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

Ophthalmic formulation containing loteprednol etabonate for treatment of dry eye Download PDF

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Publication number
WO2007032997A1
WO2007032997A1 PCT/US2006/034914 US2006034914W WO2007032997A1 WO 2007032997 A1 WO2007032997 A1 WO 2007032997A1 US 2006034914 W US2006034914 W US 2006034914W WO 2007032997 A1 WO2007032997 A1 WO 2007032997A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
synthetic
dry eye
preservative
treatment
Prior art date
Application number
PCT/US2006/034914
Other languages
French (fr)
Inventor
Robert J. Meyering
Original Assignee
Bausch & Lomb Incorporated
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bausch & Lomb Incorporated filed Critical Bausch & Lomb Incorporated
Publication of WO2007032997A1 publication Critical patent/WO2007032997A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • 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.
  • 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 ulceris 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.
  • 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 are designed to provide maximal therapeutic effect and minimal side effects.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ , preferably about 1-20 ⁇ , 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).
  • a preferred stable formulation further comprises balanced salts.
  • the balanced salts of certain embodiments preferably include NaCl, KCl, CaCl 2 and MgCl 2 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 m ⁇ sm/kg.
  • NaCl ranges from about 0.1 to about 1 % 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
  • CaCl 2 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.
  • ophthalmic preparations shall include a preservative.
  • Gentle preservatives such as stabilized oxy-chloro complex (available commercially as OcuPure TM 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.
  • the formulations of the invention herein may be preservative free.
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Inorganic Chemistry (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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
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.
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.
PCT/US2006/034914 2005-09-13 2006-09-08 Ophthalmic formulation containing loteprednol etabonate for treatment of dry eye WO2007032997A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US71659505P 2005-09-13 2005-09-13
US60/716,595 2005-09-13

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WO2007032997A1 true WO2007032997A1 (en) 2007-03-22

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103182075A (en) * 2011-12-30 2013-07-03 沈阳兴齐眼药股份有限公司 Lysozyme preparation, preparation method thereof, and application thereof

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991017469A1 (en) * 1990-05-09 1991-11-14 Vepex Contractor Ltd. Kit for contact lenses
WO1999051273A1 (en) * 1998-04-07 1999-10-14 Alcon Laboratories, Inc. Gelling ophthalmic compositions containing xanthan gum
WO2002102399A2 (en) * 2001-06-14 2002-12-27 Novo Nordisk A/S Mucosal repair by tff2 peptides
WO2003030893A1 (en) * 2001-10-11 2003-04-17 Alcon, Inc. Methods for treating dry eye by a combination of an antiinflammatory steroid and a muc-1 secretagogue
US6565861B1 (en) * 2000-02-11 2003-05-20 Isis Innovation Limited Artificial tear formulation
WO2004006801A2 (en) * 2002-07-17 2004-01-22 Biosyntrx, Inc. Treatment for dry eye syndrome
JP2005068119A (en) * 2003-08-22 2005-03-17 Nrl Pharma Inc New pharmaceutical composition and processed food for treating/preventing dry eye
WO2005044231A1 (en) * 2003-10-31 2005-05-19 Bausch & Lomb Incorporated Suspension of loteprednol etabonate and tobramycin for topical ophthalmic use
JP2005170795A (en) * 2003-12-08 2005-06-30 Lion Corp Ophthalmic composition
WO2005084635A2 (en) * 2004-03-02 2005-09-15 Institute Of Ophthalmology Pharmaceutical ocular preparations suitable for the treatment of the ocular surface and related disorders/diseases

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991017469A1 (en) * 1990-05-09 1991-11-14 Vepex Contractor Ltd. Kit for contact lenses
WO1999051273A1 (en) * 1998-04-07 1999-10-14 Alcon Laboratories, Inc. Gelling ophthalmic compositions containing xanthan gum
US6565861B1 (en) * 2000-02-11 2003-05-20 Isis Innovation Limited Artificial tear formulation
WO2002102399A2 (en) * 2001-06-14 2002-12-27 Novo Nordisk A/S Mucosal repair by tff2 peptides
WO2003030893A1 (en) * 2001-10-11 2003-04-17 Alcon, Inc. Methods for treating dry eye by a combination of an antiinflammatory steroid and a muc-1 secretagogue
WO2004006801A2 (en) * 2002-07-17 2004-01-22 Biosyntrx, Inc. Treatment for dry eye syndrome
JP2005068119A (en) * 2003-08-22 2005-03-17 Nrl Pharma Inc New pharmaceutical composition and processed food for treating/preventing dry eye
WO2005044231A1 (en) * 2003-10-31 2005-05-19 Bausch & Lomb Incorporated Suspension of loteprednol etabonate and tobramycin for topical ophthalmic use
JP2005170795A (en) * 2003-12-08 2005-06-30 Lion Corp Ophthalmic composition
WO2005084635A2 (en) * 2004-03-02 2005-09-15 Institute Of Ophthalmology Pharmaceutical ocular preparations suitable for the treatment of the ocular surface and related disorders/diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 200523, Derwent World Patents Index; AN 2005-218377, XP002414993 *
DATABASE WPI Week 200546, Derwent World Patents Index; AN 2005-450282, XP002414992 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103182075A (en) * 2011-12-30 2013-07-03 沈阳兴齐眼药股份有限公司 Lysozyme preparation, preparation method thereof, and application thereof

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