U.S. patent application number 17/480481 was filed with the patent office on 2022-01-06 for methods and apparatus for treating a wound.
The applicant listed for this patent is Chang Gung Memorial Hospital, Linkou, Chang Gung University, National Cheng Kung University. Invention is credited to Wen-Hung Chung, Chao-Kai Hsu, Yu-Shien Ko, Chun-Wei Lu, Jong-Hwei Su Pang.
Application Number | 20220000807 17/480481 |
Document ID | / |
Family ID | |
Filed Date | 2022-01-06 |
United States Patent
Application |
20220000807 |
Kind Code |
A1 |
Lu; Chun-Wei ; et
al. |
January 6, 2022 |
METHODS AND APPARATUS FOR TREATING A WOUND
Abstract
Methods for treating a wound or promote wound healing are
provided, comprising the step of administering a composition
including an effective amount of .beta.-1 adrenergic receptor
antagonist to a subject in need thereof. Also provided is apparatus
for wound healing, comprising a dressing and a composition
including an effective amount of .beta.-1 adrenergic receptor
antagonist.
Inventors: |
Lu; Chun-Wei; (Taoyuan City,
TW) ; Su Pang; Jong-Hwei; (Taoyuang City, TW)
; Ko; Yu-Shien; (Taoyuan City, TW) ; Chung;
Wen-Hung; (Taoyuan City, TW) ; Hsu; Chao-Kai;
(Tainan City, TW) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Chang Gung Memorial Hospital, Linkou
Chang Gung University
National Cheng Kung University |
Taoyuan City
Taoyuan City
Tainan City |
|
TW
TW
TW |
|
|
Appl. No.: |
17/480481 |
Filed: |
September 21, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16234867 |
Dec 28, 2018 |
11154518 |
|
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17480481 |
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International
Class: |
A61K 31/138 20060101
A61K031/138; A61P 17/02 20060101 A61P017/02; A61K 9/70 20060101
A61K009/70; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method for treating a deep fissure in a patient comprising the
step of administering a composition comprising an effective amount
of a .beta.-1 adrenergic receptor antagonist to the patient in need
thereof.
2. The method of claim 1, wherein said deep fissure is induced by
targeted therapy.
3. The method of claim 2, wherein the .beta.-1 adrenergic receptor
antagonist is atenolol, betaxolol, bisoprolol, esmolol, acebutolol,
metoprolol, nebivolol or any combination thereof.
4. The method of claim 1, wherein the .beta.-1 adrenergic receptor
antagonist is atenolol, betaxolol, bisoprolol, esmolol, acebutolol,
metoprolol, nebivolol or any combination thereof.
5. The method of claim 1, further comprising administering an
additional therapeutic agent for wound healing.
6. The method of claim 5, wherein the additional therapeutic agent
for wound healing is growth factors, cytokines, chemokines,
antibodies, antibiotics, immunosuppressive agents, steroids, zinc,
hyperbaric oxygen, anti-fungal agents, anti-viral agents, stem
cells, bioengineered skin, debriding agents or any combination
thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. patent application
Ser. No. 16/234,867, filed Dec. 28, 2018, the entire disclosure of
which is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Wound healing, initiated by whatever aetiology, is a dynamic
process encompassing a number of overlapping phases, including
inflammation, epithelialization, angiogenesis and matrix
deposition. During the epithelization phase, keratinocytes migrate
into the wound bed to initiate re-epithelization, necessary for
wound closure and restoration of skin integrity. Keratinocytes
solely express .beta.2-adrenergic receptors and the activation of
.beta.2-adrenergic receptors delays wound healing (CE Pullar et
al., Beta2-adrenergic receptor activations delays wound healing
FASEB J. 2006 Jan;20(1):76-86). Additional research demonstrates
.beta.2-adrenergic antagonists accelerate skin wound
re-epithelizliation, due to .beta.2-adrenergic blockade to prevent
the binding of endogenously synthesized epinephrine (CE Pullar et
al., Beta-adrenergic receptor antagonists accelerate skin wound
healing: evidence for a catecholamine synthesis network in the
epidermis, J Biol Chem. 2006 Jul 28;281(30):21225-35. Epub 2006 May
19).
[0003] Normally, the wound healing processes lead to a mature wound
and a certain degree of scar formation. Although a variety of
factors affect wound healing, including age, nutrition, obesity,
repetitive trauma, skin moisture, concurrent illness (e.g.,
diabetes) and medication, most wounds heal along a prescribed
course without difficulty.
[0004] The science of wound repair and care has progressed
significantly since the discovery of the first growth factor
(epidermal growth factor) in 1962 and the moist wound concept for
healing. Despite these advanced wound care treatments, a minority
of wounds will not respond to the current wound management.
[0005] There is an unmet need for the management of wound to
promote wound healing. The present invention addresses these and
other needs.
BRIEF SUMMARY OF THE INVENTION
[0006] In one embodiment, the present invention discloses methods
for treating a wound or promote wound healing, comprising the step
of administering a composition comprising an effective amount of a
.beta.-1 adrenergic receptor antagonist to a patient in need
thereof.
[0007] The present invention also discloses apparatus for treating
a wound or promote wound healing, comprising (a) a dressing; and
(b) a composition comprising an effective amont of .beta.-1
adrenergic receptor antagonist.
[0008] The terms "invention," "the invention," "this invention" and
"the present invention" used in this patent are intended to refer
broadly to all of the subject matter of this patent and the patent
claims below. Statements containing these terms should be
understood not to limit the subject matter described herein or to
limit the meaning or scope of the patent claims below. Embodiments
of the invention covered by this patent are defined by the claims
below, not this summary. This summary is a high-level overview of
various aspects of the invention and introduces some of the
concepts that are further described in the Detailed Description
section below. This summary is not intended to identify key or
essential features of the claimed subject matter, nor is it
intended to be used in isolation to determine the scope of the
claimed subject matter. The subject matter should be understood by
reference to appropriate portions of the entire specification, any
or all drawings and each claim.
[0009] The invention will become more apparent when read with the
accompanying figures and detailed description which follow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] The patent contains at least one drawing executed in color.
Copies of this patent with color drawings will be provided by the
Office upon request and payment of the necessary fee.
[0011] Illustrative embodiments of the present invention are
described in detail below with reference to the following
Figures.
[0012] FIG. 1A and FIG. 1B are photo images of a patient with
relapsing severe paronychia and pyogenic granuloma-like lesions of
the left thumb before (FIG. 1A) and after 4 weeks of topical
betaxolol treatment (FIG. 1B).
[0013] FIG. 2A and FIG. 2B are photo images of a patient with deep
figures of the right thumb before (FIG. 3A) and after 4 weeks of
topical betaxolol treatment (FIG. 3B).
[0014] FIG. 3A to FIG. 3E are a series of photo images illustrating
the effect of no treatment (control), timolast (non-selective
.beta.-adrenergic antagonist) and betaxolol .beta.1-adrenergic
antagonist) on back incisions of rats on day 0 (FIG. 3A), Day 1
(FIG. 3B), Day 4 (FIG. 3C), Day 7 (FIG. 3D) and Day 10 (FIG.
3E).
[0015] FIG. 4A to FIG. 4C are a series of microscopic images
showing the back wound of rats without any treatment (FIG. 4A), or
treated with 10 days of timolast (FIG. 4B) or betaxolol (FIG.
4C).
DETAILED DESCRIPTION OF THE INVENTION
[0016] As used herein, the articles "a" and "an" refer to one or
more than one (i.e., at least one) of the grammatical object of the
article.
[0017] The term "subject" and "patient" may be used interchangeably
and refer to a mammal diagnosed with a wound or suspected of having
a wound. Subjects include primate, and more preferably, a
human.
[0018] An "effective amount" of an antagonist refers to an amount
of the antagonist that produces a desirable effect, e.g., increases
the rate of wound healing by at least 1% compared to an untreated
subject.
[0019] As used herein, the term "treating" refers to both
therapeutic treatment and prophylactic or preventative measures.
Those in need of treatment include those already with a wound or
related disorder as well as those prone to having a wound or
related disorder or those in which the wound is to be
prevented.
[0020] All numbers herein may be understood as modified by "about."
As used herein, the term "about" is meant to encompass variations
of .+-.10%.
Methods For Wound Healing
[0021] The present invention is directed to methods of treating a
wound or promote wound healing, comprising the step of
administering a composition comprising an effective amount of a
.beta.-1 adrenergic receptor antagonist to the patient in need
thereof.
[0022] As used herein, a "wound" is any disruption, from whatever
cause, of a subject's internal or external body structure (e.g.,
epithelial tissue) including but not limited to traumatic injuries
such as mechanical (i.e. contusion, penetrating), thermal,
chemical, electrical, radiation, concussive and incisional
injuries; elective injuries such as operative surgery and resultant
incisional hernias, fistulas, etc.; acute wounds, chronic wounds,
infected wounds, and sterile wounds, as well as wounds associated
with disease states (e.g., paronychia caused by chemotherapy or
target therapy, ulcers caused by diabetic neuropathy or venous
stasis). Non limiting examples of wound include paronychia, acute
ulcer, ulcer, surgical wound dehiscence, burn, laceration, incision
or abrasion. As used herein, target therapy includes medications
which inhibit the growth of cancer cells by interfering with
specific targeted molecules needed for carcinogenesis and cancer
growth, rather than by simply interfering with rapidly dividing
cells (e.g., conventional chemotherapy), such as kinase inhibitor,
angiogenesis inhibitor, epidermal growth factor receptor (EGFR)
inhibitor, HER2/neu receptor or the combination thereof.
[0023] In some embodiments, the wound is a chronic wound. In an
exemplary embodiment, chronic wound may refer to a wound that is
characterized at least in part by one or more of 1) a chronic
self-perpetuating state of wound inflammation, 2) a deficient and
defective wound ECM, 3) poorly responding (senescent) wound cells
especially fibroblasts, limiting ECM production, and 4) failure of
re-epithelialization due in part to lack of the necessary ECM
orchestration and lack of scaffold for migration. Non limiting
examples of chronic wounds include venous ulcers, arterial ulcers,
pressure ulcers, vasculitic ulcers, and diabetic ulcers.
[0024] In some embodiments, the wound is characterized in whole or
in part by delayed or incomplete wound healing. In an exemplary
embodiment, delayed or incomplete wound healing may include a wound
that is characterized at least in part by one or more of the
following: 1) a prolonged inflammatory phase, 2) a slow forming
extracellular matrix (ECM), and 3) a stalled or decreased rate of
epithelialization.
[0025] In other embodiments, "wound healing" refers to one or more
of the following: improving of tissue repair, faster or increasing
rate of wound healing, less scaring in the resulting healed area,
the wounded area possesses tissue strength that is closer to that
of uninjured tissue, the wounded tissue attains some degree of
functional recovery. In an exemplary embodiment, the increasing
rate of wound healing aby administering the composition described
herein involves the increased migration or proliferation of
epithelial cells by at least 1%, 5%, 10%, 20%, 30%, 40%, 50%
compared to that of a subject without administering the composition
described herein.
[0026] In some embodiments, the composition comprises a .beta.-1
adrenergic receptor antagonist. In some embodiments, the
composition is substantially free of .beta.-2 adrenergic receptor
antagonist or non-selective .beta. adrenergic receptor antagonist.
The composition may be administered in a pharmaceutically
acceptable carrier.
[0027] The composition can be formulated for systemic (such as oral
or intravenous), intradermal, subcutaneous, intramuscular or
topical administration. In some embodiments, the composition is
formulated to one of the following form for topical delivery:
ointment, cream, solution, gel, suspension, spray or lotion. In
other embodiments, the composition is formulated for slow or
sustained release.
[0028] Non-limiting examples of the .beta.-1 adrenergic receptor
antagonist include atenolol, betaxolol, bisoprolol, esmolol,
acebutolol, metoprolol, nebivolol, or a combination thereof.
[0029] In one embodiment, the method further comprises the step of
administering at least one therapeutic agent useful for wound
healing. Such therapeutic agents include but are not limited to
growth factors, cytokines, chemokines, antibodies, inhibitors,
antibiotics (with or without silver), immunosuppressive agents,
steroids, zinc, hyperbaric oxygen, anti-fungals, anti-virals, other
cell types (e.g., stem cells, bioengineered skin, skin substitutes,
and skin equivalents) or debriding agents (for example, Collagenase
SANTYL and cadexomer iodine). In certain embodiments, the
therapeutic agent useful for wound healing may be used in
combination.
[0030] When the .beta.-1 adrenergic receptor antagonist composition
is administered in combination or alternation with at least one
therapeutic agent useful for wound healing, less .beta.-1
adrenergic receptor antagonist composition, fewer administration
time points and/or increased time interval may be needed to be
therapeutically effective.
[0031] In addition, one of skill in the art may readily determine
the appropriate dose and the number of doses of the .beta.-1
adrenergic receptor antagonist to be administered for a particular
type of wound, depending on, for example, severity and type of
wound, patient age, weight, sex, comorbidity and other medications
being administered to the patient. The skilled artisan will
recognize that a preferred dose is one which produces a therapeutic
effect, such as increased wound healing, in a patient in need
thereof. In certain embodiments, one dose is administered once a
day for a given number of days (i.e. for 7 days, for 1 month,
etc.). In other embodiments, multiple doses may be administered in
one day (every 2, 4, 6, or 12 hours, etc.). Multiple doses per day
for multiple days is also contemplated by the invention.
Apparatus for Wound Healing or Treating a Wound
[0032] The present invention also provides an apparatus for wound
healing or treating a wound, comprising (a) dressing and (b) a
composition comprising an effective amount of .beta.-1 adrenergic
receptor antagonist.
[0033] The term "dressing" refers to a dressing for topical
application to a wound. Non limiting examples of dressing include
at least one layer of woven or nonwoven textile/fabric material
(e.g., gauze, sponges, cellulose, cotton or rayon), foam such as
polyurethane foam, hydrogel such as polyurethane hydrogel,
hyaluronic acid hydrogel or polyacrylate hydrogel, gelatin,
carboxymethyl cellulose, pectin, alginate, silicon, collagen,
transparent films, fillers, biodegradable polymeric matrix, any
suitable biocompatible material or a combination thereof.
[0034] The dressing can be impregnated with the composition
described herein, or at least one surface of the dressing is coated
with the composition described herein. The one embodiment, the
apparatus further comprises an instruction for using the
composition contained therein for wound healing.
[0035] Embodiments of the present invention are illustrated by the
following examples, which are not to be construed in any way as
imposing limitations upon the scope thereof. On the contrary, it is
to be clearly understood that resort may be had to various other
embodiments, modifications, and equivalents thereof, which, after
reading the description herein, may suggest themselves to those
skilled in the art without departing from the spirit of the
invention. During the studies described in the following examples,
conventional procedures were followed, unless otherwise stated.
Some of the procedures are described below for illustrative
purpose.
Example 1
[0036] A female patient with severe, relapsing paronychia and
pyogenic granuloma-like lesion on her left thumb (induced by
afatinib) has been treated with topical betamethasone valerate
ointment, gentamicin sulfate cream and 10% aqueous silver nitrate
previously without any improvement (FIG. 1, A).
[0037] She was subsequently treated with topical 0.25% betaxolol
drops once daily (Alcon Laboratories, USA) for 4 weeks under
occlusion. FIG. 1B shows the complete resolution of paronychia and
pyogenic granuloma-like lesion after 4 weeks of daily 0.25%
betaxolol drop treatment.
Example 2
[0038] 10 patients with deep fissure over palms or soles induced by
EGFR inhibitors were treated with topical 0.25% betaxolol drops
(Alcon Laboratories, USA) once a day. Deep fissure wound healed
within one week of treatment in all of the 10 patients, see FIG. 2A
and FIG. 2B.
[0039] The results show 0.25% Betaxolol drop is an effective
treatment for deep fissures.
Example 3
[0040] An in vivo study was performed to examine the effectiveness
of a non-selective .beta. blocker and a .beta.1-blocker using rats.
The rats were divided into 3 groups: (a) control (n=2); (b)
non-selective blocker (n=1); and (c) .beta.1-blocker (n=1). On Day
0 of the experiment, 3 back incisions were made on each rat. The
size of the back incisions are 1.5 cm.times.1.5 cm, 1 cm.times.1 cm
and 0.5 cm.times.0.5 cm for the top, middle and bottom incisions as
shown on FIG. 4A.
[0041] The rats in the control group received no treatment, the rat
in the non-selective .beta. blocker group received 0.5% Timoptol
drop (MSD, USA) twice a day (30 .mu.l for the top incision, 13
.mu.l for the middle incision and 3.3 .mu.l for the bottom
incision) and the rat in the .beta.1-blocker group received 0.25%
Betoptic drop (Alcon Laboratories, USA) twice a day (30 .mu.l for
the top incision, 13 .mu.l for the middle incision and 3.3 .mu.l
for the bottom incision).
[0042] FIG. 3C to FIG. 3E show the back incisions treated with
0.25% Betoptic drop is less erythematous and smaller in size after
7 days of treatment compared to the back incisions treated with
0.5% Timoptol drops and no treatment. The results indicate Betoptic
(betaxolol) is more effective to promote wound healing.
[0043] FIG. 4A to FIG. 4C shows microscopic changes of the 1
cm.times.1 cm back wounds of the 3 groups of rats on Day 10. The
back incision treated with 10-day of 0.25% betaxolol drop was
almost completely healed with re-growth of fibroblasts, complete
re-epithelization of epidermis, and no evidence of debri (FIG. 4C).
The back incision treated with 10-day of 0.5% Timoptol drop shows
incompletely healing, characterized with incomplete
re-epithelization of the epidermis, less fibroblast activity and
evidence of debri.
* * * * *