U.S. patent application number 17/062972 was filed with the patent office on 2021-08-05 for sustained action formulation of cyclosporin form 2.
The applicant listed for this patent is Allergan, Inc.. Invention is credited to Mayssa Attar, Wendy M. Blanda.
Application Number | 20210236590 17/062972 |
Document ID | / |
Family ID | 1000005524977 |
Filed Date | 2021-08-05 |
United States Patent
Application |
20210236590 |
Kind Code |
A1 |
Blanda; Wendy M. ; et
al. |
August 5, 2021 |
SUSTAINED ACTION FORMULATION OF CYCLOSPORIN FORM 2
Abstract
Disclosed herein are methods of treating diseases of the eye by
administering to the subconjunctival space a formulation comprising
cyclosporin A form 2 and a hydrogel.
Inventors: |
Blanda; Wendy M.; (Tustin,
CA) ; Attar; Mayssa; (Placentia, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Family ID: |
1000005524977 |
Appl. No.: |
17/062972 |
Filed: |
October 5, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14305883 |
Jun 16, 2014 |
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17062972 |
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13676551 |
Nov 14, 2012 |
8785394 |
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14305883 |
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61559838 |
Nov 15, 2011 |
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61563199 |
Nov 23, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 7/645 20130101;
A61K 38/13 20130101; A61K 9/0048 20130101; A61K 9/0019 20130101;
C07K 1/306 20130101; A61K 47/38 20130101; A61K 47/32 20130101; A61K
47/36 20130101 |
International
Class: |
A61K 38/13 20060101
A61K038/13; A61K 9/00 20060101 A61K009/00; A61K 47/36 20060101
A61K047/36; C07K 1/30 20060101 C07K001/30; C07K 7/64 20060101
C07K007/64; A61K 47/32 20060101 A61K047/32; A61K 47/38 20060101
A61K047/38 |
Claims
1. A formulation comprising cyclosporin A form 2 and a
hydrogel.
2. The formulation of claim 1, wherein the hydrogel is selected
from hyaluronic acid, hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, hydroxyethylcellulose, polyvinyl pyrolidone,
carboxymethylcellulose hydroxyethyl cellulose, and
polyvinylpyrrolidone.
3. The formulation of claim 2, wherein the cyclosporin A form 2 is
at a concentration of about 0.01% to about 10%.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application is a continuation of U.S. patent
application Ser. No. 14/305,883, filed Jun. 16, 2014, which is a
divisional of U.S. patent application Ser. No. 13/676,551, filed
Nov. 14, 2012, now U.S. Pat. No. 8,785,394, issued Jul. 22, 2014,
which claims priority to U.S. Provisional Patent Application No.
61/559,838, filed Nov. 15, 2011, and U.S. Provisional Patent
Application No. 61/563,199, filed Nov. 23, 2011, which are herein
incorporated by reference in their entireties and serve as the
basis of a priority and/or benefit claim for the present
application.
BACKGROUND
[0002] Cyclosporin A is the active Ingredient in Restasis.RTM., a
topical ocular formulation approved in the United States for the
treatment of dry eye. Topical cyclosporin is also used in the
management of other ophthalmic conditions such as restoration of
corneal sensitivity following refractive surgery, conjunctival and
corneal inflammation, keratoconjuntivitis, graft versus host
disease, post-transplant glaucoma, corneal transplants, mycotic
keratitis, meibomian gland dysfunction, Thygeson's superficial
punctate keratitis, uveitis, and Theodore's superior limbic
keratoconjunctivitis.
[0003] Patient compliance is extremely important but many patients
fail to comply with ocular medications. Moreover, some treatments
for conditions other than dry eye dose more frequently than the
twice-a-day dosing approved for Restasis.RTM., and concentrations
of cyclosporin A higher in tissue than Restasis.RTM. can deliver
after multiple dosing would be beneficial to certain patients with
severe conditions, such as graft vs. host disease. Some ocular
diseases may require long-term therapy. For example, the National
Eye Institute (NEI) has completed a study to evaluate 1 and 2 mg
biodegradable implants of cyclosporin to treat uveitis. The NEI is
also studying the use of non-degradable cyclosporin implants for
treatment of graft vs. host disease. However, it should be noted
that removing non-degradable implants after the dose has been
depleted requires a second surgery. Some other relevant studies
also have been conducted by the NEI or are in the process of
recruiting patients for studies. Results for these NEI studies have
not been published.
[0004] A single implantation or injection, which delivers high
levels of cyclosporin constantly over a long period (weeks or
months) is desirable. The use of multi-month biodegradable or
bioerodible delivery system, which delivers cyclosporin to targeted
anterior ocular tissues--at equal or greater concentration as
Restasis.RTM.--is clearly desirable. It is also desirable to have
an injectable formulation, which would avoid surgery. A formulation
which could pass through a 22 gauge needle (or smaller) and avoid
the ocular tissue damage which may occur with trocars, larger
needles, or surgical implantation, is also desirable.
[0005] The reported success of injecting cyclosporin formulations
into the conjunctiva for long-duration therapy has been highly
limited: while short-term efficacy has been shown with some
microspheres and other formulations, no formulation has been
demonstrated to be equivalent or superior in delivering cyclosporin
to anterior tissue, when compared to Restasis.RTM. for a period of
at least 3 months.
[0006] Biodegradable implants, which can be delivered through a 22
gauge needle, do not deliver sufficient drug over a sufficient
period of time to meet the need. Biodegradable gel-forming
suspensions perform better but, still do not meet the need.
[0007] The inventors have surprisingly found that the formulations
of the invention, when delivered to the subconjunctival space of
the eye through a 22 or smaller gauge needle, deliver cyclosporin A
to most anterior ocular tissue for a sustained period of time.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 depicts characteristic X-ray powder diffraction
(XRPD) patterns of CsA in a new crystalline form (designated as
Form 2 herein), tetragonal form (designated as Form 1 herein), and
orthorhombic form (designated as Form 3 herein).
[0009] FIG. 2 depicts the XRPD diffractogram of CsA crystalline
Form 2.
[0010] FIG. 3 depicts the water sorption/desorption profile of CsA
Form 2.
[0011] FIG. 4 depicts MDSC analysis of CsA Form 2 recovered from
0.04% formulation with 1% PS80.
[0012] FIG. 5 shows the front of the eye and the different
quadrants of the conjunctiva relative to the limbus and cornea.
[0013] FIG. 6 illustrates injection of a steroid compound into the
superotemporal quadrant of the subconjunctival space of the eye.
The patient looks down while the thumb of one hand is used to
gently retract the upper lid. The syringe containing the
steroid-containing composition is placed tangential to the globe
and inserted through the bulbar conjunctiva thereby introducing the
needle into the subconjunctival space.
[0014] FIG. 7 shows a cross section of the eye and the location of
the three zones of the conjunctiva (heavy black line)--palpebral,
forniceal, and bulbar--relative to other anatomical regions in the
eye.
[0015] FIG. 8 shows the simulated XRPD pattern of cyclosporine A
forms.
DETAILED DESCRIPTION
Cyclosporin A
[0016] Cyclosporin A (CsA) is a cyclic peptide having the following
chemical structure:
##STR00001##
Its chemical name is
cyclo[[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L-2--
aminobutyryl-N-methylglycyl-N-methyl-Lleucyl-L-valyl-N-methyl-L-leucyl-L-a-
lanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-Nmethyl-L-valyl].
It is also known by the names cyclosporine, cyclosporine A,
ciclosporin, and ciclosporin A. It is the active ingredient in
Restasis.RTM. (Allergan, Inc., Irvine, Calif.), an emulsion
comprising 0.05% (w/v) cyclosporin. Restasis.RTM. is approved in
the United States to increase tear production in patients whose
tear production is presumed to be suppressed due to ocular
inflammation associated with keratoconjunctivitis sicca.
Cyclosporin A Form 2
[0017] Cyclosporin A is known to exist in an amorphous form, liquid
crystal form, tetragonal crystalline form (form 1), and an
orthorhombic form (form 3). A new crystalline form, cyclosporin A
form 2, has recently been discovered. The XRPD pattern of CsA Form
2 differs significantly from the tetragonal form and orthorhombic
form (FIG. 1). The major crystalline peaks for CsA form 2 appear at
(2.theta.) when scanned by an X-ray diffractometer with X-ray
source as Cu K.alpha. radiation, .lamda.=1.54 .ANG., at 30 kV/15
mA: 7.5, 8.8, 10.2, 11.3, 12.7, 13.8, 14.5, 15.6 and 17.5
(d-spacing in crystal lattice at about 11.8, 10.0, 8.7, 7.8, 7.0,
6.4, 6.1, 5.6 and 5.1{acute over (.ANG.)}, respectively, FIG. 2).
These major peaks are defined as those being unique to Form 2
relative to the orthorhombic or tetragonal forms; as well as, peaks
having an intensity greater than 5 times the background.
[0018] In one embodiment, the new crystalline form (Form 2) of CsA
is a nonstoichiometric hydrate of Cyclosporin A. In another
embodiment, the crystalline Form 2 is represented by the
formula:
##STR00002##
wherein X is the number of molecules of water and varies from 0 to
3. In one embodiment, X in the above formula is 2.
[0019] Form 2 appears to be a kinetically stable form of CsA in
aqueous suspensions. Suspensions containing Form 2 show no
conversion to other known polymorphic or pseudomorphic forms upon
storage. It has been found that Form 1 and the amorphous form
convert to Form 2 in the presence of water.
[0020] The single crystal structure of the hydrate form of CsA Form
2 has been determined and the crystal structure parameters are
listed in Table 2. These results indicate that Form 2 is unique
compared to other known crystalline forms of cyclosporine A.
TABLE-US-00001 TABLE 1 Crystal data and data collection parameters
of crystal structure solution of CsA Form 2. formula C H N O
formula weight 1238.67 space group P 2 2 2 (No. 19) a (.ANG.)
12.6390(5) b (.ANG.) 19.7582(6) c (.ANG.) 29.568(2) volume
(.ANG..sup.3) 7383.6(7) Z 4 d (g cm.sup.-3) 1.114 crystal
dimensions (mm) 0.27 .times. 0.18 .times. 0.12 temperature (K) 150
radiation (wavelength in .ANG.) Cu K (1.54184) monochromator
confocal optics linear abs coef (mm.sup.-1) 0.64D absorption
correction applied empirical transmission factors (min, max) 0.80,
0.93 diffractometer Rigaku RAPID-II h, k, l range -13 to 13 -21 to
21 -32 to 21 2.theta. range (deg) 5.36-115.00 mosaicity (deg) 1.31
programs used SHELXTL F 2704.0 weighting 1/[ .sup.2(F .sup.2) +
(0.0645P).sup.2 + 0.000P] where P = (F .sup.2 + 2Fc.sup.2)/3 data
collected 37360 unique data 9964 R.sub.int 0.077 data used in
refinement 9964 cutoff used in R-factor calculations F .sup.3 >
2.0 (F .sup.2) data with > 2.0a( ) 6597 number of variables 834
largest shift/esd in final cycle 0.00 R(F ) 0.061 R (F .sup.2)
0.145 goodness of fit 1.037 absolute structure determination Flack
perameter (0.0(3)) indicates data missing or illegible when
filed
[0021] The asymmetric unit of this CsA Form 2 contains one
cyclosporine A molecule and two water molecules. It is possible
that any small molecule that can hydrogen bond to water could play
the role of space filler, which would give a range of potential
structures running from the orthorhombic dihydrate to distorted
monoclinic dihydrate The XRPD pattern calculated from the
single-crystal structure is shown in FIG. 8 and it matches the
experimental pattern shown in FIG. 2. These matching patterns
further corroborate that Form 2 is a unique and pure crystalline
form of cyclosporine A.
[0022] Without wishing to be bound by theory, thermogravimetric
analysis combined with KF titration and vapor sorption desorption
analysis (VSA) suggest that CsA Form 2 is a non-stoichiometric
hydrate of CsA. The vapor sorption analysis of Cyclosporine Form 2
indicates that water content in the new crystal form reversibly
varies with relative humidity as shown in FIG. 3. Similar to the
tetragonal form, the new CsA form undergoes a phase transition to a
liquid crystal or amorphous form at 124.4.degree. C. prior to
melting as indicated by the modulated differential calorimetric
(MDSC) analysis (FIG. 4).
[0023] Cyclosporin A Form 2 may be obtained by suspending amorphous
0.05% cyclosporin A (w/v) in 1% Polysorbate 80, heating the
solution to 65.degree. C., holding it at that temperature for 24
hours, and then recovering the precipitate by vacuum filtration.
One can then use the cyclosporin A Form 2 thus obtained to generate
additional amounts, using Cyclosporin A Form 2 as a seed crystal;
in this method, one suspends about 30 g cyclosporin A in a solution
of 900 ml water containing 1% (w/v) Polysorbate 80, heats the
solution to 65.degree. C., and then seeds it with 0.2 g of
cyclosporin A Form 2 at a temperature of 52.degree. C. The solution
is then stirred for about 22 hours at a temperature of between
about 61.degree. C. and 65.degree. C., and then recovers the
precipitate that results.
[0024] Further details regarding CsA Form 2 may be found in U.S.
patent application Ser. No. 13/480,710, the entire contents of
which are incorporated by reference herein.
Sustained Action Formulations of Cyclosporin A Form 2
[0025] Compositions of the invention are ophthalmically acceptable
formulations of Cyclosporin A form 2. By "ophthalmically
acceptable," the inventors mean that the suspensions are formulated
in such a way as to be non-irritating when administered to the eye
of a mammal, such as a human.
[0026] The formulations of the invention comprise cyclosporin A
form 2 and a hydrogel such as hyaluronic acid, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, hydroxyethylcellulose,
polyvinyl pyrolidone, and carboxymethylcellulose.
[0027] In one embodiment, the formulation comprises cyclosporin A
form 2 at a concentration of about 0.001% to about 10% (w/v). In
one embodiment, the suspension comprises cyclosporin A form 2 at a
concentration of about 0.001% (w/v) to about 0.01%, about 0.001%
(w/v) to about 0.04% (w/v), about 0.001% (w/v) to about 0.03%
(w/v), about 0.001% (w/v) to about 0.02% (w/v), or about 0.001%
(w/v) to about 0.01 (w/v). In another embodiment, the suspension
comprises cyclosporin A form 2 at a concentration of about 0.01%
(w/v) to about 0.05%, about 0.01% (w/v) to about 0.04% (w/v), about
0.01% (w/v) to about 0.03% (w/v), about 0.01% (w/v) to about 0.02%
(w/v), or about 0.01% (w/v) to about 0.01% (w/v). In another
embodiment, the suspension comprises cyclosporin A form 2 at a
concentration of about 0.01% (w/v) to about 0.1%, about 0.1% (w/v)
to about 0.5% (w/v), about 0.01% (w/v) to about 1% (w/v), or about
1% (w/v) to about 10%.
[0028] For example, the formulations may comprise about 0.001%
(w/v), about 0.002% (w/v), about 0.003% (w/v), about 0.004% (w/v),
about 0.005% (w/v), about 0.006% (w/v), about 0.007% (w/v), about
0.008% (w/v), about 0.009% (w/v), about 0.01% (w/v), about 0.015%
(w/v), about 0.02% (w/v), about 0.025% (w/v), about 0.03% (w/v),
about 0.035% (w/v), about 0.04% (w/v), about 0.045% (w/v), about
0.05% (w/v), about 0.055% (w/v), about 0.06% (w/v), about 0.065%
(w/v), about 0.07% (w/v), about 0.075% (w/v), about 0.08% (w/v),
about 0.085% (w/v), about 0.09% (w/v), about 0.095% (w/v), about
0.1% (w/v), about 0.15% (w/v), about 0.2% (w/v), about 0.25% (w/v),
about 0.3% (w/v), about 0.35% (w/v), about 0.4% (w/v), about 0.45%
(w/v), about 0.5% (w/v), about 0.55% (w/v), about 0.6% (w/v), about
0.65% (w/v), about 0.7% (w/v), about 0.75% (w/v), about 0.8% (w/v),
about 0.85% (w/v), about 0.9% (w/v), about 0.95% (w/v), or about
1.0% (w/v) cyclosporin A form 2.
Methods of Treatment
[0029] Formulations of the invention may be used to treat any
condition of the eye which is known to be amenable to topical
treatment with cyclosporin A (such as with Restasis.RTM.) at the
concentrations stated here. For example, compositions of the
invention may be used to treat patients suffering from dry eye, to
treat blepharitis and meibomian gland disease, to restore corneal
sensitivity that has been impaired due to refractive surgery on the
eye, to treat allergic conjunctivitis and atopic and vernal
keratoconjunctivitis, and to treat ptyregia, conjunctival and
corneal inflammation, keratoconjuntivitis, graft versus host
disease, post-transplant glaucoma, corneal transplants, mycotic
keratitis, Thygeson's superficial punctate keratitis, uveitis, and
Theodore's superior limbic keratoconjunctivitis, among other
conditions.
[0030] The International Dry Eye Workshop (DEWS) defines dry eye as
"a multifactorial disease of the tears and ocular surface that
results in symptoms of discomfort, visual disturbance, and tear
film instability with potential damage to the ocular surface,
accompanied by increased osmolarity of the tear film and
inflammation of the ocular surface." It includes those conditions,
such as keratoconjunctivitis sicca, that are caused by tear
deficiency or excessive evaporation of tears.
[0031] Blepharitis is a chronic disorder producing inflammation of
the anterior and posterior lid margin, with involvement of skin and
its related structures (hairs and sebaceous glands), the
mucocutaneous junction, and the meibomian glands. It can also
affect the conjunctiva, tear film, and the corneal surface in
advanced stages and may be associated with dry eye. Blepharitis is
commonly classified into anterior or posterior blepharitis, with
anterior affecting the lash bearing region of the lids, and
posterior primarily affecting the meibomian gland orifices.
[0032] Meibomian gland disease most often occurs as one of three
forms: primary meibomitis, secondary meibomitis, and meibomian
seborrhea. Meibomian seborrhea is characterized by excessive
meibomian secretion in the absence of inflammation (hypersecretory
meibomian gland disease). Primary meibomitis, by contrast, is
distinguished by stagnant and inspissated meibomian secretions
(obstructive hypersecretory meibomian gland disease). Secondary
meibomitis represents a localized inflammatory response in which
the meibomian glands are secondarily inflamed in a spotty fashion
from an anterior lid margin blepharitis.
[0033] Impaired corneal sensitivity often occurs after refractive
surgery, such as photorefractive keratectomy, laser assisted
sub-epithelium keratomileusis (LASEK), EPI-LASEK, customized
transepithelial non-contact ablation, or other procedures in which
the corneal nerves are severed. Impaired corneal sensitivity may
also occur after viral infection, such as by HSV-1, HSV-2, and VZV
viruses. Patients with impaired corneal sensitivity often complain
that their eyes feel dry, even though tear production and
evaporation may be normal, suggesting that "dryness" in such
patients is actually a form of corneal neuropathy that results when
corneal nerves are severed by surgery or inflamed after viral
infection.
[0034] Allergic conjunctivitis is an inflammation of the
conjunctiva resulting from hypersensitivity to one or more
allergens. It may be acute, intermittent, or chronic. It occurs
seasonally, that is, at only certain time of the year, or it occurs
perennially, that is, chronically throughout the year. Symptoms of
seasonal and perennial allergic conjunctivitis include, in addition
to inflammation of the conjunctiva, lacrimation, tearing,
conjunctival vascular dilation, itching, papillary hyperlasia,
chemosis, eyelid edema, and discharge from the eye. The discharge
may form a crust over the eyes after a night's sleep.
[0035] Atopic keratoconjunctivitis is a chronic, severe form of
allergic conjunctivitis that often leads to visual impairment.
Symptoms include itching, burning, pain, redness, foreign body
sensation, light sensitivity and blurry vision. There is often a
discharge, especially on awakening from a night's sleep; the
discharge may be stringy, ropy, and mucoid. The lower conjunctiva
is often more prominently affected than the upper conjunctiva. The
conjunctiva may range from pale, edematous, and featureless to
having the characteristics of advanced disease, including papillary
hypertrophy, subepithelial fibrosis, formix foreshortening,
trichiasis, entropion, and madurosis. In some patients the disease
progresses to punctate epithelial erosions, corneal
neovascularization, and other features of keratopathy which may
impair vision. There is typically goblet cell proliferation in the
conjunctiva, epithelial pseudotubular formation, and an increased
number of degranulating eosinophils and mast cells in the
epithelium. CD25+T lymphocytes, macrophages, and dendritic cells
(HLA-DR.sup.+, HLA-CD1+) are significantly elevated in the
substantia propria.
[0036] Like atopic keratoconjunctivitis, vernal
keratoconjunctivitis is a severe form of allergic conjunctivitis,
but it tends to affect the upper conjunctiva more prominently than
the lower. It occurs in two forms. In the palpebral form, square,
hard, flattened, closely packed papillae are present; in the bulbar
(limbal) form, the circumcorneal conjunctiva becomes hypertrophied
and grayish. Both forms are often accompanied by a mucoid
discharge. Corneal epithelium loss may occur, accompanied by pain
and photophobia, as may central corneal plaques and Trantas'
dots.
Administration
[0037] Formulations of the invention are administered to the
subconjunctival space. As used herein, the "subconjunctival space"
refers to any of the following: (1) the potential space between the
bulbar conjunctiva and Tenon's capsule and extending from the
limbus to the fornix; (2) the potential space between the palpebral
conjunctiva and the tarsus and extending from the eye lid margin
(mucocutaneous junction of the eyelid) to the fornix; and (3) the
potential space just beneath the forniceal conjunctiva at the
junctional bay or fornix. The subconjunctival space is therefore
the potential space just beneath the conjunctiva from the limbus,
around the fornix, to the eye lid margin.
[0038] Referring to FIG. 5, the subconjunctival space around the
eye can be divided into four quadrants: the superior, nasal,
inferior, and temporal. These quadrants may be further subdivided
into sub-quadrants, such as the superotemporal, superonasal,
inferior nasal, and inferior temporal, and so on. Hence, the
formulations of the invention may be administered, for example, to
the superotemporal quadrant of the bulbar subconjunctival space, or
to any one or more of the inferior, superior, nasal, or temporal
quadrants of the bulbar, palpepral, or forniceal subconjunctival
spaces, or to the superotemporal, superonasal, inferior temporal,
or inferior nasal bulbar, palpepral, or forniceal subconjunctival
spaces (FIGS. 6 and 7). Therefore, unless further delimited,
administration into the "subconjunctival space" of the eye refers
to administration into any of the bulbar, palpepral, and/or
forniceal subconjunctival spaces in the eye in any one or more of
the four quadrants of the eye (superior, nasal, temporal, and
inferior), or any one or more of the possible sub-quadrants of the
eye, including the supertemporal, superonasal, inferior temporal,
or inferior nasal regions of the bulbar, palpepral, or forniceal
subconjunctival spaces.
[0039] In one embodiment, administration of the formulations of the
invention excludes their topical delivery (such as by eye drops) to
the surface of the eye, or more specifically the cornea, since the
subconjunctival space does not include any region or space
immediately over, under, or within the cornea. In another
embodiment, administration to the subconjunctival space further
excludes a delivery method that penetrates or perforates Tenon's
capsule or the sclera, that penetrates or extends through the
sclera into the vitreous body, or that is delivered beneath the
sclera. The "subconjunctival space", as used herein, is not
equivalent to the "sub-tenon space." Tenon's capsule is a thin,
fibrous, somewhat elastic membrane, beneath the conjunctiva, that
envelopes the eyeball from the edge of the cornea (limbus) to the
optic nerve. It attaches loosely to the sclera. Thus, the sub-tenon
space is between Tenon's capsule and the sclera. Sub-tenon
administration of a composition to an eye generally involves
elevating both the conjunctiva and Tenons' capsule using forceps
and then introducing the composition into the space between the
sclera and Tenon's capsule. A needle and syringe may be used to
pierce Tenon's capsule and inject the composition into the
sub-tenon space.
[0040] In one embodiment, the device for administering the
formulations of the invention to the subconjunctival space of an
eye is a syringe equipped with a needle or a cannula. The needle or
cannula used to inject a ophthalmic composition into the
subconjunctival space of an eye can be a 20 gauge or higher gauge
needle or cannula. The needle or cannula may have a blunt or
beveled end. In preferred embodiments, the gauge of the needle or
cannula used in the method is a 25 gauge or higher needle or
cannula, or is specifically a 22, 23, 24, 25, 26, 27, 28, 29, 30,
31, 32, 33, or 34 gauge needle or cannula.
[0041] In one embodiment of the present method for treating an
ocular surface inflammation or inflammation of the ocular surface
adnexa in a subject in need thereof, a formulation of the invention
is injected into the subconjunctival space of the eye (i.e.,
administered) according to the following procedure. With the
subject facing the practitioner, the practitioner uses a thumb (or
device such as forceps) to retract the upper or lower eye lid,
depending on whether injection into the subconjunctival space is to
take place in the superior (e.g., superotemporal) or inferior
quadrants, respectively. See FIG. 2, for example. With the other
hand, the practitioner positions the needle (attached to a syringe
containing the composition) tangential to the eye globe with the
needle bevel facing toward the globe (i.e., with the needle bevel
facing down). In certain instances, it may be preferable to orient
the needle with the bevel facing up (i.e., away from the globe).
Keeping the needle tangential to the globe and using a gentle
stabbing motion, the practitioner then directs the needle
posteriorly and just beneath the conjunctiva to introduce the
needle into the subconjunctival space. The desired volume of
composition is then injected into the subconjunctival space.
Depending on the volume injected, the composition may appear as an
elevation or small bulge in the conjunctiva. The needle is then
withdrawn. Pressure may then be applied to the eye with a gauze pad
to help distribute and diffuse the composition and stem possible
bleeding.
[0042] In certain embodiments, the same procedure may be used to
introduce anesthetic into the subconjunctival space of the eye
prior to injecting the formulation of the invention. The anesthetic
solution may appear as an elevation or bulge in the conjunctiva. If
this procedure is followed, and once the anesthetic has taken
effect, the composition is then injected into the elevated portion
of the conjunctiva but at a site other than that used to inject the
anesthetic. In some embodiments, an additional dose of formulation
of the invention may be injected into the nasal and/or inferior
(e.g., the inferior forniceal) subconjunctival space using the same
procedure outlined above.
[0043] Alternatively, an ocular anesthetic may be applied topically
to one or each eye prior to injection of the composition into the
subconjunctival space of the eye. Analgesic agents may also be
administered following subconjunctival administration of the
composition. Analgesic agents include triple antibiotic ointment or
atropine drops or ointment.
EXAMPLES
[0044] The invention is further illustrated by the following
examples. [0045] The inventors' work suggests that biodegradable
implants containing cyclosporin A, when delivered through a 22
gauge needle, do not deliver sufficient drug over a sufficient
period of time to effectively treat those conditions of the eye for
which topical cyclosporin A is prescribed or known to be effective
in treating.
[0046] The inventors prepared the following formulations, and
injected them into rabbit eyes.
TABLE-US-00002 Bulbar Lacrimal Cornea Conjunctiva Gland 5% CsA R100
(5 mg) 131 287 128 5% CsA RB (5 mg) 357 29.2 79.0 5% CsA HA (5 mg)
360 6720 132 (possible outlier or error) 1% CsA HA (1 mg) 167 192
24.9 10% CsA CMC (10 mg) TBD TBD TBD 10% CsA HPMC (10 MG) TBD TBD
TBD 10% CsA PVP (10 mg) TBD TBD TBD 10% CsA HA (10 mg) In In In
progress progress progress P1L (0.5 mg) 9.37 31700 1.51 (possible
outlier or error) P1H (1.5 mg) 54.4 143 11.4 (possible outlier or
error) P2L (0.5 mg) 10.9 80.4 1.92 P2H (1.5 mg) 15.9 201 3.47 P3L
(0.5 mg) 1.37 NC 2.09 P3H (1.5 mg) 5.98 0.801 2.73 RESTASIS (0.015
mg) 1360 237 13.8
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