U.S. patent application number 17/210648 was filed with the patent office on 2021-10-07 for methods and compositions for treating meibomian gland dysfunction.
The applicant listed for this patent is Hovione Scientia Limited. Invention is credited to George Nathaniel Magrath, III, Mohammad Salman, Courtney Rouse Smith, Carla Maria dos Santos Vozone.
Application Number | 20210308154 17/210648 |
Document ID | / |
Family ID | 1000005648542 |
Filed Date | 2021-10-07 |
United States Patent
Application |
20210308154 |
Kind Code |
A1 |
Vozone; Carla Maria dos Santos ;
et al. |
October 7, 2021 |
Methods and Compositions for Treating Meibomian Gland
Dysfunction
Abstract
The invention provides methods, compositions, and kits
containing a minocycline topical suspension, for treating meibomian
gland dysfunction and related disorders.
Inventors: |
Vozone; Carla Maria dos Santos;
(East Windsor, NJ) ; Salman; Mohammad; (East
Windsor, NJ) ; Magrath, III; George Nathaniel; (East
Windsor, NJ) ; Smith; Courtney Rouse; (Gainesville,
GA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hovione Scientia Limited |
Cork |
|
IE |
|
|
Family ID: |
1000005648542 |
Appl. No.: |
17/210648 |
Filed: |
March 24, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62993827 |
Mar 24, 2020 |
|
|
|
63106657 |
Oct 28, 2020 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/06 20130101; A61K
9/0048 20130101; A61P 27/02 20180101; A61K 47/06 20130101; A61K
47/32 20130101; A61K 31/65 20130101 |
International
Class: |
A61K 31/65 20060101
A61K031/65; A61K 9/00 20060101 A61K009/00; A61K 9/06 20060101
A61K009/06; A61K 47/06 20060101 A61K047/06; A61K 47/32 20060101
A61K047/32; A61P 27/02 20060101 A61P027/02 |
Claims
1. A method of treating meibomian gland dysfunction, comprising
topically administering to the eyelid margin of a patient in need
thereof once or twice per day a dose of a minocycline topical
suspension to treat the meibomian gland dysfunction, wherein the
dose provides from about 0.1 mg to about 1.4 mg of minocycline, and
the minocycline topical suspension comprises: a) minocycline in a
suspended form within the topical suspension; b) a liquid medium
that dissolves less than 5% (w/w) of the minocycline at room
temperature after two hours, wherein the liquid medium contains
mineral oil; and c) a polymeric hydrocarbon gelling agent; wherein
particles of minocycline in the topical suspension have a D90
particle size less than 8 microns, and the topical suspension
comprises from about 0.1% (w/w) to about 2% (w/w) minocycline.
2. The method of claim 1, wherein the dose of minocycline topical
suspension provides from about 0.1 mg to about 0.2 mg of
minocycline.
3. The method of claim 1, wherein the dose of minocycline topical
suspension provides about 0.15 mg of minocycline.
4. (canceled)
5. The method of claim 1, wherein the dose of minocycline topical
suspension provides from about 0.45 mg to about 0.55 mg of
minocycline.
6. (canceled)
7. The method of claim 1, wherein the topical suspension comprises
from about 0.3% (w/w) to about 1% (w/w) minocycline.
8. The method of claim 1, wherein the topical suspension comprises
from about 0.2% (w/w) to about 0.4% (w/w) minocycline.
9. The method of claim 1, wherein the topical suspension comprises
about 0.3% (w/w) minocycline.
10. The method of claim 1, wherein the topical suspension comprises
0.3% (w/w) minocycline.
11. (canceled)
12. The method of claim 1, wherein the topical suspension comprises
about 1% (w/w) minocycline.
13. The method of claim 1, wherein an amount of from about 35 .mu.L
to about 65 .mu.L of the minocycline topical suspension is
topically administered to the eyelid margin of the patient.
14-19. (canceled)
20. The method of claim 1, wherein the dose of minocycline topical
suspension is administered twice per day.
21. The method of claim 10, wherein the dose of minocycline topical
suspension is administered twice per day, wherein the first dose of
minocycline topical suspension is administered in the morning and
the second dose of minocycline topical suspension is administered
in the evening.
22-31. (canceled)
32. The method of claim 1, wherein the patient has an inflamed
meibomian gland.
33-38. (canceled)
39. A method of treating meibomian gland dysfunction in a patient
having a tear film matrix metalloproteinase-9 (MMP-9) concentration
greater than about 40 ng/mL, comprising topically administering to
the eye of said patient in need thereof a therapeutically effective
amount of minocycline to treat the meibomian gland dysfunction.
40. The method of claim 1, wherein the method produces a reduction
in vascular engorgement score of at least 1.
41. The method of claim 1, wherein after a duration of at least
three months where the patient has received a dose of minocycline
topical suspension each day, the patient has a vascular engorgement
score of no greater than 1.5.
42. (canceled)
43. The method of claim 1, wherein the method produces a reduction
in Eye Discomfort Visual Analog Score of at least 20 percent.
44. The method of claim 1, wherein after a duration of at least
three months where the patient has received a dose of minocycline
topical suspension each day, the patient has an Eye Discomfort
Visual Analog Score of no greater than 50.
45-56. (canceled)
57. The method of claim 1, wherein the polymeric hydrocarbon
gelling agent comprises an ethylene-propylene-styrene copolymer
having a weight-average molecular weight in the range of from about
150,000 g/mol to about 250,000 g/mol.
58-61. (canceled)
62. The method of claim 1, wherein the polymeric hydrocarbon
gelling agent comprises a butylene-ethylene-styrene copolymer
having a weight-average molecular weight in the range of from about
50,000 g/mol to about 150,000 g/mol.
63-69. (canceled)
70. The method of claim 1, wherein the polymeric hydrocarbon
gelling agent comprises at least about 80% (w/w) mineral oil.
71. (canceled)
72. The method of claim 1, wherein the minocycline topical
suspension comprises from about 60% (w/w) to about 80% (w/w) of the
polymeric hydrocarbon gelling agent.
73. (canceled)
74. (canceled)
75. (canceled)
76. The method of claim 72, wherein the minocycline topical
suspension comprises from about 20% (w/w) to about 40% (w/w) of the
liquid medium that dissolves less than 5% (w/w) of the minocycline
at room temperature after two hours, wherein the liquid medium
contains mineral oil.
77-80. (canceled)
81. The method of claim 76, wherein the liquid medium that
dissolves less than 5% (w/w) of the minocycline at room temperature
after two hours comprises at least 99% (w/w) mineral oil.
82-90. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of and priority to U.S.
Provisional Patent Application Ser. No. 62/993,827, filed Mar. 24,
2020, and U.S. Provisional Patent Application Ser. No. 63/106,657,
filed Oct. 28, 2020; the contents of each of which are hereby
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The invention provides methods, compositions, and kits
containing a minocycline topical suspension, for treating meibomian
gland dysfunction and related disorders.
BACKGROUND
[0003] Functioning meibomian glands play a critical role in
maintaining optimal ocular surface conditions. One common disorder
observed in patients by eye care professionals, including
ophthalmologists and optometrists, is meibomian gland dysfunction.
Meibomian gland dysfunction typically features meibomian glands
that either hyposecrete or are obstructed. Meibomian gland
dysfunction has historically been treated on a chronic basis
through either mechanical therapy (e.g., eyelid hygiene, eyelid
massage, or eyelid compression/expression) alone or in combination
with topical or systemic antibiotics or topical immunosuppressants
such as steroids or cyclosporine. The need exists for meibomian
gland dysfunction therapies that are more effective and/or have
reduced adverse side effects.
[0004] Minocycline crystal forms, formulations of minocycline, and
medical uses of the foregoing have been described in, for example,
U.S. Pat. Nos. 8,258,327; 9,592,246; and 10,213,443. Oral
administration of minocycline to human patients has been described
in the American Journal of Ophthalmology (December 2012). However,
oral administration of minocycline raises the risk of adverse side
effects due to systemic exposure to minocycline.
[0005] The present invention addresses the need for improved
therapies for meibomian gland dysfunction and provides other
related advantages.
SUMMARY
[0006] The invention provides methods, compositions, and kits
containing a minocycline topical suspension, for treating meibomian
gland dysfunction and related disorders. The minocycline topical
suspension is preferably topically administered to the eyelid
margin of the patient's eye. Since administering too large a dose
of minocycline topical suspension can result in the undesired side
effects (e.g., the patient experiencing eye irritation, the patient
experiencing a sensation of grit in the eye due to minocycline
topical suspension migrating onto the surface of the eye, blurry
vision due to minocycline topical suspension migrating onto the
surface of the eye, and/or the patient temporarily experiencing a
yellow hue to their vision in the effected eye due to the presence
of minocycline on the surface of the eye), it is important to
administer a dose of minocycline that avoids the foregoing side
effects and use a formulation that minimizes the foregoing side
effects, while also providing sufficient minocycline to the
appropriate tissue in order to achieve a therapeutic effect against
meibomian gland dysfunction. The method described herein comprising
topically administering minocycline topical suspension to the
eyelid margin of a patient treats meibomian gland dysfunction while
minimizing the occurrence of local and systemic adverse side
effects. Exemplary aspects and embodiments of the invention are
described below.
[0007] One aspect of the invention provides a method of treating
meibomian gland dysfunction, wherein the method comprises topically
administering to the eyelid margin of a patient in need thereof
once or twice per day a dose of a minocycline topical suspension to
treat the meibomian gland dysfunction, wherein the dose provides
from about 0.1 mg to about 1.4 mg of minocycline, and the
minocycline topical suspension comprises: [0008] a) minocycline in
a suspended form within the topical suspension; [0009] b) a liquid
medium that dissolves less than 5% (w/w) of the minocycline at room
temperature after two hours, wherein the liquid medium contains
mineral oil; and [0010] c) a polymeric hydrocarbon gelling agent;
wherein particles of minocycline in the topical suspension have a
D90 particle size less than 8 microns, and the topical suspension
comprises from about 0.1% (w/w) to about 2% (w/w) minocycline.
[0011] The method may be further characterized according to, for
example, the dose of minocycline topical suspension, the frequency
of administration of minocycline topical suspension, features of
the minocycline topical suspension, patients to receive treatment,
and results produced by the method. In certain embodiments, the
dose of minocycline topical suspension provides about 0.5 mg of
minocycline. In certain embodiments, the dose of minocycline
topical suspension is administered twice per day. In certain
embodiments, the dose of minocycline topical suspension is
administered once per day. In certain embodiments, the patient has
an inflamed meibomian gland. In certain embodiments, the patient
has resultant or associated dry eye disease. In certain
embodiments, the method reduces the patient's vascular engorgement
score of at least 1. In certain embodiments, after a duration of at
least three months where the patient has received a dose of
minocycline topical suspension each day, the patient has a vascular
engorgement score of no greater than 1. These and other features
are described in more detail herein below.
[0012] Also provided are methods for treating blepharitis,
meibomitis, and ocular rosacea. The method comprises topically
administering to the eye of a patient in need thereof a
therapeutically effective amount of a minocycline topical
suspension to treat the blepharitis, meibomitis, or ocular
rosacea.
[0013] Also provided is a minocycline topical suspension for use in
treating medical conditions described herein. Such use may employ
embodiments described herein for the therapeutic methods, such as
the dose of minocycline topical suspension, the frequency of
administration of minocycline topical suspension, patients to
receive treatment, and results produced by the use.
BRIEF DESCRIPTION OF FIGURES
[0014] FIG. 1 depicts an X-ray powder diffraction spectrum of
crystalline form I of minocycline.
[0015] FIG. 2 depicts an infrared spectrum of crystalline form I of
minocycline.
[0016] FIG. 3 depicts an X-ray powder diffraction spectrum of
crystalline form II of minocycline.
[0017] FIG. 4 depicts an infrared spectrum of crystalline form II
of minocycline.
[0018] FIG. 5 depicts an X-ray powder diffraction spectrum of
crystalline form III of minocycline.
[0019] FIG. 6 depicts an infrared spectrum of crystalline form III
of minocycline.
[0020] FIG. 7 depicts a diagram illustrating regions of a patient's
eye assessed using Fluorescein Corneal Staining to determine
corneal damage.
[0021] FIG. 8 is a line graph depicting VAS discomfort (mean change
from baseline) results from the clinical study in Example 1.
[0022] FIG. 9 is a line graph depicting VAS eye dryness (mean
change from baseline) results from the clinical study in Example
1.
[0023] FIG. 10 is a line graph depicting VAS foreign body sensation
(mean change from baseline) results from the clinical study in
Example 1.
[0024] FIG. 11 is a line graph depicting vascular engorgement (mean
change from baseline) results from the clinical study in Example
1.
[0025] FIG. 12 is a line graph depicting character of secretion
(mean change from baseline) results from the clinical study in
Example 1.
[0026] FIG. 13 is a line graph depicting expressibility of the
glands (mean change from baseline) results from the clinical study
in Example 1.
[0027] FIG. 14 is a line graph depicting total MG outcome score
(mean change from baseline) results from the clinical study in
Example 1.
[0028] FIG. 15 is a line graph depicting change in total MGD score
in Dry Eye Disease (DED)-negative subgroup results from the
clinical study in Example 1.
[0029] FIG. 16 is a line graph depicting change in total MGD score
in DED-positive subgroup results from the clinical study in Example
1.
[0030] FIG. 17 is a line graph depicting results of the shear rate
sweep experiment conducted on 0.3% Test Article and 1% Test
Article, as further described in Example 7.
[0031] FIG. 18 is a line graph depicting results of the shear rate
sweep experiment conducted on 0.3% Test Article and 1% Test
Article, as further described in Example 7.
[0032] FIG. 19 is a line graph depicting results of the shear
stress sweep experiment conducted on 0.3% Test Article and 1% Test
Article, as further described in Example 7.
[0033] FIG. 20 is a line graph depicting results of the oscillation
stress sweep experiment conducted on 0.3% Test Article and 1% Test
Article, as further described in Example 7.
[0034] FIG. 21 is a line graph depicting results of the oscillation
stress sweep experiment conducted on 0.3% Test Article and 1% Test
Article, as further described in Example 7.
DETAILED DESCRIPTION OF THE INVENTION
[0035] The invention provides methods, compositions, and kits
containing a minocycline topical suspension, for treating meibomian
gland dysfunction and related disorders. The minocycline topical
suspension is preferably topically administered to the eyelid
margin of the patient's eye. Since administering too large a dose
of minocycline topical suspension can result in the undesired side
effects (e.g., the patient experiencing eye irritation, the patient
experiencing a sensation of grit in the eye due to minocycline
topical suspension migrating onto the surface of the eye, blurry
vision due to minocycline topical suspension migrating onto the
surface of the eye, and/or the patient temporarily experiencing a
yellow hue to their vision in the effected eye due to the presence
of minocycline on the surface of the eye), it is important to
administer a dose of minocycline that avoids the foregoing side
effects and use a formulation that minimizes the foregoing side
effects, while also providing sufficient minocycline to the
appropriate tissue in order to achieve a therapeutic effect against
meibomian gland dysfunction. The method described herein comprising
topically administering minocycline topical suspension to the
eyelid margin of a patient treats meibomian gland dysfunction while
minimizing the occurrence of local and systemic adverse side
effects. Various aspects of the invention are set forth below in
sections; however, aspects of the invention described in one
particular section are not to be limited to any particular
section.
Definitions
[0036] To facilitate an understanding of the present invention, a
number of terms and phrases are defined below.
[0037] As used herein, the term "minocycline" refers to a compound
having the following chemical structure and tautomers thereof:
##STR00001##
[0038] The terms "a," "an" and "the" as used herein mean "one or
more" and include the plural unless the context is
inappropriate.
[0039] As used herein, the term "patient" refers to organisms to be
treated by the methods of the present invention. Such organisms
preferably include, but are not limited to, mammals (e.g., murines,
simians, equines, bovines, porcines, canines, felines, and the
like), and most preferably includes humans.
[0040] As used herein, the term "effective amount" refers to the
amount of a compound sufficient to effect beneficial or desired
results. Unless specified otherwise, an effective amount can be
administered in one or more administrations, applications or
dosages and is not intended to be limited to a particular
formulation or administration route. As used herein, the term
"treating" includes any effect, e.g., lessening, reducing,
modulating, ameliorating or eliminating, that results in the
improvement of the condition, disease, disorder, and the like, or
ameliorating a symptom thereof.
[0041] As used herein, the term "pharmaceutical composition" refers
to the combination of an active agent with a carrier, inert or
active, making the composition especially suitable for therapeutic
use in vivo or ex vivo.
[0042] As used herein, the term "pharmaceutically acceptable
carrier" refers to any of the standard pharmaceutical carriers,
such as a phosphate buffered saline solution, water, emulsions
(e.g., such as an oil/water or water/oil emulsions), and various
types of wetting agents. The compositions also can include
stabilizers and preservatives. For examples of carriers,
stabilizers and adjuvants, see Martin in Remington's Pharmaceutical
Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975].
[0043] As used herein, the term "pharmaceutically acceptable salt"
refers to any pharmaceutically acceptable salt (e.g., acid or base)
of a compound of the present invention which, upon administration
to a subject, is capable of providing a compound of this invention.
As is known to those of skill in the art, "salts" of the compounds
of the present invention may be derived from inorganic or organic
acids and bases. Examples of acids include, but are not limited to,
hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,
maleic, phosphoric, glycolic, lactic, salicylic, succinic,
toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,
ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,
benzenesulfonic acid, and the like. Other acids, such as oxalic,
while not in themselves pharmaceutically acceptable, may be
employed in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their pharmaceutically
acceptable acid addition salts.
[0044] Examples of bases include, but are not limited to, alkali
metals (e.g., sodium) hydroxides, alkaline earth metals (e.g.,
magnesium), hydroxides, ammonia, and compounds of formula NW.sub.3,
wherein W is C.sub.1-4 alkyl, and the like.
[0045] Examples of salts include, but are not limited to: acetate,
adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate,
oxalate, palmoate, pectinate, persulfate, phenylpropionate,
picrate, pivalate, propionate, succinate, sulfate, tartrate,
thiocyanate, tosylate, undecanoate, and the like. Other examples of
salts include anions of the compounds of the present invention
compounded with a suitable cation such as Na.sup.+, NH.sub.4.sup.+,
and NW.sub.4.sup.+ (wherein W is a C.sub.1-4 alkyl group), and the
like.
[0046] For therapeutic use, salts of the compounds of the present
invention are contemplated as being pharmaceutically acceptable.
However, salts of acids and bases that are non-pharmaceutically
acceptable may also find use, for example, in the preparation or
purification of a pharmaceutically acceptable compound.
[0047] Throughout the description, where compositions and kits are
described as having, including, or comprising specific components,
or where processes and methods are described as having, including,
or comprising specific steps, it is contemplated that,
additionally, there are compositions and kits of the present
invention that consist essentially of, or consist of, the recited
components, and that there are processes and methods according to
the present invention that consist essentially of, or consist of,
the recited processing steps.
[0048] As a general matter, compositions specifying a percentage
are by weight unless otherwise specified. Further, if a variable is
not accompanied by a definition, then the previous definition of
the variable controls. Certain numerical values herein are modified
by the term about. In certain embodiments, about a stated value is
within .+-.10% of the stated value; also provided are embodiments
that are within .+-.9%, .+-.8%, .+-.7%, .+-.6%, .+-.5%, .+-.4%,
.+-.3%, .+-.2%, or .+-.1% of the stated value.
I. Therapeutic Methods
[0049] The invention provides methods for treating patients
suffering from meibomian gland dysfunction by administering
minocycline topical suspension to the patient. The invention also
provides methods for treating blepharitis, meibomitis, and ocular
rosacea by administering minocycline topical suspension to the
patient. Various aspects and embodiments of the therapeutic methods
are described in the sections below. The sections are arranged for
convenience and information in one section is not to be limited to
that section, but may be applied to methods in other sections.
A. First Method
[0050] One aspect of the invention provides a method of treating
meibomian gland dysfunction, wherein the method comprises topically
administering to the eyelid margin of a patient in need thereof
once or twice per day a dose of a minocycline topical suspension to
treat the meibomian gland dysfunction, wherein the dose provides
from about 0.1 mg to about 1.4 mg of minocycline, and the
minocycline topical suspension comprises: [0051] a) minocycline in
a suspended form within the topical suspension; [0052] b) a liquid
medium that dissolves less than 5% (w/w) of the minocycline at room
temperature after two hours, wherein the liquid medium contains
mineral oil; and [0053] c) a polymeric hydrocarbon gelling agent;
[0054] wherein particles of minocycline in the topical suspension
have a D90 particle size less than 8 microns, and the topical
suspension comprises from about 0.1% (w/w) to about 2% (w/w)
minocycline.
B. Second Method
[0055] Another aspect of the invention provides a method of
treating meibomian gland dysfunction, wherein the method comprises
topically administering to the eye of a patient in need thereof a
therapeutically effective amount of minocycline to treat the
meibomian gland dysfunction. In a more specific embodiment, the
invention provides a method of treating meibomian gland dysfunction
in a patient having a tear film matrix metalloproteinase-9 (MMP-9)
concentration greater than about 40 ng/mL, wherein the method
comprises topically administering to the eye of said patient in
need thereof a therapeutically effective amount of minocycline to
treat the meibomian gland dysfunction. The methods may be further
characterized according to additional features. For example, in
certain embodiments, the minocycline is in the form of a topical
suspension. In certain embodiments, the topical suspension
comprises a gelling agent. In certain embodiments, the topical
suspension comprises an oil and one or more gelling polymers.
[0056] In certain embodiments, the minocycline topical suspension
comprises minocycline in a suspended form within the topical
suspension. In certain embodiments, particles of minocycline in the
topical suspension have a D90 particle size in the range of from
about 1 microns to about 10 microns. In certain embodiments,
particles of minocycline in the topical suspension have a D90
particle size in the range of from about 1 microns to about 7
microns. In certain embodiments, particles of minocycline in the
topical suspension have a D90 particle size in the range of from
about 1 microns to about 5 microns. In certain embodiments,
particles of minocycline in the topical suspension have a D90
particle size in the range of from about 2 microns to about 4
microns, or from about 3 microns to about 4 microns. In certain
embodiments, particles of minocycline in the topical suspension
have a D90 particle size less than 8, 7, 6, 5, 4, or 3 microns. In
certain embodiments, particles of minocycline in the topical
suspension have a D90 particle size less than 5 microns. In certain
embodiments, particles of minocycline in the topical suspension
have a D90 particle size less than 4 microns.
[0057] In certain embodiments, the minocycline topical suspension
comprises a liquid medium that dissolves less than 5% (w/w) of the
minocycline at room temperature after two hours, wherein the liquid
medium contains mineral oil.
[0058] In certain embodiments, the minocycline topical suspension
comprises a polymeric hydrocarbon gelling agent.
[0059] In certain embodiments, the topical suspension comprises
from about 0.1% (w/w) to about 2% (w/w) minocycline. In certain
embodiments, the topical suspension comprises from about 0.3% (w/w)
to about 1% (w/w) minocycline. In certain embodiments, the topical
suspension comprises about 0.3% (w/w) minocycline. In certain
embodiments, the topical suspension comprises about 1% (w/w)
minocycline.
[0060] In certain embodiments, the method comprises topically
administering to the eyelid margin of a patient in need thereof
once or twice per day a dose of a minocycline topical
suspension.
C. Third Method
[0061] Another aspect of the invention provides a method of
treating a disorder selected from the group consisting of
blepharitis, meibomitis, and ocular rosacea, wherein the method
comprises topically administering to the eye of a patient in need
thereof a therapeutically effective amount of a minocycline topical
suspension to treat the disorder.
[0062] In certain embodiments, the method comprises topically
administering to the eyelid margin of the patient in need thereof
once or twice per day a dose of a minocycline topical suspension,
wherein the dose provides from about 0.1 mg to about 1.4 mg of
minocycline, and the minocycline topical suspension comprises:
[0063] a) minocycline in a suspended form within the topical
suspension; [0064] b) a liquid medium that dissolves less than 5%
(w/w) of the minocycline at room temperature after two hours,
wherein the liquid medium contains mineral oil; and [0065] c) a
polymeric hydrocarbon gelling agent; wherein particles of
minocycline in the topical suspension have a D90 particle size less
than 8 microns, and the topical suspension comprises from about
0.1% (w/w) to about 2% (w/w) minocycline.
D. Additional Exemplary Features of the First, Second, and Third
Therapeutic Methods
[0066] Additional exemplary features that may characterize the
First, Second, and Third Therapeutic Methods described herein are
provided below and include, for example, features of the
minocycline topical suspension, the dosing amount of minocycline
topical suspension, and dosing regimen used to administer the
minocycline topical suspension to the patient. A more thorough
description of such features is provided below. The invention
embraces all permutations and combinations of these features.
1. Minocycline Topical Suspension
[0067] The method may be further characterized according to the
composition of the minocycline topical suspension. For example, the
method can be characterized according to the amount of minocycline
in suspended form within the topical suspension, the physical form
of minocycline, and the liquid medium that dissolves less than 5%
(w/w) of the minocycline at room temperature after two hours,
wherein the liquid medium contains mineral oil. These are described
in more detail below.
Amount of Minocycline
[0068] The method may be further characterized according to the
amount of minocycline in the topical suspension. For example, in
certain embodiments, the topical suspension comprises from about
0.3% (w/w) to about 1% (w/w) minocycline. In certain embodiments,
the topical suspension comprises from about 0.2% (w/w) to about
0.4% (w/w) minocycline. In certain embodiments, the topical
suspension comprises about 0.3% (w/w) minocycline. In certain
embodiments, the topical suspension comprises 0.3% (w/w)
minocycline. In certain embodiments, the topical suspension
comprises from about 0.9% (w/w) to about 1.1% (w/w) minocycline. In
certain embodiments, the topical suspension comprises about 1%
(w/w) minocycline. In certain embodiments, the topical suspension
comprises 1% (w/w) minocycline.
Form of Minocycline
[0069] The method may be further characterized according to the
physical form of the minocycline. For example, in certain
embodiments, the minocycline is crystalline. Particular crystalline
forms include Form I, Form II, and Form III. Additional details on
minocycline crystalline Form I, Form II, and Form III are described
herein below and in U.S. Pat. No. 8,258,327, which is hereby
incorporated by reference.
[0070] Minocycline is understood to provide advantages over
minocycline hydrochloride when used in a topical suspension for
administration to the eye. One advantage of minocycline is that it
is less acidic than minocycline hydrochloride--the less acidic
minocycline is better tolerated by the eye. That is, minocycline
causes less stinging and/or burning upon administration to the eye
than minocycline hydrochloride. An aqueous solution containing 1%
w/v minocycline has a pH in the range of 6.0 to 6.5, whereas an
aqueous solution containing 1% w/v minocycline hydrochloride has a
pH in the range of 3.5 to 4.5. A further characterization of the
acidity of minocycline is pKa values--minocycline has pKa values of
3.5, 7.6, and 9.2, whereas minocycline hydrochloride has pKa values
of 2.8, 5.0, and 9.3. Another advantage of minocycline is that it
is more lipophilic than minocycline hydrochloride. Minocycline has
a log P value of 0.11, whereas minocycline hydrochloride has a log
P value of 0.05.
A. Minocycline Crystalline Form I.
[0071] In certain embodiments, the minocycline is crystalline and
characterized by an X-ray diffraction pattern having peaks at 5.2,
7.6, 8.8, 12.8, 14.5, 15.0, 15.3, 15.9, 16.4, 17.8, 19.3, 19.5,
20.7, 21.3, 21.8, 22.3, 23.1, 24.0, 25.3, 25.7 and 26.5.+-.0.2
degrees 2.theta.. In certain embodiments, the minocycline is
crystalline and has an X-ray diffraction pattern substantially as
shown in FIG. 1. In certain embodiments, the minocycline is
crystalline and characterized by an infrared spectrum having peaks
at 1646, 1602, 1581, 1470, 1397, 1364, 1286, 1218, 1182, 1134,
1072, 1061, 1023, 1001, 969, 950, 874, 850, 716, 636, 620 and
545.+-.4 cm.sup.-1. In certain embodiments, the minocycline is
crystalline and has an infrared spectrum substantially as shown in
FIG. 2.
B. Minocycline Crystalline Form II.
[0072] In certain embodiments, the minocycline is crystalline and
characterized by an X-ray diffraction pattern having peaks at 3.4,
6.8, 8.0, 10.0, 13.0, 13.8, 22.6, and 23.9.+-.0.2 degrees 2.theta..
In certain embodiments, the minocycline is crystalline and
characterized by an X-ray diffraction pattern having peaks at 3.4,
6.8, 8.0, 10.0, 13.0, 13.8, 14.6, 14.9, 15.5, 16.1, 17.6, 17.8,
18.6, 19.5, 20.2, 20.6, 21.9, 22.6, 23.9, 24.2, 25.4, 26.3, 27.1,
27.5, 28.0 and 29.1.+-.0.2 degrees 2.theta.. In certain
embodiments, the minocycline is crystalline and has an X-ray
diffraction pattern substantially as shown in FIG. 3. In certain
embodiments, the minocycline is crystalline and characterized by an
infrared spectrum having peaks at 1644, 1607, 1582, 1469, 1453,
1413, 1396, 1358, 1287, 1251, 1217, 1186, 1166, 1136, 1061, 999,
970, 874, 716, 621 and 5854 cm.sup.-1. In certain embodiments, the
minocycline is crystalline and has an infrared spectrum
substantially as shown in FIG. 4.
C. Minocycline Crystalline Form III.
[0073] In certain embodiments, the minocycline is crystalline and
characterized by an X-ray diffraction pattern having peaks at 6.5,
10.0, 13.2, 15.1, 16.5, 17.9, 19.6, 20.2, 21.1, 22.3, 23.7, 24.8,
26.4, 28.1 and 30.5.+-.0.2 degrees 2.theta.. In certain
embodiments, the minocycline is crystalline and has an X-ray
diffraction pattern substantially as shown in FIG. 5. In certain
embodiments, the minocycline is crystalline and characterized by an
infrared spectrum having peaks at 1647, 1605, 1581, 1470, 1399,
1307, 1286, 1251, 1216, 1195, 1179, 1136, 1094, 1058, 1024, 1000,
973, 950, 870, 825, 806, 716, 680, 634, 615, 584, 515, 496 and 4134
cm.sup.-1. In certain embodiments, the minocycline is crystalline
and has an infrared spectrum substantially as shown in FIG. 6.
Size of Particles of Minocycline
[0074] The method may be further characterized according to the
size of particles of minocycline in the minocycline topical
suspension. In certain embodiments, minocycline particles in the
minocycline topical suspension have a D50 particle size that is
from about 1 micron to about 4 microns. In certain embodiments,
minocycline particles in the minocycline topical suspension have a
D50 particle size that is from about 1 micron to about 3 microns.
In certain embodiments, minocycline particles in the minocycline
topical suspension have a D50 particle size that is from about 2
micron to about 3 microns. In certain embodiments, minocycline
particles in the minocycline topical suspension have a D50 particle
size that is about 2.5 microns. In certain embodiments, minocycline
particles in the minocycline topical suspension have a D50 particle
size that is less than about 3 microns. In certain embodiments,
minocycline particles in the minocycline topical suspension have a
D50 particle size that is less than about 2 microns.
[0075] In certain embodiments, minocycline particles in the
minocycline topical suspension have a D10 particle size that is
from about 0.1 microns to about 3 microns. In certain embodiments,
minocycline particles in the minocycline topical suspension have a
D10 particle size that is from about 0.1 microns to about 2
microns. In certain embodiments, minocycline particles in the
minocycline topical suspension have a D10 particle size that is
from about 0.1 microns to about 1 micron. In certain embodiments,
minocycline particles in the minocycline topical suspension have a
D10 particle size that is from about 0.1 microns to about 1.5
microns. In certain embodiments, minocycline particles in the
minocycline topical suspension have a D10 particle size that is
from about 0.1 micron to about 2 microns. In certain embodiments,
minocycline particles in the minocycline topical suspension have a
D10 particle size that is less than 2 microns. In certain
embodiments, minocycline particles in the minocycline topical
suspension have a D10 particle size that is less than 1 micron.
[0076] In certain embodiments, minocycline particles in the
minocycline topical suspension have a D50 particle size that is
from about 1 micron to about 3 microns, and a D10 particle size
that is from about 0.1 microns to about 1 micron.
[0077] In certain embodiments, minocycline particles in the
minocycline topical suspension have a D90 particle size that is
from 1 micron to 8 microns. In certain embodiments, minocycline
particles in the minocycline topical suspension have a D90 particle
size that is from 1 micron to 7 microns. In certain embodiments,
minocycline particles in the minocycline topical suspension have a
D90 particle size that is from 1 micron to 5 microns. In certain
embodiments, minocycline particles in the minocycline topical
suspension have a D90 particle size that is from 2 microns to 5
microns. In certain embodiments, minocycline particles in the
minocycline topical suspension have a D90 particle size that is
from 2 microns to 4 microns. In certain embodiments, minocycline
particles in the minocycline topical suspension have a D90 particle
size that is from 3 microns to 4 microns. In certain embodiments,
minocycline particles in the minocycline topical suspension have a
D90 particle size that is less than 4 microns. In certain
embodiments, minocycline particles in the minocycline topical
suspension have a D90 particle size that is less than 3 microns. In
certain embodiments, minocycline particles in the minocycline
topical suspension have a D90 particle size that is one of about 3
microns, about 4 microns, about 5 microns, about 6 microns, about 7
microns, about 8 microns, or about 9 microns, or a fractional value
in between any of these values. In certain embodiments, minocycline
particles in the minocycline topical suspension have a D90 particle
size that is about 3 microns. In certain embodiments, minocycline
particles in the minocycline topical suspension have a D90 particle
size that is one of about 3.5 microns.
Polymeric Hydrocarbon Gelling Agent
[0078] The method may be further characterized according to the
amount of polymeric hydrocarbon gelling agent in the topical
suspension. For example, in certain embodiments, the minocycline
topical suspension comprises from about 60% (w/w) to about 80%
(w/w) of the polymeric hydrocarbon gelling agent. In certain
embodiments, the minocycline topical suspension comprises from
about 65% (w/w) to about 75% (w/w) of the polymeric hydrocarbon
gelling agent. In certain embodiments, the minocycline topical
suspension comprises from about 67% (w/w) to about 71% (w/w) of the
polymeric hydrocarbon gelling agent. In certain embodiments, the
minocycline topical suspension comprises about 69% (w/w) of the
polymeric hydrocarbon gelling agent.
[0079] In certain embodiments, the polymeric hydrocarbon gelling
agent comprises an ethylene-propylene-styrene copolymer. In certain
embodiments, the polymeric hydrocarbon gelling agent comprises an
ethylene-propylene-styrene copolymer having a weight-average
molecular weight in the range of from about 150,000 g/mol to about
250,000 g/mol. In certain embodiments, the polymeric hydrocarbon
gelling agent comprises an ethylene-propylene-styrene copolymer
having a weight-average molecular weight of about 200,000
g/mol.
[0080] In certain embodiments, the polymeric hydrocarbon gelling
agent comprises from about 1% (w/w) to about 15% (w/w) of
ethylene-propylene-styrene copolymer. In certain embodiments, the
polymeric hydrocarbon gelling agent comprises from about 2.5% (w/w)
to about 10% (w/w) of ethylene-propylene-styrene copolymer.
[0081] In certain embodiments, the ethylene-propylene-styrene
copolymer is a copolymer formed by polymerization of isoprene and
styrene monomers that is terminated by hydrogenation. In certain
embodiments, the ethylene-propylene-styrene copolymer is a
copolymer formed by polymerization of isoprene and styrene followed
by hydrogenation.
[0082] In certain embodiments, the polymeric hydrocarbon gelling
agent comprises a butylene-ethylene-styrene copolymer. In certain
embodiments, the polymeric hydrocarbon gelling agent comprises a
butylene-ethylene-styrene copolymer having a weight-average
molecular weight in the range of from about 50,000 g/mol to about
150,000 g/mol. In certain embodiments, the polymeric hydrocarbon
gelling agent comprises a butylene-ethylene-styrene copolymer
having a weight-average molecular weight of about 100,000
g/mol.
[0083] In certain embodiments, the polymeric hydrocarbon gelling
agent comprises from about 0.01% (w/w) to about 2.5% (w/w) of
butylene-ethylene-styrene copolymer. In certain embodiments, the
polymeric hydrocarbon gelling agent comprises from about 0.1% (w/w)
to about 2.5% (w/w) of butylene-ethylene-styrene copolymer.
[0084] In certain embodiments, the butylene-ethylene-styrene
copolymer is a copolymer formed by polymerization of 1,3-butadiene
and styrene monomers that is terminated by hydrogenation. In
certain embodiments, the butylene-ethylene-styrene copolymer is a
copolymer formed by polymerization of 1,3-butadiene and styrene
followed by hydrogenation.
[0085] In certain embodiments, the polymeric hydrocarbon gelling
agent comprises butylated-hydroxytoluene. In certain embodiments,
the polymeric hydrocarbon gelling agent comprises from about 0.01%
(w/w) to about 0.5% (w/w) of butylated-hydroxytoluene. In certain
embodiments, the polymeric hydrocarbon gelling agent comprises
butylated-hydroxytoluene in an amount less than 0.5% (w/w).
[0086] In certain embodiments, the polymeric hydrocarbon gelling
agent comprises mineral oil. In certain embodiments, the polymeric
hydrocarbon gelling agent comprises at least about 80% (w/w)
mineral oil. In certain embodiments, the polymeric hydrocarbon
gelling agent comprises at least about 90% (w/w) mineral oil. In
certain embodiments, the mineral oil component of the polymeric
hydrocarbon gelling agent has a weight-average molecular weight in
the range of from about 100 g/mol to about 1,000 g/mol. In certain
embodiments, the mineral oil component of the polymeric hydrocarbon
gelling agent has a weight-average molecular weight in the range of
from about 200 g/mol to about 700 g/mol. In certain embodiments,
the mineral oil is white mineral oil.
[0087] In certain embodiments, the polymeric hydrocarbon gelling
agent comprises (a) at least 80% (w/w) mineral oil; (b) from about
2.5% (w/w) to about 10% (w/w) of ethylene-propylene-styrene
copolymer; and (c) comprises from about 0.1% (w/w) to about 2.5%
(w/w) of butylene-ethylene-styrene copolymer.
[0088] In certain embodiments, the polymeric hydrocarbon gelling
agent comprises [0089] (a) at least 80% (w/w) mineral oil having a
weight-average molecular weight in the range of from about 100
g/mol to about 1,000 g/mol; [0090] (b) from about 2.5% (w/w) to
about 10% (w/w) of ethylene-propylene-styrene copolymer having a
weight-average molecular weight of about 200,000 g/mol; and [0091]
(c) comprises from about 0.1% (w/w) to about 2.5% (w/w) of
butylene-ethylene-styrene copolymer having a weight-average
molecular weight of about 100,000 g/mol.
[0092] In certain embodiments, the polymeric hydrocarbon gelling
agent is a mixture of mineral oil, ethylene-propylene-styrene
copolymer, butylene-ethylene-styrene copolymer, and optionally
butylated-hydroxytoluene having a viscosity in the range of from
about 13,000 to about 28,000 cps at 25.degree. C., as sold by
Calumet Specialty Products Partners, L.P. under the tradename
VERSAGEL.RTM. M200. In certain embodiments, the polymeric
hydrocarbon gelling agent is a mixture of mineral oil,
ethylene-propylene-styrene copolymer, butylene-ethylene-styrene
copolymer, and optionally butylated-hydroxytoluene having a
viscosity of about 20,0000 cps at 25.degree. C., as sold by Calumet
Specialty Products Partners, L.P. under the tradename VERSAGEL.RTM.
M200.
[0093] In certain embodiments, the polymeric hydrocarbon gelling
agent is a mixture of mineral oil, ethylene-propylene-styrene
copolymer, butylene-ethylene-styrene copolymer, and optionally
butylated-hydroxytoluene having a viscosity in the range of from
about 47,000 to about 57,000 cps at 25.degree. C., as sold by
Calumet Specialty Products Partners, L.P. under the tradename
VERSAGEL.RTM. M500. In certain embodiments, the polymeric
hydrocarbon gelling agent is a mixture of mineral oil,
ethylene-propylene-styrene copolymer, butylene-ethylene-styrene
copolymer, and optionally butylated-hydroxytoluene having a
viscosity of about 50,0000 cps at 25.degree. C., as sold by Calumet
Specialty Products Partners, L.P. under the tradename VERSAGEL.RTM.
M500.
[0094] In certain embodiments, the polymeric hydrocarbon gelling
agent is a mixture of mineral oil, ethylene-propylene-styrene
copolymer, butylene-ethylene-styrene copolymer, and optionally
butylated-hydroxytoluene having a viscosity in the range of from
about 67,000 to about 83,000 cps at 25.degree. C., as sold by
Calumet Specialty Products Partners, L.P. under the tradename
VERSAGEL.RTM. M750. In certain embodiments, the polymeric
hydrocarbon gelling agent is a mixture of mineral oil,
ethylene-propylene-styrene copolymer, butylene-ethylene-styrene
copolymer, and optionally butylated-hydroxytoluene having a
viscosity of about 75,000 cps at 25.degree. C., as sold by Calumet
Specialty Products Partners, L.P. under the tradename VERSAGEL.RTM.
M750.
[0095] In certain embodiments, the polymeric hydrocarbon gelling
agent is a mixture of mineral oil, ethylene-propylene-styrene
copolymer, butylene-ethylene-styrene copolymer, and optionally
butylated-hydroxytoluene having a viscosity of about 160,0000 cps
at 25.degree. C., as sold by Calumet Specialty Products Partners,
L.P. under the tradename VERSAGEL.RTM. M1600.
Liquid Medium
[0096] The method may be further characterized according to the
amount of liquid medium that dissolves less than 5% (w/w) of the
minocycline at room temperature after two hours. For example, in
certain embodiments, the minocycline topical suspension comprises
from about 20% (w/w) to about 40% (w/w) of the liquid medium that
dissolves less than 5% (w/w) of the minocycline at room temperature
after two hours, wherein the liquid medium contains mineral oil. In
certain embodiments, the minocycline topical suspension comprises
from about 25% (w/w) to about 35% (w/w) of the liquid medium that
dissolves less than 5% (w/w) of the minocycline at room temperature
after two hours, wherein the liquid medium contains mineral oil. In
certain embodiments, the minocycline topical suspension comprises
from about 28% (w/w) to about 32% (w/w) of the liquid medium that
dissolves less than 5% (w/w) of the minocycline at room temperature
after two hours, wherein the liquid medium contains mineral oil. In
certain embodiments, the minocycline topical suspension comprises
about 30% (w/w) of the liquid medium that dissolves less than 5%
(w/w) of the minocycline at room temperature after two hours,
wherein the liquid medium contains mineral oil.
[0097] In certain embodiments, the liquid medium that dissolves
less than 5% (w/w) of the minocycline at room temperature after two
hours comprises at least 90% (w/w) mineral oil. In certain
embodiments, the liquid medium that dissolves less than 5% (w/w) of
the minocycline at room temperature after two hours comprises at
least 99% (w/w) mineral oil. In certain embodiments, the liquid
medium that dissolves less than 5% (w/w) of the minocycline at room
temperature after two hours is mineral oil.
[0098] In certain embodiments, the mineral oil has a weight-average
molecular weight in the range of from about 100 g/mol to about
1,000 g/mol. In certain embodiments, the mineral oil has a
weight-average molecular weight in the range of from about 200
g/mol to about 700 g/mol. In certain embodiments, the mineral oil
has a weight-average molecular weight in the range of from about
230 g/mol to about 700 g/mol.
[0099] In certain embodiments, the mineral oil has a weight-average
molecular weight in the range of from about 200 g/mol to about 500
g/mol. In certain embodiments, the mineral oil has a weight-average
molecular weight in the range of from about 300 g/mol to about 600
g/mol. In certain embodiments, the mineral oil has a weight-average
molecular weight in the range of from about 400 g/mol to about 700
g/mol. In certain embodiments, the mineral oil has a weight-average
molecular weight in the range of from about 400 g/mol to about 500
g/mol. In certain embodiments, the mineral oil has a weight-average
molecular weight in the range of from about 440 g/mol to about 465
g/mol.
[0100] In certain embodiments, the mineral oil has a molecular
weight in the range of from about 440 g/mol to about 465 g/mol. In
certain embodiments, the mineral oil has a molecular weight of
about 452 g/mol.
[0101] In certain embodiments, the mineral oil has a viscosity
greater than 34.5 centistokes when measured at 40.degree. C. In
certain embodiments, the mineral oil has a viscosity in the range
of from about 34.5 centistokes to about 150 centistokes when
measured at 40.degree. C. In certain embodiments, the mineral oil
has a viscosity in the range of from about 34.5 centistokes to
about 50 centistokes, from about 50 centistokes to about 75
centistokes, from about 75 centistokes to about 100 centistokes,
from about 100 centistokes to about 125 centistokes, from about 125
centistokes to about 150 centistokes, or from about 34.5
centistokes to about 100 centistokes when measured at 40.degree.
C.
[0102] In certain embodiments, the mineral oil has a specific
gravity of from about 0.845 to about 0.905. In certain embodiments,
the mineral oil has a specific gravity of from about 0.8 to about
0.95. In certain embodiments, the mineral oil has a specific
gravity of from about 0.8 to about 0.9. In certain embodiments, the
mineral oil has a specific gravity of from about 0.84 to about
0.91. In certain embodiments, the mineral oil has a specific
gravity of from about 0.845 to about 0.905, when measured at
20.degree. C. In certain embodiments, the mineral oil has a
specific gravity of from about 0.8 to about 0.95, when measured at
20.degree. C. In certain embodiments, the mineral oil has a
specific gravity of from about 0.8 to about 0.9, when measured at
20.degree. C. In certain embodiments, the mineral oil has a
specific gravity of from about 0.84 to about 0.91, when measured at
20.degree. C. In certain embodiments, the mineral oil has a density
of about 0.83 g/mL.
[0103] In certain embodiments, the mineral oil corresponds to the
mineral oil identified by CAS registry number 8042-47-5.
[0104] In certain embodiments, the mineral oil has a viscosity less
than 34.5 centistokes when measured at 40.degree. C. In certain
embodiments, the mineral oil has a viscosity less than 33.5
centistokes when measured at 40.degree. C. In certain embodiments,
the mineral oil has a viscosity in the range of from about 1
centistoke to about 34.4 centistokes when measured at 40.degree. C.
In certain embodiments, the mineral oil has a viscosity in the
range of from about 1 centistoke to about 10 centistokes, from
about 10 centistokes to about 20 centistokes, from about 20
centistokes to about 30 centistokes, or from about 25 centistokes
to about 34.4 centistokes, when measured at 40.degree. C.
[0105] In certain embodiments, the mineral oil has a specific
gravity of from about 0.818 to about 0.88. In certain embodiments,
the mineral oil has a specific gravity of from about 0.8 to about
0.9. In certain embodiments, the mineral oil has a specific gravity
of from about 0.818 to about 0.88, when measured at 20.degree. C.
In certain embodiments, the mineral oil has a specific gravity of
from about 0.8 to about 0.9, when measured at 20.degree. C.
[0106] In certain embodiments, said liquid medium dissolves less
than 4% (w/w) of the minocycline at room temperature after two
hours. In certain embodiments, said liquid medium dissolves less
than 3% (w/w) of the minocycline at room temperature after two
hours. In certain embodiments, said liquid medium dissolves less
than 2% (w/w) of the minocycline at room temperature after two
hours. In certain embodiments, said liquid medium dissolves less
than 1% (w/w) of the minocycline at room temperature after two
hours. In certain embodiments, said liquid medium dissolves less
than 0.1% (w/w) of the minocycline at room temperature after two
hours. In certain embodiments, said liquid medium dissolves from
about 0.01% (w/w) to about 4% (w/w) of the minocycline at room
temperature after two hours. In certain embodiments, said liquid
medium dissolves from about 0.1% (w/w) to about 4% (w/w) of the
minocycline at room temperature after two hours. In certain
embodiments, said liquid medium dissolves from about 0.1% (w/w) to
about 3% (w/w) of the minocycline at room temperature after two
hours. In certain embodiments, said liquid medium dissolves from
about 0.1% (w/w) to about 2% (w/w) of the minocycline at room
temperature after two hours. In certain embodiments, said liquid
medium dissolves from about 0.1% (w/w) to about 1% (w/w) of the
minocycline at room temperature after two hours. In certain
embodiments, said liquid medium dissolves from about 0.5% (w/w) to
about 2% (w/w) of the minocycline at room temperature after two
hours. In certain embodiments, said liquid medium dissolves from
about 0.5% (w/w) to about 1% (w/w) of the minocycline at room
temperature after two hours.
[0107] In certain embodiments, the liquid medium is characterized
by dissolving less than about 4% (w/w) of minocycline when held at
room temperature for two hours. In certain embodiments, the liquid
medium is characterized by dissolving less than about 3% (w/w) of
minocycline when held at room temperature for two hours. In certain
embodiments, the liquid medium is characterized by dissolving less
than about 2% (w/w) of minocycline when held at room temperature
for two hours. In certain embodiments, the liquid medium is
characterized by dissolving less than about 1% (w/w) of minocycline
when held at room temperature for two hours.
[0108] In certain embodiments, the liquid medium is characterized
by dissolving from about 0.01% (w/w) to about 4% (w/w) minocycline
when held at room temperature for two hours. In certain
embodiments, the liquid medium is characterized by dissolving from
about 0.1% (w/w) to about 4% (w/w) minocycline when held at room
temperature for two hours. In certain embodiments, the liquid
medium is characterized by dissolving from about 0.1% (w/w) to
about 3% (w/w) minocycline when held at room temperature for two
hours. In certain embodiments, the liquid medium is characterized
by dissolving from about 0.1% (w/w) to about 2% (w/w) minocycline
when held at room temperature for two hours. In certain
embodiments, the liquid medium is characterized by dissolving from
about 0.1% (w/w) to about 1% (w/w) minocycline when held at room
temperature for two hours. In certain embodiments, the liquid
medium is characterized by dissolving from about 0.5% (w/w) to
about 2% (w/w) minocycline when held at room temperature for two
hours. In certain embodiments, the liquid medium is characterized
by dissolving less about 4%, 3%, 2%, 1%, or 0.1% (w/w) minocycline
when held at room temperature for two hours.
Stability of Minocycline Topical Suspension
[0109] The method may be further characterized according to the
stability of the minocycline topical suspension used. For example,
in certain embodiments, the minocycline topical suspension contains
less than 4% (w/w) of 4-epi-minocycline when the minocycline
topical suspension is stored for 1 month at room temperature. In
certain embodiments, the minocycline topical suspension contains
less than 3%, 2%, or 1% (w/w) of 4-epi-minocycline when the
minocycline topical suspension is stored for 1 month at room
temperature.
[0110] In certain embodiments, the minocycline topical suspension
contains less than 3%, 2%, or 1% (w/w) of 4-epi-minocycline when
the minocycline topical suspension is stored at 25.degree.
C..+-.2.degree. C. under 60%.+-.5% relative humidity for 36 months.
In certain embodiments, the minocycline topical suspension contains
less than 1% (w/w) of 4-epi-minocycline when the minocycline
topical suspension is stored at 25.degree. C..+-.2.degree. C. under
60%.+-.5% relative humidity for 36 months. In certain embodiments,
the minocycline topical suspension contains less than 3%, 2%, or 1%
(w/w) of 4-epi-minocycline when the minocycline topical suspension
is stored at 40.degree. C..+-.2.degree. C. under 75%.+-.5% relative
humidity for 6 months.
[0111] In certain embodiments, less than 1% (w/w) of minocycline in
the minocycline topical suspension degrades upon storage of the
minocycline topical suspension at 25.degree. C..+-.2.degree. C.
under 60%.+-.5% relative humidity for 36 months. In certain
embodiments, less than 1.5% (w/w) of minocycline in the minocycline
topical suspension degrades upon storage of the minocycline topical
suspension at 25.degree. C..+-.2.degree. C. under 60%.+-.5%
relative humidity for 36 months. In certain embodiments, less than
2% (w/w) of minocycline in the minocycline topical suspension
degrades upon storage of the minocycline topical suspension at
25.degree. C..+-.2.degree. C. under 60%.+-.5% relative humidity for
36 months. In certain embodiments, less than 5, 4, 3, 2, 1, 0.5, or
0.1% (w/w) of minocycline in the minocycline topical suspension
degrades upon storage of the minocycline topical suspension at
25.degree. C..+-.2.degree. C. under 60%.+-.5% relative humidity for
36 months. In certain embodiments, less than 5, 4, 3, 2, 1, 0.5, or
0.1% (w/w) of minocycline in the minocycline topical suspension
degrades upon storage of the minocycline topical suspension at
25.degree. C..+-.2.degree. C. under 60%.+-.5% relative humidity for
24 months. In certain embodiments, less than 5, 4, 3, 2, 1, 0.5, or
0.1% (w/w) of minocycline in the minocycline topical suspension
degrades upon storage of the minocycline topical suspension at
405.degree. C..+-.2.degree. C. under 75%.+-.5% relative humidity
for 6 months.
[0112] In certain embodiments, storage of the minocycline topical
suspension at 25.degree. C..+-.2.degree. C. under 60%.+-.5%
relative humidity for 36 months results in the formulation of less
than 2% (w/w) total impurities. In certain embodiments, storage of
the minocycline topical suspension at 25.degree. C..+-.2.degree. C.
under 60%.+-.5% relative humidity for 36 months results in the
formulation of less than 3% (w/w) total impurities. In certain
embodiments, storage of the minocycline topical suspension at
25.degree. C..+-.2.degree. C. under 60%.+-.5% relative humidity for
36 months results in the formulation of less than 8%, 7%, 6%, 5%,
4%, 3%, 2%, or 1% (w/w) total impurities. In certain embodiments,
storage of the minocycline topical suspension at 25.degree.
C..+-.2.degree. C. under 60%.+-.5% relative humidity for 24 months
results in the formulation of less than 8%, 7%, 6%, 5%, 4%, 3%, 2%,
or 1% (w/w) total impurities. In certain embodiments, storage of
the minocycline topical suspension at 40.degree. C..+-.2.degree. C.
under 75%.+-.5% relative humidity for 6 months results in the
formulation of less than 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% (w/w)
total impurities. Sterility Level of the Minocycline Topical
Suspension
[0113] The method may be further characterized according to the
sterility of the minocycline topical suspension used. For example,
in certain embodiments, the minocycline topical suspension has
undergone sterilization, such as by exposing the minocycline
topical suspension gamma or e-beam sterilization. The level of
sterility of the minocycline topical suspension may be
characterized, e.g., where the minocycline topical suspension has a
sterility assurance level that is more sterile than 10.sup.-1,
10.sup.-2, 10.sup.-3, 10.sup.-4, 10.sup.-5, 10.sup.-6, 10.sup.-7,
10.sup.-8, or 10.sup.-9. In certain embodiments, the minocycline
topical suspension has a sterility assurance level of from about
10.sup.-1 to 10.sup.-3, about 10.sup.-3 to about 10.sup.-4, about
10.sup.-4 to about 10.sup.-5, about 10.sup.-5 to about 10.sup.-6,
or about 10.sup.-6 to about 10.sup.-7, or a sterility assurance
level that is more sterile than 10.sup.-7. In certain embodiments,
the minocycline topical suspension has a sterility assurance level
of about 10.sup.-6.
Non-Newtonian Physical Properties
[0114] The minocycline topical suspension desirably displays
non-Newtonian physical properties. That is, minocycline topical
suspension is a non-Newtonian fluid. Such non-Newtonian physical
properties provide superior residence time on the eyelid margin
when the minocycline topical suspension is applied to the eyelid
margin. Such non-Newtonian physical properties also minimize
exposure of the cornea surface to topical minocycline suspension
when the minocycline topical suspension is applied to the eyelid
margin.
[0115] A desired non-Newtonian physical property is where the
minocycline topical suspension undergoes a reduction in viscosity
due to mechanical forces imposed on the minocycline topical
suspension due to the patient blinking their eye.
[0116] Viscosity of the topical minocycline suspension can be
measured a different shear rates. For example, in certain
embodiments, at a shear rate of 6 (l/s), the minocycline topical
suspension has a viscosity in the range of from about 1,000 cP to
about 45,000 cP, from about 3,000 cP to about 30,000 cP, from about
3,000 cP to about 25,000 cP, from about 3,000 cP to about 20,000
cP, from about 3,000 cP to about 15,000 cP, from about 5,000 cP to
about 30,000 cP, from about 5,000 cP to about 25,000 cP, from about
5,000 cP to about 20,000 cP, from about 5,000 cP to about 15,000
cP, from about 6,000 cP to about 20,000 cP. In certain embodiments,
at a shear rate of 6 (l/s), the minocycline topical suspension has
a viscosity in the range of from about 7,000 cP to about 15,000 cP.
In certain embodiments, at a shear rate of 6 (l/s), the minocycline
topical suspension has a viscosity in the range of from about 25
Pas to about 35 Pas. In certain embodiments, at a shear rate of 6
(l/s), the minocycline topical suspension has a viscosity in the
range of from about 28 Pas to about 32 Pas. In certain embodiments,
at a shear rate of 6 (l/s), the minocycline topical suspension has
a viscosity of about 30 Pas.
[0117] In certain embodiments, at a shear rate of 1000/s, the
minocycline topical suspension has a viscosity in the range of from
about 0.5 Pas to about 0.9 Pas. In certain embodiments, at a shear
rate of 1000/s, the minocycline topical suspension has a viscosity
in the range of from about 0.65 Pas to about 0.8 Pas. In certain
embodiments, at a shear rate of 1000/s, the minocycline topical
suspension has a viscosity in the range of from about 0.70 Pas to
about 0.74 Pas. In certain embodiments, at a shear rate of 1000/s,
the minocycline topical suspension has a viscosity of about 0.72
Pas.
[0118] The topical minocycline suspension can also be characterized
according to Oscillatory Stress Sweep, Oscillatory Frequency Sweep,
Yield stress, Complex Modulus, and Loss Modulus. Additionally, the
topical minocycline suspension can also be characterized according
to normal stress test, which monitors the normal stress exhibited
at a range of shear rates.
[0119] In certain embodiments, the minocycline topical suspension
has a zero shear viscosity in the range of from about 250 Pas to
about 350 Pas. In certain embodiments, the minocycline topical
suspension has a zero shear viscosity in the range of from about
275 Pas to about 315 Pas. In certain embodiments, the minocycline
topical suspension has a zero shear viscosity in the range of from
about 290 Pas to about 300 Pas. In certain embodiments, the
minocycline topical suspension has a zero shear viscosity of about
295 Pas. In certain embodiments, the minocycline topical suspension
has a zero shear viscosity in the range of from about 300 Pas to
about 350 Pas. In certain embodiments, the minocycline topical
suspension has a zero shear viscosity in the range of from about
320 Pas to about 335 Pas. In certain embodiments, the minocycline
topical suspension has a zero shear viscosity of about 328 Pas
[0120] In certain embodiments, the minocycline topical suspension
has a complex modulus plateau in the range of from about 130 Pa to
about 150 Pa. In certain embodiments, the minocycline topical
suspension has a complex modulus plateau in the range of from about
135 Pa to about 145 Pa. In certain embodiments, the minocycline
topical suspension has a complex modulus plateau in the range of
from about 138 Pa to about 141 Pa. In certain embodiments, the
minocycline topical suspension has a phase angle plateau in the
range of from about 20 degrees to about 30 degrees. In certain
embodiments, the minocycline topical suspension has a phase angle
plateau in the range of from about 24 degrees to about 28 degrees.
In certain embodiments, the minocycline topical suspension has a
phase angle plateau in the range of from about 25 degrees to about
27 degrees. In certain embodiments, the minocycline topical
suspension has a yield stress in the range of from about 15 Pa to
about 25 Pa. In certain embodiments, the minocycline topical
suspension has a yield stress in the range of from about 18 Pa to
about 24 Pa. In certain embodiments, the minocycline topical
suspension has a yield stress in the range of from about 20 Pa to
about 22 Pa.
Exemplary More Specific Embodiments
[0121] The disclosure provides the following additional specific
embodiments. Accordingly, in certain embodiments, the minocycline
topical suspension comprises: [0122] (a) about 0.3% (w/w) to about
1% (w/w) minocycline; [0123] (b) about 60% (w/w) to about 80% (w/w)
of the polymeric hydrocarbon gelling agent; and [0124] (c) about
20% (w/w) to about 40% (w/w) of the liquid medium that dissolves
less than 5% (w/w) of the minocycline at room temperature after two
hours, wherein the liquid medium contains mineral oil.
[0125] In certain embodiments, the minocycline topical suspension
comprises: [0126] (a) about 0.3% (w/w) minocycline; [0127] (b)
about 69% (w/w) of the polymeric hydrocarbon gelling agent; and
[0128] (c) about 30% (w/w) of the liquid medium that dissolves less
than 5% (w/w) of the minocycline at room temperature after two
hours, wherein the liquid medium contains mineral oil.
[0129] In certain embodiments, the minocycline topical suspension
comprises: [0130] (a) about 1% (w/w) minocycline; [0131] (b) about
69% (w/w) of the polymeric hydrocarbon gelling agent; and [0132]
(c) about 30% (w/w) of the liquid medium that dissolves less than
5% (w/w) of the minocycline at room temperature after two hours,
wherein the liquid medium contains mineral oil.
2. Dosage Considerations
[0133] The method may be further characterized according, for
example, to the dosage, location to which the dosage is
administered on the patient, and timing for the administration of
the minocycline suspension to the patient.
Dosing Amounts
[0134] The method may be further characterized according to the
dosing amount of minocycline. For example, in certain embodiments,
the dose of minocycline topical suspension provides from about 0.1
mg to about 1.2 mg of minocycline. In certain embodiments, the dose
of minocycline topical suspension provides from about 0.1 mg to
about 1 mg of minocycline. In certain embodiments, the dose of
minocycline topical suspension provides from about 0.1 mg to about
0.3 mg of minocycline. In certain embodiments, the dose of
minocycline topical suspension provides from about 0.1 mg to about
0.2 mg of minocycline. In certain embodiments, the dose of
minocycline topical suspension provides about 0.15 mg of
minocycline.
[0135] In certain embodiments, the dose of minocycline topical
suspension provides from about 0.3 mg to about 0.7 mg of
minocycline. In certain embodiments, the dose of minocycline
topical suspension provides from about 0.4 mg to about 0.6 mg of
minocycline. In certain embodiments, the dose of minocycline
topical suspension provides from about 0.45 mg to about 0.55 mg of
minocycline. In certain embodiments, the dose of minocycline
topical suspension provides about 0.5 mg of minocycline. In certain
embodiments, the dose of minocycline topical suspension provides
from about 0.9 mg to about 1.1 mg of minocycline. In certain
embodiments, the dose of minocycline topical suspension provides
about 1 mg of minocycline.
[0136] In certain embodiments, an amount of from about 35 .mu.L to
about 65 .mu.L of the minocycline topical suspension is topically
administered to the eyelid margin of the patient. In certain
embodiments, an amount of from about 40 .mu.L to about 50 .mu.L of
the minocycline topical suspension is topically administered to the
eyelid margin of the patient. In certain embodiments, an amount of
from about 45 .mu.L to about 55 .mu.L of the minocycline topical
suspension is topically administered to the eyelid margin of the
patient. In certain embodiments, an amount of about 50 .mu.L of the
minocycline topical suspension is topically administered to the
eyelid margin of the patient.
[0137] In certain embodiments, the minocycline topical suspension
is topically administered to the eyelid margin of the patient using
either a fingertip, application directly from a container
containing the minocycline topical suspension, or a device for
application of the minocycline topical suspension.
Location for Administration
[0138] The method may be further characterized according to the
location for administration of the minocycline topical suspension.
For example, in certain embodiments, the minocycline topical
suspension is topically administered to the eyelid margin of the
patient to form a strip having a width less than or equal to
one-quarter inches. In certain embodiments, the minocycline topical
suspension is topically administered to the eyelid margin of the
patient to form a strip having a width of about one-quarter inches.
In certain embodiments, the minocycline topical suspension is
topically administered across the full margin of the eyelid.
[0139] When administering minocycline topical suspension to the
eyelid margin, one embodiment is for the patient to pull down the
lower eyelid and look up, then use their finger to apply
minocycline topical suspension (e.g., a pea sized amount of
minocycline topical suspension) to the inside of the lower eyelid,
between the lower eyelid and the eye. The patient may optionally
apply the minocycline topical suspension as a thin ribbon on the
lower eyelid close to their nose (inner canthus) and direct outward
without touching the eyelash or the eye. The ribbon of minocycline
topical suspension is desirably deposited on the inside lining of
the lower eyelid.
[0140] Application of minocycline topical suspension to the eyelid
margin desirably brings the minocycline topical suspension into
contact with one or more of the tarsal conjunctiva, conjunctival
fornix, bulbar conjunctiva, or conjunctival sac. This disclosure
provides methods where, in lieu of applying minocycline topical
suspension as a strip across the eyelid margin, the minocycline
topical suspension is administered directly to one or more of the
tarsal conjunctiva, conjunctival fornix, bulbar conjunctiva, or
conjunctival sac.
[0141] In certain embodiments, the minocycline topical suspension
is administered to the eyelid margin of the patient using an
applicator. In certain embodiments, the minocycline topical
suspension is administered to the eyelid margin of the patient
using a fingertip. In certain embodiments, the minocycline topical
suspension is administered to the eyelid margin of the patient
using a container or vessel containing the minocycline topical
suspension.
Frequency of Administration
[0142] The method may be further characterized according to the
frequency of administration of the dose of minocycline topical
suspension. For example, in certain embodiments, the dose of
minocycline topical suspension is administered twice per day. In
certain embodiments, the dose of minocycline topical suspension is
administered twice per day, wherein the first dose of minocycline
topical suspension is administered in the morning and the second
dose of minocycline topical suspension is administered in the
evening. In certain embodiments, the dose of minocycline topical
suspension is administered twice per day, wherein there is from
about 8 hours to about 12 hours between administering the first
dose of minocycline topical suspension and administering the second
dose of minocycline topical suspension. In certain embodiments, the
dose of minocycline topical suspension is administered twice per
day, wherein there is at least about 8 hours between administering
the first dose of minocycline topical suspension and administering
the second dose of minocycline topical suspension. In certain
embodiments, the dose of minocycline topical suspension is
administered once per day.
[0143] In certain embodiments, for a duration of at least thirty
days the patient receives a dose of minocycline topical suspension
each day. In certain embodiments, for a duration of at least two
months the patient receives a dose of minocycline topical
suspension each day. In certain embodiments, for a duration of at
least three months the patient receives a dose of minocycline
topical suspension each day. In certain embodiments, for a duration
of at least six months the patient receives a dose of minocycline
topical suspension each day. In certain embodiments, for a duration
of at least twelve months the patient receives a dose of
minocycline topical suspension each day.
Blood Plasma Concentration
[0144] The method may be further characterized according to the
blood plasma concentration measurements of minocycline resulting
from administration of the topical minocycline topical suspension.
For example, in certain embodiments, administration of the
minocycline topical suspension results in a maximum blood plasma
concentration of minocycline in the patient that does not exceed 5,
4, 3, 2, 1, or 0.5 .mu.g/mL. In certain embodiments, administration
of the minocycline topical suspension results in a maximum blood
plasma concentration of minocycline in the patient that does not
exceed 3 .mu.g/mL. In certain embodiments, administration of the
minocycline topical suspension results in a maximum blood plasma
concentration of minocycline in the patient that does not exceed 1
.mu.g/mL.
[0145] In certain embodiments, administration of the minocycline
topical suspension results in an AUC of minocycline determined from
monitoring blood plasma amounts of minocycline that does not exceed
46, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5
h*.mu.g/mL. In certain embodiments, administration of the
minocycline topical suspension results in an AUC of minocycline
determined from monitoring blood plasma amounts of minocycline that
does not exceed 46 h*.mu.g/mL. In certain embodiments,
administration of the minocycline topical suspension results in an
AUC of minocycline determined from monitoring blood plasma amounts
of minocycline that does not exceed 1 h*.mu.g/mL.
3. Patient Populations that May Derive Particular Benefits from the
Therapeutic Methods
[0146] The method may be further characterized according to the
patient suffering from meibomian gland dysfunction that is being
treated. For example, in certain embodiments, the patient is a
human. In certain embodiments, the patient is an adult human. In
certain embodiments, the patient has mild meibomian gland
dysfunction. In certain embodiments, the patient has moderate
meibomian gland dysfunction. In certain embodiments, the patient
has severe meibomian gland dysfunction.
[0147] In certain embodiments, the patient suffers from dry eye. In
certain embodiments, the patient suffers from evaporative dry eye
disease.
[0148] In certain embodiments, the patient has an inflamed
meibomian gland.
Tear Osmolarity
[0149] The method may be further characterized according to the
tear osmolarity of the patient to be treated. For example, in
certain embodiments, the patient has a tear osmolarity value
greater than about 315 mOsmol/L. In certain embodiments, the
patient has a tear osmolarity value greater than about 310, 312,
315, 320, 325, or 330 mOsmol/L. In certain embodiments, the patient
has a tear osmolarity value in the range of from about 310 mOsmol/L
to 330 mOsmol/L. In certain embodiments, the patient has a tear
osmolarity value in the range of from about 310 mOsmol/L to 315
mOsmol/L. In certain embodiments, the patient has a tear osmolarity
value in the range of from about 315 mOsmol/L to 330 mOsmol/L.
Tear Film Matrix Metalloproteinase-9 (AIP-9) Concentration
[0150] The method may be further characterized according to the
tear film matrix metalloproteinase-9 (MMP-9) concentration of the
patient to be treated. For example, in certain embodiments, the
patient's tear film has a concentration of MMP-9 greater than about
40 ng/mL. In certain embodiments, the patient's tear film has a
concentration of MMP-9 greater than or equal 40 ng/mL. In certain
embodiments, the patient's tear film has a concentration of MMP-9
greater than about 45, 50, 55, 60, 65, 70, 75, or 80 ng/mL. In
certain embodiments, the patient's tear film has a concentration of
MMP-9 in the range of from about 40 ng/mL to about 60 ng/mL. In
certain embodiments, the patient's tear film has a concentration of
MMP-9 in the range of from about 60 ng/mL to about 80 ng/mL. In
certain embodiments, the patient's tear film has a concentration of
MMP-9 in the range of from about 40 ng/mL to about 80 ng/mL.
Tear Film Breakup Time
[0151] The method may be further characterized according to the
tear film breakup time of the patient to be treated. For example,
in certain embodiments, the patient's tear film breakup time has a
breakup time of less than 10 seconds. For example, in certain
embodiments, the tear film break up time is less than 8 seconds, 6
seconds, 4 seconds, or 2 seconds. In certain embodiments, the tear
film break up time is in the range of 1 second to 10 seconds. In
certain embodiments, the tear film break up time is in the range of
1 second to 5 seconds. In certain embodiments, the tear film break
up time is in the range of 1 second to 4 seconds. In certain
embodiments, the tear film break up time is in the range of 1
second to 2 seconds.
Meibomian Gland Dysfunction Symptom Flare Frequency
[0152] When treating meibomian gland dysfunction, the method may be
further characterized according to the frequency of symptom flare
due to meibomian gland dysfunction in the patient to be treated.
For example, in certain embodiments, the patient experiences a
symptom flare due to meibomian gland dysfunction on an average of
at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 times per
day. In certain embodiments, the patient experiences a symptom
flare due to meibomian gland dysfunction on an average of at least
one time per day. In certain embodiments, the patient experiences a
symptom flare due to meibomian gland dysfunction on an average of
at least 2 times per day. In certain embodiments, the patient
experiences a symptom flare due to meibomian gland dysfunction on
an average of at least 3 times per day. In certain embodiments, the
patient experiences a symptom flare due to meibomian gland
dysfunction on an average of at least one time per every two days.
In certain embodiments, the patient experiences a symptom flare due
to meibomian gland dysfunction on an average of from once per day
to 5 times per day.
[0153] In certain embodiments, the patient experiences a symptom
flare due to meibomian gland dysfunction on an average of at least
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30 times per week. In
certain embodiments, the patient experiences a symptom flare due to
meibomian gland dysfunction on an average of at least 5 times per
week. In certain embodiments, the patient experiences a symptom
flare due to meibomian gland dysfunction on an average of at least
10 times per week. In certain embodiments, the patient experiences
a symptom flare due to meibomian gland dysfunction on an average of
at least 20 times per week. In certain embodiments, the patient
experiences a symptom flare due to meibomian gland dysfunction on
an average of at least 40 times per week. In certain embodiments,
the patient experiences a symptom flare due to meibomian gland
dysfunction on an average of from once per week to 15 times per
week.
[0154] In certain embodiments, the patient has experienced an
average of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
20, 25, or 30 symptom flares due to meibomian gland dysfunction
during the month prior to first administration of the minocycline
topical suspension. In certain embodiments, the patient has
experienced an average of at least five symptom flares due to
meibomian gland dysfunction during the month prior to first
administration of the minocycline topical suspension. In certain
embodiments, the patient experiences a symptom flare due to
meibomian gland dysfunction on an average of from 10 times per
month to 30 times per month.
Therapeutic Improvements & Other Characteristics
[0155] The method may be further characterized according to
therapeutic benefits of administration of minocycline topical
suspension to the eyelid margin of the patient. Exemplary
therapeutic benefits that may be measured are described herein
below.
Reduction in Vascular Engorgement
[0156] The method may be further characterized according to the
reduction in vascular engorgement experienced by the patient. For
example, in certain embodiments, the method produces a reduction in
vascular engorgement score of at least 1. In certain embodiments,
the method produces a reduction in vascular engorgement score of at
least 2. For example, in certain embodiments, the method produces a
reduction in vascular engorgement score of at least 0.8, 0.9, 1,
1.1, or 1.2. In certain embodiments, after a duration of at least
three months where the patient has received a dose of minocycline
topical suspension each day, the patient has a vascular engorgement
score of no greater than 1.5. In certain embodiments, after a
duration of at least three months where the patient has received a
dose of minocycline topical suspension each day, the patient has a
vascular engorgement score of no greater than 1. In certain
embodiments, after a duration of at least three months where the
patient has received a dose of minocycline topical suspension each
day, the patient has a vascular engorgement score of 0. In certain
embodiments, after a duration of at least three months where the
patient has received a dose of minocycline topical suspension each
day, the patient has a vascular engorgement score of no greater
than 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9,
0.8, or 0.7.
Reduction in Eye Discomfort Visual Analog Score
[0157] The method may be further characterized according to the
reduction in the patient's eye discomfort visual analog score. For
example, in certain embodiments, the method produces a reduction in
Eye Discomfort Visual Analog Score of at least 20 percent. In
certain embodiments, the method produces a reduction in Eye
Discomfort Visual Analog Score of at least 20, 21, 22, 23, 24, 25,
26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 percent. In certain
embodiments, after a duration of at least three months where the
patient has received a dose of minocycline topical suspension each
day, the patient has an Eye Discomfort Visual Analog Score of no
greater than 50. In certain embodiments, after a duration of at
least three months where the patient has received a dose of
pharmaceutical composition each day, the patient has an Eye
Discomfort Visual Analog Score of no greater than 40. In certain
embodiments, after a duration of at least three months where the
patient has received a dose of pharmaceutical composition each day,
the patient has an Eye Discomfort Visual Analog Score of no greater
than 30. In certain embodiments, after a duration of at least three
months where the patient has received a dose of minocycline topical
suspension each day, the patient has an Eye Discomfort Visual
Analog Score of no greater than 25. In certain embodiments, after a
duration of at least three months where the patient has received a
dose of minocycline topical suspension each day, the patient has an
Eye Discomfort Visual Analog Score of no greater than 10. In
certain embodiments, after a duration of at least three months
where the patient has received a dose of minocycline topical
suspension each day, the patient has an Eye Discomfort Visual
Analog Score of no greater than 50, 45, 40, 39, 38, 37, 36, 35, 34,
33, 32, 31, or 30.
Reduction in Meibomian Gland Dysfunction Symptoms
[0158] When treating meibomian gland dysfunction, the method may be
further characterized according to the reduction in meibomian gland
dysfunction symptoms experienced by the patient. For example, in
certain embodiments, the method produces a reduction in the number
of symptom flares due to meibomian gland dysfunction. In certain
embodiments, the method produces at least a 5%, 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, 90%, or 100% reduction in the average number of
symptom flares per month due to meibomian gland dysfunction
compared to the average number of symptom flares due to meibomian
gland dysfunction experienced by the patient in the month prior to
first administering the minocycline topical suspension. In certain
embodiments, the method produces at least a 10% reduction in the
average number of symptom flares per month due to meibomian gland
dysfunction compared to the average number of symptom flares due to
meibomian gland dysfunction experienced by the patient in the month
prior to first administering the minocycline topical suspension. In
certain embodiments, the method produces at least a 50% reduction
in the average number of symptom flares per month due to meibomian
gland dysfunction compared to the average number of symptom flares
due to meibomian gland dysfunction experienced by the patient in
the month prior to first administering the minocycline topical
suspension. In certain embodiments, said reduction is achieved
within twelve weeks after first administering the minocycline
topical suspension. In certain embodiments, said reduction is
achieved within 4, 5, 6, 7, 8, 9 or 10 weeks after first
administering the minocycline topical suspension.
Tear Osmolarity
[0159] The method may be further characterized according to the
patient's tear osmolarity after receiving the minocycline topical
suspension. For example, in certain embodiments, the method
produces a reduction in tear osmolarity value in the patient. For
example, in certain embodiments, the patient's tear osmolarity
value is reduced to less than about 310, 312, or 315 mOsmol/L. In
certain embodiments, the patient's tear osmolarity value is reduced
to about 308 mOsmol/L.
[0160] In certain embodiments, the method produces at least a 1%,
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, or 20%
reduction in tear osmolarity value in the patient compared to the
patient's tear osmolarity value prior to starting treatment using
minocycline topical suspension. In certain embodiments, the method
produces at least a 1%, 2%, 3%, or 4% reduction in tear osmolarity
value in the patient compared to the patient's tear osmolarity
value prior to starting treatment using minocycline topical
suspension. In certain embodiments, the method produces at least a
1% to 5% reduction in tear osmolarity value in the patient compared
to the patient's tear osmolarity value prior to starting treatment
using minocycline topical suspension. In certain embodiments, the
method produces a reduction in tear osmolarity value in the range
of from about 5% to about 10%, from about 10% to about 20%, or from
about 20% to about 50% in the patient compared to the patient's
tear osmolarity value prior to starting treatment using minocycline
topical suspension.
[0161] In certain embodiments, said reduction is achieved within
twelve weeks after first administering the minocycline topical
suspension. In certain embodiments, said reduction is achieved
within 4, 5, 6, 7, 8, 9 or 10 weeks after first administering the
minocycline topical suspension.
Tear Film MMP-9 Concentration
[0162] The method may be further characterized according to the
patient's tear film MMP-9 concentration after receiving the
minocycline topical suspension. For example, in certain
embodiments, the method produces a reduction in MMP-9 concentration
in the patient's tear film. For example, in certain embodiments,
the patient's tear film MMP-9 concentration is reduced to less than
about 5, 10, 15, 20, 25, 30, 35, or 40 ng/mL. In certain
embodiments, the patient's tear film MMP-9 concentration is reduced
to less than about 20 ng/mL. In certain embodiments, the patient's
tear film MMP-9 concentration is reduced to less than about 40
ng/mL. In certain embodiments, the patient's tear film MMP-9
concentration is reduced to less than 40 ng/mL. In certain
embodiments, the patient's tear film MMP-9 concentration is reduced
to a concentration in the range of from about 3 ng/mL to about 40
ng/mL. In certain embodiments, the patient's tear film MMP-9
concentration is reduced to a concentration in the range of from
about 3 ng/mL to about 20 ng/mL. In certain embodiments, the
patient's tear film MMP-9 concentration is reduced to a
concentration in the range of from about 20 ng/mL to about 40
ng/mL. In certain embodiments, the patient's tear film MMP-9
concentration is reduced to a concentration in the range of from
about 3 ng/mL to less than 40 ng/mL.
[0163] In certain embodiments, the method produces at least a 1%,
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% 10%, 12%, 14%, 16%, 18%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in MMP-9
concentration in the patient's tear film compared to the patient's
tear film MMP-9 concentration prior to starting treatment using
minocycline topical suspension. In certain embodiments, the method
produces at least a 5% reduction in MMP-9 concentration in the
patient's tear film compared to the patient's tear film MMP-9
concentration prior to starting treatment using minocycline topical
suspension. In certain embodiments, the method produces at least a
10% reduction in MMP-9 concentration in the patient's tear film
compared to the patient's tear film MMP-9 concentration prior to
starting treatment using minocycline topical suspension. In certain
embodiments, the method produces at least a 20% reduction in MMP-9
concentration in the patient's tear film compared to the patient's
tear film MMP-9 concentration prior to starting treatment using
minocycline topical suspension.
[0164] In certain embodiments, said reduction is achieved within
twelve weeks after first administering the minocycline topical
suspension. In certain embodiments, said reduction is achieved
within 4, 5, 6, 7, 8, 9 or 10 weeks after first administering the
minocycline topical suspension.
[0165] In certain embodiments, after twelve weeks of administering
the minocycline topical suspension, at least 20% of patients that
originally had a tear film MMP-9 concentration of at least 40 ng/mL
now have a tear film MMP-9 concentration less than 40 ng/mL. In
certain embodiments, after twelve weeks of administering the
minocycline topical suspension, at least 30% of patients that
originally had a tear film MMP-9 concentration of at least 40 ng/mL
now have a tear film MMP-9 concentration less than 40 ng/mL. In
certain embodiments, after twelve weeks of administering the
minocycline topical suspension, at least 40% of patients that
originally had a tear film MMP-9 concentration of at least 40 ng/mL
now have a tear film MMP-9 concentration less than 40 ng/mL. In
certain embodiments, after twelve weeks of administering the
minocycline topical suspension, at least 32%, 34%, 36%, 38%, 40%,
42%, 44%, 46%, or 48% of patients that originally had a tear film
MMP-9 concentration of at least 40 ng/mL now have a tear film MMP-9
concentration less than 40 ng/mL.
Tear Film Breakup Time
[0166] The method may be further characterized according to the
patient's tear film breakup time after receiving the minocycline
topical suspension. For example, in certain embodiments, the method
produces an increase in tear film breakup time. For example, in
certain embodiments, the tear film break up time is increased to at
least 10, 12, 14, or 16 seconds. In certain embodiments, the tear
film break up time is increased to at least 10 seconds. In certain
embodiments, the tear film break up time is increased to within the
range of 10 seconds to 20 seconds. In certain embodiments, the tear
film break up time is increased to within the range of 10 seconds
to 14 seconds.
[0167] In certain embodiments, the method produces at least a 1%,
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, or 100% increase in tear film breakup
time compared to the patient's tear film break up time prior to
starting treatment using minocycline topical suspension. In certain
embodiments, the method produces at least a 10% increase in tear
film breakup time compared to the patient's tear film break up time
prior to starting treatment using minocycline topical suspension.
In certain embodiments, the method produces at least a 25% increase
in tear film breakup time compared to the patient's tear film break
up time prior to starting treatment using minocycline topical
suspension. In certain embodiments, the method produces at least a
50% increase in tear film breakup time compared to the patient's
tear film break up time prior to starting treatment using
minocycline topical suspension.
[0168] In certain embodiments, said increase is achieved within
twelve weeks after first administering the minocycline topical
suspension. In certain embodiments, said increase is achieved
within 4, 5, 6, 7, 8, 9 or 10 weeks after first administering the
minocycline topical suspension.
Symptom Flares Due to Meibomian Gland Dysfunction
[0169] When treating meibomian gland dysfunction, the method may be
further characterized according to the number of symptom flares due
to meibomian gland dysfunction experienced by the patient after
receiving the minocycline topical suspension. For example, in
certain embodiments, the method produces a reduction in the number
of symptom flares experienced by the patient per day due to
meibomian gland dysfunction. In certain embodiments, as a result of
the method, the average number of symptom flares experienced by the
patient per day due to meibomian gland dysfunction is less than 2.
In certain embodiments, as a result of the method, the average
number of symptom flares experienced by the patient per day due to
meibomian gland dysfunction is less than 1.
[0170] In certain embodiments, as a result of the method, the
average number of symptom flares experienced by the patient per
week due to meibomian gland dysfunction is less than 3. In certain
embodiments, as a result of the method, the average number of
symptom flares experienced by the patient per week due to meibomian
gland dysfunction is less than 2. In certain embodiments, as a
result of the method, the average number of symptom flares
experienced by the patient per week due to meibomian gland
dysfunction is less than 1.
[0171] In certain embodiments, as a result of the method, the
average number of symptom flares experienced by the patient per
month due to meibomian gland dysfunction is less than 50, 40, 30,
25, 20, 10, 5, or 1. In certain embodiments, as a result of the
method, the average number of symptom flares experienced by the
patient per month due to meibomian gland dysfunction is less than
10. In certain embodiments, as a result of the method, the average
number of symptom flares experienced by the patient per month due
to meibomian gland dysfunction is less than 4. In certain
embodiments, as a result of the method, the average number of
symptom flares experienced by the patient per month due to
meibomian gland dysfunction is less than 2.
[0172] In certain embodiments, the method produces at least a 1%,
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% 10%, 12%, 14%, 16%, 18%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the average
number of symptom flares per day due to meibomian gland dysfunction
compared to the average number of symptom flares per day prior to
starting treatment using minocycline topical suspension. In certain
embodiments, the method produces at least a 10% reduction in the
average number of symptom flares per day due to meibomian gland
dysfunction compared to the average number of symptom flares per
day prior to starting treatment using minocycline topical
suspension. In certain embodiments, the method produces at least a
50% reduction in the average number of symptom flares per day due
to meibomian gland dysfunction compared to the average number of
symptom flares per day prior to starting treatment using
minocycline topical suspension.
[0173] In certain embodiments, the method produces at least a 1%,
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% 10%, 12%, 14%, 16%, 18%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the average
number of symptom flares per week due to meibomian gland
dysfunction compared to the average number of symptom flares per
week prior to starting treatment using minocycline topical
suspension. In certain embodiments, the method produces at least a
10% reduction in the average number of symptom flares per week due
to meibomian gland dysfunction compared to the average number of
symptom flares per week prior to starting treatment using
minocycline topical suspension. In certain embodiments, the method
produces at least a 50% reduction in the average number of symptom
flares per week due to meibomian gland dysfunction compared to the
average number of symptom flares per week prior to starting
treatment using minocycline topical suspension.
[0174] In certain embodiments, the method produces at least a 1%,
2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the average
number of symptom flares per month due to meibomian gland
dysfunction compared to the average number of symptom flares per
month prior to starting treatment using minocycline topical
suspension. In certain embodiments, the method produces at least a
10% reduction in the average number of symptom flares per month due
to meibomian gland dysfunction compared to the average number of
symptom flares per month prior to starting treatment using
minocycline topical suspension. In certain embodiments, the method
produces at least a 50% reduction in the average number of symptom
flares per month due to meibomian gland dysfunction compared to the
average number of symptom flares per month prior to starting
treatment using minocycline topical suspension.
[0175] In certain embodiments, said reduction is achieved within
twelve weeks after first administering the minocycline topical
suspension. In certain embodiments, said reduction is achieved
within 4, 5, 6, 7, 8, 9 or 10 weeks after first administering the
minocycline topical suspension.
Minocycline-Induced Hyperpigmentation of the Conjunctiva
[0176] Because minocycline-induced hyperpigmentation of the
conjunctiva can occur as an adverse side effect when too large a
dose of minocycline is administered to the patient's eye, the
method can be further characterized according to number of
occurrences of minocycline-induced hyperpigmentation of the
conjunctiva. In certain embodiments, the patient experiences fewer
than 1, 2, 3, 4, or 5 occurrences of minocycline-induced
hyperpigmentation of the conjunctiva while receiving the
minocycline topical suspension. In certain embodiments, the patient
experiences no occurrences of minocycline-induced hyperpigmentation
of the conjunctiva while receiving the minocycline topical
suspension.
[0177] In certain embodiments, the foregoing occurrences of
minocycline-induced hyperpigmentation of the conjunctiva is the sum
of the occurrences that occurred over 2, 3, 4, 5, 6, 7, 8, 9 or 10
weeks of administering the minocycline topical suspension.
Minocycline-Induced Hyperpigmentation of the Retina
[0178] Because minocycline-induced hyperpigmentation of the retina
can occur as an adverse side effect when too large a dose of
minocycline is administered to the patient's eye, the method can be
further characterized according to number of occurrences of
minocycline-induced hyperpigmentation of the retina. In certain
embodiments, the patient experiences fewer than 1, 2, 3, 4, or 5
occurrences of minocycline-induced hyperpigmentation of the retina
while receiving the minocycline topical suspension. In certain
embodiments, the patient experiences no occurrences of
minocycline-induced hyperpigmentation of the retina while receiving
the minocycline topical suspension.
[0179] In embodiments, the foregoing occurrences of
minocycline-induced hyperpigmentation of the retina is the sum of
the occurrences that occurred over 2, 3, 4, 5, 6, 7, 8, 9 or 10
weeks of administering the minocycline topical suspension. 5.
Compositions for Medical Use
[0180] Minocycline topical suspensions described herein may be used
to treat a medical condition described herein. The use may be
according to a method described herein. For example, one aspect of
the invention provides a minocycline topical suspension for use in
treating meibomian gland dysfunction by topical administration to
the eyelid margin of a patient in need thereof once or twice per
day a dose of the minocycline topical suspension, wherein the dose
provides from about 0.1 mg to about 1.4 mg of minocycline, and the
minocycline topical suspension comprises: [0181] a) minocycline in
a suspended form within the topical suspension; [0182] b) a liquid
medium that dissolves less than 5% (w/w) of the minocycline at room
temperature after two hours, wherein the liquid medium contains
mineral oil; and [0183] c) a polymeric hydrocarbon gelling agent;
[0184] wherein particles of minocycline in the topical suspension
have a D90 particle size less than 8 microns, and the topical
suspension comprises from about 0.1% (w/w) to about 2% (w/w)
minocycline.
[0185] Embodiments described herein in connection with the methods
for treatment may be applied in connection with the minocycline
topical suspensions for use.
6. Preparation of a Medicament
[0186] Minocycline topical suspensions described herein may be used
in the preparation of a medicament to treat a medical condition
described herein. For example, one aspect of the invention provides
for the use a minocycline topical suspension described herein in
the preparation of a medicament treating meibomian gland
dysfunction by topical administration to the eyelid margin of a
patient in need thereof once or twice per day a dose of the
minocycline topical suspension, wherein the dose provides from
about 0.1 mg to about 1.4 mg of minocycline, and the minocycline
topical suspension comprises: [0187] a) minocycline in a suspended
form within the topical suspension; [0188] b) a liquid medium that
dissolves less than 5% (w/w) of the minocycline at room temperature
after two hours, wherein the liquid medium contains mineral oil;
and [0189] c) a polymeric hydrocarbon gelling agent; and [0190]
wherein particles of minocycline in the topical suspension have a
D90 particle size less than 8 microns, and the topical suspension
comprises from about 0.1% (w/w) to about 2% (w/w) minocycline.
[0191] Embodiments described herein in connection with the methods
for treatment may be applied in connection with the minocycline
topical suspensions for use in the preparation of a medicament.
II. Medical Kits
[0192] Another aspect of the invention provides a medical kit
comprising, for example, (i) a composition described herein, and
(ii) instructions for treating meibomian gland dysfunction
according to methods described herein.
EXAMPLES
[0193] The invention now being generally described, will be more
readily understood by reference to the following examples, which
are included merely for purposes of illustrating certain aspects
and embodiments of the present invention, and are not intended to
limit the invention.
Example 1--Treatment of Meibomian Gland Dysfunction by Minocycline
Topical Suspension in Human Subjects
[0194] The ability of minocycline topical suspension to treat a
human subject suffering from meibomian gland dysfunction was
evaluated according to the clinical study described below in which
minocycline topical suspension was administered to the eyelid
margin of the patient, and then the patient was evaluated for
improvement. Experimental procedures and results are described
below.
Part I--Experimental Procedures
A. Study Summary
[0195] In order to evaluate the efficacy and safety of two
strengths of minocycline topical suspension (Test Article) versus
Vehicle administered twice daily for twelve weeks in subjects with
a diagnosis of inflamed meibomian gland dysfunction, the following
procedures are carried out.
[0196] The trial is structured as a multi-center, double-masked,
randomized, vehicle-controlled, parallel-group study. Subjects are
randomized into three groups: 0.3% BID Test Article, 1% BID Test
Article or Vehicle BID in a 1:1:1 ratio. BID refers to twice daily
administration.
[0197] Double-Masked Investigational Product (IP), which is 0.3%
Test Article or 1% Test Article, is administered BID to both eyes
for twelve weeks. Each dose is delivered using a fingertip, as an
instillation of approximately 14 inch strip (equivalent to
approximately 50 .mu.L drop) in each eye. IP is instilled to full
eyelid margin. Subjects are instructed to wash hands thoroughly
prior to administration of IP. Following administration of the IP,
subjects are allowed to blot or clean the lower eyelid skin, if
necessary.
[0198] At Visit 1 (Screening) informed consent is obtained from
subjects and eligibility is determined. After the screening
assessment, eligible subjects are entered into a 2-week
Single-Masked Run-In period, during which a Single-Masked Vehicle
BID is instilled in each eye.
[0199] At Visit 2 (Randomization/Baseline) eligibility is
reconfirmed and subjects are randomly assigned to one of the three
Double-Masked treatment groups (0.3% or 1% Test Article or Vehicle)
and IP is instilled BID for twelve weeks. The randomization is
stratified on the presence/absence of evaporative dry eye disease
(DED) diagnosis. At Visit 3 (Week 2), Visit 4 (Week 4), Visit 5
(Week 8), and Visit 6 (Week 12) subjects attend clinic visits where
efficacy and safety evaluations are performed. Treatment with
Double-Masked IP is discontinued at Visit 6. Subjects who
discontinue before Visit 6 undergo Visit 6 evaluations (at the
Early Termination visit).
[0200] At Visit 7 (Week 16) Post-Treatment Follow-up Visit,
efficacy and safety evaluations are performed.
[0201] Since the Vehicle is not color matched with the active
product, there is a Dedicated Dosing Coordinator who is responsible
for handling of IP and activities surrounding the use of IP.
Further, the subjects are informed via the Informed Consent (IC)
Process and document, that they will receive Vehicle at some
unspecified time in the study. This supports masking efforts as the
subjects are unable to differentiate which product is Vehicle and
which is active.
B. Investigational Product (IP)
[0202] Test Article is supplied as a sterile ointment. Test Article
is packaged in a 5 gm lacquer-lined aluminum tube with a nasal tip
and a low density polyethylene cap closure. Subjects randomized to
the Vehicle control arm receive the same tubes containing all
components at the concentrations used in the Test Article except
for the active component.
TABLE-US-00001 TABLE 1-A COMPOSITION OF 0.3% TEST ARTICLE Component
Amount Function Minocycline base 0.3% w/w active ingredient
Polymeric hydrocarbon gelling agent 69.8% w/w gelling agent
commercially available under the tradename VERSAGEL .RTM. M-750
Mineral oil 29.9% w/w wetting agent
TABLE-US-00002 TABLE 2-B COMPOSITION OF 1% TEST ARTICLE Component
Amount Function Minocycline base 1% w/w active ingredient Polymeric
hydrocarbon gelling agent 69.3% w/w gelling agent commercially
available under the tradename VERSAGEL .RTM. M-750 Mineral oil
29.7% w/w wetting agent
TABLE-US-00003 TABLE 3 COMPOSITION OF VEHICLE Component Function
Polymeric hydrocarbon gelling agent gelling agent commercially
available under the tradename VERSAGEL .RTM. M-750 Mineral oil
wetting agent
[0203] The minocycline base is minocycline base in crystalline Form
II. The polymeric hydrocarbon gelling agent commercially available
under the tradename VERSAGEL.RTM. M-750 is a mixture of
ethylene-propylene-styrene copolymer, butylene-ethylene-styrene
copolymer, butylated-hydroxytoluene, and mineral oil. The
ethylene-propylene-styrene copolymer (e.g., weight-average
molecular weight of about 200,000 g/mol) is present in an amount
within the range of 2.5% to 10% (w/w), the
butylene-ethylene-styrene copolymer (e.g., weight-average molecular
weight of about 100,000 g/mol) is present in an amount within the
range of 0.1% to 2.5% (w/w), the butylated-hydroxytoluene is
present in an amount <0.5% (w/w), and the remainder is mineral
oil (e.g., having a weight-average molecular weight in the range of
230-700 g/mol).
[0204] The Single-Masked Run-In product contains a tube of IP which
is sufficient for 3-weeks of dosing. Each randomized, double-masked
IP kit contains six tubes of IP, each sufficient for 3 weeks of
dosing.
C. IP Dispensation Instructions
[0205] At Visit 1, (Day -14/Screening), subjects receive their
first dose of Single-Masked Run-In product which is
self-administered in the clinic under the supervision of the
Dedicated Dosing Coordinator. IP is instilled to the full eyelid
margin. Subjects are instructed to wash hands thoroughly prior to
administration of IP. (Following administration of the IP, subjects
are allowed to blot or clean the lower eyelid skin, if
necessary.)
[0206] They then receive one tube of Run-In from a general supply
to take home for self-administration. The tube of Single-Masked
Run-In is returned to the site at Visit 2 (Day
1/Randomization).
[0207] At Visit 2, randomized subjects are assigned to an
Investigational Product Kit which contains six tubes of
Double-Masked IP (Test Article or Vehicle). The first dose of
Double-Masked IP (Test Article or Vehicle) is self-administered in
the clinic by the subject under the supervision of the Dedicated
Dosing Coordinator. They then receive one tube of Double-Masked IP
from their assigned kit to take home for self-administration.
Subjects are instructed to apply IP to the full eyelid margin and
to wash hands thoroughly prior to administration of IP as was the
same at Visit 1.
[0208] Subjects will return the used tube of IP at Visit 3 and at
Visit 3 will receive one new tube of IP which is returned at Visit
4. At Visits 4 and 5, subjects will receive two new tubes of IP at
each visit which are returned at Visits 5 and 6, respectively. The
Double-Masked box labels and the tubes will contain the following
information: sponsor name, protocol number, kit number, storage
temperature, and required statement(s) per the appropriate
regulatory agency.
[0209] Test Article is stored at 20-25.degree. C. (68-77.degree.
F.); excursions permitted between 15-30.degree. C. (59-86.degree.
F.). IP is protected from light and moisture.
[0210] To minimize bias, the following measures are taken: [0211]
Investigational product allocation (Test Article versus Vehicle) is
randomized and masked to the Sponsor, subjects, and select
investigative staff. [0212] The randomization schedule is generated
by and independent unmasked statistician (who is not on the project
team) or designee and maintained in a secure and limited-access
location separate from the study Investigator and members of the
project team. [0213] To account for the use of a non-color matched
Vehicle, a Dedicated Dosing Coordinator, who is otherwise
uninvolved in study assessments, dispense the tube of
investigational product to the subject and supervise the subjects'
in clinic instilled dose. [0214] To account for potential bias, the
investigative staff should acknowledge and report any instance
where unmasking may have occurred (outside of the dedicated dosing
coordinator role). This report should include which individual(s)
were involved (e.g., investigator, study coordinator, subject,
monitor, etc.).
D. Timing of Self-Administration
[0215] At Visit 1, subjects self-administer the first dose of
Single-Masked Run-In product in the clinic under the supervision of
the Dedicated Dosing Coordinator. Subjects then self-administer
additional doses of investigational product during the remainder of
the Run-In period. At Visit 2, subjects self-administer their first
dose of Double-Masked IP under the supervision of the Dedicated
Dosing Coordinator. Subjects then self-administer additional doses
of IP during the remainder of the study. It is recommended that
visits be scheduled in the morning to allow subjects to receive the
two daily doses 8 to 12 hours apart, with the AM dose occurring in
the clinic for Visit 2/Day 1.+-.2 days.
[0216] Subjects are asked to instill the first daily dose upon
awakening and then the second daily dose approximately 8 to 12
hours later. The two daily doses are described as "Morning (AM)
Dose" and "Evening (PM) Dose."
[0217] Following Visit 2, clinic visits are scheduled prior to the
subject administration of their morning dose if possible. If the
subject does take a dose, the visit is scheduled at least 2 hours
following the morning dose to prevent the subject from being
evaluated with residual investigational product on the eyelids.
E. Efficacy Endpoints
1. Primary Efficacy Endpoints
[0218] The primary endpoints of this study are evaluated using
hierarchical statistical testing in the following sequence (Note:
the analysis are performed on the intent-to-treat (ITT) population
as well as a subset of subjects who meet the criteria for both
inflamed meibomian gland dysfunction and evaporative dry eye
disease): [0219] Changes in Vascular Engorgement at the study
eyelid margin as graded by the investigator at Week 12 (Visit 6)
from Randomization/Baseline (Visit 2) in 1% Test Article compared
to Vehicle [0220] Change in Eye Discomfort Visual Analogue Score
(VAS) at Week 12 (Visit 6) from Randomization/Baseline (Visit 2) in
1% Test Article compared to Vehicle [0221] Changes in Vascular
Engorgement at the study eyelid margin as graded by the
investigator at Week 12 (Visit 6) from Randomization/Baseline
(Visit 2) in 0.3% Test Article compared to Vehicle [0222] Change in
Eye Discomfort VAS at Week 12 (Visit 6) from Randomization/Baseline
(Visit 2) in 0.3% Test Article compared to Vehicle 2. Secondary
Efficacy Endpoints
[0223] The secondary endpoints of the study include: [0224] Change
in Fluorescein Corneal Staining (FCS) total score (NEI/Industry
Workshop 0-15 scale) in the study eye at Week 4 (Visit 4), Week 8
(Visit 5), Week 12 (Visit 6), and Week 16 (Visit 7) from
Randomization/Baseline (Visit 2). [0225] Change in FCS inferior,
nasal, and central combined score (NEI/Industry Workshop section 1,
4 and 5 with a 0-9 scale) in the study eye at Week 4 (Visit 4),
Week 8 (Visit 5), Week 12 (Visit 6), and Week 16 (Visit 7) from
Randomization/Baseline (Visit 2). [0226] Change in FCS inferior
score (NEI/Industry Workshop section 5 with a 0-3 scale) in the
study eye at Week 4 (Visit 4), Week 8 (Visit 5), Week 12 (Visit 6),
and Week 16 (Visit 7) from Randomization/Baseline (Visit 2). [0227]
Changes in Eye Discomfort Visual Analogue Score (VAS) at Week 4
(Visit 4), Week 8 (Visit 5), Week 12 (Visit 6), and Week 16 (Visit
7) from Randomization/Baseline (Visit 2). [0228] Changes in
Investigator-rated assessments of objective signs of meibomian
gland dysfunction (MGD) including change from
Randomization/Baseline (Visit 2) at each follow up visit using
individual severity scores: [0229] Vascular engorgement of the
eyelid margin [0230] Plugging of Meibomian Gland [0231] Character
of Secretion Expressed [0232] Expressibility of the Meibomian Gland
[0233] Changes in Investigator reported scores on objective signs
of Meibomian Gland Dysfunction for Total Clinical Outcome Severity
Score from Randomization/Baseline (Visit 2) defined as the sum of
the four individual severity scores for the clinical signs of:
[0234] Vascular Engorgement of eyelid margin [0235] Plugging of
Meibomian Gland [0236] Character of Secretion Expressed [0237]
Expressibility of the Meibomian Gland [0238] Changes in
Investigator reported scores on objective Conjunctival Tarsal
Erythema change from Randomization/Baseline (Visit 2) at each
follow up visit. [0239] Changes in Tear Film Break-Up Time (TFBUT)
from Randomization/Baseline (Visit 2) at each follow up visit.
[0240] Changes in the following Dry Eye-related ocular symptoms at
each follow-up visit: [0241] VAS Scale Symptoms (other than eye
discomfort): [0242] Eye Dryness [0243] Foreign Body Sensation
[0244] SANDE change in the square root of the product of the two
questions at each timepoint compared to baseline and the change
from baseline of each individual question within the SANDE [0245]
The mean tear osmolarity score at each follow up visit compared to
baseline. (This are evaluated at a subset of clinical sites.)
[0246] The proportion of subjects converting from positive point of
care matrix metalloproteinase-9 (MMP-9) to negative point of care
MMP-9 at Week 12 (Visit 6). [0247] Number of symptom flares during
the 12 weeks of treatment. [0248] The change from baseline in the
unanesthetized Schirmer score.
3. Safety Endpoints
[0249] Safety endpoints of the study include: [0250] Adverse Event
(AE) Monitoring [0251] Best Corrected Visual Acuity (BCVA) [0252]
Slit Lamp Biomicroscopy and External Eye Exam [0253] Intraocular
Pressure (IOP) Measurement [0254] Dilated Ophthalmoscopy [0255]
Follow-Up Assessment
F. Selection of Subjects
1. Subject Inclusion Criteria
[0256] At Visit 1, individuals of any gender or any race is
eligible for study participation if they: [0257] 1. Have provided
written informed consent prior to any study procedures. [0258] 2.
Are 18 years of age or above. [0259] 3. Have a clinical diagnosis
of moderate to severe MGD and who meet the following criteria, in a
qualifying eyelid, at both Visit 1 (Screening) and Visit 2
(Randomization) examinations: [0260] a. Clinical sign severity
score of at least 2 (moderate) on vascular engorgement at the
eyelid margin and [0261] b. Clinical sign severity score of at
least 2 (moderate) on plugging of the meibomian glands. [0262] c.
Eye Discomfort Symptom score of .gtoreq.40 using VAS (0-100 point
scale) [0263] 4. Meet the following criteria, in a qualifying eye
(same eye that qualifies for Inclusion #3), at both the Visit 1
(Screening) and Visit 2 (Randomization) examinations: [0264] a.
Fluorescein corneal staining (FCS) total score .gtoreq.3 in the
inferior, central, and nasal region combined score (NEI/Industry
Workshop sections 1, 4 and 5 with 0-9 scale) [0265] b. Schirmer
score of >7 mm without topical anesthesia [0266] 5. Are willing
and able to follow instructions and can be present for the required
study visits for the duration of the study. [0267] 6. Have a BCVA,
using corrective lenses if necessary, in both eyes of at least +0.7
as assessed by Early Treatment of Diabetic Retinopathy Study
(ETDRS) or modified ETDRS. [0268] 7. If female, are non-pregnant,
non-lactating and women of childbearing potential (WOCBP) must be
using an acceptable method of birth control [e.g., an Intrauterine
Contraceptive Device (IUCD) with a failure rate of <1%, hormonal
contraceptives, or a barrier method] for the duration of the study.
If a female subject is currently abstinent, they must agree to use
one of the acceptable methods of birth control before they become
sexually active.
2. Subject Exclusion Criteria
[0269] In order for subjects to be eligible at Visit 1 they may
not: [0270] 1. Have presence of inflammation and/or active
structural change in the iris or anterior chamber. [0271] 2. Have
lid structural abnormalities such as entropion or ectropion. [0272]
3. In the eyelid that qualifies (based on Inclusion #3), have grade
level 4 (Obstructed) on Character of Secretion of Meibomian Glands
or grade level 4 (No glands are expressible) on the Expressibility
of Meibomian Glands. [0273] 4. Subjects with ocular inflammatory
conditions (e.g., conjunctivitis, keratitis, anterior blepharitis,
etc.) not related to MGD. [0274] 5. Subjects who have FCS total
score=15 or a score=3, in either eye, in the superior region
NEI/Industry Workshop scale or subjects who have FCS with diffuse
confluent staining, filaments or frank epithelial defects. [0275]
6. Have suspected ocular fungal, viral or bacterial infection.
[0276] 7. Have had penetrating intraocular surgery in the past 90
days or require penetrating intraocular surgery during the study.
[0277] 8. Have had ocular surface surgery within 12 months of Visit
1 (e.g., LASIK, refractive, pterygium removal). [0278] 9. Subjects
who within the past 90 days have had cauterization of the punctum
or changes to the status (insertion or removal) of punctal plug(s)
before the Screening Visit. [0279] 10. Have used topical ocular or
oral antibiotics within 30 days of the study or expect to use
during the study. [0280] 11. Have used LipiFlow or hypochlorous
acid spray within 30 days of the study or expect to use during the
study. [0281] 12. If using inhaled or intranasal corticosteroids,
unable to maintain a stable dose for the duration of the study.
[0282] 13. Have ever used isotretinoin. [0283] 14. If using Omega-3
supplements, dose must be stable for 3 months prior to Visit 1 and
for the duration of the study. [0284] 15. Have used topical
cyclosporine within 30 days of the study or during the study.
[0285] 16. Have used topical lifitegrast within 30 days of the
study or during the study. [0286] 17. Have used systemic
corticosteroids within 30 days prior to study entry or during study
participation. [0287] 18. Have used topical ocular corticosteroids
or ocular non-steroidal anti-inflammatory drugs (NSAIDs) within 30
days prior to study entry and during study participation. [0288]
19. Have used topical ocular antihistamine and/or mast cell
stabilizers within 30 days prior to study entry or during study
participation. [0289] 20. Are unable or unwilling to discontinue
using any preserved or unpreserved topical ocular medications
(including artificial tears) upon Screening and for the duration of
the study. [0290] 21. Are unwilling to discontinue use of contact
lenses during the study. [0291] 22. Are unwilling to discontinue
use of cosmetic makeup applied to the eyelids or eye lashes at the
Screening Visit and during the study. If makeup was used, it should
be removed at least 12 hours prior to the Visit 1. [0292] 23. Have
a known hypersensitivity to minocycline, any other tetracycline
antibiotic, or to any of the other ingredients in the
investigational product. [0293] 24. Are unable or unwilling to
withhold the use of eyelid scrubs or use of mechanical therapy
during the study. [0294] 25. Have been diagnosed with glaucoma or
are currently using any glaucoma medication. [0295] 26. Have a
history of herpetic keratitis. [0296] 27. Have a concomitant ocular
pathology other than condition under study assessed as potentially
confounding by the investigator. [0297] 28. Have a serious systemic
disease or uncontrolled medical condition that in the judgment of
the investigator could confound study assessments or limit
compliance. [0298] 29. Have been exposed to any investigational
drug or investigational device within the preceding 30 days. [0299]
30. Are an employee of the site that is directly involved in the
management, administration, or support of this study or be an
immediate family member of the same. [0300] 31. Have trigger
factors including conjunctivochalasis, allergic conjunctivitis,
contact lens intolerance, trichiasis, epithelial basement membrane
dystrophy, infectious keratitis or conjunctivitis [0301] 32. Have a
documented history of ocular allergies, which, in the judgment of
the investigator, are likely to have an acute increase in severity
due to the expected timing of the exposure to the allergen to which
the subject is sensitive. Subjects sensitive to seasonal allergens
that are not expected to be present during the study are
permitted.
3. Study Eye Selection
[0302] The study eye is the eye with the eyelid at Visit 2, having
the worst (higher) score defined as the sum of the following two
severity scores for the clinical signs of Meibomian Gland Disease
(Note, the study eye and eyelid must have met qualifying
eligibility criteria at Visit 1 and Visit 2): [0303] 1. Vascular
Engorgement of eyelid margin [0304] 2. Plugging of the Meibomian
Gland
[0305] If both eyes, and eyelids, have the same score, then the
right eye and upper eyelid is selected.
G. Randomization
[0306] At the Randomization Visit (Visit 2), an eligible subject
must continue to meet all clinical inclusion/exclusion criteria as
defined above. Subjects must meet all criteria from Visit 1 and
inflamed MGD criteria in the same qualifying eye and/or qualifying
eyelid as in Visit 1. Further, subjects must be 80% compliant with
respect to dosing of Run-In IP and diary completion.
[0307] Randomization is stratified by absence and presence of
evaporative DED in the study eye (identified prior to
randomization). A clinical diagnosis of evaporative DED in the
study eye, is defined as meeting the following criteria at Visit 2
(Randomization/Baseline): [0308] 1. Fluorescein corneal staining
(FCS) total score .gtoreq.6 in the inferior, central, and nasal
region combined score (NEI/Industry Workshop section 1, 4 and 5
with 0-9 scale) and [0309] 2. Symptom Severity score of .gtoreq.50
using the SANDE questionnaire
H. Visit Descriptions
[0310] Written Informed Consent and Health Insurance Portability
and Accountability Act (HIPAA) authorization are obtained from all
subjects prior to any study procedures being performed. Visit
assessments are performed in the order suggested in both eyes.
1. Visit 1 (Screening): 14 (.+-.2) days prior to Visit 2
[0311] The following is performed/assessed in the order suggested
below and in both eyes: [0312] Explain the purpose and conduct of
the study to the subject, answer the subject's questions, and
obtain written informed consent. [0313] Obtain information
including: demographics, concomitant medications, ocular and
systemic medical and medication history and surgical history.
[0314] A Screening ID is assigned to the Subject once any Visit 1
procedures are performed. [0315] Subject Rated Symptom Assessments
(in this order): [0316] 1. Individual Symptom Assessment via VAS
[0317] 2. SANDE [0318] For all eligible women of childbearing
potential, perform a urine pregnancy test (UPT) to confirm that the
subject is not pregnant. [0319] BCVA [0320] Tear Osmolarity
(conducted at a subset of sites) [0321] External Eye Exam [0322]
Slit-lamp biomicroscopy [0323] Investigator-rated assessment of
Meibomian Gland Dysfunction (in both eyes for upper and lower lids)
[0324] See Section N. Assessment of Efficacy for full description
of investigator-rated assessments for objective signs of change
from baseline using five individual severity scores [0325] TFBUT
[0326] FCS (NEI/Industry Workshop scale) [0327] Unanesthetized
Schirmer test [0328] Wait 10 minutes prior to MMP-9 Assessment
[0329] MMP-9 Point of Care Assessment [0330] IOP [0331] Dilated
Ophthalmoscopy [0332] Determine if the subject is eligible to
continue in the study. Do not continue screening any subject who
does not meet eligibility requirements. Any subject who does not
meet eligibility requirements are designated as a Screen Failure.
[0333] Instruct the subject to discontinue using all ophthalmic
medications that he/she had been using before the screening visit.
Remind the subject that they are not to use artificial tears or any
other OTC or prescription or any other topical eye medication other
than the investigational drug they have been given during the
remainder of the study. [0334] If the subject is qualified, a
three-week supply of Single-Masked Vehicle IP is dispensed.
[0335] The first dose of IP is taken in the clinic under the
supervision of a designated Dosing Coordinator. This Dosing
Coordinator, who is not responsible for study assessments, is
required to dispense and retrieve investigational product to/from
the subjects and dispense investigational product dosing
instructions and daily dosing diaries. The following is the process
regarding administration of investigational product whereby the
Dosing Coordinator conducts the following procedures: [0336]
Explain the proper method of investigational product
administration. Subjects are instructed to thoroughly wash their
hands prior to administration of IP. [0337] Following
administration of the IP, subjects are allowed to blot or clean the
lower eyelid skin, if necessary. [0338] Observe subject
instillation of first dose of Single-Masked IP [0339] Assess for
occurrence of any IP related AEs [0340] Dispense Single-Masked
Vehicle IP to the subject. [0341] Dispense Daily Dosing Diary
(without symptom exacerbation question) [0342] Give the subject
instructions to instill IP in each eye, BID and to record each
administration on the daily dosing diary. [0343] Schedule the
subject to return for Visit 2 (Randomization), Day 1-14 days later
plus or minus 2 days. [0344] Remind subjects to withhold their
morning dose prior to attending the next clinic visit. If subject
forgets to withhold the dose prior to the clinic visit, the ocular
clinical assessments are scheduled at least 2 hours following the
dose to prevent the subject from being evaluated with residual
investigational product on the eyelids. 2. Visit 2 (Randomization):
Day 1 (.+-.2 days)
[0345] Visit 2 occurs 14 (.+-.2) days after Visit 1 (Screening).
The following is performed/assessed in both eyes: [0346] Subject
Rated Symptom Assessments (in this order): [0347] 1. Individual
Symptom Assessment via VAS [0348] 2. SANDE [0349] Subject is asked
the following question regarding symptom flare experienced the day
prior to the visit: [0350] During the prior day, did you experience
any discrete and severe episodes of eye discomfort (related to your
MGD) lasting more than a minute, and if so, how many episodes?
[0351] Use of any concomitant medications since the last visit
[0352] Occurrence of any AEs since the last visit [0353] Compliance
is assessed via review of the daily dosing information recorded by
the subject. Subjects must be 80% compliant with respect to dosing
and diary completion for eligibility. [0354] BCVA [0355] Tear
Osmolarity (at a subset of sites) [0356] External Eye Exam [0357]
Slit-lamp biomicroscopy [0358] Investigator-rated assessment of
signs of Meibomian Gland Dysfunction (in both eyes for upper and
lower lids) [0359] See Section N. Assessment of Efficacy for full
description of investigator-rated assessments for objective signs
of change from baseline using five individual severity scores
[0360] TFBUT [0361] FCS (NEI/Industry Workshop scale) [0362]
Unanesthetized Schirmer test [0363] IOP [0364] Determine if subject
is eligible for randomization [0365] Enter subject information into
IWRS to determine randomization code and Kit Number
[0366] For eligible subjects, the following is the process
regarding administration of Double-Masked IP whereby the Dosing
Coordinator conducts the following procedures: [0367] Receive,
weigh and record weight of returned Single-Masked IP dispensed at
Visit 1 [0368] Observe subject instillation of first dose of AM
self-administration of Double-Masked IP [0369] Following
administration of the investigational product, subjects are allowed
to blot or clean the lower eyelid skin, if necessary. [0370] Assess
for occurrence of any IP related AEs [0371] Dispense 1 tube of
Double-Masked IP to the subject. [0372] Collect Daily Dosing diary
(without symptom exacerbation question) [0373] Dispense Daily
Dosing Diary (with symptom exacerbation question) [0374] Give the
subject instructions to instill IP in each eye, BID and to record
each administration on the daily dosing diary. [0375] Schedule the
subject to return for Visit 3 (Day 15 plus or minus 2 days). [0376]
Remind subjects to withhold their morning dose prior to attending
the next clinic visit. If subject forgets to withhold the dose
prior to the clinic visit, the ocular clinical assessments are
scheduled at least 2 hours following the dose to prevent the
subject from being evaluated with residual investigational product
on the eyelids. [0377] Remind subjects to bring their IP and
diaries to the next visit. 3. Visit 3: Day 15 (.+-.2 days)
[0378] This visit occurs on Day 15 as calculated from Visit 2: Day
1, and the following is performed in both eyes: [0379] Subject
Rated Symptom Assessments (in this order): [0380] 1. Individual
Symptom Assessment via VAS [0381] 2. SANDE [0382] Use of any
concomitant medications since the last visit [0383] Occurrence of
any AEs since the last visit [0384] BCVA [0385] Tear Osmolarity (at
a subset of sites) [0386] External Eye Exam [0387] Slit-lamp
biomicroscopy [0388] Investigator-rated assessment of signs of
Meibomian Gland Dysfunction [0389] See Section N. Assessment of
Efficacy for full description of investigator-rated assessments for
objective signs of change from baseline using five individual
severity scores [0390] TFBUT [0391] FCS (NEI/Industry Workshop
scale) [0392] IOP
[0393] The following is the process regarding administration of
Double-Masked IP whereby the Dosing Coordinator conducts the
following procedures: [0394] Compliance is assessed via review of
the daily dosing information recorded by the subject. [0395]
Receive, weigh and record weight of returned Double-Masked IP
dispensed at Visit 2. [0396] Dispense one tube of Double-Masked IP
to the subject from their assigned kit. [0397] Collect Daily Dosing
Diary (with symptom exacerbation question). [0398] Dispense Daily
Dosing Diary (with symptom exacerbation question). [0399] Schedule
the subject to return for Visit 4 (Day 29 plus or minus 2 days).
[0400] Remind subjects to withhold their morning dose prior to
attending the next clinic visit. If subject forgets to withhold the
dose prior to the clinic visit, the ocular clinical assessments are
scheduled at least 2 hours following the dose to prevent the
subject from being evaluated with residual investigational product
on the eyelids. 4. Visit 4: Day 29 (.+-.2 days)
[0401] This visit occurs on Day 29 as calculated from Visit 2: Day
1, and the following is performed in both eyes: [0402] For all
eligible women of childbearing potential, perform a urine pregnancy
test to confirm that the subject is not pregnant. [0403] Subject
Rated Symptom Assessments (in this order): [0404] 1. Individual
Symptom Assessment via VAS [0405] 2. SANDE [0406] Use of any
concomitant medications since the last visit [0407] Occurrence of
any AEs since the last visit [0408] BCVA [0409] Tear Osmolarity (at
a subset of sites) [0410] External Eye Exam [0411] Slit-lamp
biomicroscopy [0412] Investigator-rated assessment of signs of
Meibomian Gland Dysfunction [0413] See Section N. Assessment of
Efficacy for full description of investigator-rated assessments for
objective signs of change from baseline using five individual
severity scores [0414] TFBUT [0415] FCS (NEI/Industry Workshop
scale) [0416] IOP
[0417] The following is the process regarding administration of
Double-Masked IP whereby the Dosing Coordinator conduct the
following procedures: [0418] The Dosing Coordinator reviews
compliance of the daily dosing information recorded by the subject.
[0419] Receive, weigh and record weight of returned Double-Masked
IP dispensed at Visit 3. [0420] Dispense two tubes of Double-Masked
IP to the subject from their assigned kit. [0421] Collect Daily
Dosing Diary (with symptom exacerbation question.) [0422] Dispense
Daily Dosing Diary (with symptom exacerbation question). [0423]
Schedule the subject to return for Visit 5 (Day 57 plus or minus 2
days). [0424] Remind subjects to withhold their morning dose prior
to attending the next clinic visit. If subject forgets to withhold
the dose prior to the clinic visit, the ocular clinical assessments
are scheduled at least 2 hours following the dose to prevent the
subject from being evaluated with residual investigational product
on the eyelids. 5. Visit 5: Day 57 (.+-.2 days)
[0425] This visit occurs on Day 57 as calculated from Visit 2: Day
1, and the following is performed in both eyes: [0426] Subject
Rated Symptom Assessments (in this order):
[0427] 1. Individual Symptom Assessment via VAS
[0428] 2. SANDE [0429] Use of any concomitant medications since the
last visit [0430] Occurrence of any AEs since the last visit [0431]
BCVA [0432] Tear Osmolarity (at a subset of sites) [0433] External
Eye Exam [0434] Slit-lamp biomicroscopy [0435] Investigator-rated
assessment of signs of Meibomian Gland Dysfunction [0436] See
Section N. Assessment of Efficacy for full description of
investigator-rated assessments for objective signs of change from
baseline using five individual severity scores [0437] TFBUT [0438]
FCS (NEI/Industry Workshop scale) [0439] IOP
[0440] The following is the process regarding administration of
Double-Masked IP whereby the Dosing Coordinator conduct the
following procedures: [0441] Compliance is assessed via review of
the daily dosing information recorded by the subject [0442]
Receive, weigh and record weight of returned Double-Masked IP
dispensed at Visit 4 (two tubes). [0443] Dispense two tubes
Double-Masked IP to the subject. [0444] Collect Daily Dosing Diary
(with symptom exacerbation question). [0445] Dispense Daily Dosing
Diary (with symptom exacerbation question). [0446] Schedule the
subject to return for Visit 6 (Day 85 plus or minus 2 days). [0447]
Remind subjects to withhold their morning dose prior to attending
the next clinic visit. If subject forgets to withhold the dose
prior to the clinic visit, the ocular clinical assessments are
scheduled at least 2 hours following the dose to prevent the
subject from being evaluated with residual investigational product
on the eyelids. 6. Visit 6 (End of Treatment): Day 85 (+2 days)
[0448] This visit occurs on Day 85 as calculated from Visit 2: Day
1, and the following is performed in both eyes: [0449] UPT [0450]
Subject Rated Symptom Assessments (in this order): [0451] 1.
Individual Symptom Assessment via VAS [0452] 2. SANDE [0453] Use of
any concomitant medications since the last visit [0454] Occurrence
of any AEs since the last visit [0455] BCVA [0456] Tear Osmolarity
(at a subset of sites) [0457] External Eye Exam [0458] Slit-lamp
biomicroscopy [0459] Investigator-rated assessment of signs of
Meibomian Gland Dysfunction [0460] See Section N. Assessment of
Efficacy for full description of investigator-rated assessments for
objective signs of change from baseline using five individual
severity scores [0461] TFBUT [0462] FCS (NEI/Industry Workshop
scale) [0463] Unanesthetized Schirmer test [0464] Wait 10 minutes
prior to MMP-9 point of care test [0465] MMP-9 point of care test
[0466] IOP [0467] Dilated Ophthalmoscopy
[0468] The following is the process regarding administration of
Double-Masked IP whereby the Dosing Coordinator conduct the
following procedures: [0469] Compliance is assessed via review of
the daily dosing information recorded by the subject. [0470]
Collect Used/Unused Double-Masked IP. Weigh and record weight of
used IP (two tubes). Subject discontinues use of all IP following
this visit. [0471] Collect Daily Dosing Diary (with symptom
exacerbation question) [0472] Schedule the subject to return for
Visit 7 (Day 113 plus or minus 2 days). 7. Visit 7 (Post-Treatment
Follow-Up): Day 113 (.+-.2 days)
[0473] This visit occurs on Day 113 as calculated from Visit 6 (End
of Treatment), and the following is performed in both eyes: [0474]
UPT [0475] Subject Rated Symptom Assessments: [0476] 1. Individual
Symptom Assessment via VAS [0477] 2. SANDE [0478] Use of any
concomitant medications since the last visit [0479] Occurrence of
any AEs since the last visit [0480] BCVA [0481] Tear Osmolarity (at
a subset of sites) [0482] External Eye Exam [0483] Slit-lamp
biomicroscopy [0484] Investigator-rated assessment of signs of
Meibomian Gland Dysfunction [0485] TFBUT [0486] FCS (NEI/Industry
Workshop scale) [0487] Unanesthetized Schirmer test [0488] IOP
[0489] The subject may be discharged from the study at this
visit.
8. Unscheduled Visit
[0490] Any visits or procedures performed beyond those specified
within the protocol must be documented in the Unscheduled Visit
pages of the electronic case report form (eCRF). Unscheduled visits
may include but are not limited to reporting AEs, changes in
concomitant medications, or ophthalmic assessments as deemed
appropriate by an appropriately qualified physician.
9. Early Termination Visit
[0491] In the event of termination prior to Visit 6, every attempt
is made to ensure that all the following Visit 6 assessments are
performed in both eyes at the Early Termination Visit prior to
discharge from the study: [0492] Subject Rated Symptom Assessments:
SANDE and Individual Symptom Assessment via VAS [0493] Use of any
concomitant medications since the last visit [0494] Occurrence of
any AEs since the last visit [0495] Used and unused IP collected
and compliance assessed via the daily dosing information recorded
by the subject [0496] UPT [0497] BCVA [0498] External Eye Exam
[0499] Slit lamp biomicroscopy [0500] Investigator-rated assessment
of Meibomian Gland Dysfunction [0501] Tear Osmolarity (at a subset
of sites) [0502] TFBUT [0503] FCS (NEI/Industry Workshop scale)
[0504] Unanesthetized Schirmer test [0505] Wait 10 minutes prior to
MMP-9 point of care test [0506] MMP-9 point of care test [0507] IOP
measurement [0508] Dilated Ophthalmoscopy
[0509] Include subject withdrawal criteria (i.e., terminating
investigational product treatment/trial treatment).
I. Subject Withdrawal and/or Discontinuation
[0510] Any subject who wishes to discontinue IP use or withdraw
from participation in the study for any reason is entitled to do so
without obligation. The Investigator may also discontinue any
subject from investigational product use or from study
participation, if deemed necessary.
[0511] Investigational product use may be discontinued, and any
subject may be discontinued from study participation at any time
during the study at the discretion of the Investigator or the
Sponsor for any reason including but not limited to: [0512] 1.
Occurrence of any medical condition or circumstance that exposes
the subject to substantial risk and/or does not allow the subject
to adhere to the requirements of the protocol. [0513] 2. Any
Serious Adverse Event (SAE), clinically significant AE, severe
laboratory abnormality, intercurrent illness, or other medical
condition that indicates to the Investigator that continued
participation is not in the best interest of the subject. [0514] 3.
Subject's decision to withdraw. [0515] 4. Any woman who becomes
pregnant while participating in the study. Information on the
pregnancy and outcome is requested. [0516] 5. Subject's failure to
comply with protocol requirements or study related procedures.
[0517] 6. Termination of the study by the Sponsor, FDA, or other
regulatory authorities.
[0518] In the event study discontinuation of a randomized subject
is necessary, the Investigator should make every attempt to have
the subject complete Visit 6 assessments as possible. If a
non-serious AE is unresolved at the time of the subject's final
study visit, an effort is made to follow up until the AE is
resolved or stabilized, the subject is lost to follow-up, or there
is some other resolution of the event. The Investigator should make
every attempt to follow all SAEs to resolution. The reason for
premature discontinuation is entered into the eCRF and recorded in
the subject chart.
[0519] Subjects who withdraw from the study are not replaced.
[0520] Additionally, the trial or parts of the trial may be
discontinued by the Sponsor or at the recommendation of the
Investigator after consultation with Hovione Scientia, Ltd. This
may be based on a significant number of AEs of a similar nature
that warrant such action.
J. Collection of Data
[0521] Source documentation for data collected in this study is
maintained at the investigative site. In cases where no source is
used (e.g., dosing diary), it is noted in the Investigator
files.
K. Treatment of Subjects
1. Investigational Products to be Administered
[0522] All subjects meeting eligibility criteria at Visit 1 is
provided with a Single-Masked Run-In product (Vehicle). One tube of
Run-In is allocated to each subject at Visit 1 and returned at
Visit 2. All subjects meeting Randomization criteria at Visit 2 are
randomized to either Test Article or Vehicle. A 3-week supply (one
tube) of randomized Double-Masked IP is allocated to each subject
at Visit 2 for self-administration. The used tube of IP is returned
to the site at Visit 3 and at Visit 3 the subjects receive one new
tube of IP which is returned at Visit 4. At Visits 4 and 5,
subjects receive two new tubes of IP at each visit which is
returned at Visits 5 and 6, respectively. The IP is stored at the
site in a secure area with limited access at controlled room
temperature (20-25.degree. C. [68-77.degree. F.] with excursions
permitted between 15-30.degree. C. [59-86.degree. F.]).
[0523] Subjects are asked to administer IP BID. It is important
that IP is instilled to full eyelid margin. Subjects are instructed
to wash hands thoroughly prior to administration of IP. (Following
administration of the IP, subjects are allowed to blot or clean the
lower eyelid skin, if necessary.)
[0524] The subjects record the date and time of administration of
each dose of IP at the time of instillation in a dosing diary.
Compliance with instillation of investigational product is reviewed
and assessed at Visits 2 through Visit 6.
2. Concomitant Medications
[0525] All medications that the subject has taken 60 days prior to
Visit 1 and through Visit 7 or discontinuation from the study is
recorded in the eCRF and the subject chart. The generic name of the
drug, dose, route of administration, duration of treatment
(including start and stop dates), frequency, indication, and
whether or not the medication was taken due to an AE are recorded
for each medication. Medications and therapies not specifically
excluded below may be taken as necessary. Omega-3 supplements are
permitted if the dose is stable within 3 months of Visit 1. Inhaled
or intranasal corticosteroids are permitted if the dose is stable
for the duration of the study.
[0526] The following procedures and medications are not allowed for
the time periods specified: [0527] Previous use of isotretinoin is
not permitted. [0528] Within 12 months prior to Screening (Visit 1)
and for the duration of the study: [0529] Have had ocular surface
surgery (e.g., LASIK, refractive, pterygium removal). [0530] Within
90 days prior to Screening (Visit 1) and for the duration of the
study: [0531] Have had or require penetrating intraocular surgery
during the study [0532] Have had or require cauterization of the
punctum or changes in the status of punctal plugs [0533] Within 30
days prior to Screening (Visit 1) and for the duration of the
study: [0534] Systemic corticosteroids [0535] Topical ocular
corticosteroids or ocular non-steroidal anti-inflammatory drugs
(NSAIDs) [0536] Topical ocular or oral antibiotics [0537] Topical
ocular antihistamines or mast cell stabilizers [0538] Any
investigational drug [0539] Topical cyclosporine (RESTASIS.RTM.)
[0540] Topical lifitegrast (XIIDRA.RTM.) [0541] LipiFlow [0542]
Hypochlorous Acid Spray [0543] From Visit 1
(Screening/Randomization) and for the duration of the study: [0544]
Preserved or unpreserved topical ocular medications including
artificial tears [0545] Any glaucoma medications [0546] Eyelid
scrubs or use of mechanical therapy
3. Investigational Product Use Compliance
[0547] Compliance is assessed by comparing investigational product
accountability records with the dosing information recorded daily
by the subject. The Dedicated Dosing Coordinator documents this
comparison along with verification of returned used investigational
product tubes. The number of missed doses as assessed at each
clinic visit is documented in the eCRF.
L. Drug Accountability
[0548] Sponsor study monitors or designees conduct accountability
of investigational product (Test Article or Vehicle).
Accountability is ascertained by performing reconciliation between
the number of kits/tubes sent to the site and those accounted for
at the time of reconciliation during routine monitoring and at the
end of the study.
M. Maintenance of Randomization and Procedure for Breaking the
Code
[0549] The Sponsor, the project teams at the designated Contract
Research Organizations (CROs), and investigative staff responsible
for assessments of study endpoints are masked to investigational
product assignments. A designated dosing coordinator, who is not
responsible for study assessments, is required to dispense and
retrieve double-masked, investigational product and daily dosing
diaries to the subjects. In case of medical emergency, or
occurrence of an SAE, the randomization code may be unmasked and
made available to the Investigator, Sponsor, and/or other personnel
involved in the monitoring or conduct of this study. In the absence
of medical need, the randomization code is not available to the
above individuals until after the study is completed and the
database is locked.
[0550] In the event of a medical need, the Investigator treats each
subject as needed. Since there is no specific antidote to Test
Article, immediate emergency unmasking is not necessary. If the
Investigator feels it is necessary to unmask a subject's assignment
after an emergency situation, the Investigator may call the medical
monitor and notify the Sponsor. The investigational product
assignment is revealed on a subject-by-subject basis with the
approval of the medical monitor and Sponsor, thus leaving the
masking of the remaining subjects intact.
[0551] A randomization code is computer-generated by the Sponsor or
designee. Randomization team members work independently of other
team members at the CRO. Study personnel, study subjects, the
Sponsor, and project teams at the CROs involved in the study are
masked to investigational product assignments.
N. Assessment of Efficacy
[0552] Efficacy assessments include the following:
O. Assessment of Safety
[0553] Safety parameters include:
1. Adverse Event Monitoring
[0554] See Section O. Adverse Event Definitions
2. ETDRS Best Corrected Visual Acuity
[0555] BCVA is conducted at each visit. Visual acuity testing
should precede any examination requiring contact with the eye or
instillation of study dyes, as is detailed in the order of
assessments for each Visit in Section 5.1. Logarithm of the Minimal
Angle of Resolution (Log MAR) visual acuity must be assessed using
an ETDRS or modified ETDRS chart. Visual acuity testing is
performed with best correction using subject's own corrective
lenses (spectacles only) or pinhole refraction.
[0556] An ETDRS or modified ETDRS chart may be used. If a
Lighthouse chart is used (24.5'' by 25''; either reflectance or
retro-illuminated), the subject must view the chart from a distance
of exactly 4 meters (13.1 feet). If smaller reproductions (18'' by
18'', e.g., Prevent Blindness) are used, the subject viewing
distance is exactly 10 feet. Reflectance wall charts are frontally
illuminated (60 watt bulb or a well-lit room).
[0557] The subject is positioned according to the elevation of the
chart (either seated or standing) so that the chart is at a
comfortable viewing angle. The right eye is tested first. The
subject should attempt to read each letter, line-by-line, left to
right, beginning with line 1 at the top of the chart. The subject
is told that the chart has letters only, no numbers. If the subject
reads a number, he or she is reminded that the chart contains no
numbers, and the examiner should then request a letter instead of
the number. The subject is asked to read slowly, about 1 letter per
second, to achieve the best identification of each letter. He/she
is not to proceed to the next letter until he/she has given a
definite response. If the subject changes a response before he has
read aloud the next letter, then the change must be accepted.
[0558] Maximum effort is made to identify each letter on the chart;
the subject is encouraged to guess. When it becomes evident that no
further meaningful readings can be made, the examiner should stop
the test. The number of letters missed or read incorrectly is
noted.
[0559] In order to provide standardized and well-controlled
assessments of visual acuity during the study, the same lighting
conditions must be used consistently throughout the study.
Calculations: log MAR VA=Baseline value+(n.times.0.02)
where: the baseline value is the log MAR number of the last line
read (at least 1 letter read correctly in this line), and "n" is
the total number of letters missed up to and including the last
line read, and "0.02" is the value for each letter
3. Slit Lamp Biomicroscopy and External Eye Exam
[0560] The biomicroscopy exam is performed at each visit. It is
performed with the slit lamp using a beam width and intensity that
provide optimal evaluation of the anterior segment. This procedure
is performed in the same manner for all subjects observed at the
Investigator's site. [0561] Lashes [0562] 0=Normal [0563]
1=Abnormal [0564] Eyelid [0565] Edema [0566] 0=Normal, no swelling
of the lid tissue [0567] 1=Abnormal [0568] Conjunctiva [0569] Edema
[0570] 0=Normal, no swelling of the conjunctiva [0571] 1=Abnormal
[0572] Palpebral Conjunctival Erythema [0573] 0=Normal, no redness
of the conjunctiva [0574] 1=Abnormal [0575] Cornea [0576]
Infiltrates [0577] 0=Absent [0578] 1=Present [0579] Endothelial
Changes [0580] 0=Normal, None [0581] 1=Abnormal, pigment,
keratoprecipitates, guttata [0582] Edema [0583] 0=Normal None,
transparent and clear [0584] 1=Abnormal [0585] Anterior Chamber
[0586] Cells [0587] 0=Normal, No cells seen [0588] 1=Abnormal (+ to
+++ cells) [0589] Flare [0590] 0=Normal, No Tyndall effect [0591]
1=Abnormal, Tyndall beam in the anterior chamber [0592] Lens
Pathology [0593] 0=Normal; no opacity in the lens [0594]
1=Abnormal; existing opacity in the lens; aphakic or pseudophakic
eyes or other abnormal findings. [0595] Sclera [0596] Injection
[0597] 0=Normal, without any redness [0598] 1=Abnormal
4. IOP Measurement
[0599] IOP measurements are performed utilizing Goldmann
applanation tonometry according to the Investigator's standard
procedure. All pressures are recorded in mmHg.
5. Dilated Ophthalmoscopy
[0600] Dilated ophthalmoscopy includes assessment of the optic
nerve head for pallor and cupping (cup to disc ratio), and is
performed at Visit 1 and Visit 6. After the ophthalmoscopy
procedure, the Investigator determines if findings are within
normal limits or are abnormal. For abnormal findings at Visit 1,
the Investigator determines whether or not the abnormality would
exclude subject from study participation.
P. Adverse Event Definitions
[0601] Adverse Event (AE): Any untoward medical occurrence
associated with the use of an investigational product in humans,
whether or not considered drug related.
[0602] Adverse Reaction (AR): any AE caused by a drug. Adverse
reactions are a subset of all suspected adverse reactions where
there is reason to conclude that the drug caused the event.
[0603] Suspected Adverse Reaction (SAR): Any AE for which there is
a reasonable possibility that the drug caused the AE. For the
purposes of IND safety reporting, "reasonable possibility" means
there is evidence to suggest a causal relationship between the drug
and the AE. A SAR implies a lesser degree of certainty about
causality than adverse reaction, which means any AE caused by a
drug.
[0604] Unexpected: An AE or SAR is considered "unexpected" if it is
not listed in the Investigator's Brochure or is not listed at the
specificity or severity that has been observed; or, if an
Investigator's Brochure is not required or available, is not
consistent with the risk information described in the general
investigational plan or elsewhere in the current application.
[0605] Life-threatening: An AE or SAR is considered
"life-threatening" if, in the view of either the Investigator or
Sponsor, its occurrence places the patient or subject at immediate
risk of death. It does not include an AE or suspected adverse
reaction that, had it occurred in a more severe form, might have
caused death.
[0606] Serious Adverse Event (SAE): any AE or suspected adverse
reaction occurring at any dose that: [0607] Results in death.
[0608] Is life-threatening. [0609] Results in a persistent or
significant incapacity or substantial disruption of the ability to
conduct normal life functions. [0610] Requires inpatient
hospitalization. [0611] Prolongs inpatient hospitalization. [0612]
Is a congenital anomaly/birth defect. [0613] Is a significant
medical event (i.e., one that may jeopardize the subject or may
require intervention to prevent one or more of the other outcomes
listed above).
[0614] Non-Serious Adverse Event: any AE that does not meet the
definitions for SAEs as described above.
[0615] Each AE is classified as SERIOUS or NON-SERIOUS using the
definitions provided above.
[0616] The SEVERITY of each AE is classified as MILD, MODERATE, or
SEVERE.
[0617] The Investigator reviews each event and assess its
relationship to use of investigational product (unrelated,
unlikely, possibly, probably, definitely). The AE is assessed using
the following definitions:
[0618] Unrelated: [0619] Event occurring before dosing. [0620]
Event or intercurrent illness due wholly to factors other than
investigational product use.
[0621] Unlikely: [0622] Poor temporal relationship with
investigational product use. [0623] Event easily explained by
subject's clinical state or other factors.
[0624] Possible: [0625] Reasonable temporal relationship with
investigational product use. [0626] Event could be explained by
subject's clinical state or other factors.
[0627] Probable: [0628] Reasonable temporal relationship with
investigational product use. [0629] Likely to be known reaction to
agent or chemical group, or predicted by known pharmacology. [0630]
Event cannot easily be explained by subject's clinical state or
other factors.
[0631] Definite: [0632] Distinct temporal relationship with
investigational product use. [0633] Known reaction to agent or
chemical group, or predicted by known pharmacology. [0634] Event
cannot be explained by subject's clinical state or other
factors.
Q. Procedures for AE Reporting by the Investigator
[0635] AEs are monitored throughout the study and are recorded on
the eCRF with the date and time of onset, date and time of
resolution, severity, seriousness, causality (relationship to use
of investigational product), treatment required, and the outcome.
To elicit AEs, simple questions with minimal suggestions or
implications are used as the initial questions at all evaluation
points during the trial. For example: [0636] How have you felt
since your last assessment? [0637] Have you had any health problems
since your last assessment?
[0638] The severity of each AE is categorized as mild, moderate, or
severe. The causality of use of investigational product in relation
to the AE is assessed by the Principal Investigator after careful
medical consideration and categorized as unrelated, unlikely,
possible, probable, or definite. If an AE occurs, the Investigator
institutes support and/or treat as deemed appropriate. If a non-SAE
is unresolved at the time of the last day of the study, an effort
is made to follow up until the AE is resolved or stabilized, the
subject is lost to follow-up, or there is some other resolution of
the event. The Investigator should make every attempt to follow
SAEs to resolution.
[0639] It is the responsibility of the Investigators or their
designees to report any event of this nature to the Sponsor or a
designee within 24 hours of the event being brought to the
Investigators' or their staffs' attention. It is also the
responsibility of the Investigator to report all SAEs reported at
their site to their Institutional Review Board (IRB), as required.
The Investigator should make every attempt to follow all SAEs to
resolution.
[0640] The following information is provided when an SAE is
reported to the Sponsor or designee:
[0641] 1. Protocol Number
[0642] 1. Site Number
[0643] 2. Subject Number
[0644] 3. Subject Demographic information, including: [0645] Date
of Birth [0646] Sex [0647] Race
[0648] 4. Investigational product start date
[0649] 5. Date of last dose of investigational product
[0650] 6. Date investigational product reinitiated (if
investigational product interrupted)
[0651] 7. SAE information, including: [0652] SAE term (diagnosis
only; if known or serious signs/symptoms) [0653] Description of
SAE/narrative [0654] Date/time of onset [0655] Severity [0656]
Outcome [0657] Date/time of resolution or death (if duration <24
hours) [0658] Relationship to investigational product [0659] Action
taken with investigational product
[0660] 8. Criteria for classifying the event as serious, including
whether the SAE: [0661] Resulted in death. [0662] Was
life-threatening [0663] Required inpatient hospitalization. [0664]
Prolonged inpatient hospitalization. [0665] Resulted in a
persistent or significant incapacity or substantial disruption of
the ability to conduct normal life functions. [0666] Was a
congenital anomaly/birth defect [0667] Important medical events
that may not result in death, were not life-threatening, or did not
require hospitalization may be considered serious when, based upon
appropriate medical judgment, they may jeopardize the patient or
subject and may require medical or surgical intervention to prevent
one of the outcomes listed in this definition. Examples of such
medical events include allergic bronchospasm requiring intensive
treatment in an emergency room or at home, blood dyscrasias or
convulsions that do not result in inpatient hospitalization, or the
development of drug dependency or drug abuse.
[0668] 9. Concomitant medications
[0669] 10. Relevant history
[0670] 11. Possible causes of SAE other than investigational
product
[0671] 12. Copy of AE page from the CRF
[0672] If an SAE occurs in any study involving Test Article or
Vehicle that is unexpected and is determined to be related or
possibly related to investigational product, all sites are notified
by the Sponsor and each site should report it to its TRB.
R. Statistical Methods
[0673] Continuous measures (e.g., age) are summarized descriptively
by the mean, standard deviation, median, minimum and maximum
values. Categorical measures are summarized by the number and
percent of subjects. The statistical analyses are performed in
accordance with the Statistical Analysis Plan. All study data is
listed by treatment, patient and visit (as applicable). Subject
disposition, demographic characteristics, and background variables
are summarized by treatment group.
1. Analysis of Efficacy
[0674] Analysis Populations: [0675] Intent-to-Treat (ITT)
Population: The ITT population includes all randomized subjects who
took at least 1 dose of study drug. This population is the primary
population for efficacy analyses and is used to summarize all
efficacy variables by treatment group as randomized. [0676] Per
Protocol (PP) Population: The PP population is a subset of the ITT
population, which includes those subjects who do not have important
protocol deviations likely to seriously affect the primary efficacy
outcomes of the study. This population is the secondary population
for efficacy analyses by treatment group as treated. The Per
Protocol Population is defined and documented by the clinical study
team and the biostatistician prior to database lock and unmasking
of the subjects. [0677] Evaporative Dry Eye Disease (DED)
Population: The Evaporative DED population is a subset of PP
population, which includes those subjects with associated
evaporative DED as determined at baseline. Further a positive
Screening for MMP-9 is evaluated as a subset of the PP
population.
[0678] To assess whether Test Article is more effective than
Vehicle, a repeated measures mixed model analysis of covariance
(ANCOVA) is used where change from baseline is the outcome,
treatment group is a fixed effect with baseline score as a
covariate and visit as a repeated measure. The presence/absence of
DED and its interaction with treatment may be included in the model
as appropriate. Least squares means are used to test each
concentration of Test Article compared to Vehicle. Statistical
testing is carried out at the 0.05 significance level. A
hierarchical testing scheme is implemented for the Primary
Endpoints in the following sequential order: [0679] 1. Changes in
Vascular Engorgement at the study eyelid margin as graded by the
investigator at Week 12 (Visit 6) from Randomization/Baseline
(Visit 2) in 1% Test Article compared to Vehicle [0680] 2. Change
in Eye Discomfort Visual Analogue Score (VAS) at Week 12 (Visit 6)
from Randomization/Baseline (Visit 2) in 1% Test Article compared
to Vehicle [0681] 3. Changes in Vascular Engorgement at the study
eyelid margin as graded by the investigator at Week 12 (Visit 6)
from Randomization/Baseline (Visit 2) in 0.3% Test Article compared
to Vehicle [0682] 4. Change in Eye Discomfort Visual Analogue Score
(VAS) at Week 12 (Visit 6) from Randomization/Baseline (Visit 2) in
0.3% Test Article compared to Vehicle
[0683] Each comparison is made in the above pre-specified order to
determine if the difference is statistically significant
(p-value.ltoreq.0.05). If the difference is statistically
significant, then the same test is repeated for the next
comparison. If, at any time, the p-value is >0.05 then testing
is stopped. Secondary endpoints are tabulated by descriptive
statistics: [0684] Change in FCS total score (NEI/Industry Workshop
0-15 scale) in the study eye at Week 4 (Visit 4), Week 8 (Visit 5),
Week 12 (Visit 6), and Week 16 (Visit 7) from
Randomization/Baseline (Visit 2). [0685] Change in FCS inferior,
nasal, and central combined score (NEI/Industry Workshop Section 1,
4 and 5 with a 0-9 scale) in the study eye at Week 4 (Visit 4),
Week 8 (Visit 5), Week 12 (Visit 6) and Week 16 (Visit 7) from
Randomization/Baseline (Visit 2). [0686] Change in FCS inferior
score (NEI/Industry Workshop sections 5 with a 0-3 scale) in the
study eye at Week 4 (Visit 4), Week 8 (Visit 5), Week 12 (Visit 6),
and Week 16 (Visit 7) from Randomization/Baseline (Visit 2). [0687]
Changes in Eye Discomfort Visual Analogue Score (VAS) at Changes in
Eye Discomfort Visual Analogue Score (VAS) at Week 4 (Visit 4),
Week 8 (Visit 5), Week 12 (Visit 6), and Week 16 (Visit 7) from
Randomization/Baseline (Visit 2). [0688] Investigator reported
scores on objective signs of inflamed MGD including change from
baseline at each follow up visit for four individual severity
scores: [0689] 1. Plugging of Meibomian Gland [0690] 2. Character
of Meibomian Gland Secretion [0691] 3. Vascular Engorgement of
eyelid margin [0692] 4. Expressibility of Meibomian Glands [0693]
Total Clinical Outcome Severity Score defined as the sum of the
following four severity scores for the clinical signs of: [0694] 1.
Plugging of Meibomian Gland [0695] 2. Character of Meibomian Gland
Secretion [0696] 3. Vascular Engorgement of eyelid margin [0697] 4.
Expressibility of Meibomian Glands [0698] Changes in Investigator
reported scores on objective Conjunctival Tarsal Erythema change
from Randomization/Baseline (Visit 2) at each follow up visit.
[0699] Tear Film Break-Up Time (TFBUT) change from baseline at each
follow up visit. [0700] Other Dry Eye-related ocular symptoms at
each follow-up visit: [0701] VAS Scale Symptoms (other than eye
discomfort): [0702] Eye Dryness [0703] Foreign Body Sensation
[0704] SANDE change in the square root of the product of the two
questions at each timepoint compared to baseline and the change
from baseline of each individual question within the SANDE [0705]
The mean tear osmolarity score at each follow up visit compared to
baseline. (Analysis is conducted at a subset of sites.) [0706] The
change from baseline in the unanesthetized Schirmer score. [0707]
The portion of subjects who are positive at Screening for MMP-9
point of care test and convert to negative at the final treatment
visit. [0708] Number of symptom flares during the twelve weeks of
treatment.
2. Analysis of Safety
[0709] Analysis of safety data is presented for all subjects in the
Safety population (i.e., all subjects receiving randomized
investigational product). AEs are coded using Medical Dictionary
for Regulatory Activities (MedDRA, most current version) and
categorized by system organ class using preferred terms. AEs are
tabulated by treatment group with respect to their Severity and
relationship to the investigational product. Ophthalmoscopy
findings are summarized descriptively. IOP measurements, BCVA,
dilated ophthalmoscopy, external eye exam, and slit-lamp
biomicroscopy are summarized as safety outcomes.
3. Sample Size Estimation
[0710] Based on other similar clinical studies, assuming the
treatment effect size is at least 0.43, a sample of 85 subjects per
group provides a power of 80% on a two-sided t-test at an alpha
level of 0.05.
4. Level of Significance
[0711] The primary assessment of the dose-response is evaluated
using a 5% level of significance. All other reported p-values are
considered descriptive and hypothesis generating.
Part II--Results
[0712] The clinical study included randomized 270 subjects, of
which 91 subjects received 0.3% Test Article, 89 subjects received
1% Test Article, and 90 subjects received only Vehicle according to
the dosing protocol described above. Results of the clinical study
are provided in Tables 4-29 and FIGS. 8-16. Experimental results in
Table 4 demonstrate that the 0.3% Test Article has superior
tolerability compared to the 1% Test Article or Vehicle alone--only
8.8% of subjects that received 0.3% Test Article left the study
early, whereas 12.4% of subjects that received 1% Test Article left
the study early and 12.2% of subjects that received only Vehicle
left the study early.
[0713] Additionally, experimental results in Tables 5, 6, 11, and
12 demonstrate that the 0.3% Test Article produced superior results
in the primary efficacy endpoints of VAS Discomfort Mean Change
from Baseline and Vascular Engorgement Mean Change from Baseline
compared to 1% Test Article or Vehicle alone. At day 113 of the
study, VAS Discomfort mean Change from Baseline was -32.4 for
subjects that received 0.3% Test Article, whereas VAS Discomfort
Mean Change from Baseline was -26.2 for subjects that received 1%
Test Article and VAS Discomfort mean Change from Baseline was -27.1
for subjects that received Vehicle alone. At day 113 of the study,
Vascular Engorgement Mean Change from Baseline was -1 for subjects
that received 0.3% Test Article, whereas Vascular Engorgement Mean
Change from Baseline was -0.8 for subjects that received 1% Test
Article or Vehicle alone.
TABLE-US-00004 TABLE 4 0.3% Test 1% Test Article Article Vehicle
Total Subjects n % n % n % n % Subjects Who 83 91.2 78 87.6 79 87.8
240 88.9 Completed the Study Subjects Who 8 8.8 11 12.4 11 12.2 30
11.1 Discontinued the Study Adverse Event 3 3.3 7 7.9 5 5.6 15 5.6
Withdrawn by Subject 5 5.5 3 3.4 3 3.3 11 4.1 Lost to Follow-Up 0 0
1 1.1 2 2.2 3 1.1 Other 0 0 0 0 1 1.1 1 0.4
TABLE-US-00005 TABLE 5 VAS Discomfort Mean VAS Score 0.3% Test 1%
Test Timepoint Article Article Vehicle Baseline 67.8 66.7 65.9 Day
15 49.3 52 53.5 Day 29 45.6 49.4 44.4 Day 57 42.8 45.4 41.4 Day 85
38 41 35.8 Day 113 36.1 40.1 37.7
TABLE-US-00006 TABLE 6 VAS Discomfort Mean Change From Baseline
0.3% Test 1% Test Timepoint Article Article Vehicle Baseline 0 0 0
Day 15 -18.1 -15.2 -14 Day 29 -22.2 -17.7 -20.8 Day 57 -25 -21.5
-24 Day 85 -30.1 -25.4 -28.7 Day 113 -32.4 -26.2 -27.1
TABLE-US-00007 TABLE 7 VAS Eye Dryness Mean VAS Score 0.3% Test 1%
Test Timepoint Article Article Vehicle Baseline 64.4 62.8 60.1 Day
15 51.3 50.6 49.7 Day 29 46.3 47.7 44 Day 57 44.5 45.4 43.1 Day 85
39.6 41.2 36.5 Day 113 39.6 42.4 40
TABLE-US-00008 TABLE 8 VAS Eye Dryness Mean Change From Baseline
0.3% Test 1% Test Timepoint Article Article Vehicle Baseline 0 0 0
Day 15 -12.6 -12.7 -9.7 Day 29 -18.3 -16.1 -15.1 Day 57 -20.2 -18.1
-16.2 Day 85 -25.2 -22.2 -22.2 Day 113 -25.5 -21 -18.9
TABLE-US-00009 TABLE 9 VAS Foreign Body Sensation Mean VAS Score
0.3% Test 1% Test Timepoint Article Article Vehicle Baseline 59 57
59.4 Day 15 45.9 47.3 43.9 Day 29 39.5 46.7 41.3 Day 57 40.1 41.3
37.9 Day 85 34.8 39.3 33.5 Day 113 33.3 37.4 35.8
TABLE-US-00010 TABLE 10 VAS Foreign Body Sensation Mean Change From
Baseline 0.3% Test 1% Test Timepoint Article Article Vehicle
Baseline 0 0 0 Day 15 -12.5 -10.1 -14.8 Day 29 -18.8 -11.2 -17.3
Day 57 -18 -16 -20.6 Day 85 -23.8 -18.1 -25 Day 113 -25.4 -19.9
-22.5
TABLE-US-00011 TABLE 11 Vascular Engorgement Mean Score 0.3% Test
1% Test Timepoint Article Article Vehicle Baseline 2.3 2.3 2.3 Day
15 1.8 2 1.9 Day 29 1.7 1.7 1.8 Day 57 1.6 1.6 1.6 Day 85 1.4 1.5
1.5 Day 113 1.3 1.4 1.5
TABLE-US-00012 TABLE 12 Vascular Engorgement Mean Change From
Baseline 0.3% Test 1% Test Timepoint Article Article Vehicle
Baseline 0 0 0 Day 15 -0.5 -0.3 -0.4 Day 29 -0.7 -0.6 -0.5 Day 57
-0.8 -0.7 -0.7 Day 85 -0.9 -0.8 -0.7 Day 113 -1 -0.8 -0.8
TABLE-US-00013 TABLE 13 Tarsal Conjunctival Erythema Mean Score
0.3% Test 1% Test Timepoint Article Article Vehicle Baseline 2.2
2.3 2.2 Day 15 1.9 2 2 Day 29 1.8 1.8 1.8 Day 57 1.7 1.7 1.6 Day 85
1.5 1.7 1.5 Day 113 1.4 1.5 1.4
TABLE-US-00014 TABLE 14 Tarsal Conjunctival Erythema Mean Change
From Baseline 0.3% Test 1% Test Timepoint Article Article Vehicle
Baseline 0 0 0 Day 15 -0.3 -0.2 -0.2 Day 29 -0.4 -0.5 -0.4 Day 57
-0.5 -0.5 -0.6 Day 85 -0.8 -0.6 -0.7 Day 113 -0.8 -0.7 -0.9
TABLE-US-00015 TABLE 15 Total FCS Mean Score 0.3% Test 1% Test
Timepoint Article Article Vehicle Baseline 6 6.2 5.9 Day 15 4.5 4.9
4.7 Day 29 4.3 4.4 4.2 Day 57 4 4 4.1 Day 85 3.7 4.3 3.8 Day 113
3.5 3.4 3.5
TABLE-US-00016 TABLE 16 Total FCS Mean Change From Baseline 0.3%
Test 1% Test Timepoint Article Article Vehicle Baseline 0 0 0 Day
15 -1.5 -1.3 -1.2 Day 29 -1.8 -1.9 -1.4 Day 57 -2.2 -2.3 -1.7 Day
85 -2.4 -2 -2 Day 113 -2.6 -2.9 -2.4
TABLE-US-00017 TABLE 17 Inferior FCS Mean Score 0.3% Test 1% Test
Timepoint Article Article Vehicle Baseline 1.9 2 1.9 Day 15 1.6 1.8
1.6 Day 29 1.5 1.6 1.5 Day 57 1.4 1.5 1.5 Day 85 1.4 1.5 1.5 Day
113 1.3 1.2 1.4
TABLE-US-00018 TABLE 18 Inferior FCS Mean Change From Baseline 0.3%
Test 1% Test Timepoint Article Article Vehicle Baseline 0 0 0 Day
15 -0.3 -0.2 -0.3 Day 29 -0.4 -0.4 -0.4 Day 57 -0.5 -0.5 -0.4 Day
85 -0.5 -0.5 -0.4 Day 113 -0.6 -0.8 -0.5
TABLE-US-00019 TABLE 19 Combined FCS Mean Score 0.3% Test 1% Test
Timepoint Article Article Vehicle Baseline 4.3 4.5 4.3 Day 15 3.3
3.6 3.5 Day 29 3.1 3.2 3.1 Day 57 2.9 2.9 3.1 Day 85 2.7 3.1 2.8
Day 113 2.4 2.5 2.5
TABLE-US-00020 TABLE 20 Combined FCS Mean Change From Baseline 0.3%
Test 1% Test Timepoint Article Article Vehicle Baseline 0 0 0 Day
15 -1 -0.9 -0.8 Day 29 -1.2 -1.3 -1.2 Day 57 -1.4 -1.6 -1.2 Day 85
-1.6 -1.4 -1.5 Day 113 -1.9 -2 -1.8
TABLE-US-00021 TABLE 21 VAS Discomfort MMP9-Positive Subgroup Mean
VAS Score 0.3% Test 1% Test Timepoint Article Article Vehicle
Baseline 69 66.7 65.3 Day 15 48.1 47.7 54.8 Day 29 44.9 45 47.5 Day
57 41.3 42.7 45.6 Day 85 36 39.5 38.9 Day 113 34.6 36.9 41.2
TABLE-US-00022 TABLE 22 VAS Discomfort MMP9-Positive Subgroup Mean
Percentage Change From Baseline 0.3% Test 1% Test Timepoint Article
Article Vehicle Baseline 0 0 0 Day 15 -30.29% -28.49% -16.08% Day
29 -34.93% -32.53% -27.26% Day 57 -40.14% -35.98% -30.17% Day 85
-47.83% -40.78% -40.43% Day 113 -49.86% -44.68% -36.91%
TABLE-US-00023 TABLE 23 Vascular Engorgement MMP9-Positive Subgroup
Mean VAS Score 0.3% Test 1% Test Timepoint Article Article Vehicle
Baseline 2.3 2.3 2.3 Day 15 1.8 2 1.9 Day 29 1.7 1.8 1.8 Day 57 1.6
1.6 1.6 Day 85 1.5 1.5 1.5 Day 113 1.4 1.5 1.5
TABLE-US-00024 TABLE 24 Vascular Engorgement MMP9-Positive Subgroup
Mean Percent Change From Baseline 0.3% Test 1% Test Timepoint
Article Article Vehicle Baseline 0 0 0 Day 15 -21.74% -13.04%
-17.39% Day 29 -26.09% -21.74% -21.74% Day 57 -30.43% -30.43%
-30.43% Day 85 -34.78% -34.78% -34.78% Day 113 -39.13% -34.78%
-34.78%
TABLE-US-00025 TABLE 25 FCS Combined Score MMP9-Positive Subgroup
FCS Combined Score 0.3% Test 1% Test Timepoint Article Article
Vehicle Baseline 4.3 4.4 4.2 Day 15 3.3 3.5 3.4 Day 29 3.1 3.3 3.2
Day 57 2.9 2.9 3.4 Day 85 2.7 2.9 3 Day 113 2.3 2.3 2.6
TABLE-US-00026 TABLE 26 FCS Combined Score MMP9-Positive Subgroup
Mean Percent Change from Baseline 0.3% Test 1% Test Timepoint
Article Article Vehicle Baseline 0 0 0 Day 15 -23.26% -20.45%
-19.05% Day 29 -27.91% -25.00% -23.81% Day 57 -32.56% -34.09%
-19.05% Day 85 -37.21% -34.09% -28.57% Day 113 -46.51% -47.73%
-38.10%
TABLE-US-00027 TABLE 27 FCS Inferior Score MMP9-Positive Subgroup
FCS Inferior Score 0.3% Test 1% Test Timepoint Article Article
Vehicle Baseline 1.9 1.9 1.8 Day 15 1.7 1.6 1.6 Day 29 1.5 1.6 1.6
Day 57 1.4 1.4 1.7 Day 85 1.4 1.5 1.5 Day 113 1.2 1.1 1.4
TABLE-US-00028 TABLE 28 FCS Inferior Score MMP9-Positive Subgroup
Mean Percent Change from Baseline 0.3% Test 1% Test Timepoint
Article Article Vehicle Baseline 0 0 0 Day 15 -10.53% -15.79%
-11.11% Day 29 -21.05% -15.79% -11.11% Day 57 -26.32% -26.32%
-5.56% Day 85 -26.32% -21.05% -16.67% Day 113 -36.84% -42.11%
-22.22%
TABLE-US-00029 TABLE 29 Outcome of MMP9 Point of Care Test (Quidel
InflammaDry Test) Performed After 12 Weeks of Treatment in Subject
Subgroup That Was MMP-9 Positive at Visit 1 at the Beginning of the
Clinical Study 0.3% Test 1% Test Article Article Vehicle Positive
MMP-9 Test Result 60% 65% 79% After 12 Weeks of Treatment Negative
MMP-9 Test Result 40% 35% 21% After 12 Weeks of Treatment
[0714] Results in Table 29 are test results of a MMP-9 Point of
Care Test (Quidel InflammaDry Test) on subjects that had a baseline
positive test result in the MMP-9 Point of Care Test (Quidel
InflammaDry Test) conducted on Visit 1 at the beginning of the
clinical study. The results in Table 29 show that for the subset of
subjects having a baseline positive test result in the MMP-9 Point
of Care Test (Quidel InflammaDry Test) on Visit 1 at the beginning
of the clinical study who then received 0.3% Test Article during
the clinical study, 40% of those subjects tested negative in the
MMP-9 Point of Care Test (Quidel InflammaDry Test) performed on the
subject after the subject had received 12 weeks of treatment in the
clinical study. Results in Table 29 show that a greater percentage
of subjects converted to a negative test result in the MMP-9 Point
of Care Test (Quidel InflammaDry Test) when 0.3% Test Article was
administered compared to 1% Test Article or Vehicle.
Example 2--Efficacy Study for Treatment of Meibomian Gland
Dysfunction by Minocycline Topical Suspension in Human Subjects
[0715] A multi-center, Phase 3, double-masked, randomized,
vehicle-control study is undertaken to study the efficacy and
safety of minocycline topical suspension (Test Article) versus
Vehicle administered twice daily for twelve weeks in subjects with
a diagnosis of meibomian gland dysfunction.
[0716] In order to test the safety and efficacy of the minocycline
topical suspension Test Article, 750 subjects are randomized into
two groups: Test Article or Vehicle BID in a 1:1 ratio. After the
screening assessment, Single-Masked Vehicle is administered BID for
2 weeks. Following this Single-Masked Run-In period, Double-Masked
Investigational Product (IP) is administered BID to both eyes for
12 weeks. The Test Article and Vehicle correspond to those
described in Example 1.
[0717] The safety endpoints of this study include (see Example 1
for additional details): [0718] Adverse Event (AE) Monitoring
[0719] Best Corrected Visual Acuity (BCVA) [0720] Slit Lamp
Biomicroscopy and External Eye Exam [0721] Intraocular Pressure
(IOP) Measurement [0722] Dilated Ophthalmoscopy [0723] Follow-Up
Assessment
[0724] The primary efficacy endpoints of this study are evaluated
using hierarchical statistical testing in the following sequence.
(Note: the analysis is performed on the intent-to-treat (ITT)
population): [0725] 1. Changes in Vascular Engorgement at the study
eyelid margin as graded by the investigator at Week 12 (Visit 6)
from Randomization/Baseline (Visit 2) in Test Article compared to
Vehicle [0726] 2. Change in Eye Discomfort Visual Analogue Score
(VAS) at Week 12 (Visit 6) from Randomization/Baseline (Visit 2) in
Test Article compared to Vehicle
[0727] The secondary efficacy endpoints of this study include (see
Example 1 for additional details regarding specific testing
procedures): [0728] 1. Change in Fluorescein Corneal Staining (FCS)
total score (National Eye Institute [NEI]/Industry Workshop 0-15
scale) in the study eye at Week 4 (Visit 4), Week 8 (Visit 5), and
Week 12 (Visit 6) from Randomization/Baseline (Visit 2). [0729] 2.
Change in FCS inferior, nasal, and central combined score
(NEI/Industry Workshop section 1, 4 and 5 with a 0-9 scale) in the
study eye at Week 4 (Visit 4), Week 8 (Visit 5), and Week 12 (Visit
6) from Randomization/Baseline (Visit 2). [0730] 3. Change in FCS
inferior score (NEI/Industry Workshop section 5 with a 0-3 scale)
in the study eye at Week 4 (Visit 4), Week 8 (Visit 5), and Week 12
(Visit 6), from Randomization/Baseline (Visit 2). [0731] 4. Changes
in Eye Discomfort VAS at Week 4 (Visit 4), Week 8 (Visit 5), and
Week 12 (Visit 6), from Randomization/Baseline (Visit 2). [0732] 5.
Changes in Investigator reported scores on objective signs of
inflamed MGD including change from Randomization/Baseline (Visit 2)
at each follow up visit for individual severity scores: [0733]
Vascular Engorgement of eyelid margin [0734] Plugging of Meibomian
Gland [0735] Character of Meibomian Gland Secretion [0736]
Expressibility of the Meibomian Gland [0737] 6. Changes in
Investigator reported scores on objective signs of MGD for Total
Clinical Outcome Severity Score from Randomization/Baseline (Visit
2) defined as the sum of the four individual severity scores for
the clinical signs of: [0738] Plugging of Meibomian Gland [0739]
Character of Meibomian Gland Secretion [0740] Vascular Engorgement
of eyelid margin [0741] Expressibility of the Meibomian Gland
[0742] 7. Changes in Investigator reported scores on objective
Conjunctival Tarsal Erythema change from Randomization/Baseline
(Visit 2) at each follow up visit. [0743] 8. Changes in Tear Film
Break-Up Time (TFBUT) from Randomization/Baseline (Visit 2) at each
follow-up visit. [0744] 9. Changes in the following Dry Eye-related
ocular symptoms at each follow-up visit: [0745] VAS Scale Symptoms
(other than eye discomfort): [0746] Eye Dryness [0747] Foreign Body
Sensation [0748] SANDE change in the square root of the product of
the two questions at each timepoint compared to baseline and the
change from baseline of each individual question within the SANDE
[0749] 10. Number of symptom flares during the 12 weeks of
treatment. [0750] 11. The change from baseline in the
unanesthetized Schirmer score.
[0751] At Visit 1, individuals of any gender or any race are
eligible for study participation if they: [0752] 1. Have provided
written informed consent prior to any study procedures. [0753] 2.
Are 18 years of age or above. [0754] 3. Have a clinical diagnosis
of moderate to severe MGD and who meet the following criteria, in a
qualifying eyelid, at both Visit 1 (Screening) and Visit 2
(Randomization) examinations: [0755] a. Clinical sign severity
score of at least 2 (moderate) on vascular engorgement at the
eyelid margin and [0756] b. Clinical sign severity score of at
least 2 (moderate) on plugging of the meibomian glands. [0757] c.
Eye Discomfort Symptom score of .gtoreq.40 using VAS (0-100 point
scale) [0758] 4. Meet the following criteria, in a qualifying eye
(same eye that qualifies for Inclusion #3), at both the Visit 1
(Screening) and Visit 2 (Randomization) examinations: [0759] a.
Fluorescein corneal staining (FCS) total score .gtoreq.3 in the
inferior, central, and nasal region combined score (NEI/Industry
Workshop sections 1, 4 and 5 with 0-9 scale) [0760] b. Schirmer
score of >7 mm without topical anesthesia [0761] 5. Are willing
and able to follow instructions and can be present for the required
study visits for the duration of the study. [0762] 6. Have a BCVA,
using corrective lenses if necessary, in both eyes of at least +0.7
as assessed by Early Treatment of Diabetic Retinopathy Study
(ETDRS) or modified ETDRS. [0763] 7. If female, are non-pregnant,
non-lactating and women of childbearing potential (WOCBP) must be
using an acceptable method of birth control [e.g., an Intrauterine
Contraceptive Device (IUCD) with a failure rate of <1%, hormonal
contraceptives, or a barrier method] for the duration of the study.
If a female subject is currently abstinent, they must agree to use
one of the acceptable methods of birth control before they become
sexually active.
[0764] In order for subjects to be eligible at Visit 1 they may
not: [0765] 1. Have presence of inflammation and/or active
structural change in the iris or anterior chamber. [0766] 2. Have
lid structural abnormalities such as entropion or ectropion. [0767]
3. In the eyelid that qualifies (based on Inclusion #3), have grade
level 4 (Obstructed) on Character of Secretion of Meibomian Glands
or grade level 4 (No glands are expressible) on the Expressibility
of Meibomian Glands. [0768] 4. Subjects with ocular inflammatory
conditions (e.g., conjunctivitis, keratitis, anterior blepharitis,
etc.) not related to MGD. [0769] 5. Subjects who have FCS total
score=15 or a score=3, in either eye, in the superior region
NEI/Industry Workshop scale or subjects who have FCS with diffuse
confluent staining, filaments or frank epithelial defects. [0770]
6. Have suspected ocular fungal, viral or bacterial infection.
[0771] 7. Have had penetrating intraocular surgery in the past 90
days or require penetrating intraocular surgery during the study.
[0772] 8. Have had ocular surface surgery within 12 months of Visit
1 (e.g., LASIK, refractive, pterygium removal). [0773] 9. Subjects
who within the past 90 days have had cauterization of the punctum
or changes to the status (insertion or removal) of punctal plug(s)
before the Screening Visit. [0774] 10. Have used topical ocular or
oral antibiotics within 30 days of the study or expect to use
during the study. [0775] 11. Have used LipiFlow or hypochlorous
acid spray within 30 days of the study or expect to use during the
study. [0776] 12. If using inhaled or intranasal corticosteroids,
unable to maintain a stable dose for the duration of the study.
[0777] 13. Have ever used isotretinoin. [0778] 14. If using Omega-3
supplements, dose must be stable for 3 months prior to Visit 1 and
for the duration of the study. [0779] 15. Have used topical
cyclosporine within 30 days of the study or during the study.
[0780] 16. Have used topical lifitegrast within 30 days of the
study or during the study. [0781] 17. Have used systemic
corticosteroids within 30 days prior to study entry or during study
participation. [0782] 18. Have used topical ocular corticosteroids
or ocular non-steroidal anti-inflammatory drugs (NSAIDs) within 30
days prior to study entry and during study participation. [0783]
19. Have used topical ocular antihistamine and/or mast cell
stabilizers within 30 days prior to study entry or during study
participation. [0784] 20. Are unable or unwilling to discontinue
using any preserved or unpreserved topical ocular medications
(including artificial tears) upon Screening and for the duration of
the study. [0785] 21. Are unwilling to discontinue use of contact
lenses during the study. [0786] 22. Are unwilling to discontinue
use of cosmetic makeup applied to the eyelids or eye lashes at the
Screening Visit and during the study. If makeup was used, it should
be removed at least 12 hours prior to Visit 1. [0787] 23. Have a
known hypersensitivity to minocycline, any other tetracycline
antibiotic, or to any of the other ingredients in the
investigational product. [0788] 24. Are unable or unwilling to
withhold the use of eyelid scrubs or use of mechanical therapy
during the study. [0789] 25. Have been diagnosed with glaucoma or
are currently using any glaucoma medication. [0790] 26. Have a
history of herpetic keratitis. [0791] 27. Have a concomitant ocular
pathology other than condition under study assessed as potentially
confounding by the investigator. [0792] 28. Have a serious systemic
disease or uncontrolled medical condition that in the judgment of
the investigator could confound study assessments or limit
compliance. [0793] 29. Have been exposed to any investigational
drug or investigational device within the preceding 30 days. [0794]
30. Are an employee of the site that is directly involved in the
management, administration, or support of this study or be an
immediate family member of the same. [0795] 31. Have trigger
factors including conjunctivochalasis, allergic conjunctivitis,
contact lens intolerance, trichiasis, epithelial basement membrane
dystrophy, infectious keratitis or conjunctivitis. [0796] 32. Have
a documented history of ocular allergies, which, in the judgment of
the investigator, are likely to have an acute increase in severity
due to the expected timing of the exposure to the allergen to which
the subject is sensitive. Subjects sensitive to seasonal allergens
that are not expected to be present during the study are
permitted.
Example 3--Open Label Long Term Efficacy Study for Treatment of
Meibomian Gland Dysfunction by Minocycline Topical Suspension in
Human Subjects
[0797] An open label study is undertaken to study the long term
efficacy and safety of minocycline topical suspension (Test
Article) administered twice daily for 9 months in subjects with a
diagnosis of meibomian gland dysfunction.
[0798] In order to test the long term safety and efficacy of the
minocycline topical suspension Test Article, 400 subjects are given
Test Article to use twice daily for 9 months. The subjects will be
evaluated for safety and efficacy monthly for the duration of the
trial. The Test Article and Vehicle correspond to those described
in Example 1.
[0799] The safety endpoints of this study include (see Example 1
for additional details): [0800] Adverse Event (AE) Monitoring
[0801] Best Corrected Visual Acuity (BCVA) [0802] Slit Lamp
Biomicroscopy and External Eye Exam [0803] Intraocular Pressure
(IOP) Measurement [0804] Dilated Ophthalmoscopy [0805] Follow-Up
Assessment
[0806] The primary efficacy endpoints of this study are evaluated
using hierarchical statistical testing in the following sequence.
(Note: the analysis is performed on the intent-to-treat (ITT)
population): [0807] 1. Changes in Vascular Engorgement at the study
eyelid margin as graded by the investigator at Month 9 from
Baseline in Test Article compared to Vehicle. [0808] 2. Change in
Eye Discomfort Visual Analogue Score (VAS) at Month 9 from Baseline
in Test Article compared to Vehicle.
[0809] The secondary efficacy endpoints of this study include (see
Example 1 for additional details regarding specific testing
procedures): [0810] 1. Change in Fluorescein Corneal Staining (FCS)
total score (National Eye Institute [NEI]/Industry Workshop 0-15
scale) in the study eye at each visit from Baseline. [0811] 2.
Change in FCS inferior, nasal, and central combined score
(NEI/Industry Workshop section 1, 4 and 5 with a 0-9 scale) in the
study eye at each visit from Baseline. [0812] 3. Change in FCS
inferior score (NEI/Industry Workshop section 5 with a 0-3 scale)
in the study eye at each visit from Baseline. [0813] 4. Changes in
Eye Discomfort VAS at each visit from Baseline. [0814] 5. Changes
in Investigator reported scores on objective signs of inflamed MGD
including change from Baseline at each follow up visit for
individual severity scores: [0815] Vascular Engorgement of eyelid
margin [0816] Plugging of Meibomian Gland [0817] Character of
Meibomian Gland Secretion [0818] Expressibility of the Meibomian
Gland. [0819] 6. Changes in Investigator reported scores on
objective signs of MGD for Total Clinical Outcome Severity Score
from Baseline defined as the sum of the four individual severity
scores for the clinical signs of: [0820] Plugging of Meibomian
Gland [0821] Character of Meibomian Gland Secretion [0822] Vascular
Engorgement of eyelid margin [0823] Expressibility of the Meibomian
Gland. [0824] 7. Changes in Investigator reported scores on
objective Conjunctival Tarsal Erythema change from Baseline at each
follow up visit. [0825] 8. Changes in Tear Film Break-Up Time
(TFBUT) from Baseline at each follow-up visit. [0826] 9. Changes in
the following Dry Eye-related ocular symptoms at each follow-up
visit: [0827] VAS Scale Symptoms (other than eye discomfort):
[0828] Eye Dryness [0829] Foreign Body Sensation [0830] SANDE
change in the square root of the product of the two questions at
each timepoint compared to baseline and the change from baseline of
each individual question within the SANDE [0831] 10. Number of
symptom flares during the 12 weeks of treatment. [0832] 11. The
change from baseline in the unanesthetized Schirmer score.
[0833] At Visit 1, individuals of any gender or any race are
eligible for study participation if they: [0834] 1. Have provided
written informed consent prior to any study procedures. [0835] 2.
Are 18 years of age or above. [0836] 3. Have met the criteria for
inclusion and successfully completed the phase 3 trial described in
Example 2. [0837] 4. Did not have worsening of VAS symptom or
eyelid vascularity over the course of the phase 3 trial described
in Example 2.
Example 4--Pharmacokinetic Profile Study for Treatment of Meibomian
Gland Dysfunction by Minocycline Topical Suspension in Human
Subjects
[0838] An open label, multiple dose study is undertaken to assess
the pharmacokinetic profile of minocycline topical suspension (Test
Article) in subjects with a diagnosis of meibomian gland
dysfunction.
[0839] In order to test the pharmacokinetic profile of the
minocycline topical suspension Test Article, 20 subjects are given
Test Article to use twice daily for 4 weeks. On days 1, 2, 3, 7, 9,
14, 21, and 28 blood will be drawn for pharmacokinetic analysis.
End of study follow up will take place 7-10 days following
cessation of treatment. Adverse events, vital signs, physical exam,
and subject symptoms will be recorded at each visit. The Test
Article and Vehicle correspond to those described in Example 1.
[0840] The safety endpoints of this study include (see Example 1
for additional details): [0841] Adverse Event (AE) Monitoring
[0842] Best Corrected Visual Acuity (BCVA) [0843] Slit Lamp
Biomicroscopy and External Eye Exam [0844] Intraocular Pressure
(IOP) Measurement [0845] Dilated Ophthalmoscopy [0846] Follow-Up
Assessment
[0847] The primary efficacy endpoints of this study include: [0848]
1. The maximal plasma concentration of minocycline (Cmax) [0849] 2.
The time to maximal plasma minocycline concentration (Tmax) [0850]
3. The exposure over 4 weeks of treatment to minocycline by
evaluating the area under the curve (AUC). [0851] 4. The half life
of plasma minocycline (T.sub.1/2).
[0852] At Visit 1, individuals of any gender or any race are
eligible for study participation if they: [0853] 1. Have provided
written informed consent prior to any study procedures. [0854] 2.
Are 18 years of age or above. [0855] 3. Have a clinical diagnosis
of moderate to severe MGD and who meet the following criteria, in a
qualifying eyelid, at both Visit 1 examinations: [0856] a. Clinical
sign severity score of at least 2 (moderate) on vascular
engorgement at the eyelid margin and [0857] b. Clinical sign
severity score of at least 2 (moderate) on plugging of the
meibomian glands. [0858] c. Eye Discomfort Symptom score of
.gtoreq.40 using VAS (0-100 point scale) [0859] 4. Are willing and
able to follow instructions and can be present for the required
study visits for the duration of the study. [0860] 5. Have a BCVA,
using corrective lenses if necessary, in both eyes of at least +0.7
as assessed by Early Treatment of Diabetic Retinopathy Study
(ETDRS) or modified ETDRS. [0861] 6. If female, are non-pregnant,
non-lactating and women of childbearing potential (WOCBP) must be
using an acceptable method of birth control [e.g., an Intrauterine
Contraceptive Device (IUCD) with a failure rate of <1%, hormonal
contraceptives, or a barrier method] for the duration of the study.
If a female subject is currently abstinent, they must agree to use
one of the acceptable methods of birth control before they become
sexually active. [0862] 7. Have a negative HIV, Hepatitis B, and
Hepatitis C serology at screening. [0863] 8. No significant
abnormalities in hematology, blood chemistry, or urinalysis at
screening. [0864] 9. Body mass index (BMI) 19-30 kg/m2 [0865] 10.
Otherwise healthy subjects
[0866] In order for subjects to be eligible at Visit 1 they may not
be in violation of any of the exclusion criteria described in
Example 2.
Example 5--Comparative Dosing Frequency Study for Treatment of
Meibomian Gland Dysfunction by Minocycline Topical Suspension in
Human Subjects
[0867] A multi-center, double-masked, randomized,
vehicle-controlled study of the noninferiority of once daily
administration of minocycline topical suspension (Test Article), as
compared to twice daily administration is undertaken to assess the
optimal dosing regimen to treat subjects with a diagnosis of
meibomian gland dysfunction.
[0868] In order to evaluate the noninferiority of efficacy and
safety of Test Article administration twice daily versus once daily
for twelve weeks, subjects will be randomized into two groups: Test
Article administered twice daily (BID) or Test Article administered
once daily in a 1:1 ratio. After the screening assessment,
Single-Masked Vehicle will be administered for 2 weeks. Following
this Single-Masked Run-In period, Double-Masked Investigational
Product (IP) will be administered to both eyes for 12 weeks. The
Test Article and Vehicle correspond to those described in Example
1.
[0869] The safety end points, primary efficacy endpoints, inclusion
criteria and exclusion criteria are the same as those noted in
Example 2.
Example 6--Preparation of Minocycline Topical Suspension
[0870] A minocycline topical suspension was prepared according to
the experimental procedures described below.
[0871] Particles of minocycline crystalline Form II (having a D90
particle size less than 5 microns, in an amount sufficient to
result in the final minocycline topical suspension containing 1%
(w/w) minocycline) were added to mineral oil (the amount of mineral
oil corresponded to 29.7% (w/w) of the final minocycline topical
suspension, and the mineral oil was Mineral Oil USP having a
specific gravity in the range of 0.845 to 0.905 and a viscosity
greater than 34.5 centistokes when the viscosity is measured at
40.degree. C.) and the resulting mixture was stirred for about 30
minutes at room temperature. To the resulting mixture was added the
polymeric hydrocarbon gelling agent commercially available under
the tradename VERSAGEL.RTM. M-750 (in an amount corresponding to
69.3% (w/w) of the final minocycline topical suspension) and the
mixture was stirred for about one hour at room temperature. Samples
from different parts of the mixing vessel were analyzed by HPLC to
determine content homogeneity. The mixture was then dispensed,
filled in aluminum tubes, and terminally sterilized to provide
tubes of the minocycline topical suspension containing 1% (w/w)
minocycline. Composition of the 1% (w/w) minocycline topical
suspension is set forth in the table below.
TABLE-US-00030 Component Amount Function Minocycline base 1% w/w
active ingredient Polymeric hydrocarbon gelling agent 69.3% w/w
gelling agent commercially available under the tradename VERSAGEL
.RTM. M-750 Mineral oil 29.7% w/w wetting agent
[0872] Particles of minocycline crystalline Form II having a D90
particle size less than 5 microns were obtained by controlled
jet-milling micronization of minocycline crystalline Form II. The
polymeric hydrocarbon gelling agent commercially available under
the tradename VERSAGEL.RTM. M-750 is a mixture of
ethylene-propylene-styrene copolymer, butylene-ethylene-styrene
copolymer, butylated-hydroxytoluene, and mineral oil. The
ethylene-propylene-styrene copolymer (e.g., weight-average
molecular weight of about 200,000 g/mol) is present in an amount
within the range of 2.5% to 10% (w/w), the
butylene-ethylene-styrene copolymer (e.g., weight-average molecular
weight of about 100,000 g/mol) is present in an amount within the
range of 0.1% to 2.5% (w/w), the butylated-hydroxytoluene is
present in an amount <0.5% (w/w), and the remainder is mineral
oil (e.g., having a weight-average molecular weight in the range of
230-700 g/mol).
Example 7--Rheological Evaluation of Minocycline Topical
Suspensions
[0873] Minocycline topical suspensions were subjected to
rheological evaluation. Experimental procedures and results are
described below.
Part I--Experimental Procedures
[0874] The following rheological tests were conducted on a sample
of the 0.3% Test Article and 1% Test Article described in Tables 30
and 31 below: Shear Rate Sweep, Sear Stress Sweep, and Oscillation
Stress Sweep.
TABLE-US-00031 TABLE 30 COMPOSITION OF 0.3% TEST ARTICLE Component
Amount Function Minocycline base 0.3% w/w active ingredient
Polymeric hydrocarbon gelling agent 69.8% w/w gelling agent
commercially available under the tradename VERSAGEL .RTM. M-750
Mineral oil 29.9% w/w wetting agent
TABLE-US-00032 TABLE 31 COMPOSITION OF 1% TEST ARTICLE Component
Amount Function Minocycline base 1% w/w active ingredient Polymeric
hydrocarbon gelling agent 69.3% w/w gelling agent commercially
available under the tradename VERSAGEL .RTM. M-750 Mineral oil
29.7% w/w wetting agent
[0875] The minocycline base was minocycline base in crystalline
Form II. The polymeric hydrocarbon gelling agent commercially
available under the tradename VERSAGEL.RTM. M-750 is a mixture of
ethylene-propylene-styrene copolymer, butylene-ethylene-styrene
copolymer, butylated-hydroxytoluene, and mineral oil. The
ethylene-propylene-styrene copolymer (e.g., weight-average
molecular weight of about 200,000 g/mol) is present in an amount
within the range of 2.5% to 10% (w/w), the
butylene-ethylene-styrene copolymer (e.g., weight-average molecular
weight of about 100,000 g/mol) is present in an amount within the
range of 0.1% to 2.5% (w/w), the butylated-hydroxytoluene is
present in an amount <0.5% (w/w), and the remainder is mineral
oil (e.g., having a weight-average molecular weight in the range of
230-700 g/mol).
Shear Rate Sweep
[0876] The Shear Rate Sweep analysis was performed as follows:
following a 30 s equilibration time at 34.degree. C., the sample
was exposed to a 30 s pre-shear at a rate of 1 s.sup.-1 before
leading directly into a shear rate sweep, 1.0 s.sup.-1 to 1000
s.sup.-1, logarithmically scaled, 6 points per decade of shear
rate, shear applied for 30 s at each rate with viscosity calculated
over the final 5 seconds of each step.
Shear Stress Sweep
[0877] The Shear Stress Sweep analysis was performed as follows:
following a 60 s equilibration time at 25.degree. C., the sample
was subjected to a shear stress sweep from 0.1 Pa to 100 Pa,
logarithmically spaced, 8 points per decade of shear stress.
Steady-state sensing was employed to ensure individual viscosity
readings reached an acceptable degree of elastic or thixotropic
equilibrium before being recorded. At each step of the test,
viscosity was monitored every 5 seconds. Viscosity was recorded
only when 3 successive measurements were within 5% of each other. A
60 s timeout was set: if an equilibrium viscosity was not achieved
after that time the viscosity at that instant was recorded
regardless of degree of equilibrium.
Oscillation Stress Sweep
[0878] The Oscillation Stress Sweep analysis was performed as
follows: following a 60 s equilibration time at 25.degree. C., the
sample was exposed to an oscillatory stress sweep ranging from 0.1
Pa to 1000 Pa, 10 points per decade, at 1 Hz oscillation frequency.
A step termination was set such that if at any point the
oscillation strain exceeded 1500%, the test would immediately
end.
[0879] Part I--Results
[0880] Results of the rheological tests are depicted in Tables
32-35 below along with FIGS. 17-21.
TABLE-US-00033 TABLE 32 CONTROLLED RATE VISCOSITY DATA Viscosity at
1 s.sup.-1 (Pa s) Viscosity at 1000 s.sup.-1 (Pa s) Sample Run 1
Run 2 Mean Run 1 Run 2 Mean 0.3% Test 31.7 29.1 30.4 0.659 0.777
0.718 Article 1% Test 30.7 30.2 30.5 0.796 0.700 0.748 Article
TABLE-US-00034 TABLE 33 ZERO SHEAR VISCOSITY - QUANTIFIED AS THE
AVERAGE OF THE OBSERVED PLATEAU Zero Shear Viscosity (Pa s) Sample
Run 1 Run 2 Mean 0.3% Test Article 303 286 295 1% Test Article 322
334 328
TABLE-US-00035 TABLE 34 OSCILLATION STRESS SWEEP DATA Complex
Modulus Plateau (Pa) Phase Angle Plateau (.degree.) Sample Run 1
Run 2 Mean Run 1 Run 2 Mean 0.3% Test 140 138 139 26.2 25.9 26.1
Article 1% Test 143 136 140 25.9 25.5 25.7 Article
TABLE-US-00036 TABLE 35 OSCILLATION STRESS SWEEP ADDITIONAL DATA
Yield Stress (Pa) Sample Run 1 Run 2 Mean 0.3% Test Article 21.1
20.5 20.8 1% Test Article 20.6 21.8 21.2
[0881] The results demonstrate a clear soft solid structure present
under low stress conditions, yielding to non-Newtonian shear
thinning flow as the applied stress is increased past a certain
yielding stress. The 0.3% Test Article has slightly lower viscosity
under zero shear conditions than the 1% Test Article.
INCORPORATION BY REFERENCE
[0882] The entire disclosure of each of the patent documents and
scientific articles referred to herein is incorporated by reference
for all purposes.
EQUIVALENTS
[0883] The invention may be embodied in other specific forms
without departing from the spirit or essential characteristics
thereof. The foregoing embodiments are therefore to be considered
in all respects illustrative rather than limiting the invention
described herein. Scope of the invention is thus indicated by the
appended claims rather than by the foregoing description, and all
changes that come within the meaning and range of equivalency of
the claims are intended to be embraced therein.
* * * * *