HRP20220165T1 - Postupak priprave sterilnih oftalmoloških vodenih suspenzija nanokristala flurikazona-propionata oblika a - Google Patents
Postupak priprave sterilnih oftalmoloških vodenih suspenzija nanokristala flurikazona-propionata oblika a Download PDFInfo
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- HRP20220165T1 HRP20220165T1 HRP20220165TT HRP20220165T HRP20220165T1 HR P20220165 T1 HRP20220165 T1 HR P20220165T1 HR P20220165T T HRP20220165T T HR P20220165TT HR P20220165 T HRP20220165 T HR P20220165T HR P20220165 T1 HRP20220165 T1 HR P20220165T1
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- nanocrystals
- fluticasone
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- propionate
- nanosuspension
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- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical group C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 title claims 34
- 239000002159 nanocrystal Substances 0.000 title claims 31
- 238000000034 method Methods 0.000 title claims 25
- 238000002360 preparation method Methods 0.000 title claims 11
- 239000000725 suspension Substances 0.000 title claims 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 24
- 239000006070 nanosuspension Substances 0.000 claims 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 16
- 229960000289 fluticasone propionate Drugs 0.000 claims 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 12
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims 12
- 229920000053 polysorbate 80 Polymers 0.000 claims 12
- 239000000243 solution Substances 0.000 claims 11
- 229960000686 benzalkonium chloride Drugs 0.000 claims 10
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims 10
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims 10
- 229940068968 polysorbate 80 Drugs 0.000 claims 10
- 229920000609 methyl cellulose Polymers 0.000 claims 9
- 239000001923 methylcellulose Substances 0.000 claims 9
- 235000010981 methylcellulose Nutrition 0.000 claims 9
- 238000002156 mixing Methods 0.000 claims 9
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 claims 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims 8
- 239000004327 boric acid Substances 0.000 claims 8
- 239000000203 mixture Substances 0.000 claims 8
- 239000002055 nanoplate Substances 0.000 claims 8
- 239000002245 particle Substances 0.000 claims 8
- 239000011780 sodium chloride Substances 0.000 claims 8
- 230000000699 topical effect Effects 0.000 claims 8
- 238000001914 filtration Methods 0.000 claims 7
- 230000001954 sterilising effect Effects 0.000 claims 7
- 235000011187 glycerol Nutrition 0.000 claims 6
- 210000000744 eyelid Anatomy 0.000 claims 5
- 238000002441 X-ray diffraction Methods 0.000 claims 4
- 208000010217 blepharitis Diseases 0.000 claims 4
- 210000000720 eyelash Anatomy 0.000 claims 4
- 238000001228 spectrum Methods 0.000 claims 4
- 238000004659 sterilization and disinfection Methods 0.000 claims 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 3
- 229920012266 Poly(ether sulfone) PES Polymers 0.000 claims 3
- 239000007853 buffer solution Substances 0.000 claims 3
- 238000011200 topical administration Methods 0.000 claims 3
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 2
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims 2
- 206010065062 Meibomian gland dysfunction Diseases 0.000 claims 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims 2
- 239000002202 Polyethylene glycol Substances 0.000 claims 2
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 claims 2
- 239000007900 aqueous suspension Substances 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- 238000002347 injection Methods 0.000 claims 2
- 239000007924 injection Substances 0.000 claims 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims 2
- 229920001223 polyethylene glycol Polymers 0.000 claims 2
- 238000005406 washing Methods 0.000 claims 2
- 238000005119 centrifugation Methods 0.000 claims 1
- 239000007979 citrate buffer Substances 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 239000007799 cork Substances 0.000 claims 1
- 238000010790 dilution Methods 0.000 claims 1
- 239000012895 dilution Substances 0.000 claims 1
- KDQPSPMLNJTZAL-UHFFFAOYSA-L disodium hydrogenphosphate dihydrate Chemical compound O.O.[Na+].[Na+].OP([O-])([O-])=O KDQPSPMLNJTZAL-UHFFFAOYSA-L 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 229940054534 ophthalmic solution Drugs 0.000 claims 1
- 239000002997 ophthalmic solution Substances 0.000 claims 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims 1
- 229920001451 polypropylene glycol Polymers 0.000 claims 1
- 229920000136 polysorbate Polymers 0.000 claims 1
- 229950008882 polysorbate Drugs 0.000 claims 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 claims 1
- 208000024891 symptom Diseases 0.000 claims 1
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- A61K31/567—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 position 17 alpha, e.g. mestranol, norethandrolone
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- 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
- A61K31/569—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 substituted in position 17 alpha, e.g. ethisterone
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Claims (23)
1. Postupak priprave sterilnih topičkih oftalmoloških vodenih nanosuspenzija, koje sadrže nanokristale flutikazon-propionat Oblika A koji imaju srednju veličinu čestica 100 nm do 1000 nm i koncentraciju flutikazon-propionata je od 0.001% w/w do 1% w/w, a spomenuti postupak obuhvaća sljedeće:
a) priprava vodenog vezikula 1 koji sadrži 0.5 % w/w metilceluloze 4000 mPa s, 1.0 % w/w borne kiseline, 0.1 % w/w edetat-dinatrij dihidrata, 0.055 % w/w natrijeva klorida, 0.01 % w/w benzalkonijeva klorida, 0.2 % w/w polisorbata 80, klorovodične kiseline IN i/ili natrijeva hidroksida IN da se pH podesi na 7.3-7.5 i vode do 100 % w/w;
b) miješanje količine nanokristala flutikazon-propionata Oblika A koji imaju srednju veličinu čestica od 100 nm do 1000 nm s količinom vezikula 1 pri čemu se dobiva viskozna smjesa u kojoj je koncentracija sadržnog flutikazon-propionata 2 % w/w;
c) primjena visoko-smične miješalice velike brzine na viskoznu smjesu iz koraka b) najmanje 10 minuta;
d) priprava vodenog vezikula 2 koji sadrži sljedeće: 1.8 % w/w glicerina, 0.5 % w/w metilceluloze 4000 mPa s, 1.0 % w/w borne kiseline, 0.1 % edetat-dinatrij dihidrata, 0.055 % w/w natirjeva klorida, 0.01 % w/w benzalkonijeva klorida, 0.2 % w/w polisorbata 80, klorovodične kiseline 1M i/ili natrijeva hidroksida 1M da se pH podesi na 7.3-7.5 i vode q.s. do 100 % w/w;
e) dodavanje alikvota vodenog vezikula 2 u viskoznu smjesu iz koraka c) čime se dobiva flutikazon-propionat koncentracije oko 1 % w/w;
f) primjena visoko-smične miješalice velike brzine na viskoznu smjesu iz koraka e) dok se ne dobiju čestice ciljane srednje veličine;
g) steriliziranje nanosuspenzije iz koraka f) autoklaviranjem;
h) priprava vodenih vezikula 3 koji sadrže: 0.9 % w/w glicerina, 0.5 % w/w metilceluloze 4000 mPa·s, 1.0 % w/w borne kiseline, 0.1 % w/w edetat-dinatrij dihidrata, 0.055 % w/w natirjeva klorida, 0.01 % w/w benzalkonijeva klorida, 0.2 % w/w polisorbata 80, klorovodične kiseline IN i/ili natrijeva hidroksida (IN) da se pH podesi na 7.3-7.5 i vode do 100 % w/w, te steriliziranje vodenih vezikula 3 filtracijom;
i) aseptično dodavanje alikvote sterilnog vodenog vezikula 3 u steriliziranu nanosuspenziju iz koraka g) čime se pripravlja sterilna topička oftalmološka vodena nanosuspenzija koja sadrži ciljanu koncentraciju nanokristala flutikazon-propionata Oblika A;
gdje nanokristali flutikazon-propionata Oblika A imaju spektar difrakcije X-zraka spomenutih nanokristala koji uključuje signale oko 7.8, 15.7, 20.8, 23.7, 24.5 te 32.5 stupnja 2Θ, nadalje uključuje signale pri oko 9.9, 13.0, 14.6, 16.0, 16.9, 18.1 te 34.3 stupnja 2Θ, te pri čemu su nanokristali nano-ploče koje imaju [001] kristalografsku os koja je uglavnom normalna na površinu koju definira debljina nano-ploče.
2. Postupak prema patentnom zahtjevu 1, naznačen time da koncentracija flutikazon-propionata u konačnoj sterilnoj topičkoj oftalmološkoj vodenoj nanosuspenziji jest od 0.001% do 0.5% w/w.
3. Postupak prema patentnom zahtjevu 1, naznačen time da koncentracija flutikazon-propionata u konačnoj sterilnoj topičkoj oftalmološkoj vodenoj nanosuspenziji jest 0.5% w/w, 0.25% w/w, 0.2% w/w, 0.1% w/w, 0.05% w/w, 0.03% w/w, 0.01% w/w ili 0.005% w/w.
4. Postupak prema bilo kojem od patentnih zahtjeva 1 do 3, naznačen time da su koraci miješanja visoko-smičnom miješalicom velike brzine iz koraka c) i f) provedena pri 6000 rpm.
5. Postupak prema patentnom zahtjevu 1, naznačen time da je u koraku f) miješanje visoko-smičnom miješalicom velike brzine provedeno kroz najmanje 10 minuta.
6. Postupak prema bilo kojem od patentnih zahtjeva 1 do 5, naznačen time da su vodeni vezikuli 1 i 2 prije njihove upotrebe filtrirani kroz filter od 0.2 µm.
7. Postupak prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time da je sterilizacija u koraku g) provedena autoklaviranjem nanosuspenzije iz koraka f) pri oko 122 °C kroz oko 40 minuta.
8. Postupak priprave sterilne topičke oftalmološke vodene nanosuspenzije koja sadrži nanokristala flutikazon-propionata Oblika A koji imaju srednju veličinu čestica od 100 do 1000 nm i koncentraciju i koncentraciju flutikazon-propionata je od 0.001% w/w do 1% w/w, a spomenuti postupak obuhvaća sljedeće:
a-1) sterilizacija nanokristala flutikazon-propionata Oblika A koji imaju srednju veličinu čestica od 100 nm do 1000 nm;
b-) priprava vodenih vezikula 1 koji sadrže: 0.5% w/w metilceluloze 4000 mPa s, 1.0% w/w borne kiseline, 0.1% w/w edetat-dinatrij dihidrata, 0.055% w/w natrijeva klorida, 0.01% w/w benzalkonijeva klorida, 0.2% w/w polisorbata 80, klorovodične kiseline IN i/ili natrijeva hidroksida IN da se pH podesi na 7.3-7.5 i vode q.s. do 100% w/w, te sterilizacija spomenutog vodenog vezikula 1 filtracijom;
c-1) aseptično miješanje količine steriliziranih nanokristala flutikazon-propionata Oblika A s količinom vodenog vezikula 1 pri čemu nastaje viskozna smjesa u kojoj koncentracija flutikazon-propionata jest 2% w/w;
d-1) primjena visoko-smične miješalice velike brzine na viskoznu smjesu iz koraka c-1) najmanje 10 minuta;
e-1) priprava vodenog vezikula 2 koji sadrži: 1.8% w/w glicerina, 0.5% w/w metilceluloze 4000 mPa s, 1.0% w/w borne kiseline, 0.1% edetat-dinatrij dihidrata, 0.055% w/w natirjeva klorida, 0.01% w/w benzalkonijeva klorida, 0.2% w/w polisorbata 80, klorovodične kiseline IN i/ili natrijeva hidroksida IN da se pH podesi na 7.3-7.5 i vode q.s. do 100% w/w, te sterilizacija spomenutog vodenog vezikula 2 filtracijom;
f-1) aseptično dodavanje alikvota steriliziranog vezikula 2 u viskoznu smjesu iz koraka d-1) za dobivanje koncentracije nanokrilstala flutikazon-propionata od oko 1% w/w;
g-1) primjena visoko-smične miješalice velike brzine na viskoznu smjesu iz koraka f-1) dok se ne dobiju čestice ciljane srednje veličine;
h-1) priprava vodenih vezikula 3 koji sadrže: 0.9% w/w glicerina, 0.5% w/w metilceluloze 4000 mPa·s, 1.0% w/w borne kiseline, 0.1% w/w edetat-dinatrij dihidrata, 0.055% w/w natirjeva klorida, 0.01% w/w benzalkonijeva klorida, 0.2% w/w polisorbata 80, klorovodične kiseline IN i/ili natrijeva hidroksida IN da se pH podesi na 7.3-7.5 i vode do 100% w/w, te steriliziranje spomenutog vodenog vezikula 3 filtracijom;
i-1) aseptično dodavanje alikvota steriliziranog vodenog vezikula 3 u nanosuspenziju iz koraka g-1) za pripravu sterilne topičke oftalmološke otopine koja sadrži konačnu koncentraciju nanokristala flutikazon-propionata Oblika A;
gdje nanokristali flutikazon-propionata Oblika A imaju spektar difrakcije X-zraka spomenutih nanokristala koji uključuje signale oko 7.8, 15.7, 20.8, 23.7, 24.5 te 32.5 stupnjeva 2Θ, nadalje uključuje signale pri oko 9.9, 13.0, 14.6, 16.0, 16.9, 18.1 te 34.3 stupnjeva 2Θ, te pri čemu su nanokristali nano-ploče koje imaju [001] kristalografsku os koja je uglavnom normalna na površinu koju definira debljina nano-ploče.
9. Postupak prema patentnom zahtjevu 8, naznačen time da koncentracija flutikazon-propionata u konačnoj sterilnoj topičkoj oftalmološkoj vodenoj nanosuspenziji jest od 0.001% do 0.5% w/w.
10. Postupak prema patentnom zahtjevu 8, naznačen time da koncentracija flutikazon-propionata u konačnoj sterilnoj topičkoj oftalmološkoj vodenoj nanosuspenziji jest 0.5% w/w, 0.25% w/w, 0.2% w/w, 0.1% w/w, 0.05% w/w, 0.03% w/w, 0.01% w/w ili 0.005% w/w.
11. Postupak prema bilo kojem od patentnih zahtjeva 8 do 10, naznačen time da su u korku a-1) nanokristali flutikazon-propionata Oblika A sterilizirani autoklaviranjem vodene suspenzije nanokristala flutikazon-propionata Oblika A za injekciju, a koncentracija flutikazon-propionata jest između 2% w/w i 20% w/w.
12. Postupak prema patentnom zahtjevu 11, naznačen time da je vodena suspenzija nanokristala flutikazon-propionata Oblika A autoklavirana pri oko 122 °C kroz oko 30 minuta.
13. Postupak prema bilo kojem od patentnih zahtjeva 8 do 12, naznačen time da je u koraku d-1) i koraku g-1) miješanje visoko-smičnom miješalicom velike brzine provedeno pri 6000 rpm.
14. Postupak prema patentnom zahtjevu 13, naznačen time da je u koraku g-1) miješanje visoko-smičnom miješalicom velike brzine provedeno najmanje 10 minuta.
15. Postupak prema bilo kojem od patentnih zahtjeva 1 do 14, naznačen time da su nanokristali flutikazon-propionata Oblika A pripravljeni prema sljedećim koracima:
1) priprava otopine faze I koja sadrži 0.45 % w/w flutikazon-propionata polimorfa 1, 23.2 % w/w polietilen-glikola 400 (PEG 400), 68,8% w/w polipropilen-glikola 400 (PEG 400),, 7.6 w/w polisorbata 80 (Tween 80), te filtriranje otopine faze I kroz 0.8/0.2 µm polietersulfonski (PES) filter,
2) pripava otopine faze II koja sadrži 0.01 % w/w benzalkonijeva klorida, 0.40 % (w/w) metil-celuloze polisorbata 15 mPa s, 0.1 w/w polietilen-glikol 40 stearata (PEG-40 stearat), citratni pufer do pH 3.4 do 3.8 u vodi q.s. do 100 % w/w i filtriranje otopine faze II kroz 0.8/0.2 µm polietersulfonski (PES) filter,
3) hlađenje filtriranih otopina faze I i faze II do temperature od 0 do 4 °C,
4) miješanje otopina faze I i faze II u reaktoru snabdjevenog s ultrazvučnim transduktorom (QSonica Q2000 Ultrasonic transducer) da se dobije suspenzija nanokristala faze III, gdje;
- otopina faze I i otopina faze II su kontinuirano pumpani u reaktor pri brzini protoka od 600 mL/min (otopina faze I), odnosno 2400 mL/min (otopina faze II) i dobiva se suspenzija faze III,
- volumni omjer faze I i faze II je 1 : 4,
- sonifikacija se primjenjuje tijekom miješanja s vanjskom snagom od 60 %.
- prosječna temperatura suspenzije faze III je oko 11 °C, te
5) nisko-smično miješanje suspenzije faze III iz koraka 4) pri dovoljnoj brzini da nastane vrtlog, pri sobnoj temperaturi kroz najmanje 30 minuta u odsutnosti sonifikatora,
6) zagrijavanje suspenzije faze III pri 40 °C u periodu ne manjem od 16 sati,
7) priprava puferske otopine koja sadrži 0.2% polietilen-glikol 40 sterata (PEG-40 stearat) 0.2% w/w polisorbata 80 (Tween 80), 0.001% w/w benzalkonijeva klorida, 0.05% natrijeva fosfata monobaznog monohidrata, 0.02% w/w natrijeva fosfata dibaznog dihidrata i vode q.s. do 100%, koja ima pH 6.3 ± 0.2, te filtriranje otopine faze kroz 0.8/0.2 µm polietersulfonski (PES) filter,
8) razrjeđivanje suspenzije faze III iz koraka 6) s filtriranom puferskom otopinom gdje volumni omjer puferske otopine i faze III jest 1 : 1,
9) centrifugiranje razrijeđene suspenzije faze III čime se izoliraju nanokristali flutikazon-propionata Oblika A i ispiranje izoliranih nanokristala,
10) pranje vodom izoliranih nanokristala za injekciju.
16. Oftalmološka vodena nanosuspenzija koja se može davati topički na kapke, trepavice ili rub kapaka, naznačen time da se sastoji od sljedećih:
(a) 0.001% do 1 % w/w nanokristalia flutikazon-propionata Oblika A,
(b) 0.50% w/w metilceluloza 4000 mPa·s,
(c) 0.2% w/w polisorbat 80,
(d) 0.10% w/w edetat-dinatije dihidrat,
(e) 1.0% w/w borna kiselina,
(f) 0.9% w/w glicerin,
(g) 0.01% w/w benzalkonijev klorid,
(h) 0.055% w/w natrijev klorid,
(i) klorovodična kiselina IN i/ili natrijev hidroksid IN kao reagensi za podešavanje u količini dovoljnoj da pH bude 7.3-7.5, te
(j) voda q.s. do 100% w/w,
gdje spomenuti nanokristali flutikazon-propionata Oblika A imaju srednju veličinu čestica od 100 nm do 1000 nm, te spektar difrakcije X-zraka spomenutih nanokristala koji uključuje signale oko 7.8, 15.7, 20.8, 23.7, 24.5 te 32.5 stupnja 2Θ, nadalje uključuje signale pri oko 9.9, 13.0, 14.6, 16.0, 16.9, 18.1 te 34.3 stupnja 2Θ, te pri čemu su nanokristali nano-ploče koje imaju [001] kristalografsku os koja je uglavnom normalna na površinu koju definira debljina nano-ploče.
17. Oftalmološka vodena nanosuspenzija prema patentnom zahtjevu 16, naznačena time da koncentracija flutikazon-propionata jest od 0.001% do 0.5% w/w.
18. Oftalmološka vodena nanosuspenzija prema patentnom zahtjevu 16, naznačena time da koncentracija flutikazon-propionata jest 0.5% w/w, 0.25% w/w, 0.2% w/w, 0.1% w/w, 0.05% w/w, 0.03% w/w, 0.01% w/w ili 0.005% w/w.
19. Oftalmološka vodena nanosuspenzija prema patentnom zahtjevu 16, naznačena time da je koncentracija flutikazon-propionata jest 0.2 % w/w ili 0.1 % w/w ili 0.05% w/w..
20. Oftalmološka vodena nanosuspenzija prema bilo kojem od patentnih zahtjeva 16 do 19 za upotrebu u metodi liječenja blefaritisa, stražnji blefaritisa, disfunkcije meibomovih žlijezda, bolesti suhog oka, gdje metoda obuhvaća topičko davanje na kapke, trepavice ili rub kapaka učinkovite količine oftalmološke vodene nanosuspenzije.
21. Oftalmološka vodena nanosuspenzija prema bilo kojem od patentnih zahtjeva 16 do 19 za upotrebu u metodi smanjivanja simptoma i/ili kliničkih znakova blefaritisa, stražnjeg blefaritis, disfunkcije meibomovih žlijezda, bolesti suhog oka, gdje metoda obuhvaća topičko davanje na kapke, trepavice ili rub kapaka učinkovite količine oftalmološke vodene nanosuspenzije.
22. Oftalmološka vodena nanosuspenzija prema patentnom zahtjevu 16 za upotrebu u metodi prema patentnom zahtjevu 20 ili 21, gdje se oftalmološka vodena nanosuspenzija sastoji od:
(a) 0.00 1 % do 1 % w/w nanokristalia flutikazon-propionata Oblika A,
(b) 0.50 % w/w metilceluloza 4000 mPa·s,
(c) 0.2 % w/w polisorbat 80,
(d) 0.10 % w/w edetat-dinatije dihidrat,
(e) 1.0 % w/w borna kiselina,
(f) 0.9 % w/w glicerin,
(g) 0.01 % w/w benzalkonijev klorid,
(h) 0.055 % w/w natrijev klorid,
(i) klorovodična kiselina IN i/ili natrijev hidroksid IN kao reagensi za podešavanje, u količini dovoljnoj da pH bude 7.3-7.5, te
(j) voda q.s. do 100 % w/w,
gdje spomenuti nanokristali flutikazon-propionata Oblika A imaju srednju veličinu čestica od 100 nm do 1000 nm, te spektar difrakcije X-zraka spomenutih nanokristala koji uključuje signale oko 7.8, 15.7, 20.8, 23.7, 24.5 te 32.5 stupnja 2Θ, nadalje uključuje signale pri oko 9.9, 13.0, 14.6, 16.0, 16.9, 18.1 te 34.3 stupnja 2Θ, te pri čemu su nanokristali nano-ploče koje imaju [001] kristalografsku os koja je uglavnom normalna na površinu koju definira debljina nano-ploče.
23. Oftalmološka vodena nanosuspenzija za upotrebu po metodi prema bilo kojem od patentnih zahtjeva 20 do 22, gdje metoda obuhvaća topičko davanje na kapke, trepavice ili rub kapaka oftalmološku vodene nanosuspenzije najmanje jedanput dnevno kroz dva tjedna.
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