U.S. patent application number 11/741366 was filed with the patent office on 2007-09-27 for low immunogenicity corticosteroid compositions.
Invention is credited to James N. Chang, Sam W. Lam, Robert T. Lyons, Michael R. Robinson, John T. Trogden, Scott M. Whitcup.
Application Number | 20070224278 11/741366 |
Document ID | / |
Family ID | 39101654 |
Filed Date | 2007-09-27 |
United States Patent
Application |
20070224278 |
Kind Code |
A1 |
Lyons; Robert T. ; et
al. |
September 27, 2007 |
LOW IMMUNOGENICITY CORTICOSTEROID COMPOSITIONS
Abstract
Triamcinolone compositions, and methods of using such
compositions, useful for injection into the vitreous of human eyes
or into a joint are provided. Such compositions can include
triamcinolone particles present in a therapeutically effective
amount, a viscosity inducing component, and an aqueous carrier
component. The compositions have viscosities of at least about 10
cps or about 100 cps at a shear rate of 0.1/second. In a preferred
embodiment, the viscosity is in the range of from about 80,000 cps
to about 300,000 cps. In a most preferred embodiment, the viscosity
is in the range of from about 140,000 cps to about 280,000 cps t a
shear rate of 0.1/second at 25.degree. C. The compositions
advantageously suspend the triamcinolone particles for prolonged
periods of time.
Inventors: |
Lyons; Robert T.; (Laguna
Hills, CA) ; Robinson; Michael R.; (Irvine, CA)
; Chang; James N.; (Newport Beach, CA) ; Lam; Sam
W.; (Oceanside, CA) ; Trogden; John T.;
(Anaheim, CA) ; Whitcup; Scott M.; (Laguna Hills,
CA) |
Correspondence
Address: |
ALLERGAN, INC.
2525 DUPONT DRIVE, T2-7H
IRVINE
CA
92612-1599
US
|
Family ID: |
39101654 |
Appl. No.: |
11/741366 |
Filed: |
April 27, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11354415 |
Feb 14, 2006 |
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11741366 |
Apr 27, 2007 |
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10966764 |
Oct 14, 2004 |
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11354415 |
Feb 14, 2006 |
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60519237 |
Nov 12, 2003 |
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60530062 |
Dec 16, 2003 |
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Current U.S.
Class: |
424/489 ;
514/169 |
Current CPC
Class: |
A61K 9/0048 20130101;
A61K 31/715 20130101; A61K 47/02 20130101; A61K 31/58 20130101;
A61K 31/573 20130101; A61K 31/56 20130101; A61P 29/00 20180101;
A61K 47/36 20130101; A61K 9/0019 20130101; A61K 47/40 20130101;
A61P 19/02 20180101; A61K 47/34 20130101 |
Class at
Publication: |
424/489 ;
514/169 |
International
Class: |
A61K 9/14 20060101
A61K009/14; A61K 31/56 20060101 A61K031/56 |
Claims
1. A pharmaceutical composition for treating a posterior ocular
condition, the pharmaceutical composition comprising: (a) a
plurality of corticosteroid particles mixed with; (b) a viscous
polymer, wherein the pharmaceutical composition has a viscosity of
between about 130,000 cps and about 300,000 cps at a shear rate of
about 0.1/second at about 25.degree. C., and the pharmaceutical
composition can be injected into the vitreous of a human eye
through a 25 to 33 gauge needle.
2. The pharmaceutical composition of claim 1, wherein the
corticosteroid particles have a substantially uniform diameter.
3. The pharmaceutical composition of claim 1, wherein substantially
all the corticosteroid particles are embedded within the viscous
polymer.
4. The pharmaceutical composition of claim 1, wherein the
corticosteroid is a triamcinolone.
5. The pharmaceutical composition of claim 1, wherein the viscous
polymer is a polymeric hyaluronate or a polymeric hyaluronic
acid.
6. A pharmaceutical composition for treating a posterior ocular
condition, the composition comprising: (a) a plurality of
triamcinolone particles with a substantially uniform diameter, and;
(b) a viscous polymeric hyaluronate or polymeric hyaluronic acid,
wherein the pharmaceutical composition has a viscosity of between
about 130,000 cps and about 300,000 cps at a shear rate of about
0.1/second at about 25.degree. C. and can be injected into the
vitreous of a human eye through a 25 to 33 gauge needle, wherein
the triamcinolone particles are mixed with the viscous polymer
substantially all the corticosteroid particles are embedded within
and coated by the viscous polymeric hyaluronate or a polymeric
hyaluronic acid.
7. A method for treating a posterior ocular condition, the method
comprising the step of injecting into the vitreous of a patient's
eye with a posterior ocular condition a viscous pharmaceutical
composition comprising a plurality of corticosteroid particles
mixed into a viscous polymeric matrix, wherein the pharmaceutical
composition has a viscosity of between about 130,000 cps and about
300,000 cps at a shear rate of about 0.1/second at about 25.degree.
C., such that about one hour after the intravitreal injection only
about 10% or less of the corticosteroid particles are present in
the vitreous free of the polymeric matrix.
8. The method of claim 7, wherein about one hour after the
intravitreal injection only about 5% or less of the corticosteroid
particles are present in the vitreous free of the is polymeric
matrix.
9. The method of claim 7, wherein about one hour after the
intravitreal injection only about 3% or less of the corticosteroid
particles are present in the vitreous free of the polymeric
matrix.
10. A process for making an intraocular pharmaceutical composition,
the method comprising the step of mixing an aqueous suspension of a
plurality of corticosteroid particles and an aqueous solution of a
viscous polymeric matrix, so that the resulting pharmaceutical
composition has a viscosity of between about 130,000 cps and about
300,000 cps at a shear rate of about 0.1/second at about 25.degree.
C.
11. The process of claim 10, wherein the corticosteroid particles
have a median particle size of between about 4 microns and about 5
microns.
12. The process of claim 10, wherein the corticosteroid particles
have a stable diameter for at least three months after the
pharmaceutical has been made and stored for three months in a
syringe placed horizontally at about 25.degree. C. at about 60%
relative humidity.
13. The pharmaceutical composition made by the method of claim
10.
14. A pharmaceutical composition for treating an articular
pathology, the pharmaceutical composition comprising: (a) a
plurality of corticosteroid particles mixed with; (b) a viscous
polymer, wherein the pharmaceutical composition has a viscosity of
between about 130,000 cps and about 300,000 cps at a shear rate of
about 0.1/second at about 25.degree. C.,
15. A method for treating an articular pathology, the method
comprising the step of is injecting into a joint of a patient with
an articular pathology a viscous pharmaceutical composition
comprising a plurality of corticosteroid particles mixed into a
viscous polymeric matrix, wherein the pharmaceutical composition
has a viscosity of between about 130,000 cps and about 300,000 cps
at a shear rate of about 0.1/second at about 25.degree. C.
Description
CROSS REFERENCE
[0001] This application is a continuation in part of application
Ser. No. 11/354,415, filed Feb. 14, 2006, which is a continuation
in part of application Ser. No. 10/966,764, filed Oct. 14, 2004,
which application claims the benefit of provisional patent
application Ser. No. 60/519,237, filed Nov. 12, 2003 and
provisional is patent application Ser. No. 60/530,062, filed Dec.
16, 2003, all of which applications are hereby incorporated herein
by reference in their entireties.
BACKGROUND
[0002] The present invention relates to corticosteroid compositions
and methods for treating and/or preventing ocular conditions, such
as anterior ocular conditions and posterior ocular conditions, as
well as for treating various articular pathologies. In particular
the present invention relates to extended release and sustained
release triamcinolone compositions, including injectable implants,
for treating posterior ocular conditions, as well as for treating
joint inflammation and/or joint pain.
[0003] A pharmaceutical composition (synonymously a composition) is
a formulation which contains at least one active ingredient (for
example a corticosteroid such as a triamcinolone) as well as, for
example, one or more excipients, buffers, carriers, stabilizers,
preservatives and/or bulking agents, and is suitable for
administration to a patient to achieve a desired effect or result.
The pharmaceutical compositions disclosed herein can have
diagnostic, therapeutic, cosmetic and/or research utility in
various species, such as for example in human patients or
subjects.
[0004] An ocular condition can include a disease, aliment or
condition which affects or involves the eye or one of the parts or
regions of the eye. Broadly speaking the eye includes the eyeball
and the tissues and fluids which constitute the eyeball, the
periocular muscles (such as the oblique and rectus muscles) and the
portion of the optic nerve which is within or adjacent to the
eyeball. An anterior ocular condition is a disease, ailment or
condition which affects or which involves an anterior (i.e. front
of the eye) ocular region or site, such as a periocular muscle, an
eye lid or an eye ball tissue or fluid which is located anterior to
the posterior wall of the lens capsule or ciliary muscles. Thus, an
anterior ocular condition primarily affects or involves, the
conjunctiva, the cornea, the conjunctiva, the anterior chamber, the
iris, the posterior chamber (behind the retina but in front of the
posterior wall of the lens capsule), the lens or the lens capsule
and blood vessels and nerve which vascularize or innervate an
anterior ocular region or site. A posterior ocular (also referred
to herein synonymously as a "posterior segment") condition is a
disease, ailment or condition which primarily affects or involves a
posterior ocular region or site such as choroid or sclera (in a
position posterior to a plane through the posterior wall of the
lens capsule), vitreous, vitreous chamber, retina, optic nerve
(i.e. the optic disc), and blood vessels and nerves which
vascularize or innervate a posterior ocular (or posterior segment)
region or site.
[0005] Thus, a posterior ocular condition can include a disease,
ailment or condition, such as for example, macular degeneration
(such as non-exudative age related macular degeneration and
exudative age related macular degeneration); choroidal
neovascularization; acute macular neuroretinopathy; macular edema
(such as cystoid macular edema and diabetic macular edema);
Behcet's disease, retinal disorders, diabetic retinopathy
(including proliferative diabetic retinopathy); retinal arterial
occlusive disease; central retinal vein occlusion; uveitis
(including intermediate and anterior uveitis); retinal detachment;
ocular trauma which affects a posterior ocular site or location; a
posterior ocular condition caused by or influenced by an ocular
laser treatment; posterior ocular conditions caused by or
influenced by a photodynamic therapy; photocoagulation; radiation
retinopathy; epiretinal membrane disorders; branch retinal vein
occlusion; anterior ischemic optic neuropathy; non-retinopathy
diabetic retinal dysfunction, retinitis pigmentosa and glaucoma.
Glaucoma can be considered a posterior ocular condition because a
therapeutic goal can be to prevent the loss of or reduce the
occurrence of loss of vision due to damage to or loss of retinal
cells or optic nerve cells (i.e. neuroprotection).
[0006] An anterior ocular condition can include a disease, ailment
or condition, such as for example, aphakia; pseudophakia;
astigmatism; blepharospasm; cataract; conjunctival diseases;
conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes;
eyelid diseases; lacrimal apparatus diseases; lacrimal duct
obstruction; myopia; presbyopia; pupil disorders; refractive
disorders and strabismus. Glaucoma can also be considered to be an
anterior ocular condition because a clinical goal of glaucoma
treatment can be to reduce a hypertension of aqueous fluid in the
anterior chamber of the eye (i.e. reduce intraocular pressure).
[0007] Macular edema is a major cause of visual loss in patients
with diabetes, central retinal vein occlusion (CRVO) and branch
retinal vein occlusion (BRVO). Although laser photocoagulation can
reduce further vision loss in patients with diabetic macular edema
(DME), vision that has already been decreased by macular edema
usually does not improve by use of laser photocoagulation.
Currently, there is no FDA (U.S. Food and Drug Administration)
approved treatment for macular edema associated with CRVO. For
macular edema associated with BRVO, grid laser photocoagulation may
be an effective treatment for some patients.
[0008] Diabetic macular edema results from abnormal leakage of
macromolecules, such as lipoproteins, from retinal capillaries into
the extravascular space followed by an oncotic influx of water into
the extravascular space. Abnormalities in the retinal pigment
epithelium may also cause or contribute to diabetic macular edema.
These abnormalities can allow increased fluid from the
choriocapillaries to enter the retina or they may decrease the
normal efflux of fluid from the retina to the choriocapillaries.
The mechanism of breakdown of the blood-retina barrier at the level
of the retinal capillaries and the retinal pigment epithelium may
be due to changes to tight junction proteins such as occludin.
Antcliff R., et al Marshall J., The pathogenesis of edema in
diabetic maculopathy, Semin Opthalmol 1999; 14:223-232.
[0009] Macular edema from venous occlusive disease can result from
thrombus formation at the lamina cribrosa or at an arteriovenous
crossing. These changes can result in an increase in retinal
capillary permeability and accompanying retinal edema. The increase
in retinal capillary permeability and subsequent retinal edema can
ensue from of a breakdown of the blood retina barrier mediated in
part by vascular endothelial growth factor (VEGF), a 45 kD
glycoprotein, as it is known that VEGF can increase vascular
permeability. VEGF may regulate vessel permeability by increasing
phosphorylation of tight junction proteins such as occludin and
zonula occluden. Similarly, in human non-ocular disease states such
as ascites, VEGF has been characterized as a potent vascular
permeability factor (VPF).
[0010] The normal human retina contains little or no VEGF; however,
hypoxia causes upregulation of VEGF production. Disease states
characterized by hypoxia-induced VEGF upregulation include CRVO and
BRVO. This hypoxia induced upregulation of VEGF can be inhibited
pharmacologically. Pe'er J. et al., Vascular endothelial growth
factor upregulation in human central retinal vein occlusion,
Opthalmology 1998; 105:412-416. It has been demonstrated that
anti-VEGF antibodies can inhibit VEGF driven capillary endothelial
cell proliferation. Thus, attenuation of the effects of VEGF
introduces a rationale for treatment of macular edema from venous
occlusive disease.
[0011] Corticosteroids, a class of substances with
anti-inflammatory properties, have been demonstrated to inhibit the
expression of the VEGF gene. Nauck M. et al., Induction of vascular
endothelial growth factor by platelet-activating factor and
platelet-derived growth factor is downregulated by corticosteroids,
Am J Resp Cell Mol Biol 1997; 16:398-406. Additionally,
corticosteroids can downregulate the induction of VEGF by the
pro-inflammatory mediators PDGF and platelet-activating factor
(PAF) in a time and dose-dependent manner. Nauck M. et al.,
Corticosteroids inhibit the expression of the vascular endothelial
growth factor gene in human vascular smooth muscle cells, Euro J
Pharmacol 1998; 341:309-315. Thus, corticosteroids can to
down-regulate VEGF production and reduce breakdown of the
blood-retinal barrier. Certain steroids can also have
antiangiogenic properties possibly due to attenuation of the
effects of VEGF. It should be noted that although certain
corticosteroids can apparently down regulate VEGF production there
are a number of other physiological mechanisms by which
corticosteroids can effect the pathogenesis of an ocular condition,
such as macular edema.
[0012] Triamcinolone
[0013] Triamcinolone is a corticosteroid and it has been reported
that a saline suspension is of triamcinoline (1 mg triamcinolone
acetonide in 0.1 ml saline) is non-toxic upon intravitreal
injection. McCuen B. et al., The lack of toxicity of intravitreally
administered triamcinolone acetonide, Am J Opthalmol 1981;
91:785-788. Intravitreal triamcinolone has been used to treat
proliferative vitreoretinopathy (Jonas J. et al., Intravitreal
injection of crystalline cortisone as adjunctive treatment of
proliferative vitreoretinopathy, Br J Opthalmol 2000;
84:1064-1067), as well as choroidal neovascularization (Challa J.
et al., Exudative macular degeneration and intravitreal
triamcinolone: 18 month follow up, Aust N Z J Opthalmol 1998;
26:277-281; Penfold P. et al., Exudative macular degeneration and
intravitreal triamcinolone: A pilot study, Aust N Z J Opthalmol
1995; 23:293-298, and; Danis R. et al., Intravitreal triamcinolone
acetonide in exudative age-related macular degeneration, Retina
2000; 20:244-250).
[0014] Additionally, European patent application 244 178 A2
(Keller) discloses intravitreal injection of an aqueous solution of
dexamethasone and a hyaluronic acid, and a topical triamcinolone
suspension for ear treatment is discussed in Chang H. et al.,
Development of a topical suspension containing three active
ingredient, Drug Dev and Ind Pharm, 28(1), 29-39 (2002). Einmahl S.
et al, Evaluation of a novel biomaterial in the suprachoroidal
space of the rabbit eye, Invest Ophthal & V is Sci 43(5);
1533-1539 (2002) discusses injection of a poly(ortho ester) into
the suprachoroidal space, and Einmahl S. et al, Therapeutic
applications of viscous and injectable poly(ortho esters), Adv Drug
Del Rev 53 (2001) 45-73, discloses that a poly ortho ester polymer
containing fluorouracil markedly degrades five days after
intravitreal administration. See also U.S. Pat. No. 5,770,589
(Billson) which discusses intravitreal injection of a
corticosteroid, such as triamcinolone acetonide. U.S. Pat. No.
5,209,926 (Babcock) discusses ophthalmic use of various amino
substituted steroids.
[0015] Known formulations of triamcinolone clear (diffuses out of
and/or is removed by one or more active transport mechanisms) from
the vitreous within at most about 90 days, although it has been
speculated that with a known formulation (Kenalog) the
triamcinolone may be detectable in the vitreous for no more than
four months after intravitreal injection. Thus, McCuen B. et al.
(1981) supra at page 786 noted that after three months no
triamcinolone was visible in any treated eyes. Others have reported
that the triamcinolone present in a saline or other aqueous
suspension or solution is upon intravitreal administration cleared
from the vitreous in about 21-41 days; using opthalmoscopic and
spectrophotometric detection means to determine disappearance of
the injected triamcinolone, in non-vitrectomized rabbit eyes the
average clearance rate of intravitreally triamcinolone (0.5 mg) was
41 days, while in eyes having undergone vitrectomy or combination
vitrectomy and lensectomy the average clearance rate was 17 days
and 7 days, respectively. Schindler R. et al., The clearance of
intravitreal triamcinolone acetonide, Am J Opthalmol 1982;
93:415-417. Using high-performance liquid chromatography (HPLC)
complete clearance of intravitreally injected triamcinolone (0.4
mg) in 24 rabbit eyes was observed by 21 days. Scholes G. et al.,
Clearance of triamcinolone from vitreous, Arch Opthalmol 1985;
103:1567-1569.). Such rapid clearance from the vitreous can
necessitate frequent re-administration (re-dosing) in order to
effectively treat an ocular condition.
[0016] A triamcinolone pharmaceutical composition available under
the trade name Kenalog.RTM. (Bristol-Myers-Squibb, Princeton N.J.)
has been widely used off-label to treat various ocular conditions,
including by intravitreal administration. Significantly,
Kenalog.RTM. is approved by the U.S. Food and Drug Administration
only for intramuscular or intrabursal use, but not for the
treatment of any ocular conditions. Each milliliter (ml) of
Kenalog.RTM. 40 composition comprises 40 milligrams (mg) of
triamcinolone acetonide, sodium chloride as a tonicity agent, 10 mg
(0.99%) benzyl alcohol as a preservative, 7.5 mg (0.75%) of
carboxymethylcellulose sodium and 0.4 mg (0.04%) of polysorbate 80
as resuspension aids.
[0017] It has been reported that Kenalog has a 15 day half life in
the vitreous with an effect on central macular thickness being
observed for up to 140 days after intravitreal injection of the
Kenalog. Aubren, F. et al., Pharmacokinetic-Pharmacodynamic
modeling of the effect of Triamcinolone Acetonide on Central
Macular Thickness in is Patients with Diabetic Macular Edema, Inv
Ophth & V is Sci, 45(10); 3435-3441: October 2004. It has also
been reported that triamcinolone can be detected in the vitreous up
to 93 days after a single intravitreal injection of Kenalog (Beer
P. et al., Intraocular concentration and pharmacokinetics of
triamcinolone acetonide after a single intravitreal injection,
Opthal 110(4); 681-686: April 2003), with the triamcinolone
estimated to be potentially detectable in the vitreous for about 4
months. Inoue M. et al., Vitreous concentrations of triamcinolone
acetonide in human eyes after intravitreal or subtenon injection,
Am J Opth 138(6); 1046-1048: 2004.
[0018] Noninfectious endophthalmitis have been reported upon
intravitreal Kenalog.RTM. injection, possibly related to the
preservative, excipients and/or resuspension aids present in
Kenalog.RTM. (Roth D. et al., Noninfectious endophthalmitis
associated with intravitreal triamcinolone injection, Arch
Opthalmol 2003; 121: 1279-1282; Sutter F. et al.,
Pseudo-endophthalmitis after intravitreal injection of
triamcinolone, Br J Opthalmol 2003; 87:972-974).
[0019] Additionally, the presence of benzyl alcohol preservative
and polysorbate 80 surfactant in Kenalog.RTM. can potentially
damage or be toxic to sensitive ocular tissues, such as retinal
cells, and for this reason clinicians routinely wash the
triamcinolone acetonide precipitate (which forms when Kenalog.RTM.
is left standing) several times with saline to reduce the
concentration of these undesirable non-active materials from the
formulation. Additionally, methods have been developed to filter
out of Kenalog.RTM. and from identical formulations such as
Kenacort-A the preservative, surfactant, and/or resuspension
(suspending agents) aids present in these formulations. Nishimura
A. et al., Isolating Triamcinolone acetonide particles for
intravitreal use with a porous membrane filter, Retina, vol 23(6);
777-779 (2003). Such washing and/or filtering steps are
inconvenient, time consuming, and increase the possibility of
microbial or endotoxin contamination that could lead to intraocular
infection and inflammation.
[0020] Significantly, the triamcinolone acetonide in Kenalog.RTM.
40 tends to rapidly separate and precipitate from the remainder of
the composition. For example, if Kenalog.RTM. is left standing for
as short a time as about five to ten minutes a substantial
separation of a triamcinolone acetonide precipitate from the
remainder of the composition occurs. Unfortunately, such rapid
settling of the triamcinolone also occurs with other known saline
based suspensions of triamcinolone (with or with preservatives and
stabilizers). Thus, if the composition is to be injected into the
eye it must first be vigorously shaken and used promptly after
being so shaken in order to provide a substantially uniform
suspension. A substantially uniform suspension (which is not
provided by Kenalog or other saline based suspensions of
triamcinolone) is required in order to provide a consistent and
accurate dose upon administration of the suspension to the eye. In
addition, resuspension processing requires the use of the
resuspension aids noted above, at least one of which is less than
totally desirable for sensitive ocular tissues. At least because of
the potential risk of noninfectious endophthalmitis from use of the
Kenalog.RTM. vehicle, development of a preservative-free
triamcinolone formulation for intraocular use to treat an ocular
condition (such as a posterior ocular condition) is desirable.
[0021] Elevated intraocular pressure, that is elevated anterior
chamber intraocular pressure, depends on the comparative rates of
aqueous production and aqueous drainage, primarily through the
trabecular meshwork. Increased intraocular pressure occurs from a
variety of mechanisms such as primary or secondary angle-closure
glaucoma, primary or secondary open-angle glaucoma, or
combined-mechanism glaucoma. If inadequately treated, increased
intraocular pressure may result in glaucomatous optic nerve changes
and loss of visual field.
[0022] Known formulations of corticosteroids administered by a
topical, systemic or peribulbar route can cause an increase in
anterior chamber intraocular pressure. For example, following 4 to
6 weeks of topical corticosteroid administration, 5% of subjects
can show an elevation in intraocular pressure of >16 mmHg and
30% of subjects may is show an elevation of 6 to 15 mmHg (Armaly
M., Statistical attributes of the steroid hypertensive response in
the clinically normal eye, Invest Opthalmol V is Sci 1965;
4:187-197; Becker B,. Intraocular pressure response to topical
corticosteroid, Invest Opthalmol V is Sci 1965; 4:198-205).
Additionally, intravitreal administration of known formulations of
a corticosteroid, such as triamcinolone can also result in
increased intraocular pressure (Martidis A. et al., Intravitreal
triamcinolone for refractory diabetic macular edema, Opthalmology
2002; 109:920-927; Jonas J. et al., Intravitreal injection of
triamcinolone for diffuse diabetic macular edema, Arch Opthalmol
2003; 121:57-61), possibly due to the burst or high release rates
of triamcinolone from the known formulations.
[0023] As well as causing an increase in intraocular pressure,
corticosteroids can also cause an increase in cataract formation.
Corticosteroid-induced cataracts typically show an axial, posterior
subcapsular opacity, which gradually increases in size. Nuclear
sclerosis is not a typical lens change from corticosteroids.
Topical, systemic and peribulbar corticosteroid administration have
all been associated with an increased risk of cataract formation
(Butcher J. et al., Bilateral cataracts and glaucoma induced by
long term use of steroid eye drops. BMJ 1994; 309-343).
[0024] The intravitreal administration of known triamcinolone
formulations can therefore also be expected to be associated with
an increased risk of both elevated intraocular pressure and
cataract formation.
[0025] A further adverse effect from ocular corticosteroid
administration can be inflammation. Endophthalmitis is a type of
intraocular inflammation that can be due to infection with
pathogens such as bacteria of fungi or can be noninfectious.
Clinical features include lid edema, conjunctival injection,
corneal edema, anterior chamber and vitreous inflammation and
hypotonia. Infectious endophthalmitis can occur following an
intraocular procedure (i.e. cataract surgery, vitrectomy surgery,
intravitreal injection), as a result of systemic infection, as a
result of trauma, or occur as a late is feature of conjunctival
filtering blebs.
[0026] The most common dose of triamcinolone used to treat eyes
with macular edema associated with diabetes, CRVO or BRVO is 4 mg
(Martidis A. et al., Intravitreal triamcinolone for refractory
diabetic macular edema, Opthalmology 2002; 109:920-927). The use of
25 mg of triamcinolone has less commonly been used to treat eyes
with macular edema (Jonas J. et al., Intraocular injection of
crystalline cortisone as adjunctive treatment of diabetic macular
edema, Am J Opthalmol 2001; 132:425-427).
[0027] Thus, there are significant drawbacks and deficiencies with
the known triamcinolone formulations used by intravitreal
administration to treat an ocular condition, including for example
rapid clearance from the vitreous, elevated intraocular pressure,
cataract formation, retinal toxicity, and intraocular inflammation,
such as endophthalmitis.
[0028] Hence, a sterile, preservative-free, sustained release
triamcinolone preparation is desirable. Additionally, because
corticosteroids have known ocular toxicities (as manifested in the
occurrence or development of for example elevated IOP, glaucoma and
cataract) it is desirable to have a triamcinolone formulation for
intraocular (i.e. intravitreal) use which does not result in an
increased incidence of elevated IOP, glaucoma, cataract formation
and/or intraocular inflammation, or which has, subsequent to
intraocular administration of a triamcinolone formulation, a
reduced incidence of elevated IOP, glaucoma, cataract formation
and/or intraocular inflammation as compared to currently used or
known intraocular (i.e. intravitreal) use triamcinolone.
DRAWINGS
[0029] FIG. 1 is a bar graph of observed angiographic leakage (as
assessed on a 1-5 grading scale) on the Y-axis versus time of the
observation on the X-axis for three groups of rabbit eyes: rabbit
control (untreated) eyes, rabbit eyes intravitreally injected with
the 1 mg triamcinolone acetonide gel suspension (TAA.sub.gs)
formulation of Example 8, and rabbit eyes intravitreally injected
with the 4 mg TAA.sub.gs of Example 9. The grading (scale 1-5) of
late-phase angiograms from rabbit eyes was measured over a thirty
week period after intravitreal injection of either the 1 mg
TAA.sub.gs or 4 mg TAA.sub.gs. All eyes received intravitreal
injection of 500 ng VEGF at each of the time points shown on the
X-axis followed by angiography 48 hrs later.
[0030] FIG. 2 is a bar graph of observed vitreoretinal fluorescence
(as area under the curve) on the Y-axis versus time of the
observation on the X-axis for the same three groups of rabbit eyes:
rabbit control (untreated) eyes, rabbit eyes intravitreally
injected with the 1 mg TAA.sub.gs, and rabbit eyes intravitreally
injected with the 4 mg TAA.sub.gs (as in FIG. 1). Scanning vitreal
fluorophotometry measurements of VEGF-induced BRB breakdown in
rabbit eyes was measured over the same thirty week period after
intravitreal injection of the 1 mg or 4 mg TAA.sub.gs. As in FIG.
1, all eyes had received intravitreal injection of 500 ng VEGF at
the time points shown on the X-axis followed by fluorophotometry 48
hrs later. The area under the fluorescence curve (AUC) was
calculated for each eye.
[0031] FIG. 3 is a bar graph of observed retinal blood vessel
caliber and tortuosity (grade) on the Y-axis versus time of the
observation on the X-axis for the same rabbit control (untreated)
eyes, rabbit eyes intravitreally injected with 1 mg TAA.sub.gs or
with 4 mg TAA.sub.gs (as in FIG. 1). Subjective grading (on a 1-5
scale) of VEGF-induced changes in vessel caliber and tortuosity
from fundus images of rabbit eyes was measured over the same thirty
week period after intravitreal injection of the 1 or 4 mg
TAA.sub.gs. As in FIG. 1, all eyes received intravitreal injection
of 500 ng VEGF at the indicated time points followed by fundus
image capture 48 hrs later.
[0032] FIG. 4 is a bar graph of observed anterior chamber
fluorescence (as area under the curve) on the Y-axis versus time of
the observation on the X-axis for the same rabbit control
(untreated) eyes, rabbit eyes intravitreally injected with 1 mg
TAA.sub.gs or with 4 mg TAA.sub.gs, (as in FIG. 1). Scanning ocular
fluorophotometry of VEGF-induced blood-aqueous barrier breakdown in
rabbit eyes was measured over a thirty week period after
intravitreal injection of either 1 or 4 mg TAA.sub.gs. As in FIG.
1, all eyes received intravitreal injection of 500 ng VEGF at the
indicated time points followed by anterior chamber fluorophotometry
48 hrs later. The area under the fluorescence curve (AUC) was
calculated for each eye.
[0033] FIG. 5 is a negative image of a photograph of the eye of a
rabbit thirty weeks after intravitreal injection of 50 .mu.L of the
Example 94 mg TAA.sub.gs formulation. The photograph was taken with
an 11.0 megapixel, digital Zeiss FF450 fundus camera coupled to the
Zeiss 481 Visupac image capture and analysis system.
[0034] FIG. 6 is a flow chart which summarizes a preferred
manufacturing process for making the triamcinolone formulations of
Examples 1 to 9.
[0035] FIG. 7 consists of three bar graphs showing the size
(diameter) in microns .alpha.-axis) of triamcinolone acetonide
particles in three commercial lots of Kenalog-40 vs the frequency
of occurrence of the measured particles diameters. Triamcinolone
acetonide particle size diameter and distribution was determined by
laser light scattering using a Horiba LA 300 instrument.
[0036] FIG. 8 consists of four bar graphs (A, B, C and D) showing
the size (diameter) in microns (x-axis) of triamcinolone acetonide
particles in four lots of the Example 9 (8% Trivaris) formulation
vs the frequency of occurrence of the measured particles diameters.
The line graph in FIGS. 8A to 8D shows the area under the curve for
cummulative (%) triamcinolone acetonide particle size (right hand
side y axis). Triamcinolone acetonide particle size diameter and
distribution was determined by laser light scattering using a
Horiba LA 300 instrument.
SUMMARY
[0037] The present invention provides sterile, preservative-free,
sustained release triamcinolone formulations for treating ocular
conditions with the desirable characteristics of low ocular
toxicities, as manifested in the low or nominal occurrence or
development of an elevated IOP, glaucoma, cataract and/or
intraocular inflammation.
[0038] Definitions
[0039] As used herein, the words or terms set forth below have the
following definitions.
[0040] "About" means that the item, parameter or term so qualified
encompasses a range of plus or minus ten percent above and below
the value of the stated item, parameter or term.
[0041] "Administration", or "to administer" means the step of
giving (i.e. administering) a pharmaceutical composition to a
subject. The pharmaceutical compositions disclosed herein can be
"locally administered", that is administered at or in the vicinity
of the site at which a therapeutic result or outcome is desired.
For example to treat an ocular condition (such as for example a
macular edema, uveitis or macular degeneration) intravitreal
injection or implantation of a sustained release device such as
active agent containing polymeric implant can be carried out.
"Sustained release" means release of an active agent (such as a
triamcinolone) over a period of about seven days or more, while
"extended release" means release of an active agent over a period
of time of less than about seven days.
[0042] "Entirely free (i.e. "consisting of" terminology) means that
within the detection range of the instrument or process being used,
the substance cannot be detected or its presence cannot be
confirmed.
[0043] "Essentially free" (or "consisting essentially of") means
that only trace amounts of the substance can be detected.
[0044] "Pharmaceutical composition" means a formulation in which an
active ingredient (the active agent) can be a steroid, such as a
corticosteroid, such as a triamcinolone. The word "formulation"
means that there is at least one additional ingredient in the
pharmaceutical composition besides the steroid active ingredient. A
pharmaceutical composition is therefore a formulation which is
suitable for diagnostic or therapeutic administration (i.e. by
intraocular injection or by insertion of a depot or implant) to a
subject, such as a human patient.
[0045] "Substantially free" means present at a level of less than
one percent by weight of the pharmaceutical composition.
[0046] All the viscosity values set forth herein were determined at
25.degree. C. (unless another temperature is specified).
Additionally, all the viscosity values set forth herein were
determined at a shear rate of about 0.1/second (unless another
shear rate is specified).
[0047] The present compositions are highly suitable for
intravitreal administration into the posterior segments of eyes
without requiring any washing step, while providing for reduced
ocular, for example, retinal, damage when used in an eye. The
present compositions are advantageously substantially free of added
preservative components, for example, contain no benzyl alcohol
preservative. In addition, the present compositions advantageously
require no resuspension aid or aids. Overall, the present
compositions are easily and effectively injectable into the
posterior segment of an eye of a human or animal and can be
maintained as a substantially uniform suspension for long periods
of time, for example, at least about one week or more, without
resuspension processing, for example, without requiring shaking or
other agitating of the composition to obtain substantial suspension
uniformity. In short, is the present compositions and methods
provide substantial enhancements and advantages, for example,
relative to the prior art Kenalog.RTM. 40 composition and methods
of using such prior art composition, in the posterior segments of
human or animal eyes.
[0048] In one broad aspect of the present invention, compositions
useful for injection into a posterior segment of an eye of a human
or animal are provided. Such compositions comprise a corticosteroid
component, a viscosity inducing component, and an aqueous carrier
component. The corticosteroid component is present in a
therapeutically effective amount. The corticosteroid component is
present in the compositions in a plurality of particles.
[0049] The present compositions may include a corticosteroid
component in an amount of up to about 25% (w/v) or more of the
composition. In one very useful embodiment, the corticosteroid
component is present in an amount of at least about 80 mg/ml of
composition. Preferably, the corticosteroid component is present in
an amount in a range of about 1% to about 10% or about 20% (w/v) of
the composition.
[0050] In one very useful embodiment, the corticosteroid component
comprises triamcinolone acetonide. The viscosity inducing component
is present in an amount effective in increasing the viscosity of
the composition. Any suitable, preferably ophthalmically
acceptable, viscosity inducing component may be employed in
accordance with the present invention. Many such viscosity inducing
components have been proposed and/or used in ophthalmic
compositions used on or in the eye. Advantageously, the viscosity
inducing component is present in an amount in a range of about 0.5%
to about 20% (w/v) of the composition. In one particularly useful
embodiment, the viscosity inducing component is a hyaluronic acid
polymer component, such as sodium hyaluronate.
[0051] In one embodiment, the present compositions have a viscosity
of at least about 10 cps or at least about 100 cps, preferably at
least about 1,000 cps, more preferably at least about 10,000 cps
and still more preferably at least about 70,000 cps, for example,
up to about 250,000 cps, or about 300,000 cps, at a shear rate of
0.1/second. The present compositions are structured or have
make-ups so as to be effectively, for example, manually, injected
into a posterior segment of an eye of a human or animal, preferably
through a 27 gauge needle, more preferably through a 29 or 30 gauge
needle.
[0052] Without wishing to limit the invention to any particular
theory of operation, it is believed that the use of relatively high
viscosity compositions, as described herein, provides for
effective, and preferably substantially uniform, suspension of the
steroid component particles while, at the same time, being
injectable into the posterior segment of an eye through
conventionally, or even smaller than conventionally, used
needles.
[0053] In one embodiment of the invention, the corticosteroid
component is present in a plurality of particles which are
substantially uniformly suspended in the composition and remain
substantially uniformly suspended in the composition for at least
about 1 week, preferably at least about 2 weeks or at least about 1
month, and still more preferably at least about 6 months or at
least about 1 year or at least about 2 years, without requiring
resuspension processing, that is, without requiring being shaken or
otherwise agitated to maintain the corticosteroid component
particles substantially uniformly suspended in the composition.
[0054] Compositions having such substantially uniform suspension of
corticosteroid component particles, so as to be able to provide a
consistent and accurate dose upon administration to an eye, provide
substantial advantages relative to the prior art. In particular,
the present compositions may be manufactured, shipped and stored
for substantial periods of time without the corticosteroid
component particles precipitating is from the remainder of the
composition. Having the corticosteroid component particles
maintained substantially uniformly suspended in the composition
allows the composition to provide long term dosing consistency and
accuracy per unit dose amount administered, without any need to
resuspend the corticosteroid particles.
[0055] The aqueous carrier component is advantageously
ophthalmically acceptable and may include one or more conventional
expedients useful in ophthalmic compositions. For example, the
carrier component may include an effective amount of at least one
of a preservative component, a tonicity component and a buffer
component. In one advantageous embodiment, the present compositions
include no added preservative component. This feature reduces or
minimizes or even substantially eliminates adverse reactions in the
eye which may be caused by or linked to the presence of a
preservative component. Although a resuspension component may be
employed in accordance with the present invention, in many
instances, because of the ability of the present composition to
remain a substantially uniform suspension for a long period of time
without requiring resuspension processing, the compositions
advantageously contain no added resuspension components.
[0056] Methods of treating posterior segments of the eyes of humans
or animals are also disclosed and are included within the scope of
the present invention. In general, such methods comprise
administering, e.g. injecting a corticosteroid component-containing
composition, for example, a composition in accordance with the
present intention, to a posterior segment of an eye of a human or
animal. Such administering is effective in providing a desired
therapeutic effect. The administering step advantageously comprises
at least one of intravitreal injecting, subconjunctival injecting,
sub-tenon injecting, retrobulbar injecting, suprachoroidal
injecting and the like.
[0057] Our invention encompasses a pharmaceutical composition for
treating a posterior ocular condition. The composition can comprise
a triamcinolone present in a therapeutically effective amount as a
plurality of particles; a viscosity inducing component in an amount
effective to increase the viscosity of the composition, and; an
aqueous carrier component. The composition can have a viscosity of
at least about 10 cps at a shear rate of about 0.1/second and is
injectable into the vitreous of a human eye, for example through a
27 gauge needle. By reducing the viscosity of our formulation it
can be injected into the vitreous through a 28, 29 or 30 gauge
needle.
[0058] Preferably, the triamcinolone particles of the
pharmaceutical composition are substantially uniformly suspended in
the composition and the viscosity inducing component is a polymeric
hyaluronate.
[0059] A detailed embodiment within the scope of our invention is a
pharmaceutical composition for treating a posterior ocular
condition, comprising triamcinolone particles; polymeric
hyaluronate, in which the triamcinolone particles are suspended;
sodium chloride; sodium phosphate, and water. The pharmaceutical
composition can have a viscosity at a shear rate of about
0.1/second of between about 80,000 cps to about 300,000, preferably
from about 100,000 cps to about 300,000 cps, and most preferably
from about 1280,000 cps to about 225,000 cps. Note that the
pharmaceutical composition can have a viscosity at a shear rate of
about 0.1/second of between about 80,000 cps and about 300,000 cps,
and that when the pharmaceutical composition has a viscosity at a
shear rate of about 0.1/second of between about 100,000 cps and
about 150,000 cps it can be injected into the vitreous through a
27, 28, 29 or 30 gauge needle. We have found that even with a
300,000 cps our formulations can be injected through a 30 gauge
needle due to shear thinning once the formulation is in movement in
the syringe. The sodium phosphate present in the pharmaceutical
composition can comprise both monobasic sodium phosphate and
dibasic sodium phosphate. Additionally, the pharmaceutical
composition can comprise between about 2% w/v triamcinolone and
about 8% w/v triamcinolone, between about 2% w/v hyaluronate and
about 3% w/v hyaluronate, about 0.6% w/v sodium chloride and about
0.03% w/v sodium phosphate to about 0.04% w/v sodium phosphate.
Alternately, the pharmaceutical composition of claim 5 can comprise
between about is 0.5% w/v hyaluronate and about 6% w/v hyaluronate.
If desired the hyaluronate can be heated (see Example 15) to
decrease its molecular weight (and therefore its viscosity) in the
formulation.
[0060] The pharmaceutical composition can also comprises between
about 0.6% w/v sodium chloride to about 0.9% w/v sodium chloride.
Generally, more sodium chloride is used in the formulation as less
phosphate is used in the formulation, for example 0.9% sodium
chloride can be used if no phosphate is present in the formulation,
as in this manner the tonicity of the formulation can be adjusted
to obtain the desired isotonicity with physiological fluid. The
pharmaceutical composition can comprise between about 0.0% w/v
sodium phosphate and 0.1% w/v sodium phosphate. As noted, more
phosphate can be used in the formulation if less sodium chloride is
present in the formulation so as to obtain a desired pH 7.4
buffering effect.
[0061] A more detailed embodiment within the scope of our invention
is a pharmaceutical composition for treating a posterior ocular
condition, the pharmaceutical composition consisting essentially of
triamcinolone particles, polymeric hyaluronate, in which polymeric
hyaluronate the triamcinolone particles are suspended, sodium
chloride, sodium phosphate, and water. The pharmaceutical
composition can have a viscosity at a shear rate 0.1/second at
25.degree. C. of between about 128,000 cps and about 225,000 cps
and the sodium phosphate present in the pharmaceutical composition
can be present as both monobasic sodium phosphate and dibasic
sodium phosphate. The most preferable viscosity range is 140,000 to
280,000 cps at a shear rate 0.1/second at 25.degree. C.
[0062] A further embodiment of our invention is a triamcinolone
suspension for treating a posterior ocular condition, consisting of
triamcinolone particles, polymeric hyaluronate, in which the
triamcinolone particles are suspended, sodium chloride, dibasic
sodium phosphate heptahydrate, monobasic sodium phosphate
monohydrate, and water, wherein the composition has a viscosity at
a shear rate 0.1/second of between about is 128,000 cps and about
225,000 cps.
[0063] Our invention also includes a method for treating a
posterior ocular condition by administering (as by injecting) the
pharmaceutical composition of claim 1 to the vitreous of a human or
animal, thereby treating the posterior ocular condition. Thus we
have invented a method for treating macula edema by administering
to the vitreous of a human eye a pharmaceutical composition
comprising a triamcinolone, and a hyaluronate, wherein the
pharmaceutical composition having a viscosity at a shear rate
0.1/second of between about 128,000 cps and about 225,000 cps.
[0064] A pharmaceutical composition within the scope of our
invention for treating a posterior ocular condition can comprise a
triamcinolone present in a therapeutically effective amount as a
plurality of particles, a viscosity inducing component in an amount
effective to increase the viscosity of the composition, and an
aqueous carrier component, wherein the composition has a viscosity
of at least about 10 cps at a shear rate of 0.1/second and is
injectable into the vitreous of a human eye and wherein the
pharmaceutical composition releases the triamcinolone with
substantially first order release kinetics over a period of at
least about 45 days after the intravitreal injection. This
pharmaceutical composition can exhibit reduced generation of
intraocular inflammation, no plume effect (that is no wide
dispersion of the triamcinolone into the vitreous as soon as the
triamcinolone is intravitreally injected), and cohesiveness (as
shown by the retention of the form of the triamcinolone gel for 30
weeks or longer after intravitreal injection of the triamcinolone
gel formulation) upon intravitreal injection of the pharmaceutical
composition.
[0065] Our invention encompasses a method for treating a posterior
ocular condition, the method comprising the step of intravitreal
administration of a sustained release pharmaceutical composition
implant comprising a triamcinolone present in a therapeutically
effective amount as a plurality of particles, a viscosity inducing
component in an amount effective to increase the viscosity of the
composition, and an is aqueous carrier component, wherein the
composition has a viscosity of at least about 10 cps at a shear
rate of 0.1/second and is injectable into the vitreous of a human
eye, and wherein the posterior ocular condition is treated for up
to about 30 weeks by the triamcinolone released from the implant.
In this method the pharmaceutical composition can comprise
triamcinolone particles, polymeric hyaluronate, in which the
triamcinolone particles are suspended, sodium chloride, sodium
phosphate, and water. Additionally, the intravitreal administration
can be injected through a 27 gauge needle into the vitreous of a
human eye, and in an aggregate number of patients practise of the
method results in less intraocular inflammation than does practise
of the same method with a second pharmaceutical composition which
is a saline solution or suspension of a triamcinolone.
[0066] Our invention also includes a process for making a
pharmaceutical composition by (a) mixing triamcinolone particles
about 4 microns to about 8 microns in diameter with sodium chloride
crystals, and about 35% to about 40% of the total volume of the
water (water for injection) used to make the formulation; (b)
heating the triamcinolone and sodium chloride mixture to a
temperature between about 120.degree. C. and about 140.degree. C.,
thereby preparing a first part; (c) mixing a sodium phosphate and
water, thereby preparing a second part; (d) dissolving sodium
hyaluronate with a molecular weight between about 1.0 million
Daltons and about 1.9 million Daltons in another about 35% to about
40% of the total water volume used to make the formulation,
followed by sterile filtration after the dissolving; (e)
lyophilization of the dissolved sodium hyaluronate; (f)
reconstitution of the lyophilized, sterile sodium hyaluronate,
thereby preparing a third part; and; (g) aseptically combining the
first, second and third parts, thereby making a sterile, uniform
triamcinolone pharmaceutical composition which is, an opaque white
gel suspension suitable for intravitreal injection to treat an
ocular condition. Water is added as needed (q.s.) to make the
desired gel suspension which is about 80% to about 90% by weight
water.
[0067] Also within the scope of our invention is a pharmaceutical
composition for treating a posterior ocular condition, the
pharmaceutical composition comprising a plurality of corticosteroid
particles mixed with a viscous polymer, wherein the pharmaceutical
composition has a viscosity of between about 130,000 cps and about
300,000 cps at a shear rate of about 0.1/second at about 25.degree.
C., and the pharmaceutical composition can be injected into the
vitreous of a human eye through a 25 to 33 gauge needle. The
corticosteroid particles can have a substantially uniform diameter,
as shown for example by FIGS. 8A, 8B, 8C and 8D. Additionally,
preferably substantially all (i.e. up to 90-97%) of the
corticosteroid particles are embedded within the viscous polymer.
The corticosteroid can be a triamcinolone and the viscous polymer
can be a polymeric hyaluronate or a polymeric hyaluronic acid.
[0068] An alternate method for treating a posterior ocular
condition can comprise the step of injecting into the vitreous of a
patient's eye with a posterior ocular condition a viscous
pharmaceutical composition comprising a plurality of corticosteroid
particles mixed into a viscous polymeric matrix, wherein the
pharmaceutical composition has a viscosity of between about 130,000
cps and about 300,000 cps at a shear rate of about 0.1/second at
about 25.degree. C., such that about one hour after the
intravitreal injection only about 10% or less (or only about 5% or
less or only about 3% or less) of the corticosteroid particles are
present in the vitreous free of the polymeric matrix.
[0069] An alternate process for making an intraocular
pharmaceutical composition can comprise the step of mixing an
aqueous suspension of a plurality of corticosteroid particles and
an aqueous solution of a viscous polymeric matrix, so that the
resulting pharmaceutical composition has a viscosity of between
about 130,000 cps and about 300,000 cps at a shear rate of about
0.1/second at about 25.degree. C. The corticosteroid particles can
have a median particle size of between about 4 microns and about 5
microns. By use of this process for making an intraocular
pharmaceutical composition the corticosteroid particles can have a
stable diameter for at least three months after the pharmaceutical
has been made and stored for three months in a syringe placed
horizontally at about 25.degree. C. at about 60% relative
humidity.
[0070] Our invention also includes a pharmaceutical composition for
treating an articular pathology, the pharmaceutical composition
comprising a plurality of corticosteroid particles mixed with a
viscous polymer, wherein the pharmaceutical composition has a
viscosity of between about 130,000 cps and about 300,000 cps at a
shear rate of about 0.1/second at about 25.degree. C.
[0071] Finally, our invention also includes a method for treating
an articular pathology, the method comprising the step of injecting
into a joint of a patient with an articular pathology (such as a
joint or spine inflammation) a viscous pharmaceutical composition
comprising a plurality of corticosteroid particles mixed into a
viscous polymeric matrix, wherein the pharmaceutical composition
has a viscosity of between about 130,000 cps and about 300,000 cps
at a shear rate of about 0.1/second at about 25.degree. C.
Description
[0072] The present invention is based upon our discovery of
triamcinolone formulations specifically designed for intravitreal
injection to treat various ocular conditions, such a macula edema.
Our triamcinolone formulations have numerous superior
characteristics and advantages, including the following: (1) the
triamcinolone present in our formulations does not rapidly settle
out from or precipitate from the formulations. Importantly our
formulations have a shelf life of at least two years, meaning that
our formulations can be left standing for up to about two years
before administration to an eye, and after two years the
formulation can still provide a consistent and accurate dose of
triamcinolone upon injection to the formulation to an eye; (2) our
formulations are free of preservatives and resuspension aids, such
as benzyl alcohol and/or a polysorbate; (3) concomitantly, our
formulations have a much reduced retinal and photoreceptor
toxicity; (4) as well as being sterile and preservative-free our
triamcinolone formulations can provide sustained release of
therapeutic amounts of the triamcinolone over multi-month periods
upon intravitreal injection of such formulations. Thus, our viscous
suspension triamcinolone formulations can be characterized as
sustained release implants; (5) intravitreal administration of our
triamcinolone formulations is not associated with an increased
incidence of adverse events such as elevated intra ocular pressure,
glaucoma, cataract and/an intraocular inflammation; (6)
intravitreal administration of our triamcinolone formulations is
not associated with an increased incidence of adverse events such
elevated intra ocular pressure, glaucoma, cataract and/an
intraocular inflammation as compared to currently used or known
intraocular (i.e. intravitreal) use triamcinolone formulations; (7)
our formulations permit triamcinolone particles (crystals) to be
released (as they solubilize in the viscous fluid of the posterior
chamber) from a discrete unitary location, thereby avoiding the
plume effect (rapid dispersion) characteristic of aqueous
triamcinolone formulations upon intravitreal administration; (8)
avoidance of plume formation or rapid dispersion upon intravitreal
administration beneficially reduces visual field obscuration; (9)
the sustained release characteristic of our formulations reduces
the need for intravitreal administration of large drug quantities
to achieve a desired therapeutic effect; (10) upon intravitreal
administration, the triamcinolone present in our formulations can
preferentially be eliminated in posterior direction (that is
through the retina and optic nerve) as opposed to elimination
through an anterior route (see eg Table 5). This can result in
superior treatment of a retinal disease with for example reduced
ocular hypertension.
[0073] Advantage (1) above can be provided by formulating the
triamcinolone as a viscous, gel suspension, as opposed to
formulating it as an aqueous or saline based formulation.
Additionally, advantages (4) and (8) above can be provided by
particular characteristics of our formulations, such as suspension
of the triamcinolone in one or more particular high molecular
weight hydrogel polymers which permit sustained release of the
triamcinolone from a biocompatible, biodegradable polymeric matrix,
and other implant-like characteristics to the formulations,
including substantially zero-order in vivo (i.e. intravitreal)
release kinetics (see eg Table 4).
[0074] The pluming effect occurs when a saline suspension of a
triamcinolone (such as Kenalog) is injected into the vitreous.
Pluming prevents visualization of the back of the eye (i.e. the
retina is obscured) and also reduces the patient's visual field
(reduced vision).
[0075] Generally, the present invention provides compositions
useful for placement, preferably by injection, into a posterior
segment of an eye of a human or animal. Such compositions in the
posterior, e.g., vitreous, of the eye are therapeutically effective
against one or more conditions and/or diseases of the posterior of
the eye, and/or one or more symptoms of such conditions and/or
diseases of the posterior of the eye.
[0076] It is important to note that while preferably the
compositions disclosed herein are preferably administered by
intravitreal injection to treat a posterior ocular condition, our
compositions (i.e. those of Examples 8 and 9) can also be
administered (as by injection) by other routes, such as for example
subconjuctival, sub-tenon, periocular, retrobulbar, suprachoroidal,
and/or intrascleral to effectively treat an ocular condition.
Additionally, a sutured on refillable dome can be placed over the
administration site to prevent or to reduce wash out, leaching
and/or diffusion of the active agent in a non-preferred
direction.
[0077] Compositions within the scope of our invention can comprise
a corticosteroid component; a viscosity inducing component; and an
aqueous carrier component. The compositions are advantageously
ophthalmically acceptable. One of the important advantages of the
present compositions is that they are more compatible with or
friendly to the tissues in the posterior segment of the eye, for
example, the retina of the eye, relative to compositions previously
proposed for intravitreal injection into a posterior segment of an
eye, for example, a composition sold under the trademark
Kenalog.RTM.-40. In particular, the present compositions
advantageously are substantially free of added preservative
components or include effective preservative components which are
more compatible with or friendly to the posterior segment, e.g., is
retina, of the eye relative to benzyl alcohol, which is included in
the Kenalog.RTM.-40 composition as a preservative.
[0078] In addition, the present compositions preferably include no
added resuspension component, such as polysorbate-80, which is
included in the Kenalog.RTM.-40 composition. Many of the other
features of the present compositions, as described elsewhere
herein, also render the present compositions more compatible with
or friendly to the posterior segments of the eyes into which the
compositions are placed relative to prior art compositions, such as
Kenalog.RTM.-40.
[0079] As noted above, the present compositions include a
corticosteroid component. Such corticosteroid component is present
in the compositions in a therapeutically effective amount, that is
in an amount effective in providing a desired therapeutic effect in
the eye into which the composition is placed. The corticosteroid
component is present in the composition in a plurality of
particles. Any suitable corticosteroid component may be employed in
according to the present invention. Such corticosteroid component
advantageously has a limited solubility in water, for example, at
25.degree. C. For example, the corticosteroid component preferably
has a solubility in water at 25.degree. C. of less than 10 mg/ml.
Of course, the corticosteroid component should be ophthalmically
acceptable, that is, should have substantially no significant or
undue detrimental effect of the eye structures or tissues. One
particularly useful characteristic of the presently useful
corticosteroid components is the ability of such component to
reduce inflammation in the posterior segment of the eye into which
the composition is placed caused by the result of one or more
diseases and/or conditions in the posterior segment of the eye.
[0080] Examples of useful corticosteroid components include,
without limitation, cortisone, prednesolone, triamcinolone,
triamcinolone acetonide, fluorometholone, dexamethosone, medrysone,
loteprednol, derivatives thereof and mixtures thereof. As is used
herein, the term "derivative" refers to any substance which is
sufficiently structurally similar to the material of which it is
identified as a derivative so as to have substantially similar
functionality or activity, for example, therapeutic effectiveness,
as the material when the substance is used in place of the
material. In one very useful embodiment, the corticosteroid
component comprises triamcinolone acetonide.
[0081] The corticosteroid component advantageously is present in an
amount of at least about 10 mg per ml of the composition. One
important advantage of the present invention is the effective
ability of the present compositions to include relatively large
amounts or concentrations of the corticosteroid component. Thus,
the corticosteroid component may be present in the present
compositions in an amount in the range of about 1% or less to about
5% or about 10% or about 20% or about 30% or more (w/v) of the
composition. Providing relatively high concentrations or amounts of
corticosteroid component in the present compositions is beneficial
in that reduced amounts (volumes for injection) of the composition
may be required to be placed or injected into the posterior segment
of the eye in order to provide the same amount or more
corticosteroid component in the posterior segment of the eye
relative to compositions, such as Kenalog.RTM.-40, which include
less than 4% (w/v) of the corticosteroid component. Thus, in one
very useful embodiment, the present compositions include more than
about 4% (w/v), for example at least about 5% (w/v), to about 10%
(w/v) or about 20% (w/v) or about 30% (w/v) of the corticosteroid
component. For example, about 50 .mu.L of our Example 8 or 9
formulation provide respectively 2 mg and 4 mg of triamcinolone.
This is in contrast to other formulations (such as Kenalog 40)
which require 100 .mu.L to provide 4 mg of triamcinolone. Injection
of 100 .mu.L or more of a fluid into the vitreous can result in an
excess of fluid in the vitreous with elevated intraocular pressure
and leakage of the fluid from the vitreous then potentially
occurring.
[0082] The viscosity inducing component is present in an effective
amount in increasing, advantageously substantially increasing, the
viscosity of the composition. Without is wishing to limit the
invention to any particular theory of operation, it is believed
that increasing the viscosity of the compositions to values well in
excess of the viscosity of water, for example, at least about 100
cps at a shear rate of 0.1/second, compositions which are highly
effective for placement, e.g., injection, into the posterior
segment of an eye of a human or animal are obtained. Along with the
advantageous placement or injectability of the present compositions
into the posterior segment, the relatively high viscosity of the
present compositions are believed to enhance the ability of the
present compositions to maintain the corticosteroid component
particles in substantially uniform suspension in the compositions
for prolonged periods of time, for example, for as long as 1 to 2
years, without requiring resuspension processing. The relatively
high viscosity of the present compositions may also have an
additional benefit of at least assisting the compositions to have
the ability to have an increased amount or concentration of the
corticosteroid component, as discussed elsewhere herein, for
example, while maintaining such corticosteroid component in
substantially uniform suspension for prolonged periods of time.
[0083] Advantageously, the present compositions have viscosities of
at least about 10 cps or at least about 100 cps or at least about
1000 cps, more preferably at least about 10,000 cps and still more
preferably at least about 70,000 cps or more, for example up to
about 200,000 cps or about 250,000 cps, or about 300,000 cps or
more, at a shear rate of 0.1/second. The present compositions not
only have the relatively high viscosity as noted above but also
have the ability or are structured or made up so as to be
effectively placeable, e.g., injectable, into a posterior segment
of an eye of a human or animal, preferably through a 27 gauge
needle, or even through a 30 gauge needle.
[0084] The presently useful viscosity inducing components
preferably are shear thinning components in that as the present
composition containing such a shear thinning viscosity inducing
component is passed or injected into the posterior segment of an
eye, for example, through a narrow space, such as 27 gauge needle,
under high shear conditions the viscosity of the composition is
substantially reduced during such passage. After such passage, the
composition regains substantially its pre-injection viscosity so as
to maintain the corticosteroid component particles in suspension in
the eye.
[0085] Any suitable viscosity inducing component, for example,
ophthalmically acceptable viscosity inducing component, may be
employed in accordance with the present invention. Many such
viscosity inducing components have been proposed and/or used in
ophthalmic compositions used on or in the eye. The viscosity
inducing component is present in an amount effective in providing
the desired viscosity to the composition. Advantageously, the
viscosity inducing component is present in an amount in a range of
about 0.5% or about 1.0% to about 5% or about 10% or about 20%
(w/v) of the composition. The specific amount of the viscosity
inducing component employed depends upon a number of factors
including, for example and without limitation, the specific
viscosity inducing component being employed, the molecular weight
of the viscosity inducing component being employed, the viscosity
desired for the present composition being produced and/or used and
the like factors, such as shear thinning. The viscosity inducing
component is chosen to provide at least one advantage, and
preferably multiple advantages, to the present compositions, for
example, in terms of each of injectability into the posterior
segment of the eye, viscosity, sustainability of the corticosteroid
component particles in suspension, for example, in substantially
uniform suspension, for a prolonged period of time without
resuspension processing, compatibility with the tissues in the
posterior segment of the eye into which the composition is to be
placed and the like advantages. More preferably, the selected
viscosity inducing component is effective to provide two or more of
the above-noted benefits, and still more preferably to provide all
of the above-noted benefits.
[0086] The viscosity inducing component preferably comprises a
polymeric component and/or at least one viscoelastic agent, such as
those materials which are useful in ophthalmic surgical
procedures.
[0087] Examples of useful viscosity inducing components include,
but are not limited to, hyaluronic acid (such as a polymeric
hyaluronic acid), carbomers, polyacrylic acid, cellulosic
derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin,
polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl
acetate, derivatives thereof and mixtures and copolymers
thereof.
[0088] The molecular weight of the presently useful viscosity
inducing components may be in a range of about 10,000 Daltons or
less to about 2 million Daltons or more. In one particularly useful
embodiment, the molecular weight of the viscosity inducing
component is in a range of about 100,000 Daltons or about 200,000
Daltons to about 1 million Daltons or about 1.5 million Daltons.
Again, the molecular weight of the viscosity inducing component
useful in accordance with the present invention, may vary over a
substantial range based on the type of viscosity inducing component
employed, and the desired final viscosity of the present
composition in question, as well as, possibly one or more other
factors.
[0089] In one very useful embodiment, a viscosity inducing
component is a polymeric hyaluronate component, for example, a
metal hyaluronate component, preferably selected from alkali metal
hyaluronates, alkaline earth metal hyaluronates and mixtures
thereof, and still more preferably selected from sodium
hyaluronates, and mixtures thereof. The molecular weight of such
hyaluronate component (i.e. a polymeric hyaluronic acid) preferably
is in a range of about 50,000 Daltons or about 100,000 Daltons to
about 1.3 million Daltons or about 2 million Daltons. In one
embodiment, the present compositions include a polymeric
hyaluronate component in an amount in a range about 0.05% to about
0.5% (w/v). In a further useful embodiment, the hyaluronate
component is present in an amount in a range of about 1% to about
4% (w/v) of the composition. In this latter case, the very high
polymer viscosity forms a gel that slows particle sedimentation
rate to the extent that often no resuspension processing is
necessary over the estimated shelf life, for example, at least
about 2 years, of the composition. Such a composition may be
marketed in pre-filled syringes since the gel cannot be easily
removed by a needle and syringe from a bulk container. Pre-filled
syringes have the advantages of convenience for the injector and
the safety which results from less handling.
[0090] The aqueous carrier component is advantageously
ophthalmically acceptable and may include one or more conventional
excipients useful in ophthalmic compositions. The present
compositions preferably include a major amount of liquid water. The
present compositions may be, and are preferably, sterile, for
example, prior to being used in the eye.
[0091] The present compositions preferably include at least one
buffer component in an amount effective to control the pH of the
composition and/or at least one tonicity component in an amount
effective to control the tonicity or osmolality of the
compositions. More preferably, the present compositions include
both a buffer component and a tonicity component.
[0092] The buffer component and tonicity component may be chosen
from those which are conventional and well known in the ophthalmic
art. Examples of such buffer components include, but are not
limited to, acetate buffers, citrate buffers, phosphate buffers,
borate buffers and the like and mixtures thereof. Phosphate buffers
are particularly useful. Useful tonicity components include, but
are not limited to, salts, particularly sodium chloride, potassium
chloride, mannitol and other sugar alcohols, and other suitable
ophthalmically acceptably tonicity component and mixtures
thereof.
[0093] The amount of buffer component employed preferably is
sufficient to maintain the pH of the composition in a range of
about 6 to about 8, more preferably about 7 to about 7.5. The
amount of tonicity component employed preferably is sufficient to
provide an osmolality to the present compositions in a range of
about 200 to about 400, more preferably about 250 to about 350,
mOsmol/kg respectively. Advantageously, the present compositions
are substantially isotonic.
[0094] The present compositions may include one or more other
components in amounts effective to provide one or more useful
properties and/or benefits to the present compositions. For
example, although the present compositions may be substantially
free of added preservative components, in other embodiments, the
present compositions include effective amounts of preservative
components, preferably such components which are more compatible
with or friendly to the tissue in the posterior segment of the eye
into which the composition is placed than benzyl alcohol. Examples
of such preservative components include, without limitation,
benzalkonium chloride, chlorhexidine, PHMB (polyhexamethylene
biguamide), methyl and ethyl parabens, hexetidine, chlorite
components, such as stabilized chlorine dioxide, metal chlorites
and the like, other ophthalmically acceptable preservatives and the
like and mixtures thereof. The concentration of the preservative
component, if any, in the present compositions is a concentration
effective to preserve the composition, and is often in a range of
about 0.00001% to about 0.05% or about 0.1% (w/v) of the
composition.
[0095] In addition, the present composition may include an
effective amount of resuspension component effective to facilitate
the suspension or resuspension of the corticosteroid component
particles in the present compositions. As noted above, in certain
embodiments, the present compositions are free of added
resuspension components. In other embodiments of the present
compositions effective amounts of resuspension components are
employed, for example, to provide an added degree of insurance that
the corticosteroid component particles remain in suspension, as
desired and/or can be relatively easily resuspended in the present
compositions, such resuspension be desired. Advantageously, the
resuspension component employed in accordance with the present
invention, if any, is chosen to be more compatible with or friendly
to the tissue in the posterior segment of the eye into which the
composition is placed than polysorbate 80.
[0096] Any suitable resuspension component may be employed in
accordance with the present invention. Examples of such
resuspension components include, without limitation, surfactants
such as poloxanes, for example, sold under the trademark
Pluronic.RTM.; tyloxapol; sarcosinates; polyethoxylated castor
oils, other surfactants and the like and mixtures thereof.
[0097] One very useful class of resuspension components are those
selected from vitamin derivatives. Although such materials have
been previously suggested for use as surfactants in ophthalmic
compositions, they have been found to be effective in the present
compositions as resuspension components. Examples of useful vitamin
derivatives include, without limitation, Vitamin E tocopheryl
polyethylene glycol succinates, such as Vitamin E tocopheryl
polyethylene glycol 1000 succinate (Vitamin E TPGS). Other useful
vitamin derivatives include, again without limitation, Vitamin E
tocopheryl polyethylene glycol succinamides, such as Vitamin E
tocopheryl polyethylene glycol 1000 succinamide (Vitamin E TPGSA)
wherein the ester bond between polyethylene glycol and succinic
acid is replaced by an amide group.
[0098] The presently useful resuspension components are present, if
at all, in the compositions in accordance with the present
invention in an amount effective to facilitate suspending the
particles in the present compositions, for example, during
manufacture of the compositions or thereafter. The specific amount
of resuspension component employed may vary over a wide range
depending, for example, on the specific resuspension component
being employed, the specific composition in which the resuspension
component is being employed and the like factors. Suitable
concentrations of the resuspension component, if any, in the
present compositions are often in a range of about 0.01% to about
5%, for example, about 0.02% or about 0.05% to about 1.0% (w/v) of
the composition.
[0099] The availability of minimally soluble corticosteroid
components, such as triamcinolone acetonide, to intraocular tissues
may be limited by the dissolution rate for these substances. Slow
dissolution is both good and bad for the patient. On the one hand,
after a single intravitreal injection of the present composition,
the mean elimination half-life for triamcinolone acetonide is
advantageously quite long, for example, about 19 days in
nonvitrectonized patients and measurable drug levels are detected
for up to about 3 months. On the other hand, therapeutic drug
levels in the vitreous compartment of the eye may not be achieved
for about 1 to about 3 days, due to the slow dissolution rate of
the corticosteroid component particles.
[0100] In one embodiment of the present invention, an effective
amount of a solubilizing component is provided in the composition
to solubilize a minor amount, that is less than 50%, for example in
a range of 1% or about 5% to about 10% or about 20% of the
corticosteroid component. For example, the inclusion of a
cyclodextrin component, such as .beta.-cyclodextrin,
sulfo-butylether .beta.-cyclodextrin (SBE), other cyclodextrins and
the like and mixtures thereof, at about 0.5 to about 5.0% (w/v)
solubilizes about 1 to about 10% of the initial dose of
triamcinolone acetonide. This presolubilized fraction provides a
readily bioavailable loading dose, thereby avoiding any delay time
in therapeutic effectiveness.
[0101] The use of such a solubilizing component is advantageous to
provide any relatively quick release of the corticosteroid
component into the eye for therapeutic effectiveness. Such
solubilizing component, of course, should be ophthalmically
acceptable or at least sufficiently compatible with the posterior
segment of the eye into which the composition is placed to avoid
undue damage to the tissue in such posterior segment.
[0102] The pharmacokinetics of the corticosteroid component, for
example, triamcinolone acetonide, following intravitreal
administration may involve both the rate of drug dissolution and
the rate of drug efflux via the anterior route. For example,
following a is single intravitreal injection of a composition
containing 4% (w/v) of triamcinolone acetonide, triamcinolone
acetonide concentration peaks (monitored in aqueous humor) after
several days at thousands of nanograms per mL. This peak
(C.sub.max) is followed by a rapid decrease lasting about 200
hours, and ends in a slow elimination phase with a half-life of
about 19 days. Patients typically require repeat dosing, for
example about every three months.
[0103] In one embodiment of the present invention, the compositions
further contain sustained release components, for example, polymers
(in the form for example of gels and microspheres), such as poly
(D,L,-lactide) or poly(D,L-lactide co-glycolide), in amounts
effective to reduce local diffusion rates and/or corticosteroid
particle dissolution rates. The result is a flatter elimination
rate profile with a lower C.sub.max and a more prolonged
therapeutic window, thereby extending the time between required
injections for many patients.
[0104] Any suitable, preferably conditionally acceptable, release
component may be employed. Useful examples are set forth above. The
sustained release component is preferably biodegradable or
bioabsorbable in the eye so that no residue remains over the long
term. The amount of the delayed release component included may very
over a relatively wide range depending, for example, on the
specific sustained release component is being employed, the
specific release profile desired and the like factors. Typical
amounts of delayed release components, if any, included in the
present compositions are in a range of about 0.05 to 0.1 to about
0.5 or about 1 or more percent (w/v) (weight of the ingredient in
the total volume of the composition) of the composition.
[0105] The present compositions can be prepared using suitable
blending/processing techniques or techniques, for example, one or
more conventional blending techniques. The preparation processing
should be chosen to provide the present compositions in is forms
which are useful for placement or injection into the posterior
segments of eyes of humans or animals. In one useful embodiment a
concentration corticosteroid component dispersion is made by
combining the corticosteroid component with water, and the
excipient (other than the viscosity inducing component) to be
included in the final composition. The ingredients are mixed to
disperse the corticosteroid component and then autoclaved.
Alternatively, the steroid powder may be y-irradiated before
addition to the sterile carrier. The viscosity inducing component
may be purchased sterile or sterilized by conventional processing,
for example, by filtering a dilute solution followed by
lyophylization to yield a sterile powder. The sterile viscosity
inducing component is combined with water to make an aqueous
concentrate. Under aseptic conditions, the concentrated
corticosteroid component dispersion can be blended or mixed and
added or combined as a slurry to the viscosity inducing component
concentrate. Water is added in a quantity sufficient (q.s.) to
provide the desired composition and the composition is mixed until
homogenous.
[0106] Methods of using the present composition are provided and
are included within the scope of the present invention. In general,
such methods comprise administering a composition in accordance
with the present invention to a posterior segment of an eye of a
human or animal, thereby obtaining a desired therapeutic effect.
The administering step advantageously comprises at least one of
intravitreal injecting, subconjunctival injecting, sub-tenon
injecting, retrobulbar injecting, suprachoroidal injecting and the
like. A syringe apparatus including an appropriately sized needle,
for example, a 27 gauge needle or a 30 gauge needle, can be
effectively used to inject the composition with the posterior
segment of an eye of a human or animal.
[0107] Ocular conditions which can be treated or addressed in
accordance with the present invention include, without limitation,
the following:
[0108] Maculopathies/retinal degeneration: macular degeneration,
including age related macular degeneration (ARMD), such as
non-exudative age related macular degeneration and exudative age
related macular degeneration, choroidal neovascularization,
retinopathy, including diabetic retinopathy, acute and chronic
macular neuroretinopathy, central serous chorioretinopathy, and
macular edema, including cystoid macular edema, and diabetic
macular edema. Uveitis/retinitis/choroiditis: acute multifocal
placoid pigment epitheliopathy, Behcet's disease, birdshot
retinochoroidopathy, infectious (syphilis, lyme, tuberculosis,
toxoplasmosis), uveitis, including intermediate uveitis (pars
planitis) and anterior uveitis, multifocal choroiditis, multiple
evanescent white dot syndrome (MEWDS), ocular sarcoidosis,
posterior scleritis, serpignous choroiditis, subretinal fibrosis,
uveitis syndrome, and Vogt-Koyanagi-Harada syndrome. Vascular
diseases/exudative diseases: retinal arterial occlusive disease,
central retinal vein occlusion, disseminated intravascular
coagulopathy, branch retinal vein occlusion, hypertensive fundus
changes, ocular ischemic syndrome, retinal arterial microaneurysms,
Coat's disease, parafoveal telangiectasis, hemi-retinal vein
occlusion, papillophlebitis, central retinal artery occlusion,
branch retinal artery occlusion, carotid artery disease (CAD),
frosted branch angitis, sickle cell retinopathy and other
hemoglobinopathies, angioid streaks, familial exudative
vitreoretinopathy, Eales disease. Traumatic/surgical: sympathetic
ophthalmia, uveitic retinal disease, retinal detachment, trauma,
laser, PDT, photocoagulation, hypoperfusion during surgery,
radiation retinopathy, bone marrow transplant retinopathy.
Proliferative disorders: proliferative vitreal retinopathy and
epiretinal membranes, proliferative diabetic retinopathy.
Infectious disorders: ocular histoplasmosis, ocular toxocariasis,
presumed ocular histoplasmosis syndrome (POHS), endophthalmitis,
toxoplasmosis, retinal diseases associated with HIV infection,
choroidal disease associated with HIV infection, uveitic disease
associated with HIV Infection, viral retinitis, acute retinal
necrosis, progressive outer retinal necrosis, fungal retinal
diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral
subacute neuroretinitis, and myiasis. Genetic disorders: retinitis
pigmentosa, systemic disorders with associated retinal dystrophies,
congenital stationary night blindness, cone dystrophies,
Stargardt's disease and fundus flavimaculatus, Bests disease,
pattern dystrophy of the retinal pigmented epithelium, X-linked
retinoschisis, Sorsby's is fundus dystrophy, benign concentric
maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma
elasticum. Retinal tears/holes: retinal detachment, macular hole,
giant retinal tear. Tumors: retinal disease associated with tumors,
congenital hypertrophy of the RPE, posterior uveal melanoma,
choroidal hemangioma, choroidal osteoma, choroidal metastasis,
combined hamartoma of the retina and retinal pigmented epithelium,
retinoblastoma, vasoproliferative tumors of the ocular fundus,
retinal astrocytoma, intraocular lymphoid tumors. Miscellaneous:
punctate inner choroidopathy, acute posterior multifocal placoid
pigment epitheliopathy, myopic retinal degeneration, acute retinal
pigment epithelitis and the like.
[0109] The present methods may comprise a single injection into the
posterior segment of an eye or may involve repeated injections, for
example over periods of time ranging from about one week or about 1
month or about 3 months to about 6 months or about 1 year or
longer.
EXAMPLES
[0110] The following non-limiting Examples are presented to
exemplify aspects of the present invention.
Examples 1 to 4
[0111] Four compositions are as follows: TABLE-US-00001 TABLE 1
Ingredient Example 1 Example 2 Example 3 Example 4 Triamcinolone
acetonide 2% (w/v) 2% (w/v) 4% (w/v) 4% (w/v) Sodium Hyaluronate
0.05% 0.5% 0.05% 0.5% (0.6 .times. 10.sup.6 DALTONS) (w/v) (w/v)
(w/v) (w/v) Sodium Phosphate 0.4% 0.4% 0.4% 0.4% (w/v) (w/v) (w/v)
(w/v) Vitamin E-TPGS 0.5% 0.5% 0.0 0.0 (w/v) (w/v)
.gamma.-cyclodextrin 0.5% 0.5% 0.0 0.0 (w/v) (w/v) Water for
Injection q.s. q.s. q.s. q.s. Viscosity at shear rate 20 cps 500
cps 20 cps 500 cps 0.1/second
[0112] Each of these compositions is prepared as follows.
[0113] A concentrated triamcinolone acetonide dispersion is made by
combining triamcinolone acetonide with water, Vitamin E-TPGS and
.gamma.-cyclodextrin, if any. These ingredients are mixed to
disperse the triamcinolone acetonide, and then autoclaved. The
sodium hyaluronate may be purchased as a sterile powder or
sterilized by filtering a dilute solution followed by
lyophylization to yield a sterile powder. The sterile sodium
hyaluronate is dissolved in water to make an aqueous concentrate.
The concentrated triamcinolone acetonide dispersion is mixed and
added as a slurry to the sodium hyaluronate concentrate. Water is
added q.s. (quantum sufficit, as much as suffices, in this case as
much as is required to prepare the homogenous mixture, dispersion,
gel or suspension) and the mixture is mixed until homogenous.
[0114] Each of these compositions produced a loose flocculation of
triamcinolone acetonide that is easily re-suspended by gentle
inversion. These compositions can be marketed in small volume
pharmaceutical grade glass bottles, and are found to be
therapeutically effective against macular edema when injected
intravitreally into human eyes.
Examples 5 to 7
[0115] Three compositions are as follows: TABLE-US-00002 TABLE 2
Ingredient Example 5 Example 6 Example 7 Triamcinolone acetonide
2.0% (w/v) 4.0% (w/v) 8.0% (w/v) Sodium hyaluronate 3.0% (w/v) 2.5%
(w/v) 2.0% (w/v) Sodium Phosphate 0.4% (w/v) 0.4% (w/v) 0.4% (w/v)
Water for Injection q.s. q.s. q.s. Viscosity at shear rate 300,000
cps 180,000 cps 100,000 cps 0.1/second
[0116] These compositions are prepared in a manner substantially
analogous to that set forth in Example 1.
[0117] The high viscosities of the compositions substantially slows
the particle sedimentation rate to an extent that no resuspension
processing is necessary or required over the estimated shelf life,
e.g., about 2 years, of the compositions. These compositions can be
marketed in prefilled syringes since they can not easily be removed
by a needle and syringe from a container. However, with the
compositions in prefilled syringes, the compositions can be
effectively injected into the posterior segment of an eye of a
human using a 27 gauge or a 30 gauge needle to provide a desired
therapeutic effect in the human eye.
[0118] The compositions of Examples 5 to 7 employ or contain a
sufficient concentration of high molecular weight sodium
hyaluronate so as to form a gelatinous plug or drug depot upon
intravitreal injection into a human eye. Triamcinolone acetonide
particles are, in effect, trapped or held within this viscous plug,
so that undesirable pluming does not occur, and the risk of drug
particles disadvantageously settling directly on the retinal tissue
is substantially reduced, for example, relative to using a
composition with a water-like viscosity, such as Kenalog.RTM. 40.
Since sodium hyaluronate solutions are subject to dramatic shear
thinning, these formulations are easily injected through 27 gauge
or even 30 gauge needles.
Examples 8 and 9
[0119] Two compositions are as follows: TABLE-US-00003 TABLE 3
Ingredient Example 8 Example 9 Triamcinolone acetonide 2.0% (w/v)
8.0% (w/v) Sodium hyaluronate (polymeric) 2.5% (w/v) 2.3% (w/v)
Sodium chloride 0.63% (w/v) 0.63% (w/v) dibasic sodium phosphate,
0.30% (w/v) 0.30% (w/v) heptahydrate Monobasic sodium phosphate,
0.04% (w/v) 0.04% (w/v) monohydrate Water for Injection q.s. q.s.
Viscosity at shear rate 170,000 .+-. 200,000 .+-. 25% cps
0.1/second 25% cps
[0120] These compositions are prepared in a manner substantially
analogous to that set forth in Example 1.
[0121] The high viscosities of the compositions substantially slows
the particle sedimentation rate to an extent that no resuspension
processing is necessary or required over the estimated shelf life,
e.g., about 2 years, of the compositions. These compositions can be
marketed in prefilled syringes since they can not easily be is
removed by a needle and syringe from a container. However, with the
compositions in prefilled syringes, the compositions can be
effectively injected into the posterior segment of an eye of a
human using a 27 gauge or a 30 gauge needle to provide a desired
therapeutic effect in the human eye.
[0122] The sodium hyaluronate powders used in these compositions
(as well as in the other compositions identified in the Examples
herein) have water contents in a range of about 4% to about 20%,
preferably about 4% to about 8%, by weight. Differences in the
average molecular weight of the hyaluronate used can result in
variation in the viscosity of compositions in accordance with the
present invention which have the same nominal chemical make-ups.
Thus, the viscosities indicated herein should be understood to be
target viscosities, with the composition being acceptable for use
if the actual viscosity of the composition is within plus or minus
(.+-.) about 25% or about 30% or about 35% of the target
viscosity.
[0123] Because each of the compositions set forth in the Examples
has a density of about 1 gm/ml, the percentages set forth herein as
being based on weight per volume (w/v) can also be considered as
being based on weight per weight (w/w).
[0124] The compositions of Examples 8 and 9 employ or contain a
sufficient concentration of high molecular weight (i.e. polymeric)
sodium hyaluronate so as to form a gelatinous plug or drug depot
upon intravitreal injection into a human eye. Preferably the
average molecular weight of the hyaluronate used is less than about
2 million, and more preferably the average molecular weight of the
hyaluronate used is between about 1.3 million and 1.6 million. The
triamcinolone acetonide particles are, in effect, trapped or held
within this viscous plug of hyaluronate, so that undesirable
pluming does not occur upon intravitreal injection of the
formulation. Thus, the risk of drug particles disadvantageously
settling directly on the retinal tissue is substantially reduced,
for example, relative to using a composition with a water-like
viscosity, such as Kenalog.RTM. 40. Since sodium hyaluronate
solutions are subject to dramatic shear thinning, these
formulations are easily injected through 27 gauge or even 30 gauge
needles.
[0125] The most preferred viscosity range for the Example 8 and 9
formulations is 140,000 cps to 280,000 cps at a shear rate
0.1/second at 25.degree. C.
[0126] The triamcinolone acetonide used in the formulations set
forth herein has the chemical name 9-Fluoro-11,21-dihydroxy-1
6,17-[1-methylethylidenebis(oxy)]pregna-1,4-diene-3,20-dione, and
can have the following structure ##STR1##
[0127] The molecular formula of triamcinolone acetonide is
C.sub.24H.sub.31FO.sub.6 and its molecular weight is 434.49. The
solubility of triamcinolone acetonide in water is about 25.4
.mu.L/mL.
[0128] The Examples 8 and 9 formulations are prepared as sterile
products of a uniform, opaque white dispersion of microfine
triamcinolone acetonide particles suspended in a hyaluronate-based
polymeric hydrogel, intended for intravitreal injection.
[0129] The Examples 8 and 9 formulations can be used top treat, for
example, macular edema in patients with diabetes, central retinal
vein occlusion, and branch retinal vein occlusion. Notable the
Examples 8 and 9 formulations are formulated using only excipients
that are fully compatible (i.e. non-toxic) to the eye, particularly
to the retina. The Examples 8 and 9 formulations (2% (w/w) and 8%
(w/w) triamcinolone acetonide, respectively) are buffered at
physiological pH with a low concentration of sodium phosphate
salts; rendered isotonic with sodium chloride, and use Water for
Injection, USP, as the vehicle.
[0130] A target dosage of 1 mg of the triamcinolone acetonide
active agent can be delivered in a 50 mg (approximately 48 .mu.L)
injection of the Example 82% (w/w) triamcinolone acetonide gel
suspension formulation. A target dosage of 4 mg of the
triamcinolone acetonide active agent can be delivered in a 50 mg
(approximately 48 .mu.L) injection of the Example 98% (w/w)
triamcinolone acetonide gel suspension formulations.
[0131] As noted, the triamcinolone present in our formulations does
not rapidly, or even slowly, settle out from or precipitate from
the formulations. Significantly our Example 8 and 9 formulations
have a shelf life of at least two years, meaning that these
formulations can be left standing (without agitation) for up to
about two years before administration to an eye, and after two
years the same formulations can still provide a consistent and
accurate dose of triamcinolone upon injection to the formulation to
an eye. For example, upon preparation (as set froth in Example 15),
50 .mu.L of our 8% formulation provides 4 mg of triamcinolone
acetonide, and if left standing for up to about 2 years 50 .mu.L of
our 8% formulation stills provides 4 mg.+-.15% of triamcinolone
acetonide, thereby meeting the U.S.P. definition of consistent
dosage after storage.
[0132] As noted, the composition of triamcinolone 2% injectable gel
suspension (Example 8) is triamcinolone 2.0% (w/w), sodium
hyaluronate, sodium chloride, dibasic sodium phosphate
(heptahydrate), monobasic sodium phosphate (monohydrate), and water
for injection.). The composition of triamcinolone 8% injectable gel
suspension (Example 9) is triamcinolone 8.0% (w/w), sodium
hyaluronate, sodium chloride, dibasic sodium phosphate
(heptahydrate), monobasic sodium phosphate (monohydrate), and water
for injection.
[0133] The triamcinolone acetonide injectable gel suspension we
have invented is a viscous suspension of triamcinolone acetonide
formulated at concentrations of 8% and 2% with sodium hyaluronate,
sodium chloride, dibasic sodium phosphate (heptahydrate), monobasic
sodium phosphate (monohydrate), and water for injection (i.e. the
formulations of Examples 8 and 9 respectively). The suspensions are
prepared to have physiologic pH, and to be isotonic, and
preservative-free. The Examples 8 and 9 suspensions can be supplied
in single-use glass syringes with fixed 27 gauge needles. The
syringes are overfilled to 0.17-0.18 mL, and calibrated to deliver
0.05 mL when primed to a black or blue mark on the barrel of the
syringe to thereby provide the 2% and 8% suspensions to deliver 1
mg and 4 mg of triamcinolone, respectively (the pre-filled syringes
are made by Allergan, Inc., Irvine, Calif.). These syringes have a
shelf life of at least about two years when stored at 2-8.degree.
C.
Example 10
Ocular and Systemic Pharmacokinetics of a 4% (4 mg) Triamcinolone
Acetonide Gel Suspension Formulation upon Intravitreal
Injection
[0134] An experiment was carried out to evaluate the intraocular
and systemic pharmacokinetics of triamcinolone acetonide gel
suspensions (TAA.sub.gs) following intravitreal administration. The
formulations used were: (1) 4% w/v (40 mg/mL) triamcinolone
acetonide formulated as a high viscosity borate-buffered 2.5% (w/w)
hyaluronic acid suspension, and; (2) 16% w/v (160 mg/mL)
triamcinolone acetonide formulated as a high viscosity
borate-buffered 2.5% (w/w). 100 .mu.L of each formulation was
injected into separate rabbit eyes using a 25-gauge needle syringe
to provide 4 mg or 16 mg of triamcinolone actinide, respectively.
Except as noted the formulations used in this Example 10 were the
same as the Example 8 and 9 formulations. For example, the same
type of sodium hyaluronate was used in these Example 10
formulations.
[0135] Following a single intravitreal injection (New Zealand
albino rabbits) of 100 .mu.L of the 4% w/v triamcinolone acetonide
formulation (4 mg triamcinolone acetonide), aqueous humor, vitreous
humor, retina and plasma were collected on days 1, 3, 10, 17, 31
and 45 and analyzed for triamcinolone acetonide by liquid
chromatography tandem mass spectrometry. In vitreous humor, the
maximal triamcinolone acetonide concentration (C.sub.max) was 385
.mu.g/g on Day 10. The relatively constant concentrations (i.e.
sustained release) of triamcinolone acetonide were observed from
Day 1 to Day 45. (Tables 4 and 5) Therefore, the TAA.sub.gs
formulation delivers a relatively stable concentration (i.e.
approximately zero-order release kinetics) of triamcinolone
acetonide to the retina over at least 45-day period following
single intravitreal injection.
[0136] Table 4 also shows that the ratio of the amount of
triamcinolone acetonide present in the vitreous to the amount of
triamcinolone acetonide present in the aqueous chamber can be
greater than 1000:1 at all time points.
[0137] Table 5 shows that ratio of the total amount of
triamcinolone acetonide present in the vitreous over the 45 day
study period to the total amount of triamcinolone acetonide present
in the aqueous humor over the 45 day study period can be greater
than about 5,000:1. TABLE-US-00004 TABLE 4 Triamcinolone acetonide
concentration in aqueous humor, retina and vitreous humor after a
single intravitreal injection of a 4% triamcinolone acetonide
formulation in albino rabbits Triamcinolone Acetonide (.mu.g/mL or
.mu.g/g) Timepoint (Day) Aqueous Humor Vitreous Humor 1 0.319 382 3
0.200 335 10 0.052 385 17 0.033 338 31 0.014 185 45 0.011 222
[0138] TABLE-US-00005 TABLE 5 Pharmacokinetic parameters of
triamcinolone acetonide in ocular tissues after a single
intravitreal injection of 4% triamcinolone acetonide formulation in
albino rabbits C.sub.max AUC.sub.0-45day Treatment (.mu.g/mL or
.mu.g/g) (.mu.g day/mL or .mu.g day/g) Vitreous Humor 4%
Triamcinolone 385 12500 Acetonide Injectable Aqueous Humor 4%
Triamcinolone 0.319 2.36 Acetonide Injectable
[0139] Following intravitreal administration of the 4% TAA.sub.gs
formulation in albino rabbits, triamcinolone acetonide was absorbed
into the systemic circulation with mean plasma C.sub.max of 15.8
ng/mL at 1 day postdose. Between days 2 and 45, plasma levels drop
to 7 and 1 ng/mL, respectively. Thus, our the triamcinolone
acetonide gel suspension formulations are free of excipients with
known ocular toxicity, and through sustained release from the gel
delivers prolonged levels of triamcinolone acetonide to the
vitreous and retina.
Example 11
Triamcinolone Gel Suspensions to Treat Ocular Conditions
[0140] Introduction
[0141] As set forth herein, we have invented triamcinolone
acetonide gel suspensions (TAA.sub.gs) and their use to treat
various ocular conditions, including macular edema, such as macular
edema associated with diabetes and/or a retinal vein occlusion,
(branch or central), and to maintain or to improve visual acuity.
Our TAA.sub.gs formulations can contain a polymeric hyaluronic
acid.
[0142] The blood-aqueous barrier ("BAB") is a membrane of the
capillary bed of the ciliary body of the eye that influences or
controls two-way transfer of fluids between the aqueous chamber of
the eye and the blood. The BAB acts as an anatomical mechanism to
reduce or prevent exchange of materials between the chambers of the
eye and the blood.
[0143] The blood-retinal barrier ("BRB") is composed of specialized
nonfenestrated tightly-joined (tight junction) retinal epithelium
and adjacent retinal blood vessel endothelium cells that forming a
transport barrier for certain substances between the retinal
capillaries and the retinal tissue. BRB breakdown is symptomatic of
various retinal ocular conditions, including reduced visual acuity,
macular edema, macula degeneration, retinal swelling, and other
retinopathies, including diabetic retinopathy.
[0144] This experiment was designed to assess efficacy and duration
of action of particular TAA.sub.gs polymeric hyaluronic acid
formulations injected intravitreally to treat break down
(deterioration) of the blood-aqueous barrier ("BAB") and of the
blood-retinal barrier ("BRB") in mammal eyes. Generally, a reduced
BRB breakdown is a is desirable condition or state, as it indicates
a stabilized or more normal or more healthy retina (tightened
barrier). On the other hand, where in a model system a BAB
breakdown is induced, it is considered a positive or beneficial
result if upon intravitreal administration of a steroid, such as a
corticosteroid or an anti-inflammatory steroid into an eye with BAB
breakdown, an improvement of the BAB breakdown is not observed.
Failure of BAB breakdown to be reduced or repaired is an indication
that the steroid intravitreally administered has not in significant
quantity made it's way (i.e. by diffusion and/or by an active
transport mechanism) to the aqueous (or anterior) chamber ("AC") of
the eye. It is known that AC presence of various steroids can cause
increased intraocular (i.e. aqueous humor) pressure (elevated IOP
is symptomatic of glaucoma) and/or cataract generation.
SUMMARY
[0145] The experiment was carried out using intravitreal injection
of either a 1 mg or 4 mg triamcinolone acetonide gel suspension
(TAA.sub.gs) (the Example 8 and 9 formulations, respectively) in a
rabbit model of VEGF-mediated blood-aqueous barrier (BAB) and
blood-retinal barrier (BRB) breakdown. The model system used is set
forth in Edelman et al., Corticosteroids inhibit VEGF-induced
vascular leakage in a rabbit model of blood-retinal and
blood-aqueous barrier breakdown, Exp Eye Res 2005 February;
80(2):249-58, although instead of intravitreal injection of a
triamcinolone acetonide saline suspension, the formulation of
Examples 8 and 9 above were used in this experiment.
[0146] BAB breakdown was measured by anterior chamber
fluorophotometry. BRB breakdown was measured by vitreal
fluorophotometry and subjective grading of fluorescein angiograms.
In addition, VEGF-induced changes in vessel caliber and tortuosity
(AVC-T) were assessed by subjective scoring of fundus images. The
equipment and procedures used to obtain anterior chamber
fluorophotometry, vitreal fluorophotometry, fluorescein angiograms,
and fundus images were as set forth in Edelman (2005) supra.
[0147] The results obtained in this experiment can be summarized as
follows:
1. intravitreal 1 mg TAA.sub.gs had no effect on VEGF-induced BAB
at any time point as compared to control eyes.
2. intravitreal 1 mg TAA.sub.gs significantly inhibited
VEGF-induced BRB and AVC-T through at least 6 weeks.
3. intravitreal 4 mg TAA.sub.gs did not significantly inhibit
VEGF-induced BAB breakdown at 10, 22, and 30 weeks.
[0148] 4. intravitreal 4 mg TAA.sub.gs significantly blocked
VEGF-induced angiographic BRB breakdown for at least about 14
weeks, fluorophotometric BRB breakdown for at least about 22 weeks,
and .DELTA.VC-T for at least about 14 weeks, and in at least some
rabbit eyes for up to at least about 30 weeks.
[0149] Methods
[0150] Female Dutch Belt rabbits (5 to 6 months old) were randomly
assigned to a no treatment group (control; n=12 eyes), to a group
to receive intravitreal injection of 1 mg TAA.sub.gs (n=8 eyes), or
to a group to receive intravitreal injection of 4 mg TAA.sub.gs
(n=10 eyes). 50 .mu.L of the 2% or 8% (Example 8 and Example 9
formulations respectively) TAA.sub.gs formulations were
intravitreally injected into eyes of the later two groups on Day 1.
Since the VEGF responses are transient and return to baseline by
one week (See Edelman et al.(2005), supra), the TAA.sub.gs duration
of action was determined by injecting VEGF intravitreally at
multiple times points over a 10 week for 1 mg TAA.sub.gs and over a
30 week for the 4 mg TAA.sub.gs. Thus, the VEGF was injected
intravitreally at 2 weeks, 6 weeks and 10 weeks after study
initiation for the 1 mg TAA.sub.gs study rabbits. The VEGF was
injected intravitreally at 2 weeks, 6 weeks and 10 weeks, 14 weeks,
22 weeks, and 30 weeks after study initiation for the 4 mg
TAA.sub.gs is study rabbits.
[0151] Drug (FAA.sub.gs) Injection
[0152] General anesthesia was initiated by isoflurane inhalation
and the ocular surface was anesthetized with 1-2 drops of 1%
proparacaine. Rabbits were then placed on a heated pad, covered
with a sterile drape, and both eyes were treated with Betadine for
30 seconds and rinsed with sterile saline. 50 .mu.L of the 1 mg or
4 mg TAA.sub.gs formulations (the Example 8 and 9 formulations,
respectively) were administered via their original glass syringes
and 27 gauge needle, and each syringe was calibrated to the blue
line prior to injection). The syringe needle was inserted about 3
mm posterior to the limbus and aimed inferior and posterior. After
injection, the needle was removed and the eye was checked for
leakage.
[0153] Rabbit Model of VEGF-Induced Vasculopathologies
[0154] The Edelman (2005) A model of BRB and BAB breakdown was used
to determine the pharmacologic duration of action after
intravitreal injection of 1 and 4 mg TAA.sub.gs. Rabbits were
placed on a heated pad, covered with a sterile drape, and 500 ng of
recombinant human vascular endothelial growth factor (165 amino
acid variant; VEGF.sub.165, obtained from R & D Systems,
Minneapolis, Minn.) in 50 .mu.L sterile phosphate buffered saline
was injected intravitreally into all eyes via a 27G needle.
[0155] Forty-Eight hours after VEGF injection, eyes were dilated
with 10% phenylephrine HCl and 1% cyclopentolate HCl. Anesthesia
was induced via subcutaneous injection of 50 mg/kg ketamine and 10
mg/kg xylazine. Once anesthetized, the rabbit fundus was visualized
with a Zeiss retinal camera and fundus images were obtained and
stored on a personal computer. Sodium fluorescein was administered
intravenously (11.75 mg/kg) and late phase angiograms were obtained
after 5-10 min. Fifty minutes after fluorescein injection BRB and
BAB integrity were measured using scanning ocular fluorophotometry
(Fluorotron Master).
[0156] Fundus images were graded on a scale of 1 (normal) to 5
(maximal blood vessel dilation and tortuosity) by three masked
observers. Retinal fluorescein leakage was scored from angiograms
read by masked observers on a scale of 1 (no fluorescein
leakage=normal) to 5 (maximum fluorescein leakage).
[0157] Angiogram and fundus image scores were compared with an
unpaired non-parametric Wilcoxon Rank Sum/Mann-Whitney U-Test.
Fluorophotometric measurements (area under the curve) were analyzed
with a two tailed Students t-test. P-values.ltoreq.0.05 are
determined to be significant.
[0158] Results
[0159] 2% TAA.sub.gs: 1 mg dose
1. Effect on blood-retinal barrier (BRB) breakdown. Subjective
grading of angiograms (FIG. 1) or vitreal fluorophotometry (FIG. 2)
shows that VEGF-induced BRB breakdown was suppressed in eyes
treated with 1 mg TAA.sub.gs through at least about six weeks.
2. Effect on changes in retinal vessel caliber-tortuosity
(.DELTA.VC-T). Subjective grading of fundus images (FIG. 3) shows
that VEGF-induced .DELTA.VC-T was suppressed in eyes treated with 1
mg TAA.sub.gs through at least about six weeks.
3. Effect on blood-aqueous barrier (BAB) breakdown. Anterior
chamber fluorophotometry shows that the extent of VEGF-induced BAB
breakdown was not suppressed in rabbit eyes treated with the 1 mg
TAA.sub.gs for at least at about 10 weeks (FIG. 4).
8% TAA.sub.gs: 4 mg Dose
[0160] 1. Effect on BRB breakdown. Subjective grading of angiograms
(FIG. 1) or is vitreal fluorophotometry (FIG. 2) shows that
VEGF-induced BRB breakdown was suppressed in eyes treated with 4 mg
TAA.sub.gs for between about fourteen weeks (FIG. 1) and twenty
weeks (FIG. 2).
[0161] 2. Effect on .DELTA.VC-T. Subjective grading of fundus
images (FIG. 3) shows that VEGF-induced .DELTA.VC-T was clearly
suppressed in all eyes treated with 4 mg TAA.sub.gs for at least
fourteen weeks, and for some rabbits through twenty two to thirty
weeks (210 days or about 7.5 months).
3. Effect on BAB breakdown. Anterior chamber fluorophotometry (FIG.
4) shows that the extent of VEGF-induced BAB breakdown was not
significantly suppressed at 10, 22, and 30 weeks.
[0162] These results showed significant inhibition of VEGF-induced
BRB responses for at least six weeks with intravitreal 1 mg
TAA.sub.gs (FIGS. 1-3), and for at least 30 weeks with intravitreal
4 mg TAA.sub.gs (FIG. 3). Note that FIG. 5 (a negative image of a
photograph of the eye of a rabbit in this Example 11 thirty weeks
after intravitreal injection of 50 .mu.L of the 4 mg TAA.sub.gs
formulation) shows that our TAA.sub.gs. formulation can remain
intact in the vitreous for a prolonged period. In FIG. 5 item A is
the intact, single object (bolus) intravitreal 4 mg, 50 .mu.L TAA
gel suspension 30 weeks after intravitreal injection. B is the
vitreous chamber and C is a light reflection artifact.
[0163] Thus, based upon a demonstrated therapeutic effect for as
long as thirty weeks after intravitreal injection of a TAA.sub.gs
formulation, which TAA.sub.gs which remains intact in the vitreous
for the same period, our TAA.sub.gs formulation can be
characterized as a sustained release, biocompatible, biodegradable
implant.
[0164] Thus, the results from this experiment demonstrate that
intravitreal administration of a TAA.sub.gs formulation can be used
to treat a retinal disease or condition (such as a retinal disease
or condition which includes BRB breakdown or deterioration) with no
or is little diffusion of drug to the anterior chamber (as
determined for example by the Example 10 data, and by the lack of
or of a reduced effect on BAB breakdown set forth in this Example
11). It can therefore be concluded that our TAA.sub.gs formulations
can be used to advantageously treat a retinal disease or condition
with, for example, little or no IOP elevation (with reduced
incidence of glaucoma therefore) and with no or little inducement
of cataract formation or intraocular inflammation.
[0165] Our TAA.sub.gs formulations have numerous novel and
advantageous characteristics making them well suited for the
treatment of ocular conditions, such as posterior ocular
conditions, such as macular edema, such as diabetic macula edema.
For example our TAA.sub.gs formulation (for example the Examples 8
and 9 formulations) do not contain any preservatives or excipients
such as an alcohol (such as a benzyl alcohol) or a polysorbate
(such as a polysorbate 80). Thus our TAA.sub.gs formulations have a
reduced retinal toxicity.
[0166] Additionally, our TAA.sub.gs formulations have superior
depot and release characteristics. Intravitreal injection of an
aqueous (i.e. in saline) solution of a triamcinolone provides
active agent which quickly (in a matter of hours) diffuses out of
the retina. Our TAA.sub.gs formulations have a longer duration of
intravitreal therapeutic activity because therapeutic amounts of
the triamcinolone can diffuse out of the gel over a period of
thirty weeks or more. Thus, use of a suspending agent such as a
polymeric hyaluronate can provide the consistency permitting
substantially zero order kinetics release of the triamcinolone form
the hyaluronate, proving thereby both an extended duration of
effect of the triamcinolone and reduced levels and therefore a
reduced effect of the triamcinolone upon the anterior chamber of
the eye and a reduced systemic exposure to the active agent.
[0167] Our invention comprises triamcinolone acetonide injectable
gel suspensions formulated viscous suspensions of triamcinolone
acetonide at concentrations of, for example, 8% and 2% with sodium
hyaluronate, sodium chloride, dibasic sodium phosphate
(heptahydrate), monobasic sodium phosphate (monohydrate), and water
for injection. The triamcinolone acetonide injectable gel
suspensions are preferably at physiologic pH, isotonic, and
preservative-free. Triamcinolone acetonide injectable gel
suspensions within the scope of our invention can be supplied in
single-use glass syringes with fixed 27 gauge needles. The syringes
can be overfilled to 0.17-0.18 mL, and calibrated to deliver 0.05
mL when primed to a black mark on the barrel of the syringe to
thereby deliver, for example, 2% and 8% suspensions of 1 mg and 4
mg of triamcinolone, respectively. Our triamcinolone acetonide
injectable gel suspensions can be defined as implants which upon
injection (i.e. implantation) into the vitreous provided sustained
release (i.e. over a period of up to seven months or longer) from
the compact gel bolus injected.
[0168] Our triamcinolone acetonide injectable gel suspensions are
preferably not used as visualizing agents, for example in
conjunction with a vitrectomy (see eg U.S. Pat. No. 6,395,294)
because the viscous, gel nature of our formulations prevents them
for rapidly spreading out within the vitreous, as is required for a
vitreal visualization agent (such as for example triptan vision
blue, or water or saline based triamcinolone solutions or
formulation, such as Kenalog.RTM.). A lower molecular weight
hyaluronate with triamcinolone acetonide can be used for
visualization (for example with a viscosity at a shear rate of
about 0.1/second of less than about 90,000 cps, such as for example
about 1,000 to 10,000 cps), whereas the higher molecular weight
hyaluronate of Examples 8 and 9 are preferred for use as in situ
forming vitreous implants.
Example 12
Treatment of Macular Edema with Intravitreal Triamcinolone
Acetonide Suspension
[0169] A 64 year old obese female patient with symptoms of diabetes
presents with vision loss due to macula edema with central retinal
vein occlusion and/or branch retinal vein occlusion. She receives
intravitreal injection of 4 mg of a high viscosity triamcinolone
acetonide (polymeric hyaluronate based) suspension, such as the
Example 9 formulation.
[0170] Twelve months after injection she demonstrates an improved
best corrected visual acuity of fifteen or more letters from
baseline as determined using the Early Treatment of Diabetic
Retinopathy Study (ETDRS) visual acuity chart.
Example 13
Treatment of a Posterior Ocular Condition with Intravitreal
Triamcinolone Acetonide Suspension
[0171] Patients with a posterior ocular condition (such as a
macular edema, uveitis, or macular degeneration) can be treated by
intravitreal injection of 1 mg or 4 mg of a high viscosity
triamcinolone acetonide gel (polymeric hyaluronate based)
suspension, such as the Example 8 or Example 9 formulation.
Alternately, the formulation can be administered by subconjunctival
injection to treat the posterior ocular condition. These patients
can demonstrate twelve months after injection an improved best
corrected visual acuity of fifteen or more letters from baseline as
determined using the Early Treatment of Diabetic Retinopathy Study
(ETDRS) visual acuity chart.
[0172] In clinical studies being carried out for the treatment of
macula edema, participated in, or supervised by the inventors or
their colleagues over one thousands patients have received
intravitreal injection of the Example 8 or Example 9 formulations.
Yet the incidence of aseptic endophthalmitis in these numerous
patients has been 0%. This is striking when one notes that the
incidence of endophthalmitis upon intravitreal injection of Kenalog
is about 1% to 2%.
[0173] Thus, it is important to note that the desired therapeutic
result (maintained or improved vision) can be obtained with little
or no incidence of intraocular inflammation. Without wishing to be
bound by theory we can postulate reasons for this exceptional
result. Macrophages are involved with the removal of particulate
material from the body through phagocytosis. However, particles of
large morphology and irregular is geometry can be toxic to
macrophages and lead to cell death. The death of macrophages can
lead to release of pro-inflammatory cytokines that cause both acute
and chronic inflammation. Clinical examples of toxicity from
particles include gouty arthritis, where urate crystals that range
from 5 to 20 microns cause a debilitating arthritis. Helliwell P.,
Use of an objective measure of articular stiffness to record
changes in fingerjoints after intra-articular injection of
corticosteroid, Ann Rheum Dis 1997; 56:71-73. Macrophages are
injured when phagocytosing the urate crystals and this initiates
the inflammatory response. When patients are treated with
medication that reduces macrophage activity, such as colchicine,
this leads to a dramatic improvement in the arthritis. Another
example of joint inflammation related to particles is
`crystal-induced synovitis,` where 1-2% of patients that receive
intra-articular injections of Lederspan, Kenalog, or other
corticosteroid depot formulation, develop a post-injection
exacerbation of the joint inflammation. McCarty D., et al.,
Inflammatory reaction after intrasynovial injection of
microcrystalline adrenocorticosteroid esters, Arthritis and
Rheumatism, 7(4); 359-367 (1964). The particles in these
formulations, which are on the average over 10 microns and have
irregular morphology, are very similar to the urate crystals in
joint of patients with gout. Significantly, in our formulations the
triamcinolone particles (crystals) are not available to and/or are
substantially ignored by macrophages due to the aggregation
(suspension) of the triamcinolone particles in the high molecular
weight hyaluronate used in our formulations. The fact that our
triamcinolone formulations are in situ forming implants can also
limit the exposure of whole or individual triamcinolone crystals to
sensitive ocular tissues, concomitantly thereby limiting macrophage
activation and hence also limiting or preventing an intraocular
inflammatory response. It is important to note that with our
formulation the particular high viscosity hyaluronic acid polymer
chosen maintains the triamcinolone crystals in a collective matrix
that acts as a sustained-release reservoir which decrease the need
for frequent repeat injections. Thus, our formulation forms a
cohesive agglomerate upon intravitreal injection. The reduced
surface area of such an agglomerate facilitates provision and
maintenance of a lower release rate of the triamcinolone, as
compared to much larger surface area saline suspension of a
triamcinolone (such as Kenalog). The cohesiveness of our
formulation is exemplified by the fact that the formulation
maintains its internal consistency (i.e. its shape after injection)
for at least about 30 weeks after intravitreal injection (see FIG.
5).
[0174] Additionally, the compositions of our invention are
preferably formulated with hyaluronic acid, a material known for
its anti-inflammatory abilities. Dea I. et al., Hyaluronic acid: a
novel, double helical molecule, Science, 1973 Feb. 9; 1
79(73):560-2.).
[0175] Furthermore, the absence of preservatives and/or stabilizers
(such as benzyl alcohol and polysorbate 80) in our formulation
reduces the retinal toxicity of our formulations as compared to
formulations which contain one or more preservatives and/or
stabilizers.
[0176] The combination of these five factors (lack of injury to
macrophages, low availability of the triamcinolone crystal to
macrophages, use of a biocompatible polymer, use of a high
viscosity biocompatible polymer, and absence of preservatives and
stabilizers provides an optimal ophthalmic delivery system which
limits the incidence of post-injection aseptic endophthalmitis.
[0177] A preferred embodiment of our invention can be the Example 8
and 9 formulations in which the average diameter of the
triamcinolone particles present in the formulations is less than 10
microns and preferably less than 5 microns, and additionally with a
uniform (spherical) morphology. It has been shown in the pulmonary
literature that micronized particles of corticosteroids, <10
microns, and preferably <5 microns, are less injurious to
macrophages, and have the potential for less inflammation. (Robert
A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes
Bioscience, Georgetown, Tex., 2003). Thus, preparing our
formulations with a is median triamcinolone particle size of <5
microns and with uniform shape provides formulation which are even
more biocompatible in the vitreous and with less propensity to
cause intraocular inflammation.
Example 14
Six Month Ocular and Systemic Pharmacokinetics of Triamcinolone
Acetonide Following Intravitreal Injection of 2% (1 mg) and 8% (4
mg) Triamcinolone Acetonide Injectable Gel Suspension Formulations
in Rabbit Eves
[0178] An experiment was carried out to compare the ocular and
systemic pharmacokinetics of triamcinolone acetonide (TA) following
a single unilateral intravitreal injection of 2% (1 mg) and 8% (4
mg) TA injectable gel suspensions in new Zealand white rabbit eyes.
These suspensions are the TA formulations of Examples 8 and 9,
respectively.
[0179] Seventy-two female New Zealand White rabbits were obtained
from Harlan (Indianapolis, Ind.). The rabbits were specific
pathogen free (SPF), 17-18 weeks old and weighed 2.58-3.15 kg at
the time of dosing. The seventy-two female rabbits were
intravitreally injected with one of two TA doses (2% or 8%) and
ocular and systemic pharmacokinetics monitored. Rabbits (four per
group) were sacrificed on days 2, 4, 11, 32, 64, 92, 121, 151 and
183 for aqueous humor (AH), vitreous humor (VH) and plasma drug
levels determined at each such time point at each of these three
physiological locations. Samples were quantified using validated
LC-MS/MS methods with assay range for TA of 0.2-20 ng/mL in plasma,
1-500 ng/mL in AH and 0.4-100 pg/mL in VH.
[0180] This study was a single treatment, parallel design, with 18
treatment groups and non-serial samples collected from each animal,
as shown by Table 6. TABLE-US-00006 TABLE 6 Study Design Euthanasia
and Number of Treatment (Right Eye Only) Necropsy Group Rabbits
(Day 1 = Day of intravitreal injection) TA Dosed (Day) A 4 2% (1
mg) Triamcinolone Gel Suspension 1 mg 2 B 4 2% (1 mg) Triamcinolone
Gel Suspension 1 mg 4 C 4 2% (1 mg) Triamcinolone Gel Suspension 1
mg 11 D 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 32 E 4 2% (1
mg) Triamcinolone Gel Suspension 1 mg 64 F 4 2% (1 mg)
Triamcinolone Gel Suspension 1 mg 92 G 4 2% (1 mg) Triamcinolone
Gel Suspension 1 mg 121 H 4 2% (1 mg) Triamcinolone Gel Suspension
1 mg 151 I 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 183 J 4 8%
(4 mg) Triamcinolone Gel Suspension 4 mg 2 K 4 8% (4 mg)
Triamcinolone Gel Suspension 4 mg 4 L 4 8% (4 mg) Triamcinolone Gel
Suspension 4 mg 11 M 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg
32 N 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 64 O 4 8% (4 mg)
Triamcinolone Gel Suspension 4 mg 92 P 4 8% (4 mg) Triamcinolone
Gel Suspension 4 mg 121 Q 4 8% (4 mg) Triamcinolone Gel Suspension
4 mg 151 R 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 183
[0181] The seventy-two rabbits received a single unilateral (right
eye) intravitreal injection of either 2% (1 mg) or 8% (4 mg) TA gel
suspension. On day 1 each rabbit received an intravitreal injection
into the midvitreous region through the dorsotemporal quadrant of
the right eye, approximately 2-3 mm posterior to the limbus. For
each injection, the needle of a pre-filled syringe (2% and 8% TA
pre-filled syringes) was introduced through the dorsotemporal
quadrant of the eye, approximately 2-3 mm posterior to the limbus,
with the bevel of the needle directed downward and posteriorly to
avoid the lens. 50 .mu.L of either the 2% or 8% formulation was
injected in a single bolus at a location roughly in the center of
the vitreous.
[0182] There were no drug-related effects on body weight and
mortality. Following a single intravitreal injection of either 2 or
8% TA gel suspension, TA was detected in the is AH, VH and plasma
at the earliest timepoint of Day 2. No contralateral diffusion of
TA to the untreated eyes was detected in AH. The AH mean maximal
concentrations (C.sub.max) for 2% and 8% TA gel suspension were
27.6 ng/mL (Day 2) and 29.5 ng/mL (Day 11), respectively. The AH
drug levels for the 2% and 8% dose were detectable up to Day 32
(4.15 ng/mL) and Day 151 (3.55 ng/mL), respectively. The area under
the AH concentration time curve (AUC.sub.0-tlast) was
dose-dependent for the 2% (328 ng-day/mL) and 8% (1311 ng-day/mL)
gel suspension with half-life (t.sub.1/2) of 12.4 and 94.1 days,
respectively.
[0183] Following intravitreal injection of 2% and 8% TA gel
suspension, VH concentration of TA declined from 444 pg/g (57.6%
dose remaining) at 2 days postdose to 22.1 .mu.g/g (3.4% dose
remaining) by 32 days post dose and 1460 .mu.g/g (51.2% dose
remaining) at 2 days to 33 .mu.g/g (1.3% dose remaining) by 151
days post dose, respectively. No contralateral diffusion of TA to
the untreated eyes was detected in VH at all timepoints except for
the 8% dose on Day 2 (0.306 pg/g). The AUC.sub.0-tlast for the 2%
and 8% doses were 3410 pg-day/g and 68800 pg-day/g, respectively.
The t.sub.1/2 for the 2% and 8% doses were 8.57 and 32.8 days,
respectively. This 33 day half life is significantly greater than
the 15 day half life reported for a saline suspension of TA (such
as is Kenalog) in the vitreous (Aubren (2004), supra). The 33 day
half life can be expected to increase significantly to a half life
of about 50-60 days in the VH of pathological and/or vitrectomized
eyes.
[0184] The plasma C.sub.max (Day 2) for the 2% and 8% doses were
4.12 ng/mL and 3.59 ng/mL, respectively. Plasma TA was detected for
the 2 and 8% dose up to Day 11 and Day 64, respectively. The
AUC.sub.0-tlast for the 2% and 8% doses were 18.1 ng-day/mL and
83.6 ng-day/mL, respectively. The t.sub.12 for the 2% and 8% doses
were 3.11 and 16.2 days, respectively.
[0185] Significantly (as noted above), TA was detected in the VH
for the 2% (1 mg) and 8% (4 mg) TA gel suspension for up to 1 and 5
months postdose, respectively. The systemic exposure to TA
following intravitreal injection was low and is expected to be
relatively safe compared to systemic exposure of oral TA. Thus, it
can be concluded that at least our 8% TA gel suspension can release
TA into the vitreous over at least a 5 month (151 day) period, in
the manner therefore of an in situ forming sustained release
implant.
Example 15
Method for Making Injectable Triamcinolone Acetonide Gel Suspension
Formulations
[0186] Preferred methods were developed for making the formulations
of Examples 1 to 9.
[0187] The triamcinolone formulations are made as sterile, uniform,
opaque white gel suspensions suitable for intraocular (such as
intravitreal) injection. The manufacturing process involves two
main stages: 1) sterile suspension bulk compounding and 2) aseptic
filling. The bulk product manufacture includes preparations of
three separate parts, followed by aseptic combination of these
three parts. The aseptic filling operation is conducted in a class
100 environment, and the sterile bulk product may be filled into
pre-sterilized ready-to-use syringes.
[0188] Micronized triamcinolone acetonide, USP, was purchased from
Pfizer, Inc., Kalamazoo Mi. Typical and most useful particle sizes
for this drug are 4-8 microns in diameter. Sodium hyaluronate
powder was purchased from Hyaluron, Woburn, Mass. Typical and most
useful molecular weights for this polymer are 1.0 to 1.9 million
Daltons. When used, SBE7-.beta.-cyclodextrin (Captisol.RTM.) was
obtained from CyDex, Inc., Overland Park, Kans.
[0189] Part I is prepared in a main batch vessel that has
capabilities of bulk heat sterilization and viscous fluid mixing.
First, water for injection (WFI) at 40% of batch size is charged
into the vessel and sodium chloride is dissolved. Triamcinolone
powder is then added and dispersed with strong agitation. The
suspension is heated and sterilized at above 121.degree. C. for a
sufficient time period by steam passing through the jacket of the
vessel. After the bulk heat cycle is completed, the suspension is
cooled down to room temperature.
[0190] Part II is prepared in an open vessel equipped with a top
entering, variable speed mixer. First, WFI at 10% of batch size is
charged into the vessel. Sodium phosphate salts and, optionally, a
.beta.-cyclodextrin derivative is added and dissolved. If
necessary, the pH of the solution is adjusted with 1 N sodium
hydroxide and/or 1 N hydrochloric acid. When a beta cyclodextrin is
used in the formulation is can be dissolved along with the
phosphate salts in this part II.
[0191] Part III is prepared in a Class 100 environment through a
series of aseptic procedures. First, sodium hyaluronate is
dissolved in WFI at dilute concentration, e.g., 0.2% w/w. The
solution is sterile-filtered and sodium hyaluronate powder is
recovered through bulk lyophilization. Finally, the sodium
hyaluronate powder is reconstituted with sterile WFI at 50% of
batch size.
[0192] Sterile bulk suspension is compounded by aseptically
combining (mixing) the three parts. First, Part II solution is
filtered into sterile Part I in the main batch vessel using a 0.2
micron sterilizing grade filter. Part III is then aseptically
transferred into the main batch vessel. Finally, the bulk is
blended (mixed) under low shear conditions to achieve uniformity.
The final bulk suspension is held in a controlled area before
aseptic filling.
[0193] Aseptic filling operations are performed in a Class 100
environment. Sterile bulk suspension is first filtered through a
clarification screen into a sterile holding container. The bulk is
then transferred to the filling machine and filled into
pre-sterilized syringes. The filled units are transferred to the
packaging area for application of tamper-evident seals, labeling
and cartoning.
[0194] The pharmaceutical manufacturing process of this Example 15
for making triamcinolone sterile suspensions is illustrated by the
FIG. 6 process flow chart.
[0195] Although not shown in FIG. 6, after Part III has been made
(and before the lyophilization step is applied to Part III), Part
III can be heated at between about 120.degree. C. and about
130.degree. C. for between about 25-35 minutes. Doing so both
sterilizes the hyaluronate and can reduce the initial 1 million to
1.9 million Daltons molecular weight of the hyaluronate used in our
formulation by about 20% to about 30% (i.e. to between about 0.7
million to about 1.3 million Daltons), thereby permitting use of a
higher (i.e. 30 gauge) gauge injection needle.
Example 16
Low Immunogenicity, Stable Intraocular Triamcinolone
Compositions
[0196] We carried out further experiments with the formulation of
Example 9, a pharmaceutical composition comprising 8% triamcinolone
acetonide in polymeric hyaluronic acid, referred to herein by the
trade name Trivaris or Trivaris 8%. The findings set forth herein
apply as well to the Example 8 formulation (Trivaris 2%). We
confirmed the low immunogenicity or anti-inflammatory nature of
Trivaris and determined that upon intraocular administration
substantially all the Trivaris triamcinolone acetonide particles
are embedded within the polymeric matrix of the hyaluronic acid and
that Trivaris is storage stable.
[0197] Sterile endophthalmitis is an inflammatory response that can
exacerbate macular edema, cause retinal detachment, and lead to
vision loss. Sterile endophthalmitis can occur upon intravitreal
injections of prior, known triamcinolone acetonide (TA)
formulations. For example, sterile endophthalmitis has been
reported with aqueous (low viscosity) TA formulations, such as
Kenalog-40, that contain the preservative benzyl alcohol.
Significantly, sterile endophthalmitis has also been reported with
intravitreal injection of preservative free TA formulations so the
presence of the preservative in Kenalog-40 may not be the primary
cause of the cases of sterile endophthalmitis it can cause.
[0198] A major factor associated with the inflammatory reaction
characteristic of sterile endophthalmitis can be the drug particle
burden in the vitreous cavity, as evidenced by the plume effect,
which occurs upon intravitreal injection of an aqueous (low
viscosity) TA formulation. Thus, individual drug particles are
recognized by macrophages resident in the vitreous as they attempt
to phagocytose free floating drug particles. Phagocytosis leads to
cytokine release and both neutrophils and macrophages are thereby
recruited to the vitreous cavity. The enormous numbers of
indigestible drug particles released into the vitreous by a aqueous
TA formulation (with or without a preservative) can be lethal to
macrophages and neutrophils, causing these cells die and release
lysosomal contents, oxidative enzymes, and more proinflammatory
cytokines. This results in an acceleration of the inflammatory
reaction and hence the clinical manifestations of sterile
endophthalmitis.
[0199] Due to their higher density triamcinolone acetonide drug
particles injected into the is vitreous agglomerate into
consolidated drug depots within the first week following
intravitreal injection. Therefore, the risk of sterile
endophthalmitis occurring is generally within the 48 hour period
after intravitreal injection as this is the time when the
macrophages have greatest access to the still free floating,
individual drug particles.
[0200] Three lots of Kenalog-40 were examined (see FIG. 7) and it
was determined that the TA particles in Kenalog can be as large as
80 microns, with high particles size variability. The heterogeneous
population of drug particles in Kenalog-40 ranging in size from
about 2 to about 80 microns can be injurious to phagocytes since
larger and irregularly shaped drug particles are poorly ingested by
such cells resulting in phagocyte cell death. This toxic
inflammatory reaction to corticosteroid crystals has also been
observed following intra-articular injections where an inflammatory
joint reaction occurs within 48 hours after injection is called
crystal synovitis. Other more remote causes of sterile
endophthalmitis with use of intravitreal corticosteroid
formulations include the presence of endotoxins, extraneous
particles and/or excipients in the formulation and the formulation
having a pH less than 5 or greater than pH 8.
[0201] The particles size distribution of four lots of Trivaris was
also examined. As shown by FIGS. 8A to 8D, the median TA particles
size in Trivaris was between about 4 microns and 5 microns and 90%
of the TA particles in Trivaris had a diameter of 10 microns or
less. FIG. 8 also shows that about 40% of the Trivaris TA particles
had a diameter between about 4 microns and about 8 microns and that
about 60% of the Trivaris TA particles had a diameter between about
3.5 microns and about 9 microns.
[0202] The TA particle size distribution data in FIGS. 7 and 8 was
obtained by light scattering using a Horiba LA 300 instrument. The
line graph in FIGS. 8A, B, C and 8D shows the cummulative TA
particle size % (area under the curve) (right hand side Y axis).
Trivaris is a viscous TA formulation in which the TA drug particles
are embedded in and coated by the polymeric matrix of the
hyaluronic acid (HA) to thereby form a viscoelastic hydrogel with a
viscosity of between about 130 k and about 300 k centipoises (cps)
at a shear rate of about 0.1/second at 25.degree. C. Significantly,
the TA drug particle sizes in Trivaris are deliberately uniform in
distribution with a median particle size ranging from about 4 to
about 6 microns. This hydrogel formulation of Trivaris can be
injected through a hypodermic (syringe) needle having a needle
gauge as small as 33 gauge.
[0203] The HA in Trivaris creates a physical barrier to free
movement of the embedded TA drug particles, thereby reducing the
potential for free floating TA particle exposure in the vitreous
and resulting macrophage activation. Importantly, HA is recognized
by scavenging intravitreal macrophages as a native
(non-immunogenic) because there is a high concentration of HA
naturally present in the vitreous humor. Thus coating the TA drug
particles with HA renders the injected Trivaris formulation
non-antigenic, lowering the potential of the TA drug particles to
instigate an inflammatory response. Use of HA encapsulation as an
`immunologic disguise` is used in a similar fashion by some
streptococcus bacterial species to evade detection and phagocytosis
by macrophages and increasing the virulence of the organism.
Importantly, the hydrogel formulation of Trivaris permits the TA
particles to become free drug as the TA is solubilized (dissolves)
in the vitreous, thereby permitting the solubilized TA to enter
solution in the vitreous and then diffuse or be actively
transported to the retina to treat a retinal disease or condition.
The close proximity of the TA drug particles in the Trivaris HA
hydrogel allows for controlled and rapid agglomeration of the TA
particles as the HA gradually diffuses over time out of the depot
formed upon intravitreal Trivaris injection.
[0204] An additional experiment was carried out to determine free
TA particle exposure and pupillary obscuration in patients
receiving either intravitreal Kenalog-40 or Trivaris. Thus a fundus
photography evaluation of patients was performed one hour after
each is patient had received an intravitreal injection of 4 mg of
either Kenalog-40 (n=4) or Trivaris (n=3). A 48 .mu.L (50 mg)
injection of the Example 98% formulation (Trivaris 8%) provided the
4 mg of TA. Note that about 100 .mu.L of the Kenalog-40 was
required to provide 4 mg of TA. The required greater (double)
volume of Kenalog-40 to obtain the same amount of injected TA can
by itself cause deleterious effects (such as acute elevation of
intraocular pressure leading to central retnal artery occlusion)
due to the limited normal intravitreal volume. As shown by Table 7
it was determined that about 83% of the TA particles were floating
free in the vitreous after the Kenalog injections, whereas only
about 6% of the TA particles were free floating in the patients
injected with Trivaris. Significantly, therefore about 84% of the
Trivaris TA particles were upon intravitreal injection embedded
within the HA. Additionally, the pupil was obscured with drug
particles in a mean of 29.8% of the patients who received Kenalog,
versus only a 1.7% pupil obscuration by TA particles in the
patients who had received Trivaris.
[0205] Hence, Trivaris has minimal free TA drug particle exposure
and pupil obscuration, compared with Kenalog, following
intravitreal injection.
[0206] The low numbers of drug particles in an unbound state
following injection of Trivaris can be expected to reduce
activation of scavenging macrophages compared with other TA
suspensions, such as Kenalog-40, where the majority of the TA
particles are upon intravitreal injection exposed to macrophages
and inflammatory consequences can then ensue. The effectiveness of
the Trivaris formulation to reduce the inflammatory potential has
been observed in recent clinical trials. In over 1000 patients in
phase 3 clinical trials that have received injections of Trivaris
formulation, some multiple times, there have been no reported cases
of sterile endophthalmitis. The consolidation of the drug particles
in the Trivaris HA hydrogel, with a clear view through the
pupillary axis, also enables immediate recovery of vision after
injection & enables PDT, thermal laser and diagnostic
procedures to be performed.
[0207] A further experiment was carried out to examine the
stability of the TA particles in Trivaris. We determined that the
TA drug particles in the HA hydrogel suspension of is Trivaris were
remarkably stable, with minimal crystal agglomeration or
degradation during extended storage. Thus, 0.5 mL glass syringes
were filled with 0.2 mL of the Example 9 formulation. The filled
syringes were stored horizontally at 25.degree. C. in 60% relative
humidity. Upon syringe filling (time zero), at 5 weeks, at 6 weeks
and after three months of storage, TA particle size was determined
using laser light scattering with Horiba LA 300 instrument, after
dilution of a Trivaris sample in distilled water just prior to the
light scattering analysis. 90th percentile of volume-weighted size
distribution data from three different lots showed that at time
zero 90% of the TA particles had a diameter of 11 microns or less,
at +5 weeks and at +6 weeks 90% of the TA particles still had a
diameter of about 11 microns or less. Finally at +3 months 90% of
the TA particles still had a diameter of about 13 microns or less.
These results mean that even with prolonged storage the TA
particles remain suspended in the HA and undergo neither
substantial agglomeration or degradation. Hence, even after
prolonged storage Trivaris retains its syringability without needle
occlusion.
[0208] In addition to limiting particle exposure, the HA of
Trivaris has additional inherent anti-inflammatory properties.
Hyaluronic acid inhibits movement of macrophages, down regulates
the production of proinflammatory cytokines and chemokines in
models and human diseases, scavenges oxygen free radicals, and
inhibits matrix metalloproteinases. Trivaris can include additional
features to minimize an inflammatory reaction upon intravitreal
injection, such as preparing Trivaris to have a pH between 6 and 7
range, and strict endotoxin and extraneous particle control.
[0209] Furthermore, the uniform population of micronized TA
particles in Trivaris (see FIG. 7) provides a predictable ocular TA
release pharmacokinetics with increased TA vitreous half-life.
[0210] The Example 8 and 9 Trivaris formulations can also be used
as an injectable pharmaceutical composition to treat various
articular (joints and spine) pathologies while at the same time
reducing the potential for occurrence of post-injection
inflammation (crystal synovitis).
[0211] In summary, the Trivaris formulation creates a physical
barrier to free movement of drug particles to reduce the potential
for particle exposure, macrophage activation, and the potential for
sterile endophthalmitis. The consolidation of the TA drug particles
in the HA hydrogel enables immediate recovery of vision after
injection & enables PDT, thermal laser and diagnostic
procedures to be performed. Incorporating a uniform population of
micronized TA particles in the formulation facilitates management
by macrophages when outside of the drug depot, but also leads to
predictable ocular pharmacokinetics with an increased vitreous
half-life. Trivaris is supplied in pre-loaded syringes with little
or no endotoxin and extraneous particle content, to thereby further
limit post-injection inflammation. Trivaris does not contain benzyl
alcohol or any other preservatives thereby reducing toxicity to
retinal cells. TABLE-US-00007 TABLE 7 Photographic evaluation in
patients following an intravitreal injection of Kenalog-40 or
Trivaris 8% Free Posterior particles Consolidated PoleView Pupil
Subject Kenalog-40 Trivaris exposed % depot % obscuration*
Obscuration** 1 X 80 20 2+ 10 2 X 95 5 1+ 30 3 X 5 95 0 0 4 X 10 90
0 0 5 X 75 25 0 4 6 X 3 97 0 5 7 X 80 20 3+ 75 TOTALS Kenalog 4
82.5 17.5 +1.5 29.8 Mean (SD) (8.7) (8.7) (1.29) (32.1) Trivaris
Mean 3 6.0 94.0 0 1.7 (SD) (3.6) (3.6) (2.9) *graded as Vitreous
Haze (SUN Criteria) 0 through 4+ **grade as % of pupillary area
(dilated) obscured by drug as measured with the red reflex
photo
[0212] While this invention has been described with respect to
various specific examples and embodiments, it is to be understood
that the invention is not limited thereto. For example, the
corticosteroid formulations set forth herein can be used to treat
conditions including articular pathologies, such as rheumatoid and
osteoarthritis, and spinal conditions, such as facet arthritis, and
the treatment of chronic pain by epidural or spinal root injections
of a formulation such as a Trivaris formulation
[0213] Additionally, although preferably the polymeric hyaluronate
in Trivaris is a non-cross linked hyaluronate (so as to obtain,
upon application of force to the plunger of the syringe used to
administer Trivaris, a high shear rate and hence relative ease of
injection of Trivaris through a 27-33 gauge needle), the
hyaluronate can alternately be is a cross linked hyaluronate (to
form a true hydrogel therefore) with a significantly lower
viscosity (i.e. with a viscosity of about 5,000 cps at a shear rate
of about 0.1/second at about 25.degree. C.). Such a cross-linked
hyaluronate can have the same or similar excellent corticosteroid
suspension property of Trivaris, and have the additional advantage
of longer residency (i.e. biodegradable at a slower rate) of the
hyaluronate in the vitreous, with resulting prolonged nominal
immunogenicity of such a cross-linked hyaluronate formulation in
the vitreous, due to a longer period of intravitreal (or
intraocular) retention of the corticosteroid particles in the
polymeric matrix of the cross-linked hyaluronate.
[0214] Furthermore, besides hyaluronate other cross-linked polymers
can be used, such as for example a polycarbophil.
[0215] All references, articles, publications, patents and
applications set forth above are incorporated herein by reference
in their entireties.
* * * * *