Rektumda jelleşen sıvı supozituvar şekilleri üzerinde çalışmalar

Bu çalışmada, iki farklı poloxamer tipi (P407 ve P188), ketoprofen ve farklı biyoadezif polimerler kullanılarak, fizyolojik ortamda jelleşen ve rektal mukozaya yapışarak dışarıya akması önlenen sıvı supozituvarlar geliştirildi. Öncelikle formülasyonlarda kullanılacak etken maddenin standardizasyonu ve saflık kontrolleri yapıldı. Daha sonra sadece poloxamer karışımı, poloxamer karışımı ve ketoprofen, poloxamer karışımı, ketoprofen ve farklı konsantrasyonda biyoadezif polimer içeren formülasyonlar hazırlanarak dijital bir termometre yardımıyla, bir soğutmalı su banyosu kullanılarak jelleşme sıcaklıkları ölçüldü. Hazırlanan formülasyonlar arasından en uygun jelleşme sıcaklığı olan 37.1ºC ye sahip sıvı supozituvar formülasyonu, %4/%20/%2.5 P407/P188/ketoprofen olarak belirlendi. Daha sonra bu formülasyona % 0.2, 0.4, 0.6 ve 0.8 oranlarında karbopol, HPMC, CMC ve PVP biyoadezif polimer olarak ilave edildi. Elde edilen biyoadezif sıvı supozituvar formülasyonlarının jelleşme sıcaklıkları kontrol edildikten sonra mekanik özellikleri Texture Analyzer aleti yardımıyla belirlendi. Bir viskozimetre yardımıyla da formülasyonların oda sıcaklığındaki ve 37ºC’deki viskoziteleri ölçüldü. Ketoprofenin sıvı supozituvar formülasyonlarından in vitro salım hızı tayini USP XXII döner palet metodu ile yarıgeçirgen membran yöntemi kullanılarak, PEG karışımıyla hazırlanan konvensiyonal supozituvar formülasyonundan salım hızı tayini ise USP XXII döner palet metodu membransız yöntem kullanılarak yapıldı. Formülasyonların in vitro salım hızı çalışmaları tamamlandıktan sonra elde edilen sonuçlar sıfırıncı derece, birinci derece, Higuchi ve Hixson Crowell kinetiklerine uygulanarak en uygun kinetik model belirlendi. Salım mekanizmasının daha ileri analizi için Peppas eşitliği uygulandı. Sıvı suppozituvar lokalizasyonunu in vivo olarak belirlemek amacıyla, jelleşme sıcaklığı 34.2ºC olan % 4/20/2.5/0.8 P407/P188/Ketoprofen/Karbopol ve jelleşme sıcaklığı 35.7ºC olan %6/20/2.5/0.8 P407/P188/Ketoprofen/Karbopol karışımlarına %1 oranında metilen mavisi eklenerek sıvı supozituvar formülasyonları hazırlandı. Bir kateter yardımıyla iki ayrı tavşanın rektumuna enjekte edildi. Yarım saat sonra tavşanlar sakrifiye edilip rektumları çıkartıldı. Rektumda maviye boyanmış ve jelleşmiş sıvı supozituvar formülasyonları tespit edildi

Properties of bioadhesive ketoprofen liquid suppositories: preparation, determination of gelation temperature, viscosity studies and evaluation of mechanical properties using texture analyzer by 4 x 4 factorial design

WOS: 000328148400008PubMed ID: 24156540Context: Development and evaluation of thermosensitive and bioadhesive liquid suppositories containing ketoprofen (KP). Objective: This study was conducted to develope thermosensitive and bioadhesive liquid suppositories containing KP using poloxamer and different bioadhesive polymers and to investigate their gelation temperature, viscosity and mechanical properties. Materials and methods: Bioadhesive liquid suppositories were prepared by the cold method using poloxamer 407 (P 407), Poloxamer 188 (P 188) and various amounts of different bioadhesive polymers. Their gelation temperatures, viscosity values and mechanical properties were determined using texture analyzer by 4 x 4 factorial design. Results: It was seen that in presence of KP, gelation temperature of formulation P 407/P 188 (4/20%) significantly decreased from 64 to 37.1 degrees C. It is to be noted that addition of increasing concentrations of bioadhesive polymers lowered gelation temperature and its decrease was highest with addition of Carbopol 934 P (C). Results of texture profile analysis (TPA) showed that formulations containing C have significantly higher hardness and adhesiveness values than other bioadhesive formulations. According to TPA, gel structure of liquid suppository formulation F5, containing P 407/P 188/KP/C (4/20/2.5/0.8%), exhibited the greatest hardness, compressibilty, adhesiveness and besides greatest viscosity. Discussion and conclusion: According to mechanical properties and viscosity values, it was concluded that F5 could be a promising formulation.Research Foundation of Ege UniversityEge University [06/ECZ/005]The authors wish to thank Research Foundation of Ege University for financial support given to this study. Project number: 06/ECZ/005

In vitro-in vivo evaluation of in situ gelling and thermosensitive ketoprofen liquid suppositories

WOS: 000344741300007PubMed ID: 24096820The main objective of this study was to investigate the release and pharmacokinetic profiles of ketoprofen (KP) from developed thermosensitive and mucoadhesive liquid suppositories. Thermosensitive liquid suppositories were prepared using KP, poloxamer 407 (P 407), poloxamer 188 (P 188) and various amounts of different mucoadhesive polymers. In vitro release studies was monitored by the USP XXVI paddle method. The results thus obtained were evaluated kinetically and mechanism of release was analyzed. Identification of poloxamer gel localization in vivo was conducted using white male rabbits by adding 1 % methylene blue. For in vivo studies, twenty-four white male rabbits were randomly divided into three groups. The rabbits in each group were administered with liquid suppository F1 [P407/P188/KP (4/20/2.5 %)], F5 [P407/P188/KP/C (4/20/2.5/0.8 %)] or conventional suppository (F-C) into the rectum. The plasma concentration of KP was analyzed by high performance liquid chromatography (HPLC). C (max), AUC, MRT and T (max) were evaluated. The release of KP was variously affected by the mucoadhesive polymers. In vitro release studies showed that Carbopol 934 P(C) has significant effect on release rate among the mucoadhesive polymers. When the formulations were evaluated kinetically, different kinetic models were obtained. Formulation F6 [P407/P188/KP/C (4/20/2.5/1.6 %)] which contains the highest C concentration and very high viscosity, shows a significantly better fit with Higuchi kinetic model. n value of this formulation was also found approximately 0.5. n exponent results of the other formulations showed that KP might be released from the suppositories by non-Fickian diffusion. Identification of poloxamer gel localization in vivo showed that the suppositories remain in the rectum without leakage after administration. With regard to the results of in vivo studies, the AUC(6 -> 14) values of KP in liquid suppository containing C are significantly higher than those in liquid suppository without C. MRT0 -> 24 and MRT0 -> a values of liquid suppository containing C are significantly higher than those in liquid suppository without C and conventional suppository. Conventional suppository and liquid suppository without C significantly gave faster time to reach the maximum plasma concentrations of KP. With regard to the in vitro and in vivo experiments, liquid suppository formulation F5 might be a promising formulation for the development of an effective rectal dosage form.Research Foundation of Ege UniversityEge University [06/ECZ/005]The authors wish to thank Research Foundation of Ege University for financial support given to this study. Project number: 06/ECZ/005