U.S. patent application number 16/794974 was filed with the patent office on 2020-08-20 for method for treatment of moderate to severe erythema symptoms in rosacea patients.
The applicant listed for this patent is Sol-Gel Technologies Ltd.. Invention is credited to Ofra LEVY-HACHAM, Ori NOV, Vered RAM, Ofer TOLEDANO.
Application Number | 20200261402 16/794974 |
Document ID | 20200261402 / US20200261402 |
Family ID | 1000004840203 |
Filed Date | 2020-08-20 |
Patent Application | download [pdf] |
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United States Patent
Application |
20200261402 |
Kind Code |
A1 |
TOLEDANO; Ofer ; et
al. |
August 20, 2020 |
METHOD FOR TREATMENT OF MODERATE TO SEVERE ERYTHEMA SYMPTOMS IN
ROSACEA PATIENTS
Abstract
A regimen for the therapeutic treatment of moderate to severe
erythema symptoms in rosacea patients, the regimen comprising
topically applying to the skin of a subject in need of said
treatment a pharmaceutical composition, the pharmaceutical
composition comprising about 1% w/w to about 10% w/w benzoyl
peroxide as an active ingredient, and a pharmaceutically acceptable
carrier or excipient, wherein the benzoyl peroxide is the only
active ingredient in said pharmaceutical composition, wherein said
pharmaceutical composition is applied once daily for a period of at
least about 12 weeks, to achieve a percentage decrease of about 60%
in a population exhibiting moderate to severe erythema symptoms
when measured at about 12 weeks after initial treatment of the
population with the pharmaceutical composition.
Inventors: |
TOLEDANO; Ofer; (Kfar Saba,
IL) ; LEVY-HACHAM; Ofra; (Ness Ziona, IL) ;
NOV; Ori; (Tarum, IL) ; RAM; Vered; (Rehovot,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sol-Gel Technologies Ltd. |
Ness Ziona |
IL |
US |
|
|
Family ID: |
1000004840203 |
Appl. No.: |
16/794974 |
Filed: |
February 19, 2020 |
Related U.S. Patent Documents
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Application
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Patent Number |
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62977974 |
Feb 18, 2020 |
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62977952 |
Feb 18, 2020 |
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62972896 |
Feb 11, 2020 |
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62972310 |
Feb 10, 2020 |
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62960384 |
Jan 13, 2020 |
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62925258 |
Oct 24, 2019 |
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62871286 |
Jul 8, 2019 |
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62871283 |
Jul 8, 2019 |
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62807356 |
Feb 19, 2019 |
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62807368 |
Feb 19, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/10 20130101; A61K
9/06 20130101; A61K 9/50 20130101; A61P 17/00 20180101; A61K 31/327
20130101; A61K 9/0014 20130101 |
International
Class: |
A61K 31/327 20060101
A61K031/327; A61P 17/00 20060101 A61P017/00 |
Claims
1. A regimen for the therapeutic treatment of moderate to severe
erythema symptoms in rosacea patients, the regimen comprising
topically applying to the skin of a subject in need of said
treatment a pharmaceutical composition, the pharmaceutical
composition comprising about 2.5% w/w to about 10% w/w benzoyl
peroxide as an active ingredient, and a pharmaceutically acceptable
carrier or excipient, wherein the benzoyl peroxide is the only
active ingredient in said pharmaceutical composition, wherein said
pharmaceutical composition is applied once daily for a period of at
least about 12 weeks, to achieve a percentage decrease of about 60%
in a population exhibiting moderate to severe erythema symptoms
when measured at about 12 weeks after initial treatment of the
population with the pharmaceutical composition, and wherein the
percentage decrease in the population exhibiting erythema symptoms
after treatment with pharmaceutical composition is at least about
10% to about 30% higher than a corresponding decrease in the
population exhibiting erythema symptoms after treatment with a
vehicle alone.
2. The regimen of claim 1, wherein the percentage decrease in the
population exhibiting erythema symptoms after treatment with
pharmaceutical composition is at least about 18% higher than a
corresponding decrease in the population exhibiting erythema
symptoms after treatment with a vehicle alone.
3. The regimen of claim 1, wherein the benzoyl peroxide is the sole
active ingredient administered to the subject during the duration
of the regimen.
4. The regimen of claim 1, wherein the pharmaceutical composition
comprises about 5% w/w of the benzoyl peroxide.
5. The regimen of claim 1, wherein the benzoyl peroxide is in a
solid, solution or suspension form.
6. The regimen of claim 1, wherein the regimen is a first line
therapy for the treatment of moderate to severe rosacea.
7. The regimen of claim 1, wherein the moderate to severe rosacea
is any of erythematotelengietatic rosacea, papulopustular rosacea,
phymatous rosacea or ocular rosacea.
8. The regimen of claim 1, wherein said pharmaceutical composition
is a cream or an emulsion.
9. The regimen of claim 1, wherein said pharmaceutical composition
is an extended-release formulation.
10. The regimen of claim 9, wherein an extended-release effect from
the extended-release formulation is obtained by encapsulation,
microencapsulation, microspheres or coating.
11. The regimen of claim 10, wherein the benzoyl peroxide is
encapsulated or microencapsulated.
12. The regimen of claim 10, wherein the benzoyl peroxide is
included in a microsphere or a coating.
13. A regimen for the therapeutic treatment of moderate to severe
erythema symptoms in rosacea patients, the regimen comprising
topically applying to the skin of a subject in need of said
treatment a pharmaceutical composition, the pharmaceutical
composition comprising about 2.5% w/w to about 10% w/w benzoyl
peroxide as an active ingredient, and a pharmaceutically acceptable
carrier or excipient, wherein the benzoyl peroxide is the only
active ingredient in said pharmaceutical composition, and wherein
after about 2 weeks of treatment with the pharmaceutical
composition there is no increase in erythema symptoms.
14. The regimen of claim 13, wherein the number of patients with no
erythema symptoms does not increase after treatment for about 2
weeks with the pharmaceutical composition.
15. The regimen of claim 13, wherein the pharmaceutical composition
comprises about 5% w/w of the benzoyl peroxide.
16. The regimen of claim 13, wherein the benzoyl peroxide is in a
solid, solution or suspension form.
17. The regimen of claim 13, wherein the regimen is a first line
therapy for the treatment of moderate to severe rosacea.
18. The regimen of claim 13, wherein the moderate to severe rosacea
is any of erythematotelengietatic rosacea, papulopustular rosacea,
phymatous rosacea or ocular rosacea.
19. The regimen of claim 13, wherein said pharmaceutical
composition is a cream or an emulsion.
20. The regimen of claim 13, wherein said pharmaceutical
composition is an extended-release formulation.
21. The regimen of claim 20, wherein an extended-release effect
from the extended-release formulation is obtained by encapsulation,
microencapsulation, microspheres or coating.
22. The regimen of claim 21, wherein the benzoyl peroxide is
encapsulated or microencapsulated.
23. The regimen of claim 21, wherein the benzoyl peroxide is
included in a microsphere or a coating.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) from U.S. Provisional Application No. 62/977,974, filed Feb.
18, 2020, U.S. Provisional Application No. 62/977,952, filed Feb.
18, 2020, U.S. Provisional Application No. 62/972,896, filed Feb.
11, 2020, U.S. Provisional Application No. 62/972,310, filed Feb.
10, 2020, U.S. Provisional Application No. 62/960,384, filed Jan.
13, 2020, U.S. Provisional Application No. 62/925,258, filed Oct.
24, 2019, U.S. Provisional 62/871,286, filed Jul. 8, 2019, U.S.
Provisional 62/871,283, filed Jul. 8, 2019, U.S. Provisional
62/807,356, filed Feb. 19, 2019, and U.S. Provisional 62/807,368,
filed Feb. 19, 2019, the contents of which are incorporated in
their entirety as if fully set forth herein.
TECHNICAL FIELD
[0002] This application relates to methods for the therapeutic
treatment of symptoms and considerations associated with skin
conditions and afflictions, such as rosacea, including moderate to
severe rosacea, including topically applying to the skin of a
subject in need of said treatment a pharmaceutical composition
comprising benzoyl peroxide.
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, and 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. The various stages of the disease
are:
[0006] 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 emotions, meals and temperature changes.
[0007] Stage 2 (stage of couperosis, i.e., of permanent erythema
with telangiectasia): certain patients also have oedema on the
cheeks and the forehead.
[0008] Stage 3 (inflammatory stage, papulopustular rosacea):
patients exhibit appearance of inflammatory papules and pustules,
but without affecting the sebaceous follicles, and thus, does not
include cysts and comedones.
[0009] 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.
[0010] Erythema is a symptom of rosacea, and includes an abnormal
and/or superficial reddening and inflammation of the skin, usually
localized or patchy, caused by the congestion and dilation of blood
capillaries.
[0011] Typical treatment of rosacea includes oral or topical
administration of antibiotics such as tetracyclines, salicylic
acid, anti-fungal agents, steroids, metronidazole (an
anti-bacterial agent) and isotretinoin, or treatment with
anti-infectious agents such as azelaic acid.
SUMMARY
[0012] An exemplary embodiment of this application is a regimen for
the therapeutic treatment of moderate to severe erythema symptoms
in rosacea patients, the regimen comprising topically applying to
the skin of a subject in need of said treatment a pharmaceutical
composition, the pharmaceutical composition comprising about 1% w/w
to about 10% w/w benzoyl peroxide as an active ingredient, and a
pharmaceutically acceptable carrier or excipient, wherein the
benzoyl peroxide is the only active ingredient in said
pharmaceutical composition, wherein said pharmaceutical composition
is applied once daily for a period of at least about 12 weeks, to
achieve a percentage decrease of about 60% in a population
exhibiting moderate to severe erythema symptoms when measured at
about 12 weeks after initial treatment of the population with the
pharmaceutical composition.
[0013] Another exemplary embodiment of this application is a
regimen for the therapeutic treatment of moderate to severe
erythema symptoms in rosacea patients, the regimen comprising
topically applying to the skin of a subject in need of said
treatment a pharmaceutical composition, the pharmaceutical
composition comprising about 1% w/w to about 10% w/w benzoyl
peroxide as an active ingredient, and a pharmaceutically acceptable
carrier or excipient, wherein the benzoyl peroxide is the only
active ingredient in said pharmaceutical composition, and wherein
after about 2 weeks of treatment with the pharmaceutical
composition there is no increase in erythema symptoms.
[0014] In other exemplary embodiments, the number of patients with
no erythema symptoms does not increase after treatment for about 2
weeks with the pharmaceutical composition.
[0015] In other exemplary embodiments, the percentage decrease in
the population exhibiting erythema symptoms after treatment with
pharmaceutical composition is at least about 10% to about 30%
higher than a corresponding decrease in the population exhibiting
erythema symptoms after treatment with a vehicle alone.
[0016] In other exemplary embodiments, the percentage decrease in
the population exhibiting erythema symptoms after treatment with
pharmaceutical composition is at least about 18% higher than a
corresponding decrease in the population exhibiting erythema
symptoms after treatment with a vehicle alone.
[0017] In other exemplary embodiments, the benzoyl peroxide is the
sole active ingredient administered to the subject during the
duration of the regimen.
[0018] In other exemplary embodiments, the pharmaceutical
composition comprises about 2.5% w/w to about 10% w/w of the
benzoyl peroxide.
[0019] In other exemplary embodiments, the pharmaceutical
composition comprises about 5% w/w of the benzoyl peroxide.
[0020] In other exemplary embodiments, the benzoyl peroxide is in a
solid, solution or suspension form.
[0021] In other exemplary embodiments, the regimen is a first line
therapy for the treatment of moderate to severe rosacea.
[0022] In other exemplary embodiments, the moderate to severe
rosacea is any of erythematotelengietatic rosacea, papulopustular
rosacea, phymatous rosacea or ocular rosacea.
[0023] In other exemplary embodiments, the pharmaceutical
composition is a cream or an emulsion.
[0024] In other exemplary embodiments, the pharmaceutical
composition is an extended-release formulation.
[0025] In other exemplary embodiments, an extended-release effect
from the extended-release formulation is obtained by encapsulation,
microencapsulation, microspheres or coating.
[0026] In other exemplary embodiments, the benzoyl peroxide is
encapsulated or microencapsulated.
[0027] In other exemplary embodiments, the benzoyl peroxide is
included in a microsphere or a coating.
[0028] Details of other exemplary embodiments of the present
disclosure will be included in the following detailed description
and the accompanying drawings. It is appreciated that certain
features of the exemplary embodiments described in this
application, which are, for clarity, described in the context of
separate embodiments, can also be provided in combination in a
single embodiment.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] In order to understand the disclosure and to see how it can
be carried out in practice, embodiments will now be described, by
way of non-limiting examples only, with reference to the
accompanying drawings, in which:
[0030] FIGS. 1A and 1B are graphs presenting the percentage of
patients with erythema at baseline and after treatment with a BPO
composition for a period of about 12 weeks compared with the
percentage of patients with erythema after treatment with vehicle
alone.
DETAILED DESCRIPTION
[0031] Multiple studies have been directed to the treatment of
rosacea using a pharmaceutical or dermatological active agent such
as metronidazole, azelaic acid, sulfacetamide, brimonidine,
ivermectin, permethrin and clindamycin, and with doxycycline, which
is identified as the only FDA-approved treatment for rosacea (Oge
et al., "Rosacea: Diagnosis and Treatment," American Family
Physician, v. 92(3), pp. 187-198 (2015); Gul et al., "A case of
granulomatous rosacea successfully treated with pimecrolimus
cream," J. Derm. Treatment, 19, 313-315 (2008)).
[0032] Benzoyl peroxide (BPO) is generally identified as an
anti-acne agent, used alone (U.S. Pat. No. 9,439,857; Wester et
al., "Controlled release of benzoyl peroxide from a porous
microsphere polymeric system can reduce topical irritancy," J. Am.
Acad. Derma. 24, 720-726 (1991); Sawleshwarkar, "Multicenter study
to evaluate efficacy and irritation potential of benzoyl peroxide
4% cream in hydrophase base (Brevoxyl) in acne vulgaris," Ind. J.
Derm. Vener. Lepro., 69(1), 19-22 (2003)) or in combination with a
primary active such as avermectin (U.S. 2011/0052515).
[0033] One such study includes a therapeutic regimen involving
treatment of acne rosacea in a group of patients in need of such
treatment with 5% BPO-acetone gel for four weeks, followed by
treatment of the same group of patients with 10% BPO-acetone gel
for an additional four weeks. (Montes et al., "Topical Treatment of
Acne Rosacea with Benzoyl Peroxide Acetone Gel," Therapeutics for
the Clinician: New Reports on Treatment Modalities of Possible
Interest to Patient-Caring Physicians, 32, 185-190 (1983)). The
Montes study showed a significantly better response during the five
to eight weeks of treatment with 10% BPO-acetone gel compared to
the first four weeks of treatment with 5% BPO-acetone gel.
Moreover, although Montes 1983 claims success in the treatment of
rosacea using a BPO-acetone gel, 25% of the patients in the study
showed no improvement and 40% of the patients developed an
irritation. Additionally, this study required increasing the amount
of BPO administered to the patients from 5% to 10% after week four.
The results of the Montes 1983 study make it clear that BPO would
not be suitable for regular use in the treatment of rosacea,
especially as a first line treatment of rosacea.
[0034] Other studies show that, when used in the treatment of
rosacea, BPO is generally combined with a primary active agent such
as clindamycin (Breneman et al., "Double-blind, randomized,
vehicle-controlled clinical trial of once-daily benzoyl
peroxide/clindamycin topical gel in the treatment of patients with
severe rosacea," Int. J. Derm., 43, 381-387 (2004); Gold et al.,
"Use of Benzoyl Peroxide/Clindamycin gel in the once daily
treatment of moderate rosacea," J. Amer. Acad. Dermat., 52(3),
sup., P25 (2004); Leyden et al., "Blind photographic review for a
double blind, multicenter, placebo-controlled study comparing
Benzoyl Peroxide/Clindamycin and placebo for the treatment of
rosacea," J. Amer. Acad. Dermat., 52(3), sup., P14 (2004); Goldgar
et al., "Treatment Options for Acne Rosacea," J Amer. Fam.
Physician, 80(5), 461-468 (2009)).
[0035] BPO is generally identified as only a possible second-line
treatment of rosacea following the use of another, different
active. (Oge 2015, Table 5; Goldgar 2009, "Key Recommendations for
Practice"). Goldgar 2009, in particular, recommends the use of BPO
only as a tertiary therapy for the treatment of rosacea.
[0036] When BPO was used as the sole active agent for the treatment
of rosacea, lesions were found to be unresponsive. (Gul 2008).
[0037] These previous rosacea treatments with BPO alone or in
combination with other agents, have been shown to have several
drawbacks such as irritation and intolerance phenomena, especially
when they are administered for a prolonged period. (Crawford et
al., "Rosacea: I. Etiology, pathogenesis, and subtype
classification," J. Am. Acad. Dermatol., 51, 327-341 (2004)). These
treatments are only suppressive and not curative, acting especially
on the pustulous spasms occurring during the inflammatory
stage.
[0038] Such drawbacks associated with the treatment of rosacea
involving the use of BPO result in exclusion of BPO from standard
rosacea treatment methods. For example, A Review of the Current
Modalities for the Treatment of Papulopustular Rosacea identifies
metronidazole, ivermectin and azelaic acid as topical therapies
that were proven effective for the treatment of rosacea. (McGregor
et al., "A Review of the Current Modalities of the Treatment of
Papulopustular Rosacea," Dermatol. Clin. (2017)). While McGregor
2017 mentions alternate therapies, such as sodium
sulfacetanide/sulfur cream, clindamycin, tretinoin, calcineurin
inhibitors and oral tretinoin, that may have some effectiveness in
the treatment of rosacea, notably, McGregor 2017 does not include
BPO in the long list of possible treatment therapies described
therein. The absence of BPO as a known treatment for rosacea is
also evident in other studies. (Feaster et al., "Clinical
effectiveness of novel rosacea therapies," Current Op. Pharmacol.,
46, 14-18 (2019); Del Rosso et al., "Update on the Management of
Rosacea from the American Acne & Rosacea Society (AARS); J.
Clinical & Aesthetic Dermat., 12 (6), 17-24 (2019)). The
absence of BPO as a recognized first-line treatment for rosacea is
especially evident in Del Rosso, which is a well-known and
respected authority on the treatment of rosacea. The AARS review
lists the Society's recommendation for rosacea treatment, including
topical metronidazole, topical azelaic acid, oral tetracyclines,
ivermectin, topical alpha agonists, and oral isotretinoin, as well
as "alternative therapies," such as sulfacetamide/sulfur,
calcineurin inhibitors, retinoids, and permethrin. (See e.g., Table
1 of the AARS review.) BPO is not mentioned in the AARS review
either as a leading or an alternative therapeutic agent for the
treatment of rosacea.
[0039] Considering the chronic nature of rosacea, there is a need
for early onset of action, and a prolonged use and/or treatment of
the disease, its symptoms and associated conditions, in a safe and
effective manner. Thus, there exists a need for compositions that
show early onset of action, and improved efficacy in the treatment
of rosacea, that impart greater tolerance to the active principles
and that reduce, substantially minimize or do not have the side
effects described in the prior art.
[0040] Advantages and features of the present disclosure, and
methods for accomplishing the same will be more clearly understood
from exemplary embodiments described below with reference to any
accompanying drawings and figures. However, the present disclosure
is not limited to the following exemplary embodiments and can be
implemented in various different forms. The exemplary embodiments
are provided only to provide sufficient disclosure of the present
discoveries and to fully provide a person having ordinary skill in
the art to which the present disclosure pertains within the
technical field, and the present disclosure will be defined by any
appended claims and combinations thereof.
[0041] As used herein, like reference numerals generally denote
like elements throughout the present specification. Further, in the
following description, a detailed explanation of well-known related
technologies can be omitted to avoid unnecessarily obscuring the
subject matter of the present disclosure.
[0042] As used herein, terms such as "including" and "having" are
generally intended to allow other components to be included unless
the terms are used in conjunction with the term "only."
[0043] As used herein, the term "topical use" is meant to encompass
the topical administration of an exemplary composition 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.
[0044] As used herein, the term "treating" or "treatment" includes
curing a condition, treating a condition, preventing or
substantially preventing a condition, treating symptoms of a
condition, curing symptoms of a condition, ameliorating, reducing
and/or minimizing symptoms of a condition, treating effects of a
condition, ameliorating, reducing and/or minimizing effects of a
condition, and preventing and/or substantially preventing results
of a condition.
[0045] As used herein, the term "first-line therapy" or "first-line
treatment" means a therapy or treatment for which its label does
not include a requirement or recommendation that said therapy or
treatment should be used only after other therapies or treatments
were shown to be unsatisfactory or unsuccessful. It can also
include a therapy and/or treatment wherein no other actives (beyond
the main active) are administered to the individual subject in
need.
[0046] As used herein, the term "success rate" corresponds to a
percentage increase in the number of subjects achieving clear or
almost clear skin on the investor global assessment (IGA) scale
after treatment with the pharmaceutical composition.
[0047] As used herein, the term "early onset" or "early onset of
action" means achieving a desired result and/or effect at a point
in time that is earlier or even much early than achieved using a
vehicle or other, conventional treatment approach. For example, it
can mean achieving a desired result and/or effect no later than
about 8 weeks from initial treatment, preferably no later than
about 4 weeks from initial treatment, and more preferably no later
than about 2 weeks from initial treatment.
[0048] As used herein, the term "pharmaceutical composition" refers
to a composition comprising one or more active ingredients with
other components such as, for example, pharmaceutically acceptable
ingredients and/or excipients. The purpose of a pharmaceutical
composition is to facilitate administration of an active ingredient
to a subject.
[0049] As used herein, the terms "pharmaceutically active agent" or
"active agent" or "active pharmaceutical ingredient" are
interchangeable and mean the ingredient is a pharmaceutical drug,
which is biologically- and/or chemically-active and is
regulatory-approved or approvable as such.
[0050] As used herein, the term "ingredient" refers to a
pharmaceutically acceptable ingredient, which is included or is
amenable to be included in The FDA's Inactive Ingredient (IIG)
database. Inactive ingredients can sometimes exhibit some
therapeutic effects, although they are not drugs.
[0051] As used herein, the term "adverse events values" refers to
an average percentage of subjects that experience any adverse
events associated with the treatment of rosacea with a composition
described and/or claimed herein (usually on a surface of the skin
of a subject treated with a composition described and/or claimed
herein). A non-limiting list of such adverse events includes:
irritation, dryness, scaling, itching purities, burning, stinging,
combinations thereof and the like.
[0052] As used herein, the term "inflammatory lesion" refers to
papules and pustules present on the skin of a patient, and does not
include nodules and cysts.
[0053] As used herein, the term "papule" refers to a solid,
elevated inflammatory lesion equal to or less than about 5 mm in
diameter.
[0054] As used herein, the term "pustule" refers to an elevated
inflammatory, pus-containing lesion equal to or less than about 5
mm in diameter.
[0055] As used herein, the term "nodule" and/or "cyst" refers to
palpable solid inflammatory lesion, greater than about 5 mm in
diameter. The nodule and/or cyst may have depth but does not
necessarily include elevation.
[0056] Whenever a numerical range is indicated herewith, it is
meant to include any cited numeral (fractional or integral) within
the indicated range. The phrases "ranging/ranges between" a first
indicated number and a second indicated number and "ranging/ranges
from" a first indicated number "to" a second indicated number are
used herein interchangeable and are meant to include the first and
second indicated numbers and all fractional and integral numerals
therebetween.
[0057] The dimensions and values disclosed herein are not to be
understood as being strictly limited to the exact numerical values
recited. Instead, unless otherwise specified, each such dimension
is intended to mean both the recited value and a functionally
equivalent range surrounding that value. For example, a dimension
disclosed as "10 .mu.m" is intended to mean "about 10 .mu.m."
[0058] As used herein, numbers and/or numerical ranges preceded by
the term "about" should not be considered to be limited to the
recited range. Rather, numbers and/or numerical ranges preceded by
the term "about" should be understood to include a range accepted
by those skilled in the art for any given element in formations
according to the subject invention.
[0059] As used herein, when a numerical value is preceded by the
term "about," the term "about" is intended to indicate +/-10%.
[0060] As used herein, the singular form "a," "an" and "the"
include plural references unless the context clearly dictates
otherwise. For example, the term "a compound" or "at least one
compound" can include a plurality of compounds, including
combinations and/or mixtures thereof.
[0061] As used herein, the term "method" refers to manners, means,
techniques and procedures for accomplishing a given task including,
but not limited to, those manners, means, technical and procedures
either known to, or readily developed from known manners, means,
techniques and procedures by practitioners of the chemical,
pharmacological, biological, biochemical and medical arts.
[0062] It is appreciated that certain features of the exemplary
embodiments described herein, which are, for clarity, described in
the context of separate embodiments, can also be provided in
combination in a single embodiment. Conversely, various features of
the exemplary embodiments, which are, for brevity, described in the
context of a single embodiment, can also be provided separately or
in any suitable sub-combination or as suitable in any other
described embodiment. Certain features described in the context of
various embodiments are not to be considered essential features of
those embodiments, unless the embodiment is inoperative without
those elements.
[0063] An exemplary embodiment of this application is a regimen for
the therapeutic treatment of moderate to severe erythema symptoms
in rosacea patients, the regimen comprising topically applying to
the skin of a subject in need of said treatment a pharmaceutical
composition, the pharmaceutical composition comprising about 1% w/w
to about 10% w/w benzoyl peroxide as an active ingredient, and a
pharmaceutically acceptable carrier or excipient, wherein the
benzoyl peroxide is the only active ingredient in said
pharmaceutical composition, wherein said pharmaceutical composition
is applied once daily for a period of at least about 12 weeks, to
achieve a percentage decrease of about 60% in a population
exhibiting moderate to severe erythema symptoms when measured at
about 12 weeks after initial treatment of the population with the
pharmaceutical composition.
[0064] In another exemplary embodiment, the percentage decrease in
the population exhibiting erythema symptoms after treatment with
pharmaceutical composition is at least about 10% to about 30%
higher than a corresponding decrease in the population exhibiting
erythema symptoms after treatment with a vehicle alone.
[0065] In another exemplary embodiment, the percentage decrease in
the population exhibiting erythema symptoms after treatment with
pharmaceutical composition is at least about 18% higher than a
corresponding decrease in the population exhibiting erythema
symptoms after treatment with a vehicle alone.
[0066] Another exemplary embodiment of this application is a
regimen for the therapeutic treatment of moderate to severe
erythema symptoms in rosacea patients, the regimen comprising
topically applying to the skin of a subject in need of said
treatment a pharmaceutical composition, the pharmaceutical
composition comprising about 1% w/w to about 10% w/w benzoyl
peroxide as an active ingredient, and a pharmaceutically acceptable
carrier or excipient, wherein the benzoyl peroxide is the only
active ingredient in said pharmaceutical composition, and wherein
after about 2 weeks of treatment with the pharmaceutical
composition there is no increase in erythema symptoms.
[0067] In other exemplary embodiments, the benzoyl peroxide is the
sole active ingredient administered to the subject during the
duration of the regimen.
[0068] In other exemplary embodiments, the pharmaceutical
composition comprises about 2.5% w/w to about 10% w/w of benzoyl
peroxide, preferably about 3% to about 9%, about 4% to about 8%,
and more preferably about 5% w/w of benzoyl peroxide.
[0069] In other exemplary embodiments, the benzoyl peroxide is
selected from solid, solution or suspension form.
[0070] In other exemplary embodiments, the regimen is a first line
therapy for the treatment of rosacea.
[0071] In other exemplary embodiments, the rosacea is any one of
erythematotelengietatic rosacea, papulopustular rosacea, phymatous
rosacea or ocular rosacea.
[0072] In other exemplary embodiments, the rosacea is moderate to
severe rosacea, preferably severe rosacea.
[0073] In other exemplary embodiments, the pharmaceutical
composition is a cream or an emulsion.
[0074] In other exemplary embodiments, the pharmaceutical
composition is an extended release formulation. The
extended-release effect can be obtained by encapsulation,
microencapsulation, microspheres or coating. The benzoyl peroxide
can be encapsulated or microencapsulated, the benzoyl peroxide can
be included in a microsphere or a coating, and the like.
[0075] In some further embodiments, the composition 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 and/or
combination thereof.
[0076] In other embodiments, the composition is formulated into a
topically applicable, physiologically acceptable medium comprising
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 and/or combinations thereof.
[0077] In some embodiments the composition is formulated as an
emulsion (including an oil-in-water emulsion, a water-in-oil
emulsion, multiple emulsions and microemulsions). In other
embodiments, the composition is formulated as a cream.
[0078] The compositions described in exemplary embodiments herein
are pharmaceutical compositions, and especially dermatological
compositions, which can be in any galenical form conventionally
used for topical application. By addition of a fatty or oily phase,
they can 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 (O/W)
or conversely (W/O), or suspensions or emulsions of soft,
semiliquid or solid consistency of the cream, gel or ointment type,
or alternatively multiple emulsions (W/O/W or O/W/O),
microemulsions, microcapsules, microparticles and/or vesicular
dispersions of ionic and/or nonionic type, and/or wax/aqueous phase
dispersions. These compositions are formulated according to the
usual methods.
[0079] In further embodiments, the composition comprises, 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. Various methods for the preparation of the
BPO-containing compositions are described in U.S. Application
Publication Nos. 2010/0016443, 2017/0281571 and 2018/0147165 and
U.S. Pat. No. 9,687,465.
[0080] In some embodiments, the ratio of said polyoxylstearate to
said glycerylstearate is in the range of about 0.1:10 to about
10:0.1.
[0081] In yet further embodiments, said polyoxylstearate is
selected from the group consisting of Polyoxyl-8 stearate,
Polyoxyl-20 stearate, Polyoxyl-40 stearate, Polyoxyl-100 stearate
and combinations and/or mixtures thereof.
[0082] In further embodiments, said glycerylstearate is selected
from the group consisting of glyceryl mono-stearate, glyceryl
di-stearate and combinations and/or mixtures thereof.
[0083] In other embodiments, said polyoxylstearate in said
composition is in the range of from about 0.1% w/w to about 30%
w/w.
[0084] In further embodiments, the amount of said glycerylstearate
in said composition is in the range of from about 0.1% w/w to about
30% w/w.
[0085] In other embodiments, said composition further comprises at
least one fatty alcohol.
[0086] 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
combinations and/or mixtures thereof.
[0087] In further embodiments, the amount of said at least one
fatty alcohol in said composition is in the range of from about
0.2% w/w to about 50% w/w.
[0088] In yet other embodiments, said composition further comprises
a polyacrylic acid homopolymer or copolymer.
[0089] 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 combinations and/or
mixtures thereof.
[0090] In further embodiments, said oil in present in the
composition in an amount in the range of from about 0.05% w/w to
about 50% w/w.
[0091] In some embodiments, said water in said oil in water
emulsion further comprises at least one water soluble
humectant.
[0092] In other embodiments, said at least one water soluble
humectant is selected from the group consisting of propylene
glycol, glycerin, polyethylene glycol-X and combinations and/or
mixtures thereof, where X is in the range of from about 200 to
about 10,000.
[0093] In some embodiments, the composition comprises said solid
BPO in a controlled and/or slowed release drug delivery system. In
further embodiments, said controlled and/or slowed release drug
delivery system is an encapsulation in a microcapsule, wherein said
solid BPO is embedded in said microcapsule. When referring to a
"controlled and/or slowed release drug delivery system" it should
be understood to relate to a delivery system (which in the present
application 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 and/or a porous matrix structure, such as,
for example, a microsponge. 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.
[0094] In some embodiments, said core of said microcapsule
comprises or consists of said solid BPO.
[0095] 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).
[0096] In some embodiments, said microcapsule comprises a metal
oxide or semi-metal oxide coating or layer (shell) and a core
comprising or consisting of solid BPO.
[0097] In some embodiments, said microcapsule comprises a metal
oxide or semi-metal oxide coating or layer (shell) and a core
comprising solid BPO is prepared by a process comprising the steps
of:
[0098] (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;
[0099] (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;
[0100] (c) repeating step (b) at least 4 more times: and
[0101] (d) aging said coating layer.
[0102] As used herein, the term "solid BPO particulate matter"
refers to a solid BPO having solubility in water of less than about
1% w/w, typically less than about 0.5% and at times less than about
0.1% w/w at room temperature (about 20.degree. C.). 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 from about 0.3 to about 50 microns. Such a particulate
matter can be readily suspended in an aqueous systems by stirring,
with or without the aid of a surfactant.
[0103] The terms "solid BPO particulate matter" and "particulate
matter" will be used interchangeably.
[0104] In the present application, 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 need not always be complete or uniform and
need 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.
[0105] 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. Step (a) of the process can further comprise
reducing the particle size of the particulate matter to the desired
particle size, for example, by milling or homogenization.
[0106] The core (i.e., solid, BPO particulate matter) can be of any
shape, for example, rod-like, plate-like, ellipsoidal, cubic,
spherical shape, combinations thereof and the like.
[0107] Reference to the size of particles will be made through
their D.sub.90, which means that about 90% of the particles have
the stated dimension or less (measured by volume). Thus, for
example, for spherical particles stated to have a diameter of about
10 micrometer ("microns"), this means that the particles have a
D.sub.90 of about 10 microns. The D.sub.90 can 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.
[0108] In the case of cores having a spherical shape, the D.sub.90
can be in the range of from about 0.3 to 90 microns, in some
embodiments from about 0.3 to about 50 microns, in some other
embodiments from about 1 to about 50 microns, in some further
embodiments from about 5 to about 30 microns. As used herein, the
phrase "D.sub.90 can be in the range of from about 0.3 microns to
about 90 microns" means about 90% by volume of the particles (in
this case the particle's core) can be less than or equal to a value
in the range of from about 0.3 microns to about 90 microns.
[0109] For generally cubic-shaped cores or cores having a shape
resembling that of a cube, the mean size of a side can be in the
range of from about 0.3 to about 80 microns, in some embodiments
from about 0.3 to about 40 microns, in some further embodiments
from about 0.8 to about 40 microns, in some further embodiments
from about 4 to about 15 microns.
[0110] For rod-like shaped, ellipsoidal-shaped and plate-like
shaped cores, the largest dimension (that of the longest axis) is
typically in the range of from about 10 to about 100 microns, in
some embodiments from about 15 to about 50 microns; and the
smallest dimension is typically in the range of from about 0.5 to
about 20 microns, in some further embodiments from about 2 to about
10 microns.
[0111] As used herein, unless otherwise indicated, the term
"particle" refers to the metal oxide or semi-metal oxide coated
particulate matter.
[0112] It is appreciated that some of the particles obtained by the
process can at times be formed from two or more original particles
of the solid BPO particulate and can accordingly include at times
more than one core, such cores being separated from each other by a
metal oxide region.
[0113] The weight of the solid BPO particulate (core material)
based on the total weight of the particle can be in the range of
from about 99% w/w to about 50% w/w, in some embodiments in the
range of from about 97% w/w to about 50% w/w. The core material can
be in a crystalline form, amorphous form, or combination thereof.
The core material can be a cosmetic, pharmaceutical or an
agrochemical active ingredient.
Exemplary Embodiments
[0114] BPO-containing compositions were prepared following the
various preparation methods described in U.S. Application
Publication Nos. 2010/0016443, 2017/0281571 and 2018/0147165 and
U.S. Pat. No. 9,687,465, the contents of which are incorporated
herein, by reference, in their entirety.
[0115] Description:
[0116] A randomized, double-blind, multi-center, parallel group,
active- and vehicle-controlled study of encapsulated 5% benzoyl
peroxide cream (E-BPO) and vehicle cream was performed to assess
the efficacy and safety of E-BPO compared to vehicle. Study
duration was 12 weeks and included approximately 350 male and
female patients afflicted with papulopustular rosacea. Patients
were at least 18 years of age.
[0117] Patients were admitted into the study after meeting all
inclusion/exclusion criteria, including a clinical diagnosis of
rosacea. Subjects with moderate to severe rosacea who were
appropriate for systemic treatment were counseled regarding their
treatment options by the Principal Investigator. At each visit, a
5-point IGA scale of rosacea and inflammatory lesion counts were
performed and recorded.
[0118] Dosing:
[0119] Patients were randomly organized in a 2:1 ratio to the study
product or vehicle treatment group, respectively. Patients applied
the study product once daily for 12 weeks on the face in a thin
layer to provide even distribution.
[0120] Clinical and Safety Evaluations were performed at Baseline
and Weeks 2, 4, 8 and 12.
[0121] Evaluation of Erythema:
[0122] Erythema is defined as redness of the skin. Erythema was
scored on a scale of 0 (none) to 3 (severe) at all visits.
[0123] The percentage of patients with no erythema at baseline with
5% E-BPO and vehicle cream at Baseline and about 2 weeks is shown
in Tables 1A and 1B below. As seen from these results, the
percentage of patients with no erythema symptoms does not increase
after treatment with 5% E-BPO for two weeks.
TABLE-US-00001 TABLE 1A Comparative Example 1A Example 1A (5%
E-BPO) (vehicle alone) Baseline Percentage of 0.4 0.0 (N = 243 for
5% Patients with E-BPO; N = 118 for No Erythema vehicle) Symptoms
Week 2 Percentage of 0.4 0.0 (N = 221 for 5% Patients with E-BPO; N
= 107 for No Erythema vehicle) Symptoms Change from 0.0 0.0
baseline Percentage 0.0 0.0 change from baseline
TABLE-US-00002 TABLE 1B Comparative Example 1B Example 1B (5%
E-BPO) (vehicle alone) Baseline Percentage of 0.4 0.0 (N = 243 for
5% Patients with E-BPO; N = 118 for No Erythema vehicle) Symptoms
Week 2 Percentage of 1.2 0.0 (N = 221 for 5% Patients with E-BPO; N
= 107 for No Erythema vehicle) Symptoms Change from 0.8 0.0
baseline Percentage 20 0.0 change from baseline
[0124] The Rosacea Erythema Assessment Scale for patient groups
treated with 5% E-BPO and vehicle cream at Baseline and about 12
weeks is shown in Tables 2A and 2B below. As seen from these
results, a percentage decrease of about 60% is observed in a
population exhibiting moderate to severe erythema symptoms when
measured at about 12 weeks after initial treatment of the
population with the pharmaceutical composition. This observed
decrease in erythema symptoms is at least about 10% to about 30%
higher than a corresponding decrease in the population exhibiting
erythema symptoms after treatment with a vehicle alone. These
results are shown in FIGS. 1A and 1B.
TABLE-US-00003 TABLE 2A Comparative Example 1A Example 1A (5%
E-BPO) (vehicle alone) Baseline Percentage of 85.6 87.2 (N = 243
for 5% Patients with E-BPO; N = 118 for Moderate and vehicle)
Severe Erythema Week 12 Percentage of 33.0 57.9 (N = 221 for 5%
Patients with E-BPO; N = 107 for Moderate and vehicle) Severe
Erythema Change from -52.6 -29.3 baseline Percentage -61.4 -33.6
change from baseline
TABLE-US-00004 TABLE 2B Comparative Example 1B Example 1B (5%
E-BPO) (vehicle alone) Baseline Percentage of 94.0 95.9 (N = 250
for 5% Patients with E-BPO; N = 122 for Moderate and vehicle)
Severe Erythema Week 12 Percentage of 38.7 48.7 (N = 235 for 5%
Patients with E-BPO; N = 113 for Moderate and vehicle) Severe
Erythema Change from -55.3 -47.2 baseline Percentage -58.8 -49.2
change from baseline
[0125] The above-discussed results demonstrate the unexpected
superiority of the benzoyl peroxide composition described in this
application in the treatment of severe rosacea in patients in need
of such treatment.
[0126] Although the exemplary embodiments of the present disclosure
have been described in detail with reference to the accompanying
examples and drawings, the present disclosure is not limited
thereto and can be embodied in many different forms without
departing from the technical concept of the present disclosure.
Therefore, the exemplary embodiments of the present disclosure are
provided for illustrative purposes only and are not intended to
limit the technical concept of the present disclosure. The
protective scope of the present disclosure should be construed
based on any appended claims and combinations thereof, and all the
technical concepts in the equivalent scope thereof should be
construed as falling within the scope of the present disclosure. As
various changes could be made in the above methods and compositions
without departing from the scope of the invention, it is intended
that all matter contained in the above description shall be
interpreted as illustrative and not in a limiting sense. Other
embodiments within the scope of the claims herein will be apparent
to one skilled in the art from consideration of the specification
or practice of the exemplary embodiments disclosed herein. It is
intended that the specification be considered exemplary only, with
the scope and spirit of the described subject matter being
indicated by the claims.
* * * * *