Tasarımda kalite yaklaşımı kullanılarak biyofarmasötik sınıf II/IV' te yer alan nano ve mikro boyutta etkin madde ile tablet formülasyonunun geliştirilmesi ve in-vitro salım profillerinin kıyaslanması
Küçük Resim Yok
Tarih
2024
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Yayıncı
Trakya Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Giriş ve Amaç: Bu tez çalışmasında, biyofarmasötik sınıflandırma sistemi sınıf II' de yer alan düşük çözünürlüğe sahip Rivaroksaban (RXB) etkin maddesinin nanopartiküllerini içeren, tasarımla kalite (QbD) metodu kullanılarak hızlı salımlı tablet formülasyonlarının geliştirilmesi ve in-vitro çözünme profilinin hızlandırılması hedeflenmiştir. Gereç ve Yöntemler: Tasarımla kalite metodolojisi uygulanarak Rivaroksaban'ın bir polimer ve yüzey aktif madde ile dispersiyonu hazırlanmış bilyeli öğütücü yardımıyla partikül boyutu küçültülmüştür. Hazırlanan nanosüspansiyonlar akışkan yataklı kurutucuda sprey granülasyon yöntemi ile püskürtülerek kurutulmuş ve akışkan toz elde edilmiştir. Final tozlar, tablet baskı makinesinde basılmış ardından tablet kaplama makinesinde film kaplanmıştır. Rivaroksaban nanopartiküllerini içeren film kaplı tablet prototipleri referans ürün Xarelto® 20 mg film kaplı tablet ile pH 4.5 asetat tamponunda in-vitro çözünme profilleri kıyaslanmıştır. Bulgular: Çalışmalara referans ürün Xarelto® 20 mg film tablet karakterizasyonu ile başlanıp referans ürünün çözünme profili incelenmştir. Başlangıç risk değerlendirmesi yapılarak bilyeli öğütme prosesinde ve formülasyonda kesirli faktöriyel deney tasarımına hangi faktörlerin yer alacağı belirlendi. Proses olarak makine hızı, peristaltik pompa hızı, mekanik karıştırma hızı ve işlem süresi seçilmiş olup formülasyon bileşenlerinden etkin madde konsantrasyonu, sodyum lauril sülfat (SLS) konsantrasyonu ve hidroksipropil selüloz (HPC) konsantrasyonu seçilmiştir. Toplam öğütme süresinin etkisini değerlendirebilmek adına süre de faktörlere eklendi. Deney tasarımı ile belirlenen 8 adet çalışma yapılmış ve partikül boyutunu küçültmeye hangi faktörlerin daha etkili olduğu belirlenmiştir. Makine hızı ve sürenin yanı sıra hem formülasyona hem de öğütme prosesinde etkili olan SLS konsantrasyonu ve HPC konsantrasyonu etkili faktörler olarak belirlenmiştir. Nanopartikül içeren Rivaroksaban 20 mg film kaplı tabletlerin in-vitro çözünme profilleri incelendiğinde ph 4.5 asetat ortamında Xarelto® 20 mg film kaplı tabletlere kıyasla 60. Dakikada % 15 ila % 20 arasında daha hızlı çözünen prototipler elde edilmiştir. Sonuç: Rivaroksaban nanopartiküllerini içeren film kaplı tablet formülasyonu; Kesirli faktöriyel deney tasarımı kullanılarak tasarımda kalite yaklaşımı çerçevesinde geliştirilmiştir ve referans ürüne kıyasla daha hızlı in-vitro çözünme profilini sağladığı ispat edilmiştir.
Background and Aim: In this thesis study, it was aimed to develop immediate-release tablet formulations containing nanoparticles of the low-solubility rivaroxaban (RXB) active ingredient in class II of the BCS (biopharmaceutical classification system) and to accelerate the in-vitro dissolution profile. Prototypes were developed with the quality by design (QbD) approach and design of experiments (DOE) were created using statistical software, and the factors effective in obtaining stable and consistent rivaroxaban nanoparticles were determined. Material and Methods: Using the quality by design method, the dispersion of rivaroxaban with a polymer and surfactant was prepared and the particle size was reduced by the help of wet ball milling. The prepared nanosuspensions were spray dried with spray granulation method in a fluidized bed dryer and free flow powder was obtained. The final blends were pressed by tablet compressing machine and then coated in a tablet coating machine. The in-vitro dissolution profiles of the film-coated tablet prototypes containing rivaroxaban nanoparticles were compared with the reference product Xarelto® 20 mg film-coated tablets in pH 4.5 acetate buffer. Results: The studies was started with the characterization of the reference product Xarelto® 20 mg film tablet and the dissolution profile of the reference product was investigated. Initial risk assessment was performed to determine which factors in the wet ball milling process and formulation would be included in the fractional factorial experimental design. Dyno-mill machine speed, peristaltic pump speed, mechanical mixing speed were selected as the process and active ingredient concentration, SLS concentration and HPC concentration were selected as the formulation components. Time was added to the factors in order to evaluate the effect of total milling time. Eight studies were conducted with the experimental design and it was determined which factors were more effective in reducing the particle size. Along with the machine speed and time, SLS concentration and HPC concentration, which are effective in both formulation and wet milling process, were determined as effective factors. When the in-vitro dissolution profiles of Rivaroxaban 20 mg film-coated tablets containing nanoparticles were analyzed, it was observed that Rivaroxaban 20 mg film-coated tablets containing nanoparticles dissolved 15% to 20% faster at 60 minutes compared to Xarelto® 20 mg film-coated tablets in pH 4.5 acetate medium. Conclusion: Film-coated tablet formulation containing rivaroxaban nanoparticles; It was developed within the framework of quality approach in design using fractional factorial experimental design and has been proven to provide a faster in-vitro dissolution profile compared to the reference product.
Background and Aim: In this thesis study, it was aimed to develop immediate-release tablet formulations containing nanoparticles of the low-solubility rivaroxaban (RXB) active ingredient in class II of the BCS (biopharmaceutical classification system) and to accelerate the in-vitro dissolution profile. Prototypes were developed with the quality by design (QbD) approach and design of experiments (DOE) were created using statistical software, and the factors effective in obtaining stable and consistent rivaroxaban nanoparticles were determined. Material and Methods: Using the quality by design method, the dispersion of rivaroxaban with a polymer and surfactant was prepared and the particle size was reduced by the help of wet ball milling. The prepared nanosuspensions were spray dried with spray granulation method in a fluidized bed dryer and free flow powder was obtained. The final blends were pressed by tablet compressing machine and then coated in a tablet coating machine. The in-vitro dissolution profiles of the film-coated tablet prototypes containing rivaroxaban nanoparticles were compared with the reference product Xarelto® 20 mg film-coated tablets in pH 4.5 acetate buffer. Results: The studies was started with the characterization of the reference product Xarelto® 20 mg film tablet and the dissolution profile of the reference product was investigated. Initial risk assessment was performed to determine which factors in the wet ball milling process and formulation would be included in the fractional factorial experimental design. Dyno-mill machine speed, peristaltic pump speed, mechanical mixing speed were selected as the process and active ingredient concentration, SLS concentration and HPC concentration were selected as the formulation components. Time was added to the factors in order to evaluate the effect of total milling time. Eight studies were conducted with the experimental design and it was determined which factors were more effective in reducing the particle size. Along with the machine speed and time, SLS concentration and HPC concentration, which are effective in both formulation and wet milling process, were determined as effective factors. When the in-vitro dissolution profiles of Rivaroxaban 20 mg film-coated tablets containing nanoparticles were analyzed, it was observed that Rivaroxaban 20 mg film-coated tablets containing nanoparticles dissolved 15% to 20% faster at 60 minutes compared to Xarelto® 20 mg film-coated tablets in pH 4.5 acetate medium. Conclusion: Film-coated tablet formulation containing rivaroxaban nanoparticles; It was developed within the framework of quality approach in design using fractional factorial experimental design and has been proven to provide a faster in-vitro dissolution profile compared to the reference product.
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Eczacılık ve Farmakoloji, Pharmacy and Pharmacology
