U.S. patent application number 16/912058 was filed with the patent office on 2021-05-20 for treatment of skin disorders by topical administration of vegf inhibitors.
This patent application is currently assigned to AMD THERAPEUTICS LLC. The applicant listed for this patent is AMD THERAPEUTICS LLC. Invention is credited to Hiroaki Serizawa.
Application Number | 20210145826 16/912058 |
Document ID | / |
Family ID | 1000005370533 |
Filed Date | 2021-05-20 |
![](/patent/app/20210145826/US20210145826A1-20210520-D00001.png)
![](/patent/app/20210145826/US20210145826A1-20210520-D00002.png)
United States Patent
Application |
20210145826 |
Kind Code |
A1 |
Serizawa; Hiroaki |
May 20, 2021 |
TREATMENT OF SKIN DISORDERS BY TOPICAL ADMINISTRATION OF VEGF
INHIBITORS
Abstract
Topical administration of VEGF inhibitors such as, without
limitation, rifamycin compounds are useful for treating skin
disorders such as treating and/or reducing scars such as
hypertrophic scars, and useful for treating acne and underlying
acne symptoms such as skin redness.
Inventors: |
Serizawa; Hiroaki; (Palo
Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMD THERAPEUTICS LLC |
Palo Alto |
CA |
US |
|
|
Assignee: |
AMD THERAPEUTICS LLC
Palo Alto
CA
|
Family ID: |
1000005370533 |
Appl. No.: |
16/912058 |
Filed: |
June 25, 2020 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15766340 |
Apr 5, 2018 |
10709702 |
|
|
PCT/US2016/056096 |
Oct 7, 2016 |
|
|
|
16912058 |
|
|
|
|
62239208 |
Oct 8, 2015 |
|
|
|
62271993 |
Dec 28, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/438 20130101;
A61K 31/395 20130101; A61K 31/437 20130101; A61K 31/496 20130101;
A61P 17/02 20180101; A61K 31/538 20130101; A61K 9/0014 20130101;
A61P 17/10 20180101 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/395 20060101 A61K031/395; A61K 31/437 20060101
A61K031/437; A61K 31/438 20060101 A61K031/438; A61K 31/538 20060101
A61K031/538; A61P 17/10 20060101 A61P017/10; A61P 17/02 20060101
A61P017/02; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method of reducing or preventing skin redness, eczema, or
dermatitis comprising administering to a subject in need thereof a
therapeutically effective amount of a formulation consisting
essentially of from 1 to 5% of a rifamycin compound as the sole
active ingredient in the formulation.
2. (canceled)
3. (canceled)
4. The method of claim 1, wherein the rifamycin compound is
selected from rifampicin, rifabutin, rifapentine, rifalazil, or
rifaximin.
5. A method of reducing hypertrophic scar or a method of preventing
scar formation comprising administering topically to a patient in
need thereof a therapeutically effective amount of a VEGF
inhibitor, wherein the scar formation results at least in part from
neovascularization.
6. The method of claim 5, wherein the VEGF inhibitor is a rifamycin
compound.
7. The method of claim 6, wherein the rifamycin compound is
rifampicin, rifabutin, rifapentine, rifalazil, or rifaximin.
8. A method of treating acne, or of reducing the size of an acne,
or of inhibiting neovascularization in an acne comprising
administering topically to the acne of a subject in need thereof a
therapeutically effective amount of a formulation consisting
essentially from 1 to 5% of a rifamycin compound as the sole active
ingredient in the formulation.
9. The method of claim 8 of treating acne, wherein the rifamycin
compound is rifampicin, rifabutin, rifapentine, rifalazil, or
rifaximin.
10. The method of claim 8 of reducing the size of an acne
comprising administering topically to the acne of a subject in need
thereof a therapeutically effective amount of a formulation
consisting essentially from 1 to 5% of a rifamycin compound.
11. The method of claim 10, wherein the rifamycin compound is
rifampicin, rifabutin, rifapentine, rifalazil, or rifaximin.
12. The method of claim 8 wherein the method inhibits of
neovascularization of acne in a subject in need thereof.
13. The method of claim 12, wherein the rifamycin compound is
rifampicin, rifabutin, rifapentine, rifalazil, or rifaximin.
14. (canceled)
15. The method of claim 1, wherein the reduction or prevention of
skin redness, eczema, or dermatitis is associated with acne or a
hypertrophic scar.
16. The method of claim 5, wherein the topical administration is to
the area of neovascularization.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a U.S. Continuation application claiming
priority to U.S. National Stage application Ser. No. 15/766,340,
filed on Apr. 5, 2018; which claims priority to International
Patent Application No. PCT/US2016/056096, filed on Oct. 7, 2016;
which claims priority to U.S. Provisional Application No.
62/239,208, filed Oct. 8, 2015 and U.S. Provisional Application No.
62/271,993, filed Dec. 28, 2015, the content of each of these
applications is incorporated herein in its entirety by
reference.
FIELD OF THE DISCLOSURE
[0002] Provided herein are methods for treatment of skin disorders
by topical administration of vascular endothelial growth factor
(VEGF) inhibitors, including without limitation, a rifamycin
compound. Accordingly, provided herein are methods of treating
and/or reducing scar formation or hypertrophic scar formation by
administering topically to a patient in need thereof a
therapeutically effective amount of a VEGF inhibitor. Further,
Provided herein are methods of treating and/or reducing acne in a
subject in need thereof by topically administering a
therapeutically effective amount of a rifamycin compound.
BACKGROUND
[0003] Hypertrophic scar (HS) formation is a common complication of
wound healing, particularly after a burn injury. Current possible
treatments available for HS formation include chemical peels,
filler injections, dermabrasion, laser treatment, radiotherapy,
dressing, steroids, and/or vitamins. However, these treatments can
be invasive and/or ineffective. Additionally, there is no
FDA-approved drug available on the market for treating HS. Thus, a
need exists for a non-invasive yet effective therapy for treating
HS. Further, approximately 17 million people in the US suffer from
acne. Approximately 85% of people between ages 12 and 24 develop
acne. There is a need for additional and effective acne
treatments.
SUMMARY
[0004] Provided herein are methods for treatment of skin disorders
by topical administration of VEGF inhibitors, including without
limitation, a rifamycin compound.
[0005] In one aspect, provided herein is a method of reducing
hypertrophic scar or a method of preventing scar formation
comprising administering topically to a patient in need thereof a
therapeutically effective amount of a VEGF inhibitor. In one
embodiment, hypertrophic scar is reduced. In another embodiment,
scar formation is prevented.
[0006] In another aspect, provided herein is a method of reducing
hypertrophic scar or a method of preventing scar formation
comprising administering topically to a patient in need thereof a
therapeutically effective amount of a VEGF inhibitor, wherein the
scar formation results at least in part from neovascularization. In
one embodiment, hypertrophic scar is reduced. In another
embodiment, scar formation is prevented.
[0007] In another aspect, provided herein is a method of treating
acne comprising administering topically to the acne of a subject in
need thereof a therapeutically effective amount of a VEGF
inhibitor, such as, without limitation, a rifamycin compound. In
another aspect, provided herein is a method of reducing the size of
an acne comprising administering topically to the acne of a subject
in need thereof a therapeutically effective amount of a rifamycin
compound. In another aspect, provided herein is a method of
inhibiting neovascularization in an acne in a subject in need
thereof, comprising administering topically to the acne of the
subject a therapeutically effective amount of a rifamycin compound.
See, e.g., EP2016944, which is incorporated herein in its entirety
by reference. As used herein, neovascularization refers to a
formation of functional microvascular networks with red blood cell
perfusion. In one embodiment, the rifamycin compound is rifampicin,
rifabutin, rifapentine, rifalazil, or rifaximin. In a preferred
embodiment, the rifamycin compound is rifampicin or rifampin. The
topical treatment provided herein is surprising because oral
administration of rifampicin in combination with standard treatment
was previously found to be ineffective. See, Khorvasha et al., 2013
Iran J. Pharm. Res., 12(1):223-7.
[0008] In another aspect, provided herein is a method of reducing
skin redness, such as those associated with acne, or reducing
eczema or dermatitis, comprising administering to a subject in need
thereof a therapeutically effective amount of a VEGF inhibitor,
such as, without limitation, a rifamycin compound. In another
aspect, provided herein is a method of preventing skin redness,
eczema or dermatitis comprising administering the compounds and
compositions utilized herein. In one embodiment, skin redness is
prevented. In another embodiment, eczema is prevented. In another
embodiment, dermatitis is prevented. In another aspect, provided
herein is a method of reducing or preventing skin redness, eczema,
or dermatitis, such as those associated with a hypertrophic scar,
comprising administering to a subject in need thereof a
therapeutically effective amount of a VEGF inhibitor, such as,
without limitation, a rifamycin compound, preferably rifampicin. In
another aspect, provided herein is a method of reducing skin
redness such as those associated with hypertrophic scar or a method
of preventing scar formation comprising administering topically to
a patient in need thereof a therapeutically effective amount of a
vascular endothelial growth factor (VEGF) inhibitor.
[0009] In another aspect, provided herein is a pharmaceutically
acceptable composition for treatment, reduction, or prevention of
skin redness, eczema or dermatitis, comprising a therapeutically
effective amount of a VEGF inhibitor, such as, without limitation,
a rifamycin compound, preferably rifampicin, and at least a
pharmaceutically acceptable excipient. In one embodiment, the
excipient is petroleum jelly. In another embodiment, the VEGF
inhibitor, such as, without limitation, a rifamycin compound,
preferably rifampicin, is formulated at a concentration of 1-5%,
preferably, 1.5-4%, more preferably, 2-3% w/w concentration.
[0010] While a treatment for eczema or dermatitis involves
steroidal creams or ointments, by topically applying steroids to
eczema or dermatitis, the treated skin of the patients gets thin or
atrophy. Accordingly, absent quick therapy, the steroid application
needs to be discontinued. As a result, the redness associated with
the skin condition is not reduced and/or eliminated.
[0011] In one embodiment, the rifamycin compound utilized herein is
rifampicin. The various compounds utilized herein include their
pharmaceutically acceptable salts.
[0012] It was observed, surprisingly, that a rifampicin ointment
containing petroleum jelly, such as those used herein, is smooth,
like a lotion. Petroleum jelly being thick and sticky, when applied
to skin, plugs the pores in the skin, which, in relation to acne,
eczema, or dermatitis, can increase the redness associated with
these disorders. However, as evident by the results provided
herein, a petroleum jelly formulation of rifampicin did not
substantially plug skin pores, and skin redness was reduced. It is
contemplated that a composition of this invention will be stable
for weeks of time at room temperature.
[0013] Absorption of rifampicin in skin tissue was rapid. In about
1-2 hr after a topical skin application, the rifampicin was almost
completely absorbed in skin tissue.
BRIEF DESCRIPTION OF THE FIGURES
[0014] FIG. 1 shows two images of reduced redness of skin as acne
as treated by rifampicin.
[0015] FIG. 2 shows in four images (FIGS. 2A-2D) that topical
application of 2.5% rifampicin ointment improved skin redness
persisting for more than 3 years.
[0016] FIG. 3 shows in two images that the effectiveness of 2.5%
rifampicin ointment in removing skin redness persists after
termination of the topical treatment.
DETAILED DESCRIPTION
[0017] Various embodiments are described hereinafter. It should be
noted that the specific embodiments are not intended as an
exhaustive description or as a limitation to the broader aspects
discussed herein. One aspect described in conjunction with a
particular embodiment is not necessarily limited to that embodiment
and can be practiced with any other embodiment(s). The description
of the preferred embodiment as set forth herein, and as depicted in
the drawings, is provided for illustrative purposes only.
Definitions
[0018] It must be noted that as used herein and in the appended
claims, the singular forms "a", "an", and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a solvent" includes a plurality of such
solvents.
[0019] The term "acne" as used herein refers to a chronic disorder
associated with an increase in sebum secretion. It is characterized
by open comedones (blackheads) and closed comedones (whiteheads).
Acne is more severe in some people than in others and can be
characterized as mild, moderate and severe acne. There are also
inflammatory and non-inflammatory types of acne. Non-inflammatory
acne is, e.g., a milder type of acne. Unlike normal pimples, acne
develops over a longer period of time and stays longer. It
sometimes leaves red marks or scars. "Normal" pimples usually form
quickly and then disappear again soon afterwards. [0020] Mild acne:
People with mild acne have comedones (blackheads or whiteheads),
which are clogged pores in the skin. The dark color of blackheads
has nothing to do with dirt: They look dark because this kind of
blackhead is "open," and the skin pigment melanin reacts with
oxygen in the air. Whiteheads are closed, and have a white or
yellowish head. Mild acne can lead to inflammatory acne. [0021]
Moderate acne: People who have moderate acne have noticeably more
pimples. Inflamed pimples are called "papules" (small bumps) or
"pustules" (filled with yellow pus). [0022] Severe acne: People who
have severe forms of acne have a lot of papules and pustules, as
well as nodules on their skin. These nodules are often reddish and
painful, and can cause scarring.
[0023] As used herein, the term "comprising" or "comprises" is
intended to mean that the compositions and methods include the
recited elements, but not excluding others. "Consisting essentially
of" when used to define compositions and methods, shall mean
excluding other elements of any essential significance to the
combination for the stated purpose. Thus, a composition or process
consisting essentially of the elements as defined herein would not
exclude other materials or steps that do not materially affect the
basic and novel characteristic(s) of the claimed invention.
"Consisting of" shall mean excluding more than trace elements of
other ingredients and substantial method steps. Embodiments defined
by each of these transition terms are within the scope of this
invention.
[0024] Unless otherwise indicated, all numbers expressing
quantities of ingredients, reaction conditions, and so forth used
in the specification and claims are to be understood as being
modified in all instances by the term "about." Accordingly, unless
indicated to the contrary, the numerical parameters set forth in
the following specification and attached claims are approximations.
Each numerical parameter should at least be construed in light of
the number of reported significant digits and by applying ordinary
rounding techniques. The term "about" when used before a numerical
designation, e.g., temperature, time, amount, and concentration,
including range, indicates approximations which may vary by (+) or
(-) 10%, 5% or 1%.
[0025] The terms "pharmaceutically acceptable" or
"pharmacologically acceptable," as used herein, refers to
compositions that are generally safe, non-toxic and neither
biologically nor otherwise undesirable and do not substantially
produce adverse allergic or immunological reactions when
administered to a host (e.g., an animal or a human). Such
formulations include any pharmaceutically acceptable dosage
form.
[0026] "Pharmaceutically acceptable salts" or "salts thereof" mean
salts which are pharmaceutically acceptable, as defined above, and
which possess the desired pharmacological activity. Such salts
include acid addition salts formed with organic and inorganic
acids, such as hydrogen chloride, hydrogen bromide, hydrogen
iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid,
maleic acid, malonic acid, oxalic acid, methanesulfonic acid,
trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid,
citric acid, benzoic acid, ascorbic acid and the like. Base
addition salts may be formed with organic and inorganic bases, such
as sodium, ammonia, potassium, calcium, ethanolamine,
diethanolamine, N-methylglucamine, choline and the like. Included
are pharmaceutically acceptable salts or compounds of any of the
Formulae herein.
[0027] Depending on its structure, the phrase "pharmaceutically
acceptable salt," as used herein, refers to a pharmaceutically
acceptable organic or inorganic acid or base salt of a compound.
Representative pharmaceutically acceptable salts include, e.g.,
alkali metal salts, alkali earth salts, ammonium salts,
water-soluble and water-insoluble salts, such as the acetate,
amsonate (4,4-diaminostilbene-2, 2-disulfonate), benzenesulfonate,
benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,
butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,
citrate, clavulariate, dihydrochloride, edetate, edisylate,
estolate, esylate, fumarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexafluorophosphate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, 3 hydroxy 2 naphthoate, oleate, oxalate, palmitate,
pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate),
pantothenate, phosphate/diphosphate, picrate, polygalacturonate,
propionate, p toluenesulfonate, salicylate, stearate, subacetate,
succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate salts.
[0028] The terms "treat", "treating" or "treatment", as used
herein, include alleviating, abating or ameliorating a disease or
condition or one or more symptoms thereof, preventing additional
symptoms, ameliorating or preventing the underlying metabolic
causes of symptoms, inhibiting the disease or condition, e.g.,
arresting or suppressing the development of the disease or
condition, relieving the disease or condition, causing regression
of the disease or condition, relieving a condition caused by the
disease or condition, or suppressing the symptoms of the disease or
condition, and are intended to include prophylaxis. The terms also
include relieving the disease or conditions, e.g., causing the
regression of clinical symptoms. The terms further include
achieving a therapeutic benefit and/or a prophylactic benefit. By
therapeutic benefit is meant eradication or amelioration of the
underlying disorder being treated. Also, a therapeutic benefit is
achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the individual, notwithstanding
that the individual is still be afflicted with the underlying
disorder. For prophylactic benefit, the compositions are
administered to an individual at risk of developing a particular
disease, or to an individual reporting one or more of the
physiological symptoms of a disease, even though a diagnosis of
this disease has not been made. Treatment methods include treatment
of scars, including hypertrophic scars, treatment of acne and its
symptoms, for example, and without limitation, reducing the size,
such as the diameter of the acne, and/or reducing the redness of
the acne, and the likes.
[0029] The terms "preventing" or "prevention" refer to a reduction
in risk of acquiring a disease or disorder (i.e., causing at least
one of the clinical symptoms of the disease not to develop in a
subject that may be exposed to or predisposed to the disease but
does not yet experience or display symptoms of the disease). The
terms further include causing the clinical symptoms not to develop,
for example, in a subject at risk of suffering from such a disease
or disorder, thereby substantially averting onset of the disease or
disorder. Prevention includes preventing scars, including
hypertrophic scars, preventing acne and redness resulting
thereforom, and the likes.
[0030] The term "therapeutically effective amount" or dose of a
compound or a composition refers to that amount of the compound or
the composition that results in treatment, including reduction or
inhibition of symptoms in a patient. The results may require
multiple doses of the compound or the composition.
[0031] The terms "carrier" and "vehicles" as used herein, refers to
relatively nontoxic chemical compounds or agents that facilitate
the incorporation of a compound into cells, e.g., dermal cells, or
tissues. Carriers and vehicles useful herein include any such
materials known in the art, which are nontoxic and do not interact
with other components of the formulation in which it is contained
in a deleterious manner. As used herein, "pharmaceutically
acceptable carrier" includes any and all solvents, dispersion
media, and the like, which are pharmaceutically acceptable.
[0032] As used herein, a "prodrug" is a compound that, after
administration, is metabolized or otherwise converted to an active
or more active form with respect to at least one property. To
produce a prodrug, a pharmaceutically active compound can be
modified chemically to render it less active or inactive, but the
chemical modification is such that an active form of the compound
is generated by metabolic or other biological processes. A prodrug
may have, relative to the drug, altered metabolic stability or
transport characteristics, fewer side effects or lower toxicity.
For example, see the reference Nogrady, 1985, Medicinal Chemistry A
Biochemical Approach, Oxford University Press, New York, pages
388-392. Prodrugs can also be prepared using compounds that are not
drugs. Prodrugs of VEGF inhibitors, such as, without limitation,
rifamycin compounds are included in one embodiment of this
invention.
[0033] The term "rifamycin compound" refers to a group of
antibiotic compounds that belong to the family of ansamycins, which
is a family of secondary metabolites that exhibit antimicrobial
activity against many gram-positive and some gram-negative
bacteria. Rifamycin compounds includes, but is not limited to,
rifamycin B, rifamycin SV, rifampicin, rifabutin, rifapentine,
rifalazil, or rifaximin, or a pharmaceutically acceptable salt
thereof, or a derivative, such as an ester, thereof.
[0034] The rifamycin class of antibiotics was originally isolated
from cultures of Streptomyces mediterranei. Large number of
analogues and derivatives of rifamycin are available or generated
synthetically.
[0035] Syntheses of rifamycin compounds are well known in the art,
for example, the synthesis of rifampin (U.S. Pat. No. 3,342,810),
rifabutin (U.S. Pat. No. 4,219,478), and rifalazil (U.S. Pat. No.
4,983,602) are known in the art and incorporated herein by
reference.
[0036] The term "subject" as used herein refers to organisms to be
treated by the compositions of the present invention. Such
organisms include animals (domesticated animal species, wild
animals), preferably a mammal, including a human or non-human
mammal, preferably, a human. The terms patient and subject may be
used interchangeably.
[0037] The term "surfactant" refers to any molecule having both a
polar head group, which energetically prefers solvation by water,
and a hydrophobic tail which is not well solvated by water.
Surfactants can be ionic or non-ionic. The term "ionic surfactant"
includes cationic, anionic, and zwitterionic surfactants. The term
"cationic surfactant" refers to a surfactant with a cationic head
group. The term "anionic surfactant" refers to a surfactant with an
anionic head group.
Methods and Administration
[0038] In one aspect, provided herein is a method of reducing
hypertrophic scar formation comprising administering topically to a
patient in need thereof a therapeutically effective amount of a
VEGF inhibitor.
[0039] In another aspect, provided herein is a method of reducing
scar formation comprising administering topically to a patient in
need thereof a therapeutically effective amount of an inhibitor of
a VEGF inhibitor, wherein the scar formation results at least in
part from neovascularization.
[0040] In one embodiment, the VEGF inhibitor is a rifamycin
compound or a salt thereof or a carboxyl ester of each thereof. In
one embodiment, the rifamycin compound is rifampicin. In one
embodiment, the rifamycin compound is rifabutin. In one embodiment,
the rifamycin compound is rifapentine. In one embodiment, the
rifamycin compound is rifalazil. In one embodiment, the rifamycin
compound is rifaximin. In one embodiment, the rifamycin compound is
rifamycin B. In one embodiment, the rifamycin compound is rifamycin
SV. In one embodiment, the rifamycin compound includes a salt or a
carboxyl ester of any of the foregoing.
[0041] In one embodiment, the VEGF inhibitor is pegaptanib. In one
embodiment, the VEGF inhibitor is bevacizumab. In one embodiment,
the VEGF inhibitor is ranibizumab. In one embodiment, the VEGF
inhibitor is lapatinib. In one embodiment, the VEGF inhibitor is
sorafenib. In one embodiment, the VEGF inhibitor is sunitinib. In
one embodiment, the VEGF inhibitor is axitinib. In one embodiment,
the VEGF inhibitor is pazopanib. In one embodiment, the VEGF
inhibitor is aflibercept.
[0042] In one embodiment, the VEGF inhibitor is administered as a
pharmaceutical composition comprising a therapeutically effective
amount of a VEGF inhibitor and at least one pharmaceutically
acceptable excipient.
[0043] The VEGF inhibitors can be formulated in various ways for
administration as per the present invention. In one embodiment, the
VEGF inhibitor is administered as a gel. In another embodiment, the
VEGF inhibitor is administered as a cream. In another embodiment,
the VEGF inhibitor is administered as a patch. In another
embodiment, the VEGF inhibitor is administered as a spray.
[0044] The VEGF inhibitor, the rifamycin compound, and/or
compositions utilized herein may be used alone or in combination
with other compounds. When administered with another agent, the
co-administration can be in any manner in which the pharmacological
effects of both are manifest in the patient at the same time. Thus,
co-administration does not require that a single pharmaceutical
composition, the same dosage form, or even the same route of
administration be used for administration of both the compound of
this invention and the other agent or that the two agents be
administered at precisely the same time. However, co-administration
will be accomplished most conveniently by the same dosage form and
the same route of administration, at substantially the same time.
Obviously, such administration most advantageously proceeds by
delivering both active ingredients simultaneously in a
pharmaceutical composition in accordance with the present
invention.
[0045] An effective amount of a rifamycin compound, as provided
herein, is the amount required to produce a therapeutically
beneficial effect in vitro or in vivo. In some embodiments the
effective amount in vitro is about from 0.1 nM to about 1 mM. In
some embodiments the effective amount in vitro is from about 0.1 nM
to about 0.5 nM or from about 0.5 nM to about 1.0 nM or from about
1.0 nM to about 5.0 nM or from about 5.0 nM to about 10 nM or from
about 10 nM to about 50 nM or from about 50 nM to about 100 nM or
from about 100 nM to about 500 nM or from about 500 nM to about 1
mM or from about 1 mM to about 200 mM. In some embodiments, the
effective amount for an effect in vivo is about 0.1 mg to about 100
mg, or preferably, from about 1 mg to about 50 mg, or more
preferably, from about 1 mg to about 25 mg per kg/day, or from
about 1 mg to about 12 mg per kg/day. In some other embodiments,
the effective amount in vivo is from about 10 mg/kg/day to about
100 mg/kg/day, about 20 mg/kg/day to about 90 mg/kg/day, about 30
mg/kg/day to about 80 mg/kg/day, about 40 mg/kg/day to about 70
mg/kg/day, or about 50 mg/kg/day to about 60 mg/kg/day. In some
embodiments, the effective amount in vivo is from about 1 mg/kg/day
to about 5 mg/kg/day. In some embodiments, the effective amount in
vivo is from about 6 mg/kg/day to about 12 mg/kg/day. In one
embodiment, the effective amount in vivo is about 3 mg/kg/day. In
another embodiment, the effective amount in vivo is about 6
mg/kg/day. In another embodiment, the effective amount in vivo is
about 12 mg/kg/day.
[0046] In some embodiments the compositions may optionally comprise
a stabilizer or anti-oxidant. Suitable stabilizers and
anti-oxidants are known in the art and include, but not limited to,
ascorbate, ascorbic acid, isoascorbic acid, glutathione sodium
bisulfate, sodium metabisulfite, acetyl cysteine,
8-hydroxyquinoline, thiourea, tocopherols, EDTA, Sodium
Formaldehyde Sulfoxylate Dihydrate, and combinations thereof. In
some embodiments, the composition comprises about 0.01 wt %-20 wt
%, about 0.1 wt %-15 wt %, about 0.15 wt %-10 wt %, about 0.2 wt
%-5 wt %, about 0.25 wt %-3 wt %, about 0.3 wt %-2 wt %, about 0.1
wt %-20 wt %, about 1 wt %-10 wt %, about 2 wt %-10 wt %, about 2
wt %-8 wt %, about 2 wt %-5 wt %, about 5 wt %-10 wt %, about 5 wt
%-20 wt % of an anti-oxidant or stabilizer. In some embodiments,
the composition comprises about 0.01 wt %-10 wt % of anti-oxidant
or stabilizer.
[0047] In some embodiments the compositions may optionally comprise
a lubricant. Examples of suitable lubricants include, but are not
limited to, glycerol, hydroxypropylmethyl cellulose, carboxy
propylmethyl cellulose, sorbitol, polyvinyl pyrrolidone,
polyethylene glycol, polyvinyl acetate, and combinations thereof.
In some embodiments, the composition comprises about 0.01 wt %-20
wt %, about 0.1 wt %-15 wt %, about 0.15 wt %-10 wt %, about 0.2 wt
%-5 wt %, about 0.25 wt %-3 wt %, about 0.3 wt %-2 wt %, about 0.1
wt %-20 wt %, about 1 wt %-10 wt %, about 2 wt %-10 wt %, about 2
wt %-8 wt %, about 2 wt %-5 wt %, about 5 wt %-10 wt %, about 5 wt
%-20 wt % of lubricant. In some embodiments, the composition
comprises about 0.01 wt %-10 wt % of lubricant.
[0048] In some embodiments, the compositions may optionally include
preservatives. Examples of preservatives include, but are not
limited to, midazolidinyl urea, methylparaben, propylparaben,
phenoxyethanol, disodium EDTA, thimerosal, chlorobutanol sorbic
acid, and combinations thereof. In some embodiments, the
composition comprises about 0.01 wt %-20 wt %, about 0.1 wt %-15 wt
%, about 0.15 wt %-10 wt %, about 0.2 wt %-5 wt %, about 0.25 wt
%-3 wt %, about 0.3 wt %-2 wt %, about 0.1 wt %-20 wt %, about 1 wt
%-10 wt %, about 2 wt %-10 wt %, about 2 wt %-8 wt %, about 2 wt
%-5 wt %, about 5 wt %-10 wt %, about 5 wt %-20 wt % of the
preservative. In some embodiments, the composition comprises about
0.01 wt %-10 wt % % of the preservative.
[0049] In some embodiments, the compositions may optionally include
one or more buffering agents to maintain the pH of the composition
at a range generally acceptable for topical compositions. In some
embodiments, the compositions are buffered to a pH of about 4-8,
preferably 3-7.5 or about 7. In some embodiments, the pH range is
from about 6.8 to about 7.8. Examples of suitable buffering agents
include, but are not limited to, citrates, phosphates, borates,
bicarbonates, sodium salts, potassium including acids such as
acetic, boric, citric, lactic, phosphoric and hydrochloric acids;
bases such as sodium hydroxide, sodium phosphate, sodium borate,
sodium citrate, sodium acetate, sodium lactate; and buffers such as
citrate/dextrose, sodium bicarbonate and ammonium chloride and
combinations thereof. The acids, bases and buffers are included in
an amount required to maintain pH of the composition in an
transdermally acceptable range.
[0050] The compositions may additionally include suitable diluents
known in the art. In some embodiments, the diluent is a transdermal
carrier, buffered to a suitable pH, e.g. in the range of from about
4.0 to about 8.0, and containing effective amount of a wetting
agent and an anti-bacterial agent.
[0051] In one embodiment, the VEGF inhibitor is administered as a
gel. In another embodiment, the VEGF inhibitor is administered as a
cream. In another embodiment, the VEGF inhibitor is administered as
a patch. In another embodiment, the VEGF inhibitor is administered
as a spray. The composition can be manufactured by methods known in
the art.
[0052] In one embodiment, the rifamycin compound is administered as
a gel. In another embodiment, the rifamycin compound is
administered as a cream. In another embodiment, the rifamycin
compound is administered as a patch. In another embodiment, the
rifamycin compound is administered as a spray. The composition can
be manufactured by methods known in the art.
[0053] A gel formulation can be applied anywhere on the subject's
body. Gels are distinguished by a variety of parameters, including
but not limited to, pH, homogeneity, grittiness, drug content,
viscosity, spreadability, extrudability, skin irritation, and
stability. Without being bound by theory, a gel is a cross-linked
three dimensional network of structural materials that are
interspersed by a large amount of liquid. The structural materials
form a rigid structure that immobilizes and contains the liquid
within the structure. The structural materials can be made from
inorganic or organic materials, including polymers. Gel forming
polymers include, but are not limited to, natural polymers,
semisynthetic polymers, synthetic polymers, inorganic substances,
and/or surfactants. Non-limiting examples of natural polymers
include proteins, such as gelatin and collagen, and
polysaccharides, such as alginic acid, agar, tragacanth, sodium or
potassium carrageenan, pectin, gellum gum, xanthin, cassia tora,
and guar gum. Non-limiting examples of semisynthetic polymers
include cellulose derivatives, such as hydroxyethyl cellulose,
methylcellulose, hydroxypropyl methyl cellulose, hydroxypropyl
cellulose, and carboxymethyl cellulose. Non-limiting examples of
synthetic polymers include carbomer, carbopol-941, carbopol-940,
carbopol-934, poloxamer, polyvinyl alcohol, polyacrylamide,
polyethylene and copolymers of polyethylene. Non-limiting examples
of inorganic substances include bentonite and aluminum hydroxide.
Non-limiting examples of surfactants include Brij-96 and
cetostearyl alcohol. See Kaur, et al., Topical Gel: A Recent
Approach for Novel Drug Delivery, Asian Journal of Biomedical and
Pharmaceutical Sciences, 3(17) 2015, p. 1-5, which is incorporated
herein by reference in its entirety.
[0054] The gels of this disclosure can be made by gel preparation
techniques well-known to a skilled artisan. Sterile and/or purified
water can be mixed with a VEGF inhibitor until the VEGF inhibitor
is dissolves. Similarly, sterile and/or purified water can be mixed
with a rifamycin compound until the rifamycin compound dissolves. A
gelling agent, such as those described above, can be slowly added
until homogeneity is reached. Propylene glycol and other additives,
including preservatives, can then be added. Examples of
preservatives include, but are not limited to, methylparaben and
propylparaben.
[0055] For example, and without limitation, oil-in-water or
water-in-oil systems, as well as a base (vehicle or carrier) for
the topical formulation can be selected to provide effectiveness of
the active ingredients and/or avoid allergic and irritating
reactions (e.g., contact dermatitis) caused by ingredients of the
base or by the active ingredients.
[0056] The VEGF inhibitors or the rifamycin compound can be
formulated with an emulsifier. Non-limiting examples of emulsifiers
useful in this regard include glycol esters, fatty acids, fatty
alcohols, fatty acid glycol esters, fatty esters, fatty ethers,
esters of glycerin, esters of propylene glycol, fatty acid esters
of polyethylene glycol, fatty acid esters of polypropylene glycol,
esters of sorbitol, esters of sorbitan anhydrides, carboxylic acid
copolymers, esters and ethers of glucose, ethoxylated ethers,
ethoxylated alcohols, alkyl phosphates, polyoxyethylene fatty ether
phosphates, fatty add amides, acyl lactylates, soaps, polyethylene
glycol 20 sorbitan monolaurate (polysorbate 20), polyethylene
glycol 5 soya sterol, steareth-2, steareth-20, steareth-21,
ceteareth-20, PPG-2 methyl glucose ether distearate, ceteth-10,
polysorbate 80, cetyl phosphate, potassium cetyl phosphate,
diethanolamine cetyl phosphate, polysorbate 60, glyceryl stearate,
PEG-100 stearate, tragacanth gum, poly(acrylamide-b-acrylic acid),
10-30 alkyl acrylate crosspolymers, derivatives thereof, and
mixtures thereof.
[0057] Certain components of a transdermal patch include, without
limitation: a liner, which protects the patch during storage and is
removed prior to use; the VEGF inhibitor (or the drug) or the
rifamycin compound as a solution or suspension, e.g., in direct
contact with release liner; an adhesive, which serves to adhere the
components of the patch together along with adhering the patch to
the skin; optionally a membrane, which controls the release of the
drug from a reservoir and multi-layer patches; a backing, which
protects the patch from the outer environment; optionally a
permeation enhancer, which increases delivery of drug; and
optionally a matrix filler, which provides bulk to the matrix as
well as some of fillers acts as matrix stiffening agent. Other
components may include: stabilizer (anti oxidants), preservatives
and the likes. A formulation utilized in this invention can be
prepared by methods well known to the skilled artisan or by
adapting such methods in view of the present disclosure. See, e.g.,
Japanese Journal of Hospital Pharmacy Vol. 13 (1987) No. 3 P
163-167 (incorporated herein by reference).
EXAMPLES
[0058] The following examples illustrate but do not limit the
invention(s) provided herein.
Example 1A
[0059] Rifampicin powder was dissolved in petroleum jelly and in a
conventional skin cream, e.g., at a concentration of 2% in these
topical skin formulations.
Example 2A
[0060] Female FVB mice (8 weeks old) will be used to examine dermal
delivery of rifampicin. Under isoflurane (Abbott Laboratories)
anesthesia, the dorsum of each mouse will be shaved and wiped with
70% isopropyl alcohol. A 3-cm, full-thickness linear incisional
wound will be made to the right of the spine on each mouse. The
wounds will be closed with three stainless steel staples. Topical
cream or ointment containing rifampicin will be applied to the
wounds produced in mice. Those mice will be sacrificed in the
following time points: (1) 1 hr, (2) 3 hr, (3) 7 hr, (4) 24 hr, (5)
48 hr, and (6) 120 hr (5 days). Rifampicin applied (topically) skin
tissue will be extracted, and frozen in liquid nitrogen for LC/MS
analysis to quantify rifampicin absorbed in the wound tissues.
[0061] To clarify whether an incision wound will increase delivery
efficiency to dermal tissue, rifampicin cream or ointment will be
applied for normal skin that will not have any incision wound, and
it will also be applied for incision injury in a day after suture
staples have been removed. Time-dependent experiments similar to
those described here will be performed. Rifampicin delivered to
dermal tissue will be quantified by LC/MS.
Example 1
[0062] Powdered rifampicin was dissolved in Petroleum jelly. A
concentration of the compound was increased to 2.5% to prepare the
topical skin formulation.
Example 2
[0063] A 16 years old male had acne in his face. 6 different sites
of acne which had approximately 3 mm of diameter were selected on
his face, and these diameters were recorded at Day 0. 2.5%
rifampicin ointment was topically applied to the specific acne
sites twice daily, and diameters of the acne sites were recorded
once daily. Diameters of the acne site were significantly reduced
in 3 days with statistical evaluation of p=0.0009. See also, FIG.
1.
[0064] In the control test, 5 different sites of acne which had
approximately 3 mm of diameter were selected on his face, and these
diameters were recorded at Day 0. 1% clindamycin gel was topically
applied to the specific sites twice daily, and diameters of the
acne sites were recorded once daily. Diameters of the acne site
were not changed.
TABLE-US-00001 Day 0 Day 1 Day 2 Day 3 Average diameters (mm) of
3.00* 2.83 1.75 1.00** acne sites in 2.5% SCR101 treatment SE
0.2582 0.3073 0.3096 0.3416 Average diameters (mm) of 2.80* 3.20
2.80 2.80** acne sites in 1% Clindamycin treatment SE 0.3742 0.2000
0.2000 0.3742 *Evaluated at p value of 0.6633 **Evaluated at p
value of 0.0066
Example 3
[0065] Pre-clinical efficacy study is performed to demonstrate that
rifampicin delivered to wound skin tissue by topical application
inhibits neovascularization. A 3-cm full-thickness linear
incisional wound will be made to the right of the spine on each
mouse. The wounds will be closed with three stainless steel
staples. Topical cream or skin patches containing rifampicin will
be applied to the wounds produced in mice. The staples will be
removed after 5 days. Mice will be sacrificed and wound or scar
tissue samples will be harvested 24 h or 14 days post injury.
Samples will be fixed for histological analysis. To determine
capillary vessels in wound tissues, immune-histochemical staining
for platelet endothelial cell adhesion molecule (PECAM) will be
used to identify blood vessels in wounds. To determine scar size in
wounds, tissues will be stained by Masson's trichrome, as described
e.g., in a paper published by Wilgus et al. in 2008.
Example 4
[0066] Powdered rifampicin was dissolved in Petroleum jelly. A
concentration of the compound was increased to 2.5% to prepare the
topical skin formulation.
Example 5
[0067] A 53 years old female had redness in her arm. A size of the
redness was 1-2 inches in both dimensions. The redness was
persisting for more than 3 years. No treatment was effective to
remove it although she attempted many treatments. 2.5% rifampicin
ointment was topically applied to the redness twice daily. In 2-3
days after the treatment was initiated, effectiveness of reducing
the redness was seen. In 15 days of the initiation, redness of the
scar was significantly removed. In 17 days of the initiation, the
treatment was terminated. In 24 days, the effectiveness of reducing
the redness was continued, and the redness was not returned. See,
FIGS. 2-3.
Example 6
[0068] Powdered rifampicin was dissolved in Petroleum jelly at 2.5%
concentration. A physicochemical feature of the 2.5% rifampicin
ointment was somewhat similar to that of lotion, and it was smooth
when applied to skin tissue. It is contemplated that the rifampicin
ointment did not plug pores in skin tissue. The rifampicin ointment
was stable at room temperature for weeks of time.
Example 7
[0069] 2.5% rifampicin ointment was topically applied to a hand of
a 54 years old male. In 1-2 hr, red color of the compound was
disappeared in skin tissue by absorption, and in 3 hr, the red
color became almost invisible. These observations suggest that the
compound has high affinity to skin tissue to be absorbed.
Example 8
[0070] The rapid skin absorption of 2.5% rifampicin ointment
allowed the 54 years old male and others apply the product to hands
and faces. The compound was readily dissolved in detergent, and the
product was cleaned and washable by a regular washer when attached
to fabric materials.
* * * * *