TR2023013011A2 - ORAL THIN FILM (OTF) FORMULATIONS CONTAINING MESARTAN AND HYDROCHLOROTHIAZIDE (HCTZ) NANOPARTICLES TOGETHER BE EFFECTIVE IN HYPERTENSION TREATMENT - Google Patents
ORAL THIN FILM (OTF) FORMULATIONS CONTAINING MESARTAN AND HYDROCHLOROTHIAZIDE (HCTZ) NANOPARTICLES TOGETHER BE EFFECTIVE IN HYPERTENSION TREATMENTInfo
- Publication number
- TR2023013011A2 TR2023013011A2 TR2023/013011 TR2023013011A2 TR 2023013011 A2 TR2023013011 A2 TR 2023013011A2 TR 2023/013011 TR2023/013011 TR 2023/013011 TR 2023013011 A2 TR2023013011 A2 TR 2023013011A2
- Authority
- TR
- Turkey
- Prior art keywords
- amount
- sodium
- feature
- complies
- nanocrystals
- Prior art date
Links
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 229960002003 hydrochlorothiazide Drugs 0.000 title claims abstract description 65
- 239000000203 mixture Substances 0.000 title claims abstract description 26
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- 206010020772 Hypertension Diseases 0.000 title abstract description 26
- 238000011282 treatment Methods 0.000 title description 14
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002552 dosage form Substances 0.000 claims abstract description 25
- 230000000694 effects Effects 0.000 claims abstract description 22
- 238000009472 formulation Methods 0.000 claims abstract description 20
- 239000013543 active substance Substances 0.000 claims abstract description 11
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 57
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 45
- 239000002159 nanocrystal Substances 0.000 claims description 43
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 claims description 19
- 235000015165 citric acid Nutrition 0.000 claims description 19
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 claims description 16
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 claims description 16
- 229960001199 olmesartan medoxomil Drugs 0.000 claims description 16
- 235000011187 glycerol Nutrition 0.000 claims description 15
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims description 15
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims description 15
- 235000012141 vanillin Nutrition 0.000 claims description 15
- 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 claims description 14
- 239000011734 sodium Substances 0.000 claims description 14
- 235000015424 sodium Nutrition 0.000 claims description 14
- 229910052708 sodium Inorganic materials 0.000 claims description 14
- 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 13
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- 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 4
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
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- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 claims description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 3
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 3
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 3
- -1 Polyethylene Polymers 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
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 3
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- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 claims description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
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Abstract
Bu buluş; hipertansiyon hastaları için ayrı ayrı kullanılan iki ilaç etkin maddesi tek bir kombine ilaç formu haline getirilmiş, bu sayede farmakolojik etki hızlandırılmış, yan etki azaltılmış ve/veya en aza indirilmiş, aynı zamanda iki ayrı ilacı ayrı ayrı temin etmenin ekonomik açıdan dezavantajı giderilmiş, katı dozaj şekillerini yutma güçlüğü çeken veya yatalak veya mental problemi olan hastalar için alternatif bir dozaj formu olarak, suya erişimin olmadığı anlarda dahi güvenle kullanabilecek ve hipertansiyon hastalarının yaşam standardını artırabilecek yenilikçi ilaç taşıyıcı sistemle ince film (OTF) olarak Olmesartan medoksimil ve Hidroklorotiyazid (HCTZ) kombinasyonunu içeren oral ince film dozaj formunda hazırlanan formülasyonlar ile ilgilidir.This invention; Two drug active substances used separately for hypertension patients have been turned into a single combined drug form, thereby accelerating the pharmacological effect, reducing and/or minimizing side effects, and at the same time eliminating the economic disadvantage of providing two separate drugs separately, solid dosage. It contains the combination of Olmesartan medoximil and Hydrochlorothiazide (HCTZ) as a thin film (OTF) with an innovative drug carrier system that can be used safely even when there is no access to water and can increase the standard of living of hypertension patients, as an alternative dosage form for patients who have difficulty swallowing or who are bedridden or have mental problems. It relates to formulations prepared in oral thin film dosage form.
Description
TARIFNAME HIPERTANSIYON TEDAVISINDE ETKILI OLMESARTAN VE HIDROKLOROTIYAZID (HCTZ) NANOPARTIKÜLLERINI BIRLIKTE IÇEREN ORAL INCE FILM (OTF) FORMÜLASYONLARI Teknik Alan Bu bulus; hipertansiyon hastalari için ayri ayri kullanilan veya kombine halde yalnizca tablet halinde kullanilan iki ilaç etkin maddesini suya ve yutmaya gereksinim duymayan yeni bir dozaj formu olarak halinde sunarak; farmakolojik etkiyi hizlandirmak, yan etkiyi de azaltmak ve/veya en aza indirmek, iki ayri ilaci ayri ayri almanin ekonomik açidan dezavantajini gidermek, kati dozaj sekillerini yutma güçlügü çeken veya yatalak veya mental problemi olan hastalar için alternatif bir dozaj formu gelistirmek, suya erisimin olmadigi anlarda dahi güvenle ilaci kullanabilmek ve hepsinden önemlisi hipertansiyon hastalarinin yasam standardini artiracak yenilikçi bir formülasyonlari (oral ince filmler, OTF) ile ilgilidir. Bu bulusa konu olan üründe hipertansiyon tedavisinde ayri ayri kullanilan veya kombine halde yalnizca tablet halinde ilaç pazarinda mevcut olan Olmesartan medoksimil ve Hidroklorotiyazid (HCTZ) etkin maddeleri, yenilikçi bir dozaj sekli (OTF) içerisinde birlestirilerek hem ekonomik hem de hasta uyuncu açisindan avantajli bir ürün haline getirilmistir. Teknigin Bilinen Durumu Hipertansiyon, dünya genelinde kardiyovasküler hastaliklarda özellikle böbrek yetmezligi gibi hastaliklara yol açan önemli bir risk faktörüdür. Insanlarin yasi ilerledikçe kan basincinda degismeler meydana gelerek hipertansiyon hastaligi riski artar. 65 yas üstü insanlarin yarisindan fazlasinda hipertansiyon vardir ve yasam boyunca bu hastaliga yakalnma olasiligi %90 dan fazladir. Sistolik kan basinci 140 mmHg, diyastolik kan basincinin da 90 mmHg veya daha yüksek olmasi hipertansiyon olarak adlandirilmaktadir. Sistolik kan basinci 120-139 mmHg, diyastolik kan basinci 80-89 mmHg araliginda olan duruma da baslangiç hipertansiyonu yani prehipertansiyon denir. ESH/ESC klavuzlarina göre, hastalara yasam tarzi degisikligi ile beraber ilaç tedavileri önerilmistir. Hipertansiyon çok yönlü bir patofizyolojiye sahip oldugu için kan basincini tek bir ilaçla degil kombine ilaç tedavisiyle daha iyi etki edecegi yapilan arastirmalarda görülmüstür. Ayrica iki terapötik ajanin tek seferlik dozuna kiyasla daha düsük dozlarda birlestirilmesi de daha az yan etki olsumuna sebebiyet vereceginden avantajlidir. Günümüzde hipertansiyon tedavisinde birçok ilaç kombinasyonu tedavisi mevcuttur. Kardiyovasküler riskinin oldugu hastalarda tek bir antihipertansif ajanla kan basincinin normal seviyeye getirilmesi zor oldugu için ikili kombinasyonlar ilk tercih sebebidir. Yapilan çalismalarda dirençli hipertansiyonu olan hastalarda diüretik ile yapilan kombine tedavilerde, nefronun distal segmentlerinde sodyum reabsorpsiyonunu azaltarak kan basincini düsürmede yararli bir etkisi oldugu görülmüstür. Anjiyotensin Dönüstürücü Enzim (ACE) inhibitörleri ya da Anjiotensin II Reseptör Antagonistlerinin (ARB) diüretiklerle yapilan kombinasyonlari güçlü bir etki göstermesi bakimindan en çok tercih edilen kombine ilaçlardandir. Bunun sebebi diüretikler ile indüklenen negatif sodyum dengesi renin sistemi tetikler dolayisiyla anjiyotensin II üretimi de tetiklenerek kan basincinin kontrol edilmesi anjiyotensin Il"ye bagimli hale gelir. Bu durumda renin anjiyotensin sistemini hedef alan ilaçlar (ACE ya da ARB) anjiyotensin Il'nin üretimini bloke ederek diüretiklerin kan basincini düsürücü etkilerini artirmis olurlar. Ayrica diger bir durum ise diüretikle indüklenen aldosteronun stimülasyonu ile ortaya çikan hipokalemi, ACE ya da ARB"lerin kullanilmasiyla baskilanarak potasyum dengesi korunur. Tek basina ACE ya da ARB blokörleri kullanimina kiyasla kan basinci kontrolü bu kombinasyonlarda daha üstündür. Renin Anjiyotensin Sistemini Hedef Alan (RAS) ilaçlarin diüretiklerle kombinasyonu, bir kalsiyum kanal blokörü ile diüretik kombinasyonuna göre kardiyovasküler hastalik riskini ve kronik böbrek hastaliginin ilerleme riskini belirgin sekilde azaltigi bildirilmistir. Bu kombinasyonlarda, ACE inhibitörleri bradikinin benzeri peptidlerin yikimina bagli hastalarda kuru öksürük ve anjiyoödeme sebep olurken ARB"lerde ise bu tür yan etkiler görülmez. Anjiyotensin reseptör blokeri (ARB) grubu ilaçlardan biri olan Olmesartan (Olmesartan medoksomil) bir ön ilaçtir. Olmesartan medoksomil endotelyal düz kastaki anjiyotensin I reseptörlerine seçici olarak baglanarak anjiyotensin Il'nin vazokonstriktör ve aldosteron salgilayan etkilerini inhibe eder böylece yüksek kan basincini düsürmektedir. Olmesartan, Biyofarmasötik Siniflandirma Sistemi'nde (BCS) Sinif II ilaç grubunda oldugundan iki önemli dezavantaja sahiptir. Bunlar suda düsük çözünürlük ve zayif biyoyararlanimidir. Olmesartan, hipertansiyonda günde bir kez 20 mg'lik dozda verilir. Gerek oldugu durumlarda günlük dozu 40 mg'a çikartilabilir. Oral yoldan kullanildiktan sonra emilimi hizlidir (tmax 1-3) ve maksimum serum konsantrasyonuna (Cmax) ise 2 saatte ulasir. Gastrointestinal sistemden emildikten sonra gastrointestinal mukozada, portal kanda ve karacigerde esterazlarla metabolite olarak aktif olan Olmesartan'a dönüsür. Sitokrom p450 enzimleri ve diger ilaçlarla etkilesime girme potansiyeli düsüktür. Yarilanma ömrü ise 10-15 saat arasinda degisirken vücuttan atilimi büyük oranda feçes ve idrarla olur. Hipertansiyon tedavisinde genellikle kombine tedavilerde HCTZ, oral yoldan 12.5 mg'lik bir baslangiç dozu ile kullanilirken gerekirse dozu günde 25 ila 50 mg'a kadar çikarilabilir. Gastrointestinal sistemde emilimi hizli ve biyoyararlanimi oldukça iyidir (%65-%70). Oral yolla kullanimindan sonra etkisi 2 saat sonra baslar ve 4 saat sonra maksimum degere ulasir. Etkisi 6-12 saat sürer. HCTZ metabolize olmadigindan idrarla degismeden atilir. Hipertansiyon tedavisinde kullanilan ilaç gruplari günümüzde daha çok tablet seklinde olmaktadir. Bu tedaviler, hastaliga sahip kisiler için istenmeyen yan etkiler olusturmakla birlikte kullanim için suya gereksinim duyulmasi ve özellikle yutma problemi çekilmesi gibi uyunç sorunlarini da beraberinde getirmektedir. Bu problemleri üstesinden gelebilmek için ilaç endüstrisi ve günümüz ilaç teknolojileri yeni ilaç tasiyici sistemler üzerinde çalismaktadir. Oral olarak uygulanan tabletler önceden belirlenmis dozlarin uygulamanin invaziv olmayan avantajiyla en yaygin ilaç uygulama sekli olurken zayif biyoyararlanim, zayif çözünürlük, sinirli etkinlik veya toksik düzeyinin üstüne çikmasi gibi dezavantajlara sahiptirler. Yeni ilaç tasiyici sistemler farmasötik bilesiklerin uygulanmasini ve etkinligini gelistirmeyi amaçlayarak tasarlanmaktadirlar. Bu sayede, çözünürlük sorunu düzeltilebilir, pH degisiklikleri tolore edilebilir, ilacin salim mekanizmasi konrol edilebilir. Böylece etkin maddenin dozu azaltilarak ve uygulama sikligi degistirilerek yan ve toksik etkiler azaltilabilir ve/veya ortadan kaldirilabilir. Sonuçta hasta uyuncu iyilestirilebilir ve hastanin yasam konforu artirilabilir. Bu yeni ilaç tasiyici sistemler içerisinde nanoteknoloji kullanilarak hazirlanan nanopartiküler ilaç tasiyici sistemler güncel olarak oldukça fazla çalisilmaktadir. Bu sistemler arasinda nanokapsüller, nanoküreler, nanosüngerler, nanoemülsiyonlar, nanopartiküller, nanoveziküler sistemler (lipozomlar, niozomlar), moleküler sistemler (inklüzyon bilesikleri) ve nanokristaller (nanosüspansiyonlar) bulunmaktadir. Nanopartiküllerin sivi ortamda dagitilmasi sonucu nanosüspansiyonlar olusur. Nanosüspansiyonlar oral, topikal ve parenteral uygulama için gelistirilmis genellikle su bazli, ortalama parçacik boyutu 200 ile 600 nm arasinda olan kati ilaç partikülleri içeren yeni ilaç tasiyici sistemlerden biri olarak tanimlanir. Nanosüspansiyonlar, çözünürlük problemini ortadan kaldirmanin yani sira ilaçlarin biyoyararlanimini da artirarak ilaç konsantrasyonunu maksimum plazma seviyesine daha çabuk ulasmasina yardimci olurlar. Ayrica liyofilize ya da püskürterek kurutma yöntemiyle nanopartikül haline de getirilip kullanilacagi zaman süspande edilebilir bir özellige de sahiptirler. Bulusa konu olan üründeki her iki etkin maddenin (Olmesartan ve HCTZ) suda çözünürlügü düsük olmasi sebebiyle nanosüspansiyonlari (nanokristalleri) hazirlanmistir. Ilaç uygulama yollarindan oral yol, uygulama kolayligi yaninda hasta uyuncunun yüksek ve kabul edilebilirliginden dolayi en çok kullanilan ilaç uygulama yollarindan birisidir. Ancak, oral uygulama geriatri, pediatri, yatalak, anksiyete ve panik bozuklugu olan hastalarda yutma zorlugu, bogulma, mide bulantisi gibi uyumsuzluklara sebep oldugundan oral yoldan uygulanabilecek alternatif yöntemler gelistirilmeye baslanmistir. Basta yutma zorlugunun üstesinden gelmek için 1970'lerin sonlarina dogru hizli çözünen oral uygulama sistemleri ve OTF fikri ortaya çikmistir. tablet/kapsül yutmanin getirdigi psikolojik faktörlerin de ortadan kaldirilmasi önemlidir. Bunun disinda konvansiyonel kati dozaj sekillerinin (tablet, kapsül) su gerektirmeden kullanilabilmesi mümkün degildir. Yolculuk esnasinda ya da suya ulasilamayan durumlarda kullanilamamaktadirlar. Bunun yani sira asil bu dozaj seklinin majör dezavantaj ise ilacin farmakolojik etkilerinin hemen görülememesidir. Mideye ulasip çözünüp/dagilmasi için geçen süre ile farmakolojik etkinin ortaya çikmasi ortalama olarak 30-60 dakikayi bulmaktadir. Farmakolojik etkinin bir an evvel baslanmasi istenen durumlarda konvansiyonel tablet ve kapsüller yetersiz kalmaktadir. Sonuç olarak eski teknik/yöntemdeki: i. Olmesartan ve HCTZ ayri ayri iki ilaç olarak ya da bir arada yalnizca kati dozaj sekli olan tablet halinde dünya ilaç pazarinda yer almaktadir. Dolayisiyla bu iki ilaç etkin maddesini kullanmak isteyen hastalar ya ayri ayri bu ilaçlari almak durumundalar ya da ikisini bir arada mecburen tablet olarak kullanmak zorundadirlar, ii. Bazi hasta gruplari, özellikle pediatrik ve geriatrik hastalar, kati dozaj formlarini yutma veya çignemekte güçlük çekmektedirler. Birçok pediatrik ve geriatrik hasta, bogulma korkusu nedeniyle kati dozaj sekillerini (tablet, kapsül) alma konusunda isteksizdirler, iii. Hipertansiyon hastalari için antihipertansif etkiyi özellikle de kati dozaj sekilleri ile sunan (tablet veya kapsül) ve alternatifsiz olarak olarak ilaç iv. Hali hazirda ilaç pazarinda var olan konvansiyonel dozaj sekilleri (tablet veya kapsül) ile kisisellestirilmis tedaviyi saglayamamak, v. Iki ayri ilaci ayri ayri almanin ekonomik açidan dezavantaj olusturmasi, vi. Kati dozaj sekillerini yutma güçlügü çeken veya yatalak veya mental problemi olan hipertansif hastalar için alternatif bir dozaj formu olmamasi, vii. Suya erisimin olmadigi anlarda dahi ilacin güvenle kullanilamamasi, gibi eksiklikler ve dezavantajlar bulunmaktadir. Mevcut teknikte yer alan çalismalar incelendiginde birden fazla probleme ayni anda çözüm olmayi hedefleyen, hem ekonomik hem de hasta uyuncu açisindan avantajli bir ürün haline getiren oral kullanim için gelistirilmis formülasyonlara ihtiyaç duyuldugu görülmektedir. Bulusun Açiklamasi Bu açiklamada bulus sadece konunun daha iyi anlasilmasina yönelik olarak ve hiçbir sinirlayici etki olusturmayacak sekilde açiklanmaktadir. Bulusun yapisal ve karakteristik özellikleri ve tüm avantajlari asagida yazilan detayli açiklama sayesinde daha net olarak anlasilacaktir ve bu nedenle degerlendirmenin de bu açiklama göz önüne alinarak yapilmasi gerekmektedir. Mevcut bulus, yukarida bahsedilen gereksinimleri karsilayan, tüm dezavantajlari ortadan kaldiran ve ilave bazi avantajlar getiren agizda hizli dagilan tablet dozaj formunda formülasyonlar ile ilgilidir. Agizda hizli dagilan tablet dozaj formunda bir formülasyon en temel halinde; Olmesartan medoksimil ve Hidroklorotiyazid (HCTZ) kombinasyonunu içeren oral ince film dozaj formunda formülasyonlari içermektedir. Nanoteknoloji kullanilarak Olmesartan medoksimil ve Hidroklorotiyazid (HCTZ)'yi nano boyuta indirilerek daha düsük dozda bu ilaçlarin kullanilabilmelerine imkan saglanmistir. Ayni zamanda absorpsiyonlarini artiracak ve de farmakolojik etkilerini hizlandiracak yenilikçi bir dozaj formu (OTF) seklinde tasarlanarak hipertansiyon hastalarinin yasam standardinin ve konforunun artirilmasi amaçlanmistir. Agizda hizli dagilan tablet formunda olan bu bulus dilin ucuna veya tabanina yerlestirilir ve tükürük ile 30-60 saniye içerisinde islanir. Bu sekilde, tabletin içerisinde yer alan ilaç etkin maddeleri serbestleserek lokal ve/veya sistemik absorpsiyon için dagiIir ve/veya çözünür. Gelistirilen bulus ile her iki etkin maddeyi de ayni anda içeren ve hizli bir etki baslangici sunan ilaç dozaj formlari seklindedir. Dünya ilaç pazarinda kullanimda olan dozaj sekilleri incelendiginde her iki ilaci da ayni anda içeren ve hizli bir etki baslangici sunan ilaç dozaj formu ne ilaç pazarinda ne de literatür çalismalarinda yer almaktadir. Birçok farmasötik preparat, tablet, granül, toz ve sivi formda uygulanmaktadir. Genel olarak tablet tasarimi hastalara kesin bir ilaç dozu vermek amaciyla yutulan veya çignenen bir formdadir. Bununla birlikte bazi hasta gruplari, özellikle pediatrik ve geriatrik hastalar, kati dozaj formlarini yutma veya çignemekte güçlük çekmektedirler. Birçok pediatrik ve geriatrik hasta, bogulma korkusu nedeniyle bu kati dozaj sekillerini alma konusunda isteksizdir. Tabletler tüm oral dozaj formlari içerisinde yüksek doz homojenligi saglayabilen ve en iyi içerik tekdüzeligine sahip dozaj formudur. Ayrica tüm oral dozaj formlarinin içerisinde en uygun üretim maliyetine sahip dozaj formu da tabletlerdir. Ancak çocuk ve yasli popülasyon için uygulanmasi güç olan bu yöntem, oral yoldan kullanilabilecek yeni bir ilaç formuna ihtiyaç oldugunu göstermistir. Teknolojideki son gelismeler tablet ve kapsül gibi kati dozaj formundaki ilaçlari yutmakta zorluk çeken (disfaji) hastalar için yeni nesil "Oral Ince Film" ler (OTF) gibi alternatif dozaj sekilleri gelistirmeye baslamistir. Bugün gelinen noktada pek çok reçeteli ve reçetesiz ürün grubunda özellikle öksürükte, soguk alginliginda, bogaz agrilarinda, erektil disfonksiyon bozukluklarinda, alerjik reaksiyonlarda, astimda, gastrointestinal bozukluklarda, hipertansiyonda, agri tedavilerinde, horlama sikâyetlerinde, uyku problemlerinde, multivitamin kombinasyonlarinda OTF'lerin kullanimlari giderek artmakta ve ilaç endüstrisi tarafindan konvansiyonel ilaçlarin OTF'ye dönüsümleri de devam etmektedir. Bu yeni nesil dozaj formu ile disfaji de denilen yutma güçlügü çeken tüm yas gruplarindaki hastalar için, tablet/kapsül kullanmanin olusturdugu psikolojik faktörlerin de ortadan kaldirilmasi hedeflenmektedir. Bunun yani sira su gerektirmeden kullanilabilmesi ile yolculuk esnasinda ya da suya ulasilamayan durumlarda dahi kolaylikla ilacin kullanimi gerçeklestirilebilmektedir. Asil bu dozaj seklinin sundugu majör avantaj ise ilacin farmakolojik etkilerinin hemen görülmesidir. Gelistirdigimiz formülasyonlarimiz içerisinde Olmesartan ve HCTZ'yi nano boyutlu partiküller halinde sunmanin avantaji olarak agiz içi ve dilalti mukozadan çok hizli bir absorpsiyon saglamak ve hizli bir farmakolojik etki baslatmak, tansiyonu bir an önce toparlamak mümkün olacaktir. Özellikle yanak içi ve dilaltindan geçen kilcal damarlar vasitasiyla agizda hizli bir dagililma ya da çözünmeye ugrayan bu dozaj sekli içerisindeki etkin maddelerin kana hizla karismasi ve farmakolojik etkinin hizli bir biçimde baslatilmasi da söz konusu olacaktir. Daha düsük doz Olmesartan ve HCTZ nanokristalleri kullanarak etkin bir tedavi sunmanin yani sira etkin maddelerden kaynakli yan etkileri azaltmak ve/veya en aza indirmek de mümkün olabilecektir. Gastrointestinal sisteme geçmeden önce agiz içerisinde tamamen çözünmüs ve dagilmis olan bu ilaç formülasyonu ile ilk geçis etkisi ve mide bagirsak sistemindeki absorpsiyondan kaynakli gecikmelerin de önü alinmis olacaktir. OTF sistemleri, agiza yerlestirildiginde 1 dakika içinde parçalanan/çözünebilen/dagilabilen; çigneme, yutma ve su gereksinimi duyulmadan kullanilabilen kati dozaj formlardir. OTF'ler, hidrofilik polimerler kullanilarak hazirlanan, dil üstüne veya tabanina yerlestirilerek kullanilan, tükürük ile temasta hizli bir çözünme saglayan birkaç mikron kalinliginda ilaç formülasyonlaridir. Amerikan Ilaç ve Gida Dairesi (FDA) ise OTF'yi, bir veya daha fazla etkin madde içeren, gastrointestinal sisteme geçmeden önce dil üzerine yerlestirilerek tükürük içinde hizlica çözünen/parçalanan esnek ve kirilgan olmayan bir serit ifadeleriyle tanimlanmaktadir. OTF'ler pekçok essiz avantaja sahiptir. Bunlar arasinda: i. Etkin maddelerin ilk geçis etkisine ugramamasi ve düsük dozlarda dahi hizli etki sunmasi, ii. Su gereksiniminin olmamasi, iii. Bogulma riskinin olmamasi, iv. Düsük doz etkin madde içermesinden kaynakli daha az yan etki riski tasimasi, v. Acil durumlarda hizli etki saglamasi, vi. Tadin kolay maskelenmesi ve agizda hos bir tat birakmasi, vii. Uygulama kolayligi sunmasi, viii. Kullanimindan sonra agizda çok az veya hiç kalinti kalmamasi, ix. Stabilitenin korunmasi, x. Agiz fonksiyonlarinin isleyisini etkilememesi, xi. Suda çözünmeyen hidrofobik ilaçlar için uygulanabilir olmasi ve biyoyararlanimlarinin artirmasi sayilabilir. Bulusun öncelikli amaci; oral ince film formunda olmasi sebebiyle daha hizli etki baslangici sunmasinin yani sira hipertansiyondan muzdarip disfajik, geriatrik, yatalak veya mental engelli hastalarin ihtiyaç duyduklari her an ve her ortamda yutma gereksinimi olmadan, suya ihtiyaç duymadan ilaçlarini konforlu bir sekilde kullanabilmelerinin saglanmasi, ekonomik olarak iki ayri ilaca ödenen harcamanin azaltilmasidir. Bulusun bir diger amaci; amaci suya erisimin mümkün olmadigi durumlarda yine tüm hipertansif hasta gruplarinin rahatça kullanabildigi yenilikçi ilaç dozaj formülasyonlarinin gelistirilmesidir. Ayrica bulusta yer alan OTF formülasyonlari ile hipertansiyon hastalari için antihipertansif etkiyi hizlandirmak (özellikle de kati dozaj sekli ile sunulan ve alternatifsiz olarak yalnizca tablet olarak ilaç pazarinda var olan konvansiyonel tablete kiyasla), Olmesartan ve HCTZ"yi nanokristaller halinde OTF'lere yükleyerek agiz içi ve dilalti mukozadan çok hizli bir absorpsiyon ile bu hizli etkiyi saglamak, daha düsük doz Olmesartan ve HCTZ nanokristalleri içeren OTF'ler ile etkin maddelerden kaynakli yan etkileri azaltmak ve/veya en aza indirmek saglanabilecektir. Oral ince film dozaj formunda bir formülasyon en temel halinde; Olmesartan medoksimil ve Hidroklorotiyazid (HCTZ) kombinasyonunu içermektedir. Bulusta tercihen Olmesartan medoksimilin Hidroklorotiyazid (HCTZ)'e orani tercihen 1:2,5'tir. Bulusun tercih edilen tüm uygulamalarinda gelistirilen film 5 mg bir miktarda Olmesartan medoksimil ile 12,5 mg bir miktarda Hidroklorotiyazid (HCTZ) içermektedir. Oral ince film formunda olan bulus dilin ucuna veya tabanina yerlestirilir ve tükürük ile 30-60 saniye içerisinde islanir. Bu sekilde, filmde bulunan etkin maddeler serbestleserek lokal ve/veya sistemik absorpsiyon için dagilir ve/veya çözünür. Gelistirilen bulus ile her iki etkin maddeyi de ayni anda içeren ve hizli bir etki baslangici sunan ilaç dozaj formlari hazirlanmistir. Gelistirilen formülasyon içerisinde kullanilan tüm yardimci maddeler suda çözünmektedir. Olmesartan medoksimil ve Hidroklorotiyazid (HCTZ) ise Poloksamer 407 yüzey aktif madde varliginda "Nanopresipitasyon" teknigi kullanilarak 500 nm'nin altinda partikül boyutuna sahip olacak sekilde nanokristaller halinde formülasyonlarda kullanilmistir. Yani hazirlanan bu OTF'ler dilaltina veya ucuna yerlestirildiginde tükürük ile çok çabuk bir sekilde çözünmektedir. Dolayisiyla hizli bir etki alinabilmesi, suya ihtiyaç duyulmadan ve yutma güçlügü yasanmadan kullanilabilmesi mümkün olmaktadir. Bu sayede hem hizli bir etki baslangici ortaya çikmakta hem de hastanin sikayetleri kisa sürede karsiligini bulmaktadir. Çünkü dilalti mukozasinin ince membran yapisi ve oldukça fazla kan damarina sahip olmasi sebebiyle permeabilitesi yüksektir. Bu hizli kanlanma sebebiyle çok çabuk bir biyoyararlanim söz konusudur. Mide- bagirsaktan emilim (absorpsiyon) kismi atlandigi için karacigerden ilk geçis etkisi de ortadan kalkmis olmaktadir. Bu hizli biyoyararlanim, ilk geçis etkisinin atlanmasindan ve daha iyi permeabiliteden kaynaklidir. Ayrica emilim için genis yüzey alani ve uygulama kolayligi, sistemik ilaç tasinmasinda oral mukozayi çok etkili ve seçici bir yol yapmaktadir. Bu sayede tüm hipertansif hasta bireylerin tablet veya kapsül kullanmadan, bu ilaçlari kombine halde dil üstüne veya altina koyarak su gerektirmeden kolayca alabilmeleri saglanir. Bulusun tercih edilen bir uygulamasinda gelistirilen formülasyon tercihen Tablo 1, Tablo 2 ve Tablo 3"te verilen miktarlara uygun olarak asagida belirtilen en az bir yardimci madde içermektedir: i. Pektin, Jelatin, Sodyum aljinat, Polimerize reçine, Hidroksi propil metil selüloz (HPMC), Hidroksi etil selüloz (HEC), Karboksi metil selüloz (CMC), Sodyum karboksi metil selüloz (NaCMC), Metil selüloz (MC), Pullulan, Polivinilpirolidon (PVP), Polivinil alkol (PVA), Polietilen glikol (PEG) veya bunlarin kombinasyonunu içeren gruptan seçilen en az bir dogal polimer (daha tercihen Pullulan ve Sodyum aljinat kombinasyonu; Pektin, Jelatin, Sodyum aljinat, Polimerize reçine, Hidroksi propil metil selüloz (HPMC), Hidroksi etil selüloz (HEC), Karboksi metil selüloz (CMC), Sodyum karboksi metil selüloz (NaCMC), Metil selüloz (MC), Pullulan, Polivinilpirolidon (PVP), Polivinil alkol (PVA), Polietilen glikol (PEG) veya bunlarin kombinasyonunu içeren gruptan seçilen en az bir dogal polimer (daha tercihen Pullulan, Sodyum aljinat ve Jelatin kombinasyonu; Tablo 2); Pektin, Jelatin, Sodyum aljinat, Polimerize reçine, Hidroksi propil metil selüloz (HPMC), Hidroksi etil selüloz (HEC), Karboksi metil selüloz (CMC), Sodyum karboksi metil selüloz (NaCMC), Metil selüloz (MC), Pullulan, Polivinilpirolidon (PVP), Polivinil alkol (PVA), Polietilen glikol (PEG) veya bunlarin kombinasyonunu içeren gruptan seçilen en az bir dogal polimer (daha tercihen Pullulan ve Sodyum aljinat kombinasyonu; Gliserol, Propilen glikol, Sorbitol çözeltisi (% 50, %60 veya %70"lik), PEG 800, PEG 400 PEG 300 veya bunlarin kombinasyonunu içeren gruptan seçilen ve filmin esnekligini saglayan en az bir elastiklestirici (daha tercihen Gliserol); Sitrik asit, Askorbik asit, Laktik asit veya Tartarik asit içeren bir gruptan seçilen en az bir tükrük salgilatici ajan (daha tercihen Sitrik asit); 407, Poloksamer 188, Lesitin, Etil oleat veya Izopropil myristat'tan biri ya da bunlarin kombinasyonunu içeren gruptan seçilen ve etkin maddelerin nanokristallerinin eldesinde kullanilan en az bir yüzey aktif madde (daha tercihen Poloksamer 407); 407, Poloksamer 188, Lesitin, Etil oleat veya Izopropil myristat'tan biri ya da bunlarin kombinasyonunu içeren gruptan seçilen ve OTF hazirlamada yüzey aktiflik saglayan en az bir yüzey aktif madde (daha tercihen Tween viii.Aspartam, Sodyum sakarin, Stevia, Sükraloz veya Asesülfam içeren bir gruptan seçilen en az bir tatlandirici ajani (daha tercihen Sodyum sakarin); ix. Korskarmelloz sodyum, Kollidon CL, Ksantan zamki, Krospovidon, Sodyum nisasta glikolat, Hidroksipropil selüloz, Ac-Di-Sol®, Solutab®, Nymce ZSX®, Primellose®, Vivasol®, Polyplasdone®, Explotab®, Primojel®, Satialgine®, Sodyum bikarbonat veya bunlarin kombinasyonunu içeren gruptan seçilen ve filmin hizli parçalanmasini saglayan en az bir süper dagitici (daha tercihen Sodyum nisasta glikolat); x. Vanilin yerine, Karamel, Neroli, Ökaliptol, Nane, Portakal, Tarçin veya Çikolata aromasi içeren bir gruptan seçilen en az bir aroma verici ajan (daha tercihen Vanilin); xi. Distile su veya aromatik su içermektedir. Bilesen Adi Agirlikça kullanilabilir miktar (%) Olmesartan medoksomil nanokristalleri 2,5-10,0 Hidroklorotiyazid (HCTZ) nanokristalleri 10,0-25,0 Sodyum aljinat 20,0-40,0 Gliserol 10,0-25,0 Sitrik asit 2,5-10,0 Sodyum sakarin 2,5-10,0 Sodyum nisasta glikolat 2,5-10,0 Distile Su kullanilip buharlastirildigi için agirliga etkisi bulunmamaktir Bilesen Adi Agirlikça kullanilabilir miktar (%) Olmesartan medoksomil nanokristalleri 2,5-10,0 Hidroklorotiyazid (HCTZ) nanokristalleri 10,0-25,0 Sodyum aljinat 5,0-20,0 Jelatin 5,0-20,0 Gliserol 10,0-30,0 Sitrik asit 2,5-10,0 Sodyum sakarin 2,5-10,0 Sodyum nisasta glikolat 2,5-10,0 Distile Su kullanilip buharlastirildigi için agirliga etkisi bulunmamaktir Bilesen Adi Agirlikça kullanilabilir miktar (%) Olmesartan medoksomil nanokristalleri 2,5-10,0 Hidroklorotiyazid (HCTZ) nanokristalleri 10,0-25,0 Sodyum aljinat 15,0-35,0 Gliserol 10,0-25,0 Sitrik asit 2,5-10,0 Sodyum sakarin 2,5-10,0 Sodyum nisasta glikolat 5,0-20,0 Distile Su kullanilip buharlastirildigi için agirliga etkisi bulunmamaktir Bulusun tercih edilen bir uygulamasinda gelistirilen formülasyon; Olmesartan medoksomil nanokristalleri, Hidroklorotiyazid (HCTZ) nanokristalleri, Sodyum aljinat, Pullulan, Gliserol, Sitrik asit, Sodyum sakarin, Sodyum nisasta glikolat, Tween 80 ve Vanilin çermektedir. Bulusun tercih edilen bir uygulamasinda gelistirilen formülasyon; Olmesartan medoksomil nanokristalleri, Hidroklorotiyazid (HCTZ) nanokristalleri, Sodyum aljinat, Pulluan , Jelatin, Gliserol, Sitrik asit, Sodyum sakarin, Sodyum nisasta glikolat, Tween 80 ve Vanilin içermektedir. Bulusun tercih edilen bir uygulamasinda gelistirilen formülasyon; Olmesartan medoksomil nanokristalleri, Hidroklorotiyazid (HCTZ) nanokristaller, Sodyum aljinat, Pullulan, Gliserol, Sitrik asit, Sodyum sakarin, Sodyum nisasta glikolat, Tween 80 ve Vanilin içermektedir. Bulusun örnek bir uygulamasinda gelistirilen formülasyon su islem adimlari izlenerek hazirlanmaktadir: Olmesartan medoksimiI nanokristalleri için en az 1 mg hassasiyete sahip hassas terazide bir viyal içerisine 1,0 mg Poloksamer 407 ve 1,0 mL distiIe su tartilir. Baska bir viyal içerisine de 5.0 mg Olmesartan ve 1.0 mL Metanol tartilir. Çok noktali manyetik karistirici üzerinde 750 rpm hizda su fazi üzerine organik faz 228 enjektör yardimi ile damla damla ilave edilir. Damlatma bitiminde ek olarak 5 dk bu sekilde homojen bir karistirma saglanir. Organik fazin uzaklastirilmasi amaciyla 45 °C"de 5 dk süreyle vakum altinda buharlastirma islemi uygulanir (bir rotovapor araciligiyla). Bu esnada Olmesartan medoksimil nanokristalleri elde edilir. Elde edilen nanokristaller saf su ile süspande edilip, bir gece -20 °C'de dondurulurlar. Devaminda 24 saat süreyle de liyofilize edilerek kuru toz hale getirilirler (bir liyofilizatör araciligiyla). HCTZ nanokristalleri için en az 1 mg hassasiyete sahip hassas terazide bir viyal içerisine 2,5 mg Poloksamer 407 ve 2,5 mL distile su tartilir. Baska bir viyal içerisine de 12,5 mg HCTZ ve 2,5 mL Metanol tartilir. Çok noktali manyetik karistirici üzerinde 750 rpm hizda su fazi üzerine organik faz 22G enjektör yardimi ile damla damla ilave edilir. Damlatma bitiminde ek olarak 5 dk bu sekilde homojen bir karistirma saglanir. %50 güç, siklus 4"te ve 5 dk süreyle bu karisim üzerine sonikasyon uygulanir. Organik fazin uzaklastirilmasi amaciyla 45 °C"de 5 dk süreyle vakum altinda buharlastirma islemi uygulanir (bir rotovapor araciligiyla). Bu esnada HCTZ nanokristalleri elde edilir. Elde edilen nanokristaller saf su ile süspande edilip, bir gece -20 °C'de dondurulurlar. Devaminda 24 saat süreyle de liyofilize edilerek kuru toz hale getirilirler (bir liyofilizatör araciligiyla). OTF'ler için formülasyonu olusturan tüm bilesenler tüm bilesenlerinin en az 1 mg hassasliga sahip hassas bir terazide tartilmasi; tartilan bilesenlerin tercihen 2-4 saat süreyle distile su (tercihen 24 fomülasyonluk kalip için 24 mL) içerisinde karistirilmasi; karisimin tercihen 20-60 °C (daha tercihen 40 °C) sicakliga ayarlanmis bir manyetik karistirici üzerinde tercihen 5-60 dk (tercihen 10 dk) daha karistirilmaya devam edilerek isitilmasi ve çözündürülmesi; sicak eriyik hale gelen karisimin bir kaliba dökülmesi; kaliba dökülen karisimin tercihen 6-72 saat (tercihen 48 saat) süreyle oda sicakliginda (tercihen 25 °C) kurutulmasi ve esit oranda Olmesartan medoksimil ve HCTZ içerecek sekilde her bir bagimsiz kaliptan çikarilmasi; ayri ayri kilitli posetler içerisinde, nemden, isidan ve isiktan uzak bir sekilde, oda sicakliginda (25 °C), kullanilacagi ana kadar saklanmasi. TR DESCRIPTION ORAL THIN FILM (OTF) FORMULATIONS CONTAINING TOGETHER MESARTAN AND HYDROCHLOROTHIAZIDE (HCTZ) NANOPARTICLES EFFECTIVE IN THE TREATMENT OF HYPERTENSION Technical Field This invention; By presenting two active pharmaceutical ingredients, which are used separately or in combination only in tablet form for hypertension patients, as a new dosage form that does not require water and swallowing; To accelerate the pharmacological effect, reduce and/or minimize side effects, to eliminate the economic disadvantage of taking two separate drugs separately, to develop an alternative dosage form for patients who have difficulty swallowing solid dosage forms or who are bedridden or have mental problems, when there is no access to water. It is about innovative formulations (oral thin films, OTF) that will enable you to use the drug safely and, most importantly, increase the standard of living of hypertension patients. In the product subject to this invention, the active ingredients Olmesartan medoximil and Hydrochlorothiazide (HCTZ), which are used separately in the treatment of hypertension or are only available in the pharmaceutical market in combination as tablets, are combined in an innovative dosage form (OTF) and become an advantageous product in terms of both economic and patient compliance. has been brought. State of the Art Hypertension is an important risk factor that causes cardiovascular diseases worldwide, especially diseases such as kidney failure. As people get older, changes in blood pressure occur and the risk of hypertension increases. More than half of people over the age of 65 have hypertension, and the probability of developing this disease throughout life is more than 90%. Systolic blood pressure of 140 mmHg and diastolic blood pressure of 90 mmHg or higher is called hypertension. The situation where systolic blood pressure is between 120-139 mmHg and diastolic blood pressure is between 80-89 mmHg is called initial hypertension, that is, prehypertension. According to ESH/ESC guidelines, patients were recommended drug treatments along with lifestyle changes. Since hypertension has a multifaceted pathophysiology, studies have shown that combined drug therapy will have a better effect on blood pressure rather than a single drug. In addition, combining two therapeutic agents in lower doses compared to a single dose is advantageous as it will cause fewer side effects. Today, many drug combination treatments are available for the treatment of hypertension. Since it is difficult to normalize blood pressure with a single antihypertensive agent in patients with cardiovascular risk, dual combinations are the first choice. Studies have shown that combined treatments with diuretics in patients with resistant hypertension have a beneficial effect on reducing blood pressure by reducing sodium reabsorption in the distal segments of the nephron. Combinations of Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin II Receptor Antagonists (ARB) with diuretics are among the most preferred combination drugs as they have a strong effect. The reason for this is that the negative sodium balance induced by diuretics triggers the renin system, thus angiotensin II production is also triggered and blood pressure control becomes dependent on angiotensin II. In this case, drugs targeting the renin-angiotensin system (ACE or ARB) block the production of angiotensin II. They increase the blood pressure lowering effects of diuretics. In addition, hypokalemia, which occurs due to diuretic-induced aldosterone stimulation, is suppressed by the use of ACEs or ARBs and potassium balance is maintained. Blood pressure control is superior with these combinations compared to the use of ACE or ARB blockers alone. It has been reported that the combination of drugs targeting the Renin Angiotensin System (RAS) with diuretics significantly reduces the risk of cardiovascular disease and the risk of progression of chronic kidney disease compared to the combination of a calcium channel blocker and a diuretic. In these combinations, ACE inhibitors cause dry cough and angioedema in patients due to the destruction of bradykinin-like peptides, whereas such side effects are not observed in ARBs. Olmesartan (Olmesartan medoxomil), one of the angiotensin receptor blocker (ARB) group drugs, is a prodrug. Olmesartan medoxomil is an endothelial smooth It inhibits the vasoconstrictor and aldosterone-releasing effects of angiotensin II by selectively binding to angiotensin I receptors in the muscle, thus reducing high blood pressure. Since Olmesartan is in the Class II drug group in the Biopharmaceutical Classification System (BCS), it has two important disadvantages: low water solubility and weakness. Olmesartan is given at a dose of 20 mg once a day in hypertension. If necessary, the daily dose can be increased to 40 mg. After oral use, its absorption is rapid (tmax 1-3) and maximum serum concentration (Cmax) is reached in 2 hours. After being absorbed from the gastrointestinal tract, it is converted into the active Olmesartan by metabolites by esterases in the gastrointestinal mucosa, portal blood and liver. It has a low potential to interact with cytochrome p450 enzymes and other drugs. While its half-life varies between 10-15 hours, it is eliminated from the body largely through feces and urine. In the treatment of hypertension, HCTZ is generally used in combined treatments with an initial dose of 12.5 mg orally, and if necessary, the dose can be increased up to 25 to 50 mg per day. Its absorption in the gastrointestinal tract is rapid and its bioavailability is quite good (65%-70%). After oral use, its effect begins after 2 hours and reaches its maximum value after 4 hours. Its effect lasts 6-12 hours. Since HCTZ is not metabolized, it is excreted unchanged in the urine. Drug groups used in the treatment of hypertension are mostly in tablet form today. These treatments not only create undesirable side effects for people with the disease, but also cause compliance problems, such as the need for water for use and especially difficulty swallowing. In order to overcome these problems, the pharmaceutical industry and today's pharmaceutical technologies are working on new drug delivery systems. While orally administered tablets are the most common form of drug administration with the non-invasive advantage of administering predetermined doses, they have disadvantages such as poor bioavailability, poor solubility, limited efficacy or exceeding toxic levels. New drug delivery systems are designed with the aim of improving the administration and effectiveness of pharmaceutical compounds. In this way, the solubility problem can be corrected, pH changes can be tolerated, and the release mechanism of the drug can be controlled. Thus, side and toxic effects can be reduced and/or eliminated by reducing the dose of the active substance and changing the frequency of application. As a result, patient compliance can be improved and the patient's life comfort can be increased. Among these new drug carrier systems, nanoparticulate drug carrier systems prepared using nanotechnology are currently being studied extensively. These systems include nanocapsules, nanospheres, nanosponges, nanoemulsions, nanoparticles, nanovesicular systems (liposomes, niosomes), molecular systems (inclusion compounds) and nanocrystals (nanosuspensions). Nanosuspensions are formed as a result of dispersing nanoparticles in a liquid medium. Nanosuspensions are defined as one of the new drug carrier systems developed for oral, topical and parenteral application, containing solid drug particles, generally water-based, with an average particle size between 200 and 600 nm. Nanosuspensions, in addition to eliminating the solubility problem, also increase the bioavailability of drugs and help the drug concentration reach the maximum plasma level more quickly. They also have the feature of being turned into nanoparticles by lyophilizing or spray drying and can be suspended when used. Nanosuspensions (nanocrystals) of both active substances (Olmesartan and HCTZ) in the product subject to the invention were prepared due to their low water solubility. Among the drug administration routes, the oral route is one of the most commonly used drug administration routes due to its ease of administration and high patient compliance and acceptability. However, since oral administration causes incompatibilities such as difficulty in swallowing, choking, and nausea in geriatrics, pediatrics, bedridden patients, and patients with anxiety and panic disorders, alternative methods that can be administered orally have begun to be developed. To overcome difficulty swallowing, the idea of rapid-dissolving oral delivery systems and OTF emerged in the late 1970s. It is also important to eliminate the psychological factors caused by swallowing tablets/capsules. Apart from this, it is not possible to use conventional solid dosage forms (tablets, capsules) without requiring water. They cannot be used while traveling or when water is not accessible. In addition, the major disadvantage of this dosage form is that the pharmacological effects of the drug cannot be seen immediately. The time it takes for it to reach the stomach and dissolve/disperse, and for the pharmacological effect to appear, takes an average of 30-60 minutes. Conventional tablets and capsules are inadequate in cases where the pharmacological effect is desired to begin as soon as possible. As a result, in the old technique/method: i. Olmesartan and HCTZ are available in the world pharmaceutical market as two drugs separately or together only in tablet form, which is a solid dosage form. Therefore, patients who want to use these two active substances must either take these drugs separately or must use them together as tablets. ii. Some patient groups, especially pediatric and geriatric patients, have difficulty swallowing or chewing solid dosage forms. Many pediatric and geriatric patients are reluctant to take solid dosage forms (tablets, capsules) due to fear of choking, iii. For hypertension patients, drugs that offer antihypertensive effects, especially in strict dosage forms (tablets or capsules) and without any alternative, are iv. Inability to provide personalized treatment with conventional dosage forms (tablets or capsules) currently available in the pharmaceutical market, v. Taking two different drugs separately creates an economic disadvantage, vi. There is no alternative dosage form for hypertensive patients who have difficulty swallowing solid dosage forms or who are bedridden or have mental problems, vii. There are shortcomings and disadvantages such as the fact that the medicine cannot be used safely even when there is no access to water. When the studies in the current technique are examined, it is seen that there is a need for improved formulations for oral use, which aim to solve more than one problem at the same time and make it an advantageous product in terms of both economical and patient compliance. Description of the Invention In this explanation, the invention is explained only for a better understanding of the subject and in a way that does not create any limiting effect. The structural and characteristic features and all the advantages of the invention will be more clearly understood thanks to the detailed explanation below, and therefore the evaluation should be made taking this explanation into consideration. The present invention relates to formulations in tablet dosage form that disperse quickly in the mouth, meeting the above-mentioned requirements, eliminating all disadvantages and bringing some additional advantages. In its most basic form, a formulation in tablet dosage form that disperses quickly in the mouth; It contains formulations in oral thin film dosage form containing the combination of Olmesartan medoximil and Hydrochlorothiazide (HCTZ). By using nanotechnology, Olmesartan medoximil and Hydrochlorothiazide (HCTZ) have been reduced to nano size, allowing the use of these drugs in lower doses. At the same time, it is aimed to increase the standard of living and comfort of hypertension patients by designing an innovative dosage form (OTF) that will increase their absorption and accelerate their pharmacological effects. This invention, which is in the form of a tablet that disperses quickly in the mouth, is placed on the tip or base of the tongue and gets wet with saliva within 30-60 seconds. In this way, the active pharmaceutical ingredients contained in the tablet are released and dispersed and/or dissolved for local and/or systemic absorption. The invention developed is in the form of drug dosage forms that contain both active ingredients at the same time and offer a rapid onset of action. When the dosage forms in use in the world pharmaceutical market are examined, the drug dosage form that contains both drugs simultaneously and offers a rapid onset of action is neither in the pharmaceutical market nor in the literature studies. Many pharmaceutical preparations are administered in tablet, granule, powder and liquid forms. In general, the tablet design is in a form that can be swallowed or chewed to give patients a precise dose of medication. However, some patient groups, especially pediatric and geriatric patients, have difficulty swallowing or chewing solid dosage forms. Many pediatric and geriatric patients are reluctant to take these solid dosage forms due to fear of choking. Tablets are the dosage form that can provide high dose homogeneity and have the best content uniformity among all oral dosage forms. In addition, among all oral dosage forms, the dosage form with the most affordable production costs is tablets. However, this method, which is difficult to apply for children and the elderly population, has shown that there is a need for a new drug form that can be used orally. Recent developments in technology have begun to develop alternative dosage forms such as new generation "Oral Thin Films" (OTF) for patients who have difficulty swallowing drugs in solid dosage forms such as tablets and capsules (dysphagia). Today, the use of OTFs is increasing in many prescription and non-prescription product groups, especially in coughs, colds, sore throats, erectile dysfunction disorders, allergic reactions, asthma, gastrointestinal disorders, hypertension, pain treatments, snoring complaints, sleep problems, and multivitamin combinations. and the conversion of conventional drugs to OTF by the pharmaceutical industry continues. With this new generation dosage form, it is aimed to eliminate the psychological factors caused by using tablets/capsules for patients of all age groups who have difficulty swallowing, also called dysphagia. In addition, since it can be used without requiring water, the drug can be used easily even during travel or in situations where water is not available. The major advantage offered by this dosage form is that the pharmacological effects of the drug are seen immediately. The advantage of presenting Olmesartan and HCTZ as nano-sized particles in our formulations is that it will be possible to achieve very rapid absorption from the oral and sublingual mucosa, initiate a rapid pharmacological effect, and recover blood pressure as soon as possible. The active substances in this dosage form, which undergo a rapid distribution or dissolution in the mouth, especially through the capillaries passing through the cheek and under the tongue, will be rapidly mixed into the blood and the pharmacological effect will be initiated quickly. In addition to providing an effective treatment by using lower doses of Olmesartan and HCTZ nanocrystals, it will also be possible to reduce and/or minimize the side effects caused by the active substances. With this drug formulation, which is completely dissolved and dispersed in the mouth before passing into the gastrointestinal system, the first pass effect and delays due to absorption in the gastrointestinal system will be prevented. OTF systems can be disintegrated/dissolved/dispersed within 1 minute when placed in the mouth; They are solid dosage forms that can be used without chewing, swallowing or needing water. OTFs are drug formulations with a thickness of a few microns, prepared using hydrophilic polymers, placed on or at the base of the tongue, and provide rapid dissolution upon contact with saliva. The American Food and Drug Administration (FDA) defines OTF as a flexible and non-brittle strip containing one or more active substances, which is placed on the tongue and quickly dissolves/disintegrates in saliva before passing into the gastrointestinal tract. OTFs have many unique advantages. Among these: i. Active substances do not suffer from first-pass effects and provide a rapid effect even at low doses, ii. No need for water, iii. No risk of drowning, iv. It carries less risk of side effects due to its low dose of active ingredient, v. Providing rapid effect in emergency situations, vi. Easily masking the taste and leaving a pleasant aftertaste, vii. Offering ease of application, viii. Little or no residue left in the mouth after use, ix. Maintaining stability, x. It does not affect the functioning of oral functions, xi. It can be applied to water-insoluble hydrophobic drugs and increases their bioavailability. The primary purpose of the invention is; In addition to offering a faster onset of action due to being in oral thin film form, it also enables dysphagic, geriatric, bedridden or mentally disabled patients suffering from hypertension to use their medicines comfortably whenever and wherever they need, without the need for swallowing or water, and it is economically equivalent to two separate drugs. is to reduce the expenditure paid. Another purpose of the invention is; Its aim is to develop innovative drug dosage formulations that can be used comfortably by all hypertensive patient groups in cases where access to water is not possible. In addition, to accelerate the antihypertensive effect for hypertension patients with the OTF formulations included in the invention (especially compared to the conventional tablet, which is offered in a solid dosage form and exists in the pharmaceutical market only as a tablet without any alternative), by loading Olmesartan and HCTZ into OTFs in the form of nanocrystals, oral and To achieve this rapid effect with a very rapid absorption from the sublingual mucosa, to reduce and/or minimize the side effects caused by the active substances with lower doses of Olmesartan and HCTZ nanocrystals, a formulation in oral thin film dosage form can be achieved; In the invention, the ratio of Olmesartan medoximil to Hydrochlorothiazide (HCTZ) is preferably 1:2.5. In all preferred embodiments of the invention, the developed film contains 5 mg of Olmesartan medoximil and 12.5 mg of Hydrochlorothiazide. The invention, which is in the form of an oral thin film, is placed on the tip or base of the tongue and is wetted with saliva within 30-60 seconds. In this way, the active substances contained in the film are released and dispersed and/or dissolved for local and/or systemic absorption. With the developed invention, drug dosage forms that contain both active ingredients simultaneously and offer a rapid onset of action have been prepared. All excipients used in the developed formulation are soluble in water. Olmesartan medoximil and Hydrochlorothiazide (HCTZ) were used in formulations in the form of nanocrystals with particle size below 500 nm using the "Nanoprecipitation" technique in the presence of Poloxamer 407 surfactant. In other words, these prepared OTFs dissolve very quickly with saliva when placed under the tongue or at the tip. Therefore, it is possible to get a rapid effect, use it without needing water and without experiencing difficulty in swallowing. In this way, a rapid onset of effect occurs and the patient's complaints are resolved in a short time. Because the sublingual mucosa has a high permeability due to its thin membrane structure and many blood vessels. Due to this rapid blood circulation, there is a very rapid bioavailability. Since the absorption part from the gastrointestinal tract is skipped, the first pass effect through the liver is eliminated. This rapid bioavailability is due to bypassing the first pass effect and better permeability. In addition, its large surface area for absorption and ease of administration make the oral mucosa a very effective and selective route for systemic drug delivery. In this way, all hypertensive patients can easily take these medications in combination, without using tablets or capsules, by placing them on or under the tongue, without requiring water. In a preferred embodiment of the invention, the developed formulation preferably contains at least one excipient specified below, in accordance with the amounts given in Table 1, Table 2 and Table 3: i. Pectin, Gelatin, Sodium alginate, Polymerized resin, Hydroxy propyl methyl cellulose (HPMC). , Hydroxy ethyl cellulose (HEC), Carboxy methyl cellulose (CMC), Sodium carboxy methyl cellulose (NaCMC), Methyl cellulose (MC), Pullulan, Polyvinylpyrrolidone (PVP), Polyvinyl alcohol (PVA), Polyethylene glycol (PEG) or combination thereof At least one natural polymer selected from the group containing (more preferably the combination of Pullulan and Sodium alginate; Pectin, Gelatin, Sodium alginate, Polymerized resin, Hydroxy propyl methyl cellulose (HPMC), Hydroxy ethyl cellulose (HEC), Carboxy methyl cellulose (CMC), Sodium At least one natural polymer (more preferably Pullulan, Sodium alginate and Gelatin combination; Table 2); Pectin, Gelatin, Sodium alginate, Polymerized resin, Hydroxy propyl methyl cellulose (HPMC), Hydroxy ethyl cellulose (HEC), Carboxy methyl cellulose (CMC), Sodium carboxy methyl cellulose (NaCMC), Methyl cellulose (MC), Pullulan, Polyvinylpyrrolidone ( At least one natural polymer selected from the group consisting of PVP), Polyvinyl alcohol (PVA), Polyethylene glycol (PEG) or a combination thereof (more preferably a combination of Pullulan and Sodium alginate; Glycerol, Propylene glycol, Sorbitol solution (50%, 60% or 70%) at least one elasticizer (more preferably Glycerol) selected from the group consisting of PEG 800, PEG 400 PEG 300 or a combination thereof and providing flexibility of the film; at least one saliva selected from the group consisting of Citric acid, Ascorbic acid, Lactic acid or Tartaric acid. at least one surfactant (more preferably Poloxamer 407) selected from the group consisting of releasing agent (more preferably Citric acid); At least one surfactant selected from the group consisting of one or a combination of 407, Poloxamer 188, Lecithin, Ethyl oleate or Isopropyl myristate and providing surface activity in the preparation of OTF (more preferably Tween viii. Aspartame, Sodium saccharin, Stevia, Sucralose or Acesulfame at least one sweetening agent selected from the group consisting of (more preferably, Sodium saccharin, Kollidon CL, Xanthan gum, Crospovidone, Sodium starch glycolate, Hydroxypropyl cellulose, Ac-Di-Sol®, Solutab®, Nymce ZSX®, At least one superdisintegrant selected from the group consisting of Primellose®, Vivasol®, Polyplasdone®, Explotab®, Primojel®, Satialgine®, Sodium bicarbonate or a combination thereof, which ensures rapid disintegration of the film (more preferably Sodium starch glycolate, instead of Vanillin); x. Contains at least one flavoring agent selected from the group consisting of Neroli, Eucalyptol, Mint, Orange, Cinnamon or Chocolate flavor (more preferably Vanillin); xi. Ingredient Name Usable amount by weight (%) Olmesartan medoxomil nanocrystals 2 .5-10.0 Hydrochlorothiazide (HCTZ) nanocrystals 10.0-25.0 Sodium alginate 20.0-40.0 Glycerol 10.0-25.0 Citric acid 2.5-10.0 Sodium saccharin 2.5- 10.0 Sodium starch glycolate 2.5-10.0 Distilled Water is used and evaporated so it has no effect on weight. Component Name Usable amount by weight (%) Olmesartan medoxomil nanocrystals 2.5-10.0 Hydrochlorothiazide (HCTZ) nanocrystals 10.0-25, 0 Sodium alginate 5.0-20.0 Gelatin 5.0-20.0 Glycerol 10.0-30.0 Citric acid 2.5-10.0 Sodium saccharin 2.5-10.0 Sodium starch glycolate 2.5 -10.0 It has no effect on weight as Distilled Water is used and evaporated. Ingredient Name Usable amount by weight (%) Olmesartan medoxomil nanocrystals 2.5-10.0 Hydrochlorothiazide (HCTZ) nanocrystals 10.0-25.0 Sodium alginate 15.0-35, 0 Glycerol 10.0-25.0 Citric acid 2.5-10.0 Sodium saccharin 2.5-10.0 Sodium starch glycolate 5.0-20.0 Since distilled water is used and evaporated, it has no effect on weight. In a preferred embodiment of the invention Developed formulation; It contains Olmesartan medoxomil nanocrystals, Hydrochlorothiazide (HCTZ) nanocrystals, Sodium alginate, Pullulan, Glycerol, Citric acid, Sodium saccharin, Sodium starch glycolate, Tween 80 and Vanillin. The formulation developed in a preferred embodiment of the invention; Olmesartan contains medoxomil nanocrystals, Hydrochlorothiazide (HCTZ) nanocrystals, Sodium alginate, Pulluan, Gelatin, Glycerol, Citric acid, Sodium saccharin, Sodium starch glycolate, Tween 80 and Vanillin. The formulation developed in a preferred embodiment of the invention; It contains Olmesartan medoxomil nanocrystals, Hydrochlorothiazide (HCTZ) nanocrystals, Sodium alginate, Pullulan, Glycerol, Citric acid, Sodium saccharin, Sodium starch glycolate, Tween 80 and Vanillin. In an exemplary embodiment of the invention, the developed formulation is prepared by following the water treatment steps: 1.0 mg of Poloxamer 407 and 1.0 mL of distilled water are weighed into a vial on a precision scale with at least 1 mg sensitivity for olmesartan medoximide nanocrystals. Weigh 5.0 mg Olmesartan and 1.0 mL Methanol into another vial. The organic phase is added dropwise onto the water phase on a multi-point magnetic stirrer at 750 rpm with the help of a 228 injector. At the end of the dripping, homogeneous mixing is ensured for an additional 5 minutes. In order to remove the organic phase, evaporation is carried out under vacuum for 5 minutes at 45 °C (through a rotovapor). Meanwhile, Olmesartan medoximil nanocrystals are obtained. The obtained nanocrystals are suspended in pure water and frozen at -20 °C overnight. Afterwards, they are lyophilized for 24 hours and turned into dry powder (by means of a lyophilizer). 2.5 mg of Poloxamer 407 and 2.5 mL of distilled water are weighed into a vial on a sensitive balance with a sensitivity of at least 1 mg for HCTZ nanocrystals. 12.5 mg HCTZ and 2.5 mL Methanol are weighed. The organic phase is added dropwise onto the water phase at 750 rpm on a multi-point magnetic stirrer, with the help of a 22G syringe. At the end of the dripping, homogeneous mixing is ensured for an additional 5 minutes. Sonicate this mixture at 50 power, cycle 4, for 5 minutes. In order to remove the organic phase, evaporation is carried out under vacuum for 5 minutes at 45 °C (via a rotovapor). In the meantime, HCTZ nanocrystals are obtained. The obtained nanocrystals are suspended in pure water and frozen at -20 °C overnight. Subsequently, They are lyophilized for 24 hours and turned into dry powder (by means of a lyophilizer). Weighing all the components that make up the formulation for OTFs on a precision balance with at least 1 mg precision; 24 mL for formulation mold); heating and dissolving the mixture preferably on a magnetic stirrer set at 20-60 °C (more preferably 40 °C) for another 5-60 minutes (preferably 10 minutes); pouring the resulting mixture into a mold; drying the molded mixture at room temperature (preferably 25 °C) for 6-72 hours (preferably 48 hours) and removing it from each independent mold, containing equal amounts of Olmesartan medoximil and HCTZ; Store in separate locked bags, away from moisture, heat and light, at room temperature (25 °C) until use. TR
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