HRP20191732T1 - Terapijska modulacija lubrikacije okularne površine - Google Patents
Terapijska modulacija lubrikacije okularne površine Download PDFInfo
- Publication number
- HRP20191732T1 HRP20191732T1 HRP20191732T HRP20191732T1 HR P20191732 T1 HRP20191732 T1 HR P20191732T1 HR P20191732 T HRP20191732 T HR P20191732T HR P20191732 T1 HRP20191732 T1 HR P20191732T1
- Authority
- HR
- Croatia
- Prior art keywords
- pharmaceutical composition
- use according
- prg4
- group
- androgen
- Prior art date
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- 238000005461 lubrication Methods 0.000 title claims 6
- 230000001225 therapeutic effect Effects 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 15
- 101001123332 Homo sapiens Proteoglycan 4 Proteins 0.000 claims 9
- 102100028965 Proteoglycan 4 Human genes 0.000 claims 9
- 239000003098 androgen Substances 0.000 claims 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 4
- 239000000203 mixture Substances 0.000 claims 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- 150000001875 compounds Chemical class 0.000 claims 3
- 230000001965 increasing effect Effects 0.000 claims 3
- 239000000849 selective androgen receptor modulator Substances 0.000 claims 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 2
- 229940083324 Selective androgen receptor modulator Drugs 0.000 claims 2
- 229920002125 Sokalan® Polymers 0.000 claims 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 239000003974 emollient agent Substances 0.000 claims 2
- 239000012634 fragment Substances 0.000 claims 2
- 230000001939 inductive effect Effects 0.000 claims 2
- 230000014759 maintenance of location Effects 0.000 claims 2
- 239000011780 sodium chloride Substances 0.000 claims 2
- YVXVTLGIDOACBJ-SFHVURJKSA-N (2S)-3-(4-acetamidophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide Chemical compound C1=CC(NC(=O)C)=CC=C1OC[C@](C)(O)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 YVXVTLGIDOACBJ-SFHVURJKSA-N 0.000 claims 1
- 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 compound 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 claims 1
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims 1
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 claims 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims 1
- 206010002261 Androgen deficiency Diseases 0.000 claims 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims 1
- 229920002307 Dextran Polymers 0.000 claims 1
- 206010013774 Dry eye Diseases 0.000 claims 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims 1
- 206010020751 Hypersensitivity Diseases 0.000 claims 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 claims 1
- QSLJIVKCVHQPLV-PEMPUTJUSA-N Oxandrin Chemical compound C([C@@H]1CC2)C(=O)OC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@](C)(O)[C@@]2(C)CC1 QSLJIVKCVHQPLV-PEMPUTJUSA-N 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 108091005804 Peptidases Proteins 0.000 claims 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims 1
- 229920000148 Polycarbophil calcium Polymers 0.000 claims 1
- 239000004365 Protease Substances 0.000 claims 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 1
- 208000021386 Sjogren Syndrome Diseases 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 229920002385 Sodium hyaluronate Polymers 0.000 claims 1
- 230000032683 aging Effects 0.000 claims 1
- 230000007815 allergy Effects 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 229940030486 androgens Drugs 0.000 claims 1
- 239000003212 astringent agent Substances 0.000 claims 1
- 239000003855 balanced salt solution Substances 0.000 claims 1
- 239000008366 buffered solution Substances 0.000 claims 1
- 239000001110 calcium chloride Substances 0.000 claims 1
- 229910001628 calcium chloride Inorganic materials 0.000 claims 1
- 229960001631 carbomer Drugs 0.000 claims 1
- 239000001768 carboxy methyl cellulose Substances 0.000 claims 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims 1
- 208000037976 chronic inflammation Diseases 0.000 claims 1
- 230000006020 chronic inflammation Effects 0.000 claims 1
- 229920001577 copolymer Polymers 0.000 claims 1
- 230000007812 deficiency Effects 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 239000003792 electrolyte Substances 0.000 claims 1
- 239000000262 estrogen Substances 0.000 claims 1
- 229940011871 estrogen Drugs 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 229920002674 hyaluronan Polymers 0.000 claims 1
- 229960003160 hyaluronic acid Drugs 0.000 claims 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims 1
- 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 1
- 229910001629 magnesium chloride Inorganic materials 0.000 claims 1
- 210000004175 meibomian gland Anatomy 0.000 claims 1
- 229960004719 nandrolone Drugs 0.000 claims 1
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims 1
- 150000003904 phospholipids Chemical class 0.000 claims 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims 1
- 229920002401 polyacrylamide Polymers 0.000 claims 1
- 229950005134 polycarbophil Drugs 0.000 claims 1
- 239000004926 polymethyl methacrylate Substances 0.000 claims 1
- 229920001184 polypeptide Polymers 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 239000001103 potassium chloride Substances 0.000 claims 1
- 235000011164 potassium chloride Nutrition 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- 102000004196 processed proteins & peptides Human genes 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims 1
- 229940080818 propionamide Drugs 0.000 claims 1
- 239000000661 sodium alginate Substances 0.000 claims 1
- 235000010413 sodium alginate Nutrition 0.000 claims 1
- 229940005550 sodium alginate Drugs 0.000 claims 1
- 239000001509 sodium citrate Substances 0.000 claims 1
- 229940010747 sodium hyaluronate Drugs 0.000 claims 1
- 239000001488 sodium phosphate Substances 0.000 claims 1
- 229910000162 sodium phosphate Inorganic materials 0.000 claims 1
- 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 1
- 238000001356 surgical procedure Methods 0.000 claims 1
- 208000024891 symptom Diseases 0.000 claims 1
- 229960003604 testosterone Drugs 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 238000011200 topical administration Methods 0.000 claims 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims 1
- 229940038773 trisodium citrate Drugs 0.000 claims 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims 1
- 239000005526 vasoconstrictor agent Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
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- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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- 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
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Ophthalmology & Optometry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Dermatology (AREA)
- Marine Sciences & Fisheries (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Inorganic Chemistry (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
- Eyeglasses (AREA)
- Materials For Medical Uses (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Claims (15)
1. Farmaceutska kompozicija za primjenu u liječenju nedostatka okularne lubrikacije ili simptoma udruženih sa njim koja sadrži PRG4 ili njegov fragment za lubrikaciju u kombinaciji sa terapijski efikasnom koncentracijom PRG4-inducirajućeg spoja odabranog iz grupe koja se sastoji od androgena, selektivnog modulatora receptora androgena, i analoga androgena, pri čemu navedeni analog androgena je odabran iz grupe koja se sastoji od 17α-metil-17β-hidroksi-2-oksa-5α-androstan-3-ona, 4,5α-dihidrotestosterona, i 19-nortestosterona, pri čemu navedeno liječenje obuhvaća topikalnu administraciju navedenog spoja na okularnu površinu.
2. Farmaceutska kompozicija za primjenu prema patentnom zahtjevu 1, pri čemu nedostatak okularne lubrikacije je neželjena okularna granična lubrikacija koja nastaje od bolesti suhog oka uslijed nedostatka vodenog filma ili isparavanja, Sjögren-ovog sindroma, keratoconjunctivitis sicca, nedostatka androgena, bolesti meibomian žlijezda, zamjenske terapije estrogena, nošenja kontaktnih leća, refraktivne operacije, smanjenog vremena prekida suznog filma, alergije, poremećaja okularne površine, povećanih nivoa proteaze u suznom filmu i na okularnoj površini, kronične inflamacije, hiperosmolarnosti ili starenja.
3. Farmaceutska kompozicija za primjenu prema patentnom zahtjevu 1, pri čemu selektivni modulator receptora androgena je odabran iz grupe koja se sastoji od aril-propionamidskog spoja odabranog iz grupe koja se sastoji od S-3-(4-acetilamino-fenoksi)-2-hidroksi-2-metil-N-(4-nitro-3-trifluorometil-fenil)-propionamida [S4], i S-3-(4-fluorofenoksi)-2-hidroksi-2-metil-N-(4-nitro-3-trifluorometil-fenil)-propionamida [S-1]).
4. Farmaceutska kompozicija za primjenu prema patentnim zahtjevima 1 ili 2 pri čemu navedeni androgen je testosteron.
5. Farmaceutska kompozicija za primjenu prema bilo kojem od patentnih zahtjeva 1 do 4, pri čemu kompozicija sadrži 10-10,000 µg/mL PRG4.
6. Farmaceutska kompozicija za primjenu prema bilo kojem od patentnih zahtjeva 1 do 5, pri čemu kompozicija sadrži 50-500 µg/mL PRG4.
7. Farmaceutska kompozicija za primjenu prema patentnom zahtjevu 1, pri čemu kompozicija sadrži 0.0001-0.1% m/v androgena, analoga androgena, ili selektivnog modulatora receptora androgena.
8. Farmaceutska kompozicija za primjenu prema bilo kojem od patentnih zahtjeva 1 do 6, pri čemu PRG4 ima prosječnu molarnu masu između 50 kDa i 400kDa sadržavajući jedan ili više fragmenata za lubrikaciju.
9. Farmaceutska kompozicija za primjenu prema bilo kojem od patentnih zahtjeva 1 do 6, pri čemu PRG4 je rekombinantni ili izolirani polipeptid.
10. Farmaceutska kompozicija za primjenu prema bilo kojem od patentnih zahtjeva 1 do 6, pri čemu PRG4 je izolirani aminokiselinski homolog sa aminokiselinskom sekvencom koja je najmanje 75% identična sa SEQ ID NO. 1 (SEK ID BR. 1).
11. Farmaceutska kompozicija za primjenu prema patentnom zahtjevu 1, koja dalje sadrži natrij hijaluronat ili hijaluronsku kiselinu u terapijski efikasnoj koncentraciji od 10-100,000 µg/mL.
12. Farmaceutska kompozicija za primjenu prema patentnom zahtjevu 1, koja dalje sadrži jedan ili više površinski aktivnih fosfolipida odabranih iz grupe koja se sastoji od L-α-dipalmitoilfosfatidilholina, fosfatidilholina, fosfatidil-etanolamina i sfinogomijelina u terapijski efikasnoj koncentraciji od 10-10,000 µg/mL.
13. Farmaceutska kompozicija za primjenu prema patentnom zahtjevu 1, koja dalje sadrži fosfatom puferiranu otopinu natrij-klorida u vodi, ili oftalmički prihvatljivu balansiranu otopinu soli koji sadrži terapijski efikasnu koncentraciju jednog ili više elektrolita odabranih iz grupe koja se sastoji od natrij fosfata, natrij klorida, kalij klorida, natrij bikarbonata, kalij bikarbonata, kalcij klorida, magnezij klorida, trinatrij citrata, klorovodične kiseline, i natrij hidroksida.
14. Farmaceutska kompozicija za primjenu prema patentnom zahtjevu 1, koja dalje sadrži terapijski efikasnu koncentraciju jednog ili više oftalmičkih ublaživača, ekscipijenasa, astringenasa, vazokonstriktora, emolijenasa, ili agens za povećavanje vremena zadržavanja, pri čemu po izboru agens za povećanje vremena zadržavanja je odabran iz grupe koja se sastoji od hidroksipropilmetilceluloze, karboksimetilceluloze, karbomera, polimera akrilne kiseline, polimetilmetakrilata, poliakrilamida, polikarbofila, polietilen oksida, akrilna kiselina/butil akrilat kopolimera, natrij alginata, dekstrana, ili njihovu kombinaciju.
15. Farmaceutska kompozicija za primjenu prema bilo kojem od patentnih zahtjeva 1 do 13, pri čemu kompozicija sadrži 100-300 µg/mL PRG4 i 0.0001-0.1% m/v navedenog PRG4-inducirajućeg spoja.
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| PCT/US2009/043015 WO2009137602A1 (en) | 2008-05-07 | 2009-05-06 | Therapeutic modulation of ocular surface lubrication |
| EP09743588.7A EP2276496B1 (en) | 2008-05-07 | 2009-05-06 | Therapeutic modulation of ocular surface lubrication |
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| HRP20191732 HRP20191732T1 (hr) | 2008-05-07 | 2019-09-25 | Terapijska modulacija lubrikacije okularne površine |
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