U.S. patent application number 13/368580 was filed with the patent office on 2012-11-08 for corticosteroids for the treatment of joint pain.
Invention is credited to Robert C. Blanks, Neil Bodick, Michael D. Clayman, Anjali Kumar, Mark Moran.
Application Number | 20120282298 13/368580 |
Document ID | / |
Family ID | 45559826 |
Filed Date | 2012-11-08 |
United States Patent
Application |
20120282298 |
Kind Code |
A1 |
Bodick; Neil ; et
al. |
November 8, 2012 |
CORTICOSTEROIDS FOR THE TREATMENT OF JOINT PAIN
Abstract
Corticosteroid microparticle formulations are provided for use
for treating pain, including pain caused by inflammatory diseases
such as osteoarthritis or rheumatoid arthritis, and for slowing,
arresting or reversing structural damage to tissues caused by an
inflammatory disease, for example damage to articular and/or
peri-articular tissues caused by osteoarthritis or rheumatoid
arthritis. Corticosteroid microparticle formulations are
administered locally as a sustained release dosage form (with or
without an immediate release component) that results in efficacy
accompanied by clinically insignificant or no measurable effect on
endogenous cortisol production.
Inventors: |
Bodick; Neil; (Boston,
MA) ; Blanks; Robert C.; (Auburndale, MA) ;
Kumar; Anjali; (Belmont, MA) ; Clayman; Michael
D.; (Gloucester, MA) ; Moran; Mark; (Orinda,
CA) |
Family ID: |
45559826 |
Appl. No.: |
13/368580 |
Filed: |
February 8, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13198168 |
Aug 4, 2011 |
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13368580 |
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61370666 |
Aug 4, 2010 |
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Current U.S.
Class: |
424/400 ;
514/174 |
Current CPC
Class: |
A61P 5/44 20180101; A61K
9/0019 20130101; A61P 29/00 20180101; A61K 9/1694 20130101; A61P
19/00 20180101; A61K 9/1647 20130101; A61P 19/02 20180101; A61P
43/00 20180101; A61K 31/58 20130101; A61K 31/573 20130101; A61K
47/34 20130101; A61K 9/1641 20130101; A61P 25/00 20180101; A61P
25/04 20180101; A61K 9/14 20130101; A61K 9/0024 20130101; A61P
37/06 20180101; A61P 19/06 20180101 |
Class at
Publication: |
424/400 ;
514/174 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61P 25/00 20060101 A61P025/00; A61P 29/00 20060101
A61P029/00; A61K 9/14 20060101 A61K009/14 |
Claims
1. A long-term controlled or sustained release preparation of a
Class B corticosteroid comprising a lactic acid-glycolic acid
copolymer microparticle containing the Class B corticosteroid,
wherein the Class B corticosteroid comprises between 5% to 15% of
the lactic acid-glycolic acid copolymer microparticle matrix, and
wherein the lactic acid-glycolic acid copolymer microparticle
releases the Class B corticosteroid for a period of at least 90
days.
2. A formulation comprising long-term controlled- or
sustained-release microparticles comprising a Class B
corticosteroid and a lactic acid-glycolic acid copolymer matrix,
wherein the lactic acid-glycolic acid copolymer microparticles
release the Class B corticosteroid for a period of at least 90
days, wherein the lactic acid-glycolic acid copolymer
microparticles comprise a mixture of lactic acid-glycolic acid
copolymers, wherein the Class B corticosteroid comprises between 5%
to 15% of the microparticles and wherein the mixture of lactic
acid-glycolic acid copolymer comprises a first lactic acid-glycolic
acid copolymer having one of more of the following characteristics:
(i) a molecular weight in the range of about 110 to 150 kDa; (ii)
an inherent viscosity in the range of 0.6 to 1.0 dL/g; or (iii) a
lactide:glycolide molar ratio of 80:20 to 60:40 or a
lactide:glycolide molar ratio of 80:20 to 50:50 and a second lactic
acid-glycolic acid copolymer having one of more of the following
characteristics: (i) a molecular weight in the range of about 40 to
70 kDa; (ii) an inherent viscosity in the range of 0.2 to 0.5 dL/g;
or (iii) a lactide:glycolide molar ratio of 80:20 to 60:40 a
lactide:glycolide molar ratio of 80:20 to 50:50.
3. The preparation of claim 1, wherein the copolymer is
biodegradable.
4. The preparation of claim 1, wherein the lactic acid-glycolic
acid copolymer is a poly(lactic-co-glycolic) acid copolymer
(PLGA).
5. The preparation of claim 1, wherein the Class B corticosteroid
is triamcinolone acetonide or a commercially available chemical
analogue or a pharmaceutically-acceptable salt thereof.
6. The preparation of claim 1, wherein the microparticles have a
mean diameter of between 10 .mu.m to 100 .mu.m.
7. The preparation of claim 1, wherein the lactic acid-glycolic
acid copolymer, the first lactic acid-glycolic acid copolymer or
the second lactic acid-glycolic acid copolymer has a molar ratio of
lactic acid:glycolic acid from the range of about 80:20 to
60:40.
8. The preparation of claim 1, wherein the lactic acid-glycolic
acid copolymer, the first lactic acid-glycolic acid copolymer or
the second lactic acid-glycolic acid copolymer has a molar ratio of
lactic acid:glycolic acid of 75:25.
9. The preparation of claim 1, wherein the microparticles further
comprise a polyethylene glycol (PEG) moiety, wherein the PEG moiety
comprises between 25% to 0% weight percent of the
microparticle.
10. The preparation of claim 1, wherein the Class B corticosteroid
is released for at least 90 days.
11. The preparation of claim 1, wherein the lactic acid-glycolic
acid copolymer comprises an ester endcap.
12. A population of microparticles comprising a Class B
corticosteroid or a pharmaceutically acceptable salt thereof
incorporated in a lactic acid-glycolic acid copolymer matrix,
wherein the Class B corticosteroid comprises between 22% to 28% of
the microparticles, and wherein the Class B corticosteroid is
budesonide or a commercially available chemical analogue or a
pharmaceutically-acceptable salt thereof.
13. A controlled or sustained release preparation of a Class B
corticosteroid comprising a lactic acid-glycolic acid copolymer
microparticle containing the Class B corticosteroid, wherein the
Class B corticosteroid comprises between 22% to 28% of the lactic
acid-glycolic acid copolymer microparticle matrix, and wherein the
Class B corticosteroid is budesonide or a commercially available
chemical analogue or a pharmaceutically-acceptable salt
thereof.
14. A formulation comprising controlled- or sustained-release
microparticles comprising a Class B corticosteroid and a lactic
acid-glycolic acid copolymer matrix, wherein the Class B
corticosteroid is budesonide or a commercially available chemical
analogue or a pharmaceutically-acceptable salt thereof, wherein the
budesonide comprises between 22% to 28% of the microparticles and
wherein the lactic acid-glycolic acid copolymer has one of more of
the following characteristics: (i) a molecular weight in the range
of about 40 to 70 kDa; (ii) an inherent viscosity in the range of
0.35 to 0.5 dL/g; or (iii) a lactide:glycolide molar ratio of 80:20
to 60:40 or a lactide:glycolide molar ratio of 80:20 to 50:50.
15. The population of claim 12, wherein the copolymer is
biodegradable.
16. The population of claim 12, wherein the lactic acid-glycolic
acid copolymer is a poly(lactic-co-glycolic) acid copolymer
(PLGA).
17. The population of claim 12, wherein the lactic acid-glycolic
acid copolymer comprises an acid endcap.
18. The population of claim 12, wherein the microparticles have a
mean diameter of between 10 .mu.m to 100 .mu.m.
19. The population of claim 12, wherein the lactic acid-glycolic
acid copolymer has a molar ratio of lactic acid:glycolic acid from
the range of about 80:20 to 60:40.
20. The population of claim 12, wherein the lactic acid-glycolic
acid copolymer has a molar ratio of lactic acid:glycolic acid of
75:25.
21. The population of claim 12, wherein the microparticles further
comprise a polyethylene glycol (PEG) moiety, wherein the PEG moiety
comprises between 25% to 0% weight percent of the
microparticle.
22. The population of claim 12, wherein the budesonide or
commercially available chemical analogue or pharmaceutically
acceptable salt thereof is released for between 14 days and 90
days.
23. A method of treating pain or inflammation in a patient
comprising administering to said patient a therapeutically
effective amount of the controlled or sustained release preparation
of claim 1.
24. A method of treating pain or inflammation in a patient
comprising administering to said patient a therapeutically
effective amount of the controlled or sustained release preparation
of claim 1, wherein the controlled or sustained release preparation
releases the corticosteroid for at least 14 days at a rate that
does not adversely suppress the hypothalamic-pituitary-adrenal axis
(HPA axis).
25. A method of slowing, arresting or reversing progressive
structural tissue damage associated with chronic inflammatory
disease in a patient comprising administering to said patient a
therapeutically effective amount of the controlled or sustained
release preparation of claim 1.
26. A method of slowing, arresting or reversing progressive
structural tissue damage associated with chronic inflammatory
disease in a patient comprising administering to said patient a
therapeutically effective amount of the controlled or sustained
release preparation of claim 1, wherein the controlled or sustained
release preparation releases the corticosteroid for at least 14
days at a rate that does not adversely suppress the
hypothalamic-pituitary-adrenal axis (HPA axis).
27. The method of any one of claim 23, wherein the controlled or
sustained release preparation is administered as one or more
injections.
28. The method of any one of claim 23, wherein the patient has
osteoarthritis, rheumatoid arthritis, acute gouty arthritis, and
synovitis.
29. A method of manufacturing the controlled or sustained release
preparation of claim 1, wherein the microparticles are manufactured
using a solvent evaporation process wherein the Class B
corticosteroid is dispersed in a lactic acid-glycolic acid
copolymer organic solution and the mixture is treated to remove the
solvent from the mixture, thereby producing microparticles.
30. The method of manufacture of claim 29, wherein the solvent
evaporation process utilizes a spray drying or fluid bed apparatus
to remove the solvent and produce microparticles.
31. The method of manufacture of claim 29, wherein the solvent
evaporation process utilizes a spinning disk.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 13/198,168, filed Aug. 4, 2011, which claims
the benefit of U.S. Provisional Application No. 61/370,666, filed
Aug. 4, 2010. The contents of each application are hereby
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to the use of corticosteroids to
treat pain, including pain caused by inflammatory diseases such as
osteoarthritis or rheumatoid arthritis, and to slow, arrest or
reverse structural damage to tissues caused by an inflammatory
disease, for example damage to articular and/or peri-articular
tissues caused by osteoarthritis or rheumatoid arthritis. More
specifically, a corticosteroid is administered locally as a
sustained release dosage form (with or without an immediate release
component) that results in efficacy accompanied by clinically
insignificant or no measurable effect on endogenous cortisol
production.
BACKGROUND OF THE INVENTION
[0003] Corticosteroids influence all tissues of the body and
produce various cellular effects. These steroids regulate
carbohydrate, lipid, protein biosynthesis and metabolism, and water
and electrolyte balance. Corticosteroids influencing cellular
biosynthesis or metabolism are referred to as glucocorticoids while
those affecting water and electrolyte balance are
mineralocorticoids. Both glucocorticoids and mineralocorticoids are
released from the cortex of the adrenal gland.
[0004] The administration of corticosteroids, particularly for
extended periods of time, can have a number of unwanted side
effects. The interdependent feedback mechanism between the
hypothalamus, which is responsible for secretion of
corticotrophin-releasing factor, the pituitary gland, which is
responsible for secretion of adrenocorticotropic hormone, and the
adrenal cortex, which secretes cortisol, is termed the
hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis may be
suppressed by the administration of corticosteroids, leading to a
variety of unwanted side effects.
[0005] Accordingly, there is a medical need to extend the local
duration of action of corticosteroids, while reducing the systemic
side effects associated with that administration. Thus, there is a
need in the art for methods and compositions for the sustained
local treatment of pain and inflammation, such as joint pain, with
corticosteroids that results in clinically insignificant or no
measurable HPA axis suppression. In addition, there is a medical
need to slow, arrest, reverse or otherwise inhibit structural
damage to tissues caused by inflammatory diseases such as damage to
articular tissues resulting from osteoarthritis or rheumatoid
arthritis.
SUMMARY OF THE INVENTION
[0006] Described herein are compositions and methods for the
treatment of pain and inflammation using corticosteroids. The
compositions and methods provided herein use one or more
corticosteroids in a microparticle formulation. The corticosteroid
microparticle formulations provided herein are effective at
treating pain and/or inflammation with minimal long-term side
effects of corticosteroid administration, including for example,
prolonged suppression of the HPA axis. The corticosteroid
microparticle formulations are suitable for administration, for
example, local administration by injection into a site at or near
the site of a patient's pain and/or inflammation. The
corticosteroid microparticle formulations provided herein are
effective in slowing, arresting, reversing or otherwise inhibiting
structural damage to tissues associated with progressive disease
with minimal long-term side effects of corticosteroid
administration, including for example, prolonged suppression of the
HPA axis. The corticosteroid microparticle formulations are
suitable for administration, for example, local administration by
injection into a site at or near the site of structural tissue
damage. As used herein, "prolonged" suppression of the HPA axis
refers to levels of cortisol suppression greater than 35% by day 14
post-administration, for example post-injection. The corticosteroid
microparticle formulations provided herein deliver the
corticosteroid in a dose and in a controlled or sustained release
manner such that the levels of cortisol suppression are at or below
35% by day 14 post-administration, for example post-injection. In
some embodiments, the corticosteroid microparticle formulations
provided herein deliver the corticosteroid in a dose and in a
controlled or sustained release manner such that the levels of
cortisol suppression are negligible and/or undetectable by 14
post-administration, for example post-injection. In some
embodiments, the corticosteroid microparticle formulations provided
herein deliver the corticosteroid in a dose and in a controlled or
sustained release manner such that the levels of cortisol
suppression are negligible at any time post-injection. Thus, the
corticosteroid microparticle formulations in these embodiments are
effective in the absence of any significant HPA axis suppression.
Administration of the corticosteroid microparticle formulations
provided herein can result in an initial "burst" of HPA axis
suppression, for example, within the first few days, within the
first two days and/or within the first 24 hours post-injection, but
by day 14 post-injection, suppression of the HPA axis is less than
35%.
[0007] In certain embodiments, a sustained release form of
corticosteroids is administered locally to treat pain and
inflammation. Local administration of a corticosteroid
microparticle formulation can occur, for example, by injection into
the intra-articular space, peri-articular space, soft tissues,
lesions, epidural space, perineural space, or the foramenal space
at or near the site of a patient's pain. In certain embodiments,
the formulation additionally contains an immediate release
component. In certain preferred embodiments of the invention, a
sustained release form of corticosteroids is administered (e.g., by
single injection or as sequential injections) into an
intra-articular space for the treatment of pain, for example, due
to osteoarthritis, rheumatoid arthritis, gouty arthritis, bursitis,
tenosynovitis, epicondylitis, synovitis or other joint disorder. In
certain preferred embodiments of the invention, a sustained release
form of corticosteroids is administered (e.g., by single injection
or as sequential injections) into soft tissues or lesions for the
treatment of inflammatory disorders, for example, the inflammatory
and pruritic manifestations of corticosteroid-responsive dermatoses
such as psoriasis. In certain preferred embodiments of the
invention, a sustained release form of corticosteroids is
administered (e.g., by single injection or as sequential
injections) into an epidural space, a perineural space, a foramenal
space or other spinal space for the treatment of
corticosteroid-responsive degenerative musculoskeletal disorders
such as Neurogenic Claudication. In certain preferred embodiments
of the invention, a sustained release form of corticosteroids is
administered (e.g., by single injection or as sequential
injections) into an intra-articular space or into soft tissues to
slow, arrest, reverse or otherwise inhibit structural damage to
tissues associated with progressive disease such as, for example,
the damage to cartilage associated with progression of
osteoarthritis.
[0008] In certain embodiments of the invention, a combination of an
immediate release form and a sustained release form of
corticosteroids is administered (e.g., by single injection or as
sequential injections) into an intra-articular space for the
treatment of pain, for example, due to osteoarthritis, rheumatoid
arthritis or other joint disorder(s). In certain embodiments of the
invention, a combination of an immediate release form and a
sustained release form of corticosteroids is administered (e.g., by
single injection or as sequential injections) into an
intra-articular space or into soft tissues to slow, arrest, reverse
or otherwise inhibit structural damage to tissues associated with
progressive disease such as, for example, the damage to cartilage
associated with progression of osteoarthritis. The formulations and
methods of embodiments of the invention can achieve immediate
relief of the acute symptoms (e.g., pain and inflammation) of these
diseases or conditions and additionally provide a sustained or long
term therapy (e.g., slowing, arresting, reversing or otherwise
inhibiting structural damage to tissues associated with progressive
disease), while avoiding long term systemic side effects associated
with corticosteroid administration, including HPA suppression.
[0009] In one aspect, a formulation is provided wherein a
microparticle matrix (such as PLGA, PLA, hydrogels, hyaluronic
acid, etc.) incorporates a corticosteroid, and the corticosteroid
microparticle formulation provides at least two weeks, preferably
at least three weeks, including up to and beyond 30 days, or 60
days, or 90 days of a sustained, steady state release of the
corticosteroid. In one aspect, a formulation is provided wherein a
microparticle matrix (such as PLGA, PLA, hydrogels, hyaluronic
acid, etc.) incorporates a corticosteroid, and the corticosteroid
microparticle formulation provides at least two weeks, preferably
at least three weeks, including up to and beyond 30 days, or 60
days, or 90 days of a sustained, steady state release of the
corticosteroid at a rate that does not adversely suppress the HPA
axis.
[0010] The corticosteroid microparticle formulation retains
sustained efficacy even after the corticosteroid is no longer
resident at the site of administration, for example, in the
intra-articular space, and/or after the corticosteroid is no longer
detected in the systemic circulation. The corticosteroid
microparticle formulation retains sustained efficacy even after the
corticosteroid microparticle formulation is no longer resident at
the site of administration, for example, in the intra-articular
space, and/or the corticosteroid microparticle formulation is no
longer detected in the systemic circulation. The corticosteroid
microparticle formulation retains sustained efficacy even after the
corticosteroid microparticle formulation ceases to release
therapeutically effective amounts of corticosteroid. For example,
in some embodiments, the corticosteroid released by the
microparticle formulation retains efficacy for at least one week,
at least two weeks, at least three weeks, at least four weeks, at
least five weeks, at least six weeks, at least seven weeks, at
least eight weeks, at least nine weeks, at least twelve weeks, or
more than twelve-weeks post-administration. In some embodiments,
the corticosteroid released by the microparticle formulation
retains efficacy for a time period that is at least twice as long,
at least three times as long, or more than three times as long as
the residency period for the corticosteroid and/or the
corticosteroid microparticle formulation. In some embodiments, the
sustained, steady state release of corticosteroid will not
adversely suppress the HPA axis.
[0011] In some embodiments, a controlled or sustained-release
formulation is provided wherein a microparticle matrix (such as
PLGA, hydrogels, hyaluronic acid, etc.) incorporates a
corticosteroid, and the formulation may or may not exhibit an
initial rapid release, also referred to herein as an initial
"burst" of the corticosteroid for a first length of time of between
0 and 14 days, for example, between the beginning of day 1 through
the end of day 14, in addition to the sustained, steady state
release of the corticosteroid for a second length of time of at
least two weeks, preferably at least three weeks, including up to
and beyond 30 days, or 60 days, or 90 days. It should be noted that
when corticosteroid levels are measured in vitro, an occasional
initial burst of corticosteroid release from the microparticle
formulation can be seen, but this initial burst may or may not be
seen in vivo. In another embodiment, a controlled or
sustained-release formulation is provided wherein a microparticle
matrix (such as PLGA, hydrogels, hyaluronic acid, etc.)
incorporates a corticosteroid, and the formulation may or may not
exhibit an initial rapid release, also referred to herein as an
initial "burst" of the corticosteroid for a first length of time of
between 0 and 14 days, e.g., between the beginning of day 1 through
the end of day 14, in addition to the sustained, steady state
release of the corticosteroid for a second length of time of at
least two weeks, preferably at least three weeks, including up to
and beyond 30 days, or 60 days, or 90 days where the sustained,
steady state release of corticosteroid is released at a rate that
does not suppress the HPA axis at a level greater than 50% at day
14 post-administration. In some embodiments, the sustained, steady
state release of corticosteroid will not adversely suppress the HPA
axis, for example, the level of HPA axis suppression at or less
than 35% by day 14 post-administration. In some embodiments, the
sustained, steady state release of corticosteroid does not
significantly suppress the HPA axis, for example, the level of HPA
axis suppression is negligible and/or undetectable by day 14
post-injection. In some embodiments, the sustained, steady state
release of corticosteroid does not significantly suppress the HPA
axis, for example, the level of HPA axis suppression is negligible
at all times post-injection. In some embodiments, the length of
sustained release is between 21 days and 90 days. In some
embodiments, the length of sustained release is between 21 days and
60 days. In some embodiments, the length of sustained release is
between 14 days and 30 days. In some embodiments, the length of
release of the initial "burst" component is between 0 and 10 days,
for example between the beginning of day 1 through the end of day
10. In some embodiments, the length of release of the initial
"burst" component is between 0 and 6 days, for example between the
beginning of day 1 through the end of day 6. In some embodiments,
the length of initial "burst," component is between 0 and 2 days,
for example between the beginning of day 1 through the end of day
2. In some embodiments, the length of initial "burst" component is
between 0 and 1 day, for example between the beginning of day 1
through the end of day 1.
[0012] The corticosteroid microparticle formulations provided
herein can be used in combination with any of a variety of
therapeutics, also referred to herein as "co-therapies." For
example, the corticosteroid microparticle formulations can be used
in combination with an immediate release corticosteroid solution or
suspension, which provides high local exposures for between 1 day
and 14 days following administration and which produce systemic
exposures that may be associated with transient suppression of the
HPA axis. For example, 40 mg of immediate release triamcinolone
acetonide co-administered with the corticosteroid microparticle
formulation in the intra-articular space would be expected to
produce high local concentrations lasting for about 12 days. These
high local concentrations would be associated with peak plasma
concentration of triamcinolone acetonide of approximately 10 ng/ml
on day 1, and over the course of the first 12 days of release of
the triamcinolone acetonide from the intra-articular space would be
associated with transient suppression of the HPA axis with a
maximal effect of approximately 60% suppression of cortisol on day
1-2 (Derendorf et al., "Pharmacokinetics and pharmacodynamics of
glucocorticoid suspensions after intra-articular administration."
Clin Pharmacol Ther. 39(3) (1986):313-7). By day 12, the
contribution of the immediate release component to the plasma
concentration would be small, less than 0.1 ng/ml, and the
contribution to the intra articular concentration of the immediate
release component would also be small. However at day 12 and
beyond, the corticosteroid microparticle formulation would continue
to release corticosteroid in the intra articular space at a rate
that extends the duration of therapeutic effect and does not
suppress the HPA axis. In some embodiments, the same corticosteroid
is used in both the immediate release and sustained release
components. In some embodiments, the immediate release component
contains a corticosteroid that is different from that of the
sustained release component. In some embodiments, the sustained,
steady state release of corticosteroid will not adversely suppress
the HPA axis. In some embodiments, the period of sustained release
is between 21 days and 90 days. In some embodiments, the period of
sustained release is between 21 days and 60 days. In some
embodiments, the period of sustained release is between 14 days and
30 days. In some embodiments, the high local exposure attributable
to the immediate release component lasts for between 1 day and 14
days. In some embodiments, the high local exposure attributable to
the immediate release component lasts for between 1 day and 10
days. In some embodiments, the high local exposure attributable to
the immediate release component lasts between 1 days and 8 days. In
some embodiments, the high local exposure attributable to the
immediate release component lasts between 1 days and 6 days. In
some embodiments, the high local exposure attributable to the
immediate release component lasts for between 1 day and 4 days.
[0013] Upon administration, the corticosteroid microparticle
formulation may provide an initial release of corticosteroid at the
site of administration, for example, in the intra-articular space
and/or peri-articular space. Once the initial release of
corticosteroid has subsided, the controlled or sustained release of
the corticosteroid microparticle formulations continues to provide
therapeutic (e.g., intra-articular and/or peri-articular)
concentrations of corticosteroid to suppress inflammation, maintain
analgesia, and/or slow, arrest or reverse structural damage to
tissues for an additional period of therapy following
administration (FIG. 1, top tracings). However, the systemic
exposure associated with the sustained release component does not
suppress the HPA axis (FIG. 1, bottom tracings). Thus, the
invention includes therapies and formulations that may exhibit an
initial release of corticosteroid followed by controlled or
sustained release where the therapy comprises a period of therapy
wherein the corticosteroid is released from the sustained release
component and the plasma levels of the corticosteroid does not
adversely suppress the HPA axis.
[0014] In some embodiments, the length of sustained release is
between 21 days and 90 days. In some embodiments, the length of
sustained release is between 21 days and 60 days. In some
embodiments, the length of sustained release is between 14 days and
30 days. In some embodiments, the length of release of the
immediate release form is In some embodiments, the length of
release of the immediate release form is between 1 day and 14 days.
In some embodiments, the length of release of the immediate release
form is between 1 day and 10 days. In some embodiments, the length
of release of the immediate release form is between 1 day and 8
days. In some embodiments, the length of release of the immediate
release form is between 1 day and 6 days. In some embodiments, the
length of release of the immediate release form is between 1 day
and 4 days.
[0015] The invention provides populations of microparticles
including a Class B corticosteroid or a pharmaceutically acceptable
salt thereof incorporated in, admixed, encapsulated or otherwise
associated with a lactic acid-glycolic acid copolymer matrix,
wherein the Class B corticosteroid is between 22% to 28% of the
microparticles.
[0016] The invention also provides controlled or sustained release
preparation of a Class B corticosteroid that include a lactic
acid-glycolic acid copolymer microparticle containing the Class B
corticosteroid, wherein the Class B corticosteroid is between 22%
to 28% of the lactic acid-glycolic acid copolymer microparticle
matrix.
[0017] The invention also provides formulations that include (a)
controlled- or sustained-release microparticles comprising a Class
B corticosteroid and a lactic acid-glycolic acid copolymer matrix,
wherein the Class B corticosteroid comprises between 22% to 28% of
the microparticles and wherein the lactic acid-glycolic acid
copolymer has one of more of the following characteristics: (i) a
molecular weight in the range of about 40 to 70 kDa; (ii) an
inherent viscosity in the range of 0.3 to 0.5 dL/g; (iii) a
lactide:glycolide molar ratio of 80:20 to 60:40; and/or (iv) the
lactic acid-glycolic acid copolymer is carboxylic acid
endcapped.
[0018] In some embodiments of these populations, preparations
and/or formulations, the copolymer is biodegradable. In some
embodiments, the lactic acid-glycolic acid copolymer is a
poly(lactic-co-glycolic) acid copolymer (PLGA). In some
embodiments, the lactic acid-glycolic acid copolymer has a molar
ratio of lactic acid:glycolic acid from the range of about 80:20 to
60:40. In some embodiments, the lactic acid-glycolic acid copolymer
has a molar ratio of lactic acid:glycolic acid of 75:25.
[0019] The invention also provides populations of microparticles
including a Class B corticosteroid or a pharmaceutically acceptable
salt thereof incorporated in, admixed, encapsulated or otherwise
associated with a mixed molecular weight lactic acid-glycolic acid
copolymer matrix, wherein the Class B corticosteroid is between 12%
to 28% of the microparticles. In some embodiments, the
corticosteroid microparticle formulation includes a Class B
corticosteroid and a microparticle made using 75:25 PLGA
formulation with two PLGA polymers, one of low molecular weight and
one of high molecular weight in a two to one ratio, respectively.
The low molecular weight PLGA has a molecular weight of range of
15-35 kDa and an inherent viscosity range from 0.2 to 0.35 dL/g and
the high molecular weight PLGA has a range of 70-95 kDa and an
inherent viscosity range of 0.5 to 0.70 dL/g. In these TCA/75:25
PLGA corticosteroid microparticle formulations, the microparticles
have a mean diameter in the range of 10-100 .mu.M. In some
embodiments, the microparticles have a mean diameter in the range
of 20-100 .mu.M, 20-90 .mu.M, 30-100 .mu.M, 30-90 .mu.M, or 10-90
.mu.M. It is understood that these ranges refer to the mean
diameter of all microparticles in a given population. The diameter
of any given individual microparticle could be within a standard
deviation above or below the mean diameter.
[0020] The invention also provides populations of microparticles
including a Class B corticosteroid or a pharmaceutically acceptable
salt thereof incorporated in, admixed, encapsulated or otherwise
associated with a lactic acid-glycolic acid copolymer matrix
containing 10-20% triblock (PEG-PLGA-PEG) having an inherent
viscosity in the range from 0.6 to 0.8 dL/g, wherein the Class B
corticosteroid is between 22% to 28% of the microparticles. In some
embodiments, the corticosteroid microparticle formulation includes
a Class B corticosteroid and a microparticle made using 75:25 PLGA
formulation and containing 10-20% triblock (PEG-PLGA-PEG) having an
inherent viscosity in the range from 0.6 to 0.8 dL/g. In these
TCA/75:25 PLGA corticosteroid microparticle formulations, the
microparticles have a mean diameter in the range of 10-100 .mu.M.
In some embodiments, the microparticles have a mean diameter in the
range of 20-100 .mu.M, 20-90 .mu.M, 30-100 .mu.M, 30-90 .mu.M, or
10-90 .mu.M. It is understood that these ranges refer to the mean
diameter of all microparticles in a given population. The diameter
of any given individual microparticle could be within a standard
deviation above or below the mean diameter.
[0021] These Class B corticosteroid microparticle formulations,
preparations, and populations thereof, when administered to a
patient, exhibit reduced undesirable side effects in patient, for
example, undesirable effects on a patient's cartilage or other
structural tissue, as compared to the administration, for example
administration into the intra-articular space of a joint, of an
equivalent amount of the Class B corticosteroid absent any
microparticle or other type of incorporation, admixture, or
encapsulation.
[0022] In some embodiments, the Class B corticosteroid is
triamcinolone acetonide or a commercially available chemical
analogue or a pharmaceutically-acceptable salt thereof. In some
embodiments, the total dose of corticosteroid contained in the
microparticles is in the range of 10-90 mg, where the Class B
corticosteroid is between 12-28% of the microparticle, for example,
between 22-28% of the microparticle (i.e., when the corticosteroid
is 28% of the microparticle, the microparticle is in the range of
35.7-321.4 mgs, and so on for all values between 22-28% load dose,
when the corticosteroid is 25% of the microparticle, the
microparticle is in the range of 40-360 mgs, when the
corticosteroid is 22% of the microparticle, the microparticle is in
the range of 45.5-409.1 mgs, when the corticosteroid is 12% of the
microparticle, the microparticle is in the range of 83.3-750 mgs,
and so on for all values between 12-28% load dose). In some
embodiments, the Class B corticosteroid contained in the
microparticles is 12-28% of the microparticle, for example, between
22-28% of the microparticle and the total dose of corticosteroid is
in a range selected from 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg,
10-40 mg, 10-30 mg, 10-20 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60
mg, 20-50 mg, 20-40 mg, 20-30 mg, 30-90 mg, 30-80 mg, 30-70 mg,
30-60 mg, 30-50 mg, 30-40 mg, 40-90 mg, 40-80 mg, 40-70 mg, 40-60
mg, 40-50 mg, 50-90 mg, 50-80 mg, 50-70 mg, 50-60 mg, 60-90 mg,
60-80 mg, 60-70 mg, 70-90 mg, 70-80 mg, and 80-90 mg. In some
embodiments, the Class B corticosteroid is released for between 14
days and 90 days.
[0023] In some embodiments, the microparticles have a mean diameter
of between 10 .mu.m to 100 .mu.m, for example, the microparticles
have a mean diameter in the range of 20-100 .mu.M, 20-90 .mu.M,
30-100 .mu.M, 30-90 .mu.M, or 10-90 .mu.M. It is understood that
these ranges refer to the mean diameter of all microparticles in a
given population. The diameter of any given individual
microparticle could be within a standard deviation above or below
the mean diameter.
[0024] In some embodiments, the microparticles further comprise a
polyethylene glycol (PEG) moiety, wherein the PEG moiety comprises
between 25% to 0% weight percent of the microparticle. In some
embodiments of the microparticles that include a PEG moiety, the
populations, preparations and/or formulations of the invention do
not require the presence of PEG to exhibit the desired
corticosteroid sustained release kinetics and bioavailability
profile.
[0025] In one embodiment of these populations, preparations and/or
formulations, the corticosteroid microparticle formulation includes
triamcinolone acetonide (TCA) and a microparticle made using 75:25
PLGA formulation having an inherent viscosity in the range from 0.3
to 0.5 dL/g and/or a molecular weight in the range of 40-70 kDa,
for example between 50-60 kDa. In these TCA/75:25 PLGA
corticosteroid microparticle formulations, the microparticles have
a mean diameter in the range of 10-100 .mu.m. In some embodiments,
the microparticles have a mean diameter in the range of 20-100
.mu.M, 20-90 .mu.M, 30-100 .mu.M, 30-90 .mu.M, or 10-90 .mu.M. It
is understood that these ranges refer to the mean diameter of all
microparticles in a given population. The diameter of any given
individual microparticle could be within a standard deviation above
or below the mean diameter.
[0026] For the TCA/75:25 PLGA microparticle formulations, the range
of TCA load percentage is between 22-28%. In one embodiment, the
load percentage of TCA in the microparticles in 25%.
[0027] The microparticles in the TCA PLGA microparticle
formulations can be formulated using PLGA polymers having a range
of molecular weights from 40 to 70 kDa, most preferably from 50 to
60 kDa and range of inherent viscosities from 0.5 to 0.5 dL/g, most
preferably from 0.38 to 0.42 dL/g.
[0028] For the TCA/75:25 PLGA microparticle formulations, the total
dose of corticosteroid contained in the microparticles is in the
range of 10-90 mg, where TCA is between 22-28% of the microparticle
(i.e., when TCA is 25% of the microparticle, the microparticle is
in the range of 40-360 mgs, when TCA is 22% of the microparticle,
the microparticle is in the range of 45.5-409.1 mgs, when TCA is
28% of the microparticle, the microparticle is in the range of
35.7-321.4 mgs, and so on for all values between 22-28% load dose).
In some embodiments, total dose of corticosteroid contained in the
microparticles is in a range selected from 10-80 mg, 10-70 mg,
10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg, 20-90 mg, 20-80
mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg, 30-90 mg,
30-80 mg, 30-70 mg, 30-60 mg, 30-50 mg, 30-40 mg, 40-90 mg, 40-80
mg, 40-70 mg, 40-60 mg, 40-50 mg, 50-90 mg, 50-80 mg, 50-70 mg,
50-60 mg, 60-90 mg, 60-80 mg, 60-70 mg, 70-90 mg, 70-80 mg, and
80-90 mg.
[0029] In some embodiments of the TCA/75:25 PLGA microparticle
formulations, the microparticles further comprise a polyethylene
glycol (PEG) moiety, wherein the PEG moiety comprises between 25%
to 0% weight percent of the microparticle. In some embodiments of
the microparticles that include a PEG moiety, the populations,
preparations and/or formulations of the invention do not require
the presence of PEG to exhibit the desired corticosteroid sustained
release kinetics and bioavailability profile.
[0030] In one embodiment of these populations, preparations and/or
formulations, the corticosteroid microparticle formulation includes
triamcinolone acetonide (TCA) and a microparticle made using 75:25
PLGA formulation and containing 10-20% triblock (PEG-PLGA-PEG)
having an inherent viscosity in the range from 0.6 to 0.8 dL/g. In
these TCA/75:25 PLGA corticosteroid microparticle formulations, the
microparticles have a mean diameter in the range of 10-100 .mu.M.
In some embodiments, the microparticles have a mean diameter in the
range of 20-100 .mu.M, 20-90 .mu.M, 30-100 .mu.M, 30-90 .mu.M, or
10-90 .mu.M. It is understood that these ranges refer to the mean
diameter of all microparticles in a given population. The diameter
of any given individual microparticle could be within a standard
deviation above or below the mean diameter.
[0031] In one embodiment of these populations, preparations and/or
formulations, the corticosteroid microparticle formulation includes
triamcinolone acetonide (TCA) and a microparticle made using 75:25
PLGA formulation with two PLGA polymers, one of low molecular
weight and one of high molecular weight in a two to one ratio,
respectively. The low molecular weight PLGA has a molecular weight
of range of 15-35 kDa and an inherent viscosity range from 0.2 to
0.35 dL/g and the high molecular weight PLGA has a range of 70-95
kDa and an inherent viscosity range of 0.5 to 0.70 dL/g. In these
TCA/75:25 PLGA corticosteroid microparticle formulations, the
microparticles have a mean diameter in the range of 10-100 .mu.M.
In some embodiments, the microparticles have a mean diameter in the
range of 20-100 .mu.M, 20-90 .mu.M, 30-100 .mu.M, 30-90 .mu.M, or
10-90 .mu.M. It is understood that these ranges refer to the mean
diameter of all microparticles in a given population. The diameter
of any given individual microparticle could be within a standard
deviation above or below the mean diameter.
[0032] These TCA microparticle formulations, preparations, and
populations thereof, when administered to a patient, exhibit
reduced undesirable side effects in patient, for example,
undesirable effects on a patient's cartilage or other structural
tissue, as compared to the administration, for example
administration into the intra-articular space of a joint, of an
equivalent amount of TCA absent any microparticle or other type of
incorporation, admixture, or encapsulation.
[0033] In some embodiments, the Class B corticosteroid is
budesonide or a commercially available chemical analogue or
pharmaceutically acceptable salt thereof. In some embodiments, the
budesonide is incorporated in a lactic acid-glycolic acid copolymer
matrix, wherein the budesonide (or a commercially available
chemical analogue or pharmaceutically acceptable salt thereof)
comprises between 22% to 28% of the microparticles.
[0034] In some embodiments, the budesonide or commercially
available chemical analogue or pharmaceutically acceptable salt
thereof is incorporated in a controlled or sustained release
preparation that includes a lactic acid-glycolic acid copolymer
microparticle containing the budesonide (or a commercially
available chemical analogue or pharmaceutically acceptable salt
thereof), wherein the budesonide comprises between 22% to 28% of
the lactic acid-glycolic acid copolymer microparticle matrix.
[0035] In some embodiments, the copolymer is biodegradable. In some
embodiments, the lactic acid-glycolic acid copolymer is a
poly(lactic-co-glycolic) acid copolymer (PLGA). In some
embodiments, the lactic acid-glycolic acid copolymer comprises an
acid endcap. In some embodiments, the microparticles have a mean
diameter of between 10 .mu.m to 100 .mu.m. In some embodiments, the
microparticles have a mean diameter in the range of 20-100 .mu.M,
20-90 .mu.M, 30-100 .mu.M, 30-90 .mu.M, or 10-90 .mu.M. It is
understood that these ranges refer to the mean diameter of all
microparticles in a given population. The diameter of any given
individual microparticle could be within a standard deviation above
or below the mean diameter. In some embodiments, the lactic
acid-glycolic acid copolymer has a molar ratio of lactic
acid:glycolic acid from the range of about 80:20 to 60:40. In some
embodiments, the lactic acid-glycolic acid copolymer has a molar
ratio of lactic acid:glycolic acid of 75:25. In some embodiments,
the microparticles further include a polyethylene glycol (PEG)
moiety, wherein the PEG moiety is between 25% to 0% weight percent
of the microparticle. In some embodiments of the microparticles
that include a PEG moiety, the populations, preparations and/or
formulations of the invention do not require the presence of PEG to
exhibit the desired corticosteroid sustained release kinetics and
bioavailability profile. In some embodiments, budesonide or
commercially available chemical analogue or pharmaceutically
acceptable salt thereof is released for between 14 days and 90
days.
[0036] In some embodiments, the budesonide or commercially
available chemical analogue or pharmaceutically acceptable salt
thereof is incorporated in a formulation that includes controlled
or sustained-release microparticles including the budesonide or a
commercially available chemical analogue or a
pharmaceutically-acceptable salt thereof, wherein the budesonide
comprises between 22% to 28% of the microparticles and wherein the
lactic acid-glycolic acid copolymer has one of more of the
following characteristics: (i) a molecular weight in the range of
about 40 to 70 kDa; (ii) an inherent viscosity in the range of 0.35
to 0.5 dL/g; or (iii) a lactide:glycolide molar ratio of 80:20 to
60:40 or a lactide:glycolide molar ratio of 80:20 to 50:50.
[0037] In some embodiments, the copolymer is biodegradable. In some
embodiments, the lactic acid-glycolic acid copolymer is a
poly(lactic-co-glycolic) acid copolymer (PLGA). In some
embodiments, the lactic acid-glycolic acid copolymer comprises an
acid endcap. In some embodiments, the microparticles have a mean
diameter of between 10 .mu.m to 100 .mu.m. In some embodiments, the
microparticles have a mean diameter in the range of 20-100 .mu.M,
20-90 .mu.M, 30-100 .mu.M, 30-90 .mu.M, or 10-90 .mu.M. It is
understood that these ranges refer to the mean diameter of all
microparticles in a given population. The diameter of any given
individual microparticle could be within a standard deviation above
or below the mean diameter. In some embodiments, the lactic
acid-glycolic acid copolymer has a molar ratio of lactic
acid:glycolic acid from the range of about 80:20 to 60:40. In some
embodiments, the lactic acid-glycolic acid copolymer has a molar
ratio of lactic acid:glycolic acid of 75:25. In some embodiments,
the microparticles further include a polyethylene glycol (PEG)
moiety, wherein the PEG moiety is between 25% to 0% weight percent
of the microparticle. In some embodiments, budesonide or
commercially available chemical analogue or pharmaceutically
acceptable salt thereof is released for between 14 days and 90
days.
[0038] In another embodiment, the corticosteroid microparticle
formulation includes a Class A, C, or D corticosteroid and a
microparticle made using 50:50 PLGA formulation. For example, in
some embodiments, the Class A corticosteroid is prednisolone. In
some embodiments, the Class C corticosteroid is betamethasone. In
some embodiments, the Class D corticosteroid is fluticasone or
fluticasone propionate. In these Class A, C, or D corticosteroid
microparticle formulations, the microparticles have a mean diameter
in the range of 10-100 .mu.M. In some embodiments, the
microparticles have a mean diameter in the range of 20-100 .mu.M,
20-90 .mu.M, 30-100 .mu.M, 30-90 .mu.M, or 10-90 .mu.M. It is
understood that these ranges refer to the mean diameter of all
microparticles in a given population. The diameter of any given
individual microparticle could be within a standard deviation above
or below the mean diameter.
[0039] For the Class A and/or Class C PLGA microparticle
formulations, the range of corticosteroid load percentage is
between 10-40%, for example, between 15%-30%. For the Class D PLGA
microparticle formulations, the range of corticosteroid load
percentage is between 8-20%.
[0040] The microparticles in the Class A, C or D PLGA microparticle
formulations can be formulated using PLGA polymers having a range
of inherent viscosities from 0.35 to 0.5 dL/g and approximated
molecular weights from 40 kDa to 70 kDa.
[0041] These Class A, C or D corticosteroid microparticle
formulations, preparations, and populations thereof, when
administered to a patient, exhibit reduced undesirable side effects
in patient, for example, undesirable effects on a patient's
cartilage or other structural tissue, as compared to the
administration, for example administration into the intra-articular
space of a joint, of an equivalent amount of the Class A, C or D
corticosteroid absent any microparticle or other type of
incorporation, admixture, or encapsulation.
[0042] The invention provides populations of microparticles
including a Class A corticosteroid or a pharmaceutically acceptable
salt thereof incorporated in, admixed, encapsulated or otherwise
associated with a lactic acid-glycolic acid copolymer matrix,
wherein the Class A corticosteroid is between 15% to 30% of the
microparticles.
[0043] The invention also provides controlled or sustained release
preparations of a Class A corticosteroid including a lactic
acid-glycolic acid copolymer microparticle containing the Class A
corticosteroid, wherein the Class A corticosteroid is between 10%
to 40%, for example between 15% to 30% of the lactic acid-glycolic
acid copolymer microparticle matrix.
[0044] The invention provides formulations that include (a)
controlled- or sustained-release microparticles including a Class A
corticosteroid and a lactic acid-glycolic acid copolymer matrix,
wherein the Class A corticosteroid is between 15% to 30% of the
microparticles and wherein the lactic acid-glycolic acid copolymer
has one of more of the following characteristics: (i) a molecular
weight in the range of about 40 to 70 kDa; (ii) an inherent
viscosity in the range of 0.35 to 0.5 dL/g; (iii) a
lactide:glycolide molar ratio of 60:40 to 45:55; and/or (iv) the
lactic acid-glycolic acid copolymer is carboxylic acid
endcapped
[0045] In some embodiments, the copolymer is biodegradable. In some
embodiments, the lactic acid-glycolic acid copolymer is a
poly(lactic-co-glycolic) acid copolymer (PLGA). In some
embodiments, the lactic acid-glycolic acid copolymer has a molar
ratio of lactic acid:glycolic acid from the range of about 60:40 to
45:55. In some embodiments, the lactic acid-glycolic acid copolymer
has a molar ratio of lactic acid:glycolic acid of 50:50.
[0046] In some embodiments, the Class A corticosteroid is
prednisolone or a commercially available chemical analogue or a
pharmaceutically-acceptable salt thereof. In some embodiments,
total dose of the Class A corticosteroid contained in the
microparticles is in a range selected from 10-250 mg, where the
Class A corticosteroid is between 10-40%, for example, between
15-30% of the microparticle (i.e., when the corticosteroid is 10%
of the microparticle, the microparticle is in the range of 100-2500
mgs, when the corticosteroid is 15% of the microparticle, the
microparticle is in the range of 66.7-1666.7 mgs, when the
corticosteroid is 20% of the microparticle, the microparticle is in
the range of 50-1250 mgs, when the corticosteroid is 25% of the
microparticle, the microparticle is in the range of 40-1000 mgs,
when the corticosteroid is 30% of the microparticle, the
microparticle is in the range of 33.3-833.3 mgs, when the
corticosteroid is 40% of the microparticle, the microparticle is in
the range of 25-625 mgs and so on for all values between 10-40%
load dose). For example, in some embodiments, the total dose of
corticosteroid is in the range of 10-225 mg, 10-200 mg, 10-175 mg,
10-150 mg, 10-120 mg, 10-100 mg, 10-75 mg, 10-50 mg, 10-25 mg,
20-250 mg, 20-225 mg, 20-200 mg, 20-175 mg, 20-150 mg, 20-125 mg,
20-100 mg, 20-75 mg, 20-50 mg, 30-250 mg, 30-225 mg, 30-200 mg,
30-175 mg, 30-150 mg, 30-120 mg, 30-100 mg, 30-75 mg, 30-50 mg,
40-250 mg, 40-225 mg, 40-200 mg, 40-175 mg, 40-150 mg, 40-120 mg,
40-100 mg, 40-75 mg, 50-250 mg, 50-225 mg, 50-200 mg, 50-175 mg,
50-150 mg, 50-120 mg, 50-100 mg, 50-75 mg, 60-250 mg, 60-225 mg,
60-200 mg, 60-175 mg, 60-150 mg, 60-120 mg, 60-100 mg, 60-75 mg,
70-250 mg, 70-225 mg, 70-200 mg, 70-175 mg, 70-150 mg, 70-120 mg,
70-100 mg, 80-250 mg, 80-225 mg, 80-200 mg, 80-175 mg, 80-150 mg,
80-120 mg, 80-100 mg, 90-250 mg, 90-225 mg, 90-200 mg, 90-175 mg,
90-150 mg, or 90-120 mg. In some embodiments, the Class A
corticosteroid is released for between 14 days and 90 days.
[0047] In some embodiments, the microparticles have a mean diameter
of between 10 .mu.m to 100 .mu.m, for example, the microparticles
have a mean diameter in the range of 20-100 .mu.M, 20-90 .mu.M,
30-100 .mu.M, 30-90 .mu.M, or 10-90 .mu.M. It is understood that
these ranges refer to the mean diameter of all microparticles in a
given population. The diameter of any given individual
microparticle could be within a standard deviation above or below
the mean diameter.
[0048] In some embodiments, the microparticles further comprise a
polyethylene glycol (PEG) moiety, wherein the PEG moiety comprises
between 25% to 0% weight percent of the microparticle. In some
embodiments of the microparticles that include a PEG moiety, the
populations, preparations and/or formulations of the invention do
not require the presence of PEG to exhibit the desired
corticosteroid sustained release kinetics and bioavailability
profile.
[0049] In one embodiment of these populations, preparations and/or
formulations, the corticosteroid microparticle formulation includes
prednisolone and a microparticle made using 50:50 PLGA formulation
having a molecular weight in the range of 40 kDa to 70 kDa. In
these prednisolone/50:50 PLGA corticosteroid microparticle
formulations, the microparticles have a mean diameter in the range
of 10-100 .mu.M. In some embodiments, the microparticles have a
mean diameter in the range of 20-100 .mu.M, 20-90 .mu.M, 30-100
.mu.M, 30-90 .mu.M, or 10-90 .mu.M.
[0050] For the prednisolone/50:50 PLGA microparticle formulations,
the range of prednisolone load percentage is between 10-40%, for
example, between 15-30%.
[0051] In some embodiments of the prednisolone/50:50 PLGA
microparticle formulations, the microparticles further comprise a
polyethylene glycol (PEG) moiety, wherein the PEG moiety comprises
between 25% to 0% weight percent of the microparticle. In some
embodiments of the microparticles that include a PEG moiety, the
populations, preparations and/or formulations of the invention do
not require the presence of PEG to exhibit the desired
corticosteroid sustained release kinetics and bioavailability
profile.
[0052] The invention provides populations of microparticles
including a Class C corticosteroid or a pharmaceutically acceptable
salt thereof incorporated in, admixed, encapsulated or otherwise
associated with a lactic acid-glycolic acid copolymer matrix,
wherein the Class C corticosteroid is between 10% to 40% of the
microparticles, for example between 15% to 30% of the
microparticles.
[0053] The invention also provides controlled or sustained release
preparations of a Class C corticosteroid including a lactic
acid-glycolic acid copolymer microparticle containing the Class C
corticosteroid, wherein the Class C corticosteroid is between 15%
to 30% of the lactic acid-glycolic acid copolymer microparticle
matrix.
[0054] The invention provides formulations that include (a)
controlled- or sustained-release microparticles having a Class C
corticosteroid and a lactic acid-glycolic acid copolymer matrix,
wherein the Class C corticosteroid is between 15% to 30% of the
microparticles and wherein the lactic acid-glycolic acid copolymer
has one of more of the following characteristics: (i) a molecular
weight in the range of about 40 to 70 kDa; (ii) an inherent
viscosity in the range of 0.35 to 0.5 dL/g; (iii) a
lactide:glycolide molar ratio of 60:40 to 45:55; and/or (iv) the
lactic acid-glycolic acid copolymer is carboxylic acid
endcapped.
[0055] In one embodiment of these populations, preparations and/or
formulations, the copolymer is biodegradable. In some embodiments,
the lactic acid-glycolic acid copolymer is a
poly(lactic-co-glycolic) acid copolymer (PLGA). In some
embodiments, the lactic acid-glycolic acid copolymer has a molar
ratio of lactic acid:glycolic acid from the range of about 60:40 to
45:55. In some embodiments, the lactic acid-glycolic acid copolymer
has a molar ratio of lactic acid:glycolic acid of 50:50.
[0056] In some embodiments, the Class C corticosteroid is
betamethasone or a commercially available chemical analogue or a
pharmaceutically-acceptable salt thereof. In some embodiments,
total dose of the Class C corticosteroid contained in the
microparticles is in a range selected from 2-250 mg, where the
Class C corticosteroid is between 10-40%, for example, between
15-30% of the microparticle (i.e., when the corticosteroid is 10%
of the microparticle, the microparticle is in the range of 20-2500
mgs, when the corticosteroid is 15% of the microparticle, the
microparticle is in the range of 13.3-1666.7 mgs, when the
corticosteroid is 20% of the microparticle, the microparticle is in
the range of 10-1250 mgs, when the corticosteroid is 25% of the
microparticle, the microparticle is in the range of 8-1000 mgs,
when the corticosteroid is 30% of the microparticle, the
microparticle is in the range of 6.67-833.3 mgs, when the
corticosteroid is 40% of the microparticle, the microparticle is in
the range of 5-625 mgs and so on for all values between 10-40% load
dose). For example, in some embodiments, the total dose of
corticosteroid is in the range of 2-225 mg, 2-200 mg, 2-175 mg,
2-150 mg, 2-120 mg, 2-100 mg, 2-75 mg, 2-60 mg, 2-55 mg, 2-50 mg,
2-45 mg, 2-40 mg, 2-35 mg, 2-30 mg, 2-25 mg, 2-20 mg, 2-15 mg, 2-10
mg, 4-225 mg, 4-200 mg, 4-175 mg, 4-150 mg, 4-120 mg, 4-100 mg,
4-75 mg, 4-60 mg, 4-55 mg, 4-50 mg, 4-45 mg, 4-40 mg, 4-35 mg, 4-30
mg, 4-25 mg, 4-20 mg, 4-15 mg, 4-10 mg, 5-225 mg, 5-200 mg, 5-175
mg, 5-150 mg, 5-120 mg, 5-100 mg, 5-75 mg, 5-60 mg, 5-55 mg, 5-50
mg, 5-45 mg, 5-40 mg, 5-35 mg, 5-30 mg, 5-25 mg, 5-20 mg, 5-15 mg,
5-10 mg, 6-225 mg, 6-200 mg, 6-175 mg, 6-150 mg, 6-120 mg, 6-100
mg, 6-75 mg, 6-60 mg, 6-55 mg, 6-50 mg, 6-45 mg, 6-40 mg, 6-35 mg,
6-30 mg, 6-25 mg, 6-20 mg, 6-15 mg, 6-10 mg, 8-225 mg, 8-200 mg,
8-175 mg, 8-150 mg, 8-120 mg, 8-100 mg, 8-75 mg, 8-60 mg, 8-55 mg,
8-50 mg, 8-45 mg, 8-40 mg, 8-35 mg, 8-30 mg, 8-25 mg, 8-20 mg, 8-15
mg, 8-10 mg, 10-225 mg, 10-200 mg, 10-175 mg, 10-150 mg, 10-120 mg,
10-100 mg, 10-75 mg, 10-50 mg, 10-25 mg, 20-250 mg, 20-225 mg,
20-200 mg, 20-175 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-75 mg,
20-50 mg, 30-250 mg, 30-225 mg, 30-200 mg, 30-175 mg, 30-150 mg,
30-120 mg, 30-100 mg, 30-75 mg, 30-50 mg, 40-250 mg, 40-225 mg,
40-200 mg, 40-175 mg, 40-150 mg, 40-120 mg, 40-100 mg, 40-75 mg,
50-250 mg, 50-225 mg, 50-200 mg, 50-175 mg, 50-150 mg, 50-120 mg,
50-100 mg, 50-75 mg, 60-250 mg, 60-225 mg, 60-200 mg, 60-175 mg,
60-150 mg, 60-120 mg, 60-100 mg, 60-75 mg, 70-250 mg, 70-225 mg,
70-200 mg, 70-175 mg, 70-150 mg, 70-120 mg, 70-100 mg, 80-250 mg,
80-225 mg, 80-200 mg, 80-175 mg, 80-150 mg, 80-120 mg, 80-100 mg,
90-250 mg, 90-225 mg, 90-200 mg, 90-175 mg, 90-150 mg, or 90-120
mg. In some embodiments, the Class C corticosteroid is released for
between 14 days and 90 days.
[0057] In some embodiments, the microparticles have a mean diameter
of between 10 .mu.m to 100 .mu.m, for example, the microparticles
have a mean diameter in the range of 20-100 .mu.M, 20-90 .mu.M,
30-100 .mu.M, 30-90 .mu.M, or 10-90 .mu.M. It is understood that
these ranges refer to the mean diameter of all microparticles in a
given population. The diameter of any given individual
microparticle could be within a standard deviation above or below
the mean diameter.
[0058] In some embodiments, the microparticles further comprise a
polyethylene glycol (PEG) moiety, wherein the PEG moiety comprises
between 25% to 0% weight percent of the microparticle. In some
embodiments of the microparticles that include a PEG moiety, the
populations, preparations and/or formulations of the invention do
not require the presence of PEG to exhibit the desired
corticosteroid sustained release kinetics and bioavailability
profile.
[0059] In one embodiment of these populations, preparations and/or
formulations, the corticosteroid microparticle formulation includes
betamethasone and a microparticle made using 50:50 PLGA formulation
having a molecular weight in the range of 40 kDa to 70 kDa. In
these betamethasone/50:50 PLGA corticosteroid microparticle
formulations, the microparticles have a mean diameter in the range
of 10-100 .mu.M. In some embodiments, the microparticles have a
mean diameter in the range of 20-100 .mu.M, 20-90 .mu.M, 30-100
.mu.M, 30-90 .mu.M, or 10-90 .mu.M. It is understood that these
ranges refer to the mean diameter of all microparticles in a given
population. The diameter of any given individual microparticle
could be within a standard deviation above or below the mean
diameter.
[0060] For the betamethasone/50:50 PLGA microparticle formulations,
the range of prednisolone load percentage is between 10-40%, for
example, between 15-30%.
[0061] In some embodiments of the betamethasone/50:50 PLGA
microparticle formulations, the microparticles further comprise a
polyethylene glycol (PEG) moiety, wherein the PEG moiety comprises
between 25% to 0% weight percent of the microparticle. In some
embodiments of the microparticles that include a PEG moiety, the
populations, preparations and/or formulations of the invention do
not require the presence of PEG to exhibit the desired
corticosteroid sustained release kinetics and bioavailability
profile.
[0062] The invention provides populations of microparticles
including a Class D corticosteroid or a pharmaceutically acceptable
salt thereof incorporated in, admixed, encapsulated or otherwise
associated with a lactic acid-glycolic acid copolymer matrix,
wherein the Class D corticosteroid is between 8% to 20% of the
microparticles, for example, between 10% to 20% of the
microparticles.
[0063] The invention also provides controlled or sustained release
preparation of a Class D corticosteroid including a lactic
acid-glycolic acid copolymer microparticle containing the Class D
corticosteroid, wherein the Class D corticosteroid is between 8% to
20%, for example, between 10% to 20% of the microparticles of the
lactic acid-glycolic acid copolymer microparticle matrix.
[0064] The invention provides formulations including (a)
controlled- or sustained-release microparticles having a Class D
corticosteroid and a lactic acid-glycolic acid copolymer matrix,
wherein the Class D corticosteroid is between 8% to 20% of the
microparticles, for example, between 10% to 20% of the
microparticles, and wherein the lactic acid-glycolic acid copolymer
has one of more of the following characteristics: (i) a molecular
weight in the range of about 40 to 70 kDa; (ii) an inherent
viscosity in the range of 0.35 to 0.5 dL/g; (iii) a
lactide:glycolide molar ratio of 60:40 to 45:55; and/or (iv) the
lactic acid-glycolic acid copolymer is carboxylic acid
endcapped.
[0065] In one embodiment of these populations, preparations and/or
formulations, the copolymer is biodegradable. In some embodiments,
the lactic acid-glycolic acid copolymer is a
poly(lactic-co-glycolic) acid copolymer (PLGA). In some
embodiments, the lactic acid-glycolic acid copolymer has a molar
ratio of lactic acid:glycolic acid from the range of about 60:40 to
45:55. In some embodiments, the lactic acid-glycolic acid copolymer
has a molar ratio of lactic acid:glycolic acid of 50:50.
[0066] In some embodiments, the Class D corticosteroid is
fluticasone propionate, fluticasone, or a commercially available
chemical analogue or a pharmaceutically-acceptable salt thereof. In
some embodiments, total dose of the Class D corticosteroid
contained in the microparticles is in a range selected from 1-250
mg, where the Class D corticosteroid is between 8-20% of the
microparticle (i.e., when the corticosteroid is 8% of the
microparticle, the microparticle is in the range of 12.5-3125 mgs,
when the corticosteroid is 10% of the microparticle, the
microparticle is in the range of 10-2500 mgs, when the
corticosteroid is 15% of the microparticle, the microparticle is in
the range of 6.67-1666.7 mgs, when the corticosteroid is 20% of the
microparticle, the microparticle is in the range of 5-1250 mgs, and
so on for all values between 10-20% load dose). For example, in
some embodiments, the total dose of corticosteroid is in the range
of 1-225 mg, 1-200 mg, 1-175 mg, 1-150 mg, 1-120 mg, 1-100 mg, 1-75
mg, 1-60 mg, 1-55 mg, 1-50 mg, 1-45 mg, 1-40 mg, 1-35 mg, 1-30 mg,
1-25 mg, 1-20 mg, 1-15 mg, 1-10 mg, 2-225 mg, 2-200 mg, 2-175 mg,
2-150 mg, 2-120 mg, 2-100 mg, 2-75 mg, 2-60 mg, 2-55 mg, 2-50 mg,
2-45 mg, 2-40 mg, 2-35 mg, 2-30 mg, 2-25 mg, 2-20 mg, 2-15 mg, 2-10
mg, 3-225 mg, 3-200 mg, 3-175 mg, 3-150 mg, 3-120 mg, 3-100 mg,
3-75 mg, 3-60 mg, 3-55 mg, 3-50 mg, 3-45 mg, 3-40 mg, 3-35 mg, 3-30
mg, 3-25 mg, 3-20 mg, 3-15 mg, 3-10 mg, 4-225 mg, 4-200 mg, 4-175
mg, 4-150 mg, 4-120 mg, 4-100 mg, 4-75 mg, 4-60 mg, 4-55 mg, 4-50
mg, 4-45 mg, 4-40 mg, 4-35 mg, 4-30 mg, 4-25 mg, 4-20 mg, 4-15 mg,
4-10 mg, 5-225 mg, 5-200 mg, 5-175 mg, 5-150 mg, 5-120 mg, 5-100
mg, 5-75 mg, 5-60 mg, 5-55 mg, 5-50 mg, 5-45 mg, 5-40 mg, 5-35 mg,
5-30 mg, 5-25 mg, 5-20 mg, 5-15 mg, 5-10 mg, 6-225 mg, 6-200 mg,
6-175 mg, 6-150 mg, 6-120 mg, 6-100 mg, 6-75 mg, 6-60 mg, 6-55 mg,
6-50 mg, 6-45 mg, 6-40 mg, 6-35 mg, 6-30 mg, 6-25 mg, 6-20 mg, 6-15
mg, 6-10 mg, 8-225 mg, 8-200 mg, 8-175 mg, 8-150 mg, 8-120 mg,
8-100 mg, 8-75 mg, 8-60 mg, 8-55 mg, 8-50 mg, 8-45 mg, 8-40 mg,
8-35 mg, 8-30 mg, 8-25 mg, 8-20 mg, 8-15 mg, 8-10 mg, 10-225 mg,
10-200 mg, 10-175 mg, 10-150 mg, 10-120 mg, 10-100 mg, 10-75 mg,
10-50 mg, 10-25 mg, 20-250 mg, 20-225 mg, 20-200 mg, 20-175 mg,
20-150 mg, 20-125 mg, 20-100 mg, 20-75 mg, 20-50 mg, 30-250 mg,
30-225 mg, 30-200 mg, 30-175 mg, 30-150 mg, 30-120 mg, 30-100 mg,
30-75 mg, 30-50 mg, 40-250 mg, 40-225 mg, 40-200 mg, 40-175 mg,
40-150 mg, 40-120 mg, 40-100 mg, 40-75 mg, 50-250 mg, 50-225 mg,
50-200 mg, 50-175 mg, 50-150 mg, 50-120 mg, 50-100 mg, 50-75 mg,
60-250 mg, 60-225 mg, 60-200 mg, 60-175 mg, 60-150 mg, 60-120 mg,
60-100 mg, 60-75 mg, 70-250 mg, 70-225 mg, 70-200 mg, 70-175 mg,
70-150 mg, 70-120 mg, 70-100 mg, 80-250 mg, 80-225 mg, 80-200 mg,
80-175 mg, 80-150 mg, 80-120 mg, 80-100 mg, 90-250 mg, 90-225 mg,
90-200 mg, 90-175 mg, 90-150 mg, or 90-120 mg. In some embodiments,
the Class D corticosteroid is released for between 14 days and 90
days.
[0067] In some embodiments, the microparticles have a mean diameter
of between 10 .mu.m to 100 .mu.m, for example, the microparticles
have a mean diameter in the range of 20-100 .mu.M, 20-90 .mu.M,
30-100 .mu.M, 30-90 .mu.M, or 10-90 .mu.M. It is understood that
these ranges refer to the mean diameter of all microparticles in a
given population. The diameter of any given individual
microparticle could be within a standard deviation above or below
the mean diameter.
[0068] In some embodiments, the microparticles further comprise a
polyethylene glycol (PEG) moiety, wherein the PEG moiety comprises
between 25% to 0% weight percent of the microparticle. In some
embodiments of the microparticles that include a PEG moiety, the
populations, preparations and/or formulations of the invention do
not require the presence of PEG to exhibit the desired
corticosteroid sustained release kinetics and bioavailability
profile.
[0069] In one embodiment of these populations, preparations and/or
formulations, the corticosteroid microparticle formulation includes
fluticasone propionate or fluticasone, and a microparticle made
using 50:50 PLGA formulation having a molecular weight in the range
of 40 kDa to 70 kDa. In these fluticasone or fluticasone
propionate/50:50 PLGA corticosteroid microparticle formulations,
the microparticles have a mean diameter in the range of 10-100
.mu.M. In some embodiments, the microparticles have a mean diameter
in the range of 20-100 .mu.M, 20-90 .mu.M, 30-100 .mu.M, 30-90
.mu.M, or 10-90 .mu.M. It is understood that these ranges refer to
the mean diameter of all microparticles in a given population. The
diameter of any given individual microparticle could be within a
standard deviation above or below the mean diameter.
[0070] For the fluticasone or fluticasone propionate/50:50 PLGA
microparticle formulations, the range of prednisolone load
percentage is between 10-20%.
[0071] In some embodiments of the fluticasone or fluticasone
propionate/50:50 PLGA microparticle formulations, the
microparticles further comprise a polyethylene glycol (PEG) moiety,
wherein the PEG moiety comprises between 25% to 0% weight percent
of the microparticle. In some embodiments of the microparticles
that include a PEG moiety, the populations, preparations and/or
formulations of the invention do not require the presence of PEG to
exhibit the desired corticosteroid sustained release kinetics and
bioavailability profile.
[0072] These embodiments of corticosteroid microparticle
formulations have been selected because the combination of class of
corticosteroid, type of microparticle, molecular weight of polymers
used to create the microparticles, lactide:glycolide molar ratio,
and/or load percentage of the corticosteroid exhibit the desired
release kinetics. These embodiments also exhibit the desired
release kinetics with minimal prolonged HPA axis suppression.
[0073] The invention provides methods of treating pain or
inflammation in a patient comprising administering to said patient
a therapeutically effective amount of a population of
microparticles selected from the following populations: (i) a
population of microparticles comprising a Class B corticosteroid or
a pharmaceutically acceptable salt thereof incorporated in a lactic
acid-glycolic acid copolymer matrix, wherein the Class B
corticosteroid comprises between 22% to 28% of the microparticles;
(ii) a population of microparticles comprising a Class A
corticosteroid or a pharmaceutically acceptable salt thereof
incorporated in a lactic acid-glycolic acid copolymer matrix,
wherein the Class A corticosteroid comprises between 15% to 30% of
the microparticles; (iii) a population of microparticles comprising
a Class C corticosteroid or a pharmaceutically acceptable salt
thereof incorporated in a lactic acid-glycolic acid copolymer
matrix, wherein the Class C corticosteroid comprises between 15% to
30% of the microparticles; and (iv) a population of microparticles
comprising a Class D corticosteroid or a pharmaceutically
acceptable salt thereof incorporated in a lactic acid-glycolic acid
copolymer matrix, wherein the Class D corticosteroid comprises
between 8% to 20% of the microparticles. In some embodiments, the
population of microparticles releases the corticosteroid for at
least 14 days at a rate that does not adversely suppress the
hypothalamic-pituitary-adrenal axis (HPA axis). In some
embodiments, the population of microparticles releases the
corticosteroid in a controlled or sustained release manner such
that the levels of cortisol suppression are at or below 35% by day
14 post-administration, for example post-administration. In some
embodiments, the population of microparticles releases the
corticosteroid in a controlled or sustained release manner such
that the levels of cortisol suppression are negligible and/or
undetectable by 14 post-administration. In some embodiments, the
population of microparticles releases the corticosteroid in a
controlled or sustained release manner such that the levels of
cortisol suppression are negligible at any time
post-administration.
[0074] The invention provides methods of treating pain or
inflammation in a patient comprising administering to said patient
a therapeutically effective amount of a controlled or sustained
release preparation selected from the following preparations: (i) a
controlled or sustained release preparation of a Class B
corticosteroid comprising a lactic acid-glycolic acid copolymer
microparticle containing the Class B corticosteroid, wherein the
Class B corticosteroid comprises between 22% to 28% of the lactic
acid-glycolic acid copolymer microparticle matrix; (ii) a
controlled or sustained release preparation of a Class A
corticosteroid comprising a lactic acid-glycolic acid copolymer
microparticle containing the Class A corticosteroid, wherein the
Class A corticosteroid comprises between 15% to 30% of the lactic
acid-glycolic acid copolymer microparticle matrix; (iii) a
controlled or sustained release preparation of a Class C
corticosteroid comprising a lactic acid-glycolic acid copolymer
microparticle containing the Class C corticosteroid, wherein the
Class C corticosteroid comprises between 15% to 30% of the lactic
acid-glycolic acid copolymer microparticle matrix; and (iv) a
controlled or sustained release preparation of a Class D
corticosteroid comprising a lactic acid-glycolic acid copolymer
microparticle containing the Class D corticosteroid, wherein the
Class D corticosteroid comprises between 8% to 20% of the lactic
acid-glycolic acid copolymer microparticle matrix. In some
embodiments, the controlled or sustained release preparation
releases the corticosteroid for at least 14 days at a rate that
does not adversely suppress the hypothalamic-pituitary-adrenal axis
(HPA axis). In some embodiments, the controlled or sustained
release preparation releases the corticosteroid in a controlled or
sustained release manner such that the levels of cortisol
suppression are at or below 35% by day 14 post-administration, for
example post-administration. In some embodiments, the controlled or
sustained release preparation releases the corticosteroid in a
controlled or sustained release manner such that the levels of
cortisol suppression are negligible and/or undetectable by 14
post-administration. In some embodiments, the controlled or
sustained release preparation releases the corticosteroid in a
controlled or sustained release manner such that the levels of
cortisol suppression are negligible at any time
post-administration.
[0075] The invention provides methods of treating pain or
inflammation in a patient comprising administering to said patient
a therapeutically effective amount of a formulation selected from
the following preparations: (i) a formulation comprising (a)
controlled- or sustained-release microparticles comprising a Class
B corticosteroid and a lactic acid-glycolic acid copolymer matrix,
wherein the Class B corticosteroid comprises between 22% to 28% of
the microparticles and wherein the lactic acid-glycolic acid
copolymer has one of more of the following characteristics: (1) a
molecular weight in the range of about 40 to 70 kDa; (2) an
inherent viscosity in the range of 0.5 to 0.5 dL/g; or (3) a
lactide:glycolide molar ratio of 80:20 to 60:40; (ii) a formulation
comprising (a) controlled- or sustained-release microparticles
comprising a Class A corticosteroid and a lactic acid-glycolic acid
copolymer matrix, wherein the Class A corticosteroid comprises
between 15% to 30% of the microparticles and wherein the lactic
acid-glycolic acid copolymer has one of more of the following
characteristics: (1) a molecular weight in the range of about 40 to
70 kDa; (2) an inherent viscosity in the range of 0.35 to 0.5 dL/g;
or (3) a lactide:glycolide molar ratio of 60:40 to 45:55; (iii) a
formulation comprising (a) controlled- or sustained-release
microparticles comprising a Class C corticosteroid and a lactic
acid-glycolic acid copolymer matrix, wherein the Class C
corticosteroid comprises between 15% to 30% of the microparticles
and wherein the lactic acid-glycolic acid copolymer has one of more
of the following characteristics: (1) a molecular weight in the
range of about 40 to 70 kDa; (2) an inherent viscosity in the range
of 0.35 to 0.5 dL/g; or (3) a lactide:glycolide molar ratio of
60:40 to 45:55; and (iv) a formulation comprising (a) controlled-
or sustained-release microparticles comprising a Class D
corticosteroid and a lactic acid-glycolic acid copolymer matrix,
wherein the Class D corticosteroid comprises between 8% to 20% of
the microparticles and wherein the lactic acid-glycolic acid
copolymer has one of more of the following characteristics: (1) a
molecular weight in the range of about 40 to 70 kDa; (2) an
inherent viscosity in the range of 0.35 to 0.5 dL/g; or (3) a
lactide:glycolide molar ratio of 60:40 to 45:55. In some
embodiments, the formulation releases the corticosteroid for at
least 14 days at a rate that does not adversely suppress the
hypothalamic-pituitary-adrenal axis (HPA axis). In some
embodiments, the formulation releases the corticosteroid in a
controlled or sustained release manner such that the levels of
cortisol suppression are at or below 35% by day 14
post-administration, for example post-administration. In some
embodiments, the formulation releases the corticosteroid in a
controlled or sustained release manner such that the levels of
cortisol suppression are negligible and/or undetectable by 14
post-administration. In some embodiments, the formulation releases
the corticosteroid in a controlled or sustained release manner such
that the levels of cortisol suppression are negligible at any time
post-administration.
[0076] In some embodiments, the population of microparticles, the
controlled or sustained release preparation or formulation is
administered as one or more intra-articular injections. In some
embodiments, the patient has osteoarthritis, rheumatoid arthritis,
acute gouty arthritis, and synovitis. In some embodiments, the
patient has acute bursitis, sub-acute bursitis, acute nonspecific
tenosynovitis, or epicondylitis.
[0077] In one aspect, a method of treating pain and/or inflammation
in a joint of a patient is provided that includes administering
intra-articularly (e.g., by one or more injections) to a patient
with joint disease (e.g., osteoarthritis or rheumatoid arthritis) a
formulation that contains one or more corticosteroids, such as
those formulations described herein. Therapeutically effective
amounts of the one or more corticosteroids are released for a
period of time at a rate that does not suppress (e.g., adversely
and/or measurably) the HPA axis.
[0078] In another aspect, a method of treating pain and/or
inflammation in a joint of a patient is provided that includes
administering intra-articularly (e.g., by one or more injections) a
therapeutically effective amount of one or more corticosteroids in
a formulation to a patient with joint disease (e.g., osteoarthritis
or rheumatoid arthritis). The formulation has a sustained release
microparticle formulation that may or may not release detectable
levels of corticosteroid for a length of time following
administration and that releases a detectable amount of
corticosteroid(s) following administration, where the rate of
corticosteroid release from the sustained release microparticle
formulation does not adversely suppress the HPA axis. In some
embodiments, corticosteroid released from the sustained release
microparticle formulation will not measurably suppress the HPA
axis.
[0079] According to certain embodiments of the foregoing methods,
the formulation comprises a population of biodegradable polymer
microparticles that contain the corticosteroids. In some
embodiments, the corticosteroids are 2% to 75% (w/w) of the
microparticles, preferably about 5% to 50% (w/w) of the
microparticles, and more preferably 5% to 40% or 10% to 30% (w/w)
of the microparticles. In some embodiments, the microparticles have
a mass mean diameter of between 10 .mu.m to 100 .mu.m. In some
embodiments, the microparticles are formed from a hydrogel,
hyaluronic acid, PLA or PLGA. For example, the microparticles are
formed from PLGA with a lactide to glycolide co-polymer ratio of
about 45:55 to about 80:20. In some embodiments, the corticosteroid
is betamethasone, dexamethasone, triamcinolone acetonide,
triamcinolone hexacetonide, prednisolone, methylprednisolone,
budesonide, mometasone, ciclesonide, fluticasone, salts thereof,
esters thereof or combinations thereof.
[0080] In yet another aspect, a composition is provided that
includes a population of biodegradable polymer microparticles that
contain corticosteroid(s). For example, the corticosteroid is
betamethasone, dexamethasone, triamcinolone acetonide,
triamcinolone hexacetonide, prednisolone, methylprednisolone,
budesonide, mometasone, ciclesonide, fluticasone, salts thereof,
esters thereof or combinations thereof. When the composition is
administered intra-articularly (e.g., by one or more injections), a
therapeutically effective amount of corticosteroid(s) is released
for a period of time at a rate that does not suppress the HPA axis.
In some embodiments, the corticosteroid(s) released will not
adversely suppress the HPA axis. In some embodiments, the
corticosteroid(s) released will not measurably suppress the HPA
axis.
[0081] In yet a further aspect, a composition is provided that
includes a population of biodegradable polymer microparticles that
contain corticosteroid(s). For example, the corticosteroid is
betamethasone, dexamethasone, triamcinolone acetonide,
triamcinolone hexacetonide, prednisolone, methylprednisolone,
budesonide, mometasone, ciclesonide, fluticasone, salts thereof,
esters thereof or combinations thereof. When the composition is
administered intra-articularly (e.g., by one or more injections),
therapeutically effective amounts of corticosteroid(s) are released
following administration from a first component for a first length
of time and from a sustained release component for a second length
of time. Furthermore, the rate of corticosteroid(s) released from
the sustained release component does not suppress the HPA axis. In
some embodiments, the corticosteroid(s) released from the sustained
release component during the second length of time will not
adversely suppress the HPA axis. In some embodiments, the
corticosteroid(s) released from the sustained release component
during the second length of time will not measurably suppress the
HPA axis. In some embodiments, the first component comprises a
corticosteroid containing solution or suspension. In some
embodiments, the first component contains a corticosteroid that is
different from that of the sustained release component. In other
embodiments, the same corticosteroid is used in both the first and
sustained release components.
[0082] According to certain embodiments of the foregoing
compositions, the corticosteroids are 2% to 75% (w/w) of the
microparticles, preferably about 5% to 50% (w/w) of the
microparticles, and more preferably 5% to 40% (w/w) of the
microparticles. In some embodiments, the microparticles have a mass
mean diameter of between 10 .mu.m to 100 .mu.m. In some
embodiments, the microparticles are formed from a hydrogel,
hyaluronic acid, PLA or PLGA. For example, the microparticles are
formed from PLGA with a lactide to glycolide co-polymer ratio of
about 45:55 to about 80:20. In some embodiments, the compositions
further comprise a corticosteroid containing solution or
suspension. In some embodiments, the corticosteroid containing
solution or suspension contains a corticosteroid that is different
from that found in the microparticles.
[0083] The invention also provides methods of slowing, arresting or
reversing progressive structural tissue damage associated with
chronic inflammatory disease in a patient comprising administering
to said patient a therapeutically effective amount of a population
of microparticles selected from the following populations: (i) a
population of microparticles comprising a Class B corticosteroid or
a pharmaceutically acceptable salt thereof incorporated in a lactic
acid-glycolic acid copolymer matrix, wherein the Class B
corticosteroid comprises between 22% to 28% of the microparticles;
(ii) a population of microparticles comprising a Class A
corticosteroid or a pharmaceutically acceptable salt thereof
incorporated in a lactic acid-glycolic acid copolymer matrix,
wherein the Class A corticosteroid comprises between 15% to 30% of
the microparticles; (iii) a population of microparticles comprising
a Class C corticosteroid or a pharmaceutically acceptable salt
thereof incorporated in a lactic acid-glycolic acid copolymer
matrix, wherein the Class C corticosteroid comprises between 15% to
30% of the microparticles; and (iv) a population of microparticles
comprising a Class D corticosteroid or a pharmaceutically
acceptable salt thereof incorporated in a lactic acid-glycolic acid
copolymer matrix, wherein the Class D corticosteroid comprises
between 8% to 20% of the microparticles. In some embodiments, the
population of microparticles releases the corticosteroid for at
least 14 days at a rate that does not adversely suppress the
hypothalamic-pituitary-adrenal axis (HPA axis).
[0084] The invention also provides methods of slowing, arresting or
reversing progressive structural tissue damage associated with
chronic inflammatory disease in a patient comprising administering
to said patient a therapeutically effective amount of a controlled
or sustained release preparation selected from the following
preparations: (i) a controlled or sustained release preparation of
a Class B corticosteroid comprising a lactic acid-glycolic acid
copolymer microparticle containing the Class B corticosteroid,
wherein the Class B corticosteroid comprises between 22% to 28% of
the lactic acid-glycolic acid copolymer microparticle matrix; (ii)
a controlled or sustained release preparation of a Class A
corticosteroid comprising a lactic acid-glycolic acid copolymer
microparticle containing the Class A corticosteroid, wherein the
Class A corticosteroid comprises between 15% to 30% of the lactic
acid-glycolic acid copolymer microparticle matrix; (iii) a
controlled or sustained release preparation of a Class C
corticosteroid comprising a lactic acid-glycolic acid copolymer
microparticle containing the Class C corticosteroid, wherein the
Class C corticosteroid comprises between 15% to 30% of the lactic
acid-glycolic acid copolymer microparticle matrix; and (iv) a
controlled or sustained release preparation of a Class D
corticosteroid comprising a lactic acid-glycolic acid copolymer
microparticle containing the Class D corticosteroid, wherein the
Class D corticosteroid comprises between 8% to 20% of the lactic
acid-glycolic acid copolymer microparticle matrix. In some
embodiments, the controlled or sustained release preparation
releases the corticosteroid for at least 14 days at a rate that
does not adversely suppress the hypothalamic-pituitary-adrenal axis
(HPA axis).
[0085] The invention also provides methods of slowing, arresting or
reversing progressive structural tissue damage associated with
chronic inflammatory disease in a patient comprising administering
to said patient a therapeutically effective amount of a formulation
selected from the following preparations: (i) a formulation
comprising (a) controlled- or sustained-release microparticles
comprising a Class B corticosteroid and a lactic acid-glycolic acid
copolymer matrix, wherein the Class B corticosteroid comprises
between 22% to 28% of the microparticles and wherein the lactic
acid-glycolic acid copolymer has one of more of the following
characteristics: (1) a molecular weight in the range of about 40 to
70 kDa; (2) an inherent viscosity in the range of 0.3 to 0.5 dL/g;
or (3) a lactide:glycolide molar ratio of 80:20 to 60:40; (ii) a
formulation comprising (a) controlled- or sustained-release
microparticles comprising a Class A corticosteroid and a lactic
acid-glycolic acid copolymer matrix, wherein the Class A
corticosteroid comprises between 15% to 30% of the microparticles
and wherein the lactic acid-glycolic acid copolymer has one of more
of the following characteristics: (1) a molecular weight in the
range of about 40 to 70 kDa; (2) an inherent viscosity in the range
of 0.35 to 0.5 dL/g; or (3) a lactide:glycolide molar ratio of
60:40 to 50:50; (iii) a formulation comprising (a) controlled- or
sustained-release microparticles comprising a Class C
corticosteroid and a lactic acid-glycolic acid copolymer matrix,
wherein the Class C corticosteroid comprises between 15% to 30% of
the microparticles and wherein the lactic acid-glycolic acid
copolymer has one of more of the following characteristics: (1) a
molecular weight in the range of about 40 to 70 kDa; (2) an
inherent viscosity in the range of 0.35 to 0.5 dL/g; or (3) a
lactide:glycolide molar ratio of 60:40 to 50:50; and (iv) a
formulation comprising (a) controlled- or sustained-release
microparticles comprising a Class D corticosteroid and a lactic
acid-glycolic acid copolymer matrix, wherein the Class D
corticosteroid comprises between 8% to 20% of the microparticles
and wherein the lactic acid-glycolic acid copolymer has one of more
of the following characteristics: (1) a molecular weight in the
range of about 40 to 70 kDa; (2) an inherent viscosity in the range
of 0.35 to 0.5 dL/g; or (3) a lactide:glycolide molar ratio of
60:40 to 50:50. In some embodiments, the formulation releases the
corticosteroid for at least 14 days at a rate that does not
adversely suppress the hypothalamic-pituitary-adrenal axis (HPA
axis).
[0086] In some embodiments, the population of microparticles, the
controlled or sustained release preparation or formulation is
administered as one or more intra-articular injections. In some
embodiments, the patient has osteoarthritis, rheumatoid arthritis,
acute gouty arthritis, and synovitis. In some embodiments, the
patient has acute bursitis, sub-acute bursitis, acute nonspecific
tenosynovitis, or epicondylitis.
[0087] The invention also provides methods to slow, arrest, reverse
or otherwise inhibit progressive structural tissue damage
associated with chronic inflammatory disease, for example, damage
to cartilage associated with osteoarthritis. In one embodiment, the
method includes the administration to a patient, for example local
administration, of a therapeutically effective amount of one or
more corticosteroids in a formulation, wherein the formulation
releases the corticosteroid(s) for at least 14 days at a rate that
does not adversely suppress the hypothalamic-pituitary-adrenal axis
(HPA axis). The methods to assess the effect of corticosteroid
formulations on disease progression include controlled clinical
studies that assess clinical end points and/or employ imaging
technologies such as, for example Magnetic Resonance Imaging (MRI),
to determine effects on the structure in chronically inflamed
tissues, for example the effects on cartilage volume and other
articular and peri-articular structures in osteoarthritis and
rheumatoid arthritis. (See e.g., Eckstein F, et al. "Magnetic
resonance imaging (MRI) of articular cartilage in knee
osteoarthritis (OA): morphological assessment." Osteoarthritis
Cartilage 14 Suppl A (2006): A46-75; Lo G H, et al. "Bone marrow
lesions in the knee are associated with increased local bone
density." Arthritis Rheum 52 (2005): 2814-21; and Lo G H, et al.
"The ratio of medial to lateral tibial plateau bone mineral density
and compartment-specific tibiofemoral osteoarthritis."
Osteoarthritis Cartilage 14 (2006): 984-90 the contents of each of
which are hereby incorporated by reference in their entirety.) The
corticosteroid microparticle formulations provided herein appear to
exhibit little to no negative effects, e.g., structural tissue
damage, and from preliminary data and studies described in the
Examples below, these corticosteroid microparticle formulations
appear to have a positive effect, e.g., slowing, arresting or
reversing structural tissue damage.
[0088] The invention also provides methods of treating pain and/or
inflammation of a patient by administering to the patient a
therapeutically effective amount of one or more corticosteroids in
a formulation, wherein the formulation releases the
corticosteroid(s) for at least 14 days at a rate that does not
adversely suppress the hypothalamic-pituitary-adrenal axis (HPA
axis).
[0089] The invention also provides methods of manufacturing the
corticosteroid microparticle formulations. The microparticle
formulations provided herein can be manufactured using any of a
variety of suitable methods.
[0090] For the Class B corticosteroid microparticle formulations,
in some embodiments, the microparticles are manufactured as
described in the Examples provided below. For the Class B
corticosteroid microparticle formulations, in some embodiments, the
microparticles are manufactured as described in U.S. Pat. No.
7,261,529 and U.S. Pat. No. 7,758,778, the contents of each of
which are hereby incorporated by reference in their entirety. For
example, the microparticles are manufactured using a solvent
evaporation process wherein the Class B corticosteroid is dispersed
in a lactic acid-glycolic acid copolymer organic solution and the
mixture is treated to remove the solvent from the mixture, thereby
producing microparticles.
[0091] In some embodiments, the solvent evaporation process
utilizes a spray drying or fluid bed apparatus to remove the
solvent and produce microparticles. In some embodiments, the
solvent evaporation process utilizes a spinning disk. For example,
the spinning disk is the spinning disk as described in U.S. Pat.
No. 7,261,529 and U.S. Pat. No. 7,758,778.
[0092] For the Class B corticosteroid microparticle formulations,
in some embodiments where the Class B corticosteroid is TCA, the
microparticles are manufactured using a solid in oil in water
emulsion process wherein TCA is dispersed in a lactic acid-glycolic
acid copolymer organic solution and added to an aqueous solvent to
produce microparticles.
[0093] For the Class A, C and/or D corticosteroid microparticle
formulations, in some embodiments, the microparticles are
manufactured as described in the Examples provided below. For Class
A, C and/or D corticosteroid formulations, in some embodiments, the
microparticles are manufactured as described in PCT Publication No.
WO 95/13799, the contents of which are hereby incorporated by
reference in their entirety. For example, the microparticles are
manufactured using a solid in oil in water emulsion process wherein
the Class A corticosteroid, Class C corticosteroid and/or Class D
corticosteroid is dispersed in a lactic acid-glycolic acid
copolymer organic solution and added to an aqueous solvent to
produce microparticles.
[0094] The invention also provides long-term sustained or
controlled release formulations that include a corticosteroid
incorporated or otherwise associated with a lactic acid-glycolic
acid copolymer microparticle matrix, wherein the microparticle
releases the corticosteroid for a period of greater than 45 days,
greater than 60 days, greater than 75 days or for at least 90 days.
In a preferred embodiment, the long-term formulation is a
"Ninety-Day Formulation" in which the corticosteroid is released
from the microparticle for a period of at least 90 days.
[0095] In some embodiments of these long-term formulations, e.g.,
Ninety-Day Formulations, the long-term controlled or sustained
release preparation includes a Class B corticosteroid that is
incorporated or otherwise associated with a lactic acid-glycolic
acid copolymer microparticle containing the Class B corticosteroid,
wherein the Class B corticosteroid comprises between 5% to 15%, for
example, between 6% and 15%, between 7% and 15%, between 8% and
15%, between 9% and 15%, between 10% and 15%, between 6% and 14%,
between 7% and 14%, between 8% and 14%, between 9% and 14%, between
10% and 14%, between 6% and 13%, between 7% and 13%, between 8% and
13%, between 9% and 13%, between 10% and 13%, between 6% and 12%,
between 7% and 12%, between 8% and 12%, between 9% and 12%, between
10% and 12%, between 6% and 11%, between 7% and 11%, between 8% and
11%, between 9% and 11%, between 10% and 11%, of the lactic
acid-glycolic acid copolymer microparticle matrix, and wherein the
lactic acid-glycolic acid copolymer microparticle releases the
Class B corticosteroid for a period of at least 75 days. In some
embodiments, the Class B corticosteroid comprises about 10% of the
lactic acid-glycolic acid copolymer microparticle matrix.
[0096] In some embodiments, the copolymer is biodegradable. In some
embodiments, the lactic acid-glycolic acid copolymer is a
poly(lactic-co-glycolic) acid copolymer (PLGA). In some
embodiments, the Class B corticosteroid is triamcinolone acetonide
or a commercially available chemical analogue or a
pharmaceutically-acceptable salt thereof. In some embodiments, the
microparticles have a mean diameter of between 10 .mu.m to 100
.mu.m. In some embodiments, the microparticles have a mean diameter
in the range of 20-100 .mu.M, 20-90 .mu.M, 30-100 .mu.M, 30-90
.mu.M, or 10-90 .mu.M. It is understood that these ranges refer to
the mean diameter of all microparticles in a given population. The
diameter of any given individual microparticle could be within a
standard deviation above or below the mean diameter. In some
embodiments, the lactic acid-glycolic acid copolymer has a molar
ratio of lactic acid:glycolic acid from the range of about 80:20 to
60:40 or from the range of about 80:20 to 50:50. In some
embodiments, the lactic acid-glycolic acid copolymer has a molar
ratio of lactic acid:glycolic acid of 75:25. In some embodiments,
the microparticles further include a polyethylene glycol (PEG)
moiety, wherein the PEG moiety is between 25% to 0% weight percent
of the microparticle. In some embodiments of the microparticles
that include a PEG moiety, the populations, preparations and/or
formulations of the invention do not require the presence of PEG to
exhibit the desired corticosteroid sustained release kinetics and
bioavailability profile. In some embodiments, the Class B
corticosteroid is released for at least 90 days. In some
embodiments, the lactic acid-glycolic acid copolymer includes an
ester endcap.
[0097] In some embodiments of these long-term formulations, e.g.,
Ninety-Day Formulations, the formulation includes long-term
controlled- or sustained-release microparticles having a Class B
corticosteroid and a lactic acid-glycolic acid copolymer matrix,
wherein the lactic acid-glycolic acid copolymer microparticles
release the Class B corticosteroid for a period of at least 75
days, wherein the lactic acid-glycolic acid copolymer
microparticles include a mixture of lactic acid-glycolic acid
copolymers, wherein the Class B corticosteroid comprises between 5%
to 15% of the microparticles, for example, between 6% and 15%,
between 7% and 15%, between 8% and 15%, between 9% and 15%, between
10% and 15%, between 6% and 14%, between 7% and 14%, between 8% and
14%, between 9% and 14%, between 10% and 14%, between 6% and 13%,
between 7% and 13%, between 8% and 13%, between 9% and 13%, between
10% and 13%, between 6% and 12%, between 7% and 12%, between 8% and
12%, between 9% and 12%, between 10% and 12%, between 6% and 11%,
between 7% and 11%, between 8% and 11%, between 9% and 11%, between
10% and 11%, and wherein the mixture of lactic acid-glycolic acid
copolymer comprises a first lactic acid-glycolic acid copolymer
having one of more of the following characteristics: (i) a
molecular weight in the range of about 110 to 150 kDa; (ii) an
inherent viscosity in the range of 0.6 to 1.0 dL/g; or (iii) a
lactide:glycolide molar ratio of 80:20 to 60:40 or a
lactide:glycolide molar ratio of 80:20 to 50:50 and a second lactic
acid-glycolic acid copolymer having one of more of the following
characteristics: (i) a molecular weight in the range of about 40 to
70 kDa; (ii) an inherent viscosity in the range of 0.2 to 0.4 dL/g;
or (iii) a lactide:glycolide molar ratio of 80:20 to 60:40 or a
lactide:glycolide molar ratio of 80:20 to 50:50.
[0098] In some embodiments, the copolymer is biodegradable. In some
embodiments, the lactic acid-glycolic acid copolymer is a
poly(lactic-co-glycolic) acid copolymer (PLGA). In some
embodiments, the Class B corticosteroid is triamcinolone acetonide
or a commercially available chemical analogue or a
pharmaceutically-acceptable salt thereof. In some embodiments, the
microparticles have a mean diameter of between 10 .mu.m to 100
.mu.m. In some embodiments, the microparticles have a mean diameter
in the range of 20-100 .mu.M, 20-90 .mu.M, 30-100 .mu.M, 30-90
.mu.M, or 10-90 .mu.M. It is understood that these ranges refer to
the mean diameter of all microparticles in a given population. The
diameter of any given individual microparticle could be within a
standard deviation above or below the mean diameter. In some
embodiments, the first lactic acid-glycolic acid copolymer, the
second lactic acid-glycolic acid copolymer or both have a molar
ratio of lactic acid:glycolic acid from the range of about 80:20 to
60:40. In some embodiments, the first lactic acid-glycolic acid
copolymer, the second lactic acid-glycolic acid copolymer or both
have a molar ratio of lactic acid:glycolic acid of 75:25. In some
embodiments, the microparticles further include a polyethylene
glycol (PEG) moiety, wherein the PEG moiety is between 25% to 0%
weight percent of the microparticle. In some embodiments, the Class
B corticosteroid is released for at least 90 days. In some
embodiments, the first lactic acid-glycolic acid copolymer, the
second lactic acid-glycolic acid copolymer or both includes an
ester endcap.
[0099] In some embodiments of these long-term controlled or
sustained release formulations, the Class B corticosteroid is
triamcinolone acetonide or a commercially available chemical
analogue or a pharmaceutically-acceptable salt thereof, and the
total dose of corticosteroid contained in the microparticles is in
the range of 10-100 mg, where the Class B corticosteroid is between
5%-15% of the microparticle, for example, about 10% of the
microparticle (i.e., when the corticosteroid is 10% of the
microparticle, the microparticle is in the range of 90-1000 mgs,
and so on for all values between 5%-15% load dose, e.g., when the
corticosteroid is 15% of the microparticle, the microparticle is in
the range of 66.67-666.67 mgs, when the corticosteroid is 13% of
the microparticle, the microparticle is in the range of 76.9-692.3
mgs, when the corticosteroid is 7% of the microparticle, the
microparticle is in the range of 142.9-1285.7 mgs, when the
corticosteroid is 5% of the microparticle, the microparticle is in
the range of 200-2000 mgs). In some embodiments, the Class B
corticosteroid contained in the microparticles is 5%-15% of the
microparticle, for example, about 10% of the microparticle and the
total dose of corticosteroid is in a range selected from 10-80 mg,
10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg, 20-90
mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg,
30-90 mg, 30-80 mg, 30-70 mg, 30-60 mg, 30-50 mg, 30-40 mg, 40-90
mg, 40-80 mg, 40-70 mg, 40-60 mg, 40-50 mg, 50-90 mg, 50-80 mg,
50-70 mg, 50-60 mg, 60-90 mg, 60-80 mg, 60-70 mg, 70-90 mg, 70-80
mg, and 80-90 mg. In some embodiments, the Class B corticosteroid
is released for between 14 days and 90 days, preferably at least 45
days, at least 60 days, at least 75 days or greater than 90
days.
[0100] The invention also provides methods of treating pain or
inflammation in a patient by administering to the patient a
therapeutically effective amount of a long-term controlled or
sustained release preparation, e.g., a Ninety-Day Formulation.
[0101] The invention also provides methods of treating pain or
inflammation in a patient by administering to the patient a
therapeutically effective amount of a long-term controlled or
sustained release preparation, e.g., a Ninety-Day Formulation,
wherein the controlled or sustained release preparation or the
formulation releases the corticosteroid for at least 14 days at a
rate that does not adversely suppress the
hypothalamic-pituitary-adrenal axis (HPA axis).
[0102] The invention also provides methods of slowing, arresting or
reversing progressive structural tissue damage associated with
chronic inflammatory disease in a patient by administering to the
patient a therapeutically effective amount of a long-term
controlled or sustained release preparation, e.g., a Ninety-Day
Formulation.
[0103] The invention also provides methods of slowing, arresting or
reversing progressive structural tissue damage associated with
chronic inflammatory disease in a patient by administering to the
patient a therapeutically effective amount of a controlled or
sustained release preparation, e.g., a Ninety-Day Formulation,
wherein the population of microparticles, the controlled or
sustained release preparation or the formulation releases the
corticosteroid for at least 14 days at a rate that does not
adversely suppress the hypothalamic-pituitary-adrenal axis (HPA
axis).
[0104] In some embodiments of these methods, the controlled or
sustained release preparation or formulation is administered as one
or more injections. In some embodiments of these methods, the
patient has osteoarthritis, rheumatoid arthritis, acute gouty
arthritis, and synovitis.
[0105] The invention also provides methods of manufacturing
long-term controlled or sustained released preparations, e.g.,
Ninety Day Formulations, using a solvent evaporation process
wherein the Class B corticosteroid is dispersed in a lactic
acid-glycolic acid copolymer organic solution and the mixture is
treated to remove the solvent from the mixture, thereby producing
microparticles. In some embodiments of these methods, the solvent
evaporation process utilizes a spray drying or fluid bed apparatus
to remove the solvent and produce microparticles. In some
embodiments of these methods, the solvent evaporation process
utilizes a spinning disk.
[0106] It is contemplated that whenever appropriate, any embodiment
of the present invention can be combined with one or more other
embodiments of the present invention, even though the embodiments
are described under different aspects of the present invention.
BRIEF DESCRIPTION OF THE FIGURES
[0107] FIG. 1 is a graph depicting the intra-articular
concentrations (top solid line) and the systemic concentrations
(bottom solid line) of the glucocorticoid administered according to
certain embodiments of the present invention following
intra-articular injection. The systemic glucocorticoid
concentration associated with clinically significant suppression of
the HPA axis is shown as the bottom dotted line. The top dotted
line represents the minimal intra-articular concentration required
to maintain efficacy (defined as relief of pain and inflammation,
or slowing, arrest, or reversal of structural damage to tissues
caused by inflammatory diseases. Sustained release of the
corticosteroid provides sufficient intra-articular concentrations
to maintain efficacy in the longer term, and has transient,
clinically insignificant effect on the HPA axis.
[0108] FIG. 2 is a graph depicting the change in sensitivity over
time to suppression of endogenous cortisol production (EC.sub.50
(ng/mL) vs. time) for triamcinolone acetonide 40 mg given by
intra-articular administration.
[0109] FIG. 3 is a graph depicting the change in sensitivity over
time to suppression of endogenous cortisol production (EC.sub.50
(ng/mL) vs. time) for various corticosteroids administered as a
single, intra-articular injection in the listed dose.
[0110] FIG. 4 is a graph depicting plasma levels of endogenous
cortisol over time, without (Column 1) adjustment for a change in
the sensitivity of the HPA axis after intra-articular
corticosteroids and with (Column 2) adjustment for a change in the
sensitivity of the HPA axis after intra-articular corticosteroids.
These data demonstrate that the sensitivity of the HPA axis varies
with corticosteroid, dose, and time with clinically important
implications for the selection of doses for sustained delivery into
an intra-articular space.
[0111] FIG. 5 is a graph depicting the cumulative percent release
of a nominal 25% (w/w) triamcinolone acetonide in PLGA 75:25
microparticles.
[0112] FIG. 6 is a graph depicting the calculated human dose to
achieve transient cortisol suppression and within 14 days achieve
less than 35% cortisol suppression using nominal 25% TCA PLGA 75:25
microparticles. The dotted lines represent, from top to bottom of
the graph, 50% cortisol inhibition dose, 40% cortisol inhibition
dose, 35% cortisol inhibition dose and 5% cortisol inhibition
dose.
[0113] FIG. 7 is a graph depicting calculated human dose that does
not affect the HPA axis, less than 35% cortisol suppression using
nominal 25% TCA PLGA 75:25 microparticles. The dotted lines
represent, from top to bottom of the graph, 50% cortisol inhibition
dose, 40% cortisol inhibition dose, 35% cortisol inhibition dose
and 5% cortisol inhibition dose.
[0114] FIG. 8 is a graph depicting cumulative percent release of a
second preparation of nominal 25% triamcinolone acetonide in PLGA
75:25 microparticles using an alternate preparation.
[0115] FIG. 9 is a graph depicting calculated human dose to achieve
transient cortisol suppression and within 14 days achieve less than
35% cortisol suppression using a second preparation of nominal 25%
TCA PLGA 75:25 microparticles made by an alternate preparation. The
dotted lines represent, from top to bottom of the graph, 50%
cortisol inhibition dose, 40% cortisol inhibition dose, 35%
cortisol inhibition dose and 5% cortisol inhibition dose.
[0116] FIG. 10 is a graph depicting: calculated human dose that
does not affect the HPA axis, less than 35% cortisol suppression
using a second preparation of nominal 25% TCA PLGA 75:25
microparticles made by an alternate preparation. The dotted lines
represent, from top to bottom of the graph, 50% cortisol inhibition
dose, 40% cortisol inhibition dose, 35% cortisol inhibition dose
and 5% cortisol inhibition dose.
[0117] FIG. 11 is a graph depicting cumulative percent release of
nominal 25% triamcinolone acetonide in 5% PEG 1450/PLGA 75:25
microparticles.
[0118] FIG. 12 is a graph depicting cumulative percent release of
nominal 25% triamcinolone acetonide in 10% PEG 3350/PLGA 75:25
microparticles.
[0119] FIG. 13 is a graph depicting calculated human dose to
achieve transient cortisol suppression and within 14 days achieve
less than 35% cortisol suppression using nominal 25% TCA 5% PEG
1450/PLGA 75:25 microparticles. The dotted lines represent, from
top to bottom of the graph, 50% cortisol inhibition dose, 40%
cortisol inhibition dose, 35% cortisol inhibition dose and 5%
cortisol inhibition dose.
[0120] FIG. 14 is a graph depicting calculated human dose to
achieve transient cortisol suppression and within 14 days achieve
less than 35% cortisol suppression using nominal 25% TCA 10% PEG
3350/PLGA 75:25 microparticles. The dotted lines represent, from
top to bottom of the graph, 50% cortisol inhibition dose, 40%
cortisol inhibition dose, 35% cortisol inhibition dose and 5%
cortisol inhibition dose.
[0121] FIG. 15 is a graph depicting calculated human dose that does
not affect the HPA axis, less than 35% cortisol suppression using
nominal 25% TCA 5% PEG 1450/PLGA 75:25 microparticles. The dotted
lines represent, from top to bottom of the graph, 50% cortisol
inhibition dose, 40% cortisol inhibition dose, 35% cortisol
inhibition dose and 5% cortisol inhibition dose.
[0122] FIG. 16 is a graph depicting calculated human dose that does
not affect the HPA axis, less than 35% cortisol suppression using
nominal 25% TCA 10% PEG 3350/PLGA 75:25 microparticles. The dotted
lines represent, from top to bottom of the graph, 50% cortisol
inhibition dose, 40% cortisol inhibition dose, 35% cortisol
inhibition dose and 5% cortisol inhibition dose.
[0123] FIG. 17 is a graph depicting cumulative percent
triamcinolone acetonide release of nominal 40%, 25% 20%, 15% and
10% TCA containing PLGA 75:25 microparticles.
[0124] FIG. 18 is a graph depicting cumulative percent release of
nominal 25% TCA PLGA 75:25 (29 kDa) and PLGA 75:25 (54 kDa)
containing microparticles.
[0125] FIG. 19 is a graph depicting cumulative percent release of
triamcinolone acetonide in PLGA 50:50 microparticle
formulations.
[0126] FIG. 20 is a graph depicting cumulative percent release of
nominal 28.6% triamcinolone acetonide in PLGA 75:25 plus Triblock
microparticle formulations.
[0127] FIG. 21 is a graph depicting calculated human dose to
achieve transient cortisol suppression and within 14 days achieve
less than 35% cortisol suppression using nominal 28.6% TCA 10%
Triblock/PLGA 75:25 microparticles. The dotted lines represent,
from top to bottom of the graph, 50% cortisol inhibition dose, 40%
cortisol inhibition dose, 35% cortisol inhibition dose and 5%
cortisol inhibition dose.
[0128] FIG. 22 is a graph depicting calculated human dose to
achieve transient cortisol suppression and within 14 days achieve
less than 35% cortisol suppression using nominal 28.6% TCA 20%
Triblock/PLGA 75:25 microparticles. The dotted lines represent,
from top to bottom of the graph, 50% cortisol inhibition dose, 40%
cortisol inhibition dose, 35% cortisol inhibition dose and 5%
cortisol inhibition dose.
[0129] FIG. 23 is a graph depicting calculated human dose that does
not affect the HPA axis, less than 35% cortisol suppression using
nominal 28.6% TCA 10% Triblock/PLGA 75:25 microparticles. The
dotted lines represent, from top to bottom of the graph, 50%
cortisol inhibition dose, 40% cortisol inhibition dose, 35%
cortisol inhibition dose and 5% cortisol inhibition dose.
[0130] FIG. 24 is a graph depicting calculated human dose that does
not affect the HPA axis, less than 35% cortisol suppression using
nominal 28.6% TCA 20% Triblock/PLGA 75:25 microparticles. The
dotted lines represent, from top to bottom of the graph, 50%
cortisol inhibition dose, 40% cortisol inhibition dose, 35%
cortisol inhibition dose and 5% cortisol inhibition dose.
[0131] FIG. 25 is a graph depicting cumulative percent release of
nominal 16.7% triamcinolone acetonide in mixed molecular weight
PLGA 75:25 microparticle formulations.
[0132] FIG. 26 is a graph depicting calculated human dose to
achieve transient cortisol suppression and within 14 days achieve
less than 35% cortisol suppression using nominal 16.7% TCA mixed
molecular weight PLGA 75:25 microparticles. The dotted lines
represent, from top to bottom of the graph, 50% cortisol inhibition
dose, 40% cortisol inhibition dose, 35% cortisol inhibition dose
and 5% cortisol inhibition dose.
[0133] FIG. 27 is a graph depicting calculated human dose that does
not affect the HPA axis, less than 35% cortisol suppression using
nominal 16.7% TCA mixed molecular weight PLGA 75:25 microparticles.
The dotted lines represent, from top to bottom of the graph, 50%
cortisol inhibition dose, 40% cortisol inhibition dose, 35%
cortisol inhibition dose and 5% cortisol inhibition dose.
[0134] FIG. 28 is a graph depicting cumulative percent release of
nominal 28.6% triamcinolone acetonide in various polymer
microparticle formulations.
[0135] FIG. 29 is a graph depicting cumulative percent release of
nominal 28.6% Prednisolone in PLGA 50:50 microparticle
formulation.
[0136] FIG. 30 is a graph depicting calculated human dose to
achieve transient cortisol suppression and within 14 days achieve
less than 35% cortisol suppression using nominal 28.6% PRED PLGA
50:50 microparticles. The dotted lines represent, from top to
bottom of the graph, 50% cortisol inhibition dose, 40% cortisol
inhibition dose, 35% cortisol inhibition dose and 5% cortisol
inhibition dose.
[0137] FIG. 31 is a graph depicting calculated human dose that does
not affect the HPA axis, less than 35% cortisol suppression using
nominal 28.6% PRED PLGA 50:50 microparticles. The dotted lines
represent, from top to bottom of the graph, 50% cortisol inhibition
dose, 40% cortisol inhibition dose, 35% cortisol inhibition dose
and 5% cortisol inhibition dose.
[0138] FIG. 32 is a graph depicting cumulative percent release of
nominal 28.6% Betamethasone PLGA 50:50 microparticle
formulation.
[0139] FIG. 33 is a graph depicting calculated human dose to
achieve transient cortisol suppression and within 14 days achieve
less than 35% cortisol suppression using nominal 28.6% BETA PLGA
50:50 microparticles. The dotted lines represent, from top to
bottom of the graph, 50% cortisol inhibition dose, 40% cortisol
inhibition dose, 35% cortisol inhibition dose and 5% cortisol
inhibition dose.
[0140] FIG. 34 is a graph depicting calculated human dose that does
not affect the HPA axis, less than 35% cortisol suppression using
nominal 28.6% BETA PLGA 50:50 microparticles. The dotted lines
represent, from top to bottom of the graph, 50% cortisol inhibition
dose, 40% cortisol inhibition dose, 35% cortisol inhibition dose
and 5% cortisol inhibition dose.
[0141] FIG. 35 is a graph depicting cumulative percent release of
nominal 16.7% Fluticasone Propionate PLGA 50:50 microparticle
formulation.
[0142] FIG. 36 is a graph depicting calculated human dose to
achieve transient cortisol suppression and within 14 days achieve
less than 35% cortisol suppression using nominal 16.7% FLUT PLGA
50:50 microparticles. The dotted lines represent, from top to
bottom of the graph, 50% cortisol inhibition dose, 40% cortisol
inhibition dose, 35% cortisol inhibition dose and 5% cortisol
inhibition dose.
[0143] FIG. 37 is a graph depicting calculated human dose that does
not affect the HPA axis, less than 35% cortisol suppression using
nominal 16.7% FLUT PLGA 50:50 microparticles. The dotted lines
represent, from top to bottom of the graph, 50% cortisol inhibition
dose, 40% cortisol inhibition dose, 35% cortisol inhibition dose
and 5% cortisol inhibition dose.
[0144] FIG. 38 is a graph depicting cumulative percent release of
various Fluticasone Propionate PLGA microparticle formulations.
[0145] FIG. 39 is a graph depicting cumulative percent release of
nominal 28.6% DEX PLGA 50:50 microparticle formulation.
[0146] FIG. 40 is a graph depicting calculated human dose to
achieve transient cortisol suppression and within 14 days achieve
less than 35% cortisol suppression and does not affect the HPA
axis, less than 35% cortisol suppression using nominal 28.6% DEX
PLGA 50:50 microparticles. The dotted lines represent, from top to
bottom of the graph, 50% cortisol inhibition dose, 40% cortisol
inhibition dose, 35% cortisol inhibition dose and 5% cortisol
inhibition dose.
[0147] FIGS. 41A-41D are a series of graphs depicting the mean
concentration-time profiles of various doses of TCA IR and FX006 in
rat plasma following single intra-articular doses. A microparticle
formulation of TCA in 75:25 PLGA formulation microparticles,
referred to as FX006, dosed at 1.125 mg resulted in a very slow
absorption of TCA in the systemic circulation and a markedly lower
C.sub.max as compared to TCA IR. Concentrations for the first 72 hr
are presented in FIGS. 41C and 41D on a larger time scale.
[0148] FIG. 42 is a graph depicting corticosteroid inhibition and
recovery with TCA IR (immediate release) and FX006 (microparticle
formulation) in rats.
[0149] FIG. 43 is a graph depicting the
pharmacokinetic/pharmacodynamic (PK/PD) relationship of systemic
TCA levels and corticosterone inhibition.
[0150] FIGS. 44A-44C are a series of graphs depicting the gait
analysis scores, an indicator of pain, in rats injected with doses
of either immediate release triamcinolone acetonide (TCA IR) or TCA
microparticles (FX006) in a model of osteoarthritis. In FIG. 44A,
FX006 at 0.28, 0.12 and 0.03 mg (TCA doses) is expressed as TCA
concentrations of the dosing formulation (4.67, 2 and 0.5 mg/ml).
In FIG. 44B, FX006 at 0.28 mg (TCA dose) is expressed as TCA
concentrations of the dosing formulation (4.67 mg/ml). Similarly,
TCA IR at 0.03 mg is expressed as triamcinolone at 0.5 mg/ml. In
FIG. 44C, FX006 at 0.28, 0.12 and 0.03 mg (TCA doses) is expressed
as TCA concentrations of the dosing formulation (4.67, 2 and 0.5
mg/ml). Similarly, TCA IR at 0.06 and 0.03 mg is expressed as
triamcinolone at 1 and 0.5 mg/ml.
[0151] FIG. 45 is a graph depicting peak pain response following
repeated reactivations of arthritis in the right knee. All
treatments were administered as a single IA dose in the right knee
on Day 0.
[0152] FIG. 46 is a graph depicting the time course of
corticosterone recovery for various groups in the rat study in a
model of osteoarthritis.
[0153] FIGS. 47A-47B are a series of graphs depicting the plasma
TCA concentration-time data for various groups in the rat study in
a model of osteoarthritis. Only the groups that received injections
of TCA microparticles (FX006 groups) are shown in FIG. 47B on an
expanded scale.
[0154] FIG. 48 is a graph depicting the end-of-study histopathology
scores for various treatment groups in the rat study in a model of
osteoarthritis.
[0155] FIG. 49 is a graph depicting the cumulative percent release
of nominal 10% triamcinolone acetonide in mixed molecular weight
PLGA 75:25 microparticle formulation, 15% PLGA emulsion.
[0156] FIG. 50 is a graph depicting the nominal 10% TCA mixed
molecular weight PLGA 75:25 microparticles, 15% PLGA Emulsion and
the calculated human dose to achieve transient cortisol suppression
and, within 14 days achieve less than 35% cortisol suppression. The
dotted lines represent, from top to bottom of the graph, 50%
cortisol inhibition dose, 40% cortisol inhibition dose, 35%
cortisol inhibition dose and 5% cortisol inhibition dose.
[0157] FIG. 51 is a graph depicting the nominal 10% TCA mixed
molecular weight PLGA 75:25 microparticles, 15% PLGA emulsion, and
the calculated human dose that does not affect the HPA Axis, less
than 35% cortisol suppression. The dotted lines represent, from top
to bottom of the graph, 50% cortisol inhibition dose, 40% cortisol
inhibition dose, 35% cortisol inhibition dose and 5% cortisol
inhibition dose.
[0158] FIG. 52 is a graph depicting the cumulative percent release
of nominal 10% triamcinolone acetonide in mixed molecular weight
PLGA 75:25 microparticle formulation, 20% PLGA emulsion.
[0159] FIG. 53 is a graph depicting the nominal 10% TCA mixed
molecular weight PLGA 75:25 microparticles, 20% PLGA emulsion, and
the calculated human dose to achieve transient cortisol suppression
and, within 14 days achieve less than 35% cortisol suppression. The
dotted lines represent, from top to bottom of the graph, 50%
cortisol inhibition dose, 40% cortisol inhibition dose, 35%
cortisol inhibition dose and 5% cortisol inhibition dose.
[0160] FIG. 54 is a graph depicting the nominal 10% TCA mixed
molecular weight PLGA 75:25 microparticles, 20% PLGA emulsion, and
the calculated human dose that does not affect the HPA axis, less
than 35% cortisol suppression. The dotted lines represent, from top
to bottom of the graph, 50% cortisol inhibition dose, 40% cortisol
inhibition dose, 35% cortisol inhibition dose and 5% cortisol
inhibition dose.
[0161] FIG. 55 is a graph depicting the cumulative percent release
of nominal 25% budesonide in PLGA 75:25 microparticle
formulation.
[0162] FIG. 56 is a graph depicting the nominal 25% budesonide PLGA
75:25 microparticles, and the calculated human dose to achieve
transient cortisol suppression and, within 14 days achieve less
than 35% cortisol suppression. The dotted lines represent, from top
to bottom of the graph, 50% cortisol inhibition dose, 40% cortisol
inhibition dose, 35% cortisol inhibition dose and 5% cortisol
inhibition dose.
[0163] FIG. 57 is a graph depicting the nominal 25% Budesonide PLGA
75:25 microparticles, and the calculated human dose that does not
affect the HPA axis, less than 35% cortisol suppression. The dotted
lines represent, from top to bottom of the graph, 50% cortisol
inhibition dose, 40% cortisol inhibition dose, 35% cortisol
inhibition dose and 5% cortisol inhibition dose.
DETAILED DESCRIPTION OF THE INVENTION
[0164] The invention provides compositions and methods for the
treatment of pain and inflammation using corticosteroids. The
compositions and methods provided herein use one or more
corticosteroids in a microparticle formulation. The corticosteroid
microparticle formulations provided herein are effective at
treating pain and/or inflammation with minimal prolonged
suppression of the HPA axis and/or other long term side effects of
corticosteroid administration. The corticosteroid microparticle
formulations provided herein are effective in slowing, arresting,
reversing or otherwise inhibiting structural damage to tissues
associated with progressive disease with minimal prolonged
suppression of the HPA axis and/or other long term side effects of
corticosteroid administration. The corticosteroid microparticle
formulations provided herein deliver the corticosteroid in a dose
and in a sustained release manner such that the levels of cortisol
suppression are at or below 35% by day 14 post-injection. In some
embodiments, the corticosteroid microparticle formulations provided
herein deliver the corticosteroid in a dose and in a controlled or
sustained release manner such that the levels of cortisol
suppression are negligible and/or undetectable by 14
post-injection. Thus, the corticosteroid microparticle formulations
in these embodiments are effective in the absence of any
significant HPA axis suppression. Administration of the
corticosteroid microparticle formulations provided herein can
result in an initial "burst" of HPA axis suppression, for example,
within the first few days, within the first two days and/or within
the first 24 hours post-injection, but by day 14 post-injection,
suppression of the HPA axis is less than 35%.
[0165] The use of microparticles to administer corticosteroids is
known (See, e.g., U.S. Patent Application Publication. No.
20080317805). In addition, corticosteroids are known to be useful
for the symptomatic treatment of inflammation and pain.
[0166] New data also suggest that synovitis may be associated with
the structural damage, for example, the deterioration of cartilage
and other peri-articular associated with the progression of
osteoarthritis and rheumatoid arthritis. (See e.g., Hill C L, et
al. "Synovitis detected on magnetic resonance imaging and its
relation to pain and cartilage loss in knee osteoarthritis." Ann
Rheum Dis 66 (2007):1599-603; van den Berg W B, et al. "Synovial
mediators of cartilage damage and repair in osteoarthritis." In:
Brandt K D, Doherty M, Lohmander L S, eds. Osteoarthritis. Second
ed. Oxford: Oxford University Press (2003):147-55; Ayral X, et al.
"Synovitis: a potential predictive factor of structural progression
of medial tibiofemoral knee osteoarthritis--results of a 1 year
longitudinal arthroscopic study in 422 patients." Osteoarthritis
Cartilage 13 (2005):361-7; and Kirwan J R, et al. "Effects of
glucocorticoids on radiological progression in rheumatoid
arthritis." Cochrane Database Syst Rev 2007:CD006356).
[0167] The administration of corticosteroids, particularly for
extended periods of time, can have a number of unwanted side
effects. The HPA axis, the interdependent feedback mechanism
between the hypothalamus, the pituitary gland and the adrenal
cortex, may be suppressed by the administration of corticosteroids,
leading to a variety of unwanted side effects. The extent of HPA
axis suppression, and related inhibition of endogenous cortisol
production, has been attributed to the potency of the
corticosteroid, the dose, systemic concentration, protein binding,
rate of elimination (Meibohm et al. "Mechanism-based PK/PD model
for the lymphocytopenia induced by endogenous and exogenous
corticosteroids." Int J Clin Pharmacol Ther. 37(8) (1999):367-76)
and, for one corticosteroid, a change in sensitivity of the HPA
axis (Derendorf et al. "Clinical PK/PD modelling as a tool in drug
development of corticosteroids." Int J Clin Pharmacol Ther. 35(10)
1997: 481-8). Furthermore, intra-articular doses of corticosteroids
associated with only limited anti-inflammatory and short-term
analgesic benefit (Hepper et al. "The efficacy and duration of
intra-articular corticosteroid injection for knee osteoarthritis: a
systematic review of level I studies." J Am Acad Orthop Surg.
17(10) 2009: 638-46) have been associated with HPA axis suppression
(Habib, "Systemic effects of intra-articular corticosteroids." Clin
Rheumatol. 28(7) (2009): 749-56).
[0168] The changes in sensitivity to corticosteroid effects over
time should alter clinical steroid dosing, but prior to the instant
invention, this has not been understood.
[0169] The details of one or more embodiments of the invention are
set forth in the accompanying description below. Although any
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the methods and materials are now described. Other
features, objects, and advantages of the invention will be apparent
from the description. In the specification, the singular forms also
include the plural unless the context clearly dictates otherwise.
Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. In the
case of conflict, the present Specification will control.
DEFINITIONS
[0170] The terms below have the following meanings unless indicated
otherwise.
[0171] An amount of a corticosteroid that does not "suppress the
hypothalamic-pituitary-adrenal axis (HPA axis)" refers to the
amount of the sustained release corticosteroid delivered locally to
relieve pain due to inflammation, which provides a systemic
concentration that will not have a clinically significant effect or
"adverse effect" on the HPA axis. Suppression of the HPA axis is
generally manifested by a reduction in endogenous glucocorticoid
production. It is useful to consider both basal and augmented
production of endogenous glucocorticoids. Under ordinary,
"unstressed" conditions, glucocorticoid production occurs at a
normal, basal level. There is some natural variation of production
during the course of the 24-hour day. Under extraordinary,
"stressed" conditions associated with, e.g., infection or trauma
and the like, augmented endogenous production of glucocorticoids
occurs. Endogenous cortisol production may be determined by
measuring glucocorticoid concentrations in plasma, saliva, urine or
by any other means known in the art. It is known that systemic
concentrations of corticosteroids can suppress the HPA axis. For
example, on day 3 after an intra-articular injection of 20 mg
triamcinolone hexacetonide plasma levels, of approximately 3-4
ng/mL have been observed. These resulted in a transient but highly
statistically significant 75% HPA-axis suppression (Derendorf et
al., "Pharmacokinetics and pharmacodynamics of glucocorticoid
suspensions after intra-articular administration." Clin Pharmacol
Ther. 39(3) (1986):313-7) which, however, does not necessarily
portend complete HPA failure (Habib, "Systemic effects of
intra-articular corticosteroids." Clin Rheumatol 28 (2009):
749-756, see p752 col. 1, para 2, final sentence). While such
transient suppression is generally considered to be acceptable
without clinically significant effect, more persistent suppression,
i.e., weeks, would be deemed clinically detrimental. In embodiments
of the present invention, administration of the formulation may
result in a clinically acceptable HPA suppression, particularly
during the initial release period of the therapy. In some
embodiments of the present invention, administration of the
formulation will not result in any significant level of HPA
suppression, including no detectable HPA suppression, particularly
during the initial release period of the therapy. During the
subsequent or sustained release period of the therapy, additional
corticosteroid may be released into the plasma. However, the plasma
levels during this period will generally be less than those during
the initial release period, if any corticosteroid release occurs,
and will not be associated with HPA axis suppression. Further, the
adverse events associated with exogenous corticosteroid
administration, e.g., hyperglycemia, hypertension, altered mood,
etc. will generally not be observed. Preferably, the number of
clinical adverse events during this period will not substantially
exceed the number achieved by an immediate release formulation
alone or by KENALOG.TM. or its bioequivalent and will, preferably,
be fewer than during the prior, initial release period of the
therapy, if any corticosteroid release occurs. Alternatively, one
can determine the suppression of the formulation on HPA by
measuring endogenous cortisol production. Thus, the formulation can
be considered as avoiding clinically significant (or adverse)
suppression of the HPA axis where the endogenous cortisol level is
substantially the same in the steady state between a patient
population receiving a therapeutically beneficial amount of an
immediate release formulation and those receiving a therapeutically
beneficial amount of a sustained release formulation. Such a
formulation would be deemed to have no clinically significant
effect on the HPA axis. Alternatively or additionally, a small but
measurable reduction in steady-state glucocorticoid production can
result from the formulation during the sustained release period of
the therapy with adequate preservation of the augmented, stress
response needed during infection or trauma can be deemed a
clinically insignificant suppression of the HPA axis. Endogenous
glucocorticoid production may be assessed by administering various
doses of adrenocorticotropin hormone or by other tests known to
those skilled in the art. Embodiments of the current invention
provide for controlling the release of corticosteroid, as may be
desired, to achieve either no measurable effect on endogenous
glucocorticoid production or a target, or a measurable effect that
is, however, without adverse clinical consequence. In this regard,
it has been found that intra-articular doses of corticosteroids
that suppress cortisol production by 20-35%, and sometimes more,
provide very useful sustained anti-inflammatory and analgesic
activity. These benefits are achieved without acute risks of
hypoadrenalism and without excessive risks, after sustained
intra-articular dosing, of developing an adrenal unresponsiveness
in times of stress or of developing frank adrenal failure.
[0172] As shown further below, the studies presented herein have
demonstrated that the HPA axis sensitivity appears to diminish with
time, steroid, and dose. In this regard, it has been determined
that standard doses of familiar corticosteroids, when examined from
the viewpoint of steady-state HPA axis suppression (i.e., after
desensitization has occurred), provide clinically useful
benchmarks. For example, while oral prednisolone given at 20 mg QD
produces a 73% cortisol suppression, even 5 mg QD (considered a
"low dose") is associated with a 40% suppression of endogenous
cortisol production. Doses at or below 5 mg of prednisolone per day
are generally considered to be well tolerated and are not
associated with clinically meaningful HPA axis suppression (La
Rochelle et al., "Recovery of the hypothalamic-pituitary-adrenal
(HPA) axis in patients with rheumatic diseases receiving low-dose
prednisolone." Am. J. Med. 95 (1993): 258-264). Therefore, up to
approximately 40% suppression will be clinically well tolerated and
very unlikely to be associated with importantly adverse clinical
events such as hypoadrenalism or soft-tissue or bony or metabolic
changes indicative of long-term glucocorticoid excess.
[0173] "Patient" refers to a human diagnosed with a disease or
condition that can be treated in accordance to the inventions
described herein. In some embodiments it is contemplated that the
formulations described herein may also be used in horses.
[0174] "Delivery" refers to any means used to place the drug into a
patient. Such means may include without limitation, placing
matrices into a patient that release the drug into a target area.
One of ordinary skill in the art recognizes that the matrices may
be delivered by a wide variety of methods, e.g., injection by a
syringe, placement into a drill site, catheter or canula assembly,
or forceful injection by a gun type apparatus or by placement into
a surgical site in a patient during surgery.
[0175] The terms "treatment" and "treating" a patient refer to
reducing, alleviating, stopping, blocking, or preventing the
symptoms of pain and/or inflammation in a patient. As used herein,
"treatment" and "treating" includes partial alleviation of symptoms
as well as complete alleviation of the symptoms for a time period.
The time period can be hours, days, months, or even years.
[0176] By an "effective" amount or a "therapeutically effective
amount" of a drug or pharmacologically active agent is meant a
nontoxic but sufficient amount of the drug or agent to provide the
desired effect, e.g., analgesia. An appropriate "effective" amount
in any individual case may be determined by one of ordinary skill
in the art using routine experimentation.
[0177] "Site of a patient's pain" refers to any area within a body
causing pain, e.g., a knee joint with osteoarthritis, nerve root
causing sciatic pain, nerve fibers growing into annular tears in
discs causing back pain, temporomandibular joint (TMJ) pain, for
example TMJ pain associated with temporomandibular joint disorder
(TMD) or pain radiating from epidural or perineural spaces. The
pain perceived by the patient may result from inflammatory
responses, mechanical stimuli, chemical stimuli, thermal stimuli,
as well as allodynia.
[0178] Additionally, the site of a patient's pain can comprise one
or multiple sites in the spine, such as between the cervical,
thoracic, or lumbar vertebrae, or can comprise one or multiple
sites located within the immediate area of inflamed or injured
joints such as the shoulder, hip, or other joints.
[0179] A "biocompatible" material refers to a material that is not
toxic to the human body, it is not carcinogenic and it should
induce limited or no inflammation in body tissues. A
"biodegradable" material refers to a material that is degraded by
bodily processes (e.g., enzymatic) to products readily disposable
by the body or absorbed into body tissue. The biodegraded products
should also be biocompatible with the body. In the context of
intra-articular drug delivery systems for corticosteroids, such
polymers may be used to fabricate, without limitation:
microparticles, micro-spheres, matrices, microparticle matrices,
micro-sphere matrices, capsules, hydrogels, rods, wafers, pills,
liposomes, fibers, pellets, or other appropriate pharmaceutical
delivery compositions that a physician can administer into the
joint. The biodegradable polymers degrade into non-toxic residues
that the body easily removes or break down or dissolve slowly and
are cleared from the body intact. The polymers may be cured ex-vivo
forming a solid matrix that incorporates the drug for controlled
release to an inflammatory region. Suitable biodegradable polymers
may include, without limitation natural or synthetic biocompatible
biodegradable material. Natural polymers include, but are not
limited to, proteins such as albumin, collagen, gelatin synthetic
poly(aminoacids), and prolamines; glycosaminoglycans, such as
hyaluronic acid and heparin; polysaccharides, such as alginates,
chitosan, starch, and dextrans; and other naturally occurring or
chemically modified biodegradable polymers. Synthetic biocompatible
biodegradable materials include, but are not limited to,
poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide
(PG), polyhydroxybutyric acid, poly(trimethylene carbonate),
polycaprolactone (PCL), polyvalerolactone, poly(alpha-hydroxy
acids), poly(lactones), poly(amino-acids), poly(anhydrides),
polyketals poly(arylates), poly(orthoesters), polyurethanes,
polythioesters, poly(orthocarbonates), poly(phosphoesters),
poly(ester-co-amide), poly(lactide-co-urethane, polyethylene glycol
(PEG), polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer
(polyactive), methacrylates, poly(N-isopropylacrylamide),
PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, and PLGA-PEO-PLGA
blends and copolymers thereof and any combinations thereof. The
biocompatible biodegradable material can include a combination of
biocompatible biodegradable materials. For example, the
biocompatible biodegradable material can be a triblock, or other
multi-block, formation where a combination of biocompatible
biodegradable polymers are joined together. For example, the
triblock can be PLGA-PEG-PLGA.
[0180] Diseases that May be Treated Using the Formulations of this
Invention
[0181] Descriptions of various embodiments of the invention are
given below. Although these embodiments are exemplified with
reference to treat joint pain associated with osteoarthritis,
rheumatoid arthritis and other joint disorders, it should not be
inferred that the invention is only for these uses. Rather, it is
contemplated that embodiments of the present invention will be
useful for treating other forms of joint pain by administration
into articular and periarticular spaces. In addition, it will be
understood that for some embodiments injection near a joint may be
equivalent to injections in that joint. It is also contemplated
that embodiments of the present invention may be useful for
injection or administration into soft tissues or lesions. Any and
all uses of specific words and references are simply to detail
different embodiments of the present invention.
[0182] Local administration of a corticosteroid microparticle
formulation can occur, for example, by injection into the
intra-articular space, peri-articular space, soft tissues, lesions,
epidural space, perineural space, or the foramenal space at or near
the site of a patient's pain and/or structural tissue damage. Local
injection of the formulations described herein into articular or
periarticular spaces may be useful in the treatment of, for
example, juvenile rheumatoid arthritis, sciatica and other forms of
radicular pain (e.g., arm, neck, lumbar, thorax), psoriatic
arthritis, acute gouty arthritis, Morton's neuroma, acute and
subacute bursitis, acute and subacute nonspecific tenosynovitis and
epicondylitis, acute rheumatic carditis and ankylosing spondylitis.
Injection of the microparticles described herein into soft tissues
or lesions may be useful in the treatment of, for example, alopecia
greata, discoid lupus, erythematosus; keloids, localized
hypertrophic, infiltrated inflammatory lesions of granuloma
annulare, lichen planus, lichen simplex chronicus
(neurodermatitis), psoriasis and psoriatic plaques; necrobiosis
lipoidica diabeticorum, and psoriatic arthritis. Injection of the
microparticles described herein into epidural spaces may be useful
in the treatment of, for example, neurogenic claudication.
Intramuscular or other soft tissues or lesions injections may also
be useful in providing systemic exposures that are effective in the
control of incapacitating allergic conditions (including but not
limited to asthma, atopic dermatitis, contact dermatitis, drug
hypersensitivity reactions, seasonal or perennial allergic
rhinitis, serum sickness, transfusion reactions), bullous
dermatitis herpetiformis, exfoliative dermatitis, mycosis
fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson
syndrome), Primary or secondary adrenocortical insufficiency in
conjunction with mineralocorticoids where applicable; congenital
adrenal hyperplasia, hypercalcemia associated with cancer,
nonsupportive thyroiditis, exacerbations of regional enteritis and
ulcerative colitis, acquired (autoimmune) hemolytic anemia,
congenital (erythroid) hypoplastic anemia (Diamond blackfan
anemia), pure red cell aplasia, select cases of secondary
thrombocytopenia, trichinosis with neurologic or myocardial
involvement, tuberculous meningitis with subarachnoid block or
impending block when used concurrently with appropriate
antituberculous chemotherapy, palliative management of leukemias
and lymphomas, acute exacerbations of multiple sclerosis, cerebral
edema associated with primary or metastatic brain tumor or
craniotomy, to induce diuresis or remission of proteinuria in
idiopathic nephrotic syndrome, or to induce diuresis or remission
of proteinuria in lupus erythematosus, berylliosis, symptomatic
sarcoidosis, fulminating or disseminated pulmonary tuberculosis
(when used concurrently with appropriate antituberculous
chemotherapy), idiopathic eosinophilic pneumonias, symptomatic
sarcoidosis, dermatomyositis, polymyositis, and systemic lupus
erythematosus, post-operative pain and swelling.
[0183] In one embodiment, the corticosteroid microparticle
formulations provided herein are useful in treating, alleviating a
symptom of, ameliorating and/or delaying the progression of
sciatica. In one embodiment, corticosteroid microparticle
formulations provided herein are useful in treating, alleviating a
symptom of, ameliorating and/or delaying the progression of
temporomandibular joint disorder (TMD).
[0184] In one embodiment, the corticosteroid microparticle
formulations provided herein are useful in treating, alleviating a
symptom of, ameliorating and/or delaying the progression of
neurogenic claudication secondary to lumbar spinal stenosis (LSS).
LSS implies spinal canal narrowing with possible subsequent neural
compression (classified by anatomy or etiology). Neurogenic
Claudication (NC) is a hallmark symptom of lumbar stenosis, in
which the column of the spinal cord (or the canals that protect the
nerve roots) narrows at the lower back. This narrowing can also
occur in the spaces between the vertebrae where the nerves leave
the spine to travel to other parts of the body.
[0185] The microparticles of the invention are used to treat,
alleviate a symptom of, ameliorate and/or delay the progression
patients suffering from NC secondary to LSS. The corticosteroid
microparticle formulations can be administered, for example, by
epidural steroid injection (ESI).
[0186] Administration of a corticosteroid microparticle
formulation, e.g., a TCA microparticle formulation, to a patient
suffering from an inflammatory disease such as osteoarthritis or
rheumatoid arthritis, is considered successful if any of a variety
of laboratory or clinical results is achieved. For example,
administration of a corticosteroid microparticle formulation is
considered successful if one or more of the symptoms associated
with the disease is alleviated, reduced, inhibited or does not
progress to a further, i.e., worse, state. Administration of a
corticosteroid microparticle formulation is considered successful
if the disease, e.g., an arthritic or other inflammatory disease,
enters remission or does not progress to a further, i.e., worse,
state.
[0187] Also, any and all alterations and further modifications of
the invention, as would occur to one of ordinary skill in the art,
are intended to be within the scope of the invention
[0188] Selection of Corticosteroids and Drug Dosage
[0189] Corticosteroids associated with embodiments of the present
invention can be any naturally occurring or synthetic steroid
hormone. Naturally occurring corticosteroids are secreted by the
adrenal cortex or generally the human body.
[0190] Corticosteroid molecules have the following basic
structure:
##STR00001##
[0191] Corticosteroids have been classified into four different
groups (A, B, C, and D). (See e.g., Foti et al. "Contact Allergy to
Topical Corticosteroids: Update and Review on Cross-Sensitization."
Recent Patents on Inflammation & Allergy Drug Discovery 3
(2009): 33-39; Coopman et al., "Identification of cross-reaction
patterns in allergic contact dermatitis to topical
corticosteroids." Br J Dermatol 121 (1989): 27-34). Class A
corticosteroids are hydrocortisone types with no modification of
the D ring or C20-C21 or short chain esters on C20-C21. Main
examples of Class A corticosteroids include prednisolone,
hydrocortisone and methylprednisolone and their ester acetate,
sodium phosphate and succinate, cortisone, prednisone, and
tixocortol pivalate. Class B corticosteroids are triamcinolone
acetonide (TCA) types with cis/ketalic or diolic modifications on
C16-C17. Main examples of Class B corticosteroids include
triamcinolone acetonide (TCA), fluocinolone acetonide, amcinonide,
desonide, fluocinonide, halcinonide, budesonide, and flunisolide.
Class C corticosteroids are betamethasone types with a --CH3
mutilation on C16, but no esterification on C17-C21. Main examples
of Class C corticosteroids include betamethasone, dexamethasone,
desoxymethasone, fluocortolone, and halomethasone. Class D
corticosteroids are clobetasone or hydrocortisone esterified types
with a long chain on C17 and/or C21 and with no methyl group on
C16. Main examples of Class D corticosteroids include fluticasone,
clobetasone butyrate, clobetasol propionate,
hydrocortisone-17-aceponate, hydrocortisone-17-butyrate,
beclomethasone dipropionate, betamethasone-17-valerate,
betamethasone dipropionate, methylprednisolone aceponate, and
prednicarbate.
[0192] For the present invention non-limiting examples of
corticosteroids may include: betamethasone, betamethasone acetate,
betamethasone dipropionate, betamethasone 17-valerate, cortivazol,
dexamethasone, dexamethasone acetate, dexamethasone sodium
phosphate, hydrocortisone, hydrocortisone aceponate, hydrocortisone
acetate, hydrocortisone butyrate, hydrocortisone cypionate,
hydrocortisone probutate, hydrocortisone sodium phosphate,
hydrocortisone sodium succinate, hydrocortisone valerate,
methylprednisolone, methylprednisolone aceponate,
methylprednisolone acetate, methylprednisolone sodium succinate,
prednisolone, prednisolone acetate, prednisolone
metasulphobenzoate, prednisolone sodium phosphate, prednisolone
steaglate, prednisolone tebutate, triamcinolone, triamcinolone
acetonide, triamcinolone acetonide 21-palmitate, triamcinolone
benetonide, triamcinolone diacetate, triamcinolone hexacetonide,
alclometasone, alclometasone dipropionate, amcinonide,
amelometasone, beclomethasone, beclomethasone dipropionate,
beclomethasone dipropionate monohydrate, budesonide, butixocort,
butixocort propionate, ciclesonide, ciprocinonide, clobetasol,
clobetasol propionate, clocortolone, clobetasone, clobetasone
butyrate, clocortolone pivalate, cloprednol, cortisone, cortisone
acetate, deflazacort, domoprednate, deprodone, deprodone
propionate, desonide, desoximethasone, desoxycortone, desoxycortone
acetate, dichlorisone, diflorasone, diflorasone diacetate,
diflucortolone, difluprednate, fluclorolone, fluclorolone
acetonide, fludrocortisone, fludrocortisone acetate,
fludroxycortide, flumethasone, flumethasone pivalate, flunisolide,
fluocinolone, fluocinolone acetonide, fluocortin, fluocortolone,
fluorometholone, fluticasone, fluticasone furoate, fluticasone
propionate, fluorometholone acetate, fluoxymesterone, fluperolone,
fluprednidene, fluprednidene acetate, fluprednisolone, formocortal,
halcinonide, halobetasol propionate, halometasone, halopredone,
halopredone acetate, hydrocortamate, isoflupredone, isoflupredone
acetate, itrocinonide, loteprednol etabonate, mazipredone,
meclorisone, meclorisone dibutyrate, medrysone, meprednisone,
mometasone, mometasone furoate, mometasone furoate monohydrate,
nivacortol, paramethasone, paramethasone acetate, prednazoline,
prednicarbate, prednisolone, prednylidene, procinonide,
rofleponide, rimexolone, timobesone, tipredane, tixocortol,
tixocortol pivalate and tralonide.
[0193] Embodiments of the invention include using sustained release
corticosteroids delivered to treat pain at dosages that do not
adversely suppress the HPA axis. Such amounts delivered locally to
relieve pain due to inflammation, will provide a systemic
concentration that does not have a measurable adverse effect on the
HPA axis (differences if any are not significant because any such
differences are within normal assay variability) or, as desired,
may have a measurable but clinically insignificant effect on the
HPA axis (basal cortisol is suppressed to some measurable extent
but stress responses are adequately preserved). Further embodiments
of the invention include doses during a second period of time
selected to adjust for a change in sensitivity of the HPA axis to
suppression following exposure during a first period of time to the
corticosteroid (FIG. 1).
[0194] Additional embodiments include doses during first and/or the
second period of time selected to adjust for
corticosteroid-specific (or corticosteroid- and potentially
dose-specific) changes in the rate of change of sensitivity of the
HPA axis to suppression that begin with initial exposure. For
clinically effective corticosteroids, the rate of change of the
sensitivity of the HPA axis to exogenous corticosteroids is both
non-uniform and non-linear (FIG. 2). The rate and pattern of change
in such sensitivity varies widely as a function of the particular
corticosteroid that is selected (FIG. 3).
[0195] Finally, it is possible to usefully characterize the change
in sensitivity vs. time mathematically as the (non-linear,
exponential) "decay" of the sensitivity from the initial to final
value, wherein the decay parameters (Table 1) has been determined
from the data further described herein.
TABLE-US-00001 TABLE 1 HPA Axis Change-in-Sensitivity
Decay-Parameter .delta. vs. Corticosteroid and Dose* Corticosteroid
Decay Parameter .delta. (time.sup.-1) Betamethasone
Phosphate/Acetate (7 mg) 0.024 Triamcinolone Acetonide (40 mg)
0.005 Triamcinolone Hexacetonide (20 mg) 0.070 *The inhibition of
endogenous cortisol synthesis can be related to the exogenous
corticosteroid concentration by the following equations: 1. E =
(E.sub.max C.sup.n)/[(EC.sub.50).sup.n + C.sup.n] wherein E =
effect, E.sub.max = maximal effect, C = concentration of exogenous
corticosteroid, EC.sub.50 = concentration at 1/2 E.sub.max, and n =
the Hill ("shape", or "slope") factor; and .sup.2.EC.sub.50 - final
= EC.sub.50 - initial + [EC.sub.50 - final - EC.sub.50 - initial]
[1 - e.sup.(-.delta.time)]
[0196] Using this approach permits the determination of ".delta.",
the parameter describing the exponential decay from the initial to
the final EC.sub.50. Minimization of least-squares differences was
utilized to obtain the best-fit .delta..
[0197] These new findings regarding the rate and pattern of change
of sensitivity to inhibition and the lack of predictability of such
rates and patterns on the basis of, for example, steroid potency,
have significant implications for clinically appropriate
dose-selection. Those skilled in the art will appreciate the
importance of a changing sensitivity to HPA axis suppression and
will also appreciate both the complexity and counterintuitive
aspects of several of these new findings (Table 1).
[0198] As a result of these clinical findings, the dose range to
achieve clinically useful analgesia, with minimal or controlled
modulation of the HPA axis, at steady state concentrations of
various corticosteroids has been determined (Table 2). In
particular, it appears that the daily corticosteroid doses at
steady state concentrations, are approximately 3- to 7-times
greater than are predicted by prior art (Meibohm, 1999).
TABLE-US-00002 TABLE 2 Dose (mg/d), adjusted for individual
intra-articular corticosteroid characteristics, for expected
suppression of endogenous cortisol production at steady state.
Cortisol Inhibition (%) Corticosteroid 5% 10% 20% 35% 50%
betamethasone (mg/d) 0.1 0.2 0.5 1.0 1.8 budesonide (mg/d) 0.1 0.2
0.6 1.2 2.2 des-ciclesonide (mg/d) 3.0 6.3 14.3 30.7 57.0
dexamethasone (mg/d) 0.1 0.2 0.4 0.9 1.6 flunisonide (mg/d) 0.3 0.5
1.2 2.6 4.8 fluticasone (mg/d) 0.1 0.1 0.3 0.6 1.1 mometasone
(mg/d) 0.2 0.4 0.9 2.0 3.7 methylprednisolone (mg/d) 0.3 0.7 1.6
3.5 6.5 prednisolone (mg/d) 0.4 0.8 1.9 4.0 7.5 triamcinolone
acetonide 0.2 0.4 0.8 1.7 3.2 (mg/d) triamcinolone hexacetonide 0.1
0.2 0.4 0.9 1.6 (mg/d)
TABLE-US-00003 TABLE 2A Total Dose Delivered (mg/month), adjusted
for individual intra-articular corticosteroid characteristics, for
expected suppression of endogenous cortisol production at steady
state. Cortisol Inhibition (%) Corticosteroid 5% 10% 20% 35% 50%
betamethasone 3.0 6.0 15.0 30.0 54.0 budesonide 3.0 6.0 18.0 36.0
66.0 des-ciclesonide 90.0 189.0 429.0 921.0 1710.0 dexamethasone
3.0 6.0 12.0 27.0 48.0 flunisonide 9.0 15.0 36.0 78.0 144.0
fluticasone 3.0 3.0 9.0 18.0 33.0 mometasone 6.0 12.0 27.0 60.0
111.0 methylprednisolone 9.0 21.0 48.0 105.0 195.0 prednisolone
12.0 24.0 57.0 120.0 225.0 triamcinolone acetonide 6.0 12.0 24.0
51.0 96.0 triamcinolone hexacetonide 3.0 6.0 12.0 27.0 48.0
[0199] That higher doses of corticosteroids can be administered
successfully by intra-articular injection, maximizing the
likelihood of observing anti-inflammatory and analgesic responses
while minimizing or eliminating adverse events from HPA axis
suppression or otherwise excessive tissue exposure, is of profound
clinical consequence for improving the treatment of patients with
arthritis.
[0200] In addition, with these continuous daily doses of
intra-articular corticosteroids, it is possible to determine the
related systemic plasma level concentrations (Table 3) that will
produce the target cortisol inhibition and not beyond, this while
retaining clinically important anti-inflammatory and analgesic
activity within the joint. These plasma concentrations were
predicted on the basis of data from short term (i.e., less than 8
days) exposure to corticosteroids. With longer exposure to
corticosteroids, the "decay" (i.e., decline) of the sensitivity to
corticosteroids may continue resulting in values higher than those
listed in Table 3. The levels calculated in Table 3 were purely
hypothetical calculations based on human data with immediate
release-level doses from the literature. With sustained release
dosages, more drug may be able to be delivered without seeing an
increased level of cortisol inhibition after the initial burst
period. A given level of plasma concentration may actually provide
less inhibition that would have been predicted or calculated using
the human IR levels from the literature.
TABLE-US-00004 TABLE 3 Plasma corticosteroid concentrations
associated with target levels of cortisol inhibition at steady
state. Corticosteroid Concentration in Plasma (ng/mL) associated
with the Target Levels of Cortisol Inhibition (%) Corticosteroid 5%
10% 20% 35% 50% betamethasone (ng/mL) 0.33 0.70 1.57 3.38 6.27
budesonide (ng/mL) 0.60 1.27 2.85 6.14 11.40 des-ciclesonide
(ng/mL) 0.55 1.16 2.61 5.63 10.45 dexamethasone (ng/mL) 0.21 0.44
1.00 2.15 3.99 flunisonide (ng/mL) 0.18 0.38 0.86 1.84 3.42
fluticasone (ng/mL) 0.04 0.08 0.19 0.41 0.76 mometasone (ng/mL)
0.15 0.32 0.71 1.54 2.85 methylprednisolone (ng/mL) 0.68 1.44 3.23
6.96 12.92 prednisolone (ng/mL) 1.64 3.46 7.79 16.79 31.16
triamcinolone acetonide 0.19 0.40 0.90 1.95 3.61 (ng/mL)
triamcinolone hexacetonide 0.10 0.21 0.48 1.02 1.90 (ng/mL)
[0201] The studies presented herein demonstrate for the first time
the discovery of the time-course of changes in sensitivity of the
HPA axis to exogenous corticosteroids. In addition, both the mean
doses and mean plasma levels shown in Tables 2 and 3 above are
those after steady state has been achieved, requiring approximately
4 to 24 days depending upon the corticosteroid in question. The
companion post-dose but pre-steady-state transients for several
corticosteroids have been described in FIGS. 2, 3, and 4. It is
also important to note that the data suggest that the carefully
controlled benefits from the intra-articular, sustained release of
a corticosteroid of interest will persist as long as release
continues.
[0202] In one preferred embodiment, a single component sustained
release formulation releases a dose (in mg/day) that suppresses the
HPA axis by no more than between 5-40% at steady state as shown in
Table 2, more preferably no more than between 10-35% at steady
state as shown in Table 2. These doses are therapeutically
effective without adverse side effects.
[0203] In another preferred embodiment, a single component
sustained release formulation releases a dose (in mg/day) that does
not measurably suppress the HPA axis at steady state. These doses
are therapeutically effective without adverse side effects.
[0204] In another embodiment where both an immediate release
component and sustained release component of the formulation are
present, immediate release dose would be as shown in Table 4 and
the sustained release dose would be a dose (in mg/day) that
suppresses the HPA axis by no more than between 5-40% as shown in
Table 2, more preferably no more than between 10-35% as shown in
Table 2. In addition, it is expected that sustained release doses
described previously will follow immediate release doses as shown
in Table 4.
TABLE-US-00005 TABLE 4 Immediate release relative doses (mg)
Immediate Release Dose Corticosteroid (mg) betamethasone.sup.1 5-20
budesonide.sup.2 7-28 des-ciclesonide.sup.2 177-713
dexamethasone.sup.2 5-20 flunisonide.sup.2 15-60 fluticasone.sup.2
3-12 mometasone.sup.2 11-44 methylprednisolone.sup.1 40-160
prednisolone.sup.1 25-100 triamcinolone acetonide.sup.1 10-40
triamcinolone hexacetonide.sup.1 10-40 .sup.1clinical doses
.sup.2calculated doses
[0205] Sustained Release Delivery Platforms
[0206] The manufacture of microparticles or methods of making
biodegradable polymer microparticles are known in the art.
Microparticles from any of the biodegradable polymers listed below
can be made by, but not limited to, spray drying, solvent
evaporation, phase separation, spray drying, fluidized bed coating
or combinations thereof.
[0207] In certain embodiments of the invention, the microparticles
are made from a biodegradable polymer that may include, without
limitation, natural or synthetic biocompatible biodegradable
materials. Natural polymers include, but are not limited to,
proteins such as albumin, collagen, gelatin synthetic
poly(aminoacids), and prolamines; glycosaminoglycans, such as
hyaluronic acid and heparin; polysaccharides, such as alginates,
chitosan, starch, and dextrans; and other naturally occurring or
chemically modified biodegradable polymers. Synthetic biocompatible
biodegradable materials include, but are not limited to the group
comprising of, poly(lactide-co-glycolide) (PLGA), polylactide
(PLA), polyglycolide (PG), polyhydroxybutyric acid,
poly(trimethylene carbonate), polycaprolactone (PCL),
polyvalerolactone, poly(alpha-hydroxy acids), poly(lactones),
poly(amino-acids), poly(anhydrides), polyketals poly(arylates),
poly(orthoesters), poly(orthocarbonates), poly(phosphoesters),
poly(ester-co-amide), poly(lactide-co-urethane, polyethylene glycol
(PEG), polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT
copolymer(polyactive), polyurethanes, polythioesters,
methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO
(pluronics), PEO-PPO-PAA copolymers, and PLGA-PEO-PLGA blends and
copolymers thereof, multi-block polymer configurations such as
PLGA-PEG-PLGA, and any combinations thereof. These polymers may be
used in making controlled release or sustained release compositions
disclosed herein.
[0208] In a preferred embodiment, the microparticles are formed
from poly(d,l-lactic-co-glycolic acid) (PLGA), which is
commercially available from a number of sources. Biodegradable PLGA
copolymers are available in a wide range of molecular weights and
ratios of lactic to glycolic acid. If not purchased from a
supplier, then the biodegradable PLGA copolymers may be prepared by
the procedure set forth in U.S. Pat. No. 4,293,539 (Ludwig, et
al.), the disclosure of which is hereby incorporated by reference
in its entirety. Ludwig prepares such copolymers by condensation of
lactic acid and glycolic acid in the presence of a readily
removable polymerization catalyst (e.g., a strong acid ion-exchange
resin such as Dowex HCR--W2-H). However, any suitable method known
in the art of making the polymer can be used.
[0209] In the coacervation process, a suitable biodegradable
polymer is dissolved in an organic solvent. Suitable organic
solvents for the polymeric materials include, but are not limited
to acetone, halogenated hydrocarbons such as chloroform and
methylene chloride, aromatic hydrocarbons such as toluene,
halogenated aromatic hydrocarbons such as chlorobenzene, and cyclic
ethers such as dioxane. The organic solvent containing a suitable
biodegradable polymer is then mixed with a non-solvent such as
silicone based solvent. By mixing the miscible non-solvent in the
organic solvent, the polymer precipitates out of solution in the
form of liquid droplets. The liquid droplets are then mixed with
another non-solvent, such as heptane or petroleum ether, to form
the hardened microparticles. The microparticles are then collected
and dried. Process parameters such as solvent and non-solvent
selections, polymer/solvent ratio, temperatures, stirring speed and
drying cycles are adjusted to achieve the desired particle size,
surface smoothness, and narrow particle size distribution.
[0210] In the phase separation or phase inversion procedures entrap
dispersed agents in the polymer to prepare microparticles. Phase
separation is similar to coacervation of a biodegradable polymer.
By addition of a nonsolvent such as petroleum ether, to the organic
solvent containing a suitable biodegradable polymer, the polymer is
precipitates from the organic solvent to form microparticles.
[0211] In the salting out process, a suitable biodegradable polymer
is dissolved in an aqueous miscible organic solvent. Suitable water
miscible organic solvents for the polymeric materials include, but
are not limited to acetone, as acetone, acetonitrile, and
tetrahydrofuran. The water miscible organic solvent containing a
suitable biodegradable polymer is then mixed with an aqueous
solution containing salt. Suitable salts include, but are not
limited to electrolytes such as magnesium chloride, calcium
chloride, or magnesium acetate and non-electrolytes such as
sucrose. The polymer precipitates from the organic solvent to form
microparticles, which are collected and dried. Process parameters
such as solvent and salt selection, polymer/solvent ratio,
temperatures, stirring speed and drying cycles are adjusted to
achieve the desired particle size, surface smoothness, and narrow
particle size distribution.
[0212] Alternatively, the microparticles may be prepared by the
process of Ramstack et al., 1995, described in published
international patent application WO 95/13799, the disclosure of
which is incorporated herein in its entirety. The Ramstack et al.
process essentially provides for a first phase, including an active
agent and a polymer, and a second phase, that are pumped through a
static mixer into a quench liquid to form microparticles containing
the active agent. The first and second phases can optionally be
substantially immiscible and the second phase is preferably free
from solvents for the polymer and the active agent and includes an
aqueous solution of an emulsifier.
[0213] In the spray drying process, a suitable biodegradable
polymer is dissolved in an organic solvent and then sprayed through
nozzles into a drying environment provided with sufficient elevated
temperature and/or flowing air to effectively extract the solvent.
Adding surfactants, such as sodium lauryl sulfate can improve the
surface smoothness of the microparticles.
[0214] Alternatively, a suitable biodegradable polymer can be
dissolved or dispersed in supercritical fluid, such as carbon
dioxide. The polymer is either dissolved in a suitable organic
solvent, such as methylene chloride, prior to mixing in a suitable
supercritical fluid or directly mixed in the supercritical fluid
and then sprayed through a nozzle. Process parameters such as spray
rate, nozzle diameter, polymer/solvent ratio, and temperatures, are
adjusted to achieve the desired particle size, surface smoothness,
and narrow particle size distribution.
[0215] In a fluidized bed coating, the drug is dissolved in an
organic solvent along with the polymer. The solution is then
processed, e.g., through a Wurster air suspension coating apparatus
to form the final microcapsule product.
[0216] The microparticles can be prepared in a size distribution
range suitable for local infiltration or injection. The diameter
and shape of the microparticles can be manipulated to modify the
release characteristics. In addition, other particle shapes, such
as, for example, cylindrical shapes, can also modify release rates
of a sustained release corticosteroid by virtue of the increased
ratio of surface area to mass inherent to such alternative
geometrical shapes, relative to a spherical shape. The
microparticles have a mass mean diameter ranging between about 0.5
to 500 microns. In a preferred embodiment, the microparticles have
a mass mean diameter of between 10 to about 100 microns.
[0217] Biodegradable polymer microparticles that deliver sustained
release corticosteroids may be suspended in suitable aqueous or
non-aqueous carriers which may include, but is not limited to
water, saline, pharmaceutically acceptable oils, low melting waxes,
fats, lipids, liposomes and any other pharmaceutically acceptable
substance that is lipophilic, substantially insoluble in water, and
is biodegradable and/or eliminatable by natural processes of a
patient's body. Oils of plants such as vegetables and seeds are
included. Examples include oils made from corn, sesame, cannoli,
soybean, castor, peanut, olive, arachis, maize, almond, flax,
safflower, sunflower, rape, coconut, palm, babassu, and cottonseed
oil; waxes such as carnoba wax, beeswax, and tallow; fats such as
triglycerides, lipids such as fatty acids and esters, and liposomes
such as red cell ghosts and phospholipid layers.
[0218] Corticosteroid Loading of and Release from Biodegradable
Polymer Microparticles
[0219] When an intra-articularly delivered corticosteroid is
incorporated into a biodegradable polymer for sustained release
into a joint at a dosage that does not suppress the HPA axis,
preferred loadings of said corticosteroid are from about 5% to
about 40% (w/w) of the polymer, preferably about 5% to about 30%,
more preferably about 5% to about 28% of the polymer.
[0220] As the biodegradable polymers undergo gradual bio-erosion
within the joint, the corticosteroid is released to the
inflammatory site. The pharmacokinetic release profile of the
corticosteroid by the biodegradable polymer may be first order,
zero order, bi- or multi-phasic, to provide desired treatment of
inflammatory related pain. In any pharmacokinetic event, the
bio-erosion of the polymer and subsequent release of the
corticosteroid may result in a controlled release of a
corticosteroid from the polymer matrix. The rate of release at
dosages that do not suppress the HPA axis are described above.
Excipients
[0221] The release rate of the corticosteroid from a biodegradable
polymer matrix can be modulated or stabilized by adding a
pharmaceutically acceptable excipient to the formulation. An
excipient may include any useful ingredient added to the
biodegradable polymer depot that is not a corticosteroid or a
biodegradable polymer. Pharmaceutically acceptable excipients may
include without limitation lactose, dextrose, sucrose, sorbitol,
mannitol, starches, gum acacia, calcium phosphate, alginates,
tragacanth, gelatin, calcium silicate, microcrystalline cellulose,
PEG, polysorbate 20, polysorbate 80, polyvinylpyrrolidone,
cellulose, water, saline, syrup, methyl cellulose, and
carboxymethyl cellulose. An excipient for modulating the release
rate of a corticosteroid from the biodegradable drug depot may also
include without limitation pore formers, pH modifiers, reducing
agents, antioxidants, and free radical scavengers.
Delivery of Corticosteroid Microparticles
[0222] Parenteral administration of formulations of the invention
can be effected by intra-articular injection or other injection
using a needle. To inject the microparticles into a joint, needles
having a gauge of about 14-28 gauge are suitable. It will be
appreciated by those skilled in the art that formulations of the
present invention may be delivered to a treatment site by other
conventional methods, including catheters, infusion pumps, pens
devices, injection guns and the like.
[0223] All references, patents, patent applications or other
documents cited are hereby incorporated by reference.
EXAMPLES
[0224] The present invention is further defined in the following
Examples. It should be understood that these Examples, while
indicating preferred embodiments of the invention, are given by way
of illustration only. From the above discussion and these Examples,
one skilled in the art can ascertain the essential characteristics
of this invention, and without departing from the spirit and scope
thereof, can make various changes and modifications of the
invention to adapt it to various uses and conditions.
Example 1
Sustained-Release Betamethasone or Triamcinolone Acetonide
Microparticles
[0225] In one embodiment, the microparticle formulation contains a
copolymer of DL-lactide (or L-lactide) and glycolide in a 45:55
molar ratio (up to 75:25 molar ratio) with an inherent viscosity
ranging from 0.15 to 0.60 dL/g with either an ester or acid end
group plus either the corticosteroid betamethasone or triamcinolone
acetonide. If betamethasone is used, then the betamethasone is in
the form of either betamethasone acetate, betamethasone
diproprionate or a combination thereof. The total amount of
betamethasone or triamcinolone acetonide incorporated into the
microparticle ranges from 10% to 30% (w/w). The microparticles are
formulated to mean mass range in size from 10 to 100 microns. The
population of microparticles is formulated to be delivered through
a 19 gauge or higher needle. Additional excipients may be added
such as, but not limited to, carboxymethylcellulose sodium,
mannitol, polysorbate-80, sodium phosphate, sodium chloride,
polyethylene glycol to achieve isotonicity and promote
syringeability. If betamethasone is used, then the betamethasone
incorporated into the microparticle population provides an initial
release (burst) of about 5-20 mg of drug over a period of 1 to 12
hours, followed by a steady state release of drug at a rate of
about 0.1 to 1.0 mg/day over a period of 14 to 90 days. If
triamcinolone acetonide is used, then the drug incorporated into
the microparticle population provides an initial release (burst) of
about 10-40 mg of drug over a period of 1 to 12 hours, followed by
a steady state release of drug at a rate of about 0.2 to 1.7 mg/day
over a period of 14 to 90 days.
Example 2
Sustained-Release Betamethasone or Triamcinolone Acetonide
Microparticles with an Immediate Release Form
[0226] In another embodiment, the microparticle formulation of
Example 1 is further admixed with an immediate release
betamethasone or triamcinolone acetonide component, such as a
betamethasone or triamcinolone acetonide containing solution. If
betamethasone is used, then the betamethasone in the immediate
release component is in the form of either betamethasone acetate,
betamethasone diproprionate or a combination thereof. If
betamethasone is used, then the immediate release component
provides an initial release of a total of about 5 to 20 mg of
betamethasone over the first 1-10 days, while the sustained release
component releases betamethasone at a rate of about 0.1 to 1.0
mg/day over the first 14 to 90 days following administration. If
triamcinolone acetonide is used, then the immediate release
component provides an initial release of a total of 10 to 40 mg of
drug over the first 1-10 days, while the sustained release
component releases drug at a rate of about 0.2 to 1.7 mg/day over
the first 14 to 90 days following administration.
Example 3
Determination of Time-Variance in HPA Axis Sensitivity
[0227] Adult volunteers (N=4 to 9 per group) give appropriate
informed consent. Each individual in each group receives a single
intra-articular administration of an exogenous corticosteroid
(triamcinolone acetonide 40 mg; triamcinolone hexacetonide 20;
betamethasone 7 mg (disodium phosphate 4 mg/acetate 3 mg). Blood
samples for measurement of corticosteroid concentrations and/or
cortisol concentrations are drawn at 8 AM at baseline and on days
1, 7, 9, 10, 12, 14, 18, and 21. The extent of suppression of
endogenous cortisol was measured in each subject in each group. The
extent of cortisol suppression predicted by previously published
models (Meibohm, 1999) was determined and compared to observations
(FIG. 4 Column 1). The change (decrease) in HPA axis sensitivity
vs. time is then determined on a day-by-day and final basis (FIG.
4, Column 2), permitting determination of the correct steady-state
intra-articular doses of corticosteroid to achieve, or limit, HPA
axis suppression to the desired level.
Example 4
Preparation of Triamcinolone Acetonide Microparticles by Spinning
Disk
[0228] A pharmaceutical depot was prepared comprised of the
corticosteroid, triamcinolone acetonide (TCA,
9.alpha.-Fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxy-1,4-pregnadi-
ene-3,20-dione 16,17-acetonide;
9.alpha.-Fluoro-16.alpha.-hydroxyprednisolone
16.alpha.,17.alpha.-acetonide) incorporated into PLGA
microparticles.
[0229] In one suitable thirty day formulation, 250 mg of
triamcinolone acetonide and 750 mg of PLGA (lactide:glycolide molar
ratio of 75:25, inherent viscosity of 0.4 dL/g and molecular weight
of 54 kDa) were dispersed in 14.25 grams of dichloromethane. The
dispersion was atomized into micro-droplets by adding the
dispersion to the feed well of a rotating disk, rotating at a speed
of approximately 3300 rpm inside a temperature controlled chamber
maintained at 38-45.degree. C. The solvent was evaporated to
produce solid microparticles. The microparticles were collected
using a cyclone separator and, subsequently, sieved through a 150
.mu.m sieve.
[0230] Particle size of the TCA incorporated microparticles was
determined using laser diffraction (Malvern Mastersizer 2000) by
dispersing a 250 mg aliquot in water, with the refractive index
(RI) for water and PLGA, set at 1.33 and 1.46 respectively.
Sonication was maintained as the sample was stirred at 2500 rpm and
measurements taken every 15 seconds, with the average of three
measurements reported. 10 mg of TCA containing microparticles were
added to 10 mL of dimethylsulfoxide (DMSO), mixed until dissolved
and an aliquot analyzed by HPLC to determine the microparticle drug
load. Another 4 mg of TCA containing microparticles were suspended
in 20 mL of phosphate buffered saline (PBS) containing 0.5% sodium
dodecyl sulfate (SDS) maintained at 37.degree. C. 0.5 mL of the
media was removed at regular intervals, replaced at each interval
with an equivalent amount of fresh media to maintain a constant
volume, and analyzed by HPLC to determine microparticle in vitro
release. Analysis by HPLC was conducted using a C18 (Waters
Nova-Pack C-18, 3.9.times.150 mm) and 35% acetonitrile mobile phase
at 1 ml/min flow rate with UV detection at 240 nm. The results are
shown in Table 5.
TABLE-US-00006 TABLE 5 Analytical Results for 25% Triamcinolone
Acetonide PLGA 75:25 Microparticles PLGA (lactide:glycolide molar
ratio Drug ratio/inherent load viscosity/ (% molecular TCA
weight/target % by Incorporation Particle size In vitro TCA weight)
efficiency (%) (Dv, .mu.m) release (%) 75:25 carboxylic 24 96 D0.1:
32 .mu.m 0.2 day: 5.1 acid end-capped D0.5: 49 .mu.m 1 day: 13.5
0.4 dL/g D0.9: 73 .mu.m 3 day: 29.6 54 kDa 7 day: 52.6 25% 14 day
70.9 21 day: 76.4 28 day: 79.1
[0231] The in vitro cumulative release profile is graphed in FIG.
5.
[0232] In one iteration of these data, the amount of TCA released
per day was calculated based on a human dose, as exemplified in
Table 2, that would achieve a transient suppression of endogenous
cortisol (greater than 50%) and, within 14 days, achieve cortisol
suppression of endogenous cortisol of less than 35% as shown in
FIG. 6. In a second iteration of these data, the amount of
triamcinolone acetonide released per day was calculated based on a
human dose, as exemplified in Table 2 that would not suppress the
HPA axis, i.e. endogenous cortisol suppression never exceeding 35%
as shown in FIG. 7. These calculated doses equal 376 mg of
microparticles containing 94 mg of TCA and 80 mg of microparticles
containing 20 mg of TCA, respectively.
[0233] In a second preparation of the same formulation, analyzed
and in vitro release plotted in the same manner, the results are
equivalent as shown in Table 6, and FIGS. 8, 9 and 10. The
calculated human dose, as exemplified in Table 2 that would achieve
a transient suppression of endogenous cortisol (greater than 50%)
and, within 14 days, achieve cortisol suppression of endogenous
cortisol of less than 35% equals 280 mg of microparticles
containing 70 mg of TCA. The calculated human dose, as exemplified
in Table 2 that would not suppress the HPA axis, i.e. endogenous
cortisol suppression never exceeding 35% equals 68 mg of
microparticles containing 17 mg of TCA.
TABLE-US-00007 TABLE 6 Analytical Results for Alternate Preparation
of a Nominal 25% Triamcinolone Acetonide PLGA 75:25 Microparticles
PLGA (lactide:glycolide molar ratio ratio/inherent viscosity/ Drug
Incor- molecular load poration weight/target % (% TCA efficiency
Particle size In vitro TCA by weight) (%) (Dv, .mu.m) release (%)
75:25 carboxylic 27.5 110 D0.1: 30.9 .mu.m 0.2 day: 4.8 acid
end-capped D0.5: 48.2 .mu.m 1 day: 15 0.4 dL/g D0.9: 71.0 .mu.m 3
day: 28.5 54 kDa 7 day: 50.2 25% 14 day 67.1 21 day: 74.2 28 day:
75.7
[0234] Influence of PEG on PLGA 75:25 Formulations:
[0235] In other suitable formulations, polyethylene glycol was
added to the PLGA 75:25 polymers while keeping the target amount of
triamcinolone acetonide constant. PEG/PLGA blends are known to
allow for more complete and faster release of pharmaceutical agents
incorporated into microparticles than PLGA alone (Cleek et al.
"Microparticles of poly(DL-lactic-coglycolic acid)/poly(ethylene
glycol) blends for controlled drug delivery." J Control Release 48
(1997): 259-268; Morlock, et al. "Erythropoietin loaded
microspheres prepared from biodegradable LPLG-PEO-LPLG triblock
copolymers: protein stabilization and in-vitro release properties."
J Control Release, 56 (1-3) (1998): 105-15; Yeh, "The stability of
insulin in biodegradable microparticles based on blends of lactide
polymers and polyethylene glycol." J Microencapsul, 17(6) (2000):
743-56).
[0236] In one iteration, 250 mg of triamcinolone acetonide, 50 mg
of polyethylene glycol (PEG 1450) and 700 mg of PLGA
(lactide:glycolide molar ratio of 75:25, inherent viscosity of 0.4
dL/g and molecular weight of 54 kDa) were dispersed in 14 grams of
dichloromethane. In another iteration, 250 mg of triamcinolone
acetonide, 100 mg of polyethylene glycol (PEG 3350) and 650 mg of
PLGA (lactide:glycolide molar ratio of 75:25, inherent viscosity of
0.4 dL/g and molecular weight of 54 kDa) were dispersed in 13 grams
of dichloromethane. The dispersions were atomized into
micro-droplets by adding the dispersion to the feed well of a
rotating disk, rotating at a speed of approximately 3300 rpm inside
a temperature controlled chamber maintained at 38-45.degree. C. The
solvent was evaporated to produce solid microparticles. The
microparticles were collected using a cyclone separator and,
subsequently, sieved through a 150 .mu.m sieve.
[0237] The microparticles were analyzed as described above and the
data is shown in Table 7.
TABLE-US-00008 TABLE 7 Analytical Results of Nominal 25%
Triamcinolone Acetonide PLGA 75:25 Microparticles containing
Polyethylene Glycol (PEG) Additive PLGA (lactide:glycolide molar
ratio Drug ratio/inherent load viscosity/ (% Incor- molecular TCA
poration weight/target % by efficiency Particle size In vitro
release TCA/% PEG weight) (%) (Dv, .mu.m) (%) 75:25 carboxylic 29.4
118 D0.1: 36.2 .mu.m 0.2 day: 3.6 acid end-capped D0.5: 59.0 .mu.m
1 day: 13.8 0.4 dL/g D0.9: 95.5 .mu.m 3 day: 30.1 54 kDa 7 day:
49.5 25% 14 day 65.5 5% PEG 1450 21 day: 74.0 28 day: 78.5 75:25
carboxylic 24.5 98 D0.1: 32.0 .mu.m 0.2 day: 4.1 acid end-capped
D0.5: 52.4 .mu.m 1 day: 11.7 0.4 dL/g D0.9: 79.0 .mu.m 3 day: 24.5
54 kDa 7 day: 40.8 25% 14 day: 55.8 10% PEG 3350 21 day: 63.7 28
day: 69.5
[0238] The in vitro cumulative release profile is graphed in FIG.
11 and FIG. 12. PEG did not seem to enhance the release of the TCA
in either formulation, as would be expected. In fact, at higher
percentages of PEG, albeit a different molecular weight (higher
percentages of PEG 1350 were unmanageable due to the agglomeration
of microparticles), the release rate was slower.
[0239] In one iteration of these in vitro release data, the amount
of TCA released per day was calculated based on a human dose, as
exemplified in Table 2, that would achieve a temporary suppression
of endogenous cortisol (greater than 50%) and, within 14 days,
achieve cortisol suppression of endogenous cortisol of less than
35% as shown in FIG. 13 and FIG. 14. These calculated doses equal
296 mg of microparticles containing 74 mg of TCA and 316 mg of
microparticles containing 79 mg of TCA, respectively. In a second
iteration of these data, the amount of triamcinolone acetonide
released per day was calculated based on a human dose, as
exemplified in Table 2 that would not suppress the HPA axis, i.e.
endogenous cortisol suppression never exceeding 35% as shown in
FIGS. 15 and 16. These calculated doses equal 68 mg of
microparticles containing 17 mg of TCA and 88 mg of microparticles
containing 22 mg of TCA, respectively.
[0240] Other TCA containing formulations were tried with PEG and
PLGA 75:25 without success. A PLGA microparticle formulation
containing 25% TCA and 25% PEG 1450 agglomerated during manufacture
and storage. Another PLGA formulation containing 40% TCA and 15%
PEG 1450 gave similar results to the microparticles containing 40%
TCA and no PEG.
[0241] Influence of Triamcinolone Acetonide Content in PLGA 75:25
Microparticles:
[0242] Triamcinolone acetonide containing microparticle depots were
prepared and analyzed, as described above, with the exception of
using 100 mg, 150 mg, 200 mg and 400 mg triamcinolone acetonide and
adding to a 5% PLGA dichloromethane solution. The physical
characteristics of these formulations are shown in Table 8.
TABLE-US-00009 TABLE 8 Analytical Results of PLGA 75:25
Microparticles containing varying amounts of Triamcinolone
Acetonide PLGA (lactide:glycolide molar ratio Drug ratio/inherent
load viscosity/ (% Incor- molecular TCA poration weight/target % by
efficiency Particle size In vitro release TCA weight) (%) (Dv,
.mu.m) (%) 75:25 carboxylic 43.4 109 D0.1: 40.7 .mu.m 0.2 day: 6.6
acid end-capped D0.5: 70.7 .mu.m 1 day: 24.2 0.4 dL/g D0.9: 167
.mu.m 3 day: 53.8 54 kDa 7 day: 82.5 40% 14 day 89.4 21 day: 89.6
28 day: 87.5 75:25 carboxylic 20.2 101 D0.1: 28.7 .mu.m 0.2 day:
5.3 acid end-capped D0.5: 45.2 .mu.m 1 day: 13.5 0.4 dL/g D0.9:
70.5 .mu.m 3 day: 23.7 54 kDa 7 day: 35.3 20% 14 day 44.4 21 day:
48.1 28 day: 50.6 75:25 carboxylic 15.9 106 D0.1: 30.7 .mu.m 0.2
day: 3.9 acid end-capped D0.5: 47.8 .mu.m 1 day: 9.0 0.4 dL/g D0.9:
74.8 .mu.m 3 day: 14.2 54 kDa 7 day: 19.3 15% 14 day 22.7 21 day:
24.6 28 day: 27.6 75:25 carboxylic 11.7 117 D0.1: 31.0 .mu.m 0.2
day: 2.3 acid end-capped D0.5: 57.9 .mu.m 1 day: 4.4 0.4 dL/g D0.9:
118 .mu.m 3 day: 5.9 54 kDa 7 day: 7.5 10% 14 day 9.9 21 day: 11.7
28 day: 15.8
[0243] The in vitro cumulative release profiles for these four
other TCA containing PLGA 75:25 microparticle depots are graphed in
FIG. 17, along with the preferred formulation (25% TCA). The
tabulated data and graph show the impact of the percent TCA
incorporated in the PLGA microparticles on the in vitro release
profile. The 10%, 15% and 20% TCA containing PLGA microparticles
exhibit a slower release profile, with a significant less
cumulative release over 28 days, less than 20%, 30% and 55%
respectively, than the 25% TCA PLGA depot exemplified in Example 4.
The 40% TCA containing depot exhibits a faster release profile,
with greater than 80% of the triamcinolone released by day 7 with a
similar total cumulative release, than the 25% TCA PLGA depot
exemplified in Example 4.
[0244] Influence of Molecular Weight on TCA PLGA 75:25
Microparticle Formulations:
[0245] In another microparticle formulation, triamcinolone
acetonide was incorporated in PLGA of the same lactide to glycolide
molar ratio as cited in Example 4 but of a lower molecular weight.
Low molecular weight PLGA is known to allow for more complete and
faster release of pharmaceutical agents incorporated into
microparticles than their higher molecular weight counterparts.
(Anderson et al. "Biodegradation and biocompatibility of PLA and
PLGA microspheres." Advanced Drug Delivery Reviews 28 (1997): 5-24;
Bouissou et al., "Poly(lactic-co-glycolicacid) Microspheres."
Polymer in Drug Delivery (2006): Chapter 7).
[0246] 250 mg of triamcinolone acetonide and 750 mg of PLGA
(lactide:glycolide molar ratio of 75:25, inherent viscosity of 0.27
dL/g and molecular weight of 29 kDa) were dispersed in 14.25 grams
of dichloromethane. The dispersion was atomized into micro-droplets
by adding the dispersion to the feed well of a rotating disk,
rotating at a speed of approximately 3300 rpm inside a temperature
controlled chamber maintained at 38-45.degree. C. The solvent was
evaporated to produce solid microparticles. The microparticles were
collected using a cyclone separator and, subsequently, sieved
through a 150 .mu.m sieve.
[0247] Particle size of the TCA incorporated microparticles was
determined using laser diffraction (Malvern Mastersizer 2000) by
dispersing a 250 mg aliquot in water, with the refractive index
(RI) for water and PLGA, set at 1.33 and 1.46 respectively.
Sonication was maintained as the sample was stirred at 2500 rpm and
measurements taken every 15 seconds, with the average of three
measurements reported. 10 mg of TCA containing microparticles were
added to 10 mL of dimethylsulfoxide (DMSO), mixed until dissolved
and an aliquot analyzed by HPLC to determine the microparticle drug
load. Another 4 mg of TCA containing microparticles were suspended
in 20 mL of phosphate buffered saline (PBS) containing 0.5% sodium
dodecyl sulfate (SDS) maintained at 37.degree. C. 0.5 mL of the
media was removed at regular intervals, replaced at each interval
with an equivalent amount of fresh media to maintain a constant
volume, and analyzed by HPLC to determine microparticle in vitro
release. Analysis by HPLC was conducted using a C18 (Waters
Nova-Pack C-18, 3.9.times.150 mm) and 35% acetonitrile mobile phase
at 1 ml/min flow rate with UV detection at 240 nm. The results are
shown in Table 9.
TABLE-US-00010 TABLE 9 Analytical Results of a Nominal 25%
Triamcinolone Acetonide PLGA 75:25 (29 kDa) Microparticles PLGA
(lactide:glycolide molar ratio Drug ratio/inherent load viscosity/
(% Incor- molecular TCA poration weight/target % by efficiency
Particle size In vitro release TCA/% PEG weight) (%) (Dv, .mu.m)
(%) 75:25 carboxylic 29.4 118 D0.1: 34.1 .mu.m 0.2 day: 4.0 acid
end-capped D0.5: 56.5 .mu.m 1 day: 11.3 0.27 dL/g D0.9: 95.2 .mu.m
3 day: 22.5 29 kDa 7 day: 35.9 25% 14 day: 48.3 21 day: 53.4 28
day: 56.5
[0248] In vitro cumulative release data is graphed in FIG. 18,
along with the preferred formulation using a higher molecular PLGA
75:25. The use of lower molecular weight PLGA (29 kDa) did not
improve the release of the triamcinolone acetonide from the
microparticles as expected, in fact the rate of release decreased
and the release was incomplete as compared to higher molecular
weight PLGA (PLGA, 54 kDa).
[0249] In another formulation of low molecular weight PLGA 75:25(29
kDa), polyethylene glycol, 10% PEG 3350, was added while
maintaining the same amount of triamcinolone acetonide. As shown
with other PEG containing formulations, there was no impact of this
additive on the cumulative percent in vitro release profile as
compared to the formulation not containing PEG (data not
shown).
[0250] Influence of PLGA Lactide to Glycolide Ratio:
[0251] In other triamcinolone acetonide microparticle formulations,
PLGA of equimolar lactide to glycolide ratio were employed instead
of PLGA (75:25). PLGA (50:50) is known to allow for faster
degradation and release of pharmaceutical agents incorporated into
microparticles than PLGA's with greater lactide versus glycolide
content (Anderson et al. "Biodegradation and biocompatibility of
PLA and PLGA microspheres." Advanced Drug Delivery Reviews 28
(1997): 5-24; Bouissou et al., "Poly(lactic-co-glycolicacid)
Microspheres." Polymer in Drug Delivery (2006): Chapter 7).
Multiple formulations using PLGA 50:50 with differing amounts of
triamcinolone acetonide, with and without PEG, different PLGA
molecular weights and different PLGA endcaps were exemplified.
[0252] Formulations were prepared with 200 mg, 250 mg, 300 mg and
350 mg of triamcinolone acetonide and corresponding amount of PLGA
(lactide:glycolide molar ratio of 50:50, inherent viscosity of 0.48
dL/g and molecular weight of 66 kDa) to yield 1000 mg total solids
were dispersed into a quantity of dichloromethane to a achieve a 5%
PLGA solution. In another iteration, 300 mg of triamcinolone
acetonide, 100 mg of polyethylene glycol (PEG 3350) and 650 mg of
PLGA (lactide:glycolide molar ratio of 50:50, inherent viscosity of
0.48 dL/g and molecular weight of 66 kDa) were dispersed in 14.25
grams of dichloromethane. In another iteration, 300 mg of
triamcinolone acetonide and 700 mg of PLGA (lactide:glycolide molar
ratio of 50:50, inherent viscosity of 0.18 dL/g and molecular
weight of 18 kDa) to yield 1000 mg total solids were dispersed in
14.25 grams of dichloromethane. The dispersions were atomized into
micro-droplets by adding the dispersion to the feed well of a
rotating disk, rotating at a speed of approximately 3300 rpm inside
a temperature controlled chamber maintained at 38-45.degree. C. The
solvent was evaporated to produce solid microparticles. The
microparticles were collected using a cyclone separator and,
subsequently, sieved through a 150 .mu.m sieve.
[0253] Particle size of the TCA incorporated microparticles was
determined using laser diffraction (Malvern Mastersizer 2000) by
dispersing a 250 mg aliquot in water, with the refractive index
(RI) for water and PLGA, set at 1.33 and 1.46 respectively.
Sonication was maintained as the sample was stirred at 2500 rpm and
measurements taken every 15 seconds, with the average of three
measurements reported. 10 mg of TCA containing microparticles were
added to 10 mL of dimethylsulfoxide (DMSO), mixed until dissolved
and an aliquot analyzed by HPLC to determine the microparticle drug
load. Another 4 mg of TCA containing microparticles were suspended
in 20 mL of phosphate buffered saline (PBS) containing 0.5% sodium
dodecyl sulfate (SDS) maintained at 37.degree. C. 0.5 mL of the
media was removed at regular intervals, replaced at each interval
with an equivalent amount of fresh media to maintain a constant
volume, and analyzed by HPLC to determine microparticle in vitro
release. Analysis by HPLC was conducted using a C18 (Waters
Nova-Pack C-18, 3.9.times.150 mm) and 35% acetonitrile mobile phase
at 1 ml/min flow rate with UV detection at 240 nm. The results are
shown in Table 10.
TABLE-US-00011 TABLE 10 Analytical Results of Triamcinolone
Acetonide PLGA 50:50 Microparticle Formulations PLGA
(lactide:glycolide molar ratio ratio/inherent Drug Incor-
viscosity/ load poration molecular (% TCA effi- weight/target % by
ciency Particle size In vitro release TCA/% PEG weight) (%) (Dv,
.mu.m) (%) 50:50 carboxylic 19.2 96 D0.1: 30.0 .mu.m 0.2 day: 2.1
acid end-capped D0.5: 48.5 .mu.m 1 day: 3.3 0.48 dL/g D0.9: 77.0
.mu.m 3 day: 17.0 66 kDa 7 day: 18.7 20% TCA 14 day: 21.0 21 day:
23.5 28 day: 25.6 50:50 carboxylic 23.9 95.6 D0.1: 30.2 .mu.m 0.2
day: 4.0 acid end-capped D0.5: 48.2 .mu.m 1 day: 7.8 0.48 dL/g
D0.9: 75.8 .mu.m 3 day: 21.1 66 kDa 7 day: 32.1 25% TCA 14 day:
39.2 21 day: 40.0 28 day: 40.8 50:50 carboxylic 29.3 97.6 D0.1:
31.5 .mu.m 0.2 day: 5.1 acid end-capped D0.5: 48.0 .mu.m 1 day:
16.0 0.48 dL/g D0.9: 68.9 .mu.m 3 day: 33.6 66 kDa 7 day: 49.9 30%
TCA 14 day: 54.0 21 day: 53.2 28 day: 52.2 50:50 carboxylic 27.2 91
D0.1: 37.6 .mu.m 0.2 day: 4.4 acid end-capped D0.5: 59.8 .mu.m 1
day: 9.8 0.18 dL/g D0.9: 93.9 .mu.m 3 day: 13.8 18 kDa 7 day: 17.7
30% TCA 14 day: 21.9 21 day: 26.3 28 day: 36.6 50:50 carboxylic
30.4 101 D0.1: 38.1 .mu.m 0.2 day: 4.2 acid end-capped D0.5: 56.6
.mu.m 1 day: 14.6 0.48 dL/g D0.9: 82.1 .mu.m 3 day: 32.2 66 kDa 7
day: 51.0 30% TCA 14 day: 60.1 10% PEG 3350 21 day: 61.1 28 day:
60.1 50:50 carboxylic 34.4 98.3 D0.1: 35.1 .mu.m 0.2 day: 7.1 acid
end-capped D0.5: 52.3 .mu.m 1 day: 23.3 0.48 dL/g D0.9: 75.6 .mu.m
3 day: 47.6 66 kDa 7 day: 66.9 35% TCA 14 day: 69.3 21 day: 68.3 28
day: 66.7 50:50 ester 23.2 93 D0.1: 34.2 .mu.m 0.2 day: 3.1
endcapped D0.5: 51.7 .mu.m 1 day: 7.8 0.4 dL/g D0.9: 77.4 .mu.m 3
day: 12.5 66 kDa 7 day: 15.4 25% TCA 14 day: 16.2 21 day: 16.0 28
day: 16.4
[0254] In-vitro release profiles of the various PLGA (50:50)
formulations are shown in the FIG. 19. The use of PLGA (50:50) did
not improve the release kinetics of the triamcinolone acetonide as
compared to the PLGA (75:25). Unexpectedly, 25% triamcinolone
acetonide microparticles in PLGA (50:50) release the corticosteroid
at a slower rate and give an incomplete release as compared to the
equivalent amount of triamcinolone acetonide incorporated in PLGA
75:25. All the PLGA 50:50 formulation show a substantial lag phase,
where little or any TCA is being released after 7 days, which
continues to about day 50. As observed with TCA PLGA 75:25
formulations, increasing the amount of TCA increases the rate of
release and allows for more TCA to be released before entering the
lag phase. Similarly, the addition of PEG has minimal influence on
the release rate of TCA, while lower molecular weight PLGA 50:50
decrease the release rate as observed with PLGA 75:25
formulations.
[0255] Based on the studies described herein, the Class B
corticosteroid microparticle formulations, for example, the TCA
microparticle formulations, exhibiting the desired release kinetics
have the following characteristics: (i) the corticosteroid is
between 22%-28% of the microparticle; and (ii) the polymer is PLGA
having a molecular weight in the range of about 40 to 70 kDa,
having an inherent viscosity in the range of 0.3 to 0.5 dL/g, and
or having a lactide:glycolide molar ratio of 80:20 to 60:40.
Example 5
Preparation of Triamcinolone Acetonide PLGA Microparticles by Solid
in Oil in Water (S/O/W) Emulsion
[0256] A pharmaceutical depot was prepared comprised of the
corticosteroid, triamcinolone acetonide (TCA,
9.alpha.-Fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxy-1,4-pregnadi-
ene-3,20-dione 16,17-acetonide;
9.alpha.-Fluoro-16.alpha.-hydroxyprednisolone
16.alpha.,17.alpha.-acetonide) incorporated into
microparticles.
[0257] Formulations were prepared by dissolving approximately 1
gram of PLGA in 6.67 mL of dichloromethane (DCM). To the polymer
solution, 400 mg of triamcinolone acetonide was added and
sonicated. Subsequently, the corticosteroid containing dispersion
was poured into 200 mL of 0.3% polyvinyl alcohol (PVA) solution
while homogenizing with a Silverson homogenizer using a rotor fixed
with a Silverson Square Hole High Shear Screen.TM., set to rotate
at approximately 2,000 rpm to form the microparticles. After two
minutes, the beaker was removed, and a glass magnetic stirrer)
added to the beaker, which was then placed onto a multi-way
magnetic stirrer and stirred for four hours at 300 rpm to evaporate
the DCM. The microparticles were then washed with 2 liters of
distilled water, sieved through a 100 micron screen. The
microparticles were then lyophilized for greater than 96 hours and
vacuum packed.
[0258] Particle size of the TCA incorporated microparticles was
determined using laser diffraction (Beckman Coulter LS 230) by
dispersing a 50 mg aliquot in water, with the refractive index (RI)
for water and PLGA, set at 1.33 and 1.46 respectively. The sample
was stirred at the particle size measurement measurements taken and
the results reported. Drug load was determined by suspending a
nominal 10 mg of microparticles in 8 ml HPLC grade methanol and
sonicating for 2 hours. Samples were then centrifuged at 14,000 g
for 15 mins before an aliquot of the supernatant was assayed via
HPLC as described below. Corticosteroid-loaded microparticle
samples, nominally 1 g were placed in 22 ml glass vials in 8-20 ml
of 0.5% v/v Tween 20 in 100 mM phosphate buffered saline and stored
in a 37.degree. C. incubator with magnetic stirring at 130 rpm.
Each test sample was prepared and analyzed in duplicate to monitor
possible variability. At each time point in the release study,
microparticles were allowed to settle, and an aliquot of between
4-16 ml of supernatant were taken, and replaced with an equal
volume of fresh 0.5% v/v Tween 20 in 100 mM phosphate buffered
saline. Drug load and in vitro release samples were analyzed by
HPLC using a Hypersil C18 column (100 mm, i.d. 5 mm, particle size
5 .mu.m; ThermoFisher) and Beckman HPLC. All samples were run using
a sample injection volume of 5 .mu.m, and column temperature of
40.degree. C. An isocratic mobile phase of 60% methanol and 40%
water was used at a flow rate of 1 ml/min, with detection at a
wavelength of 254 nm.
[0259] In one group of suitable thirty day formulations, the PLGA
is an ester end capped PLGA (lactide:glycolide molar ratio of
75:25, inherent viscosity of 0.71 dL/g and molecular weight of 114
kDa) with 10% or 20% triblock (TB) polymer (PLGA-PEG-PLGA).
Triblock polymer was synthesized using a method described by
Zentner et al 2001 (Zentner et al. "Biodegradable block copolymers
for delivery of proteins and water-insoluble drugs." J Control
Release 72 (2001): 203-15) and refined by Hou et al 2008 (Hou et
al., "In situ gelling hydrogels incorporating microparticles as
drug delivery carriers for regenerative medicine." J Pharm Sci
97(9) (2008): 3972-80). It is synthesized using a ring opening
polymerization of cyclic dimmers of D,L-lactide and glycolide with
PEG 1,500 kDa in the presence of stannous octoate. In vitro release
(lactide:glycolide molar ratio of 50:50, inherent viscosity of 0.40
dL/g and molecular weight of 66 kDa). The analytical results for
these formulations are shown in Table 11.
TABLE-US-00012 TABLE 11 Analytical Results of Nominal 28.6%
Triamcinolone Acetonide in PLGA 75:25 plus Triblock Microparticle
Formulations PLGA (lactide:glycolide molar ratio ratio/inherent
Drug Incor- viscosity/ load poration molecular (% TCA effi-
weight/target % by ciency Particle size In vitro release TCA/% PEG
weight) (%) (Dv, .mu.m) (%) 75:25 ester 23.8 83.2 D0.1: 38.9 .mu.m
1 day: 8.2 endcapped D0.5: 74.7 .mu.m 2 day: 14.2 0.71 dL/g D0.9:
103.0 .mu.m 3 day: 15.7 114 kDa 4 day 18.2 28.6% TCA 6 day: 28.8
10% Triblock 9 day: 38.9 12 day: 49.8 16 day: 61.6 20 day: 66.4 24
day: 68.7 30 day: 72:3 35 day: 72.8 75:25 ester 24.8 86.7 D0.1:
39.5 .mu.m 1 day: 5.5 endcapped D0.5: 74.6 .mu.m 2 day: 8.9 0.71
dL/g D0.9: 104.2 .mu.m 3 day: 12.8 114 kDa 4 day 14.5 28.6% TCA 6
day: 28.4 20% Triblock 9 day: 35.6 (TB) 12 day: 47.8 16 day: 53.0
20 day: 64.3 24 day: 67.3 30 day: 73.0 35 day: 73.0
[0260] The in vitro cumulative release profiles for both triblock
containing formulations are shown in FIG. 20. The amount of
triblock in the tested formulations did not influence the
cumulative percent release.
[0261] In one iteration of these data, the amount of TCA released
per day was calculated based on a human dose, as exemplified in
Table 2, that may achieve a temporary suppression of endogenous
cortisol (greater than 50%) and, within 14 days, achieve cortisol
suppression of endogenous cortisol of less than 35%. These
calculated doses equal 149 mg of microparticles containing 35 mg of
TCA and 252 microparticles containing 62 mg of TCA, for the 10% and
20% triblock formulations respectively (FIG. 21 and FIG. 22). In a
second iteration of these data, the amount of TCA released per day
was calculated based on a human dose, as exemplified in Table 2,
that would not have an suppress the HPA axis, i.e. endogenous
cortisol suppression more than 35%. These calculated doses equal 66
mg of microparticles containing 16 mg of TCA and 47 microparticles
containing 12 mg of TCA, for the 10% and 20% triblock formulations
respectively (FIG. 23 and FIG. 24).
[0262] In another suitable formulation lasting greater than 30 days
and up to 90 days, the PLGA polymer consists of two different
molecular weight PLGA 75:25 polymers in a two to one ratio, PLGA
75:25 (lactide:glycolide molar ratio of 75:25, inherent viscosity
of 0.27 dL/g and molecular weight of 29 kDa) and ester end capped
PLGA 5.5 E (lactide:glycolide molar ratio of 75:25, inherent
viscosity of 0.58 dL/g and molecular weight of 86 kDa),
respectively. The formulation was processed as described above with
the exception that 200 mg of triamcinolone acetonide was used in
the formulation instead of 400 mg and similarly analyzed as
describe for other formulations. The results are shown in the Table
12.
TABLE-US-00013 TABLE 12 Analytical Results of a Nominal 16.7%
Triamcinolone Acetonide in Mixed Molecular Weight PLGA 75:25
Microparticle Formulation PLGA (lactide:glycolide molar ratio
ratio/inherent Drug viscosity/ load Incor- molecular (% TCA
poration weight/target % by efficiency Particle size In vitro TCA/%
PEG weight) (%) (Dv, .mu.m) release (%) 75:25 ester 14.6 87.7 D0.1:
36.5 .mu.m 1 day: 12.4 endcapped D0.5: 54.0 .mu.m 2 day: 21.6 0.58
dL/g D0.9: 69.4 .mu.m 3 day: 27.3 86 kDa 4 day 33.6 And 6 day: 41.2
75:25 carboxylic 9 day: 50.7 acid endcapped 12 day: 54.3 0.27 dL/g
17 day: 62.0 29 kDa 20 day: 73.1 16.7% TCA 25 day: 75.5 30 day:
82.9 35 day: 84.6 42 day: 87.4 49 day: 89.2
[0263] In vitro cumulative percent TCA release data is graphed in
FIG. 25.
[0264] In one iteration of these in vitro release data, the amount
of TCA released per day was calculated based on a human dose, as
exemplified in Table 2, which may achieve a temporary suppression
of endogenous cortisol (greater than 50%) and, within 14 days,
achieve cortisol suppression of endogenous cortisol of less than
35%. This calculated dose equals 317 mg of microparticles
containing 46 mg of TCA. In a second iteration of these data, the
amount of TCA released per day was calculated based on a human
dose, as exemplified in Table 2, that would not have an suppress
the HPA axis, i.e. endogenous cortisol suppression more than 35%.
This calculated dose equals 93 mg of microparticles containing 14
mg of TCA.
[0265] Several other triamcinolone acetonide PLGA depots were
formulated in the same manner as described above with different
polymers including polycaprolactone (14 kDa), PLGA 50:50
(carboxylic acid end-capped, 0.44 dL/g, MW 56 kDa), PLGA 85:15
(carboxylic acid end-capped, 0.43 dL/g, 56 kDa) and a mixed
molecular weight formulation using PLGA 75:25 (carboxylic acid end
capped, 0.27 dL/g, MW 29 kDa) and PLGA 75:25 (ester end-capped,
0.57 dL/g, MW 86 kDa) in a two to one ratio. The in vitro
cumulative percent release of triamcinolone acetonide is shown in
FIG. 28. None of these formulations were suitable for a nominal
thirty day or longer duration pharmaceutical depot.
Polycaprolactone release all the triamcinolone acetonide prior to
14 days. The PLGA 50:50 microparticles released about 35% of its
content by day 12 and then entered a lag phase where no drug was
released up to 30 days. The PLGA 85:15 microparticles exhibited
similar in vitro release kinetics as the PLGA 50:50, releasing
about 30% of its content by day 12 and then entered a lag phase
where no drug was released up to 30 days (See FIG. 28). A similar
phenomenon is seen as shown in Example 4, where the mixed molecular
weight PLGA 75:25 unexpectedly exhibits faster initial release of
the triamcinolone acetonide than PLGA 50:50.
[0266] Based on the studies described herein, the Class B
corticosteroid microparticle formulations, for example, the TCA
microparticle formulations, exhibiting the desired release kinetics
have the following characteristics: (i) the corticosteroid is
between 12%-28% of the microparticle; and (ii) the polymer is (1)
PLGA having a molecular weight in the range of about 40 to 70 kDa,
having an inherent viscosity in the range of 0.3 to 0.5 dL/g,
containing 10%-20% Triblock and/or having a lactide:glycolide molar
ratio of 80:20 to 60:40 or (2) a mixture of low and high molecular
weight PLGAs in a two to one ratio. The low molecular weight PLGA
has a molecular weight of range of 15-35 kDa and an inherent
viscosity range from 0.2 to 0.35 dL/g, and the high molecular
weight PLGA has a range of 70-95 kDa and an inherent viscosity
range of 0.5 to 0.70 dL/g.
Example 6
Preparation of Prednisolone PLGA Microparticles by Solid in Oil in
Water (S/O/W) Emulsion
[0267] A pharmaceutical depot was prepared comprised of the
corticosteroid, prednisolone (PRED,
11.beta.,17,21-trihydroxypregna-1,4-diene-3,20-dione) incorporated
into microparticles in PLGA 50:50.
[0268] Formulations were prepared by dissolving approximately 1
gram of PLGA 50:50 (lactide:glycolide molar ratio of 50:50,
inherent viscosity 0.44 dL/g, MW 56 kDa) in 6.67 mL of
dichloromethane (DCM). To the polymer solution, 400 mg of
prednisolone was added and sonicated. Subsequently, the
corticosteroid containing dispersion was poured into 200 mL of 0.3%
polyvinyl alcohol (PVA) solution while homogenizing with a
Silverson homogenizer using a rotor fixed with a Silverson Square
Hole High Shear Screen.TM., set to spin at 2,000 rpm to form the
microparticles. After two minutes, the beaker was removed, and a
glass magnetic stirrer) added to the beaker, which was then placed
onto a multi-way magnetic stirrer and stirred for four hours at 300
rpm to evaporate the DCM. The microparticles were then washed with
2 liters of distilled water, sieved through a 100 micron screen.
The microparticles were then lyophilized for greater than 96 hours
and vacuum packed.
[0269] Particle size of the PRED incorporated microparticles was
determined using laser diffraction (Beckman Coulter LS 230) by
dispersing a 50 mg aliquot in water, with the refractive index (RI)
for water and PLGA, set at 1.33 and 1.46 respectively. The sample
was stirred at the particle size measurement measurements taken and
the results reported. Drug load was determined by suspending a
nominal 10 mg of microparticles in 8 ml HPLC grade methanol and
sonicating for 2 hours. Samples were then centrifuged at 14,000 g
for 15 mins before an aliquot of the supernatant was assayed via
HPLC as described below. Corticosteroid-loaded microparticle
samples, nominally 1 g were placed in 22 ml glass vials in 8-20 ml
of 0.5% v/v Tween 20 in 100 mM phosphate buffered saline and stored
in a 37.degree. C. incubator with magnetic stirring at 130 rpm.
Each test sample was prepared and analyzed in duplicate to monitor
possible variability. At each time point in the release study,
microparticles were allowed to settle, and an aliquot of between
4-16 ml of supernatant were taken, and replaced with an equal
volume of fresh 0.5% v/v Tween 20 in 100 mM phosphate buffered
saline. Drug load and in vitro release samples were analyzed by
HPLC using a Hypersil C18 column (100 mm, i.d. 5 mm, particle size
5 .mu.m; ThermoFisher) and Beckman HPLC. All samples were run using
a sample injection volume of 5 .mu.m, and column temperature of
40.degree. C. An isocratic mobile phase of 60% methanol and 40%
water was used at a flow rate of 1 ml/min, with detection at a
wavelength of 254 nm. The analytical results are shown in the Table
13.
TABLE-US-00014 TABLE 13 Analytical Results of a Nominal 28.6%
Prednisolone in PLGA 50:50 Microparticle Formulation PLGA
(lactide:glycolide molar ratio Drug ratio/inherent load viscosity/
(% Incor- molecular PRED poration weight/target % by efficiency
Particle size In vitro release TCA/% PEG weight) (%) (Dv, .mu.m)
(%) 50:50 carboxylic 19.0 66.4 D0.1: 34.4 .mu.m 1 day: 7.2 acid
endcapped D0.5: 66.9 .mu.m 2 day: 11.5 0.44 dL/g D0.9: 87.5 .mu.m 3
day: 15.6 56 kDa 4 day: 20.2 28.6% PRED 5 day: 24.0 6 day: 28.4 7
day: 32.7 9 day: 36.5 11 day: 41.4 13 day: 45.0 15 day: 49.3 18
day: 52.0 21 day: 55.2 24 day: 58.3 27 day: 62.3 30 day: 65.9
[0270] In vitro release profile of the prednisolone PLGA
microparticles is shown in FIG. 29. This formulation is suitable
for a 30 day formulation or greater.
[0271] In one iteration of the cumulative percent in vitro release
data, the amount of prednisolone released per day was calculated
based on a human dose, as exemplified in Table 2, which may achieve
a temporary suppression of endogenous cortisol (greater than 50%)
and, within 14 days, achieve cortisol suppression of endogenous
cortisol of less than 35% (FIG. 30). The calculated dose equals 699
mg of microparticles containing 133 mg of PRED. In a second
iteration of these data, the amount of PRED released per day was
calculated based on a human dose, as exemplified in Table 2 that
would not suppress the HPA axis, i.e. endogenous cortisol
suppression of less than 35% (FIG. 31). This calculated dose equals
377 mg of microparticles containing 72 mg of PRED.
[0272] Based on the studies described herein, the Class A
corticosteroid microparticle formulations, for example, the
prednisolone microparticle formulations, exhibiting the desired
release kinetics have the following characteristics: (i) the
corticosteroid is between 10%-40% of the microparticle, for
example, between 15%-30% of the microparticle; and (ii) the polymer
is PLGA having a molecular weight in the range of about 45 to 75
kDa, having an inherent viscosity in the range of 0.35 to 0.5 dL/g,
and or having a lactide:glycolide molar ratio of 60:40 to
45:55.
Example 7
Preparation of Betamethasone PLGA Microparticles by Solid in Oil in
Water (S/O/W) Emulsion
[0273] A pharmaceutical depot was prepared comprised of the
corticosteroid, betamethasone (BETA,
9-Fluoro-11.beta.,17,21-trihydroxy-16.beta.-methylpregna-1,4-diene-3,20-d-
ione) incorporated into microparticles in PLGA 50:50.
[0274] A formulation was prepared by dissolving approximately 1
gram of PLGA 50:50 (lactide:glycolide molar ratio of 50:50,
inherent viscosity 0.44 dL/g, MW 56 kDa) in 6.67 mL of
dichloromethane (DCM). To the polymer solution, 400 mg of
betamethasone was added and sonicated. Subsequently, the
corticosteroid containing dispersion was poured into 200 mL of 0.3%
polyvinyl alcohol (PVA) solution while homogenizing with a
Silverson homogenizer using a rotor fixed with a Silverson Square
Hole High Shear Screen.TM., set to spin at 2,000 rpm to form the
microparticles. After two minutes, the beaker was removed, and a
glass magnetic stirrer) added to the beaker, which was then placed
onto a multi-way magnetic stirrer and stirred for four hours at 300
rpm to evaporate the DCM. The microparticles were then washed with
2 liters of distilled water, sieved through a 100 micron screen.
The microparticles were then lyophilized for greater than 96 hours
and vacuum packed.
[0275] Particle size of the BETA incorporated microparticles was
determined using laser diffraction (Beckman Coulter LS 230) by
dispersing a 50 mg aliquot in water, with the refractive index (RI)
for water and PLGA, set at 1.33 and 1.46 respectively. The sample
was stirred at the particle size measurement measurements taken and
the results reported. Drug load was determined by suspending a
nominal 10 mg of microparticles in 8 ml HPLC grade methanol and
sonicating for 2 hours. Samples were then centrifuged at 14,000 g
for 15 mins before an aliquot of the supernatant was assayed via
HPLC as described below. Corticosteroid-loaded microparticle
samples, nominally 1 g were placed in 22 ml glass vials in 8-20 ml
of 0.5% v/v Tween 20 in 100 mM phosphate buffered saline and stored
in a 37.degree. C. incubator with magnetic stirring at 130 rpm.
Each test sample was prepared and analyzed in duplicate to monitor
possible variability. At each time point in the release study,
microparticles were allowed to settle, and an aliquot of between
4-16 ml of supernatant were taken, and replaced with an equal
volume of fresh 0.5% v/v Tween 20 in 100 mM phosphate buffered
saline. Drug load and in vitro release samples were analyzed by
HPLC using a Hypersil C18 column (100 mm, i.d. 5 mm, particle size
5 .mu.m; ThermoFisher) and Beckman HPLC. All samples were run using
a sample injection volume of 5 .mu.m, and column temperature of
40.degree. C. An isocratic mobile phase of 60% methanol and 40%
water was used at a flow rate of 1 ml/min, with detection at a
wavelength of 254 nm. The analytical characteristics of the
betamethasone PLGA microparticles are shown in the Table 14.
TABLE-US-00015 TABLE 14 Analytical Results of a Nominal 28.6%
Betamethasone PLGA 50:50 Microparticle Formulation PLGA
(lactide:glycolide molar ratio Drug ratio/inherent load viscosity/
(% Incor- molecular BETA poration- weight/target % by efficiency
Particle size In vitro release TCA/% PEG weight) (%) (Dv, .mu.m)
(%) 50:50 carboxylic 22.8 79.7 D0.1: 42.1 .mu.m 1 day: 2.0 acid
endcapped D0.5: 71.7 .mu.m 2 day: 3.1 0.44 dL/g D0.9: 102.7 .mu.m 3
day: 4.8 56 kDa 4 day: 7.7 28.6% BETA 5 day: 12.5 6 day: 21.4 7
day: 30.8 9 day: 38.6 11 day: 43.9 13 day: 49.6 15 day: 55.5 18
day: 57.5 21 day: 59.2 24 day: 60.8 27 day: 62.9 30 day: 72.4
[0276] In vitro release profile of the betamethasone PLGA
microparticles is shown in FIG. 32. This formulation is suitable
for a 30 day formulation or greater.
[0277] In one iteration of the in vitro release data, the amount of
betamethasone released per day was calculated based on a human
dose, as exemplified in Table 2, which may achieve a temporary
suppression of endogenous cortisol (greater than 50%) and, within
14 days, achieve cortisol suppression of endogenous cortisol of
less than 35%. This calculated dose equals 111 mg of microparticles
containing 25 mg of betamethasone. In a second iteration of these
data, the amount of betamethasone released per day was calculated
based on a human dose, as exemplified in Table 2 that would not
suppress the HPA axis, i.e. endogenous cortisol suppression never
exceeding 35%. This calculated dose equals 38 mg of microparticles
containing 9 mg of betamethasone. These doses are both graphically
represented in FIGS. 33 and 34.
[0278] Based on the studies described herein, the Class C
corticosteroid microparticle formulations, for example, the
betamethasone microparticle formulations, exhibiting the desired
release kinetics have the following characteristics: (i) the
corticosteroid is between 10%-40% of the microparticle, for
example, between 15%-30% of the microparticle; and (ii) the polymer
is PLGA having a molecular weight in the range of about 40 to 70
kDa, having an inherent viscosity in the range of 0.35 to 0.5 dL/g,
and or having a lactide:glycolide molar ratio of 60:40 to
45:55.
Example 8
Preparation of Fluticasone Propionate PLGA Microparticles by Solid
in Oil in Water (S/O/W) Emulsion
[0279] A pharmaceutical depot was prepared comprised of the
corticosteroid, fluticasone propionate (FLUT, S-(fluoromethyl)
6.alpha.,9-difluoro-11.beta.,17-dihydroxy-16.alpha.-methyl-3-oxoandrosta--
1,4-diene-17.beta.-carbothioate, 17-propionate) incorporated into
microparticles in PLGA 50:50.
[0280] A formulation was prepared by dissolving approximately 1
gram of PLGA 50:50 (lactide:glycolide molar ratio of 50:50,
inherent viscosity 0.45 dL/g, molecular weight 66 kDa) in 6.67 mL
of dichloromethane (DCM). To the polymer solution, 200 mg of
fluticasone propionate was added and sonicated. Subsequently, the
corticosteroid containing dispersion was poured into 200 mL of 0.3%
polyvinyl alcohol (PVA) solution while homogenizing with a
Silverson homogenizer using a rotor fixed with a Silverson Square
Hole High Shear Screen.TM., set to spin at 2,000 rpm to form the
microparticles. After two minutes, the beaker was removed, and a
glass magnetic stirrer) added to the beaker, which was then placed
onto a multi-way magnetic stirrer and stirred for four hours at 300
rpm to evaporate the DCM. The microparticles were then washed with
2 liters of distilled water, sieved through a 100 micron screen.
The microparticles were then lyophilized for greater than 96 hours
and vacuum packed.
[0281] Particle size of the FLUT incorporated microparticles was
determined using laser diffraction (Beckman Coulter LS 230) by
dispersing a 50 mg aliquot in water, with the refractive index (RI)
for water and PLGA, set at 1.33 and 1.46 respectively. The sample
was stirred at the particle size measurement measurements taken and
the results reported. Drug load was determined by suspending a
nominal 10 mg of microparticles in 8 ml HPLC grade methanol and
sonicating for 2 hours. Samples were then centrifuged at 14,000 g
for 15 mins before an aliquot of the supernatant was assayed via
HPLC as described below. Corticosteroid-loaded microparticle
samples, nominally 1 g were placed in 22 ml glass vials in 8-20 ml
of 0.5% v/v Tween 20 in 100 mM phosphate buffered saline and stored
in a 37.degree. C. incubator with magnetic stirring at 130 rpm.
Each test sample was prepared and analyzed in duplicate to monitor
possible variability. At each time point in the release study,
microparticles were allowed to settle, and an aliquot of between
4-16 ml of supernatant were taken, and replaced with an equal
volume of fresh 0.5% v/v Tween 20 in 100 mM phosphate buffered
saline. Drug load and in vitro release samples were analyzed by
HPLC using a Hypersil C18 column (100 mm, i.d. 5 mm, particle size
5 .mu.m; ThermoFisher) and Beckman HPLC. All samples were run using
a sample injection volume of 5 .mu.m, and column temperature of
40.degree. C. An isocratic mobile phase of 60% methanol and 40%
water was used at a flow rate of 1 ml/min, with detection at a
wavelength of 254 nm. Theanalytical results of the fluticasone
propionate PLGA microparticles are shown in Table 15.
TABLE-US-00016 TABLE 15 Analytical Results of a Nominal 16.7%
Fluticasone PLGA 50:50 Microparticle Formulation PLGA
(lactide:glycolide molar ratio Drug ratio/inherent load viscosity/
(% Incor- molecular FLUT poration weight/target % by efficiency
Particle size In vitro release FLUT/ weight) (%) (Dv, .mu.m) (%)
50:50 carboxylic 8.5 51.1 D0.1: 34.1 .mu.m 1 day: 29.5 acid
endcapped D0.5: 65.5 .mu.m 2 day: 43.5 0.45 dL/g D0.9: 95.0 .mu.m 3
day: 46.7 66 kDa 4 day: 50.9 16.7% FLUT 5 day: 55.5 6 day: 58.6 7
day: 60.1 9 day: 63 11 day: 66.8 13 day: 67.8 15 day: 68.7 18 day:
73.7 21 day: 81.8 24 day: 93.7 26 day: 97.1 31 day: 100.8
[0282] In vitro release profile of the fluticasone propionate PLGA
microparticles is shown in FIG. 35. This formulation is suitable
for a 30 day formulation or greater.
[0283] In one iteration of the in vitro release data, the amount of
fluticasone propionate released per day was calculated based on a
human dose, as exemplified in Table 2, which may achieve a
temporary suppression of endogenous cortisol (greater than 50%)
and, within 14 days, achieve cortisol suppression of endogenous
cortisol of less than 35%. This calculated dose equals 178 mg of
microparticles containing 15 mg of fluticasone propionate. In a
second iteration of these data, the amount of fluticasone
propionate released per day was calculated based on a human dose,
as exemplified in Table 2 that would not suppress the HPA axis,
i.e. endogenous cortisol suppression never exceeding 35%. This
calculated dose equals 24 mg of microparticles containing 2 mg of
fluticasone propionate. These doses are both graphically
represented in FIGS. 36 and 37.
[0284] Other fluticasone propionate PLGA depots were formulated in
the same manner as described above with different PLGA polymers or
amounts fluticasone propionate. In one formulation, a PLGA polymer
with a higher lactide to glycolide ratio (PLGA 75:25 (ester
end-capped PLGA 75:25, lactide:glycolide molar ratio of 75:25, 0.58
dL/g, MW 86 kDa) was used instead of the PLGA 50:50 as previously
described. Unlike the triamcinolone acetonide preparations
described in Example 5, but typically expected as described in the
literature, the higher lactide to glycolide ratio resulted in a
slower release, where 30% release in 14 days, followed by a
substantial lag phase where little drug is released for a minimum
of thirty days. In another example, 400 mg of fluticasone
propionate instead of 200 mg was used in preparation of PLGA 50:50
microparticles (target drug load 28.6%). Unlike triamcinolone
acetonide microparticle preparations, the higher drug load did not
result in a significantly different release of fluticasone
propionate; FIG. 38 shows the in vitro release of all three
fluticasone propionate formulations.
[0285] Based on the studies described herein, the Class D
corticosteroid microparticle formulations, for example, the
fluticasone or fluticasone propionate microparticle formulations,
exhibiting the desired release kinetics have the following
characteristics: (i) the corticosteroid is between 8%-20% of the
microparticle, and (ii) the polymer is PLGA having a molecular
weight in the range of about 40 to 70 kDa, having an inherent
viscosity in the range of 0.35 to 0.5 dL/g, and or having a
lactide:glycolide molar ratio of 60:40 to 45:55.
Example 9
Preparation of Dexamethasone Microparticles by Solvent Dispersion
in PLGA
[0286] A pharmaceutical depot was prepared comprised of the
corticosteroid, dexamethasone (DEX,
9-Fluoro-11.beta.,17,21-trihydroxy-16.alpha.-methylpregna-1,4-diene-3,20--
dione) incorporated into microparticles in PLGA 50:50.
[0287] A formulation was prepared by dissolving approximately 1
gram of PLGA 50:50 (lactide:glycolide molar ratio of 50:50,
inherent viscosity 0.45 dL/g, molecular weight 66 kDa) in 6.67 mL
of dichloromethane (DCM). To the polymer solution, 200 mg of
dexamethasone was added and sonicated. Subsequently, the
corticosteroid containing dispersion was poured into 200 mL of 0.3%
polyvinyl alcohol (PVA) solution while homogenizing with a
Silverson homogenizer using a rotor fixed with a Silverson Square
Hole High Shear Screen.TM., set to spin at 2,000 rpm to form the
microparticles. After two minutes, the beaker was removed, and a
glass magnetic stirrer) added to the beaker, which was then placed
onto a multi-way magnetic stirrer and stirred for four hours at 300
rpm to evaporate the DCM. The microparticles were then washed with
2 liters of distilled water, sieved through a 100 micron screen.
The microparticles were then lyophilized for greater than 96 hours
and vacuum packed.
[0288] Particle size of the DEX incorporated microparticles was
determined using laser diffraction (Beckman Coulter LS 230) by
dispersing a 50 mg aliquot in water, with the refractive index (RI)
for water and PLGA, set at 1.33 and 1.46 respectively. The sample
was stirred at the particle size measurement measurements taken and
the results reported. Drug load was determined by suspending a
nominal 10 mg of microparticles in 8 ml HPLC grade methanol and
sonicating for 2 hours. Samples were then centrifuged at 14,000 g
for 15 mins before an aliquot of the supernatant was assayed via
HPLC as described below. Corticosteroid-loaded microparticle
samples, nominally 1 g were placed in 22 ml glass vials in 8-20 ml
of 0.5% v/v Tween 20 in 100 mM phosphate buffered saline and stored
in a 37.degree. C. incubator with magnetic stirring at 130 rpm.
Each test sample was prepared and analyzed in duplicate to monitor
possible variability. At each time point in the release study,
microparticles were allowed to settle, and an aliquot of between
4-16 ml of supernatant were taken, and replaced with an equal
volume of fresh 0.5% v/v Tween 20 in 100 mM phosphate buffered
saline. Drug load and in vitro release samples were analyzed by
HPLC using a Hypersil C18 column (100 mm, i.d. 5 mm, particle size
5 .mu.m; ThermoFisher) and Beckman HPLC. All samples were run using
a sample injection volume of 5 .mu.m, and column temperature of
40.degree. C. An isocratic mobile phase of 60% methanol and 40%
water was used at a flow rate of 1 ml/min, with detection at a
wavelength of 254 nm. The analytical results for the dexamethasone
PLGA microparticles are shown in Table 16.
TABLE-US-00017 TABLE 16 Analytical Results of a Nominal 28.6%
Dexamethasone PLGA 50:50 Microparticle Formulation PLGA
(lactide:glycolide molar ratio Drug ratio/inherent load viscosity/
(% Incor- molecular DEX poration weight/target % by efficiency
Particle size In vitro release FLUT/ weight) (%) (Dv, .mu.m) (%)
50:50 carboxylic 22.1 77.2 D0.1: 41.2 .mu.m 1 day: 2.9 acid
endcapped D0.5: 71.9 .mu.m 2 day: 4.6 0.45 dL/g D0.9: 99.1 .mu.m 3
day: 6.3 66 kDa 4 day: 8.7 28.6% DEX 5 day: 10.9 6 day: 12.7 7 day:
15.0 9 day: 16.4 11 day: 18.0 13 day: 20.7 15 day: 24.6 18 day:
26.2 21 day: 28.1 24 day: 30.3 27 day: 34.0 30 day: 46.3
[0289] In vitro cumulative percent release of the dexamethasone is
shown in 39, and results in suitable formulation for a minimum of
thirty days and, assuming linear release, likely up to 60 days.
[0290] In one iteration of the in vitro release data, the amount of
dexamethasone released per day was calculated based on a human
dose, as exemplified in Table 2, which may achieve a temporary
suppression of endogenous cortisol (greater than 50%) and, within
14 days, achieve cortisol suppression of endogenous cortisol of
less than 35%. In a second iteration of these data, the amount of
dexamethasone released per day was calculated based on a human
dose, as exemplified in Table 2 that would not suppress the HPA
axis, i.e. endogenous cortisol suppression never exceeding 35%. In
the case of dexamethasone, where the data is truncated, both
calculated human doses are the same; 36 mg of microparticles
containing 8 mg of dexamethasone. The doses are graphically
represented in FIG. 40.
Example 10
Pharmacology, Pharmacokinetics and Exploratory Safety Study of
Corticosteroid Formulations
[0291] In an exploratory safety study in rats, single
intra-articular (IA) doses of TCA immediate release (TCA IR) (0.18
and 1.125 mg) and doses of TCA in 75:25 PLGA formulation
microparticles (FX006) (0.28, 0.56 and 1.125 mg (i.e., the maximum
feasible dose) of TCA) were evaluated. Blood samples were collected
at various time points for determination of plasma concentrations.
Plasma concentration-time data from this study and pharmacokinetic
(PK) analysis thereof are shown in FIGS. 41-43 and Tables
17-20.
[0292] As seen in FIGS. 41A-41D, FX006 dosed at 1.125 mg resulted
in a very slow absorption of TCA in the systemic circulation and a
markedly lower C.sub.max as compared to TCA IR.
[0293] As shown in Table 17, the mean AUC.sub.0-t values of TCA
following 1.125 mg administration of FX006 were 2.1-fold lower than
those observed for TCA IR (i.e., 2856 vs. 6065 ngh/mL,
respectively). The mean C.sub.max values of TCA following 1.125 mg
administration of FX006 were 15-fold lower than those observed for
TCA IR (i.e., 125 vs. 8.15 ng/mL, respectively). The absorption of
TCA following administration of FX006 was slower than that observed
for TCA IR, with mean T.sub.max values observed at 3.33 and 1.00 h,
respectively. The elimination half-life of TCA following
administration of 1.125 mg FX006 and TCA IR were 451 and 107 h,
respectively.
TABLE-US-00018 TABLE 17 Summary of TCA Plasma Pharmacokinetic
Parameters Treatment FX006 (0.28 mg) FX006 (0.56 mg) FX006 (1.125
mg) TCA IR (0.18 mg) TCA IR (1.125 mg) Variable Mean (CV %) Mean
(CV %) Mean (CV %) Mean (CV %) Mean (CV %) AUC.sub.0-24 31.0 (76.0)
33.0 (19.1) 136 (6.0) 297 (21.5) 1403 (13.2) (ng h/mL) AUC.sub.0-
356 (62.0) 572 (21.5) 2856 (17.2) 479 (32.6) 6065 (3.7) (ng h/mL)
AUC.sub.0-t 335 (66.5) 532 (23.8) 2142 (14.4) 456 (31.3) 6013 (3.4)
(ng h/mL) CL/F 1308 (96.6) 1014 (24.4) 403 (19.1) 400 (27.6) 186
(3.6) (mL/h) C.sub.max 1.82 (66.2) 1.91 (10.2) 8.15 (12.5) 41.6
(25.1) 125 (5.3) (ng/mL) T 99.5 (39.9) 180 (27.0) 451 (20.8) 35.6
(63.5) 107 (56.7) (h) T 17.7 (148.9) 16.7 (162.8) 3.33 (69.3) 2.00
(0.0) 1.00 (0.0) (h) V.sub.cc/F 274215 (117.0) 326966 (30.2) 240481
(17.7) 12069 (53.4) 23829 (34.4) (mL) indicates data missing or
illegible when filed
[0294] The above results suggest a slower distribution and
bioavailability of TCA in the systemic circulation following
administration of FX006 as compared to TCA IR. Without wishing to
be bound by theory, the slower distribution FX006 into the systemic
circulation may be related to the longer residence time of FX006 at
the site of injection. This is supported by the lesser availability
of the FX006 microparticle formulation in the early "burst" phase,
where only 4-9% of product is released, compared to at least 23% of
the IR product.
[0295] Bioavailability of TCA in the systemic circulation following
administration of FX006 was 3-fold lower than that observed for TCA
IR, as shown in Table 18.
TABLE-US-00019 TABLE 18 Bioavailability of TCA in Plasma Absolute
Bioavailability Comparison FX006 (0.28 mg) TCA IR (0.18 mg)
F.sub.abs (%) 17.9 58.6
[0296] For the 0.56 and 1.125 mg dose levels of FX006, apparent F %
were 23.1% and 58.1%, respectively. The IV data in rats shown in
Table 19 was used as a reference to calculate F.
TABLE-US-00020 TABLE 19 Pharmacokinetic Parameters of TCA in Rat
Plasma After i.v. (50 mg/kg bolus + 23 mg/kg/h Infusion)
Administration of Triamcinolone Acetonide Phosphate Parameter Rat 1
Rat 2 Rat 3 Mean .+-. SD V.sub.c (L/kg) 0.684 0.856 1.29 0.944 .+-.
0.314 CL (L/h/kg) 1.15 0.790 0.872 0.937 .+-. 0.188 k.sub.12
(h.sup.1) 1.64 1.79 1.59 11.67 .+-. 0.102 k.sub.21 (h.sup.1) 1.04
0.640 1.13 0.937 .+-. 0.261 T.sub.1/2.beta. (h) 1.55 3.71 2.87 2.71
.+-. 1.09 f.sub.u 0.084 0.110 0.085 0.093 .+-. 0.015
[0297] from Rojas et al., "Microdialysis of triamcinolone acetonide
in rat muscle." J Pharm Sci 92(2) (2003):394-397.
[0298] The initial "burst" (i.e., exposure up to 24 h) accounted
for less than 10% of the total systemic exposure of FX006. The
initial burst accounted for .about.23-62% of the total exposure for
the TCA IR product, as shown in Table 20.
TABLE-US-00021 TABLE 20 Relative Availability of TCA in Plasma
(Initial Burst vs. Delayed Release) Treatment FX006 (0.28 mg) FX006
(0.56 mg) FX006 (1.125 mg) TCA IR (0.18 mg) TCA IR (1.125 mg)
Variable Mean Mean Mean Mean Mean AUC.sub.0-24 (ng h/mL) 31.0 33.0
136 297 1403 AUC.sub.0-.infin. (ng h/mL) 356 572 2856 479 6065
AUC.sub.24- (ng h/mL) 325 539 2720 182 4662 % Initial Burst 8.69
5.76 4.76 62.1 23.1 indicates data missing or illegible when
filed
[0299] In this same study, groups of animals were sacrificed 28
days after dosing, and the remaining were terminated on Day 42.
Body weights were monitored throughout the study and key organs
(spleen, adrenal glands, thymus) were weighed upon necropsy. The
injected knee and the contralateral control joints were prepared
for histological assessment. Toluidine blue stained sections of
joints were evaluated for treatment-related alterations. Histologic
changes were described, wherever possible, according to their
distribution, severity, and morphologic character.
[0300] Histological analysis demonstrated the following
observations. First, injected joints from placebo (blank PLGA
microspheres)-treated animals had minimal multifocal macrophage
infiltration in associated with 20-130 .mu.m diameter microspheres,
whereas none of the active FX006-injected joints showed the
presence of any microspheres at Day 28. Placebo-treated rat joints
had no cartilage or joint changes save for the presence of
spontaneous cartilage cysts in a few joints (1 at Day 28, 2 at Day
42) in the right (injected) knees. The left knees in the
placebo-treated rat joints were normal. In comparison, both knees
in the high dose TCA IR and the high and mid-dose FX006--groups
showed some mild bone marrow hypocellularity and growth plate
atrophy (dose dependent for FX006). Both knees in the low dose TCA
IR and FX006 animals were normal. Spontaneous cartilage cysts noted
in placebo animals were also noted in all groups dosed with FX006
with no increase in incidence or severity. High dose TCA IR
increased cartilage cysts at Day 42 but not at Day 28. In general,
FX006-treated animals had normal articular cartilage despite the
presence of catabolic effects on other joint structures, which was
likely more readily observed on account of the young age of the
animals.
[0301] Overall, all observed effects of FX006, especially at the
high dose, such as body weight loss and reduced organ weights were
also seen with TCA IR. The time course of inhibition of the HPA
axis (measured as corticosterone levels) is shown in FIG. 42. It
should be noted that at the lowest dose of FX006 (0.28 mg; circles)
corticosterone levels were initially inhibited but recovered back
to near baseline by Day 14 post-dose. Similarly, with TCA IR at the
lowest dose (0.18 mg), corticosterone levels recovered by Day 7
(squares). With the mid (0.56 mg) and high (1.125 mg) doses of
FX006 and the high dose of TCA IR (1.125 mg), corticosterone levels
were inhibited longer as shown in FIG. 42.
[0302] A PK-PD analysis demonstrated that inhibition of
corticosterone was correlated with systemic TCA levels and followed
a classical inhibitory model as shown in FIG. 43. The IC.sub.50 was
about 1 ng/mL and the E.sub.max was achieved at 50-80 ng/mL.
Example 11
Evaluation of Efficacy of Single Doses of TCA Immediate Release and
TCA Microparticle Formulation in Animal Model of Osteoarthritis
[0303] The studies described herein were designed to test and
evaluate the efficacy of the corticosteroid microparticle
formulations provided herein as compared to immediate release
corticosteroid formulations. While the studies herein use TCA, it
is understood that other corticosteroids, including other Class B
corticosteroids, Class A corticosteroids, Class C corticosteroids,
and Class D corticosteroids, can be evaluated using these
materials, methods and animal models.
[0304] Efficacy of single intra-articular (IA) doses of FX006 (TCA
in 75:25 PLGA formulation microparticles) and TCA IR (immediate
release) was evaluated in a rat model of osteoarthritis of the knee
via sensitization and challenge by peptidoglycan polysaccharide
(PGPS). The model involves priming the animals with an
intra-articular injection of PGPS in the right knee. The following
day, any animals with no knee discomfort were eliminated from the
test article groups and placed into the baseline group. Two weeks
later, knee inflammation was reactivated by a tail vein injection
of PGPS, 2.5 hr following IA dosing with FX006 or TCA IR at the
doses selected (n=10/group). Differences in weight-bearing and gait
(as a measure of joint pain experienced by the animals),
histopathology, plasma PK etc. were evaluated.
[0305] Doses of FX006 (0.28, 0.12, 0.03 mg) and TCA IR (0.06, 0.03
mg) for this study were selected based on data from the study
described above in Example 10 and an initial run of the PGPS model
in which only TCA IR was evaluated at two IA dose levels. The goals
of the present study were to demonstrate the following: [0306]
FX006 is efficacious at doses that do not inhibit the HPA axis
[0307] The duration of efficacy is a function of dose [0308] FX006
provides more prolonged pain relief as compared to TCA IR--Since
only about 10% of the TCA payload is expected to be released from
FX006 in the first 24 hr, one TCA IR dose group (0.03 mg) was
chosen to match 10% of the TCA in FX006 at a dose of 0.28 mg [0309]
Effects of matched doses of FX006 and TCA IR (0.03 mg)
[0310] The duration of efficacy was assessed by 3 different
reactivations, 2 weeks apart. After that point, the arthritis
observed in the animals becomes more wide-spread making the
efficacy in the index knee more difficult to assess.
[0311] At the first reactivation, vehicle treated animals
demonstrate painful gait as demonstrated by high pain scores (3.5
out of a maximum of 4 possible) as shown in FIGS. 44A, 44B, and
44C. FX006 at 0.28 mg (squares) showed good efficacy. In the
previous study described in Example 10, this dose was demonstrated
to inhibit the HPA axis immediately after dosing but a return to
baseline function was demonstrated by Day 14. Interestingly, this
dose of FX006 continued to be efficacious upon the 2.sup.nd and
3.sup.rd reactivations on Days 14 and 28 when the HPA axis function
was presumably normal. It should also be noted that since HPA axis
function returned to baseline by Day 7 at a 0.18 mg dose of TCA IR
in the previous study described in Example 10, the effects of the
doses of TCA IR used in the present study (0.06 and 0.03 mg) were
also in the presence of normal HPA axis function following an
initial transient inhibition. Corticosterone measurements from the
present study (as an indicator of HPA axis function) are presented
as change from baseline for each treatment group in FIG. 46. As
demonstrated from these data, corticosterone levels for all groups
recovered by Day 14; hence the goal of prolonged efficacy with
FX006 in the presence of normal HPA axis function was achieved.
[0312] Overall, a clear dose-dependence of response was noted for
both FX006 and TCA IR. Also, if less than 10% of this dose is
available by the day after dosing (Day 1), it should be noted in
FIG. 44B that the efficacy of FX006 at 0.28 mg (squares) is greater
than TCA IR at 0.03 mg (triangles) at all evaluations. Further, the
duration of efficacy of TCA (both FX006 and IR) appears to be a
function of dose, however, the prolonged release of TCA from the
PLGA microspheres in FX006 results in more sustained efficacy. This
is more clearly depicted in another representation of the data in
FIG. 45 in which peak response for each dose as determined by
gait/pain scores on Day 1 following each reactivation (Days 1, 15
and 29) are plotted. FIG. 46 plots the time course of
corticosterone recovery for all study groups. On balance, across
all groups that received the corticosteroid, there was
recovery.
[0313] Plasma levels of TCA were measured in samples taken from all
rats at baseline (Day -4), Days 0 (2 hr post dosing), 1, 3, 8, 14,
17, 21, 28, and 31. Concentration-time curves for all treatment
groups are shown in FIG. 47A. FIG. 47B shows only the FX006 dose
groups on a larger scale since maximal plasma concentrations with
FX006 were far lower than those with TCA IR.
[0314] Histopathological evaluation of the knees taken from all
animals at the end of the study (Day 32 at the end of the 3.sup.rd
reactivation of arthritis) demonstrated statistically significant
improvement by FX006 at the high and mid-range doses (0.28 and 0.12
mg) in the composite histological score and each component score
(inflammation, pannus, cartilage damage and bone resorption) as
shown in FIG. 48. As described above, the dose of 0.28 mg FX006
demonstrated strong efficacy (i.e. analgesic activity) throughout
all 3 reactivations, whereas the dose of 0.12 mg was active but to
a lesser degree through all 3 reactivations. At the doses of TCA IR
used, the duration of efficacy was mostly through the first
reactivation of arthritis, with partial efficacy of the higher
(0.06 mg) dose in the second reactivation, and this also translated
into a much smaller non-significant improvement in histological
scores. Importantly, these data demonstrate that TCA has no
deleterious effect on cartilage and as has been described in other
settings, it actually reduces cartilage damage in an inflammatory
milieu.
[0315] In conclusion, the prolonged residence of TCA in the joint
upon IA dosing with FX006 resulted in extending the duration of
efficacy in the rat PGPS model of arthritis with a significant
histological improvement in inflammation, pannus formation,
cartilage damage and bone resorption. FX006 had these effects
without inhibiting HPA axis function as demonstrated by the return
to baseline of corticosterone levels within 14 days after dosing.
The clinical implications for the treatment of patients with
osteoarthritis, rheumatoid arthritis and other inflammatory joint
disorders are as follows: [0316] Intra-articular injection of
sustained release corticosteroid microparticle formulations
provides prolonged pain relief relative to intra-articular
injection of immediate release steroids. [0317] Intra-articular
injection of sustained release corticosteroid microparticle
formulations is efficacious in reducing pain and inflammation at
doses that do not inhibit the HPA axis. [0318] The duration of
efficacy of sustained release of intra-articular corticosteroid
microparticle formulations is a function of dose. [0319]
Intra-articular injection of sustained release corticosteroid
microparticle formulations slows, arrests, reverses, or otherwise
inhibits structural damage to tissues caused by inflammation.
Example 12
Preparation of Triamcinolone Acetonide Mixed Molecular Weight PLGA
Microparticles by Solid in Oil in Water (S/O/W) Emulsion (Ninety
Day Formulations)
[0320] A pharmaceutical depot for Ninety-Day sustained release
formulations was prepared comprised of the corticosteroid,
triamcinolone acetonide (TCA,
9.alpha.-Fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxy-1,4-pregnadi-
ene-3,20-dione 16,17-acetonide;
9.alpha.-Fluoro-16.alpha.-hydroxyprednisolone
16.alpha.,17.alpha.-acetonide) incorporated into
microparticles.
[0321] These 90-day formulations were prepared by dissolving
approximately 1 gram of PLGA in 6.67 mL or 4.5 mL of
dichloromethane (DCM), to form a 15% % or 20% PLGA w/v solution. To
the polymer solution, 110 to 140 mg of triamcinolone acetonide was
added and sonicated. Subsequently, the corticosteroid containing
dispersion was poured into 200 mL of 0.3% polyvinyl alcohol (PVA)
solution while homogenizing with a Silverson homogenizer using a
rotor fixed with a Silverson Square Hole High Shear Screen.TM., set
to rotate at approximately 2,000 rpm to 3000 rpm to form the
microparticles. After two minutes, the beaker was removed, and a
glass magnetic stirrer) added to the beaker, which was then placed
onto a multi-way magnetic stirrer and stirred for four hours at 300
rpm to evaporate the DCM. The microparticles were then washed with
2 liters of distilled water, sieved through a 100 micron screen.
The microparticles were then lyophilized for greater than 96 hours
and vacuum packed.
[0322] Particle size of the TCA incorporated microparticles was
determined using laser diffraction (Beckman Coulter LS 230) by
dispersing a 50 mg aliquot in water, with the refractive index (RI)
for water and PLGA, set at 1.33 and 1.46 respectively. The sample
was stirred at the particle size measurement measurements taken and
the results reported. Drug load was determined by suspending a
nominal 10 mg of microparticles in 8 ml HPLC grade methanol and
sonicating for 2 hours. Samples were then centrifuged at 14,000 g
for 15 mins before an aliquot of the supernatant was assayed via
HPLC as described below. Corticosteroid-loaded microparticle
samples, nominally 1 g were placed in 22 ml glass vials in 8-20 ml
of 0.5% v/v Tween 20 in 100 mM phosphate buffered saline and stored
in a 37.degree. C. incubator with magnetic stirring at 130 rpm.
Each test sample was prepared and analyzed in duplicate to monitor
possible variability. At each time point in the release study,
microparticles were allowed to settle, and an aliquot of between
4-16 ml of supernatant were taken, and replaced with an equal
volume of fresh 0.5% v/v Tween 20 in 100 mM phosphate buffered
saline. Drug load and in vitro release samples were analyzed by
HPLC using a Hypersil C18 column (100 mm, i.d. 5 mm, particle size
5 .mu.m; ThermoFisher) and Beckman HPLC. All samples were run using
a sample injection volume of 5 .mu.m, and column temperature of
40.degree. C. An isocratic mobile phase of 60% methanol and 40%
water was used at a flow rate of 1 ml/min, with detection at a
wavelength of 254 nm.
[0323] In suitable ninety day formulations, the PLGA is a
combination of ester end capped PLGA 8 E (lactide:glycolide molar
ratio of 75:25, inherent viscosity of 0.81 dL/g and molecular
weight of 129 kDa) with PLGA 3.5 E (lactide:glycolide molar ratio
of 75:25, inherent viscosity of 0.36 dL/g and molecular weight of
49 kDa) in a 2:1 ratio. The analytical results for these
formulations are shown in Table 21, and the TCA cumulative release
profiles are shown in FIGS. 49 and 52.
TABLE-US-00022 TABLE 21 Analytical Results of a Nominal 10%
Triamcinolone Acetonide in Mixed Molecular Weight PLGA 75:25
Microparticle Ninety Day Formulation PLGA (lactide:glycolide molar
ratio/inherent Drug Incor- viscosity/ load poration molecular (%
TCA effi- weight/target % by ciency Particle size In vitro release
TCA/% PEG weight) (%) (Dv, .mu.m) (%) 75:25 ester 9.8 96.9 D0.1:
17.4 .mu.m 1 day: 2.6 endcapped D0.5: 40.6 .mu.m 2 day: 5.0 (0.81
dl/g D0.9: 66.7 .mu.m 3 day: 7.2 129 kDa and 4 day: 9.4 0.36 dL/g
49 kDa 6 day: 11.7 mixture 7 day: 15.6 10% TCA 9 day: 17.7 15% PLGA
12 day: 19.9 solution 16 day: 22.7 20 day: 26.3 24 day: 30.0 30
day: 35.2 35 day: 41.5 42 day: 47.5 49 day: 52.3 56 day 55.8 63
day: 58.6 70 day: 63.0 77 day: 72.9 84 day: 75.4 91 day: 78.4 75:25
ester 8.5 84.6 D0.1: 19.7 .mu.m 1 day: 2.3 endcapped D0.5: 40.1
.mu.m 2 day: 5.7 (0.81 dl/g D0.9: 62.5 .mu.m 3 day: 8.2 129 kDa and
4 day: 10.8 0.36 dL/g 49 kDa 6 day: 13.3 mixture 7 day: 16.0 10%
TCA 9 day: 19.3 20% PLGA 12 day: 24.5 solution 16 day: 31.0 20 day:
36.8 24 day: 40.8 30 day: 47.8 35 day: 53.9 42 day: 61.2 49 day:
65.3 56 day: 69.0 63 day: 71.8 70 day: 75.9 77 day: 81.1 84 day:
83.6 91 day: 87.3
[0324] In one iteration of the in vitro release data for the 15%
PLGA emulsion, the amount of TCA released per day was calculated
based on a human dose, as exemplified in Table 2, which may achieve
a temporary suppression of endogenous cortisol (greater than 50%)
and, within 14 days, achieve cortisol suppression of endogenous
cortisol of less than 35% (FIG. 50). This calculated dose equal 769
mg of microparticles containing 75 mg of TCA. In a second iteration
of these data, the amount of TCA released per day was calculated
based on a human dose, as exemplified in Table 2, that would not
have an suppress the HPA axis, i.e. endogenous cortisol suppression
more than 35% (FIG. 51). This calculated dose equals 410 mg of
microparticles containing 40 mg of TCA.
[0325] In one iteration of the in vitro release data for the 20%
PLGA emulsion, the amount of TCA released per day was calculated
based on a human dose, as exemplified in Table 2, which may achieve
a temporary suppression of endogenous cortisol (greater than 50%)
and, within 14 days, achieve cortisol suppression of endogenous
cortisol of less than 35% (FIG. 53). This calculated dose equal 909
mg of microparticles containing 77 mg of TCA. In a second iteration
of these data, the amount of TCA released per day was calculated
based on a human dose, as exemplified in Table 2, that would not
have an suppress the HPA axis, i.e. endogenous cortisol suppression
more than 35% (FIG. 54). This calculated dose equals 483 mg of
microparticles containing 41 mg of TCA.
Example 12
Preparation of Budesonide PLGA Microparticles by Solid in Oil in
Water (S/O/W) Emulsion (Thirty Day Formulation)
[0326] A pharmaceutical depot was prepared comprised of the
corticosteroid, budesonide
((RS)-11.beta.,16.alpha.,17,21-tetrahydroxypregna-1,4-diene-3,20-dione
cyclic 16,17-acetal) incorporated into microparticles.
[0327] Formulations were prepared by dissolving approximately 1
gram of PLGA in 6.67 mL of ethyl acetate, to form a PLGA solution.
To the polymer solution, 400 mg of budesonide was added and
sonicated. Subsequently, the corticosteroid containing dispersion
was poured into 200 mL of 0.3% polyvinyl alcohol (PVA) solution
while homogenizing with a Silverson homogenizer using a rotor fixed
with a Silverson Square Hole High Shear Screen.TM., set to rotate
at approximately 4,000 rpm to 6000 rpm to form the microparticles.
After two minutes, the beaker was removed, and a glass magnetic
stirrer) added to the beaker, which was then placed onto a
multi-way magnetic stirrer and stirred for four hours at 300 rpm to
evaporate the ethyl acetate. The microparticles were then washed
with 2 liters of distilled water, sieved through a 100 micron
screen. The microparticles were then lyophilized for greater than
96 hours and vacuum packed.
[0328] Particle size of the budesonide incorporated microparticles
was determined using laser diffraction (Beckman Coulter LS 230) by
dispersing a 50 mg aliquot in water, with the refractive index (RI)
for water and PLGA, set at 1.33 and 1.46 respectively. The sample
was stirred at the particle size measurement measurements taken and
the results reported. Drug load was determined by suspending a
nominal 10 mg of microparticles in 8 ml HPLC grade methanol and
sonicating for 2 hours. Samples were then centrifuged at 14,000 g
for 15 mins before an aliquot of the supernatant was assayed via
HPLC as described below. Corticosteroid-loaded microparticle
samples, nominally 1 g were placed in 22 ml glass vials in 8-20 ml
of 0.5% v/v Tween 20 in 100 mM phosphate buffered saline and stored
in a 37.degree. C. incubator with magnetic stirring at 130 rpm.
Each test sample was prepared and analyzed in duplicate to monitor
possible variability. At each time point in the release study,
microparticles were allowed to settle, and an aliquot of between
4-16 ml of supernatant were taken, and replaced with an equal
volume of fresh 0.5% v/v Tween 20 in 100 mM phosphate buffered
saline. Drug load and in vitro release samples were analyzed by
HPLC using a Hypersil C18 column (100 mm, i.d. 5 mm, particle size
5 .mu.m; ThermoFisher) and Beckman HPLC. All samples were run using
a sample injection volume of 5 .mu.m, and column temperature of
40.degree. C. An isocratic mobile phase of 60% methanol and 40%
water was used at a flow rate of 1 ml/min, with detection at a
wavelength of 254 nm.
[0329] In suitable thirty day formulations, the PLGA is an acid end
capped PLGA 4.5 A (lactide:glycolide molar ratio of 75:25, inherent
viscosity of 0.44 dL/g and molecular weight of 57 kDa). The
analytical results for these formulations are shown in Table 22,
and the cumulative release profile is shown in FIG. 55.
TABLE-US-00023 TABLE 22 Analytical Results of a Nominal 25%
Budesonide in PLGA 75:25 Microparticle Thirty Day Formulation PLGA
(lactide:glycolide molar ratio ratio/inherent Drug load Incor-
viscosity/ (% poration molecular Budesonide effi- weight/target %
by ciency Particle size In vitro Budesonide weight) (%) (Dv, .mu.m)
release (%) 75:25 acid 23.2 93.2 D0.1: 19 .mu.m 1 day: 0.0
endcapped D0.5: 43.3 .mu.m 3 day: 2.9 0.44 dl/g D0.9: 70.6 .mu.m 4
day: 7.0 57 kDa 5 day: 11.5 25% Budesonide 6 day: 16.3 7 day: 21.9
9 day: 27.6 11 day: 34.6 13 day: 40.4 15 day: 45.2 18 day: 50.0 21
day: 54.7 24 day: 60.5 27 day: 66.5 30 day: 70.3
[0330] In one iteration of the in vitro release data, the amount of
budesonide released per day was calculated based on a human dose,
as exemplified in Table 2, which may achieve a temporary
suppression of endogenous cortisol (greater than 50%) and, within
14 days, achieve cortisol suppression of endogenous cortisol of
less than 35% (FIG. 56). This calculated dose equal 175 mg of
microparticles containing 41 mg of budesonide. In a second
iteration of these data, the amount of budesonide released per day
was calculated based on a human dose, as exemplified in Table 2,
that would not have an suppress the HPA axis, i.e. endogenous
cortisol suppression more than 35% (FIG. 57). This calculated dose
equals 91 mg of microparticles containing 21 mg of budesonide.
[0331] Although particular embodiments have been disclosed herein
in detail, this has been done by way of example for purposes of
illustration only, and is not intended to be limiting with respect
to the scope of the appended claims, which follow. In particular,
it is contemplated by the inventors that various substitutions,
alterations, and modifications may be made to the invention without
departing from the spirit and scope of the invention as defined by
the claims. Other aspects, advantages, and modifications are
considered to be within the scope of the following claims. The
claims presented are representative of the inventions disclosed
herein. Other, unclaimed inventions are also contemplated.
Applicants reserve the right to pursue such inventions in later
claims.
* * * * *