TR2022007385A2 - COMPOSITION CONTAINING P2Y2 RECEPTOR - Google Patents
COMPOSITION CONTAINING P2Y2 RECEPTORInfo
- Publication number
- TR2022007385A2 TR2022007385A2 TR2022/007385 TR2022007385A2 TR 2022007385 A2 TR2022007385 A2 TR 2022007385A2 TR 2022/007385 TR2022/007385 TR 2022/007385 TR 2022007385 A2 TR2022007385 A2 TR 2022007385A2
- Authority
- TR
- Turkey
- Prior art keywords
- sodium
- eye drop
- adjusting agent
- diquafosol
- composition according
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 51
- 102000001744 Purinergic P2Y2 Receptors Human genes 0.000 title abstract description 3
- 108010029812 Purinergic P2Y2 Receptors Proteins 0.000 title abstract description 3
- 239000003889 eye drop Substances 0.000 claims abstract description 21
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims abstract description 14
- 206010013774 Dry eye Diseases 0.000 claims abstract description 14
- 230000002265 prevention Effects 0.000 claims abstract description 7
- NMLMACJWHPHKGR-NCOIDOBVSA-N P(1),P(4)-bis(uridin-5'-yl) tetraphosphate Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O NMLMACJWHPHKGR-NCOIDOBVSA-N 0.000 claims description 23
- 229950003529 diquafosol Drugs 0.000 claims description 23
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 8
- 239000002997 ophthalmic solution Substances 0.000 claims description 8
- 239000003002 pH adjusting agent Substances 0.000 claims description 8
- 239000003755 preservative agent Substances 0.000 claims description 8
- 230000002335 preservative effect Effects 0.000 claims description 8
- 239000004034 viscosity adjusting agent Substances 0.000 claims description 8
- 229940054534 ophthalmic solution Drugs 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 6
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 229960004926 chlorobutanol Drugs 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 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 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- 229960001631 carbomer Drugs 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 3
- 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 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 239000000022 bacteriostatic agent Substances 0.000 claims description 3
- 239000000440 bentonite Substances 0.000 claims description 3
- 229910000278 bentonite Inorganic materials 0.000 claims description 3
- 235000012216 bentonite Nutrition 0.000 claims description 3
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 claims description 3
- 239000006172 buffering agent 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
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 3
- 239000007951 isotonicity adjuster Substances 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 229960003742 phenol Drugs 0.000 claims description 3
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- 229940001607 sodium bisulfite Drugs 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- 229940001482 sodium sulfite Drugs 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- 239000000243 solution Substances 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 206010065062 Meibomian gland dysfunction Diseases 0.000 description 1
- 102100028045 P2Y purinoceptor 2 Human genes 0.000 description 1
- 101710096700 P2Y purinoceptor 2 Proteins 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000008484 agonism Effects 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
- 239000011230 binding agent Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- OWTGMPPCCUSXIP-FNXFGIETSA-J tetrasodium;[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] [[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O OWTGMPPCCUSXIP-FNXFGIETSA-J 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Abstract
Mevcut buluş, kuru göz sendromunun önlenmesinde ve/veya tedavisinde kullanılmak üzere P2Y2 reseptörünü ağırlıkça %0,1 ? 10 aralığında bir konsantrasyonda ihtiva eden bir göz damlası bileşimi ile ilgilidir.The present invention contains 0.1% by weight P2Y2 receptor for use in the prevention and/or treatment of dry eye syndrome. It relates to an eye drop composition containing a concentration in the range of 10.
Description
Tarifname PZYZ RESEPTÖRÜ IÇEREN BILESIM Bulusun Ilgili Oldugu Alan Mevcut bulus, kuru göz sendromunun önlenmesinde ve /veya tedavisinde kullanilmak üzere P2Y2 reseptörünü agirlikça %0,1 - 10 araliginda bir konsantrasyonda ihtiva eden bir göz damlasi bilesimi ile ilgilidir. Teknigin Bilinen Durumu Diquafosol (ticari adi Diquas®), kuru göz sendromunun tedavisi için farmasötik bir ilaçtir ve söz konusu ilaç, 2010 yilinda Japonya'da kullanim için onaylanmistir. Tetrasodyum tuzunun %3 oftalmik solüsyonu olarak formüle edilmistir. Etki mekanizmasi, P2Y2 pürinojenik reseptörünün agonizmini içerir. Diquafosole ait kimyasal yapi, asagida yer alan Formül l'de verilmektedir. Formül] Diquafosol %3'lük oftalmik solüsyonu ayrica, sulu-eksik kuru göz, kisa TBUT-tip kuru göz, obstrüktif meibomian bezi disfonksiyonu, lazer in situ keratomileusis ve katarakt cerrahisi ile ilgili olarak kuru göz ve ayrica kontakt lens kullanicilari ve görsel ekran terminali kullanicilari da dahil olmak üzere çesitli spesifik kuru göz bozukluklarinda etkinlik göstermistir. belgesi, diquafosol veya bunun bir tuzu ve polivinilpirolidon içeren sulu bir oftalmik bilesim ile ilgilidir. Söz konusu doküman ayrica göz kurulugunu önlemek veya tedavi etmek için sulu bir oftalmik bilesime yöneliktir ve bahsedilen bilesim %3 (a/h) konsantrasyonunda sodyum diquafosol, 90 K degerine sahip polivinilpirolidon ve gümüs nitrat ihtiva etmektedir. Teknigin bilinen durumunda yer alan diquafosol oftalmik çözeltilerinde yasanan en yaygin problem, söz konusu çözeltinin çökelti olusturmaksizinn saklanabilirlige, dayanikliliga ve stabiliteye sahip olmamasidir. Özellikle, ilacin muhafaza edilmesi sürecinde çözelti içerisinde birtakim çökeltiler meydana gelmekte ve bu çökeltiler sonrasinda uzaklastirilamamaktadir. Bilinen çözelti bilesimleri, bu sorununun üstesinden gelmeye yönelik tedbirler içerse de bilesimlerde yer alan yardimci maddelerle geçimsizlik sorunlari devam etmektedir. Ayrica isi, isik ve nem gibi dis faktörlere karsi yeterince dayaniklilik da saglanamamaktadir. Dolayisiyla teknikte çözelti içerisinde çökelti olusumunun engellendigi, stabilitesi, dayanikliligi ve çözünürlügü yüksek diquafosol oftalmik çözelti bilesimlerine yönelik ihtiyaç devam etmektedir. Yukaridaki bilgiler isiginda görülmektedir ki, ilgili teknik alanda, diquafosol içeren bilesimlerin yüksek stabilitesinin ve dayanikliliginin saglandigi, kuru göz sendromunun önlenmesinde ve/veya tedavisinde endike ve bunlara ek olarak çözünürlügü yüksek oftalmik çözelti bilesimlerine yönelik bir ihtiyaç bulunmaktadir. Mevcut bulus kapsaminda bu amaçla, kuru göz sendromunun önlenmesinde ve/veya tedavisinde kullanilmak üzere diquafosol veya bunun farmasötik olarak kabul edilebilir bir tuzunu agirlikça %0,1 - 10 araliginda bir konsantrasyonda ihtiva eden bir göz damlasi bilesimi sunulmaktadir. Bulusun Kisa Açiklamasi Mevcut bulus bir yönüyle, kuru göz sendromunun önlenmesinde ve /veya tedavisinde kullanilmak üzere diquafosol veya bunun farmasötik olarak kabul edilebilir bir tuzunu ihtiva eden bir göz damlasi bilesimi sunmakta olup, söz konusu bilesimde yer alan diquafosol veya bunun tuzu %0,1 - 10 (a/h] araliginda bir konsantrasyonda saglanmaktadir. Buna ek olarak, söz konusu bilesimde yer alan diquafosol veya bunun farmasötik olarak kabul edilebilir bir tuzunun konsantrasyonu tercihen %1 - 5 (a/h] araliginda, daha tercihen %3 (a/h]'tür. Mevcut bulusa ait bilesim, steril bir sulu oftalmik solüsyondur. Söz konusu bilesimin viskozitesi tercihen 25 °C'de 2 ila 25 mPa ~ s araligindadir. Mevcut bulusa ait bilesim ayrica, tamponlayici ajan, izotonik ajan, bakteriyostatik madde, pH ayarlayici ajan, tonisite ayarlayici ajan, viskozite ayarlayici ajan, yüzey aktif madde, stabilizatör, koruyucu veya bunlarin kombinasyonlarini içeren bir gruptan seçilen en az bir yardimci madde ihtiva edebilir. Söz konusu viskozite ayarlayici ajan tercihen, karbomer, bentonit, hidroksipropil metil selüloz, metil selüloz, karboksimetil selüloz, polivinil prolidon, sodyum karboksi metil selüloz veya bunlarin kombinasyonlarini içeren bir gruptan seçilmektedir. Bahsedilen pH ayarlayici ajan ise tercihen, hidroklorik asit, sodyum hidroksit, sodyum karbonat, sitrik asit, sodyum aljinat veya bunlarin kombinasyonlarini içeren bir gruptan seçilmektedir. Ayrica, söz konusu koruyucu da tercihen, sodyum sülfit, sodyum bisülfit, sodyum metabisülfit, askorbik asit, fenol, benzil alkol, benzalkonyum klorür, klorbutanol veya bunlarin kombinasyonlarini içeren bir gruptan seçilmektedir. Bulusun Ayrintili Açiklamasi Bu ayrintili açiklamada, mevcut bulusa göre olan diquafosol veya bunun farmasötik olarak kabul edilebilir bir tuzunu ihtiva eden göz damlasi bilesimi konunun daha iyi anlasilmasi için açiklanmaktadir. Mevcut bulus bir yönüyle, kuru göz sendromunun önlenmesinde ve/veya tedavisinde kullanilmak üzere diquafosol veya bunun farmasötik olarak kabul edilebilir bir tuzunu ihtiva eden bir göz damlasi bilesimi sunmakta olup, söz konusu bilesimde yer alan diquafosol veya bunun tuzu %0,1 - 10 (a/h] araliginda bir konsantrasyonda saglanmaktadir. Buna ek olarak, söz konusu bilesimde yer alan diquafosol veya bunun farmasötik olarak kabul edilebilir bir tuzunun konsantrasyonu tercihen %1 - 5 (a/h] araliginda, daha tercihen %3 (a/h]'tür. Mevcut bulus sahipleri, ilgili etken maddenin bu agirlikça miktarda kullanilmasinin bulusa ait kullanima uygun göz damlasi bilesimini kuru göz sendromunun önlenmesinde ve/veya tedavisinde daha etkili hale getirdigini görmüslerdir. Mevcut bulusa ait bilesim terapötik miktarlarda diquafosol veya bunun farmasötik olarak kabul edilebilir bir tuzunu ihtiva etmektedir. Bahsi geçen farmasötik olarak kabul edilebilir tuz tercihen, diquafosolün bir sodyum tuzu olabilir. Özellikle tercihen diquafosol tetrasodyum tuzudur. Mevcut bulusa ait bilesim ayrica, steril bir sulu oftalmik solüsyondur. Söz konusu bilesimin viskozitesi tercihen 25 °C'de 2 ila 25 mPa ~ s araligindadir. Mevcut bulusa ait bilesim ayrica, tamponlayici ajan, izotonik ajan, bakteriyostatik madde, pH ayarlayici ajan, bir tonisite ayarlayici ajan, viskozite ayarlayici ajan, yüzey aktif madde, stabilizatör, koruyucu veya bunlarin kombinasyonlarini içeren bir gruptan seçilen en az bir yardimci madde ihtiva edebilir. Bulus kapsaminda farmasötik olarak kabul edilebilir yardimci maddeler ile tasarlanmis göz damlasi bilesimi problemlere bir çözüm sunularak ilgili teknik alanda yer alan bilesimlere kiyasla daha yüksek çözünürlüge, kararliliga ve dayanikliliga sahip bir göz damlasi bilesimi saglanmaktadir. Söz konusu viskozite ayarlayici ajan tercihen, karbomer, bentonit, hidroksipropil metil selüloz, metil selüloz, karboksimetil selüloz, polivinil prolidon, sodyum karboksi metil selüloz veya bunlarin kombinasyonlarini içeren bir gruptan seçilmektedir. Bahsedilen pH ayarlayici ajan ise tercihen, hidroklorik asit, sodyum hidroksit, sodyum karbonat, sitrik asit, sodyum aljinat veya bunlarin kombinasyonlarini içeren bir gruptan seçilmektedir. Mevcut bulusa ait çözeltinin pH degeri 4 ila 8 araliginda bir degere, daha tercihen 7,5 pH degerine ayarlanmaktadir. Ayrica, söz konusu koruyucu da tercihen, sodyum sülfit, sodyum bisülfit, sodyum metabisülfit, askorbik asit, fenol, benzil alkol, benzalkonyum klorür, klorobütanol veya bunlarin kombinasyonlarini içeren bir gruptan seçilmektedir. Mevcut bulus sahipleri, yukarida bahsedilen katki maddelerinden en az birinin mevcut bilesime eklenmesi ile göz damlasi solüsyonunun saklanmasi sürecinde çözelti içerisinde çökelti olusumunu sürpriz bir sekilde engelleyebildigini kesfetmislerdir. Böylelikle, viskozite ayarlayici ajan, pH ayarlayici ajan ve /veya koruyucunun bir arada kullanildigi yapilanmalarda söz konusu göz damlasi bilesiminin sebep oldugu göz irritasyonunun sasirtici bir sekilde azaldigi ve ayrica çözeltinin muhafaza sürecinin de güçlendigi ortaya koyulmaktadir. Mevcut bulusun ileri yapilanmalari, yukarida bahsedilenlerin haricinde bulusa göre sunulan kullanima uygun farmasötik olarak kabul edilebilir eksipiyanlar, çözücüler, baglayicilar, yaglayicilar, kaydiricilar, dolgu maddeleri, selatlayici ajan, islatma maddelerini de içerebilir. Söz konusu yardimci maddelerin yukarida bahsedilmeyen kombinasyonlari da mevcut bulusun kapsami disinda birakilmamalidir. Dolayisiyla, mevcut bulus çözelti içerisinde çökelti olusumunu engelleyerek iyi bir çözünürlük ve kararliliga sahip bir göz damlasi bilesimi sunmasi sebebiyle avantajlidir ve bu yönüyle teknikte bir ilerleme saglamaktadir. Mevcut bulusa ait bilesimin teknik etkisinin çözünürlüge fayda sagladigi ve bu sebeple mevcut bilesimlere kiyasla daha avantajli oldugu ortaya koyulmaktadir. ÖRNEKLER Tercih edilen yapilanmalarda, mevcut bulusa ait göz damlasi bilesimi asagidaki bilesenleri ihtiva etmektedir: Bilesen Agirlikça (%) (a/h) Diquafosol veya bunun tuzu 0,1 - 10 Viskozite ayarlayici ajan 0,1 - 10 pH ayarlayici ajan 0,1 - 10 Koruyucu madde 0,1 - 10 Katki maddesi 0,001 - 0,1 Bilesen Agirlik (g) Diquafasol sodyum 2.000 PoliVinil prolidon 0.300 Sodyum hidroksit 0.510 Sodyum sülfit 0.250 Gliserin 0.100 Benzalkonyum klorür 0.003 Saf su Yeterli miktarda 2 g diquafasol sodyum, 0.3 g poliVinil prolidon, 0.51 g sodyum hidroksit, 0.25 g sodyum sülfit ve 0.1 g gliserin ve 0.003 benzalkonyum klorür, saf su içerisinde çözünmesi saglanmistir. Böylece elde edilen çözeltinin hacmi 100 mL olmustur. Bilesen Agirlik (g) Diquafasol sodyum 3.000 Karbomer 0.200 Sitrik asit 0.420 Gliserin 0.180 Potasyum klorür 0.120 Klorobütanol 0.002 Saf su Yeterli miktarda Toplam 3.922 ve 0.002 klorobütanol, saf su içerisinde çözünmesi saglanmistir. Böylece elde edilen çözeltinin hacmi 100 mL olmustur. Bilesen Agirlik (g) Diquafasol sodyum 4.000 Hidroksipropil metil selüloz 0.400 Sitrik asit 0.620 Sodyum sülfat 0.340 Dekstroz 0.200 Benzalkonyum klorür 0.004 Saf su Yeterli miktarda 4 g diquafasol sodyum, 0.4 g hidroksipropil metil selüloz, 0.62 g sitrik asit, 0.34 g sodyum sülfat ve 0.2 g dekstroz ve 0.004 benzetonyum klorür, saf su içerisinde çözünmesi saglanmistir. Böylece elde edilen çözeltinin hacmi 100 mL olmustur. Yukarida tarif edilen örnek bilesimlerin her biri, bir cam kap içerisinde 25°C'de üç ay boyunca saklanmis ve ardindan söz konusu bilesimlerin görünüslerinde herhangi bir degisiklik olmadigi saptanmistir. Ayrica, bu süreçlerdeki çökelti içerisinde meydana gelen çökeltilerin miktarinin azaldigi da ortaya koyulmustur. Mevcut bulus, diquafasol etken maddesinin veya bunun tuzunun farmasötik olarak kabul edilebilir yardimci maddeler ile bir araya getirilerek saglanan spesifik bilesimi ile çözelti içerisinde çökelti olusumunu engelleyerek iyi bir çözünürlük ve kararliliga sahip ve ayrica isi, isik ve nem gibi dis faktörlere karsi yeterince dayaniklilik gösteren göz damlasi bilesimleri saglamasi bakimindan avantajlidir. Bulusun koruma kapsami ekte verilen istemlerde belirtilmis olup teknikte uzman bir kisinin, bulusun ana temasindan ayrilmadan yukarida anlatilanlar isiginda benzer yapilanmalar ortaya koyabilecegi açiktir. TR Description COMPOSITION CONTAINING PZYZ RECEPTOR Field of the Invention The present invention relates to an eye drop composition containing the P2Y2 receptor in a concentration between 0.1 and 10% by weight for use in the prevention and/or treatment of dry eye syndrome. State of the Art Diquafosol (trade name Diquas®) is a pharmaceutical drug for the treatment of dry eye syndrome and was approved for use in Japan in 2010. It is formulated as a 3% ophthalmic solution of tetrasodium salt. Its mechanism of action involves agonism of the P2Y2 purinogenic receptor. The chemical structure of diquafosol is given in Formula 1 below. Formula] Diquafosol 3% ophthalmic solution is also used for aqueous-incomplete dry eye, short TBUT-type dry eye, obstructive meibomian gland dysfunction, dry eye in relation to laser in situ keratomileusis and cataract surgery, as well as contact lens wearers and visual display terminal It has demonstrated effectiveness in a variety of specific dry eye disorders, including The document relates to an aqueous ophthalmic composition comprising diquafosol or a salt thereof and polyvinylpyrrolidone. The subject document is also directed to an aqueous ophthalmic composition for preventing or treating dry eye, said composition comprising sodium diquafosol at a concentration of 3% (w/v), polyvinylpyrrolidone having a 90 K value, and silver nitrate. The most common problem experienced in diquafosol ophthalmic solutions in the state of the art is that the solution in question does not have the storability, durability and stability without forming precipitates. In particular, during the preservation of the drug, some precipitates form in the solution and these precipitates cannot be removed afterwards. Although known solution compositions contain measures to overcome this problem, incompatibility problems with the auxiliary substances in the compositions continue. In addition, sufficient resistance against external factors such as heat, light and humidity cannot be provided. Therefore, there is still a need in the art for diquafosol ophthalmic solution compositions that prevent precipitate formation in the solution and have high stability, durability and solubility. In the light of the above information, it can be seen that there is a need in the relevant technical field for ophthalmic solution compositions with high solubility, which are indicated in the prevention and/or treatment of dry eye syndrome, where the high stability and durability of diquafosol-containing compositions are ensured. For this purpose, within the scope of the present invention, there is provided an eye drop composition containing diquafosol or a pharmaceutically acceptable salt thereof in a concentration in the range of 0.1 to 10% by weight, for use in the prevention and/or treatment of dry eye syndrome. Brief Description of the Invention In one aspect, the present invention provides an eye drop composition containing diquafosol or a pharmaceutically acceptable salt thereof for use in the prevention and/or treatment of dry eye syndrome, said composition containing diquafosol or its salt 0.1% - It is provided at a concentration in the range of 10 (w/v). In addition, the concentration of diquafosol or a pharmaceutically acceptable salt thereof in the composition in question is preferably in the range of 1 - 5% (w/v), more preferably 3% (w/v). The composition of the present invention is a sterile aqueous ophthalmic solution. The viscosity of said composition is preferably in the range of 2 to 25 mPa ~ s at 25 °C. The composition of the present invention also contains buffering agent, isotonic agent, bacteriostatic agent, pH adjuster. The agent may contain at least one excipient selected from the group consisting of a tonicity adjusting agent, a viscosity adjusting agent, a surfactant, a stabilizer, a preservative, or combinations thereof. The viscosity adjusting agent is preferably selected from the group consisting of carbomer, bentonite, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, polyvinyl prolidone, sodium carboxy methyl cellulose or combinations thereof. Said pH adjusting agent is preferably selected from a group consisting of hydrochloric acid, sodium hydroxide, sodium carbonate, citric acid, sodium alginate or combinations thereof. Furthermore, said preservative is preferably selected from the group consisting of sodium sulfite, sodium bisulfite, sodium metabisulfite, ascorbic acid, phenol, benzyl alcohol, benzalkonium chloride, chlorbutanol or combinations thereof. Detailed Description of the Invention In this detailed description, the eye drop composition containing diquafosol or a pharmaceutically acceptable salt thereof according to the present invention is described for a better understanding of the subject. In one aspect, the present invention provides an eye drop composition comprising diquafosol or a pharmaceutically acceptable salt thereof for use in the prevention and/or treatment of dry eye syndrome, wherein diquafosol or its salt is 0.1 to 10% (a) In addition, the concentration of diquafosol or a pharmaceutically acceptable salt thereof in the composition in question is preferably in the range of 1 to 5% (w/v), more preferably 3% (w/v). The present inventors have found that the use of this weight amount of active ingredient makes the eye drop composition of the invention more effective in preventing and/or treating dry eye syndrome. The composition of the present invention contains therapeutic amounts of diquafosol or a pharmaceutically acceptable salt thereof. Said pharmaceutically acceptable salt may preferably be a sodium salt of diquafosol. Particularly preferably diquafosol is the tetrasodium salt. The composition of the present invention is also a sterile aqueous ophthalmic solution. The viscosity of the composition in question is preferably in the range of 2 to 25 mPa s at 25 °C. The composition of the present invention may further contain at least one excipient selected from the group consisting of a buffering agent, an isotonic agent, a bacteriostatic agent, a pH adjusting agent, a tonicity adjusting agent, a viscosity adjusting agent, a surfactant, a stabilizer, a preservative, or combinations thereof. Within the scope of the invention, eye drop composition designed with pharmaceutically acceptable excipients provides a solution to the problems and provides an eye drop composition with higher solubility, stability and durability compared to the compositions in the relevant technical field. The viscosity adjusting agent is preferably selected from the group consisting of carbomer, bentonite, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, polyvinyl prolidone, sodium carboxy methyl cellulose or combinations thereof. Said pH adjusting agent is preferably selected from a group consisting of hydrochloric acid, sodium hydroxide, sodium carbonate, citric acid, sodium alginate or combinations thereof. The pH of the solution of the present invention is adjusted to a value in the range of 4 to 8, more preferably to a pH of 7.5. Furthermore, said preservative is preferably selected from the group consisting of sodium sulfite, sodium bisulfite, sodium metabisulfite, ascorbic acid, phenol, benzyl alcohol, benzalkonium chloride, chlorobutanol or combinations thereof. The present inventors have discovered that adding at least one of the above-mentioned additives to the present composition can surprisingly prevent the formation of precipitates in the solution during the storage of the eye drop solution. Thus, it is revealed that in embodiments where viscosity adjusting agent, pH adjusting agent and/or preservative are used together, the eye irritation caused by the eye drop composition in question is surprisingly reduced and the preservation process of the solution is also strengthened. Further embodiments of the present invention may include, in addition to those mentioned above, pharmaceutically acceptable excipients, solvents, binders, lubricants, lubricants, fillers, chelating agents, wetting agents suitable for use according to the invention. Combinations of these excipients not mentioned above should not be excluded from the scope of the present invention. Therefore, the present invention is advantageous as it provides an eye drop composition with good solubility and stability by preventing precipitate formation in solution, and in this respect it provides an advance in the technique. It is revealed that the technical effect of the composition of the present invention benefits the solubility and is therefore more advantageous compared to existing compositions. EXAMPLES In preferred embodiments, the eye drop composition of the present invention contains the following ingredients: Component By Weight (%) (w/v) Diquafosol or its salt 0.1 - 10 Viscosity adjusting agent 0.1 - 10 pH adjusting agent 0.1 - 10 Preservative 0.1 - 10 Additive 0.001 - 0.1 Component Weight (g) Diquafasol sodium 2.000 PolyVinyl prolidone 0.300 Sodium hydroxide 0.510 Sodium sulfite 0.250 Glycerin 0.100 Benzalkonium chloride 0.003 Pure water Sufficient amount of 2 g diquafasol sodium, 0. 3 g polyVinyl prolidone , 0.51 g sodium hydroxide, 0.25 g sodium sulfite, 0.1 g glycerin and 0.003 benzalkonium chloride were dissolved in pure water. Thus, the volume of the solution obtained was 100 mL. Component Weight (g) Diquafasol sodium 3.000 Carbomer 0.200 Citric acid 0.420 Glycerin 0.180 Potassium chloride 0.120 Chlorobutanol 0.002 Pure water A sufficient amount of total 3.922 and 0.002 chlorobutanol was dissolved in pure water. Thus, the volume of the solution obtained was 100 mL. Component Weight (g) Diquafasol sodium 4.000 Hydroxypropyl methyl cellulose 0.400 Citric acid 0.620 Sodium sulfate 0.340 Dextrose 0.200 Benzalkonium chloride 0.004 Pure water Sufficient amount of 4 g diquafasol sodium, 0.4 g hydroxypropyl methyl cellulose, 0.62 g citric acid, 0. 34 g sodium sulfate and 0.2 g dextrose and 0.004 benzethonium chloride were dissolved in pure water. Thus, the volume of the solution obtained was 100 mL. Each of the exemplary compositions described above were stored in a glass container at 25°C for three months and thereafter it was determined that there was no change in the appearance of the compositions. It has also been revealed that the amount of precipitates formed in the sediment in these processes decreases. The present invention provides eye drops with good solubility and stability by preventing the formation of precipitates in solution, and also with sufficient resistance to external factors such as heat, light and moisture, with the specific composition of the active ingredient diquafasol or its salt combined with pharmaceutically acceptable excipients. It is advantageous in terms of providing combinations. The protection scope of the invention is specified in the attached claims, and it is clear that a person skilled in the art can produce similar structures in the light of what is explained above, without departing from the main theme of the invention. TR
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Publication Number | Publication Date |
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TR2022007385A2 true TR2022007385A2 (en) | 2023-11-21 |
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