WO2004043480A2

WO2004043480A2 - Intraocular administration of cyclosporin a for the treatment of macular degeneration, retinopathy or retinitis pigmentosa

Info

Publication number: WO2004043480A2
Application number: PCT/US2003/028315
Authority: WO
Inventors: Gholam A. Peyman
Original assignee: Peyman Gholam A
Priority date: 2002-11-07
Filing date: 2003-09-10
Publication date: 2004-05-27
Also published as: US20040092435A1; WO2004043480A3; US7354574B2; AU2003301961A8; AU2003301961A1

Abstract

A method and article to treat ocular disease with Cyclosporin A alone or with compounds related to Cyclosporin A for intraocular injection or implantation. Treatment does not result in ocular toxicity and encompasses age related macular degeneration, retinitis pigmentosa, and retinopathy such as diabetic retinopathy.

Description

TREATMENT OF OCULAR DISEASE

Field of the Invention

The invention is directed to therapeutic treatment of age-related

macular degeneration, retinitis pigmentosa, and diabetic retinopathy with Cyclosporin

A.

Background

The immunomodulator Cyclosporin A (cyclosporine, topical formulation

Arrestase®, Allergan Inc.) has been used to treat glaucoma, corticosteroid-induced

ocular hypertension, aliograft rejection, infections, and ocular surface disease. Its use

has been reported for the treatment of uveitis (inflammation of the uvea) by topical,

intravitreal or systemic administration with doses of 0.05%, 0.1%, and 0.5%.

Cyclosporin A has good penetration into the cornea but not into the anteriorchamber,

and does not increase intraocular pressure orcause cataracts. Its known toxicity had previously limited its use for other ocular diseases.

Summary of the Invention

A method of treating age-related macular degeneration, retinitis

pigmentosa, and diabetic retinopathy in the absence of substantial toxicity by

administering Cyclosporin A in an effective amount and in a pharmaceutically

acceptable formulation. "Treating" includes preventing progression of pre-existing disease, delaying onset and/or severity of disease, and ameliorating or reducing the

severity, frequency, duration, etc., of one or more symptoms of disease.

In one embodiment, Cyclosporin A is injected intraocularly, for example

bysubconjuctival, intravitreal, subretinal, or retrobulbar injection. Forsubconjuctival

injection, a concentration in the range of about 1 ng/ml to about 500 μg/ml may be

used. For intravitreal injection, a concentration in the range of about 1 μg/0.1 ml to

about 1000 μg/0.1 ml may be used; one concentration that may be used is about

50 μg/0.1 ml. Forsubretinal injection, a concentration in the rangeof about 1 μg/0.1

ml to about 100 μg/0.1 ml may be used. For retrobulbar injection, a concentration in

the range of about 20 μg/ml to about 1000 μg/ml may be used. Cyclosporin A may

be administered in an aqueous-based solution, for example, bound to liposomes, or

it may be dissolved in an organic solvent. In another alternative embodiment,

Cyclosporin A may also be provided in an inert physiologically acceptable carrier

such as a microsphere, liposome, capsule or polymeric matrix by injection or by

surgical implantation in the eye or on the eye. Aqueous solvents that may be used

include, but are not limited to, 0.9% saline and 5% dextrose. Organic solvents that

may be used include, but are not limited to, dimethylsulfoxide (DMSO) or an alcohol.

An implant may provide a time-release form of Cyclospoπn A to achieve a constant

dose of drug.

A method is also disclosed to reduce the onset or progression of

diabetic retinopathy, age-related macular degeneration and/or retinitis pigmentosa,

by intraocularly administering a composition containing Cyclosporin A, either alone

or with other compounds that are related to Cyclosporin A, as the active agent in a

pharmaceutically acceptable formulation and in an effective amount without causing

substantial toxicity. The composition may contain Cyclosporin A as the sole active agent, the other agents being those that do not materially affect the basic properties

of Cyclosporin A. Alternatively, the composition may contain other active agents,

such as tacrolimus, besides Cyclosporin A. The composition may be injected or

implanted in the eye.

The invention encompasses a method to treat a patient by intraocularly

administering a composition containing Cyclosporin A as the active agent in a

pharmaceutically acceptable formulation and in an amount effective to treat macular

degeneration, retinopathy, or retinitis pigmentosa without substantial ocular toxicity.

The composition is injected or implanted in the eye, and may be administered in a

time-release formulation.

A sustained release formulation, such as a matrix, may be loaded with

an amount of Cyclosporin A that would be toxic if released at a non-controlled rate,

or a supratherapeutic amount, but which is formulated to release a non-toxic

therapeutic amount of Cyclosporin A over a period of time. For example, a matrix

may contain at least about 1 mg Cyclosporin A and may sustainedly release a non-

toxic maintenance dose of Cyclosporin A. Such a matrix may be a diffusible walled

reservoir and may be lipid, polyvinyl alcohol, polyvinyl acetate, polycaprolactone,

poly(glycolic) acid, and/or poly(lactic)acid.

The invention will further be appreciated with respect to the following

detailed description.

Detailed Description

Cyclosporin A is a cyclic peptide produced by Trichoderma

polysporum. It is available commercially, for example, from Sigma Chemicals (St.

Louis, MO). It is an immunosuppressant and acts in a particular subset of T lymphocytes, the helper T cells. Cyclosporin A exerts an immunosuppressant effect

by inhibiting production of the cytokine interleukin 2. Each of Cyclosporin A and

tacrolimus, another immunosuppressant, produce significant renal and hepatic

toxicity when each is administered systemically; because of this toxicity, they are not

administered together.

Direct intraocular injection of200 μg Cyclosporin A or less is non-toxic.

Oculartoxicity may manifest as a gross and/or histologic retinal and/orvitreous toxic

reaction. Evidence of such a toxic reaction may include one or more of white vitreous

bodies, white vitreous opacities, electroretinography abnormalities such as reduction

in mean B-wave amplitude in both scotopic and photopic conditions, occlusion of the

temporal retinal vessels, and fibrin deposits.

Cyclosporin A may be injected intraocularly using intravitreal (into the

vitreous), subconjuctival (into the subconjuctival), subretinal (under the retina), or

retrobulbar (behind the eyeball) injection. Forsubconjuctival injection, a Cyclosporin

A dose in the range of about 1 ng/ml to about 500 μg/ml may be used. For intravitreal

injection, a Cyclosporin A dose in the range of about 1 μg/0.1 ml to about

1000 μg/0.1 ml may be used. For retrobulbar injection, a Cyclosporin A dose in the

range of about 20 μg/ml to about 1000 μg/ml may be used. Forsubretinal injection,

a Cyclosporin A dose in the range of about 1 μg/0.1 ml to about 100 μg/0.1 ml may

be used.

Cyclosporin A may be administered intraocularly in a composition in

which it is the only active agent. Alternatively, Cyclosporin A may be administered

intraocularly in a composition with related compounds. Related compounds are

other immunosuppressants that include, but are not limited to, tacrolimus,

cyclophosphamide, sirolimus, atoposide, thioepa, methotrexate, azathioprine (imuran), interferons, infliximab, etanercept, mycophenolate mofetil, 15-

deoxyspergualin, thalidomide, glatiramer, leflunomide, vincristine, cytarabine, etc.

In one embodiment, the composition containing Cyclosporin A is

administered in an amount or at a dose that does not result in substantial toxicity to

the eye. As used herein, a lack of substantial toxicity encompasses both the absence

of any manifestations of toxicity, as well as manifestations of toxicity which one skilled

in the art would consider not sufficiently detrimental to decrease or cease treatment.

As one example, fibrin deposits may be present indicating some toxicity, but less

, than substantial toxicity if their duration, number, etc., does not warrant that treatment

be curtailed orstopped. As another example, white vitreous bodies and fibrin bodies

may be present indicating some toxicity, but less than substantial toxicity if their

duration, number, etc., does not warrant that treatment be curtailed or stopped.

Direct intraocular injection of a dose up to about 200 μg Cyclosporin

A occurs without substantial toxicity to the patient. The intravenous solution form of

Cyclosporin A may be diluted to achieve the indicated concentration using 0.9% NaCI

or 5% dextrose, or an organic solvent such as dimethylsulfoxide (DMSO) or alcohol .

Intraocular administration may be by any of the routes and formulations previously

described. For injection, either a solution, emulsion, suspension, capsular

formulation of microspheres or liposomes, etc. may be used.

Cyclosporin A may be administered surgically as an ocular implant. As

one example, a reservoir container having a diffusible wall of polyvinyl alcohol or

polyvinyl acetate and containing milligram quantities of Cyclosporin A may be

implanted in or on the sclera. As another example, Cyclosporin A in milligram

quantities may be incorporated into a polymeric matrix having dimensions of about

2 mm by4 mm, and made of a polymersuch as polycaprolactone, poly(glycolic) acid, poly(lactic) acid, or a polyanhydride, or a lipid such as sebacic acid, and may be

implanted on the sclera or in the eye. This is usually accomplished with the patient

receiving either a topical or local anesthetic and using a small (3-4 mm incision)

made behind the cornea. The matrix, containing Cyclosporin A, is then inserted

through the incision and sutured to the sclera using 9-0 nylon.

Cyclosporin A may be contained within an inert matrix for injection into

the eye. As one example of an inert matrix, liposomes may be prepared from

dipalmitoyl phosphatidylcholine (DPPC), such as egg phosphatidylcholine (PC), a

lipid having a low heat transition. Liposomes are made using standard procedures

as known to one skilled in the art. Cyclosporin A, in amounts ranging from nanogram

to microgram to milligram quantities, is added to a solution of egg PC, and the

lipophilic drug binds to the liposome.

A time-release drug delivery system may be implanted intraocularly to

result in sustained release of the active agent over a period of time. The implantable

structure may be in the form of a capsule of any of the polymers previously disclosed

(e.g., polycaprolactone, poly(giycolic)acid, poly(lactic)acid, polyanhydride) or lipids

that may be formulation as microspheres. As an illustrative example, Cyclosporin A

may be mixed with polyvinyl alcohol (PVA), the mixture then dried and coated with

ethylene vinyl acetate, then cooled again with PVA. In a formulation for intraocular

injection, the liposome capsule degrades due to cellular digestion and can be a slow

release drug delivery system, allowing the patient a constant exposure to the drug

over time.

In a time-release formulation, the microsphere, capsule, liposome, etc.

may contain a concentration of Cyclosporin A that could be toxic if it were

administered as a bolus dose. The time-release administration, however, is formulated so that the concentration released over any period of time does not

exceed a toxic amount. This is accomplished, for example, through various

formulations of the vehicle (coated or uncoated microsphere, coated or uncoated

capsule, lipid or polymer components, unilamellar or multilamellar structure, and

combinations of the above, etc.). Other variables may include the patient's

pharmacokinetic-pharmacodynamic parameters (e.g., body mass, gender, plasma

clearance rate, hepatic function, etc.).

Depending upon the amount of Cyclosporin A provided in the

formulation, a patient could be dosed over a period of years from a single implant or

injection. As illustrative but non-limiting examples, a capsule can be loaded with 1 -2

mg of Cyclosporin A; if the capsule is formulated to release a few micrograms of drug

per day, the patient could be dosed for about 1000 days, or almost three years. As

another example, If the capsule is loaded with 5 mg of drug, the patient could be

dosed for about fifteen years. Such a formulation provides benefits which include

accurate dosing with heightened patient convenience, because intervention is

required in some cases only once or twice a decade or even less frequently.

The formation and loading of microspheres, microcapsules, liposomes,

etc. and their ocular implantation are standard techniques known by one skilled in the

art, for example, the use a ganciclovir sustained-release implant to treat

cytomegalovirus retinitis, disclosed in Vitreoretinal Surgical Techniques, Peyman et

al., Eds. (Martin Dunitz. London 2001 , chapter 45); Handbook of Pharmaceutical

Controlled Release Technology, Wise, Ed. (Marcel Dekker, New York 2000), the

relevant sections of which are incorporated by reference herein in their entirety.

Cyclosporin A, either alone or in combination with other agents, may

be administered intraocularly and without substantial toxicity, to treat retinopathy such as occurs in diabetic patients, maculardegeneration, and retinitis pigmentosa, using

the methods and formulations previously described. As described, this may be

achieved by one or a combination of factors, such as by slowing disease

progression, lessening its severity, lengthening the time of onset, etc.

Diabetic retinopathy is a leading cause of blindness. Patients with

diabetes mellitus have an absolute or relative lack of circulating insulin and, through

a variety of factors, frequently present with vascular changes in the retina. These

changes manifest in retinal microaneurysms, small hemorrhages, and exudates, and

lead to the formation of scar tissue. New blood vessels may form around the optic

disk (proliferative retinopathy). Overtime, the cumulative results of such vascular

effects lead to ocular pathologies which, ultimately, decrease vision in the diabetic

patient. Thus, compositions and methods which reduce these vascular changes, or

reduce their effects, improve the chances of a diabetic patient either maintaining

vision, or at least slowing loss of vision.

Maculardegeneration, also called age-related macular degeneration

is a pathological condition that results in proliferation of new blood vessels in the

subretinal area. While the presence of the new vessels themselves is not

problematic, the new vessels leak blood and other serous fluid which accumulate in

surrounding spaces. It is this fluid accumulation that leads to visual impairment. For

example, in the retina, both the large vessels and the capillaries normally have intact

vessei walls. In the choroid, the large vessels normally have intact vessel walls, but

the capillary walls or membranes contain fenestratioπs or openings. Any endogenous

or exogenous fluid present in these capillaries, for example, blood, serous fluid,

solubilized drug, etc. will leak outside the vessels and into the surrounding area. The

accumulation of fluid can result in serous and hemorrhagic detachment of the retinal pigment epithelium and neurosensory retina, and can lead to loss of vision due to

fibrous deform scarring. Patients with an early stage of age-related macular

degeneration can be diagnosed by the presence in the eye of abnormal clumps of

pigments, termed drusen, which are dead outer segments of photoreceptor cells

under the retinal pigment epithelium. The presence of large, soft drusen in the eye

indicates a pre-stage of exudative age-related macular degeneration, and places

these patients at higher-than-average risk for developing neovascularizations,

especially if one eye is already affected.

Retinitis pigmentosa is a general term that encompasses a disparate

group of disorders of rods and cones, which are the sensory structures in the retina.

While retinitis pigmentosa is a genetic disorder, and is not an inflammatory process,

one manifestation of the disease is the presence of irregular black deposits of

clumped pigment in the peripheral retina. Thus, there is likely at least some immune

component to retinitis pigmentosa.

While not being bound by a specific theory or mechanism, it is possible

that the therapeutic efficacy of Cyclosporin A may involve its immunosuppressant

activity. For example, diabetic patients treated with immunosuppressant drugs for

reasons unrelated to vision develop less retinopathy overtime than other diabetic

patients. As another example, the drusen that is present in age-related macular

degeneration constitutes a chronic inflammatory stimulus that becomes the target for

encapsulation by a variety of inflammatory mediators, such as compliment.

Treatment with immunosuppressant drugs may ameliorate this reaction.

Immunosuppressant therapy results in decreased numbers of circulating

immunocompetent cells such as lymphocytes. These cells otherwise have the

potential to participate in an immune response, to lodge within the small capillaries and arterioles of the eye to form blockages and hence occlude blood flow, etc In

addition to lymphocytes, other hematopoietic cells may also be affected by

immunotherapy, and include erythrocytes (red blood cells), megakaryocytes

(precursors to platelets) and thrombocytes (platelets), and other leukocytes (white

blood cells), such as monocytes and granulocytes. Local or in situ administration of

immunosuppressant agents to the eye decreases the number of these cells. This

results in reduction in the immune response, less blockage, increased blood flow, and

increased patency of the ocular vessels.

Cyclosporin A in any of the previously described formulations, dosages,

compositions, routes of administration, etc. may be employed. Because

Cyclosporin A is injected or implanted directly in the eye, the undesirable effects

brought about by administration of systemic therapy with Cyclosporin A (e.g.,

decreased peripheral blood leukocyte count, susceptibility to infections, hepatic and

renal toxicity of the immunosuppressant agent itself, etc.) are absent. Cyclosporin A

and related compounds may be administered by intraocular injection and/or

intraocularimplantation ofa loaded capsule, microsphere, etc. (collectively termed

an implant) to treat retinopathy, maculardegeneration, and/or retinitis pigmentosa.

The implant may release Cyclosporin A over a period of time, as previously

described, so that high doses of drug can be loaded into the implant, but the patient

will receive a low dose sustained concentration. That is, the matrix may be loaded

or formulated so that it contains what would otherwise be a toxic or supratherapeutic

amount of Cyclosporin A if the drug was released in a non-controlled manner.

It should be understood that the embodiments of the invention shown

and described in the specification are only preferred embodiments of the inventor

who is skilled in the art and are not limiting in anyway. Therefore, various changes, modifications or alterations to these embodiments may be made or resorted to

without departing from the spirit of the invention and the scope of the following claims. What is claimed is:

Claims

1. A method to treat a patient comprising intraocularly administering to the

patient a composition consisting essentially of Cyclosporin A in a pharmaceutically

acceptable formulation and amount effective to treat macular degeneration,

retinopathy, or retinitis pigmentosa without substantial toxicity to the patient.

2. The method of claim 1 comprising administering by intraocular injection

or intraocular implantation.

3. The method of claim 1 comprising administering by retrobulbar,

intravitreal, intraretinal, or subconjuctival injection.

4. The method of claim 1 comprising administering by implanting a matrix

comprising Cyclosporin A.

5. The method of claim 4 providing sustained release of Cyclosporin A.

6. The method of claim 4 wherein the matrix is sutured to the sclera.

7. The method of claim 4 wherein the matrix contains at least about 1 mg

Cyclosporin A and sustainedly releases a non-toxic maintenance dose of Cyclosporin

A.

8. The method of claim 2 wherein injection is subconjuctival at a dose in

the range of about 1 ng/ml to about 500 μg/ml, intravitreal at a dose in the range of

about l μg/0.1 ml to about 1000 μg/0.1 ml, retrobulbarat a dose in the range of about 20 μg/ml to about 1000 μg/ml, or subretinal at a dose in the range of about 1 μg/0.1

ml to about 100 μg/0.1 ml.

9. The method of claim 2 wherein Cyclosporin A is injected at a dose in the range of about 20 μg/ml to about 1000 μg/ml.

10. The method of claim 1 for treating diabetic retinopathy.

11. A method to treat a patient comprising intraocularly administering to the

patient a composition comprising Cyclosporin A in a pharmaceutically acceptable

formulation and amount effective to treat macular degeneration, retinopathy, or

retinitis pigmentosa without substantial toxicity to the patient.

12. The method of claim 11 comprising administering by intraocular

injection or intraocular implantation.

13. The method of claim 11 comprising administering by retrobulbar,

intravitreal, intraretinal, or subconjuctival injection.

14. The method of claim 11 comprising administering by implanting a

matrix comprising Cyclosporin A.

15. The method of claim 14 providing sustained release of Cyclosporin A.

16. The method of claim 14 wherein the matrix is sutured to the sclera.

17. The method of claim 14 wherein the matrix contains at least about l mg

A.

18. The method of claim 12 wherein injection is subconjuctival at a dose

in the range of about 1 ng/ml to about 500 μg/ml, intravitreal at a dose in the range

of about l μg/0.1 ml to about 1000 μg/0.1 ml, retrobulbar at a dose in the range of

about 20 μg/ml to about 1000 μg/ml, or subretinal at a dose in the range of about 1

μg/0.1 ml to about 100 μg/0.1 ml.

19. The method of claim 12 wherein Cyclosporin A is injected at a dose in

the range of about 20 μg/ml to about 1000 μg/ml.

20. The method of claim 11 for treating diabetic retinopathy.

21. The method of claim 11 wherein the composition further comprises an

immunosuppressant selected from the group consisting of tacrolimus,

cyclosphosphamide, sirolimus, atoposide, thioepa, methotrexate, azathioprine,

interferons, infliximab, etanercept, mycophenolate mofetil, 15-deoxyspergualin,

thalidomide, glatiramer, Ieflunomide, vincristine, cytarabine, and combinations

thereof.

22. An article of manufacture comprising a physiologically acceptable

implantable matrix comprising a supratherapeutic amount of Cyclosporin A.

23. The article of claim 22 wherein Cyclosporin A is in or on the matrix.

24. The article of claim 22 wherein the matrix is a diffusible walled

reservoir.

25. The article of claim 22 wherein the matrix comprises a substance

selected from the group consisting of lipid, polyvinyl alcohol, polyvinyl acetate,

polycaprolactone, poly(glycolic)acid, poly(lactic)acid, and combinations thereof.

26. The article of claim 22 wherein the matrix contains at least about 1 mg

Cyclosporin A.

27. The article of claim 22 wherein the matrix contains Cyclosporin A in an

amount ranging from about 1 mg Cyclosporin A to about 10 mg Cyclosporin A.

28. The article of claim 22 wherein the matrix further comprises an

immunosuppressant selected from the group consisting of tacrolimus,

cyclosphosphamide, sirolimus, atoposide, thioepa, methotrexate, azathioprine,

interferons, infliximab, etanercept, mycophenolate mofetil, 15-deoxyspergualin,

> thalidomide, glatiramer, Ieflunomide, vincristine, cytarabine, and combinations

thereof.