WO2007032997A1

WO2007032997A1 - Ophthalmic formulation containing loteprednol etabonate for treatment of dry eye

Info

Publication number: WO2007032997A1
Application number: PCT/US2006/034914
Authority: WO
Inventors: Robert J. Meyering
Original assignee: Bausch & Lomb Incorporated
Priority date: 2005-09-13
Filing date: 2006-09-08
Publication date: 2007-03-22

Abstract

This invention relates to formulations for topical use comprising a steroid in combination with electrolytes, synthetic glycoproteins, synthetic proteins, synthetic enzymes and/or synthetic peptides in both a preservative and preservative free formulation/system for the treatment of dry eye and attendant inflammation.

Description

OPHTHALMIC FORMULATION CONTAINING LOTEPREDNOL ETABONATE

FOR TREATMENT OF DRY EYE

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Topical steroids such as corticosteroids are commonly used for anti-inflammatory therapy of the eye, especially for treating inflammatory conditions of the palpebral or bulbar conjunctiva, cornea and anterior segment of the globe. Common therapeutic applications for steroids include allergic-conjunctivitis, acne rosacea, superficial punctate keratitis and iritis cyclitis. Steroids also are used to ameliorate inflammation associated with corneal injury due to chemical or thermal burns, or penetration of foreign bodies. Such conditions may result from surgery, injury, allergy or infection to the eye and can cause severe discomfort.

Despite their therapeutic advantages, topical ocular use of corticosteroids is associated with a number of complications, including posterior subcapsular cataract formation, elevation of intraocular pressure, secondary ocular infection, retardation of corneal wound healing, uveitis, mydriasis, transient ocular discomfort and ptosis. Numerous systemic complications also may arise from the topical ocular application of corticosteroids. These complications include adrenal insufficiency, Cushing's syndrome, peptic ulceration, osteoporosis, hypertension, muscle weakness or atrophy, inhibition of growth, diabetes, activation of infection, mood changes and delayed wound healing. Topical steroids for treating ocular inflammations can be based on soft drugs. Soft drugs, as is known in the art, are designed to provide maximal therapeutic effect and minimal side effects. By one approach, synthesis of a "soft drug" can be achieved by structurally modifying a known inactive metabolite of a known active drug to produce an active metabolite that undergoes a predictable one-step transformation in-vivo back to the parent, inactive metabolite (see, U.S. Pat. Nos. 6,610,675, 4,996,335 and 4,710,495 for soft steroids). "Soft drugs" therefore are biologically active chemical components characterized by predictable in vivo metabolism to non-toxic derivatives after they provide their therapeutic effect. Formulations of cortico steroids suitable for ophthalmic use are known. For example, US patents 4,710,495, 4,996,335, 5,540,930, 5,747,061, 5,916,550, 6,368,616 and 6,610,675, the contents of each of which is incorporated by reference herein, describe soft steroids and formulations containing soft steroids.

DESCRIPTION OF THE INVENTION

Scientific study of dry eye patients has demonstrated that ocular inflammation can lead to cellular destruction. This destruction can adversely impact the neural transmission that occurs between the ocular surface and internal human ocular structures which create, maintain and adjust tear film quality and quantity. Inflammatory mediators can also accumulate on the ocular surface as a result of hyperosmolarity (which draws out aqueous) caused by systemic disease and/or tear film dysfunction. Increased concentrations of inflammatory mediators can lead to cellular and neural damage if left untreated. With over 500 different proteins now identified in natural tears, the present invention calls for the use of a corticosteroid in concert with synthetic versions of naturally occurring proteins/enzymes to help reduce inflammatory mediators. This will help minimize the interference and "down regulation" of neural feedback occurring typically caused by inflammatory mediators which will ultimately help with the improvement of tear film quality and dry eye symptoms. This activity, in concert with the anti-inflammatory properties of the steroid, will provide for symptomatic relief and improved control and management of dry eye.

SUMMARY OF THE INVENTION

Disclosed herein are formulations for topical use comprising corticosteroids in combination with electrolytes, synthetic glycoproteins, synthetic proteins, synthetic enzymes and/or synthetic peptides in both a preservative and preservative free formulation/system for the treatment of dry eye and attendant inflammation.

Having briefly summarized the invention, the invention will now be described in detail by reference to the following specification.

DETAILED DESCRIPTION OF THE INVENTION

Therapeutic suspensions for ophthalmic or otolaryngological uses are made by aseptic preparation. Purity levels of all materials employed in the suspensions of the invention exceed those required by regulation.

Steroids of the invention herein, preferably rapidly metabilized steroids, most preferably LE, can be employed. Also other steroids, such as beclomethasone, decamethasone, betamethasone, fluocinolone, fluorometholone, exednisolone, may be employed. The suspensions of steroids of the invention have a particle size of about 0.1- 30 μ, preferably about 1-20 μ, most preferably about 2-10 microns in mean diameter. LE in this size range is commercially available from suppliers such as the Sipsy Co., (Avrille, France).

In one embodiment, a preferred stable formulation further comprises balanced salts. The balanced salts of certain embodiments preferably include NaCl, KCl, CaCl₂ and MgCl₂ in a ratio that provides an osmolality range of about 140 to about 400, preferably about 240 to about 330 mOsm/kg, preferably about 260 to about 300 mOsm/kg, with the most preferred osmolality of approximately 270 mθsm/kg. In one embodiment, NaCl ranges from about 0.1 to about 1 % w/v. preferably about 0.2 to about 0.8% w/v, more preferably about 0.39%w/v, KCl ranges from about 0.02 to about 0.5% w/v., preferably about 0.05 to about 0.3 % w/v, more preferably about 0.14%w/v, CaCl₂ ranges from about 0.00005 to about 0.1 % w/v, preferably about 0.0005 to about 0.1 % w/v, preferably about 0.005 to about 0.08 w/v, more preferably about 0.06 % w/v.

Health regulations in various countries generally require that ophthalmic preparations shall include a preservative. Many well known preservatives that have been used in ophthalmic preparations of the prior art, however, cannot be used in the preparations of the invention, since those preservatives may no longer be considered safe for ocular use. Gentle preservatives such as stabilized oxy-chloro complex (available commercially as OcuPure ™ from Advanced medical optics, Purite ®from Allergan, and Purogene from Biocide have received some recommendation as preservatives that cause less irritation to the end user. Alternatively the formulations of the invention herein may be preservative free.

Although there are over 500 different proteins identified in natural tears, techniques such as those disclosed in Molecular Biomethods Handbook, Eds. Ralph Rapley and John M. Walker, the contents of which are incorporated herein, make it possible to isolate the proteins and enzymes and produce them or the active component thereof synthetically, for example, using recombinant methodologies. These synthetic proteins and en2ymes will be present in the formulations of the invention herein in amounts that will mimic or serve to stabilize the naturally occurring proteins and enzymes of the tear film at their normal, non-dry eye, levels.

Preferred formulations are prepared using standard compounding, filtration, fill and packaging equipment. In one embodiment preferred formulations are prepared in scaled up version capable of mass production. In another embodiment preferred formulations are prepared in small laboratory scale batches. In one embodiment the packaging used consists of single use containers. In some single use embodiments, an alternative formulation may include non-preserved formulations. The non-preserved embodiments may also replace the borate/boric acid buffer system with a milder buffer system such as about 0.3% sodium lactate. In another embodiment, the formulation is packaged in eye dropper bottles of varying sizes. Preferred packaging includes, but is not limited to, materials that will shield the invention from light and/or oxygen. One embodiment of the packaging consists of teal bottles. Other embodiments include bottles of various colors, for example blue, opaque white, black, or brown bottles can be used.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.

Claims

What is claimed is:

1. A composition for ophthalmic use comprising: a corticosteroid; balanced salts;and, at least one synthetic version of a protein or enzyme normally found in tears.

2. The composition of claim 1 further including a preservative for preventing microbial formation in said composition and in an amount of about 0.01 to 0.025% by weight.

3. The composition of claim 2 wherein the preservative is a stabilized oxychloro complex.

4. The composition of claim 1 wherein the synthetic protein is mucin.

5. The composition of claim 1 wherein the synthetic protein is lysozyme.

6. The composition of claim 1 wherein the synthetic protein is lactoferrin.

7. The composition of claim 2 wherein said preservative is benzalkonium chloride.

8. The composition of claim 7 further comprising disodium edentate.

9. The composition of claim 1 wherein the corticosteroid is Loteprednol etabonate.