U.S. patent application number 16/794923 was filed with the patent office on 2020-08-20 for method for treatment of rosacea including patient reported outcomes thereof.
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 | 20200261401 16/794923 |
Document ID | 20200261401 / US20200261401 |
Family ID | 1000004839068 |
Filed Date | 2020-08-20 |
Patent Application | download [pdf] |
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United States Patent
Application |
20200261401 |
Kind Code |
A1 |
TOLEDANO; Ofer ; et
al. |
August 20, 2020 |
METHOD FOR TREATMENT OF ROSACEA INCLUDING PATIENT REPORTED OUTCOMES
THEREOF
Abstract
A regimen is described for the therapeutic treatment of rosacea
including topically applying to the skin of a subject in need of
the treatment a pharmaceutical composition. The pharmaceutical
composition includes about 1% w/w to about 10% w/w benzoyl peroxide
as an active ingredient, and a pharmaceutically acceptable carrier
or excipient. The benzoyl peroxide is the only active ingredient in
said pharmaceutical composition, and the pharmaceutical composition
is applied once daily for a period of at least about 2 weeks, about
4 weeks, about 8 weeks or about 12 weeks. A decrease in Patient
Assessment of Papulopustular Rosacea Signs and Symptoms (PAPSS) is
at least about 40% after treatment with the pharmaceutical
composition for about 4 weeks, and a decrease in Patient Assessment
of Papulopustular Rosacea Impacts (PAPI) is from about 60% to about
70% after treatment with the pharmaceutical composition for at
least about 8 weeks.
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 |
|
|
Family ID: |
1000004839068 |
Appl. No.: |
16/794923 |
Filed: |
February 19, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
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
9/0014 20130101; A61K 9/50 20130101; A61P 17/00 20180101; A61K
31/327 20130101; A61K 9/06 20130101 |
International
Class: |
A61K 31/327 20060101
A61K031/327; A61P 17/00 20060101 A61P017/00; A61K 9/00 20060101
A61K009/00; A61K 9/06 20060101 A61K009/06; A61K 9/10 20060101
A61K009/10; A61K 9/50 20060101 A61K009/50 |
Claims
1. A regimen for the therapeutic treatment of rosacea, 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Signs and Symptoms (PAPSS) is at least about 30% after
treatment with said pharmaceutical composition for about 2 weeks
compared with a decrease of about 20% after 2-week treatment with
vehicle alone.
2. The regimen of claim 1, wherein the decrease in PAPSS is at
least about 40% after treatment with said pharmaceutical
composition for about 4 weeks compared with a decrease of less than
about 40% after 4-week treatment with vehicle alone.
3. The regimen of claim 1, wherein the decrease in PAPSS is from
about 50% to about 65% after treatment with said pharmaceutical
composition for at least about 8 weeks compared with a decrease
from about 25% to about 40% after 8-week treatment with vehicle
alone.
4. The regimen of claim 1, wherein the benzoyl peroxide is the sole
active ingredient administered to the subject in need of said
treatment during the duration of the regimen.
5. The regimen of claim 1, wherein the pharmaceutical composition
comprises about 5% w/w of benzoyl peroxide.
6. The regimen of claim 1, wherein said benzoyl peroxide is in a
form selected from solid, solution or suspension.
7. The regimen of claim 1, wherein the rosacea is any of
erythematotelengietatic, papulopustular, phymatous 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, wherein the extended-release
effect is obtained by encapsulation, microencapsulation,
microspheres or coating.
10. The regimen of claim 1, wherein the papulopustular rosacea
signs and symptoms are selected from burning, itching, redness,
bumps, and combinations thereof, on the skin of a subject.
11. A regimen for the therapeutic treatment of rosacea, 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Impacts (PAPI) is at least about 35% after treatment with
said pharmaceutical composition for about 2 weeks compared with a
decrease of about 23% after treatment with vehicle alone.
12. The regimen of claim 11, wherein the decrease in PAPI is from
about 60% to about 70% after treatment with said pharmaceutical
composition for at least about 8 weeks compared with a decrease of
about 35% after 8-week treatment with vehicle alone.
13. The regimen of claim 11, wherein the benzoyl peroxide is the
sole active ingredient administered to the subject in need of said
treatment during the duration of the regimen.
14. The regimen of claim 11, wherein the pharmaceutical composition
comprises about 5% w/w of benzoyl peroxide.
15. The regimen of claim 11, wherein said benzoyl peroxide is in a
form selected from solid, solution or suspension.
16. The regimen of claim 11, wherein the rosacea is any of
erythematotelengietatic, papulopustular, phymatous or ocular
rosacea.
17. The regimen of claim 11, wherein said pharmaceutical
composition is a cream or an emulsion.
18. The regimen of claim 11, wherein said pharmaceutical
composition is an extended release formulation, wherein the
extended-release effect is obtained by encapsulation,
microencapsulation, microspheres or coating.
19. The regimen of claim 11, wherein an average decrease in the
PAPI after treatment with said pharmaceutical composition for at
least about 8 weeks is approximately about 1.2 to two times an
average decrease in the PAPI after 8-week treatment with vehicle
alone.
20. The regimen of claim 11, wherein the papulopustular rosacea
impact is selected from embarrassment, self-consciousness and
frustration.
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 providing
therapeutic treatment of skin conditions and afflictions, such as
rosacea and symptoms and considerations associated therewith,
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, with
absence of 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] 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 even with
anti-infectious agents such as azelaic acid.
SUMMARY
[0011] An exemplary embodiment of this application is a regimen for
the therapeutic treatment of rosacea, 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Signs and Symptoms (PAPSS) is at least about 32% after
treatment with said pharmaceutical composition for about 2 weeks,
and about 40% after treatment with said pharmaceutical composition
for about 4 weeks.
[0012] In another exemplary embodiment, the decrease in PAPSS is
less than about 40% after treatment with vehicle alone for about 4
weeks.
[0013] Another exemplary embodiment of this application is a
regimen for the therapeutic treatment of rosacea, 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in PAPSS is from about 50% to about 65%
after treatment with said pharmaceutical composition for at least
about 8 weeks.
[0014] In another exemplary embodiment, the decrease in PAPSS is
from about 25% to about 40% after treatment with vehicle alone for
at least about 8 weeks.
[0015] In another exemplary embodiment, the papulopustular rosacea
signs and symptoms are selected from burning, itching, redness,
bumps, and combinations thereof, on the skin of a subject.
[0016] Another exemplary embodiment of this application is a
regimen for the therapeutic treatment of rosacea, 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Impacts (PAPI) is at least about 35%, preferably 40%, after
treatment with said pharmaceutical composition for about 2
weeks.
[0017] In another exemplary embodiment, the decrease in PAPI is
about 23%, preferably 25%, after treatment with vehicle alone for
about 2 weeks.
[0018] Another exemplary embodiment of this application is a
regimen for the therapeutic treatment of rosacea, 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in PAPI is from about 60% to about 70%
after treatment with said pharmaceutical composition for at least
about 8 weeks.
[0019] In another exemplary embodiments, the decrease in patient
assessment of papulopustular rosacea impacts is about 35%,
preferably 40%, more preferably 45%, after treatment with vehicle
alone for at least about 8 weeks.
[0020] In another exemplary embodiment, an average decrease in the
patient assessment of papulopustular rosacea impacts after
treatment with said pharmaceutical composition for at least about 8
weeks is approximately about 1.2 times to two times, preferably 1.5
times to two times, more preferably 1.6 times, an average decrease
in the PAPI after treatment with vehicle alone.
[0021] In another exemplary embodiment, the papulopustular rosacea
impact is selected from embarrassment, self-consciousness and
frustration.
[0022] Another exemplary embodiment of this application is a
pharmaceutical composition for use as a medicament for the
therapeutic treatment of rosacea, the pharmaceutical composition
comprising from 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Signs and Symptoms (PAPSS) is at least about 32% after
treatment with said pharmaceutical composition for about 2 weeks,
and about 40% after treatment with said pharmaceutical composition
for about 4 weeks.
[0023] In another exemplary embodiment, the decrease in PAPSS is
less than about 40% after treatment with vehicle alone for about 4
weeks.
[0024] Another exemplary embodiment of this application is a
pharmaceutical composition for use as a medicament for the
therapeutic treatment of rosacea, the pharmaceutical composition
comprising from 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Impacts (PAPI) is from about 60% to about 70% after
treatment with said pharmaceutical composition for at least about 8
weeks.
[0025] In another exemplary embodiment, the decrease in PAPI is
about 35% after treatment with vehicle alone for at least about 8
weeks. In certain embodiments the decrease in PAPI is about 40%,
preferably 45% after treatment with vehicle alone for at least
about 8 weeks.
[0026] Another exemplary embodiment of this application is the use
of a pharmaceutical composition for the treatment of rosacea, the
pharmaceutical composition comprising from 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 2 weeks, about
4 weeks, about 8 weeks or about 12 weeks, wherein a decrease in
Patient Assessment of Papulopustular Rosacea Signs and Symptoms
(PAPSS) is from about 50% to about 65% after treatment with said
pharmaceutical composition for at least about 8 weeks.
[0027] In another exemplary embodiment, the decrease in PAPSS is
from about 25% to about 40% after treatment with vehicle alone for
at least about 8 weeks.
[0028] Another exemplary embodiment of this application is the use
of a pharmaceutical composition for the treatment of rosacea, the
pharmaceutical composition comprising from 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 2 weeks, about
4 weeks, about 8 weeks or about 12 weeks, wherein a decrease in
Patient Assessment of Papulopustular Rosacea Impacts (PAPI) is from
about 60% to about 70% after treatment with said pharmaceutical
composition for at least about 8 weeks.
[0029] In another exemplary embodiment, the decrease in PAPI is
about 35%, preferably about 40%, more preferably 45%, after
treatment with vehicle alone for at least about 8 weeks.
[0030] In other exemplary embodiments, the benzoyl peroxide is the
sole active ingredient administered to the subject in need of said
treatment during the duration of the regimen; the pharmaceutical
composition comprises about 2.5% w/w to about 10% w/w of benzoyl
peroxide, preferably about 5% w/w of benzoyl peroxide; the benzoyl
peroxide is in a form selected from solid, solution or suspension;
the rosacea is any of erythematotelengietatic, papulopustular,
phymatous or ocular rosacea; the pharmaceutical composition is a
cream or an emulsion; the pharmaceutical composition is an extended
release formulation; and/or the extended-release effect is obtained
by encapsulation, microencapsulation, microspheres or coating,
preferably the benzoyl peroxide is encapsulated and/or
microencapsulated and/or the benzoyl peroxide is included in a
microsphere and/or a coating.
[0031] 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
[0032] 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:
[0033] FIGS. 1A to 1D are graph presenting each of the Patient
Assessment of Papulopustular Rosacea Signs and Symptoms (PAPSS) of
burning, itching, redness and bumps after treatment with BPO
composition as compared with vehicle alone over a period of about 2
weeks (FIG. 1A), about 4 weeks (FIG. 1B), about 8 weeks (FIG. 1C)
and about 12 weeks (FIG. 1D).
[0034] FIG. 2 is a graph presenting the total of all Patient
Assessment of Papulopustular Rosacea Signs and Symptoms (PAPSS)
after treatment with BPO composition as compared with vehicle alone
over a period of about 2 weeks, about 4 weeks, about 8 weeks and
about 12 weeks.
[0035] FIGS. 3A to 3D are graph presenting each of the Patient
Assessment of Papulopustular Rosacea Impacts (PAPI) of
embarrassment, self-consciousness and frustration after treatment
with BPO composition as compared with vehicle alone over a period
of about 2 weeks (FIG. 2A), about 4 weeks (FIG. 2B), about 8 weeks
(FIG. 2C) and about 12 weeks (FIG. 2D).
[0036] FIG. 4 is a graph presenting the total of all Patient
Assessment of Patient Assessment of Papulopustular Rosacea Impacts
(PAPI) after treatment with BPO composition as compared with
vehicle alone over a period of about 2 weeks, about 4 weeks, about
8 weeks and about 12 weeks.
DETAILED DESCRIPTION
[0037] 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)).
[0038] 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).
[0039] 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.
[0040] 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)).
[0041] 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.
[0042] When BPO was used as the sole active agent for the treatment
of rosacea, lesions were found to be unresponsive. (Gul 2008).
[0043] 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.
[0044] 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,
or even mention, 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 even an alternative, therapeutic agent for
the treatment of rosacea.
[0045] Considering the chronic nature of rosacea, there is a need
for early onset of action, and 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 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. As described herein, patient
reported outcomes demonstrate the unexpectedly superior therapeutic
effects of treating the symptoms of rosacea, such as, for example,
burning, itching, redness and burns, with the BPO composition of
the present invention. The patient reported outcomes also
demonstrate the unexpected decrease in the impact of papulopustular
rosacea, such as embarrassment, self-consciousness and
frustration.
[0046] 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. 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.
[0047] 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.
[0048] 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."
[0049] 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.
[0050] 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,
[0051] 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.
[0052] 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.
[0053] 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.
[0054] As used herein, "Patient Reported Outcome" and/or "PRO"
refers to patient reported outcomes of Patient Assessment of
Papulopustular Rosacea Signs and Symptoms (PAPSS) and/or Patient
Assessment of Papulopustular Rosacea Impacts (PAPI) as determined
from answers to relevant validated questionnaires provided by
subjects of the studies described herein.
[0055] As used herein, "Patient Assessment of Papulopustular
Rosacea Signs and Symptoms" and/or "PAPSS" refers to assessment by
subjects of the studies described herein of various symptoms of
rosacea, such as burning and/or stinging, itching, redness,
flushing, bumps, spider veins, swollen and/or sensitive skin, dry
skin, roughness or scaling, thickening of the skin, and the
like.
[0056] As used herein, "Patient Assessment of Papulopustular
Rosacea Impacts" and/or "PAPI" refers to assessment by subjects of
the studies described herein of various impacts of rosacea, such as
embarrassment, self-consciousness, frustration, worry, low
self-esteem, problems with interacting with people, anxiety and
depression, and the like.
[0057] 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.
[0058] 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."
[0059] 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.
[0060] As used herein, when a numerical value is preceded by the
term "about," the term "about" is intended to indicate +/-10%.
[0061] 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.
[0062] 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.
[0063] 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.
[0064] An exemplary embodiment of this application is a regimen for
the therapeutic treatment of rosacea, 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Signs and Symptoms (PAPSS) is at least about 40%, at least
about 50%, at least about 60%, at least about 70%, at least about
80%, at least about 90%, and the like, after treatment with said
pharmaceutical composition for about 4 weeks.
[0065] In another exemplary embodiment, the decrease in PAPSS is
less than about 40%, less than about 30%, less than about 20%, less
than about 10%, less than about 5%, and the like, after treatment
with vehicle alone for about 4 weeks.
[0066] Another exemplary embodiment of this application is a
regimen for the therapeutic treatment of rosacea, 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in PAPSS is from about 50% to about 65%,
from about 52% to about 63%, from about 54% to about 61%, from
about 56% to about 59%, and the like, after treatment with said
pharmaceutical composition for at least about 8 weeks.
[0067] In another exemplary embodiment, the decrease in PAPSS is
from about 25% to about 40%, from about 27% to about 38%, from
about 29% to about 36%, from about 27% to about 34%, from about 29%
to about 32%, and the like, after treatment with vehicle alone for
at least about 8 weeks.
[0068] In another exemplary embodiment, the papulopustular rosacea
signs and symptoms are selected from burning, itching, redness,
bumps, and combinations thereof, on the skin of a subject.
[0069] Another exemplary embodiment of this application is a
regimen for the therapeutic treatment of rosacea, 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Impacts (PAPI) is at least about 35%, at least about 40%,
at least about 50%, at least about 60%, at least about 70%, at
least about 80%, at least about 90%, and the like, after treatment
with said pharmaceutical composition for about 2 weeks.
[0070] In another exemplary embodiment, the decrease in PAPI is
about 15%, about 20%, about 25%, about 30%, about 34%, and the
like, after treatment with vehicle alone for about 2 weeks.
[0071] Another exemplary embodiment of this application is a
regimen for the therapeutic treatment of rosacea, 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Impacts (PAPI) is from about 60% to about 70%, from about
61% to about 69%, from about 62% to about 68%, from about 63% to
about 67%, from about 64% to about 66%, and the like, after
treatment with said pharmaceutical composition for at least about 8
weeks.
[0072] In another exemplary embodiments, the decrease in PAPI is
about 30%, about 35%, about 45%, about 50%, about 55%, and the
like, after treatment with vehicle alone for at least about 8
weeks.
[0073] In another exemplary embodiment, an average decrease in the
PAPI after treatment with said pharmaceutical composition for at
least about 8 weeks is approximately about 1.2 times to two times,
preferably 1.5 times to two times, more preferably more than two
times, an average decrease in the PAPI after treatment with vehicle
alone.
[0074] In another exemplary embodiment, the papulopustular rosacea
impact is selected from embarrassment, self-consciousness and
frustration.
[0075] Another exemplary embodiment of this application is a
pharmaceutical composition for use as a medicament for the
therapeutic treatment of rosacea, the pharmaceutical composition
comprising from 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Signs and Symptoms (PAPSS) is at least about 40%, at least
about 50%, at least about 60%, at least about 70%, at least 80%, at
least about 90%, and the like, after treatment with said
pharmaceutical composition for about 4 weeks.
[0076] In another exemplary embodiment, the decrease in PAPSS is
less than about 40%, less than about 35%, less than about 30%, less
than about 25%, less than about 20%, less than about 15%, less than
about 10%, less than about 5%, and the like, after treatment with
vehicle alone for about 4 weeks.
[0077] Another exemplary embodiment of this application is a
pharmaceutical composition for use as a medicament for the
therapeutic treatment of rosacea, the pharmaceutical composition
comprising from 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 2 weeks, about 4 weeks, about 8 weeks or about 12
weeks, wherein a decrease in Patient Assessment of Papulopustular
Rosacea Impacts (PAPI) is from about 60% to about 70%, from about
61% to about 69%, from about 62% to about 68%, from about 63% to
about 67%, from about 64% to about 68%, from about 65% to about
67%, and the like, after treatment with said pharmaceutical
composition for at least about 8 weeks.
[0078] In another exemplary embodiment, the decrease in PAPI is
about 30%, about 35%, about 45%, about 50%, about 55%, and the
like, after treatment with vehicle alone for at least about 8
weeks.
[0079] Another exemplary embodiment of this application is the use
of a pharmaceutical composition for the treatment of rosacea, the
pharmaceutical composition comprising from 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 2 weeks, about
4 weeks, about 8 weeks or about 12 weeks, wherein a decrease in
Patient Assessment of Papulopustular Rosacea Signs and Symptoms
(PAPSS) is from about 50% to about 65%, from about 52% to about
63%, from about 54% to about 61%, from about 56% to about 59%, and
the like, after treatment with said pharmaceutical composition for
at least about 8 weeks.
[0080] In another exemplary embodiment, the decrease in PAPSS is
from about 25% to about 40%, from about 27% to about 38%, from
about 29% to about 36%, from about 31% to about 34%, and the like,
after treatment with vehicle alone for at least about 8 weeks.
[0081] Another exemplary embodiment of this application is the use
of a pharmaceutical composition for the treatment of rosacea, the
pharmaceutical composition comprising from 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 2 weeks, about
4 weeks, about 8 weeks or about 12 weeks, wherein a decrease in
Patient Assessment of Papulopustular Rosacea Impacts (PAPI) is from
about 60% to about 70%, from about 62% to about 68%, from about 64%
to about 66%, and the like, after treatment with said
pharmaceutical composition for at least about 8 weeks.
[0082] In another exemplary embodiment, the decrease in PAPI is
about 30%, about 35%, about 45%, about 50%, about 55%, and the
like, after treatment with vehicle alone for at least about 8
weeks.
[0083] In another exemplary embodiment, the benzoyl peroxide is the
only active ingredient in said pharmaceutical composition and/or in
the regimen and/or in the method of treatment. In another exemplary
embodiment, the benzoyl peroxide is the sole active ingredient
administered to the subject during the duration of the regimen.
[0084] In another exemplary embodiment, the pharmaceutical
composition comprises about 2.5% w/w to about 10% w/w of benzoyl
peroxide, preferably about 3.0% to about 10% of benzoyl peroxide,
more preferably about 3% to about 5% of benzoyl peroxide, and more
preferably about 5% w/w of benzoyl peroxide.
[0085] In another exemplary embodiment, the benzoyl peroxide is in
a form selected from solid, solution, and suspension.
[0086] In another exemplary embodiment, the rosacea is any of
erythematotelengietatic, papulopustular, phymatous or ocular
rosacea.
[0087] In another exemplary embodiment, the pharmaceutical
composition is a cream, cream gel, an emulsion, a gel or a foam;
preferably a cream or an emulsion.
[0088] In another exemplary embodiment, the pharmaceutical
composition can be an extended- and/or controlled-release
formulation, and the extended-release and/or controlled-release
effect is obtained by any one of encapsulation, microencapsulation,
microspheres and/or coating, or can be encapsulated and/or
microencapsulated or included in a microsphere and/or a
coating.
[0089] In some embodiments, said rosacea is papulopustular rosacea
(i.e., inflammatory rosacea; Rapini 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).
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] 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.
[0097] In further embodiments, said glycerylstearate is selected
from the group consisting of glyceryl mono-stearate, glyceryl
di-stearate and combinations and/or mixtures thereof.
[0098] In other embodiments, said polyoxylstearate in said
composition is in the range of from about 0.1% w/w to about 30%
w/w.
[0099] 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.
[0100] In other embodiments, said composition further comprises at
least one fatty alcohol.
[0101] 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.
[0102] 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.
[0103] In yet other embodiments, said composition further comprises
a polyacrylic acid homopolymer or copolymer.
[0104] 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.
[0105] 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.
[0106] In some embodiments, said water in said oil in water
emulsion further comprises at least one water soluble
humectant.
[0107] 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.
[0108] 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.
[0109] In some embodiments, said core of said microcapsule
comprises or consists of said solid BPO.
[0110] 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).
[0111] 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.
[0112] 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:
[0113] (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;
[0114] (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;
[0115] (c) repeating step (b) at least 4 more times: and
[0116] (d) aging said coating layer.
[0117] 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 D90 (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.
[0118] The terms "solid BPO particulate matter" and "particulate
matter" will be used interchangeably.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] Reference to the size of particles will be made through
their D90, 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 D90 of
about 10 microns. The D90 can be measured by laser diffraction. For
particles having a shape other than spheres, the D90 refers to the
mean average of the diameter of a plurality of particles.
[0123] In the case of cores having a spherical shape, the D90 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, and in some
embodiments all values therebetween, including about 0.5 microns,
about 1 micron, about 2 micron, about 3 micron, about 4 micron,
about 5 micron, about 10 microns, about 20 microns, about 30
microns, about 40 microns, about 50 microns, about 60 microns,
about 70 microns, about 80 microns, and the like. By the term "D90
can be in the range of from about 0.3 microns to about 90 microns"
is meant that 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.
[0124] 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.
[0125] 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.
[0126] As used herein, unless otherwise indicated, the term
"particle" refers to the metal oxide or semi-metal oxide coated
particulate matter.
[0127] 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.
[0128] 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
[0129] 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.
[0130] Description:
[0131] A multi-center, double-blind, randomized,
vehicle-controlled, dose-range study of encapsulated 5% benzoyl
peroxide (E-BPO) Cream and vehicle cream was performed to assess
the efficacy and safety of E-BPO compared to vehicle. Study
duration was 12 weeks (84 days) and included approximately 350 male
and female patients afflicted with papulopustular rosacea. Patients
were at least 18 years of age, and met the inclusion/exclusion
criteria described herein.
[0132] Dosing:
[0133] Patients were randomized 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.
[0134] Clinical and Safety Evaluations will be performed at:
[0135] 1. Visit 1/Screening
[0136] 2. Visit 2/Baseline, Day 1
[0137] 3. Visit 3/Week 2, Day 15
[0138] 4. Visit 4/Week 4, Day 29
[0139] 5. Visit 5/Week 8, Day 57
[0140] 6. Visit 6/Week 12, Day 85
[0141] Patients were admitted into the study after a clinical
diagnosis of rosacea.
[0142] Patients completed a Patient Reported Outcomes (PRO)
questionnaire at Baseline and Visit 2, 3, 4, 5 and 6.
[0143] Patient Reported Outcomes (PRO):
[0144] Patient Reported Outcome (PRO) questionnaires, including
Patient Assessment of Papulopustular Rosacea Signs and Symptoms
(PAPSS) and Patient Assessment of Papulopustular Rosacea Impacts
(PAPI), were administered to all patients during the designated
study visits with instruction from the study staff that they be
completed: [0145] Only by the patient without amendment or
interpretation of the patient's response by a clinician or anyone
else. [0146] Prior to any other assessments or procedures.
[0147] The PAPSS is a 4-item questionnaire that asks patients to
assess the severity of their rosacea symptoms (burning, itching,
redness, and bumps) in the 24 hours prior to assessment on an
11-point numeric rating scale (NRS) ranging from "0=none" to
"10=worst possible symptom. Items can be scored individually as
well as together to form a total score. In the subject study,
scores of the symptoms burning, itching and bumps were added to
create a total score used to evaluate efficacy hypotheses.
[0148] The PAPI is a 3-item questionnaire that asks patients to
assess the papulopustular rosacea related embarrassment,
self-consciousness, and frustration in the 7 days prior to
assessment on an 11-point NRS ranging from 0 ["not at all"] to 10
["extremely"]. Items can be scored individually as well as together
to form a total score.
[0149] Results:
[0150] Baseline Characteristics:
[0151] The Baseline characteristics were similar among the
treatment groups. Patients selected for the treatment groups of
this study suffered from moderate and severe rosacea, with a
numerically higher percentage of subjects suffering from moderate
rosacea. The baseline numerical percentage of treatment groups
suffering from moderate and severe rosacea were similar for 5%
E-BPO Cream and for Vehicle Cream.
[0152] Patient Reported Outcome--PAPSS:
[0153] Patient reported outcomes of several papulopustular signs
and symptoms--burning, itching, redness and burning--were recorded
at Baseline and Weeks 2, 4, 8 and 12. Subjects treated with 5%
E-BPO Cream and subjects treated with Vehicle Cream completed the
PAPSS questionnaire, and rated the appearance of the papulopustular
signs and symptoms on the numerical range scale from "0=none" to
"10=worst possible symptom". The results for each of Weeks 2, 4, 8
and 12 are shown in Table 1 below, and presented in FIGS. 1A to
1D.
TABLE-US-00001 TABLE 1 PAPSS Assessment 5% E-BPO Cream Vehicle
Cream Change % Change Change % Change Base- from from Base- from
from line Baseline Baseline line Baseline Baseline Week Burning 2.9
-0.9 -31.0 2.6 -0.7 -26.9 2 Itching 3.3 --1.3 -39.4 3.1 -1.1 -35.5
Redness 5.8 -1.9 -32.8 5.7 -1.0 -17.5 Bumps 5.0 -2.0 -40.0 4.8 -1.0
-20.8 Week Burning 2.9 -1.5 -51.7 2.6 -0.8 -30.8 4 Itching 3.3 -1.8
-54.5 3.1 -1.2 -38.7 Redness 5.8 -2.6 -44.8 5.7 -1.4 -24.6 Bumps
5.0 -2.5 -50.0 4.8 -1.4 -29.2 Week Burning 2.9 -1.8 -62.1 2.6 -1.0
-38.5 8 Itching 3.3 -2.1 -63.6 3.1 -1.3 -41.9 Redness 5.8 -3.0
-51.7 5.7 -1.8 -31.6 Bumps 5.0 -3.2 -64.0 4.8 -1.8 -37.5 Week
Burning 2.9 -1.8 -62.1 2.6 -0.7 -26.9 12 Itching 3.3 -2.1 -63.6 3.1
-1.3 -41.9 Redness 5.8 -3.1 -53.4 5.7 -1.8 -31.6 Bumps 5.0 -3.2
-64.0 4.8 -1.5 -31.3
[0154] The total assessment of three of the four symptoms--burning,
itching and bumps--are shown in Table 2 below, and presented in
FIG. 2.
TABLE-US-00002 TABLE 2 Total Change in PAPSS Assessment Change from
% Change from Baseline Baseline Baseline 5% E-BPO Cream Week 2 17.0
-6.1 -35.9 Week 4 17.0 -8.4 -49.4 Week 8 17.0 -10.1 -59.4 Week 12
17.0 -10.2 -60.0 Vehicle Cream Week 2 16.1 -3.7 -23.0 Week 4 16.1
-4.8 -29.8 Week 8 16.1 -5.9 -36.6 Week 12 16.1 -5.2 -32.3
[0155] Patient Reported Outcome--PAPI:
[0156] Patient reported outcomes of several impacts of
papulopustular rosacea--embarrassment, self-consciousness and
frustration--were recorded at Baseline and Weeks 2, 4, 8 and 12.
Subjects treated with 5% E-BPO Cream and subjects treated with
Vehicle Cream completed the PAPSS questionnaire, and rated the
appearance of the papulopustular signs and symptoms on the
numerical range scale from "0=none" to "10=worst possible symptom".
The results for each of Weeks 2, 4, 8 and 12 are shown in Table 3
below, and presented in FIGS. 3A to 3D.
TABLE-US-00003 TABLE 3 PAPI Assessment 5% E-BPO Cream Vehicle Cream
Change % Change Change % Change from from from from Baseline
Baseline Baseline Baseline Baseline Baseline Week 2 Embarrassment
5.8 -2.2 -37.9 5.7 -1.4 -24.6 Self- 6.1 -2.2 -36.1 6.0 -1.5 -25.0
consciousness Frustration 6.2 -2.5 -40.3 6.1 -1.4 -23.0 Week 4
Embarrassment 5.8 -2.7 -46.6 5.7 -1.8 -31.6 Self- 6.1 -2.8 -48.3
6.0 -1.8 -31.6 consciousness Frustration 6.2 -3.1 -53.4 6.1 -2.0
-35.1 Week 8 Embarrassment 5.8 -3.6 -62.1 5.7 -2.1 -36.58 Self- 6.1
-3.6 -62.1 6.0 -2.3 -40.4 consciousness Frustration 6.2 -4.0 -69.0
6.1 -2.5 -43.9 Week Embarrassment 5.8 -3.5 -60.3 5.7 -2.1 -36.8 12
Self- 6.1 -3.7 -63.8 6.0 -2.3 -40.4 consciousness Frustration 6.2
-3.9 -67.2 6.1 -2.1 -36.8
[0157] The average assessment of the impact of papulopustular
rosacea is shown in Table 4 below, and presented in FIG. 4.
TABLE-US-00004 TABLE 4 Average Change in PAPI Assessment Change
from % Change from Baseline Baseline Baseline 5% E-BPO Cream Week 2
6.03 -2.31 -38.25 Week 4 6.03 -2.86 -47.35 Week 8 6.03 -3.72 -61.59
Week 12 6.03 -3.69 -61.09 Vehicle Cream Week 2 5.92 -1.46 -24.66
Week 4 5.92 -1.85 -31.25 Week 8 5.92 -2.30 -38.85 Week 12 5.92
-2.15 -36.32
[0158] As shown in Table 1 above, and FIGS. 1A to 1D, the decrease
in signs and symptoms of papulopustular rosacea, such as burning,
itching, redness and burning, based on patient reported outcome,
decreases at a much higher rate when treated with 5% E-BPO cream
compared to treatment with vehicle cream alone. For example, in as
little as about 4 weeks, the percentage change from baseline for
burning, itching redness and bumps is between about 40% and about
55% when treated with 5% E-BPO compared to a percentage decrease
from baseline of less than about 40% when treated with vehicle
alone.
[0159] This result is even more significant after treatment for
about 8 weeks to about 12 weeks. For example, the patient
assessment of signs and symptom is significantly improved by about
52% to about 64% in burning, itching, redness and bumps after
treatment with 5% E-BPO whereas the patient reported improvement in
burning, itching, redness and bumps is only from about 25% to about
42%. In addition, the 5% E-BPO cream works very fast and maximum
improvement was achieved after as little as about 8 weeks of
treatment. These results are summarized as a total change in signs
and symptoms in Table 2 and FIG. 2.
[0160] Similar results are also observed for patient reported
outcome for papulopustular rosacea-related impacts, such as
embarrassment, self-consciousness and frustration. For example, as
shown in Table 3, and FIGS. 3A to 3D, the decrease in the
psychological effects of embarrassment, self-consciousness and
frustration on study subjects decreased significantly after
treatment with 5% E-BPO. For example, the decrease in
embarrassment, self-consciousness and frustration in study subjects
decrease by about 60% to about 70% after treatment with 5% E-BPO
after only about 8 weeks, whereas the decrease in these effects was
less than about 45% after treatment with vehicle cream alone. The
average decrease in these impacts after about 2 weeks, about 4
weeks, about 8 weeks and about 12 weeks is shown in Table 4 and
FIG. 4.
[0161] Rapid onset of the decrease in feelings of embarrassment,
self-consciousness and frustration was observed in study subjects.
For example, as shown in Table 4, there was an improvement of about
40% in a patient's assessment of these feelings after treatment
with 5% E-BPO for only about 2 weeks compared to a decrease of only
about 25% after treatment with vehicle cream alone for about 2
weeks. As also shown in Table 4, the average improvement in PAPI
values after treatment with 5% E-BPO after only about 8 weeks of
treatment was approximately about twice the values observed after
treatment with vehicle cream alone.
[0162] 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.
* * * * *