U.S. patent application number 17/016542 was filed with the patent office on 2020-12-31 for methods for the treatment of rosacea.
This patent application is currently assigned to SOL-GEL TECHNOLOGIES LTD.. The applicant listed for this patent is SOL-GEL TECHNOLOGIES LTD.. Invention is credited to Haim Bar-Simantov, Hanan SERTCHOOK, Ofer Toledano.
Application Number | 20200405665 17/016542 |
Document ID | / |
Family ID | 1000005078920 |
Filed Date | 2020-12-31 |
United States Patent
Application |
20200405665 |
Kind Code |
A1 |
SERTCHOOK; Hanan ; et
al. |
December 31, 2020 |
METHODS FOR THE TREATMENT OF ROSACEA
Abstract
The present invention relates to pharmaceutical compositions for
topical use (including also dermatological compositions), for
treating skin conditions and afflictions, such as rosacea and
symptoms and conditions associated there from.
Inventors: |
SERTCHOOK; Hanan; (Gedera,
IL) ; Toledano; Ofer; (Kfar Saba, IL) ;
Bar-Simantov; Haim; (Netanya, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SOL-GEL TECHNOLOGIES LTD. |
Ness Ziona |
|
IL |
|
|
Assignee: |
SOL-GEL TECHNOLOGIES LTD.
Ness Ziona
IL
|
Family ID: |
1000005078920 |
Appl. No.: |
17/016542 |
Filed: |
September 10, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15879600 |
Jan 25, 2018 |
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17016542 |
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15496344 |
Apr 25, 2017 |
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15879600 |
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13686533 |
Nov 27, 2012 |
9687465 |
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15496344 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/7056 20130101;
A61K 31/327 20130101; A61K 31/165 20130101; A61K 9/00 20130101;
A61K 31/704 20130101; A61K 9/0014 20130101; A61K 31/192 20130101;
A61K 9/1075 20130101; A61K 47/10 20130101; A61K 9/06 20130101; A61K
2300/00 20130101; A61K 9/501 20130101; A61K 47/14 20130101; A61K
31/7052 20130101 |
International
Class: |
A61K 31/165 20060101
A61K031/165; A61K 31/327 20060101 A61K031/327; A61K 9/00 20060101
A61K009/00; A61K 47/10 20060101 A61K047/10; A61K 47/14 20060101
A61K047/14; A61K 9/107 20060101 A61K009/107; A61K 9/50 20060101
A61K009/50; A61K 9/06 20060101 A61K009/06; A61K 31/192 20060101
A61K031/192; A61K 31/704 20060101 A61K031/704; A61K 31/7052
20060101 A61K031/7052; A61K 31/7056 20060101 A61K031/7056 |
Claims
1. A composition for the topical treatment of rosacea, comprising
as a sole pharmaceutical active agent benzoyl peroxide in solid
form, wherein the composition comprises 5% by weight of said
benzoyl peroxide and said composition is an oil-in-water emulsion;
wherein said solid benzoyl peroxide is encapsulated as the core of
a microcapsule having a shell comprising between 5-100 layers of
metal oxide, and wherein said composition has a dissolution rate of
less than 80% weight/h as measured in a medium of 55%:45% mixture
of water and acetonitrile at ambient temperature.
2. The composition of claim 1, wherein said benzoyl peroxide has a
dissolution rate of less than about 60% weight/h.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation application from U.S.
application Ser. No. 15/879,600, filed Jan. 25, 2018; which is a
Continuation application from U.S. application Ser. No. 15/496,344,
filed Apr. 25, 2017; which is a Continuation application of U.S.
application Ser. No. 13/686,533, filed Nov. 27, 2012, now U.S. Pat.
No. 9,687,465, granted Jun. 27, 2017; which are all incorporated in
their entirety herein by reference.
TECHNOLOGICAL FIELD
[0002] This invention relates to pharmaceutical compositions for
topical use (including also dermatological compositions), for
treating skin conditions and afflictions, such as rosacea and
symptoms and conditions associated there from.
BACKGROUND
[0003] Rosacea is a chronic disease of inflammatory dermatitis that
mainly affects the median part of the face and the eyelids of
certain adults. It is characterized by telangiectatic erythema,
dryness of the skin, papules and pustules. Conventionally, rosacea
develops in adults from the ages of 30 to 50; it more frequently
affects women, although the condition is generally more severe in
men. Rosacea is a primitively vascular condition whose inflammatory
stage lacks the cysts and comedones characteristic of common
acne.
[0004] Factors that have been described as possibly contributing
towards the development of rosacea include for example: the
presence of parasites such as the Demodex folliculorum, the
presence of bacteria such as Helicobacter pylori (a bacterium
associated with gastrointestinal disorders), hormonal factors (such
as endocrine factors), climatic and immunological factors, and so
forth.
[0005] Rosacea develops in four stages over several years, in
spasms aggravated by variations in temperature, alcohol, spices,
exposure to sunlight and stress.
[0006] The various stages of the disease are the following:
[0007] Stage 1: stage of erythema episodes. The patients have
erythrosis spasms due to the sudden dilation of the arterioles of
the face, which then take on a congestive, red appearance. These
spasms are caused by the emotions, meals and temperature
changes.
[0008] Stage 2: stage of couperosis, i.e., of permanent erythema
with telangiectasia. Certain patients also have oedema on the
cheeks and the forehead.
[0009] Stage 3: inflammatory stage (papularpostular rosacea) with
appearance of inflammatory papules and pustules, but without
affecting the sebaceous follicles and thus with absence of cysts
and comedones.
[0010] Stage 4: rhinophyma stage. This late phase essentially
affects men. The patients have a bumpy, voluminous red nose with
sebaceous hyperplasia and fibrous reordering of the connective
tissue.
[0011] Typical treatment of rosacea include oral or topical
administration of antibiotics such as tetracyclines, salicylic
acid, anti-fungal agents, steroids, metronidazole (an
anti-bacterial agent) or with isotretinoin in severe cases, or even
with anti-infectious agents such as azelaic acid.
[0012] US 20110052515 described a pharmaceutical/dermatological
topically applicable formulation for treating rosacea, comprising
at least one avermectin compound and benzoyl peroxide (BPO, an
anti-acne agent).
[0013] Breneman et al. (Int. J. Derma. 43, 381-387 (2004)) reported
the results of a double blind randomized vehicle-controlled
clinical trial of once-daily BPO and clindamycin topical gel in the
treatment of moderate to severe rosacea.
[0014] Montes et al. (Cutis, 32, 185-190 (1983)) disclosed the use
of BPO dissolved in acetone gel formulation for the treatment of
rosacea.
[0015] Wester et al. (J. Am. Acad. Derma. 24, 720-726 (1991))
related to the controlled release of BPO from porous microsphere
polymeric systems in the treatment of acne.
[0016] These previous rosacea treatments with BPO alone or in
combination with other agents, have been shown to have severe
drawbacks such as irritation and intolerance phenomena, especially
when they are administered for a prolonged period. On the other
hand, these treatments are only suppressive and not curative,
acting especially on the pustulous spasms occurring during the
inflammatory stage.
[0017] Considering the chronic nature of rosacea, there is a need
for a prolonged use treatment of the disease, its symptoms and
associated conditions, in a safe and effective manner. Thus, there
exists a need for compositions that show improved efficacy in the
treatment of rosacea, that impart greater tolerance to the active
principles and that do not have the side effects described in the
prior art.
GENERAL DESCRIPTION
[0018] Accordingly, the present invention provides a composition
comprising benzoyl peroxide for topical use in the treatment of
rosacea, wherein said benzoyl peroxide is in a solid form.
[0019] In some embodiments said BPO comprises between about 2.5
weight % to about 5 weight % of the composition. In some
embodiments the BPO is the single pharmaceutical active agent in
the composition. In other embodiments the composition further
comprises a further active agent (pharmaceutical active agent or a
cosmetically active agent).
[0020] The term "topical use" is meant to encompass the topical
administration of a composition of the invention by formulating
said composition in any way known in the art, or in formulations
disclosed herein, which are compatible with the skin, mucous
membranes and/or the integuments.
[0021] The invention further provides a composition comprising
benzoyl peroxide for topical use in the treatment of rosacea,
wherein the dissolution rate of the benzoyl peroxide from
composition is less than about 80% weight/h. In some embodiments of
this aspect, said benzoyl peroxide is the single pharmaceutical
active agent in said composition.
[0022] In some embodiments, said dissolution rate is between about
20% weight/h to about 80% weight/h. In other embodiments, said
dissolution rate is between about 40 to 60% weight/h. In yet other
embodiments, said dissolution rate is less than about 40% weight/h.
In further embodiments said dissolution rate is less than about 20%
weight/h. In some further embodiments said dissolution rate is
between about 10% weight/h to about 50 weight %/h (i.e. 10, 15, 20,
25, 30, 35, 40, 45, 50%/h).
[0023] In the context of the present invention the term
"dissolution rate" relates to the rate in weight per time units of
dissolution of solid BPO from the composition of the invention to
the surrounding immediate environment. The dissolution rate as
disclosed in the present application is measured as disclosed in
Example 5 below.
[0024] The invention further provides a composition comprising
benzoyl peroxide for topical use in the treatment of rosacea,
wherein the dissolution rate of the benzoyl peroxide from
composition is less than about 40 mg/h.
[0025] It has been found by the inventors of the present
application that a composition comprising BPO, having dissolution
rate of less than about 80%/h provides a safer and more effective
treatment of rosacea with respect to the tolerance and adverse
effect as compared with compositions having similar amount of
pharmaceutical active agent with faster dissolution. It was shown
by the inventors of the application that as the dissolution rate of
BPO is lowered to less than 80%/h the treatment of a chronic skin
disease such as rosacea, including its symptoms and conditions
associated therewith, was dramatically improved since the
controlled release of the pharmaceutical active agent was slow
enough to allow for controlled and slow release of the
pharmaceutical active agent over a prolonged period of time,
releasing an amount of BPO able to treat the disease, symptoms
and/or conditions associated with rosacea, but on the other hand
not allowing for intolerance or adverse effects to appear. In some
embodiments when the composition comprises BPO as a single
pharmaceutical active agent, treatment results of rosacea were
comparable to the compositions know in the art comprising BPO and
an antibacterial agent.
[0026] The present invention discloses pharmaceutical compositions,
including dermatological compositions, comprising benzoyl peroxide
as a single pharmaceutical active agent in the solid form. In some
embodiments said compositions are formulated into a physiologically
acceptable form.
[0027] In further embodiments a composition of the invention may
comprise at least one further pharmaceutical active agent (in
addition to the BPO).
[0028] In some embodiments a composition of the invention comprises
at least one further pharmaceutical active agent selected from the
group consisting of an antibiotic agent, a tetracycline agent, a
retinoid, an antimicrobial agent and any combinations thereof.
[0029] In some embodiments said at least one further pharmaceutical
active agent is selected from the following non-limiting list:
Antibiotics such as clindamycin or erythromycin. Tetracyclines such
as minocycline or doxycycline. Retinoids and other compounds that
bind to and activates the RAR and/or RXR receptors such as all
trans retinoic acid (tretinoin), tazarotene, adapalene, a
acitretin, 13 cis retinoic acid (isotretinoin), 9 cis retinoic acid
(alitretinoin) or betaxorene and their metabolic and chemical
derivatives. Antimicrobial agents such as metronidazole, sodium
sulfacetamide-sulfur or azaleic acid, .alpha.-adrenergic receptor
agonist such as brimonidine, oxymetazoline, naphazoline,
tetrahydrozoline, xylometazoline, phenylephrine, methoxamine,
mephentermine, metaraminol, midodrine, epinephrine, clonidine or
norepinephrine.
[0030] Under such embodiments, at least one of said at least one
further pharmaceutical active agent and/or said BPO are
encapsulated in a microcapsule.
[0031] This invention also features compositions formulated as
medicaments for improving, preventing and/or treating a skin
condition, notably rosacea, and which substantially reduce the
duration of the treatment and which provide a greater reduction of
the symptoms of rosacea.
[0032] In some embodiments, said benzoyl peroxide is present in the
composition in an amount of at least about 1.0% by weight of said
composition.
[0033] In some further embodiments, said benzoyl peroxide is
present in the composition in an amount between about 2.5% to about
10% by weight of said composition. In further embodiments said
benzoyl peroxide is present in the composition in an amount of
between about 2.5% to about 5% by weight of said composition.
[0034] In further embodiments, said benzoyl peroxide is in a
crystalline form.
[0035] In some embodiments, said rosacea is papularpostular rosacea
(i.e. inflammatory rosacea, see Rapini, Ronald P. et al. (2007).
Dermatology: 2-Volume Set. St. Louis: Mosby and James, William et
al. (2005). Andrews' Diseases of the Skin: Clinical Dermatology.
(10th ed.). Saunders p. 245).
[0036] In other embodiments, said composition of the invention
demonstrates adverse events value of no more than about (less than
about) 50% upon topical use in the treatment of rosacea. In some
embodiments wherein said composition demonstrates adverse events
values of no more than about (less than about) 40%, 30%, 20% upon
topical use in the treatment of rosacea.
[0037] The term "adverse events values" refers to average
percentage of subjects that experience any adverse events
associated with the treatment of rosacea with a composition of the
invention (usually on the skin of a subject treated with a
composition of the invention). A non-limiting list of such adverse
events includes: irritation, dryness, scaling, purities, burning
and stinging.
[0038] A composition of the invention was shown to demonstrate a
high percentage of subjects having a 2-grade improvement in the IGA
(Investigator General Assessment) and reached a clear or almost
clear condition of the disease, relative to baseline, at week
12.
[0039] In some embodiments said 2-grade improvement in the IGA was
between about 20% to about 80%, in some other embodiments 30% to
70%, in some further embodiments 40-60%.
[0040] The term "dissolution rate of BPO from composition" refers
to the quantitative amount of BPO dissolved from the composition of
the invention in units of mg of BPO per time (h).
[0041] It is to be understood that the inventors of the present
application have surprisingly found that a controlled dissolution
rate of less than about 80% weight/h of BPO from a composition of
the invention provides a safe, tolerable and effective treatment of
a chronic skin disease such as rosacea, causing minimal adverse
effects upon prolonged use of the skin.
[0042] In some further embodiments, a composition of the invention
further comprises at least one non pharmaceutical active additive
selected from the group consisting of chelating agents,
antioxidants, sunscreens, preservatives, fillers, electrolytes,
humectants, dyes, mineral or organic acids or bases, fragrances,
essential oils, moisturizers, vitamins, essential fatty acids,
sphingolipids, self-tanning compounds, calmatives and
skin-protecting agents, pro-penetrating agents and gelling agents,
or a mixture thereof.
[0043] In other embodiments, a composition of the invention is
formulated into a topically applicable, physiologically acceptable
medium consisting of: (a) at least one member selected from the
group consisting of water, alcohols, oils, fatty substances and
waxes; and (b) at least one additive selected from the group
consisting of chelating agents, antioxidants, sunscreens,
preservatives, fillers, electrolytes, humectants, dyes, mineral
acids, mineral bases, organic acids, organic bases, fragrances,
essential oils, moisturizers, vitamins, essential fatty acids,
sphingolipids, self-tanning compounds, calmatives, skin-protecting
agents, pro-penetrating agents, gelling agents, emulsifiers,
co-emulsifiers, and mixtures thereof.
[0044] In some embodiments a composition of the invention is
formulated to an emulsion (including an oil-in-water emulsion, a
water-in-oil emulsion, multiple emulsions and microemulasions). In
other embodiments a composition of the invention is formulated to a
cream. In further embodiments, a composition of the invention is
formulated to a gel.
[0045] The compositions according to the invention are
pharmaceutical compositions, and especially dermatological
compositions, which may be in any galenical form conventionally
used for topical application and especially in the form of aqueous
gels, and aqueous or aqueous-alcoholic solutions. By addition of a
fatty or oily phase, it may also be in the form of dispersions of
the lotion or serum type, emulsions of liquid or semi-liquid
consistency of the milk type obtained by dispersing a fatty phase
in an aqueous phase (0/W) or conversely (W/O), or suspensions or
emulsions of soft, semi-liquid or solid consistency of the cream,
gel or ointment type, or alternatively multiple emulsions (W/O/W or
O/W/O), microemulsions, microcapsules, microparticles or vesicular
dispersions of ionic and/or nonionic type, or wax/aqueous phase
dispersions. These compositions are formulated according to the
usual methods.
[0046] In further embodiments, a composition of the invention
comprising, as a single pharmaceutical active agent, benzoyl
peroxide in a solid form, for topical use in the treatment of
rosacea, is an oil in water emulsion comprising a polyoxylstearate
and a glycerylstearate.
[0047] In some embodiments the ratio of said polyoxylstearate to
said glycerylstearate is in the range of 0.1:10 to 10:0.1.
[0048] In yet further embodiments, said polyoxylstearate is
selected from the group consisting of Polyoxyl-8 stearate,
Polyoxyl-20 stearate, Polyoxyl-40 stearate, and Polyoxyl-100
stearate.
[0049] In further embodiments, said glycerylstearate is selected
from the group consisting of glyceryl mono-stearate, glyceryl
di-stearate and mixtures thereof.
[0050] In other embodiments, said polyoxylstearate in said
composition is in the range of about 0.1% w/w to about 30% w/w.
[0051] In further embodiments, the amount of said glycerylstearate
in said composition is in the range of about 0.1% w/w to about 30%
w/w.
[0052] In other embodiments, said composition further comprises at
least one fatty alcohol.
[0053] In other embodiments, said at least one fatty alcohol is
selected from the group consisting of octyl alcohol, 2-ethyl
hexanol, nonyl alcohol, decyl alcohol, undecanol, dodecyl alcohol,
tridecyl alcohol, tetradecyl alcohol, pentadecyl alcohol, cetyl
alcohol, palmitoleyl alcohol, heptadecyl alcohol, cetostearyl
alcohol, stearyl alcohol, isostearyl alcohol, elaidyl alcohol,
oleyl alcohol, linoleyl alcohol, elaidolinolenyl alcohol,
ricinoleyl alcohol, nonadecyl alcohol, arachidyl alcohol,
heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl
alcohol, ceryl alcohol, montanyl alcohol, cluytyl alcohol, myricyl
alcohol, melissyl alcohol, geddyl alcohol, cetearyl alcohol and
mixtures thereof.
[0054] In further embodiments, the amount of said at least one
fatty alcohol in said composition is in the range of about 0.2% w/w
to about 50% w/w.
[0055] In yet other embodiments, said composition further comprises
a polyacrylic acid homopolymer or copolymer.
[0056] In other embodiments, said oil in said oil in water emulsion
is selected from the group consisting of paraffin oil, isopropyl
myristate, caprylic/capric triglyceride, squalane, squalene, almond
oil, castor oil, olive oil, jojoba oil, sunflower oil, soybean oil,
grape seed oil, dimethicone, cyclomethicone and mixtures
thereof.
[0057] In further embodiments, said oil in present in the
composition in an amount in the range of about 0.05% w/w to about
50% w/w.
[0058] In some embodiments, said water in said oil in water
emulsion further comprises at least one water soluble
humectant.
[0059] In other embodiments, said at least one water soluble
humectant is selected from the group consisting of propylene
glycol, glycerin, and polyethylene glycol-X, where X is in the
range of 200 to 10,000.
[0060] In yet other embodiments, a composition of the invention
comprising, as a single pharmaceutical active agent, benzoyl
peroxide in a solid form, for topical use in the treatment of
rosacea, is in a gel form comprising at least one non-ionic
polymeric dispersant and at least one thickening agent.
[0061] In some embodiments, said at least one non-ionic polymeric
dispersant is selected from the group consisting of poly vinyl
pyrrolidone (PVP), poly vinyl pyrrolidone-co-vinyl acetate,
polyamide, polyurethane, polyurea and mixtures thereof.
[0062] In some further embodiments, said at least one thickening
agent is selected from the group consisting of hydroxy propyl
cellulose (HPC), hydroxyl ethyl cellulose (HEC), hydroxyl methyl
cellulose (HMC), polyacrylic acid homopolymer, polyacrylic acid
copolymer, fatty alcohol, silica and its derivatives, xanthan gum,
arabic gum, poly vinyl alcohol, veegum, laponite, clay, and
mixtures thereof.
[0063] In other embodiments, said at least one thickening agent is
a non-ionic agent.
[0064] In further embodiments, said at least one thickening agent
is an ionic agent.
[0065] In other embodiments, said at least one thickening agent is
present in the composition in an amount in the range of about 0.01%
w/w to about 10% w/w.
[0066] In further embodiments, said composition further comprises
glycerin.
[0067] In other embodiments, said non-ionic polymeric dispersant is
present in the composition in an amount in the range of about 0.05%
w/w to about 20% w/w.
[0068] In some embodiments, said composition of the invention
comprises said solid BPO is in a controlled release drug delivery
system.
[0069] In further embodiments, said controlled or slowed release
drug delivery system is an encapsulation in a microcapsule, wherein
said solid BPO is embedded in said microcapsule.
[0070] When referring to a "controlled or slowed release drug
delivery system" it should be understood to relate to a delivery
system (which in the present invention is a topical delivery
system) that enables the release of the pharmaceutical active agent
in predetermined amounts over a specified period. In some
embodiments said system is a core-shell system of a microcapsule or
a porous matrix structure, such as for example a microsponge.
[0071] The term "embedded" should be understood to encompass an
inert system that provides a barrier between the pharmaceutical
active agent, i.e. BPO, and its surrounding environment in the
composition. In some embodiments said agent is entrapped and/or
encapsulated in said controlled release system.
[0072] In some embodiments said core of said microcapsule consists
of said solid BPO.
[0073] In some further embodiments, said microcapsules are a core
shell microcapsule. The shell comprises at least one inorganic
polymer. In some other embodiments, said inorganic polymer of said
shell is a metal oxide or semi-metal oxide shell (layer).
[0074] In some embodiments of the invention said microcapsule
consists of a metal oxide or semi-metal oxide coating or layer
(shell) and a core consisting of solid BPO.
[0075] In some embodiments said microcapsule consisting of a metal
oxide or semi-metal oxide coating or layer (shell) and a core
consisting of solid BPO is prepared by a process comprising the
steps of: [0076] (a) contacting a solid BPO particulate matter with
an ionic additive and an aqueous medium to obtain a dispersion of
said particulate matter having positive charges on its surface;
[0077] (b) subjecting the particulate matter to a coating procedure
comprising precipitating a metal oxide salt onto the surface of the
particulate matter to form a metal oxide layer thereon thereby to
obtain particulate matter coated by a metal oxide coating layer;
[0078] (c) repeating step (b) at least 4 more times; and [0079] (d)
aging said coating layer.
[0080] As used herein the term "solid BPO particulate matter"
refers to a solid BPO having solubility in water of less than 1%
w/w, typically less than 0.5% and at times less than 0.1% w/w at
room temperature (20.degree. C.).
[0081] The "solid BPO particulate matter" constitutes the "core" of
the particles obtained by the process. The solid BPO particulate
matter, is, in some embodiments, in such a state of subdivision
that it can be suspended in water, e.g. in the form of a
finely-divided powder having a D.sub.90 (see definition below), in
some embodiments in the range of 0.3-50 micron. Such a particulate
matter can readily be suspended in an aqueous systems by stirring,
with or without the aid of a surfactant.
[0082] The terms "solid BPO particulate matter" and "particulate
matter" will be used interchangeably.
[0083] In the present invention the terms "layer", "coating" or
"shell" and similar terms, refer to a layer of metal oxide or
semi-metal oxide formed around a particle or particulate matter.
The layer or coating may not always be complete or uniform and may
not necessarily lead to complete coverage of the particulate matter
or particle surface. It is appreciated that upon repetition of the
coating steps as the coating process proceeds a more uniform
coating and more complete coverage of the particulate matter is
obtained.
[0084] The term "dispersion" as used herein in step (a) of the
process refers to a solid dispersion of the particulate matter in
the aqueous medium.
[0085] Step (a) of the process may further comprise reducing the
particle size of the particulate matter to the desired particle
size for example by milling or homogenization.
[0086] The core (i.e. solid, BPO particulate matter) may be of any
shape for example rod-like, plate-like, ellipsoidal, cubic, or
spherical shape.
[0087] Referring to size of particles will be through their
D.sub.90 meaning that 90% of the particles have the stated
dimension or less (measured by volume). Thus, for examples, for
spherical particles stated to have a diameter of 10 micrometer
("microns"), this means that the particles have a D.sub.90 of 10
microns. The D.sub.90 may be measured by laser diffraction. For
particles having a shape other than spheres, the D.sub.90 refers to
the mean average of the diameter of a plurality of particles.
[0088] In the case of cores having a spherical shape, the diameter
(D.sub.90) may be in the range of 0.3 to 90 microns, in some
embodiments 0.3 to 50 microns, in some other embodiments 1 to 50,
in some further embodiments 5 to 30 microns.
[0089] By the term "D.sub.90 may be in the range of 0.3 to 90
microns" is meant that 90% by volume of the particles (in this case
the particle's core) may be less than or equal to a value in the
range of 0.3 to 90 microns.
[0090] For generally cubic-shaped cores or cores having a shape
resembling that of a cube, the mean size of a side may be in the
range 0.3 to 80 microns, in some embodiments 0.3 to 40 microns, in
some further embodiments 0.8 to 40, in some further embodiments 4
to 15 microns.
[0091] For rod-like shaped, ellipsoidal-shaped and plate-like
shaped cores, the largest dimension (that of the longest axis) is
typically in the range 10 to 100 microns, in some embodiments 15 to
50 microns; and the smallest dimension is typically in the range
0.5 to 20 microns, in some further embodiments 2 to 10 microns.
[0092] As used herein, unless otherwise indicated, the term
"particle" refers to the metal oxide or semi-metal oxide coated
particulate matter.
[0093] It is appreciated that some of the particles obtained by the
process may at times be formed from two or more original particles
of the solid BPO particulate and may accordingly include at times
more than one core, such cores being separated from each other by a
metal oxide region.
[0094] The weight of the solid BPO particulate (core material)
based on the total weight of the particle may be in the range
99%-50% w/w, in some embodiments in the range 97%-50% w/w. The core
material may be in a crystalline form, amorphous form, or
combination thereof. The core material may be a cosmetically,
pharmaceutically or an agrochemical active ingredient.
[0095] In some embodiments, step (c) of the process described above
is repeated 4 to about 1000 times. This means that in some
embodiments step (b) of the process described above is repeated 4
to about 1000 times.
[0096] In further embodiments, the process comprising repeating
step (c) 4 to about 300 times, and in some further embodiments 4 to
about 100 times. In some other embodiments step (c) of the process
described above is repeated 5-80 times in some embodiments 5-50
times. This means that in some embodiments step (b) is repeated as
indicated above with respect to step (c).
[0097] By the term "repeated 4 to about 1000 times" is meant that
the process may be repeated 4, 5, 6, 7, 8, 9 . . . , etc. times up
to and including about 1000 times.
[0098] According to some embodiments of the present invention step
(d) further comprising after aging, separating the coated
particulate matter from the dispersing aqueous medium, such as by
filtration, centrifugation or decantation and optionally rinsing
and re-dispersing the obtained coated particulate matter in an
aqueous medium.
[0099] In some embodiments, during the coating process at least 50%
of the content the particulate matter (pharmaceutical active agent)
in the aqueous medium is in a solid state during the coating
process.
[0100] According to some embodiments of the present invention the
process comprising: [0101] (a) contacting the solid, BPO
particulate matter, with a first cationic additive and an aqueous
medium to obtain a dispersion of said particulate matter having
positive charges on its surface; [0102] (b) subjecting the
particulate matter to a coating procedure comprising precipitating
a metal oxide salt onto the surface of the particulate matter to
form a metal oxide coating layer on the particulate matter; [0103]
(b1) in an aqueous medium, contacting the coated particulate matter
with a surface adhering additive being one or both of (i) a second
cationic additive, and (ii) a non-ionic additive; [0104] (b2)
subjecting the particulate matter obtained in step (b 1) to a
coating procedure as in step (b); [0105] (c) repeating steps (b1)
and (b2) at least 3 more times; and [0106] (d) aging the metal
oxide coating layer.
[0107] In some embodiments, the process comprising repeating step
(c) 3 to about 1000 times.
[0108] In some other embodiments, the process comprising repeating
step (c) 3 to about 300 times, and in yet further embodiments 3 to
about 100 times.
[0109] As used herein by the term "repeating step (c) 3 to about
1000 times" is meant that the process may be repeated 3, 4, 5, 6,
7, 8, 9, . . . etc. times up to and including about 1000 times.
[0110] This means that in some embodiments steps (b1) and (b2) are
repeated as indicted above with respect to step (c).
[0111] Additionally according to some embodiments of the present
invention the process comprising: [0112] (a) contacting the solid,
BPO particulate matter, with an anionic additive, a first cationic
additive and an aqueous medium to obtain a dispersion of said
particulate matter having positive charges on its surface; [0113]
(b) subjecting the particulate matter to a coating procedure
comprising precipitating a metal oxide salt onto the surface of the
particulate matter to form a metal oxide coating layer on the
particulate matter; [0114] (b1) in an aqueous medium, contacting
the coated particulate matter with a surface adhering additive
being one or both of (i) a second cationic additive, and (ii) a
non-ionic additive; [0115] (b2) subjecting the particulate matter
obtained in step (b1) to a coating procedure as in step (b); [0116]
(c) repeating steps (b1) and (b2) at least 3 more times; and [0117]
(d) aging the metal oxide coating layer.
[0118] When an anionic additive and first cationic additive are
used in step (a) of the process, in some embodiments the anionic
additive is added before the first cationic additive.
[0119] Step (c) may be repeated 3 to about 1000 times. In some
embodiments, step (c) is repeated 3 to about 300 times, in some
other embodiments, 3 to about 100 times. This means that in some
embodiments steps (b1) and (b2) are repeated as indicted above with
respect to step (c).
[0120] The ionic additive (such as first cationic additive) used in
step (a) of the process have a dual effect: to form positive
charges on the surface of the particulate matter as will be
described below, and also to serve as a wetting agent, thus
allowing dispersion of the particulate matter as discrete core
particles, where each core particle is individually suspended in
the aqueous medium.
[0121] Step (a) of the process may be conducted for example by (i)
contacting the particulate matter with dry ionic additives and then
suspending both in an aqueous medium to obtain a dispersion of said
particulate matter having positive charges on its surface, or
alternatively by (ii) suspending the solid BPO particulate in an
aqueous medium comprising ionic additives to obtain a dispersion of
said particulate matter having positive charges on its surface.
[0122] According to another embodiment the process may comprise (a)
contacting the solid, BPO particulate matter, with an ionic
additive selected from (i) an anionic additive; (ii) a first
cationic additive, and a combination thereof, and an aqueous medium
to obtain a dispersion of said particulate matter having positive
charges on its surface; (b), (b1), (b2), (c), (d) are as described
herein.
[0123] The concentration of the ionic additives in the dispersion
can be about 0.001% to about 30%, in some embodiments about 0.01%
to about 10% w/w and in some other embodiments about 0.1% up to
about 5% w/w.
[0124] The solid content of the water dispersion can be about 0.1%
to about 80% w/w, in some embodiments about 1% to about 60% w/w, in
some further embodiments about 3% to about 50% w/w.
[0125] The purpose of step (a) is to modify the electrical charge
of the particulate matter by using ionic additives such that it
will be made reactive to the attachment of the metal oxide layer.
For preparing the core material of the particles, the particulate
matter ought to be suitably coated with an ionic additive (e.g.
cationic additive), such that it can be attached to the
precipitated metal oxide salt.
[0126] In some embodiments, the ionic additive is selected from a
cationic additive, an anionic additive, and a combination thereof.
The cationic additive may be a cationic surfactant and/or cationic
polymer. The anionic additive may be an anionic surfactant and/or
anionic polymer.
[0127] The particulate matter is contacted with an ionic additive,
for example by mixing it with a solution of a cationic surfactant
and/or cationic polymer or an anionic surfactant and a cationic
additive (e.g. cationic surfactant and/or cationic polymer).
Cationic and anionic surfactants are particularly effective in
being adsorbed upon the surface of the particulate matter. The
ionic additive may also be anionic polymers used in combination
with a cationic additive. The cationic surfactant and/or the
cationic polymer and optionally further the anionic surfactant (or
anionic polymer) need to be used in sufficient amount to provide
positive charges on the surface of the particulate matter. The
coating need not be continues. It is sufficient that there are at
least spots of cationic additive. These spots will then serve as
anchors for the attachment of the metal oxide layer. In some
embodiments, there are uniform distribution of these anchoring
points on the core surface so that as the metal oxide layer builds
up it will bridge over and be firmly attached to the core.
[0128] According to some embodiments said first and said second
cationic additive are the same.
[0129] According to another embodiment said first and said second
cationic additive are different.
[0130] In some other embodiments, the first ionic additive is an
anionic surfactant and the second ionic additive is a cationic
polymer. In some further embodiments the first cationic additive is
a cationic surfactant and the second cationic additive is a
cationic polymer.
[0131] According to further embodiments, the first cationic
additive is a cationic surfactant and the additive in step (b1) is
a non-ionic additive (e.g. a non-ionic polymer).
[0132] In some further embodiments, the coated particulate matter
and the second cationic additive are mixed, and most preferable
said mixing is under vigorous stirring (e.g. mixer speed above 1000
rpm).
[0133] According to a preferred embodiment of the present invention
the process further comprising following step (d): (e) separating
the coated particulate matter from the aqueous medium and
optionally rinsing and re-dispersing the coated particulate matter
in an aqueous medium.
[0134] In some embodiments, the separation of the coated
particulate matter is conducted by a method such as filtration,
centrifugation, decantation, dialysis, or by evaporation of the
aqueous medium.
[0135] Additionally according to a preferred embodiment of the
present invention, step (b) comprises adding a metal oxide salt to
the aqueous medium; and optionally acidifying the aqueous
medium.
[0136] Further according to some embodiments of the present
invention, step (b2) comprises adding a metal oxide salt to the
aqueous medium; and optionally acidifying the aqueous medium.
[0137] In some embodiments step (b1) further comprising adjusting
the pH of the dispersion obtained in (b) to a value higher than the
isoelectric point of the metal oxide before adding the second
cationic additive, in some further embodiments to a pH value of at
least about 1 unit higher than the isoelectric point of the metal
oxide, before adding the second cationic additive.
[0138] In some embodiments, step (b1) further comprising adjusting
the pH of the dispersion obtained in (b) to a value higher than the
isoelectric point of the metal oxide before adding one or both of
(i) a second cationic additive, and (ii) a non-ionic additive, in
some embodiments to a pH value of at least about 1 unit higher than
the isoelectric point of the metal oxide, before adding one or both
of (i) a second cationic additive, and (ii) a non-ionic
additive.
[0139] For example, in case the metal oxide is silica (e.g. having
an isoelectric point in the range 1.7-2.5) the preferred pH may be
at least in the range of about 2.5-6.5.
[0140] The purpose of the pH adjustment of the dispersion to a
value higher than the isoelectric point of the metal oxide is to
form negatively charged metal oxide on the particulate matter
surface that will be bound to the positive charges of the second
cationic additive thus enabling the attachment of the second
cationic additive to the surface of the particulate matter.
[0141] The non-ionic additive is of a kind that adheres to the
surface ("surface-adherent"). An example is a non-ionic polymer.
The non-ionic additive may be used alone or in addition to the
second cationic surfactant. Without wishing to be bound by theory,
the surface-adherent property may be through hydrogen-binding
groups such as hydroxyl or amine groups. This allows adhesion of a
further layer of metal oxide on the preceding precipitated metal
oxide layer.
[0142] In some embodiments, the particulate matter/metal oxide salt
weight ratio, in each of the steps (b) or (b2) is about 5,000/1 to
about 20/1, in some embodiments about 5,000/1 to about 30/1, or
about 5,000/1 to about 40/1, in some further embodiments about
1,000/1 to about 40/1, and in yet some further embodiments about
500/1 to about 80/1.
[0143] In some embodiments, the particulate matter/cationic
additive ratio, in step (b 1) is about 25,000/1 to about 50/1,
preferably about 5,000/1 to about 100/1, and most preferably about
2000/1 to about 200/1.
[0144] According to some embodiments the particulate matter/metal
oxide salt weight ratio, in each of the steps (b) or (b2) is about
5,000/1 to about 65/1, and in some further embodiments about 1000/1
to about 100/1.
[0145] In some embodiments, the particulate matter/cationic
additive weight ratio, in step (b1) is about 10,000/1 to about
100/1, and in some further embodiments about 5000/1 to about
200/1.
[0146] The aging in step (d) is crucial for obtaining a
strengthened and dense layer of metal oxide.
[0147] In some embodiments step (d) comprises raising the pH to a
value in the range 3-9 and mixing the suspension in this pH.
[0148] According to a preferred embodiment of the present invention
step (d) comprises raising the pH to a value in the range 3-9 and
mixing the suspension in this pH for a period of at least 2 h.
[0149] According to some embodiments of the present invention step
(d) comprises raising the pH to a value in the range 3-9, in some
further embodiments to a range of 5-7, and mixing, e.g. by
stirring, the suspension (dispersion) in this pH range e.g. for a
period of at least 2 h (two hours). In some embodiments, stirring
is for 2-96 h, in some embodiments 2-72 h, in some other
embodiments at least 10 h (for example 10-72 h). In some
embodiments the stirring is a gentle stirring, in some embodiments
in the range 200-500 rpm.
[0150] Upon completion of aging, the separation (e.g. filtration,
centrifugation or decantation) will be easy to perform (due to the
hard metal oxide layer formed) and the obtained cake or
concentrated dispersion will be easily re-dispersed in an aqueous
medium to form a dispersion of particles.
[0151] The purpose of aging in step (d) is to obtain a strengthened
and denser layer of metal oxide.
[0152] In the absence of the aging step a thinner and softer layer
of metal oxide would be obtained since the metal oxide salt upon
precipitation forms a gel layer of metal oxide which may
disintegrate or erode upon separation and washing or by mechanical
stirring.
[0153] The aging may be conducted at a temp of 4-90.degree. C., in
some embodiments at 15-60.degree. C. and in further embodiments the
aging is conducted at a temperature 20.degree. C.-40.degree. C.
[0154] Thus the repeated steps of coating and aging at the end of
the process also enable the growth of thicker and stronger layer of
metal oxide. In some embodiments aging is not conducted between the
repeated coating steps (i.e. between the repeated coating step
(b)), but only at the end of the process. Thus in some embodiments
the aging is conducted only at the end of the process described
herein.
[0155] According to certain embodiments, the process may further
comprise adding a colloidal metal oxide suspension, in some
embodiments aqueous-based suspension (comprising nanometric metal
oxide (nanoparticles of metal oxide) during the coating procedure.
In some embodiments the colloidal metal oxide suspension is
selected from colloidal silica suspension, colloidal titania
suspension, colloidal alumina suspension, colloidal zirconia
suspension, colloidal ZnO suspension, and mixtures thereof. The
colloidal metal oxide suspension may be added during the coating
process (e.g. in step (b) in one or more of its repeated steps). In
some other embodiments the size of the nanometric metal oxide in
diameter is in the range between 5-100 nm (average particle size
diameter). The weight ratio of the nanometric metal oxide to the
metal oxide salt may be in the range 95:5 to 1:99 in some
embodiments 80:20 to 5:95 in some other embodiments 70:30 to 10:90,
in yet other embodiments about 60:40 to 20:80. The weight ratio of
the nanometric metal oxide to the metal oxide salt may be about
50:50.
[0156] According to other embodiments, the process does not include
addition of colloidal metal oxide suspension during the coating
process. According to this embodiment nanometric metal oxide
particles (nanoparticles of metal oxide) are not added during the
coating process.
[0157] As used herein, the term "metal oxide coating layer" or
"metal oxide layer" encompasses the product of both a single
processing step as well as a product of the process in which the
initially coated particles are further processed, by the repeated
processing steps of step (c), described above.
BRIEF DESCRIPTION OF THE DRAWINGS
[0158] In order to understand the disclosure and to see how it may
be carried out in practice, embodiments will now be described, by
way of non-limiting example only, with reference to the
accompanying drawings, in which:
[0159] FIG. 1 is a graph presenting the mean IGA per time of BPO
composition of the invention (1% and 5% encapsulated BPO as
described in example 1) as compared with vehicle alone over a
period of time of 12 weeks.
[0160] FIG. 2 is a graph presenting the is the mean inflammatory
lesion count per time of BPO composition of the invention (1% and
5% encapsulated BPO as described in example 1) as compared with
vehicle alone over a period of time of 12 weeks.
[0161] FIG. 3 is a graph presenting the dissolution rate of BPO
over a period of 60 minutes of a composition of the invention (5%
E-BPO, produced according to Example #3), and Benzac.RTM. AC 5% BPO
and NeoBenz.RTM. Micro 5.5%.
DETAILED DESCRIPTION OF EMBODIMENTS
Example 1: Encapsulation of BPO
[0162] Step 1: Milling:
[0163] 110 g. of hydrous BPO 75% (USP grade from Sigma) were
suspended in 152 g. of 0.4% CTAC solution containing 0.001% silicon
antifoam. The BPO was milled using a stator rotor mixer (Kinematika
polytron 6100 operated at 15,000 rpm/25 m/s). The milling was
stopped when the particle size distribution (PSD) of the suspension
was d(0.9)<35 .mu.m or the temperature has reached 50 C. The
final suspension was cooled to room temperature.
[0164] Step 2a: Coating Option #1:
[0165] During the coating procedure the suspension was stirred with
a mechanical dissolver, 80 mm, at 500 RPM at all times. The pH of
the milled BPO suspension was corrected to 8 using NaOH 5N
solution. A portion of 1 g of 15% sodium silicate solution (15% w/w
as SiO.sub.2) was added and the suspension was stirred for 5 min. A
portion of 1 g of 3% Polyquaternium 7 was added and the suspension
was stirred for 5 min. pH was adjusted to 6-7 using 5N HCl
solution.
[0166] This procedure was repeated for 5-100 times in order to
create a series of silica layers around BPO having different
thickness.
[0167] Step 2b: Coating Option #2:
[0168] During the coating procedure the suspension was stirred with
a mechanical dissolver, 80 mm, at 500 RPM at all times. The pH of
the milled BPO suspension was corrected to 8 using NaOH 5N
solution. A portion of 2.5 g of 15% sodium silicate solution (15%
w/w as SiO.sub.2) was added and the suspension was stirred for 5
min. A portion of 2.5 g of 3% Polyquaternium 7 was added and the
suspension was stirred for 5 min. pH was adjusted to 6-7 using 5N
HCl solution.
[0169] This procedure was repeated for 5-100 times in order to
create a series of silica layers around BPO having different
thickness.
[0170] The Aging Step:
[0171] The coated BPO suspension at pH 6.5 was kept for aging at
room temperature (25 C+/-2) under gentle agitation for 24 hrs.
Example 2: Preparation of Encapsulated BPO (15% E-BPO Water
Suspension)
[0172] a) Preparation of Benzoyl Peroxide Dispersion and Acid
Cocktail
[0173] A benzoyl peroxide (BPO) dispersion was prepared by mixing
125.67 grams of CTAC CT-429 (Cetrimonium Chloride 30%), 3008 grams
of hydrous benzoyl peroxide, and 5200 grams water under high shear.
The dispersion was homogenized for 60 minutes at 33.degree. C. (no
more than 45.degree. C.), and then the pH of the dispersion was
adjusted to 7.0 using sodium hydroxide solution (20%).
[0174] An acid cocktail was prepared using 493 grams Hydrochloric
acid (37%), 98 grams anhydrous Citric Acid, 147 grams Lactic Acid
(90%), and 794 grams water.
[0175] b) Coating Cycle
[0176] The coating cycle was started by adding 38 grams sodium
silicate solution extra pure (28%) to the benzoyl peroxide
dispersion prepared in step a) under high shear, followed by adding
the acid cocktail prepared in step (a) to adjust the pH to be lower
than 6.8, and followed by adding 57 grams PDAC (3%) solution to the
mixture. The cycle was repeated 50 times while the mixture was
stirred under high shear for 17 hours. After the 50 cycles, the pH
of the mixture was adjusted to 5.0 using the acid cocktail, and
water was added to complete the total weight of the mixture to 15
kilograms. The composition of the final BPO water suspension
product is shown in Table 1.
TABLE-US-00001 TABLE 1 Composition of the encapsulated BPO 15%
water suspension Ingredient % of ingredient in the suspension
Polyquarternium-7 0.53 Hydrochloric Acid 0.87 Citric Acid,
Anhydrous 0.46 Lactic Acid 0.63 Silicon Dioxide 3.42 Sodium
hydroxide 0.01 Cetrimonium Chloride 0.25 Hydrous Benzoyl Peroxide
15.00 Sterile Water for Irrigation Up to 100%
Example 3: Preparation of Formulation of Encapsulated BPO (5%) Gel
(Formulation I)
[0177] Oil Phase: 720.0 of grams Cyclomethicone 5-N, 540.0 of grams
Cetyl Alcohol, 360.0 grams Polyoxyl 100 Stearate, and 540.0 grams
of Glyceryl Monosterate were mixed at 70.degree. C. Water phase:
18.0 grams of Ethylendiaminetetraacetate Disodium salt were
dissolved in 6500 grams of water. 720.0 grams of glycerin (99.5%)
were added to the solution. After the solution was heated to
70.degree. C., 72.0 grams of Carbopol 980 NF were added and the
resulting mixture was homogenized at 3300 rpm for 10 minutes to
ensure that all materials completely melted and dissolved. 76.5
grams if sodium hydroxide (20%) were then added and the mixture was
stirred under high shear for 10 minutes at no less than 70.degree.
C.
[0178] The oil phase was added to the water phase under high shear
at 78.degree. C., and the resulting emulsion was homogenized at
3300 rpm for 10 minutes. 72.0 grams of Citric Acid and 6,000 grams
of encapsulated BPO 15% water suspension made as described in
Example 2 were mixed. The resulting mixture was added to the
emulsion at 65.degree. C. and mixed at 1400 rpm for 10 minutes. The
emulsion was cooled to 35.degree. C. and the pH of the emulsion was
adjusted to 4.0 using HCl 5N solution. The emulsion was stirred at
1400 rpm for 10 minutes and then water was added until the total
weight of the emulsion reached 18 kilograms. The composition of the
formulation prepared in this example is shown in Table 2.
TABLE-US-00002 TABLE 2 Composition of Formulation I Ingredient % of
pure ingredient in the composition Polyquarternium-7 0.17
Hydrochloric Acid 0.37 Citric Acid, Anhydrous 0.38 Lactic Acid 0.21
Silicon Dioxide 1.14 Sodium hydroxide 0.08 Cetrimonium Chloride 0.1
Hydrous Benzoyl Peroxide 5.00 Glycerin 4.00 Polyoxyl 100 stearate
2.00 Cetyl alcohol 3.00 Cyclomethicone 4.00 Glyceryl monostearate
3.00 Edetate Disodium 0.10 Carbopol 980 0.40 Sterile Water for
Irrigation up to 100%
Example 4: Preparation of Placebo of Encapsulated BPO Water
Suspension
[0179] a) Preparation of Placebo Dispersion and Acid Cocktail
[0180] A placebo dispersion was prepared by mixing 125.67 grams of
CTAC CT-429 (Cetrimonium Chloride 30%), and 5200 grams and then the
pH of the solution was adjusted to 7.0 using sodium hydroxide
solution (20%).
[0181] An acid cocktail was prepared using 493 grams Hydrochloric
acid (37%), 98 grams anhydrous Citric Acid, 147 grams Lactic Acid
(90%), and 794 grams water.
[0182] b) Coating Cycle
[0183] The coating cycle was started by adding 38 grams sodium
silicate solution extra pure (28%) to the placebo solution prepared
in step a) under high shear, followed by adding the acid cocktail
prepared in step (a) to adjust the pH to be lower than 6.8, and
followed by adding 57 grams PDAC (3%) solution to the mixture. The
cycle was repeated 50 times while the mixture was stirred under
high shear for 17 hours. After the 50 cycles, the pH of the mixture
was adjusted to 5.0 using the acid cocktail, and water was added to
complete the total weight of the mixture to 15 kilograms. The
composition of the final placebo water suspension product is shown
in Table 3.
TABLE-US-00003 TABLE 3 Composition of placebo of encapsulated BPO
water suspension Ingredient % of ingredient in the suspension
Polyquarternium-7 0.53 Hydrochloric Acid 0.87 Citric Acid,
Anhydrous 0.46 Lactic Acid 0.63 Silicon Dioxide 3.42 Sodium
hydroxide 0.01 Cetrimonium Chloride 0.25 Sterile Water for
Irrigation Up to 100%
Example 5: Preparation of Formulation of Vehicle of Encapsulated
BPO Gel (Formulation II)
[0184] Oil Phase: 720.0 of grams Cyclomethicone 5-N, 540.0 of grams
Cetyl Alcohol, 360.0 grams Polyoxyl 100 Stearate, and 540.0 grams
of Glyceryl Monosterate were mixed at 70.degree. C.
[0185] Water phase: 18.0 grams of Ethylendiaminetetraacetate
Disodium salt were dissolved in 6500 grams of water. 720.0 grams of
glycerin (99.5%) were added to the solution. After the solution was
heated to 70.degree. C., 72.0 grams of Carbopol 980 NF were added
and the resulting mixture was homogenized at 3300 rpm for 10
minutes to ensure that all materials completely melted and
dissolved. 76.5 grams if sodium hydroxide (20%) were then added and
the mixture was stirred under high shear for 10 minutes at no less
than 70.degree. C.
[0186] The oil phase was added to the water phase under high shear
at 78.degree. C., and the resulting emulsion was homogenized at
3300 rpm for 10 minutes. 72.0 grams of Citric Acid and 6,000 grams
of placebo of encapsulated BPO water suspension made as described
in Example 4 were mixed.
[0187] The resulting mixture was added to the emulsion at
65.degree. C. and mixed at 1400 rpm for 10 minutes. The emulsion
was cooled to 35.degree. C. and the pH of the emulsion was adjusted
to 4.0 using HCl 5N solution. The emulsion was stirred at 1400 rpm
for 10 minutes and then water was added until the total weight of
the emulsion reached 18 kilograms. The composition of the
formulation prepared in this example is shown in Table 4.
TABLE-US-00004 TABLE 4 Composition of Formulation II Ingredient %
of pure ingredient in the composition Polyquarternium-7 0.17
Hydrochloric Acid 0.37 Citric Acid, Anhydrous 0.38 Lactic Acid 0.21
Silicon Dioxide 1.14 Sodium hydroxide 0.08 Cetrimonium Chloride 0.1
Glycerin 4.00 Polyoxyl 100 stearate 2.00 Cetyl alcohol 3.00
Cyclomethicone 4.00 Glyceryl monostearate 3.00 Edetate Disodium
0.10 Carbopol 980 0.40 Sterile Water for Irrigation up to 100%
Example 6: Preparation of Formulation of Encapsulated BPO (1%) Gel
(Formulation III)
[0188] Oil Phase: 720.0 of grams Cyclomethicone 5-N, 540.0 of grams
Cetyl Alcohol, 360.0 grams Polyoxyl 100 Stearate, and 540.0 grams
of Glyceryl Monosterate were mixed at 70.degree. C.
[0189] Water phase: 18.0 grams of Ethylendiaminetetraacetate
Disodium salt were dissolved in 6500 grams of water. 720.0 grams of
glycerin (99.5%) were added to the solution. After the solution was
heated to 70.degree. C., 72.0 grams of Carbopol 980 NF were added
and the resulting mixture was homogenized at 3300 rpm for 10
minutes to ensure that all materials completely melted and
dissolved. 76.5 grams if sodium hydroxide (20%) were then added and
the mixture was stirred under high shear for 10 minutes at no less
than 70.degree. C.
[0190] The oil phase was added to the water phase under high shear
at 78.degree. C., and the resulting emulsion was homogenized at
3300 rpm for 10 minutes. 72.0 grams of Citric Acid, 1200 grams of
encapsulated BPO 15% water suspension made as described in Example
2 and 4800 grams of placebo of encapsulated BPO water suspension as
described in Example 4 were mixed. The resulting mixture was added
to the emulsion at 65.degree. C. and mixed at 1400 rpm for 10
minutes. The emulsion was cooled to 35.degree. C. and the pH of the
emulsion was adjusted to 4.0 using HCl 5N solution. The emulsion
was stirred at 1400 rpm for 10 minutes and then water was added
until the total weight of the emulsion reached 18 kilograms. The
composition of the formulation prepared in this example is shown in
Table 5.
TABLE-US-00005 TABLE 5 Composition of Formulation III Ingredient %
of pure ingredient in the composition Polyquarternium-7 0.17
Hydrochloric Acid 0.37 Citric Acid, Anhydrous 0.38 Lactic Acid 0.21
Silicon Dioxide 1.14 Sodium hydroxide 0.08 Cetrimonium Chloride 0.1
Hydrous Benzoyl Peroxide 1.00 Glycerin 4.00 Polyoxyl 100 stearate
2.00 Cetyl alcohol 3.00 Cyclomethicone 4.00 Glyceryl monostearate
3.00 Edetate Disodium 0.10 Carbopol 980 0.40 Sterile Water for
Irrigation up to 100%
Example 7: Efficacy Study of BPO in a Composition of the
Invention
[0191] A multi-center, double-blind, randomized,
vehicle-controlled, dose-range study was performed. Study duration
was 12 weeks on mild to severe facial rosacea patients using
encapsulated benzoyl peroxide gel, 1% (as described in Example 6)
and 5% (as described in Example 3), and vehicle gel (as described
in Example 5) once daily.
[0192] A total of 92 subjects were randomly assigned in a 1:1:1
ratio to 5% E-BPO Gel, 1% E BPO Gel, or Vehicle Gel.
[0193] The investigator performed the Investigator Global
Assessment (IGA) and inflammatory lesion (papules and pustules)
counts at Screening, Baseline, and Weeks 4, 8, and 12 (end of
study).
[0194] Evaluation of Efficacy:
[0195] The first application of the test product was applied at the
investigational site at the end of the Baseline visit (Day 0) under
the supervision and instruction of the designated investigational
site staff. The investigator performed the Investigator Global
Assessment (IGA) and inflammatory lesion (papules and pustules)
counts at Screening, Baseline, and Weeks 4, 8, and 12 (end of
study) and erythema and telangiectasia assessments at Baseline, and
Weeks 4, 8, and 12 (end of study). The evaluator also assessed
local application site irritation (dryness, scaling, pruritus,
stinging and burning) at Baseline and Weeks 2, 4, 8 and 12 (end of
study). At selected investigational site(s), standardized
photography of facial rosacea also was performed at Baseline and
Week 8 and 12 (end of study). Information on adverse events (AEs)
was collected at all visits.
[0196] Efficacy endpoints were: Proportion of subjects with the
primary measure of success, defined as a 2-grade improvement in the
IGA relative to Baseline at Week 12, with the Week 12 IGA of clear
or almost clear. Change in inflammatory lesion count at Week
12.
[0197] Results:
[0198] Baseline Characteristics: The Baseline characteristics were
similar among the treatment groups for IGA and telangiectasia.
While the median inflammatory lesion counts were similar among the
treatment groups, the mean inflammatory lesion count was
numerically higher for 1% E-BPO Gel than for 5% E-BPO Gel and for
1% E-BPO Gel and 5% E-BPO Gel than for Vehicle Gel, and a
numerically higher proportion of subjects in 1% E-BPO Gel than in
5% E-BPO Gel and 1% E-BPO Gel and 5% E-BPO Gel than in Vehicle Gel
had severe inflammatory lesion erythema at Baseline. A numerically
higher proportion of subjects in 1% E-BPO Gel and 5% E-BPO Gel than
in Vehicle Gel had severe rosacea erythema
[0199] Primary Efficacy Analyses
[0200] For the Primary Efficacy Endpoints:
[0201] The proportions of subjects with the primary measure of
success (defined as a 2-grade improvement in the IGA relative to
Baseline at Week 12, with the Week 12 IGA of clear or almost clear)
were 20.0% (6/30) for Vehicle Gel, 37.5% (12/32) for 1% E-BPO Gel,
and 53.3% (16/30) for 5% E-BPO Gel. The improvement in mean IGA is
described in FIG. 1.
[0202] The proportions of subjects with the 2.sup.nd primary
measure of success (defined as mean inflammatory lesion count
percent change from Baseline at Week 12) were about 30.0% for
Vehicle Gel and more than 60% for 1% E-BPO Gel and 5% E-BPO Gel
[0203] The improvement in inflammatory lesion count is described in
FIG. 2.
Example 8: Measuring the Dissolution Rate of BPO from a Composition
of the Invention
[0204] Weighing of Samples
[0205] A sample was weighed according to its BPO content in amount
equivalent to 40 mg of BPO. Examples for weight of samples are
given in the table below.
TABLE-US-00006 Concentration of BPO in the sample (C.sub.0) 1%
(w/w) 5% (w/w) 10% (w/w) Weight of sample, mg 3200-4800 640-960
320-480
[0206] Preparation of Samples and Measurement Procedure
[0207] The sample was weighed into a 250 mL Erlenmeyer flask, 200
mL of "medium" were added and a 3.0 cm length magnetic bar was
inserted, the flask was placed on the stirrer and stirring at 400
rpm was started. 2 mL at specified time intervals were withdrawn
and filtered through 0.2 .mu.m GHP Acrodisc syringe filter (first
mL discarded). The concentration of BPO (in % w/w) dissolved in
each time interval (C.sub.n) were calculated.
[0208] The "medium" was prepared by mixing 550 mL of water with 450
mL of acetonitrile, which were than equilibrated to ambient
temperature.
[0209] The dissolution rate was measured according to the following
formula:
The dissolution rate (%)=(C.sub.n/C.sub.0)*100%
[0210] Dissolution Rate of BPO in Compositions of the Invention
[0211] The dissolution rate of a composition of the invention
comprising 5% E-BPO, produced according to Example #3, were
compared with the dissolution of Benzac.RTM. AC 5% BPO and
NeoBenz.RTM. Micro 5.5%. As can be seen from the results presented
in FIG. 3, the dissolution rate of a composition of the invention
was much lower than the dissolution of the above commercial
products.
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