US20170128484A1 - HyperOsmolar Composition of Hyaluronic Acid - Google Patents

HyperOsmolar Composition of Hyaluronic Acid Download PDF

Info

Publication number: US20170128484A1
Authority: US; United States
Prior art keywords: composition; hyaluronic acid; application; weight; minutes
Prior art date: 2014-04-02
Legal status (The legal status 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 status listed.): Abandoned

Application number

US15/301,045

Other languages

English (en)

Inventor

Jean-François Rouland

Martine Claret

Claude Claret

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Horus Pharma SAS

Original Assignee

Horus Pharma SAS

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.)

2014-04-02

Filing date

2015-04-01

Publication date

2017-05-11

2015-04-01 Application filed by Horus Pharma SAS filed Critical Horus Pharma SAS

2017-01-17 Assigned to HORUS PHARMA reassignment HORUS PHARMA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROULAND, Jean-François, CLARET, CLAUDE, CLARET, MARTINE

2017-05-11 Publication of US20170128484A1 publication Critical patent/US20170128484A1/en

Status Abandoned legal-status Critical Current

Links

239000000203 mixture Substances 0.000 title claims abstract description 104
KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 26
229920002674 hyaluronan Polymers 0.000 title claims abstract description 26
229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 26
230000002727 hyperosmolar Effects 0.000 title claims abstract description 11
206010011033 Corneal oedema Diseases 0.000 claims abstract description 24
201000004778 corneal edema Diseases 0.000 claims abstract description 24
238000011282 treatment Methods 0.000 claims abstract description 22
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 36
238000000034 method Methods 0.000 claims description 26
239000003795 chemical substances by application Substances 0.000 claims description 21
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 18
239000011780 sodium chloride Substances 0.000 claims description 18
WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 12
YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 12
229920002385 Sodium hyaluronate Polymers 0.000 claims description 11
229940010747 sodium hyaluronate Drugs 0.000 claims description 11
229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 10
235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 10
150000003839 salts Chemical class 0.000 claims description 8
239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 7
UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 7
239000001103 potassium chloride Substances 0.000 claims description 6
235000011164 potassium chloride Nutrition 0.000 claims description 6
230000001684 chronic effect Effects 0.000 claims description 4
239000000499 gel Substances 0.000 claims description 4
229920001817 Agar Polymers 0.000 claims description 3
229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
229920002125 Sokalan® Polymers 0.000 claims description 3
239000008272 agar Substances 0.000 claims description 3
239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
239000000243 solution Substances 0.000 description 24
239000003755 preservative agent Substances 0.000 description 10
238000002360 preparation method Methods 0.000 description 7
239000000872 buffer Substances 0.000 description 6
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
238000004090 dissolution Methods 0.000 description 5
WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
238000011109 contamination Methods 0.000 description 4
244000052769 pathogen Species 0.000 description 4
230000002335 preservative effect Effects 0.000 description 4
230000001954 sterilising effect Effects 0.000 description 4
238000003756 stirring Methods 0.000 description 4
230000004304 visual acuity Effects 0.000 description 4
239000000607 artificial tear Substances 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
210000004087 cornea Anatomy 0.000 description 3
230000000694 effects Effects 0.000 description 3
238000001914 filtration Methods 0.000 description 3
238000000265 homogenisation Methods 0.000 description 3
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 3
-1 4 to 6% by weight Chemical compound 0.000 description 2
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 2
206010030113 Oedema Diseases 0.000 description 2
238000001793 Wilcoxon signed-rank test Methods 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
244000052616 bacterial pathogen Species 0.000 description 2
OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
229960002303 citric acid monohydrate Drugs 0.000 description 2
239000000470 constituent Substances 0.000 description 2
230000008595 infiltration Effects 0.000 description 2
238000001764 infiltration Methods 0.000 description 2
239000007788 liquid Substances 0.000 description 2
238000004519 manufacturing process Methods 0.000 description 2
238000004806 packaging method and process Methods 0.000 description 2
239000002504 physiological saline solution Substances 0.000 description 2
229920005862 polyol Polymers 0.000 description 2
150000003077 polyols Chemical class 0.000 description 2
159000000001 potassium salts Chemical class 0.000 description 2
238000004321 preservation Methods 0.000 description 2
QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
239000008213 purified water Substances 0.000 description 2
201000002002 recurrent corneal erosion Diseases 0.000 description 2
159000000000 sodium salts Chemical class 0.000 description 2
238000001356 surgical procedure Methods 0.000 description 2
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
208000003556 Dry Eye Syndromes Diseases 0.000 description 1
206010013774 Dry eye Diseases 0.000 description 1
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
241001465754 Metazoa Species 0.000 description 1
239000013543 active substance Substances 0.000 description 1
230000001476 alcoholic effect Effects 0.000 description 1
150000001409 amidines Chemical class 0.000 description 1
230000003110 anti-inflammatory effect Effects 0.000 description 1
208000010668 atopic eczema Diseases 0.000 description 1
229960000686 benzalkonium chloride Drugs 0.000 description 1
229960001950 benzethonium chloride Drugs 0.000 description 1
UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
229940073464 benzododecinium bromide Drugs 0.000 description 1
KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
150000001735 carboxylic acids Chemical class 0.000 description 1
229960000228 cetalkonium chloride Drugs 0.000 description 1
SXPWTBGAZSPLHA-UHFFFAOYSA-M cetalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SXPWTBGAZSPLHA-UHFFFAOYSA-M 0.000 description 1
229960002798 cetrimide Drugs 0.000 description 1
229960001927 cetylpyridinium chloride Drugs 0.000 description 1
YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
239000002738 chelating agent Substances 0.000 description 1
238000006243 chemical reaction Methods 0.000 description 1
229960004926 chlorobutanol Drugs 0.000 description 1
229960004106 citric acid Drugs 0.000 description 1
230000004453 corneal transparency Effects 0.000 description 1
230000003247 decreasing effect Effects 0.000 description 1
230000003511 endothelial effect Effects 0.000 description 1
230000006353 environmental stress Effects 0.000 description 1
BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
239000012530 fluid Substances 0.000 description 1
238000009472 formulation Methods 0.000 description 1
229940036998 hypertonic sodium chloride Drugs 0.000 description 1
230000036512 infertility Effects 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
230000007794 irritation Effects 0.000 description 1
238000013532 laser treatment Methods 0.000 description 1
238000011866 long-term treatment Methods 0.000 description 1
239000006210 lotion Substances 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
229960002216 methylparaben Drugs 0.000 description 1
239000002674 ointment Substances 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
230000003204 osmotic effect Effects 0.000 description 1
RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 description 1
LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
230000003071 parasitic effect Effects 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
150000002989 phenols Chemical class 0.000 description 1
229940067107 phenylethyl alcohol Drugs 0.000 description 1
PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
229960003415 propylparaben Drugs 0.000 description 1
125000001453 quaternary ammonium group Chemical group 0.000 description 1
239000002994 raw material Substances 0.000 description 1
238000010517 secondary reaction Methods 0.000 description 1
235000010199 sorbic acid Nutrition 0.000 description 1
239000004334 sorbic acid Substances 0.000 description 1
229940075582 sorbic acid Drugs 0.000 description 1
238000011285 therapeutic regimen Methods 0.000 description 1
230000008719 thickening Effects 0.000 description 1
239000002562 thickening agent Substances 0.000 description 1
RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
229960004906 thiomersal Drugs 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
238000002054 transplantation Methods 0.000 description 1
230000002618 waking effect Effects 0.000 description 1
239000008215 water for injection Substances 0.000 description 1
238000005303 weighing Methods 0.000 description 1

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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
- 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
- A61K47/02—Inorganic compounds
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
- 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
- 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
- A61K9/08—Solutions
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents

Definitions

the present invention concerns a novel hyperosmolar composition of hyaluronic acid for use in the treatment of corneal oedema.
Corneal oedema results from an infiltration of liquid in the layers of the cornea. It appears as a thickening of the cornea with a loss of corneal transparency and a lowering of the visual acuity of the subject suffering from this affection.
Common treatments of corneal oedema consist of the topical application of anti-inflammatory and anti-oedematous eye lotions, in particular hypertonic sodium chloride solutions. These treatments, however, which provide temporary relief for corneal oedema subjects, prove to be not very effective for chronic oedemas since they do not prevent new infiltrations of liquid.
Saline compositions comprising hyaluronic acid are known in the state of the art. They are however “artificial tears”, which are isotonic, or very slightly hypertonic, but very close to the osmolarity (isotonicity) of tears.
artificial tears are isotonic, or very slightly hypertonic, but very close to the osmolarity (isotonicity) of tears.
EP 323 522 describes several exemplary compositions identified as artificial tears comprising hyaluronic acid and sodium chloride, with an osmolarity ratio relative to isotonic saline solution of 1 to 1.1. These artificial tears are used to treat dry eye.
WO 2013/043832 also describes an ophthalmic composition for treating recurrent corneal erosion (RCE) comprising, in particular, hyaluronic acid and sodium chloride.
RCE recurrent corneal erosion
This composition is presented as hypertonic, but with an osmotic pressure between 320 to 350 mOsmol/kg, a pressure very close to an isotonic saline solution of the same order as that of the exemplary formulations of application EP 323 522. None of these saline solutions of hyaluronic acid has an osmolarity sufficient to treat corneal oedema, with no one even envisaging the use of hyaluronic acid in a hyperosmolar solution to treat corneal oedema.
the present invention concerns a hyperosmolar ophthalmic composition
a hyperosmolar ophthalmic composition comprising hyaluronic acid or an acceptable salt thereof and a hyperosmolarity agent, the composition having an osmolarity of 650 to 2000 mOsm/l.
the invention also concerns a hyperosmolar ophthalmic composition
a hyperosmolar ophthalmic composition comprising hyaluronic acid or an acceptable salt thereof and a hyperosmolarity agent for use in the treatment of corneal oedema, and more particularly in the treatment of chronic corneal oedema (CCE).
CCE chronic corneal oedema
the object of the present invention is an ophthalmic composition, i.e. a composition intended to be applied to the eye of a human or animal subject, more particularly a human subject. Consequently, the ophthalmic composition must satisfy the specific technical characteristics of ophthalmic compositions, and more particularly those related to the selection of its components. These “ophthalmically acceptable” components must not, individually or combined in the composition, cause secondary reactions of the eye apart from the effect sought by the composition and the active agents thereof.
the eye being an organ which is particularly sensitive to environmental stress, the composition must not cause parasitic irritations or allergic-type reactions to the detriment of the effect sought, more particularly in the case of ophthalmic compositions intended to treat an ophthalmic affection.
the choice of the constituents of the composition is thus very important, which distinguishes the ophthalmic composition from a simple composition unsuited to ophthalmic use.
the person skilled in the art is able to choose said components and to differentiate an ophthalmic composition from a simple composition intended for another use.
the ophthalmic composition preferably has a pH between 6 and 7. It thus usually comprises a buffer suitable for ophthalmic use, known to the person skilled in the art. Particular mention may be made of trisodium citrate dihydrate and citric acid monohydrate employed alone or in mixture.
the ophthalmic composition must also be sterile in order not to introduce pathogens likely to develop and to lead to ophthalmic complications.
sterile is understood, within the meaning of the present invention, to mean the absence of germs within the meaning of the European Pharmacopoeia, 8th Edition (2014).
compositions comprise preservatives for preventing their contamination by germs, such as quaternary ammoniums, particularly benzalkonium chloride, alkyl-dimethyl-benzylammonium, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, cetalkonium chloride, mercurial preservatives, such as phenylmercuric nitrate/acetate/borate, thiomersal, alcoholic preservatives, such as chlorobutanol, benzylic alcohol, phenylethanol, phenylethyl alcohol, carboxylic acids, such as sorbic acid, phenols, particularly methyl/propyl paraben, amidines, for example chlorhexidine digluconate and/or chelating agents such as EDTA alone or in combination with at least one other preservative.
preservatives for preventing their contamination by germs, such as quaternary ammoniums
composition according to the invention is substantially free of such preservatives in order to satisfy a “preservative-free” indication.
Its preservative content is 10 ppm or less, more particularly 1 ppm or less, preferentially equal to 0 ppm, with no preservative in its composition.
a preservative-free ophthalmic composition is distinguished from a simple composition comprising hyaluronic acid obtained without pointing out special precautions or describing the steps of the method making it possible to obtain this sterility characteristic of ophthalmic compositions.
Ophthalmic compositions are generally in the form of solutions, but also in the form of gels or ointments.
the composition according to the invention is preferably a solution applied by placing one or more drops in the eye.
the viscosity of the solution is nevertheless selected so as to allow it to remain on the eye, particularly on the cornea, for a period sufficient to allow it to act.
the ophthalmic composition according to the invention preferably has a viscosity of 15 to 100 centipoises. This viscosity is measured according to the recommendations of the European Pharmacopoeia 2.2.10, with a rotating viscometer, at 25° C., and 100 s ⁇ 1 . Other measuring devices and methods suitable for measuring the viscosity of solutions are known to the person skilled in the art and provide similar results.
the viscosity of the ophthalmic composition according to the invention is due first to the amount of hyaluronic acid present. It is then adapted by adding “ophthalmically acceptable” viscosity agents.
ophthalmically acceptable viscosity agents The person skilled in the art is well familiar with the viscosity agents able to be employed for the preparation of ophthalmic compositions and the amounts to be used to obtain the viscosity sought. Particular mention may be made of hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carbomers, agar gels, polyvinylpyrrolidone and polyvinyl alcohol.
the ophthalmic composition according to the invention comprises hydroxypropylmethylcellulose, preferentially in an amount of 0.05 to 0.5% by weight of hydroxypropylmethylcellulose, advantageously 0.1 to 0.4% by weight, more advantageously 0.2 to 0.3% by weight, particularly about 0.25% by weight.
the composition according to the invention is a hyperosmolar composition.
This hyperosmolarity is defined in relation to a standard value which is that of physiological saline representative of tear fluid.
a “hyperosmolar” composition is also called “hypertonic”.
Physiological saline has an osmolarity value of 300 mOsm/l measured with an osmometer according to the method described in paragraph 2.2.35 of the European Pharmacopoeia.
the ophthalmic composition according to the invention has an osmolarity of 650 to 2000 mOsm/l.
the composition has an osmolarity greater than 1500 mOsm/l, more preferentially between 1600 and 1900 mOsm/l, advantageously about 1750 mOsm/l.
osmolarity agents for ophthalmic use. Particular mention may be made of sodium salts or potassium salts such as sodium chloride and potassium chloride and polyols such as glycerol. These osmolarity agents can be employed alone or in mixture, such as for example a mixture of potassium salts and sodium salts, for example NaCl+KCl, or a mixture of one or more salts and one or more polyols, such as the mixtures NaCl+glycerol, KCl+glycerol, or NaCl+KCl+glycerol. The person skilled in the art knows how to employ these osmolarity agents and the amounts to be employed in order to obtain the desired osmolarity ratio in the ophthalmic composition according to the invention, particularly also according to the viscosity sought.
the osmolarity agent is sodium chloride.
the ophthalmic composition advantageously comprises 2 to 10% by weight of sodium chloride, advantageously 4 to 6% by weight, more advantageously about 5% by weight.
the ophthalmic composition according to the invention comprises hyaluronic acid or a physiologically acceptable salt thereof.
hyaluronic acid is present in the composition in the form of sodium hyaluronate.
the ophthalmic composition according to the invention being a preservative-free composition, it is necessary to treat it during its manufacture so as to avoid and prevent contamination by pathogens. These steps can have negative consequences on the composition, its turbidity or its stability over time.
a hyperosmolar composition of hyaluronic acid preferably preservative-free, it is advantageous to employ hyaluronic acid having an intrinsic viscosity of 1.4 to 1.9 ms/kg.
composition according to the invention preferentially comprises 0.01 to 0.025% by weight of hyaluronic acid, particularly in its sodium hyaluronate form, advantageously 0.1 to 0.2% by weight, particularly about 0.15% by weight.
the composition comprises
the ophthalmic composition comprises
the ophthalmic composition consists of
the invention also concerns a method for manufacturing an ophthalmic composition as defined above and in the examples.
the ophthalmic composition according to the invention combines several difficulties with regard to its preparation since it is a solution which:
composition obtained is preferably packaged in sterile packaging, advantageously in devices suited to its preservation and use.
composition according to the invention is packaged in a suitable device allowing both its preservation protected from contamination by pathogens and the release of a suitable amount of the composition when applied on the eye, preferably in the lower conjunctival sac.
the release is achieved in the form of drops.
the device for packaging and dispensing the composition according to the invention make it possible to release drops weighing between 0.03 and 0.15 g.
the invention also concerns the ophthalmic composition as defined above and in the examples, for use in the treatment of corneal oedema, more particularly for the treatment of chronic corneal oedema (CCE).
CCE chronic corneal oedema
the treatment usually consists in instilling 1 to 2 drops of the composition according to the invention up to 4 times per day, preferably beginning in the morning upon the waking of the subject with corneal oedema, particularly with CCE.
the interval between the applications is between 15 minutes and 3 hours, preferably about 30 minutes, ranging between 1 to 2 hours, on average 90 minutes between each application, more preferentially about 30 minutes.
the treatment comprises a first application in the eye of the subject with corneal oedema, more particularly with CCE, of a suitable dose of the composition followed by a second application of a suitable dose.
the second application can take place 1 with 2 hours after the first application. It can also take place preferably 30 minutes after the first application.
the suitable dose corresponds to 1 or 2 drops of the composition.
the treatment advantageously comprises a third application of a suitable dose, preferably 30 minutes after the second application, ranging up to 1 to 2 hours after the second application, optionally followed by a fourth application of a suitable dose, preferably 30 minutes after the third application, ranging up to 1 to 3 hours after the third application.
the treatment comprises the application in the eye of the subject with corneal oedema, more particularly with CCE, of a suitable dose of the composition repeated at least 3 times per day, preferably 4 times per day, with an interval between the applications between 15 minutes and 3 hours, preferably about 30 minutes, ranging from 1 to 2 hours, on average 90 minutes between each application, more preferentially about 30 minutes.
the first application takes place in the morning when the patient awakens or shortly thereafter.
the invention also concerns a method for treating corneal oedema, particularly chronic corneal oedema, in a subject having corneal oedema, said method consisting in applying in the eye of said subject one or more drops of the composition according to the invention, according to the therapeutic regimens described above.
the present invention concerns a method for treating corneal oedema in a corneal oedema patient, the method comprising the application in the eye of the subject with corneal oedema, more particularly with CCE, of a suitable dose of the composition according to the invention repeated at least 3 times per day, preferably 4 times per day.
the interval between the applications is preferably about 30 minutes, ranging from 1 to 2 hours, on average 90 minutes between each application.
the first application takes place in the morning when the patient awakens or shortly thereafter.
composition is achieved by the instillation of drops, preferably in the lower conjunctival sac of the eye, with the subject looking upward and while pulling the lower lid slightly downward. After the instillation, it is recommended to keep the eye closed for 1 to 2 minutes.
the treatment is advantageously given for a period of at least 2 weeks, ranging up to 4 weeks or more.
the composition according to the invention is particularly suited to a long-term treatment, i.e. ranging up to several months.
An ophthalmic composition comprising the following components is prepared:
composition is prepared according to the following procedure.
HPMC HPMC is added with stirring to heated purified water. The solution is then cooled to room temperature. Trisodium citrate dihydrate is then added with stirring until complete dissolution, then sodium chloride until complete dissolution, then citric acid until complete dissolution.

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US15/301,045 2014-04-02 2015-04-01 HyperOsmolar Composition of Hyaluronic Acid Abandoned US20170128484A1 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
FR1452929		2014-04-02
FR1452929A FR3019465B1 (fr)	2014-04-02	2014-04-02	Composition hyperosmolaire d'acide hyaluronique et son utilisation pour le traitement de l'oedeme corneen
PCT/EP2015/057186 WO2015150459A1 (fr)	2014-04-02	2015-04-01	Composition hyperosmolaire d'acide hyaluronique

Related Parent Applications (1)

Application Number	Title	Priority Date	Filing Date
PCT/EP2015/057186 A-371-Of-International WO2015150459A1 (fr)	2014-04-02	2015-04-01	Composition hyperosmolaire d'acide hyaluronique

Related Child Applications (1)

Application Number	Title	Priority Date	Filing Date
US16/439,804 Continuation US11110116B2 (en)	2014-04-02	2019-06-13	Hyperosmolar composition of hyaluronic acid

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US20170128484A1 true US20170128484A1 (en)	2017-05-11

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Application Number	Title	Priority Date	Filing Date
US15/301,045 Abandoned US20170128484A1 (en)	2014-04-02	2015-04-01	HyperOsmolar Composition of Hyaluronic Acid
US16/439,804 Active US11110116B2 (en)	2014-04-02	2019-06-13	Hyperosmolar composition of hyaluronic acid
US17/467,918 Active 2035-07-11 US11642367B2 (en)	2014-04-02	2021-09-07	Hyperosmolar composition of hyaluronic acid

Family Applications After (2)

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US16/439,804 Active US11110116B2 (en)	2014-04-02	2019-06-13	Hyperosmolar composition of hyaluronic acid
US17/467,918 Active 2035-07-11 US11642367B2 (en)	2014-04-02	2021-09-07	Hyperosmolar composition of hyaluronic acid

Country Status (11)

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US (3)	US20170128484A1 (da)
EP (2)	EP3998062A1 (da)
JP (1)	JP6770436B2 (da)
CA (1)	CA2960884C (da)
DK (1)	DK3125867T3 (da)
ES (1)	ES2899759T3 (da)
FR (1)	FR3019465B1 (da)
MX (1)	MX376191B (da)
PL (1)	PL3125867T3 (da)
PT (1)	PT3125867T (da)
WO (1)	WO2015150459A1 (da)

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IT201800010796A1 (it)	2018-12-04	2020-06-04	Vincenzo Orfeo	Unguenti oftalmici ipertonici stabili contenenti una fase idrofila satura di sodio cloruro
EP3970751A1 (en)	2020-09-22	2022-03-23	Omnivision GmbH	Ophthalmic composition for the treatment of corneal edema
EP4667000A1 (en)	2024-06-17	2025-12-24	Omnivision GmbH	Hyperosmolar ophthalmic composition comprising carboxymethyl chitosan

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JP6785797B2 (ja)	2015-05-21	2020-11-18	オフタルミモナコＯｐｈｔａｌｍｉｓＭｏｎａｃｏ	リポ酸および粘膜模倣ポリマーを含んでなる眼科用組成物
CA2985013C (fr)	2015-05-21	2024-04-16	Ophtalmis Monaco	Association d'acide lipoique et de taurine en tant qu'agent osmoprotecteur

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2014
- 2014-04-02 FR FR1452929A patent/FR3019465B1/fr active Active
2015
- 2015-04-01 JP JP2016560353A patent/JP6770436B2/ja active Active
- 2015-04-01 EP EP21196652.8A patent/EP3998062A1/fr not_active Withdrawn
- 2015-04-01 MX MX2016012758A patent/MX376191B/es active IP Right Grant
- 2015-04-01 US US15/301,045 patent/US20170128484A1/en not_active Abandoned
- 2015-04-01 ES ES15723135T patent/ES2899759T3/es active Active
- 2015-04-01 CA CA2960884A patent/CA2960884C/fr active Active
- 2015-04-01 DK DK15723135.8T patent/DK3125867T3/da active
- 2015-04-01 PL PL15723135T patent/PL3125867T3/pl unknown
- 2015-04-01 EP EP15723135.8A patent/EP3125867B1/fr active Active
- 2015-04-01 WO PCT/EP2015/057186 patent/WO2015150459A1/fr not_active Ceased
- 2015-04-01 PT PT157231358T patent/PT3125867T/pt unknown
2019
- 2019-06-13 US US16/439,804 patent/US11110116B2/en active Active
2021
- 2021-09-07 US US17/467,918 patent/US11642367B2/en active Active

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IT201800010796A1 (it)	2018-12-04	2020-06-04	Vincenzo Orfeo	Unguenti oftalmici ipertonici stabili contenenti una fase idrofila satura di sodio cloruro
WO2020114875A1 (en)	2018-12-04	2020-06-11	Orfeo Vincenzo	Hypertonic ophthalmic ointment
EP3970751A1 (en)	2020-09-22	2022-03-23	Omnivision GmbH	Ophthalmic composition for the treatment of corneal edema
WO2022063765A1 (en)	2020-09-22	2022-03-31	Omnivision Gmbh	Ophthalmic composition for the treatment of corneal edema
EP4667000A1 (en)	2024-06-17	2025-12-24	Omnivision GmbH	Hyperosmolar ophthalmic composition comprising carboxymethyl chitosan

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Publication number	Publication date
US20210401872A1 (en)	2021-12-30
US11642367B2 (en)	2023-05-09
ES2899759T3 (es)	2022-03-14
PT3125867T (pt)	2021-12-02
CA2960884A1 (fr)	2015-10-08
WO2015150459A1 (fr)	2015-10-08
FR3019465A1 (fr)	2015-10-09
JP2017509668A (ja)	2017-04-06
MX376191B (es)	2025-03-07
US11110116B2 (en)	2021-09-07
PL3125867T3 (pl)	2022-03-21
EP3998062A1 (fr)	2022-05-18
DK3125867T3 (da)	2021-12-06
CA2960884C (fr)	2023-08-15
EP3125867A1 (fr)	2017-02-08
FR3019465B1 (fr)	2017-06-23
JP6770436B2 (ja)	2020-10-14
MX2016012758A (es)	2017-04-27
EP3125867B1 (fr)	2021-09-15
US20190307789A1 (en)	2019-10-10

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