U.S. patent application number 16/915017 was filed with the patent office on 2021-04-22 for ocular implant made by a double extrusion proces.
The applicant listed for this patent is Allergan, Inc.. Invention is credited to Rahul Bhagat, Wendy M. Blanda, David Chou, Thierry Nivaggioli, Lin Peng, Jane-Guo Shiah, David A. Weber.
Application Number | 20210113592 16/915017 |
Document ID | / |
Family ID | 1000005312718 |
Filed Date | 2021-04-22 |
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United States Patent
Application |
20210113592 |
Kind Code |
A1 |
Shiah; Jane-Guo ; et
al. |
April 22, 2021 |
OCULAR IMPLANT MADE BY A DOUBLE EXTRUSION PROCES
Abstract
The invention provides biodegradable implants sized for
implantation in an ocular region and methods for treating medical
conditions of the eye. The implants are formed from a mixture of
hydrophilic end and hydrophobic end PLGA, and deliver active agents
into an ocular region without a high burst release.
Inventors: |
Shiah; Jane-Guo; (Irvine,
CA) ; Bhagat; Rahul; (Irvine, CA) ; Blanda;
Wendy M.; (Tustin, CA) ; Nivaggioli; Thierry;
(Atherton, CA) ; Peng; Lin; (South San Francisco,
CA) ; Chou; David; (Palo Alto, CA) ; Weber;
David A.; (Danville, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Family ID: |
1000005312718 |
Appl. No.: |
16/915017 |
Filed: |
June 29, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16132857 |
Sep 17, 2018 |
10702539 |
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16915017 |
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14949454 |
Nov 23, 2015 |
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13922482 |
Jun 20, 2013 |
9192511 |
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14949454 |
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13797230 |
Mar 12, 2013 |
8778381 |
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13922482 |
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13213473 |
Aug 19, 2011 |
8506987 |
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13797230 |
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11932101 |
Oct 31, 2007 |
8034366 |
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13213473 |
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10918597 |
Aug 13, 2004 |
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11932101 |
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10340237 |
Jan 9, 2003 |
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10918597 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 9/0017 20130101;
A61K 9/1647 20130101; A61K 9/204 20130101; A61K 9/1694 20130101;
A61K 31/573 20130101; A61K 9/0051 20130101; A61K 31/56
20130101 |
International
Class: |
A61K 31/573 20060101
A61K031/573; A61K 9/16 20060101 A61K009/16; A61K 31/56 20060101
A61K031/56; A61K 9/00 20060101 A61K009/00; A61F 9/00 20060101
A61F009/00 |
Claims
1. A method for treating uveitis or macular edema in the eye of a
patient, the method comprising implanting into an ocular region of
an eye of a patient in need thereof a bioerodible implant
comprising particles of an active agent dispersed within a
biodegradable polymer matrix, wherein at least 75% of the particles
of the active agent have a diameter of less than 20 .mu.m, the
biodegradable polymer comprises poly(lactic-co-glycolic)acid (PLGA)
copolymer, the ratio of lactic to glycolic acid monomers in the
PLGA copolymer is 50/50 weight percentage, and the bioerodible
implant is prepared by milling the biodegradable polymer and
subjecting the active agent and the biodegradable polymer to a
double extrusion process.
2. The method of claim 1, wherein at least 99% of the particles of
the active agent have a diameter of less than 20 .mu.m.
3. The method of claim 1, wherein the active agent is selected from
the group consisting of ace-inhibitors, endogenous cytokines,
agents that influence basement membrane, agents that influence the
growth of endothelial cells, adrenergic agonists or blockers,
cholinergic agonists or blockers, aldose reductase inhibitors,
analgesics, anesthetics, antiallergics, anti-inflammatory agents,
steroids, antihypertensives, pressors, antibacterials, antivirals,
antifungals, antiprotozoals, anti-infective agents, antitumor
agents, antimetabolites and antiangiogenic agents.
4. The method of claim 1, wherein the active agent comprises an
anti-inflammatory agent or any derivative thereof.
5. The method of claim 4, wherein the anti-inflammatory agent
comprises a steroidal anti-inflammatory agent.
6. The method of claim 5, wherein the steroidal anti-inflammatory
agent is selected from the group consisting of cortisone,
dexamethasone, fluocinolone, hydrocortisone, methylprednisolone,
prednisolone, prednisone, triamcinolone and any derivative
thereof.
7. The method of claim 6, wherein the steroidal anti-inflammatory
agent comprises dexamethasone.
8. The method of claim 1, wherein the implant is sized for
implantation in an ocular region.
9. The method of claim 8, wherein the ocular region is selected
from the group consisting of the anterior chamber, the posterior
chamber, the vitreous cavity, the choroid, the suprachoroidal
space, the conjunctiva, the subconjunctival space, the episcleral
space, the intracorneal space, the epicorneal space, the sclera,
the pars plana, surgically-induced avascular regions, the macula
and the retina.
10. The method of claim 9, wherein the ocular region is the
vitreous cavity.
11. The method of claim 1, wherein the PLGA copolymer is 40% by
weight of the bioerodible implant.
12. The method of claim 7, wherein the method is effective to treat
uveitis.
13. The method of claim 7, wherein the method is effective to treat
macular edema.
Description
CROSS REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/132,857, filed Sep. 17, 2018, which is a
continuation of U.S. patent application Ser. No. 14/949,454, filed
Nov. 23, 2015, now U.S. Pat. No. 10,076,526, issued Sep. 18, 2018,
which is a continuation of U.S. patent application Ser. No.
13/922,482, filed Jun. 20, 2013, now U.S. Pat. No. 9,192,511,
issued Nov. 24, 2015, which is a continuation of U.S. patent
application Ser. No. 13/797,230, filed Mar. 12, 2013, now U.S. Pat.
No. 8,778,381, issued Jul. 15, 2014, which is a continuation of
U.S. patent application Ser. No. 13/213,473, filed Aug. 19, 2011,
now U.S. Pat. No. 8,506,987, issued Aug. 13, 2013, which is a
divisional of U.S. patent application Ser. No. 11/932,101, filed
Oct. 31, 2007, now U.S. Pat. No. 8,034,366, issued Oct. 11, 2011,
which is a continuation of U.S. patent application Ser. No.
10/918,597, filed Aug. 13, 2004, now abandoned, which is a
continuation-in-part of U.S. patent application Ser. No.
10/340,237, filed Jan. 9, 2003, now abandoned, the entire contents
of all seven applications are herein incorporated by reference in
their entirety.
BACKGROUND
[0002] This invention relates to implants and methods for treating
an ocular condition. In particular the present invention relates to
implants and methods for treating an ocular condition by implanting
into an ocular region or site a bioerodible implant comprising an
active agent and a bioerodible polymer matrix, wherein the implant
is made by a double extrusion process. The bioerodible implants of
this invention have varying and extended release rates to provide
for improved kinetics of release of one or more active
(therapeutic) agents over time.
[0003] 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 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 region or site.
[0004] 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; uveitic retinal
disease; 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 the therapeutic
goal is 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).
[0005] 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).
[0006] The present invention is concerned with and directed to an
implant and methods for the treatment of an ocular condition, such
as an anterior ocular condition or a posterior ocular condition or
to an ocular condition which can be characterized as both an
anterior ocular condition and a posterior ocular condition.
[0007] Therapeutic compounds useful for the treatment of an ocular
condition can include active agents with, for example, an
anti-neoplastic, anti-angiogenesis, kinase inhibition,
anticholinergic, anti-adrenergic and/or anti-inflammatory
activity.
[0008] Macular degeneration, such as age related macular
degeneration ("AMD") is a leading cause of blindness in the world.
It is estimated that thirteen million Americans have evidence of
macular degeneration. Macular degeneration results in a break down
the macula, the light-sensitive part of the retina responsible for
the sharp, direct vision needed to read or drive. Central vision is
especially affected. Macular degeneration is diagnosed as either
dry (atrophic) or wet (exudative). The dry form of macular
degeneration is more common than the wet form of macular
degeneration, with about 90% of AMD patients being diagnosed with
dry AMD. The wet form of the disease usually leads to more serious
vision loss. Macular degeneration can produce a slow or sudden
painless loss of vision. The cause of macular degeneration is not
clear. The dry form of AMD may result from the aging and thinning
of macular tissues, depositing of pigment in the macula, or a
combination of the two processes. With wet AMD, new blood vessels
grow beneath the retina and leak blood and fluid. This leakage
causes retinal cells to die and creates blind spots in central
vision.
[0009] Macular edema ("ME") can result in a swelling of the macula.
The edema is caused by fluid leaking from retinal blood vessels.
Blood leaks out of the weak vessel walls into a very small area of
the macula which is rich in cones, the nerve endings that detect
color and from which daytime vision depends. Blurring then occurs
in the middle or just to the side of the central visual field.
Visual loss can progress over a period of months. Retinal blood
vessel obstruction, eye inflammation, and age-related macular
degeneration have all been associated with macular edema. The
macula may also be affected by swelling following cataract
extraction. Symptoms of ME include blurred central vision,
distorted vision, vision tinted pink and light sensitivity. Causes
of ME can include retinal vein occlusion, macular degeneration,
diabetic macular leakage, eye inflammation, idiopathic central
serous chorioretinopathy, anterior or posterior uveitis, pars
planitis, retinitis pigmentosa, radiation retinopathy, posterior
vitreous detachment, epiretinal membrane formation, idiopathic
juxtafoveal retinal telangiectasia, Nd:YAG capsulotomy or
iridotomy. Some patients with ME may have a history of use of
topical epinephrine or prostaglandin analogs for glaucoma. The
first line of treatment for ME is typically anti-inflammatory drops
topically applied.
[0010] Macular edema is a non-specific response of the retina to a
variety of insults. It is associated with a number of diseases,
including uveitis, retinal vascular abnormalities (diabetic
retinopathy and retinal vein occlusive disease), a sequelae of
cataract surgery (post-cataract cystoid macular oedema), macular
epiretinal membranes, and inherited or acquired retinal
degeneration. Macular edema involves the breakdown of the inner
blood retinal barrier at the level of the capillary endothelium,
resulting in abnormal retinal vascular permeability and leakage
into the adjacent retinal tissues. The macula becomes thickened due
to fluid accumulation resulting in significant disturbances in
visual acuity (Ahmed I, Ai E. Macular disorders: cystoid macular
oedema. In: Yanoff M, Duker J S, eds. Ophthalmology. London: Mosby;
1999:34; Dick J, Jampol L M, Haller J A. Macular edema. In: Ryan S,
Schachat A P, eds. Retina. 3rd ed. St. Louis, Mo.: CV Mosby; 2001,
v2, Section 2 chap 57:967-979).
[0011] Macular edema may occur in diseases causing cumulative
injury over many years, such as diabetic retinopathy, or as a
result of more acute events, such as central retinal vein occlusion
or branch retinal vein occlusion.
[0012] In some cases macular edema resolves spontaneously or with
short-term treatment. Therapeutic choices for macular oedema depend
on the cause and severity of the condition. Currently there are no
approved pharmacological therapies for macular edema. Focal/grid
laser photocoagulation has been shown to be efficacious in the
prevention of moderate visual loss for macular oedema due to
diabetic retinopathy (Akduman L, Olk R S. The early treatment
diabetic retinopathy study. In: Kertes P S, Conway M D, eds.
Clinical trials in ophthalmology: a summary and practice guide.
Baltimore, Md.: Lippincott Williams & Wilkins; 1998:15-35;
Frank R N. Etiologic mechanisms in diabetic retinopathy. In: Ryan
S, Schachat A P, eds. Retina. 3rd ed. St. Louis, Mo.: CV Mosby;
2001, v2, Section 2, chap 71:1259-1294). Argon laser
photocoagulation increased the likelihood of vision improvement in
patients with macular oedema due to branch retinal vein occlusion
(BRVO) (Orth D. The branch vein occlusion study. In: Kertes P,
Conway M, eds. Clinical trials in ophthalmology: a summary and
practice guide. Baltimore, Md.: Lippincott Williams & Wilkins;
1998:113-127; Fekrat S, Finkelstein D. The Central Vein Occlusion
Study. In: Kertes P S, Conway M D, eds. Clinical trials in
ophthalmology: a summary and practice guide. Baltimore, Md.:
Lippincott Williams & Wilkins; 1998:129-143), but not in
patients with macular oedema due to central retinal vein occlusion
(CRVO) (Fekrat and Finkelstein 1998, supra; Clarkson J G. Central
retinal vein occlusion. In: Ryan S, Schachat A P, eds. Retina. 3rd
ed. St. Louis, Mo.: CV Mosby; 2001, v2, chap 75:1368-1375). For
CRVO, there are no known effective therapies.
[0013] An anti-inflammatory (i.e. immunosuppressive) agent can be
used for the treatment of an ocular condition, such as a posterior
ocular condition, which involves inflammation, such as an uveitis
or macula edema. Thus, topical or oral glucocorticoids have been
used to treat uveitis. A major problem with topical and oral drug
administration is the inability of the drug to achieve an adequate
(i.e. therapeutic) intraocular concentration. See e.g. Bloch-Michel
E. (1992). Opening address: intermediate uveitis, In Intermediate
Uveitis, Dev. Ophthalmol, W. R. F. Mike et al. editors., Basel:
Karger, 23:1-2; Pinar, V., et al. (1997). "Intraocular inflammation
and uveitis" In Basic and Clinical Science Course. Section 9
(1997-1998) San Francisco: American Academy of Ophthalmology, pp.
57-80, 102-103, 152-156; Mike, W. (1992). Clinical picture of
intermediate uveitis, In Intermediate Uveitis, Dev. Ophthalmol. W.
R. F. Boke et al. editors., Basel: Karger, 23:20-7; and Cheng C-K
et al. (1995). Intravitreal sustained-release dexamethasone device
in the treatment of experimental uveitis, Invest. Ophthalmol. Vis.
Sci. 36:442-53.
[0014] Systemic glucocorticoid administration can be used alone or
in addition to topical glucocorticoids for the treatment of
uveitis. However, prolonged exposure to high plasma concentrations
(administration of 1 mg/kg/day for 2-3 weeks) of steroid is often
necessary so that therapeutic levels can be achieved in the
eye.
[0015] Unfortunately, these high drug plasma levels commonly lead
to systemic side effects such as hypertension, hyperglycemia,
increased susceptibility to infection, peptic ulcers, psychosis,
and other complications. Cheng C-K et al. (1995). Intravitreal
sustained-release dexamethasone device in the treatment of
experimental uveitis, Invest. Ophthalmol. Vis. Sci. 36:442-53;
Schwartz, B. (1966). The response of ocular pressure to
corticosteroids, Ophthalmol. Clin. North Am. 6:929-89; Skalka, H.
W. et al. (1980). Effect of corticosteroids on cataract formation,
Arch Ophthalmol 98:1773-7; and Renfro, L. et al. (1992). Ocular
effects of topical and systemic steroids, Dermatologic Clinics
10:505-12.
[0016] Additionally, delivery to the eye of a therapeutic amount of
an active agent can be difficult, if not impossible, for drugs with
short plasma half-lives since the exposure of the drug to
intraocular tissues is limited. Therefore, a more efficient way of
delivering a drug to treat a posterior ocular condition is to place
the drug directly in the eye, such as directly into the vitreous.
Maurice, D. M. (1983). Micropharmaceutics of the eye, Ocular
Inflammation Ther. 1:97-102; Lee, V. H. L. et al. (1989). Drug
delivery to the posterior segment" Chapter 25 In Retina. T. E.
Ogden and A. P. Schachat eds., St. Louis: CV Mosby, Vol. 1, pp.
483-98; and Olsen, T. W. et al. (1995). Human scleral permeability:
effects of age, cryotherapy, transscleral diode laser, and surgical
thinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903.
[0017] Techniques such as intravitreal injection of a drug have
shown promising results, but due to the short intraocular half-life
of active agent, such as glucocorticoids (approximately 3 hours),
intravitreal injections must be frequently repeated to maintain a
therapeutic drug level. In turn, this repetitive process increases
the potential for side effects such as retinal detachment,
endophthalmitis, and cataracts. Maurice, D. M. (1983).
Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102;
Olsen, T. W. et al. (1995). Human scleral permeability: effects of
age, cryotherapy, transscleral diode laser, and surgical thinning,
Invest. Ophthalmol. Vis. Sci. 36:1893-1903; and Kwak, H. W. and
D'Amico, D. J. (1992). Evaluation of the retinal toxicity and
pharmacokinetics of dexamethasone after intravitreal injection,
Arch. Ophthalmol. 110:259-66.
[0018] Additionally, topical, systemic, and periocular
glucocorticoid treatment must be monitored closely due to toxicity
and the long-term side effects associated with chronic systemic
drug exposure sequelae. Rao, N. A. et al. (1997). Intraocular
inflammation and uveitis, In Basic and Clinical Science Course.
Section 9 (1997-1998) San Francisco: American Academy of
Ophthalmology, pp. 57-80, 102-103, 152-156; Schwartz, B. (1966).
The response of ocular pressure to corticosteroids, Ophthalmol Clin
North Am 6:929-89; Skalka, H. W. and Pichal, J. T. (1980). Effect
of corticosteroids on cataract formation, Arch Ophthalmol
98:1773-7; Renfro, L and Snow, J. S. (1992). Ocular effects of
topical and systemic steroids, Dermatologic Clinics 10:505-12;
Bodor, N. et al. (1992). A comparison of intraocular pressure
elevating activity of loteprednol etabonate and dexamethasone in
rabbits, Current Eye Research 11:525-30.
[0019] U.S. Pat. No. 6,217,895 discusses a method of administering
a corticosteroid to the posterior segment of the eye, but does not
disclose a bioerodible implant.
[0020] U.S. Pat. No. 5,501,856 discloses controlled release
pharmaceutical preparations for intraocular implants to be applied
to the interior of the eye after a surgical operation for disorders
in retina/vitreous body or for glaucoma.
[0021] U.S. Pat. No. 5,869,079 discloses combinations of
hydrophilic and hydrophobic entities in a biodegradable sustained
release implant, and describes a polylactic acid polyglycolic acid
(PLGA) copolymer implant comprising dexamethasone. As shown by in
vitro testing of the drug release kinetics, the 100-120 .mu.g 50/50
PLGA/dexamethasone implant disclosed did not show appreciable drug
release until the beginning of the fourth week, unless a release
enhancer, such as HPMC was added to the formulation.
[0022] U.S. Pat. No. 5,824,072 discloses implants for introduction
into a suprachoroidal space or an avascular region of the eye, and
describes a methylcellulose (i.e. non-biodegradable) implant
comprising dexamethasone. WO 9513765 discloses implants comprising
active agents for introduction into a suprachoroidal or an
avascular region of an eye for therapeutic purposes.
[0023] U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose
biodegradable ocular implants comprising microencapsulated drugs,
and describes implanting microcapsules comprising hydrocortisone
succinate into the posterior segment of the eye.
[0024] U.S. Pat. No. 5,164,188 discloses encapsulated agents for
introduction into the suprachoroid of the eye, and describes
placing microcapsules and plaques comprising hydrocortisone into
the pars plana. U.S. Pat. Nos. 5,443,505 and 5,766,242 discloses
implants comprising active agents for introduction into a
suprachoroidal space or an avascular region of the eye, and
describes placing microcapsules and plaques comprising
hydrocortisone into the pars plana.
[0025] Zhou et al. disclose a multiple-drug implant comprising
5-fluorouridine, triamcinolone, and human recombinant tissue
plasminogen activator for intraocular management of proliferative
vitreoretinopathy (PVR). Zhou, T, et al. (1998). Development of a
multiple-drug delivery implant for intraocular management of
proliferative vitreoretinopathy, Journal of Controlled Release 55:
281-295.
[0026] U.S. Pat. No. 6,046,187 discusses methods and compositions
for modulating local anesthetic by administering one or more
glucocorticosteroid agents before, simultaneously with or after the
administration of a local anesthetic at a site in a patient.
[0027] U.S. Pat. No. 3,986,510 discusses ocular inserts having one
or more inner reservoirs of a drug formulation confined within a
bioerodible drug release rate controlling material of a shape
adapted for insertion and retention in the "sac of the eye," which
is indicated as being bounded by the surfaces of the bulbar
conjunctiva of the sclera of the eyeball and the palpebral
conjunctiva of the eyelid, or for placement over the corneal
section of the eye.
[0028] U.S. Pat. No. 6,369,116 discusses an implant with a release
modifier inserted in a scleral flap.
[0029] EP 0 654256 discusses use of a scleral plug after surgery on
a vitreous body, for plugging an incision.
[0030] U.S. Pat. No. 4,863,457 discusses the use of a bioerodible
implant to prevent failure of glaucoma filtration surgery by
positioning the implant either in the subconjunctival region
between the conjunctival membrane overlying it and the sclera
beneath it or within the sclera itself within a partial thickness
sclera flap.
[0031] EP 488 401 discusses intraocular implants, made of certain
polylactic acids, to be applied to the interior of the eye after a
surgical operation for disorders of the retina/vitreous body or for
glaucoma.
[0032] EP 430539 discusses use of a bioerodible implant which is
inserted in the suprachoroid.
[0033] U.S. Pat. No. 6,726,918 discusses implants for treating
inflammation mediated conditions of the eye.
[0034] Significantly, it is known that PLGA co-polymer formulations
of a bioerodible polymer comprising an active agent typically
release the active agent with a characteristic sigmoidal release
profile (as viewed as time vs percent of total active agent
released), that is after a relatively long initial lag period (the
first release phase) when little if any active agent is released,
there is a high positive slope period when most of the active agent
is released (the second release phase) followed by another near
horizontal (third) release phase, when the drug release reaches a
plateau.
[0035] One of the alternatives to intravitreal injection to
administer drugs is the placement of biodegradable implants under
the sclera or into the subconjunctival or suprachoroidal space, as
described in U.S. Pat. No. 4,863,457 to Lee; WO 95/13765 to Wong et
al.; WO 00/37056 to Wong et al.; EP 430,539 to Wong; in Gould et
al., Can. J. Ophthalmol. 29(4):168-171 (1994); and in Apel et al.,
Curr. Eye Res. 14:659-667 (1995).
[0036] Furthermore, the controlled release of drugs from
polylactide/polyglycolide (PLGA) copolymers into the vitreous has
been disclosed, e.g., in U.S. Pat. No. 5,501,856 to Ohtori et al.
and EP 654,256 to Ogura.
[0037] Recent experimental work has demonstrated that uncapped PLGA
degrades faster than capped (end-capped) PLGA (Park et al., J.
Control. Rel. 55:181-191 (1998); Tracy et al., Biomaterials
20:1057-1062 (1999); and Jong et al., Polymer 42:2795-2802 (2001).
Accordingly, implants containing mixtures of uncapped and capped
PLGA have been formed to modulate drug release. For example, U.S.
Pat. No. 6,217,911 to Vaughn et al. ('911) and U.S. Pat. No.
6,309,669 to Setterstrom et al. (669) disclose the delivery of
drugs from a blend of uncapped and capped PLGA copolymer to curtail
initial burst release of the drugs. In the '911 patent, the
composition delivers non-steroidal anti-inflammatory drugs from
PLGA microspheres made by a solvent extraction process or PLGA
microcapsules prepared by a solvent evaporation process over a
duration of 24 hours to 2 months. In the '669 patent, the
composition delivers various pharmaceuticals from PLGA
microcapsules over a duration of 1-100 days. The PLGA microspheres
or microcapsules are administered orally or as an aqueous
injectable formulation. As mentioned above, there is poor
partitioning of drug into the eye with oral administration.
Furthermore, use of an aqueous injectable drug composition (for
injecting into the eye) should be avoided since the eye is a closed
space (limited volume) with intraocular pressure ranges that are
strictly maintained. Administration of an injectable may increase
intraocular volume to a point where intraocular pressures would
then become pathologic.
[0038] Potent corticosteroids such as dexamethasone suppress
inflammation by inhibiting edema, fibrin deposition, capillary
leakage and phagocytic migration, all key features of the
inflammatory response. Corticosteroids prevent the release of
prostaglandins, some of which have been identified as mediators of
cystoid macular oedema (Leopold I H. Nonsteroidal and steroidal
anti-inflammatory agents. In: Sears M, Tarkkanen A, eds. Surgical
pharmacology of the eye. New York, N.Y.: Raven Press; 1985:83-133;
Tennant J L. Cystoid maculopathy: 125 prostaglandins in
ophthalmology. In: Emery J M, ed. Current concepts in cataract
surgery: selected proceedings of the fifth biennial cataract
surgical congress, Section 3. St. Louis, Mo.: CV Mosby; 1978;
360-362). Additionally, corticosteroids including dexamethasone
have been shown to inhibit the expression of vascular endothelial
growth factor (VEGF), a cytokine which is a potent promoter of
vascular permeability (Nauck M, Karakiulakis G, Perruchoud A P,
Papakonstantinou E, Roth M. Corticosteroids inhibit the expression
of the vascular endothelial growth factor gene in human vascular
smooth muscle cells. Eur J Pharmacol 1998; 341:309-315).
[0039] The use of dexamethasone to date, by conventional routes of
administration, has yielded limited success in treating retinal
disorders, including macular oedema, largely due to the inability
to deliver and maintain adequate quantities of the drug to the
posterior segment without resultant toxicity. After topical
administration of dexamethasone, only about 1% reaches the anterior
segment, and only a fraction of that amount moves into the
posterior segment (Lee V H L, Pince K J, Frambach D A, Martini B.
Drug delivery to the posterior segment. In: Ogden T E, Schachat A
P, eds. Retina. St. Louis, Mo.: CV Mosby, 1989, chap 25:483-498).
Although intravitreal injections of dexamethasone have been used,
the exposure to the drug is very brief as the half-life of the drug
within the eye is approximately 3 hours (Peyman G A, Herbst R.
Bacterial endophthalmitis. Arch Ophthalmol 1974; 91:416-418).
Periocular and posterior sub-Tenon's injections of dexamethasone
also have a short term treatment effect (Riordan-Eva P, Lightman S.
Orbital floor steroid injections in the treatment of uveitis. Eye
1994; 8 (Pt 1):66-69; Jennings T, Rusin M, Tessler H, Cunha-Vaz J.
Posterior sub-Tenon's injections of corticosteroids in uveitis
patients with cystoid macular edema. Jpn J Ophthalmol 1988;
32:385-391).
[0040] Adverse reactions listed for conventional ophthalmic
dexamethasone preparations include: ocular hypertension, glaucoma,
posterior subcapsular cataract formation, and secondary ocular
infection from pathogens including herpes simplex (Lee et al, 1989
supra; Skalka H W, Prchal J T. Effect of corticosteroids on
cataract formation. Arch Ophthalmol 1980; 98:1773-1777; Renfro L,
Snow J S. Ocular effects of topical and systemic steroids. Dermatol
Clin 1992; 10(3):505-512; Physician's Desk Reference, 2003).
Systemic doses are associated with additional hazardous
side-effects including hypertension, hyperglycemias, increased
susceptibility to infection, and peptic ulcers (Physician's Desk
Reference, 2003).
[0041] By delivering a drug directly into the vitreous cavity,
blood eye barriers can be circumvented and intraocular therapeutic
levels can be achieved with minimal risk of systemic toxicity (Lee
et al, 1989 supra). This route of administration typically results
in a short half-life unless the drug can be delivered using a
formulation capable of providing sustained release.
[0042] Consequently, a biodegradable implant for delivering a
therapeutic agent to an ocular region may provide significant
medical benefit for patients afflicted with a medical condition of
the eye.
DRAWINGS
[0043] FIG. 1 shows the in vivo concentration of dexamethasone in
the vitreous of rabbit eyes over a 42 day period after implantation
of compressed and extruded biodegradable implants containing 350
.mu.g dexamethasone into the posterior segment of rabbit eyes.
[0044] FIG. 2 shows the in vivo cumulative percentage release of
dexamethasone in the vitreous of rabbit eyes over a 42 day period
after implantation of compressed and extruded biodegradable
implants containing 350 .mu.g dexamethasone and 700 .mu.g
dexamethasone into the posterior segment of rabbit eyes.
[0045] FIG. 3 shows the in vivo concentration of dexamethasone in
the aqueous humor of rabbit eyes over a 42 day period after
implantation of compressed and extruded biodegradable implants
containing 350 .mu.g dexamethasone into the posterior segment of
rabbit eyes.
[0046] FIG. 4 shows the in vivo concentration of dexamethasone in
the plasma (from a rabbit blood sample) over a 42 day period after
implantation of compressed and extruded biodegradable implants
containing 350 .mu.g dexamethasone into the posterior segment of
rabbit eyes.
[0047] FIG. 5 shows the in vivo concentration of dexamethasone in
the vitreous of rabbit eyes over a 42 day period after implantation
of compressed and extruded biodegradable implants containing 700
.mu.g dexamethasone into the posterior segment of rabbit eyes.
[0048] FIG. 6 shows the in vivo concentration of dexamethasone in
the aqueous humor of rabbit eyes over a 42 day period after
implantation of compressed and extruded biodegradable implants
containing 700 .mu.g dexamethasone into the posterior segment of
rabbit eyes.
[0049] FIG. 7 shows the in vivo concentration of dexamethasone in
the plasma (from a rabbit blood sample) over a 42 day period after
implantation of compressed and extruded biodegradable implants
containing 700 .mu.g dexamethasone into the posterior segment of
rabbit eyes.
[0050] FIG. 8 shows the in vivo concentration of dexamethasone in
the vitreous of rabbit eyes over a 42 day period after implantation
of compressed and extruded biodegradable implants containing 350
.mu.g dexamethasone and 700 .mu.g dexamethasone into the posterior
segment of rabbit eyes.
[0051] FIG. 9 shows the in vitro total cumulative percentage
release of dexamethasone into a saline solution at 37.degree. C.
from 60/40 w/w dexamethasone/PLGA implants having a weight ratio of
40:0 hydrophobic end to hydrophilic end PLGA (312-140-2), weight
ratio of 30:10 hydrophobic end to hydrophilic end PLGA (312-140-4),
weight ratio of 20:20 hydrophobic end to hydrophilic end PLGA
(312-140-3), and weight ratio of 0:40 hydrophobic end to
hydrophilic end PLGA (312-140-1).
[0052] FIG. 10 compares the in vitro cumulative percentage release
of dexamethasone into a saline solution at 37.degree. C. for six
lots of extruded implants having 60% by weight dexamethasone, 30%
by weight hydrophilic end PLGA, and 10% by weight hydrophobic end
PLGA.
[0053] FIG. 11 is a flow chart illustrating manufacturing processes
for tablet, single and double extrusion methods for making an
ocular implant within the scope of the present invention.
[0054] FIG. 12 is a graph which shows the cumulative amount of
dexamethasone released in vitro over time for an ocular implant
made by either tabletting or a single extrusion processes.
[0055] FIG. 13 are scanning electromicrographs (SEM) pictures of
DEX PS DDS implants made by a tabletting process and by a single
extrusion process.
[0056] FIG. 14 shows two graphs of batch to batch vs within batch
variability of % LC (% of total dexamethasone) for implants made
from either unmilled or milled PLGAs.
[0057] FIG. 15 is a graph showing in vitro release of dexamethasone
from DEX PS DDS implants made by either a single extrusion or by a
double extrusion process.
[0058] FIG. 16 is a flow chart illustrating a double extrusion
manufacturing processes for making an ocular implant within the
scope of the present invention.
[0059] FIG. 17 provides a cut-away side view of an applicator to
implant an ocular implant within the scope of the present
invention.
SUMMARY
Definitions
[0060] The following terms as used herein have the following
meanings:
[0061] "About" means approximately or nearly and in the context of
a numerical value or range set forth herein means.+-.10% of the
numerical value or range recited or claimed.
[0062] "Active agent" and "drug" are used interchangeably and refer
to any substance used to treat an ocular condition.
[0063] "Bioerodible polymer" means a polymer which degrades in
vivo, and wherein erosion of the polymer over time is required to
achieve the active agent release kinetics according to the present
invention. Thus, hydrogels such as methylcellulose which act to
release drug through polymer swelling are specifically excluded
from the term "bioerodible (or biodegradable) polymer". The words
"bioerodible" and "biodegradable" are synonymous and are used
interchangeably herein.
[0064] "Concentration equivalent to dexamethasone", or
"dexamethasone equivalent" means a concentration of an active
agent, such as a steroidal anti-inflammatory agent, necessary to
have approximately the same efficacy in vivo as a particular dose
of dexamethasone. For example, hydrocortisone is approximately
twenty five fold less potent than dexamethasone, and thus a 25 mg
dose of hydrocortisone would be equivalent to a 1 mg dose of
dexamethasone. One of ordinary skill in the art would be able to
determine the concentration equivalent to dexamethasone for a
particular steroidal anti-inflammatory agent from one of several
standard tests known in the art. Relative potencies of selected
corticosteroids may be found, for example, in Gilman, A. G., et
al., eds. (1990). Goodman and Gilman's: The Pharmacological Basis
of Therapeutics. 8th Edition, Pergamon Press: New York, p.
1447.
[0065] "Cumulative release profile" means to the cumulative total
percent of an active agent released from an implant into an ocular
region or site in vivo over time or into a specific release medium
in vitro over time.
[0066] "Glaucoma" means primary, secondary and/or congenital
glaucoma. Primary glaucoma can include open angle and closed angle
glaucoma. Secondary glaucoma can occur as a complication of a
variety of other conditions, such as injury, inflammation, vascular
disease and diabetes.
[0067] "Inflammation-mediated" in relation to an ocular condition
means any condition of the eye which can benefit from treatment
with an anti-inflammatory agent, and is meant to include, but is
not limited to, uveitis, macular edema, acute macular degeneration,
retinal detachment, ocular tumors, fungal or viral infections,
multifocal choroiditis, diabetic uveitis, proliferative
vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt
Koyanagi-Harada (VKH) syndrome, histoplasmosis, and uveal
diffusion.
[0068] "Injury" or "damage" are interchangeable and refer to the
cellular and morphological manifestations and symptoms resulting
from an inflammatory-mediated condition, such as, for example,
inflammation.
[0069] "Measured under infinite sink conditions in vitro," means
assays to measure drug release in vitro, wherein the experiment is
designed such that the drug concentration in the receptor medium
never exceeds 5% of saturation. Examples of suitable assays may be
found, for example, in USP 23; NF 18 (1995) pp. 1790-1798.
[0070] "Ocular condition" means a disease, aliment or condition
which affects or involves the eye or one or the parts or regions of
the eye, such as a retinal disease. 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. :"Ocular condition" is synonymous with "medical condition
of the eye".
[0071] "Plurality" means two or more.
[0072] "Posterior ocular condition" means a disease, ailment or
condition which 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 nerve which vascularize or innervate a posterior ocular
region or site.
[0073] "Steroidal anti-inflammatory agent" and "glucocorticoid" are
used interchangeably herein, and are meant to include steroidal
agents, compounds or drugs which reduce inflammation when
administered at a therapeutically effective level.
[0074] "Substantially" in relation to the release profile or the
release characteristic of an active agent from a bioerodible
implant as in the phrase "substantially continuous rate" of the
active agent release rate from the implant means, that the rate of
release (i.e. amount of active agent released/unit of time) does
not vary by more than 100%, and preferably does not vary by more
than 50%, over the period of time selected (i.e. a number of days).
"Substantially" in relation to the blending, mixing or dispersing
of an active agent in a polymer, as in the phrase "substantially
homogenously dispersed" means that there are no or essentially no
particles (i.e. aggregations) of active agent in such a homogenous
dispersal.
[0075] "Suitable for insertion (or implantation) in (or into) an
ocular region or site" with regard to an implant, means an implant
which has a size (dimensions) such that it can be inserted or
implanted without causing excessive tissue damage and without
unduly physically interfering with the existing vision of the
patient into which the implant is implanted or inserted.
[0076] "Therapeutic levels" or "therapeutic amount" means an amount
or a concentration of an active agent that has been locally
delivered to an ocular region that is appropriate to safely treat
an ocular condition so as to reduce or prevent a symptom of an
ocular condition.
[0077] The meaning of abbreviations used herein is explained
below:
TABLE-US-00001 Term Meaning .sup.1H-NMR Proton nuclear magnetic
resonance ABS Poly acrylonitrile butadiene styrene ACC Anterior
chamber cell ALT Alanine aminotransferase API Active pharmaceutical
ingredient AVC Anterior vitreous cells BCVA Best-corrected visual
acuity BI Boehringer Ingelheim BRVO Branch retinal vein occlusion
BSE Bovine Spongiform Encephalopathy BVOS Branch Vein Occlusion
Study B/N Batch number .degree. C. Degrees Centigrade CA California
CAS Chemical abstract services CF Count fingers CFU Colony forming
unit cGMP Current Good Manufacturing Practice CI Confidence
interval CIB Clinical Investigator's Brochure CO.sub.2 Carbon
dioxide COEX Co-extruded CRVO Central retinal vein occlusion CVOS
Central Vein Occlusion Study DDS Drug delivery system DEX
Dexamethasone DEX PS DDS Dexamethasone posterior segment drug
delivery system (implant) DEX PS DDS Dexamethasone posterior
segment Applicator system drug delivery system (medicinal product)
DME Diabetic macular oedema EMEA European medicine evaluation
agency ETDRS Early Treatment of Diabetic Retinopathy Study EU
Endotoxin unit .degree. F. Degrees Fahrenheit G Gram GLP Good
Laboratory Practice GRB Geographical BSE (Bovine Spongiform
Encephalopathies) risk H.sub.2O Water HDPE High density
polyethylene HPLC High performance liquid chromatography IEC
Independent Ethics Committee IMPD Investigational medicinal product
dossier INN International Non-proprietary Name IOP Intraocular
pressure IPC In process control IR Infrared IRB Institutional
Review Board ISO International standard organisation Kg Kilogram
kGy Kilo Grey LAF Laminar Air Flow LAL Limulus Amebocytes Lisat LC
Label Claim LOCF Last observation carried forward LS Label strength
ME Macular oedema g Microgram Mg Milligram J Microjoules mL
Millilitre(s) Mm Millimetre(s) mmHg Millimeters of mercury mol Mole
n or N Number n/a Not applicable ND Not detected Ng Nanogram(s)
NSAID Nonsteroidal anti-inflammatory drug NT Not tested OCT Optical
Coherence Tomography PDE Permitted daily exposure PET Polyethylene
terephtalate pH Hydrogen potential Ph. Eur. European Pharmacopoeia
PK Pharmacokinetics pKa Acid dissociation constant PLGA, PLG Poly
(D,L-lactide-co-glycolide). PME Persistent macular edema ppm Part
per million PS Posterior segment PVR Proliferative
vitreoretinopathy RH Relative humidity SAE Serious adverse event SD
Standard deviation SEM Scanning electron microscope TSE
Transmissible spongiform encephalopathy USA United States of
America USP United States Pharmacopoeia UV Ultra violet VEGF
Vascular endothelial growth factor WPE Ultrahigh molecular weight
polyethylene
[0078] Our invention encompasses a bioerodible implant for treating
a medical condition of the eye comprising an active agent dispersed
within a biodegradable polymer matrix, wherein at least about 75%
of the particles of the active agent have a diameter of less than
about 10 .mu.m. Preferably, at least about 99% of the particles
have a diameter of less than about 20 .mu.m.
[0079] The active agent can be selected from the group consisting
of ace-inhibitors, endogenous cytokines, agents that influence
basement membrane, agents that influence the growth of endothelial
cells, adrenergic agonists or blockers, cholinergic agonists or
blockers, aldose reductase inhibitors, analgesics, anesthetics,
antiallergics, anti-inflammatory agents, steroids (such as a
steroidal anti-inflammatory agent), antihypertensives, pressors,
antibacterials, antivirals, antifungals, antiprotozoals,
anti-infective agents, antitumor agents, antimetabolites, and
antiangiogenic agents. Thus, the active agent can be cortisone,
dexamethasone, fluocinolone, hydrocortisone, methylprednisolone,
prednisolone, prednisone, triamcinolone, and any derivative
thereof.
[0080] The bioerodible implant is sized for implantation in an
ocular region. The ocular region can be any one or more of the
anterior chamber, the posterior chamber, the vitreous cavity, the
choroid, the suprachoroidal space, the conjunctiva, the
subconjunctival space, the episcleral space, the intracorneal
space, the epicorneal space, the sclera, the pars plana,
surgically-induced avascular regions, the macula, and the
retina.
[0081] An alternate embodiment of the bioerodible implant can
comprise a steroid active agent dispersed within a biodegradable
polymer matrix, wherein at least about 75% of the particles of the
active agent have a diameter of less than about 20 .mu.m.
[0082] Our present invention also encompasses a method for making a
bioerodible implant for treating a medical condition of the eye,
the method comprising a plurality of extrusions of a biodegradable
polymer. This method can also comprise the step of milling the
biodegradable polymer prior to the extrusion. The biodegradable
polymer can be a poly(lactic-co-glycolic)acid (PLGA) copolymer. The
ratio of lactic to glycolic acid monomers in the polymer can be
about 50/50 weight percentage. Additionally, the PLGA copolymer can
be about 20 to about 90 weight percent of the bioerodible implant.
Alternately, the PLGA copolymer can be about 40 percent by weight
of the bioerodible implant.
[0083] A detailed method for making a bioerodible implant for
treating a medical condition of the eye can have the steps of: (a)
milling a biodegradable polymer; (b) blending the milled
biodegradable polymer and particles of an active agent, to thereby
obtain a blended mixture of the milled biodegradable polymer and
the particles of the active agent, wherein at least about 75% of
the particles of the active agent have a diameter of less than
about 20 .mu.m; (c) carrying out a first extrusion of the blended
mixture, to thereby obtain a first extrusion product; (d)
pelletizing the first extrusion product, and; (e) carrying out a
second extrusion of the pelletized first extrusion product, thereby
obtaining a bioerodible implant for treating a medical condition of
the eye. Our invention also includes a bioerodible implant for
treating a medical condition of the eye made by this detailed
method.
DESCRIPTION
[0084] The present invention provides biodegradable ocular implants
and methods for treating medical conditions of the eye. Usually,
the implants are formed to be monolithic, i.e., the particles of
active agent are distributed throughout the biodegradable polymer
matrix. Furthermore, the implants are formed to release an active
agent into an ocular region of the eye over various time periods.
The active agent may be release over a time period including, but
is not limited to, approximately six months, approximately three
months, approximately one month, or less than one month.
[0085] Biodegradable Implants for Treating Medical Conditions of
the Eye
[0086] The implants of the invention include an active agent
dispersed within a biodegradable polymer. The implant compositions
typically vary according to the preferred drug release profile, the
particular active agent used, the condition being treated, and the
medical history of the patient. Active agents that may be used
include, but are not limited to, ace-inhibitors, endogenous
cytokines, agents that influence basement membrane, agents that
influence the growth of endothelial cells, adrenergic agonists or
blockers, cholinergic agonists or blockers, aldose reductase
inhibitors, analgesics, anesthetics, antiallergics,
anti-inflammatory agents, antihypertensives, pressors,
antibacterials, antivirals, antifungals, antiprotozoals,
anti-infectives, antitumor agents, antimetabolites, and
antiangiogenic agents.
[0087] In one variation the active agent is methotrexate. In
another variation, the active agent is retinoic acid. In a
preferred variation, the anti-inflammatory agent is a nonsteroidal
anti-inflammatory agent. Nonsteroidal anti-inflammatory agents that
may be used include, but are not limited to, aspirin, diclofenac,
flurbiprofen, ibuprofen, ketorolac, naproxen, and suprofen. In a
more preferred variation, the anti-inflammatory agent is a
steroidal anti-inflammatory agent.
[0088] Steroidal Anti-Inflammatory Agents The steroidal
anti-inflammatory agents that may be used in the ocular implants
include, but are not limited to, 21-acetoxypregnenolone,
alclometasone, algestone, amcinonide, beclomethasone,
betamethasone, budesonide, chloroprednisone, clobetasol,
clobetasone, clocortolone, cloprednol, corticosterone, cortisone,
cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,
diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,
flucloronide, flumethasone, flunisolide, fluocinolone acetonide,
fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,
fluperolone acetate, fluprednidene acetate, fluprednisolone,
flurandrenolide, fluticasone propionate, formocortal, halcinonide,
halobetasol propionate, halometasone, halopredone acetate,
hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,
medrysone, meprednisone, methylprednisolone, mometasone furoate,
paramethasone, prednicarbate, prednisolone, prednisolone
25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,
prednival, prednylidene, rimexolone, tixocortol, triamcinolone,
triamcinolone acetonide, triamcinolone benetonide, triamcinolone
hexacetonide, and any of their derivatives.
[0089] In one variation, cortisone, dexamethasone, fluocinolone,
hydrocortisone, methylprednisolone, prednisolone, prednisone, and
triamcinolone, and their derivatives, are preferred steroidal
anti-inflammatory agents. In another preferred variation, the
steroidal anti-inflammatory agent is dexamethasone. In another
variation, the biodegradable implant includes a combination of two
or more steroidal anti-inflammatory agents.
[0090] The steroidal anti-inflammatory agent may constitute from
about 10% to about 90% by weight of the implant. In one variation,
the agent is from about 40% to about 80% by weight of the implant.
In a preferred variation, the agent comprises about 60% by weight
of the implant.
[0091] The Biodegradable Polymer Matrix
[0092] In one variation, the active agent may be homogeneously
dispersed in the biodegradable polymer matrix of the implants. The
selection of the biodegradable polymer matrix to be employed will
vary with the desired release kinetics, patient tolerance, the
nature of the disease to be treated, and the like. Polymer
characteristics that are considered include, but are not limited
to, the biocompatibility and biodegradability at the site of
implantation, compatibility with the active agent of interest, and
processing temperatures. The biodegradable polymer matrix usually
comprises at least about 10, at least about 20, at least about 30,
at least about 40, at least about 50, at least about 60, at least
about 70, at least about 80, or at least about 90 weight percent of
the implant. In one variation, the biodegradable polymer matrix
comprises about 40% by weight of the implant.
[0093] Biodegradable polymer matrices which may be employed
include, but are not limited to, polymers made of monomers such as
organic esters or ethers, which when degraded result in
physiologically acceptable degradation products. Anhydrides,
amides, orthoesters, or the like, by themselves or in combination
with other monomers, may also be used. The polymers are generally
condensation polymers. The polymers may be crosslinked or
non-crosslinked. If crosslinked, they are usually not more than
lightly crosslinked, and are less than 5% crosslinked, usually less
than 1% crosslinked.
[0094] For the most part, besides carbon and hydrogen, the polymers
will include oxygen and nitrogen, particularly oxygen. The oxygen
may be present as oxy, e.g., hydroxy or ether, carbonyl, e.g.,
non-oxo-carbonyl, such as carboxylic acid ester, and the like. The
nitrogen may be present as amide, cyano, and amino. An exemplary
list of biodegradable polymers that may be used are described in
Heller, Biodegradable Polymers in Controlled Drug Delivery, In:
"CRC Critical Reviews in Therapeutic Drug Carrier Systems", Vol. 1.
CRC Press, Boca Raton, Fla. (1987).
[0095] Of particular interest are polymers of hydroxyaliphatic
carboxylic acids, either homo- or copolymers, and polysaccharides.
Included among the polyesters of interest are homo- or copolymers
of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic
acid, caprolactone, and combinations thereof. Copolymers of
glycolic and lactic acid are of particular interest, where the rate
of biodegradation is controlled by the ratio of glycolic to lactic
acid. The percent of each monomer in poly(lactic-co-glycolic)acid
(PLGA) copolymer may be 0-100%, about 15-85%, about 25-75%, or
about 35-65%. In a preferred variation, a 50/50 PLGA copolymer is
used. More preferably, a random copolymer of 50/50 PLGA is
used.
[0096] Biodegradable polymer matrices that include mixtures of
hydrophilic and hydrophobic ended PLGA may also be employed, and
are useful in modulating polymer matrix degradation rates.
Hydrophobic ended (also referred to as capped or end-capped) PLGA
has an ester linkage hydrophobic in nature at the polymer terminus.
Typical hydrophobic end groups include, but are not limited to
alkyl esters and aromatic esters. Hydrophilic ended (also referred
to as uncapped) PLGA has an end group hydrophilic in nature at the
polymer terminus. PLGA with a hydrophilic end groups at the polymer
terminus degrades faster than hydrophobic ended PLGA because it
takes up water and undergoes hydrolysis at a faster rate (Tracy et
al., Biomaterials 20:1057-1062 (1999)). Examples of suitable
hydrophilic end groups that may be incorporated to enhance
hydrolysis include, but are not limited to, carboxyl, hydroxyl, and
polyethylene glycol. The specific end group will typically result
from the initiator employed in the polymerization process. For
example, if the initiator is water or carboxylic acid, the
resulting end groups will be carboxyl and hydroxyl. Similarly, if
the initiator is a monofunctional alcohol, the resulting end groups
will be ester or hydroxyl.
[0097] The implants may be formed from all hydrophilic end PLGA or
all hydrophobic end PLGA. In general, however, the ratio of
hydrophilic end to hydrophobic end PLGA in the biodegradable
polymer matrices of this invention range from about 10:1 to about
1:10 by weight. For example, the ratio may be 3:1, 2:1, or 1:1 by
weight. In a preferred variation, an implant with a ratio of
hydrophilic end to hydrophobic end PLGA of 3:1 w/w is used.
[0098] Additional Agents
[0099] Other agents may be employed in the formulation for a
variety of purposes. For example, buffering agents and
preservatives may be employed. Preservatives which may be used
include, but are not limited to, sodium bisulfate, sodium
bisulfate, sodium thiosulfate, benzalkonium chloride,
chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric
nitrate, methylparaben, polyvinyl alcohol and phenylethyl alcohol.
Examples of buffering agents that may be employed include, but are
not limited to, sodium carbonate, sodium borate, sodium phosphate,
sodium acetate, sodium bicarbonate, and the like, as approved by
the FDA for the desired route of administration. Electrolytes such
as sodium chloride and potassium chloride may also be included in
the formulation.
[0100] The biodegradable ocular implants may also include
additional hydrophilic or hydrophobic compounds that accelerate or
retard release of the active agent. Furthermore, the inventors
believe that because hydrophilic end PLGA has a higher degradation
rate than hydrophobic end PLGA due to its ability to take up water
more readily, increasing the amount of hydrophilic end PLGA in the
implant polymer matrix will result in faster dissolution rates.
FIG. 9 shows that the time from implantation to significant release
of active agent (lag time) increases with decreasing amounts of
hydrophilic end PLGA in the ocular implant. In FIG. 9, the lag time
for implants having 0% hydrophilic end PLGA (40% w/w hydrophobic
end) was shown to be about 21 days. In comparison, a significant
reduction in lag time was seen with implants having 10% w/w and 20%
w/w hydrophilic end PLGA.
[0101] Release Kinetics
[0102] The inventors believe the implants of the invention are
formulated with particles of an active agent dispersed within a
biodegradable polymer matrix. Without being bound by theory, the
inventors believe that release of the active agent is achieved by
erosion of the biodegradable polymer matrix and by diffusion of the
particulate agent into an ocular fluid, e.g., the vitreous, with
subsequent dissolution of the polymer matrix and release of the
active agent. The inventors believe that the factors that influence
the release kinetics include such characteristics as the size of
the active agent particles, the solubility of the active agent, the
ratio of active agent to polymer(s), the method of manufacture, the
surface area exposed, and the erosion rate of the polymer(s). The
release kinetics achieved by this form of active agent release are
different than that achieved through formulations which release
active agents through polymer swelling, such as with crosslinked
hydrogels. In that case, the active agent is not released through
polymer erosion, but through polymer swelling, which releases agent
as liquid diffuses through the pathways exposed.
[0103] The inventors believe that the release rate of the active
agent depends at least in part on the rate of degradation of the
polymer backbone component or components making up the
biodegradable polymer matrix. For example, condensation polymers
may be degraded by hydrolysis (among other mechanisms) and
therefore any change in the composition of the implant that
enhances water uptake by the implant will likely increase the rate
of hydrolysis, thereby increasing the rate of polymer degradation
and erosion, and thus increasing the rate of active agent
release.
[0104] The release kinetics of the implants of the invention are
dependent in part on the surface area of the implants. A larger
surface area exposes more polymer and active agent to ocular fluid,
causing faster erosion of the polymer matrix and dissolution of the
active agent particles in the fluid. The size and shape of the
implant may also be used to control the rate of release, period of
treatment, and active agent concentration at the site of
implantation. At equal active agent loads, larger implants will
deliver a proportionately larger dose, but depending on the surface
to mass ratio, may possess a slower release rate. For implantation
in an ocular region, the total weight of the implant preferably
ranges, e.g., from about 100-5000 usually from about 500-1500
.mu.g. In one variation, the total weight of the implant is about
600 .mu.g. In another variation, the total weight of the implant is
about 1200 .mu.g.
[0105] The bioerodible implants are typically solid, and may be
formed as particles, sheets, patches, plaques, films, discs,
fibers, rods, and the like, or may be of any size or shape
compatible with the selected site of implantation, as long as the
implants have the desired release kinetics and deliver an amount of
active agent that is therapeutic for the intended medical condition
of the eye. The upper limit for the implant size will be determined
by factors such as the desired release kinetics, toleration for the
implant at the site of implantation, size limitations on insertion,
and ease of handling. For example, the vitreous chamber is able to
accommodate relatively large rod-shaped implants, generally having
diameters of about 0.05 mm to 3 mm and a length of about 0.5 to
about 10 mm. In one variation, the rods have diameters of about 0.1
mm to about 1 mm. In another variation, the rods have diameters of
about 0.3 mm to about 0.75 mm. In yet a further variation, other
implants having variable geometries but approximately similar
volumes may also be used.
[0106] As previously discussed, the release of an active agent from
a biodegradable polymer matrix may also be modulated by varying the
ratio of hydrophilic end PLGA to hydrophobic end PLGA in the
matrix. Release rates may be further manipulated by the method used
to manufacture the implant. For instance, as illustrated in
Examples 4-7, extruded 60/40 w/w dexamethasone/PLGA implants having
a ratio of hydrophilic end and hydrophobic end PLGA of 3:1,
compared to compressed tablet implants, demonstrate a different
drug release profile and concentration of agent in the vitreous
over about a one month period. Overall, a lower burst of agent
release and a more consistent level of agent in the vitreous is
demonstrated with the extruded implants.
[0107] As shown in FIG. 2 and Examples 4 and 5, a higher initial
burst of active agent release occurs on day one after implantation
with the 350 .mu.g dexamethasone compressed tablet implant (350T)
in comparison to the 350 .mu.g dexamethasone extruded implant
(350E). A higher initial burst of active agent release also occurs
with the 700 .mu.g dexamethasone compressed implant (700T) in
comparison to the 700 .mu.g dexamethasone extruded implant (700E)
on day 1, as shown in FIG. 2 and Examples 6 and 7.
[0108] The proportions of active agent, biodegradable polymer
matrix, and any other additives may be empirically determined by
formulating several implants with varying proportions and
determining the release profile in vitro or in vivo. A USP approved
method for dissolution or release test can be used to measure the
rate of release in vitro (USP 24; NF 19 (2000) pp. 1941-1951). For
example, a weighed sample of the implant is added to a measured
volume of a solution containing 0.9% NaCl in water, where the
solution volume will be such that the active agent concentration
after release is less than 20% of saturation. The mixture is
maintained at 37.degree. C. and stirred or shaken slowly to
maintain the implants in suspension. The release of the dissolved
active agent as a function of time may then be followed by various
methods known in the art, such as spectrophotometrically, HPLC,
mass spectroscopy, and the like, until the solution concentration
becomes constant or until greater than 90% of the active agent has
been released.
[0109] In one variation, the extruded implants described herewith
(ratio of hydrophilic end PLGA to hydrophobic end PLGA of 3:1) may
have in vivo cumulative percentage release profiles with the
following described characteristics, as shown in FIG. 2, where the
release profiles are for release of the active agent in vivo after
implantation of the implants into the vitreous of rabbit eyes. The
volume of rabbit eyes is approximately 60-70% of human eyes.
[0110] At day one after implantation, the percentage in vivo
cumulative release may be between about 0% and about 15%, and more
usually between about 0% and about 10%. At day one after
implantation, the percentage in vivo cumulative release may be less
than about 15%, and more usually less than about 10%.
[0111] At day three after implantation, the percentage in vivo
cumulative release may be between about 0% and about 20%, and more
usually between about 5% and about 15%. At day three after
implantation, the percentage in vivo cumulative release may be less
than about 20%, and more usually less than about 15%.
[0112] At day seven after implantation, the percentage in vivo
cumulative release may be between about 0% and about 35%, more
usually between about 5% and about 30%, and more usually still
between about 10% and about 25%. At day seven after implantation,
the percentage in vivo cumulative release may be greater than about
2%, more usually greater than about 5%, and more usually still
greater than about 10%.
[0113] At day fourteen after implantation, the percentage in vivo
cumulative release may be between about 20% and about 60%, more
usually between about 25% and about 55%, and more usually still
between about 30% and about 50%. At day fourteen after
implantation, the percentage in vivo cumulative release may be
greater than about 20%, more usually greater than about 25%, and
more usually still greater than about 30%.
[0114] At day twenty-one after implantation, the percentage in vivo
cumulative release may be between about 55% and about 95%, more
usually between about 60% and about 90%, and more usually still
between about 65% and about 85%. At day twenty-one after
implantation, the percentage in vivo cumulative release may be
greater than about 55%, more usually greater than about 60%, and
more usually still greater than about 65%.
[0115] At day twenty-eight after implantation, the percentage in
vivo cumulative release may be between about 80% and about 100%,
more usually between about 85% and about 100%, and more usually
still between about 90% and about 100%. At day twenty-eight after
implantation, the percentage in vivo cumulative release may be
greater than about 80%, more usually greater than about 85%, and
more usually still greater than about 90%.
[0116] At day thirty-five after implantation, the percentage in
vivo cumulative release may be between about 95% and about 100%,
and more usually between about 97% and about 100%. At day
thirty-five after implantation, the percentage in vivo cumulative
release may be greater than about 95%, and more usually greater
than about 97%.
[0117] In one variation, the percentage in vivo cumulative release
has the following characteristics: one day after implantation it is
less than about 15%; three days after implantation it is less than
about 20%; seven days after implantation it is greater than about
5%; fourteen days after implantation it is greater than about 25%;
twenty-one days after implantation it is greater than about 60%;
and twenty-eight days after implantation it is greater than about
80%. In another variation, the percentage in vivo cumulative
release has the following characteristics: one day after
implantation it is less than about 10%; three days after
implantation it is less than about 15%; seven days after
implantation it is greater than about 10%; fourteen days after
implantation it is greater than about 30%; twenty-one days after
implantation it is greater than about 65%; twenty-eight days after
implantation it is greater than about 85%.
[0118] In yet another variation, the extruded implants described in
this patent may have in vitro cumulative percentage release
profiles in saline solution at 37.degree. C. with the following
characteristics, as further described below, and as shown in FIG.
10.
[0119] The percentage in vitro cumulative release at day one may be
between about 0% and about 5%, and more usually between about 0%
and about 3%. The percentage in vitro cumulative release at day one
may be less than about 5%, and more usually less than about 3%.
[0120] The percentage in vitro cumulative release at day four may
be between about 0% and about 7%, and more usually between about 0%
and about 5%. The percentage in vitro cumulative release at day
four may be less than about 7%, and more usually less than about
5%.
[0121] The percentage in vitro cumulative release at day seven may
be between about 1% and about 10%, and more usually between about
2% and about 8%. The percentage in vitro cumulative release at day
seven may be greater than about 1%, and more usually greater than
about 2%.
[0122] The percentage in vitro cumulative release at day 14 may be
between about 25% and about 65%, more usually between about 30% and
about 60%, and more usually still between about 35% and about 55%.
The percentage in vitro cumulative release at day 14 may be greater
than about 25%, more usually greater than about 30%, and more
usually still greater than about 35%.
[0123] The percentage in vitro cumulative release at day 21 may be
between about 60% and about 100%, more usually between about 65%
and about 95%, and more usually still between about 70% and about
90%. The percentage in vitro cumulative release at day 21 may be
greater than about 60%, more usually greater than about 65%, and
more usually still greater than about 70%.
[0124] The percentage in vitro cumulative release at day 28 may be
between about 75% and about 100%, more usually between about 80%
and about 100%, and more usually still between about 85% and about
95%. The percentage in vitro cumulative release at day 28 may be
greater than about 75%, more usually greater than about 80%, and
more usually still greater than about 85%.
[0125] The percentage in vitro cumulative release at day 35 may be
between about 85% and about 100%, more usually between about 90%
and about 100%, and more usually still between about 95% and about
100%. The percentage in vitro cumulative release at day 35 may be
greater than about 85%, more usually greater than about 90%, and
more usually still greater than about 95%.
[0126] In one variation, the percentage in vitro cumulative release
has the following characteristics: after one day it is less than
about 1%; after four days it is less than about 7%; after seven
days it is greater than about 2%; after 14 days it is greater than
about 30%; after 21 days it is greater than about 65%; after 28
days it is greater than about 80%; and after 35 days it is greater
than about 90%. In another variation, the percentage in vitro
cumulative release has the following characteristics: after one day
it is less than about 3%; after four days it is less than about 5%;
after seven days it is greater than about 2%; after 14 days it is
greater than about 35%; after 21 days it is greater than about 70%;
after 28 days it is greater than about 85%; and after 35 days it is
greater than about 90%.
[0127] Besides showing a lower burst effect for the extruded
implants, FIGS. 2 and 10 also demonstrate that after 28 days in
vivo in rabbit eyes, or in vitro in a saline solution at 37.degree.
C., respectively, almost all of the active agent has been released
from the implants. Furthermore, FIGS. 2 and 10 show that the active
agent release profiles for the extruded implants in vivo (from the
time of implantation) and in vitro (from the time of placement into
a saline solution at 37.degree. C.) are substantially similar and
follow approximately a sigmoidal curve, releasing substantially all
of the active agent over 28 days. From day one to approximately day
17, the curves show approximately an upward curvature (i.e., the
derivative of the curve increases as time increases), and from
approximately day 17 onwards the curves show approximately a
downward curvature (i.e., the derivative of the curve decreases as
time increases).
[0128] In contrast, the plots shown in FIG. 2 for the 350 .mu.g and
700 .mu.g dexamethasone compressed tablet implants exhibit a higher
initial burst of agent release generally followed by a gradual
increase in release. Furthermore, as shown in FIGS. 1 and 5,
implantation of a compressed implant results in different
concentrations of active agent in the vitreous at various time
points from implants that have been extruded. For example, as shown
in FIGS. 1 and 5, with extruded implants there is a gradual
increase, plateau, and gradual decrease in intravitreal agent
concentrations. In contrast, for compressed tablet implants, there
is a higher initial active agent release followed by an
approximately constant decrease over time. Consequently, the
intravitreal concentration curve for extruded implants results in
more sustained levels of active agent in the ocular region.
[0129] In addition to the previously described implants releasing
substantially all of the therapeutic agent within 35 days, by
varying implant components including, but not limited to, the
composition of the biodegradable polymer matrix, implants may also
be formulated to release a therapeutic agent for any desirable
duration of time, for example, for about one week, for about two
weeks, for about three weeks, for about four weeks, for about five
weeks, for about six weeks, for about seven weeks, for about eight
weeks, for about nine weeks, for about ten weeks, for about eleven
weeks, for about twelve weeks, or for more than 12 weeks.
[0130] Another important feature of the extruded implants is that
different concentration levels of active agent may be established
in the vitreous using different doses of the active agent. As
illustrated in FIG. 8, the concentration of agent in the vitreous
is significantly larger with the 700 .mu.g dexamethasone extruded
implant than with the 350 .mu.g dexamethasone extruded implant.
Different active agent concentrations are not demonstrated with the
compressed tablet implant. Thus, by using an extruded implant, it
is possible to more easily control the concentration of active
agent in the vitreous. In particular, specific dose-response
relationships may be established since the implants can be sized to
deliver a predetermined amount of active agent.
[0131] Applications
[0132] Examples of medical conditions of the eye which may be
treated by the implants and methods of the invention include, but
are not limited to, uveitis, macular edema, macular degeneration,
retinal detachment, ocular tumors, fungal or viral infections,
multifocal choroiditis, diabetic retinopathy, proliferative
vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt
Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion,
and vascular occlusion. In one variation, the implants are
particularly useful in treating such medical conditions as uveitis,
macular edema, vascular occlusive conditions, proliferative
vitreoretinopathy (PVR), and various other retinopathies.
[0133] Method of Implantation
[0134] The biodegradable implants may be inserted into the eye by a
variety of methods, including placement by forceps, by trocar, or
by other types of applicators, after making an incision in the
sclera. In some instances, a trocar or applicator may be used
without creating an incision. In a preferred variation, a hand held
applicator is used to insert one or more biodegradable implants
into the eye. The hand held applicator typically comprises an 18-30
GA stainless steel needle, a lever, an actuator, and a plunger.
[0135] The method of implantation generally first involves
accessing the target area within the ocular region with the needle.
Once within the target area, e.g., the vitreous cavity, the lever
on the hand held device is depressed to cause the actuator to drive
the plunger forward. As the plunger moves forward, it pushes the
implant into the target area.
[0136] Extrusion Methods
[0137] The use of extrusion methods allows for large-scale
manufacture of implants and results in implants with a homogeneous
dispersion of the drug within the polymer matrix. When using
extrusion methods, the polymers and active agents that are chosen
are stable at temperatures required for manufacturing, usually at
least about 50.degree. C. Extrusion methods use temperatures of
about 25.degree. C. to about 150.degree. C., more preferably about
60.degree. C. to about 130.degree. C.
[0138] Different extrusion methods may yield implants with
different characteristics, including but not limited to the
homogeneity of the dispersion of the active agent within the
polymer matrix. For example, using a piston extruder, a single
screw extruder, and a twin screw extruder will generally produce
implants with progressively more homogeneous dispersion of the
active. When using one extrusion method, extrusion parameters such
as temperature, extrusion speed, die geometry, and die surface
finish will have an effect on the release profile of the implants
produced.
[0139] In one variation of producing implants by extrusion methods,
the drug and polymer are first mixed at room temperature and then
heated to a temperature range of about 60.degree. C. to about
150.degree. C., more usually to about 130.degree. C. for a time
period of about 0 to about 1 hour, more usually from about 0 to
about 30 minutes, more usually still from about 5 minutes to about
15 minutes, and most usually for about 10 minutes. The implants are
then extruded at a temperature of between about 60.degree. C. to
about 130.degree. C., preferably at a temperature of between about
75.degree. C. and 110.degree. C., and more preferably at a
temperature of about 90.degree. C.
[0140] In a preferred extrusion method, the powder blend of active
agent and PLGA is added to a single or twin screw extruder preset
at a temperature of about 80.degree. C. to about 130.degree. C.,
and directly extruded as a filament or rod with minimal residence
time in the extruder. The extruded filament or rod is then cut into
small implants having the loading dose of active agent appropriate
to treat the medical condition of its intended use.
[0141] DEX PS DDS
[0142] The present invention is based upon the discovery of an
intraocular drug delivery system which can address many of the
problems associated with conventional therapies for the treatment
of ocular conditions, such as posterior segment inflammation,
including fluctuating drug levels, short intraocular half-life, and
prolonged systemic exposure to high levels of corticosteroids. The
intraocular drug delivery system of the present invention
encompasses use of dexamethasone as the active pharmaceutical
agent, in which case the intraocular drug delivery system of the
present invention can be referred to as a Dexamethasone Posterior
Segment Drug Delivery System (DEX PS DDS). The DEX PS DDS is
intended for placement into the posterior segment by a pars plana
injection, a familiar method of administration for
ophthalmologists. The DEX PS DDS can be comprised of a
biodegradable copolymer, poly(lactic glycolic) acid (PLGA),
containing micronised dexamethasone. The DEX PS DDS can release
dexamethasone, providing a total dose of approximately 350 or 700
.mu.g over approximately 35 days. In comparison, other routes of
administration (topical, periocular, systemic and standard
intravitreal injections) require much higher daily doses to deliver
equivalent levels of dexamethasone to the posterior segment while
also exposing non-target organs to corticosteroids. Topical
administration of 2 drops of dexamethasone ophthalmic suspension
0.1% four times daily to both eyes is equivalent to almost 500
.mu.g per day. Systemic doses may be as high as 1,000 .mu.g/kg/day
(Pinar V. Intermediate uveitis. Massachusetts Eye & Ear
Infirmary Immunology Service.
http://www.immunology.meei.harvard.edu/imed.htm. 1998; Wei sbecker
C A, Fraunfelder F T, Naidoff M, Tippermann R, eds. 1999
Physicians' Desk Reference for Ophthalmology, 27th ed. Montvale,
N.J.: Medical Economics Company, 1998; 7-8, 278-279). With the DEX
PS DDS, substantially lower daily doses of dexamethasone can be
administered directly to the posterior segment compared to the
doses needed with conventional topical, systemic, or intravitreal
therapies, thereby minimizing potential side effects. While
releasing dexamethasone, the polymer can gradually degrades
completely over time so there is no need to remove the DEX PS DDS
after it's placement into the posterior segment of a patient
eye.
[0143] To facilitate delivery of DEX PS DDS into the posterior
segment of the eye, an applicator has been designed to deliver the
DEX PS DDS directly into the vitreous. The DDS Applicator allows
placement of the DEX PS DDS into the posterior segment through a
small hollow gauge needle, thereby decreasing the morbidity
associated with surgery and pars plana injection at vitrectomy. The
extruded DEX PS DDS is placed in the Applicator during the
manufacturing of the sterile finished drug product. The DEX PS DDS
Applicator System can be a single-use only device.
[0144] 700 .quadrature.g and 350 .quadrature.g Dexamethasone
Posterior Segment Drug Delivery System (DEX PS DDS Applicator
System) can be used in the treatment of, for example, patients with
macular oedema following central retinal vein occlusion or branch
retinal vein occlusion.
[0145] Dexamethasone can be obtained from Aventis Pharma, Montvale,
N.J., U.S.A. The chemical name of dexamethasone is
pregna-1,4-diene-3,20-dione-9-fluoro-11,17,21-trihydroxy-16-methyl-,
(11.beta.,16.alpha.), and it's chemical structure can be
represented diagrammatically as follows:
##STR00001##
Other characteristics of dexamethasone are: Molecular Formula:
C.sub.22H.sub.29FO.sub.5
Molecular Weight: 392.47
[0146] Chirality/Stereochemistry: Dexamethasone has 8 chiral
centres and is optically active Description: White or almost white,
crystalline powder pH and pKa: Dexamethasone has no ionisable
groups
Melting Point: 253.degree. C. to 255.degree. C.
[0147] Solubility: Water: practically insoluble [0148] Ethanol:
Sparingly soluble [0149] Methylene chloride: slightly soluble
[0150] Further information on the physical and chemical properties
of dexamethasone is summarised in the current European
Pharmacopoeia (Ph. Eur.).
[0151] An embodiment of our invention can be referred to as a DEX
PS DDS. DEX PS DDS is an implant (a drug delivery system or DDS)
for intravitreal (i.e. posterior segment, or PS) use, comprised of
dexamethasone (i.e. DEX) (drug substance) and a polymer matrix of
50:50 poly (D,L-lactide-co-glycolide) PLGA, constituted of two
grades of PLGA (50:50 PLGA ester and 50:50 PLGA acid). See Table 1
for details. This biodegradable drug delivery system is designed to
release the drug substance into the posterior segment of the eye
over a 35-day period. DEX PS DDS can be implanted into the vitreous
humour of the eye using an applicator system.
[0152] Two dose levels, one containing 350 .mu.g and one containing
700 .mu.g of dexamethasone, have been evaluated in a clinical
trial. Both dose levels have the same formulation as detailed in
Table 2. They are prepared using the same bulk and double extrusion
process, but cut to different lengths to obtain the appropriate
dosage strength.
TABLE-US-00002 TABLE 1 Qualitative composition of a sample DEX PS
DDS Quality Component Standard Function Dexamethasone Ph. Eur.
Active ingredient 50:50 PLGA ester Allergan, Inc. Biodegradable
extended release polymer matrix 50:50 PLGA acid Allergan, Inc.
Biodegradable extended release polymer matrix
TABLE-US-00003 TABLE 2 Quantitative Composition of a sample DEX PS
DDS (manufacturing batch formula) 350 g 700 g Representative
Formula number 80 g Batch Component 9635X 9632X Quantity
Dexamethasone 350 g 700 g 48 grams 50:50 PLGA ester 58 g 116 g 8
grams (hydrophobic) (10%) 50:50 PLGA acid 175 g 350 g 24 grams
(hydrophilic)
[0153] The drug substance used in the DEX PS DDS is dexamethasone
micronised.
[0154] DEX PS DDS can contain two excipients (i.e. non-active
ingredients) which can be present as two different grades of the
same biodegradable polymer 50:50 Poly (D,L lactide-co-glycolide)
(PLGA), which can be supplied by Boehringer Ingelheim: 50:50 PLGA
ester and 50:50 PLGA acid.
[0155] Poly D,L lactide-co-glycolide has been used for more than 15
years in parenteral products and is a main component of absorbable
sutures. A list of some of the medical products commercially
available is supplied in Table 3.
TABLE-US-00004 TABLE 3 List of commercial medical products
containing PLGA Drug Dosage Mode of Name Manufacturer Substance
form administration Vicryl .RTM. Ethicon Suture used in ocular
surgery Enantone .RTM. Tadeka Leuprorelin Microsphere Injection (SC
or IM) suspension Prostap .RTM. Wyeth Leuprorelin Microsphere
Injection (SC or IM) acetate suspension Bigonist .RTM. Aventis
Buserelin Implant Injection (SC) Somatuline .RTM. Beaufour Ipsen
Lanreotide Microparticle Injection (IM) Pharma acetate suspension
Sandostatin .RTM. Novartis Octreotide Microsphere Injection (IM)
acetate suspension Zoladex .RTM. Astra Zeneca Goserilin Implant
Injection (SC) acetate Risperdal consta .RTM. Janssen-Cilag
Risperidone Microparticle Injection (IM) suspension Decapeptyl
.RTM. Ipsen Triptorelin Injection (IM) Gonapeptyl Depot .RTM.
Ferring Triptorelin Microparticle Injection (SC or IM)
Pharmaceutica 1 acetate suspension
PLGA exists in different grades depending on the ratio of lactide
to glycolide and polymer chain ending. All PLGAs degrade via
backbone hydrolysis (bulk erosion), and the degradation products,
lactic acid and glycolic acid, are ultimately metabolised by the
body into CO.sub.2 and H.sub.2O. The two PLGAs combination as
presented in Table 2 was chosen in order to obtain a drug substance
release over a 35-day period. General properties of the chosen
PLGAs are presented in Table 4.
TABLE-US-00005 TABLE 4 General properties of PLGAs 50:50 PLGA ester
50:50 PLGA acid Common Resomer RG 502, PLG, PLGA, Poly Resomer RG
502H, PLG acid end, PLGA Names (lactic-glycolic) acid, 50:50 Poly
(D,L- acid end, 50:50 Poly (D,L-lactide-co- lactide-co-glycolide),
glycolide) acid end Polylactic/Polyglycolic acid, Polyglactin 910
Structure ##STR00002## ##STR00003## Where: Where: n = m n = m n =
number of lactide repeating units n = number of lactide repeating
units m = number of glycolide repeating units m = number of
glycolide repeating units z = overall number of lactide-co- z =
overall number of lactide-co-glycolide glycolide repeating units
repeating units CAS Number 34346-01-5 26780-50-7 Empirical
[(C3H4O2)x.cndot.(C2H2O2)y]CH3, [(C3H4O2)x.cndot.(C2H2O2)y]OH,
Formula x:y = 50:50 x:y = 50:50 Description white to off white
powder white to near white powder
[0156] DEX PS DDS was designed to release dexamethasone in the
posterior segment of the eye over an extended period of 35 days.
This extended release is achieved by including dexamethasone in a
biodegradable polymer matrix. The polymer chosen is 50:50 PLGA. The
rate of release is mainly linked to the rate of degradation of the
PLGA, depending on several factors such as molecular weight and
weight distribution, lactide to glycolide ratio, polymeric chain
endings, etc. The mechanism for the degradation of PLGA is a
hydrolysis triggered by the presence of body fluids i.e. vitreous
humour in the case of DEX PS DDS.
[0157] Early formulations contained only one grade of PLGA (50/50
ratio with ester end) custom synthesised. Subsequently, it was
discovered that the "acid end" form of PLGA designated 50:50 PLGA
acid, combined with the 50:50 PLGA ester (equivalent to the initial
PLGA), produced the desired drug release profile. "Acid end" PLGA
is slightly more hydrophilic and therefore degrades faster in
water. Both polymer backbones are identical, but the polymerisation
process used to produce acid end PLGA involves a different chain
termination agent leading to carboxylic moieties at the end of the
polymer chains. During biodegradation of the implant, the
degradation products are the same for both polymers, i.e. lactic
acid and glycolic acid. Details of the formulation proposed can be
found above. In addition, the stability of DEX PS DDS was
evaluated.
EXAMPLES
[0158] The following examples serve to more fully describe the
manner of using the above-described invention. It is understood
that these examples in no way serve to limit the scope of this
invention, but rather are presented for illustrative purposes.
Example 1
Manufacture of Compressed Tablet Implants
[0159] Micronized dexamethasone (Pharmacia, Peapack, N.J.) and
micronized hydrophobic end 50/50 PLGA (Birmingham Polymers, Inc.,
Birmingham, Ala.) were accurately weighed and placed in a stainless
steel mixing vessel. The vessel was sealed, placed on a Turbula
mixer and mixed at a prescribed intensity, e.g., 96 rpm, and time,
e.g., 15 minutes. The resulting powder blend was loaded one unit
dose at a time into a single-cavity tablet press. The press was
activated at a pre-set pressure, e.g., 25 psi, and duration, e.g.,
6 seconds, and the tablet was formed and ejected from the press at
room temperature. The ratio of dexamethasone to PLGA was 70/30 w/w
for all compressed tablet implants.
Example 2
Manufacture of Extruded Implants
[0160] Micronized dexamethasone (Pharmacia, Peapack, N.J.) and
unmicronized PLGA were accurately weighed and placed in a stainless
steel mixing vessel. The vessel was sealed, placed on a Turbula
mixer and mixed at a prescribed intensity, e.g., 96 rpm, and time,
e.g., 10-15 minutes. The unmicronized PLGA composition comprised a
30/10 w/w mixture of hydrophilic end PLGA (Boehringer Ingelheim,
Wallingford, Conn.) and hydrophobic end PLGA (Boehringer Ingelheim,
Wallingford, Conn.). The resulting powder blend was fed into a DACA
Microcompounder-Extruder (DACA, Goleta, Calif.) and subjected to a
pre-set temperature, e.g., 115.degree. C., and screw speed, e.g.,
12 rpm. The filament was extruded into a guide mechanism and cut
into exact lengths that corresponded to the designated implant
weight. The ratio of dexamethasone to total PLGA (hydrophilic and
hydrophobic end) was 60/40 w/w for all extruded implants.
Example 3
Method for Placing Implants into the Vitreous
[0161] Implants were placed into the posterior segment of the right
eye of New Zealand White Rabbits by incising the conjunctiva and
sclera between the 10 and 12 o'clock positions with a 20-gauge
microvitreoretinal (MVR) blade. Fifty to 100 .mu.L of vitreous
humor was removed with a 1-cc syringe fitted with a 27-gauge
needle. A sterile trocar, preloaded with the appropriate implant
(drug delivery system, DDS), was inserted 5 mm through the
sclerotomy, and then retracted with the push wire in place, leaving
the implant in the posterior segment. Sclerae and conjunctivae were
than closed using a 7-0 Vicryl suture.
Example 4
In Vivo Release of Dexamethasone from 350 .mu.g Dexamethasone
Compressed Tablet Implants
[0162] Example 4 demonstrates the high initial release but
generally lower intravitreal concentration of dexamethasone from
compressed tablet implants as compared to extruded implants. The
350 .mu.g compressed tablet implant (350T) was placed in the right
eye of New Zealand White Rabbits as described in Example 3.
Vitreous samples were taken periodically and assayed by LC/MS/MS to
determine in vivo dexamethasone delivery performance. As seen in
FIG. 1, dexamethasone reached detectable mean intravitreal
concentrations from day 1 (142.20 ng/ml) through day 35 (2.72
ng/ml), and the intravitreal concentration of dexamethasone
gradually decreased over time.
[0163] In addition to the vitreous samples, aqueous humor and
plasma samples were also taken. The 350T showed a gradual decrease
in aqueous humor dexamethasone concentrations over time, exhibiting
a detectable mean dexamethasone aqueous humor concentration at day
1 (14.88 ng/ml) through day 21 (3.07 ng/ml), as demonstrated in
FIG. 3. The levels of dexamethasone in the aqueous humor strongly
correlated with the levels of dexamethasone in the vitreous humor,
but at a much lower level (approximately 10-fold lower). FIG. 4
shows that only trace amounts of dexamethasone was found in the
plasma.
Example 5
In Vivo Release of Dexamethasone from 350.mu.g Dexamethasone
Extruded Implants
[0164] Example 5 demonstrates the lower initial release and
generally more sustained intravitreal concentration of
dexamethasone from extruded implants. The 350 .mu.g extruded
implant (350E) was placed in the right eye of New Zealand White
Rabbits as described in Example 3. Vitreous samples were taken
periodically and assayed by LC/MS/MS to determine in vivo
dexamethasone delivery performance. Referring to FIG. 1, 350E
showed detectable mean vitreous humor concentrations on day 1
(10.66 ng/ml) through day 28 (6.99 ng/ml). The 350T implant had
statistically significant higher dexamethasone concentrations on
day 1 (p=0.037) while the 350E had a statistically significant
higher dexamethasone level on day 21 (p=0.041).
[0165] In addition to the vitreous samples, aqueous humor and
plasma samples were also taken. In FIG. 3, the 350E showed
detectable mean dexamethasone aqueous humor concentrations at day 1
(6.67 ng/ml) through day 42 (2.58 ng/ml) with the exception of day
35 in which the values were below the quantification limit. On the
whole, the levels of dexamethasone in the aqueous strongly
correlated with the levels of dexamethasone in the vitreous humor,
but at a much lower level (approximately 10-fold lower). FIG. 4
demonstrates that only a trace amount of dexamethasone was found in
the plasma.
Example 6
In Vivo Release of Dexamethasone from 700 .mu.g Dexamethasone
Compressed Tablet Implants
[0166] Example 6 also shows the high initial release and generally
lower intravitreal concentration of dexamethasone from compressed
tablet implants. The 700 .mu.g compressed tablet dosage form (700T)
was placed in the right eye of New Zealand White Rabbits as
described in Example 3. Vitreous samples were taken periodically
and assayed by LC/MS/MS to determine in vivo dexamethasone delivery
performance. As seen in FIG. 5, the 700T reached detectable mean
dexamethasone vitreous humor concentrations at day 1 (198.56 ng/ml)
through day 42 (2.89 ng/ml), and a gradual decrease in the
intravitreal dexamethasone concentration over time.
[0167] In addition to the vitreous samples, aqueous humor and
plasma samples were also obtained. As seen in FIG. 6, the 700T
exhibited a gradual decrease in aqueous humor dexamethasone
concentrations over time, and reached detectable mean dexamethasone
aqueous humor concentrations at day 1 (25.90 ng/ml) through day 42
(2.64 ng/ml) with the exception of day 35 in which the values were
below the quantification limit. The levels of dexamethasone in the
aqueous humor strongly correlated with the levels of dexamethasone
in the vitreous humor, but at a much lower level (approximately
10-fold lower). FIG. 7 demonstrates that only a trace amount of
dexamethasone was found in the plasma.
Example 7
In Vivo Release of Dexamethasone from 700 .mu.g Dexamethasone
Extruded Implants
[0168] Example 7 also illustrates the lower initial release and
generally higher intravitreal concentration of dexamethasone from
extruded implants. The 700 .mu.g extruded implant (700E) was placed
in the right eye of New Zealand White Rabbits as described in
Example 3. Vitreous samples were taken periodically and assayed by
LC/MS/MS to determine in vivo dexamethasone delivery performance.
As seen in FIG. 5, the 700E had a mean detectable vitreous humor
concentration of dexamethasone from day 1 (52.63 ng/ml) through day
28 (119.70 ng/ml).
[0169] In addition to the vitreous samples, aqueous humor and
plasma samples were also taken. As seen in FIG. 6, the 700E reached
a detectable mean aqueous humor concentration on day 1 (5.04 ng/ml)
through day 28 (5.93 ng/ml). The levels of dexamethasone in the
aqueous strongly correlated with the levels of dexamethasone in the
vitreous humor, but at a much lower level (approximately 10-fold
lower). FIG. 7 demonstrates that only a trace amount of
dexamethasone was found in the plasma.
Example 8
Extrusion Methods for Making an Implant
[0170] 1. DEX PS DDS implants were made by a tabletting process, by
a single extrusion process and by a double extrusion process.
[0171] The excipients (polymers) used for the DEX PS DDS implant
made were two grades of 50:50 Poly (D,L lactide-co-glycolide) ester
end and acid end. Both excipients were a pharmaceutical grade of
non-compendial material.
[0172] The preferred specifications of three batches of both 50:50
Poly PLGA ester used to make implants are shown in Table A. The
preferred specifications of three batches of 50:50 Poly PLGA acid
use to make implants are shown in Table B.
TABLE-US-00006 TABLE A Preferred Specifications for 50:50 PLGA
ester Tests Specifications 1001933 1004907 1004925 Appearance:
Colour and White to off white Off white Off white Off white shape
Odour Odourless to almost odourless almost almost almost odourless
odourless odourless Identification 1.sup.H-NMR spectra conforms
conforms conforms conforms to reference Polymer composition
DL-Lactide units 48 to 52% 51 51 51 Glycolide units 52 to 48% 49 49
49 Inherent viscosity 0.16 to 0.24 dl/g 0.24 0.19 0.19 Water
.ltoreq.0.5% Conforms Conforms Conforms Residual monomers
DL-lactide .ltoreq.0.5% Conforms Conforms Conforms Glycolide
.ltoreq.0.5% Conforms Conforms Conforms Residual solvents Acetone
.ltoreq.0.1% Conforms Conforms Conforms Toluene .ltoreq.0.089%
Conforms Conforms Conforms Total .ltoreq.0.1% Conforms Conforms
Conforms Tin .ltoreq.100 ppm 30 31 35 Heavy metals .ltoreq.10 ppm
Conforms Conforms Conforms Sulphated ashes .ltoreq.0.1% Conforms
Conforms Conforms
TABLE-US-00007 TABLE B Preferred Specifications for 50:50 PLGA acid
Test Specification 1006825 1008386 1009848 Appearance: Colour White
to nearly White White Off white and shape white Odour Odourless to
nearly odourless Odourless Odourless Almost odourless
Identification 1.sup.H-NMR spectra conforms to Conforms Conforms
Conforms reference Polymer composition DL-Lactide units 48 to 52%
51 51 51 Glycolide units 52 to 48% 49 49 49 Inherent viscosity 0.16
to 0.24 dl/g 0.19 0.19 0.19 Water .ltoreq.0.5% Conforms Conforms
Conforms Residual monomers DL-lactide .ltoreq.0.5% Conforms
Conforms Conforms Glycolide .ltoreq.0.5% Conforms Conforms Conforms
Residual solvents Acetone .ltoreq.0.1% Conforms Conforms Conforms
Toluene .ltoreq.0.089% Conforms Conforms Conforms Tin .ltoreq.200
ppm 149 83 141 Heavy metals .ltoreq.10 ppm Conforms Conforms
Conforms Sulphated ashes .ltoreq.0.1% Conforms Conforms Conforms
Acid number .gtoreq.6.5 Mg.sub.KOH/g 11 9 12
[0173] Preferred Specifications of Polymers Use to Make
Implants
[0174] Polymer composition: It was determined that the ratio of
lactide to glycolide is essential for the kinetic of degradation of
the polymer and hence the dexamethasone release profile of the
implant. It was controlled in a 48% to 52% (wt %) range to ensure
consistency of active agent release.
[0175] Inherent viscosity: the inherent viscosity is essential for
the kinetics of degradation of the polymer and hence the
dexamethasone release profile of the implant. It is a measure of
the size of the polymer backbone and the size distribution (i.e.
molecular weight and weight distribution). It was controlled in a
0.16 to 0.24 dl/g range to ensure consistency of release.
[0176] Water: The moisture content of the polymer influences its
stability during the shelf life and is a facilitating factor for
the biodegradation of the polymer matrix. It was controlled below
0.5% to ensure stability of the excipients as well as the drug
substance (dexamethasone) and to ensure consistency of the
(dexamethasone) release profile.
[0177] Residual monomers: residual monomers indicate the completion
of the synthesis of the polymer and was controlled below 0.5 wt.
%.
[0178] Residual solvents: [0179] Acetone was controlled to below
0.1 wt. %. [0180] Toluene was controlled to be kept below 0.0890
wt. %.
[0181] Acid number: the acid number measures the number of chain
ends in the PLGA acid polymer. The number of acid polymer endings
facilitates the ingress of moisture upon injection of the implant
and influences the release profile of the implant. It was
controlled to be higher than 6.5 mg KOH/g to ensure consistency of
release profile.
[0182] Preferred Dexamethasone Characteristics
[0183] The particle size and particle size distribution of the
dexamethasone is regarded as a critical parameter for the
homogeneity of the DEX PS DDS. A preferred dexamethasone particle
size distribution has at least 75% of the particles of
dexamethasone smaller than (i.e. diameter less than) 10 .mu.m. A
more preferred dexamethasone particle size distribution has at
least 99% of the particles of dexamethasone smaller than (i.e.
diameter less than) 20 .mu.m. We found that use of such small
particles of dexamethasone in the implant provides for a more
uniform distribution of the active agent in the implant (i.e. no
clumping) which leads to a more uniform release of the active agent
from the implant upon implantation of the implant.
[0184] In addition to all the Ph. Eur. tests for dexamethasone,
additional tests were performed on the dexamethasone using a
particle size analyser and an additional analytical method, so as
to ensure that the dexamethasone used in the DEX PS DDS had the
preferred or the more preferred particle size and particle size
distribution.
[0185] In our invention dexamethasone a particle size and particle
size distribution is an important factor because homogeneity of the
dexamethasone affects release characteristics.
[0186] It is additionally preferred that the dexamethasone used in
the present invention comprise .ltoreq.1% of total impurities,
including .ltoreq.0.50% of dexamethasone acetate, .ltoreq.0.25% of
betamethasone, .ltoreq.0.25% of 3 keto delta 4 derivative and
.ltoreq.0.10% of any other impurity.
[0187] A representative formula for a typical 80 g manufacturing
batch (used to make an implant manufactured by the tabletting,
single extrusion or double extrusion process) is provided in Table
2. For the 350 .mu.g and 700 .mu.g dosages, the bulk manufacturing
and terminal sterilisation processes are identical.
[0188] A flow diagram of the three different manufacturing
processes is shown by FIG. 11.
[0189] 2. A single extrusion process was used to made an implant.
In a continuous extrusion, single extrusion manufacturing process,
the micronised dexamethasone and un-micronised polymer was blended,
before being loaded into a twin-screw compound extruder, and then
subjected to a set temperature and screw speed. The filament was
extruded into a guide mechanism and cut into exact lengths that
correspond to the correct DEX PS DDS weight. This continuous
extrusion process was more controllable and more predictable than
the tabletting process. This is illustrated in the in vitro release
profiles of the DEX PS DDS as show in FIG. 12.
[0190] Four lots of 700 .mu.g DEX PS DDS, two manufactured by the
tabletting process and two by the single extrusion process were
studied. With the single extrusion process the only difference
between the two doses is that the 350 .mu.g dose filament is cut
from the same extrudate (same formulation) as 700 .mu.g dose
filament but is half as long. At 5 time points, over a 28-day
period, 12 DEX PS DDS units from each lot were tested. The standard
deviations for the mean dexamethasone release rates were found
larger for the two tabletted lots than for the two extruded lots. A
three-fold reduction in standard deviations across the release
profile was observed with the extruded versus the tabletted
product. In addition, the initial burst release is reduced with
implants manufactured by a single extrusion process, as compared to
implants made by a tabletting process.
[0191] These results were confirmed in a GLP in vivo
pharmacokinetics study in rabbits comparing the release of
dexamethasone from the tabletted and the extruded DEX PS DDS. It
was shown that the tabletted and the single extruded DEX PS DDS
release the same amount of dexamethasone over the same period,
providing approximately a 35-day delivery.
[0192] To further characterise and compare the DEX PS DDS
manufactured by the tabletting and single extrusion processes,
scanning electron microscope (SEM) photographs were taken to assess
physical appearance. FIG. 13 shows that the single extruded DEX PS
DDS is more uniform than was the tabletted implant. It was found
that not only is this gives a more consistent in vitro release
profile from the single extruded implant, but also with its
increased resistance to crushing. Using a texture analyser it was
shown that a 3-fold increase in force (1200 g compared to 400 g)
was required to crush a single extruded implant compared to a
tabletted one. This demonstrates that the extruded product is more
able to withstand handling.
[0193] Additionally, it was determined that the DEX PS DDS made by
single extrusion and by double extrusion processes is stable during
a minimum of 12 months (and for as long as 18-24 months) when
stored at 25.degree. C./60% RH and a minimum of 6 months at
40.degree. C./75% RH. Stability was determined based upon
dexamethasone potency, dexamethasone impurities (acid, ketone,
aldehyde and total impurities), moisture content, applicator
actuation force, implant fracture force/fracture energy and in
vitro dissolution dexamethasone release profile and sterility.
[0194] 3. The inventors improved the single extrusion process by
(1) micronising the polymers prior to blending and (2) adding a
second extrusion after pelletisation of the first extruded
filament. When both 50:50 PLGA acid and 50:50 PLGA ester were
micronised an acceptable DEX PS DDS homogeneity was obtained.
Homogeneity promotes a more even and regular dissolution of the
polymer and release of the dexamethasone active agent. The PLGAs
were milled using an air jet process. FIG. 14 presents
batch-to-batch versus in-batch variability from batches made of
milled (i.e. micronised) and un-milled (i.e. unmicronized) PLGAs.
It clearly demonstrates that the double extrusion process allows
better control, especially where in-batch variability was reduced
from a 94.7% LC to 107.0% LC range (unmilled PLGAs) to a 98.9% LC
to 101.5% LC range (milled PLGAs. "LC" means label claim (a
regulatory term), that is the amount of dexamethasone present in
the implant (350 .mu.g or 700 .mu.g), as measured by various in
vitro assays, such as by HPLC.
[0195] Single and double extrusion processes were compared. As
shown by FIG. 15 implants made by a double extrusion process had
released about 60% of the dexamethasone by day 14, while the single
extrusion implants had released about 40% of its dexamethasone load
by day 14, although total dexamethasone released was comparable by
day 21. Therefore, where more release of dexamethasone is desired
sooner, the double extrusion process is a preferred process for
making the DEX PS DDS. A double extrusion process also provides for
a higher yield of the desired filament implant, i.e. with a uniform
distribution of dexamethasone throughout the implant polymer.
[0196] A detailed manufacturing schematic flow diagram for the
double extrusion implant is provided by FIG. 16. The major
equipment used in the manufacture of DEX PS DDS is listed in Table
C.
TABLE-US-00008 TABLE C Major Equipment Used in the Manufacture of
DEX PS DDS Step Purpose Equipment Description 1 Milling both PLGAs
Jet Mill 2 Powder blending Shaker 3 First extrusion Extruder and
Force Feeder, Puller Assembly and Filament Cutter 4 Pelletising
Stainless steel ball and bottle Shaker 5 Second extrusion Extruder
and Force Feeder, Puller Assembly and Filament Cutter 6 Automated
DDS Guillotine Cutter and cutting and inspection Vision Inspection
procedure System 7-8 Applicator Assembly Applicator loading fixture
and Heat sealer
[0197] 4. The specifics of the double extrusion process used are as
follows
[0198] (a) Milling of PLGAs (Resomers RG502 and RG502H)
[0199] 30 grams of RG502 (50:50 PLGA ester) were milled using the
Jet-Mill (a vibratory feeder) at milling pressures of 60 psi, 80
psi and 80 psi for the pusher nozzle, grinding nozzle, and grinding
nozzle, respectively. Next, 60 grams of RG502H were milled using
the Jet-Mill at milling pressure of 20 psi, 40 psi and 40 psi for
the pusher nozzle, grinding nozzle, and grinding nozzle,
respectively. The mean particle size of both RG502 and RG502H was
measured using a TSI 3225 Aerosizer DSP Particle Size Analyzer.
Preferably, both milled polymers must have a mean particle size of
no greater than 20 um.
[0200] (b) Blending of PLGAs and Dexamethasone
[0201] 48 grams of dexamethasone, 24 grams of milled RG502H and 8
grams of milled RG502 were blended using the Turbula Shaker set at
96 RPM for 60 minutes.
[0202] (c) First Extrusion
[0203] (1) All 80 grams of the blended dexamethasone/RG502H/RG502
mixture was added to the hopper of a Haake Twin Screw Extruder. The
Haake extruder was turned on and set the following parameters:
[0204] Barrel Temperature: 105 degrees C.
[0205] Nozzle Temperature: 102 degrees C.
[0206] Screw Speed: 120 RPM
[0207] Feed Rate Setting: 250
[0208] Guide Plate Temperature: 50-55 degrees C.
[0209] Circulating water bath: 10 degrees C.
[0210] (2) Filament were collected. The first filament comes out
about 15-25 minutes after the addition of the powder blend. Discard
the first 5 minute of extruded filaments. Collecting the remaining
filaments until exhaustion of extrudates; this normally takes 3-5
hours.
[0211] (d) Pelletization
[0212] The filaments from step 3 above were pelletized using the
Turbula Shaker and one 19 mm stainless steel ball set at 96 RPM for
5 minutes.
[0213] (e) Second Extrusion
[0214] (1) All pellets were added into the same hopper and the
Haake extruder was turned on.
[0215] The following parameters were set on the Haake extruder:
[0216] Barrel Temperature: 107 degrees C.
[0217] Nozzle temperature: 90 degrees C.
[0218] Screw speed: 100 RPM
[0219] Guide Plate Temperature: 60-65 degrees C.
[0220] Circulation water bath:10 degrees C.
[0221] (2) All extruded filaments were collected until exhaustion
of extrudates. This normally takes about 3 hours.
[0222] (f) Processing of Bulk Filament to Dosage Strengths--350
.mu.g or 700
[0223] DEX PS DDS was be prepared as 350 .mu.g or 700 .mu.g dosage
forms by cutting the filaments to the appropriate length.
[0224] (g) Insertion of DEX PS DDS into the Applicator
[0225] The DEX PS DDS was inserted into the Applicator System
during the applicator assembly process. All operations took place
in a Class 10 000 clean room.
[0226] (h) Packaging of DEX PS DDS Applicator System
[0227] The assembled DEX PS DDS Applicator System was placed into a
foil pouch containing a small bag of desiccant and heat-sealed.
Samples for pre-sterilisation bioburden testing were taken prior to
step 9.
[0228] (i) Gamma Radiation Sterilization of DEX PS DDS Applicator
System
[0229] The sealed foil pouches containing the finished DEX PS DDS
Applicator System and a small desiccant bag were placed into a
cardboard box and the box sealed. Terminal sterilisation of these
product containing boxes was accomplished by exposure to a dose
within the range of 25-40 kGy of gamma-radiation. Samples from each
batch were tested for sterility according to Ph. Eur. and USP
requirement.
[0230] (j) Labelling of DEX PS DDS Applicator
[0231] The single and double extruded implants had the preferred
characteristics shown by Tables D and E, respectively.
TABLE-US-00009 TABLE D In Process Controls results for the first
extrusion Batch Number 03J001 0311004 03M001 Batch size Parameter
Specifications 80 g 80 g 80 g Filament 0.85 to 1.14 g/cm.sup.3 1.03
1.01 1.04 density Uniformity 85.0 to 115.0%.sup.(1) 99.3 100.5 98.7
Potency 97.0 to 103.0% 100.1 100.0 99.8 label strength Degradation
.ltoreq.1.5% total 0.2 0.2 0.2 products .ltoreq.0.75% acid ND ND ND
.ltoreq.0.75% ketone .ltoreq.0.08 .ltoreq.0.10 .ltoreq.0.13
.ltoreq.0.75% aldehyde .ltoreq.0.15 .ltoreq.0.10 .ltoreq.0.12
.sup.(1)Percentage of target weight
TABLE-US-00010 TABLE E In Process Control results for the second
extrusion Batch number 03J001 0311004 03M001 Batch size Parameter
Specifications 80 g 80 g 80 g Appearance White to off white pass
pass pass Filament density 1.10 to 1.30 g/cm.sup.3 1.18 1.13 1.19
Diameter .gtoreq.80% within 0.0175 to 0.0185 inch 100 100 100
Fracture force .gtoreq.2 g 9.88 9.39 9.52 Fracture energy
.gtoreq.0.9 .mu.J 5.88 4.54 4.64 Moisture .ltoreq.1.0% 0.4 0.4 0.4
Foreign particulate No visible foreign materials Pass Pass Pass
Insoluble mater Particle count (for information Diameter
.ltoreq.101 .mu.m 17 26 2.6 only) Diameter .ltoreq.25 .mu.m 0.5 1 0
Dexamethasone Positive for dexamethasone positive positive positive
identity Potency 95.0 to 105.0 % label strength 98.5 101.2 99.9
Degradation .ltoreq.2% total 1.1 0.6 1.0 products .ltoreq.0.5% acid
ND ND ND .ltoreq.1.0% ketone 0.4 0.2 0.4 .ltoreq.1.0% aldehyde 0.7
0.4 0.5 Dexamethasone See Table 2.1.P.5.1-1 Pass Pass Pass release
Uniformity 85.0-115.0% Label Strength (LS) 97.0% 97.1% 98.0% Stage
1 (n = 10): If one unit is outside all values all values all values
the range and between 75% and 125% LS within within within or RSD
.gtoreq.6.0%, test 20 more units. range range range Stage 2 (n =
20): pass if no more than 1 unit is outside the range, and is
between 75% and 125% LS, and the RSD .ltoreq.7.8%.
[0232] Table F sets forth further preferred specifications for both
the DEX PS DDS implant and the applicator.
TABLE-US-00011 TABLE F Preferred specifications Attribute
Specifications Implant appearance White to off-white, rod shaped
Drug Delivery System (DDS), essentially free of foreign matter.
Fracture Force Minimum 2.0 g Energy Minimum 0.85 .mu.joule Moisture
content No more than 1% Foreign particulates No visible foreign
material Insoluble matter Record particle count for information
only (diameter .gtoreq.10.mu.m and .gtoreq.25 .mu.m) Dexamethasone
identity Positive for dexamethasone Dexamethasone potency 90.0 to
110.0% LC Impurities Dexamethasone acid not greater than 0.5% HPLC
area Dexamethasone ketone not greater than 1.0% HPLC area
Dexamethasone aldehyde not greater than 1.0% HPLC area Total
degradation not greater than 2% HPLC area Weight Range 700 .mu.g
dose: 1.050 mg to 1.284 mg (1.167 mg +/- 10%) 350 .mu.g dose: 0.525
mg to 0.642 mg (0.583 mg +/- 10%) Content uniformity 85% to 115%
Label Claim In vitro Dissolution test Ranges: 24 hours: not greater
than 10.0% (% of total amount of 7 days: not greater than 30.0%
dexamethasone released) 14 days: 25.0% to 85.0% 21 days: not less
than 50% Applicator Actuation force No more than 5.0 lbs
required
[0233] Implants and Applicators made as set forth above were found
to be within the parameters of the preferred specifications.
[0234] Preferred Applicator A preferred applicator to use to
implant the DEX PS DDS is shown in international patent publication
WO 2004/026106, published Apr. 1, 2004. The applicator was designed
to facilitate the insertion of the implant in the posterior segment
of the eye. The implant is housed in the needle of the applicator.
The applicator is designed to fit comfortably into the hand of the
physician, and to allow for single-handed operation. It is similar
in size to retinal forceps, measuring 165 mm in length by 13 mm in
width. FIG. 17 provides a cut-away side view of the applicator
illustrating the typical functions and positions of all the
elements.
[0235] As the lever is depressed, it applies a force on the
linkage, which collapses and moves the plunger forward into the
needle, pushing the DEX PS DDS into the posterior chamber of the
eye. Once the DEX PS DDS is delivered, the lever then latches
within the Applicator housing to signal use and prevent any reuse.
The needle used is a 22-gauge thin-wall hypodermic needle. A
silicone o-ring, is placed into a slot in the needle to retain the
DEX PS DDS within the needle and remains outside the eye, in
contact with the conjunctiva. To ensure that air is not introduced
into the eye, the applicator has been designed to vent. A small gap
between the DEX PS DDS and inner needle wall allows air to move
back through and out of the needle as the DEX PS DDS is being
delivered. The small size of this gap prevents fluid from flowing
out of the eye through the needle. The components of the Applicator
that may contact the patient during use are the plunger, needle and
o-ring. The plunger and needle are manufactured from materials of
known biocompatibility, and with a history of human use.
Biocompatibility of the o-ring was evaluated through cytotoxicity
testing.
[0236] The applicator is packed with desiccant in a pouch designed
to protect the implant from humidity. The packaged implant in the
applicator is then sterilised by gamma irradiation. The pouch also
ensures that the product remains sterile during the shelf life.
[0237] The DEX PS DDS is terminally sterilised by gamma
irradiation, in its applicator as presented packed in the foil
pouch, using a 25 to 40 kGy dose. Terminal sterilisation process
steam sterilisation (autoclaving) is not used because the polymers
used for the controlled release are extremely sensitive to moisture
and heat and degrade even with non-compendial low temperature
sterilisation cycles.
[0238] The DEX PS DDS Applicator System is a sterile, single use
applicator intended to deliver one DEX PS DDS. The DEX PS DDS is
loaded into the needle of the Applicator during the assembly
process. It is then packaged in a foil pouch with desiccant and
terminally sterilised by gamma irradiation.
[0239] All publications, patents, and patent applications cited
herein are hereby incorporated by reference in their entirety for
all purposes to the same extent as if each individual publication,
patent, or patent application were specifically and individually
indicated to be so incorporated by reference. Although the
foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding,
it will be readily apparent to those of ordinary skill in the art
in light of the teachings of this invention that certain changes
and modifications may be made thereto without departing from the
spirit and scope of the appended claims.
* * * * *
References