KONTROLLÜ SALIM YAPAN BİYOADEZİF YENİ VAJİNAL İLAÇ ŞEKİLLERİ ÜZERİNDE ÇALIŞMALAR

Tezin amacı, sistemik ve topik etkili iki ayrı etkin maddenin kontrollü salım yapan biyoadezif vajinal sistemlerinin geliştirilmesi ve etkinliklerinin ölçülmesidir. Çalışmada etkin madde olarak, sistemik etki için oksibütinin, topik etki için ise cidofovir seçilmiştir. Seçilen bu etkin maddeler ile biyoadezif jel, biyoadezif lipozom-jel ve biyoadezif mikroküre-jel şeklinde yeni vajinal ilaç şekilleri geliştirilmiştir. Vajinal ilaç şekillerinin hazırlanması amacıyla polimer olarak hidroksipropilmetilselüloz (HPMC), kitosan, Carbopol, poloksamer ve karışımları kullanılmıştır. Etkin madde ve polimerlerin gerekli karakteristik özellikleri belirlenmiştir. Hazırlanan jellerin görünüş, pH, viskosite, akış, Franz Difuzyon hücresinden geçiş ve mukoadezyon özellikleri incelenmiştir. Sistemik etkili olması nedeniyle oksibütinin içeren jellerin ayrıca horizontal difüzyon hücresi kullanılarak tavşan vajinal dokusundan geçiş çalışmaları yapılmıştır. Cidofovir içeren formülasyonlar ile yapılan in vitro deneyler sonucunda kontrollu salım yapan ve mukoadezyon özelliği iyi olan HPMC ile hazırlanan CV-HPMCK100M2 biyoadezif vajinal jel formülasyonu sonuç formülasyon olarak seçilmiştir. Bu preparatın antiviral etkinliği hücre kültürü çalışmaları ile incelenmiş ve etkili olduğu sonucuna varılmıştır. Oksibütinin hidroklorürün HPMC ile hazırlanan OXB-HPMCK100M2 ve kitosan ile hazırlanan OXB-KITH3 biyoadezif vajinal jel preparatlarının ve çözeltisinin etkinliği tavşanlarda in vivo denenerek oral tablet ile karşılaştırılmıştır. Oksibütininin OXB-HPMCK100M2 formülasyonunun 2 gün süreyle sabit kan konsantrasyonu gösterdiği ve bağıl biyoyararlanımının % 179 olduğu görülmüştür. Ancak histolojik çalışmalar sonucunda OXB-HPMCK100M2 jeli uygulanan tavşanlarda vajinal epitelde hasar olduğu gözlenmiştir. Bu hasar OXB-KITH3 uygulanan grupta gözlenmemiştir.The aim of this study is to develop the controlled release, bioadhesive vaginal system of two different drugs which are used for systemic or topical effect and to measure their effectiveness. Cidofovir and oxybutynin hydrochloride are selected for local and systemic effect, respectively. Various new formulations for vaginal administration, such as bioadhesive gels, liposomal gels and microspheregels were developed. Hydroxpropylmethycellulose (HPMC), chitosan, Carbopol, poloxamer and their mixtures were used for the preparation of the vaginal dosage forms. The required properties of active ingredients and polymers were determined. Some properties of the gel formulations such as appearance, pH, viscosity, flow, diffusion (in Franz Diffusion cell) and mucoadhesion were investigated. Since oxybutynin is a systemically effective drug, the diffusion experiments of the gel formulations containing oxybutinin through the rabbit vaginal tissue were also carried out using horizontal diffusion cell. The vaginal gel formulation of cidofovir CV-HPMCK100M2 formulation prepared with HPMC showing optimum controlled release and mucoadhesive properties based on the in vitro studies of the cidofovir formulations developed. The effectiveness of this final formulation was tested with cell culture studies and it was found to be effective. The effectiveness of oxybutynin vaginal formulations of OXBHPMCK100M2 (with HPMC), OXB-KITH3 (with chitosan) and OXB solution were compared with the oral tablet formulation in rabbits. Sustained plasma profile was obtained with OXB-HPMCK100M2 formulation. The relative bioavailability was found to be 179 %. However damage on vaginal epitel cells was observed in this group; based on histological studies. No damage was observed in OXB-KITH3 group

Vaginal Delivery of Benzydamine Hydrochloride through Liposomes Dispersed in Mucoadhesive Gels

Liposomal vaginal drug delivery systems are important strategy in the treatment of both topical and systemic diseases. The aim of this study was to develop a vaginal delivery system for benzydamine hydrochloride (BNZ) loaded liposomes dispersed into mucoadhesive gels. The delivery system was also designed for a once a day dosage and to obtain controlled release of the BNZ. For this purpose BNZ containing gel formulations using hydroxypropyl methylcellulose (HPMC) K100M and Carbopol® 974P, which are composed of polymers that show promising potential as mucoadhesive vaginal delivery systems, were developed. In addition, a BNZ containing liposome formulation was developed for vaginal administration. To improve the vaginal retention time, liposome was incorporated in HPMC K100M and Carbopol® 974P gel formulations. This system is called lipogel. The developed BNZ liposomes have a slightly negative zeta potential (-1.50±0.16 mV), a 2.25±0.009 µm particle size and a 34% entrapment efficiency. These gels and lipogels have appropriate pH, viscosity, textural properties and mucoadhesive value for vaginal administration. Lipogels were found to be the best formulations for in vitro diffusion and ex vivo mucoadhesion. The work of mucoadhesion obtained from liposomes was in the range of 0.027±0.045 and 0.030±0.017 mJ/cm2, while the value obtained from lipogels was between 0.176±0.037 and 0.243±0.53 mJ/cm2. N1 and N2 lipogel formulations diffused 57 and 67% of BNZ respectively at the end of 24 h. Moreover, a higher mucoadhesion, which increases drug residence time in comparison to liposomes, could improve BNZ efficacy. In conclusion, BNZ mucoadhesive vaginal lipogel formulations can be promising alternatives to traditional dosage forms for vaginal topical therapy

Comparison of oxidative effects of two different administration form of oxybutynin in the potential target tissues

DEMIROZ, FATMA NUR TUGCU/0000-0002-9468-3329;WOS: 000455602100001PubMed: 30675153Oxybutynin is an important anticholinergic agent that prevents uncontrolled contractions in the treatment of overactive bladder (OAB). However, drugs containing oxybutynin have significant side effects such as dry eyes, dry mouth, increased heart rate, constipation, blurred vision, and confusion. In recent years, new delivery methods for this agent are being searched. One of them is vaginal delivery. In this study, we aimed to compare the effects of oxybutynin on oxidative parameters in the potential target tissues of the oral and vaginal delivery. Female New Zealand white rabbits (n=12) were divided into two groups: oral delivery and vaginal delivery. The animals were sacrificed 48h after administration and nitric oxide (NOx), thiobarbituric acid-reactive substances (TBARs), and glutathione (GSH) levels were determined spectrophotometrically in the aorta, salivary gland, and small intestine tissue samples. Vaginal delivery significantly decreased NOx levels in all tissue samples as compared to oral delivery (p<0.05). Moreover, it reduced TBARs levels in salivary gland and aorta tissue samples (p<0.05). In the light on these findings, it can be said that vaginal delivery may decrease the oxidant-induced side effects of oxybutynin as compared to oral delivery

Development and Evaluation of Sustained Release Tablet Formulations of Venlafaxine Hydrochloride

Aim: Depression is a mental disorder which affects more than 250 million people independently of their age. Venlafaxine is an antidepressant drug and used also for the treatment of panic attack and anxiety with fewer side effects than older antidepressant therapeutics. However, venlafaxine hydrochloride (VH) has a short half-life which requires three times dosing daily to maintain sufficient plasma drug concentration. The aim of this study is to develop sustained release VH tablets to be given once a day. Material and Methods: Polyethylene oxide, sodium alginate, hydroxypropyl methyl cellulose, guar gum and polyacrylic acid were used as controlled release agent. Tablets were prepared by direct compression method. Powder (angle of repose, flow rate, Carr index and Hausner ratio) and tablet (weight uniformity, hardness, friability,) characterizations were evaluated. In vitro release studies were carried out for 24 h and drug release kinetics were evaluated using different models. Results: All formulations showed suitable Carr index and Hausner ratio except the formulation prepared with guar gum. The tablets which had been manufactured via direct compression method were compared to the commercial tablet. Sustained release of VH was observed for all formulations. Based on the in-vitro dissolution studies, the drug release from F1 formulation which comprising HPMC and Carbopol polymers was found similar as compared to the commercial tablets. Conclusion: Directly compressed VH tablets could be a preferable alternative to the commercial tablets on behalf of patient compliance and fewer manufacturing steps compared to other production methods