Preparation and Evaluation of Inflammation Targeted Nano-micellar Formulation of Celecoxib

Objective: Celecoxib (CLX), brand named Celebrex, which belongs to non-steroidal anti-inflammatory drugs family, selectively inhibits the cytokine related cyclooxygenase-2 isoenzyme and thus, possesses less gastrointestinal side effects, have shown to cause stroke, myocard infarction and even death in some cases. In this study we aimed to target inflammation site using CLX uploaded nano-micelles (nano-CLX) made of poly (lactic-co-glycolic) acid (PLGA) to protect other tissues from its side effects. Methods: CLX was physically entrapped in PLGA micelles using w/o/w emulsion method, resulted in obtaining mono-dispersed particles with 112 nm size. 50 mg PLGA was able to carry 50 mg CLX in 20 mL (2.5 mg/mL) with encapsulation efficiency of 85%. Rheumatoid arthritis model was achieved by injection of complete Freund’s Adjuvant to the hint paw of Wistar rats. Infected groups received oral Celebrex, intravenous (i.v.) Celebrex and nano-CLX. Each group was compared with a healthy control group receiving the drug via the same routes. The obtained serums and the hint paw sizes were studied for 6 hours in 3 time periods. Results: Prostaglandin E2 and tumor necrosis factor-α levels were found to be decreased for longer time period by application of nanoCLX compared to oral and i.v. Celebrex. Interleukin-1 (IL-1) and IL-6 levels showed a dramatic decrease at orally administered Celebrex groups, showing the accumulation of these pro-inflammatory factors at inflammation area. Conclusion: Based on the hypothesis that the ratio of blood parameters is inversely proportional to accumulation at inflammation site, thus, our nano-formulation is targeted to the tissues in the systemic blood flow and have a better selective inhibition.

Celecoxib’in İnflamasyon Bölgesini Hedefleyen Nano Formülasyonunun Hazırlanması ve Değerlendirilmesi

Amaç: Non steroidal anti-enflamatuvar ilaçlar ailesine ait Celebrex markalı Celecoxib (CLX), selektif olarak sitokine bağlı siklooksijenaz-2 izoenzimini inhibe eder ve böylece daha az gastrointestinal yan etkilere sebep olur, fakat yan etki olarak inme, miyokard enfarktüsüne ve hatta bazı durumlarda ölüme neden olduğu gösterilmiştir. Bu çalışmada, diğer dokuları bu ilacın yan etkilerinden korumak için poli (laktik-ko-glikolik) asitten (PLGA) oluşan CLX yüklenen nano-miselleri (nano-CLX) kullanarak inflamasyon bölgesini hedef almak amaçlanmıştır. Yöntemler: CLX, w/o/w emülsiyon yöntemi kullanılarak PLGA misellerinde fiziksel olarak tuzağa düşürülmüş ve 112 nm büyüklüğünde tek boyutlu partiküller elde edilmiştir. 50 mg PLGA, 50 mg CLX’i %85’i taşıma verimliliği ile 20 mL (2,5 mg/mL) içinde taşıyabilmiştir. Romatoid artrit modeli, Wistar sıçanların avuç içlerine “Freund Adjuvanı”nın enjeksiyonu ile sağlanmıştır. Enfekte olmuş gruplar oral Celebrex, intravenöz (i.v.) Celebrex ve nano-CLX ile tedavi edilmeye çalışılmıştır. Her grup, aynı uygulamayı kullanarak ilacı alan sağlıklı bir kontrol grubu ile karşılaştırılmıştır. Elde edilen serum örnekleri ve avuç içi boyutları 6 saat içinde 3 aralıkta incelenmiştir. Bulgular: Nano-CLX uygulaması oral ve i.v. Celebrex’e nazaran daha uzun süre prostaglandin E2 ve tümör nekroz faktörü-α değererini düşürmeyi başarmıştır. İnterlökin-1 (IL-1) ve IL-6 seviyeleri, oral yoldan verilen Celebrex gruplarında, dramatik bir düşüş göstermiştir. Bu veri bu pro-enflamatuvar faktörlerin enflamasyon alanında birikimini gösteremektedir. Sonuç: Enflamasyon parametrelerinin kandaki oranının, inflamasyon bölgesinde birikimiyle ters orantılı olduğu hipotezine dayanarak, nano formülasyonumuzun sistemik kan akışında, inflamasyon dokularını hedeflendiği ve daha iyi selektif bir inhibisyona sahip olduğu kanıtlanmıştır.

Kaynakça

Peakman M,Vergani D. Basic and Clinical Immunology. Elsevier Health Sciences;2009.

Simon LS, Lanza FL, Lipsky PE, Hubbard RC, Talwalker S, Schwartz BD et al. Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Arthritis Rheum 1998;41:1591-602.

Katori M, Majima M. Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors. Inflamm Res 2000;49:367-92

de Gaetano G, Donati MB,Cerletti C. Prevention of thrombosis and vascular inflammation: benefits and limitations of selective or combined COX-1, COX-2 and 5-LOX inhibitors. Trends Pharmacol Sci 2003;24:245-52.

Qiao W, Wang B, Wang Y, Yang L, Zhang Y, Shao P. Cancer therapy based on nanomaterials and nanocarrier systems. J Nanomater 2010;2010:7.

Maeda H. Macromolecular therapeutics in cancer treatment: the EPR effect and beyond. J Control Release 2012;164:138-44.

Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog Polym Sci 2007;32:762-98.

Tian H, Tang Z, Zhuang X, Chen X, Jing X. Biodegradable synthetic polymers: preparation, functionalization and biomedical application. Prog Polym Sci 2012;37:237-80. Gupta AP, Kumar V. New emerging trends in synthetic biodegradable polymers–Polylactide: A critique. Eur Polym J 2007;43:4053-74.

Mohamed F, van der Walle CF. Engineering biodegradable polyester particles with specific drug targeting and drug release properties. J Pharm Sci 2008;97:71-87.

Muthu MS. Nanoparticles based on PLGA and its co‐polymer: An overview. AJP 2019;3:266-73.

Bahadori F, Kocyigit A, Onyuksel H, Dag A, Topcu G. Cytotoxic, Apoptotic and Genotoxic Effects of Lipid-Based and Polymeric Nano Micelles, an In Vitro Evaluation. Toxics 2017;6:7.

Banerjee A,Onyuksel H. Human pancreatic polypeptide in a phospholipid-based micellar formulation. Pharm Res 2012;29:1698-711.

Amrite AC, Ayalasomayajula SP, Cheruvu NP, Kompella UB. Single periocular injection of celecoxib-PLGA microparticles inhibits diabetes-induced elevations in retinal PGE2, VEGF, and vascular leakage. Invest Ophthalmol Vis Sci 2006;47:1149-60.

Bahadori F, Topçu G, Eroğlu MS, Önyüksel H. A new lipid-based nano formulation of vinorelbine. AAPS PharmSciTech 2014;15:1138-48.

Emami J, Fallah R, Ajami A. A rapid and sensitive HPLC method for the analysis of celecoxib in human plasma: application to pharmacokinetic studies. DARU 2008;16:211-17.

Baboota S, Faiyaz S, Ahuja A, Ali J, Shafiq S, Ahmad S. Development and validation of a stability-indicating HPLC method for analysis of celecoxib (CXB) in bulk drug and microemulsion formulations. Acta Chromatogr 2007;18:116.

Wong HL, Bendayan R, Rauth AM, Wu XY. Development of solid lipid nanoparticles containing ionically complexed chemotherapeutic drugs and chemosensitizers. J Pharm Sci 2004;93:1993-2008.

Cakal B, Akoz AG, Ustundag Y, Yalinkilic M, Ulker A, Ankarali H. Red cell distribution width for assessment of activity of inflammatory bowel disease. Dig Dis Sci 2009;54:842-47.

Bello AE, Holt RJ. Cardiovascular risk with non-steroidal anti-inflammatory drugs: clinical implications. Drug Saf 2014;37:897-902.

Whittle B. COX-1 and COX-2 products in the gut: therapeutic impact of COX-2 inhibitors. Gut 2000;47:320-25.

Fries JF. NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal. J Rheumatology Suppl 1991;28:6-10.

Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-49.

Harirforoosh S, West K, Murrell D, Denham J, Panus P, Hanley G. Assessment of celecoxib poly (lactic-co-glycolic) acid nanoformulation on drug pharmacodynamics and pharmacokinetics in rats. Eur Rev Med Pharmacol Sci 2016;20:4818-29.

Kim T-H, Jeong Y-I, Jin S-G, Pei J, Jung T-Y, Moon K-S, et al. Preparation of polylactide-co-glycolide nanoparticles incorporating celecoxib and their antitumor activity against brain tumor cells. Int J Nanomedicine 2011;6:2621-31.

Kaynak Göster

  • ISSN: 2148-2373
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 2013
  • Yayıncı: Galenos Yayınevi

7.5b 3.5b

Sayıdaki Diğer Makaleler

The Inhibitory Effect of Ileal Mucosal Media Originated from FVB/N Mice Strain on Escherichia coli LF82 Invasion

Hüsamettin AYGÜN, MURAT KARAMEŞE, Fikret UYAR

Malaria Prophylaxis and Vaccinations Among Turkish International Travelers: National Data, 2011-2016

Gülay OKAY, Cemal AYAZOĞLU, Osman KAN, Meliha Meriç KOÇ, TURAN ASLAN

Genotype-phenotype Correlation in Pelizaeus Merzbacher Disease and Pelizaeus Merzbacher-like Disease

Elif GÖKÇAL, Birdal BİLİR, Esra BATTALOĞLU, AYŞE RESA AYDIN, Zuhal YAPICI

Palyatif Bakım Hastasındaki İnatçı Hıçkırık Tedavisinde Bilateral Frenik Sinir Bloğu: Olgu Sunumu

MUSTAFA SÜREN, Vildan KÖLÜKÇÜ, SELİM ADATEPE, SERKAN DOĞRU, Ahmet AKBAŞ, İSMAİL OKAN

Preparation and Evaluation of Inflammation Targeted Nano-micellar Formulation of Celecoxib

Fatemeh Bahadori, AYŞE ŞEYMA BÜYÜK, Ahmet Serdar KOZANOĞLU, Zehra ESKANDARI, HANDAN ANKARALI, Şerife Evrim KEPEKÇİ TEKKELİ, Hümeyra Nur KALELİ, Abdurrahim KOÇYİĞİT

Karaciğer Transplantasyonu Yapılan Hastalarda Uzamış Mekanik Ventilasyon Prediktörleri

MELTEM GÜNER CAN, ALİ ÖZER

Diş Hekimliği Pratiğinde Oral Antikoagülan Ajan Kullanan Hastalara Yaklaşım

Özge DOĞANAY

Huzursuz Bacaklar Sendromu Hastalarında Obsesif Kompülsif Belirti Düzeylerinin Araştırılması ve Klinik Önemi

Yıldızhan ŞENGÜL, ONUR YILMAZ, Hakan Serdar ŞENGÜL, Fatma Büşra PARLAKKAYA, AHMET ÖZTÜRK

Measurement of Impedance Values of Different Erythrocyte Suspensions

MEHMET ÜYÜKLÜ

The Value of Magnetic Resonances Imaging in Localized Lipoatrophy

Amber EKER, Pembe Hare YİĞİTOĞLU, Aslı Feride KAPTANOĞLU