WO2002074281A1 - Ophthalmic compositions and use thereof - Google Patents
Ophthalmic compositions and use thereof Download PDFInfo
- Publication number
- WO2002074281A1 WO2002074281A1 PCT/EP2002/002873 EP0202873W WO02074281A1 WO 2002074281 A1 WO2002074281 A1 WO 2002074281A1 EP 0202873 W EP0202873 W EP 0202873W WO 02074281 A1 WO02074281 A1 WO 02074281A1
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- WIPO (PCT)
- Prior art keywords
- ophthalmic
- zwitterionic phospholipid
- sub
- concentration
- nsaid
- Prior art date
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
Definitions
- the present invention is related to the use of non-steroidal antiinflammatory drugs by noncovalent association with zwitterionic phospholipids, and optionally neutral lipids, such as the triglycerides, in the preparation of a medicament for the treatment of an ocular inflammation.
- the present invention illustrates the ability of one or more zwitterionic phospholipids to enhance the anti-inflammatory potential of an NSAID.
- Pharmacological activity of low dose NSA1D to reduce inflammation and pain may also be observed, and in some cases enhanced by chemically associating the NSAID with zwitterionic phospholipid, such as phosphatidyl choline (PC), dipalmitoylphosphatidylcholine (DPPC), and other disaturated phosphatidyl cholines, and the like, preferably the association of NSAID and zwitterionic phospholipid is of an non-covalent nature.
- the NSAID and zwitterionic phospholipid compositions may be further described as including more or less equimolar amounts of these ingredients.
- the present invention provides in one aspect a method for enhancing the ocular pharmacological efficacy of a nonsteroidal anti-inflammatory drug (NSAID).
- This method comprises providing a non-covalently associated combination of a zwitterionic phospholipid with an amount of a nonsteroidal anti-inflammatory drug that provides a reduced pharmacological activity in the absence of said zwitterionic phospholipid.
- zwitterionic phospholipid embraces a wide range of phospholipids including but not limited to phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, spingomyelin and other ceramides, as well as various other zwitterionic phospholipids.
- the amount of nonsteroial anti-inflammatory drug is defined as an amount that provides reduced pharmacological efficacy in the absence of the zwitterionic phospholipid. This efficacy or lack of efficacy is observed in the absence of the zwitterionic phospholipid while the same or about the same amount of the NSAID does demonstrate pharmacological efficacy in the presence of zwitterionic phospholipid. In this regard the phenomenon is observed that the combination of low amounts of nonsteroidal anti-inflammatory drugs with phospholipid have potent pharmacological efficacy while doses of the drug alone (i.e. without zwitterionic phospholipid) do not.
- NSAID may include any variety of those drugs generally classified as nonsteroidal anti-inflammatory drugs.
- NSAID include cyclooxygenase-inhibitors
- a preferred class of compounds is cyclo-oxygenase-2 inhibitors (COX-2).
- NSAID include ibuprofen, piroxicam, salicylate, aspirin, naproxen, indomethacin, 5-methyl-2-(2'-chloro-6'-fluoroanilino) phenyl acetic acid, diclofenac or any pharmaceutically acceptable salt and/or any mixture thereof.
- a preferred example is selected from diclofenac sodium and 5-methyl-2-(2'-chloro-6'- fluoroanilino) phenyl acetic acid.
- VLA-4-inhibitors include for example compounds as being disclosed in WO 99/37605, and in particular compounds of formula Ic:
- R a is H, CH 3 , Cl or NH 2 ;
- R 2 is (CH 2 ) 3 OCH 3 or (CH 2 ) 4 OCH 3 ;
- Another preferred NSAID is selected from a VLA-4 inhibitor and is shown infra, wherein the variables in formula Ic denote: R a is methyl, T is NH, R 2 is (CH 2 ) 3 OCH 3 , and R is 3,4- dimethoxyphenyl:
- a preferred zwitterionic phospholipid in an addressed composition is dipalmitoyl phosphatidylcholine, phosphatidyl choline or a mixture thereof.
- compositions are expected to be particularly efficacious in reducing e.g. an inflammation and/or improving the tolerance of an addressed NSAID.
- a sub-therapeutically effective amount of NSAID is defined as an amount that provides reduced pharmacological efficacy in the absence of a zwitterionic phospholipid.
- the sub-therapeutically effective amount of an NSAID is typically from 0.005 wt. % - 0.1 wt. %, preferably in the range from 0.01 wt. % - 0.05 wt. %.
- the amount of zwitterionic phospholipid is typically from 5 - 100 times the concentration of an NSAID, preferably from 10 - 50 times the concentration of a NSAID, and in particular from 15 - 30 times the concentration of an NSAID in wt. % of the total amount of an addressed composition.
- a particular preferred concentration is 25 times the concentration of an NSAID.
- the term "sub-therapeutically effective amount" is defined as an amount of the NSAID that provides reduced pharmacological (i.e. anti-inflammatory) efficacy in the absence of non-covalent association with a zwitterionic phospholipid. Accordingly, in one aspect the invention is related to the use of a topical ophthalmic composition for the preparation of an eye medicament for the treatment of an ocular inflammation, which ophthalmic composition comprises
- Ophthalmic compositions as used in the context of the present invention are either so-called unpreserved single dose compositions, or alternatively so-called preserved multi dose compositions.
- the multi dose compositions contain a preservative being compatible with the ocular tissue.
- a preservative is typically a quaternary ammonium salt, and in particular benzalkonium chloride.
- the amount of preservative needed in a multi dose composition of the present invention can significantly be reduced as compared to a composition not containing a zwitterionic phospholipid.
- a synergistically increased efficacy and tolerability of a corresponding ophthalmic composition will result.
- quaternary ammonium salts useful in eye medicaments for preservation are in contrast with the large number of known quaternary ammonium salts ("quats") which are employed for preservation in other fields. This is clearly restricted by the ocular tolerability of an addressed preservative. Accordingly in the present invention quaternary ammonium salts with excellent ocular tolerability are highly preferred.
- the quaternary ammonium salts useful in accordance with the present invention may be selected from a wide variety of especially ophthalmically acceptable salts and are in particular selected from sepazonium chloride, cetyltrimethylammonium bromide (cetrimide), cetylpyridinium chloride, benzoxonium chloride, benzethonium chloride, domiphen bromide (Bradosol ® ) and benzalkonium chloride
- a further aspect of the invention is a method of increasing the ocular tolerability in a preserved and/or unpreserved ophthalmic composition, which composition comprises:
- Still a further aspect relates to a method of treating an ocular inflammation in a subject in need of anti-inflammatory treatment, which method comprises the topical administration of an eye medicament comprising:
- ophthalmic carriers are for example water, mixtures of water and water- miscible solvents, such as C to C 7 -alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% by weight hydroxyethylcellulose, ethyl oleate, carboxymethyl-cellulose, polyvinyl- pyrrolidone and other non-toxic water-soluble polymers for ophthalmic uses, such as, for example, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxy- methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropyl- cellulose and hydroxypropylcellulose, acrylates or methacrylates, such as salts of polyacrylic acid or ethyl acrylate, polyacrylamides, natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such
- Preferred carriers are water, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, neutral Carbopol, or mixtures thereof.
- concentration of an ophthalmic carrier is, for example, from 1 to 100000 times the concentration of the active ingredient.
- Buffers, tonicity enhancing agents and preservatives different from quaternary ammonium salts may be used in an ophthalmic composition of the present invention as well.
- buffer substances are acetate, ascorbate, borate, hydrogen carbonate /carbonate, citrate, gluconate, lactate, phosphate, propionate and TRIS (tromethamine) buffers.
- Tromethamine and borate buffer are preferred buffers.
- the amount of buffer substance added is, for example, that necessary to ensure and maintain a physiologically tolerable pH range.
- the pH range is typically in the range of from 5 to 9, preferably from 6 to 8.5 and more preferably from 6.5 to 8.2.
- Tonicity enhancing agents are, for example, ionic compounds, such as alkali metal or alkaline earth metal halides, such as, for example, CaCI 2) KBr, KCI, LiCI, Nal, NaBr or NaCI, or boric acid.
- Non-ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose.
- sufficient tonicity enhancing agent is added to impart to the ready-for-use ophthalmic composition an osmolality of approximately from 50 to 1000 mOsmol, preferred from 100 to 400 mOsmol, more preferred from 200 to 400 mOsmol and even more preferred from 250 to 350 mOsmol.
- compositions of the above-described methods may further include a neutral lipid, such as a triglyceride.
- a neutral lipid such as a triglyceride.
- saturated and unsaturated triglycerides may be employed in the present compositions, and include such triglycerides as tripalmitin (saturated) triolein and trilinolein (unsaturated).
- tripalmitin saturated
- triolein trilinolein
- these particular triglycerides are listed here for convenience only, and are merely representative of a variety of useful triglycerides, and is further not intended to be of limiting character.
- the amount of a neutral lipid is typically from 5 - 100 times the concentration of an NSAID, preferably from 10 - 50 times the concentration of a NSAID, and in particular from 15 - 30 times the concentration of an NSAID in wt. % of the total amount of an addressed composition.
- a particular preferred concentration is 25 times the concentration of an NSAID.
- the invention also pertains to the use of a topical ophthalmic composition for the preparation of an eye medicament for the treatment of an ocular inflammation, which ophthalmic composition comprises
- composition comprises:
Abstract
The present invention is related to the use of non-steroidal antiinflammatory drugs by noncovalent association with zwitterionic phospholipids, and optionally neutral lipids, such as the triglycerides, in the preparation of a medicament for the treatment of an ocular inflammation.
Description
Ophthalmic Compositions and Use Thereof
The present invention is related to the use of non-steroidal antiinflammatory drugs by noncovalent association with zwitterionic phospholipids, and optionally neutral lipids, such as the triglycerides, in the preparation of a medicament for the treatment of an ocular inflammation.
The present invention illustrates the ability of one or more zwitterionic phospholipids to enhance the anti-inflammatory potential of an NSAID. Pharmacological activity of low dose NSA1D to reduce inflammation and pain may also be observed, and in some cases enhanced by chemically associating the NSAID with zwitterionic phospholipid, such as phosphatidyl choline (PC), dipalmitoylphosphatidylcholine (DPPC), and other disaturated phosphatidyl cholines, and the like, preferably the association of NSAID and zwitterionic phospholipid is of an non-covalent nature. In addition the NSAID and zwitterionic phospholipid compositions may be further described as including more or less equimolar amounts of these ingredients.
Accordingly, the present invention provides in one aspect a method for enhancing the ocular pharmacological efficacy of a nonsteroidal anti-inflammatory drug (NSAID). This method comprises providing a non-covalently associated combination of a zwitterionic phospholipid with an amount of a nonsteroidal anti-inflammatory drug that provides a reduced pharmacological activity in the absence of said zwitterionic phospholipid.
As used in within the terms of the present invention, the term zwitterionic phospholipid embraces a wide range of phospholipids including but not limited to phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, spingomyelin and other ceramides, as well as various other zwitterionic phospholipids.
The amount of nonsteroial anti-inflammatory drug is defined as an amount that provides reduced pharmacological efficacy in the absence of the zwitterionic phospholipid. This efficacy or lack of efficacy is observed in the absence of the zwitterionic phospholipid while the same or about the same amount of the NSAID does demonstrate pharmacological efficacy in the presence of zwitterionic phospholipid. In this regard the phenomenon is observed that the combination of low amounts of nonsteroidal anti-inflammatory drugs with
phospholipid have potent pharmacological efficacy while doses of the drug alone (i.e. without zwitterionic phospholipid) do not.
As used herein, NSAID may include any variety of those drugs generally classified as nonsteroidal anti-inflammatory drugs. In particular, NSAID include cyclooxygenase-inhibitors
(COX), VLA-4-inhibitors and the like.
A preferred class of compounds is cyclo-oxygenase-2 inhibitors (COX-2).
By way of example a NSAID include ibuprofen, piroxicam, salicylate, aspirin, naproxen, indomethacin, 5-methyl-2-(2'-chloro-6'-fluoroanilino) phenyl acetic acid, diclofenac or any pharmaceutically acceptable salt and/or any mixture thereof.
A preferred example is selected from diclofenac sodium and 5-methyl-2-(2'-chloro-6'- fluoroanilino) phenyl acetic acid.
As used herein, VLA-4-inhibitors include for example compounds as being disclosed in WO 99/37605, and in particular compounds of formula Ic:
wherein
Ra is H, CH3, Cl or NH2; R2 is (CH2)3OCH3or (CH2)4OCH3;
R4 is -(CH)=(CH)-CH3, phenyl, 4-methoxyphenyl, or 3,4-dimethoxyphenyl; and T is NH or CH2; or a pharmaceutically acceptable salt thereof.
Another preferred NSAID is selected from a VLA-4 inhibitor and is shown infra, wherein the variables in formula Ic denote: Ra is methyl, T is NH, R2 is (CH2)3OCH3, and R is 3,4- dimethoxyphenyl:
As used herein, a preferred zwitterionic phospholipid in an addressed composition is dipalmitoyl phosphatidylcholine, phosphatidyl choline or a mixture thereof.
The pharmacological, particularly anti-inflammatory efficacy of a NSAID is shown to be enhanced several fold over preparations with similar doses without zwitterionic phospholipid. Surprisingly, the combination of a afore-described nonsteroidal anti-inflammatory drug with zwitterionic phospholipid dramatically enhances the anti-inflammatory efficacy and potency of the drug, even at sub-therapeutically active doses and in some cases from about 2-fold to about 6-fold relative to non-phospholipid containing preparations. Hence, the compositions are expected to be particularly efficacious in reducing e.g. an inflammation and/or improving the tolerance of an addressed NSAID.
As used herein, a sub-therapeutically effective amount of NSAID is defined as an amount that provides reduced pharmacological efficacy in the absence of a zwitterionic phospholipid. The sub-therapeutically effective amount of an NSAID is typically from 0.005 wt. % - 0.1 wt. %, preferably in the range from 0.01 wt. % - 0.05 wt. %.
As used herein, the amount of zwitterionic phospholipid is typically from 5 - 100 times the concentration of an NSAID, preferably from 10 - 50 times the concentration of a NSAID, and in particular from 15 - 30 times the concentration of an NSAID in wt. % of the total amount of an addressed composition. A particular preferred concentration is 25 times the concentration of an NSAID.
As used in the description of the present invention, the term "sub-therapeutically effective amount" , particularly as it is used to describe the amount of NSAID employed, is defined as an amount of the NSAID that provides reduced pharmacological (i.e. anti-inflammatory) efficacy in the absence of non-covalent association with a zwitterionic phospholipid.
Accordingly, in one aspect the invention is related to the use of a topical ophthalmic composition for the preparation of an eye medicament for the treatment of an ocular inflammation, which ophthalmic composition comprises
- a non-steroidal anti-inflammatory drug in a sub-therapeutical concentration
- a zwitterionic phospholipid, and
- an ophthalmic carrier.
Ophthalmic compositions as used in the context of the present invention are either so-called unpreserved single dose compositions, or alternatively so-called preserved multi dose compositions. The multi dose compositions contain a preservative being compatible with the ocular tissue. Such a preservative is typically a quaternary ammonium salt, and in particular benzalkonium chloride. In analogy to the above, it was surprisingly found that the amount of preservative needed in a multi dose composition of the present invention can significantly be reduced as compared to a composition not containing a zwitterionic phospholipid. In conclusion, a synergistically increased efficacy and tolerability of a corresponding ophthalmic composition will result.
The very small number of quaternary ammonium salts useful in eye medicaments for preservation is in contrast with the large number of known quaternary ammonium salts ("quats") which are employed for preservation in other fields. This is clearly restricted by the ocular tolerability of an addressed preservative. Accordingly in the present invention quaternary ammonium salts with excellent ocular tolerability are highly preferred.
The quaternary ammonium salts useful in accordance with the present invention may be selected from a wide variety of especially ophthalmically acceptable salts and are in particular selected from sepazonium chloride, cetyltrimethylammonium bromide (cetrimide), cetylpyridinium chloride, benzoxonium chloride, benzethonium chloride, domiphen bromide (Bradosol®) and benzalkonium chloride
A further aspect of the invention is a method of increasing the ocular tolerability in a preserved and/or unpreserved ophthalmic composition, which composition comprises:
- a non-steroidal anti-inflammatory drug in a sub-therapeutical concentration
- a zwitterionic phospholipid,
- an ophthalmic carrier, and optionally
- a preservative.
Still a further aspect relates to a method of treating an ocular inflammation in a subject in need of anti-inflammatory treatment, which method comprises the topical administration of an eye medicament comprising:
- a non-steroidal anti-inflammatory drug in a sub-therapeutical concentration
- a zwitterionic phospholipid, and
- an ophthalmic carrier.
As used herein ophthalmic carriers are for example water, mixtures of water and water- miscible solvents, such as C to C7-alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% by weight hydroxyethylcellulose, ethyl oleate, carboxymethyl-cellulose, polyvinyl- pyrrolidone and other non-toxic water-soluble polymers for ophthalmic uses, such as, for example, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxy- methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropyl- cellulose and hydroxypropylcellulose, acrylates or methacrylates, such as salts of polyacrylic acid or ethyl acrylate, polyacrylamides, natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products, such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid, such as neutral Carbopol, or mixtures of those polymers. Preferred carriers are water, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, neutral Carbopol, or mixtures thereof. The concentration of an ophthalmic carrier is, for example, from 1 to 100000 times the concentration of the active ingredient.
Buffers, tonicity enhancing agents and preservatives different from quaternary ammonium salts may be used in an ophthalmic composition of the present invention as well.
Examples of buffer substances are acetate, ascorbate, borate, hydrogen carbonate /carbonate, citrate, gluconate, lactate, phosphate, propionate and TRIS (tromethamine) buffers. Tromethamine and borate buffer are preferred buffers. The amount of buffer
substance added is, for example, that necessary to ensure and maintain a physiologically tolerable pH range. The pH range is typically in the range of from 5 to 9, preferably from 6 to 8.5 and more preferably from 6.5 to 8.2.
Tonicity enhancing agents are, for example, ionic compounds, such as alkali metal or alkaline earth metal halides, such as, for example, CaCI2) KBr, KCI, LiCI, Nal, NaBr or NaCI, or boric acid. Non-ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose. For example, sufficient tonicity enhancing agent is added to impart to the ready-for-use ophthalmic composition an osmolality of approximately from 50 to 1000 mOsmol, preferred from 100 to 400 mOsmol, more preferred from 200 to 400 mOsmol and even more preferred from 250 to 350 mOsmol.
The compositions of the above-described methods may further include a neutral lipid, such as a triglyceride. Both saturated and unsaturated triglycerides may be employed in the present compositions, and include such triglycerides as tripalmitin (saturated) triolein and trilinolein (unsaturated). However, these particular triglycerides are listed here for convenience only, and are merely representative of a variety of useful triglycerides, and is further not intended to be of limiting character.
As used herein, the amount of a neutral lipid is typically from 5 - 100 times the concentration of an NSAID, preferably from 10 - 50 times the concentration of a NSAID, and in particular from 15 - 30 times the concentration of an NSAID in wt. % of the total amount of an addressed composition. A particular preferred concentration is 25 times the concentration of an NSAID.
Accordingly, the invention also pertains to the use of a topical ophthalmic composition for the preparation of an eye medicament for the treatment of an ocular inflammation, which ophthalmic composition comprises
- a non-steroidal anti-inflammatory drug in a sub-therapeutical concentration
- a zwitterionic phospholipid,
- a neutral lipid, optionally a preservative and
- an ophthalmic carrier.
It further relates to a method of increasing the ocular tolerability in a preserved and/or unpreserved ophthalmic composition, which composition comprises:
- a non-steroidal anti-inflammatory drug in a sub-therapeutical concentration
- a zwitterionic phospholipid,
- a neutral lipid,
- an ophthalmic carrier, and optionally
- a preservative.
Claims
1. Use of a of a topical ophthalmic composition for the preparation of an eye medicament for the treatment of an ocular inflammation, which ophthalmic composition comprises
- a non-steroidal anti-inflammatory drug in a sub-therapeutical concentration
- a zwitterionic phospholipid, and
- an ophthalmic carrier.
2. Use of claim 1 , wherein said composition further contains a preservative.
3. Use of claim 1 , wherein said zwitterionic phospholipid is selected from dipalmitoyl phosphatidylcholine, phosphatidyl choline and a mixture thereof.
4. Use of claim 1 , wherein said non-steroidal anti-inflammatory drug is a COX-2 inhibitor.
5. Use of claim 1 , wherein said non-steroidal anti-inflammatory drug is selected from diclofenac sodium and dexketoprofen trometamol, and preferably diclofenac sodium.
6. Use of claim 1 , wherein said sub-therapeutical concentration is in the range of from 0.005 wt. % - 0.1 wt. %, preferably in the range from 0.01 wt. % - 0.05 wt. %.
7. Method of increasing the ocular tolerability in a preserved and/or unpreserved ophthalmic composition, which composition comprises:
- a non-steroidal anti-inflammatory drug in a sub-therapeutical concentration
- a zwitterionic phospholipid,
- an ophthalmic carrier, and optionally
- a preservative.
8. Method of treating an ocular inflammation in a subject in need of anti-inflammatory treatment, which method comprises the topical administration of an eye medicament, which medicament comprises:
- a non-steroidal anti-inflammatory drug in a sub-therapeutical concentration
- a zwitterionic phospholipid, and - an ophthalmic carrier.
9. Method of claim 7-8 wherein said drug is a COX-2 inhibitor.
10. Method of claims 7-9, wherein said drug is diclofenac sodium.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01106548.9 | 2001-03-15 | ||
| EP01106548 | 2001-03-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2002074281A1 true WO2002074281A1 (en) | 2002-09-26 |
Family
ID=8176799
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2002/002873 WO2002074281A1 (en) | 2001-03-15 | 2002-03-14 | Ophthalmic compositions and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2002074281A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990011781A1 (en) * | 1989-04-04 | 1990-10-18 | Alcon Laboratories, Inc. | The use of liposomes for the delivery of therapeutic agents to wounds, cuts and abrasions |
| JPH05331048A (en) * | 1992-05-28 | 1993-12-14 | Pola Chem Ind Inc | Antiphlogistic and analgesic medicine for external use |
| JPH05331050A (en) * | 1992-05-27 | 1993-12-14 | Pola Chem Ind Inc | Antiphlogistic and analgesic medicine for external use |
| WO1994005298A1 (en) * | 1992-08-28 | 1994-03-17 | Pharmos Corporation | Submicron emulsions as ocular drug delivery vehicles |
| US5955451A (en) * | 1995-05-12 | 1999-09-21 | The University Of Texas System Board Of Regents | Methods of enhancing the therapeutic activity of NSAIDS and compositions of zwitterionic phospholipids useful therein |
-
2002
- 2002-03-14 WO PCT/EP2002/002873 patent/WO2002074281A1/en not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990011781A1 (en) * | 1989-04-04 | 1990-10-18 | Alcon Laboratories, Inc. | The use of liposomes for the delivery of therapeutic agents to wounds, cuts and abrasions |
| JPH05331050A (en) * | 1992-05-27 | 1993-12-14 | Pola Chem Ind Inc | Antiphlogistic and analgesic medicine for external use |
| JPH05331048A (en) * | 1992-05-28 | 1993-12-14 | Pola Chem Ind Inc | Antiphlogistic and analgesic medicine for external use |
| WO1994005298A1 (en) * | 1992-08-28 | 1994-03-17 | Pharmos Corporation | Submicron emulsions as ocular drug delivery vehicles |
| US5955451A (en) * | 1995-05-12 | 1999-09-21 | The University Of Texas System Board Of Regents | Methods of enhancing the therapeutic activity of NSAIDS and compositions of zwitterionic phospholipids useful therein |
Non-Patent Citations (2)
| Title |
|---|
| DATABASE WPI Section Ch Week 199403, Derwent World Patents Index; Class B05, AN 1994-022817, XP002065029 * |
| PATENT ABSTRACTS OF JAPAN vol. 018, no. 163 (C - 1181) 18 March 1994 (1994-03-18) * |
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