U.S. patent application number 16/255760 was filed with the patent office on 2019-08-22 for ophthalmic compositions of rifamycins and uses thereof.
The applicant listed for this patent is Hiroaki Serizawa. Invention is credited to Hiroaki Serizawa.
Application Number | 20190255065 16/255760 |
Document ID | / |
Family ID | 55163601 |
Filed Date | 2019-08-22 |
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United States Patent
Application |
20190255065 |
Kind Code |
A1 |
Serizawa; Hiroaki |
August 22, 2019 |
OPHTHALMIC COMPOSITIONS OF RIFAMYCINS AND USES THEREOF
Abstract
Provided herein are ophthalmic pharmaceutical formulations
comprising a rifamycin compound. Also provided herein are methods
of treating ocular diseases or disorders by administering such
ophthalmic formulations.
Inventors: |
Serizawa; Hiroaki; (Palo
Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Serizawa; Hiroaki |
Palo Alto |
CA |
US |
|
|
Family ID: |
55163601 |
Appl. No.: |
16/255760 |
Filed: |
January 23, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15327951 |
Jan 20, 2017 |
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PCT/US15/41196 |
Jul 20, 2015 |
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16255760 |
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62174884 |
Jun 12, 2015 |
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62136222 |
Mar 20, 2015 |
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62027189 |
Jul 21, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 47/10 20130101; A61K 9/0048 20130101; A61P 25/00 20180101;
A61K 9/08 20130101; A61K 31/496 20130101; A61K 47/02 20130101; A61K
47/26 20130101; A61K 31/5383 20130101; A61K 47/14 20130101; A61P
27/02 20180101; A61K 31/435 20130101 |
International
Class: |
A61K 31/5383 20060101
A61K031/5383; A61K 31/496 20060101 A61K031/496; A61K 9/00 20060101
A61K009/00; A61K 9/08 20060101 A61K009/08; A61K 31/435 20060101
A61K031/435; A61K 47/18 20060101 A61K047/18; A61K 47/02 20060101
A61K047/02; A61K 47/10 20060101 A61K047/10; A61K 47/14 20060101
A61K047/14; A61K 47/26 20060101 A61K047/26 |
Claims
1. A method of treating an ocular disease, disorder or condition
resulting from neovascularization comprising topically
administering to a patient in need thereof a pharmaceutically
acceptable ophthalmic ointment composition comprising: an effective
amount of a rifamycin compound selected from the group consisting
of rifampicin, rifabutin, rifapentine and rifaximin, or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable viscosity inducing agent.
2. The method of claim 1, wherein the ocular disease, disorder or
condition is selected from age related macular degeneration (AMD),
ocular neovascularization, or retinal ganglion cell injury.
3. The method of claim 2, wherein the ocular neovascularization
comprises retinal neovascularization.
4. A method of inhibiting ocular neovascularization in a retina of
a patient in need thereof, comprising administering topically a
pharmaceutically acceptable ophthalmic ointment composition
comprising up to about 1% (w/v) of rifampicin, and one or more
pharmaceutically acceptable viscosity inducing agent to an eye of
the patient.
5. The method of claim 4, wherein the pharmaceutically acceptable
ophthalmic ointment composition comprises from about 0.1% to about
1% of rifampicin.
6. The method of claim 4, wherein the pharmaceutically acceptable
ophthalmic ointment composition comprises from about 0.25% to about
1% of rifampicin.
7. The method of claim 4, wherein the pharmaceutically acceptable
ophthalmic ointment composition comprises from about 0.5% to about
1% of rifampicin.
8. The method of claim 4, wherein the pharmaceutically acceptable
ophthalmic ointment composition comprises from about 0.1% to about
0.5% of rifampicin.
9. The method of claim 4, wherein the pharmaceutically acceptable
ophthalmic ointment composition comprises from about 0.25% to about
0.5% of rifampicin.
10. The method of claim 4, wherein the pharmaceutically acceptable
ophthalmic ointment composition comprises from about 0.25% of
rifampicin.
11. The method of claim 4, wherein the pharmaceutically acceptable
ophthalmic ointment composition comprises from about 0.5% of
rifampicin.
12. The method of claim 1, wherein the pharmaceutically acceptable
ophthalmic ointment composition further comprises from about 0.1 wt
%-10 wt % of a surfactant selected from polysorbate 80, tween 80,
tween 20, polyoxyethylene hydrogenated castor oil, and lecithin, or
combinations thereof.
13. The method of claim 4, wherein the pharmaceutically acceptable
ophthalmic ointment composition further comprises about 0.1 wt %-10
wt % of a surfactant selected from polysorbate 80, tween 80, tween
20, polyoxyethylene hydrogenated castor oil, and lecithin, or
combinations thereof.
14. The method of claim 1, wherein the one or more pharmaceutically
acceptable viscosity inducing agent is selected from the group
consisting of carboxyvinyl polymer, a cellulosic polymer, a
polysaccharide, polyvinyl pyrrolidone, polyvinyl alcohol, and
combinations thereof.
15. The method of claim 4, wherein the one or more pharmaceutically
acceptable viscosity inducing agent is selected from the group
consisting of carboxyvinyl polymer, a cellulosic polymer, a
polysaccharide, polyvinyl pyrrolidone, polyvinyl alcohol, and
combinations thereof.
16. A method of inhibiting ocular neovascularization in a retina of
a patient in need thereof, comprising administering topically a
pharmaceutically acceptable ophthalmic ointment composition
comprising from about 1% to about 10% (w/v) of rifampicin, and one
or more pharmaceutically acceptable viscosity inducing agent to an
eye of the patient.
17. The method of claim 16, comprising from about 1.5% to about 5%
(w/v) of rifampicin.
18. The method of claim 16, comprising from about 2% to about 2.5%
(w/v) of rifampicin.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Non-Provisional
application Ser. No. 15/327,951 filed Jan. 20, 2017, which is a
National Stage Entry of International PCT Application No.
PCT/US15/41196 filed Jul. 20, 2015, which claims priority to U.S.
Provisional Application Ser. No. 62/027,189 filed Jul. 21, 2014,
62/136,222 filed Mar. 20, 2015, and 62/174,884 filed Jun. 12, 2015,
the content of each of which is incorporated herein in its entirety
by reference.
FIELD OF THE INVENTION
[0002] Provided herein are pharmaceutically acceptable compositions
or compositions suitable for topical administration to an eye, the
composition comprising a therapeutically-effective amount of an
antimicrobial agent, which, in a preferred embodiment comprises a
rifamycin derivative, methods for their preparation, and methods
for their use in treating various disorders.
BACKGROUND
[0003] Loss of visual acuity is a common problem associated with
aging and with various diseases of the eye such as macular
degeneration, ocular histoplasmosis syndrome, myopia, diabetic
retinopathy and inflammatory diseases all of which result from
neovascularization in the cornea, retina or choroid.
[0004] Age-Related Macular Degeneration (AMD) is a common eye
condition which usually affects older adults and results in a loss
of vision in the center of the visual field (the macula) due to
retinal damage. Although some peripheral vision remains, it is
difficult or impossible to read or recognize faces. There are two
major forms of macular degeneration: atrophic (dry) and exudative
(wet). In dry (non-exudative) form, cellular debris called drusen
accumulates between retina and choroid. In more severe wet
(exudative) form, blood vessels grow up from the choroid behind the
retina. AMD is a leading cause of blindness among people older than
65 years and is caused by abnormal development of blood vessels
behind retina. The advanced AMD population will grow by 11% to 3.3
million due to the aging population. Intravitreal injection with
anti-vascular endothelial growth factor (anti-VEGF) therapy has
become the criterion standard for treatment of choroidal
neovascular membranes (CNVs) associated with AMD. Treatment options
in wet AMD include bevacizumab (Avastin, Genentech, San Francisco,
Calif.), which is a full-length anti-VEGF antibody, ranibizumab
(Lucentis, Genentech), which is an affinity-matured fragment,
pegaptanib sodium (Macugen, OSI/Eyetech Inc.), and aflibercept
(Eylea, Regeneron, Tarrytown, N.Y.), and other anti-VEGF drugs.
However, intravitreal injection is a process that requires great
precision, because it is performed with the help of a needle under
local anesthesia. In this process, the needle must be inserted into
the vitreous liquid that fills the cavity between the lens and
retina, and one must be very careful not to damage the retina.
Accordingly, easy treatment method for AMD is highly desirable.
Therefore, a need exists for additional therapeutics and
administration routes and methods for treating ocular disorders
such as AMD.
SUMMARY OF THE INVENTION
[0005] This invention relates generally to pharmaceutical
compositions or formulations suitable for administration to an eye.
In some aspects, this invention relates to ophthalmic
pharmaceutical compositions or formulations comprising one or more
rifamycin compounds selected from the group consisting of
rifampicin, rifabutin, rifapentine.
[0006] In one aspect, the invention relates to methods of treating
an ocular disease, disorder or condition comprising administering
to a patient in need thereof an ophthalmic composition comprising
an effective amount of a rifamycin compound selected from the group
consisting of rifampicin, rifabutin, rifapentine and rifaximin. In
some aspects, this invention relates to methods for treating
disorders mediated by inhibition of neovascularization in retina
tissues. In other aspects, this invention relates to methods of
treating age-related macular degeneration using ophthalmic
compositions of rifamycin compounds. In yet other aspects, the
invention related to methods for protecting retina ganglion cells
and/or brain damage using ophthalmic compositions of rifamycin
compounds. In further aspects, the invention relates to methods of
reducing retina thickness in a patient in need thereof comprising
administering to the patient an ophthalmic composition comprising
an effective amount of a rifamycin compound selected from the group
consisting of rifampicin, rifabutin, rifapentine and rifaximin or a
pharmaceutically acceptable salt thereof.
[0007] In one aspect, provided herein is a method of inhibiting
ocular neovascularization in a retina of a patient in need thereof,
comprising administering topically a pharmaceutically acceptable
composition comprising up to about 1% (g/100 mL of the composition
weight/volume or (w/v)), or about 0.1% to about 1%, or about 0.25%
to about 1%, or about 0.5% to about 1%, or about 0.1% to about
0.5%, or about 0.25% to about 0.5%, or about 0.25%, or about 0.5%
of rifampicin and at least one pharmaceutically acceptable
excipient to an eye of the patient containing the retina.
[0008] In other aspects, eye drop and injectable formulations of
AMD101 (Rifampicin) are provided. In H.sub.2O, the AMD101 can
dissolve at approximately 1.4 mg/ml only. However, the
concentration was increased as provided herein employing suitable
excipients. Those formulations are stable for weeks.
[0009] In another aspect, provided herein is a pharmaceutically
acceptable composition, preferably a topical eye drop composition
comprising up to about 1% (g/100 mL of the composition
weight/volume or (w/v)), or about 0.1% to about 1%, or about 0.25%
to about 1%, or about 0.5% to about 1%, or about 0.1% to about
0.5%, or about 0.25% to about 0.5%, or about 0.25%, or about 0.5%
of rifampicin and at least one pharmaceutically acceptable
excipient.
[0010] In one aspect, provided herein is a pharmaceutically
acceptable composition for subcutaneous injection comprising up to
about 1% (g/100 mL of the composition weight/volume or (w/v)), or
about 0.1% to about 1%, or about 0.25% to about 1%, or about 0.5%
to about 1%, or about 0.1% to about 0.5%, or about 0.25% to about
0.5%, or about 0.25%, or about 0.5% of rifampicin and at least one
pharmaceutically acceptable excipient.
[0011] In some embodiment, the pharmaceutically acceptable
composition provided or utilized herein is at a pH of 7-8.5,
7.5-8.0, 7.5-9.0, or 7.5-12.0. In some embodiment, the
pharmaceutically acceptable composition provided or utilized herein
is at a pH of 2.0-7.0, 3.0-7.0, and 4.0-7.0. In some embodiment,
the pharmaceutically acceptable composition provided or utilized
herein are at a physiological salt concentration. In some
embodiment, the pharmaceutically acceptable composition provided or
utilized herein comprise one or more of an anti-oxidant, a
preservative, and other pharmaceutically acceptable excipients.
[0012] The foregoing general description and the detailed
description are exemplary and explanatory and are intended to
provide further explanation of the invention as claimed. Other
objects, advantages, and novel features will be readily apparent to
those skilled in the art from the following detailed description of
the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 shows histology sections of retinas treated with
AMD101 topical eye drop formulation, AMD101 SC injection, and a
vehicle only control, in which oxygen-induced retinopathy was
induced in the retinas; and a retina in which retinopathy was not
induced.
[0014] FIG. 1A shows the 200.times. histological section of a
retina treated with a vehicle only control.
[0015] FIG. 1B shows the 400.times. histological section of a
retina treated with a vehicle only control.
[0016] FIG. 1C shows the 200.times. histological section of a
retina treated with AMD101 topical eye drop formulation. FIG. 1D
shows the 400.times. histological section of a retina treated with
AMD101 topical eye drop formulation. FIG. 1E shows the 200.times.
histological section of a retina treated with AMD101 SC injection.
FIG. 1F shows the 400.times. histological section of a retina
treated with AMD101 SC injection. FIG. 1G shows the 200.times.
histological section of a retina for which retinopathy was not
induced. FIG. 1H shows the 400.times. histological section of a
retina for which retinopathy was not induced.
DETAILED DESCRIPTION OF THE INVENTION
[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] 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.
[0020] 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%.
[0021] Combinations of substituents and variables are only those
that result in the formation of stable compounds. The term
"stable," as used herein, refers to compounds which possess
stability sufficient to allow manufacture and which maintains the
integrity of the compound for a sufficient period of time to be
useful for the purposes detailed herein.
[0022] As used herein, "hydrate" is a form of a compound wherein
water molecules are combined in a certain ratio as an integral part
of the structure complex of the compound.
[0023] As used herein, "solvate" is a form of a compound where
solvent molecules are combined in a certain ratio as an integral
part of the structure complex of the compound.
[0024] The terms "pharmaceutically acceptable" or
"pharmacologically acceptable," as used herein, refer 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.
[0025] "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.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] The term "effective amount" refers to an amount that is
effective for the treatment of a condition or disorder by an
intranasal administration of a compound or composition described
herein. In some embodiments, an effective amount of any of the
compositions or dosage forms described herein is the amount used to
treat a disorder mediated by hemoglobin or a disorder that would
benefit from tissue and/or cellular oxygenation of any of the
compositions or dosage forms described herein to a subject in need
thereof.
[0030] 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., ocular 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, coatings, wetting agents (e.g., sodium lauryl sulfate),
isotonic and absorption delaying agents, disintegrants (e.g.,
potato starch or sodium starch glycolate), and the like.
[0031] 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.
[0032] The term "ophthalmically acceptable" with respect to a
formulation, composition or ingredient herein means having no
persistent detrimental effect on the treated eye or the functioning
thereof, or on the general health of the subject being treated,
baring transient effects such as minor irritation or a "stinging"
sensation.
[0033] The term "active agent" or "active ingredient" is used
herein to refer to a chemical material or compound that induces a
desired beneficial effect when administered to a patient. Also
included are salts, derivatives and analogs of those compounds or
classes of compounds specifically mentioned (e.g., rifamycin
compounds) that also induce the desired effect. For example,
"rifampicin" as used herein includes pharmaceutically acceptable
salts thereof and derivatives thereof.
[0034] The terms "buffer" or "buffering agents" refer to materials
which when added to a solution, cause the solution to resist
changes in pH.
[0035] The term "dilution" refers to dilution of the formulations
of the present invention or those derived from the formulations of
the present invention using, for example, an aqueous system
comprised of physiologically balanced saline solution (PBS), such
as phosphate buffered saline, or water, or other water soluble
components, to the desired final concentration.
[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. 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.
[0038] "Macular degeneration" refers to a variety of degenerative
conditions characterized by central visual loss due to
deterioration of the macula. One of these conditions is age related
macular degeneration (AMD), which exists in both "dry" and "wet"
forms.
[0039] "Ocular neovascularization" refers to the abnormal
development, proliferation, and/or growth of blood vessels on or in
the eye, e.g., on the retinal surface.
Methods
[0040] Some embodiments provided herein describe a method of
treating visual disorders such as age-related macular degeneration
(AMD), ocular neovascularization, optic neuropathy, glaucoma,
degeneration of optic nerves, and ophthalmoplegia. Any ophthalmic
formulation and/or compounds described above are useful in the
methods described herein.
[0041] In some embodiments, a method of treating an ocular disease,
disorder, injury or condition is provided, the method comprising
administering to a patient in need thereof an ophthalmic
composition comprising an effective amount of a rifamycin compound
selected from the group consisting of rifampicin, rifabutin,
rifapentine and rifaximin.
[0042] In some embodiments, the ocular disease, disorder, injury or
condition is selected from the group consisting of macular
degeneration, diabetic retinopathy, chronic glaucoma, retinal
detachment, sickle cell retinopathy, age related macular
degeneration (AMD), retinal ganglion cell injury, rubeosis iritis,
inflammatory diseases, chronic uveitis, neoplasms, Fuchs'
heterochromic iridocyclitis, neovascular glaucoma, corneal
neovascularization, choroidal neovascularization, retinal
neovascularization, retinal angiomatous proliferation, and the
like.
[0043] In some embodiments, a method of treating ocular
neovascularization is provided, the method comprising administering
to a patient in need thereof an ophthalmic composition comprising
an effective amount of a rifamycin compound selected from the group
consisting of rifampicin, rifabutin, rifapentine and rifaximin. In
some embodiments, the said treatment reduces or reverses the loss
of visual acuity secondary to neovascularization of cornea, iris,
retina or choroid. In some embodiments, ocular neovascularization
includes neovascularization resulting following a combined
vitrectomy and lensectomy, retinal ischemia, choroidal vascular
insufficiency, choroidal thrombosis, carotid artery ischemia,
neovascularization of the optic nerve, and neovascularization due
to penetration of the eye or contusive ocular injury.
[0044] In some embodiments, a method of treating age-related
macular degeneration (AMD) is provided, the method comprising
administering to a patient in need thereof an ophthalmic
composition comprising a therapeutically effective amount of a
rifamycin compound selected from the group consisting of
rifampicin, rifabutin, rifapentine and rifaximin. In some
embodiments, the method includes treatment of dry form of AMD. In
other embodiments, the method includes treatment of wet form of
AMD.
[0045] In some embodiments, a method of treating retinal
neovascularization is provided, the method comprising administering
to a patient in need thereof an ophthalmic composition comprising a
therapeutically effective amount of a rifamycin compound selected
from the group consisting of rifampicin, rifabutin, rifapentine and
rifaximin.
[0046] In some embodiments, a method of protecting optic nerve
cells is provided, the method comprising administering to a patient
in need thereof an ophthalmic composition comprising a
therapeutically effective amount of a rifamycin compound selected
from the group consisting of rifampicin, rifabutin, rifapentine and
rifaximin. In some embodiments, the optic nerve cells are retinal
ganglion cells.
[0047] In some embodiments, a method of inhibiting brain damage is
provided, the method comprising administering to a patient in need
thereof an ophthalmic composition comprising a therapeutically
effective amount of a rifamycin compound selected from the group
consisting of rifampicin, rifabutin, rifapentine and rifaximin.
[0048] In some embodiments of the methods, the rifamycin compound
is rifampicin. In some embodiments, the rifamycin compound is
rifabutin. In some embodiments, the rifamycin compound is
rifapentine. In some embodiments, the rifamycin compound is
rifaximin. In some embodiments, the ophthalmic composition further
comprises at least one of a non-ionic tonicity adjusting agent, a
salt, a preservative, a buffering agent, a surfactant, an
anti-oxidant, a solubilizing agent and a stabilizer. In some
embodiments, the composition is administered topically. In some
embodiments, the composition is in the form of eye drops, a gel,
lotion, cream, or an ointment, or is incorporated into a conformer,
an implant, a stent, or an ophthalmic spray drug delivery
device.
[0049] Compounds and pharmaceutical compositions of this invention
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 novel pharmaceutical
composition in accordance with the present invention.
[0050] In some embodiments, in addition to the administration of
ophthalmic compositions, the method comprises oral administration
of an effective amount of the active ingredient (e.g., rifamycin
compound). Suitable oral formulations of the rifamycin compound
selected from the group consisting of rifampicin, rifabutin,
rifapentine and rifaximin are known in the art. Thus, the methods
include a combination therapy whereby the active ingredient (e.g.,
rifamycin compound) is administered by to the patient via any
suitable mode of administration, including topical, ocular, oral,
subcutaneous, mucosal, intradermal, intranasal, buccal, sublingual,
pulmonary or the like.
[0051] An effective amount of rifamycin compound is the amount
required produce a protective 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. 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
viva 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. In still some other
embodiments, the effective amount in viva is from about 100
mg/kg/day to about 1000 mg/kg/day.
Compositions
[0052] In one aspect, provided herein are compositions, preferably
ophthalmic compositions comprising an effective amount of rifamycin
compound, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
[0053] The rifamycin class of antibiotics was originally isolated
from cultures of Streptomyces mediterranei. Due to the large number
of available analogues and derivatives generated synthetically,
rifamycins have been widely utilized in the elimination of
pathogenic bacteria that have become resistant to commonly used
antibiotics.
[0054] Rifamycins are primarily effective against mycobacteria and
are therefore used to treat chronic infections including
tuberculosis (TB), leprosy and mycobcterium avium complex (MAC)
infections. Along with its pulmonary effects, TB is also known to
affect other organs including ocular tissues. Therefore, the
effects of rifamycin on ocular TB and other ocular disorders have
been studied. When chronic administration of rifampicin in HCV
patients was monitored, it was observed that alpha fetoprotien
which is the liver cancer marker was strongly inhibited. Rifampicin
exhibits strong neovascularization effects whereby major
neovascularization genes such as VEGF, HGF etc. are strongly
inhibited.
[0055] Suitable rifamycin compounds include for example, rifampicin
(rifampin), rifabutin, rifapentine, rifalazil and rifaximin, or a
pharmaceutically acceptable salt thereof, or a derivative thereof.
Syntheses of simple rifamycin derivatives is 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.
[0056] In some embodiments, provided herein are compositions,
preferably ophthalmic compositions or an eye drop composition
comprising an effective amount of rifamycin compound, or a
pharmaceutically acceptable salt thereof and an inert, non-eye
irritating, non-toxic eye drop carrier. Such carriers are well
known, and commonly referred to in, for example, the Physician's
Desk Reference for Ophthalmology (1982 Edition, published by
Medical Economics Company, Inc., Oridell, N.J.), wherein numerous
sterile ophthalmologic ocular solutions are reported, e.g., see pp.
112-114, which are incorporated by reference.
[0057] In some embodiments, the composition, including ophthalmic
compositions described herein include for example, eye drops,
solutions, ocular solutions such as contact lens solutions,
suspensions, gels, creams and ointments intended for ophthalmic
use. In some embodiments, the eye drops are administered with an
eye dropper. In some embodiments, the ophthalmic composition is in
the form of a topical eye drop. In one embodiment, the ophthalmic
composition is a solution. In another embodiment, the ophthalmic
composition is a suspension.
[0058] In some embodiments, the composition, including ophthalmic
compositions are included in various drug delivery systems known in
the art. For example, the composition can be included in an ocular
solution used to clean, preserve, soak or immerse contact lenses.
Soft contact lenses comprising a body formed of a hydrophilic gel
material, such as 2-hydroxyethyl methacrylate (HEMA), and ocular
solutions for cleaning or soaking them are known in the art and are
commercially available. In one embodiment, the ophthalmic
compositions are incorporated in an ocular solution used to soak
and swell the hydrophilic gel containing lenses. The lens imbibes
the solution comprising the active ingredient and slowly releases
it upon insertion in the eye. Thus, therapeutically effective doses
of the active ingredient, i.e. rifamycin compounds, are delivered
to the patient wearing the contact lens. In one embodiment, contact
lenses, after use in the eye can be soaked again in the ocular
solution comprising a therapeutic level of the active ingredient to
replenish the drug. In some embodiments, the active ingredient can
be dispersed in to the matrix of the lens via the polymerization
medium.
[0059] In some embodiments, provided herein are compositions,
including ophthalmic compositions, wherein the concentration of the
rifamycin compound is about 0.01 wt % to about 50 wt %, about 0.05
wt % to about 40 wt %, about 0.1 wt % to about 30 wt %, about 0.5
wt % to about 20 wt %, about 1.0 wt % to about 10 wt %, about 1.5
wt % to about 5 wt %, about 2.0 wt % to about 3.0 wt %, and ranges
between any two of these values or less than any one of these
values. In some embodiments, the ophthalmic compositions comprise
about 50 wt %, 30 wt %, 20 wt %, 10 wt %, about 8 wt %, about 7 wt
%, about 5 wt %, about 4 wt %, about 3.5 wt %, about 3 wt %, about
2.5 wt %, about 2 wt %, about 1.5 wt %, about 1 wt %, about 0.5 wt
%, about 0.1 wt %, or about 0.05 wt % of the rifamycin
compound.
[0060] In some embodiments, the composition, including an
ophthalmic composition comprises a vehicle. Examples of suitable
vehicles for the ophthalmic compositions include but are not
limited to purified water and vegetable oils (e.g., olive oil,
castor oil, sesame oil, etc.).
[0061] In some embodiments, the composition, including an
ophthalmic composition further comprises one or more tonicity
adjusting agents. In some embodiments, the tonicity adjusting agent
is saline. Suitable tonicity adjusting agents are known in the art
and include, but are not limited to, sodium chloride, potassium
chloride, buffer salts, dextrin, glycerin, propylene glycol and
mannitol.
[0062] In some embodiments, the composition, including an
ophthalmic composition optionally comprises one or more surfactant.
In some embodiments, non-ionic surfactants aid in dispersing the
active ingredient (e.g., rifamycin compound) in suspensions and
improve solution clarity. Suitable surfactants are known in the art
and include, but are not limited to, sorbitan ether esters of oleic
acid (e.g., polysorbate 80 or Tween 20 and 80), polyoxyethylene
hydrogenated castor oil, cremophor, sodium alkylbenzene sulfonate,
glycerol, lecithin, sucrose ester, polyoxyethylene-alkyl ether,
polyoxyl stearate, polyoxyl 40 stearate, polymers of oxyethylated
octyl phenol (tyloxapol) and polyoxyethylene polyoxypropylene
glycol, or combinations thereof. In some embodiments, the
ophthalmic composition comprises polysorbate 80, polyoxyethylene
hydrogenated castor oil, lecithin or combinations thereof. In some
embodiments, the amount of surfactant in the composition is about
0.1 to about 50 wt %, about 0.5 to about 40 wt %, about 0.1 to
about 30 wt %, about 1 to about 20 wt %, about 2 to about 10 wt %.
In some embodiments, the ophthalmic 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 surfactant. In some embodiments, the
ophthalmic composition comprises about 0.1 wt %-10 wt % of a
surfactant selected from polysorbate 80, tween 80, tween 20,
polyoxyethylene hydrogenated castor oil, and lecithin, or
combinations thereof.
[0063] In some embodiments the compositions, including ophthalmic
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 ophthalmic 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 ophthalmic composition comprises about 0.01 wt
%-10 wt % of anti-oxidant or stabilizer.
[0064] In some embodiments the compositions, including ophthalmic
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
ophthalmic 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 ophthalmic composition
comprises about 0.01 wt %-10 wt % of lubricant.
[0065] In some embodiments the compositions, including ophthalmic
compositions may optionally comprise a deturgescent agent. Examples
of suitable deturgescent agents include, but are not limited to,
low or high molecular weight polysaccharide, such as dextran,
dextran sulfate, polyvinyl pyrrolidone, polyethylene glycol,
polyvinyl acetate, hydroxypropylmethyl cellulose, carboxymethyl
cellulose, carboxypropylmethyl cellulose, dextrose, sucrose, other
sugars, and combinations thereof. Any suitable molecular weight
dextran or mixture thereof may be used, including dextran 40,
dextran 70, and/or dextran 500. In some embodiments, the ophthalmic
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
deturgescent agent. In some embodiments, the ophthalmic composition
comprises about 0.01 wt %-10 wt % of deturgescent agent.
[0066] In some embodiments the compositions, including ophthalmic
compositions may further comprise one or more viscosity imparting
agents. In some embodiments, viscosity imparting agents increase
the viscosity of ophthalmic solution and suspension. In some
embodiments, viscosity imparting agents increase ocular contact
time, thereby decreasing the drainage rate. In some embodiments,
viscosity imparting agents increase mucoadhesion, ocular
bioavailability and/or impart a lubricating effect. Examples of
suitable viscosity imparting agents include, but are not limited
to, carboxyvinyl polymer (e.g., Carbopol 934P or 974P), cellulosic
polymers (e.g., carboxymethyl cellulose, hydroxypropylmethyl
cellulose, hydroxyethyl cellulose or the like), polysaccharides
(e.g., xanthan gum), polyvinyl pyrrolidone, polyvinyl alcohol, and
combinations thereof. In some embodiments, the ophthalmic
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 viscosity
imparting agent. In some embodiments, the ophthalmic composition
comprises about 0.01 wt %-10 wt % of viscosity imparting agent.
[0067] In some embodiments, the compositions, including ophthalmic
compositions may include one or more phospholipid compounds.
Suitable phospholipids are known in the art and include, but are
not limited to, small alkyl chain phospholipids,
phosphatidylcholine, egg phosphatidylcholine, soybean
phosphatidylcholine, dipalmitoylphosphatidylcholine, soy
phosphatidylglycerol, egg phosphatidylglycerol,
distearoylphosphatidylglycerol, dimyristoylphosphatidylcholine,
distearoylphosphatidylcholine, dilaurylphosphatidylcholine,
1-myristoyl-2-palmitoylphosphatidylcholine,
1-paimitoyl-2-myristoylphosphatidylcholine,
1-palmitoyl-2-stearoylphosphatidylcholine,
1-stearoyl-2-palmitoylphosphatidylcholine,
dioleoylphosphatidylcholine,
1-palmitoyl-2-oleoylphosphatidylcholine,
1-oleoyl-2-palmitylphosphatidylcholine,
dioleoylphosphatidylethanolamine, dilauroylphosphatidylglycerol,
phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol,
phosphatidylglycerol, diphosphatidylglycerol,
dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol,
distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol,
phosphatidic acid, dimyristoylphosphatidic acid,
dipaimitoylphosphatidic acid, dimyristoylphosphatidylethanolamine,
dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylserine,
dipalmitoylphosphatidylserine, brain phosphatidylserine,
sphingomyelin, sphingolipids, brain sphingomyelin,
dipalmitoylsphingomyelin, distearoylsphingomyelin,
galactocerebroside, gangliosides, cerebrosides,
phosphatidylglycerol, phosphatidic acid, lysolecithin,
lysophosphatidylethanolamine, cephalin, cardiolipin,
dicetylphosphate, distearoyl-phosphatidylethanolamine or
combinations thereof. The phospholipid can also be a derivative or
analogue of any of the above phospholipids. In some embodiments,
the ophthalmic 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 phospholipid compound. In some embodiments, the ophthalmic
composition comprises about 0.01 wt %-10 wt % % of the phospholipid
compound.
[0068] In some embodiments, the composition, including ophthalmic
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 ophthalmic 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
ophthalmic composition comprises about 0.01 wt %-10 wt % % of the
preservative.
[0069] In some embodiments, the composition, including ophthalmic
compositions may optionally include one or more buffering agents to
maintain the pH of the composition at a range generally acceptable
for eye drop 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 ophthalmically acceptable
range.
[0070] The composition, including ophthalmic compositions may
additionally include suitable diluents known in the art. In some
embodiments, the diluent is an isotonic eye treatment 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.
[0071] The components of the composition, including ophthalmic
compositions described above, if present, can be incorporated in
the composition at a concentration in the range of about 0.001 wt
%, about 0.01 wt %, about 0.02 wt %, about 0.05 wt %, about 0.1 wt
%, about 0.5 wt %, about 1.0 wt %, about 2 wt %, about 5 wt %,
about 10.0 wt %, about 15.0 wt %, about 20.0 wt %, about 30.0 wt %,
about 40.0 wt %, about 50.0 wt %, about 60.0 wt %, about 70.0 wt %,
about 90.0 wt %, and ranges between any two of these values or less
than any one of these values.
[0072] The composition, including ophthalmic composition can be
manufactured by methods known in the art. For example, the active
ingredient i.e., the rifamycin compound is dissolved in purified
water or saline and a surfactant is added to it and mixed. Further
additives such as an isotonic agent such as sodium chloride and
glycerin, buffer such as sodium phosphate or sodium borate, a
pH-adjusting agent such as dilute hydrochloric acid and sodium
hydroxide, preservatives such as potassium sorbate, an
anti-oxidizing agent such as tocophenol, ascorbic acid etc., are
optionally added to the mixture to obtain the ophthalmic
composition.
[0073] The composition, including ophthalmic compositions are
tested for various physicochemical, in vitro, and in vivo
properties. Clarity is measured using visual and fluorescent
microscopic methods. The presence of particulate matter is also
determined to ensure that ophthalmic solutions are free from
foreign particles. Light obscuration or microscopic methods are
used for counting and or measuring the particle size. Isotonicity
and pH of the composition is tested.
[0074] Drug content of the ophthalmic composition is evaluated by
suitable analytical methods such as UV and HPLC. The compositions
are tested also for preservative effectiveness, stability and shelf
life as per standard guidelines. The composition can be further
subjected to sterilization using various sterilization methods
known in the art.
[0075] The compositions of the invention are tested for various
physicochemical, in vitro, and in vivo properties. For example, the
compositions are evaluated for inhibition of gene expression of
neovascularization genes in vitro and protection of retina ganglion
cells using suitable methods known in the art.
[0076] The ophthalmic compositions of the invention have high
efficiency and are expected to exhibit high affinity to mucosa
tissues, including eye ball. Some embodiments described herein
relate to compositions which deliver a therapeutically effective
amount of drug to the systemic circulation via the mucosa. In some
embodiments, the compositions of the invention provide advantages
over other forms of administration routes (e.g. oral, intravitreal
etc.) which include but are not limited to avoiding first pass
metabolism of drug(s), avoiding irritation of the GI mucosa,
avoiding fluctuation in drug levels, predictable and extended
duration of activity, minimizing undesirable side effects,
suitability for drugs with short half-life and narrow therapeutic
index, maintaining steady plasma concentrations of potent drugs,
greater patient compliance due to elimination of multiple doses and
dosage forms (oral and systemic), no requirement for local
anaesthesia, no pain associated with injections, ease of
administration, suitability for self-administration, and ease of
terminating of therapy at any point in time.
[0077] In some embodiments, provided herein is an ophthalmic
composition for use in the manufacture of a medicament for
treatment of an ocular or visual disorder. In some embodiments, the
ocular disease, disorder or condition is selected from age related
macular degeneration (AMD), ocular neovascularization, retinal
ganglion cell injury and brain damage.
[0078] In some embodiments, provided herein are formulations for
treatment of an ocular disease, disorder or condition, comprising
an selected from the group consisting of rifampicin, rifabutin,
rifapentine and rifaximin, and at least one pharmaceutically
acceptable carrier material. In some embodiments, the carrier
material comprises an ocular/ophthalmic carrier. Suitable
ocular/ophthalmic carrier materials are known in the art and
include solution, gel or ointment, and the like. In some
embodiments, the ocular/ophthalmic carrier is sterile aqueous
solution. In some embodiments, the formulation further comprises
one or more of a surfactant, an anti-bacterial agent, a pH
buffering agent, an antioxidant agent, a preservative agent, or a
combination thereof.
[0079] In some embodiments, provided herein is a composition,
including an ophthalmic composition for treating age-related
macular degeneration, said composition comprising an effective
amount of a rifamycin compound selected from the group consisting
of rifampicin, rifabutin, rifapentine and rifaximin.
[0080] In some embodiments, provided herein is a composition,
including an ophthalmic composition for treating retinal
neovascularization, said composition comprising an effective amount
of a rifamycin compound selected from the group consisting of
rifampicin, rifabutin, rifapentine and rifaximin.
[0081] In some embodiments, provided herein is a composition,
including an ophthalmic composition for protecting optic nerve
cells, said composition comprising an effective amount of a
rifamycin compound selected from the group consisting of
rifampicin, rifabutin, rifapentine and rifaximin.
[0082] In some embodiments, provided herein is a composition,
including an ophthalmic composition for inhibiting brain damage,
said composition comprising an effective amount of a rifamycin
compound selected from the group consisting of rifampicin,
rifabutin, rifapentine and rifaximin.
[0083] In another embodiment, provided herein is a composition,
including a stabilized ophthalmic composition comprising rifamycin
compounds wherein the composition is stable for more than three
months, preferably more than six months, more preferably more than
twelve months.
EXAMPLES
Example 1: Eye Drop Formulation of Rifamycin Compounds
[0084] The active ingredient, i.e. rifamipicin, rifabutin,
rifapentine, rifalazil or rifaximin is dissolved in saline or water
and a surfactant such as polysorbate 80, tween 80 or tween 20 is
added and mixed. Further, various additives such as glycerin,
xanthan gum, hydroxypropylmethylcellulose (HPMC), cyclodextrin
derivatives such as hydroxypropyl-.beta.-cyclodextrin, isotonic
agents such as such as sodium chloride, potassium chloride or
sodium bisulfate, preservative such as disodium EDTA or
methylparaben, anti-oxidant such as ascorbic acid are optionally
added and mixed to form a clear solution. The solution is
optionally filtered to remove particulate matter and the pH is
adjusted by adding an acid such as hydrochloric acid or a base such
as sodium chloride to obtain the desired pH.
Example 2
[0085] 16 different formulations were prepared for topical eye drop
application of rifampicin, as disclosed in Tables 1-3. The
formulations of Example 1A and Example 6A were used in the
following studies.
[0086] The following eye drop formulations were prepared at room
temperature (Tables 1 and 2), and Rifampicin was added to the eye
drop formulations to the final concentrations listed:
TABLE-US-00001 TABLE 1 Example Example Example Example Example 1A
2A 3A 4A 5A pH of input buffer (50 mM Boric pH 8.7 pH 8.7
Acid-Borax) pH of input buffer (100 mM pH 8.3 pH 8.3 pH 8.3 Boric
Acid-NaOH) Final concentrations of input 10 mM 10 mM 20 mM 25 mM 25
mM buffers Final pH detected after addition pH 7.64 pH 7.37 pH 8.01
pH 8.30 of Rifampicin NaCl* 150 mM 150 mM 0.9% 0.9% 0.9% Tween 80*
0.5% 0.5% 0.5% 0.5% 0.5% EDTA* 0.1% 0.1% 0.1% 0.1% 0.1%
Benzalkonium chloride* 0.01% 0.01% 0.01% 0.01% 0.01% Rifampicin*
0.25% 0.5% 0.5% 1% 0.5% *Final concentrations
TABLE-US-00002 TABLE 2 Exam- Exam- Exam- Exam- Exam- ple 6A ple 7A
ple 8A ple 9A ple 10A pH of input buffer pH 8.7 pH 8.7 pH 8.5 pH
8.5 pH 8.3 (50 mM Boric Acid-Borax) Final concentrations 18 mM 14
mM 25 mM 18 mM 25 mM of input buffers Final pH detected pH 8.01 pH
8.02 pH 7.81 pH 7.69 pH 7.47 after addition of Rifampicin NaCl*
0.9% 0.9% 0.9% 0.9% 0.9% Tween 80* 0.5% 0.5% 0.5% 0.5% 0.5% EDTA*
0.1% 0.1% 0.1% 0.1% 0.1% Benzalkonium chloride* 0.01% 0.01% 0.01%
0.01% 0.01% Rifampicin* 0.5% 0.5% 0.5% 0.5% 0.5% *Final
concentrations*
[0087] Rifampicin was completely dissolved at room temperature in
the eye drop formulations of Example 1A and Examples 5A-8A listed
in Tables 1 and 2, and rifampicin was not precipitated in these
formulations for weeks. Rifampicin solutions were stored at room
temperature or in a refrigerator.
[0088] Input buffers that were added in Example 1A-10A were 50 mM
Bric acid-Borax or 100 mM Boric acid-NaOH, and pH values of these
input buffers were listed in Tables 1 and 2. Liquid formulations
were prepared by mixing components listed in the tables, and powder
of rifampicin was added and mixed in the formulations for 2-3 hr.
After mixing rifampicin in the formulations, values of pH were
measured, and these pH values were listed in the tables.
TABLE-US-00003 TABLE 3 Example Example Example Example Example
Example 11A 12A 13A 14A 15A 16A pH of input buffers pH 8.7 pH 8.7
(50 mM Boric Acid- Borax) pH of input buffer pH 8.3 pH 8.3 pH 8.3
pH 8.3 (100 mM Boric Acid- NaOH) Final concentrations 10 mM 10 mM
10 mM 10 mM 18 mM 18 mM of input buffers Final pH after addition pH
8.03 pH 8.10 pH 4.07 pH 3.32 pH 5.23 pH 3.67 of all components,
including rifampicin NaCl* 150 mM 150 mM 150 mM 150 mM 0.90% 0.90%
Tween 80* 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% EDTA* 0.1% 0.1% 0.1% 0.1%
0.1% 0.1% Benzalkonium 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%
chloride* Rifampicin* 2.5 mg/ml 2.5 mg/ml 2.5 mg/ml 2.5 mg/ml 5
mg/ml 5 mg/ml Sodium formaldehyde 0.04 mg/ml 0.21 mg/ml sulfoxylete
dyhydrate* L-ascorbic acid* 0.25% 1% 0.25% 1% *Final
concentrations
[0089] Buffers, NaCl, Tween80, and EDTA that are listed in Table 3
were mixed in a beaker at room temperature, and rifampicin was
added and completely dissolved in these liquid formulations at room
temperature. Stock solutions of sodium formaldehyde sulfoxylete
dyhydrate or L-ascorbic acid were added in the formulations, and
then values of pH in the formulations were measured (Examples
11A-16A). The formulations of Example 11A and 12A were stable at
room temperature for more than several days, and they did not
produce any precipitate. The formulations of Example 13A-16A were
stable in a refrigerator for more than several days, and they did
not produce any precipitate.
Example 3
[0090] Rifampicin was delivered to retina by topical eye drop
application. 0.25% rifampicin eye drop formulation was used for the
studies. It showed good delivery efficiency, and retina tissue got
micro gram concentrations of rifampicin per g of tissue by the eye
drop application.
[0091] Four male Sprague-Dawley rats (250-300 g) were used to
determine retina exposure levels of rifampicin following
applications of eye drops. Two rats received 3 drops of an eye drop
formulation (0.25% Rifampicin) which is presented as Example 1A
listed in Table 1 in each eye under isoflurane sedation. The
remaining two rats received the same applications, but 10 drops, to
each eye under isoflurane sedation. A single drop contained 5 micro
L of the formulation, and applications of each drop had 30 min
interval. After the eye drop application, retinas were extracted
under a dissection microscope. In addition, "Non-treatment"
negative control was taken, and retina was extracted from two rats
without any treatment. Retinas were placed in a 1.5 ml
microcentrifuge tubes (1 retina/tube), and they were extensively
washed by DPBS. After the washing procedure, retina tissue in a
microcentrifuge tube was frozen in dry ice, and it was stored for
quantification by LC/MS analysis. Table 4 shows quantifications of
rifampicin which was extracted from the retina tissues. Rifampicin
was delivered to retina by the eye drop formulation (0.25%
rifampicin) with dose dependent manner.
TABLE-US-00004 TABLE 4 Amounts of Rifampicin which was delivered to
retina by topical eye drop application (0.25% Rifampicin)
Non-Treatment 3 drops 10 drops Rifampicin extracted from retinas
BDL 1,288* 2,939* (average of n = 3, ng/g tissue) SE N/A 394 50.54
BDL: Blow Detection Limit *Evaluated at p value of 0.014
[0092] Efficacy of retinal delivery of AMD101 by eye drop
formulation >X100 of Dexamethasone retina delivery.
TABLE-US-00005 Compound (Brand name) MOA for indication or Drug
amount Drug amount usage dosed detected in retina Ref. Betoptic
0.5% (MW 307) 0.5% ~300 ng/g retina Osborne et al betal receptor
blocker for 4 drops tissue (1999) Glaucoma (120-200 microL,
(Rabbit) 600-1,000 micro g) Betoptic 0.5% (MW 307) 0.5% ~480 ng/g
retina Osborne et al betal receptor blocker for 8 drops tissue
(1999) Glaucoma (240-400 microL, (Rabbit) 1200-2000 micro g)
Dexamethasone (MW 392) 0.5% ~33 ng/g retina tissue Sigurdsson et al
Glucocorticoid for 50 microL, 250 (Rabbit) (2007) inflammation
micro g AMD101 0.25%, 3 drops ~1,288 ng/g retina This study (15
microL, tissue 37.5 micro g) (Rat) AMD101 0.25%, 10 ~2,939 ng/g
retina This study drops (50 microL, tissue 125 (Rat) micro g)
Example 4
[0093] This example provides experimental procedures and results of
PK studies that showed rifampicin was delivered to retina by
subcutaneous (SC) injection. Amounts detected by SC and by topical
eye drop were equivalent.
[0094] Six male Sprague-Dawley rats (250-300 g) were used to
determine retina exposure levels of rifampicin following
subcutaneous injection (20 mg/Kg). A formulation which is presented
as Example 6A listed in Table 2 was used to dose Rifampicin by the
SC injection in this study. At time points of 1 hr, 3 hr, and 7 hr
after the SC injection, retina tissues were extracted from the rats
under a dissection microscope. In addition, "Non-treatment"
negative control was taken, and retina was extracted from two rats
without any treatment. Retinas were placed in a 1.5 ml
microcentrifuge tubes (1 retina/tube), and they were extensively
washed by DPBS. After the washing procedure, retina tissue in a
microcentrifuge tube was frozen in dry ice, and it was stored for
quantification by LC/MS analysis. Table 5 shows quantifications of
rifampicin which was extracted from the retina tissues. Amounts
detected in retina by the SC injection were equivalent to those
delivered by the eye drop application (See Table 3).
TABLE-US-00006 TABLE 5 Amounts of Rifampicin which was delivered to
retina by subcutaneous injection (20 mg/Kg) Non-treatment 1 hr 3 hr
7 hr Rifampicin extracted from BDL 2,655 3,864 2,516 retinas
(average of n = 4, ng/g tissue) SE N/A 348 402 447 BDL: Blow
Detection Limit
Example 5
[0095] Experimental procedures and results of PK studies using
0.25% rifampicin eye drop formulation were provided.
[0096] Six male Sprague-Dawley rats (250-300 g) were used to
determine retina exposure levels of rifampicin following topical
eye drop application. 15 microL of an eye drop formulation which is
presented as Example 1A listed in Table 1 was used to dose the
compound to a single eye of a rat. 15 micro L of the formulation
contained 37.5 micro gram of rifampicin. At time points of 1 hr, 3
hr, and 7 hr after the eye drop application, retina tissues were
extracted from the rats under a dissection microscope. In addition,
"Non-treatment" negative control was taken, and retina was
extracted from a single rat without any treatment. Retinas were
placed in a 1.5 ml microcentrifuge tubes (1 retina/tube), and they
were extensively washed by DPBS. After the washing procedure,
retina tissue in a microcentrifuge tube was frozen in dry ice, and
it was stored for quantification by LC/MS analysis. Table 6 shows
quantifications of rifampicin which was extracted from the retina
tissues. Rifampicin was delivered to retina by the eye drop
formulation (0.25% rifampicin).
TABLE-US-00007 TABLE 6 Amounts of Rifampicin which was delivered to
retina by topical eye drop application (0.25% Rifampicin)
Non-treatment 1 hr 3 hr 7 hr Rifampicin extracted from BDL 1,576
1,151 104 retinas (average of n = 4, ng/g tissue) SE N/A 868 538 16
BDL: Below Detection Limit Tmax: ~1 hr, T1/2: ~3-4 hr
Example 6
[0097] Experimental procedures and results of dose-response studies
using 0.25% and 0.5% rifampicin eye drop formulation were
provided.
[0098] Four male Sprague-Dawley rats (250-300 g) were used to
determine retina exposure levels of rifampicin following topical
eye drop application. 15 microL of eye drop formulations which are
presented as Example 1A and 6A listed in Table 1 and Table 2,
respectively, were used to dose the compound to a single eye of a
rat. 15 micro L of the formulations contained 37.5 and 75 micro
gram of rifampicin, respectively. In 1 hr after the eye drop
application, retina tissues were extracted from the rats under a
dissection microscope. In addition, "Non-treatment" negative
control was taken, and retina was extracted from a single rat
without any treatment. Retinas were placed in a 1.5 ml
microcentrifuge tubes (1 retina/tube), and they were extensively
washed by DPBS. After the washing procedure, retina tissue in a
microcentrifuge tube was frozen in dry ice, and it was stored for
quantification by LC/MS analysis. Table 7 shows quantifications of
rifampicin which was extracted from the retina tissues. Rifampicin
was delivered to retina by both eye drop formulations with
dose-response manner (0.25% and 0.5% rifampicin).
TABLE-US-00008 TABLE 7 Amounts of Rifampicin which was delivered to
retina by topical eye drop application (0.25% and 0.5% Rifampicin)
0.25% 0.5% Non- Rifampicin Rifampicin treatment 15 microL 15 microL
Rifampicin extracted from BDL 1,576 6,068 retinas (average of n =
4, ng/g tissue) SE N/A 868 2,634 BDL: Below Detection Limit
Example 7
[0099] Experimental procedures of pre-clinical efficacy studies in
Oxygen-Induced Retinopathy rat model using 0.25% rifampicin eye
drop formulation were provided.
[0100] The Oxygen-Induced Retinopathy rat model was produced
according to the protocol of Yanni et al (2010) and Dorfmann et al
(2008). Sprague-Dawley rat pups (and their nursing mothers) were
exposed to a cycling oxygen environment (80% and 21%, .about.one
day each) for 15 days starting from the day of birth (Day 0). On
Day 15 (P15), the animals were moved to room air. 6 pups, 7 pups,
and 6 pups were assigned to dosing groups of vehicle only control,
AMD101 (Rifampicin) eye drop formulation, and SC injection,
respectively. An eye drop formulation which is presented as Example
1A listed in Table 1 or vehicle only was daily administered to eyes
of pups for 5 days between P15 and P19 in the morning, about noon,
and in the evening. A formulation which is presented as Example 6A
listed in Table 2 was used to dose AMD101 (Rifampicin) to pups by
the SC injection at 20 mg/Kg once daily from P15 to P19. At P20,
all animals were euthanized, the retinas were visualized in
histology sections. In those histology sections, neovascularization
were quantified by counting capillaries in retina tissue in 3 eye
balls (the dosing groups of AMD101 topical application, AMD101 SC
injection, and non-induction of retinopathy) or 5 eye balls (the
dosing group of vehicle only control). These eye balls were
selected from different animals in the dosing groups.
Representative images of the histology sections are presented (see
FIGS. 1A-H). The retina treated with the vehicle only control
showed increased numbers of small new capillaries on the retinal
surface (see FIGS. 1A and 1B). The retina treated with the AMD101
topical eye drop formulation showed small foci of new capillaries
on the retinal surface but fewer than in the control group (see
FIGS. 1C and 1D). The retina treated with the AMD101 SC injection
showed small foci of new capillaries on the retinal surface but
fewer than in the control group (see FIGS. 1E and 1F). The retina
for which retinopathy was not induced showed a few small vessel
cross sections but did not show any new capillaries (see FIGS. 1G
and 1H). Table 8 shows quantifications of detected capillaries in
the histology sections.
TABLE-US-00009 TABLE 8 Neovascularization in retina in
Oxygen-Induced Retinopathy rat model was quantified by detecting
capillaries in histology sections Non-induction of Vehicle only
0.25% AMD101 0.5% AMD101 retinopathy control topical eye-drop SC
injection (n = 3) (n = 5) (n = 3) (n = 3) Average numbers of 3.33
16.3 7.78 9.28 capillaries in high power field per eye SE
1.109721353 1.338468851 1.348295678 0.895463216 Vehicle only vs
0.25% AMD101 eye-drop: P-value = 0.0058 Vehicle only vs 0.5% AMD101
SC: P-value = 0.0102
Example 8
Delivery of Ophthalmic Formulation of Rifamycin Compounds Via a
Device Such as a Contact Lens.
[0101] The ophthalmic formulation comprising the active ingredient,
i.e. rifamipicin, rifabutin, rifapentine, rifalazil or rifaximin,
and a pharmaceutically acceptable carrier and optionally additives
as disclosed herein are incorporated in to ocular solutions used to
soak or wash the contact lenses. A hydrophilic gel based contact
lens is optionally dried at ambient temperature and then dipped,
washed or immersed in a solution of a soaking agent or swelling
agent containing an effective amount of the ophthalmic
formulation.
[0102] It will be apparent to those skilled in the art that various
modifications and variations can be made in the methods and
compositions of the present invention without departing from the
spirit or scope of the invention. Thus, it is intended that the
present invention cover the modifications and variations of this
invention provided they come within the scope of the appended
claims and their equivalents.
* * * * *