereof.
[0347] In one or more embodiments, the NSAID is an indole or an
indole--acetic acid derivative (e.g., indomethacin, sulindac,
etodolac) and salts and derivatives thereof.
[0348] In one or more embodiments, the NSAID is an aryl acetic
acids (e.g., tolmetin, diclofenac, ketorolac) and salts and
derivatives thereof.
[0349] In one or more embodiments, the NSAID is an arylpropionic
acid and salts and derivatives thereof. Exemplary arylpropionic
acid derivative include, in a non limiting fashion, are ibuprofen,
naproxen, flubiprofen, ketoprofen, fenoprofen, oxaprozin.
[0350] In one or more embodiments, the NSAID is anthranilic acids
or an anthranilic acid derivative, also termed "fenamates" (e.g.,
mefenamic acid, meclofenamic acid) and salts and derivatives
thereof.
[0351] In one or more embodiments, the NSAID is selected from the
group of enolic acids, enolic acid salts, enolic acid esters,
amides, anhydrides and salts and derivatives thereof. Non-limiting
examples of enolic acid derivatives include oxicams (piroxicam,
tenoxicam) and pyrazolidinediones (phenylbutazone,
oxyphenthratrazone)
[0352] Yet, in additional embodiments, the NSAID is an alkanone
(e.g., nabumetone).
[0353] Selective COX-2 Inhibitors include, in an exemplary manner
diaryl-substituted furanones (e.g., Rofecoxib); diaryl-substituted
pyrazoles (e.g., Celecoxib); indole acetic acids (e.g., Etodolac);
and sulfonanilides (e.g., Nimesulide) and salts and derivatives
thereof.
[0354] Many NSAIDs are typically insoluble or partially soluble in
hydrophobic solvents.
Local Anesthetic Agents
[0355] In an embodiment, the active agent is a local anesthetic
agent. Without limiting the scope, the anesthetic agent can be
selected from the group consisting of benzocaine, lidocaine,
bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine,
tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine,
pramoxine, phenol, any pharmaceutically acceptable salts thereof
and mixtures of such anesthetic agents. Any mixture of
synergistically beneficial anesthetic agents is contemplated.
Keratolytically Active Agents
[0356] A keratolytic agent may be included as an active agent of
the composition. The term "keratolytically active agent" as used
herein includes a compound that loosens and removes the stratum
corneum of the skin, or alters the structure of the keratin layers
of skin. Keratolytically active agents are used in the prevention
or treatment of dermatological disorders that involve dry skin,
hyperkeratinization (such as psoriasis), skin itching (such as
xerosis), acne and rosacea.
[0357] Suitable keratolytically active agents include phenol and
substituted phenolic compounds. Such compounds are known to
dissolve and loosen the intracellular matrix of the
hyperkeratinized tissue. As such, they are used in the prevention
or treatment of dermatological disorders. Dihydroxybenzene and
derivatives thereof have been recognized as potent keratolytic
agents. Resorcinol (m-dihydroxybenzene) and derivatives thereof are
used in anti-acne preparations. In addition to hydroquinone
(p-dihydroxybenzene) having anti-pigmentation properties,
hydroquinone is also known to be keratolytic. These compounds also
exhibit antiseptic properties. Cresols also possess bactericidal
and keratolytic properties.
[0358] Vitamin A and vitamin A derivatives, also termed herein
"retinoids", such as retinoic acid, isoretinoic acid, retinol and
retinal, as well as adapalene, tazarotene, isotretinoin, acitretin
and additional retinoids known in the art of pharmaceuticals and
cosmetics are another class of keratolytically active agents.
[0359] Another group of keratolytically active agents include
alpha-hydroxy acids, such as lactic acid and glycolic acid and
their respective salts and derivatives; and beta-hydroxy acids,
such as salicylic acid (o-hydroxybenzoic acid) and salicylic acid
salts and pharmaceutically acceptable derivatives.
[0360] Another class of keratolytically active agents includes urea
and urea derivatives.
Immunomodulators
[0361] In an embodiment, the active agent is an immunomodulator.
Immunomodulators are chemically or biologically-derived agents that
modify the immune response or the functioning of the immune system.
Immunomodulators suitable for use according to the present
invention include, among other options, cyclic peptides, such as
cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus,
verolimus, laflunimus, laquinimod and imiquimod, as well as
analogs, derivatives, salts, ions and complexes thereof. Such
compounds, delivered in the foam, are especially advantageous in
skin disorders such as psoriasis, eczema and atopic dermatitis,
where the large skin areas are to be treated.
Retinoids
[0362] In an embodiment, the active agent is a retinoid. Retinoids
suitable for use according to the present invention include, among
other options, retinol, retinal, retinoic acid, isotretinoin,
tazarotene, adapalene, 13-cis-retinoic acid, acitretin all-trans
beta carotene, alpha carotene, lycopene, 9-cis-beta-carotene,
lutein and zeaxanthin, as well as any additional retinoids known in
the art of pharmaceuticals and cosmetics; and analogs, derivatives,
salts, ions and complexes thereof.
Anti-Acne and Anti-Rosacea Active Agents
[0363] In an embodiment, the active agent is an anti-acne or an
anti-rosacea agent. The anti-acne agent can be selected from the
group consisting of resorcinol, sulfur, salicylic acid and
salicylates, alpha-hydroxy acids, nonsteroidal anti-inflammatory
agents, benzoyl peroxide, retinoic acid, isoretinoic acid and other
retinoid compounds, adapalene, tazarotene, azelaic acid and azelaic
acid derivatives, antibiotic agents, such as erythromycin and
clyndamycin, coal tar, zinc salts and complexes, and combinations
thereof, in a therapeutically effective concentration.
Antipsoriasis Agents
[0364] In an embodiment, the active agent is an anti-psoriasis
agent. Such anti-psoriasis agents can be selected, among other
options, from the group of keratolytically-active agents, salicylic
acid, coal tar, anthralin, corticosteroids, vitamin D and
derivatives and analogs thereof, including vitamin D3 analogs such
as calcitriol, calcipotriol; retinoids, and photodynamic therapy
agents.
Antiinfective Agents
[0365] In an embodiment, the active agent is an anti-infective
agent. Such anti-infective agent can be selected from the group of
an antibiotic agent, an antibacterial agent, an antifungal agent,
an agent that controls yeast, an antiviral agent and an
antiparasitic agent. Exemplary antiinfective agents are exemplified
by beta-lactam antibiotic, an aminoglycoside, an ansa-type
antibiotic, an anthraquinone, an azole, metronidazole, an
antibiotic glycopeptide, a macrolide, erythromycin, clindamycin, an
antibiotic nucleoside, an antibiotic peptide, polymyxin B, an
antibiotic polyene, an antibiotic polyether, an antibiotic
quinolone, an antibiotic steroid, fucidic acid, mupirocin,
chloramphenicol, a sulfonamide, tetracycline, an antibiotic metal,
silver, copper, zinc, mercury, tin, lead, bismuth, cadmium,
chromium, an oxidizing agent, iodine, iodate, a periodate, a
hypochlorite, a permanganate, a substance that release free
radicals and/or active oxygen, a cationic antimicrobial agent, a
quaternary ammonium compound, a biguanide, chlorohexidine, a
triguanide, a bisbiguanide, a polymeric biguanide and a naturally
occurring antibiotic compound, as well as analogs, derivatives,
salts, ions and complexes thereof.
The Composition Essential Ingredients as Active Agents
[0366] In certain embodiments, a hydrophobic solvent possesses
therapeutic properties on its own and therefore, it can be regarded
as "active agent." For example, some essential oils kill
microorganisms and can be effective in the treatment or prevention
of conditions that involve microbial infection, such as bacterial,
fungal and viral conditions. Additionally, the occlusive effect of
hydrophobic solvents is useful for the treatment of conditions
which involve damaged skin, such as psoriasis or atopic dermatitis.
The combination of a hydrophobic solvent and a therapeutically
effective fatty alcohol or fatty acid may afford a synergistic
beneficial effect in conditions characterized, for example, by
infection and/or inflammation.
Combination of Active Agents
[0367] Several disorders involve a combination of more than one
etiological factor; and therefore, the use of more that one active
agents is advantageous. For example, psoriasis involves excessive
cell proliferation and inadequate cell differentiation as well as
inflammation. Atopic dermatitis involves keratinocyte growth
abnormality, skin dryness and inflammation. Bacterial, fungal and
viral infections involve pathogen colonization at the affected site
and inflammation. Hence, in many cases, the inclusion of a
combination of active agents in the pharmaceutical composition can
be desirable. Thus, in one or more embodiments, the composition
further includes at least two active agents, in a therapeutically
effective concentration.
[0368] In an embodiment one of the active agents is a vitamin, a
vitamin derivative or analogue thereof. In a preferred embodiment
the vitamin, vitamin derivative or analogue thereof is oil
soluble.
Microsponges
[0369] Microsponges (or microspheres) are rigid, porous and
sponge-like round microscopic particles of cross-linked polymer
beads (e.g., polystyrene or copolymers thereof), each defining a
substantially non-collapsible pore network. Microsponges can be
loaded with an active ingredient and can provide a controlled time
release of the active ingredient to skin or to a mucosal membrane
upon application of the formulation. The slow release is intended
to reduce irritation by the active. Microsponge.RTM. delivery
technology was developed by Advanced Polymer Systems. In one or
more embodiments the composition comprises one or more active
agents loaded into Microsponges with a waterless carrier described
herein, which may also comprise a modulating agent.
Fields of Applications
[0370] The carrier of the present disclosure is suitable for
treating any inflicted surface or preventing onset of an
anticipated disorder or disease or for achieving a period of
remission. In one or more embodiments, carrier is suitable for
administration to the skin, a body surface, a body cavity or
mucosal surface, e.g., the cavity and/or the mucosa of the nose,
mouth, eye, respiratory system, vagina, urethra, rectum and the ear
canal (severally and interchangeably termed herein "target
site").
[0371] The foamable carrier of the present disclosure is also
suitable for preventing a disorder or disease prior to its onset.
The foamable composition comprising for example a tetracycline may
be applied to a body surface or a body cavity to try and prevent
apoptosis, a disorder or disease prior to onset thereof. For
example, prior to an anticipated inflammatory reaction or risk
thereof, or prior to an anticipated onset of apoptosis or a risk
thereof, or prior to an anticipated onset of inflammatory cytokines
or risk thereof, prior to a medical procedure requiring
intervention such as chemo therapy; radiotherapy, photodynamic
therapy, laser therapy, etc. In an embodiment the composition is
applied to prevent or reduce the risk of spreading.
[0372] According to an embodiment a none limiting of list of
disorders where a tetracycline antibiotic might be used to prevent
a disease or disorder includes prophylaxis of gonococcal and
chlamydial ophthalmia, neonatal conjunctivitis, periodontal
disease, postoperative tetracycline, prophylaxis in pregnancy
termination, for prevention of skin rash/acneiform skin eruption
during cancer therapy, intraoperative topical tetracycline
sclerotherapy following mastectomy for prevention of postoperative
mastectomy seromas etc.
[0373] By selecting a suitable active agent, or a combination of at
least two active agents, the composition of the present disclosure
is useful in alleviating or treating an animal or a human patient
having or anticipated to have any one of a variety of
dermatological diseases or disorders, or where such agent or agents
have shown proficiency in preventative therapy in preventing such
diseases or disorders, including, but not limited to a bacterial
infection, a benign tumor, a bullous disease, a burn, a Chlamydia
infection, a condition which respond to hormone therapy, a cut, a
dermatitis, a dermatophyte infection, a dermatose, a disorder of a
body cavity, a disorder of cornification, a disorder of the nose, a
disorder of the penile urethra or ear canal, a disorder of the
rectum, a disorder of the respiratory system, a disorder of the
vagina, a disorder which responds to hormone replacement therapy, a
disorder which responds to transdermal nicotine administration, a
disorders of hair follicles, a disorders of sebaceous glands, a
disorders of sweating, a fungal infection, a gonorrhea infection, a
gynecological disorders that respond to hormonal therapy, a
malignant tumor, a non-dermatological disorder which responds to
topical or transdermal delivery of an active agent, a parasitic
infection, a pelvic inflammation, a pigmentation disorder, a
scaling papular diseases, a sexual dysfunction disorder, a sexually
transmitted disease, a vaginal disorder, a viral infection, a
vulvar disorder, a vulvovaginal infection, a wound, a yeast
infection, abscess, acne, acne conglobata, acne fulminans, acne
scars, acne vulgaris, actinic keratosis, acute and chronic
salpingitis, acute febrile neutrophilic dermatosis, acute
lymphangitis, acute pelvic inflammatory disease, acute soft tissue
injury, albinism, allergic contact dermatitis, alopecia, alopecia
areata, alopecia totalis, alopecia universalis, an allergy, an anal
abscess or fistula, an anal and rectal disease, an anal disorder,
an anal fissure, an anal wart, an ear disorder, an hormonal
disorder, an inflammatory reaction, an intra-vaginal or rectal
sexually-transmitted and non-sexually-transmitted infectious
disease, anal cancer, anal excoriation, anal fissures, anal itch,
anal pruritus, anal soreness, anal warts, angiomas, arthritis,
athlete's foot, atopic dermatitis, back pain, bacterial skin
infections, bacterial vaginosis, baldness, basal cell carcinoma,
benign tumors, blisters, bromhidrosis, bullous diseases, bullous
pemphigoid, burn, calluses, calluses candidiasis, cancer of the
cervix, cancer of the vagina, cancer of the vulva, candidal
vaginitis, candidiasis, carbuncles, cellulitis, cervical cancer,
cervicitis, chancroid, chemical burns, chicken pox, chloasma,
cholesteatoma, cholinergic urticaria, chronic dermatitis, chronic
effects of sunlight, cold sores, cold urticaria, comedones,
constipation, contact dermatitis, corns, creeping eruption, Crohn's
disease, cutaneous abscess, cutaneous larva migrans, cutaneous
myiasis, dark spots, delusional parasitosis, Dercum disease,
dermatitis, dermatitis herpetiformis, dermatofibroma,
dermatological inflammation, dermatological pain, dermatophytoses,
dermographism, diaper rash, drug eruptions and reactions,
drug-induced hyperpigmentation, dyshidrotic eczema, dysmenorrhea,
dyspareunia, dysplastic nevi, ecthyma, ectodermal dysplasia,
ectopic pregnancy, eczema, endometriosis, endometritis, epidermal
necrolysis, epidermoid cyst, erysipelas, erythema multiforme,
erythema nodosum, erythrasma, exfoliative dermatitis, fallopian
tube cancer and gestational trophoblastic disease, fecal
incontinence, female orgasmic disorder, folliculitis, fungal nail
infections, fungal skin infections, furuncles, gangrene,
generalized exfoliative dermatitis, genital cancer, genital herpes,
genital ulcer, genital warts, granuloma annulare, granuloma
inguinale, gynecological neoplasms including endometrial cancer,
head lice, hemorrhoids, hepatitis B, herpes, herpes simplex,
hidradenitis suppurativa, hirsutism, HIV/AIDS, hives, human
papillomavirus (HPV), hyperhidrosis, hyperpigmentation melasma,
hypertrichosis, hypohidrosis, hypopigmentation, ichthyosis,
impetigo, inflammatory acne, inflammatory reactions, ingrown nails,
intertrigo, irritant contact dermatitis, ischemic necrosis,
itching, jock itch, joint pain, Kaposi's sarcoma, keloid,
keratinous cyst, keratoacanthoma, keratosis pilaris, lichen planus,
lichen sclerosus, lichen simplex chronicus, linear immunoglobulin A
disease, lipomas, localized pain in general, lymphadenitis,
lymphangitis, lymphogranloma venereum, male pattern baldness,
malignant melanoma, malignant tumors, mastocytosis, measles,
melanoma, midcycle pain, midcycle pain due to ovulation, miliaria,
mittelschmerz, moles, molluscum contagiosum, MRSA, mucopurulent
cervicitis (MPC), muscle pain, necrotizing fasciitis, necrotizing
myositis, necrotizing subcutaneous infection, necrotizing
subcutaneous infections, nodular papulopustular acne, nongonococcal
urethritis (NGU), non-inflammatory acne, nummular dermatitis,
oophoritis, oral herpes, osteoarthritis, ostheoarthritis, ovarian
cancer, ovarian cysts and masses, paget's disease of the nipples,
panniculitis, papules, parapsoriasis paronychia, parasitic
infections, parasitic skin infections, paronychial infection,
pediculosis, pelvic congestion syndrome, pelvic inflammatory
disease, pelvic pain, pemphigus, perianal pruritus, perianal
thrush, perioral dermatitis, photo-allergy, photo-damage,
photo-irritation, photosensitivity, pigmentation disorders,
pimples, pityriasis Lichenoides, pityriasis rosea, pityriasis rubra
pilaris, poison ivy, poison oak, polyps of the colon and rectum,
postinflammatory hyperpigmentation, postinflammatory
hypopigmentation, post-operative or post-surgical skin conditions,
premenstrual syndrome, pressure sores, pressure ulcers, pressure
urticaria, pruritis, pruritus ani, pseudofolliculitis barbae,
psoriasis, PUPPP, purpura, pustules, pyogenic granuloma, rash,
reactions to sunlight, rectal abscess, rectal fistula, rheumatic
pain, ringworm, rosacea, roseola, rubella, salpingitis, scabies,
scalded skin syndrome, scaling papular diseases, scarring,
scleroderma, sebaceous cyst, seborrheic dermatitis, seborrheic
keratoses, seborrheic keratosis, sexual arousal disorder, shingles,
skin aging, skin cancer, skin neoplasia, skin neoplasms, skin rash,
skin tags, skin ulcers, sports injuries, squamous cell carcinoma,
staphylococcal scalded skin syndrome, stasis dermatitis,
Stevens-Johnson syndrome, sun spots, sunburn, thermal burns, tinea
corporis, tinea cruris, tinea pedis, tinea versicolor, toxic
epidermal necrolysis, trauma or injury to the skin, Trichomonas
vaginalis, trichomoniasis, vaginal cancer, vaginal dryness,
vaginismus, varicella zoster virus, viral skin infections, vitamin
D deficiency, vitiligo, vulvar cancer, vulvar disorders, vulvar
dystrophy, vulvar intraepithelial neoplasia (VIN), vulvar pain,
vulvodynia, warts, water hives, wrinkles, xerosis, yeast skin
infections, zoster.
[0374] Likewise, the composition of the present disclosure is
suitable for preventing or treating or alleviating a disorder or
anticipated disorder of a body cavity or mucosal surface, e.g., the
mucosa of the nose, mouth, eye, ear, respiratory system, vagina,
urethra, or rectum. Non limiting examples of such conditions
include chlamydia infection, gonorrhea infection, hepatitis B,
herpes, HIV/AIDS, human papillomavirus (HPV), genital warts,
bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale,
lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscum
contagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvar
disorders, vulvodynia, vulvar pain, yeast infection, vulvar
dystrophy, vulvar intraepithelial neoplasia (VIN), contact
dermatitis, pelvic inflammation, endometritis, salpingitis,
oophoritis, genital cancer, cancer of the cervix, cancer of the
vulva, cancer of the vagina, vaginal dryness, dyspareunia, anal and
rectal disease, anal abscess/fistula, anal cancer, anal fissure,
anal warts, Crohn's disease, hemorrhoids, anal itch, pruritus ani,
fecal incontinence, constipation, polyps of the colon and
rectum.
[0375] In an embodiment of the present disclosure, the composition
is useful for the treatment of an infection. In one or more
embodiments, the composition is suitable for the treatment or
prevention of an infection, selected from the group of a bacterial
infection, a fungal infection, a yeast infection, a viral infection
and a parasitic infection.
[0376] In an embodiment of the present disclosure, the composition
is useful for the treatment of wound, ulcer and burn. This use is
particularly important since the composition of the present
disclosure creates a thin, semi-occlusive layer, which coats the
damaged tissue, while allowing exudates to be released from the
tissue.
[0377] The composition of the present disclosure is also suitable
for administering a hormone to the skin or to a mucosal membrane or
to a body cavity, in order to deliver the hormone into the tissue
of the target organ, in any disorder that responds to treatment
with a hormone.
[0378] In one embodiment the disorder is an inflammation, skin
inflammation, acne, rosacea, actinic keratosis, skin cancer, a
local pain, joint pain and ostheoarthritis; the active agent is a
nonsteroidal anti-inflammatory drug, given at a therapeutically
effective concentration.
[0379] In light of the hygroscopic nature of the composition, it is
further suitable for the treatment and prevention of post-surgical
adhesions. Adhesions are scars that form abnormal connections
between tissue surfaces. Post-surgical adhesion formation is a
natural consequence of surgery, resulting when tissue repairs
itself following incision, cauterization, suturing, or other means
of trauma. When comprising appropriate protective agents, the foam
is suitable for the treatment or prevention of post surgical
adhesions. The use of foam is particularly advantageous because
foam can expand in the body cavity and penetrate into hidden areas
that cannot be reached by any other alternative means of
administration.
Cosmetic Use
[0380] In one or more embodiments, the composition may be used for
cosmetic use. For example it may be used as part of a cosmetic
formulation to prevent a cosmetic disorder or to improve the skin.
Alternatively it may be used with cosmetic effect for example as a
cosmetic remover. It can be dispensed in small quantities targeted
to a surface and applied locally with mechanical force causing the
foam or gel to break.
Route of Administration
[0381] In one or more embodiments the formulations are prepared
without propellant and are applied as a gel or ointment, for
example, with the tetracycline as a suspension. Alternatively, in
one or more embodiments the formulations are prepared with a
propellant and are applied as a foam.
[0382] In one or more embodiments, the gel is capable of forming a
foamable composition when packaged into an aerosol canister,
equipped with a valve and pressurized with a liquid or pressurized
gas propellant and is capable of releasing a foam of quality that
is breakable upon application of shear force but is not
thermolabile at about or close to body temperature (about
36.degree. C.).
[0383] In one or more embodiments, upon addition of between about
8% to about 12% propellant, the formulations 238P, 238A, 238B,
238C, 238D, 244A, 244B, 244P in Examples 4, 6 and 7 provided a foam
of good or excellent quality that had a collapse time in excess of
3 minutes.
[0384] Application can be hourly, 2 hourly, 3 hourly, four hourly,
six hourly or eight hourly, twelve hourly, daily, alternate-day or
intermittent, as necessary. For reasons of compliance less frequent
applications, where possible are preferable such as twice--daily or
daily single applications. In cases where prolonged or long term
treatment is required a higher initial dose is provided followed by
a gradual reduction to a lower maintenance dose, which can be
increased if further outbreaks occur.
[0385] The formulations are suitable for administration directly or
indirectly to an inflicted area, in need of treatment, through the
following routes of administration: [0386] 1. Topical
administration: for local effect, it is applied directly where its
action is desired; [0387] 2. Enteral: when the desired effect is
systemic (non-local), it is given via the digestive tract; and
[0388] 3. Parenteral: when the desired effect is systemic, it is
given by other routes than the digestive tract
[0389] The following list more specifically exemplifies some routes
of administration.
1. Topical
[0390] Topical administration is any form of administration that
reaches a body organ topically, such as epicutaneous administration
(application onto the skin), inhalation, enema, eye drops (onto the
conjunctiva), ear drops, intranasal (into the nose) and
vaginal.
[0391] Exemplary dosage forms that are suitable for topical
administration of the stable tetracycline formulations include
cream, gel, liniment, lotion, ointment, paste, spray, foam, mousse,
lacquer (e.g., for nail treatment) and transdermal patch.
Additionally, topical vaginal dosage forms may include a douche, an
intrauterine device, a pessary (vaginal suppository), a vaginal
ring and a vaginal tablet. Rectal dosage forms include enema and
suppositories. Inhaled dosage forms include aerosol inhalers,
metered dose inhalers and solutions for nebulizer. Ophthalmic
dosage forms include eye drop (solution or suspension), ophthalmic
gel and ophthalmic ointment. In another embodiment the dosage form
is a foam that is quickly breaking (non thermally stable) or
breakable under shear force which allows comfortable application
and well directed administration to the target area.
2. Enteral
[0392] Enteral is any form of administration that involves any part
of the gastrointestinal tract by mouth (orally), as buccal or
sublingual tablets, capsules, suspensions, solutions, powder or
drops; by gastric feeding tube, duodenal feeding tube, or
gastrostomy; and rectally, in suppository or enema form.
3. Parenteral by Injection or Infusion
[0393] Intravenous (into a vein); intraarterial (into an artery);
intramuscular (into a muscle); intracardiac (into the heart);
subcutaneous (under the skin); intraosseous infusion (into the bone
marrow); intradermal, (into the skin itself); intrathecal (into the
spinal canal); and intraperitoneal (into the peritoneum).
4. Other Parenteral
[0394] Transdermal (diffusion through the intact skin);
transmucosal (diffusion through a mucous membrane), e.g.
insufflation (snorting), sublingual, buccal (absorbed through cheek
near gumline) and vaginal; and inhalational; epidural (synonym:
peridural) (injection or infusion into the epidural space); and
intravitreal.
EXAMPLES
[0395] The invention is described with reference to the following
examples, in a non-limiting manner. The following examples
exemplify the compositions and methods described herein. The
examples are for the purposes of illustration only and are not
intended to be limiting. Many variations will suggest themselves
and are within the full intended scope.
Example 1--General Manufacturing Procedures
[0396] The following procedures are used to produce gel and foam
samples described in the examples below, in which only the steps
relevant to each formulation are performed depending on the type
and nature of ingredients used.
[0397] Step 1: Hydrophobic solvent are heated to 60-70.degree.
C.
[0398] Step 2: Fatty alcohols if present, fatty acids if present,
surfactants if present are added to the hydrophobic solvent and the
formulation is mixed until complete melting.
[0399] Step 3: The formulation is cooled down to 30-40.degree. C.,
active ingredients if present are added and the formulation is
mixed until homogeneity is obtained.
[0400] Step 4--for Gels: The formulation is cooled down to room
temperature under mixing and packaged into suitable containers.
[0401] Step 4--for Foams: The formulation is packaged in aerosol
canisters which are crimped with a valve, pressurized with
propellant and equipped with an actuator suitable for foam
dispensing. Optionally a metered dosage unit can utilized, to
achieve delivery of repeatable measured doses of foam.
Materials
TABLE-US-00002 [0402] TABLE 1 Exemplary possible ingredients
suitable for the production of gels and/or foamable compositions
disclosed herein. Equivalent materials from other manufacturers can
also be used satisfactorily. Chemical Name Function Commercial Name
Supplier Alpha-tocopherol Antioxidant Alpha-tocopherol
Sigma-Aldrich Beeswax white Foam adjuvant Beeswax white Henry
Lamotte Behenyl alcohol Foam adjuvant Lanette 22 Cognis Benzoyl
peroxide Active agent Benzoyl peroxide Spectrum BHA Antioxidant
Butylhydroxyanisole Merk BHT Antioxidant Butylated Hydroxitoluene
Spectrum C12-C15 alkyl benzoate Solvent C12-C15 alkyl benzoate
Finetex Castor oil Solvent Castor oil Fluka Ceteareth-20 Surfactant
Sympatens acs 200G Colb Cetearyl octanoate Solvent Luvitol EHO BASF
Ceteth-2 Surfactant Lipocol C-2 Lipo Cetostearyl alcohol Foam
adjuvant Speziol C16-C18 Cognis Cetyl alcohol Foam adjuvant Speziol
C16 Cognis Cholesterol Wax Cholesterol Spectrum Cocoglycerides
Solvent Novata A Cognis Coconut oil Solvent Coconut oil Henry
Lamotte Cyclomethicone-5 Solvent ST-cyclomethicone-5 Dow Diclofenac
Sodium Active agent Diclofenac Sodium Spectrum Diethylene glycol
Solvent Transcutol Gattefosse monoethyl ether Dimethyl Isosorbide
Solvent Dimethyl Isosorbide Dotticon Dimethyl Sulfoxide Solvent
Dimethyl Sulfoxide Fluka Diisopropyl adipate Solvent Isoadipate
Symrise GmbH Doxycycline Hyclate Active agent Doxycycline Hyclate
Yangzhou Ethanol Absolute Solvent Ethanol Absolute J. T. Baker
Ethylcellulose Polymer EC-Ethocel 100 cP FP Colorcon Dow Gelled
mineral oil Solvent Versagel M 750 Penreco PPG-20 Methyl Glucose
Humectant Glucam P20 Distearate Lubrizol Ether Distearate Glycerin
Solvent Glycerin Cognis Glyceryl monostearate Surfactant Cutina GMS
V PH Cognis Hard Fat Wax Softisan 378 Sasol Heavy Mineral Oil
Solvent Paraffin oil liquid heavy Gadot Hexylene Glycol Solvent
Hexylene Glycol Sigma-Aldrich Hydrogenated castor oil Foam adjuvant
Cutina HR Cognis Isododecane Solvent AB117128 ABCR GmbH & Co.
KG Isopropyl myristate Solvent Isopropyl Myristate Ph. Cognis
Isostearic acid Foam adjuvant Isostearic acid Stearinerie Dubois
Isostearyl alcohol Solvent Prisorine 3515 Croda Lanolin Foam
adjuvant Lanolin Spectrum Laureth-4 Surfactant Dehydol LS 4 DEO N
Cognis Light Mineral Oil Solvent Pioner 2076P Hansen &
Rosenthal MCT Oil Solvent Captex 355 Abitec Menthol Additive
Menthol Premium Ingredients Int. Methyl glucose Surfactant Tego
Care PS Evonik Goldeshmidt sesquistearate Metronidazole Active
agent Metronidazole Galdetma Minocycline HCl Active agent
Minocycline HCl Hovione Mometasone furoate Active agent Mometasone
furoate Sicor de Mexico Cetearyl alcohol & Surfactant Montanov
S Seppic coconut alcohol Myristyl alcohol Foam adjuvant Speziol C14
Cognis Octyldodecanol Solvent Eutanol G Cognis Oleic acid Solvent
Oleic acid Spectrum Oleth-20 Surfactant Emulgin O 0 S Cognis Oleyl
alcohol Solvent HD Eutanol V PH Cognis Palmitic acid Foam adjuvant
Edenor C16 98-100GW Cognis Paraffin wax 42-44 Wax Paraffin 42-44
Merck Paraffin wax 51-53 Wax Paraffin 51-53 Merck Paraffin wax
58-62 Wax Paraffin 58-62 Merck PEG-40 Hydrogenated Surfactant
Emulgin HRE 40 Cognis castor oil Polyethylene glycol-200 Solvent
PEG 200 Merck Polyethylene glycol-400 Solvent PEG 400 Sigma-Aldrich
PEG-75 Lanolin Surfactant SOLULAN 75 Lubrizol PEG-100 Stearate
Surfactant Myrj 59 P Croda PEG-150 distearate Surfactant Emulgin EO
33 Cognis Permethrin Active agent Permethrin Sigma Petrolatum
Carrier Sofmetic LMP Sofmetic Pimecrolimus Active agent
Pimecrolimus -- PPG 15 stearyl ether Solvent Arlamol E Uniqema
PPG-20-methyl Humectant Glucam P-20 Lubrizol glucose ether
Propane/Isobutane/ Propellant A-46 Aeropress Butane (20:78:2)
Propane/Isobutane/ Propellant AP-70 Aeropress Butane (55:18:27)
Propyl gallate Antioxidant Propyl gallate Sigma-Aldrich Propylene
glycol Solvent Propylene glycol Gadot Salicylic acid Active agent
Salicylic acid Merck Silicon dioxide Dispersant Aerosil R 972 PH
Evonik-Goldschmidt GmbH Sorbitan sesquistearate Surfactant Tego
care PS Degussa Soybean oil Solvent Soybean oil Spectrum Sorbitan
monopalmitate Surfactant SPAN 40 Spectrum Sorbitan monostearate
Surfactant SPAN 60 Uniqema Steareth-2 Surfactant Brij 72 Spectrum
Steareth-21 Surfactant Brij 721 Spectrum Stearic acid Foam adjuvant
Edenol ST1M Cognis Stearyl Alcohol Foam adjuvant Speziol C18 Cognis
Sucrose stearic acid Surfactant Surfhope SE D1803 Mitsubishi
estersD1803 Sucrose stearic acid Surfactant Surfhope SE D1807
Mitsubishi estersD1807 Sucrose stearic acid Surfactant Surfhope SE
D1811 Mitsubishi estersD1811 Sucrose stearic acid Surfactant
Surfhope SE D1813 Mitsubishi estersD1813 Terbinafine HCl Active
agent Terbinafine HCl Taro Tetracycline HCl Active agent
Tetracycline HCl Xian lijun Titanium dioxide -- Kemira AFDC Kermira
Polysorbate 20 Surfactant Tween 20 Merck Polysorbate 60 Surfactant
Tween 60 Merck Urea Active agent Urea Gadot Vitamin E Antioxydant
Tocopherol Sigma White Petrolatum Carrier Vaseline codex GAL Aiglon
(hard) White Petrolatum Carrier Sofmetic LMF MMP (soft)
1,3-Butandiol Solvent Butylene Glycol Sigma-Aldrich C12-15 Alkyl
Lactate Emollient C12-15 Alkyl Lactate A&E Connock
Canisters Filling and Crimping
[0403] Each aerosol canister is filled with the bulk formulation)
and crimped with valve using vacuum crimping machine. The process
of applying a vacuum will cause most of the oxygen present to be
eliminated. Addition of hydrocarbon propellant may, without being
bound by any theory, further help to reduce the likelihood of any
remaining oxygen reacting with the active ingredient. It may do so,
without being bound by any theory, by one or more of dissolving in,
to the extent present, the oil or hydrophobic phase of the
formulation, by dissolving to a very limited extent in the aqueous
phase, by competing with some oxygen from the formulation, by
diluting out any oxygen, by a tendency of oxygen to occupy the dead
space, and by oxygen occupying part of the space created by the
vacuum being the unfilled volume of the canister or that remaining
oxygen is rendered substantially ineffective in the
formulation.
Pressurizing & Propellant Filling
[0404] Pressurizing is carried out using a hydrocarbon gas or gas
mixture. Canisters are filled and then warmed for 30 seconds in a
warm bath at 50.degree. C. and well shaken immediately
thereafter.
[0405] By way of non-limiting example, tests are briefly set out
below as would be appreciated by a person of the art.
[0406] Viscosity is measured with Brookfield LVDV-II+PRO with
spindle SC4-25 at ambient temperature and 20, 10, 5 and/or 1 RPM.
Viscosity is usually measured at 10 RPM or 20 RPM. However, at
about the apparent upper limit for the spindle of .about.<50,000
CP, the viscosity at 1 RPM may be measured, although the figures
are of a higher magnitude.
[0407] Chemical Stability: the amount of active agent present is
analyzed chromatographically. Analysis is carried out after
formulation preparation and at appropriate time intervals
thereafter. The samples are typically stored in controlled
temperature incubators at one or more of 5.degree. C., 25.degree.
C. and 40.degree. C. for several weeks or months. At appropriate
time intervals samples are removed from the incubators and the
concentration of active agent and/or a degradation product is
measured.
Example 2--Oleaginous Formulations with Low Viscosity
[0408] The different hydrophobic solvents suitable for use in
topical pharmaceutical compositions are generally liquid oils that
have a low viscosity. When these oils are used as-is for active
agents topical delivery, they have inter alia two non desirable
properties: (1) because of their low viscosity, they tend to drop
and to be runny and therefore not easy for the patient to apply
onto the skin, (2) they have poor suspending properties leading to
the rapid sedimentation of non-dissolved active ingredients (APIs),
as described in Table 2.
TABLE-US-00003 TABLE 2 Low viscosity oleaginous preparations
Formulations 001P 001 002P 002 008P 008 % w/w % w/w % w/w % w/w %
w/w % w/w Ingredients Heavy mineral oil 75.00 75.00 -- -- -- --
Light mineral oil 25.00 25.00 -- -- -- -- Soybean oil -- -- 100 100
-- -- Petrolatum -- -- -- -- 50 50 C12-C15 alkyl -- -- -- -- 50 50
benzoate Total 100.00 100.00 100.00 100.00 100.00 100.00
Minocycline HCl -- 0.1 -- 0.1 -- 0.1 Results Viscosity at 10 96 92
47 49 488 303 rpm (cP)
[0409] As shown in formulations 001P and 002P, mixtures of mineral
oils and soybean oil have a low viscosity. Formulations 001 and 002
show that after the addition of Minocycline HCl, the viscosity of
the formulation remains unchanged and that the active ingredient
sediments (as observed visually).
[0410] Similarly, as shown in formulations 008P and 008, the
viscosity of mixtures of petrolatum and alkyl benzoate remains
unchanged after the addition of Minocycline HCl.
Example 3--Oleaginous Formulations with High Viscosity
[0411] The influence of the combination of a tetracycline with
fatty alcohols, fatty acids and waxes on formulation viscosity was
assessed, as described in Table 3a. Formulations were prepared
containing petrolatum or coconut oil, alone or in combination with
fatty alcohols or fatty acids, and their viscosity was measured
before and after the addition of 0.1% of a tetracycline, namely
Minocycline HCl. Table 3 below presents the results of formulation
viscosity before and after the addition of a tetracycline, as well
as the percentage of viscosity increase due to the addition of the
active ingredient. Apparently, as observed in this experiment, when
the viscosity of the composition without minocycline is high, such
as about or more than 25,000 cPs, the synergistic effect between
the minocycline (at a low level of 0.1%) and the second rheology
modifying agent is not discernable or is not expressed or does not
prevail.
TABLE-US-00004 TABLE 3 High viscosity oleaginous preparations
Formulations 018 019 020 021 022 023 Ingredients % w/w % w/w % w/w
% w/w % w/w % w/w Petrolatum 100 90 90 90 -- -- Coconut oil -- --
-- -- 100 90 Stearyl alcohol -- 10 -- 5 -- 10 Stearic acid -- -- 10
5 -- -- Total 100.00 100.00 100.00 100.00 100.00 100.00 Viscosity
Results at 10 rpm (cP) Without Minocycline HCl 17692 24347 21611
41511 20604 24571 With 0.1% Minocycline HCl 20252 21499 22011 40151
19340 22459 % Viscosity Change +14% -12% +2% -3% -6% -9%
Example 4--Mineral Oil-Based Formulations with Controlled
Viscosity
[0412] Part A--Combination of a Tetracycline with a Fatty Alcohol,
a Fatty Acid or a Wax
[0413] The influence of the combination of a tetracycline with
fatty alcohols, fatty acids and waxes on formulation viscosity was
assessed, as described in Table 4a. Formulations containing a
mixture of mineral oils with fatty alcohols, fatty acids, waxes and
combinations thereof were prepared, and their viscosity was
measured before and after the addition of a tetracycline, namely
Minocycline HCl. Table 4a below presents the results of formulation
viscosity before and after the addition of a tetracycline, as well
as the percentage of viscosity increase due to the addition of the
active ingredient.
TABLE-US-00005 TABLE 4a Combination of a tetracycline with fatty
alcohols, fatty acid and waxes Formulations 003 004 005 024 027 036
028 Ingredients % w/w % w/w % w/w % w/w % w/w % w/w % w/w Heavy
mineral oil 65 65 65 65 65 65 65 Light mineral oil 25 25 25 30 25
25 25 Stearyl alcohol 10 -- -- -- 5 -- 5 Stearic acid -- 10 -- --
-- 5 -- Beeswax -- -- 10 -- -- -- 2.5 Hydrogenated -- -- -- 5 5 5
2.5 castor oil Total 100.00 100.00 100.00 100.00 100.00 100.00
100.00 Viscosity Results at 10 rpm (cP) Without Minocycline HCl 951
1858 942 848 10718 6719 5823 With 0.1% Minocycline HCl 2652 8142
1695 6223 38936 26762 16924 % Viscosity Change +179% +338% +80%
+634% +263% +298% +191%
[0414] Surprisingly, it was discovered that the addition of
minocycline HCl to mineral oil-based formulations 003 to 005 led to
a substantial increase in viscosity, despite the very low
concentration of minocycline HCL used, namely 0.1%. These totally
unexpected results show that the combination of a tetracycline,
even at very low concentrations, with fatty alcohols, or fatty
acids or waxes has a strong synergistic effect on oleaginous
formulation viscosity. Without being bound by any theory it seems
that tetracyclines can interact with fatty acids or fatty alcohols
to produce a rheology viscosity effect and may interact to
form--without being bound by any theory a complex of some sort in
the formulation, which provides for the rheology effect
observed.
[0415] As shown in formulations 027, 036 and 028, the same effect
of low concentrations of tetracycline on formulation viscosity is
observed when the oleaginous composition contains a combination of
a fatty alcohol or fatty acid with hydrogenated castor oil, with or
without beeswax.
[0416] The results also indicate a strong role for hydrogenated
caster oil as a rheology modulator in combination with minocycline
as well as on its own to a lesser extent.
Part B--Combination of a Tetracycline with Different Fatty
Alcohols
[0417] The influence of the combination of a tetracycline with
different fatty alcohols on formulation viscosity was assessed, as
described in Table 4b. Formulations containing a mixture of mineral
oils with different fatty alcohols were prepared, and their
viscosity was measured before and after the addition of a
tetracycline, namely minocycline HCl. Table 4b below presents the
results and shows, the percentage of viscosity change due to the
addition of the active ingredient.
TABLE-US-00006 TABLE 4b Combination of a tetracycline with
different fatty alcohols Formulations 037 038 039 041 Ingredients %
w/w % w/w % w/w % w/w Heavy mineral oil 65 65 65 65 Light mineral
oil 25 25 25 25 Myristyl alcohol 10 -- -- -- Cetyl alcohol -- 10 --
-- Stearyl alcohol -- -- 10 -- Behenyl alcohol -- -- -- 10 Total
100.00 100.00 100.00 100.00 Viscosity Results at 10 rpm (cP)
Without Minocycline HCl 336 1808 960 5679 With 0.1% Minocycline HCl
1040 5775 4591 6527 % Viscosity Change +210% +219% +378% +15%
[0418] The results indicate that an increase in formulation
viscosity upon addition of Minocyclineminocycline HCl is observed
with myristyl alcohol, cetyl alcohol and stearyl alcohol. However,
in this experiment the corresponding effect of behenyl alcohol
alone (with low minocycline concentration) is lower.
Part C--Formulation with Increased Viscosity and Various
Concentrations of Minocycline
[0419] The influence of the combination of different concentrations
of a tetracycline with fatty alcohols, fatty acids, waxes and
combinations thereof on formulation viscosity was assessed, as
described in Table 4c. Formulations containing a mixture of mineral
oils with fatty alcohols, fatty acids, waxes and combinations
thereof were prepared, and their viscosity was measured before and
after the addition of different concentrations of a tetracycline,
namely minocycline HCl.
TABLE-US-00007 TABLE 4c Formulation with increased viscosity and
various concentrations of Minocycline Formulations 014 015 016 017
024 Ingredients % w/w % w/w % w/w % w/w % w/w Heavy mineral oil 65
65 65 65 65 Light mineral oil 30 30 30 30 30 Stearyl alcohol 5 --
-- 2.5 1.25 Stearic acid -- 5 -- -- 1.25 Beeswax -- -- -- -- 1.25
Hydrogenated -- -- 5 2.5 1.25 castor oil Total 100.00 100.00 100.00
100.00 100.00 Viscosity Results at 10 rpm (cP) Without Minocycline
HCl 152 135 848 4527 2815 With 0.1% Minocycline HCl 234 779 6223
7007 4191 % Viscosity Change +54% +477% +634% +55% +49% Without
Minocycline HCl 152 135 848 4527 2815 With 0.5% Minocycline HCl
1212 1107 14973 12717 9054 % Viscosity Change +697% +720% +1666%
+181% +222% Without Minocycline HCl 152 135 848 4527 2815 With 1.0%
Minocycline HCl 878 819 20108 10510 7806 % Viscosity Change +478%
+507% +2271% +132% +177%
[0420] Surprisingly, it was discovered that the addition of
minocycline HCl to mineral oil-based formulations 014 to 017 and
024, containing as low as 5% of a fatty alcohol, a fatty acid a wax
and combinations thereof, led to a very substantial increase in
viscosity, where the increase in viscosity is dependent of the
concentration of the active ingredient. It was noticed that
formulations having a higher concentration of active ingredient
have a higher viscosity.
[0421] Therefore, the combination of a tetracycline with a fatty
alcohol, a fatty acid and/or a wax has a strong synergistic effect
in the viscosity of oleaginous formulation. The results may
indicate that subject to the second rheology agent used the effect
of a certain concentration of tetracycline may reach a plateau or
peak beyond which increasing the amount of minocycline will not
significantly increase the rheology effect as reflected in the
viscosity measurements.
[0422] A first glass vial was filed with a placebo of formulation
016, and a second glass vial was filed with formulation 016
containing 0.1% minocycline HCl. As depicted in FIG. 2, both vials
were photographed in horizontal and vertical position showing that
the placebo formulation is a liquid which freely flows, while the
formulation containing 0.1% minocycline HCl is a semi-solid
gel-like. Therefore, the addition of an amount as small as 0.1%
minocycline HCl to said formulation has an outstanding effect both
of the formulation viscosity and on the formulation physical state
which changes from a liquid to a semi-solid.
[0423] The influence of the addition of different concentrations of
a tetracycline on a mineral oils-based formulation was then studied
when the active ingredient is combined with a mixture of mineral
oils, fatty alcohols, fatty acids and waxes, as described in Table
4d and 4e.
TABLE-US-00008 TABLE 4d Oleaginous stock formulation Stock
Formulation 238P Ingredients % w/w Heavy mineral oil 59.25 Light
mineral oil 25.00 Cyclomethicone 5.00 Stearyl alcohol 1.50 Beeswax
2.00 Stearic acid 2.00 Hydrogenated castor oil 1.50 Behenyl alcohol
1.00 Cetostearyl alcohol 2.50 Silicon dioxide 0.25 Total 100.00
TABLE-US-00009 TABLE 4e Oleaginous preparations with increased
viscosity Formulations 238P 238A 238B 238C 238D Ingredients % w/w %
w/w % w/w % w/w % w/w Stock Formulation 238P 100.00 99.90 99.80
99.50 99.00 Minocycline HCl -- 0.10 0.20 0.50 1.00 Viscosity
Results 6639 15789 18476 20876 20748 at 10 rpm (cP) % Viscosity
Change -- +138% +178% +214% +213%
[0424] The combination of a tetracycline with a mixture of mineral
oils, fatty alcohols, fatty acids and waxes has a strong
synergistic effect and increases the formulation viscosity. The
viscosity of a formulation containing 0.50% minocycline HCl is
about three times higher than the viscosity of the placebo
formulation. The effect on the formulation viscosity is clearly
related to the concentration of the tetracycline: the higher the
tetracycline concentration, the higher the viscosity of the
formulation. In formulation 238, it appears that the viscosity
increasing effect of Minocycline HCl reaches a plateau when the
active ingredient is present at a concentration of about 0.50%.
[0425] In one or more embodiments, there is provided an oleaginous
formulation containing mineral oils and a tetracycline in
synergistic combination with a fatty alcohol, and/or a fatty acid
and/or a wax, wherein the viscosity of the formulation is increased
by the addition of the active ingredient by more than about 50%,
more than about 100%, more than about 200%, more than about 300%,
or more than about 500%.
[0426] In one or more embodiments, there is provided an oleaginous
formulation containing hydrophobic solvents, an active ingredient
in synergistic combination with a second rheology modulator,
wherein the viscosity of the formulation is increased by the
addition of the active ingredient by more than about 50%, more than
about 100%, more than about 200%, more than about 300%, or more
than about 500%.
[0427] In one or more embodiments, the increase in the formulation
viscosity is related to the concentration of the active agent.
[0428] In one or more embodiments, the viscosity of the formulation
is proportional to the concentration of the active agent: the
higher the concentration of the active ingredient, the higher the
formulation viscosity.
[0429] In one or more embodiments, the viscosity increasing effect
of the active ingredient reaches a plateau when the concentration
of the active ingredient is increased.
[0430] In one or more embodiments, the viscosity of the formulation
containing the active ingredient is at least twice the viscosity of
the sample formulation without the active ingredient when the
active ingredient when present is present at a concentration of
less than about 10%, less than about 5%, less than about 1%, less
than about 0.5%, less than about 0.1%, less than about 0.05%, or
less than about 0.01%.
Example 5--Mixture of Petrolatum and Mineral Oil-Based Formulations
with Increased Viscosity
[0431] In formulation based on petrolatum and various amounts of
mineral oil, the influence of the combination of a tetracycline
with fatty alcohols on formulation viscosity was assessed, as
described in Table 5. Formulations containing a mixture of
petrolatum and light mineral oil with a fatty alcohol were
prepared, and their viscosity was measured before and after the
addition of a tetracycline, namely minocycline HCl.
TABLE-US-00010 TABLE 5 Petrolatum and Mineral oil-based
formulations with increased viscosity Formulations 009 010 011 012
013 Ingredients % w/w % w/w % w/w % w/w % w/w Petrolatum 90 65 40
15 10 Light Mineral oil -- 25 50 75 90 Stearyl alcohol 10 10 10 10
10 Total 100.00 100.00 100.00 100.00 110.00 Viscosity Results at 10
rpm (cP) Without Minocycline HCl 26234 10510 3263 378 341 With 0.1%
Minocycline HCl 28058 12254 5039 1204 1307 % Viscosity Change +7%
+17% +54% +219% +283%
[0432] When the viscosity of the placebo formulation is high, as in
formulation 009, and the concentration of minocyline is low (e.g.
0.1%) no significant increase in viscosity was noticed. Formulation
010, which contains low amounts of mineral oil, exhibited a minor
increase in viscosity upon the addition of 0.1% minocycline HCl
(which with higher amounts of minocycline could have been more
substantial). However, very surprisingly, it was observed that the
addition of a very low amount of minocycline HCl greatly increases
formulation viscosity, when the viscosity of the placebo
formulation is lower, as in formulations 011, 012 and 013, which
contain increasingly higher amounts of mineral oil.
[0433] As shown in FIG. 1, the percentage of change in viscosity by
the addition of Minocycline HCl is exponentially related to the
viscosity of the formulation placebo.
[0434] In one or more embodiments, there is provided an oleaginous
formulation containing hydrophobic solvents and a tetracycline in
synergistic combination with a fatty alcohol, wherein the viscosity
of the formulation is increased by the addition of the active
ingredient by more than about 50%, more than about 100%, more than
about 200%, more than about 300%, more than about 500%.
[0435] In one or more embodiments, the lower the viscosity of the
placebo formulation, the greater the increase in formulation
viscosity after addition of the active ingredient.
Example 6--Other Oils-Based Formulations with Increased
Viscosity
[0436] The influence of the addition of a tetracycline on vegetable
oils-based formulations was then studied when the active ingredient
is combined with a mixture of vegetable oils, fatty alcohols, fatty
acids and waxes, as described in Table 6.
TABLE-US-00011 TABLE 6 Formulation based on vegetable oils with
increased viscosity Formulations 244P 244B 244A Ingredients % w/w %
w/w % w/w Soybean oil 50.00 50.00 50.00 Coconut oil 23.60 23.60
23.60 Light Mineral oil 5.55 4.40 0.95 Cyclomethicone 5.00 5.00
5.00 Cetostearyl alcohol 3.50 3.50 3.50 Stearic acid 3.00 3.00 3.00
Myristyl alcohol 2.50 2.50 2.50 Hydrogenated castor oil 2.00 2.00
2.00 Beeswax 2.00 2.00 2.00 Stearyl alcohol 1.50 1.50 1.50 Behenyl
alcohol 1.10 1.10 1.10 Silicon dioxide 0.25 0.25 0.25 Total 100.00
100.00 100.00 Minocycline HCl -- 1.15 4.60 Viscosity Results at 10
rpm (cP) 7214 14429 17084 % Viscosity Change -- +100% +137%
[0437] The combination of a tetracycline with a mixture of
vegetable oils, fatty alcohols, fatty acids and waxes has a strong
synergistic effect and increases the formulation viscosity. The
viscosity of a formulation containing 1.15% minocycline HCl is
about twice higher than the viscosity of the placebo formulation.
Moreover, the effect on the formulation viscosity is directly
related to the concentration of the tetracycline: the higher the
tetracycline concentration, the higher the viscosity of the
formulation. Formulation 244 is a solid gel which spreads easily
upon application of shear force.
[0438] In one or more embodiments, there is provided an oleaginous
formulation containing vegetable oils and a tetracycline in
synergistic combination with a fatty alcohol, a fatty acid and a
wax, wherein the viscosity of the formulation is increased by the
addition of the active ingredient by more than about 50%, more than
about 100%, more than about 200%, more than about 300%, or more
than about 500%.
Example 7--Stability of a Tetracycline in Viscosity Controlled
Formulations
[0439] Tetracycline antibiotics are known to be very unstable
active agents that are degraded by a wide range of commonly used
pharmaceutical excipients. For example, it has been found that
minocycline is degraded in 1 to 2 days in the presence of various
hydrophilic solvents (such as water, glycerin, sodium PCA,
propylene glycol and polyethylene glycols), by water dispersed
polymers (such as xanthan gum, poloxamers, carbomers, methocel,
sodium carboxymethylcellulose) and by surfactants (such as
polysorbates, sorbitan esters, polyoxyalkyl esters and
lanolin-based surfactants). Thus, the achievement of a long term
stable formulation of tetracycline antibiotics described herein,
was a major challenge and required both extensive research and
creativity.
[0440] The following example illustrates the chemical stability of
Minocycline HCl (MCH) in an oleaginous formulation as described in
Tables 7a. In an accelerated stability study, samples were stored
at 40.degree. C., and the concentration of Minocycline HCl was
determined by chromatographic methods. The stability test results
following, 3 weeks and 6 months of storage at 40.degree. C. are
shown in Table 7b.
TABLE-US-00012 TABLE 7a Composition of formulation incubated at
40.degree. C. Formulations 244B Ingredients % w/w Soybean oil 50.00
Coconut oil 23.60 Light Mineral oil 4.40 Cyclomethicone 5.00
Cetostearyl alcohol 3.50 Stearic acid 3.00 Myristyl alcohol 2.50
Hydrogenated castor oil 2.00 Beeswax 2.00 Stearyl alcohol 1.50
Behenyl alcohol 1.10 Silicon dioxide 0.25 Total 100.00 Minocycline
HCl 1.11
TABLE-US-00013 TABLE 7b Analytical Stability results of composition
244B containing Minocycline HCl after 3 after 6 weeks months T0 at
40.degree. C. at 40.degree. C. Minocycline 101.5% 99.1% 95.3%
content (%)
[0441] Very surprisingly, and despite the known instability of
tetracycline antibiotics, the accelerated stability results of
formulation 244B after 3 weeks and 6 months at 40.degree. C. showed
minimal degradation of the active agent in the formulations. The
formulations disclosed herein thus show an extended accelerated
stability for the tetracycline antibiotic active agent, an
outstanding physical stability, wherein the viscosity of the
formulation is substantially increased by the addition of the
active ingredient.
[0442] In another experiment, a sample of formulation 244B was
stored during 6 months at 40.degree. C. and tested for active
ingredient content uniformity and physical stability. It was found
that minocycline HCl was homogeneously dispersed into formulation
even after prolonged incubation at 40.degree. C. Furthermore, it
was found that the formulation remained as a homogeneous gel after
6 months of incubation at 40.degree. C.
[0443] In one or more embodiments, there is provided a formulation
wherein the active ingredient is homogeneously dispersed in the
formulation and remains homogeneously dispersed after 6 months of
incubation at 40.degree. C.
Example 8--Formulations with Improved Viscosity and Various Active
Ingredients
[0444] Formulation with different active ingredients were prepared
as described in Table 8a, to study the influence of the combination
of various active ingredients with a fatty alcohol on formulation
viscosity.
TABLE-US-00014 TABLE 8a Formulations of fatty alcohol and oil with
improved viscosity with various active ingredients Formulations 029
030 031 032 033 Ingredients % w/w % w/w % w/w % w/w % w/w Heavy
Mineral oil 65 65 65 65 65 Light mineral oil 25 25 25 25 25 Stearyl
alcohol 10 10 10 10 10 Total 100.00 100.00 100.00 100.00 100.00
Minocycline HCl 0.05 -- -- -- -- micronized Minocycline HCl -- 0.10
-- -- -- non micronized Tetracycline HCl -- -- 0.10 -- --
Cholesterol -- -- -- 0.10 -- Benzoyl peroxide -- -- -- -- 0.10
Viscosity Results at 10 rpm (cP) Placebo 1152 1152 1152 1152 1152
With Active ingredient 2655 2128 2655 1888 2112 % Viscosity Change
+130% +85% +130% +64% +83%
[0445] It was found that the increase in viscosity observed after
the addition of the active ingredient minocycline is also observed
with other active ingredients. A strong increase in formulation
viscosity was observed with tetracycline HCl which is another
compound of the tetracycline class. To a lesser extent, an increase
in formulation viscosity was observed with Cholesterol which is
also a 4-ring compound and with benzoyl peroxide. It can be note
that the strongest effect was observed with tetracycline compounds,
such as Minocycline HCl and Tetracycline HCl. It can be further
noted that even at concentrations as low as 0.05%, the addition of
Minocycline HCl to the formulations more than doubled the
viscosity. It is further noted that micronized preparations appear
to have a more pronounced effect. Without being bound by any theory
a possible explanation might be that the rheology change is
improved when smaller particles are used providing a higher surface
area exposure of the active therapeutic, which facilitates more
interactions within the composition.
[0446] Formulation with different active ingredients were prepared
as described in Table 8b and Table 8c, to study the influence of
the combination of various active ingredients with a wax on
formulation viscosity.
TABLE-US-00015 TABLE 8b Formulations of wax and oil with improved
viscosity with various active ingredients (continued) Formulations
042 043 044 045 046 047 048 049 Ingredients % w/w % w/w % w/w % w/w
% w/w % w/w % w/w % w/w Heavy Mineral oil 65 65 65 65 65 65 65 65
Light mineral oil 30 30 30 30 30 30 30 30 Hydrogenated Castor oil 5
5 5 5 5 5 5 5 Total 100.00 100.00 100.00 100.00 100.00 100.00
100.00 100.00 Minocycline HCl 0.10 -- -- -- -- -- -- -- micronized
Minocycline HCl -- 0.10 -- -- -- -- -- -- non micronized
Tetracycline HCl -- -- 0.10 -- -- -- -- -- Cholesterol -- -- --
0.10 -- -- -- -- Benzoyl peroxide -- -- -- -- 0.10 -- -- --
Mometasone Furoate -- -- -- -- -- 0.10 -- -- Doxycycline Hyclate --
-- -- -- -- -- 0.10 -- Salicylic acid -- -- -- -- -- -- -- 0.10
Viscosity Results at 10 rpm(cP) Placebo 816 816 816 816 816 816 816
816 With Active ingredient 3343 13357 8126 2415 7039 10606 7566
8974 % Viscosity Change +310% +1537% +896% +196% +763% +1200% +827%
+1000%
TABLE-US-00016 TABLE 8c Formulations of wax and oil with improved
viscosity with various active ingredients (further continued)
Formulations 050 051 052 053 054 055 056 Ingredients % w/w % w/w %
w/w % w/w % w/w % w/w % w/w Heavy Mineral oil 65 65 65 65 65 65 65
Light mineral oil 30 30 30 30 30 30 30 Hydrogenated 5 5 5 5 5 5 5
Castor oil Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00
Vitamin E 0.10 -- -- -- -- -- -- Diclofenac -- 0.10 -- -- -- -- --
Urea -- -- 0.10 -- -- -- -- Terbinafine -- -- -- 0.10 -- -- --
Permethrin -- -- -- -- 0.10 -- -- Metronidazole -- -- -- -- -- 0.10
-- Pimecrolimus -- -- -- -- -- -- 0.10 Viscosity Results at 10
rpm(cP) Placebo 816 816 816 816 816 816 816 With Active ingredient
7310 5663 5551 12733 6623 11246 12909 % Viscosity Change +796%
+594% +580% +1461% +712% +1278% +1482%
[0447] It was noted that after various active ingredient were added
separately to an oil and wax oleaginous formulation a viscosity
increase is observed over a wide range of active ingredients.
Example 9--Formulation with Beeswax Alone in Mineral Oil
[0448] The influence of a low concentration of tetracycline with
beeswax on formulation viscosity was compared in Table 9.
TABLE-US-00017 TABLE 9 Oleaginous preparations Formulations 005
Ingredients % w/w Heavy mineral oil 65 Light mineral oil 25 Beeswax
10 Total 100.00 Viscosity Results at 10 rpm (cP) Without
Minocycline HCl 942 With 0.1% Minocycline HCl 1695 % Viscosity
Change +80%
Example 10--Compatibility Study
[0449] Procedure: Minocycline hydrochloride ("MCH") was incubated
as a suspension with various excipients at 25.degree. C. and
40.degree. C. for maximum of sixty days or to the point where
degradation was suspected. The ratio between MCH and the tested
excipient is detailed below. Visual inspection was the major
criterion for indication of compatibility. The color of intact MCH
suspension is pale yellow; and any change of color (e.g., to dark
orange, red, green, brown and black) indicates oxidation or
degradation.
[0450] Hydrophilic solvents were tested for compatibility with MCH
at a ratio of MCH:excipient of 1:250. Dimethyl Isosorbide,
Glycerin, Ethanol, Propylene glycol, Butylene Glycol, PEG 200,
Hexylene Glycol, PEG 400, Dimethyl Sulfoxide and Diethylene glycol
monoethyl ether were found to be incompatible with MCH.
[0451] Oily emollients and waxes were tested for compatibility with
MCH at a ratio of MCH:excipient of 1:250 for Oily emollients and
1:50 for waxes. Hydrogenated castor oil, Castor oil,
Cocoglycerides, Disopropyl adipate, Mineral oil light, Coconut oil,
Beeswax, MCT oil, Cyclomethicone, Isododecane, Cetearyl octanoate,
Gelled mineral oil, Isopropyl myristate, PPG 15 stearyl ether,
Mineral oil heavy, Octyl dodecanol, White Petrolatum, Petrolatum
(Sofmetic), Paraffin 42-44, Paraffin 51-53, Paraffin 56-62,
Calendula oil, Shea butter, Grape seed oil, Almond oil, Jojoba oil,
Avocado oil, Peanut oil, Wheat germ oil and Hard Fat were found to
be compatible with MCH. Pomegranate seed oil was found to be
incompatible with MCH.
[0452] The compatibility of MCH with hydrophobic surfactant was
tested following solubilization of the surfactant in mineral oil
(mineral oil was previously shown to be compatible with MCH).
Surfactants were tested for compatibility with MCH at a ratio of
MCH:excipient of 1:50. PEG150 distearate, Laureth 4, PEG 40
hydrogenated castor oil, PEG 75 lanolin, Glucam P20 distearate,
PEG100 stearate, Glyceryl monostearate, PEG 40 stearate, Montanov S
(Cocoyl Alcohol (and) C12-20 Alkyl Glucoside)), Alkyl lactate,
Benton gel, SPAN 60, Sorbitan sesquistearate, SPAN 40, Tween 20,
Ceteth 2, Sucrose stearic acid esters D1813, Ceteareth 20, Steareth
2/Steareth 21, Methyl glucose sesquistearate, Oleth 20, PPG 20
methyl glucose ether, Tween 60 were found to be incompatible with
MCH. Sucrose stearic acid esters D1803, Sucrose stearic acid esters
D1807 and Sucrose stearic acid esters D1811 were found to be
compatible with MCH; however, not all of them dissolved in oil
(e.g. 1811, 1813).
[0453] Foam adjuvants were tested for compatibility with MCH at a
ratio of MCH:excipient of 1:50. Isostearyl alcohol, Behenyl
alcohol, Stearyl alcohol, Cetyl alcohol, Oleyl alcohol, Myristyl
alcohol, Cetostearyl alcohol, Palmitic acid, Stearic acid and Oleic
acid were found to be compatible with MCH. Isostearic acid was not
compatible with MCH.
[0454] Additives were tested for compatibility with MCH at a ratio
of MCH:excipient of 1:50. Aerosil and Menthol were found to be
compatible with MCH. Titanium dioxide and Ethocel were not
compatible with MCH.
[0455] Additives were tested for compatibility with MCH. Minimal
quantities of water (1004) were added to MCH, suspended in
excipients that had demonstrated compatibility to examine whether
water can enhance oxidation/degradation in the absence or presence
of antioxidant. In parallel, antioxidants were added to the MCH
suspensions comprising water. Antioxidants were also added to
excipients which were found to be non compatible with MCH. Addition
of water caused prompt degradation of MCH. Addition of the
antioxidants alpha-tocopherol, BHA/BHT and propyl gallate did not
prevent MCH degradation. Compatible excipients became incompatible
in the presence of water. Addition of antioxidants did not alter
this result.
* * * * *