Journal of Literature Pharmacy Sciences

Transdermal ve Dermal Terapötik Sistemlerde İlaç Geçişini Artırma Stratejileri: Geleneksel Derleme
Strategies to Enhance Drug Pass in Transdermal and Dermal Therapeutic Systems: Traditional Review
Kutsal ÖZCANa,b, Sibel İLBASMIŞ TAMERa
aGazi Üniversitesi Eczacılık Fakültesi, Farmasötik Teknoloji ABD, Ankara, Türkiye
bKaradeniz Teknik Üniversitesi Eczacılık Fakültesi, Farmasötik Teknoloji ABD, Trabzon, Türkiye
J Lit Pharm Sci. 2023;12(3):228-41
doi: 10.5336/pharmsci.2023-96724
Article Language: TR
Full Text
ÖZET
Transdermal ve dermal terapötik sistemlerin diğer ilaç uygulama yollarına göre birçok avantajı bulunmaktadır. Transdermal yol, ilaçların oral yoldan verildiğinde ilk geçiş etkisi gibi mide-bağırsak sisteminde ortaya çıkabilecek sakıncaları önleyebilir, böylece ilaçların biyoyararlanımı artırır. Subkütan enjeksiyona göre daha düşük enfeksiyon riski ve maliyeti vardır. Hasta uyuncu daha yüksektir. Dermal uygulama ise ağrı ve sistemik yan etkileri en aza indirmesi ve kullanım kolaylığı gibi avantajlara sahiptir. Deriden ilaç geçişi hücre içi, hücreler arası, transapendageal ve gözenek yolu ile difüzyonla gerçekleşmektedir. Transdermal ve dermal sistemlerde karşılaşılan en büyük zorluklardan biri, ilaçların deriden geçişlerinin yeterli düzeyde olmamasıdır. Epidermisin en üst katmanı olan stratum korneum (SK), ilaç geçişine karşı engel özelliği göstermektedir. SK'nin hücre dışı lipid ile zenginleştirilmiş matrisi hidrofilik ilaçların geçişini sınırlamakta, lipofilik ilaçların ise birikip yavaşça salınmasına sebep olabilmektedir. Bu durum aktif bileşenlerin biyoyararlanımını düşürmektedir. İlaç taşıyıcı sistemlerin sağladığı avantajlardan faydalanarak, SK'nin engel işlevini aşmak için çeşitli aktif ve pasif yöntemler geniş çapta incelenmiştir. Bu derleme makalede de transdermal ve dermal terapötik sistemlerde ilaç geçişini artırma yöntemleri incelenmiştir. Birinci nesil transdermal ve dermal ilaç taşıyıcı sistemlerde ilaç geçişi çok sınırlıdır. Esas olarak ikinci nesil yöntemlerde ilaç geçişinin artırılması hedeflenmektedir. Bu kapsamda; ilaç-ilaç etkileşimi, SK modifikasyonu, ilaç taşıyıcı sistemler, enerji odaklı sistemler ve SK'nin atlatılması yöntemlerini içermektedir. İkincil nesildeki yöntemlerin birleştirilmesi ise üçüncü nesli oluşturmaktadır. Bu tür yenilikçi yaklaşımlar uygulanan ilaçları doz, maliyet ve terapötik etkinlik açısından daha avantajlı hâle getirebilir. Bu makale kapsamında özellikle ikinci nesil başlığı altında yer alan yöntemler özetlenerek, incelenmiştir.

Anahtar Kelimeler: Kutanöz uygulama; deri emilimi; iyontoforez; elektroporasyon; ilaç taşıyıcı sistem
ABSTRACT
Transdermal, dermal systems therapeutic systems have many advantages over other drug delivery routes. Transdermal route can prevent problems that may occur in gastrointestinal system such as first pass effect when the drugs are administered orally, increase bioavailability of drugs. It has lower infection risk, cost compared to subcutaneous injection. Patient compliance is higher. Dermal application has advantages such as minimizing pain, systemic side effects, ease of use. Drug passage through skin occurs by diffusion through intracellular, intercellular, transappendageal, pore routes. One of the biggest difficulties encountered in transdermal, dermal systems is insufficient penetration of drugs through skin. Stratum corneum (SC), uppermost layer of the epidermis, acts as barrier against drug penetration. Extracellular lipid-enriched matrix of SC restricts passage of hydrophilic drugs, causing accumulation, slow release of lipophilic drugs. This reduces bioavailability of active ingredients. Taking advantage of innovations in drug delivery systems, various active, passive methods have been extensively studied to exceed barrier function of SC. In this review article, methods of increasing drug penetration in transdermal, dermal therapeutic systems were examined. Drug pass is very limited in first generation transdermal, dermal drug delivery systems. It is aimed to increase drug pass in second generation methods. In this context; includes drug-drug interaction, SC modification, drug delivery systems, energy-focused systems, SC bypass methods. Combination of methods in second generation creates third generation. Such innovative approaches may make administered drugs more advantageous in terms of dose, cost, therapeutic efficacy. In this research article, especially methods under second generation title are summarized, examined.

Keywords: Cutaneous administration; skin absorption; iontophoresis; electroporation; drug delivery systems
REFERENCES:
  1. Sa'adon S, Abd Razak SI, Fakhruddin K. Drug-loaded poly-vinyl alcohol electrospun nanofibers for transdermal drug delivery: review on factors affecting the drug release. Procedia Comput Sci. 2019;158:436-42. [Crossref] 
  2. Alkilani AZ, McCrudden MT, Donnelly RF. Transdermal Drug delivery: innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum. Pharmaceutics. 2015;7(4):438-70. [Crossref]  [PubMed]  [PMC] 
  3. Sabbagh F, Kim BS. Recent advances in polymeric transdermal drug delivery systems. J Control Release. 2022;341:132-46. [Crossref]  [PubMed] 
  4. Sivasankarapillai V, Das S, Sabir F, Sundaramahalingam M, Colmenares J, Prasannakumar S, et al. Progress in natural polymer engineered biomaterials for transdermal drug delivery systems. Mater Today Chem. 2021;19:100382. [Crossref] 
  5. Badilli U, Gumustas M, Uslu B, Ozkan SA. Lipid-based nanoparticles for dermal drug delivery. In: Grumezescu AM, ed. Organic Materials as Smart Nanocarriers for Drug Delivery. 1st ed. Oxford, United Kingdom: William Andrew Publishing; 2018. p.369-413. [Crossref] 
  6. Değim T, İlbasmış-Tamer S. Transdermal delivery of active compounds for the treatment of erectile dysfunction. Asian Chemistry Letters. 2011;16(1):9-22. [Link] 
  7. Prausnitz MR, Elias PM, Franz TJ, Schmuth M, Tsai J-C, Menon GK, et al. Skin barrier and transdermal drug delivery. Dermatology. 2012;3:2065-73. [Link] 
  8. Ramteke K, Dhole S, Patil S. Transdermal drug delivery system: a review. J Adv Sci Res. 2012;3(1):22-35. [Link] 
  9. Ramadon D, McCrudden MTC, Courtenay AJ, Donnelly RF. Enhancement strategies for transdermal drug delivery systems: current trends and applications. Drug Deliv Transl Res. 2022;12(4):758-91. [Crossref]  [PubMed]  [PMC] 
  10. Ita KB. Prodrugs for transdermal drug delivery - trends and challenges. J Drug Target. 2016;24(8):671-8. [Crossref]  [PubMed] 
  11. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26(11):1261-8. [Crossref]  [PubMed]  [PMC] 
  12. Patel HJ, Trivedi DG, Bhandari AK, Shah DA. Penetration enhancers for transdermal drug delivery system: a review. Imp J Pharm Cosmetol. 2011;1(2):67-80. [Link] 
  13. Al-Akayleh F, Adwan S, Khanfar M, Idkaidek N, Al-Remawi M. A novel eutectic-based transdermal delivery system for risperidone. AAPS PharmSciTech. 2020;22(1):4. Erratum in: AAPS PharmSciTech. 2020;22(1):13. [Crossref]  [PubMed] 
  14. Hirakawa Y, Ueda H, Miyano T, Kamiya N, Goto M. New insight into transdermal drug delivery with supersaturated formulation based on co-amorphous system. Int J Pharm. 2019;569:118582. [Crossref]  [PubMed] 
  15. Alexander A, Dwivedi S, Ajazuddin, Giri TK, Saraf S, Saraf S, et al. Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J Control Release. 2012;164(1):26-40. [Crossref]  [PubMed] 
  16. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128-37. [Crossref] 
  17. Barnes TM, Mijaljica D, Townley JP, Spada F, Harrison IP. Vehicles for drug delivery and cosmetic moisturizers: review and comparison. Pharmaceutics. 2021;13(12):2012. [Crossref]  [PubMed]  [PMC] 
  18. Xie J, Ji Y, Xue W, Ma D, Hu Y. Hyaluronic acid-containing ethosomes as a potential carrier for transdermal drug delivery. Colloids Surf B Biointerfaces. 2018;172:323-9. [Crossref]  [PubMed] 
  19. Marren K. Dimethyl sulfoxide: an effective penetration enhancer for topical administration of NSAIDs. Phys Sportsmed. 2011;39(3):75-82. [Crossref]  [PubMed] 
  20. Mathur V, Satrawala Y, Rajput MS. Physical and chemical penetration enhancers in transdermal drug delivery system. Asian Journal of Pharmaceutics. 2010;4(3):173. [Crossref] 
  21. Chen Y, Quan P, Liu X, Wang M, Fang L. Novel chemical permeation enhancers for transdermal drug delivery. Asian Journal of Pharmaceutical Sciences. 2014;9(2):51-64. [Crossref] 
  22. Babu RJ, Chen L. Pyrrolidones as penetration enhancers. In: Dragicevic N, Maibach HI, eds. Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement. 1st ed. Germany: Springer Berlin; 2015. p.291-9. [Crossref] 
  23. Babu RJ, Chen L, Kanikkannan N. Fatty alcohols, fatty acids, and fatty acid esters as penetration enhancers. In: Dragicevic N, Maibach HI, eds. Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement. 1st ed. Germany: Springer Berlin; 2015. p.133-50. [Crossref] 
  24. Heard CM. Ethanol and other alcohols: old enhancers, alternative perspectives. In: Dragicevic N, Maibach HI, eds. Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement. 1st ed. Germany: Springer Berlin; 2015. p.151-72. [Crossref] 
  25. Anurova M, Demina N, Bakhrushina E. Permeability enhancers in transdermal delivery system technology. Pharm Chem J. 2021;54(11):1162-8. [Crossref] 
  26. Pandit J, Aqil M, Sultana Y. Terpenes and essential oils as skin penetration enhancers. In: Dragicevic N, Maibach HI, eds. Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement. 1st ed. Germany: Springer Berlin; 2015. p.173-93. [Crossref] 
  27. Fox LT, Gerber M, Plessis JD, Hamman JH. Transdermal drug delivery enhancement by compounds of natural origin. Molecules. 2011;16(12):10507-40. [Crossref]  [PMC] 
  28. Celleno L. Topical urea in skincare: a review. Dermatol Ther. 2018;31(6):e12690. [Crossref]  [PubMed] 
  29. Karande P, Mitragotri S. Enhancement of transdermal drug delivery via synergistic action of chemicals. Biochim Biophys Acta. 2009;1788(11):2362-73. [Crossref]  [PubMed] 
  30. Tuğcu-Demiröz F. Vaginal delivery of benzydamine hydrochloride through liposomes dispersed in mucoadhesive gels. Chem Pharm Bull (Tokyo). 2017;65(7):660-7. [Crossref]  [PubMed] 
  31. Sala M, Diab R, Elaissari A, Fessi H. Lipid nanocarriers as skin drug delivery systems: properties, mechanisms of skin interactions and medical applications. Int J Pharm. 2018;535(1-2):1-17. [Crossref]  [PubMed] 
  32. Rai S, Pandey V, Rai G. Transfersomes as versatile and flexible nano-vesicular carriers in skin cancer therapy: the state of the art. Nano Rev Exp. 2017;8(1):1325708. [Crossref]  [PubMed]  [PMC] 
  33. Akram MW, Jamshaid H, Rehman FU, Zaeem M, Khan JZ, Zeb A. Transfersomes: a revolutionary nanosystem for efficient transdermal drug delivery. AAPS PharmSciTech. 2021;23(1):7. [Crossref]  [PubMed] 
  34. Yücel Ç, Şeker Karatoprak G, Yalçıntaş S, Eren Böncü T. Ethosomal (-)-epigallocatechin-3-gallate as a novel approach to enhance antioxidant, anti-collagenase and anti-elastase effects. Beilstein J Nanotechnol. 2022;13:491-502. [Crossref]  [PubMed]  [PMC] 
  35. Phatale V, Vaiphei KK, Jha S, Patil D, Agrawal M, Alexander A. Overcoming skin barriers through advanced transdermal drug delivery approaches. J Control Release. 2022;351:361-80. [Crossref]  [PubMed] 
  36. Chacko IA, Ghate VM, Dsouza L, Lewis SA. Lipid vesicles: a versatile drug delivery platform for dermal and transdermal applications. Colloids Surf B Biointerfaces. 2020;195:111262. [Crossref]  [PubMed] 
  37. Ozturk A, Yenilmez E, Arslan R, Şenel B, Yazan Y. Dexketoprofen trometamol loaded solid lipid nanoparticles (SLNs): Formulation, in vitro and in vivo evaluation. JRPP. 2020;24(1):82-99. [Crossref] 
  38. Weber S, Zimmer A, Pardeike J. Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) for pulmonary application: a review of the state of the art. Eur J Pharm Biopharm. 2014;86(1):7-22. [Crossref]  [PubMed] 
  39. Sezgin-Bayindir Z, Onay-Besikci A, Vural N, Yuksel N. Niosomes encapsulating paclitaxel for oral bioavailability enhancement: preparation, characterization, pharmacokinetics and biodistribution. J Microencapsul. 2013;30(8):796-804. [Crossref]  [PubMed] 
  40. Muzzalupo R, Tavano L. Niosomal drug delivery for transdermal targeting: recent advances. Res Rep Transdermal Drug Deliv. 2015;4:23-33. [Crossref] 
  41. Yalcin TE, Tuncel E, Yucel C, Tirnaksiz F. Nanoemulsions containing megestrol acetate: development, characterization, and stability evaluation. AAPS PharmSciTech. 2022;23(5):142. [Crossref]  [PubMed] 
  42. Wu Y, Li YH, Gao XH, Chen HD. The application of nanoemulsion in dermatology: an overview. J Drug Target. 2013;21(4):321-7. [Crossref]  [PubMed] 
  43. das Neves J, Nunes R, Machado A, Sarmento B. Polymer-based nanocarriers for vaginal drug delivery. Adv Drug Deliv Rev. 2015;92:53-70. [Crossref]  [PubMed] 
  44. Gökçe BB, Boran T, Emlik Çalık F, Özhan G, Sanyal R, Güngör S. Dermal delivery and follicular targeting of adapalene using PAMAM dendrimers. Drug Deliv Transl Res. 2021;11(2):626-46. [Crossref]  [PubMed] 
  45. Junnuthula V, Kolimi P, Nyavanandi D, Sampathi S, Vora LK, Dyawanapelly S. Polymeric micelles for breast cancer therapy: recent updates, clinical translation and regulatory considerations. Pharmaceutics. 2022;14(9):1860. [Crossref]  [PubMed]  [PMC] 
  46. Makhmalzade BS, Chavoshy F. Polymeric micelles as cutaneous drug delivery system in normal skin and dermatological disorders. J Adv Pharm Technol Res. 2018;9(1):2-8. [Crossref]  [PubMed]  [PMC] 
  47. Paul W, Sharma CP. Inorganic nanoparticles for targeted drug delivery. In: Chandra Sharma, ed. Biointegration of Medical Implant Materials. 2nd ed. Oxford: Woodhead Publishing; 2020. p.333-73 [Crossref] 
  48. Ilbasmis-Tamer S, Degim IT. A feasible way to use carbon nanotubes to deliver drug molecules: transdermal application. Expert Opin Drug Deliv. 2012;9(8):991-9. [Crossref]  [PubMed] 
  49. Degim IT, Burgess DJ, Papadimitrakopoulos F. Carbon nanotubes for transdermal drug delivery. J Microencapsul. 2010;27(8):669-81. [Crossref]  [PubMed] 
  50. Ilbasmiş-Tamer S, Yilmaz S, Banoğlu E, Değim IT. Carbon nanotubes to deliver drug molecules. J Biomed Nanotechnol. 2010;6(1):20-7. [Crossref]  [PubMed] 
  51. Desai P, Patlolla RR, Singh M. Interaction of nanoparticles and cell-penetrating peptides with skin for transdermal drug delivery. Mol Membr Biol. 2010;27(7):247-59. [Crossref]  [PubMed]  [PMC] 
  52. Camlik G, Ozakca I, Bilakaya B, Ozcelikay AT, Velaro AJ, Wasnik S, et al. Development of composite carbon quantum dots-insulin formulation for oral administration. J Drug Deliv Sci Technol. 2022;76:103833. [Crossref] 
  53. İlbasmış Tamer S, Değim T. Passive and iontophoretic delivery of sildenafil through the skin. Fabad J Pharm Sci. 2007;3(32):109-19. [Link] 
  54. Wang Y, Zeng L, Song W, Liu J. Influencing factors and drug application of iontophoresis in transdermal drug delivery: an overview of recent progress. Drug Deliv Transl Res. 2022;12(1):15-26. [Crossref]  [PubMed] 
  55. Roustit M, Blaise S, Cracowski JL. Trials and tribulations of skin iontophoresis in therapeutics. Br J Clin Pharmacol. 2014;77(1):63-71. [Crossref]  [PubMed]  [PMC] 
  56. Bakshi P, Vora D, Hemmady K, Banga AK. Iontophoretic skin delivery systems: Success and failures. Int J Pharm. 2020;586:119584. [Crossref]  [PubMed] 
  57. Giri TK, Chakrabarty S, Ghosh B. Transdermal reverse iontophoresis: a novel technique for therapeutic drug monitoring. J Control Release. 2017;246:30-8. [Crossref]  [PubMed] 
  58. Degim IT, Ilbasmis S, Dundaroz R, Oguz Y. Reverse iontophoresis: a non-invasive technique for measuring blood urea level. Pediatr Nephrol. 2003;18(10):1032-7. [Crossref]  [PubMed] 
  59. Nguyen HX, Banga AK. Electrically and ultrasonically enhanced transdermal delivery of methotrexate. Pharmaceutics. 2018;10(3):117. [Crossref]  [PubMed]  [PMC] 
  60. Park D, Park H, Seo J, Lee S. Sonophoresis in transdermal drug deliverys. Ultrasonics. 2014;54(1):56-65. [Crossref]  [PubMed] 
  61. Seah BC, Teo BM. Recent advances in ultrasound-based transdermal drug delivery. Int J Nanomedicine. 2018;13:7749-63. [Crossref]  [PubMed]  [PMC] 
  62. Chen X, Zhu L, Li R, Pang L, Zhu S, Ma J, et al. Electroporation-enhanced transdermal drug delivery: Effects of logP, pKa, solubility and penetration time. Eur J Pharm Sci. 2020;151:105410. [Crossref]  [PubMed] 
  63. Murthy SN, Sammeta SM, Bowers C. Magnetophoresis for enhancing transdermal drug delivery: mechanistic studies and patch design. J Control Release. 2010;148(2):197-203. [Crossref]  [PubMed]  [PMC] 
  64. Hughes AJ, Tawfik SS, Baruah KP, O'Toole EA, O'Shaughnessy RFL. Tape strips in dermatology research. Br J Dermatol. 2021;185(1):26-35. [Crossref]  [PubMed] 
  65. Incecayir T, Agabeyoglu I, Derici U, Sindel S. Assessment of topical bioequivalence using dermal microdialysis and tape stripping methods. Pharm Res. 2011;28(9):2165-75. [Crossref]  [PubMed] 
  66. Gill HS, Andrews SN, Sakthivel SK, Fedanov A, Williams IR, Garber DA, et al. Selective removal of stratum corneum by microdermabrasion to increase skin permeability. Eur J Pharm Sci. 2009;38(2):95-103. [Crossref]  [PubMed]  [PMC] 
  67. Kaushik V, Keck CM. Influence of mechanical skin treatment (massage, ultrasound, microdermabrasion, tape stripping and microneedling) on dermal penetration efficacy of chemical compounds. Eur J Pharm Biopharm. 2021;169:29-36. [Crossref]  [PubMed] 
  68. Herndon TO, Gonzalez S, Gowrishankar TR, Anderson RR, Weaver JC. Transdermal microconduits by microscission for drug delivery and sample acquisition. BMC Med. 2004;2:12. [Crossref]  [PubMed]  [PMC] 
  69. Ma G, Wu C. Microneedle, bio-microneedle and bio-inspired microneedle: a review. J Control Release. 2017;251:11-23. [Crossref]  [PubMed] 
  70. Ahmed Saeed Al-Japairai K, Mahmood S, Hamed Almurisi S, Reddy Venugopal J, Rebhi Hilles A, et al. Current trends in polymer microneedle for transdermal drug delivery. Int J Pharm. 2020;587:119673. [Crossref]  [PubMed]  [PMC] 
  71. Lee KJ, Jeong SS, Roh DH, Kim DY, Choi HK, Lee EH. A practical guide to the development of microneedle systems - In clinical trials or on the market. Int J Pharm. 2020;573:118778. [Crossref]  [PubMed] 
  72. Waghule T, Singhvi G, Dubey SK, Pandey MM, Gupta G, Singh M, et al. Microneedles: a smart approach and increasing potential for transdermal drug delivery system. Biomed Pharmacother. 2019;109:1249-58. [Crossref]  [PubMed] 
  73. Azizoglu E, Ozer O, Prausnitz MR. Fabrication of pure-drug microneedles for delivery of montelukast sodium. Drug Deliv Transl Res. 2022;12(2):444-58. [Crossref]  [PubMed] 
  74. Chang H, Zheng M, Chew SWT, Xu C. Advances in the formulations of microneedles for manifold biomedical applications. Adv Mater Technol. 2020;5(4):1900552. [Crossref] 

.: Up To Date

.: Process List

Login



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