Journal of Literature Pharmacy Sciences

Nanopartiküler İlaç Taşıyıcı Sistemler ile Oral İnsülin Tedavisinde Son Gelişmeler: Sistematik Derleme
Recent Advances in Oral Insulin Therapy by Nanoparticulate Drug Delivery Systems: Systematic Review
Tuğçe TURANa, N. Başaran MUTLU AĞARDANa
aGazi Üniversitesi Eczacılık Fakültesi, Farmasötik Teknoloji ABD, Ankara, Türkiye
J Lit Pharm Sci. 2022;11(2):104-18
doi: 10.5336/pharmsci.2021-87457
Article Language: TR
Full Text
ÖZET
 Diabetes mellitus, yüksek kan glukoz seviyeleri ile karakterize kronik, metabolik bir hastalıktır. Tedavisinde kullanılan en önemli molekül insülindir. İnsülin, pankreasın Langerhans adacıklarının β hücreleri tarafından üretilen, kan glukoz seviyesini düzenleme etkisini monomerik formunun insülin reseptörüne bağlanmasıyla gösteren bir hormondur. İnsülin vücuda subkütan yoldan verilmektedir fakat bu yol ile hasta uyuncu oldukça düşüktür. Ayrıca subkütan uygulama, enjeksiyon bölgesinde lipodistrofiye, alerjik reaksiyonlara ve enfeksiyona neden olmaktadır. İnsülin oral yol ile uygulandığında gastrointestinal (Gİ) kanalda proteolitik enzimler ile hızla parçalanmakta, yapısı dolayısıyla da düşük absorpsiyon göstermektedir. İnsülinin Gİ kanalda parçalanmasını önlemek ve oral biyoyararlanımını artırmak için birçok çalışma yapılmakta; bu çalışmalar nanopartiküler ilaç taşıyıcı sistemler üzerinde yoğunlaşmaktadır. Doğal (kitosan, aljinat, dekstran) veya sentetik (poli-laktik-ko glikolik asit, poli-laktik asit) polimerler ile hazırlanan nanopartiküllerin; çözünürlük artırma, modifiye salım sağlama, emilimi artırma ve oral biyoyararlanımı iyileştirme gibi pek çok faydası bulunmaktadır. İnsülin taşıyan bir nanopartiküler sistemin, insülini mide asidinden ve proteazlardan koruması, Gİ kanalda kalış süresini uzatması ve absorpsiyonunu artırması beklenir. Bu amaçla, nanopartiküler ilaç taşıyıcı sistem formülasyonlarına, insülinin bağırsak absorpsiyonunu artırmak için absorpsiyon artırıcılar, insülinin proteazlarla parçalanmasını engellemek için enzim inhibitörleri ilave edilebilir. Ayrıca insülinin midede parçalanmasını engellemek için enterik kaplama yapılabilmektedir. Bu derlemede diyabet hastalığı, insülin ve insülinin oral yoldan verilmesiyle ilgili kısaca genel bilgiler verilerek, insülin yüklü nanopartiküler ilaç taşıyıcı sistemler ile ilgili güncel literatür örneklerine odaklanılmıştır.

Anahtar Kelimeler: Diabetes mellitus; oral uygulama; ilaç taşıyıcı sistem; nanopartikül; insülin
ABSTRACT
 Diabetes mellitus is a chronic, metabolic disease characterized by high blood glucose levels. The most important molecule used in its treatment is insulin. Insulin is a hormone produced by the β cells of the islets of Langerhans of the pancreas, which shows its blood glucose level regulation effect by binding its monomeric form to the insulin receptor. Insulin is applied subcutaneously, but patient compliance is very low by this route. In addition, subcutaneous administration causes lipodystrophy, allergic reactions and infection at the injection site. When insulin is administered orally, it is rapidly degraded by proteolytic enzymes in the gastrointestinal (GI) tract, and has low absorption due to its structure. Many studies are carried out to prevent the degradation of insulin in the GI tract and to increase its oral bioavailability; these studies focus on nanoparticular drug delivery systems. Nanoparticles prepared with natural (chitosan, alginate, dextran) or synthetic (poly-lactic-co-glycolic acid, poly-lactic acid) polymers, have many benefits such as increasing solubility, providing modified release, increasing absorption and improving oral bioavailability. An insulin-encapsulated nanoparticular system is expected to protect insulin from both harsh acidic conditions of stomach and degradation by proteases, prolong its residence time in the GI track and enhance its intestinal uptake. Nanoparticulate systems can also be formulated using penetration enhancers to increase intestinal penetration of insulin and enzyme inhibitors to inhibit the insulin degradation by proteases. Furthermore, enteric coating could be applied to prevent the breakdown of insulin in the stomach, In this review, brief general information about diabetes, insulin and oral administration of insulin is presented and recent literature about insulin loaded nanoparticulate drug delivery systems is focused on.

Keywords: Diabetes mellitus; oral administration; drug delivery system; nanoparticle; insulin
REFERENCES:
  1. Alai MS, Lin WJ, Pingale SS. Application of polymeric nanoparticles and micelles in insulin oral delivery. J Food Drug Anal. 2015;23(3):351-8. [Crossref]  [PubMed] 
  2. Mutlu-Agardan NB, Han S. In vitro and in vivo evaluations on nanoparticle and phospholipid hybrid nanoparticles with absorption enhancers for oral insulin delivery. Pharm Dev Technol. 2021;26(2):157-66. [Crossref]  [PubMed] 
  3. Las G, Oliveira MF, Shirihai OS. Emerging roles of β-cell mitochondria in type-2-diabetes. Mol Aspects Med. 2020;71:100843. [Crossref]  [PubMed] 
  4. Tan SY, Mei Wong JL, Sim YJ, Wong SS, Mohamed Elhassan SA, Tan SH, et al. Type 1 and 2 diabetes mellitus: a review on current treatment approach and gene therapy as potential intervention. Diabetes Metab Syndr. 2019;13(1):364-72. [Crossref]  [PubMed] 
  5. Sharma G, Sharma AR, Nam JS, Doss GP, Lee SS, Chakraborty C. Nanoparticle based insulin delivery system: the next generation efficient therapy for Type 1 diabetes. J Nanobiotechnology. 2015;13:74. [Crossref]  [PubMed]  [PMC] 
  6. Dong H, Woo SL. Hepatic insulin production for type 1 diabetes. Trends Endocrinol Metab. 2001;12(10):441-6. [Crossref]  [PubMed] 
  7. Easa N, Alany RG, Carew M, Vangala A. A review of non-invasive insulin delivery systems for diabetes therapy in clinical trials over the past decade. Drug Discov Today. 2019;24(2):440-51. [Crossref]  [PubMed] 
  8. Domon A, Katayama K, Tochigi Y, Suzuki H. Characterization of novel nonobese type 2 diabetes rat model with enlarged kidneys. J Diabetes Res. 2019:8153140. [Crossref]  [PubMed]  [PMC] 
  9. Wong CY, Al-Salami H, Dass CR. Potential of insulin nanoparticle formulations for oral delivery and diabetes treatment. J Control Release. 2017;264:247-75. [Crossref]  [PubMed] 
  10. Iyer H, Khedkar A, Verma M. Oral insulin - a review of current status. Diabetes Obes Metab. 2010;12(3):179-85. Erratum in: Diabetes Obes Metab. 2010;12(3). Erratum in: Diabetes Obes Metab. 2010;12(10):928. [Crossref]  [PubMed] 
  11. Garber AJ, Handelsman Y, Grunberger G, Einhorn D, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm-2020 Executive Summary. Endocr Pract. 2020;26(1):107-39. [Crossref]  [PubMed] 
  12. World Health Organization [Internet]. © 2022 WHO [Cited: January 25, 2022]. Diabetes. Available from: [Link] 
  13. Jirácek J, Záková L, Antolíková E, Watson CJ, Turkenburg JP, Dodson GG, et al. Implications for the active form of human insulin based on the structural convergence of highly active hormone analogues. Proc Natl Acad Sci U S A. 2010;107(5):1966-70. [Crossref]  [PubMed]  [PMC] 
  14. Mathieu C. Minimising hypoglycaemia in the real world: the challenge of insulin. Diabetologia. 2021;64(5):978-84. [Crossref]  [PubMed] 
  15. Pillai O, Panchagnula R. Insulin therapies-past, present and future. Drug Discov Today. 2001;6(20):1056-61. [Crossref]  [PubMed] 
  16. Sharma AK, Taneja G, Kumar A, Sahu M, Sharma G, Kumar A, et al. Insulin analogs: glimpse on contemporary facts and future prospective. Life Sci. 2019;219:90-9. [Crossref]  [PubMed] 
  17. Damgé C, Reis CP, Maincent P. Nanoparticle strategies for the oral delivery of insulin. Expert Opin Drug Deliv. 2008;5(1):45-68. [Crossref]  [PubMed] 
  18. Gedawy A, Martinez J, Al-Salami H, Dass CR. Oral insulin delivery: existing barriers and current counter-strategies. J Pharm Pharmacol. 2018;70(2):197-213. [Crossref]  [PubMed] 
  19. Tan X, Liu X, Zhang Y, Zhang H, Lin X, Pu C, et al. Silica nanoparticles on the oral delivery of insulin. Expert Opin Drug Deliv. 2018;15(8):805-20. [Crossref]  [PubMed] 
  20. Ji N, Hong Y, Gu Z, Cheng L, Li Z, Li C. Chitosan coating of zein-carboxymethylated short-chain amylose nanocomposites improves oral bioavailability of insulin in vitro and in vivo. J Control Release. 2019;313:1-13. [Crossref]  [PubMed] 
  21. Hu Q, Luo Y. Recent advances of polysaccharide-based nanoparticles for oral insulin delivery. Int J Biol Macromol. 2018;120(Pt A):775-82. [Crossref]  [PubMed] 
  22. Arbit E, Kidron M. Oral insulin delivery in a physiologic context: review. J Diabetes Sci Technol. 2017;11(4):825-32. [Crossref]  [PubMed]  [PMC] 
  23. Niu M, Lu Y, Hovgaard L, Guan P, Tan Y, Lian R, et al. Hypoglycemic activity and oral bioavailability of insulin-loaded liposomes containing bile salts in rats: the effect of cholate type, particle size and administered dose. Eur J Pharm Biopharm. 2012;81(2):265-72. [Crossref]  [PubMed] 
  24. Lee VHL, Dodda-Kashi S, Grass GM, Werner R. Oral route of peptide and protein drug delivery. In: Lee VHL, ed. Peptide and Protein Drug Delivery. 1st ed. New York: Marcel Dekker Inc; 1991. p.691-738.
  25. Brange J, Langkjaer L. Chemical stability of insulin. 3. Influence of excipients, formulation, and pH. Acta Pharm Nord. 1992;4(3):149-58. [PubMed] 
  26. Zhang T, Tang JZ, Fei X, Li Y, Song Y, Qian Z, et al. Can nanoparticles and nano-protein interactions bring a bright future for insulin delivery? Acta Pharm Sin B. 2021;11(3):651-67. [Crossref]  [PubMed]  [PMC] 
  27. Maderuelo C, Lanao JM, Zarzuelo A. Enteric coating of oral solid dosage forms as a tool to improve drug bioavailability. Eur J Pharm Sci. 2019;138:105019. [Crossref]  [PubMed] 
  28. Li P, Tan A, Prestidge CA, Nielsen HM, Müllertz A. Self-nanoemulsifying drug delivery systems for oral insulin delivery: in vitro and in vivo evaluations of enteric coating and drug loading. Int J Pharm. 2014;477(1-2):390-8. [Crossref]  [PubMed] 
  29. Wong CY, Martinez J, Carnagarin R, Dass CR. In-vitro evaluation of enteric coated insulin tablets containing absorption enhancer and enzyme inhibitor. J Pharm Pharmacol. 2017;69(3):285-94. [Crossref]  [PubMed] 
  30. Fonte P, Araújo F, Silva C, Pereira C, Reis S, Santos HA, et al. Polymer-based nanoparticles for oral insulin delivery: revisited approaches. Biotechnol Adv. 2015;33(6 Pt 3):1342-54. Erratum in: Biotechnol Adv. 2016;34(1):64. [Crossref]  [PubMed] 
  31. Sharma G, Wilson K, van der Walle CF, Sattar N, Petrie JR, Ravi Kumar MN. Microemulsions for oral delivery of insulin: design, development and evaluation in streptozotocin induced diabetic rats. Eur J Pharm Biopharm. 2010;76(2):159-69. [Crossref]  [PubMed] 
  32. Krauland AH, Guggi D, Bernkop-Schnürch A. Oral insulin delivery: the potential of thiolated chitosan-insulin tablets on non-diabetic rats. J Control Release. 2004;95(3):547-55. [Crossref]  [PubMed] 
  33. Su FY, Lin KJ, Sonaje K, Wey SP, Yen TC, Ho YC, et al. Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery. Biomaterials. 2012;33(9):2801-11. [Crossref]  [PubMed] 
  34. Ukai H, Iwasa K, Deguchi T, Morishita M, Katsumi H, Yamamoto A. Enhanced intestinal absorption of insulin by capryol 90, a novel absorption enhancer in rats: implications in oral insulin delivery. Pharmaceutics. 2020;12(5):462. [Crossref]  [PubMed]  [PMC] 
  35. Ukai H, Kawagoe A, Sato E, Morishita M, Katsumi H, Yamamoto A. Propylene glycol caprylate as a novel potential absorption enhancer for improving the intestinal absorption of insulin: efficacy, safety, and absorption-enhancing mechanisms. J Pharm Sci. 2020;109(4):1483-92. [Crossref]  [PubMed] 
  36. Ağardan NBM. Studies on the formulation optimization and controlled ionic gelation of chitosan nanoparticles using TPP-HP-[beta]-CD inclusion complex. Istanbul J Pharm. 2020;50(1):54-9. [Link] 
  37. Cao SJ, Xu S, Wang HM, Ling Y, Dong J, Xia RD, et al. Nanoparticles: oral delivery for protein and peptide drugs. AAPS PharmSciTech. 2019;20(5):190. [Crossref]  [PubMed]  [PMC] 
  38. Lundquist P, Artursson P. Oral absorption of peptides and nanoparticles across the human intestine: Opportunities, limitations and studies in human tissues. Adv Drug Deliv Rev. 2016;106(Pt B):256-76. [Crossref]  [PubMed] 
  39. Chen MC, Sonaje K, Chen KJ, Sung HW. A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery. Biomaterials. 2011;32(36):9826-38. [Crossref]  [PubMed] 
  40. Yeh TH, Hsu LW, Tseng MT, Lee PL, Sonjae K, Ho YC, et al. Mechanism and consequence of chitosan-mediated reversible epithelial tight junction opening. Biomaterials. 2011;32(26):6164-73. [Crossref]  [PubMed] 
  41. Song M, Wang H, Chen K, Zhang S, Yu L, Elshazly EH, et al. Oral insulin delivery by carboxymethyl-β-cyclodextrin-grafted chitosan nanoparticles for improving diabetic treatment. Artif Cells Nanomed Biotechnol. 2018;46(sup3):S774-S82. [Crossref]  [PubMed] 
  42. El Leithy ES, Abdel-Bar HM, Ali RA. Folate-chitosan nanoparticles triggered insulin cellular uptake and improved in vivo hypoglycemic activity. Int J Pharm. 2019;571:118708. [Crossref]  [PubMed] 
  43. Sudhakar S, Chandran SV, Selvamurugan N, Nazeer RA. Biodistribution and pharmacokinetics of thiolated chitosan nanoparticles for oral delivery of insulin in vivo. Int J Biol Macromol. 2020;150:281-8. [Crossref]  [PubMed] 
  44. Cheng H, Guo S, Cui Z, Zhang X, Huo Y, Guan J, et l. Design of folic acid decorated virus-mimicking nanoparticles for enhanced oral insulin delivery. Int J Pharm. 2021;596:120297. [Crossref]  [PubMed] 
  45. Fan W, Xia D, Zhu Q, Li X, He S, Zhu C, et al. Functional nanoparticles exploit the bile acid pathway to overcome multiple barriers of the intestinal epithelium for oral insulin delivery. Biomaterials. 2018;151:13-23. [Crossref]  [PubMed] 
  46. Sonia TA, Sharma CP. An overview of natural polymers for oral insulin delivery. Drug Discov Today. 2012;17(13-14):784-92. [Crossref]  [PubMed] 
  47. Chen X, Ren Y, Feng Y, Xu X, Tan H, Li J. Cp1-11 peptide/insulin complex loaded pH-responsive nanoparticles with enhanced oral bioactivity. Int J Pharm. 2019;562:23-30. [Crossref]  [PubMed] 
  48. Mukhopadhyay P, Chakraborty S, Bhattacharya S, Mishra R, Kundu PP. pH-sensitive chitosan/alginate core-shell nanoparticles for efficient and safe oral insulin delivery. Int J Biol Macromol. 2015;72:640-8. [Crossref]  [PubMed] 
  49. Li M, Sun Y, Ma C, Hua Y, Zhang L, Shen J. Design and investigation of penetrating mechanism of octaarginine-modified alginate nanoparticles for improving intestinal insulin delivery. J Pharm Sci. 2021;110(1):268-79. [Crossref]  [PubMed] 
  50. Chalasani KB, Russell-Jones GJ, Jain AK, Diwan PV, Jain SK. Effective oral delivery of insulin in animal models using vitamin B12-coated dextran nanoparticles. J Control Release. 2007;122(2):141-50. [Crossref]  [PubMed] 
  51. Woitiski CB, Neufeld RJ, Veiga F, Carvalho RA, Figueiredo IV. Pharmacological effect of orally delivered insulin facilitated by multilayered stable nanoparticles. Eur J Pharm Sci. 2010;41(3-4):556-63. [Crossref]  [PubMed] 
  52. Jamwal S, Ram B, Ranote S, Dharela R, Chauhan GS. New glucose oxidase-immobilized stimuli-responsive dextran nanoparticles for insulin delivery. Int J Biol Macromol. 2019;123:968-78. [Crossref]  [PubMed] 
  53. Bao X, Qian K, Yao P. Insulin- and cholic acid-loaded zein/casein-dextran nanoparticles enhance the oral absorption and hypoglycemic effect of insulin. J Mater Chem B. 2021;9(31):6234-45. [Crossref]  [PubMed] 
  54. Malathi S, Nandhakumar P, Pandiyan V, Webster TJ, Balasubramanian S. Novel PLGA-based nanoparticles for the oral delivery of insulin. Int J Nanomedicine. 2015;10:2207-18. [Crossref]  [PubMed]  [PMC] 
  55. Jain A, Jain SK. L-Valine appended PLGA nanoparticles for oral insulin delivery. Acta Diabetol. 2015;52(4):663-76. [Crossref]  [PubMed] 
  56. Jaradat A, Macedo MH, Sousa F, Arkill K, Alexander C, Aylott J, et al. Prediction of the enhanced insulin absorption across a triple co-cultured intestinal model using mucus penetrating PLGA nanoparticles. Int J Pharm. 2020;585:119516. [Crossref]  [PubMed] 
  57. Akhavan Farid E, Davachi SM, Pezeshki-Modaress M, Taranejoo S, Seyfi J, et al. Preparation and characterization of polylactic-co-glycolic acid/insulin nanoparticles encapsulated in methacrylate coated gelatin with sustained release for specific medical applications. J Biomater Sci Polym Ed. 2020;31(7):910-37. [Crossref]  [PubMed] 
  58. Lei C, Liu XR, Chen QB, Li Y, Zhou JL, Zhou LY, et al. Hyaluronic acid and albumin based nanoparticles for drug delivery. J Control Release. 2021;331:416-33. [Crossref]  [PubMed] 
  59. Han L, Zhao Y, Yin L, Li R, Liang Y, Huang H, et al. Insulin-loaded pH-sensitive hyaluronic acid nanoparticles enhance transcellular delivery. AAPS PharmSciTech. 2012;13(3):836-45. [Crossref]  [PubMed]  [PMC] 
  60. Tian H, He Z, Sun C, Yang C, Zhao P, Liu L, et al. Uniform core-shell nanoparticles with thiolated hyaluronic acid coating to enhance oral delivery of insulin. Adv Healthc Mater. 2018;7(17):e1800285. [Crossref]  [PubMed] 
  61. Luo YY, Xiong XY, Tian Y, Li ZL, Gong YC, Li YP. A review of biodegradable polymeric systems for oral insulin delivery. Drug Deliv. 2016;23(6):1882-91. [PubMed] 
  62. Minimol PF, Paul W, Sharma CP. PEGylated starch acetate nanoparticles and its potential use for oral insulin delivery. Carbohydr Polym. 2013;95(1):1-8. [Crossref]  [PubMed] 
  63. Zhang Z, Shan H, Chen L, He C, Zhuang X, Chen X. Synthesis of pH-responsive starch nanoparticles grafted poly (l-glutamic acid) for insulin controlled release. Eur Polym J. 2013;49(8):2082-91. [Crossref] 
  64. Zhang Z, Lv H, Zhou J. Novel solid lipid nanoparticles as carriers for oral administration of insulin. Pharmazie. 2009;64(9):574-8. [PubMed] 
  65. Muntoni E, Anfossi L, Milla P, Marini E, Ferraris C, Capucchio MT, et al. Glargine insulin loaded lipid nanoparticles: oral delivery of liquid and solid oral dosage forms. Nutr Metab Cardiovasc Dis. 2021;31(2):691-8. [Crossref]  [PubMed] 
  66. Wang T, Shen L, Zhang Y, Li H, Wang Y, Quan D. "Oil-soluble" reversed lipid nanoparticles for oral insulin delivery. J Nanobiotechnology. 2020;18(1):98. [Crossref]  [PubMed]  [PMC] 
  67. Koland M, Anchan RB, Mukund SG, Sindhoor S. Design and investigation of alginate coated solid lipid nanoparticles for oral insulin delivery. Indian J Pharm Educ Res. 2021;55(2):383-94. [Crossref] 
  68. Juère E, Caillard R, Marko D, Del Favero G, Kleitz F. Smart protein-based formulation of dendritic mesoporous silica nanoparticles: toward oral delivery of insulin. Chemistry. 2020;26(23):5195-9. [Crossref]  [PubMed]  [PMC] 
  69. Tan X, Yin N, Liu Z, Sun R, Gou J, Yin T, et al. Hydrophilic and electroneutral nanoparticles to overcome mucus trapping and enhance oral delivery of insulin. Mol Pharm. 2020;17(9):3177-91. [Crossref]  [PubMed] 
  70. Gao Y, He Y, Zhang H, Zhang Y, Gao T, Wang JH, et al. Zwitterion-functionalized mesoporous silica nanoparticles for enhancing oral delivery of protein drugs by overcoming multiple gastrointestinal barriers. J Colloid Interface Sci. 2021;582(Pt A):364-75. [Crossref]  [PubMed] 
  71. Küünal S, Rauwel P, Rauwel E. Plant extract mediated synthesis of nanoparticles. In: Makhlouf ASH, Barhoum A, eds. Emerging Applications of Nanoparticles and Architecture Nanostructures. 1st ed. New York: Elsevier Inc; 2018. p.411-46. [Crossref] 
  72. Holkar CR, Jain SS, Jadhav AJ, Pinjari DV. Scale-up technologies for advanced nanomaterials for green energy: feasibilities and challenges. In: Bhanvese BA, Pawade VB, Dhoble SJ, Sonawane SH, Ashokkumar M, eds. Nanomaterials for Green Energy. 1st ed. New York: Elsevier Inc; 2018. p.433-55. [Crossref] 
  73. Kumari Y, Singh SK, Kumar R, Kumar B, Kaur G, Gulati M, et al. Modified apple polysaccharide capped gold nanoparticles for oral delivery of insulin. Int J Biol Macromol. 2020;149:976-88. [Crossref]  [PubMed] 
  74. Cho HJ, Oh J, Choo MK, Ha JI, Park Y, Maeng HJ. Chondroitin sulfate-capped gold nanoparticles for the oral delivery of insulin. Int J Biol Macromol. 2014;63:15-20. [Crossref]  [PubMed] 

.: Up To Date

.: Process List

Login

 Forgot your password?

 New Registration  

Contact

Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com