U.S. patent application number 17/145093 was filed with the patent office on 2021-07-08 for dexamethasone prodrug compositions and uses thereof.
The applicant listed for this patent is Ripple Therapeutics Corporation. Invention is credited to Kyle BATTISTON, Roseita Esfand, Hans Christian FISCHER, Dimitra LOUKA, Wendy Alison NAIMARK, Ian Charles PARRAG, J. Paul SANTERRE, Matthew Alexander John STATHAM.
Application Number | 20210205222 17/145093 |
Document ID | / |
Family ID | 1000005464678 |
Filed Date | 2021-07-08 |
United States Patent
Application |
20210205222 |
Kind Code |
A1 |
PARRAG; Ian Charles ; et
al. |
July 8, 2021 |
DEXAMETHASONE PRODRUG COMPOSITIONS AND USES THEREOF
Abstract
The disclosure features dexamethasone prodrug dimers of
dexamethasone and pharmaceutical compositions thereof useful for,
e.g., the extended release of a drug and for the treatment of a
disease or condition.
Inventors: |
PARRAG; Ian Charles;
(Mississauga, CA) ; STATHAM; Matthew Alexander John;
(Milton, CA) ; BATTISTON; Kyle; (Toronto, CA)
; LOUKA; Dimitra; (Toronto, CA) ; FISCHER; Hans
Christian; (Toronto, CA) ; SANTERRE; J. Paul;
(Toronto, CA) ; NAIMARK; Wendy Alison; (Toronto,
CA) ; Esfand; Roseita; (Mississauga, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ripple Therapeutics Corporation |
Toronto |
|
CA |
|
|
Family ID: |
1000005464678 |
Appl. No.: |
17/145093 |
Filed: |
January 8, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16699305 |
Nov 29, 2019 |
10945958 |
|
|
17145093 |
|
|
|
|
16698372 |
Nov 27, 2019 |
10959954 |
|
|
16699305 |
|
|
|
|
16396400 |
Apr 26, 2019 |
10588862 |
|
|
16698372 |
|
|
|
|
PCT/CA2019/050136 |
Feb 1, 2019 |
|
|
|
16396400 |
|
|
|
|
62758234 |
Nov 9, 2018 |
|
|
|
62627608 |
Feb 7, 2018 |
|
|
|
62625460 |
Feb 2, 2018 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/6953 20170801;
A61K 9/167 20130101; A61K 9/0048 20130101; A61K 9/5089 20130101;
A61K 31/573 20130101; A61K 9/1682 20130101; A61K 9/0051 20130101;
A61K 9/51 20130101; A61K 47/55 20170801; A61K 9/50 20130101; A61K
47/6921 20170801; A61P 29/00 20180101; A61K 9/0092 20130101; A61K
9/7007 20130101; A61P 27/02 20180101; A61K 9/5192 20130101 |
International
Class: |
A61K 9/16 20060101
A61K009/16; A61K 9/70 20060101 A61K009/70; A61K 9/00 20060101
A61K009/00; A61K 9/51 20060101 A61K009/51; A61K 31/573 20060101
A61K031/573; A61K 9/50 20060101 A61K009/50; A61K 47/55 20060101
A61K047/55; A61K 47/69 20060101 A61K047/69; A61P 29/00 20060101
A61P029/00; A61P 27/02 20060101 A61P027/02 |
Claims
1-30. (canceled)
31. A coating comprising a compound having a structure represented
by formula (I): ##STR00040## wherein: n is an integer from 1 to 6,
or a pharmaceutically salt or solvate thereof.
32. The coating of claim 31, wherein at least 70% (w/w) of the
coating is the compound.
33. The coating of claim 32, wherein at least 90% (w/w) of the
coating is the compound.
34. The coating of claim 31, wherein n is an integer from 3-5.
35. The coating of claim 34, wherein the compound has a structure
represented by: ##STR00041##
36. The coating of claim 31, wherein the compound or dexamethasone
in its free form is released from the coating through surface
erosion.
37. The coating of claim 31, wherein less than or equal to 10% of
dexamethasone, as a percentage of the total dexamethasone present
in the coating, is released from the coating at 37.degree. C. in
100% bovine serum over a period of at least 5 days.
38. The coating of claim 31, wherein less than or equal to 2% of
dexamethasone, as a percentage of the total dexamethasone present
in the coating, is released from the coating at 37.degree. C. in
PBS over a period of at least 5 days.
39. The coating of claim 31, wherein more than or equal to 20% of
dexamethasone, as a percentage of the total dexamethasone present
in the coating, is released from the coating at 37.degree. C. in
100% bovine serum over a period of at least 6 days.
40. The coating of claim 31, wherein dexamethasone is released from
the coating at 37.degree. C. in 100% bovine serum or at 37.degree.
C. in phosphate buffered saline (PBS) at a rate such that t.sub.10
is greater than or equal to 1/10 of t.sub.50.
41. The coating of claim 31, wherein the coating resides on the
surface of an implantable device.
42. The coating of claim 31, wherein the coating resides on the
surface of a minimally invasive glaucoma surgery (MIGS) device.
43. A method of treating inflammation in a subject, the method
comprising administering to the subject an implantable device
comprising a coating in an amount sufficient to treat inflammation
in the subject, wherein the coating comprises a compound having a
structure represented by formula (I): ##STR00042## wherein: n is an
integer from 1 to 6, or a pharmaceutically salt or solvate
thereof.
44. The method of claim 43, wherein the inflammation is
post-surgical inflammation.
45. The method of claim 43, wherein at least 70% (w/w) of the
coating is the compound.
46. The method of claim 45, wherein at least 90% (w/w) of the
coating is the compound.
47. The method of claim 43, wherein the compound has a structure
represented by: ##STR00043##
48. The method of claim 43, wherein the implantable device is
administered locally to the subject.
49. The method of claim 48, wherein the implantable device is
administered in the eye of the subject.
50. The method of claim 48, wherein the implantable device is
administered into a joint space of the subject.
Description
REFERENCED TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/699,305, filed Nov. 29, 2019, which is a continuation of
U.S. application Ser. No. 16/698,372, filed Nov. 27, 2019, which is
a continuation of U.S. application Ser. No. 16/369,400, filed Apr.
26, 2019, now U.S. Pat. No. 10,588,862, issued Mar. 17, 2020, which
is a continuation of International Application No.
PCT/CA2019/050136, filed Feb. 1, 2019 which claims the benefit of
U.S. Provisional Patent Application No. 62/758,234 filed on Nov. 9,
2018, U.S. Provisional Patent Application No. 62/627,608, filed
Feb. 7, 2018, and U.S. Provisional Patent Application No.
62/625,460, filed Feb. 2, 2018, which are hereby incorporated by
reference in their entirety herein.
BACKGROUND OF THE DISCLOSURE
[0002] Dexamethasone is a useful drug in a variety of medical
fields, for example in the treatment of inflammatory diseases or
conditions and in reducing inflammation associated with surgery or
another therapy.
SUMMARY OF THE DISCLOSURE
[0003] The disclosure features prodrug dimers formed from
dexamethasone and articles formed from the dimers. The articles of
the disclosure can be machined, molded, emulsion-processed,
electrospun, electrosprayed, blow molded, or extruded to form a
fiber, fiber mesh, woven fabric, non-woven fabric, pellet,
cylinder, microparticle (e.g., a microbead), nanoparticle (e.g., a
nanobead), or any other type shaped article from which the
dexamethasone prodrug dimer is released in a controlled
fashion.
[0004] In one aspect, the disclosure features an article formed
from a compound of the disclosure, wherein the article provides
controlled release of dexamethasone at 37.degree. C. in 100% bovine
serum or at 37.degree. C. in PBS.
[0005] In another aspect, the disclosure features compound
described by the formula (I):
##STR00001##
wherein n is an integer from 1 to 6 (e.g., wherein n is 1, 2, 3, 4,
5, or 6). In some embodiments, n is 1. In further embodiments, n is
2. In particular embodiments, n is 3. In other embodiments, n is 4.
In further embodiments, n is 5. In yet other embodiments, n is
6.
[0006] In another aspect, the disclosure features a pharmaceutical
composition including the compound of the previous aspect, and a
pharmaceutically acceptable excipient.
[0007] In another aspect, the disclosure features an article
including Compound 6 or a compound of formula (I):
##STR00002##
wherein the article provides controlled release of dexamethasone at
37.degree. C. in 100% bovine serum or at 37.degree. C. in PBS;
wherein n is an integer from 1 to 6.
[0008] In some embodiments, dexamethasone is released from the
article through surface erosion.
[0009] In some embodiments, the article releases less than 10% of
dexamethasone, as a percentage of the total dexamethasone present
in the article in prodrug form, at 37.degree. C. in 100% bovine
serum over 5 days; or the surface erosion releases less than 2% of
dexamethasone, as a percentage of the total dexamethasone present
in the article in prodrug form, at 37.degree. C. in PBS over 5
days; or the surface erosion releases greater than 20% of
dexamethasone, as a percentage of the total dexamethasone present
in the article in prodrug form, at 37.degree. C. in 100% bovine
serum over not fewer than 6 days; or the surface erosion releases
greater than 5.0% of dexamethasone as a percentage of the total
dexamethasone present in the article in prodrug form, at 37.degree.
C. in PBS over not fewer than 6 days; or dexamethasone is released
from the article at a rate such that t.sub.10 is greater than or
equal to 1/10 of t.sub.50.
[0010] In some embodiments, the article further includes from 0.1%
to 10% (w/w) of one or more additives, wherein the one or more
additives are selected from plasticizers, antioxidants, binders,
lubricants, radio-opaque agents, and mixtures thereof.
[0011] In further embodiments, the article is a fiber, fiber mesh,
woven fabric, non-woven fabric, pellet, cylinder, hollow tube,
microparticle, nanoparticle, or shaped article. In other
embodiments, the article is free of controlled release excipient,
free of a crystallization inhibiting excipient, free of a
mechanical integrity enhancing excipient, and/or free of a binding
excipient. In some embodiments, the article is in a glassy
state.
[0012] In certain embodiments, the controlled release is provided
by any one of: dimensions of the article, composition of the
article, crystallinity of the article, surface area of the article,
or combinations thereof.
[0013] In another aspect, the disclosure features an article
including a compound of formula (I):
##STR00003##
wherein the article is formed by a process including the steps of:
(a) heating the compound to form a melt; and (b) heat molding the
melt to form the article, wherein n is an integer from 1 to 6. In
some embodiments, the article is free of controlled release
excipient, free of a crystallization inhibiting excipient, free of
a mechanical integrity enhancing excipient, and/or free of a
binding excipient; or the article optionally has a glassy
state.
[0014] In another aspect, the disclosure features an article
including a compound of formula (I):
##STR00004##
wherein the article is formed by a process including the steps of:
(a) heating the compound to form a melt; and (b) injection molding
the melt to form the article, wherein n is an integer from 1 to 6.
In some embodiments, the article is free of controlled release
excipient, free of a crystallization inhibiting excipient, free of
a mechanical integrity enhancing excipient, and/or free of a
binding excipient; or the article optionally has a glassy
state.
[0015] In another aspect, the disclosure features an article
including a compound of formula (I):
##STR00005##
wherein the article is formed by a process including the steps of:
(a) heating the compound to form a melt; and (b) blow molding the
melt to form the article, wherein n is an integer from 1 to 6. In
some embodiments, the article is free of controlled release
excipient, free of a crystallization inhibiting excipient, free of
a mechanical integrity enhancing excipient, and/or free of a
binding excipient; or the article optionally has a glassy
state.
[0016] In another aspect, the disclosure features an article
including a compound of formula (I):
##STR00006##
wherein the article is formed by a process including the steps of:
(a) dissolving the compound to form a solution; and (b) evaporating
the solvent to form the article, wherein n is an integer from 1 to
6. In some embodiments, the article is free of controlled release
excipient, free of a crystallization inhibiting excipient, free of
a mechanical integrity enhancing excipient, and/or free of a
binding excipient; or the article optionally has a glassy state. In
some embodiments, step (b) includes solvent casting to form a film
or a fiber.
[0017] In another aspect, the disclosure features an article
including a compound of formula (I):
##STR00007##
wherein the article is formed by a process including the steps of:
(a) dissolving the compound to form a solution; and (b)
electrospinning or electrospraying the solution to form the
article, wherein n is an integer from 1 to 6. In some embodiments,
the article is free of controlled release excipient, free of a
crystallization inhibiting excipient, free of a mechanical
integrity enhancing excipient, and/or free of a binding excipient;
or the article optionally has a glassy state.
[0018] In another aspect, the disclosure features an article
including a compound of formula (I):
##STR00008##
wherein the article is formed by a process including the steps of:
(a) heating the compound to form a melt; and (b) electrospinning or
electrospraying the melt to form the article, wherein n is an
integer from 1 to 6. In some embodiments, the article is free of
controlled release excipient, free of a crystallization inhibiting
excipient, free of a mechanical integrity enhancing excipient,
and/or free of a binding excipient; or the article optionally has a
glassy state.
[0019] In another aspect, the disclosure features an article
including a compound of formula (I):
##STR00009##
wherein the article is formed by a process including the steps of:
(a) heating the compound to form a melt; (b) extruding the melt to
form the article, wherein n is an integer from 1 to 6. In some
embodiments, the article is free of controlled release excipient,
free of a crystallization inhibiting excipient, free of a
mechanical integrity enhancing excipient, and/or free of a binding
excipient; or the article optionally has a glassy state.
[0020] In some embodiments of any of the above aspects, n is 1. In
further embodiments, n is 2. In certain embodiments of the articles
of the disclosure, n is 3. In other embodiments, n is 4. In further
embodiments, n is 5. In yet other embodiments, n is 6.
[0021] In another aspect, the disclosure features an article formed
from a compound of the disclosure.
[0022] In some embodiments of the articles of the disclosure, at
least 70% (e.g., at least 75%, at least 80%, at least 85%, at least
90%, at least 95%, or at least 99%) (w/w) of the article is the
compound of formula (I). In some embodiments, at least 90% (e.g.,
at least 91%, at least 92%, at least 93%, at least 94%, at least
95%, at least 96%, at least 97%, at least 98%, or at least 99%)
(w/w) of the article is the compound of formula (I).
[0023] In further embodiments of the articles of the disclosure,
the compound or dexamethasone is released from the article through
surface erosion. In some embodiments, the surface erosion releases
less than 10% (e.g., less than 9%, less than 8%, less than 7%, less
than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or
less than 1%) of dexamethasone, as a percentage of the total drug,
dexamethasone, present in the article in prodrug form, at
37.degree. C. in 100% bovine serum over 5 days; or the surface
erosion releases less than 2% (e.g., less than 1.8%, less than
1.5%, less than 1.2%, less than 1.0%, or less than 0.5%) of
dexamethasone, as a percentage of the total drug, dexamethasone,
present in the article in prodrug form, at 37.degree. C. in PBS
over 5 days. In still other embodiments of any of the above
articles, the surface erosion releases greater than 20% (e.g.,
greater than 22%, 24%, 26%, 28%, or 30%) of dexamethasone (as a
percentage of the total dexamethasone present in the article in
prodrug form) at 37.degree. C. in 100% bovine serum over not fewer
than 6 days, 8 days, 10 days, or 12 days (e.g., greater than 24% of
dexamethasone at 37.degree. C. in 100% bovine serum over 10 days).
In other embodiments of any of the above articles, the surface
erosion releases greater than 5.0% (e.g., greater than 6.0%, 8.0%,
10%, 12%, or 15%) of dexamethasone (as a percentage of the total
dexamethasone present in the article in prodrug form) at 37.degree.
C. in PBS over not fewer than 6 days, 8 days, 10 days, or 12 days
(e.g., greater than 5% of dexamethasone at 37.degree. C. in PBS
over 10 days). The dexamethasone can be released from the article
at a rate such that t.sub.10 is greater than or equal to 1/10 of
t.sub.50. In some embodiments, the article further includes from
0.1% to 10% (e.g., from 0.1 to 5%, from 0.1 to 2%, from 0.5 to 2%,
from 1 to 10%) (w/w) of one or more additives, wherein the one or
more additives are selected from plasticizers, antioxidants,
binders, lubricants, radio-opaque agents, and mixtures thereof.
[0024] The article may be a fiber, fiber mesh, woven fabric,
non-woven fabric, pellet, cylinder, hollow tube, microparticle
(e.g., a microbead), nanoparticle (e.g., a nanobead), or shaped
article. In some embodiments, the article is free of controlled
release excipient, free of a crystallization inhibiting excipient,
free of a mechanical integrity enhancing excipient, and/or free of
a binding excipient; or the article optionally has a glassy
state.
[0025] In another aspect, the disclosure features a fiber formed
from a compound of the disclosure.
[0026] In another aspect, the disclosure features a fiber formed
from a compound of formula (I):
##STR00010##
wherein the fiber is prepared by a process including the steps of:
(a) dissolving the compound in a solvent to form a solution; and
(b) electrospinning, dry spinning, wet spinning, or gel spinning
the solution to form the fiber, wherein n is an integer from 1 to
6. In some embodiments, the fiber is free of controlled release
excipient, free of a crystallization inhibiting excipient, free of
a mechanical integrity enhancing excipient, and/or free of a
binding excipient; or the fiber optionally has a glassy state.
[0027] In another aspect, the disclosure features a fiber formed
from a compound of formula (I):
##STR00011##
wherein the fiber is prepared by a process including the steps of:
(a) heating the compound to form a melt; and (b) extruding the melt
to form the fiber (i.e., melt spinning), wherein n is an integer
from 1 to 6. In some embodiments, the fiber is free of controlled
release excipient, free of a crystallization inhibiting excipient,
free of a mechanical integrity enhancing excipient, and/or free of
a binding excipient; or the fiber optionally has a glassy
state.
[0028] In another aspect, the disclosure features a fiber formed
from a compound of formula (I):
##STR00012##
wherein the fiber is prepared by a process including the steps of:
(a) heating the compound to form a melt; and (b) electrospinning
the melt to form the fiber, wherein n is an integer from 1 to 6. In
some embodiments, the fiber is free of controlled release
excipient, free of a crystallization inhibiting excipient, free of
a mechanical integrity enhancing excipient, and/or free of a
binding excipient; or the fiber optionally has a glassy state.
[0029] In some embodiments, n is 1. In further embodiments, n is 2.
In particular embodiments of the fibers of the disclosure, n is 3.
In another embodiment, n is 4. In further embodiments, n is 5. In
yet other embodiments, n is 6.
[0030] In some embodiments of the fibers of the disclosure, at
least 70% (e.g., at least 75%, at least 80%, at least 85%, at least
90%, at least 95%, or at least 99%) (w/w) of the fiber is the
compound of formula (I). In some embodiments, at least 90% (e.g.,
at least 91%, at least 92%, at least 93%, at least 94%, at least
95%, at least 96%, at least 97%, at least 98%, or at least 99%)
(w/w) of the fiber is the compound of formula (I).
[0031] In some embodiments of the fibers of the disclosure, the
compound or dexamethasone is released from the fiber through
surface erosion. In some embodiments, the surface erosion releases
less than 10% (e.g., less than 9%, less than 8%, less than 7%, less
than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or
less than 1%) of dexamethasone, as a percentage of the total drug,
dexamethasone, present in the fiber in prodrug form, at 37.degree.
C. in 100% bovine serum over 5 days; or the surface erosion
releases less than 2% (e.g., less than 1.8%, less than 1.5%, less
than 1.2%, less than 1.0%, or less than 0.5%) of dexamethasone, as
a percentage of the total drug, dexamethasone, present in the fiber
in prodrug form, at 37.degree. C. in PBS over 5 days. In still
other embodiments of any of the above fibers, the surface erosion
releases greater than 20% (e.g., greater than 22%, 24%, 26%, 28%,
or 30%) of dexamethasone (as a percentage of the total
dexamethasone present in the fiber in prodrug form) at 37.degree.
C. in 100% bovine serum over not fewer than 6 days, 8 days, 10
days, or 12 days (e.g., greater than 24% of dexamethasone at
37.degree. C. in 100% bovine serum over 10 days). In other
embodiments of any of the above fibers, the surface erosion
releases greater than 5.0% (e.g., greater than 6.0%, 8.0%, 10%,
12%, or 15%) of dexamethasone (as a percentage of the total
dexamethasone present in the fiber in prodrug form) at 37.degree.
C. in PBS over not fewer than 6 days, 8 days, 10 days, or 12 days
(e.g., greater than 5% of dexamethasone at 37.degree. C. in PBS
over 10 days). The dexamethasone can be released from the fiber at
a rate such that t.sub.10 is greater than or equal to 1/10 of
t.sub.50.
[0032] In further embodiments of the fibers of the disclosure, the
fiber further includes from 0.1% to 10% (e.g., from 0.1 to 5%, from
0.1 to 2%, from 0.5 to 2%, from 1 to 10%) (w/w) of one or more
additives, wherein the one or more additives are selected from
plasticizers, antioxidants, binders, lubricants, radio-opaque
agents, and mixtures thereof.
[0033] In particular embodiments of the fibers of the disclosure,
the fiber is free of controlled release excipient, free of a
crystallization inhibiting excipient, free of a mechanical
integrity enhancing excipient, and/or free of a binding excipient;
or the fiber optionally has a glassy state.
[0034] In another aspect, the disclosure features a fiber mesh or
woven fabric formed from a fiber of the disclosure. The disclosure
further features a non-woven fabric formed from a fiber of the
disclosure. The fiber mesh, woven fabric, and non-woven fabric can
be formed from the fibers using methods known in the art. In
particular embodiments, the fiber mesh is free of controlled
release excipient, free of a crystallization inhibiting excipient,
free of a mechanical integrity enhancing excipient, and/or free of
a binding excipient; or the fiber mesh optionally has a glassy
state.
[0035] In another aspect, the disclosure features a glassy state
composition formed from a compound of the disclosure.
[0036] In a further aspect, the disclosure features glassy state
composition formed from a compound of formula (I):
##STR00013##
wherein the composition is prepared by a process including the
steps of: (a) heating the compound to form a melt; and (b) cooling
the melt to form the composition, wherein n is an integer from 1 to
6. In some embodiments, the glassy state composition is free of
controlled release excipient, free of a crystallization inhibiting
excipient, free of a mechanical integrity enhancing excipient,
and/or free of a binding excipient.
[0037] In some embodiments, n is 1. In further embodiments, n is 2.
In some embodiments of the glassy state compositions of the
disclosure, n is 3. In other embodiments, n is 4. In yet other
embodiments, n is 5. In yet other embodiments, n is 6.
[0038] In some embodiments of the glassy state compositions of the
disclosure, at least 70% (e.g., at least 75%, at least 80%, at
least 85%, at least 90%, at least 95%, or at least 99%) (w/w) of
the glassy state composition is the compound of formula (I). In
further embodiments, at least 90% (e.g., at least 91%, at least
92%, at least 93%, at least 94%, at least 95%, at least 96%, at
least 97%, at least 98%, or at least 99%) (w/w) of the glassy state
composition is the compound of formula (I).
[0039] In some embodiments of the glassy state compositions of the
disclosure, the compound or dexamethasone is released from the
glassy state composition through surface erosion. In some
embodiments, the surface erosion releases less than 10% (e.g., less
than 9%, less than 8%, less than 7%, less than 6%, less than 5%,
less than 4%, less than 3%, less than 2%, or less than 1%) of
dexamethasone (as a percentage of the total drug, dexamethasone,
present in the glassy state composition in prodrug form) at
37.degree. C. in 100% bovine serum over 5 days. In other
embodiments of any of the above glassy state compositions, the
surface erosion releases less than 2.0% (e.g., less than 1.8%,
1.5%, 1.2%, 1.0%, or 0.5%) of dexamethasone (as a percentage of the
total drug, dexamethasone, present in the glassy state composition
in prodrug form) at 37.degree. C. in PBS over 5 days, 7 days, 10
days, or 14 days (e.g., less than 2% of dexamethasone at 37.degree.
C. in PBS over 5 days). In still other embodiments of any of the
above glassy state compositions, the surface erosion releases
greater than 20% (e.g., greater than 22%, 24%, 26%, 28%, or 30%) of
dexamethasone (as a percentage of the total dexamethasone present
in the glassy state composition in prodrug form) at 37.degree. C.
in 100% bovine serum over not fewer than 6 days, 8 days, 10 days,
or 12 days (e.g., greater than 24% of dexamethasone at 37.degree.
C. in 100% bovine serum over 10 days). In other embodiments of any
of the above glassy state compositions, the surface erosion
releases greater than 5.0% (e.g., greater than 6.0%, 8.0%, 10%,
12%, or 15%) of dexamethasone (as a percentage of the total
dexamethasone present in the glassy state composition in prodrug
form) at 37.degree. C. in PBS over not fewer than 6 days, 8 days,
10 days, or 12 days (e.g., greater than 5% of dexamethasone at
37.degree. C. in PBS over 10 days). The dexamethasone can be
released from the glassy state composition at a rate such that
t.sub.10 is greater than or equal to 1/10 of t.sub.50.
[0040] In further embodiments of the glassy state compositions of
the disclosure, the glassy state composition further includes from
0.1% to 10% (e.g., from 0.1 to 5%, from 0.1 to 2%, from 0.5 to 2%,
from 1 to 10%) (w/w) of one or more additives, wherein the one or
more additives are selected from plasticizers, antioxidants,
binders, lubricants, radio-opaque agents, and mixtures thereof. The
glassy state composition can be formed by machining, molding,
electrospinning, electrospraying, blow molding, fiber spinning
(e.g., wet spinning, dry spinning, gel spinning, melt spinning,
etc.), or extruding.
[0041] In some embodiments, the glassy state composition is a
fiber, fiber mesh, woven fabric, non-woven fabric, pellet,
cylinder, hollow tube, microparticle (e.g., a microbead),
nanoparticle (e.g., a nanobead), or shaped article in the shape of
a cylinder, a cube, a sheet, a star, a toroid, a pyramid, a sphere,
an irregular polygon, or a regular polygon.
[0042] In further embodiments, the glassy state composition is a
shaped article in the form of fibers having a mean diameter of from
about 0.01 to 1 mm (e.g., 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to
0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2
mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm,
0.01 to 0.7 mm, 0.01 to 0.8 mm, or 0.01 to 0.9 mm).
[0043] In other embodiments, the glassy state composition is a
shaped article in the form of pellets having a mean diameter of
from about 0.2 to 5 mm (e.g., from about 0.2 to 1 mm, from about
0.2 to 2 mm, from about 0.3 to 3 mm, from about 1.5 to 5 mm, from
about 2 to 5 mm, from about 2.5 to 5 mm, from about 3 to 5 mm, from
about 3.5 to 5 mm, from about 4 to 5 mm, or from about 4.5 to 5
mm).
[0044] In further embodiments, the glassy state composition is a
shaped article in the form of cylinders of from about 0.01 to 1 mm
in diameter (e.g., about 0.01 to 0.2 mm, about 0.1 to 0.3 mm, about
0.1 to 0.4 mm, about 0.2 to 0.5 mm, about 0.1 to 0.6 mm, about 0.1
to 0.7 mm, about 0.1 to 0.8 mm, or about 0.1 to 0.9 mm) and 0.5 to
20 mm in length (e.g., about to 0.5 to 1 mm, about 0.5 to 2 mm,
about 0.5 to 4 mm, about 0.5 to 6 mm, about 0.5 to 8 mm, about 0.5
to 10 mm, about 0.5 to 12 mm, about 0.5 to 14 mm, about 0.5 to 16
mm, or about 0.5 to 18 mm). In some embodiments, the length of the
cylinder is about 0.5 to 10 mm, or about 1 to 10 mm.
[0045] In yet other embodiments, the glassy state composition is a
shaped article in the form of microparticles having a mean diameter
of from about 1 to 1000 .mu.m (e.g., about 10 to 1000 .mu.m, about
100 to 1000 .mu.m, about 200 to 1000 .mu.m, about 500 to 1000
.mu.m, about 700 to 1000 .mu.m, or about 900 to 1000 .mu.m).
[0046] In still other embodiments, the glassy state composition is
a shaped article in the form of nanoparticles having a mean
diameter of from about 0.01 to 1 .mu.m (about 0.05 to 1 .mu.m,
about 0.1 to 1 .mu.m, about 0.2 to 1 .mu.m, about 0.3 to 1 .mu.m,
about 0.4 to 1 .mu.m, about 0.5 to 1 .mu.m, about 0.6 to 1 .mu.m,
about 0.7 to 1 .mu.m, about 0.8 to 1 .mu.m, or about 0.9 to 1
.mu.m).
[0047] In certain embodiments of the glassy state compositions of
the disclosure, the glassy state composition is free of controlled
release excipient, free of a crystallization inhibiting excipient,
free of a mechanical integrity enhancing excipient, and/or free of
a binding excipient.
[0048] In another aspect, the disclosure features a substrate
including a coating formed from a compound of the disclosure.
[0049] In another aspect, the disclosure features a substrate
including a coating formed from a compound of formula (I):
##STR00014##
wherein n is an integer from 1 to 6. In some embodiments, the
coating is free of controlled release excipient, free of a
crystallization inhibiting excipient, free of a mechanical
integrity enhancing excipient, and/or free of a binding excipient;
or the coating optionally has a glassy state.
[0050] In some embodiments, n is 1. In further embodiments, n is 2.
In certain embodiments of the substrates of the disclosure, n is 3.
In other embodiments, n is 4. In still other embodiments, n is 5.
In yet other embodiments, n is 6.
[0051] In some embodiments of the substrates of the disclosure, at
least 70% (e.g., at least 75%, at least 80%, at least 85%, at least
90%, at least 95%, or at least 99%) (w/w) of the coating is the
compound of formula (I). In some embodiments, at least 90% (e.g.,
at least 91%, at least 92%, at least 93%, at least 94%, at least
95%, at least 96%, at least 97%, at least 98%, or at least 99%)
(w/w) of the coating is the compound of formula (I).
[0052] In some embodiments of the substrates of the disclosure, the
compound or dexamethasone is released from the coating through
surface erosion. In some embodiments, the surface erosion releases
less than 10% (e.g., less than 9%, less than 8%, less than 7%, less
than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or
less than 1%) of dexamethasone, as a percentage of the total drug,
dexamethasone, present in the coating in prodrug form, at
37.degree. C. in 100% bovine serum over 5 days; or the surface
erosion releases less than 2% (e.g., less than 1.8%, less than
1.5%, less than 1.2%, less than 1.0%, or less than 0.5%) of
dexamethasone, as a percentage of the total drug, dexamethasone,
present in the coating in prodrug form, at 37.degree. C. in PBS
over 5 days. In still other embodiments of any of the above
coatings, the surface erosion releases greater than 20% (e.g.,
greater than 22%, 24%, 26%, 28%, or 30%) of dexamethasone (as a
percentage of the total dexamethasone present in the coating in
prodrug form) at 37.degree. C. in 100% bovine serum over not fewer
than 6 days, 8 days, 10 days, or 12 days (e.g., greater than 24% of
dexamethasone at 37.degree. C. in 100% bovine serum over 10 days).
In other embodiments of any of the above coatings, the surface
erosion releases greater than 5.0% (e.g., greater than 6.0%, 8.0%,
10%, 12%, or 15%) of dexamethasone (as a percentage of the total
dexamethasone present in the coating in prodrug form) at 37.degree.
C. in PBS over not fewer than 6 days, 8 days, 10 days, or 12 days
(e.g., greater than 5% of dexamethasone at 37.degree. C. in PBS
over 10 days). The dexamethasone can be released from the coating
at a rate such that t.sub.10 is greater than or equal to 1/10 of
t.sub.50.
[0053] In still other embodiments of the substrates of the
disclosure, the coating further includes from 0.1% to 10% (e.g.,
from 0.1 to 5%, from 0.1 to 2%, from 0.5 to 2%, from 1 to 10%)
(w/w) of one or more additives, wherein the one or more additives
are selected from plasticizers, antioxidants, binders, lubricants,
radio-opaque agents, and mixtures thereof. In some embodiments, the
coating is a fiber, fiber mesh, woven fabric, non-woven fabric,
pellet, cylinder, hollow tube, microparticle (e.g., a microbead),
nanoparticle (e.g., a nanobead), or other shaped article.
[0054] In some embodiments of the substrates of the disclosure, the
coating is free of controlled release excipient, free of a
crystallization inhibiting excipient, free of a mechanical
integrity enhancing excipient, and/or free of a binding excipient;
or the coating optionally has a glassy state.
[0055] In further embodiments of the substrates of the disclosure,
the coating has a glassy state and is formed from a compound of the
disclosure.
[0056] In another aspect, the disclosure features a coating having
a glassy state formed from a compound of the disclosure.
[0057] In another aspect, the disclosure features an implantable
medical device including a substrate of the disclosure, wherein the
coating resides on the surface of the implantable medical
device.
[0058] In another aspect, the disclosure features a method of
forming an article including a compound of formula (I):
##STR00015##
wherein the article is formed by a process including the steps of:
(a) heating the compound to form a melt; (b) cooling the melt to
form a glassy state composition; and (c) heating the glassy state
composition to a temperature above the glass transition temperature
of the glassy state composition and shaping the glassy state
composition to form a shaped article, wherein n is an integer from
1 to 6. Step (c) can include extruding, molding, blow molding, heat
spinning, electrospinning, or electrospraying the glassy state
composition to form the shaped article. In some embodiments, the
method forms an article free of controlled release excipient, free
of a crystallization inhibiting excipient, free of a mechanical
integrity enhancing excipient, and/or free of a binding excipient;
or the method forms an article that optionally has a glassy
state.
[0059] In yet another aspect, the disclosure features a method of
forming an article including a compound of formula (I):
##STR00016##
wherein the article is formed by a process including the steps of:
(a) dissolving the compound in a solvent to form a solution; (b)
evaporating the solvent to form a glassy state composition; and (c)
heating the glassy state composition to a temperature above the
glass transition temperature of the glassy state composition and
shaping the glassy state composition to form a shaped article,
wherein n is an integer from 1 to 6. Step (c) can include
extruding, molding, blow molding, heat spinning, electrospinning,
or electrospraying the glassy state composition to form the shaped
article. In some embodiments, the method forms an article free of
controlled release excipient, free of a crystallization inhibiting
excipient, free of a mechanical integrity enhancing excipient,
and/or free of a binding excipient; or the method forms an article
that optionally has a glassy state. In some embodiments of the
methods of the disclosure, step (c) includes molding, extruding,
blow molding, electrospinning, heat spinning, or electrospraying
the glassy state composition to form the shaped article (e.g., a
fiber, fiber mesh, woven fabric, non-woven fabric, pellet,
cylinder, microparticle (e.g., a microbead), or nanoparticle (e.g.,
a nanobead), or another shaped article). In other embodiments,
microparticles are prepared by melting the compound to form glassy
state pellets or other shaped forms, crushing the glassy state
articles into rough or irregular-shaped particles, filtering
particles through sieves, and heating the particles above the Tg to
round them into smoother spherical particles. In further
embodiments, the method produces an article free of controlled
release excipient, free of a crystallization inhibiting excipient,
free of a mechanical integrity enhancing excipient, and/or free of
a binding excipient; or the method produces an article that
optionally has a glassy state.
[0060] In a further aspect, the disclosure features a method of
forming an article comprising a compound of formula (I):
##STR00017##
wherein n is an integer from 1 to 6, and wherein the article is
formed by a process comprising the steps of: (a) dissolving the
compound in a solvent to form a solution; (b) electrospraying the
solution to form a glassy state composition; and (c) heating the
glassy state composition to a temperature above the glass
transition temperature of the glassy state composition and shaping
the glassy state composition to form a coating; wherein n is an
integer from 1 to 6. In particular embodiments, the method forms an
article that is free of controlled release excipient, free of a
crystallization inhibiting excipient, free of a mechanical
integrity enhancing excipient, and/or free of a binding excipient;
or the method forms an article that optionally has a glassy
state.
[0061] In another aspect, the disclosure features a solid
crystalline form of Compound 1 having an X-ray powder diffraction
(XRPD) pattern including three, four, five, or more angles 2.theta.
(.degree.) of 9.316.degree., 11.501.degree., 14.019.degree.,
15.982.degree., 17.268.degree., 17.685.degree., 18.658.degree.,
20.440.degree., 21.782.degree., 23.472.degree., 29.816.degree.,
and/or 33.150.degree.. In some embodiments, the solid crystalline
form of Compound 1 has an XRPD pattern including at least one peak
at diffraction angle 2.theta. (.degree.) of 9.316.degree.. In some
embodiments, the solid crystalline form of Compound 1 has an XRPD
pattern including at least one peak at diffraction angle 2.theta.
(.degree.) of 11.501.degree.. In some embodiments, the solid
crystalline form of Compound 1 has an XRPD pattern including at
least one peak at diffraction angle 2.theta. (.degree.) of
14.019.degree.. In further embodiments, the solid crystalline form
of Compound 1 has an XRPD pattern including at least one peak at
diffraction angle 2.theta. (.degree.) of 15.982.degree.. In still
further embodiments, the solid crystalline form of Compound 1 has
an XRPD pattern including at least one peak at diffraction angle
2.theta. (.degree.) of 17.268.degree.. In other embodiments, the
solid crystalline form of Compound 1 has an XRPD pattern including
at least one peak at diffraction angle 2.theta. (.degree.) of
17.685.degree.. In further embodiments, the solid crystalline form
of Compound 1 has an XRPD pattern including at least one peak at
diffraction angle 2.theta. (.degree.) of 18.658.degree.. In yet
other embodiments, the solid crystalline form of Compound 1 has an
XRPD pattern including at least one peak at diffraction angle
2.theta. (.degree.) of 20.440.degree.. In some embodiments, the
solid crystalline form of Compound 1 has an XRPD pattern including
at least one peak at diffraction angle 2.theta. (.degree.) of
21.782.degree.. In certain embodiments, the solid crystalline form
of Compound 1 has an XRPD pattern including at least one peak at
diffraction angle 2.theta. (.degree.) of 23.472.degree.. In still
other embodiments, the solid crystalline form of Compound 1 has an
XRPD pattern including at least one peak at diffraction angle
2.theta. (.degree.) of 29.816.degree.. In particular embodiments,
the solid crystalline form of Compound 1 has an XRPD pattern
including at least one peak at diffraction angle 2.theta.
(.degree.) of 33.150.degree.. In other embodiments, the solid
crystalline form of Compound 1 has an XRPD pattern including at
least one peak diffraction angle 2.theta. (.degree.) of
9.316.degree., 11.501.degree., 14.019.degree., 15.982.degree.,
17.268.degree., 17.685.degree., 18.658.degree., 20.440.degree.,
21.782.degree., 23.472.degree., 29.816.degree., and
33.150.degree..
[0062] In another aspect, the disclosure features Compound 6.
[0063] The disclosure also includes a pharmaceutical composition
comprising Compound 6 and a pharmaceutically acceptable
excipient.
Definitions
[0064] The term "free of controlled release polymer," as used
herein, refers to the absence of an amount of a polymeric material
of greater than 10 KDa in the articles of the disclosure that is
sufficient to delay or slow the release of the dexamethasone
prodrug dimer from the article in comparison to the release profile
observed for an otherwise identical article containing none of the
polymeric material, where the release profile is measured at
37.degree. C. in 100% fetal bovine serum (FBS).
[0065] The term "free of a crystallization inhibiting excipient,"
as used herein, refers to the absence of an amount of an excipient
in the articles of the disclosure that is sufficient to reduce the
amount of crystalline dexamethasone prodrug dimer in the article in
comparison to the amount of crystalline dexamethasone prodrug dimer
observed in an otherwise identical article containing none of the
excipient. The level of crystallinity can be measured using DSC or
XRD. In particular embodiments, the articles of the disclosure are
free of a crystallization inhibiting excipient that is a polymeric
material of greater than 10 KDa.
[0066] The term "free of a mechanical integrity enhancing
excipient," as used herein, refers to the absence of an amount of
an excipient in the articles of the disclosure that is sufficient
to increase the mechanical integrity of the article in comparison
to the mechanical integrity of an otherwise identical article
containing none of the excipient. The mechanical integrity of an
article can be tested using a 3- or 4-point mechanical bend test
(ASTM C1684-18) on the formulation with or without the excipient
with the article in the shape of a rod either in the dry state
(prior to drug release) or after 15-30% drug release. For articles
with a rectangular shape, the mechanical integrity can be tested
using a 3-point mechanical bend test (ASTM D790-17) or 4-point
mechanical bend test (ASTM D6272) on the formulation with or
without excipient either in the dry state (prior to drug release)
or after 15-30% drug release. A reduction in mechanical integrity
causes the articles to break apart sooner, increasing the total
surface area of the quantity of articles, and resulting in a more
rapid release profile. In particular embodiments, the articles of
the disclosure are free of a mechanical integrity enhancing
excipient that is a polymeric material of greater than 10 KDa.
[0067] The term "free of a binding excipient," as used herein,
refers to the absence of an amount of an excipient in the articles
of the disclosure that is sufficient to delay or slow the release
of the dexamethasone prodrug dimer from the article in comparison
to the release profile observed for an otherwise identical article
containing none of the binding excipient, where the release profile
is measured at 37.degree. C. in 100% FBS.
[0068] The term "cylinder," as used herein, refers to the shape of
the pharmaceutical compositions of the disclosure that has parallel
sides and a circular or oval cross section, or a shaped cross
section (e.g., a star shaped cross section). A mean diameter of the
cylinder can range from about 0.01 to 1 mm diameter, e.g., about
0.01 to 0.2 mm, about 0.1 to 0.3 mm, about 0.1 to 0.4 mm, about 0.2
to 0.5 mm, about 0.1 to 0.6 mm, about 0.1 to 0.7 mm, about 0.1 to
0.8 mm, or about 0.1 to 0.9 mm. A mean length of the cylinder can
range from about 0.05 to 20 mm, e.g., about 0.05 to 1 mm, about 0.5
to 2 mm, about 0.5 to 4 mm, about 0.5 to 6 mm, about 0.5 to 8 mm,
about 0.5 to 10 mm, about 0.5 to 12 mm, about 0.5 to 14 mm, about
0.5 to 16 mm, or about 0.5 to 18 mm. In some embodiments, the mean
diameter of the cylinder is in the range of about 0.01 to 1 mm and
the mean length of the cylinder is about 0.1 mm to 4.0 mm. In some
embodiments, the mean length of the cylinder is about 0.5 to 10 mm,
or about 1 to 10 mm.
[0069] The term "fiber," as used herein, refers to the shape of the
pharmaceutical compositions of the disclosure that is elongated or
threadlike. A mean diameter of the fiber can range from about 0.01
to 1 mm, e.g., 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2
to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to
0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7
mm, 0.01 to 0.8 mm, or 0.01 to 0.9 mm. A mean length of the fiber
can range from about 20 to 20,000 mm, e.g., about 20 to 1000 mm,
about 20 to 2,000 mm, about 100 to 2,000 mm, about 100 to 5,000 mm,
about 1,000 to 8,000 mm, about 2,000 to 8,000 mm, about 2,000 to
10,000 mm, about 2,000 to 12,000 mm, about 2,000 to 15,000 mm, or
about 5,000 to 18,000 mm.
[0070] The term "fiber mesh," as used herein refers to a web or a
net in having many attached or woven fibers. The fiber mesh can
have aligned and unaligned morphologies.
[0071] The term "glassy state," as used herein, refers to an
amorphous solid including greater than 70%, 80%, 90%, 95%, 98%, or
99% (w/w) of one or more dexamethasone prodrug dimers of the
disclosure and exhibiting a glass transition temperature in the
range of from 38 to 150.degree. C. In the glassy state, as measured
by DSC or XRD, the level of crystallinity is low, ranging from
0-15%, e.g., 0-1%, 0-3%, 0-5%, 0-7%, 0-9%, 0-10%, or 0-13%. Glass
formulations of the disclosure can be formed using heat processing
or solvent processing one or more dexamethasone prodrug dimers.
[0072] The term "microparticle," as used herein, refers to the
shape of the pharmaceutical compositions of the disclosure, which
can be regularly or irregularly shaped. A mean diameter of the
microparticle can range from about 1 to 1000 .mu.m, e.g., about 10
to 1000 .mu.m, about 100 to 1000 .mu.m, about 200 to 1000 .mu.m,
about 500 to 1000 .mu.m, about 700 to 1000 .mu.m, or about 900 to
1000 .mu.m. As used herein, a microbead is a microparticle that is
spherical.
[0073] The term "nanoparticle," as used herein, refers to the shape
of the pharmaceutical compositions of the disclosure, which can be
regularly or irregularly shaped. A mean diameter of the
nanoparticle can range from about 0.01 to 1 .mu.m, e.g., about 0.05
to 1 .mu.m, about 0.1 to 1 .mu.m, about 0.2 to 1 .mu.m, about 0.3
to 1 .mu.m, about 0.4 to 1 .mu.m, about 0.5 to 1 .mu.m, about 0.6
to 1 .mu.m, about 0.7 to 1 .mu.m, about 0.8 to 1 .mu.m, or about
0.9 to 1 .mu.m. As used herein, a "nanobead" refers to a
nanoparticle that is spherical.
[0074] The term "non-woven fabric," as used herein, refers to a web
structure bonded together by entangling fibers.
[0075] The term "pellet," as used herein, refers to the shape of
the pharmaceutical compositions of the disclosure that is rounded,
spherical, or cylindrical, or a combination thereof. A mean
diameter of the pellet can range from about 0.2 to 5 mm, e.g., from
about 0.2 to 1 mm, from about 0.2 to 2 mm, from about 0.3 to 3 mm,
from about 1.5 to 5 mm, from about 2 to 5 mm, from about 2.5 to 5
mm, from about 3 to 5 mm, from about 3.5 to 5 mm, from about 4 to 5
mm, or from about 4.5 to 5 mm.
[0076] The term "surface erosion," as used herein refers to a
process of a gradual disintegration of the pharmaceutical
compositions of the disclosure and release of a free drug from the
dexamethasone prodrug dimer. Surface erosion can be tailored to
achieve desired drug release rates. The rate of surface erosion and
release of a given drug from a dexamethasone prodrug dimer may also
depend on the quantity of the loaded dexamethasone prodrug dimer as
a percent of the final dexamethasone prodrug dimer formulation,
article size, solubility of dexamethasone prodrug dimer (e.g.,
through selection of appropriate linker), and/or surface area of
the article. For example, surface erosion mechanism of drug release
allows drug delivery articles to be tailored with specific physical
features (dimensions, diameters, surface areas, total mass, etc.)
to achieve desired drug release rates, and drug release may be
designed to be initiated within minutes or hours, and may continue
to occur over days, weeks, months, or years.
[0077] As used herein, "t.sub.50" is the time at which 50% of the
releasable drug has been released from an article of the
disclosure. Time t.sub.10 is, correspondingly, the time at which
10% of the releasable drug has been released from an article of the
disclosure. When the release curve is perfectly linear,
t.sub.10=1/5 of t.sub.50. When there is an initial burst of
released drug, t.sub.10 is much less than 1/5 of t.sub.50. In the
compositions and methods of the disclosure t.sub.10 can be equal to
or greater than 1/10 of t.sub.50. Drug release from an article or
compound of the disclosure can be measured at 37.degree. C. in 100%
bovine serum, or at 37.degree. C. in PBS, as described in Example
1.
[0078] The term "woven fabric," as used herein, refers to
pharmaceutical compositions that resemble materials that are formed
by weaving of fibers.
BRIEF DESCRIPTION OF THE DRAWINGS
[0079] FIGS. 1A-1F are a series of images and graphs showing
Compound 1 (dexamethasone-triethylene glycol-dexamethasone,
Dex-TEG-Dex) (FIG. 1A) formed into pellets (FIG. 1B) in the glassy
state. Results of testing by differential scanning calorimetry
(DSC) (FIG. 1C) and X-ray powder diffraction (XRPD) (FIG. 1D) are
shown, and drug release over time was determined (FIG. 1E). FIG. 1F
shows representative images of the pellets over time.
[0080] FIGS. 2A-2E are a series of images showing Compound 1
processed into heat-molded pellets (FIG. 2A), extruded cylinders
(FIGS. 2B and 2C), glass droplets (FIG. 2D), and fibers (FIG.
2E).
[0081] FIGS. 3A-3K are a series of images and graphs showing
Compound 1 coated onto titanium (FIG. 3A) and
poly(styrene-block-isobutylene-block-styrene) (SIBS) surfaces (FIG.
3B), as well as non-woven fibrous meshes aligned (FIG. 3C) and
unaligned (FIG. 3D) morphologies and DSC (FIG. 3E) and XRPD data
(FIG. 3F). Compound 1 was processed into fibers (FIG. 3G),
nanoparticles (FIG. 3H), microparticles (FIGS. 3I and 3J).
Microparticles were analyzed by DSC (FIG. 3K).
[0082] FIG. 4 is a graph showing drug release of pellets of
Compound 1 in 100% FBS over time.
[0083] FIG. 5 is a graph showing representative fracture force.
[0084] FIGS. 6A and 6B are a series of graphs showing purity of
Compound 1 pre- and post-ethylene oxide gas sterilization (FIG. 6A)
and drug release (FIG. 6B).
[0085] FIGS. 7A-7F are a series of images and graphs showing
Compound 1 formed into heat extruded cylinders (FIGS. 7A-7D),
purity of extrudate over time (FIG. 7E), and coating formed from
Compound 1 (FIG. 7F).
[0086] FIGS. 8A-8C are a series of an image and a graph showing
Compound 3 (FIG. 8A) (dexamethasone-pentaethylene
glycol-dexamethasone, Dex-EGS-Dex) processed into heat-molded
pellets (FIG. 8B) and drug release (FIG. 8C).
[0087] FIGS. 9A-9E are a series of images and a graph showing
Compound 6 (FIG. 9A) (dexamethasone-hexane-dexamethasone,
Dex-HEX-Dex) processed into heat-molded pellets (FIG. 9B), fibers
(FIG. 9C), extruded cylinders (FIG. 9D), and drug release (FIG.
9E).
[0088] FIGS. 10A-10D are a series of images and a graph showing
Compound 7 (FIG. 10A) (dexamethasone-polyethylene glycol
(MW=200)-dexamethasone, Dex-PEG200-Dex) processed into heat-molded
pellets (FIG. 10B), extruded cylinders (FIG. 10C), and drug release
(FIG. 10D).
[0089] FIGS. 11A and 11B are a series of images showing nano- and
microparticles formed from Compound 6.
[0090] FIG. 12 is a graph showing dexamethasone release from
heat-molded pellets of Compound 1 and Compound 6 in 100% FBS.
[0091] FIGS. 13A-13D are a series of image showing Compound 4 (FIG.
13A) (dexamethasone-heptaethylene glycol-dexamethasone,
Dex-EG7-Dex) processed into heat-molded pellets (FIG. 13B) and
extruded cylinders (FIG. 13C), the extruded cylinders after two
weeks in PBS at 37.degree. C. (FIG. 13D).
[0092] FIGS. 14A-14D are a series of image showing Compound 5 (FIG.
14A) (dexamethasone-nonaethylene glycol-dexamethasone, Dex-EG9-Dex)
processed into heat-molded pellets (FIG. 14B) and extruded
cylinders (FIG. 14C), and the extruded cylinders after two weeks in
PBS at 37.degree. C. (FIG. 14D).
[0093] FIGS. 15A-15D are a series of image showing Compound 8 (FIG.
15A) (dexamethasone-polyethylene glycol (MW=300)-dexamethasone,
Dex-PEG300-Dex) processed into heat-molded pellets (FIG. 15B) and
extruded cylinders (FIG. 15C), and the extruded cylinders after two
weeks in PBS at 37.degree. C. (FIG. 15D).
[0094] FIGS. 16A and 16B are a series of images and graphs showing
drug release from heat-molded pellets formed from Compound 4 (FIG.
16A) and Compound 5 (FIG. 16B).
[0095] FIG. 17 is a graph showing cumulative drug release from a
coating of Compound 1 (Dex-TEG-Dex) from titanium and
poly(styrene-block-isobutylene-block-styrene) (SIBS) over time.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0096] While the clinical importance of sustained drug release
delivery systems to maintain therapeutic concentration of drugs for
extended periods of time (e.g., days to weeks, to months or even
years) has been well acknowledged for decades, there has been a
limited number of successfully commercialized products on the
market to date. It is recognized in this disclosure that to develop
successful sustained drug delivery systems, technical difficulties
must be overcome ranging from drug degradation during formulation
process; lack of controlled release, including unwanted burst or
incomplete release associated with diffusion or bulk erosion
mechanisms of drug release; low encapsulation efficiency; and
formulation complexity.
[0097] For locally administered sustained release delivery systems,
it is recognized in this disclosure that additional challenges can
arise where the mass balance of the carrier or matrix for the drug
hinders drug loading, or where the carriers and matrices produce
unwanted effects (i.e., such as local inflammation). It is
recognized in this disclosure that there is an unmet need for a
sustained release drug system that is formulated to release
dexamethasone via a surface erosion process in the absence or with
a minimal amount of carrier and/or excipient agents, at a
rate-controlled manner over an extended period of time (e.g., days
to weeks, to months or even years), where the system contains
predominantly dexamethasone prodrug and minimizes side effects
associated with the use of carriers or matrices.
[0098] This disclosure describes dexamethasone prodrug dimers that
can be in a crystalline or amorphous form and have unique
properties that allow them to be processed as viscous fluids from a
melt or solution, in order yield shaped articles where most of the
material is in a glassy state. The shaped articles may be held
together by secondary (e.g., non-crystalline) interactions and have
the ability to release their prodrug/drug elements from these
shaped forms upon surface mediated degradation/dissolution. This
may provide a controlled rate of drug release over days, weeks,
months, or years, due to unique interactions between the molecules
that exist in a mostly amorphous state while holding the shaped
form intact as the surface erodes. This disclosure may alter the
need for a carrier matrix to provide shape and form to a drug
delivery depot or device, and therefore, may mitigate the issues of
phase separation of drug from the matrix, and incompatible
processing conditions between the formulations' components.
Further, such materials can minimize inflammatory responses because
the drugs/prodrugs undergoing surface erosion from the shaped
article can be released in the biological environment in a
non-particulate (e.g., non-crystalline) form and can have inherent
anti-inflammatory activity from the drugs being released from the
prodrug shaped form.
[0099] The compounds of the disclosure can be designed for the
controlled and sustained release of dexamethasone from the
dexamethasone prodrug dimer used to make the shaped article.
Articles formed from the compounds of the disclosure can yield
sustained and uniform release of the dexamethasone prodrugs,
without exhibiting any burst release (e.g., t.sub.10 can be equal
to or greater than 1/10 of t.sub.50) and without reliance upon
degradable matrices, which can cause undesirable local side effects
(such as inflammation). The high drug loading that can be present
in the articles of the disclosure are suitable for producing
locally effective concentrations of a dexamethasone for periods of
days to weeks to months or even years.
Compounds
[0100] The disclosure described herein features a compound of
formula (I):
##STR00018##
wherein n is an integer from 1 to 6.
[0101] In some embodiments, the compound is Compound 1:
##STR00019##
[0102] In some embodiments, the compound is Compound 2:
##STR00020##
[0103] In some embodiments, the compound is Compound 3:
##STR00021##
[0104] The disclosure also features Compound 6:
##STR00022##
Formulations
[0105] The pharmaceutical compositions of the disclosure can
include an article in the form of fibers, fiber meshes, woven
fabrics, non-woven fabrics, pellets, cylinders, hollow tubes,
microparticles (e.g., microbeads), nanoparticle (e.g., nanobeads),
or other shaped articles. In some embodiments, the pharmaceutical
composition of the disclosure has a non-circular shape that
affects, e.g., increases, the surface area (e.g., extruded through
star-shaped dye). Suitable pharmaceutical compositions for use with
this disclosure can be small regularly or irregularly shaped
particles, which can be solid, porous, or hollow.
[0106] Different forms of pharmaceutical compositions of the
present disclosure (e.g., fibers, fiber meshes, woven fabrics,
non-woven fabrics, pellets, cylinders, hollow tubes, microparticles
(e.g., microbeads), nanoparticles (e.g., nanobeads), or other
shaped articles) can have the advantages of providing a
controllable surface area, being easily injected, not requiring
removal after completion of drug release, and allow for tailoring
drug release rates required for a given indication. When used as an
injectable drug delivery device, drug release rate and interaction
with cells are strongly dependent on the size distribution of the
pharmaceutical composition form.
Processing Methods
[0107] Articles of the disclosure can be formed using any number of
the methods, for example, heat processing or solvent processing of
the dexamethasone prodrug dimer of formula (I). Heat processing can
include heat molding, injection molding, extrusion, 3D printing,
melt electrospinning, fiber spinning, fiber extrusion, and/or blow
molding. Solvent processing may include coating, micro printing,
emulsion processing dot printing, micropatterning, fiber spinning,
solvent blow molding, electrospraying, and electrospinning.
[0108] Electrospraying Method
[0109] In some embodiments, the pharmaceutical compositions of the
disclosure are dissolved in a solvent (e.g., acetone) at
concentrations ranging from, e.g., 10-30% w/v, and are
electrosprayed to form micro- and nanobeads. The solutions can be
loaded into a syringe and can be injected at a particular rate,
e.g., 0.5 mL/h, onto a stationary collection plate. Between the
needle and collecting surface, a potential difference of, e.g., 18
kV, can be maintained. Exemplary concentration of 10% w/v is used
to obtain nanoparticles. In other embodiments, a concentration of
30% w/v is used to obtain microbeads.
[0110] Fiber Spinning Methods
[0111] In some embodiments, the pharmaceutical compositions of the
disclosure, e.g., fibrous meshes with aligned and unaligned
morphologies are prepared by electrospinning. The pharmaceutical
compositions of the disclosure are dissolved in a solvent (e.g.,
THF, or 1:1 ratio of DCM/THF). The solutions may be injected from a
syringe at a particular rate, e.g., 0.5 mL/h, onto a cylindrical
mandrel rotating at a particular rotational speed, e.g., 1150 rpm,
to obtain aligned fibers, or onto a stationary collector surface to
obtain unaligned fibers. A potential difference (e.g., 18 kV or 17
kV) can be maintained between the needle and collecting surface for
aligned and random fibers.
[0112] In other embodiments, fibers are prepared either from the
melt at elevated temperatures, the glassy state intermediate, or
from solution by dissolving the pharmaceutical compositions of the
disclosure in a solvent (e.g., DCM, THF, or chloroform). As used
herein, melt spinning describes heat processing from the melt
state, heat spinning describes heat processing from the glassy
state, and wet, dry, and gel spinning describe solution
processing.
[0113] The viscous melt, intermediate, or solution can be fed
through a spinneret and fibers may be formed upon cooling (melt or
heat spinning) or following solvent evaporation with warm air as
the compound exits the spinneret (dry spinning). Wet spinning and
gel spinning, performed according to methods known in the art, may
also be used to produce the fibers of the disclosure. Heat spinning
describes a process that is essentially the same as the melt
spinning process, but performed with the glassy state intermediate
and heated above the glass transition temperature (Tg) to get the
viscous fluid to extrude/spin instead of the melt. Alternatively,
tweezers may be dipped into melted material or concentrated
solutions and retracted slowly in order to pull fibers. The rate of
pulling and distance pulled may be varied to yield fibers and
columnar structures of different thickness.
[0114] Emulsion Method
[0115] In some embodiments, micro-particles or nano-particles made
from the pharmaceutical composition can be formed using an emulsion
process. The pharmaceutical composition may be dissolved in an
organic solvent (e.g., DCM, THF, etc.) and a surfactant (e.g., SDS,
PVA, etc.) may be added to the solution/mixture at a low percentage
(e.g., 1%). The resulting mixture may be stirred for the
appropriate time at room temperature to form an emulsion. The
emulsion may be subsequently added to Milli-Q water under stirring
for an appropriate time (e.g., 1 h) to remove residual solvent. The
resulting micro- or nano-particles may be collected by
centrifugation and dried to obtain the desired form.
[0116] Extrusion Method
[0117] In some embodiments, injectable cylinders made from the
pharmaceutical composition may be formed by heat extrusion. The
pharmaceutical composition may be loaded into a hot melt extruder,
heated to a temperature above the melting point (for crystalline
compositions) or glass transition temperature (for pre-melted or
amorphous compositions), and extruded using a light compressive
force to push the material through the nozzle and a light tensile
force to pull the material out of the extruder. The extrudate may
be cut to the desired length for appropriate drug dosing for the
indication of interest.
[0118] Bead Sizing and Milling
[0119] In some embodiments, a milling process may be used to reduce
the size of an article of the disclosure to form sized particles,
e.g., beads, in the micrometer (microbeads) to nanometer size range
(nanobeads). The milling process may be performed using a mill or
other suitable apparatus. Dry and wet milling processes such as jet
milling, cryo-milling, ball milling, media milling, sonication, and
homogenization are known and can be used in methods described
herein. Generally, in a wet milling process, a suspension of the
material to be used as the core is agitated with or without
excipients to reduce particle size. Dry milling is a process
wherein the material to be used as the article core is mixed with
milling media with or without excipients to reduce particle size.
In a cyro-milling process, a suspension of the material to be used
as the core is mixed with milling media with or without excipients
under cooled temperatures. In some embodiments, subsequent heating
of the milled microparticle above the Tg is needed to achieve a
spherical shape, or particles with non-spherical shapes can be used
as milled.
[0120] Low Temperature Processing Using Intermediate Glassy State
Articles
[0121] In certain embodiments, the dexamethasone prodrug dimer has
a limited window (e.g., short timeframe of seconds to minutes) of
thermal stability, whereby the purity of the dimer is minimally
affected at elevated temperatures. In some embodiments, it is
beneficial to make an intermediate glassy state form (e.g., film,
pellet, micro-particles, or other shaped article). This can be
accomplished by heat or solvent processing to remove or reduce the
crystallinity of the material to form a glassy state composition.
The glassy state composition is subsequently heat processed at a
lower temperature (e.g., processing just above the glass transition
temperature (Tg), and below the melt temperature (Tm)). This can
provide a longer timeframe for heat processing the glassy state
material into the final shaped article, while reducing the impact
of processing conditions on the purity of the dexamethasone prodrug
dimer in the article.
[0122] Exemplary processing details are provided in the
Examples.
Drug Delivery
[0123] The pharmaceutical compositions of the disclosure provide
optimal delivery of dexamethasone they release the dexamethasone
from an article of the disclosure in a controlled manner, for
example, by surface erosion. The surface erosion mechanism of drug
release may allow the shaped article to maintain its physical form
(e.g. shape/geometry of the article), while gradually decreasing in
size as the surface erodes (e.g., like a bar of soap), rather than
bulk erosion that is characteristic of some polymer-based drug
release vehicles (e.g. polylactic/glycolic acid). This may inhibit
burst release and reduce the formation of inflammatory particulates
(e.g., no crystalline particulates are formed when drug is released
in the manner described herein). The drug can be controlled to be
delivered over a desired period of time. A slower and steadier rate
of delivery may in turn result in a reduction in the frequency with
which the pharmaceutical composition must be administered to a
subject, and improve the safety profile of the drug. Drug release
can also be tailored to avoid side effects of slower and longer
release of the drug by engineering the article to provide steady
release over a comparatively shorter period of time.
[0124] The rate of release of a given drug from a dexamethasone
prodrug dimer may also depend on the quantity of the loaded drug
dimer as a percent of the final drug dimer formulation, e.g., by
using a pharmaceutical excipient that acts as a bulking agent.
Another factor that can affect the release rate of a drug from, for
example a microbead, is the microbead size. In some embodiments,
drug release is tailored based on the solubility of dexamethasone
prodrug dimer (e.g., through selection of appropriate linker) that
will influence the rate of surface erosion (e.g.,
dissolution/degradation) from the article. In other embodiments,
drug release is affected by changes in surface area of the
formulation, e.g., by changing the diameter of the microbeads. By
adjusting the vide supra factors, dissolution, degradation,
diffusion, and controlled release may be varied over wide ranges.
For example, release may be designed to be initiated over minutes
to hours, and may extend over the course of days, weeks, months, or
years.
Uses and Pharmaceutical Compositions
[0125] In some embodiments, the dexamethasone prodrug dimers of the
disclosure are used as a drug delivery device (or, e.g., a drug
depot) with a minimal need for additives. This may achieve a local,
sustained release and a local biological effect, while minimizing a
systemic response. In some embodiments, when present, the additives
are in small amounts and do not affect the physical or bulk
properties. In some embodiments, when present, the additives do not
alter the drug release properties from the pharmaceutical
composition but rather act to improve processing of the prodrug
dimer into the shaped article. In some embodiments, the
pharmaceutical compositions contain additives such as a plasticizer
(e.g., to reduce thermal transition temperatures), an antioxidant
(e.g., to increase stability during heat processing), a binder
(e.g., to add flexibility to the fibers), a bulking agent (e.g., to
reduce total drug content), a lubricant, a radio-opaque agent, or
mixtures thereof. The additives may be present at 30% (w/w), e.g.,
20% (w/w), 10% (w/w), 7% (w/w), 5% (w/w), 3% (w/w), 1% (w/w), 0.5%
(w/w), or 0.1% (w/w). Examples of plasticizers are polyols, e.g.,
glycerol, ethylene glycol, diethylene glycol, triethylene glycol,
tetraethylene glycol, polyethylene glycol, propylene glycol,
triacetin, sorbitol, mannitol, xylitol, fatty acids,
monosaccharides (e.g., glucose, mannose, fructose, sucrose),
ethanolamine, urea, triethanolamine, vegetable oils, lecithin, or
waxes. Exemplary antioxidants are glutathione, ascorbic acid,
cysteine, or tocopherol. The binders and bulking agents can be,
e.g., polywinylpyrrolidone (PVP), starch paste, pregelatinized
starch, hydroxypropyl methyl cellulose (HPMC), carboxymethyl
cellulose (CMC), or polyethylene glycol (PEG) 6000.
[0126] Methods involving treating a subject may include preventing
a disease, disorder or condition from occurring in the subject
which may be predisposed to the disease, disorder and/or condition
but has not yet been diagnosed as having it; inhibiting the
disease, disorder or condition, e.g., impeding its progress; and
relieving the disease, disorder, or condition, e.g., causing
regression of the disease, disorder and/or condition. Treating the
disease or condition includes ameliorating at least one symptom of
the particular disease or condition, even if the underlying
pathophysiology is not affected (e.g., such treating the pain of a
subject by administration of an agent even though such agent does
not treat the cause of the pain).
[0127] Pharmaceutical compositions containing the dexamethasone
prodrug dimers described herein may be administered to a subject
via any route known in the art. These include, but are not limited
to, oral, sublingual, nasal, intradermal, subcutaneous,
intramuscular, rectal, vaginal, intravenous, intraarterial,
intracisternally, intraperitoneal, intravitreal, periocular,
topical (as by powders, creams, ointments, or drops), buccal and
inhalational administration. Desirably, the articles of the
disclosure are administered parenterally as injections
(intravenous, intramuscular, or subcutaneous), or locally as
injections (intraocularly or into a joint space). The formulations
are admixed under sterile conditions with a pharmaceutically
acceptable carrier or suspension or resuspension agents (e.g., for
micro- and nanoparticles) and any needed preservatives or buffers
as may be required.
[0128] The articles of the disclosure described herein including a
dexamethasone prodrug dimer may be administered to a subject to be
delivered in an amount sufficient to deliver to a subject a
therapeutically effective amount of an incorporated pharmaceutical
agent as part of prophylactic or therapeutic treatment, or as a
part of adjunctive therapy to avoid side-effects of another drug or
therapy. In general, an effective amount of a pharmaceutical agent
or component refers to the amount necessary to elicit the desired
biological response. The desired concentration of pharmaceutical
agent in the article of the disclosure will depend on numerous
factors, including, but not limited to, absorption, inactivation,
and excretion rates of the drug as well as the delivery rate of the
compound from the subject compositions, the desired biological
endpoint, the agent to be delivered, the target tissue, etc. It is
to be noted that dosage values may also vary with the severity of
the condition to be alleviated. It is to be further understood that
for any particular subject, specific dosage regimens should be
adjusted over time according to the individual need and the
professional judgment of the person administering or supervising
the administration of the compositions. Typically, dosing will be
determined using techniques known to one skilled in the art.
[0129] The concentration and/or amount of any pharmaceutical agent
to be administered to a subject may be readily determined by one of
ordinary skill in the art. Known methods are also available to
assay local tissue concentrations, diffusion rates from
dexamethasone prodrug dimers and local blood flow before and after
administration of the therapeutic formulation.
[0130] Sterilization of Formulations
[0131] Generally, it is desired that a formulation is sterile
before or upon administration to a subject. A sterile formulation
is essentially free of pathogenic microorganisms, such as bacteria,
microbes, fungi, viruses, spores, yeasts, molds, and others
generally associated with infections. In some embodiments, articles
of the disclosure may be subject to an aseptic process and/or other
sterilization process. An aseptic process typically involves
sterilizing the components of a formulation, final formulation,
and/or container closure of a drug product through a process such
as heat, gamma irradiation, ethylene oxide, or filtration and then
combining in a sterile environment. In some cases, an aseptic
process is preferred. In other embodiments, terminal sterilization
is preferred.
Treatment Methods
[0132] The formulations of the disclosure may be used in the fields
of ophthalmology, oncology, laryngology, endocrinology and
metabolic diseases, rheumatology, urology, neurology, cardiology,
dental medicine, dermatology, otology, post-surgical medicine, and
orthopedics.
[0133] Ophthalmic Uses
[0134] In certain embodiments, the articles of the disclosure may
be used prevent, treat or manage diseases or conditions at the back
of the eye, such as at the retina, macula, choroid, sclera and/or
uvea.
[0135] In some embodiments, the articles of the disclosure are used
as injectable drug delivery devices for ophthalmology (e.g.,
intravitreal injection, coating on a minimally invasive glaucoma
surgery (MIGS) devices, or implant in blebs). During an
intravitreal injection a medication is placed directly into the
space in the back of the eye called the vitreous cavity, which is
filled with a jelly-like fluid called the vitreous humor gel.
Intravitreal injections may be used to treat retinal diseases such
as diabetic retinopathy, macular degeneration, macular edema,
uveitis, and retinal vein occlusion.
[0136] In certain embodiments, the articles of the disclosure may
be used to treat, prevent, or manage an ocular condition, i.e., a
disease, ailment, or condition that affects or involves the eye or
one or more of the parts or regions of the eye. In some
embodiments, the articles of the disclosure may be used to treat,
prevent, or manage an ocular condition at the front of the eye of a
subject. A front of the eye ocular condition includes a disease,
ailment or condition, such as for example, post-surgical
inflammation; uveitis; infections; aphakia; pseudophakia;
astigmatism; blepharospasm; cataract; conjunctival diseases;
conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes;
eyelid diseases; lacrimal apparatus diseases; lacrimal duct
obstruction; myopia; presbyopia; pupil disorders; corneal
neovascularization; refractive disorders and strabismus. In some
embodiments, articles of the disclosure may be used to treat,
prevent, or manage an ocular condition at the back of the eye of a
subject. A posterior ocular condition can include a disease,
ailment, or condition, such as intraocular melanoma; acute macular
neuroretinopathy; Behcet's disease; choroidal neovascularization;
uveitis; diabetic uveitis; histoplasmosis; infections, such as
fungal or viral-caused infections; macular degeneration, such as
acute macular degeneration, non-exudative age related macular
degeneration and exudative age related macular degeneration; edema,
such as macular edema (e.g., cystoid macular edema (CME) and
diabetic macular edema (DME)); multifocal choroiditis; ocular
trauma which affects a posterior ocular site or location; ocular
tumors; retinal disorders, such as central retinal vein occlusion,
diabetic retinopathy (including proliferative diabetic
retinopathy), proliferative vitreoretinopathy (PVR), retinal
arterial occlusive disease, retinal detachment, uveitic retinal
disease; sympathetic opthalmia; Vogt Koyanagi-Harada (VKH)
syndrome; uveal diffusion; a posterior ocular condition caused by
or influenced by an ocular laser treatment; posterior ocular
conditions caused by or influenced by a photodynamic therapy,
photocoagulation, radiation retinopathy, epiretinal membrane
disorders, branch retinal vein occlusion, anterior ischemic optic
neuropathy, non-retinopathy diabetic retinal dysfunction, retinitis
pigmentosa, retinoblastoma, and glaucoma. In some embodiments, the
articles of the disclosure may be used to treat, prevent, or manage
dry eye in a subject. In some embodiments, the articles of the
disclosure may be used to treat, prevent, or manage inflammation in
the eye of a subject. Inflammation is associated with a variety of
ocular disorders. Inflammation may also result from a number of
ophthalmic surgical procedures, including cataract surgery. In some
embodiments, the pharmaceutical agent that is delivered into the
eye by the articles of the disclosure and/or methods described
herein may be a corticosteroid. In some embodiments, the
dexamethasone prodrug dimers of the disclosure are used as
adjunctive therapy to reduce inflammation and fibrosis associated
with devices (e.g., minimally invasive glaucoma surgery (MIGS)
devices). In some embodiments, articles of the disclosure may be
used to treat, prevent, or manage age-related macular degeneration
(AMD) in a subject.
[0137] Osteoarthritis Treatment
[0138] In some embodiments, the articles of the disclosure are used
for the treatment of osteoarthritis (OA). For OA of the knee,
intraarticular (IA) injection (e.g., steroids) is preferred as the
last non-operative modality, if other conservative treatment
modalities are ineffective. Steroids may be used to reduce
inflammation in tendons and ligaments in osteoarthritic joints. IA
steroid injections provide short term reduction in OA pain and can
be considered as an adjunct to core treatment for the relief of
moderate to severe pain in people with OA. Dexamethasone can be
used in the treatment of OA. In some embodiments, microspheres of
the disclosure composed of the dexamethasone prodrug dimers are
injected into a knee joint for the treatment of OA.
[0139] Surgical Procedures
[0140] In some embodiments, the articles of the disclosure are used
in conjunction with a surgical procedure. For example, an article
of the disclosure can be implanted at a surgical site to reduce the
risk of inflammation treated by the surgical procedure, or can be
used as an adjunctive to reduce the risk of infection.
EXAMPLES
[0141] The following examples are put forth to provide those of
ordinary skill in the art with a description of how the
compositions and methods described herein may be used, made, and
evaluated, and are intended to be purely exemplary of the
disclosure and are not intended to limit the scope of what the
inventors regard as their disclosure.
[0142] Compounds 1-8 can be used in the compositions, methods, and
articles of the disclosure.
TABLE-US-00001 TABLE 1 Compounds of the disclosure Compound Dimer
Abbreviation 1 Dexamethasone-Triethylene Glycol- Dex-TEG-Dex
Dexamethasone 2 Dexamethasone-Tetraethylene Glycol- Dex-EG4-Dex
Dexamethasone 3 Dexamethasone-Pentaethylene Glycol- Dex-EG5-Dex
Dexamethasone 4 Dexamethasone-Heptaethylene Glycol- Dex-EG7-Dex
Dexamethasone 5 Dexamethasone-Nonaethylene Glycol- Dex-EG9-Dex
Dexamethasone 6 Dexamethasone-Hexane-Dexamethasone Dex-HEX-Dex 7
Dexamethasone-Polyethylene Glycol Dex-PEG200- (MW =
200)-Dexamethasone Dex 8 Dexamethasone-Polyethylene Glycol
Dex-PEG300- (MW = 300)-Dexamethasone Dex
Example 1: Compound 1 (Dexamethasone-Triethylene
Glycol-Dexamethasone) can be Synthesized, Processed into Pellets in
the Glassy State by Heat Molding, and Release Drug Through Surface
Erosion from an Intact Pellet
[0143] Dexamethasone (1 mol equivalent) was suspended in
dichloromethane on an ice bath and triethylamine (2 mol equivalent)
and triethylene glycol bis(chloroformate) (0.6 mol equivalent) were
added to the mixture. The ice bath was allowed to warm to room
temperature and the reaction was stirred overnight. The solvent was
removed and the solid residue was purified by column
chromatography. Product was recrystallized twice from acetonitrile
to give Compound 1 (FIG. 1A) as an off-white crystalline solid.
[0144] Compound 1: HPLC (mobile phase: H.sub.2O/TFA and MeCN/TFA)
31.7 min; Elemental analysis: Anal. Calcd for
C.sub.52H.sub.68F.sub.2O.sub.16: C, 63.27; H, 6.94; N, 0.00; Cl,
0.00 Found: C, 62.62; H, 6.84; N, <0.50; Cl, <100 ppm.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. (ppm) 0.80 (d, J=7 Hz, 6H,
2.times.C16 .alpha.-CH.sub.3); 0.90 (s, 6H, 2.times.C18-CH.sub.3);
1.08 (m, 2H, 2.times.C16-H); 1.35 (m, 2H, 2.times.C14-H); 1.49 (s,
6H, 2.times.C19-CH.sub.3); 1.54 (q, J=13 Hz, 2H, 2.times.C13-H);
1.64 (q, J=11 Hz, 2H, 2.times.C15-CH.sub.2); 1.77 (m, 2H,
2.times.C15-CH.sub.2); 2.15 (m, 4H, 2.times.C6-CH.sub.2); 2.32 (m,
4H, 2.times.C7-CH.sub.2); 2.62 (m, 2H, 2.times.C12-CH.sub.2); 2.89
(m, 2H, 2.times.C12-CH.sub.2); 3.57 (s, 4H, 2.times.TEG OCH.sub.2);
3.65 (m, 4H, 2.times.TEG OCH.sub.2); 4.15 (m, 2H, 2.times.OCH);
4.22 (m, 4H, 2.times.TEG OCH.sub.2); 4.79 (d, 2H, AB, J=18.5 Hz,
2H, C21-CH.sub.2O--); 5.09 (d, 2H, AB, J=18.5 Hz, 2H,
C21-CH.sub.2O--); 5.18 (s, 2H, C17-OH); 5.40 (d, 2H, J=4.5 Hz,
C11-OH); 6.01 (d, 2H, J=1.9 Hz, 2.times.alkene C4-CH); 6.23 (dd,
2H, J=10.1 and 1.9 Hz, CH, 2.times.alkene C2-CH); 7.29 (d, 2H,
C1-CH 2.times.alkene CH, 10.1 Hz, 2H). MS (ESI+) m/z: [M+H]+ Calcd
for C.sub.52H.sub.69F.sub.2O.sub.16 987.46; Found 987.46.
[0145] Compound 1 was formed into pellets in the glassy state by
heat molding (FIG. 1B). Crystalline powder was melted at
185.degree. C. and pellets were formed from 1 mm.times.1 mm
cylindrical molds. The starting powder and heat-processed pellets
were tested by differential scanning calorimetry (DSC; FIG. 1C) and
X-ray powder diffraction (XRPD; FIG. 1D) to confirm heat-processing
converted Compound 1 from the crystalline state to the glassy
state.
[0146] Heat-molded pellets from Compound 1 (.about.1 mm.times.1 mm)
were then placed in 20 mL glass vials and 2 mL of release buffer
(either 100% phosphate buffered saline (PBS), 1% fetal bovine serum
(FBS) in PBS, or 100% FBS) was added. Samples were incubated at
37.degree. C. on a shaker rotating at 115 rpm. After 1 day, 3 days,
7 days, and subsequently in alternating 3 and 4 day intervals
(i.e., 1, 3, 7, 10, 14 days etc.), release buffer was sampled
directly (PBS) or syringe filtered, proteins were precipitated with
acetonitrile, and drug release products were extracted. The samples
were analyzed by high performance liquid chromatography (HPLC) to
quantify drug products. Cumulative drug release was calculated and
plotted as a percentage of the total drug in each pellet released
over time (FIG. 1E). Representative images of the pellets confirm
surface erosion over time in 100% FBS (FIG. 1F)
Example 2: Compound 1 (Dex-TEG-Dex) can be Processed into Different
Forms in the Glassy State by Multiple Processing Methods from the
Melt State
[0147] Compound 1 was processed into different forms in the glassy
state from the melt state. Heat-molded pellets (FIG. 2A) were
prepared as described in Example 1 with a cylindrical mold
(.about.0.34 mm diameter and 0.85 mm length). Extruded cylinders
(FIG. 2B) were prepared by adding Compound 1 as a crystalline
powder into a micro-extruder with different nozzles to form
extruded material of different diameters. The micro-extruder was
heated to 185.degree. C. to melt the powder and form the extrudate.
FIG. 2C shows an extruded cylinder with a 23G diameter nozzle, cut,
and loaded into a 23G needle. Glass droplets (FIG. 2D) were formed
by dispersing Compound 1 as a powder on PTFE sheet and heating it
to 185.degree. C. Fibers of Compound 1 were prepared by heat
extrusion at 185.degree. C. using a small diameter nozzle (e.g.
30-32G) combined with a tensile force to pull the extrudate out of
the nozzle. Fibers were also prepared by melting Compound 1 from a
powder at 185.degree. C. and by pulling the melted material at
different rates to yield fibers of different diameters (FIG.
2E).
Example 3: Compound 1 (Dex-TEG-Dex) can be Processed into Different
Forms in the Glassy State by Multiple Processing Methods from the
Solution State
[0148] Compound 1 was processed into different forms in the glassy
state, including coatings, non-woven fibrous meshes, fibers, and
micro- and nano-particles, from the solution state using organic
solvents. Compound 1 was coated onto titanium (FIG. 3A) and
poly(styrene-block-isobutylene-block-styrene) (SIBS) surfaces (FIG.
3B) from acetone by drop coating and can be coated using other
common techniques (e.g., dip-coating, spray coating,
electrospraying, etc.).
[0149] Non-woven fibrous meshes with aligned (FIG. 3C) and
unaligned (FIG. 3D) morphologies were prepared by electrospinning.
Compound 1 was dissolved in tetrahydrofuran (THF) and was
electrosprayed onto a cylindrical rotating mandrel to obtain
aligned fibers or onto a stationary collector surface to obtain
unaligned fibers. Compound 1 as the starting powder and
solvent-processed fibrous mesh were tested by DSC (FIG. 3E) and
XRPD (FIG. 3F) to confirm the meshes were in the glassy state.
[0150] Fibers (FIG. 3G) were prepared by dissolving Compound 1 in
dichloromethane (DCM), THF, or chloroform and by pulling Compound 1
from the solution. The rate of pulling and distance pulled were
varied to yield fibers and columnar structures of different
thickness.
[0151] Electrosprayed micro- and nano-particles were prepared by
dissolving Compound 1 in acetone. A concentration of 10% w/v was
used to electrospray Compound 1 into nanoparticles (FIG. 3H), while
a concentration of 30% w/v was used to electrospray Compound 1 into
microparticles (FIG. 3I).
[0152] Micro-particles of Compound 1 were prepared by emulsion from
DCM using sodium dodecyl sulfate (FIG. 3J). The microparticles were
analyzed by DSC (FIG. 3K) to confirm they were in the glassy state.
Different preparation conditions (solvents, concentrations,
surfactants, surfactant concentrations, mixing conditions, etc.)
resulted in different particle sizes and distributions.
Example 4: Drug Release Properties from Heat-Molded Pellets of
Compound 1 (Dex-TEG-Dex) can be Adjusted by Changing the Physical
Properties of the Pellets Due to Surface Erosion Mechanism of Drug
Release
[0153] Compound 1 was heat-molded into pellets with .about.1 mm and
.about.0.35 mm diameters using the conditions described in Example
1 and 2 above to get pellets with different masses of Compound 1
and different surface areas. Details of the samples are summarized
in Table 2, below. Drug release from the different samples was
carried out in 100% FBS as described in Example 1 over a 7 day
period. The change in drug release expected from different surface
areas due to the surface erosion mechanism of drug release is
exemplified in FIG. 4 as a plot of surface area vs. the average
drug released per day taken from the linear release curves.
TABLE-US-00002 TABLE 2 Heat-Molded Pellets Formed From Compound 1.
Different Masses and Surface Areas Were Obtained by Changing the
Number of Pellets of Given Dimensions Total Total Sample Pellet
Dimensions Number of Mass of Surface Number (diameter .times.
length) Pellets Compound 1 Area 1 ~1 mm .times. 1 mm 1 ~1 mg ~5
mm.sup.2 2 ~0.35 mm .times. ~0.8 mm 12 ~1 mg ~11 mm.sup.2 3 ~1 mm
.times. 1 mm 4 ~4 mg ~20 mm.sup.2
Example 5: Mechanical Testing of Extruded Cylinders of Compound 1
(Dex-TEG-Dex) Using a 3 Point Bend Test (ASTM C1684-18)
[0154] The mechanical properties of extruded cylinders of Compound
1 were quantified with a 3-point bend test using ASTM C1684-18
(Standard test method of Flexural strength of advanced ceramics and
ambient temperature--cylindrical rod strength). The ASTM C1684-18
was followed as closely as possible but modifications were
necessary due to the small dimensions of the extruded cylinders.
Representative fracture force data from the 3-point bend test of
Compound 1 cylinders (.about.0.25 mm.times.6 mm) are shown in FIG.
5.
Example 6: Ethylene Oxide Gas Sterilization of Heat Molded Pellets
of Compound 1 (Dex-TEG-Dex)
[0155] Heat-molded pellets from Compound 1 (.about.1 mm in
diameter) were sterilized by ethylene oxide (ETO) gas at a
temperature of 55.degree. C. Pre- and post-ETO sterilized pellets
were analyzed by HPLC to demonstrate no changes in pellet (Compound
1) purity (FIG. 6A) and drug release (FIG. 6B) to demonstrate no
changes in release properties due to the ETO sterilization process.
Drug release was carried out in either 1% FBS in PBS or 100% FBS as
described in Example 1.
Example 7: Processing Compound 1 (Dex-TEG-Dex) into an Intermediate
Glassy State to Manufacture the Final Article
[0156] Compound 1 (Dex-TEG-Dex) was formed into heat extruded
cylinders directly from the crystalline powder by heating above the
melting point (185.degree. C.), as shown in FIGS. 7A and 7B, using
the methods described above in Example 2. Compound 1 was also
formed into heat extruded cylinders by forming an intermediate
glassy state form from the melt followed by heat extrusion above
the glass transition temperature (150.degree. C.) as shown in FIGS.
7C and 7D. Purity of the extrudate over time is shown in FIG. 7E
and demonstrates longer extrusion run times using the intermediate
glassy state before Compound 1 drops in purity when compared to
extrusion from the melt state.
[0157] An intermediate glassy state was also formed from the
solution state. Compound 1 was dissolved in acetone and was
electrosprayed onto a polymer surface to form glassy state
microparticles. The sprayed surface was heated to
.about.150.degree. C. to obtain a coating as shown in FIG. 7F.
Example 8: Synthesis of Compounds 3 to 8
[0158] Compounds 3 to 8 were synthesized using standard methods
known in the art, similar to the synthesis of Compound 1 in Example
1 above. Details of synthesized Compounds 3 to 8 are shown in Table
3, below. All compounds were synthesized to HPLC purity of 98% and
structures were confirmed by .sup.1H NMR and ESI MS. Melting points
(Tm) and glass transition temperatures (Tg) were determined to
establish processing temperatures needed to heat-process the
compounds into pellets, fibers, and cylinders for further
testing.
TABLE-US-00003 TABLE 3 Structures of Compounds 3 to 8 Compound
Linking Tm & Tg (Abbreviation) Linker Moiety Structure
(.degree. C.) 3 Pentaethylene Carbonate FIG. 8A n.d.* &
(Dex-EG5-Dex) Glycol 66 4 Heptaethylene Carbonate FIG. 13A 51 &
47 (Dex-EG7-Dex) Glycol 5 Nonaethylene Carbonate FIG. 14A 41 &
37 (Dex-EG9-Dex) Glycol 6 Hexane Diol Carbonate FIG. 9A 149 &
(Dex-HEX-Dex) 146 7 Polyethylene Carbonate FIG. 10A n.d.* &
(Dex-PEG200- Glycol 96 Dex) (MW = 200) 8 Polyethylene Carbonate
FIG. 15A 77 & 75 (Dex-PEG300- Glycol Dex) (MW = 300) *n.d. =
not determined
Example 8: Formation of Pellets, Fibers, and/or Cylinders in the
Glassy State from Compounds 3, 6, and 7 and Drug Release from
Intact Glassy-State Pellets
[0159] Compounds 3, 6, and 7 were processed into heat molded
pellets (.about.1 mm.times..about.1 mm), fibers from the melt
state, and/or heat extruded cylinders from the melt or intermediate
glassy state as described in Examples 1, 2, and 7 above using the
appropriate temperature for each compound (i.e., above the Tm or Tg
as required). Processing Compounds 3, 6, and 7 into the articles
converted crystalline compounds into the glassy state and was
confirmed for heat molded pellets by DSC. Drug release from heat
molded pellets was carried out in PBS and/or 100% FBS, as described
in Example 1, for different time periods. Cumulative drug release
plotted over time demonstrated drug release from different
compounds occurs mostly linearly at different rates from intact
pellets in the timeframes tested, similar to drug release from
Compound 1. Figures corresponding to images of the pellets, fibers,
and cylinders and drug release curves from pellets are indicated in
Table 4, below.
TABLE-US-00004 TABLE 4 Compounds 3, 6, and 7 Processed in Glassy
State and Drug Release Processed Compounds in Glassy State
Heat-Molded Extruded Drug Compound Pellets Fibers Cylinders Release
3 FIG. 8B Not Not FIG. 8C (Dex-EG5-Dex) Tested Tested 6 FIG. 9B
FIG. 9C FIG. 9D FIG. 9E (Dex-Hex-Dex) 7 FIG. 10B Not FIG. 10C FIG.
10D (Dex-PEG200-Dex) Tested
Example 9: Nano- and Micro-Particle Formation in the Glassy State
from Compound 6 (Dex-HEX-Dex) Provides Sustained Release of
Drug
[0160] Electrospraying and emulsions were used to make nano- and
microparticles from Compound 6 (FIGS. 11A and 11B) using conditions
similar to that described for Compound 1 in Example 3 above.
Different preparation conditions, for example solvents,
concentrations, surfactants, surfactant concentrations, mixing
conditions, etc., resulted in different particle sizes and
distributions. DSC was used to confirm the particles were in the
glassy state.
Example 10: Methods to Adjust Release of Drug from Glassy State
Articles
[0161] The release of drug from glassy state articles can be
controlled in various ways for example by changing the environment
the article is placed or by adjusting the physical properties of
the article to take advantage of the surface erosion mechanism of
drug release. In scenarios where the environment and physical
properties of the article are fixed, other properties such as
compound structure via a change in linker can be adjusted to
engineer the article to obtain the desired drug release properties
for the application of interest. Dexamethasone release from heat
molded pellets (.about.1 mm.times.1 mm) of Compound 1 (Dex-TEG-Dex)
and Compound 6 (Dex-Hex-Dex) in 100% FBS as shown in FIG. 12
exemplifies how linker affects the drug release rates.
Example 11: Compounds 4 (Dex-EG7-Dex), 5 (Dex-EG9-Dex), and 8
(Dex-PEG300-Dex) can be Formed into Heat Molded Pellets and
Extruded Cylinders in the Glassy State but Undergo Physical (e.g.,
Shape) and Drug Release Changes Over Time in Release Medium at
37.degree. C.
[0162] Compounds 4, 5, and 8 were processed into heat molded
pellets (.about.1 mm.times..about.1 mm) and heat extruded cylinders
as described in Examples 1, 2, and 7 above using the appropriate
temperature for the compound and are shown in the table below. The
heat-processed articles from Compounds 4, 5, and 8 were in the
glassy state as confirmed by DSC. Drug release from heat molded
pellets were carried out in PBS and 100% FBS, as described in
Example 1, for Compounds 4 and 5. Physical (shape) and drug release
changes occurred for both compounds in PBS and 100% FBS and is
exemplified in FIGS. 16A and 16B for pellets of Compounds 4 and 5
respectively in PBS at 37.degree. C. Similar changes in physical
form (shape) were observed for extruded cylinders for Compounds 4,
5, and 8 where they formed into droplets on the bottom of the vial
in less than 2 weeks in PBS at 37.degree. C. as shown in Table 5,
below.
TABLE-US-00005 TABLE 5 Compounds 4, 5, and 8 Processed in Glassy
State Processed Compounds Extruded in Glassy State Cylinder Heat
after 2 weeks Molded Extruded in PBS Compound Pellets Cylinders at
37.degree. C. 4 FIG. 13B FIG. 13C FIG. 13D (Dex-EG7-Dex) 5 FIG. 14B
FIG. 14C FIG. 14D (Dex-EG9-Dex) 8 FIG. 15B FIG. 15C FIG. 15D
(Dex-PEG300-Dex)
Example 12: Drug Release from Compound 1 (Dex-TEG-Dex) Coated on
Different Surfaces
[0163] Compound 1 was coated onto titanium and SIBS as described in
Example 3 above. Drug release from the coated material was carried
out in PBS as described in Example 1 above. Cumulative drug release
was calculated and plotted as a percentage of the total drug in
each coated surface released over time (FIG. 17).
Example 13: Effect of Linker on Article Stability and Dexamethasone
Release Profiles
[0164] Each of compounds 1-8 differ in modest changes to the linker
covalently tethering two dexamethasone radicals into a dimer. All
of the compounds were observed to be capable of being processed
into articles (e.g., glassy amorphous solids). However, articles
formed from different compounds were observed to exhibit
dramatically different stability (under physiologically relevant
conditions) and dramatically different dexamethasone release
profiles.
[0165] For example, articles formed from Compounds 4, 5, and 8
(i.e., the compounds with the longer PEG linkers) appear to undergo
a change in physical form (geometric shape) in an aqueous
environment at 37.degree. C., while articles formed from Compounds
1, 3, 6, and 7 do not. As evidenced in FIGS. 13D, 14D, and 15D,
Compounds 4, 5, and 8 form into spherical droplets after two weeks
in PBS. On the other hand, FIG. 1F shows pellets formed from
Compound 1 maintaining their shape over extended periods of time,
and similar stability was observed for compounds 3, 6, and 7 in
PBS.
[0166] Articles formed from different compounds were also observed
to exhibit dramatically different dexamethasone release profiles.
For example, the dexamethasone release profiles from articles
formed from compounds 1, 3, 6, and 7 were observed to be generally
linear over the course of 12 weeks or more (see, e.g., FIGS. 1E,
8C, 9E, and 10D). In contrast, the dexamethasone release profiles
from articles formed from compounds 4 and 5 were observed to be
non-linear (see FIGS. 16A and 16B). Surprisingly, in articles
formed from compound 5 the dexamethasone release stops at only ca.
3% cumulative release after just 2 weeks in PBS.
[0167] Finally, the dexamethasone release profiles from heat molded
pellets (.about.1 mm.times.1 mm) of Compound 1 (Dex-TEG-Dex) and
Compound 6 (Dex-Hex-Dex) in 100% FBS as shown in FIG. 12
exemplifies how linker affects the drug release rates. The
difference in these release profiles show that articles formed from
Compound 1 might be preferred for use where dexamethasone release
is only needed for 1 or 2 months, while articles formed from
Compound 6 might be preferred for use where dexamethasone release
is needed for 6 months or more.
Example 14: Dexamethasone Prodrug Dimers
[0168] Compounds 9-11, described below, can be prepared by using
methods analogous to those described herein. The compounds can be
processed as described herein to produce articles capable of
producing an extended release profile following implantation into a
subject, and can be used in the methods, compositions, and articles
of the disclosure.
TABLE-US-00006 Compound Dimer Abbreviation 9 Dexamethasone-Ethylene
Glycol- Dex-EG1-Dex Dexamethasone 10 Dexamethasone-Diethylene
Glycol- Dex-DEG-Dex Dexamethasone 11 Dexamethasone-Hexaethylene
Glycol- Dex-EG6-Dex Dexamethasone
[0169] Some embodiments of the disclosure provided herein can be
defined according to the following numbered items:
[0170] 1. An article formed from the compound of any one of items
2-5 and 95, wherein the article releases less than 10% of
dexamethasone, as a percentage of the total dexamethasone present
in the article in prodrug form, at 37.degree. C. in 100% bovine
serum over 5 days.
[0171] 2. A compound described by the formula (I):
##STR00023##
[0172] wherein n is an integer from 1 to 6.
[0173] 3. The compound of item 2, wherein n is 3.
[0174] 4. The compound of item 2, wherein n is 4.
[0175] 5. The compound of item 2, wherein n is 5.
[0176] 6. A pharmaceutical composition comprising the compound of
any one of items 2-5, and a pharmaceutically acceptable
excipient.
[0177] 7. An article comprising Compound 6 or a compound of formula
(I):
##STR00024##
wherein the article provides controlled release of dexamethasone at
37.degree. C. in 100% bovine serum or at 37.degree. C. in PBS;
wherein n is an integer from 1 to 6.
[0178] 8. The article of item 7, wherein dexamethasone is released
from the article through surface erosion.
[0179] 9. The article of item 7 or 8, wherein the article releases
less than 10% of dexamethasone, as a percentage of the total
dexamethasone present in the article in prodrug form, at 37.degree.
C. in 100% bovine serum over 5 days; or the surface erosion
releases less than 2% of dexamethasone, as a percentage of the
total dexamethasone present in the article in prodrug form, at
37.degree. C. in PBS over 5 days; or the surface erosion releases
greater than 20% of dexamethasone, as a percentage of the total
dexamethasone present in the article in prodrug form, at 37.degree.
C. in 100% bovine serum over not fewer than 6 days; or the surface
erosion releases greater than 5.0% of dexamethasone as a percentage
of the total dexamethasone present in the article in prodrug form,
at 37.degree. C. in PBS over not fewer than 6 days; or
dexamethasone is released from the article at a rate such that
t.sub.10 is greater than or equal to 1/10 of t.sub.50.
[0180] 10. The article of any one of items 7-9, wherein the article
further comprises from 0.1% to 10% (w/w) of one or more additives,
wherein the one or more additives are selected from plasticizers,
antioxidants, binders, lubricants, radio-opaque agents, and
mixtures thereof.
[0181] 11. The article of any one of items 7-10, wherein the
article is a fiber, fiber mesh, woven fabric, non-woven fabric,
pellet, cylinder, hollow tube, microparticle, nanoparticle, or
shaped article.
[0182] 12. The article of any one of items 7-11, wherein the
article is free of controlled release excipient, free of a
crystallization inhibiting excipient, free of a mechanical
integrity enhancing excipient, and/or free of a binding
excipient.
[0183] 13. The article of any one of items 7-12, wherein the
article is in a glassy state.
[0184] 14. An article comprising Compound 6, or a compound of
formula (I):
##STR00025##
wherein the article is formed by a process comprising the steps
of:
[0185] (a) heating the compound to form a melt; and
[0186] (b) heat molding the melt to form the article,
[0187] wherein n is an integer from 1 to 6.
[0188] 15. An article comprising Compound 6 or a compound of
formula (I):
##STR00026##
wherein the article is formed by a process comprising the steps
of:
[0189] (a) heating the compound to form a melt; and
[0190] (b) injection molding the melt to form the article,
[0191] wherein n is an integer from 1 to 6.
[0192] 16. An article comprising Compound 6 or a compound of
formula (I):
##STR00027##
wherein the article is formed by a process comprising the steps
of:
[0193] (a) heating the compound to form a melt; and
[0194] (b) blow molding the melt to form the article,
[0195] wherein n is an integer from 1 to 6.
[0196] 17. An article comprising Compound 6 or a compound of
formula (I):
##STR00028##
wherein the article is formed by a process comprising the steps
of:
[0197] (a) dissolving the compound to form a solution; and
[0198] (b) evaporating the solvent to form the article,
[0199] wherein n is an integer from 1 to 6.
[0200] 18. The article of item 17, wherein step (b) comprises
solvent casting to form a film or a fiber.
[0201] 19. An article comprising Compound 6 or a compound of
formula (I):
##STR00029##
wherein the article is formed by a process comprising the steps
of:
[0202] (a) dissolving the compound to form a solution; and
[0203] (b) electrospinning or electrospraying the solution to form
the article,
[0204] wherein n is an integer from 1 to 6.
[0205] 20. An article comprising Compound 6 or a compound of
formula (I):
##STR00030##
wherein the article is formed by a process comprising the steps
of:
[0206] (a) heating the compound to form a melt; and
[0207] (b) electrospinning or electrospraying the melt to form the
article,
[0208] wherein n is an integer from 1 to 6.
[0209] 21. An article comprising Compound 6 or a compound of
formula (I):
##STR00031##
wherein the article is formed by a process comprising the steps
of:
[0210] (a) heating the compound to form a melt;
[0211] (b) extruding the melt to form the article,
[0212] wherein n is an integer from 1 to 6.
[0213] 22. The article of any one of items 7-21, wherein n is
3.
[0214] 23. The article of any one of items 7-21, wherein n is
4.
[0215] 24. The article of any one of items 7-21, wherein n is
5.
[0216] 25. An article formed from the compound of any one of items
2-5 and 95.
[0217] 26. The article of any one of items 7-25, wherein at least
70% (w/w) of the article is Compound 6 or the compound of formula
(I).
[0218] 27. The article of any one of items 7-26, wherein at least
90% (w/w) of the article is Compound 6 or the compound of formula
(I).
[0219] 28. The article of any one of items 7-27, wherein the
compound or dexamethasone is released from the article through
surface erosion.
[0220] 29. The article of item 28, wherein the surface erosion
releases less than 10% of dexamethasone, as a percentage of the
total drug, dexamethasone, present in the article in prodrug form,
at 37.degree. C. in 100% bovine serum over 5 days; or the surface
erosion releases less than 2% of dexamethasone, as a percentage of
the total drug, dexamethasone, present in the article in prodrug
form, at 37.degree. C. in PBS over 5 days; or the surface erosion
releases greater than 20% of dexamethasone, as a percentage of the
total dexamethasone present in the article in prodrug form, at
37.degree. C. in 100% bovine serum over not fewer than 6 days; or
the surface erosion releases greater than 5.0% of dexamethasone as
a percentage of the total dexamethasone present in the article in
prodrug form, at 37.degree. C. in PBS over not fewer than 6 days;
or dexamethasone is released from the article at a rate such that
t.sub.10 is greater than or equal to 1/10 of t.sub.50.
[0221] 30. The article of any one of items 7-29, wherein the
article further comprises from 0.1% to 10% (w/w) of one or more
additives, wherein the one or more additives are selected from
plasticizers, antioxidants, binders, lubricants, radio-opaque
agents, and mixtures thereof.
[0222] 31. The article of any one of items 7-30, wherein the
article is a fiber, fiber mesh, woven fabric, non-woven fabric,
pellet, cylinder, hollow tube, microparticle, nanoparticle, or
shaped article.
[0223] 32. The article of any one of items 7-31, wherein the
article is free of controlled release excipient, free of a
crystallization inhibiting excipient, free of a mechanical
integrity enhancing excipient, and/or free of a binding excipient;
or the article optionally has a glassy state.
[0224] 33. A fiber formed from the compound of any one of items 2-5
and 95.
[0225] 34. A fiber formed from Compound 6 or a compound of formula
(I):
##STR00032##
wherein the fiber is prepared by a process comprising the steps
of:
[0226] (a) dissolving the compound in a solvent to form a solution;
and
[0227] (b) electrospinning, dry spinning, wet spinning, or gel
spinning the solution to form the fiber,
[0228] wherein n is an integer from 1 to 6.
[0229] 35. A fiber formed from Compound 6 or a compound of formula
(I):
##STR00033##
wherein the fiber is prepared by a process comprising the steps of:
[0230] (a) heating the compound to form a melt; and [0231] (b)
extruding the melt to form the fiber (i.e., melt spinning),
[0232] wherein n is an integer from 1 to 6.
[0233] 36. A fiber formed from Compound 6 or a compound of formula
(I):
##STR00034##
wherein the fiber is prepared by a process comprising the steps
of:
[0234] (a) heating the compound to form a melt; and
[0235] (b) electrospinning the melt to form the fiber,
[0236] wherein n is an integer from 1 to 6.
[0237] 37. The fiber of any one of items 33-36, wherein n is 3.
[0238] 38. The fiber of any one of items 33-36, wherein n is 4.
[0239] 39. The fiber of any one of items 33-36, wherein n is 5.
[0240] 40. The fiber of any one of items 33-39, wherein at least
70% (w/w) of the fiber is Compound 6 or the compound of formula
(I).
[0241] 41. The fiber of any one of items 33-40, wherein at least
90% (w/w) of the fiber is Compound 6 or the compound of formula
(I).
[0242] 42. The fiber of any one of items 33-41, wherein the
compound or dexamethasone is released from the fiber through
surface erosion.
[0243] 43. The fiber of item 42, wherein the surface erosion
releases less than 10% of dexamethasone, as a percentage of the
total drug, dexamethasone, present in the fiber in prodrug form, at
37.degree. C. in 100% bovine serum over 5 days; or the surface
erosion releases less than 2% of dexamethasone, as a percentage of
the total drug, dexamethasone, present in the fiber in prodrug
form, at 37.degree. C. in PBS over 5 days; or the surface erosion
releases greater than 20% of dexamethasone, as a percentage of the
total dexamethasone present in the fiber in prodrug form, at
37.degree. C. in 100% bovine serum over not fewer than 6 days; or
the surface erosion releases greater than 5.0% of dexamethasone as
a percentage of the total dexamethasone present in the fiber in
prodrug form, at 37.degree. C. in PBS over not fewer than 6 days;
or dexamethasone is released from the fiber at a rate such that or
t.sub.10 is greater than or equal to 1/10 of t.sub.50.
[0244] 44. The fiber of any one of items 33-43, wherein the fiber
further comprises from 0.1% to 10% (w/w) of one or more additives,
wherein the one or more additives are selected from plasticizers,
antioxidants, binders, lubricants, radio-opaque agents, and
mixtures thereof.
[0245] 45. The fiber of any one of items 33-44, wherein the fiber
is free of controlled release excipient, free of a crystallization
inhibiting excipient, free of a mechanical integrity enhancing
excipient, and/or free of a binding excipient; or the fiber
optionally has a glassy state.
[0246] 46. A fiber mesh or woven fabric formed from the fiber of
any one of items 33-45.
[0247] 47. A non-woven fabric formed from the fiber of any one of
items 33-46.
[0248] 48. A glassy state composition formed from the compound of
any one of items 2-5 and 95.
[0249] 49. A glassy state composition formed from Compound 6 or a
compound of formula (I):
##STR00035##
wherein the composition is prepared by a process comprising the
steps of:
[0250] (a) heating the compound to form a melt; and
[0251] (b) cooling the melt to form the composition,
[0252] wherein n is an integer from 1 to 6.
[0253] 50. The glassy state composition of item 48 or 49, wherein n
is 3.
[0254] 51. The glassy state composition of item 48 or 49, wherein n
is 4.
[0255] 52. The glassy state composition of item 48 or 49, wherein n
is 5.
[0256] 53. The glassy state composition of any one of items 48-52,
wherein at least 70% (w/w) of the glassy state composition is
Compound 6 or the compound of formula (I).
[0257] 54. The glassy state composition of any one of items 48-53,
wherein at least 90% (w/w) of the glassy state composition is
Compound 6 or the compound of formula (I).
[0258] 55. The glassy state composition of any one of items 48-54,
wherein the compound or dexamethasone is released from the glassy
state composition through surface erosion.
[0259] 56. The glassy state composition of item 55, wherein the
surface erosion releases less than 10% of dexamethasone, as a
percentage of the total drug, dexamethasone, present in the glassy
state composition in prodrug form, at 37.degree. C. in 100% bovine
serum over 5 days; or the surface erosion releases less than 2% of
dexamethasone, as a percentage of the total drug, dexamethasone,
present in the glassy state composition in prodrug form, at
37.degree. C. in PBS over 5 days; or the surface erosion releases
greater than 20% of dexamethasone, as a percentage of the total
dexamethasone present in the glassy state composition in prodrug
form, at 37.degree. C. in 100% bovine serum over not fewer than 6
days; or the surface erosion releases greater than 5.0% of
dexamethasone as a percentage of the total dexamethasone present in
the glassy state composition in prodrug form, at 37.degree. C. in
PBS over not fewer than 6 days; or dexamethasone is released from
the glassy state composition at a rate such that or t.sub.10 is
greater than or equal to 1/10 of t.sub.50.
[0260] 57. The glassy state composition of any one of items 48-56,
wherein the glassy state composition further comprises from 0.1% to
10% (w/w) of one or more additives, wherein the one or more
additives are selected from plasticizers, antioxidants, binders,
lubricants, radio-opaque agents, and mixtures thereof.
[0261] 58. The glassy state composition of any one of items 48-57,
wherein the glassy state composition is formed by machining,
molding, electrospinning, electrospraying, blow molding, fiber
spinning, or extruding.
[0262] 59. The glassy state composition of any one of items 48-58,
wherein the glassy state composition is a fiber, fiber mesh, woven
fabric, non-woven fabric, pellet, cylinder, hollow tube,
microparticle, nanoparticle, or shaped article in the shape of a
cylinder, a cube, a sheet, a star, a toroid, a pyramid, a sphere,
an irregular polygon, or a regular polygon.
[0263] 60. The glassy state composition of item 59, wherein the
glassy state composition is a shaped article in the form of:
[0264] (i) fibers having a mean diameter of from about 0.01 to 1
mm;
[0265] (ii) pellets having a mean diameter of from about 0.2 to 5
mm;
[0266] (iii) cylinders of from about 0.01 to 1 mm in diameter and
0.5 to 20 mm in length;
[0267] (iv) microparticles having a mean diameter of from about 1
to 1000 .mu.m; or
[0268] (v) nanoparticles having a mean diameter of from about 0.01
to 1 .mu.m.
[0269] 61. The glassy state composition of any one of items 48-60,
wherein the glassy state composition is free of controlled release
excipient, free of a crystallization inhibiting excipient, free of
a mechanical integrity enhancing excipient, and/or free of a
binding excipient.
[0270] 62. A substrate comprising a coating formed from the
compound of any one of items 2-5 and 95.
[0271] 63. A substrate comprising a coating formed from Compound 6
or a compound of formula (I):
##STR00036##
wherein n is an integer from 1 to 6.
[0272] 64. The substrate of item 62 or 63, wherein n is 3.
[0273] 65. The substrate of item 62 or 63, wherein n is 4.
[0274] 66. The substrate of item 62 and 63, wherein n is 5.
[0275] 67. The substrate of any one of items 62-66, wherein at
least 70% (w/w) of the coating is Compound 6 or the compound of
formula (I).
[0276] 68. The substrate of item 62-67, wherein at least 90% (w/w)
of the coating is Compound 6 or the compound of formula (I).
[0277] 69. The substrate of any one of items 62-68, wherein the
compound or dexamethasone is released from the coating through
surface erosion.
[0278] 70. The substrate of item 69, wherein the surface erosion
releases less than 10% of dexamethasone, as a percentage of the
total drug, dexamethasone, present in the coating in prodrug form,
at 37.degree. C. in 100% bovine serum over 5 days; or the surface
erosion releases less than 2% of dexamethasone, as a percentage of
the total drug, dexamethasone, present in the coating in prodrug
form, at 37.degree. C. in PBS over 5 days; or the surface erosion
releases greater than 20% of dexamethasone, as a percentage of the
total dexamethasone present in the coating in prodrug form, at
37.degree. C. in 100% bovine serum over not fewer than 6 days; or
the surface erosion releases greater than 5.0% of dexamethasone as
a percentage of the total dexamethasone present in the coating in
prodrug form, at 37.degree. C. in PBS over not fewer than 6 days;
or dexamethasone is released from the coating at a rate such that
or t.sub.10 is greater than or equal to 1/10 of t.sub.50.
[0279] 71. The substrate of any one of items 62-70, wherein the
coating further comprises from 0.1% to 10% (w/w) of one or more
additives, wherein the one or more additives are selected from
plasticizers, antioxidants, binders, lubricants, radio-opaque
agents, and mixtures thereof.
[0280] 72. The substrate of any one of items 62-71, wherein the
coating is free of controlled release excipient, free of a
crystallization inhibiting excipient, free of a mechanical
integrity enhancing excipient, and/or free of a binding excipient;
or the coating optionally has a glassy state.
[0281] 73. The substrate of any one of items 62-72, wherein the
coating has a glassy state and is formed from the compound of any
one of items 1-4 and 87.
[0282] 74. An implantable medical device comprising the substrate
of any one of items 62-73, wherein the coating resides on the
surface of the implantable medical device.
[0283] 75. A coating having a glassy state formed from the compound
of any one of items 2-5 and 95.
[0284] 76. A method of forming an article comprising Compound 6 or
a compound of formula (I):
##STR00037##
wherein the article is formed by a process comprising the steps
of:
[0285] (a) heating the compound to form a melt;
[0286] (b) cooling the melt to form a glassy state composition;
and
[0287] (c) heating the glassy state composition to a temperature
above the glass transition temperature of the glassy state
composition and shaping the glassy state composition to form a
shaped article,
[0288] wherein n is an integer from 1 to 6.
[0289] 77. A method of forming an article comprising Compound 6 or
a compound of formula (I):
##STR00038##
wherein the article is formed by a process comprising the steps
of:
[0290] (a) dissolving the compound in a solvent to form a
solution;
[0291] (b) evaporating the solvent to form a glassy state
composition; and
[0292] (c) heating the glassy state composition to a temperature
above the glass transition temperature of the glassy state
composition and shaping the glassy state composition to form a
shaped article,
[0293] wherein n is an integer from 1 to 6.
[0294] 78. The method of item 76 or 77, wherein step (c) comprises
extruding, molding, blow molding, heat spinning, melt spinning,
electrospinning or electrospraying the glassy state composition to
form the shaped article.
[0295] 79. A method of forming an article comprising Compound 6 or
a compound of formula (I):
##STR00039##
wherein the article is formed by a process comprising the steps
of:
[0296] (a) dissolving the compound in a solvent to form a
solution;
[0297] (b) electrospraying or electrospinning the solution to form
a glassy state composition; and
[0298] (c) heating the glassy state composition to a temperature
above the glass transition temperature of the glassy state
composition and shaping the glassy state composition to form a
coating;
[0299] wherein n is an integer from 1 to 6.
[0300] 80. The method of any one of items 76-79, wherein the method
produces an article free of controlled release excipient, free of a
crystallization inhibiting excipient, free of a mechanical
integrity enhancing excipient, and/or free of a binding excipient;
or the method produces an article that optionally has a glassy
state.
[0301] 81. A solid crystalline form of Compound 1 having an X-ray
powder diffraction (XRPD) pattern comprising angles 2.theta.
(.degree.) of 9.316.degree., 11.501.degree., 14.019.degree.,
15.982.degree., 17.268.degree., 17.685.degree., 18.658.degree.,
20.440.degree., 21.782.degree., 23.472.degree., 29.816.degree.,
and/or 33.150.degree..
[0302] 82. The solid crystalline form of Compound 1 of item 81,
wherein the solid crystalline form of Compound 1 has an XRPD
pattern comprising at least one peak at diffraction angle 2.theta.
(.degree.) of 9.316.degree..
[0303] 83. The solid crystalline form of Compound 1 of item 81 or
82, wherein the solid crystalline form of Compound 1 has an XRPD
pattern comprising at least one peak at diffraction angle 2.theta.
(.degree.) of 11.501.degree..
[0304] 84. The solid crystalline form of Compound 1 of any one of
items 81-83, wherein the solid crystalline form of Compound 1 has
an XRPD pattern comprising at least one peak at diffraction angle
2.theta. (.degree.) of 14.019.degree..
[0305] 85. The solid crystalline form of Compound 1 of any one of
items 81-84, wherein the solid crystalline form of Compound 1 has
an XRPD pattern comprising at least one peak at diffraction angle
2.theta. (.degree.) of 15.982.degree.. 86. The solid crystalline
form of Compound 1 of any one of items 81-85, wherein the solid
crystalline form of Compound 1 has an XRPD pattern comprising at
least one peak at diffraction angle 2.theta. (.degree.) of
17.268.degree..
[0306] 87. The solid crystalline form of Compound 1 of any one of
items 81-86, wherein the solid crystalline form of Compound 1 has
an XRPD pattern comprising at least one peak at diffraction angle
2.theta. (.degree.) of 17.685.degree..
[0307] 88. The solid crystalline form of Compound 1 of any one of
items 81-87, wherein the solid crystalline form of Compound 1 has
an XRPD pattern comprising at least one peak at diffraction angle
2.theta. (.degree.) of 18.658.degree..
[0308] 89. The solid crystalline form of Compound 1 of any one of
items 81-88, wherein the solid crystalline form of Compound 1 has
an XRPD pattern comprising at least one peak at diffraction angle
2.theta. (.degree.) of 20.440.degree..
[0309] 90. The solid crystalline form of Compound 1 of any one of
items 81-89, wherein the solid crystalline form of Compound 1 has
an XRPD pattern comprising at least one peak at diffraction angle
2.theta. (.degree.) of 21.782.degree..
[0310] 91. The solid crystalline form of Compound 1 of any one of
items 81-90, wherein the solid crystalline form of Compound 1 has
an XRPD pattern comprising at least one peak at diffraction angle
2.theta. (.degree.) of 23.472.degree..
[0311] 92. The solid crystalline form of Compound 1 of any one of
items 81-91, wherein the solid crystalline form of Compound 1 has
an XRPD pattern comprising at least one peak at diffraction angle
2.theta. (.degree.) of 29.816.degree..
[0312] 93. The solid crystalline form of Compound 1 of any one of
items 81-92, wherein the solid crystalline form of Compound 1 has
an XRPD pattern comprising at least one peak at diffraction angle
2.theta. (.degree.) of 33.150.degree..
[0313] 94. The solid crystalline form of Compound 1 of any one of
items 81-93, wherein the solid crystalline form of Compound 1 has
an XRPD pattern comprising at least one peak diffraction angle
2.theta. (.degree.) of 9.316.degree., 11.501.degree.,
14.019.degree., 15.982.degree., 17.268.degree., 17.685.degree.,
18.658.degree., 20.440.degree., 21.782.degree., 23.472.degree.,
29.816.degree., and 33.150.degree..
[0314] 95. Compound 6.
[0315] 96. A pharmaceutical composition comprising Compound 6 and a
pharmaceutically acceptable excipient.
Other Embodiments
[0316] Although the foregoing disclosure has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, the descriptions and examples should not be
construed as limiting the scope of the disclosure. The disclosures
of all patent and scientific literature cited herein are expressly
incorporated in their entirety by reference.
* * * * *