U.S. patent application number 16/966452 was filed with the patent office on 2021-04-22 for glass formulations and uses thereof.
The applicant listed for this patent is Ripple Therapeutics Corporation. Invention is credited to Kyle BATTISTON, Hans Christian FISCHER, Dimitra LOUKA, Wendy Alison NAIMARK, Ian Charles PARRAG, J. Paul SANTERRE, Matthew Alexander John STATHAM.
Application Number | 20210113457 16/966452 |
Document ID | / |
Family ID | 1000005326792 |
Filed Date | 2021-04-22 |
View All Diagrams
United States Patent
Application |
20210113457 |
Kind Code |
A1 |
PARRAG; Ian Charles ; et
al. |
April 22, 2021 |
GLASS FORMULATIONS AND USES THEREOF
Abstract
The disclosure features pharmaceutical compositions formed from
prodrug dimers for the extended delivery of a drug and for the
treatment of a disease or condition.
Inventors: |
PARRAG; Ian Charles;
(Mississaugua, 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) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ripple Therapeutics Corporation |
Toronto |
|
CA |
|
|
Family ID: |
1000005326792 |
Appl. No.: |
16/966452 |
Filed: |
February 1, 2019 |
PCT Filed: |
February 1, 2019 |
PCT NO: |
PCT/CA2019/050135 |
371 Date: |
July 30, 2020 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62625460 |
Feb 2, 2018 |
|
|
|
62627608 |
Feb 7, 2018 |
|
|
|
62758234 |
Nov 9, 2018 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/54 20170801;
A61K 9/0051 20130101; A61K 31/573 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/573 20060101 A61K031/573; A61K 47/54 20060101
A61K047/54 |
Claims
1-36. (canceled)
37. An article comprising a steroid dimer of formula (A-VI):
D1-C(O)-L-C(O)-D2 (A-VI), or a pharmaceutically salt or solvate
thereof, wherein: D1 and D2 are each independently a steroid
radical; and L is a linker covalently linking D1 to D2, the article
comprising at least 70% (w/w) of steroid dimer of formula
(A-VI).
38. The article of claim 37, wherein either or both of D1 or D2 are
attached to L through a hydroxyl radical of the D1 or D2.
39. The article of claim 37, wherein the compound has a structure
of formula (A-VI): D1-C(O)--O--R.sup.A--O--C(O)-D2 (A-VI), wherein:
R.sup.A is C.sub.1-20 alkylene, a linear or branched heteroalkylene
of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a
linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a
cyclic system of 3 to 10 atoms, or a pharmaceutically salt or
solvate thereof.
40. The article of claim 39, wherein R.sup.A is C.sub.1-20 alkylene
or a linear heteroalkylene of 1 to 20 atoms.
41. The article of claim 39, wherein the compound has a structure
of formula (A-VI): D1-C(O)--O(CH.sub.2CH.sub.2O).sub.n--C(O)-D2
(A-VI), wherein: n is an integer from 1-10, or a pharmaceutically
salt or solvate thereof.
42. The article of claim 41, wherein n is an integer from 3-5.
43. The article of claim 42, wherein n is 3.
44. The article of claim 37, wherein L has a molecular weight from
80 to 800 Da.
45. The article of claim 37, wherein D1 and D2 are each
independently selected from the group consisting of an anabolic
steroid, an androgenic steroid, a progestin steroid, an estrogen
steroid, a cancer treatment steroid, an antibiotic steroid, a
glucocorticoid steroid, a benign steroid, an anti-angiogenic
steroid, an intraocular pressure (IOP) lowering steroid, a cholic
acid-related bile acid steroid, a cholesterol-derivative, other
steroid, a pheromone, a steroid metabolite, a progestin, a
neurosteroid, and a corticosteroid.
46. The article of claim 37, wherein D1 and D2 are the same steroid
radical.
47. The article of claim 37, wherein D1 and D2 are each
triamcinolone.
48. The article of claim 37, wherein the compound has the following
structure: ##STR00111## or a pharmaceutically salt or solvate
thereof.
49. The article of claim 37, wherein D1 and D2 are each
prednisolone.
50. The article of claim 37, wherein the compound has the following
structure: ##STR00112## or a pharmaceutically salt or solvate
thereof.
51. The article of claim 37, wherein each of D1 and D2 is released
from the article 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.
52. A compound: ##STR00113##
53. A method of treating an inflammatory disease or condition in a
subject in need thereof, the method comprising administering to the
subject an article in an amount sufficient to treat the
inflammatory disease or condition in the subject, wherein the
article comprises a steroid dimer of formula (A-VI):
D1-C(O)-L-C(O)-D2 (A-VI), or a pharmaceutically salt or solvate
thereof, wherein: D1 and D2 are each independently a steroid
radical; and L is a linker covalently linking D1 to D2, the article
comprising at least 70% (w/w) of steroid dimer of formula
(A-VI).
54. The method of claim 53, wherein the article is administered
locally.
55. The method of claim 53, wherein the article is administered in
the eye of the subject.
56. The method of claim 55, wherein the article is administered in
a cavity of the eye of the subject.
Description
RELATED APPLICATIONS
[0001] This application is US National Stage entry of PCT
application PCT/CA2019/050135, filed Feb. 1, 2019, which claims the
benefit of Provisional Patent Application No. 62/625,460, filed
Feb. 2, 2018, Provisional Patent Application No. 62/627,608, filed
Feb. 7, 2018; and Provisional Patent Application No. 62/758,234,
filed Nov. 9, 2018, each of these applications being incorporated
herein in their entirety by reference.
BACKGROUND OF THE DISCLOSURE
[0002] Steroids are useful drugs in a variety of medical fields,
for example in ophthalmology, oncology, laryngology, endocrinology
and metabolic diseases, rheumatology, urology, neurology,
cardiology, dental medicine, dermatology, otology, post-surgical
medicine, orthopedics, pain management, and gynecology.
SUMMARY OF THE DISCLOSURE
[0003] The disclosure features steroid dimers and articles formed
from the steroid dimers. The articles of the disclosure can be
machined, molded, emulsion-processed, electrospun, electrosprayed,
blow molded, fiber spun (e.g., wet spun, dry spun, melt spun, heat
spun, or gel spun), 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 prodrug steroid dimer is released in
a controlled fashion.
[0004] In a first aspect, the disclosure provides an article
including a compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0005] or a pharmaceutically acceptable salt thereof, wherein (i)
each of D1 and D2 is, independently, a radical formed from a
steroid; and L is a linker covalently linking D1 to D2, (ii) at
least 90% (w/w) of the article is the compound of formula (A-VIII),
(iii) the article is free of controlled release excipient, and (iv)
D1 and D2 is released from the article at 37.degree. C. in 100%
bovine serum or at 37.degree. C. in PBS at a rate such that t10 is
greater than or equal to 1/10 of t.sub.50.
[0006] In another aspect, the disclosure features an article
including a compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0007] or a pharmaceutically acceptable salt thereof, wherein (i)
each of D1 and D2 is, independently, a radical formed from a
steroid; and L is a linker covalently linking D1 to D2, (ii) at
least 90% (w/w) of the article is the compound of formula (A-VIII),
(iii) the article is a fiber, fiber mesh, woven fabric, non-woven
fabric, pellet, cylinder, hollow tube, microparticle, nanoparticle,
or shaped article, and (iv) the article is free of controlled
release excipient.
[0008] In some embodiments, the compound, D1, or D2 are released
from the article through surface erosion.
[0009] In another aspect, the disclosure features an article formed
from a compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0010] or a pharmaceutically acceptable salt thereof, in which the
article is prepared by a process including the steps of: (a)
heating the compound, or a pharmaceutically acceptable salt
thereof, to form a melt; and (b) cooling the melt to form the
composition, in which each of D1 and D2 is, independently, a
radical formed from a steroid; and L is a linker covalently linking
D1 to D2. In particular 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.
[0011] The disclosure further features an article including a
compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0012] or a pharmaceutically acceptable salt thereof, in which the
article is formed by a process including the steps of: (a) heating
the compound, or a pharmaceutically acceptable salt thereof, to
form a melt; and (b) injection molding the melt to form the
article, in which each of D1 and D2 is, independently, a radical
formed from a steroid; and L is a linker covalently linking D1 to
D2. In particular 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.
[0013] The disclosure also features an article including a compound
of formula (A-VIII):
D1-L-D2 (A-VIII)
[0014] or a pharmaceutically acceptable salt thereof, in which the
article is formed by a process including the steps of: (a) heating
the compound, or a pharmaceutically acceptable salt thereof, to
form a melt; and (b) blow molding the melt to form the article, in
which each of D1 and D2 is, independently, a radical formed from a
steroid; and L is a linker covalently linking D1 to D2. In
particular 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] The disclosure features an article including a compound of
formula (A-VIII):
D1-L-D2 (A-VIII)
[0016] or a pharmaceutically acceptable salt thereof, in which the
article is formed by a process including the steps of: (a)
dissolving the compound, or a pharmaceutically acceptable salt
thereof, to form a solution; and (b) evaporating the solvent to
form the article (e.g., free formed to form a film, from a mold to
form a shaped article, or from a spinneret to form a fiber), in
which each of D1 and D2 is, independently, a radical formed from a
steroid; and L is a linker covalently linking D1 to D2. In
particular embodiments, step (b) includes solvent casting to form a
film or a fiber. In particular 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.
[0017] The disclosure also features an article including a compound
of formula (A-VIII):
D1-L-D2 (A-VIII)
[0018] or a pharmaceutically acceptable salt thereof, in which the
article is formed by a process including the steps of: (a)
dissolving the compound, or a pharmaceutically acceptable salt
thereof, to form a solution; and (b) electrospinning or
electrospraying the solution to form the article, in which each of
D1 and D2 is, independently, a radical formed from a steroid; and L
is a linker covalently linking D1 to D2. In particular 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] The disclosure further features an article including a
compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0020] or a pharmaceutically acceptable salt thereof, in which the
article is formed by a process including the steps of: (a) heating
the compound, or a pharmaceutically acceptable salt thereof, to
form a melt; and (b) electrospinning or electrospraying the melt to
form the article, in which each of D1 and D2 is, independently, a
radical formed from a steroid; and L is a linker covalently linking
D1 to D2. In particular 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.
[0021] The disclosure features an article including a compound of
formula (A-VIII):
D1-L-D2 (A-VIII)
[0022] or a pharmaceutically acceptable salt thereof, in which the
article is formed by a process including the steps of: (a) heating
the compound, or a pharmaceutically acceptable salt thereof, to
form a melt; (b) extruding the melt to form the article, in which
each of D1 and D2 is, independently, a radical formed from a
steroid; and L is a linker covalently linking D1 to D2. In
particular 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.
[0023] In some embodiments of the articles of the disclosure, the
compound is processed as described herein (e.g., melt processed or
solvent processed) to form a glassy state solid. The glassy state
solid is subsequently heated above its glass transition
temperature, Tg, and heat processed (e.g., molded, blow molded,
heat spun, electrospun, electrosprayed, or extruded to form a
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.
[0024] In an embodiment of any of the above articles, L has a
molecular weight of from 80 to 800 Da, e.g., 80 to 100 Da, 80 to
200 Da, 80 to 300 Da, 80 to 400 Da, 80 to 500 Da, 80 to 600 Da, or
80 to 700 Da. In another embodiment of any of the above articles, L
is covalently linked to D1 and to D2 via one or more ester,
carbonate, carbonate ester, or anhydride linkages. In particular
embodiments, L is covalently linked to D1 and to D2 via one or more
carbonate linkages.
[0025] In a particular embodiment of any of the above articles, L
includes the radical --C(O)--(R.sup.A)--C(O)-- or
--O--(R.sup.A)--O--; R.sup.A is a radical of a polyol and includes
at least one free hydroxyl group or R.sup.A is C.sub.1-20 alkylene,
a linear or branched heteroalkylene of 1 to 20 atoms, a linear or
branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20
alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms,
(CH.sub.2CH.sub.2O).sub.qCH.sub.2CH.sub.2--,
--(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)rCH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
or --(CH.sub.2CH(CH.sub.3)O).sub.sCH.sub.2CH(CH.sub.3)--; and q, r,
and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to
10).
[0026] The disclosure features an article formed from a compound of
the disclosure.
[0027] In an embodiment of any of the above articles, each of D1
and D2 is an anabolic steroid, an androgenic steroid, a progestin
steroid, an estrogen steroid, a cancer treatment steroid, an
antibiotic steroid, a glucocorticoid steroid, a benign steroid, an
anti-angiogenic steroid, an intraocular pressure (IOP) lowering
steroid, a cholic acid-related bile acid steroid, a
cholesterol-derivative, other steroid, a pheromone, a steroid
metabolite, a progestin, a neurosteroid, and a corticosteroid. In a
particular embodiment of any of the above articles, the compound is
further described by one of formulas (II)-(LXXV), described herein.
In another embodiment of any of the above articles, each of D1 and
D2 is, independently, described by any one of formulas (I-a) to
(I-vvv), described herein.
[0028] In the articles of the disclosure, D1 and D2 can be formed
from the same steroid, or D1 and D2 can be formed from different
steroids.
[0029] In a particular embodiment of any of the above articles, the
article includes a mixture of two or more compounds of formula
(A-VIII).
[0030] In certain embodiments, at least 70% (w/w) of the article is
a compound of formula (A-VIII), e.g., at least 75% (w/w), at least
80% (w/w), at least 85% (w/w), at least 90% (w/w), at least 95%
(w/w), or at least 99% (w/w).
[0031] In another embodiment of any of the above articles, the
compound is released from the article through surface erosion. In
certain embodiments of any of the above articles, the surface
erosion releases less than 20% (e.g., less than 18%, 15%, 12%, 10%,
or 5%) of D1 or D2 (as a percentage of the total drug, D1 or D2,
present in the article in prodrug form) at 37.degree. C. in 100%
bovine serum over 5 days, 6 days, 7 days, 8 days, 9 days, 10 days,
or 12 days (e.g., less than 10% of D1 or D2 at 37.degree. C. in
100% bovine serum over 5 days). In other embodiments of any of the
above articles, the surface erosion releases less than 2.0% (e.g.,
less than 1.8%, 1.5%, 1.2%, 1.0%, or 0.5%) of D1 or D2 (as a
percentage of the total drug, D1 or D2, present in the article 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 D1 or D2 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 D1 or D2 (as a
percentage of the total drug, D1 or D2, 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
D1 or D2 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 D1 or D2 (as a percentage of the total drug, D1 or
D2, 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 D1 or D2 at 37.degree. C. in PBS over 10 days).
The compound (D1 and/or D2) can be released from the article at a
rate such that t10 is greater than or equal to 1/10 of
t.sub.50.
[0032] In still another embodiment of any of the above articles,
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, in which the one or more additives are plasticizers
(e.g., glycerol, triacetin, isopropyl alcohol, ethanol, or ethylene
glycol), antioxidants (e.g., ascorbic acid, vitamin E, sodium
metabisulfite, butylated hydroxytoluene, p-hydroxybenxyl alcohol,
or butylated hydroxy anisole), binders (e.g., polyvinyl
pyrrolidone, carboxymethyl cellulose, hydroxypropyl cellulose, or
hydroxypropyl methyl cellulose), lubricants, radio-opaque agents,
and mixtures thereof.
[0033] In still another embodiment of any of the above articles,
the article is a fiber, fiber mesh, woven fabric, non-woven fabric,
pellet, cylinder, microparticle (e.g., a microbead), nanoparticle
(e.g., a nanobead), or another shaped article. For example, the
article is a milled microbead or nanobead.
[0034] In other embodiments, the article is in the form of glassy
state 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. In some embodiments, a mean
length of the fiber can range from about 20 mm to 20 meters, e.g.,
20 to 100 mm, 75 to 300 mm, 100 mm to 1 meter, 0.5 meters to 6
meters, or 1.0 meters to 20 meters.
[0035] In certain embodiments, the article is in the form of glassy
state 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.
[0036] In some embodiments, the article is in the form of glassy
state cylinders of from about 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 article is in the form of glassy state
cylinders of from about 0.1 to 1 mm diameter, e.g., about 0.1 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. 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 length of the cylinder is about 0.5 to 10 mm, or
about 1 to 10 mm.
[0037] In some embodiments, the article is mechanically stable. For
example, the article is resistant to breaking under
deformation.
[0038] In other embodiments, the article is in the form of glassy
state microparticles, e.g., microbeads, 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.
[0039] In certain embodiments, the article is in the form of glassy
state nanoparticles, e.g., nanobeads, having a mean diameter of
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.
[0040] The disclosure features a fiber formed from a compound of
the disclosure (e.g., a compound described by one of formulas
(II)-(LXXV), described herein, or a steroid dimer in which each of
D1 and D2 is, independently, described by any one of formulas (I-a)
to (I-ii), described herein). In particular 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.
[0041] The disclosure further features a fiber formed from a
compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0042] or a pharmaceutically acceptable salt thereof, in which the
fiber is prepared by a process including the steps of: (a)
dissolving the compound, or a pharmaceutically acceptable salt
thereof, in a solvent to form a solution; and (b) electrospinning,
dry spinning, wet spinning or gel spinning the solution to form the
fiber, in which each of D1 and D2 is, independently, a radical
formed from a steroid; and L is a linker covalently linking D1 to
D2. In particular 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.
[0043] The disclosure further features a fiber formed from a
compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0044] or a pharmaceutically acceptable salt thereof, in which the
fiber is prepared by a process including the steps of: (a) heating
the compound, or a pharmaceutically acceptable salt thereof, to
form a melt; and (b) extruding the melt to form the fiber (i.e.,
melt spinning), each of D1 and D2 is, independently, a radical
formed from a steroid; and L is a linker covalently linking D1 to
D2. In particular 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.
[0045] The disclosure features a fiber formed from a compound of
formula (A-VIII):
D1-L-D2 (A-VIII)
[0046] or a pharmaceutically acceptable salt thereof, in which the
fiber is prepared by a process including the steps of: (a) heating
the compound, or a pharmaceutically acceptable salt thereof, to
form a melt; and (b) electrospinning the melt to form the fiber, in
which each of D1 and D2 is, independently, a radical formed from a
steroid; and L is a linker covalently linking D1 to D2. In
particular 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.
[0047] In an embodiment of any of the above fibers, L has a
molecular weight of from 80 to 800 Da, e.g., 80 to 100 Da, 80 to
200 Da, 80 to 300 Da, 80 to 400 Da, 80 to 500 Da, 80 to 600 Da, or
80 to 700 Da. In another embodiment of any of the above fibers, L
is covalently linked to D1 and to D2 via one or more ester,
carbonate, carbonate ester, or anhydride linkages. In particular
embodiments, L is covalently linked to D1 and to D2 via one or more
carbonate linkages.
[0048] In a particular embodiment of any of the above fibers, L
includes the radical --(C(O)--(R.sup.A)--C(O)-- or
--O--(R.sup.A)--O--; R.sup.A is a radical of a polyol and includes
at least one free hydroxyl group or R.sup.A is C.sub.1-20 alkylene,
a linear or branched heteroalkylene of 1 to 20 atoms, a linear or
branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20
alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms,
(CH.sub.2CH.sub.2O)qCH.sub.2CH.sub.2--,
--(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)rCH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
or --(CH.sub.2CH(CH.sub.3)O).sub.sCH.sub.2CH(CH.sub.3)--; and q, r,
and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to
10).
[0049] In an embodiment of any of the above fibers, each of D1 and
D2 is an anabolic steroid, an androgenic steroid, a progestin
steroid, an estrogen steroid, a cancer treatment steroid, an
antibiotic steroid, a glucocorticoid steroid, a benign steroid, an
anti-angiogenic steroid, an intraocular pressure (IOP) lowering
steroid, a cholic acid-related bile acid steroid, a
cholesterol-derivative, other steroid, a pheromone, a steroid
metabolite, a progestin, a neurosteroid, and a corticosteroid. In a
particular embodiment of any of the above fibers, the compound is
further described by one of formulas (II)-(LXXV), described herein.
In another embodiment of any of the above fibers, each of D1 and D2
is, independently, described by any one of formulas (I-a) to
(I-vvv), described herein.
[0050] In the fibers of the disclosure, D1 and D2 can be formed
from the same steroid, or D1 and D2 can be formed from different
steroids.
[0051] In a particular embodiment of any of the above fibers, the
fiber includes a mixture of two or more compounds of formula
(A-VIII).
[0052] In certain embodiments, at least 70% (w/w) of the fiber is a
compound of formula (A-VIII), e.g., at least 75% (w/w), at least
80% (w/w), at least 85% (w/w), at least 90% (w/w), at least 95%
(w/w), or at least 99% (w/w).
[0053] In another embodiment of any of the above fibers, the
compound is released from the fiber through surface erosion. In
certain embodiments of any of the above fibers, the surface erosion
releases less than 20% (e.g., less than 18%, 15%, 12%, 10%, or 5%)
of D1 or D2 (as a percentage of the total drug, D1 or D2, present
in the fiber in prodrug form) at 37.degree. C. in 100% bovine serum
over 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 12 days
(e.g., less than 10% of D1 or D2 at 37.degree. C. in 100% bovine
serum over 5 days). In other embodiments of any of the above
fibers, the surface erosion releases less than 2.0% (e.g., less
than 1.8%, 1.5%, 1.2%, 1.0%, or 0.5%) of D1 or D2 (as a percentage
of the total drug, D1 or D2, present in the fiber 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 D1 or D2 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 D1 or D2 (as a percentage of the total
drug, D1 or D2, 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 D1 or D2 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 D1 or D2 (as a
percentage of the total drug, D1 or D2, 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 D1 or D2 at
37.degree. C. in PBS over 10 days). In other embodiments, the
compound (D1 and/or D2) is released from the fiber at a rate such
that t10 is greater than or equal to 1/10 of t.sub.50.
[0054] In still another embodiment of any of the above fibers, 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, in which the one or more additives are plasticizers
(e.g., glycerol, triacetin, isopropyl alcohol, ethanol, or ethylene
glycol), antioxidants (e.g., ascorbic acid, vitamin E, sodium
metabisulfite, butylated hydroxytoluene, p-hydroxybenxyl alcohol,
or butylated hydroxy anisole), binders (e.g., polyvinyl
pyrrolidone, carboxymethyl cellulose, hydroxypropyl cellulose, or
hydroxypropyl methyl cellulose), lubricants, radio-opaque agents,
and mixtures thereof.
[0055] The disclosure features (i) a fiber mesh formed from a fiber
of the disclosure; a woven fabric formed from a fiber of the
disclosure; and 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.
[0056] In another aspect, the disclosure features a glassy state
composition formed from a compound of the disclosure (e.g., a
compound described by one of formulas (II)-(LXXV), described
herein, or a steroid dimer in which each of D1 and D2 is,
independently, described by any one of formulas (I-a) to (I-vvv),
described herein). In particular 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.
[0057] In another aspect, the disclosure further features a glassy
state composition formed from a compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0058] or a pharmaceutically acceptable salt thereof, in which the
glassy state composition is prepared by a process including the
steps of: (a) heating the compound, or a pharmaceutically
acceptable salt thereof, to form a melt; and (b) cooling the melt
to form the composition, in which each of D1 and D2 is,
independently, a radical formed from a steroid; and L is a linker
covalently linking D1 to D2. In particular 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.
[0059] In an embodiment of any of the above glassy state
compositions, L has a molecular weight of from 80 to 800 Da, e.g.,
80 to 100 Da, 80 to 200 Da, 80 to 300 Da, 80 to 400 Da, 80 to 500
Da, 80 to 600 Da, or 80 to 700 Da. In another embodiment of any of
the above glassy state compositions, L is covalently linked to D1
and to D2 via one or more ester, carbonate, carbonate ester, or
anhydride linkages. In particular embodiments, L is covalently
linked to D1 and to D2 via one or more carbonate linkages.
[0060] In a particular embodiment of any of the above glassy state
compositions, L includes the radical --(C(O)--(R.sup.A)--C(O)-- or
--O--(R.sup.A)--O--; R.sup.A is a radical of a polyol and includes
at least one free hydroxyl group or R.sup.A is C.sub.1-20 alkylene,
a linear or branched heteroalkylene of 1 to 20 atoms, a linear or
branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20
alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms,
(CH.sub.2CH.sub.2O).sub.qCH.sub.2CH.sub.2--,
--(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2CH.sub.2CH.sub-
.2--, or --(CH.sub.2CH(CH.sub.3)O)sCH.sub.2CH(CH.sub.3)--; and q,
r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to
10).
[0061] In an embodiment of any of the above glassy state
compositions, each of D1 and D2 is an anabolic steroid, an
androgenic steroid, a progestin steroid, an estrogen steroid, a
cancer treatment steroid, an antibiotic steroid, a glucocorticoid
steroid, a benign steroid, an anti-angiogenic steroid, an
intraocular pressure (IOP) lowering steroid, a cholic acid-related
bile acid steroid, a cholesterol-derivative, other steroid, a
pheromone, a steroid metabolite, a progestin, a neurosteroid, and a
corticosteroid. In a particular embodiment of any of the above
glassy state compositions, the compound is further described by one
of formulas (II)-(LXXV), described herein. In another embodiment of
any of the above glassy state compositions, each of D1 and D2 is,
independently, described by any one of formulas (I-a) to (I-vvv),
described herein.
[0062] In the glassy state compositions of the disclosure, D1 and
D2 can be formed from the same steroid, or D1 and D2 can be formed
from different steroids.
[0063] In a particular embodiment of any of the above glassy state
compositions, the glassy state composition includes a mixture of
two or more compounds of formula (A-VIII).
[0064] In certain embodiments, at least 70% (w/w) of the glassy
state composition is a compound of formula (A-VIII), e.g., at least
75% (w/w), at least 80% (w/w), at least 85% (w/w), at least 90%
(w/w), at least 95% (w/w), or at least 99% (w/w).
[0065] In another embodiment of any of the above glassy state
compositions, the compound is released from the glassy state
composition through surface erosion. In certain embodiments of any
of the above glassy state compositions, the surface erosion
releases less than 20% (e.g., less than 18%, 15%, 12%, 10%, or 5%)
of D1 or D2 (as a percentage of the total drug, D1 or D2, present
in the glassy state composition in prodrug form) at 37.degree. C.
in 100% bovine serum over 5 days, 6 days, 7 days, 8 days, 9 days,
10 days, or 12 days (e.g., less than 10% of D1 or D2 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 D1 or D2 (as a percentage of the total drug, D1 or D2,
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 D1 or D2 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 D1 or D2 (as a
percentage of the total drug, D1 or D2, 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 D1 or D2 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 D1 or D2 (as a percentage of the
total drug, D1 or D2, 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 D1 or D2 at
37.degree. C. in PBS over 10 days). In other embodiments, the
compound (D1 and/or D2) is released from the glassy state
composition at a rate such that t10 is greater than or equal to
1/10 of t.sub.50.
[0066] In still another embodiment of any of the above glassy state
compositions, 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, in which the one or
more additives are plasticizers (e.g., glycerol, triacetin,
isopropyl alcohol, ethanol, or ethylene glycol), antioxidants
(e.g., ascorbic acid, vitamin E, sodium metabisulfite, butylated
hydroxytoluene, p-hydroxybenzyl alcohol, or butylated hydroxy
anisole), binders (e.g., polyvinyl pyrrolidone, carboxymethyl
cellulose, hydroxypropyl cellulose, or hydroxypropyl methyl
cellulose), lubricants, radio-opaque agents, and mixtures
thereof.
[0067] In particular embodiments of any of the above glassy state
compositions, the glassy state composition is machined, molded,
emulsion-processed, electrospun, electrosprayed, blow molded, or
extruded.
[0068] In other embodiments of any of the above glassy state
compositions, the glassy state composition is a fiber, fiber mesh,
woven fabric, non-woven fabric, pellet, cylinder, microparticle
(e.g., a microbead), nanoparticle (e.g., a nanobead), or another
shaped article. For example, the glassy state composition is a
shaped article in the form of: (i) fibers having a mean diameter of
from about 0.01 to 1 mm; (ii) pellets having a mean diameter of
from about 0.2 to 5 mm; (iii) cylinders of from about 0.5 to 20 mm
in length and from about 0.01 to 1 mm in diameter; (iv) microbeads,
having a mean diameter of from about 1 to 1000 .mu.m; or (v)
nanobeads, having a mean diameter of from about 0.01 to 1 .mu.m.
The glassy state composition can be 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.
[0069] In another aspect, the disclosure features a substrate
including a coating formed from a compound of formula (A-VIII):
D1-L-D2 (A-VIII).
[0070] In particular 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.
[0071] In an embodiment of any of the above coatings, L has a
molecular weight of from 80 to 800 Da.
[0072] In a particular embodiment of any of the above coatings, L
is covalently linked to D1 and to D2 via one or more ester,
carbonate, carbonate ester, or anhydride linkages. In particular
embodiments, L is covalently linked to D1 and to D2 via one or more
carbonate linkages.
[0073] In certain embodiments, each of D1 and D2 are an anabolic
steroid, an androgenic steroid, a progestin steroid, an estrogen
steroid, a cancer treatment steroid, an antibiotic steroid, a
glucocorticoid steroid, a benign steroid, an anti-angiogenic
steroid, an intraocular pressure (IOP) lowering steroid, a cholic
acid-related bile acid steroid, a cholesterol-derivative, other
steroid, a pheromone, a steroid metabolite, a progestin, a
neurosteroid, and a corticosteroid.
[0074] In another embodiment of any of the above coatings, the
compound is further described by one of formulas (II)-(LXXV).
[0075] In still another embodiment of any of the above coatings, D1
and D2 are formed from the same steroid, or D1 and D2 are formed
from different steroids.
[0076] In particular embodiments of any of the above coatings, the
coating includes a mixture of two or more compounds of formula
(A-VIII).
[0077] In other embodiments of any of the above coatings, at least
70% (w/w) of the coating is a compound of formula (A-VIII).
[0078] In other embodiments of any of the above coatings, at least
90% (w/w) of the coating is the compound.
[0079] In an embodiment of any of the above coatings, the compound,
D1, or D2 are released from the coating through surface
erosion.
[0080] In certain embodiments of any of the above coatings, the
surface erosion releases less than 20% (e.g., less than 18%, 15%,
12%, 10%, or 5%) of D1 or D2 (as a percentage of the total drug, D1
or D2, present in the coating in prodrug form) at 37.degree. C. in
100% bovine serum over 5 days, 6 days, 7 days, 8 days, 9 days, 10
days, or 12 days (e.g., less than 10% of D1 or D2 at 37.degree. C.
in 100% bovine serum over 5 days). In other embodiments of any of
the above coatings, the surface erosion releases less than 2.0%
(e.g., less than 1.8%, 1.5%, 1.2%, 1.0%, or 0.5%) of D1 or D2 (as a
percentage of the total drug, D1 or D2, present in the coating 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 D1 or D2 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 D1 or D2 (as a
percentage of the total drug, D1 or D2, 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
D1 or D2 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 D1 or D2 (as a percentage of the total drug, D1 or
D2, 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 D1 or D2 at 37.degree. C. in PBS over 10 days).
In other embodiments, the compound (D1 and/or D2) is released from
the coating at a rate such that t10 is greater than or equal to
1/10 of t.sub.50.
[0081] In certain embodiments, the article further includes from
0.1% to 10% (w/w) of one or more additives, in which the one or
more additives are plasticizers, antioxidants, binders, lubricants,
radio-opaque agents, and mixtures thereof.
[0082] In particular embodiments of any of the above coatings, the
substrate includes a coating formed from a compound of the
disclosure.
[0083] In other embodiments of any of the above coatings, at least
70% (w/w) of the coating is the compound.
[0084] In an embodiment of any of the above coatings, at least 90%
(w/w) of the coating is the compound.
[0085] In an embodiment of any of the above coatings, the coating
has a glassy state and is formed from a compound of the
disclosure.
[0086] The disclosure further features a coating having a glassy
state formed from a compound of the disclosure.
[0087] The disclosure features an implantable medical device
including a coating of the disclosure, in which the coating resides
on the surface of the implantable medical device.
[0088] In an aspect, the disclosure features a compound described
by the formula (A-I):
D1-O-L-O-D2 (A-I),
[0089] or a pharmaceutically acceptable salt thereof, in which each
of D1-O and D2-O is, independently, a radical formed from a
steroid; L is --C(O)--OC(O)--(R.sup.B)--C(O)O--C(O)--; and R.sup.B
is C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to
20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or
branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms, in which the steroid is an anabolic
steroid, an androgenic steroid, a progestin steroid, an estrogen
steroid, a cancer treatment steroid, an antibiotic steroid, a
glucocorticoid steroid, a benign steroid, or a corticosteroid.
[0090] In a related aspect, the disclosure features a compound
described by the formula (A-II):
D1-O-L-O-D2 (A-II),
[0091] or a pharmaceutically acceptable salt thereof, in which each
of D1-O and D2-O is, independently, a radical formed from a
steroid; L is --C(O)O--(R.sup.A)--OC(O)--; in which O--(R.sup.A)--O
is a radical of a polyol and includes at least one free hydroxyl
group, in which the steroid is an anabolic steroid, an androgenic
steroid, a progestin steroid, an estrogen steroid, a cancer
treatment steroid, an antibiotic steroid, a glucocorticoid steroid,
a benign steroid, an anti-angiogenic steroid, an intraocular
pressure (IOP) lowering steroid, a cholic acid-related bile acid
steroid, a cholesterol-derivative, other steroid, a pheromone, a
steroid metabolite, a progestin, a neurosteroid, or a
corticosteroid.
[0092] In another aspect, the disclosure features a compound
described by the formula (A-III):
D1-O-L-O-D2 (A-III),
[0093] or a pharmaceutically acceptable salt thereof, in which each
of D1-O and D2-O is, independently, a radical formed from a
steroid; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--(R.sup.B)--C(O)--, or
--C(O)--OC(O)--(R.sup.B)--C(O)O--C(O)--; R.sup.A is C.sub.1-20
alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a
linear or branched C.sub.2-20 alkenylene, a linear or branched
C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3
to 10 atoms, or O--(R.sup.A)--O is a radical of a polyol and
includes at least one free hydroxyl group or is selected from:
[0094] --O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or --O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O--; n,
m, and p are integers from 1 to 10, and each R.sup.B is
independently C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, in which the
steroid is an anabolic steroid, an androgenic steroid, a progestin
steroid, an estrogen steroid, a cancer treatment steroid, an
antibiotic steroid, a glucocorticoid steroid, an anti-angiogenic
steroid, an intraocular pressure (IOP) lowering steroid, a cholic
acid-related bile acid steroid, a cholesterol-derivative, other
steroid, a pheromone, a steroid metabolite, a progestin, a
neurosteroid, or a benign steroid.
[0095] In a related aspect, the disclosure features a compound
described by the formula (A-IV):
##STR00001##
[0096] or a pharmaceutically acceptable salt thereof, in which L is
--C(O)O--(R.sup.A)--OC(O)--; R.sup.A includes C.sub.1-20 alkylene,
a linear or branched heteroalkylene of 1 to 20 atoms, a linear or
branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20
alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms,
or O--(R.sup.A)--O is a radical of a polyol and includes at least
one free hydroxyl group or O--(R.sup.A)--O is:
--O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O--,
[0097]
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.-
2CH.sub.2O--, or
--O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O--; n, m, and
p are integers from 1 to 10.
[0098] In an embodiment of any of the above aspects,
O--(R.sup.A)--O is a radical of a polyol formed from a cyclitol
(e.g., bornesitol, conduritol, inositol, ononitol, pinitol,
pinpollitol, quebrachitol, quinic acid, shikimic acid, valienol, or
viscumitol), a sugar alcohol (e.g., sorbitol, mannitol, xylitol,
maltitol, lactitol, erythritol, isomalt), or glycerin. In
particular embodiments, the linker L is formed from a polyol and
includes 1, 2, 3, or 4 hydroxyl groups. In another embodiment,
O--(R.sup.A)--O is a radical formed from an alkane diol (e.g., a
C.sub.1-10 diol), diethylene glycol, triethylene glycol,
tetraethylene glycol, or pentaethylene glycol.
[0099] In an embodiment of the above aspects, each of D1-O and D2-O
is, independently, described by any one of formulas (I-a) to
(I-sss), described herein. For example, at least one of D1-O and
D2-O is formed from: (i) an anabolic steroid including from
androisoxazole, androstenediol, bolandiol, bolasterone, clostebol,
ethylestrenol, formyldienol one, 4-hydroxy-19-nortestosterone,
methandriol, methenolone, methyltrienolone, nandrolone,
norbolethone, oxymesterone, stenbolone, and trenbolone; (ii) an
androgenic steroid including boldenone, fluoxymesterone,
mestanolone, mesterolone, methandrostenol one,
17-methyltestosterone, 17-.alpha.-methyltestosterone 3-cyclopentyl
enol ether, norethandrolone, normethandrone, oxandrolone,
oxymesterone, oxymetholone, prasterone, stanlolone, stanozolol,
testosterone, testosterone 17-chloral hemiacetal, testosterone
proprionate, testosterone enanthate tiomesterone
dehydroepiandrosterone (DHEA), androstenedione, androstenediol,
androsterone, dihydrotestosterone (DHT), and androstanolone; (iii)
a progestin steroid including norethisterone, norethisterone
acetate, gestodene, levonorgestrel, allylestrenol, anagestone,
desogestrel, dimethisterone, dydrogesterone, ethisterone,
ethynodiol, ethynodiol diacetate, etonogestrel, gestodene,
ethinylestradiol, haloprogesterone,
17-hydroxy-16-methylene-progesterone, 17 alpha-hydroxyprogesterone,
lynestrenol, medroxyprogesterone, melengestrol, norethindrone,
norethynodrel, norgesterone, gestonorone, norethisterone,
norgestimate, norgestrel, levonorgestrel, norgestrienone,
norvinisterone, pentagestrone, MENT (7-methyl-19-testosterone);
norelgestromin, and trimigestone drospirenone, tibolone, and
megestrol; (iv) an estrogen steroid including estrogen, eguilenin,
equilin, 17.beta.-estradiol, estradiol benzoate, estriol, ethinyl
estradiol, mestranol, moxestrol, mytatrienediol, quinestradiol, and
quinestrol; (v) a glucocorticoid including medrysone,
alclometasone, alclometasone dipropionate, amcinonide,
beclometasone, beclomethasone dipropionate, betamethasone,
betamethasone benzoate, betamethasone valerate, budesonide,
ciclesonide, clobetasol, clobetasol butyrate, clobetasol
propionate, clobetasone, clocortolone, loprednol, cortisol,
cortisone, cortivazol, deflazacort, desonide, desoximetasone,
desoxycortone, desoxymethasone, dexamethasone, diflorasone,
diflorasone diacetate, diflucortolone, diflucortolone valerate,
difluorocortolone, difluprednate, fluclorolone, fluclorolone
acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone
pivalate, flunisolide, flunisolide, fluocinolone, fluocinolone
acetonide, fluocinonide, fluocortin, fluocoritin butyl,
fluocortolone, fluorocortisone, fluorometholone, fluperolone,
fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone,
fluticasone propionate, formocortal, halcinonide, halometasone,
hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate,
hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,
meprednisone, 6.alpha.-methylprednisolone, methylprednisolone,
methylprednisolone acetate, methylprednisolone aceponate,
mometasone, mometasone furoate, mometasone furoate monohydrate,
paramethasone, prednicarbate, prednisolone, prednisone,
prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone
acetonide, and ulobetasol; (vi) a steroid including abiraterone,
cyproterone acetate, dutasteride, enzalutamide, finasteride,
galeterone, fusidic acid, cholesterol, 11-deoxycortisol,
11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic
acid, ursodeoxycholic acid, obeticholic acid, tetrahydrocortisone,
tetrahydrodeoxycortisol, tetrahydrocorticosterone,
5.alpha.-dihydrocorticosterone, and 5.alpha.-dihydropregesterone;
(vii) an anti-angiogenic steroid or an intraocular pressure (IOP)
lowering steroid including anecortave acetate, anecortave,
11-epicortisol, 17.alpha.-hydroxyprogesterone,
tetrahydrocortexolone, and tetrahydrocortisol; (viii) a cholic
acid-related bile acid steroid including deoxycholic acid,
apocholic acid, dehydrocholic acid, glycochenodeoxycholic acid,
glycocholic acid, glycodeoxycholic acid, hyodeoxycholic acid,
lithocholic acid, .alpha.-muricholic acid, .beta.-muricholic acid,
.gamma.-muricholic acid, .omega.-muricholic acid,
taurochenodeoxycholic acid, taurocholic acid, taurodeoxycholic
acid, taurolithocholic acid, and tauroursodeoxycholic acid; (ix) a
neurosteroid including alphaxalone, alphadolone, hydroxydione,
minaxolone, tetrahydrodeoxycorticosterone, allopregnanolone,
pregnanolone, ganoxolone, 3.alpha.-androstanediol, epipregnanolone,
isopregnanolone, and 24(S)-hydroxycholesterol; (x) other steroid
including flugestone, prebediolone, chlormadinone acetate,
medrogestone, and segesterone acetate; (xi) a pheromone including
androstadienol, androstadienone, androstenol, androstenone,
estratetraenol, 5-dehydroprogesterone, 6-dehydro-retroprogesterone,
allopregnanolone, and hydroxyprogesterone caproate; (xii) a steroid
metabolite including tetrahydrotriamcinolone, cortienic acid,
11-dehydrocorticosterone, 11.beta.-hydroxypregnenolone,
ketoprogesterone, 17-hydroxypregnenolone,
17,21-dihydroxypregnenolone, 18-hydroxycorticosterone,
deoxycortisone, 21-hydroxypregnenolone, and progesterone; or (xiii)
a progestin including allopregnone-3.alpha.,20.alpha.-diol,
allopregnone-3.beta.,20.beta.-diol,
allopregnane-3.beta.,21-diol-11,20-dione,
allopregnane-3.beta.,17.alpha.-diol-20-one,
3,20-allopregnanedione,3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol,
allopregnane-3.beta.,17.alpha.,20.beta.,21-tetrol,
allopregnane-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,17.alpha.,20.beta.-triol,
allopregnane-3.beta.,17.alpha.,21-triol-11,20-dione,
allopregnane-3.beta.,11.beta.,21-triol-20-one,
allopregnane-3.beta.,17.alpha.,21-triol-20-one,
allopregnane-3.alpha.-ol-20-one, allopregnane-3.beta.-ol-20-one,
pregnanediol, 3,20-pregnanedione, 4-pregnene-20,21-diol-3,11-dione,
4-pregnene-11.beta.,17.alpha.,20.beta.,21-tetrol-3-one,
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione,
4-pregnene-17.alpha.,20.beta.,21-triol-3-one, and pregnenolone.
[0100] In a related aspect, the disclosure features a compound
described by the formula (A-VI):
D1-C(O)-L-C(O)-D2 (A-VI),
[0101] or a pharmaceutically acceptable salt thereof, in which each
of D1-C(O) and D2-C(O) is, independently, a radical formed from a
steroid; L is --O--(R.sup.A)--O-- or
--OC(O)--O--(R.sup.A)--O--C(O)O--; R.sup.A is C.sub.1-20 alkylene,
a linear or branched heteroalkylene of 1 to 20 atoms, a linear or
branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20
alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms,
or O--(R.sup.A)--O is a radical of a polyol and includes at least
one free hydroxyl group or O--(R.sup.A)--O is:
--O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O--,
[0102] --O(CH2CH2CH2CH2O)mCH2CH2CH2CH2O--, or
--O(CH2CH(CH3)O)pCH2CH(CH3)O--; and n, m, and p are integers from 1
to 10.
[0103] In an embodiment of the compounds of formula (A-VI),
O--(R.sup.A)--O is a radical of a polyol formed from a cyclitol
(e.g., bornesitol, conduritol, inositol, ononitol, pinitol,
pinpollitol, quebrachitol, quinic acid, shikimic acid, valienol, or
viscumitol), a sugar alcohol (e.g., sorbitol, mannitol, xylitol,
maltitol, lactitol, erythritol, isomalt), or glycerin. In
particular embodiments, the linker L is formed from a polyol and
includes 1, 2, 3, or 4 hydroxyl groups. In another embodiment,
O--(R.sup.A)--O is a radical formed from an alkane diol (e.g., a
C1-10 diol), diethylene glycol, triethylene glycol, tetraethylene
glycol, or pentaethylene glycol.
[0104] The disclosure further features a compound described by the
formula (A-VII):
D1-C(O)-L-C(O)-D2 (A-VII),
[0105] or a pharmaceutically acceptable salt thereof, in which each
of D1-C(O) and D2-C(O) is, independently, a radical formed from a
steroid; L is --O--C(O)--O--(R.sup.A)--O--C(O)--O--; and R.sup.A is
C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20
atoms, a linear or branched C.sub.2-20 alkenylene, a linear or
branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms.
[0106] In particular embodiments of the compounds of formulas
(A-VI) and (A-VII), at least one of D1-C(O) and D2-C(O) is formed
from fusidic acid, cholic acid, chenodeoxycholic acid,
ursodeoxycholic acid, or obeticholic acid.
[0107] In an embodiment of any of the above compounds: (i) each of
D1-O and D2-O are formed from the same steroid, (ii) each of
D1-C(O) and D2-C(O) are formed from the same steroid, (iii) each of
D1-O and D2-0 are formed from different steroids, or (iv) each of
D1-C(O) and D2-C(O) are formed from different steroids.
[0108] In a particular embodiment of any of the above compounds,
R.sup.A is a C.sub.1-10 alkylene.
[0109] In still another embodiment of any of the above compounds
upon hydrolysis D1 and D2 form corticosteroids including
alclometasone, beclomethasone, betamethasone, betamethasone
valerate, budesonide, chloroprednisone, cloprednol, corticosterone,
cortisone, desonide, desoximerasone, dexamethasone, diflorasone,
diflucortolone, enoxolone, flucloronide, flumethasone, flunisolide,
fluocinolone acetonide, fluocortolone, fluprednisolone,
flurandrenolide, halometasone, hydrocortisone, hydrocortisone
butyrate, meprednisone, methylprednicolone, paramethasone,
prednisolone, prednisone, prednival, prednylidene, triamcinolone,
and triamcinolone acetonide.
[0110] In another embodiment of any of the above compounds, the
compound is further described by one of formulas (II)-(LXXV),
described herein.
[0111] In still another embodiment of any of the above compounds,
R.sup.A is --(CH.sub.2CH.sub.2O).sub.qCH.sub.2CH.sub.2--, q is an
integer of 1 to 10, and upon hydrolysis each of D1 and D2,
independently, form dexamethasone, triamcinolone, betamethasone,
prednisolone, prednisone, fluocinolone, fluocinolone acetonide,
mometosone, mometosone furoate, anecoratve, hydrocortisone,
triamcinolone acetonide, abiraterone, fusidic acid, or
cholesterol.
[0112] Articles of the disclosure can be formed by the steps of (a)
heating a compound of formula (A-VIII) above its melting point
(e.g., depending upon the compound, heating to 110-145.degree. C.,
130-185.degree. C., 150-215.degree. C., or 180-240.degree. C.) to
form a melt, and (b) cooling the melt to form an article. The
article can be shaped during step (a), prior to cooling, by
pressing the melt into a mold, by extruding the melt from an
orifice (e.g., to form a cylinder or another shape), or by forming
droplets of the melt and allowing the droplets to cool into glassy
state droplets. Fibers can be formed by spinning (e.g. melt
spinning, heat spinning, or electrospinning), or pulling the melt
(e.g., with tweezers) at different rates to yield glassy state
fibers of different diameters.
[0113] Alternatively, articles of the disclosure can be formed by
the steps of (a) dissolving a compound of formula (A-VIII) in a
volatile organic solvent (e.g., acetone, methanol, dichloromethane,
tetrahydrofuran, chloroform, or mixtures thereof) to form a
solution, and (b) removing the organic solvent to form an article.
The article can be shaped during step (b), prior to completely
removing the organic solvent, by electrospraying, electrospinning,
or fiber spinning the solution. For example, a 50:50 v/v mixture of
dichloromethane/tetrahydrofuran at 100% wt/v solution of the
compound can be loaded at a rate of 0.5 mL/h and electrospun onto a
cylindrical mandrel rotating at 1150 rpm, forming aligned glassy
state fibers. Fibers can be also formed by wet, dry, or gel
spinning to form glassy state fibers of different diameters.
Microparticles can be prepared by electrospraying a solution
containing the compound at a concentration of about 20% to 40% w/v
or 25% to 50% w/v of the solution. Nanoparticles can be prepared by
electrospraying a solution containing the compound at a
concentration of about 3% to 15% w/v or 5% to 18% w/v of the
solution. Alternatively, a shaped article can be formed by placing
the solution in a mold and evaporating the volatile organic solvent
to form a shaped article.
[0114] The disclosure features a method for forming an article
including a compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0115] or a pharmaceutically acceptable salt thereof, wherein each
of D1 and D2 is, independently, a radical formed from a steroid;
and L is a linker covalently linking D1 to D2, and wherein the
article is formed by a process including the steps of: (a) heating
the compound, or a pharmaceutically acceptable salt thereof, 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. Step (c) can include extruding, molding, blow
molding, heat spinning, electrospinning, or electrospraying the
glassy state composition to form the shaped article. In particular
embodiments, the method forms an article that is free of controlled
release excipient, free of a crystallization inhibiting excipient,
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.
[0116] In a related aspect, the disclosure features a method of
forming an article including a compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0117] or a pharmaceutically acceptable salt thereof, wherein each
of D1 and D2 is, independently, a radical formed from a steroid;
and L is a linker covalently linking D1 to D2, and wherein the
article is formed by a process including the steps of: (a)
dissolving the compound, or a pharmaceutically acceptable salt
thereof, 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. Step (c) can
include extruding, molding, blow molding, heat spinning,
electrospinning, or electrospraying the glassy state composition to
form the shaped article. 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.
In a further aspect, the disclosure features a method of forming an
article comprising a compound of formula (A-VIII):
D1-L-D2 (A-VIII)
[0118] or a pharmaceutically acceptable salt thereof, wherein each
of D1 and D2 is, independently, a radical formed from a steroid;
and L is a linker covalently linking D1 to D2, and wherein the
article is formed by a process comprising the steps of: (a)
dissolving the compound, or a pharmaceutically acceptable salt
thereof, 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. 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.
[0119] In some embodiments of the methods of the disclosure, the
compound is processed as described herein (e.g., melt processed or
solvent processed) to form a glassy state solid. The glassy state
solid is subsequently heated above its glass transition
temperature, Tg, and molded or extruded to form a 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.
[0120] In some embodiments of the methods and compositions of the
disclosure, the article is free of controlled release
excipient.
[0121] In particular embodiments of the methods and compositions of
the disclosure, the article is free of a crystallization inhibiting
excipient
[0122] In certain embodiments of the methods and compositions of
the disclosure, the article is free of a mechanical integrity
enhancing excipient.
[0123] In yet further embodiments of the methods and compositions
of the disclosure, the article is free of a binding excipient.
[0124] In another aspect, the disclosure features Compound 3. The
disclosure further features a pharmaceutical composition comprising
Compound 3 and a pharmaceutically acceptable excipient.
[0125] In another aspect, the disclosure features Compound 17. The
disclosure further features a pharmaceutical composition comprising
Compound 17 and a pharmaceutically acceptable excipient.
Definitions
[0126] 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 steroid 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).
[0127] 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 steroid dimer in the article in comparison to
the amount of crystalline steroid 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.
[0128] 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, where the release profile is measured at
37.degree. C. in 100% FBS. 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.
[0129] 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 steroid 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.
[0130] The term "anti-angiogenic steroid" refers to a steroid that
halts the process of developing new blood vessels (i.e.,
angiogenesis). Examples of anti-angiogenic steroids include
anecortave acetate, anecortave, 11-epicortisol,
17.alpha.-hydroxyprogesterone, tetrahydrocortexolone, and
tetrahydrocortisol.
[0131] The term "benign steroid" as used herein, refers to low
glucocorticoid activity and low mineralcorticoid activity. Benign
steroids include, without limitation, cholesterol, bile acids (such
as cholic acid), and phytosterols (such as beta-sitosterol).
Exemplary benign steroids include cholesterol, 11-deoxycortisol,
11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic
acid, ursodeoxycholic acid, obeticholic acid, tetrahydrocortisone,
tetrahydrodeoxycortisol, tetrahydrocorticosterone,
5.alpha.-dihydrocorticosterone, and
5.alpha.-dihydropregesterone.
[0132] The term "cholesterol-derivative" refers to steroids that
are derived from cholesterol. Examples of cholesterol-derivatives
are 22R-hydroxycholesterol, and
20.alpha.-22R-dihydroxycholesterol.
[0133] The term "cholic acid-related bile acid steroid" refers to a
steroid that is derived from cholic acid. Examples of cholic
acid-related bile acid steroids are deoxycholic acid, apocholic
acid, dehydrocholic acid, glycochenodeoxycholic acid, glycocholic
acid, glycodeoxycholic acid, hyodeoxycholic acid, lithocholic acid,
.alpha.-muricholic acid, .beta.-muricholic acid, .gamma.-muricholic
acid, .omega.-muricholic acid, taurochenodeoxycholic acid,
taurocholic acid, taurodeoxycholic acid, taurolithocholic acid, and
tauroursodeoxycholic acid.
[0134] 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.
[0135] 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.
[0136] 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.
[0137] 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 drug 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 drug dimers.
[0138] The term "intraocular pressure (IOP) lowering steroid"
refers to a steroid that lowers the intraocular pressure. Examples
of intraocular pressure (IOP) lowering steroids are anecortave
acetate, anecortave, 11-epicortisol, 17.alpha.-hydroxyprogesterone,
tetrahydrocortexolone, and tetrahydrocortisol.
[0139] 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" refers to a microparticle
that is spherical.
[0140] 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.
[0141] The term "neurosteroid" refers to an endogenous or exogenous
steroid that rapidly alters neuronal excitability through
interaction with ligand-gated ion channels and other cell surface
receptors. Exemplary neurosteroids are alphaxalone, alphadolone,
hydroxydione, minaxolone, tetrahydrodeoxycorticosterone,
allopregnanolone, pregnanolone, ganoxolone,
3.alpha.-androstanediol, epipregnanolone, isopregnanolone, and
24(S)-hydroxycholesterol.
[0142] The term "non-woven fabric," as used herein, refers to a web
structure bonded together by entangling fibers.
[0143] The term "other steroid" refers to a compound that has a
steroid-based structure. Examples of ther steroids are flugestone,
prebediolone, chlormadinone acetate, medrogestone, and segesterone
acetate.
[0144] 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.
[0145] The term "pharmaceutically acceptable salt" as used herein,
represents those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and animals without undue toxicity, irritation, allergic response
and the like and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge et al. describe pharmaceutically
acceptable salts in detail in J. Pharm. Sci. 66:1-19, 1977. The
salts can be prepared in situ during the final isolation and
purification of the compounds of the disclosure or separately by
reacting the free base group with a suitable organic acid.
Representative acid addition salts include acetate, adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphersulfonate,
carbonate, chloride, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,
glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,
hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate,
toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like, as well as
nontoxic ammonium, quaternary ammonium, and amine cations,
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like.
[0146] The term "pheromone" refers to a steroid hormone. Examples
of pheromones are androstadienol, androstadienone, androstenol,
androstenone, estratetraenol, 5-dehydroprogesterone,
6-dehydro-retroprogesterone, allopregnanolone, and
hydroxyprogesterone caproate.
[0147] The term "steroid metabolite" refers to a product of
metabolism of a steroid. Examples of steroid metabolites are
tetrahydrotriamcinolone, cortienic acid, 11-dehydrocorticosterone,
11.beta.-hydroxypregnenolone, ketoprogesterone,
17-hydroxypregnenolone, 17,21-dihydroxypregnenolone,
18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone,
and progesterone.
[0148] The term "progestin" refers to a natural or synthetic
steroid hormone. Examples of progestins are
allopregnone-3.alpha.,20.alpha.-diol,
allopregnone-3.beta.,20.beta.-diol,
allopregnane-3.beta.,21-diol-11,20-dione,
allopregnane-3.beta.,17.alpha.-diol-20-one, 3,20-allopregnanedione,
3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol,
allopregnane-3.beta.,17.alpha.,20.beta.,21-tetrol,
allopregnane-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,17.alpha.,20.beta.-triol,
allopregnane-3.beta.,17.alpha.,21-triol-11,20-dione,
allopregnane-3.beta.,11.beta.,21-triol-20-one,
allopregnane-3.beta.,17.alpha.,21-triol-20-one,
allopregnane-3.alpha.-ol-20-one, allopregnane-3.beta.-ol-20-one,
pregnanediol, 3,20-pregnanedione, 4-pregnene-20,21-diol-3,11-dione,
4-pregnene-11.beta.,17.alpha.,20.beta.,21-tetrol-3-one,
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione,
4-pregnene-17.alpha.,20.beta.,21-triol-3-one, and pregnenolone.
[0149] 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
drug dimer. Surface erosion can be tailored to achieve desired drug
release rates. Surface erosion can depend on the drug composition
of the drug dimer, and can be modulated by the cleavage of
drug-linker bond through hydrolysis and/or enzymatic degradation.
The rate of surface erosion and release of a given drug from a drug
dimer may also depend on the quantity of the loaded drug dimer as a
percent of the final drug dimer formulation, article size (e.g.
dimensions), solubility of drug dimer (e.g., through selection of
appropriate drug and/or 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.
[0150] As used herein, "t50" is the time at which 50% of the
releasable drug has been released from an article of the
disclosure. Time t10 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, t10=1/5 of
t50. When there is an initial burst of released drug, t10 is much
less than 1/5 of t50. In the compositions and methods of the
disclosure t10 can be equal to or greater than 1/10 of t50. 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.
[0151] The term "woven fabric," as used herein, refers to
pharmaceutical compositions that resemble materials that are formed
by weaving of fibers.
Chemical Definitions
[0152] By "acyl" is meant a chemical moiety with the formula
C(O)R', where R' is selected from the group consisting of
C.sub.1-10 alkyl, C.sub.2-20 alkene, heteroalkyl, C.sub.2-20
alkyne, C.sub.5-10 aryl, and cyclic system. Examples of acyl groups
include, without limitation, acetyl, propanoyl, butanoyl,
pentanoyl, and tetrahydrofuran-2-oyl.
[0153] By "aliphatic" is meant a non-aromatic chemical moiety of
hydrocarbons. Aliphatics may be cyclic, straight, or branched
chains, and may be saturated or unsaturated, and may have single,
double, or triple bonds.
[0154] By "alkoxy" is meant a chemical substituent of the formula
--OR, wherein R is an alkyl group. By "aryloxy" is meant a chemical
substituent of the formula --OR, wherein R is a C.sub.5-10 aryl
group.
[0155] As used herein, the terms "alkylene," "alkenylene,"
"alkynylene," and the prefix "alk" refer to divalent groups having
a specified size, typically C1-10 or C.sub.1-20 for the saturated
groups (e.g., alkylene or alk) and C.sub.2-20 or C.sub.2-20 for the
unsaturated groups (e.g., alkenylene or alkynylene). They include
straight-chain, branched-chain, and cyclic forms as well as
combinations of these, containing only C and H when unsubstituted.
Because they are divalent, they can link together two parts of a
molecule. Examples are methylene, ethylene, propylene,
cyclopropan-1,1-diyl, ethylidene, 2-butene-1,4-diyl, and the like.
These groups can be substituted by the groups typically suitable as
substituents for alkyl, alkenyl and alkynyl groups as set forth
herein. Thus C.dbd.O is a C1 alkylene that is substituted by
.dbd.O, for example.
[0156] By "alkylthio" is meant a chemical substituent of the
formula --SR, wherein R is an alkyl group.
[0157] By "arylthio" is meant a chemical substituent of the formula
--SR, wherein R is a C.sub.5-10 aryl group.
[0158] By "C.sub.1-20 alkyl" is meant a branched or unbranched
saturated hydrocarbon group, having 1 to 20 carbon atoms,
inclusive. An alkyl may optionally include monocyclic, bicyclic, or
tricyclic rings, in which each ring desirably has three to six
members. The alkyl group may be substituted or unsubstituted.
Exemplary substituents include alkoxy, aryloxy, sulfhydryl,
alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl,
amino, aminoalkyl, disubstituted amino, quaternary amino,
hydroxyalkyl, carboxyalkyl, and carboxyl groups.
[0159] By "C.sub.2-20 alkene" is meant a branched or unbranched
hydrocarbon group containing one or more double bonds, desirably
having from 2 to 10 carbon atoms. A C.sub.2-20 alkene may
optionally include monocyclic, bicyclic, or tricyclic rings, in
which each ring desirably has five or six members. The C.sub.2-20
alkene group may be substituted or unsubstituted. Exemplary
substituents include alkoxy, aryloxy, sulfhydryl, alkylthio,
arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino,
aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl,
carboxyalkyl, and carboxyl groups.
[0160] By "C.sub.2-20 alkyne" is meant a branched or unbranched
hydrocarbon group containing one or more triple bonds, desirably
having from 2 to 10 carbon atoms. A C.sub.2-20 alkyne may
optionally include monocyclic, bicyclic, or tricyclic rings, in
which each ring desirably has five or six members. The C.sub.2-20
alkyne group may be substituted or unsubstituted. Exemplary
substituents include alkoxy, aryloxy, sulfhydryl, alkylthio,
arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino,
aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl,
carboxyalkyl, and carboxyl groups.
[0161] By "carbonate ester" is meant a linkage group having the
formula --C(O)O--C(O)--O--.
[0162] By "carboxyalkyl" is meant a chemical moiety with the
formula
[0163] --(R)--COOH, wherein R is an alkyl group.
[0164] By "cyclic acetal" is meant a ring structure including two
oxygen atoms separated by a carbon atom which is optionally
substituted (e.g., 1,3-dioxolane). Exemplary substituents include,
without limitation, alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl,
alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl,
amino, aminoalkyl, monosubstituted amino, disubstituted amino,
quaternary amino, phosphodiester, phosphoramidate, phosphate,
phosphonate, phosphonate ester, sulfonate, sulfate, sulfhydryl,
phenol, amidine, guanidine, and imidazole groups.
[0165] The term "cyclic system" refers to a compound that contains
one or more covalently closed ring structures, in which the atoms
forming the backbone of the ring are composed of any combination of
the following: carbon, oxygen, nitrogen, sulfur, and phosphorous.
The cyclic system may be substituted or unsubstituted. Exemplary
substituents include, without limitation, alkyl, hydroxyl, alkoxy,
aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl,
carboxyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino,
disubstituted amino, and quaternary amino groups.
[0166] By "fluoroalkyl" is meant an alkyl group that is substituted
with a fluorine.
[0167] By "heteroalkyl" is meant a branched or unbranched alkyl
group in which one or more methylenes (--CH2-) are replaced by
nitrogen, oxygen, sulfur, carbonyl, thiocarbonyl, phosphoryl, or
sulfonyl moieties. Some examples include tertiary amines, ethers,
thioethers, amides, thioamides, carbamates, thiocarbamates,
phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may
optionally include monocyclic, bicyclic, or tricyclic rings, in
which each ring desirably has three to six members. The heteroalkyl
group may be substituted or unsubstituted. Exemplary substituents
include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen,
hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl,
disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl,
and carboxyl groups.
[0168] By "hydroxyalkyl" is meant a chemical moiety with the
formula --(R)--OH, wherein R is an alkyl group.
BRIEF DESCRIPTION OF THE DRAWINGS
[0169] FIG. 1A to FIG. 1F are a series of images and a graph
showing Compound 1 (dexamethasone-triethylene glycol-dexamethasone,
Dex-TEG-Dex) formed into pellets in the glassy state and drug
release through surface erosion from an intact pellet.
[0170] FIG. 2A to FIG. 2E are a series of images showing Compound 1
(Dex-TEG-Dex) processed into different glassy state forms by
multiple processing methods from the melt state.
[0171] FIG. 3A to FIG. 3K are a series of images showing Compound 1
(Dex-TEG-Dex) processed into different glassy state forms by
multiple processing methods from the solution state.
[0172] FIG. 4 is a graph showing cumulatie drug release from a
coating of Compound 1 (Dex-TEG-Dex) from titanium and
poly(styrene-block-isobutylene-block-styrene) (SIBS) over time.
[0173] FIG. 5 is a graph showing rate of drug release of Compound 1
(Dex-TEG-Dex) pellets.
[0174] FIG. 6 is an image and a graph showing mechanical testing of
extruded cylinders of Compound 1 (Dex-TEG-Dex) using a 3-point bend
test.
[0175] FIG. 7A and FIG. 7B are a series of graphs showing pre- and
post-ETO sterilized pellets analyzed by HPLC to determine change in
pellet purity, and drug release to identify changes in release
properties due to the ETO sterilization process.
[0176] FIG. 8A to FIG. 8F are a series of images and graphs showing
Compound 1 formed into heat extruded cylinders (FIGS. 8A-8D),
purity of extrudate over time (FIG. 8E), and coating formed from
Compound 1 (FIG. 8F).
[0177] FIG. 9A to FIG. 9E are a series of images and a graph
showing Compound 2 (Hydrocortisone-Triethylene
Glycol-Hydrocortisone, HC-TEG-HC) formed into heat-molded pellets,
fibers, and extruded cylinders, as well as drug release over
time.
[0178] FIG. 10A to FIG. 10E are a series of images and a graph
showing Compound 3 (Triamcinolone Acetonide-Triethylene
Glycol-Triamcinolone Acetonide, TA-TEG-TA) formed into heat-molded
pellets, fibers, and extruded cylinders, as well as drug release
over time.
[0179] FIG. 11A to FIG. 11C are an image and a graph showing
Compound 4 (Dexamethasone-Triethylene Glycol-Hydrocortisone,
Dex-TEG-HC) formed into heat-molded pellets and drug release over
time.
[0180] FIG. 12A to FIG. 12E are a series of images and a graph
showing Compound 5 (Dexamethasone-Hexane-Dexamethasone,
Dex-HEX-Dex) formed into heat-molded pellets, fibers, and extruded
cylinders, as well as drug release over time.
[0181] FIG. 13A to FIG. 13E are a series of images and a graph
showing Compound 6 (Hydrocortisone-Succinate-Hydrocortisone,
HC-SUCC-HC) formed into heat-molded pellets and fibers, as well as
drug release over time.
[0182] FIG. 14A to FIG. 14E are an image and a graph showing
Compound 7 (Anecortave-Triethylene Glycol-Anecortave,
Anec-TEG-Anec) formed into heat-molded pellets and drug release
over time.
[0183] FIG. 15A to FIG. 15C are an image and a graph showing
Compound 8 (Dexamethasone-Pentaethylene Glycol-Dexamethasone,
Dex-EGS-Dex) formed into heat-molded pellets and drug release over
time.
[0184] FIG. 16A to FIG. 16E are a series of images and a graph
showing Compound 9 (Fusidic Acid-Triethylene Glycol-Fusidic Acid
(carbonate ester), FA-TEG-FA (CE)) formed into heat-molded pellets
and fibers, as well as drug release over time.
[0185] FIG. 17A to FIG. 17D are a series of images and a graph
showing Compound 10 (Dexamethasone-Polyethylene Glycol
(MW=200)-Dexamethasone, Dex-PEG200-Dex) formed into heat-molded
pellets and extruded cylinders, as well as drug release over
time.
[0186] FIG. 18A to FIG. 18G are a series of images and graphs
showing nano- and micro-particle formation of Compounds 3 and 5 and
cumulative drug release for Compound 3 over time.
[0187] FIG. 19A and FIG. 19B are an image and a graph showing a
mixture of Compounds 1 and 2 formed into heat-molded pellets and
drug release over time.
[0188] FIG. 20A and FIG. 20B are an image and a graph showing a
mixture of Compounds 1 and 3 formed into heat-molded pellets and
drug release over time.
[0189] FIG. 21A and FIG. 21B are an image and a graph showing a
mixture of Compounds 2 and 3 formed into heat-molded pellets and
drug release over time.
[0190] FIG. 22A to FIG. 22C are a series of graphs showing
hydrocortisone release from heat-molded pellets formed from
Compounds 2, 4, 6, or 1 & 2 over time (FIG. 22A), dexamethasone
release from heat-molded pellets formed form Compounds 1, 4, or 1
& 2 over time (FIG. 22B), or dexamethasone release from
heat-molded pellets formed from Compounds 1 and 5 over time (FIG.
22C).
[0191] FIG. 23A to FIG. 23D are a series of images and a graph
showing Compound 11 (Dexamethasone-Heptaethylene
Glycol-Dexamethasone, Dex-EG7-Dex) formed into heat-molded pellets
and extruded cylinders, and the extruded cylinders after two weeks
in PBS at 37.degree. C.
[0192] FIG. 24A to FIG. 24D are a series of images and a graph
showing Compound 12 (Dexamethasone-Nonaethylene
Glycol-Dexamethasone, Dex-EG9-Dex) formed into heat-molded pellets
and extruded cylinders, and the extruded cylinders after two weeks
in PBS at 37.degree. C.
[0193] FIG. 25A to FIG. 25D are a series of images and a graph
showing Compound 13 (Dexamethasone-Polyethylene Glycol
(MW=300)-Dexamethasone, Dex-PEG300-Dex) formed into heat-molded
pellets and extruded cylinders, and the extruded cylinders after
two weeks in PBS at 37.degree. C.
[0194] FIG. 26A and FIG. 26B are a series of images and graphs
showing physical form (geometric shape) changes and drug release
from heat-molded pellets for Compounds 11 and 12 over time.
[0195] FIG. 27A to FIG. 27C are a series of images showing Compound
14 (Cholesterol-Triethylene Glycol-Cholesterol, CHS-TEG-CHS) formed
into heat-molded pellets and fibers.
[0196] FIG. 28A to FIG. 28C are a series of images showing Compound
15 (Fusidic Acid-Triethylene Glycol-Fusidic Acid (ester), FA-TEG-FA
(E)) formed into heat-molded pellets and fibers.
[0197] FIG. 29A and FIG. 29B is an image showing Compound 16
(Ethinylestradiol-Triethylene Glycol-Ethinylestradiol,
Ethin-TEG-Ethin) formed into heat-molded pellets.
[0198] FIG. 30A to FIG. 30C are a series of images showing Compound
17 (Prednisolone-Triethylene Glycol-Prednisolone, Pred-TEG-Pred)
formed into heat-molded pellets and fibers.
DETAILED DESCRIPTION
[0199] 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.
[0200] 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).
[0201] It is recognized in this disclosure that there is an unmet
need for a sustained release drug system that is formulated to
release a drug 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 drug and minimizes side effects associated with the
use of carriers or matrices.
[0202] This disclosure describes prodrug dimers that can be in a
crystallizable 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, when formed from anti-inflammatory steroids, can have
inherent anti-inflammatory activity from the drugs being released
from the prodrug shaped form.
[0203] The compounds of the disclosure can be designed for the
controlled and sustained release of a steroid drug from the prodrug
dimer used to make the shaped article. The release rate from an
article of the disclosure can be controlled through several
engineerable design parameters, including: 1) selection of the
steroid drug; 2) selection of the functional group of the drug for
conjugatation (e.g., if multiple exist); 3) selection of the
linker; 4) selection of the linkage group (i.e., esters,
carbonates, carbonate esters, or anhydrides); 5) selection of the
surface area of the shaped article; and 6) selection of the drug
loading in the shaped article (e.g., by adding traditional
pharmaceutical excipients or mixing other steroid dimers as
excipients when making the shaped article). This disclosure can
also be applied to the controlled release of two or more steroid
drugs through the use of heterodimers (i.e., different steroid
drugs on the two ends of the linkers), or by forming shaped
articles with mixtures of two or more steroid homodimers, steroid
heterodimers, or a mixture of both steroid homodimers and steroid
heterodimers. Articles formed from the compounds of the disclosure
can yield sustained and uniform release of the steroid compounds,
without exhibiting any burst release (e.g., t10 can be equal to or
greater than 1/10 of t50) 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 steroid drug for periods of days to
weeks to months or even years.
[0204] The disclosure features compounds of formula (A-VIII) and
articles formed from compounds of formula (A-VIII):
D1-L-D2 (A-VIII)
[0205] or a pharmaceutically acceptable salt thereof, wherein each
of D1 and D2 is, independently, a radical formed from a steroid;
and L is a linker covalently linking D1 to D2. Each of D1 and D2
can be, independently, formula selected from an anabolic steroid,
an androgenic steroid, a progestin steroid, an estrogen steroid, a
cancer treatment steroid, an antibiotic steroid, a glucocorticoid
steroid, a benign steroid, or a corticosteroid. L can be covalently
linked to D1 and to D2 via one or more ester, carbonate, carbonate
ester, or anhydride linkages. Ester, carbonate, carbonate ester, or
anhydride linkages formed from a functional group on D1 and D2 can
be selected from, e.g., hydroxyl or carboxy. For example, L can
include the radical --C(O)--(R.sup.A)--C(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or --O--(R.sup.A)--O--,
where R.sup.A is a radical of a polyol and includes at least one
free hydroxyl group or R.sup.A is selected from C.sub.1-20
alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a
linear or branched C.sub.2-20 alkenylene, a linear or branched
C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3
to 10 atoms, --(CH.sub.2CH.sub.2O)qCH.sub.2CH.sub.2--,
--(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2CH.sub.2CH.sub-
.2--, or --(CH.sub.2CH(CH.sub.3)O).sub.sCH.sub.2CH(CH.sub.3)--, and
q, r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5
to 10). The articles of the disclosure can be machined, molded,
emulsion-processed, electrospun, electrosprayed, blow molded, dry
spun, heat spun, melt spun, gel spun, 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 another shaped article.
[0206] The compound can be further described by the II),
D1-O-L-O-D2 (A-II),
[0207] or a pharmaceutically acceptable salt thereof, wherein each
of D1-O and D2-O is, independently, a radical formed from a
steroid.
[0208] In some embodiments, each of D1-O and D2-O is,
independently, described by any one of formulas (I-a) to
(I-SSS):
##STR00002##
[0209] where the bond between C.sub.1 and C.sub.2, C.sub.4 and
C.sub.5, C.sub.5 and C.sub.6, C.sub.9 and C.sub.10, and C.sub.11
and C.sub.12 is a single or a double bond; R1 represents H,
CH.sub.3, or HC(O); R.sub.2 represents .dbd.O, OH, or H; or R1 and
R.sub.2 taken together with carbons to which they are attached form
an isoxazole; R3 represents H, a halogen atom, or OH; R.sub.6
represents H or CH.sub.3; R.sub.12 represents H, CH.sub.3, or
CH.sub.3CH2; R13 represents CH.sub.3 or CH.sub.3CH2; R.sub.15
represents H or OH; R.sub.17 represents H or CH.sub.3; and R18
represents H or CH.sub.3;
##STR00003##
[0210] where the bond between C.sub.1 and C.sub.2, C.sub.4 and
C.sub.5, C.sub.5 and C.sub.6, C.sub.9 and C.sub.10, and C.sub.11
and C.sub.12 is a single or a double bond; R1 represents H,
CH.sub.3, or HC(O); R.sub.3 represents H, a halogen atom, or OH;
R.sub.6 represents H or CH.sub.3; R.sub.12 represents H, CH.sub.3,
or CH.sub.3CH2; R.sub.13 represents CH.sub.3 or CH.sub.3CH2;
R.sub.15 represents H or OH; R.sub.17 represents H or CH.sub.3; and
R.sub.18 represents H or CH.sub.3;
##STR00004##
[0211] where R.sub.12 represents H or CH.sub.3; and R.sub.17
represents H or CH.sub.3;
##STR00005##
[0212] where the bond between C.sub.1 and C.sub.2, C.sub.4 and
C.sub.5, and C.sub.5 and C.sub.6 is a single or a double bond;
C.sub.2 is O, C or CH.sub.2; R.sub.1 represents H, --CHOH, or is
absent; R.sub.2 represents .dbd.O or OH; or R.sub.1 and R.sub.2
taken together with carbons to which they are attached form a
pyrazole; R.sub.3 represents H or OH; R.sub.12 represents H,
CH.sub.3, optionally substituted alkynylene, C.sub.1-6 alkoxy, or
CH.sub.3CH.sub.2; R.sub.15 represents H or OH; R.sub.16 represents
H or a halogen atom; R.sub.17 represents H or CH.sub.3; and
R.sub.18 represents H or CH.sub.3;
##STR00006##
[0213] where the bond between C.sub.2 and C.sub.2, C.sub.4 and
C.sub.5, and C.sub.5 and C.sub.6 is a single or a double bond;
C.sub.2 is O, C or CH.sub.2; R.sub.1 represents H, --CHOH, or is
absent; R.sub.3 represents H or OH; R.sub.11 represents H, OH,
CH.sub.3, optionally substituted alkynylene, CH.sub.3CH2, .dbd.O,
--OC(O)CH2CH.sub.3, or is absent; R.sub.12 represents H, OH,
CH.sub.3, optionally substituted alkynylene, CH.sub.3CH.sub.2,
.dbd.O, --OC(O)CH.sub.2CH.sub.3, or is absent; R.sub.15 represents
H or OH; R.sub.16 represents H or a halogen atom; R.sub.17
represents H or CH.sub.3; and R.sub.18 represents H or
CH.sub.3;
##STR00007##
[0214] where the bond between C.sub.1 and C.sub.10, C.sub.2 and
C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and C.sub.5, C.sub.5 and
C.sub.6, C.sub.6 and C.sub.7, C.sub.5 and C.sub.10, C.sub.9 and
C.sub.10, C.sub.11 and C.sub.12, C.sub.15 and C.sub.16 is a single
or a double bond; R.sub.2 represents H, .dbd.O, OH, --NOH, or
C.sub.1-6 alkoxy; R.sub.5 represents H, CH.sub.3, or a halogen
atom; R.sub.6 represents H or CH.sub.3; or R.sub.5 and R.sub.6
taken together with carbons to which they are attached form a
cyclopropane; R.sub.9 is H; R.sub.10 is H or .dbd.CH.sub.2; or
R.sub.9 and R.sub.10 taken together with carbons to which they are
attached form a cyclopropane; R.sub.12 represents H, optionally
substituted alkynylene, --CH.sub.2CH.dbd.CH.sub.2, CH.sub.3,
--C(O)CH.sub.3, or --CH.dbd.CH.sub.2; R.sub.13 represents CH.sub.3
or CH.sub.2CH.sub.3; R.sub.15 represents H or .dbd.CH.sub.2; and
R.sub.17 represents H, CH.sub.3, or is absent;
##STR00008##
[0215] where the bond between C.sub.1 and C.sub.10, C.sub.2 and
C.sub.3, C.sub.4 and C.sub.5, C.sub.6 and C.sub.7, C.sub.5 and
C.sub.10, C.sub.9 and C.sub.10, C.sub.11 and C.sub.12, C.sub.15 and
C.sub.16 is a single or a double bond; R.sub.5 represents H,
CH.sub.3, or a halogen atom; R.sub.6 represents H or CH.sub.3; or
R.sub.5 and R.sub.6 taken together with carbons to which they are
attached form a cyclopropane; R.sub.9 is H; R.sub.10 is H or
.dbd.CH.sub.2; or R.sub.9 and R.sub.10 taken together with carbons
to which they are attached form a cyclopropane; R.sub.11 represents
H, OH, optionally substituted alkynylene, --C(O)CH.sub.3,
--CH.sub.2CH.dbd.CH.sub.2, a halogen atom, --CH.dbd.CH.sub.2,
--OC(O)CH.sub.3, CH.sub.3, --C(O)C(OH)CH.sub.3; R.sub.12 represents
H, OH, optionally substituted alkynylene, --C(O)CH.sub.3,
--CH.sub.2CH.dbd.CH.sub.2, a halogen atom, --CH.dbd.CH.sub.2,
--OC(O)CH.sub.3, CH.sub.3, --C(O)C(OH)CH.sub.3; or R.sub.11 and
R.sub.12 together with carbon to which they are attached form a
lactone; R.sub.13 represents CH.sub.3 or CH.sub.2CH.sub.3; R.sub.15
represents H or .dbd.CH.sub.2; and R.sub.17 represents H, CH.sub.3,
or is absent;
##STR00009##
[0216] where the bond between C.sub.1 and C.sub.2, C.sub.1 and
C.sub.10, C.sub.2 and C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and
C.sub.5, C.sub.6 and C.sub.7, C.sub.5 and C.sub.10, C.sub.7 and
C.sub.8, and C.sub.8 and C.sub.9 is a single or a double bond;
R.sub.2 represents OH, --OC(O)Ph, or C.sub.1-6 alkoxy; R.sub.10
represents H or OH; R.sub.12 represents H, optionally substituted
alkynylene; and R.sub.15 represents H or C.sub.1-6 alkoxy;
##STR00010##
[0217] where the bond between C.sub.1 and C.sub.2, C.sub.1 and
C.sub.10, C.sub.2 and C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and
C.sub.5, C.sub.6 and C.sub.7, C.sub.5 and C.sub.10, C.sub.7 and
C.sub.8, and C.sub.8 and C.sub.9 is a single or a double bond;
R.sub.10 represents H or OH; R.sub.11 represents H, OH, optionally
substituted alkynylene, .dbd.O, or is absent; R.sub.12 represents
H, OH, optionally substituted alkynylene, .dbd.O, or is absent; and
R.sub.15 represents H or C.sub.1-6 alkoxy;
##STR00011##
[0218] where R.sub.2 represents OH or C.sub.1-6 alkoxy; and
R.sub.10 represents H or CH.sub.3;
##STR00012##
[0219] where the bond between C.sub.1 and C.sub.2, C.sub.4 and
C.sub.5, C.sub.5 and C.sub.6, C.sub.6 and C.sub.7, and C.sub.16 and
C.sub.17 is a single or a double bond; C.sub.4 is NH, CH, or
CH.sub.2; R.sub.1 represents H; R.sub.5 represents H or a halogen
atom; R.sub.11 represents H, optionally substituted heteroaryl,
--C(O)C.sub.1-6 alkyl, --C(O)OC.sub.1-6 alkyl, or --C(O)NHR, where
R is optionally substituted alkyl or aryl; R.sub.12 represents H,
optionally substituted heteroaryl, --C(O)C.sub.1-6 alkyl,
--C(O)OC.sub.1-6 alkyl, or --C(O)NHR, where R is optionally
substituted alkyl or aryl; and R.sub.18 represents H; or R.sub.1
and R.sub.18 taken together with carbons to which they are attached
form a cyclopropane;
##STR00013##
[0220] where R.sub.12 is H or OH;
##STR00014##
[0221] where the bond between C.sub.4 and C.sub.5, and C.sub.5 and
C.sub.6 is a single or a double bond; R.sub.5 represents H or
C.sub.1-6 alkyl; R.sub.6 represents H or OH; R.sub.11 represents H,
OH, --C(O)C.sub.1-6 alkyl, --C(O)CH.sub.2OH, or
--CH(CH.sub.3)CH.sub.2CH.sub.2C(O)OH; and R.sub.12 represents H,
OH, --C(O)C.sub.1-6 alkyl, --C(O)CH.sub.2OH, or
--CH(CH.sub.3)CH.sub.2CH.sub.2C(O)OH;
##STR00015##
[0222] where R.sub.5 represents H or CH.sub.2CH.sub.3; and R.sub.14
represents H or OH;
##STR00016##
[0223] where the bond between C.sub.1 and C.sub.2 is a single or a
double bond; R.sub.1 represents H or a halogen atom; R.sub.5
represents H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6
represents H or a halogen atom; R.sub.10 represents H, C.sub.1-6
alkyl, OH, or .dbd.CH.sub.2; R.sub.11 represents H, OH, C.sub.1-6
alkyl, optionally substituted --C(O)C.sub.1-6 alkyl,
C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted
--OC(O)C.sub.1-6 alkyl, OC(O)Ph, OC(O)heterocyclyl,
CH.sub.2C(O)CH.sub.2OH, --C(O)C(O)OH, --C(O)C(O)OC.sub.1-6 alkyl,
C(O)SCH.sub.2F, or --OC(O)OC.sub.1-6 alkyl; or R.sub.10 and
R.sub.11 taken together with carbons to which they are attached
form an optionally substituted cyclic acetal or optionally
substituted heterocyclyl; R.sub.12 represents H, OH, C.sub.1-6
alkyl, optionally substituted --C(O)C.sub.1-6 alkyl,
--C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted
OC(O)C.sub.1-6 alkyl, --OC(O)Ph, --OC(O)heterocyclyl,
--CH.sub.2C(O)CH.sub.2OH, --C(O)C(O)OH, C(O)C(O)OC.sub.1-6 alkyl,
--C(O)SCH.sub.2F, or --OC(O)OC.sub.1-6 alkyl; or R.sub.10 and
R.sub.12 taken together with carbons to which they are attached
form an optionally substituted cyclic acetal or optionally
substituted heterocyclyl; R.sub.15 represents H, OH, .dbd.O, or a
halogen atom; and R.sub.16 represents H or a halogen atom;
##STR00017##
[0224] where the bond between C.sub.1 and C.sub.2 is a single or a
double bond; R1 represents H or a halogen atom; R.sub.5 represents
H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6 represents H or a
halogen atom; R.sub.10 represents H, C.sub.1-6 alkyl, OH, or
.dbd.CH.sub.2; R.sub.10b represents H, C.sub.1-6 alkyl, OH,
.dbd.CH.sub.2, or be absent; R.sub.12 represents H, OH, optionally
substituted --C(O)C.sub.1-6 alkyl, --C(O)CH.sub.2OC(O)C.sub.1-6
alkyl, optionally substituted --OC(O)C.sub.1-6 alkyl, or --OC(O)Ph;
or R.sub.10 and R.sub.11 taken together with carbons to which they
are attached form an optionally substituted cyclic acetal or
optionally substituted heterocyclyl; R.sub.15 represents H, OH,
.dbd.O, or a halogen atom; and R.sub.16 represents H or a halogen
atom;
##STR00018##
[0225] where the bond between C.sub.1 and C.sub.2 is a single or a
double bond; R.sub.1 represents H or a halogen atom; R.sub.5
represents H, a halogen atom, or CH.sub.3; R.sub.6 represents H, a
halogen atom; R.sub.10 represents H, OH, CH.sub.3, or
.dbd.CH.sub.2; R.sub.12 represents optionally substituted
--C(O)C.sub.1-6 alkyl, --C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, or
--C(O)SCH.sub.2F; R.sub.15 represents OH or .dbd.O; and R.sub.16
represents H or a halogen atom;
##STR00019##
[0226] where the bond between C.sub.1 and C.sub.2 is a single or a
double bond; R.sub.1 represents H or a halogen atom; R.sub.5
represents H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6
represents H or a halogen atom; R.sub.10 represents H, C.sub.1-6
alkyl, OH, or .dbd.CH.sub.2; R.sub.10b represents H, C.sub.1-6
alkyl, OH, or .dbd.CH.sub.2, or is absent; R.sub.11 represents H,
OH, C.sub.1-6 alkyl, optionally substituted --C(O)C.sub.1-6 alkyl,
--C(O)CH2OC(O)C.sub.1-6 alkyl, optionally substituted
--OC(O)C.sub.1-6 alkyl, --OC(O)Ph, --OC(O)heterocyclyl,
--CH2C(O)CH.sub.2OH, --C(O)C(O)OH, --C(O)C(O)OC.sub.1-6 alkyl,
C(O)SCH2F, or --OC(O)OC.sub.1-6 alkyl; or R.sub.10 and R.sub.11
taken together with carbons to which they are attached form an
optionally substituted cyclic acetal or optionally substituted
heterocyclyl; R.sub.12 represents H, OH, C.sub.1-6 alkyl,
optionally substituted --C(O)C.sub.1-6 alkyl,
--C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted
OC(O)C.sub.1-6 alkyl, --OC(O)Ph, --OC(O)heterocyclyl,
--CH.sub.2C(O)CH.sub.2OH, --C(O)C(O)OH, --C(O)C(O)OC.sub.1-6 alkyl,
--C(O)SCH.sub.2F, or --OC(O)OC.sub.1-6 alkyl; or R.sub.10 and Rig
taken together with carbons to which they are attached form an
optionally substituted cyclic acetal or optionally substituted
heterocyclyl; and R.sub.16 represents H or a halogen atom;
##STR00020##
[0227] where R.sub.5 represents H or a halogen atom; R.sub.15
represents a halogen atom or OH; and R.sub.16 represents H or a
halogen atom;
##STR00021##
[0228] where the bond between C.sub.1 and C.sub.2 is a double or a
single bond; R.sub.16 represents H or a halogen atom; R.sub.5
represents H, CH.sub.3, or a halogen atom; R.sub.11 represents H or
a halogen atom; R.sub.15 represents .dbd.O or OH; R.sub.11 and
R.sub.10 each, independently, represent --H, C.sub.1-10 alkyl,
--OH, --O-acyl, or R.sub.12 and R.sub.10 combine to form a cyclic
acetal of formula (XVIII-a) where:
##STR00022##
[0229] e is an integer from 0 to 6; R.sub.20, R.sub.21, and
R.sub.22 each, independently, represent H or C.sub.1-10 alkyl; and
W1 represents H or CH.sub.3;
##STR00023##
[0230] where the bond between C.sub.3 and R.sub.2 is a single or a
double bond; R.sub.2 represents OH or .dbd.O; R.sub.12 represents
--C(.dbd.O)CH.sub.2OC(.dbd.O)CH.sub.3, --C(.dbd.O)CH.sub.2OH, or
--C(.dbd.O)CH.sub.3; R.sub.15 represents H or OH;
##STR00024##
[0231] where the bond between C3 and R.sub.2, and C.sub.11 and
R.sub.15 is a single or a double bond; R.sub.2 represents OH or
.dbd.O; R.sub.11 represents H, OH, --C(.dbd.O)CH.sub.2OH, or
--C(.dbd.O)CH.sub.3; R.sub.12 represents H, OH,
--C(.dbd.O)CH.sub.2OH, or --C(.dbd.O)CH.sub.3; R.sub.15 represents
H, .dbd.O, or OH;
##STR00025##
[0232] where the bond between C3 and R.sub.2, C.sub.7 and R.sub.6,
and C.sub.12 and R.sub.14 is a single or a double bond; Rx
represents OH, --NHCH.sub.2C(.dbd.O)OH, or
--NHCH.sub.2CH.sub.2SO2OH; R.sub.2 represents OH or .dbd.O; R.sub.5
represents H or OH; R.sub.6 represents H, .dbd.O, or OH; R.sub.14
represents H, .dbd.O, or OH;
##STR00026##
[0233] where the bond between C3 and R.sub.2, and C.sub.11 and
R.sub.15 is a single or a double bond; R.sub.2 represents OH or
.dbd.O; R.sub.10 represents H or OH; R.sub.11 represents H, OH,
--C(.dbd.O)CH.sub.2OH, --C(.dbd.O)OH, --C(.dbd.O)CH.sub.2OH, or
--C(.dbd.O)CH.sub.3; Rig represents H, OH, --C(.dbd.O)CH.sub.2OH,
--C(.dbd.O)OH, --C(.dbd.O)CH.sub.2OH, or --C(.dbd.O)CH.sub.3; R13
represents --CH.sub.2OH or --CH.sub.3; R.sub.15 represents H, OH,
or .dbd.O; R.sub.16 represents H or F;
##STR00027##
[0234] where Ry represents H or OH;
##STR00028##
[0235] where the bond between C.sub.3 and R.sub.2, and C.sub.11 and
R.sub.15 is a single or a double bond; Rz represents H or
--CH.sub.3; R1 represents H or --OCH.sub.2CH.sub.3; R.sub.2
represents OH or .dbd.O; R.sub.12 represents --OH,
--C(.dbd.O)CH.sub.3, --C(.dbd.O)CH.sub.2OH, or
--CH(CH.sub.3)(CH.sub.2)2CH(OH)CH(CH.sub.3)2; R.sub.15 represents
H, --N(CH.sub.3)2, or .dbd.O;
##STR00029##
[0236] where the bond between C.sub.3 and R.sub.2 is a single or a
double bond; R.sub.2 represents OH or .dbd.O; R.sub.11 represents
H, --C(.dbd.O)CH.sub.3, --OC(.dbd.O)(CH.sub.2)4CH.sub.3, or is
absent; R.sub.12 represents H, --C(.dbd.O)CH.sub.3,
--OC(.dbd.O)(CH.sub.2)4CH.sub.3, or is absent; R.sub.17 represents
CH.sub.3 or is absent;
##STR00030##
[0237] where the bond between C.sub.3 and R.sub.2, and C.sub.11 and
R.sub.15 is a single or a double bond; Ry represents OH or .dbd.O;
R.sub.2 represents OH or .dbd.O; R.sub.11 represents H, OH,
--CH(OH)CH.sub.3, --C(.dbd.O)CH.sub.2OH, --C(.dbd.O)CH.sub.3, or
--CH(OH)CH.sub.2OH; R.sub.12 represents H, OH, --CH(OH)CH.sub.3,
--C(.dbd.O)CH.sub.2OH, --C(.dbd.O)CH.sub.3, or --CH(OH)CH.sub.2OH;
R.sub.15 represents H, .dbd.O, or OH;
##STR00031##
[0238] where the bond between C.sub.3 and R.sub.2, and C16 and
R.sub.10 is a single or a double bond; R.sub.2 represents OH or
.dbd.O; R.sub.5 represents H, Cl, or --CH.sub.3; R.sub.10
represents H or .dbd.CH.sub.2; R.sub.11 represents H, OH,
--CH.sub.3, --C(.dbd.O)CH.sub.3,
--C(.dbd.O)CH.sub.2OC(.dbd.O)CH.sub.3, or --OC(.dbd.O)CH.sub.3;
R.sub.12 represents H, OH, --CH.sub.3, --C(.dbd.O)CH.sub.3,
--C(.dbd.O)CH.sub.2OC(.dbd.O)CH.sub.3, or --OC(.dbd.O)CH.sub.3;
R.sub.15 represents H or OH; R16 represents F or H; R.sub.17
represents H or --CH.sub.3.
[0239] In another embodiment, the compound is described by the
formula (A-VII):
D1-C(O)-L-C(O)-D2 (A-VII),
[0240] or a pharmaceutically acceptable salt thereof, wherein each
of D1-C(O) and D2-C(O) is, independently, a radical formed from a
steroid; L is --O--C(O)--O--(R.sup.A)--O--C(O)--O--; and R.sup.A is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. Each of
D1-C(O) and D2-C(O) can, independently, be formed, for example,
from fusidic acid, cholic acid, chenodeoxycholic acid,
ursodeoxycholic acid, or obeticholic acid. In the drug dimers of
formula (A-VII), D1-C(O)-- and D2-C(O)-- can further be described,
for example, by formulas (I-hh), (I-ii), (I-ttt), (I-uuu), and
(I-vvv) below.
##STR00032##
[0241] where R.sub.5 represents H or C.sub.1-6 alkyl, R.sub.14
represents H or OH;
##STR00033##
[0242] where the bond between C.sub.3 and R.sub.2, C.sub.7 and
R.sub.6, and C.sub.12 and R.sub.14 is a single or a double bond;
R.sub.2 represents OH or .dbd.O; R.sub.5 represents H or OH;
R.sub.6 represents H, .dbd.O, or OH; R.sub.14 represents H, .dbd.O,
or OH;
##STR00034##
[0243] Drug dimers useful in the methods and compositions of the
disclosure include homodimers and heterodimers. Steroids, including
anabolic steroids, androgenic steroids, progestin steroids,
estrogen steroids, cancer treatment steroids, antibiotic steroids,
glucocorticoid steroids, benign steroids, corticosteroids,
anti-angiogenic steroids, intraocular pressure (IOP) lowering
steroids, cholic acid-related bile acid steroids, steroid
metabolites, cholesterol-derivatives, neurosteroids, pheromones,
progestins, or other steroids, can be used in drug dimers. Examples
of anabolic steroids include androisoxazole, androstenediol,
bolandiol, bolasterone, clostebol, ethylestrenol, formyldienolone,
4-hydroxy-19-nortestosterone, methandriol, methenolone,
methyltrienolone, nandrolone, norbolethone, oxymesterone,
stenbolone, and trenbolone. Androgenic steroids are, for example,
boldenone, fluoxymesterone, mestanolone, mesterolone,
methandrostenolone, 17-methyltestosterone,
17-.alpha.-methyltestosterone 3-cyclopentyl enol ether,
norethandrolone, normethandrone, oxandrolone, oxymesterone,
oxymetholone, prasterone, stanlolone, stanozolol, testosterone,
testosterone 17-chloral hemiacetal, testosterone proprionate,
testosterone enanthate tiomesterone dehydroepiandrosterone (DHEA),
androstenedione, androstenediol, androsterone, dihydrotestosterone
(DHT), androstanolone, and derivatives thereof. Exemplary progestin
steroids are norethisterone, norethisterone acetate, gestodene,
levonorgestrel, allylestrenol, anagestone, desogestrel,
dimethisterone, dydrogesterone, ethisterone, ethynodiol, ethynodiol
diacetate, etonogestrel, gestodene, ethinylestradiol,
haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17
alpha-hydroxyprogesterone, lynestrenol, medroxyprogesterone,
melengestrol, norethindrone, norethynodrel, norgesterone,
gestonorone, norethisterone, norgestimate, norgestrel,
levonorgestrel, norgestrienone, norvinisterone, pentagestrone, MENT
(7-methyl-19-testosterone); norelgestromin, and trimigestone
drospirenone, tibolone, megestrol, and derivatives thereof.
Examples of estrogen steroid are estrogen, eguilenin, equilin,
17.beta.-estradiol, estradiol benzoate, estriol, ethinyl estradiol,
mestranol, moxestrol, mytatrienediol, quinestradiol, and
quinestrol. Steroids used in cancer treatment are, for example,
abiraterone, cyproterone acetate, dutasteride, enzalutamide,
finasteride, and galeterone. Exemplary antibiotic steroid is
fusidic acid. Glucocorticoids include, for example, medrysone,
alclometasone, alclometasone dipropionate, amcinonide,
beclometasone, beclomethasone dipropionate, betamethasone,
betamethasone benzoate, betamethasone valerate, budesonide,
ciclesonide, clobetasol, clobetasol butyrate, clobetasol
propionate, clobetasone, clocortolone, loprednol, cortisol,
cortisone, cortivazol, deflazacort, desonide, desoximetasone,
desoxycortone, desoxymethasone, dexamethasone, diflorasone,
diflorasone diacetate, diflucortolone, diflucortolone valerate,
difluorocortolone, difluprednate, fluclorolone, fluclorolone
acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone
pivalate, flunisolide, flunisolide, fluocinolone, fluocinolone
acetonide, fluocinonide, fluocortin, fluocoritin butyl,
fluocortolone, fluorocortisone, fluorometholone, fluperolone,
fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone,
fluticasone propionate, formocortal, halcinonide, halometasone,
hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate,
hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,
meprednisone, 6.alpha.-methylprednisolone, methylprednisolone,
methylprednisolone acetate, methylprednisolone aceponate,
mometasone, mometasone furoate, mometasone furoate monohydrate,
paramethasone, prednicarbate, prednisolone, prednisone,
prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone
acetonide, and ulobetasol. Exemplary benign steroids are
cholesterol, 11-deoxycortisol, 11-deoxycorticosterone,
pregnenolone, cholic acid, chenodeoxycholic acid, ursodeoxycholic
acid, obeticholic acid, tetrahydrocortisone,
tetrahydrodeoxycortisol, tetrahydrocorticosterone,
5.alpha.-dihydrocorticosterone, and 5.alpha.-dihydropregesterone.
Exemplary anti-angiogenic steroids or intraocular pressure (IOP)
lowering steroids are anecortave acetate, anecortave,
11-epicortisol, 17.alpha.-hydroxyprogesterone,
tetrahydrocortexolone, and tetrahydrocortisol. Exemplary cholic
acid-related bile acid steroids are deoxycholic acid, apocholic
acid, dehydrocholic acid, glycochenodeoxycholic acid, glycocholic
acid, glycodeoxycholic acid, hyodeoxycholic acid, lithocholic acid,
.alpha.-muricholic acid, .beta.-muricholic acid, .gamma.-muricholic
acid, .omega.-muricholic acid, taurochenodeoxycholic acid,
taurocholic acid, taurodeoxycholic acid, taurolithocholic acid, and
tauroursodeoxycholic acid. Exemplary neurosteroids are alphaxalone,
alphadolone, hydroxydione, minaxolone,
tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone,
ganoxolone, 3.alpha.-androstanediol, epipregnanolone,
isopregnanolone, and 24(S)-hydroxycholesterol. Exemplary other
steroids are flugestone, prebediolone, chlormadinone acetate,
medrogestone, and segesterone acetate. Exemplary pheromones are
androstadienol, androstadienone, androstenol, androstenone,
estratetraenol, 5-dehydroprogesterone, 6-dehydro-retroprogesterone,
allopregnanolone, and hydroxyprogesterone caproate. Exemplary
steroid metabolites are tetrahydrotriamcinolone, cortienic acid,
11-dehydrocorticosterone, 11.beta.-hydroxypregnenolone,
ketoprogesterone, 17-hydroxypregnenolone,
17,21-dihydroxypregnenolone, 18-hydroxycorticosterone,
deoxycortisone, 21-hydroxypregnenolone, and progesterone. Exemplary
progestins are allopregnone-3.alpha.,20.alpha.-diol,
allopregnone-3.beta.,20.beta.-diol,
allopregnane-3.beta.,21-diol-11,20-dione,
allopregnane-3.beta.,17.alpha.-diol-20-one, 3,20-allopregnanedione,
3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol,
allopregnane-3.beta.,17.alpha.,20.beta.,21-tetrol,
allopregnane-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,17.alpha.,20.beta.-triol,
allopregnane-3.beta.,17.alpha.,21-triol-11,20-dione,
allopregnane-3.beta.,11.beta.,21-triol-20-one,
allopregnane-3.beta.,17.alpha.,21-triol-20-one,
allopregnane-3.alpha.-ol-20-one, allopregnane-3.beta.-ol-20-one,
pregnanediol, 3,20-pregnanedione, 4-pregnene-20,21-diol-3,11-dione,
4-pregnene-11.beta.,17.alpha.,20.beta.,21-tetrol-3-one,
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione,
4-pregnene-17.alpha.,20.beta.,21-triol-3-one, and pregnenolone.
[0244] The drug dimers useful in making the articles of the
disclosure can have any of formulas (A-I)-(LXXV), described
herein.
[0245] Steroid Homodimers
[0246] The disclosure features homodimers of the formula (I):
D1-L-D2 (A-VIII)
[0247] or a pharmaceutically acceptable salt thereof, wherein D1
and D2 are radicals formed from the same steroid. L can be
covalently linked to D1 and to D2 via one or more ester, carbonate,
carbonate ester, or anhydride linkages. Ester, carbonate, carbonate
ester, or anhydride linkages formed from a functional group on D1
and D2 can be selected from, e.g., hydroxyl or carboxy. For
example, L can include the radical --C(O)--(R.sup.A)--C(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or --O--(R.sup.A)--O--,
where R.sup.A is a radical of a polyol and includes at least one
free hydroxyl group or R.sup.A is selected from C.sub.1-20
alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a
linear or branched C.sub.2-20 alkenylene, a linear or branched
C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3
to 10 atoms, --(CH.sub.2CH.sub.2O)qCH.sub.2CH.sub.2--,
[0248]
--(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)rCH.sub.2CH.sub.2CH.sub.2CH.su-
b.2--, or --(CH.sub.2CH(CH.sub.3)O)sCH.sub.2CH(CH.sub.3)--, and q,
r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to
10). The homodimer can be further described by one of formulas
(II)-(LXXV), below.
[0249] In some embodiments, the steroid is an anabolic steroid and
the drug dimer is further described by the formula (II):
##STR00035##
[0250] wherein the bond between C1 and C.sub.2, C.sub.4 and
C.sub.5, C.sub.5 and C.sub.6, C9 and C10, and C.sub.11 and C.sub.12
is a single or a double bond; R1 represents H, CH.sub.3, or HC(O);
R.sub.2 represents .dbd.O, OH, or H; or R1 and R.sub.2 taken
together with carbons to which they are attached form an isoxazole;
R3 represents H, a halogen atom, or OH; R.sub.6 represents H or
CH.sub.3; R.sub.12 represents H, CH.sub.3, or CH.sub.3CH.sub.2; R13
represents CH.sub.3 or CH.sub.3CH.sub.2; R.sub.15 represents H or
OH; R.sub.17 represents H or CH.sub.3; R18 represents H or
CH.sub.3; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and
p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (II) can be formed from an anabolic steroid
selected from the group consisting of androisoxazole,
androstenediol, bolandiol, bolasterone, clostebol, ethylestrenol,
formyldienolone, 4-hydroxy-19-nortestosterone, methandriol,
methenolone, methyltrienolone, nandrolone, norbolethone,
oxymesterone, stenbolone, and trenbolone.
[0251] In certain embodiments, the steroid is an anabolic steroid
and the drug dimer is further described by the formula (III):
##STR00036##
[0252] wherein the bond between C1 and C.sub.2, C.sub.4 and
C.sub.5, C.sub.5 and C.sub.6, C9 and C10, and C.sub.11 and C.sub.12
is a single or a double bond; R1 represents H, CH.sub.3, or HC(O);
R3 represents H, a halogen atom, or OH; R.sub.6 represents H or
CH.sub.3; Rig represents H, CH.sub.3, or CH.sub.3CH.sub.2; R13
represents CH.sub.3 or CH.sub.3CH.sub.2; R15 represents H or OH;
R.sub.17 represents H or CH.sub.3; R18 represents H or CH.sub.3; L
is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
[0253]
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.s-
ub.2O--, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n,
m, and p are integers from 1 to 10; and each R.sup.B is
independently selected from C.sub.1-20 alkylene, a linear or
branched heteroalkylene of 1 to 20 atoms, a linear or branched
C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene,
a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (III) can be formed from an anabolic steroid
selected from the group consisting of androstenediol, bolandiol,
bolasterone, clostebol, formyldienolone,
4-hydroxy-19-nortestosterone, methandriol, methenolone,
methyltrienolone, nandrolone, norbolethone, oxymesterone,
stenbolone, and trenbolone.
[0254] In particular embodiments, the steroid is an anabolic
steroid and the drug dimer is further described by the formula
(IV):
##STR00037##
[0255] wherein R.sub.12 represents H or CH.sub.3; R.sub.17
represents H or CH.sub.3; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
[0256]
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.s-
ub.2O--, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n,
m, and p are integers from 1 to 10; and each R.sup.B is
independently selected from C.sub.1-20 alkylene, a linear or
branched heteroalkylene of 1 to 20 atoms, a linear or branched
C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene,
a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (IV) can be formed from an anabolic steroid
selected from 4-hydroxy-19-nortestosterone or oxymesterone.
[0257] In certain embodiments, the steroid is an androgenic steroid
and the drug dimer is further described by the formula (V):
##STR00038##
[0258] wherein the bond between C1 and C.sub.2, C.sub.4 and
C.sub.5, and C.sub.5 and C.sub.6 is a single or a double bond; C2
is O, C or CH.sub.2; R1 represents H, --CHOH, or is absent; R.sub.2
represents .dbd.O or OH; or R1 and R.sub.2 taken together with
carbons to which they are attached form a pyrazole; R3 represents H
or OH; R.sub.12 represents H, CH.sub.3, optionally substituted
alkynylene, C.sub.1-6 alkoxy, or CH.sub.3CH.sub.2; R.sub.15
represents H or OH; R.sub.16 represents H or a halogen atom;
R.sub.17 represents H or CH.sub.3; R.sub.18 represents H or
CH.sub.3; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
[0259] --O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0260] --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m,
and p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (V) can be formed from an androgenic steroid
selected from the group consisting of boldenone, fluoxymesterone,
mestanolone, mesterolone, methandrostenolone,
17-methyltestosterone, 17-.alpha.-methyltestosterone 3-cyclopentyl
enol ether, norethandrolone, normethandrone, oxandrolone,
oxymesterone, oxymetholone, prasterone, stanlolone, stanozolol,
testosterone, testosterone enanthate tiomesterone
dehydroepiandrosterone (DHEA), androstenedione, androstenediol,
androsterone, and dihydrotestosterone (DHT).
[0261] In particular embodiments, the steroid is an androgenic
steroid and the drug dimer is further described by the formula
(VI):
##STR00039##
[0262] wherein the bond between C.sub.1 and C.sub.2, C.sub.4 and
C.sub.5, and C.sub.5 and C.sub.6 is a single or a double bond;
C.sub.2 is O, C or CH.sub.2; R1 represents H, --CHOH, or is absent;
R3 represents H or OH; R.sub.11 represents H, OH, CH.sub.3,
optionally substituted alkynylene, CH.sub.3CH.sub.2, .dbd.O,
--OC(O)CH.sub.2CH.sub.3, or is absent; R.sub.12 represents H, OH,
CH.sub.3, optionally substituted alkynylene, CH.sub.3CH.sub.2,
.dbd.O, --OC(O)CH.sub.2CH.sub.3, or is absent; R.sub.15 represents
H or OH; R16 represents H or a halogen atom; R.sub.17 represents H
or CH.sub.3; R18 represents H or CH.sub.3; L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0263] --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m,
and p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (VI) can be formed from an androgenic steroid
selected from the group consisting of boldenone, fluoxymesterone,
mestanolone, mesterolone, methandrostenolone,
17-methyltestosterone, norethandrolone, normethandrone,
oxandrolone, oxymesterone, oxymetholone, prasterone, stanlolone,
testosterone, testosterone proprionate, testosterone enanthate
tiomesterone dehydroepiandrosterone (DHEA), androstenedione,
androstenediol, androsterone, and dihydrotestosterone (DHT).
[0264] In certain embodiments, the steroid is an androgenic steroid
and the drug dimer is further described by the formula (VII):
##STR00040##
[0265] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0266] --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m,
and p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (VII) can be formed from the androgenic steroid
fluoxymesterone.
[0267] In particular embodiments, the steroid is an androgenic
steroid and the drug dimer is further described by the formula
(VIII):
##STR00041##
[0268] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0269] --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m,
and p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (VIII) can be formed from the androgenic steroid
oxymesterone.
[0270] In some embodiments, the steroid is an androgenic steroid
and the drug dimer is further described by the formula (IX):
##STR00042##
[0271] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0272] --O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O--; n,
m, and p are integers from 1 to 10; and each R.sup.B is
independently selected from C.sub.1-20 alkylene, a linear or
branched heteroalkylene of 1 to 20 atoms, a linear or branched
C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene,
a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (IX) can be formed from the androgenic steroid
oxymetholone.
[0273] In particular embodiments, the steroid is a progestin
steroid and the drug dimer is further described by the formula
(X):
##STR00043##
[0274] wherein the bond between C.sub.1 and C.sub.10, C.sub.2 and
C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and C.sub.5, C.sub.5 and
C.sub.6, C.sub.6 and C.sub.7, C.sub.5 and C10, C9 and C10, C.sub.11
and C.sub.12, C15 and C16 is a single or a double bond; R.sub.2
represents H, .dbd.O, OH, --NOH, or C.sub.1-6 alkoxy; R.sub.5
represents H, CH.sub.3, or a halogen atom; R.sub.6 represents H or
CH.sub.3; or R.sub.5 and R.sub.6 taken together with carbons to
which they are attached form a cyclopropane; R9 is H; R.sub.10 is H
or .dbd.CH.sub.2; or R9 and R.sub.10 taken together with carbons to
which they are attached form a cyclopropane; R.sub.12 represents H,
optionally substituted alkynylene, --CH.sub.2CH.dbd.CH.sub.2,
CH.sub.3, --C(O)CH.sub.3, or --CH.dbd.CH.sub.2; R13 represents
CH.sub.3 or CH.sub.2CH.sub.3; R.sub.15 represents H or
.dbd.CH.sub.2; R.sub.17 represents H, CH.sub.3, or is absent; L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
[0275] --O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0276] --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m,
and p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (X) can be formed from a progestin steroid
selected from the group consisting of norethisterone, gestodene,
levonorgestrel, allylestrenol, anagestone, desogestrel,
dimethisterone, dydrogesterone, ethisterone, ethynodiol,
etonogestrel, gestodene, ethinylestradiol,
17-hydroxy-16-methylene-progesterone, 17 alpha-hydroxyprogesterone,
lynestrenol, medroxyprogesterone, melengestrol, norethindrone,
norethynodrel, norgesterone, gestonorone, norethisterone,
norgestrel, levonorgestrel, norgestrienone, pentagestrone,
7-methyl-19-testosterone (MENT), norelgestromin, tibolone, and
megestrol.
[0277] In certain embodiments, the steroid is a progestin steroid
and the drug dimer is further described by the formula (XI):
##STR00044##
[0278] wherein the bond between C.sub.1 and C.sub.10, C.sub.2 and
C.sub.3, C.sub.4 and C.sub.5, C.sub.6 and C.sub.7, C.sub.5 and C10,
C9 and C10, C.sub.11 and C.sub.12, C15 and C16 is a single or a
double bond; R.sub.5 represents H, CH.sub.3, or a halogen atom;
R.sub.6 represents H or CH.sub.3; or R.sub.5 and R.sub.6 taken
together with carbons to which they are attached form a
cyclopropane; R9 is H; R.sub.10 is H or .dbd.CH.sub.2; or R9 and
R.sub.10 taken together with carbons to which they are attached
form a cyclopropane; R.sub.11 represents H, OH, optionally
substituted alkynylene, --C(O)CH.sub.3, --CH.sub.2CH.dbd.CH.sub.2,
a halogen atom, --CH.dbd.CH.sub.2, --OC(O)CH.sub.3, CH.sub.3,
--C(O)C(OH)CH.sub.3; R.sub.12 represents H, OH, optionally
substituted alkynylene, --C(O)CH.sub.3, --CH.sub.2CH.dbd.CH.sub.2,
a halogen atom, --CH.dbd.CH.sub.2, --OC(O)CH.sub.3, CH.sub.3,
--C(O)C(OH)CH.sub.3; or R.sub.11 and R.sub.12 together with carbon
to which they are attached form a lactone; R13 represents CH.sub.3
or CH.sub.2CH.sub.3; R.sub.15 represents H or .dbd.CH.sub.2;
R.sub.17 represents H, CH.sub.3, or is absent; L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
[0279] --O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0280] --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m,
and p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XI) can be formed from a progestin steroid
selected from the group consisting of norethisterone,
norethisterone acetate, gestodene, levonorgestrel, dimethisterone,
dydrogesterone, ethisterone, ethynodiol, etonogestrel, gestodene,
ethinylestradiol, haloprogesterone,
17-hydroxy-16-methylene-progesterone, 17 alpha-hydroxyprogesterone,
medroxyprogesterone, melengestrol, norethindrone, norethynodrel,
norgesterone, gestonorone, norethisterone, norgestimate,
norgestrel, levonorgestrel, norgestrienone,
7-methyl-19-testosterone (MENT), norelgestromin, trimigestone,
drospirenone, tibolone, and megestrol.
[0281] In some embodiments, the steroid is a progestin steroid and
the drug dimer is further described by the formula (XII):
##STR00045##
[0282] Wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0283] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XII) can be formed from the progestin steroid
trimigestone.
[0284] In particular embodiments, the steroid is an estrogen
steroid and the drug dimer is further described by the formula
(XIII):
##STR00046##
[0285] wherein the bond between C.sub.1 and C.sub.2, C.sub.1 and
C10, C.sub.2 and C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and C.sub.5,
C.sub.6 and C.sub.7, C.sub.5 and C10, C.sub.7 and C8, and C8 and C9
is a single or a double bond; R.sub.2 represents OH, --OC(O)Ph, or
C.sub.1-6 alkoxy; R.sub.10 represents H or OH; R.sub.12 represents
H, optionally substituted alkynylene; R.sub.15 represents H or
C.sub.1-6 alkoxy; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0286] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XIII) can be formed from an estrogen steroid
selected from the group consisting of estrogen, eguilenin, equilin,
17.beta.-estradiol, estradiol benzoate, estriol, ethinyl estradiol,
mestranol, moxestrol, mytatrienediol, quinestradiol, and
quinestrol.
[0287] In some embodiments, the steroid is an estrogen steroid and
the drug dimer is further described by the formula (XIV):
##STR00047##
[0288] wherein the bond between C.sub.1 and C.sub.2, C.sub.1 and
C10, C.sub.2 and C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and C.sub.5,
C.sub.6 and C.sub.7, C.sub.5 and C10, C.sub.7 and C8, and C8 and C9
is a single or a double bond; R.sub.10 represents H or OH; R.sub.11
represents H, OH, optionally substituted alkynylene, .dbd.O, or is
absent; R.sub.12 represents H, OH, optionally substituted
alkynylene, .dbd.O, or is absent; R.sub.15 represents H or
C.sub.1-6 alkoxy; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
[0289]
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.s-
ub.2O--, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n,
m, and p are integers from 1 to 10; and each R.sup.B is
independently selected from C.sub.1-20 alkylene, a linear or
branched heteroalkylene of 1 to 20 atoms, a linear or branched
C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene,
a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XIV) can be formed from an estrogen steroid
selected from the group consisting of estrogen, eguilenin, equilin,
17.beta.-estradiol, estriol, ethinyl estradiol, and moxestrol.
[0290] In some embodiments, the steroid is an estrogen steroid and
the drug dimer is further described by the formula (XV):
##STR00048##
[0291] wherein R.sub.2 represents OH or C.sub.1-6 alkoxy; R.sub.10
represents H or CH.sub.3; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
[0292] --O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0293] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XV) can be formed from an estrogen steroid
selected from the group consisting of estriol, mytatrienediol, and
quinestradiol.
[0294] In particular embodiments, the steroid is a cancer treatment
steroid and the drug dimer is further described by the formula
(XVI):
##STR00049##
[0295] wherein the bond between C.sub.1 and C.sub.2, C.sub.4 and
C.sub.5, C.sub.5 and C.sub.6, C.sub.6 and C.sub.7, and C16 and C17
is a single or a double bond; C.sub.4 is NH, CH, or CH.sub.2; R1
represents H; R.sub.5 represents H or a halogen atom; R.sub.11
represents H, optionally substituted heteroaryl, --C(O)C.sub.1-6
alkyl, --C(O)OC.sub.1-6 alkyl, or --C(O)NHR, wherein R is
optionally substituted alkyl or aryl; R.sub.12 represents H,
optionally substituted heteroaryl, --C(O)C.sub.1-6 alkyl,
C(O)OC.sub.1-6 alkyl, or --C(O)NHR, wherein R is optionally
substituted alkyl or aryl; R18 represents H; or R1 and R18 taken
together with carbons to which they are attached form a
cyclopropane; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
[0296] --O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0297] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XVI) can be formed from a cancer treatment
steroid selected from the group consisting of abiraterone,
cyproterone acetate, dutasteride, finasteride, and galeterone.
[0298] In some embodiments, the steroid is an antibiotic steroid
and the drug dimer is further described by the formula (XVII):
##STR00050##
[0299] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or
[0300] O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0301] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XVII) can be formed from the steroid antibiotic
fusidic acid.
[0302] In particular embodiments, the steroid is an antibiotic
steroid and the drug dimer is further described by the formula
(XVIII):
##STR00051##
[0303] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or
[0304] O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0305] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XVIII) can be formed from the steroid antibiotic
fusidic acid.
[0306] In some embodiments, the steroid is a benign steroid and the
drug dimer is further described by the formula (XIX):
##STR00052##
[0307] wherein R.sub.12 is H or OH; L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XIX) can be
formed from a benign steroid selected from 11-deoxycortisol and
11-deoxycorticosterone.
[0308] In particular embodiments, the steroid is a benign steroid
and the drug dimer is further described by the formula (XX):
##STR00053##
[0309] wherein the bond between C.sub.4 and C.sub.5, and C.sub.5
and C.sub.6 is a single or a double bond; R.sub.5 represents H or
C.sub.1-6 alkyl; R.sub.6 represents H or OH; R.sub.11 represents H,
OH, --C(O)C.sub.1-6 alkyl, --C(O)CH.sub.2OH, or
CH(CH.sub.3)CH.sub.2CH.sub.2C(O)OH; Rig represents H, OH,
--C(O)C.sub.1-6 alkyl, --C(O)CH.sub.2OH, or
CH(CH.sub.3)CH.sub.2CH.sub.2C(O)OH; L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
[0310]
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O-
--, or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XX) can be formed from a benign steroid selected
from the group consisting of cholesterol, 11-deoxycortisol,
11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic
acid, ursodeoxycholic acid, and obeticholic acid.
[0311] In some embodiments, the steroid is a benign steroid and the
drug dimer is further described by the formula (XXI):
##STR00054##
[0312] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0313] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms.
[0314] The drug dimer of formula (XXI) can be formed from a benign
steroid including 11-deoxycortisol.
[0315] In particular embodiments, the steroid is a benign steroid
and the drug dimer is further described by the formula (XXII):
##STR00055##
[0316] wherein R.sub.5 represents H or CH.sub.2CH.sub.3; R.sub.14
represents H or OH; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
[0317] --O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0318] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XXII) can be formed from a benign steroid
selected from the group consisting of cholic acid, chenodeoxycholic
acid, ursodeoxycholic acid, and obeticholic acid.
[0319] In some embodiments, the steroid is a benign steroid and the
drug dimer is further described by the formula (XXIII):
##STR00056##
[0320] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0321] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XXIII) can be formed from the benign steroid
cholic acid.
[0322] In particular embodiments, the steroid is a glucocorticoid
steroid and the drug dimer is further described by the formula
(XXIV):
##STR00057##
[0323] wherein the bond between C1 and C.sub.2 is a single or a
double bond; R1 represents H or a halogen atom; R.sub.5 represents
H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6 represents H or a
halogen atom; R.sub.10 represents H, C.sub.1-6 alkyl, OH, or
.dbd.CH.sub.2; R.sub.11 represents H, OH, C.sub.1-6 alkyl,
optionally substituted --C(O)C.sub.1-6 alkyl,
C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted
--OC(O)C.sub.1-6 alkyl, --OC(O)Ph, --OC(O)heterocyclyl,
CH.sub.2C(O)CH.sub.2OH, --C(O)C(O)OH, --C(O)C(O)OC.sub.1-6 alkyl,
--C(O)SCH2F, or --OC(O)OC.sub.1-6 alkyl; or R.sub.10 and R.sub.11
taken together with carbons to which they are attached form an
optionally substituted cyclic acetal or optionally substituted
heterocyclyl; R.sub.12 represents H, OH, C.sub.1-6 alkyl,
optionally substituted C(O)C.sub.1-6 alkyl,
--C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted
--OC(O)C.sub.1-6 alkyl, --OC(O)Ph, --OC(O)heterocyclyl,
CH.sub.2C(O)CH.sub.2OH, --C(O)C(O)OH, --C(O)C(O)OC.sub.1-6 alkyl,
--C(O)SCH2F, or --OC(O)OC.sub.1-6 alkyl; or R.sub.10 and Rig taken
together with carbons to which they are attached form an optionally
substituted cyclic acetal or optionally substituted heterocyclyl;
R.sub.15 represents H, OH, .dbd.O, or a halogen atom; R.sub.16
represents H or a halogen atom; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(O)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--; R.sup.A is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
[0324]
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O-
--, or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XXIV) can be formed from a glucocorticoid steroid
selected from the group consisting of medrysone, alclometasone,
alclometasone dipropionate, amcinonide, beclometasone,
beclomethasone dipropionate, betamethasone, betamethasone benzoate,
betamethasone valerate, budesonide, ciclesonide, clobetasol,
clobetasol butyrate, clobetasol propionate, clobetasone,
clocortolone, cortisol, cortisone, deflazacort, desonide,
desoximetasone, desoxycortone, desoxymethasone, dexamethasone,
diflorasone, diflorasone diacetate, diflucortolone, diflucortolone
valerate, difluorocortolone, difluprednate, fluclorolone,
fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone,
flumethasone pivalate, flunisolide, flunisolide, fluocinolone,
fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin
butyl, fluocortolone, fluorocortisone, fluorometholone,
fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone,
fluticasone, fluticasone propionate, halcinonide, halometasone,
hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate,
hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,
meprednisone, 6.alpha.-methylprednisolone, methylprednisolone,
methylprednisolone acetate, methylprednisolone aceponate,
mometasone, mometasone furoate, mometasone furoate monohydrate,
paramethasone, prednicarbate, prednisolone, prednisone,
prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone
acetonide, and ulobetasol.
[0325] In some embodiments, the steroid is a glucocorticoid steroid
and the drug dimer is further described by the formula (XXV):
##STR00058##
[0326] wherein the bond between C.sub.1 and C.sub.2 is a single or
a double bond; R1 represents H or a halogen atom; R.sub.5
represents H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6
represents H or a halogen atom; R.sub.10 represents H, C.sub.1-6
alkyl, OH, or .dbd.CH.sub.2; R.sub.10b represents H, C.sub.1-6
alkyl, OH, .dbd.CH.sub.2, or be absent; R.sub.12 represents H, OH,
optionally substituted --C(O)C.sub.1-6 alkyl,
--C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted
--OC(O)C.sub.1-6 alkyl, or --OC(O)Ph; or R.sub.10 and R.sub.11
taken together with carbons to which they are attached form an
optionally substituted cyclic acetal or optionally substituted
heterocyclyl; R.sub.15 represents H, OH, .dbd.O, or a halogen atom;
R.sub.16 represents H or a halogen atom; L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and
p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10arylene, a cyclic system of 3 to 10 atoms. The drug dimer
of formula (XXV) can be formed from a glucocorticoid steroid
selected from the group consisting of alclometasone, beclometasone,
betamethasone, betamethasone benzoate, betamethasone valerate,
budesonide, cortisol, cortisone, desonide, desoximetasone,
desoxycortone, desoxymethasone, dexamethasone, diflorasone,
diflucortolone, difluorocortolone, fluclorolone, fluclorolone
acetonide, fludroxycortide, flumetasone, flumethasone, flunisolide,
flunisolide, fluocinolone, fluocinolone acetonide, fluocortolone,
fluorocortisone, fluprednidene, fluprednisolone, halometasone,
hydrocortisone, hydrocortisone butyrate, meprednisone,
6.alpha.-methylprednisolone, methylprednisolone, paramethasone,
prednisolone, prednisone, prednylidene, triamcinolone, and
triamcinolone acetonide.
[0327] In particular embodiments, the steroid is a glucocorticoid
steroid and the drug dimer is further described by the formula
(XXVI):
##STR00059##
[0328] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
--O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XXVI) can be
formed from the glucocorticoid steroid fluclorolone acetonide.
[0329] In some embodiments, the steroid is a glucocorticoid steroid
and the drug dimer is further described by the formula (XXVII):
##STR00060##
[0330] wherein the bond between C1 and C.sub.2 is a single or a
double bond; R1 represents H or a halogen atom; R.sub.5 represents
H, a halogen atom, or CH.sub.3; R.sub.6 represents H, a halogen
atom; R.sub.10 represents H, OH, CH.sub.3, or .dbd.CH.sub.2;
R.sub.12 represents optionally substituted --C(O)C.sub.1-6 alkyl,
--C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, or --C(O)SCH.sub.2F; R.sub.15
represents OH or .dbd.O; R.sub.16 represents H or a halogen atom; L
is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and
p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XXVII) can be formed from a glucocorticoid
steroid selected from the group consisting of alclometasone,
beclometasone, betamethasone, clobetasol, clobetasone, cortisol,
cortisone, dexamethasone, diflorasone, fluclorolone, flumetasone,
flumethasone, flumethasone pivalate, fluocinolone, fluorocortisone,
fluorometholone, fluperolone, fluprednidene, fluprednidene acetate,
fluprednisolone, fluticasone, halometasone, hydrocortisone,
hydrocortisone acetate, hydrocortisone butyrate, meprednisone,
6.alpha.-methylprednisolone, methylprednisolone, methylprednisolone
acetate, mometasone, paramethasone, prednisolone, prednisone,
prednylidene, tixocortol, triamcinolone, and ulobetasol.
[0331] In particular embodiments, the steroid is a glucocorticoid
steroid and the drug dimer is further described by the formula
(XXVIII):
##STR00061##
[0332] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
--O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XXVIII) can be
formed from the glucocorticoid steroid cortivazol.
[0333] In some embodiments, the steroid is a glucocorticoid steroid
and the drug dimer is further described by the formula (XXIX):
##STR00062##
[0334] wherein the bond between C1 and C.sub.2 is a single or a
double bond; R1 represents H or a halogen atom; R.sub.5 represents
H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6 represents H or a
halogen atom; R.sub.10 represents H, C.sub.1-6 alkyl, OH, or
.dbd.CH.sub.2; R.sub.10b represents H, C.sub.1-6 alkyl, OH, or
.dbd.CH.sub.2, or is absent; R.sub.11 represents H, OH, C.sub.1-6
alkyl, optionally substituted --C(O)C.sub.1-6 alkyl,
--C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted
--OC(O)C.sub.1-6 alkyl, --OC(O)Ph, --OC(O)heterocyclyl,
--CH.sub.2C(O)CH.sub.2OH, --C(O)C(O)OH, --C(O)C(O)OC.sub.1-6 alkyl,
C(O)SCH.sub.2F, or --OC(O)OC.sub.1-6 alkyl; or R.sub.10 and
R.sub.11 taken together with carbons to which they are attached
form an optionally substituted cyclic acetal or optionally
substituted heterocyclyl; R.sub.12 represents H, OH, Cu-6 alkyl,
optionally substituted --C(O)C.sub.1-6 alkyl,
--C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted
OC(O)C.sub.1-6 alkyl, --OC(O)Ph, --OC(O)heterocyclyl,
--CH.sub.2C(O)CH.sub.2OH, --C(O)C(O)OH, C(O)C(O)OC.sub.1-6 alkyl,
C(O)SCH.sub.2F, or --OC(O)OC.sub.1-6 alkyl; or R.sub.10 and Cu-6
taken together with carbons to which they are attached form an
optionally substituted cyclic acetal or optionally substituted
heterocyclyl; R.sub.16 represents H or a halogen atom; L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O,
O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XXIX) can be
formed from a glucocorticoid steroid selected from the group
consisting of medrysone, alclometasone, alclometasone dipropionate,
amcinonide, beclometasone, beclomethasone dipropionate,
betamethasone, betamethasone benzoate, betamethasone valerate,
budesonide, ciclesonide, clobetasol, clobetasol butyrate,
clobetasol propionate, clobetasone, clocortolone, cortisol,
cortisone, cortivazol, deflazacort, desonide, desoximetasone,
desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate,
diflucortolone, diflucortolone valerate, difluorocortolone,
difluprednate, fludroxycortide, flumetasone, flumethasone,
flumethasone pivalate, flunisolide, flunisolide, fluocinolone,
fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin
butyl, fluocortolone, fluorocortisone, fluorometholone,
fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone,
fluticasone, fluticasone propionate, formocortal, halcinonide,
halometasone, hydrocortisone, hydrocortisone acetate,
hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone
butyrate, loteprednol, meprednisone, 6.alpha.-methylprednisolone,
methylprednisolone, methylprednisolone acetate, methylprednisolone
aceponate, mometasone, mometasone furoate, mometasone furoate
monohydrate, paramethasone, prednicarbate, prednisolone,
prednisone, prednylidene, rimexolone, tixocortol, triamcinolone,
triamcinolone acetonide, and ulobetasol.
[0335] In particular embodiments, the steroid is a glucocorticoid
steroid and the drug dimer is further described by the formula
(XXX):
##STR00063##
[0336] Wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XXX) can be
formed from the glucocorticoid steroid cortivazol.
[0337] In some embodiments, the steroid is a glucocorticoid steroid
and the drug dimer is further described by the formula (XXXI):
##STR00064##
[0338] wherein R.sub.5 represents H or a halogen atom; R.sub.15
represents a halogen atom or OH; R.sub.16 represents H or a halogen
atom; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XXXI) can be
formed from a glucocorticoid steroid selected from the group
consisting of fluclorolone, fluocinolone, and triamcinolone.
[0339] In particular embodiments, the steroid is a glucocorticoid
steroid and the drug dimer is further described by the formula
(XXXII):
##STR00065##
[0340] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XXXII) can be
formed from fluperolone.
[0341] In some embodiments, the steroid is a glucocorticoid steroid
and the drug dimer is further described by the formula
(XXXIII):
##STR00066##
[0342] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XXXIII) can be
formed from formocortal.
[0343] In particular embodiments, the steroid is a corticosteroid
and the drug dimer is further described by the formula (XXXIV):
##STR00067##
[0344] wherein the bond between C1 and C.sub.2 is a double or a
single bond; Rib represents H or a halogen atom; R.sub.5 represents
H, CH.sub.3, or a halogen atom; C.sub.1-6 represents H or a halogen
atom; R.sub.15 represents .dbd.O or OH; C.sub.1-6 and R.sub.10
each, independently, represent --H, C.sub.1-10 alkyl, --OH,
--O-acyl, or R.sub.11 and R.sub.10 combine to form a cyclic acetal
of formula (XVIII-a) wherein:
##STR00068##
[0345] e is an integer from 0 to 6; R.sub.20, R.sub.21, and
R.sub.22 each, independently, represent H or C.sub.1-10 alkyl; W1
represents H or CH.sub.3; L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XXXIV) can be
formed from a corticosteroid selected from the group consisting of
alclometasone, beclomethasone, betamethasone, betamethasone
valerate, budesonide, chloroprednisone, cloprednol, corticosterone,
cortisone, desonide, desoximerasone, dexamethasone, diflorasone,
diflucortolone, enoxolone, flucloronide, flumethasone, flunisolide,
fluocinolone acetonide, fluocortolone, fluprednisolone,
flurandrenolide, halometasone, hydrocortisone, hydrocortisone
butyrate, meprednisone, methylprednicolone, paramethasone,
prednisolone, prednisone, prednival, prednylidene, triamcinolone,
and triamcinolone acetonide.
[0346] In any of the above formulas (II)-(XXXIV), O--(R.sup.A)--O
can be a radical of a polyol formed from a cyclitol, and sugar
alcohol, or glycerin; or O--(R.sup.A)--O can be a radical formed
from an alkane diol (e.g., a C.sub.1-10 alkane diol), diethylene
glycol, triethylene glycol, tetraethylene glycol, or pentaethylene
glycol.
[0347] In particular embodiments, the steroid is a corticosteroid
and the drug dimer is further described by the formula (XXXV):
##STR00069##
[0348] wherein L is --C(O)--(R.sup.A)--C(O)--, --(R.sup.A)--, or
--C(O)--O--(R.sup.A)--O--C(O)-- and R.sup.A is selected from
C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20
atoms, a linear or branched C.sub.2-20 alkenylene, a linear or
branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms; or L is --O--(R.sup.A)--O-- and R.sup.A is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
and
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; and n, m, and p are
integers from 1 to 10. The drug dimer of formula (XXXV) can be
formed from fusidic acid.
[0349] In particular embodiments, the steroid is a corticosteroid
and the drug dimer is further described by the formula (XXXVI):
##STR00070##
[0350] wherein R.sub.5 represents H or C.sub.1-6 alkyl; R.sub.14
represents H or OH; and L is --C(O)--(R.sup.A)--C(O)--,
--(R.sup.A)--, or --C(O)--O--(R.sup.A)--O--C(O)-- and R.sup.A is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms; or L is
--O--(R.sup.A)--O-- and R.sup.A is selected from C.sub.1-20
alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a
linear or branched C.sub.2-20 alkenylene, a linear or branched
C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3
to 10 atoms, or O--(R.sup.A)--O is a radical of a polyol and
includes at least one free hydroxyl group or O--(R.sup.A)--O is
selected from --O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
and --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; and n, m, and p
are integers from 1 to 10. The drug dimer of formula (XXXVI) can be
formed from chenodeoxycholic acid, ursodeoxycholic acid, or
obeticholic acid.
[0351] In particular embodiments, the steroid is an anti-angiogenic
steroid or an intraocular pressure (IOP) lowering steroid, and the
drug dimer is further described by the formula (XXXVII):
##STR00071##
[0352] wherein Rig represents
--C(.dbd.O)CH.sub.2OC(.dbd.O)CH.sub.3, --C(.dbd.O)CH.sub.2OH, or
--C(.dbd.O)CH.sub.3; R.sub.15 represents H or OH; and L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XXXVII) can be
formed from anecortave acetate, anecortave, 11-epicortisol,
17.alpha.-hydroxyprogesterone, tetrahydrocortexolone, or
tetrahydrocortisol.
[0353] In particular embodiments, the steroid is an anti-angiogenic
steroid or an intraocular pressure (IOP) lowering steroid, and the
drug dimer is further described by the formula (XXXVIII):
##STR00072##
[0354] wherein the bond between C.sub.3 and R.sub.2 is a single or
a double bond; R.sub.2 represents OH or .dbd.O; R.sub.12 represents
--C(.dbd.O)CH.sub.2OC(.dbd.O)CH.sub.3, --C(.dbd.O)CH.sub.2OH, or
--C(.dbd.O)CH.sub.3, R.sub.15 represents H or OH; and L is
[0355] --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0356] --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m,
and p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XXXVIII) can be formed from anecortave acetate,
anecortave, 11-epicortisol, 17.alpha.-hydroxyprogesterone,
tetrahydrocortexolone, or tetrahydrocortisol.
[0357] In particular embodiments, the steroid is an anti-angiogenic
steroid or an intraocular pressure (IOP) lowering steroid, and the
drug dimer is further described by the formula (XXXIX):
##STR00073##
[0358] wherein the bond between C.sub.3 and R.sub.2 is a single or
a double bond; R.sub.2 represents OH or .dbd.O; R.sub.15 represents
H or OH; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(O)--C(O)--; R.sup.A is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and
p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XXXIX) can be formed from anecortave,
11-epicortisol, tetrahydrocortexolone, or tetrahydrocortisol.
[0359] In particular embodiments, the steroid is an anti-angiogenic
steroid or an intraocular pressure (IOP) lowering steroid, and the
drug dimer is further described by the formula (XL):
##STR00074##
[0360] wherein the bond between C.sub.3 and R.sub.2 is a single or
a double bond; R.sub.2 represents OH or .dbd.O; and L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XL) can be
formed from 11-epicortisol or tetrahydrocortisol.
[0361] In particular embodiments, the steroid is a benign steroid
and the drug dimer is further described by the formula (XLI):
##STR00075##
[0362] wherein the bond between C.sub.11 and R.sub.15 is a single
or a double bond; R.sub.11 represents H, OH, --C(.dbd.O)CH.sub.2OH,
or --C(.dbd.O)CH.sub.3; R.sub.12 represents H, OH,
--C(.dbd.O)CH.sub.2OH, or --C(.dbd.O)CH.sub.3; R.sub.15 represents
H, .dbd.O, or OH; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XLI) can be
formed from tetrahydrocortisone, tetrahydrodeoxycortisol,
tetrahydrocorticosterone, 5.alpha.-dihydrocorticosterone, or
5.alpha.-dihydropregesterone.
[0363] In particular embodiments, the steroid is a benign steroid
and the drug dimer is further described by the formula (XLII):
##STR00076##
[0364] wherein the bond between C.sub.11 and R.sub.15 is a single
or a double bond; R.sub.15 represents H or .dbd.O; and L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XLII) can be
formed from tetrahydrocortisone, or tetrahydrodeoxycortisol.
[0365] In particular embodiments, the steroid is a benign steroid
and the drug dimer is further described by the formula (XLIII):
##STR00077##
[0366] wherein the bond between C.sub.3 and R.sub.2, and C.sub.11
and R.sub.15 is a single or a double bond; R.sub.2 represents OH or
.dbd.O; R.sub.11 represents H, or OH; R.sub.15 represents H,
.dbd.O, or OH; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
--O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XLIII) can be
formed from tetrahydrocortisone, tetrahydrodeoxycortisol,
tetrahydrocorticosterone, or 5.alpha.-dihydrocorticosterone.
[0367] In particular embodiments, the steroid is a benign steroid
and the drug dimer is further described by the formula (XLIV):
##STR00078##
[0368] wherein the bond between C3 and R.sub.2 is a single or a
double bond; R.sub.2 represents OH or .dbd.O; R.sub.11 represents H
or OH; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XLIV) can be
formed from tetrahydrocortisone, tetrahydrocorticosterone, or
5.alpha.-dihydrocorticosterone.
[0369] In particular embodiments, the steroid is a cholic
acid-related bile acid steroid and the drug dimer is further
described by the formula (XLV):
##STR00079##
[0370] wherein the bond between C.sub.7 and R.sub.6, and C.sub.12
and R.sub.14 is a single or a double bond; Rx represents OH,
--NHCH.sub.2C(.dbd.O)OH, or --NHCH.sub.2CH.sub.2SO2OH; R.sub.2
represents OH or .dbd.O; R.sub.5 represents H or OH; R.sub.6
represents H, .dbd.O, or OH; R.sub.14 represents H, .dbd.O, or OH;
and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XLV) can be
formed from deoxycholic acid, apocholic acid, dehydrocholic acid,
glycochenodeoxycholic acid, glycocholic acid, glycodeoxycholic
acid, hyodeoxycholic acid, lithocholic acid, .alpha.-muricholic
acid, .beta.-muricholic acid, .gamma.-muricholic acid,
.omega.-muricholic acid, taurochenodeoxycholic acid, taurocholic
acid, taurodeoxycholic acid, taurolithocholic acid, or
tauroursodeoxycholic acid.
[0371] In particular embodiments, the steroid is a cholic
acid-related bile acid steroid and the drug dimer is further
described by the formula (XLVI):
##STR00080##
[0372] wherein the bond between C.sub.3 and R.sub.2, and C.sub.7
and R.sub.6 is a single or a double bond; Rx represents OH,
--NHCH.sub.2C(.dbd.O)OH, or --NHCH.sub.2CH.sub.2SO2OH; R.sub.2
represents OH or .dbd.O; R.sub.6 represents H, .dbd.O, or OH; and L
is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XLVI) can be
formed from deoxycholic acid, apocholic acid, dehydrocholic acid,
glycocholic acid, glycodeoxycholic acid, taurocholic acid, or
taurodeoxycholic acid.
[0373] In particular embodiments, the steroid is a cholic
acid-related bile acid steroid and the drug dimer is further
described by the formula (XLVII):
##STR00081##
[0374] wherein R.sub.6 represents H or OH; and L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
[0375]
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O-
--, or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (XLVII) can be formed from hyodeoxycholic acid,
.alpha.-muricholic acid, .beta.-muricholic acid, .gamma.-muricholic
acid, or .omega.-muricholic acid.
[0376] In particular embodiments, the steroid is a cholic
acid-related bile acid steroid and the drug dimer is further
described by the formula (XLVIII):
##STR00082##
[0377] wherein the bond between C.sub.3 and R.sub.2, and C.sub.12
and R.sub.14 is a single or a double bond; Rx represents OH,
--NHCH.sub.2C(.dbd.O)OH, or --NHCH.sub.2CH.sub.2SO2OH; R.sub.2
represents OH or .dbd.O; R.sub.5 represents H or OH; R.sub.14
represents H, .dbd.O, or OH; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (XLVIII) can be
formed from dehydrocholic acid, glycochenodeoxycholic acid,
glycocholic acid, .alpha.-muricholic acid, .beta.-muricholic acid,
.gamma.-muricholic acid, .omega.-muricholic acid,
taurochenodeoxycholic acid, taurocholic acid, or
tauroursodeoxycholic acid.
[0378] In particular embodiments, the steroid is a cholic
acid-related bile acid steroid and the drug dimer is further
described by the formula (XLIX):
##STR00083##
[0379] wherein the bond between C.sub.3 and R.sub.2, C7 and
R.sub.6, and C.sub.12 and R.sub.14 is a single or a double bond;
R.sub.2 represents OH or .dbd.O; R.sub.5 represents H or OH;
R.sub.6 represents H, .dbd.O, or OH; R.sub.14 represents H, .dbd.O,
or OH; and L is --C(O)--(R.sup.A)--C(O)--, --(R.sup.A)--, or
--C(O)--O--(R.sup.A)--O--C(O)-- and R.sup.A is selected from
C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20
atoms, a linear or branched C.sub.2-20 alkenylene, a linear or
branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms; or L is --O--(R.sup.A)--O-- and R.sup.A is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
and
[0380] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; and n, m, and
p are integers from 1 to 10. The drug dimer of formula (XLIX) can
be formed from deoxycholic acid, apocholic acid, dehydrocholic
acid, hyodeoxycholic acid, lithocholic acid, .alpha.-muricholic
acid, .beta.-muricholic acid, .gamma.-muricholic acid, or
w-muricholic acid.
[0381] In particular embodiments, the steroid is a cholic
acid-related bile acid steroid and the drug dimer is further
described by the formula (L):
##STR00084##
[0382] wherein R.sub.6 represents H or OH; R.sub.14 represents H or
OH; and L is --C(O)--(R.sup.A)--C(O)--, --(R.sup.A)--, or
--C(O)--O--(R.sup.A)--O--C(O)-- and R.sup.A is selected from
C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20
atoms, a linear or branched C.sub.2-20 alkenylene, a linear or
branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms; or L is --O--(R.sup.A)--O-- and R.sup.A is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
and --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; and n, m, and p
are integers from 1 to 10. The drug dimer of formula (L) can be
formed from glycochenodeoxycholic acid, glycocholic acid, or
glycodeoxycholic acid.
[0383] In particular embodiments, the steroid is a steroid
metabolite and the drug dimer is further described by the formula
(LI):
##STR00085##
[0384] wherein the bond between C.sub.11 and R.sub.15 is a single
or a double bond; R.sub.2 represents OH or .dbd.O; R.sub.10
represents H or OH; R.sub.11 represents H, OH,
--C(.dbd.O)CH.sub.2OH, --C(.dbd.O)OH, --C(.dbd.O)CH.sub.2OH, or
--C(.dbd.O)CH.sub.3; R.sub.12 represents H, OH,
--C(.dbd.O)CH.sub.2OH, --C(.dbd.O)OH, --C(.dbd.O)CH.sub.2OH, or
--C(.dbd.O)CH.sub.3; R13 represents --CH.sub.2OH or --CH.sub.3;
R.sub.15 represents H, OH, or .dbd.O; R.sub.16 represents H or F;
and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0385] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LI) can be formed from tetrahydrotriamcinolone,
cortienic acid, 11-dehydrocorticosterone, 110-hydroxypregnenolone,
ketoprogesterone, 17-hydroxypregnenolone,
17,21-dihydroxypregnenolone, 18-hydroxycorticosterone,
deoxycortisone, 21-hydroxypregnenolone, or progesterone.
[0386] In particular embodiments, the steroid is a steroid
metabolite and the drug dimer is further described by the formula
(LII):
##STR00086##
[0387] wherein the bond between C.sub.3 and R.sub.2, and C.sub.11
and R.sub.15 is a single or a double bond; R.sub.2 represents OH or
.dbd.O; R.sub.10 represents H or OH; R.sub.12 represents
--C(.dbd.O)CH.sub.2OH, --C(.dbd.O)OH, --C(.dbd.O)CH.sub.2OH, or
--C(.dbd.O)CH.sub.3; R.sub.15 represents H, OH, or .dbd.O; R.sub.16
represents H or F; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LII) can be
formed from tetrahydrotriamcinolone, cortienic acid,
17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, or
deoxycortisone.
[0388] In particular embodiments, the steroid is a steroid
metabolite and the drug dimer is further described by the formula
(LIII):
##STR00087##
[0389] wherein L is --C(O)--(R.sup.A)--C(O)--, --(R.sup.A)--, or
--C(O)--O--(R.sup.A)--O--C(O)-- and R.sup.A is selected from
C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20
atoms, a linear or branched C.sub.2-20 alkenylene, a linear or
branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms; or L is --O--(R.sup.A)--O-- and R.sup.A is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
and --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; and n, m, and p
are integers from 1 to 10. The drug dimer of formula (LIII) can be
formed from cortienic acid.
[0390] In particular embodiments, the steroid is a steroid
metabolite and the drug dimer is further described by the formula
(LIV):
##STR00088##
[0391] wherein the bond between C.sub.3 and R.sub.2, and C.sub.11
and R.sub.15 is a single or a double bond; R.sub.2 represents OH or
.dbd.O; R.sub.10 represents H or OH; R.sub.11 represents H or OH;
R13 represents H, --CH.sub.2OH, or --CH.sub.3; R.sub.15 represents
H, OH, or .dbd.O; R.sub.16 represents H or F; and L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and
p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LIV) can be formed from tetrahydrotriamcinolone,
11-dehydrocorticosterone, 17,21-dihydroxypregnenolone,
18-hydroxycorticosterone, or 21-hydroxypregnenolone.
[0392] In particular embodiments, the steroid is a steroid
metabolite and the drug dimer is further described by the formula
(LV):
##STR00089##
[0393] wherein the bond between C.sub.3 and R.sub.2 is a single or
a double bond; R.sub.2 represents OH or .dbd.O; R.sub.10 represents
H or OH; R.sub.11 represents H or OH; R.sub.12 represents
--C(.dbd.O)CH.sub.2OH, --C(.dbd.O)OH, --C(.dbd.O)CH.sub.2OH, or
--C(.dbd.O)CH.sub.3; R13 represents H, --CH.sub.2OH, or --CH.sub.3;
Rib represents H or F; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(O)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--; R.sup.A is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0394] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LV) can be formed from tetrahydrotriamcinolone,
cortienic acid, 11-dehydrocorticosterone, 110-hydroxypregnenolone,
ketoprogesterone, 18-hydroxycorticosterone, or deoxycortisone.
[0395] In particular embodiments, the steroid is a steroid
metabolite and the drug dimer is further described by the formula
(LVI):
##STR00090##
[0396] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0397] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LVI) can be formed from
tetrahydrotriamcinolone.
[0398] In particular embodiments, the steroid is a steroid
metabolite and the drug dimer is further described by the formula
(LVII):
##STR00091##
[0399] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0400] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LVII) can be formed from
18-hydroxycorticosterone.
[0401] In particular embodiments, the steroid is a
cholesterol-derivative and the drug dimer is further described by
the formula (LVIII):
##STR00092##
[0402] wherein Ry represents H or OH; and L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LVIII) can be
formed from 22R-hydroxycholesterol or
20.alpha.-22R-dihydroxycholesterol.
[0403] In particular embodiments, the steroid is a
cholesterol-derivative and the drug dimer is further described by
the formula (LIX):
##STR00093##
[0404] wherein Ry represents H or OH; and L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and
p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LIX) can be formed from 22R-hydroxycholesterol or
20.alpha.-22R-dihydroxycholesterol.
[0405] In particular embodiments, the steroid is a
cholesterol-derivative and the drug dimer is further described by
the formula (LX):
##STR00094##
[0406] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
--O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LX) can be
formed from 20.alpha.-22R-dihydroxycholesterol.
[0407] In particular embodiments, the steroid is a neurosteroid and
the drug dimer is further described by the formula (LXI):
##STR00095##
[0408] wherein the bond between C.sub.11 and R.sub.15 is a single
or a double bond; Rz represents H or --CH.sub.3; R1 represents H or
--OCH.sub.2CH.sub.3; R.sub.2 represents OH or .dbd.O; R.sub.12
represents --OH, --C(.dbd.O)CH.sub.3, --C(.dbd.O)CH.sub.2OH, or
--CH(CH.sub.3)(CH.sub.2)2CH(OH)CH(CH.sub.3)2; R.sub.15 represents
H, --N(CH.sub.3)2, or .dbd.O; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0409] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LXI) can be formed from alphaxalone, alphadolone,
hydroxydione, minaxolone, tetrahydrodeoxycorticosterone,
allopregnanolone, pregnanolone, ganoxolone,
3.alpha.-androstanediol, epipregnanolone, isopregnanolone, or
24(S)-hydroxycholesterol.
[0410] In particular embodiments, the steroid is a neurosteroid and
the drug dimer is further described by the formula (LXII):
##STR00096##
[0411] wherein Rig represents --C(.dbd.O)CH.sub.3, or
--C(.dbd.O)CH.sub.2OH; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(RA)-O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LXII) can be
formed from alphaxalone or alphadolone.
[0412] In particular embodiments, the steroid is a neurosteroid and
the drug dimer is further described by the formula (LXIII):
##STR00097##
[0413] wherein the bond between C.sub.3 and R.sub.2, and CH and
R.sub.15 is a single or a double bond; R.sub.2 represents OH or
.dbd.O; R.sub.15 represents H or .dbd.O; and L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LXIII) can be
formed from alphadolone, hydroxydione, or
tetrahydrodeoxycorticosterone.
[0414] In particular embodiments, the steroid is a neurosteroid and
the drug dimer is further described by the formula (LXIV):
##STR00098##
[0415] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LXIV) can be
formed from 3.alpha.-androstanediol.
[0416] In particular embodiments, the steroid is a neurosteroid and
the drug dimer is further described by the formula (LXV):
##STR00099##
[0417] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
[0418] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LXV) can be formed from
24(S)-hydroxycholesterol.
[0419] In particular embodiments, the steroid is a pheromone and
the drug dimer is further described by the formula (LXVI):
##STR00100##
[0420] wherein R.sub.2 represents OH or .dbd.O; R.sub.11 represents
H, --C(.dbd.O)CH.sub.3, --OC(.dbd.O)(CH.sub.2)4CH.sub.3, or is
absent; R.sub.12 represents H, --C(.dbd.O)CH.sub.3,
--OC(.dbd.O)(CH.sub.2)4CH.sub.3, or is absent; R17 represents
CH.sub.3 or is absent; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0421] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LXVI) can be formed from androstadienol,
androstadienone, androstenol, androstenone, estratetraenol,
5-dehydroprogesterone, 6-dehydro-retroprogesterone,
allopregnanolone, or hydroxyprogesterone caproate.
[0422] In particular embodiments, the steroid is a progestin and
the drug dimer is further described by the formula (LXVII):
##STR00101##
[0423] wherein the bond between C.sub.11 and R.sub.15 is a single
or a double bond; R.sub.2 represents OH or .dbd.O; R.sub.11
represents H, OH, --CH(OH)CH.sub.3, --C(.dbd.O)CH.sub.2OH,
--C(.dbd.O)CH.sub.3, or --CH(OH)CH.sub.2OH; R.sub.12 represents H,
OH, --CH(OH)CH.sub.3, --C(.dbd.O)CH.sub.2OH, --C(.dbd.O)CH.sub.3,
or --CH(OH)CH.sub.2OH; R.sub.15 represents H, .dbd.O, or OH; and L
is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or
--O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LXVII) can be
formed from allopregnone-3.alpha.,20.alpha.-diol,
allopregnone-3.beta.,20.beta.-diol,
allopregnane-3.beta.,21-diol-11,20-dione,
allopregnane-3.beta.,17.alpha.-diol-20-one, 3,20-allopregnanedione,
3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol,
allopregnane-3.beta.,17.alpha.,20.beta.,21-tetrol,
allopregnane-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,17.alpha.,20.beta.-triol,
allopregnane-3.beta.,17.alpha.,21-triol-11,20-dione,
allopregnane-3.beta.,11.beta.,21-triol-20-one,
allopregnane-3.beta.,17.alpha.,21-triol-20-one,
allopregnane-3.alpha.-ol-20-one; allopregnane-3.beta.-ol-20-one,
pregnanediol, 3,20-pregnanedione, 4-pregnene-20,21-diol-3,11-dione,
4-pregnene-11.beta.,17.alpha.,20.beta.,21-tetrol-3-one,
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione,
4-pregnene-17.alpha.,20.beta.,21-triol-3-one, or pregnenolone.
[0424] In particular embodiments, the steroid is a progestin and
the drug dimer is further described by the formula (LXVIII):
##STR00102##
[0425] wherein the bond between C.sub.3 and R.sub.2, and C.sub.11
and R.sub.15 is a single or a double bond; R.sub.2 represents OH or
.dbd.O; R.sub.12 represents H, OH, --CH(OH)CH.sub.3,
--C(.dbd.O)CH.sub.2OH, --C(.dbd.O)CH.sub.3, or --CH(OH)CH.sub.2OH;
R.sub.15 represents H, .dbd.O, or OH; and L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LXVIII) can be
formed from allopregnane-3.beta.,17.alpha.-diol-20-one,
3,20-allopregnanedione,3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol,
allopregnane-3.beta.,17.alpha.,20.beta.,21-tetrol,
allopregnane-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,17.alpha.,20.beta.-triol,
allopregnane-3.beta.,17.alpha.,21-triol-11,20-dione,
allopregnane-3.beta.,17.alpha.,21-triol-20-one,
4-pregnene-11.beta.,17.alpha.,20.beta.,21-tetrol-3-one,
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione, or
4-pregnene-17.alpha.,20.beta.,21-triol-3-one.
[0426] In particular embodiments, the steroid is a progestin and
the drug dimer is further described by the formula (LXIX):
##STR00103##
[0427] wherein R11 represents H, OH, --CH(OH)CH.sub.3,
--C(.dbd.O)CH.sub.2OH, --C(.dbd.O)CH.sub.3, or --CH(OH)CH.sub.2OH;
R.sub.15 represents H or OH; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LXIX) can be
formed from allopregnone-3.alpha.,20.alpha.-diol,
allopregnone-3.beta.,20.beta.-diol or
allopregnane-3.beta.,17.alpha.,20.beta.-triol.
[0428] In particular embodiments, the steroid is a progestin and
the drug dimer is further described by the formula (LXX):
##STR00104##
[0429] wherein the bond between C.sub.3 and R.sub.2, and C.sub.11
and R.sub.15 is a single or a double bond; Ry represents OH or
.dbd.O; R.sub.2 represents OH or .dbd.O; R.sub.11 represents H, OH,
--CH(OH)CH.sub.3, --C(.dbd.O)CH.sub.2OH, --C(.dbd.O)CH.sub.3, or
--CH(OH)CH.sub.2OH; Rig represents H, OH, --CH(OH)CH.sub.3,
--C(.dbd.O)CH.sub.2OH, --C(.dbd.O)CH.sub.3, or --CH(OH)CH.sub.2OH;
R.sub.15 represents H, .dbd.O, or OH; and L is
--C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LXX) can be
formed from allopregnane-3.beta.,21-diol-11,20-dione,
3,20-allopregnanedione,3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol,
allopregnane-3.beta.,17.alpha.,20.beta.,21-tetrol,
allopregnane-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,17.alpha.,21-triol-11,20-dione,
allopregnane-3.beta.,11.beta.,21-triol-20-one,
allopregnane-3.beta.,17.alpha.,21-triol-20-one,
4-pregnene-20,21-diol-3,11-dione,
4-pregnene-11.beta.,17.alpha.,20.beta.,21-tetrol-3-one,
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione, or
4-pregnene-17.alpha.,20.beta.,21-triol-3-one.
[0430] In particular embodiments, the steroid is a progestin and
the drug dimer is further described by the formula (LXXI):
##STR00105##
[0431] wherein the bond between C.sub.3 and R.sub.2 is a single or
a double bond; R.sub.2 represents OH or .dbd.O; R.sub.11 represents
H, OH, --CH(OH)CH.sub.3, --C(.dbd.O)CH.sub.2OH,
--C(.dbd.O)CH.sub.3, or --CH(OH)CH.sub.2OH; R.sub.12 represents H,
OH, --CH(OH)CH.sub.3, --C(.dbd.O)CH.sub.2OH, --C(.dbd.O)CH.sub.3,
or --CH(OH)CH.sub.2OH; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and
p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LXXI) can be formed from
allopregnane-3.beta.,21-diol-11,20-dione,
3,20-allopregnanedione,3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol,
allopregnane-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,17.alpha.,21-triol-11,20-dione,
allopregnane-3.beta.,11.beta.,21-triol-20-one,
4-pregnene-20,21-diol-3,11-dione,
4-pregnene-11.beta.,17.alpha.,20.beta.,21-tetrol-3-one, or
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione.
[0432] In particular embodiments, the steroid is a progestin and
the drug dimer is further described by the formula (LXXII):
##STR00106##
[0433] wherein the bond between C.sub.3 and R.sub.2, and C.sub.11
and R.sub.15 is a single or a double bond; R.sub.2 represents OH or
.dbd.O; R.sub.11 represents H or OH; R.sub.15 represents H, .dbd.O,
or OH; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p are
integers from 1 to 10; and each R.sup.B is independently selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms. The drug dimer of formula (LXXII) can be
formed from
3,20-allopregnanedione,3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol,
allopregnane-3.beta.,17.alpha.,20.beta.,21-tetrol,
4-pregnene-20,21-diol-3,11-dione,
4-pregnene-11.beta.,17.alpha.,20.beta.,21-tetrol-3-one,
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione, or
4-pregnene-17.alpha.,20.beta.,21-triol-3-one.
[0434] In particular embodiments, the steroid is other steroid and
the drug dimer is further described by the formula (LXXIII):
##STR00107##
[0435] wherein the bond between C16 and R.sub.10 is a single or a
double bond; R.sub.2 represents OH or .dbd.O; R.sub.5 represents H,
Cl, or --CH.sub.3; R.sub.10 represents H or .dbd.CH.sub.2; R.sub.11
represents H, OH, --CH.sub.3, --C(.dbd.O)CH.sub.3,
--C(.dbd.O)CH.sub.2OC(.dbd.O)CH.sub.3, or --OC(.dbd.O)CH.sub.3;
R.sub.12 represents H, OH, --CH.sub.3, --C(.dbd.O)CH.sub.3,
--C(.dbd.O)CH.sub.2OC(.dbd.O)CH.sub.3, or --OC(.dbd.O)CH.sub.3;
R.sub.15 represents H or OH; Rib represents F or H; R.sub.17
represents H or --CH.sub.3; and L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m, and
p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LXXIII) can be formed from flugestone,
prebediolone, chlormadinone acetate, medrogestone, or segesterone
acetate.
[0436] In particular embodiments, the steroid is other steroid and
the drug dimer is further described by the formula (LXXIV):
##STR00108##
[0437] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0438] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; n, m, and p
are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LXXIV) can be formed from flugestone.
[0439] In particular embodiments, the steroid is a other steroid
and the drug dimer is further described by the formula (LXXV):
##STR00109##
[0440] wherein L is --C(O)O--(R.sup.A)--OC(O)--,
--C(O)--OC(O)--(R.sup.A)--C(O)O--C(O)--, or
--C(O)--(R.sup.B)--C(O)O--(R.sup.A)--OC(O)--(R.sup.B)--C(O)--;
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and includes at least one
free hydroxyl group or O--(R.sup.A)--O is selected from:
O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--
-, or
[0441] --O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; n, m,
and p are integers from 1 to 10; and each R.sup.B is independently
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. The drug
dimer of formula (LXXV) can be formed from flugestone.
[0442] Formulations
[0443] 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), nanoparticles (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 or any other form shaping process with or without a
dye mold). Suitable pharmaceutical compositions for use with this
disclosure can be small regularly or irregularly shaped particles,
which can be solid, porous, or hollow.
[0444] 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
[0445] Articles of the disclosure can be formed using any number of
the methods, for example, heat processing or solvent processing of
the drug 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.
Electrospraying Method
[0446] 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.
Fiber Spinning Methods
[0447] 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.
[0448] 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.
[0449] 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.
Emulsion Method
[0450] 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.
Extrusion Method
[0451] 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.
Bead Sizing and Milling
[0452] 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 cryo-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.
Low Temperature Processing Using Intermediate Glassy State
Articles
[0453] In certain embodiments, the 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 prodrug dimer in the
article.
[0454] Exemplary processing details are provided in the
Examples.
Drug Delivery
[0455] The pharmaceutical compositions of the disclosure provide
optimal delivery of a drug as they release the drug 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 (shape), 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 (e.g., release of less
than 10% of D1 or D2 (as a percentage of the total drug, D1 or D2,
present in the fiber in prodrug form) at 37.degree. C. in 100%
bovine serum over 5 days) 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.
Depending on the indication and the drug, the drug release can be
tailored for dose and duration appropriate to the indication of
interest.
[0456] The rate of release of a drug can depend on many factors,
for example, the drug composition of the drug dimer. Drug release
rate from the formed object of the drug dimer can be modulated by
the cleavage of drug-linker bond through hydrolysis or enzymatic
degradation. Therefore, the selection of linking moiety can affect
drug release rate. Further, the drug release rate can be controlled
by the selection of the functional group on the drug to conjugate
through to the linker, for example, a primary vs. a secondary
steroid hydroxyl group. The rate of release of a given drug from a
drug 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 (e.g., bulking agent/excipient) or a
second steroid drug (e.g., active or benign) as a homodimer
mixture, or within the same molecule as a heterodimer 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 drug dimer (e.g., through selection of appropriate drug and/or
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
[0457] In some embodiments, the drug 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., polyvvinylpyrrolidone (PVP), starch paste, pregelatinized
starch, hydroxypropyl methyl cellulose (HPMC), carboxymethyl
cellulose (CMC), or polyethylene glycol (PEG) 6000.
[0458] 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).
[0459] Pharmaceutical compositions containing the drug 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.
[0460] The articles of the disclosure described herein including a
drug 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.
[0461] 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 drug dimers
and local blood flow before and after administration of the
therapeutic formulation.
Sterilization of Formulations
[0462] 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
[0463] 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,
orthopedics, pain management, and gynecology.
[0464] The compound of the disclosure can be selected for the
desired property, such as corticosteroid dimers for use in treating
inflammatory diseases or conditions; the use of antibiotic steroid
dimers for treating an infection; or the use of an anticancer
steroid dimer for treating a proliferative disorder.
Ophthalmic Uses
[0465] 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.
[0466] 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.
[0467] 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 (e.g., where the drug dimer is formed from one
or more corticosteroids). 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 certain embodiments, the
pharmaceutical agent includes one or more of hydrocortisone,
cortisone, tixocortol, prednisolone, methylprednisolone,
prednisone, triamcinolone acetonide, mometasone, amcinonide,
budesonide, desonide, fluocinonide, fluocinolone, halcinonide,
betamethasone, dexamethasone, fluocortolone, hydrocortisone,
aclometasone, prednicarbate, clobetasone, clobetasol,
fluprednidene, glucocorticoid, mineralocorticoid, aldosterone,
deoxycorticosterone, fludrocortisone, halobetasol, diflorasone,
desoximetasone, fluticasone, flurandrenolide, alclometasone,
diflucortolone, flunisolide, and beclomethasone. In some
embodiments, the drug dimer 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.
Osteoarthritis Treatment
[0468] 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. Exemplary steroids used
in the treatment of OA are betamethasone, methylprednisolone,
dexamethasone, and triamcinolone acetonide. In some embodiments,
microspheres of the disclosure composed of the drug dimers are
injected into a knee joint for the treatment of OA.
Surgical Procedures
[0469] 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 infection, inflammation, or the recurrence of disease (such
as a cancer) treated by the surgical procedure.
EXAMPLES
[0470] 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. Compounds 1-17 can be used in
the methods, compositions, and articles of the disclosure.
TABLE-US-00001 Compound Dimer Abbreviation 1
Dexamethasone-Triethylene Dex-TEG-Dex Glycol-Dexamethasone 2
Hydrocortisone-Triethylene HC-TEG-HC Glycol-Hydrocortisone 3
Triamcinolone Acetonide- TA-TEG-TA Triethylene Glycol-
Triamcinolone Acetonide 4 Dexamethasone-Triethylene Dex-TEG-HC
Glycol-Hydrocortisone 5 Dexamethasone-Hexane- Dex-HEX-Dex
Dexamethasone 6 Hydrocortisone-Succinate- HC-SUCC-HC Hydrocortisone
7 Anecortave-Triethylene Anec-TEG-Anec Glycol-Anecortave 8
Dexamethasone-Pentaethylene Dex-EG5-Dex Glycol-Dexamethasone 9
Fusidic Acid-Triethylene FA-TEG-FA Glycol-Fusidic Acid (carbonate
(CE) ester) 10 Dexamethasone-Polyethylene Dex-PEG200- Glycol (MW =
200)- Dex Dexamethasone 11 Dexamethasone-Heptaethylene Dex-EG7-Dex
Glycol-Dexamethasone 12 Dexamethasone-Nonaethylene Dex-EG9-Dex
Glycol-Dexamethasone 13 Dexamethasone-Polyethylene Dex-PEG300-
Glycol (MW = 300)- Dex Dexamethasone 14 Cholesterol-Triethylene
CHS-TEG-CHS Glycol-Cholesterol 15 Fusidic Acid-Triethylene
FA-TEG-FA (E) Glycol-Fusidic Acid (ester) 16
Ethinylestradiol-Triethylene Ethin-TEG-Ethin
Glycol-Ethinylestradiol 17 Prednisolone-Triethylene Pred-TEG-Pred
Glycol-Prednisolone
Example 1. Compound 1 (Dex-TEG-Dex) can be Synthesized, Processed
into Pellets in the Glassy State by Heat Molding, and Release Drug
Through Surface Erosion from an Intact Pellet
[0471] 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 from acetonitrile twice
to give Compound 1 (FIG. 1A) as an off-white crystalline solid.
[0472] Compound 1: HPLC (mobile phase: H2O/TFA and MeCN/TFA) 31.7
min; Elemental analysis: Anal. Calcd for C.sub.52H68F2O16: C,
63.27; H, 6.94; N, 0.00; Cl, 0.00 Found: C, 62.62; H, 6.84; N,
<0.50; C1<100 ppm. 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.C.sub.6--CH.sub.2); 2.32 (m, 4H,
2.times.C.sub.7--CH.sub.2); 2.62 (m, 2H,
2.times.C.sub.12--CH.sub.2); 2.89 (m, 2H,
2.times.C.sub.12--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, C.sub.21-CH.sub.2O--); 5.09 (d, 2H, AB, J=18.5 Hz, 2H,
C.sub.21-CH.sub.2O--); 5.18 (s, 2H, C.sub.17--OH); 5.40 (d, 2H,
J=4.5 Hz, C.sub.11--OH); 6.01 (d, 2H, J=1.9 Hz, 2.times.alkene
C.sub.4--CH); 6.23 (dd, 2H, J=10.1 and 1.9 Hz, CH, 2.times.alkene
C.sub.2--CH); 7.29 (d, 2H, C1-CH2.times.alkene CH, 10.1 Hz, 2H). MS
(ESI+) m/z: [M+H]+ Calcd for C.sub.52H69F2O16 987.46; Found
987.46.
[0473] 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 calimetry (DSC; FIG. 1C) and
powder x-ray diffraction (PXRD; FIG. 1D) to confirm heat-processing
converted compound 1 from the crystalline state to the glassy
state.
[0474] 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
[0475] 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.0.35 mm diameter and 0.8 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
[0476] 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.).
[0477] 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
PXRD (FIG. 3F) to confirm the meshes were in the glassy state.
[0478] 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.
[0479] 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).
[0480] 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 from Compound 1 (Dex-TEG-Dex) Coated on
Different Surfaces
[0481] 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. 4).
Example 5: 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
[0482] Compound 1 was heat-molded into pellets with 1 mm and 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
the table 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. 5 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. Sample Pellet Dimensions
Number of Total Mass of Total 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 6: Mechanical Testing of Extruded Cylinders of Compound 1
(Dex-TEG-Dex) Using a 3 Point Bend Test (ASTM C1684-18)
[0483] 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.
6.
Example 7: Ethylene Oxide Gas Sterilization of Heat Molded Pellets
of Compound 1 (Dex-TEG-Dex)
[0484] 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. 7A) and drug release (FIG. 7B) 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 8: Processing Compound 1 (Dex-TEG-Dex) into an Intermediate
Glassy State to Manufacture the Final Article
[0485] 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. 8A and 8B, 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.
8C and 8D. Purity of the extrudate over time is shown in FIG. 8E
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. 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
150.degree. C. to obtain a coating as shown in FIG. 8F.
Example 9: Synthesis of Compounds
[0486] The compounds in Table 3, below, were synthesized using
standard methods known in the art, similar to the synthesis of
Compound 1 in Example 1 above. Details of the synthesized compounds
are also shown in the table below. All compounds were synthesized
to HPLC purity of >98% and structures were confirmed by 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 Structure of Compounds Compound Linking Tm
& (Abbreviation) Steroid Linker Moiety Structure Tg (.degree.
C.) 2 Hydrocortisone Triethylene Carbonate FIG. 9A 127 &
(HC-TEG-HC) Glycol 113 3 Triamcinolone Triethylene Carbonate FIG.
10A 183 & (TA-TEG-TA) Acetonide Glycol 138 4 Dexamethasone
Triethylene Carbonate FIG. 11A 143 & (Dex-TEG-HC) & Glycol
120 Hydrocortisone 5 Dexamethasone Hexane Diol Carbonate FIG. 12A
149 & (Dex-HEX-Dex) 146 6 Hydrocortisone Succinic Acid Ester
FIG. 13A 157 & (HC-SUCC-HC) 144 7 Anecortave Triethylene
Carbonate FIG. 14A 102 & (Anec-TEG- Glycol 100 Anec) 8
Dexamethasone Pentaethylene Carbonate FIG. 15A n.d.* &
(Dex-EG5-Dex) Glycol 66 9 Fusidic Acid Triethylene Carbonate FIG.
16A 91 & 85 (FA-TEG-FA Glycol Ester (CE)) 10 Dexamethasone
Polyethylene Carbonate FIG. 17A n.d.* & (Dex-PEG200- Glycol (MW
= 96 Dex) 200) 11 Dexamethasone Heptaethylene Carbonate FIG. 23D 51
& 47 (Dex-EG7-Dex) Glycol 12 Dexamethasone Nonaethylene
Carbonate FIG. 24A 41 & 37 (Dex-EG9-Dex) Glycol 13
Dexamethasone Polyethylene Carbonate FIG. 25A 77 & 75
(Dex-PEG300- Glycol (MW = Dex) 300) 14 Cholesterol Triethylene
Carbonate FIG. 27A 99 & 22 (CHS-TEG-CHS) Glycol 15 Fusidic Acid
Triethylene Ester FIG. 28A 87 & 84 (FA-TEG-FA (E)) Glycol 16
Ethinylestradiol Triethylene Carbonate FIG. 29A 61 & 53
(Ethin-TEG- Glycol Ethin) 17 Prednisolone Triethylene Carbonate
FIG. 30A 128 & (Pred-TEG-Pred) Glycol 112 *n.d. = not
determined
Example 10: Formation of Pellets, Fibers, and/or Cylinders in the
Glassy State from Compounds 2-10 & 17 and Drug Release from
Intact Glassy-State Pellets
[0487] Compounds 2-10 & 17 were processed into heat molded
pellets (.about.1 mm.times.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 2-10 & 17 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. Pellets of Compound 4, a heterodimer, released both
dexamethasone and hydrocortisone. Figures corresponding to images
of the pellets, fibers, and cylinders and drug release curves from
pellets are shown in the table below.
TABLE-US-00004 TABLE 4 Compounds processed in glassy state and drug
release Processed Compounds in Glassy State Heat-Molded Extruded
Drug Compound Pellets Fibers Cylinders Release 2 FIG. 9B FIG. 9C
FIG. 9D FIG. 9E (HC-TEG-HC) 3 FIG. 10B FIG. 10C FIG. 10D FIG. 10E
(TA-TEG-TA) 4 FIG. 11B Not tested Not tested FIG. 11C (Dex-TEG-HC)
5 FIG. 12B FIG. 12C FIG. 12D FIG. 12E (Dex-Hex-Dex) 6 FIG. 13B FIG.
13C FIG. 13D FIG. 13E (HC-SUCC-HC) 7 FIG. 14B FIG. 14C FIG. 14D
FIG. 14E (Anec-TEG- Anec) 8 FIG. 15B Not tested Not tested FIG. 15C
(Dex-EG5-Dex) 9 FIG. 16B FIG. 16C FIG. 16D FIG. 16E (FA-TEG-FA
(CE)) 10 FIG. 17B Not tested FIG. 17C FIG. 17D (Dex-PEG200- Dex) 17
FIG. 30B FIG. 30C Not tested Not tested (Pred-TEG-Pred)
Example 11. Nano- and Micro-Particle Formation in the Glassy State
from Compounds 3 (TA-TEG-TA) & 5 (Dex-HEX-Dex) Provide
Sustained Release of Drug
[0488] Electrospraying and emulsions were used to make nano- and
microparticles from Compounds 3 (FIGS. 18A and 18B) and 5 (FIGS.
18C and 18D) 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. FIG. 18E shows an example DSC
chromatogram and FIG. 18F shows particle size distribution for
microparticles made by emulsion from Compound 3 in DCM using SDS as
a surfactant. Drug release from microparticles of Compound 3 was
carried out in 50% FBS in PBS, similar to that described in Example
1. Cumulative drug release was calculated and plotted as a
percentage of the total drug released over time (FIG. 18G).
Example 12: Heat-Molded Pellets in the Glassy State can be Formed
from Mixtures of Two Dimers and Drugs are Released from Both
Compounds of the Intact Pellet
[0489] Pellets in the glassy state were formed by heat molding a
mixture of compounds as shown in the table below. The starting
crystalline compounds were mixed together and were heat molded at a
temperature above the higher melting point compound. Drug release
from the pellets (.about.1 mm.times.1 mm and .about.1 mg of total
mixture) was carried out in PBS as described in Example 1.
Cumulative drug release was calculated and plotted as a percentage
of the total drug released over time. Linear drug release from
intact pellets was observed for both compounds in the mixed
pellets.
TABLE-US-00005 TABLE 5 Heat-molded pellets formed from mixtures of
two compounds and drug release Components of Heat-Molded Drug
Mixture Mixture Ratio Pellet Release A Compound 1 (Dex-TEG- 1:1 w/w
FIG. 19A FIG. 19B Dex) & Compound 2 (HC-TEG-HC) B Compound 1
(Dex-TEG- 1:1 w/w FIG. 20A FIG. 20B Dex) & Compound 3
(TA-TEG-TA) C Compound 2 (HC-TEG- 1:1 w/w FIG. 21A FIG. 21B HC)
& Compound 3 (TA-TEG-TA)
Example 13: Methods to Adjust Release of Drug from Glassy State
Articles
[0490] 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
processing conditions, formulation, and/or 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. To exemplify this, FIG. 22A plots the release of
hydrocortisone from heat molded pellets (.about.1 mm.times.1 mm) in
PBS at 37.degree. C. from Compound 2 (HC-TEG-HC), Compound 4
(Dex-TEG-HC), and Compound 6 (HC-SUCC-HC) as shown in Example 9
above and from Mixture A (Compound 1 & 2 (1:1 w/w)) as shown in
Example 10 above. Similarly, FIG. 22B plots the release of
dexamethasone from heat molded pellets (.about.1 mm.times.1 mm) in
PBS at 37.degree. C. from Compound 1 (Dex-TEG-Dex) and Compound 4
(Dex-TEG-HC) as shown in Examples 1 and 9 above and from Mixture A
(Compound 1 & 2 (1:1 w/w)) as shown in Example 10 above. Linear
drug release from intact pellets was observed for all pellets but
differences in the rate of drug release was varied using different
linkers, using a second steroid dimer as an excipient, or by using
a second steroid in the form of a heterodimer. Dexamethasone
release from heat molded pellets (.about.1 mm.times.1 mm) of
Compound 1 (Dex-TEG-Dex) and Compound 5 (Dex-Hex-Dex) in 100% FBS
as shown in FIG. 22C further exemplifies how linker affects the
drug release rates.
Example 14: Compounds 11 (Dex-EG7-Dex), 12 (Dex-EG9-Dex), and 13
(Dex-PEG300-Dex) can be Formed into Heat Molded Pellets and
Extruded Cylinders in the Glassy State but Undergo Physical Form
(Shape) and Drug Release Changes Over Time in Release Medium at
37.degree. C.
[0491] Compounds 11, 12, and 13 were processed into heat molded
pellets (.about.1 mm.times.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 11. 12, and 13 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 11 and 12. Physical form (shape) and drug
release changes occurred for both compounds in PBS and 100% FBS and
is exemplified in FIGS. 26A and 26B for pellets of Compounds 11 and
12, respectively, in PBS at 37.degree. C. The drug release changes
corresponded to the changes in physical form (geometric shape) with
the pellets. Similar changes in physical form (shape) were observed
for extruded cylinders for Compounds 11, 12, and 13 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 the table below.
TABLE-US-00006 TABLE 5 Compounds 11, 12, and 13 processed in glassy
state Processed Compounds in Extruded Glassy State Cylinder after
Heat Molded Extruded 2 weeks in Compound Pellets Cylinders PBS at
37.degree. C. 11 FIG. 23B FIG. 23C FIG. 23D (Dex-EG7-Dex) 12 FIG.
24B FIG. 24C FIG. 24D (Dex-EG9-Dex) 13 FIG. 25B FIG. 25C FIG. 25D
(Dex-PEG300- Dex)
Example 15: Compound 14 (CHS-TEG-CHS) can be Formed into Pellets
and Fibers but have Residual Crystallinity and Pellets Fail to
Release Drug in Release Medium at 37.degree. C.
[0492] Compound 14 was processed into heat molded pellets (.about.1
mm.times.1 mm) and fibers as described in Examples 1 and 2 above
and are shown in the table below. The heat-processed pellets had
residual crystallinity as confirmed by DSC. Drug release from heat
molded pellets was carried out in PBS and 100% FBS, as described in
Example 1, but no drug was released from the pellets in either
release medium.
TABLE-US-00007 Processed Compounds in Glassy State Compound Heat
Molded Pellets Fibers 14 (CHS-TEG-CHS) FIG. 27B FIG. 27C
Example 16: Compound 15 (FA-TEG-FA (E)) and 16 (Ethin-TEG-Ethin)
can be Formed into Pellets and Fibers in the Glassy State but Fail
to Release Drug in Release Medium at 37.degree. C.
[0493] Compounds 15 and 16 were processed into heat molded pellets
(.about.1 mm.times.1 mm) and fibers as described in Examples 1 and
2 above and are shown in the table below. The heat-processed
articles were in the glassy state as confirmed by DSC. Drug release
from heat molded pellets was carried out in PBS and 100% FBS, as
described in Example 1, but no drug was released from the pellets
in either release medium.
TABLE-US-00008 TABLE 7 Compounds 15 and 16 processed in glassy
state Processed Compounds in Glassy State Compound Heat Molded
Pellets Fibers 15 (FA-TEG-FA (E)) FIG. 28B FIG. 28C 16
(Ethin-TEG-Ethin) FIG. 29B Not tested
Example 17. Microparticles and Nanoparticles for Treating Local
Inflammation
[0494] Microparticles and nanoparticles are formed from Compound 1
according to the methods described in above. The micro- and
nanoparticles are then injected into the joint of a subject
suffering from inflammation, e.g., arthritis, and releases
dexamethasone into the subject at a steady rate over three months.
Local inflammation in the joint of the subject is reduced.
Similarly, the other compounds of the disclosure can likewise be
used to form micro- and nanoparticles and injected into the joint
of a subject for the purposes of treating, e.g., inflammation, and
the drug is released at a steady rate over several months (e.g.,
three months).
Example 18. Drug Dimers
[0495] Compounds 18-20, described below, can by prepared using
method 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-00009 Compound Dimer Abbreviation 18
Dexamethasone-glycerol-Dexamethasone Dex-Gly-Dex 19
Hydrocortisone-Hexane-Hydrocortisone HC-Hex-HC 20
Prednisolone-TEG-Abiraterone Pred-TEG-Abir
Example 19. Effect of Compound on Article Stability and Drug
Release Profiles
[0496] Each of compounds 1, 4, 5, 8, and 10-13 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.
[0497] Articles formed from Compounds 11, 12, and 13 with
dexamethasone and longer PEG linkers appear to undergo physical
form (shape) changes, while articles formed from Compound 1 and 8
with dexamethasone and shorter PEG linkers do not. As evidenced in
FIGS. 23D, 24D, and 25D, Compounds 11, 12, and 13 form into
spherical droplets after two weeks in PBS. On the other hand, FIG.
1F shows pellets formed from Compound 1 maintaining their shape as
they gradually get smaller due to surface erosion.
[0498] Articles formed from different compounds were also observed
to exhibit dramatically different dexamethasone release profiles.
As a result of these physical form (shape) changes to the articles
of Compounds 11, 12, and 13, the drug release mechanism is not via
surface erosion and is therefore not linear or predictable (see
FIGS. 26A and 26B). The physical form (shape) changes observed with
the articles correspond to the changes in release rates. Further,
as shown in FIG. 26B, drug release ends up stopping completely. It
was unexpected that the longer length of the PEG linker would lead
to the articles failing to show the beneficial properties of the
shorter-length compounds. On the other hand, the dexamethasone
release profiles from articles formed from compounds 1, 5, 8, and
10 were observed to be generally linear over the course of 12 weeks
or more (see, e.g., FIGS. 1E, 12E, 15C, and 17D). In contrast, the
dexamethasone release profiles from articles formed from compounds
11 and 12 were observed to be non-linear (see FIGS. 26A and 26B).
Surprisingly, in articles formed from compound 12 the dexamethasone
release stops at only ca. 3% cumulative release after just 2 weeks
in PBS.
[0499] The dexamethasone release profiles from heat molded pellets
(.about.1 mm.times.1 mm) of Compound 1 (Dex-TEG-Dex) and Compound 5
(Dex-Hex-Dex) in 100% FBS as shown in FIG. 22C 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 (e.g., for a pellet of 1 mm.times.1 mm in 100%
FBS) where dexamethasone release is only needed for 1 or 2 months,
while articles formed from Compound 5 might be preferred for use
where dexamethasone release is needed for 6 months or more.
[0500] Furthermore, the drug itself (i.e., D1 and/or D2) can affect
the release rate of a compound. For instance, Compounds 9
(FA-TEG-FA (CE)) and 2 release very quickly in 100% FBS but in a
controlled manner, as evidenced in FIGS. 16E and 9E respectively,
compared to other drug dimers that similarly include a triethylene
glycol linker, such as Compounds 1, 3, and 7 (FIGS. 1E, 10E, and
14E, respectively). It was also observed that Compounds 14-16
showed no release after several weeks in 100% FBS at 37.degree. C.,
each of which also has a triethylene glycol linker but is formed
from a different drug or includes a different linking moiety (i.e.,
Compounds 9 and 15). The differences in these release profiles
suggest that even when the drug dimers share the same linker, the
drug itself may affect the release profile.
[0501] While all of the compounds can be processed into different
articles in the glassy/amorphous state, the differences between the
compounds become apparent once they are put in an aqueous or
biological environment.
[0502] Some embodiments of the disclosure provided herein can be
defined according to the following numbered items: [0503] 1. An
article comprising a compound of formula (A-VIII):
[0503] D1-L-D2 (A-VIII) [0504] or a pharmaceutically acceptable
salt thereof, [0505] wherein [0506] (i) each of D1 and D2 is,
independently, a radical formed from a steroid; and L is a linker
covalently linking D1 to D2, [0507] (ii) at least 90% (w/w) of the
article is the compound of formula (A-VIII), [0508] (iii) the
article is free of controlled release excipient, and [0509] (iv) D1
and D2 is released from the article at 37.degree. C. in 100% bovine
serum or at 37.degree. C. in PBS at a rate such that t10 is greater
than or equal to 1/10 of t50. [0510] 2. An article comprising a
compound of formula (A-VIII):
[0510] D1-L-D2 (A-VIII) [0511] or a pharmaceutically acceptable
salt thereof, [0512] wherein [0513] (i) each of D1 and D2 is,
independently, a radical formed from a steroid; and L is a linker
covalently linking D1 to D2, [0514] (ii) at least 90% (w/w) of the
article is the compound of formula (A-VIII), [0515] (iii) the
article is a fiber, fiber mesh, woven fabric, non-woven fabric,
pellet, cylinder, hollow tube, microparticle, nanoparticle, or
shaped article, and [0516] (iv) the article is free of controlled
release excipient. [0517] 3. The article of item 1 or 2, wherein
the compound, D1, or D2 are released from the article through
surface erosion. [0518] 4. An article comprising a compound of
formula (A-VIII):
[0518] D1-L-D2 (A-VIII) [0519] or a pharmaceutically acceptable
salt thereof, wherein the article is formed by a process comprising
the steps of: [0520] (a) heating the compound, or a
pharmaceutically acceptable salt thereof, to form a melt; and
[0521] (b) heat molding the melt to form the article, [0522]
wherein each of D1 and D2 is, independently, a radical formed from
a steroid; and L is a linker covalently linking D1 to D2. [0523] 5.
An article comprising a compound of formula (A-VIII):
[0523] D1-L-D2 (A-VIII) [0524] or a pharmaceutically acceptable
salt thereof, wherein the article is formed by a process comprising
the steps of: [0525] (a) heating the compound, or a
pharmaceutically acceptable salt thereof, to form a melt; and
[0526] (b) injection molding the melt to form the article, [0527]
wherein each of D1 and D2 is, independently, a radical formed from
a steroid; and L is a linker covalently linking D1 to D2. [0528] 6.
An article comprising a compound of formula (A-VIII):
[0528] D1-L-D2 (A-VIII) [0529] or a pharmaceutically acceptable
salt thereof, wherein the article is formed by a process comprising
the steps of: [0530] (a) heating the compound, or a
pharmaceutically acceptable salt thereof, to form a melt; and
[0531] (b) blow molding the melt to form the article, [0532]
wherein each of D1 and D2 is, independently, a radical formed from
a steroid; and L is a linker covalently linking D1 to D2. [0533] 7.
An article comprising a compound of formula (A-VIII):
[0533] D1-L-D2 (A-VIII) [0534] or a pharmaceutically acceptable
salt thereof, wherein the article is formed by a process comprising
the steps of: [0535] (a) dissolving the compound, or a
pharmaceutically acceptable salt thereof, to form a solution; and
[0536] (b) evaporating the solvent to form the article, [0537]
wherein each of D1 and D2 is, independently, a radical formed from
a steroid; and L is a linker covalently linking D1 to D2. [0538] 8.
The article of item 7, wherein step (b) comprises solvent casting
to form a film or a fiber. [0539] 9. An article comprising a
compound of formula (A-VIII):
[0539] D1-L-D2 (A-VIII) [0540] or a pharmaceutically acceptable
salt thereof, wherein the article is formed by a process comprising
the steps of: [0541] (a) dissolving the compound, or a
pharmaceutically acceptable salt thereof, to form a solution; and
[0542] (b) electrospinning or electrospraying the solution to form
the article, [0543] wherein each of D1 and D2 is, independently, a
radical formed from a steroid; and L is a linker covalently linking
D1 to D2. [0544] 10. An article comprising a compound of formula
(A-VIII):
[0544] D1-L-D2 (A-VIII) [0545] or a pharmaceutically acceptable
salt thereof, wherein the article is formed by a process comprising
the steps of: [0546] (a) heating the compound, or a
pharmaceutically acceptable salt thereof, to form a melt; and
[0547] (b) electrospinning or electrospraying the melt to form the
article, wherein each of D1 and D2 is, independently, a radical
formed from a steroid; and L is a linker covalently linking D1 to
D2. [0548] 11. An article comprising a compound of formula
(A-VIII):
[0548] D1-L-D2 (A-VIII) [0549] or a pharmaceutically acceptable
salt thereof, wherein the article is formed by a process comprising
the steps of: [0550] (a) heating the compound, or a
pharmaceutically acceptable salt thereof, to form a melt; [0551]
(b) extruding the melt to form the article, [0552] wherein each of
D1 and D2 is, independently, a radical formed from a steroid; and L
is a linker covalently linking D1 to D2. [0553] 12. The article of
one of items 1-11, wherein L has a molecular weight of from 80 to
800 Da. [0554] 13. The article of any one of items 1-12, wherein L
is covalently linked to D1 and to D2 via one or more ester,
carbonate, carbonate ester, or anhydride linkages. [0555] 14. The
article of item 13, wherein L is covalently linked to D1 and to D2
via one or more carbonate linkages. [0556] 15. The article of any
one of items 1-14, wherein [0557] L comprises the radical
--(C(O)--(RA)-C(O)-- or --O--(R.sup.A)--O--; [0558] R.sup.A is a
radical of a polyol and includes at least one free hydroxyl group
or R.sup.A is selected from C1 20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms,
(CH.sub.2CH.sub.2O)qCH.sub.2CH.sub.2--,
--(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)rCH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
or --(CH.sub.2CH(CH.sub.3)O)sCH.sub.2CH(CH.sub.3)--; and [0559] q,
r, and s are integers from 1 to 10. [0560] 16. An article formed
from the compound of any one of items 84-102, 108, and 110. [0561]
17. The article of any one of items 1-16, wherein each of D1 and D2
is selected from an anabolic steroid, an androgenic steroid, a
progestin steroid, an estrogen steroid, a cancer treatment steroid,
an antibiotic steroid, a glucocorticoid steroid, a benign steroid,
an anti-angiogenic steroid, an intraocular pressure (IOP) lowering
steroid, a cholic acid-related bile acid steroid, a
cholesterol-derivative, other steroid, a pheromone, a steroid
metabolite, a progestin, a neurosteroid, and a corticosteroid.
[0562] 18. The article of any one of items 1-17, wherein the
compound is further described by one of formulas (II)-(LXXV).
[0563] 19. The article of any one of items 1-18, wherein D1 and D2
are formed from the same steroid, or wherein D1 and D2 are formed
from different steroids. [0564] 20. The article of item 19, wherein
the article comprises a mixture of two or more compounds of formula
(A-VIII). [0565] 21. The article of any one of items 1-20, wherein
at least 70% (w/w) of the article is the compound of formula
(A-VIII). [0566] 22. The article of any one of items 1-21, wherein
at least 90% (w/w) of the article is the compound of formula
(A-VIII). [0567] 23. The article of any one of items 1-22, wherein
the compound, D1, or D2 are released from the article through
surface erosion. [0568] 24. The article of item 23, wherein the
surface erosion releases less than 10% of D1 or D2, as a percentage
of the total drug, D1 or D2, 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 D1 or D2, as a percentage
of the total drug, D1 or D2, 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 D1 or D2, as a percentage of the total
drug, D1 or D2, 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 D1 or D2, as a
percentage of the total drug, D1 or D2, present in the article in
prodrug form, at 37.degree. C. in PBS over not fewer than 6 days;
or D1 and/or D2 is released from the article at a rate such that
t10 is greater than or equal to 1/10 of t50. [0569] 25. The article
of any one of items 1-24, 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.
[0570] 26. The article of any one of items 1-25, wherein the
article is a fiber, fiber mesh, woven fabric, non-woven fabric,
pellet, cylinder, hollow tube, microparticle, nanoparticle, or
shaped article. [0571] 27. The article of any one of items 1-26,
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. [0572] 28. A fiber
formed from the compound of any one of items 84-102, 108, and 110.
[0573] 29. A fiber formed from a compound of formula (A-VIII):
[0573] D1-L-D2 (A-VIII) [0574] or a pharmaceutically acceptable
salt thereof, wherein the fiber is prepared by a process comprising
the steps of: [0575] (a) dissolving the compound, or a
pharmaceutically acceptable salt thereof, in a solvent to form a
solution; and [0576] (b) electrospinning, dry spinning, wet
spinning, or gel spinning the solution to form the fiber, [0577]
wherein each of D1 and D2 is, independently, a radical formed from
a steroid; and L is a linker covalently linking D1 to D2. [0578]
30. A fiber formed from a compound of formula (A-VIII):
[0578] D1-L-D2 (A-VIII) [0579] or a pharmaceutically acceptable
salt thereof, wherein the fiber is prepared by a process comprising
the steps of: [0580] (a) heating the compound, or a
pharmaceutically acceptable salt thereof, to form a melt; and
[0581] (b) extruding the melt to form the fiber, [0582] wherein
each of D1 and D2 is, independently, a radical formed from a
steroid; and L is a linker covalently linking D1 to D2. [0583] 31.
A fiber formed from a compound of formula (A-VIII):
[0583] D1-L-D2 (A-VIII) [0584] or a pharmaceutically acceptable
salt thereof, wherein the fiber is prepared by a process comprising
the steps of: [0585] (a) heating the compound, or a
pharmaceutically acceptable salt thereof, to form a melt; and
[0586] (b) electrospinning the melt to form the fiber, [0587]
wherein each of D1 and D2 is, independently, a radical formed from
a steroid; and L is a linker covalently linking D1 to D2. [0588]
32. The fiber of any one of items 29-31, wherein L has a molecular
weight of from 80 to 800 Da. [0589] 33. The fiber of any one of
items 29-32, wherein L is covalently linked to D1 and to D2 via one
or more ester, carbonate, carbonate ester, or anhydride linkages.
[0590] 34. The fiber of any one of items 29-33, wherein [0591] L
comprises the radical --(C(O)--(R.sup.A)--C(O)-- or
--O--(R.sup.A)--O--; [0592] R.sup.A is a radical of a polyol and
includes at least one free hydroxyl group or R.sup.A is selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms, --(CH.sub.2CH.sub.2O)qCH2CH.sub.2--,
--(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)rCH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
or --(CH.sub.2CH(CH.sub.3)O)sCH.sub.2CH(CH.sub.3)--; and [0593] q,
r, and s are integers from 1 to 10. [0594] 35. The fiber of any one
of items 29-34, wherein each of D1 and D2 is selected from an
anabolic steroid, an androgenic steroid, a progestin steroid, an
estrogen steroid, a cancer treatment steroid, an antibiotic
steroid, a glucocorticoid steroid, a benign steroid, an
anti-angiogenic steroid, an intraocular pressure (IOP) lowering
steroid, a cholic acid-related bile acid steroid, a
cholesterol-derivative, other steroid, a pheromone, a steroid
metabolite, a progestin, a neurosteroid, and a corticosteroid.
[0595] 36. The fiber of any one of items 29-34, wherein the
compound is further described by one of formulas (II)-(LXXV).
[0596] 37. The fiber of any one of items 28-36, wherein D1 and D2
are formed from the same steroid, or wherein D1 and D2 are formed
from different steroids. [0597] 38. The fiber of item 37, wherein
the fiber comprises a mixture of two or more compounds of formula
(A-VIII). [0598] 39. The fiber of any one of items 28-38, wherein
at least 70% (w/w) of the fiber is the compound of formula
(A-VIII). [0599] 40. The fiber of any one of items 28-38, wherein
at least 90% (w/w) of the fiber is the compound of formula
(A-VIII). [0600] 41. The fiber of any one of items 28-40, wherein
the compound, D1, or D2 are released from the fiber through surface
erosion. [0601] 42. The fiber of item 41, wherein the surface
erosion releases less than 10% of D1 or D2, as a percentage of the
total drug, D1 or D2, 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 D1 or D2, as a percentage of the
total drug, D1 or D2, 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 D1 or D2, as a percentage of the total drug, D1
or D2, 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 D1 or D2, as a percentage of
the total drug, D1 or D2, present in the fiber in prodrug form, at
37.degree. C. in PBS over not fewer than 6 days; or D1 and/or D2 is
released from the fiber at a rate such that t10 is greater than or
equal to 1/10 of t50. [0602] 43. The fiber of any one of items
28-42, 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. [0603] 44. The fiber of
any one of items 28-43, 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.
[0604] 45. A fiber mesh or woven fabric formed from the fiber of
any one of items 28-44. [0605] 46. A non-woven fabric formed from
the fiber of any one of items 28-44. [0606] 47. A glassy state
composition formed from a compound of any one of items 84-102, 108,
and 110. [0607] 48. A glassy state composition formed from a
compound of formula (A-VIII):
[0607] D1-L-D2 (A-VIII) [0608] or a pharmaceutically acceptable
salt thereof, wherein the composition is prepared by a process
comprising the steps of: [0609] (a) heating the compound, or a
pharmaceutically acceptable salt thereof, to form a melt; and
[0610] (b) cooling the melt to form the composition, wherein each
of D1 and D2 is, independently, a radical formed from a steroid;
and L is a linker covalently linking D1 to D2. [0611] 49. The
glassy state composition of item 47 or 48, wherein L has a
molecular weight of from 80 to 800 Da. [0612] 50. The glassy state
composition of any one of items 47-49, wherein L is covalently
linked to D1 and to D2 via one or more ester, carbonate, carbonate
ester, or anhydride linkages. [0613] 51. The glassy state
composition of any one of items 47-50, wherein [0614] L comprises
the radical --(C(O)--(R.sup.A)--C(O)-- or --O--(R.sup.A)--O--;
[0615] R.sup.A is a radical of a polyol and includes at least one
free hydroxyl group or R.sup.A is selected from C.sub.1-20
alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a
linear or branched C.sub.2-20 alkenylene, a linear or branched
C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3
to 10 atoms, (CH.sub.2CH.sub.2O)qCH.sub.2CH.sub.2--,
--(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)rCH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
or --(CH.sub.2CH(CH.sub.3)O)sCH.sub.2CH(CH.sub.3)--; and [0616] q,
r, and s are integers from 1 to 10. [0617] 52. The glassy state
composition of any one of items 47-51, wherein each of D1 and D2 is
selected from an anabolic steroid, an androgenic steroid, a
progestin steroid, an estrogen steroid, a cancer treatment steroid,
an antibiotic steroid, a glucocorticoid steroid, a benign steroid,
an anti-angiogenic steroid, an intraocular pressure (IOP) lowering
steroid, a cholic acid-related bile acid steroid, a
cholesterol-derivative, other steroid, a pheromone, a steroid
metabolite, a progestin, a neurosteroid, and a corticosteroid.
[0618] 53. The glassy state composition of any one of items 47-52,
wherein the compound is further described by one of formulas
(II)-(LXXV). [0619] 54. The glassy state composition of any one of
items 47-53, wherein D1 and D2 are formed from the same steroid, or
wherein D1 and D2 are formed from different steroids. [0620] 55.
The glassy state composition of item 54, wherein the glassy state
composition comprises a mixture of two or more compounds of formula
(A-VIII). [0621] 56. The glassy state composition of any one of
items 47-55, wherein at least 70% (w/w) of the glassy state
composition is the compound of formula (A-VIII). [0622] 57. The
glassy state composition of any one of items 47-56, wherein at
least 90% (w/w) of the glassy state composition is the compound of
formula (A-VIII). [0623] 58. The glassy state composition of any
one of items 47-57, wherein the compound, D1, or D2 are released
from the glassy state composition through surface erosion. [0624]
59. The glassy state composition of item 58, wherein the surface
erosion releases less than 10% of D1 or D2, as a percentage of the
total drug, D1 or D2, 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 D1 or D2, as a
percentage of the total drug, D1 or D2, 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 D1 or D2, as a
percentage of the total drug, D1 or D2, 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 D1 or D2, as a percentage of the total drug, D1 or D2,
present in the glassy state composition in prodrug form, at
37.degree. C. in PBS over not fewer than 6 days; or D1 and/or D2 is
released from the glassy state composition at a rate such that t10
is greater than or equal to 1/10 of t50. [0625] 60. The glassy
state composition of any one of items 47-59, 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. [0626] 61. The glassy state
composition of any one of items 47-60, wherein the glassy state
composition is formed by machining, molding, fiber spinning,
electrospinning, electrospraying, blow molding, or extruding.
[0627] 62. The glassy state composition of any one of items 47-61,
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. [0628] 63. The glassy
state composition of item 62, wherein the glassy state composition
is a shaped article in the form of: [0629] (i) fibers having a mean
diameter of from about 0.01 to 1 mm; [0630] (ii) pellets having a
mean diameter of from about 0.2 to 5 mm; [0631] (iii) cylinders of
from about 0.01 to 1 mm in diameter and 0.5 to 20 mm in length;
[0632] (iv) microparticles having a mean diameter of from about 1
to 1000 .mu.m; or [0633] (v) nanoparticles having a mean diameter
of from about 0.01 to 1 .mu.m. [0634] 64. The glassy state
composition of any one of items 47-63, 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.
[0635] 65. A substrate comprising a coating formed from a compound
of formula (A-VIII):
[0635] D1-L-D2 (A-VIII). [0636] wherein [0637] (i) each of D1 and
D2 is, independently, a radical formed from a steroid; and L is a
linker covalently linking D1 to D2 via one or more carbonate or
carbonate ester linkages, [0638] (ii) at least 90% (w/w) of the
article is the compound of formula (A-VIII), and [0639] (iii) the
article is free of controlled release excipient. [0640] 66. The
substrate of item 65, wherein L has a molecular weight of from 80
to 800 Da. [0641] 67. The substrate of item 65 or 66, wherein L is
covalently linked to D1 and to D2 via one or more carbonate
linkages. [0642] 68. The substrate of any one of items 65-67,
wherein each of D1 and D2 is selected from an anabolic steroid, an
androgenic steroid, a progestin steroid, an estrogen steroid, a
cancer treatment steroid, an antibiotic steroid, a glucocorticoid
steroid, a benign steroid, an anti-angiogenic steroid, an
intraocular pressure (IOP) lowering steroid, a cholic acid-related
bile acid steroid, a cholesterol-derivative, other steroid, a
pheromone, a steroid metabolite, a progestin, a neurosteroid, and a
corticosteroid. [0643] 69. The substrate of any one of items 65-68,
wherein the compound is further described by one of formulas
(II)-(LXXV). [0644] 70. The substrate of any one of items 65-69,
wherein D1 and D2 are formed from the same steroid, or wherein D1
and D2 are formed from different steroids. [0645] 71. The substrate
of item 70, wherein the coating comprises a mixture of two or more
compounds of formula (A-VIII). [0646] 72. The substrate of any one
of items 65-71, wherein at least 70% (w/w) of the coating is the
compound of formula (A-VIII). [0647] 73. The substrate of any one
of items 65-72, wherein at least 90% (w/w) of the coating is the
compound of formula (A-VIII). [0648] 74. The substrate of any one
of items 65-73, wherein the compound, D1, or D2 are released from
the coating through surface erosion. [0649] 75. The substrate of
item 74, wherein the surface erosion releases less than 10% of D1
or D2, as a percentage of the total drug, D1 or D2, 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 D1 or D2,
as a percentage of the total drug, D1 or D2, 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 D1 or D2, as a
percentage of the total drug, D1 or D2, 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
D1 or D2, as a percentage of the total drug, D1 or D2, present in
the coating in prodrug form, at 37.degree. C. in PBS over not fewer
than 6 days; or D1 and/or D2 is released from the coating at a rate
such that or t10 is greater than or equal to 1/10 of t50. [0650]
76. The substrate of any one of items 65-75, 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. [0651] 77. The substrate of any one of items
65-76, wherein the coating is free of controlled release excipient,
free of a crystallization inhibiting excipient, free of a
mechanical integrity enhancing excipient; or the coating optionally
has a glassy state. [0652] 78. A substrate comprising a coating
formed from the compound of any one of items 84-102, 108, and 110.
[0653] 79. The substrate of item 78, wherein at least 70% (w/w) of
the coating is the compound. [0654] 80. The substrate of item 78,
wherein at least 90% (w/w) of the coating is the compound. [0655]
81. The substrate of any one of items 78-80, wherein the coating
has a glassy state and is formed from the compound of any one of
items 84-102, 108, and 110. [0656] 82. A coating having a glassy
state formed from the compound of any one of items 84-102, 108, and
110. [0657] 83. An implantable medical device comprising the
substrate of any one of items 65-82, wherein the coating resides on
the surface of the implantable medical device. [0658] 84. A
compound described by the formula (A-I):
[0658] D1-O-L-O-D2 (A-I), [0659] or a pharmaceutically acceptable
salt thereof, wherein [0660] each of D1-O and D2-O is,
independently, a radical formed from a steroid; L is
--C(O)--OC(O)--(RB)--C(O)O--C(O)--; and [0661] R.sup.B is selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms, [0662] wherein the steroid is an anabolic
steroid, an androgenic steroid, a progestin steroid, an estrogen
steroid, a cancer treatment steroid, an antibiotic steroid, a
glucocorticoid steroid, a benign steroid, an anti-angiogenic
steroid, an intraocular pressure (IOP) lowering steroid, a cholic
acid-related bile acid steroid, a cholesterol-derivative, other
steroid, a pheromone, a steroid metabolite, a progestin, a
neurosteroid, or a corticosteroid. [0663] 85. A compound described
by the formula (A-II):
[0663] D1-O-L-O-D2 (A-II), [0664] or a pharmaceutically acceptable
salt thereof, wherein [0665] each of D1-O and D2-O is,
independently, a radical formed from a steroid; [0666] L is
--C(O)O--(R.sup.A)--OC(O)--; [0667] wherein O--(R.sup.A)--O is a
radical of a polyol and comprises at least one free hydroxyl group,
wherein the steroid is an anabolic steroid, an androgenic steroid,
a progestin steroid, an estrogen steroid, a cancer treatment
steroid, an antibiotic steroid, a glucocorticoid steroid, a benign
steroid, an anti-angiogenic steroid, an intraocular pressure (IOP)
lowering steroid, a cholic acid-related bile acid steroid, a
cholesterol-derivative, other steroid, a pheromone, a steroid
metabolite, a progestin, a neurosteroid, or a corticosteroid.
[0668] 86. A compound described by the formula (A-III):
[0668] D1-O-L-O-D2 (A-III), [0669] or a pharmaceutically acceptable
salt thereof, wherein [0670] each of D1-O and D2-O is,
independently, a radical formed from a steroid; [0671] L is
--C(O)O--(R.sup.A)--OC(O)--, --C(O)--(O)--C(O)--, or
--C(O)--OC(O)--(R.sup.B)--C(O)O--C(O)--; [0672] R.sup.A is selected
from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1
to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear
or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic
system of 3 to 10 atoms, or O--(R.sup.A)--O is a radical of a
polyol and comprises at least one free hydroxyl group or is
selected from: [0673] O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--,
[0674]
O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O--,
or [0675] O(CH.sub.2CH(CH.sub.3)O)pCH.sub.2CH(CH.sub.3)O--; [0676]
n, m, and p are integers from 1 to 10; and [0677] R.sup.B is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, [0678]
wherein the steroid is an anabolic steroid, an androgenic steroid,
a progestin steroid, an estrogen steroid, a cancer treatment
steroid, an antibiotic steroid, an anti-angiogenic steroid, an
intraocular pressure (IOP) lowering steroid, a cholic acid-related
bile acid steroid, a cholesterol-derivative, other steroid, a
pheromone, a steroid metabolite, a progestin, a neurosteroid, or a
benign steroid. [0679] 87. A compound described by the formula
(A-IV):
[0679] ##STR00110## [0680] or a pharmaceutically acceptable salt
thereof, wherein [0681] L is --C(O)O--(R.sup.A)--OC(O)--; [0682]
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and comprises at least one
free hydroxyl group or O--(R.sup.A)--O is selected from: [0683]
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--, [0684]
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or [0685] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; [0686] n,
m, and p are integers from 1 to 10; and [0687] 88. The compound of
one of items 85-87, wherein O--(R.sup.A)--O is a radical of a
polyol formed from a cyclitol, a sugar alcohol, or glycerin. [0688]
89. The compound of item 86 or 87, wherein O--(R.sup.A)--O is a
radical formed from an alkane diol, diethylene glycol, triethylene
glycol, tetraethylene glycol, or pentaethylene glycol. [0689] 90.
The compound of any one of items 84-85, 88, and 89, wherein each of
D1-O and D2-O is, independently, described by any one of formulas
(I-a) to (I-sss). [0690] 91. The compound of item 90, wherein at
least one of D1-O and D2-O is formed from: [0691] (i) an anabolic
steroid selected from androisoxazole, androstenediol, bolandiol,
bolasterone, clostebol, ethylestrenol, formyldienolone,
4-hydroxy-19-nortestosterone, methandriol, methenolone,
methyltrienolone, nandrolone, norbolethone, oxymesterone,
stenbolone, and trenbolone; [0692] (ii) an androgenic steroid
selected from boldenone, fluoxymesterone, mestanolone, mesterolone,
methandrostenolone, 17-methyltestosterone,
17-.alpha.-methyltestosterone 3-cyclopentyl enol ether,
norethandrolone, normethandrone, oxandrolone, oxymesterone,
oxymetholone, prasterone, stanlolone, stanozolol, testosterone,
testosterone 17-chloral hemiacetal, testosterone proprionate,
testosterone enanthate tiomesterone dehydroepiandrosterone (DHEA),
androstenedione, androstenediol, androsterone, dihydrotestosterone
(DHT), and androstanolone; [0693] (iii) a progestin steroid
selected from norethisterone, norethisterone acetate, gestodene,
levonorgestrel, allylestrenol, anagestone, desogestrel,
dimethisterone, dydrogesterone, ethisterone, ethynodiol, ethynodiol
diacetate, etonogestrel, gestodene, ethinylestradiol,
haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17
alpha-hydroxyprogesterone, lynestrenol, medroxyprogesterone,
melengestrol, norethindrone, norethynodrel, norgesterone,
gestonorone, norethisterone, norgestimate, norgestrel,
levonorgestrel, norgestrienone, norvinisterone, pentagestrone, MENT
(7-methyl-19-testosterone); norelgestromin, and trimigestone
drospirenone, tibolone, and megestrol; [0694] (iv) an estrogen
steroid selected from estrogen, eguilenin, equilin,
17.beta.-estradiol, estradiol benzoate, estriol, ethinyl estradiol,
mestranol, moxestrol, mytatrienediol, quinestradiol, and
quinestrol; [0695] (v) a glucocorticoid selected from medrysone,
alclometasone, alclometasone dipropionate, amcinonide,
beclometasone, beclomethasone dipropionate, betamethasone,
betamethasone benzoate, betamethasone valerate, budesonide,
ciclesonide, clobetasol, clobetasol butyrate, clobetasol
propionate, clobetasone, clocortolone, loprednol, cortisol,
cortisone, cortivazol, deflazacort, desonide, desoximetasone,
desoxycortone, desoxymethasone, dexamethasone, diflorasone,
diflorasone diacetate, diflucortolone, diflucortolone valerate,
difluorocortolone, difluprednate, fluclorolone, fluclorolone
acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone
pivalate, flunisolide, flunisolide, fluocinolone, fluocinolone
acetonide, fluocinonide, fluocortin, fluocoritin butyl,
fluocortolone, fluorocortisone, fluorometholone, fluperolone,
fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone,
fluticasone propionate, formocortal, halcinonide, halometasone,
hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate,
hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,
meprednisone, 6.alpha.-methylprednisolone, methylprednisolone,
methylprednisolone acetate, methylprednisolone aceponate,
mometasone, mometasone furoate, mometasone furoate monohydrate,
paramethasone, prednicarbate, prednisolone, prednisone,
prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone
acetonide, and ulobetasol; [0696] (vi) a steroid selected from
abiraterone, cyproterone acetate, dutasteride, enzalutamide,
finasteride, galeterone, fusidic acid, cholesterol,
11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic
acid, chenodeoxycholic acid, ursodeoxycholic acid, obeticholic
acid, tetrahydrocortisone, tetrahydrodeoxycortisol,
tetrahydrocorticosterone, 5.alpha.-dihydrocorticosterone, and
5.alpha.-dihydropregesterone; [0697] (vii) an anti-angiogenic
steroid or an intraocular pressure (IOP) lowering steroid selected
from anecortave acetate, anecortave, 11-epicortisol,
17.alpha.-hydroxyprogesterone, tetrahydrocortexolone, and
tetrahydrocortisol; [0698] (viii) a cholic acid-related bile acid
steroid selected from deoxycholic acid, apocholic acid,
dehydrocholic acid, glycochenodeoxycholic acid, glycocholic acid,
glycodeoxycholic acid, hyodeoxycholic acid, lithocholic acid,
.alpha.-muricholic acid, .beta.-muricholic acid, .gamma.-muricholic
acid, .omega.-muricholic acid, taurochenodeoxycholic acid,
taurocholic acid, taurodeoxycholic acid, taurolithocholic acid, and
tauroursodeoxycholic acid; [0699] (ix) a neurosteroid selected from
alphaxalone, alphadolone, hydroxydione, minaxolone,
tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone,
ganoxolone, 3.alpha.-androstanediol, epipregnanolone,
isopregnanolone, and 24(S)-hydroxycholesterol; [0700] (x) other
steroid selected from flugestone, prebediolone, chlormadinone
acetate, medrogestone, and segesterone acetate; (xi) a pheromone
including androstadienol, androstadienone, androstenol,
androstenone, estratetraenol, 5-dehydroprogesterone,
6-dehydro-retroprogesterone, allopregnanolone, and
hydroxyprogesterone caproate; [0701] (xi) a steroid metabolite
selected from tetrahydrotriamcinolone, cortienic acid,
11-dehydrocorticosterone, 110-hydroxypregnenolone,
ketoprogesterone, 17-hydroxypregnenolone,
17,21-dihydroxypregnenolone, 18-hydroxycorticosterone,
deoxycortisone, 21-hydroxypregnenolone, and progesterone; or [0702]
(xii) a progestin including allopregnone-3.alpha.,20.alpha.-diol,
allopregnone-3.beta.,20.beta.-diol,
allopregnane-3.beta.,21-diol-11,20-dione,
allopregnane-3.beta.,17.alpha.-diol-20-one,
3,20-allopregnanedione,3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol,
allopregnane-3.beta.,17.alpha.,20.beta.,21-tetrol,
allopregnane-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,17.alpha.,20.beta.-triol,
allopregnane-3.beta.,17.alpha.,21-triol-11,20-dione,
allopregnane-3.beta.,11.beta.,21-triol-20-one,
allopregnane-3.beta.,17.alpha.,21-triol-20-one,
allopregnane-3.alpha.-ol-20-one, allopregnane-3.beta.-ol-20-one,
pregnanediol, 3,20-pregnanedione, 4-pregnene-20,21-diol-3,11-dione,
4-pregnene-11.beta.,17.alpha.,20.beta.,21-tetrol-3-one,
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione,
4-pregnene-17.alpha.,20.beta.,21-triol-3-one, and pregnenolone.
[0703] 92. A compound described by the formula (A-VI):
[0703] D1-C(O)-L-C(O)-D2 (A-VI), [0704] or a pharmaceutically
acceptable salt thereof, wherein [0705] each of D1-C(O) and D2-C(O)
is, independently, a radical formed from a steroid; [0706] L is
--O--(R.sup.A)--O-- or --OC(O)--O--(R.sup.A)--O--C(O)O--; [0707]
R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or
O--(R.sup.A)--O is a radical of a polyol and comprises at least one
free hydroxyl group or O--(R.sup.A)--O is selected from: [0708]
--O(CH.sub.2CH.sub.2O)nCH.sub.2CH.sub.2O--, [0709]
--O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O)mCH2CH.sub.2CH.sub.2CH.sub.2O--,
or [0710] --O(CH.sub.2CH(CH.sub.3)O)pCH2CH(CH.sub.3)O--; and [0711]
n, m, and p are integers from 1 to 10. [0712] 93. The compound of
item 92, wherein O--(R.sup.A)--O is a radical of a polyol formed
from a cyclitol, a sugar alcohol, or glycerin. [0713] 94. The
compound of item 92, wherein O--(R.sup.A)--O is a radical formed
from an alkane diol, diethylene glycol, triethylene glycol,
tetraethylene glycol, or pentaethylene glycol. [0714] 95. A
compound described by the formula (A-VII):
[0714] D1-C(O)-L-C(O)-D2 (A-VII), [0715] or a pharmaceutically
acceptable salt thereof, wherein [0716] each of D1-C(O) and D2-C(O)
is, independently, a radical formed from a steroid; [0717] L is
--O--C(O)--O--(R.sup.A)--O--C(O)--O--; and [0718] R.sup.A is
selected from C.sub.1-20 alkylene, a linear or branched
heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20
alkenylene, a linear or branched C.sub.2-20 alkynylene, a
C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms. [0719] 96.
The compound of any one of items 92-95, wherein at least one of
D1-C(O) and D2-C(O) is formed from fusidic acid, cholic acid,
chenodeoxycholic acid, ursodeoxycholic acid, or obeticholic acid.
[0720] 97. The compound of any one of items 84-96, wherein D1-O and
D2-O are formed from the same steroid, or wherein D1-C(O) and
D2-C(O) are formed from the same steroid. [0721] 98. The compound
of any one of items 84-96, wherein D1-O and D2-O are formed from
different steroids, or wherein D1-C(O) and D2-C(O) are formed from
different steroids. [0722] 99. The compound of any one of items
84-98, wherein R.sup.A is a C.sub.1-10 alkylene. [0723] 100. The
compound of any one of items 84-86 and 88-99, wherein upon
hydrolysis D1 and D2 form corticosteroids selected from
alclometasone, beclomethasone, betamethasone, betamethasone
valerate, budesonide, chloroprednisone, cloprednol, corticosterone,
cortisone, desonide, desoximerasone, dexamethasone, diflorasone,
diflucortolone, enoxolone, flucloronide, flumethasone, flunisolide,
fluocinolone acetonide, fluocortolone, fluprednisolone,
flurandrenolide, halometasone, hydrocortisone, hydrocortisone
butyrate, meprednisone, methylprednicolone, paramethasone,
prednisolone, prednisone, prednival, prednylidene, triamcinolone,
and triamcinolone acetonide. [0724] 101. The compound of any one of
items 84-100, wherein the compound is further described by one of
formulas (II)-(LXXV). [0725] 102. The compound of item 101, wherein
R.sup.A comprises --(CH.sub.2CH.sub.2O)qCH.sub.2CH.sub.2--, q is an
integer of 1 to 10, and upon hydrolysis each of D1 and D2,
independently, form dexamethasone, triamcinolone, betamethasone,
prednisolone, prednisone, fluocinolone, fluocinolone acetonide,
mometosone, mometosone furoate, anecoratve, hydrocortisone,
triamcinolone acetonide, abiraterone, fusidic acid, or cholesterol.
[0726] 103. A method of forming an article comprising a compound of
formula (A-VIII):
[0726] D1-L-D2 (A-VIII) [0727] or a pharmaceutically acceptable
salt thereof, wherein each of D1 and D2 is, independently, a
radical formed from a steroid; and L is a linker covalently linking
D1 to D2, and wherein the article is formed by a process comprising
the steps of: [0728] (a) heating the compound, or a
pharmaceutically acceptable salt thereof, to form a melt; [0729]
(b) cooling the melt to form a glassy state composition; and [0730]
(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.
[0731] 104. A method of forming an article comprising a compound of
formula (A-VIII):
[0731] D1-L-D2 (A-VIII) [0732] or a pharmaceutically acceptable
salt thereof, wherein each of D1 and D2 is, independently, a
radical formed from a steroid; and L is a linker covalently linking
D1 to D2, and wherein the article is formed by a process comprising
the steps of: [0733] (a) dissolving the compound, or a
pharmaceutically acceptable salt thereof, in a solvent to form a
solution; [0734] (b) evaporating the solvent to form a glassy state
composition; and [0735] (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. [0736] 105. The method of item 103 or 104,
wherein step (c) comprises extruding, molding, blow molding, heat
spinning, electrospinning or electrospraying the glassy state
composition to form the shaped article. [0737] 106. A method of
forming an article comprising a compound of formula (A-VIII):
[0737] D1-L-D2 (A-VIII) [0738] or a pharmaceutically acceptable
salt thereof, wherein each of D1 and D2 is, independently, a
radical formed from a steroid; and L is a linker covalently linking
D1 to D2, and wherein the article is formed by a process comprising
the steps of: [0739] (a) dissolving the compound, or a
pharmaceutically acceptable salt thereof, in a solvent to form a
solution; [0740] (b) electrospraying or electrospinning the
solution to form a glassy state composition; and [0741] (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. [0742] 107. The
method of any one of items 103-106, 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. [0743] 108. Compound 3. [0744] 109. A pharmaceutical
composition comprising Compound 3 and a pharmaceutically acceptable
excipient. [0745] 110. Compound 17. [0746] 111. A pharmaceutical
composition comprising Compound 17 and a pharmaceutically
acceptable excipient.
* * * * *