TR2021019832A2

TR2021019832A2 - A topical pharmaceutical composition containing fenticonazole nitrate.

Info

Publication number: TR2021019832A2
Application number: TR2021/019832
Authority: TR
Inventors: Eski̇ Volkan; Kumar Dude Udaya
Original assignee: Abdi̇ İbrahi̇m İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇
Filing date: 2021-12-14
Publication date: 2023-06-21

Abstract

Mevcut buluş, Fentikonazol veya farmasötik olarak kabul edilebilir tuz, badem yağı ve en az bir ek eksipiyandan oluşan bir topikal farmasötik bileşim ile ilgilidir. Buluş ayrıca söz konusu farmasötik bileşimin hazırlanma yöntemi ve vulvovajinit & genital kandidiyaz tedavisinde bir ilaç olarak kullanımı ile ilgilidir.The present invention relates to a topical pharmaceutical composition comprising Fenticonazole or a pharmaceutically acceptable salt, almond oil and at least one additional excipient. The invention also relates to the method of preparation of said pharmaceutical composition and its use as a medicament for the treatment of vulvovaginitis & genital candidiasis.

Description

TARIFNAME FENTIKONAZOL NITRAT IÇEREN TOPIKAL BIR FARMASÖTIK BILESIM BULUSUN DAHIL OLDUGU TEKNIK ALAN Mevcut bulus, a) Fentikonazol veya bunun farmasötik olarak kabul edilebilir tuzu, b) badem yagi ve o) en az bir ek eksipiyan içeren topikal bir farmasötik bilesim ile ilgilidir. Bulus ayrica söz konusu farmasötik bilesimin hazirlama yöntemi ve Gram pozitif bakterilerin ve genital kandidiyazisin neden oldugu vulvovajinit ve servisit tedavisinde ilaç olarak kullanimi ile ilgilidir. TEKNIGIN BILINEN DURUMU Vajinit, vajina iltihabi, vajinal mikrobiyotayi degistiren ve akinti, kasinti ve agri ile sonuçlanan çesitli dis ve iç faktörlerden kaynaklanir. Iç faktörler, mikroorganizmalarin neden oldugu herhangi bir enfeksiyonu dis etkenler ise sigara kullanmak, diyabet, östrojen seviyesinin düsmesi vb. durumlari ifade eder. Vajinitin büyük bir kismina bakteriyel vajinozis, vulvovajinal kandidiyazis ve trikomonal vajinit neden olur, faz-1 klinik çalismalara göre üreme çagindaki kadinlarda vakalarin yaklasik %90'ini temsil eder. Patojenik bakteri türleri, vajinal ortamin pH degerinin degismesiyle bakteriyel vajinoza neden olur. Bakteriyel vajinozun yaygin semptomlari kötü koku, iltihaplanma, tahris ve vajinal akintidir. Vulvovajinal kandidiyazis, esas olarak vajinal floranin bir parçasi olan Candida albicans'in asiri büyümesinden kaynaklanir. Semptomlari bakteriyel vajinoz ile hemen hemen aynidir. Candida albicans disinda diger Candida türleri, yani Candida glabrata, Candida perapsilosis, Candida krusei, Candida cerevisiae vulvovajinal kandidiyaza neden olabilir. Teknigin bilinen durumunda bakteriyel veya fungal enfeksiyonlara bagli vajinal hastaliklarin, azol türevleri (örnegin: Fenticonazole, Clotrimazole, Flucanozole, Travozol, Butaconazole, Itrakonazole, Miconazole, Terconazole) ile krem, fitil, merhem, ovül ve yumusak kapsül gibi farkli dozaj formlariyla tedavi edildigi iyi bilinmektedir. Fentikonazol, kimyasal adiyla1-[2-(2,4-diklorofeniI)-2-{[4 (fenilsülfanil) fenil] metoksi} etiI]-1H-imidazol olarak bilinmektedir. Fentikonazol, genis antimikotik aktivite spektrumuna sahip bir imidazol türevidir. Mantar duvarinin olusumunda önemli bir adim olan ergosterol sentezini inhibe eder ve mantar hücresinin peroksit birikimi ve nekrozu ile oksitleyici enzimleri bloke eder. in vitro çalismalar, dermatofit patojenleri, Malassezia furfur ve Candida albicans dahil olmak üzere bir dizi organizmaya karsi kullanildigini göstermistir. Antifungal ilaç olarak da bilinen Fentikonazol nitrat tuzu, vulvovajinal kandidiyaz tedavisinde farkli ticari isimlerle piyasada mevcuttur. (Lomexin®, Gynoxin®, Fentizol® vb.) Fentikonazol, antitungal imidazol ilaç sinifina aittir ve bu nedenle yüksek geçirgenlige eksipiyanlarin seçimi ve üretim yöntemi kritik kalite niteliklerinin elde edilmesinde önemli bir rol oynar. Fentikonazol nitrat, Recordati ilaçtarafindan Gyno-Lomexin® ticari adi ile vulvovajinal kandidiyaz tedavisinde kullanilan bir krem olarak piyasada bulunmaktadir. Yatmadan önce vajinaya lokal olarak (gerekirse sabahlari da) 3 gün boyunca haricen uygulanir. Yeniden bulasmayi önlemek için partnerin de harici olarak uygulamasi önerilir. Gyno-Lomexin ® 3 g gliseril monostearat, 0,5 9 disodyum edetat, 0,5 9 yag asidi esteri, 1 g hidrojene lanolin, 10 g badem yagi, 5 g propilen glikol, 3 g setil alkol, 60.5 9 su içerir. (httpszllwww.vidal.ru/drugs/Iomexin__13232) US 4221803 ilk kez Fentikonazol'ü bir bilesik olarak, Fentikonazolün ve farmasötik olarak kabul edilebilir tuzlarinin hazirlanmasi için bir islemi, farmasötik bir bilesimi ve bunun mantarlar, mayalar ve gram pozitif aerobik ve anaerobik bakterilerin neden oldugu enfeksiyonlarin tedavisi için kullanimini açiklar. Antifungal ilaçlardan imidazol sinifina dahil olan Fentikonazolün özellikle lokal olarak uygulanmasiyla ilgili teknigin bilinen durumunda birçok döküman vardir. yaklasik %10 ila %50 oraninda bir yag asidi esteri; yaklasik %10 ila %250 alifatik antioksidan; pH araligini yaklasik 3.0 ila 7.0 arasinda bir degere ayarlamak için yeterli miktarda inorganik baz ve su içeren farmasötik bir bilesimle ilgilidir. içeren bir bilesimi açiklar: a) terapötik olarak etkili miktarda bir antifungal madde; ve b) enfekte olmus alanin pH'ini yaklasik 2.5 ila yaklasik 5.5 arasinda tutabilen bir tampon çözelti. miktarinda laktik asit; %5 ile %90 miktarinda çözücü ve %05 ile %10 miktarinda polimer içeren bir vajinal sprey bilesimini açiklar. mikroemülsiyonunda yag içeren farmasötik bir formülasyonu açiklar. tuzunu, b) antibakteriyel bir madde veya bunun farmasötik olarak kabul edilebilir bir tuzunu, istege bagli olarak, bir veya daha fazla analjezik veya lokal anestezik madde ve d) farmasötik olarak kabul edilebilir bir yardimci madde içeren vulvovajinal enfeksiyonlarin tedavisinde kullanilan farmasötik bir bilesimi açiklar. EP 1435907 A2 bir veya daha fazla antifungal madde, bir veya daha fazla suda çözünmeyen madde, bir veya daha fazla suda çözünen madde içeren ve antifungal maddenin Fentikonazol olabilecegi bir antifungal merhem bilesimini açiklar. CN 102240284 A etkin madde olarak Fentikonazol ve birim formüldeki Fentikonazol miktarinin 20 mg ile 100 mg arasinda oldugu ve bu farmasötik bilesimin harici olarak fitil, spray, yikama sivisi, macun olarak kullanabilecegi bir bilesimi açiklar. monostearat, %1-%9 oraninda stearik asit, %1-%9 oraninda sivi parafin, %7-%25 oraninda propilen glikol, % 0.1- %04 etil p-hidroksibenzoat, % 0.05 - %8 polisorbat, CN 103655512 B mikronize Fentikonazol nitrat içeren ve özelligi yumusak kapsül kabugu ve yumusak kapsül içermesi olan bir vajinal yumusak kapsülü açiklar. olusan bir fitil bilesimini ve üretim yöntemini açiklar. Optimum etkiyi saglamak için Fentikonazol nitrat içere stabil bir topikal farmasötik bilesim gelistirmek için teknigin bilinen durumund çesitli çalismalar yapilmistir. Ancak referans ürün Gyno-Lomexin® kremin belirli kosullar altinda stabilite sonuçlari degerlendirilirken, referans ürünün farli Iotlarinin stabilite sonuçlarinda degisiklik gösterdigi gözlemlenmistir. Bu nedenle, Fentikonazol nitrat içeren uygun geçirgenlige sahip ve tutarli stabilite gösterebilen topikal bir farmasötik bilesim gelistirmeye hala ihtiyaç oldugu açiktir. Mevcut bulusun mucitleri, sasirtici bir sekilde, badem yagi konsantrasyonunun azaltilmasiyla, orijinatör firmanin referans ürününe ait farkli lotlarinda gözlemlenen stabilite probleminin üstesinden gelmenin mümkün oldugunu bulmuslardir. BULUSUN AMACI Mevcut bulusun bir amaci, Fentikonazol nitrat içeren ve belirli bir periyot boyunca tutarli stabilite gösteren topikal bir farmasötik bilesim elde etmektir. Mevcut bulusun bir diger amaci, önceki teknikte yasanan problemlerin üstesinden gelen Fentikonazol nitrat içeren topikal bir farmasötik bilesim elde etmektir. Mevcut bulusun yine bir diger amaci, belirli bir periyot boyunca tutarli stabilite gösteren ve istenen geçirgenlige sahip, Fentikonazol nitrat içeren topikal farmasötik bir bilesim elde etmektir. BU LUSUN ÖZETI Mevcut bulus bir açidan; - agirlikça %1-10 oraninda Fentikonazol veya farmasötik olarak kabul edilebilir tuzu, - agirlikça % 0,5-1 oraninda badem yagi, - agirlikça %O.2-2 oraninda en az bir ek eksipiyan içeren bir topikal farmasötik bilesimi açiklar. Mevcut bulus baska bir açidan, nitrat tuzu olarak Fentikonazol içeren bir topikal farmasötik bilesim açiklar. Mevcut bulus baska bir açidan, tasiyici olarak badem yagi içeren Fentikonazolün topikal farmasötik bir bilesimini açiklar. Mevcut bulus bir baska açidan, emülgatör, selatlama ajani, penetrasyon ajani, tasiyici, solvent ve antioksidandan olusan bir gruptan seçilen en az bir ek eksipiyan içeren Fentikonazolün topikal farmasötik bilesimini saglar. Mevcut bulus bir baska açidan, en az bir ek eksipiyani antioksidan olarak oleik asit, pentetik asit, poloksamer, polioksietilen alki eterler, alfa tokoferol, askorbil palmitat ve bütillenmis hidroksitoluen içeren bir gruptan seçilen birtopikal farmasötik Fentikonazol bilesimi açiklar. Mevcut bulus bir baska açidan, antioksidan olarak bütillenmis hidroksitoluen içeren Fentikonazolün topikal farmasötik bir bilesimini açiklar. Mevcut bulus bir baska açidan, Fentikonazolün topikal farmasötik bir bilesimini krem olarak açiklar. Mevcut bulus halihazirda bir baska açidan, vulvovajinit ve genital kandidiyaz tedavisi için Fentikonazolün topikal farmasötik bilesiminin kullanimini saglar. SEKILLERIN AÇIKLANMASI Sekil-1, Örnek-7'nin karsilastirmali olarak farkli referans ürün lotlarina göre in vitro salim profillerini gösteren bir grafiktir. MEVCUT BULUSUN DETAYLI AÇIKLAMASI Mevcut bulus asagida daha ayrintili olarak açiklanacaktir. Mevcut bulusta kullanilan "topikal farmasötik bilesim" terimi, vücutta veya vücutta belirli bir yüzeye uygulanan farmasötik bir bilesim anlamina gelir. Çogu zaman topikal farmasötik bilesim, kremler, jeller, damlalar, losyonlar, ovül ve merhemler dahil ancak bunlarla sinirli olmayan genis bir dozaj formu sinifi yoluyla cilt veya mukoza zarlari gibi vücut yüzeylerine uygulama anlamina gelir. Mevcut bulusta kullanilan 'Fentikonazol' terimi, bunlarla sinirli olmamak üzere, Fentikonazol ve farmasötik olarak kabul edilebilir tuzlari, farmasötik olarak kabul edilebilir solvatlari, farmasötik olarak kabul edilebilir hidratlarii farmasötik olarak kabul edilebilir enantiomerleri, farmasötik olarak kabul edilebilir türevleri, farmasötik olarak kabul edilebilir polimorflari ve farmasötik olarak kabul edilebilir prodruglarini içerir. Genel uygulamalarda mevcut bulus, asagidakileri içeren bir topikal farmasötik bilesimi açiklar: - agirlikça %1-10 oraninda Fentikonazol veya farmasötik olarak kabul edilebilir - agirlikça % 0,5-1 oraninda badem yagi, - agirlikça %02- 2 oraninda en az bir ek eksipiyan. Belirli uygulamalarda mevcut bulus, Fentikonazol nitrat tuzu içeren topikal farmasötik bilesimi açiklar. Belirli uygulamalarda mevcut bulus, tasiyici olarak badem yagi içeren topikal farmasötik bilesimi açiklar. Bilesimin toplam agirligina göre agirlikça %1 ila %5 oraninda tasiyici kullanilabilir. Belirli uygulamalarda mevcut bulus, emülgatör, selatlayici ajan, penetrasyon ajani, tasiyici, çözücü ve antioksidandan olusan bir gruptan seçilen en az bir ek eksipiyan içeren bir topikal farmasötik bilesimi açiklar. Emülgatör, bunlarla sinirli olmamakla birlikte, gliseril monostearat, setil alkol, hidroksipropil nisasta, sorbitan Iaurat, sorbitan stearat, polisorbat 20, polisorbat 80, sodyum lauril sülfat, sodyum oleat ve trietanolamin oleat içeren bir gruptan seçilebilir. Bilesimin toplam agirligina göre agirlikça %2 ile %15 oraninda emülgatör kullanilabilir. Selatlayici ajan, bunlarla sinirli olmamakla birlikte sitrik asit monohidrat, disodyum edetat, edetik asit, fumarik asit, malik asit içeren bir gruptan seçilebilir. Bilesimin toplam agirligina göre agirlikça %2 ile %15 oraninda selatlayici ajan kullanilabilir. Penetrasyon ajani, bunlarla sinirli olmamakla birlikte, hidrojene Ianolin, glikofurol, polioksietilen alkil eterler, pirolidon, trikaprilin içeren bir gruptan seçilebilir. Bilesimin toplam agirligina göre agirlikça %1 ile %5 oraninda penatrasyon ajani kullanilabilir. Antioksidan, bunlarla sinirli olmamakla birlikte, badem yagi, alfa tokoferol, askorbik asit, bütillenmis hidroksianisol, bütillenmis hidroksitoluen, sitrik asit monohidrat, metionin, propiyonik asit, sodyum askorbat içeren bir gruptan seçilebilir. Bilesimin toplam agirligina göre agirlikça %0.01 ile %1 oraninda antioksidan kullanilabilir. Belirli uygulamalarda mevcut bulus, antioksidan olarak butillenmis hydroksitoluen içeren topikal farmasötik bilesimi açiklar. Belirli uygulamalarda mevcut bulus, krem olan bir topikal farmasötik bilesimi açiklar. Belirli uygulamalarda mevcut bulus, krem formunda bir topikal farmasötik bilesim olup yag ve su fazinin belirli oranlarda belirli sicaklikta homojenizatör altinda Belirli uygulamalarda mevcut bulus, vulvovajinit ve genital kandidiyaz tedavisinde kullanilan bir topikal farmasötik bilesimi açiklar. Mevcut bulus bunlarla sinirli olmamakla birlikte asagidaki örnekler araciligiyla ile daha ayrintili bir sekilde tarif edilecektir. Örnekler: Örnek-1: Referans Ürünün (Gyno-Lomexin®) farkli lotlarina ait stabilite sonuçlari Gym' Safsizlik B (%) LorrIi-:îin® 25°C 30°C 40°C numaralari T=O 3.ay 6.ay T=O 3.ay 6.ay T=O 3.ay &ay Yukarida belirtildigi gibi referans ürüne ait farkli Iotlarin 25°C, 30°C ve 40°C"de 3.ay ve 6.aylardaki Safsizlik B miktarlari degerlendirildi. Tablo-1'de belirtilen stabilite sonuçlarina göre Safsizlik B miktarinin lotlar arasinda degisiklik gösterdigi ve 6 ay boyunca belirtilen tüm sicakliklarda arttigi gözlemlenmektedir. Örnek - 2, 3 & 4: Badem yagi konsantrasyonun stabilite sonuçlarina etkisi Içindekiler Birim formül Birim formül Birim formül Fentikonazol Nitrat 2.00 2.00 2.00 Gliseril Monostearat 7.00 7.00 7.00 Disodyum Edta 0.50 0.50 0.50 Hidrojene Ianolin 2.00 2.00 2.00 Setil Alkol 5.50 5.50 5.50 Üretim Yöntemi: 1. Solüsyon Tankina Saf Su alinir. Solüsyon Tankina Disodyum Edta eklenir ve 25 rpm'de 10 dakika karistirilir. Solüsyon Tankina Propilen Glikol eklenir ve 25 rpm'de 10 dakika karistirilir. Solüsyon Tanki 75-800C'ye kadar 25 rpm' de 15 dakika karistirilarak isitilir. 91.45.93!`J Imalat tanki ESD-85°C' ye isitilir. Imalat tankina Gliseril Monostearat (40-55) ve Setil Alkol alinir. 60-65°C"de 8 rpmide 20 dakika isitilarak karistirilir. 6. Imalat tankina Hidrojene Lanolin eklenir. 60-650C"de 8 rpm'de 10 dakika karistirilir. 9. Imalat tankina Fentikonazol Nitrat eklenir ve 75-80°C'de 55 rpm'de 30 dakika karistirilir. .4. basamakta hazirlanan su fazi, 10. basamakta hazirlanan yag fazi üzerine açik karistirilir. dakikada 55 rpm'de karistirilarak getirilir. 12.Ürün sicakligi 25-30 °C'ye düstügünde imalat tankina Badem Yagi eklenir ve -300C'de 55 rpm'de 20 dakika homojenizatör açilarak karistirilir. 14.Ürün 25-30 °C`de iken imalat tankina vakum uygulanir. Vakum islemi 0.4 bar 55 rpmide 15 dakika yapilir. .Bqu ürün stok tankina 560u perlon kaba filtreden süzülerek transfer edilir ve Badem yagi konsantrasyonunun stabilite üzerindeki etkisini gözlemlemek için üç farkli prototip (Ör-2, 3 ve 4) hazirlanmistir. Asagidaki Tablo-3'te belirtilen farkli stabilite kosullarina tabi tutularak üç prototipe ait Safsizlik B miktarlari kontrol edilmistir. Tablo- 3'te gösterilen stabilite sonuçlarina göre düsük miktarda badem yaginin düsük miktarda safsizlik B ile sonuçlandigi net olarak anlasilmaktadir. Prototipler Badem Yagi (%) Safsizlik B (%) Safsizlik B (%) Safsizlik B (%) Örnek-5 & 6: Butilhidroksitoluenin Stabilite Sonuçlari Üzerindeki Etkisi Prototipler BHT Badem yagi Safsizlik B (%) Safsizlik B (%) Safsizlik B (%) Örnek-5 ve 6, Örnek-2, 3 ve 4'te kullanilan üretim yöntemi ile hazirlanmistir. Antioksidan maddenin stabilite üzerindeki etkisini degerlendirmek için iki farkli prototip (Ör-5 ve 6) hazirlanmistir. Tablo-4'ten de anlasildigi üzere BHT varliginda Safsizlik B miktarinin azaldigi gözlemlenmektedir. Örnek-7: Mevcut bulusta bahsedilen Fentikonazol nitrat içeren krem'in hazirlanmasi Içindekiler Birim formül Fentikonazol Nitrat 2.00 Gliseril Monostearat 7.70 Xalifin-15 16.50 Butylhydroxytoluene 0.075 Disodyum Edetat 0.55 Hidrojene Ianolin 2.20 Badem Yagi 1.00 Propilen Glikol 5.50 Setil Alkol 6.05 Toplam 100.00 Üretim Yöntemi: . Solüsyon Tankina Saf Su alinir. Solüsyon Tankina Disodyum Edetat eklenir ve 25 rpm'de 10 dakika karistirilir. Solüsyon Tankina Propilen Glikol eklenir ve 25 rpm'de 10 dakika karistirilir. Solüsyon Tanki 75-80°C"ye kadar 25 rpm* de 15 dakika karistirilarak isitilir. Imalat tanki (SO-85°C' ye isitilir. Imalat tankina Gliseril Monostearat (40-55) ve Setil Alkol alinir. 60-850C"de 8 rpm'de 20 dakika isitilarak karistirilir. Imalat tankina Hidrojene Lanolin eklenir. 60-65°C'de 8 rpm'de 10 dakika karistirilir. 8. Imalat tanki 75-80°C"ye isitilir ve 55 rpm'de 30 dakika karistirilir. dakika karistirilir. karistirilir. 11.4. basamakta hazirlanan su fazi, 10. basamakta hazirlanan yag fazi üzerine açik karistirilir. 12. Ürününün kademeli sogutma islemi baslatilir. Ürünün sicakligi 25-30°C'ye 120 dakikada 55 rpmide karistirilarak getirilir. 13.Ürün sicakligi 25-30 c*Ciye düstügünde imalat tankina Badem Yagi eklenir ve -30°C,de 55 rpm'de 20 dakika homojenizatör açilarak karistirilir. .Ürün 25-30 °C'de iken imalat tankina vakum uygulanir. Vakum islemi 0.4 bar 55 rpmlde 15 dakika yapilir. 16.Bqu ürün stok tankina 560u perlon kaba filtreden süzülerek transfer edilir ve Örnek-8: Örnek-Tye ait in-vitro salinim çalismalari Örnek-7'ye ait farmasötik bilesim, Dikey Difüzyon Hücresi-Model A, 47 mm izgarali ve 0,45 um Milipore S-Pack Filtresi içeren Franz Hücre Difüzyon Sistemi kullanilarak in vitro salim profilini referans ürünle karsilastirmak için degerlendirilmistir. Membran olarak Milipore S-Pack Filtre kullanilmistir. Membran, in vitro salim ortami (PBS:EtanoI) ile nemlendirilmistir ve 6 Franz hücre haznesine yerlestirilmistir. Analiz, 24 saat boyunca 500 rpm'de 37°C (±O.5°C) sicaklikta gerçeklestirilmis ve Tablo-6'de sonuçlar belirtilmistir. TR TR TR TR DESCRIPTION A TOPICAL PHARMACEUTICAL COMPOSITION CONTAINING FENTICONAZole NITRATE TECHNICAL FIELD INCLUDING THE INVENTION The present invention relates to a topical pharmaceutical composition comprising a) Fenticonazole or a pharmaceutically acceptable salt thereof, b) almond oil and o) at least one additional excipient. The invention also relates to the preparation method of the said pharmaceutical composition and its use as a medicine in the treatment of vulvovaginitis and cervicitis caused by Gram-positive bacteria and genital candidiasis. BACKGROUND OF THE ART Vaginitis, inflammation of the vagina, is caused by various external and internal factors that alter the vaginal microbiota and result in discharge, itching and pain. Internal factors are any infection caused by microorganisms, and external factors are smoking, diabetes, low estrogen levels, etc. represents situations. The majority of vaginitis is caused by bacterial vaginosis, vulvovaginal candidiasis and trichomonal vaginitis, representing approximately 90% of cases in women of reproductive age according to phase-1 clinical studies. Pathogenic bacterial species cause bacterial vaginosis by changing the pH value of the vaginal environment. Common symptoms of bacterial vaginosis are foul odor, inflammation, irritation, and vaginal discharge. Vulvovaginal candidiasis is caused by overgrowth of Candida albicans, which is primarily part of the vaginal flora. Its symptoms are almost the same as bacterial vaginosis. Apart from Candida albicans, other Candida species, namely Candida glabrata, Candida perapsilosis, Candida krusei, Candida cerevisiae, can cause vulvovaginal candidiasis. In the state of the art, it is well known that vaginal diseases due to bacterial or fungal infections are treated with azole derivatives (for example: Fenticonazole, Clotrimazole, Flucanozole, Travozol, Butaconazole, Itraconazole, Miconazole, Terconazole) and different dosage forms such as cream, suppository, ointment, pessary and soft capsule. is known. Fenticonazole is known by its chemical name as 1-[2-(2,4-dichlorophenyl)-2-{[4 (phenylsulfanyl) phenyl] methoxy} ethyl]-1H-imidazole. Fenticonazole is an imidazole derivative with a broad spectrum of antimycotic activity. It inhibits ergosterol synthesis, an important step in the formation of the fungal wall, and blocks peroxide accumulation and necrosis of the fungal cell and oxidizing enzymes. In vitro studies have demonstrated its use against a range of organisms, including dermatophyte pathogens, Malassezia furfur and Candida albicans. Fenticonazole nitrate salt, also known as an antifungal drug, is available in the market under different trade names for the treatment of vulvovaginal candidiasis. (Lomexin®, Gynoxin®, Fentizol® etc.) Fenticonazole belongs to the antitungal imidazole drug class and therefore the selection of high permeability excipients and the production method play an important role in achieving critical quality attributes. Fenticonazole nitrate is marketed by Recordati Pharmaceuticals under the trade name Gyno-Lomexin® as a cream used in the treatment of vulvovaginal candidiasis. It is applied externally to the vagina before going to bed, locally (in the morning if necessary) for 3 days. It is recommended that the partner also apply externally to prevent reinfection. Gyno-Lomexin ® contains 3 g glyceryl monostearate, 0.5 9 disodium edetate, 0.5 9 fatty acid ester, 1 g hydrogenated lanolin, 10 g almond oil, 5 g propylene glycol, 3 g cetyl alcohol, 60.5 9 water. (httpszllwww.vidal.ru/drugs/Iomexin__13232) US 4221803 first described Fenticonazole as a compound, a process for the preparation of Fenticonazole and its pharmaceutically acceptable salts, a pharmaceutical composition and its properties against fungi, yeasts and gram-positive aerobic and anaerobic bacteria. Explains its use for the treatment of infections. There are many documents in the state of the art regarding the local application of Fenticonazole, which belongs to the imidazole class of antifungal drugs. about 10% to 50% of a fatty acid ester; approximately 10% to 250% aliphatic antioxidant; It relates to a pharmaceutical composition comprising water and an inorganic base sufficient to adjust the pH range to a value between approximately 3.0 and 7.0. discloses a composition comprising: a) a therapeutically effective amount of an antifungal agent; and b) a buffer solution capable of maintaining the pH of the infected area between about 2.5 and about 5.5. amount of lactic acid; It discloses a vaginal spray composition comprising 5% to 90% solvent and 05% to 10% polymer. discloses a pharmaceutical formulation containing oil in its microemulsion. It discloses a pharmaceutical composition for use in the treatment of vulvovaginal infections comprising its salt, b) an antibacterial agent or a pharmaceutically acceptable salt thereof, optionally one or more analgesic or local anesthetic agents, and d) a pharmaceutically acceptable excipient. EP 1435907 A2 discloses an antifungal ointment composition comprising one or more antifungal agents, one or more water-insoluble substances, one or more water-soluble substances, and the antifungal agent may be Fenticonazole. CN 102240284 A describes a composition in which Fenticonazole is the active ingredient and the amount of Fenticonazole in the unit formula is between 20 mg and 100 mg, and this pharmaceutical composition can be used externally as a suppository, spray, washing liquid or paste. monostearate, 1% - 9% stearic acid, 1% - 9% liquid paraffin, 7% - 25% propylene glycol, 0.1% - 04% ethyl p-hydroxybenzoate, 0.05% - 8% polysorbate, CN 103655512 B micronized It discloses a vaginal soft capsule containing fenticonazole nitrate, characterized by a soft capsule shell and a soft capsule. It describes the composition and production method of a suppository. Various studies have been carried out within the state of the art to develop a stable topical pharmaceutical composition containing Fenticonazole nitrate to ensure optimum effect. However, while evaluating the stability results of the reference product Gyno-Lomexin® cream under certain conditions, it was observed that different Iodes of the reference product showed changes in the stability results. Therefore, it is clear that there is still a need to develop a topical pharmaceutical composition containing Fenticonazole nitrate that has appropriate permeability and can demonstrate consistent stability. Surprisingly, the inventors of the present invention have found that by reducing the concentration of almond oil, it is possible to overcome the stability problem observed in different lots of the original company's reference product. OBJECT OF THE INVENTION It is an object of the present invention to provide a topical pharmaceutical composition containing Fenticonazole nitrate that exhibits consistent stability over a period of time. Another object of the present invention is to obtain a topical pharmaceutical composition containing Fenticonazole nitrate that overcomes the problems experienced in the prior art. It is yet another object of the present invention to obtain a topical pharmaceutical composition containing Fenticonazole nitrate that exhibits consistent stability over a period of time and has the desired permeability. SUMMARY OF THE INVENTION The present invention is in one respect; It discloses a topical pharmaceutical composition comprising - 1-10% by weight of Fenticonazole or a pharmaceutically acceptable salt thereof, - 0.5-1% by weight of almond oil, - 0.2-2% by weight of at least one additional excipient. In another aspect, the present invention discloses a topical pharmaceutical composition comprising Fenticonazole as the nitrate salt. In another aspect, the present invention discloses a topical pharmaceutical composition of Fenticonazole containing almond oil as a carrier. In another aspect, the present invention provides a topical pharmaceutical composition of Fenticonazole comprising at least one additional excipient selected from the group consisting of emulsifier, chelating agent, penetrating agent, carrier, solvent and antioxidant. In another aspect, the present invention discloses a topical pharmaceutical Fenticonazole composition selected from the group comprising oleic acid, pentetic acid, poloxamer, polyoxyethylene alkyl ethers, alpha tocopherol, ascorbyl palmitate and butylated hydroxytoluene as antioxidant with at least one additional excipient. In another aspect, the present invention discloses a topical pharmaceutical composition of Fenticonazole containing butylated hydroxytoluene as an antioxidant. In another aspect, the present invention discloses a topical pharmaceutical composition of Fenticonazole as a cream. In yet another aspect, the present invention provides the use of a topical pharmaceutical composition of Fenticonazole for the treatment of vulvovaginitis and genital candidiasis. DESCRIPTION OF THE FIGURES Figure-1 is a graph showing the comparative in vitro release profiles of Example-7 compared to different reference product lots. DETAILED DESCRIPTION OF THE PRESENT INVENTION The present invention will be described in more detail below. The term "topical pharmaceutical composition" as used in the present invention means a pharmaceutical composition applied to the body or to a specific surface on the body. Most often, topical pharmaceutical composition refers to application to body surfaces such as skin or mucous membranes via a broad class of dosage forms including, but not limited to, creams, gels, drops, lotions, rubs, and ointments. The term 'Fenticonazole' as used in the present invention includes, but is not limited to, Fenticonazole and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and Contains pharmaceutically acceptable products. In general applications, the present invention discloses a topical pharmaceutical composition comprising: - 1-10% by weight of Fenticonazole or pharmaceutically acceptable - 0.5-1% by weight of almond oil, - 02-2% by weight of at least one additional excipient . In certain embodiments, the present invention discloses a topical pharmaceutical composition comprising Fenticonazole nitrate salt. In certain embodiments, the present invention discloses a topical pharmaceutical composition comprising almond oil as a carrier. Carrier can be used at a rate of 1% to 5% by weight, based on the total weight of the composition. In certain embodiments, the present invention discloses a topical pharmaceutical composition comprising at least one additional excipient selected from the group consisting of an emulsifier, chelating agent, penetrating agent, carrier, solvent and antioxidant. The emulsifier may be selected from a group including, but not limited to, glyceryl monostearate, cetyl alcohol, hydroxypropyl starch, sorbitan Iaurate, sorbitan stearate, polysorbate 20, polysorbate 80, sodium lauryl sulfate, sodium oleate and triethanolamine oleate. Emulsifier can be used at a rate of 2% to 15% by weight, depending on the total weight of the composition. The chelating agent may be selected from the group consisting of, but not limited to, citric acid monohydrate, disodium edetate, edetic acid, fumaric acid, malic acid. A chelating agent can be used at a rate of 2% to 15% by weight, depending on the total weight of the composition. The penetration agent may be selected from a group including, but not limited to, hydrogenated lanolin, glycofurol, polyoxyethylene alkyl ethers, pyrrolidone, tricapryline. Penetration agent can be used at a rate of 1% to 5% by weight, depending on the total weight of the composition. The antioxidant may be selected from a group including, but not limited to, almond oil, alpha tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, methionine, propionic acid, sodium ascorbate. Antioxidant can be used at a rate of 0.01% to 1% by weight, depending on the total weight of the composition. In certain embodiments, the present invention discloses a topical pharmaceutical composition comprising butylated hydroxytoluene as an antioxidant. In certain embodiments, the present invention discloses a topical pharmaceutical composition that is a cream. In certain embodiments, the present invention is a topical pharmaceutical composition in the form of a cream, in which the oil and water phase are mixed in certain proportions under a homogenizer at a certain temperature. In certain embodiments, the present invention discloses a topical pharmaceutical composition used in the treatment of vulvovaginitis and genital candidiasis. The present invention will be described in more detail through, but not limited to, the following examples. Examples: Example-1: Stability results of different lots of the Reference Product (Gyno-Lomexin®) Gym' Impurity B (%) LorrIi-:îin® 25°C 30°C 40°C numbers T=O 3rd month 6th month T=O 3rd month 6th month T=O 3rd month &month As stated above, the amounts of Impurity B of different Iodes of the reference product at 25°C, 30°C and 40°C in the 3rd and 6th months were evaluated. Table According to the stability results stated in -1, it is observed that the amount of Impurity B varies between lots and increases at all temperatures specified for 6 months. Example - 2, 3 & 4: Effect of almond oil concentration on stability results Contents Unit formula Unit formula Unit formula Fenticonazole Nitrate 2.00 2.00. 2.00 Glyceryl Monostearate 7.00 7.00 7.00 Disodium Edta 0.50 0.50 0.50 Hydrogenated Ianoline 2.00 2.00 2.00 Cetyl Alcohol 5.50 5.50 5.50 Production Method: 1. Pure Water is taken into the Solution Tank and Disodium Edta is added to the Solution Tank and 25 rpm. Propylene Glycol is mixed in the Solution Tank for 10 minutes. is added and mixed at 25 rpm for 10 minutes. The Solution Tank is heated to 75-800C with stirring at 25 rpm for 15 minutes. 91.45.93!` J The manufacturing tank is heated to ESD-85°C. Glyceryl Monostearate (40-55) and Cetyl Alcohol are taken into the production tank. It is mixed by heating at 60-65°C at 8 rpm for 20 minutes. 6. Hydrogenated Lanolin is added to the production tank. It is mixed at 60-650C at 8 rpm for 10 minutes. 9. Fenticonazole Nitrate is added to the production tank and mixed for 30 minutes at 55 rpm at 75-80°C. . The water phase prepared in the 4th step is mixed openly onto the oil phase prepared in the 10th step. It is mixed at 55 rpm per minute. 12.When the product temperature drops to 25-30 °C, Almond Oil is added to the manufacturing tank and mixed by opening the homogenizer for 20 minutes at 55 rpm at -300C. 14. While the product is at 25-30 °C, vacuum is applied to the manufacturing tank. Vacuum process is performed at 0.4 bar and 55 rpm for 15 minutes. . Bqu product is transferred to the stock tank by filtering through a 560u perlon coarse filter and three different prototypes (Ex-2, 3 and 4) were prepared to observe the effect of almond oil concentration on stability. Impurity B amounts of three prototypes were checked by subjecting them to different stability conditions specified in Table-3 below. According to the stability results shown in Table-3, it is clearly understood that low amount of almond oil results in low amount of impurity B. Prototypes Almond Oil (%) Impurity B (%) Impurity B (%) Impurity B (%) Example-5 & 6: Effect of Butylhydroxytoluene on Stability Results Prototypes BHT Almond oil Impurity B (%) Impurity B (%) Impurity B (% ) Examples-5 and 6 were prepared with the production method used in Examples-2, 3 and 4. Two different prototypes (Ex-5 and 6) were prepared to evaluate the effect of the antioxidant substance on stability. As can be seen from Table-4, it is observed that the amount of Impurity B decreases in the presence of BHT. Example-7: Preparation of the cream containing Fenticonazole nitrate mentioned in the present invention Ingredients Unit formula Fenticonazole Nitrate 2.00 Glyceryl Monostearate 7.70 Cetyl Alcohol 6.05 Total 100.00 Production Method: . Pure Water is taken into the Solution Tank. Disodium Edetate is added to the Solution Tank and mixed at 25 rpm for 10 minutes. Propylene Glycol is added to the Solution Tank and mixed at 25 rpm for 10 minutes. The Solution Tank is heated to 75-80°C with stirring at 25 rpm* for 15 minutes. The manufacturing tank is heated to (SO-85°C). Glyceryl Monostearate (40-55) and Cetyl Alcohol are taken into the manufacturing tank. At 60-850C It is mixed by heating at 8 rpm for 20 minutes. Hydrogenated Lanolin is added to the production tank and mixed at 8 rpm for 10 minutes. The production tank is heated to 75-80°C and mixed at 55 rpm for 30 minutes. The water phase prepared in step 11.4 is mixed openly over the oil phase prepared in step 10. 12. The gradual cooling process of the product is started. The temperature is brought to 25-30°C by mixing at 55 rpm in 120 minutes. 13. When the product temperature drops to 25-30 °C, Almond Oil is added to the manufacturing tank and the product is mixed by opening the homogenizer at 55 rpm at -30°C. Vacuum is applied to the manufacturing tank while it is at 25-30 °C. The vacuum process is carried out for 15 minutes at 0.4 bar 55 rpm. 16. The product is transferred to the stock tank by filtering through a 560u perlon coarse filter and Example-8: In-vitro release studies of Example-T. The pharmaceutical composition of Example 7 was evaluated using the Franz Cell Diffusion System with Vertical Diffusion Cell-Model A, 47 mm grid and 0.45 µm Millipore S-Pack Filter to compare its in vitro release profile with the reference product. Pack Filter was used. The membrane was moistened with in vitro release medium (PBS:Ethanol) and placed in 6 Franz cell chambers. The analysis was carried out at 500 rpm at 37°C (±O.5°C) for 24 hours and the results are shown in Table-6.TR TR TR TR

Claims

CLAIMS . It is a topical pharmaceutical composition.

- 1-10% of Fenticonazole or its pharmaceutically acceptable salt, - 0.5-1% of almond oil and - 0.

It contains at least one additional excipient at a rate of 2-2%. . A topical pharmaceutical composition according to claim 1, comprising Fenticonazole as its nitrate salt. . According to the claim, it is a topical pharmaceutical composition containing almond oil as a carrier. . A topical pharmaceutical composition according to claim 1, wherein at least one additional excipient is selected from the group consisting of emulsifier, chelating agent, penetrating agent, carrier, solvent and antioxidant. . A topical pharmaceutical composition according to claim 1 or 4, wherein the at least one additional excipient is an antioxidant selected from the group consisting of oleic acid, pentetic acid, poloxamer, polyoxyethylene alkyl ethers, alpha tocopherol, ascorbyl palmitate and butylated hydroxytoluene. . A topical pharmaceutical composition according to claim 4 or 5, comprising butylated hydroxytoluene as an antioxidant. . A topical pharmaceutical composition according to claim 5 or 6, wherein the butylated hydroxytoluene concentration is 0.075%. . A topical pharmaceutical composition according to claim 1, wherein the topical pharmaceutical composition is a cream. . A topical pharmaceutical composition according to claim 1, for use of the topical pharmaceutical composition for the treatment of vulvovaginitis and genital candidiasis.