Olmesartan medoksomil içeren kendiliğinden mikroemülsiyon oluşturan ilaç salım sistemlerinin hazırlanması ve ın vıvo olarak değerlendirilmesi
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Dosyalar
Tarih
2017
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Yayıncı
Ege Üniversitesi, Sağlık Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Çalışmada, ciddi bir halk sağlığı sorunu olan hipertansiyon tedavisinde oral yoldan kullanılan, RAS blokeri seçici bir Anjiyotensin II reseptör tip I (AT1) antagonisti olan olmesartan medoksomilin biyoyararlanımını geliştirdiğimiz mikro/nanoemülsiyonla arttırmayı hedefledik. Olmesartan medoxomil bir ön ilaçtır ve mide-barsak yolundan emilimi sırasında aktif olmesartana hidrolize edilir. Olmesartanın mutlak biyoyararlanımı yaklaşık %26'dır. Gıdadan etkilenmez. Mevcut durumda etkin maddenin piyasada sadece 10, 20, 40 mg'lık tablet formları bulunmaktadır. Yapılan klinik çalışmalar ışığında, 12.02.2010'da olmesartan medoksomilin 6-16 yaş aralığında kullanımı FDA tarafından onaylanmıştır. 20 ile 35 kg arası çocuklarda günlük 2.5- 20 mg, 35 kg ve üstü çocuklarda 5- 40 mg doz aralığında kullanımı uygun görülmüştür. Dünyada, sadece Amerika Birleşik Devletleri (ABD)'nde FDA'in yaptığı açıklamaya göre 3,6 milyon çocuk hipertansiyon hastası bulunmaktadır. ABD'de standart iki taşıyıcının (Orofix, Oroplus) karıştırılması ile elde edilen karışımda tabletin eczacı tarafından toz edilerek süspande edilip çocuklara ölçülü miktarda verilmesi önerilmektedir. Ülkemizde böyle taşıyıcı bir ürün piyasada bulunmadığından tabletin toz edilip sulandırılarak çocuk hastalara verilmesi söz konusudur. Hipertansiyonu olan çocuk hastalarda ilacın kilogram başına düşük dozlarda verilebilmesi sıkıntı yaratmaktadır. İlacın biyoyararlanımının da düşük olması göz önüne alınarak, olmesartan medoksomil SMEDDS (kendiliğinden mikro emülsifiye olabilen ilaç taşıma sistemi) ile formüle edilmesi, hem ilacın biyoyararlanımını arttıracağı, hem de uygun dozun verilmesini kolaylaştıracağı düşünülmüştür. Çalışmada elde ettiğimiz veriler, ilacın biyoyararlanımı konusunda ışık tutmuştur. Kendiliğinden mikroemülsifiye olabilen ilaç sistemlerinin biyoyararlanımı arttırma özelliği araştırılmış, çocuklara ve yetişkin hastalara uygun dozda verilebilen bir ilaç formu geliştirilmiştir. Bu çalışmada olmesartan medoksomilin tayini için HPLC (yüksek performanslı sıvı kromatografisi) analiz metodu geliştirilerek valide edilmiştir. Mikroemülsiyon formulasyonunda kullanılan çeşitli yağ, yüzey etkin madde ve yardımcı yüzey etkin maddelerde, olmesartan medoksomilin çözünürlük çalışmaları yapılmış ve bu ortamlardan etkin maddenin geri kazanımı HPLC ile belirlenmiştir. Mikroemülsiyonu oluşturacak en uygun yağ, yüzey aktif madde, yardımcı yüzey aktif madde ve su kombinasyonunun bulunabilmesi amacıyla Y/S mikroemülsiyonu eldesi için, HLB (hidrofilik lipofilik balans) hesapları yapılmış ve en yüksek oranda su tutan emülsiyon, üçgen faz diyagramı (182) yardımıyla hesaplanarak, formülasyon hayata geçirilmiştir. 6 ay boyunca yapılan stabilite testleri sonrasında, farklı pH'larda yapılan çözünürlük testleri sonuçlanmıştır. Bu aşamadan sonra hazırlanan mikroemülsiyonun, dissolüsyon testleri yapılmış, Paralel yapay membran permeabilite geçiş çalışmaları (PAMPA) Deneyi ile ilacın barsaktan transelüler geçiş etkinliği, floresan işaretleme yöntemi kullanılarak, biyodağılımı (IVIS) (in vivo görüntüleme sistemi) ile incelenmiştir. Çalışmanın son aşamasında ilacın farmakodinamisi sıçanlarda kuyruktan tansiyon ölçme metoduyla (NIBP) deneyimiz sırasında, tez kapsamında geliştirilen mikro/nanoemülsiyonun, süspansiyona o belirlenmiştir. Mikroemülsiyonun biyoyararlanımının 3- 100 kat daha fazla olduğu ispatlanmıştır. Olmesartan medoksomilin çölyak benzeri barsak enteropatisi yan etkisi FDA tarafından da kabul edilmiştir. 21 günlük NIBP deneyimiz sırasında, tez kapsamında geliştirilen mikroemülsiyonun, süspansiyona oranla enteropati ve diyare oluşturmadığı gözlenmiştir.
We aimed to increase the bioavailability of olmesartan medoxomil by means of micro/nanoemulsion that we have developed in this study. Olmesartan medoxomil which is a selective Angiotensin II Receptor Type I (AT-I) antagonist to block the Renin Angiotensin System (RAS) is utilized orally for the curement of hypertension that is a frequently seen serious society problem resulting important complications. Olmesartan medoxomil is a prodrug and hydrolyzed to be active olmesartan during absorption through the gastro-intestinal tract. Absolute bioavailability of olmesartan is approximately 26%. It is not influenced by the food. At present, only 10, 20, 40 mg tablet forms are available in the market for the active ingredient. In the light of the clinical studies, the use of olmesartan medoxomil in the 6 to 16 age range was approved by the FDA on 12.02.2010. It's daily use of 2.5- 20 mg for children between 20 and 35 kg, and between 5- 40 mg for children over 35 kg were deemed appropriate. According to the FDA's statement, there are 3.6 million children suffering with hypertension in the world. In the USA, it is suggested that the mixture obtained by mixing the standard two carriers (OROFIX, OROPLUS) is powdered and suspended by pharmacist and given to the children in a measured amount. Since there is no vehicle product in the market in our country, it is said that the tablets will be powdered and water added to give child patients. In children patients with hypertension, it is difficult to administer the medication in low doses per kilogram. Considering the low bioavailability of the drug, formulating the olmesartan medoxomil with Self Microemulsion Drug Delivery System (SMEDDS) is thought both to increase the bioavailability of the drug and to facilitate the administration of appropriate doses. The data we obtained in the study lightened the bioavailability of the drug. The increase of the bioavailability of self microemulsifying drug systems has been investigated. As a result, a drug form which can be given to children and adult patients in appropriate doses has been developed. In this study, HPLC (high performance liquid chromatography) analysis method was developed and validated for the determination of olmesartan medoxomil. Studies on solubility of olmesartan medoxomil in various oils, surfactants and coauxiliary surfactants used in microemulsion formulation were accomplished. The recovery of the active compound from these environments was determined by HPLC. In order to find the most suitable oil, surfactant, coauxiliary surfactant and water combination to form microemulsion, in order to obtain O/W microemulsion HLB (hydrophilic lipophilic balance) calculations were made and calculating the highest-water-holding emulsion by means of Triangular Phase Diagram formulation have been realized. After 6 months of stability tests implementation, dissolution tests were performed at different pHs. The microemulsion prepared after this step was subjected to dissolution tests, the Intraepithelial Transition (PAMPA) Studies Experiment was conducted to investigate the effect of drug transit, (IVIS) (in vivo imaging system) using the fluorescent marking method biodistribution was observed. In the last phase of the study, the pharmacodynamic profiles of drug were determined by measuring blood pressure in rats. It has been proved that the micro/nanoemulsion is 3 to 100 times more bioavailable. It is accepted by the FDA that olmesartan medoxomil has the adverse effects of sprue-like enteropathy as celiac. It is also observed that micro/nanoemulsion has not generated enteropathy and diarrhea during 21- day NIBP within this study. Further studies has been planned on this issue.
We aimed to increase the bioavailability of olmesartan medoxomil by means of micro/nanoemulsion that we have developed in this study. Olmesartan medoxomil which is a selective Angiotensin II Receptor Type I (AT-I) antagonist to block the Renin Angiotensin System (RAS) is utilized orally for the curement of hypertension that is a frequently seen serious society problem resulting important complications. Olmesartan medoxomil is a prodrug and hydrolyzed to be active olmesartan during absorption through the gastro-intestinal tract. Absolute bioavailability of olmesartan is approximately 26%. It is not influenced by the food. At present, only 10, 20, 40 mg tablet forms are available in the market for the active ingredient. In the light of the clinical studies, the use of olmesartan medoxomil in the 6 to 16 age range was approved by the FDA on 12.02.2010. It's daily use of 2.5- 20 mg for children between 20 and 35 kg, and between 5- 40 mg for children over 35 kg were deemed appropriate. According to the FDA's statement, there are 3.6 million children suffering with hypertension in the world. In the USA, it is suggested that the mixture obtained by mixing the standard two carriers (OROFIX, OROPLUS) is powdered and suspended by pharmacist and given to the children in a measured amount. Since there is no vehicle product in the market in our country, it is said that the tablets will be powdered and water added to give child patients. In children patients with hypertension, it is difficult to administer the medication in low doses per kilogram. Considering the low bioavailability of the drug, formulating the olmesartan medoxomil with Self Microemulsion Drug Delivery System (SMEDDS) is thought both to increase the bioavailability of the drug and to facilitate the administration of appropriate doses. The data we obtained in the study lightened the bioavailability of the drug. The increase of the bioavailability of self microemulsifying drug systems has been investigated. As a result, a drug form which can be given to children and adult patients in appropriate doses has been developed. In this study, HPLC (high performance liquid chromatography) analysis method was developed and validated for the determination of olmesartan medoxomil. Studies on solubility of olmesartan medoxomil in various oils, surfactants and coauxiliary surfactants used in microemulsion formulation were accomplished. The recovery of the active compound from these environments was determined by HPLC. In order to find the most suitable oil, surfactant, coauxiliary surfactant and water combination to form microemulsion, in order to obtain O/W microemulsion HLB (hydrophilic lipophilic balance) calculations were made and calculating the highest-water-holding emulsion by means of Triangular Phase Diagram formulation have been realized. After 6 months of stability tests implementation, dissolution tests were performed at different pHs. The microemulsion prepared after this step was subjected to dissolution tests, the Intraepithelial Transition (PAMPA) Studies Experiment was conducted to investigate the effect of drug transit, (IVIS) (in vivo imaging system) using the fluorescent marking method biodistribution was observed. In the last phase of the study, the pharmacodynamic profiles of drug were determined by measuring blood pressure in rats. It has been proved that the micro/nanoemulsion is 3 to 100 times more bioavailable. It is accepted by the FDA that olmesartan medoxomil has the adverse effects of sprue-like enteropathy as celiac. It is also observed that micro/nanoemulsion has not generated enteropathy and diarrhea during 21- day NIBP within this study. Further studies has been planned on this issue.
Açıklama
Anahtar Kelimeler
Hipertansiyon, Olmesartan Medoksomil, PA (Parallel Artificial Membrane Permeability Assay), IVIS (Floresan İşaretleme), NIBP (Kuyruktan Tansiyon Ölçümü), Hypertension, Olmesartan Medoxomil, SMEDDS, Microemülsion, HPLC, PAMPA, NIBP, Biodistribution
