Journal of Literature Pharmacy Sciences

Biyoyararlanım ve Biyoeşdeğerliği Etkileyen Farmasötik Faktörler: Etkin Maddeye Ait Fiziksel ve Kimyasal Özellikler, Geleneksel Derleme
Pharmaceutical Factors Affecting Bioavailability and Bioequivalency: Physical and Chemical Properties of the Active Substance, Traditional Review
Esra DEMİRTÜRKa , Tilbe ÇEVİKELLİa , Deniz ONANb
aÇukurova Üniversitesi Eczacılık Fakültesi, Farmasötik Teknoloji ABD, Adana, Türkiye
bÇukurova Üniversitesi Eczacılık Fakültesi, Farmasötik Biyoteknoloji ABD, Adana, Türkiye
J Lit Pharm Sci. 2024;13(1):35-45
doi: 10.5336/pharmsci.2023-99867
Article Language: TR
Full Text
ÖZET
 Katı oral dozaj şekillerinde biyoyararlanım ve biyoeşdeğerliğin değerlendirilebilmesi için uygulamadan sonra ilacın sırasıyla dağılması, sulu ortamda çözünmesi ve sistemik dolaşıma geçmesi gerekmektedir. Bu aşamalarda etkin maddeye ait fizikokimyasal özellikler, dozaj şekli tasarımına ait özellikler ve uygulama bölgesindeki anatomik ve fizyolojik özellikler uygulanan ilacın biyoyararlanım ve biyoeşdeğerliğine doğrudan etki eder. Dozaj şeklinin tipi, dağılma (dezentegrasyon), çözünme (disolüsyon), farmasötik eksipiyanlar ve üretim değişkenleri dozaj şekli tasarımına ait özellikler olmakla birlikte; partikül büyüklüğü, suda çözünürlük, dağılma katsayısı, tuz yapısı, iyonlaşma derecesi, iyonizasyon sabiti (pKa), ön ilaç formu, solvat-hidrat, polimorfizm özellikleri ise etkin maddeye ait fizikokimyasal özellikler olup, ilaç biyoyararlanım ve biyoeşdeğerliği üstünde birinci derece öneme sahiptir. Bu çalışmada, biyoyararlanım ve biyoeşdeğerliğe etki eden etkin maddeye ait fizikokimyasal özellikler için güncel literatür taranarak değerlendirilmesi yapılmış ve etkin maddenin fizikokimyasal kısıtlarından kaynaklanan biyoyararlanım sorununun iyileştirilmesi üzerine güncel yaklaşımlar sınıflandırılarak değerlendirilmiştir. Etkin maddenin biyoyararlanım ile biyoeşdeğerliğe etki eden ve biyoyararlanımı kısıtlayan fizikokimyasal özelliklerinin iyileştirilmesinde güncel yaklaşımların son yıllarda hız kazanarak ilaç araştırma ve geliştirme çalışmalarında geniş yer kazandığı ve Amerikan Gıda ve İlaç İdaresi tarafından artan onay oranları ile klinik kullanımda yaygın olarak yer almaya başladığı belirlenmiştir. Bu amaçla, konunun güncel literatür çalışmaları ile örneklendirilerek değerlendirilmesi amaçlanmıştır.

Anahtar Kelimeler: Biyoyararlanım; biyoeşdeğerlik; oral dozaj şekli
ABSTRACT
 In order to evaluate the bioavailability and bioequivalence in solid oral dosage forms, the drug must be dispersed, dissolved in the aqueous medium and enter the systemic circulation, respectively, after administration. At these stages, the physicochemical properties of the active ingredient, the properties of the dosage form design, and the anatomical and physiological characteristics of the application area directly affect the bioavailability and bioequivalence of the administered drug. Although the type of dosage form, disintegration, dissolution, pharmaceutical excipients and production variables are the features of dosage form design; particle size, water solubility, dispersion coefficient, salt structure, degree of ionization, ionization constant (pKa), prodrug form, solvate-hydrate, polymorphism properties are the physicochemical properties of the active substance and are of primary importance on drug bioavailability and bioequivalence. In this study, the physicochemical properties of the active substance that affect its bioavailability and bioequivalence were evaluated by evaluating the current literature, and current approaches to improving the bioavailability problem arising from the physicochemical limitations of the active substance were classified and evaluated. It has been determined that current approaches to improving the physicochemical properties of the active substance, which affect bioavailability and bioequivalence and restrict bioavailability, have increased in recent years and gained wide coverage in drug research and development studies, and have begun to be applied in clinical use with increasing approval rates by the American Food and Drug Administration. For this purpose, it is aimed to evaluate the subject by exemplifying it with current literature studies.

Keywords: Bioavailability; bioequivalence; oral dosage form
REFERENCES:
  1. Fang L, Uppoor R, Xu M, Sharan S, Zhu H, Tampal N, et al. Use of partial area under the curve in bioavailability or bioequivalence assessments: a regulatory perspective. Clin Pharmacol Ther. 2021;110(4):880-7. [Crossref]  [PubMed] 
  2. Rodrigues MB, Barreto ACH, Neto EMR, de Araújo TG. Comparative study among drying techniques in the development of nimesulide tablet. Journal of Young Pharmacists. 2020;12(1):42-7. [Crossref] 
  3. Shi J, Wang D, Tian Y, Wang Z, Gao J, Liu N, et al. Comparison of Paliperidone Palmitate from Different Crystallization Processes and Effect on Formulations In Vitro and In Vivo. Pharmaceutics. 2022;14(5):1094. [Crossref]  [PubMed]  [PMC] 
  4. Elmi GR, Anum K, Saleem K, Fareed R, Noreen S, Wei H, et al. Evaluation of clinical trials of ethnomedicine used for the treatment of diabetes: A systematic review. Front Pharmacol. 2023;14:1176618. [Crossref]  [PubMed]  [PMC] 
  5. Macheras P, Tsekouras AA. Revising Oral Pharmacokinetics, Bioavailability and Bioequivalence Based on the Finite Absorption Time Concept. 1st ed. Cham: Springer Nature; 2023. [Crossref]  [PMC] 
  6. Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol. 2002;42(6):620-43. [Crossref]  [PubMed] 
  7. Mudie DM, Amidon GL, Amidon GE. Physiological parameters for oral delivery and in vitro testing. Mol Pharm. 2010;7(5):1388-405. [Crossref]  [PubMed]  [PMC] 
  8. Zhao C, Jin C, Gao H, Wang L, Liu H, He Z. Effect of raw material variability of glipizide on the in vitro dissolution rate and in vivo bioavailability performance: The importance of particle size. Asian J Pharm Sci. 2019;14(2):165-73. [Crossref]  [PubMed]  [PMC] 
  9. Muselík J, Urbanova M, Bartoníčková E, Palovčík J, Vetchý D, Czernek J, et al. Structural changes of sodium warfarin in tablets affecting the dissolution profiles and potential safety of generic substitution. Pharmaceutics. 2021;13(9):1364. [Crossref]  [PubMed]  [PMC] 
  10. Gopi S, Balakrishnan P. Evaluation and clinical comparison studies on liposomal and non-liposomal ascorbic acid (vitamin C) and their enhanced bioavailability. J Liposome Res. 2021;31(4):356-64. [Crossref]  [PubMed] 
  11. Liversidge GG, Conzentino P. Drug particle size reduction for decreasing gastric irritancy and enhancing absorption of naproxen in rats. International Journal of Pharmaceutics. 1995;125(2):309-13. [Crossref] 
  12. Kayser O, Olbrich C, Yardley V, Kiderlen AF, Croft SL. Formulation of amphotericin B as nanosuspension for oral administration. Int J Pharm. 2003;254(1):73-5. [Crossref]  [PubMed] 
  13. Salazar J, Müller RH, Möschwitzer JP. Application of the combinative particle size reduction technology H 42 to produce fast dissolving glibenclamide tablets. Eur J Pharm Sci. 2013;49(4):565-77. [Crossref]  [PubMed] 
  14. Sahasrabudhe V, Matschke K, Shi H, Hickman A, Kong A, Rodríguez Spong B, et al. Relative bioavailability of ertugliflozin tablets containing the amorphous form versus tablets containing the cocrystal form. Int J Clin Pharmacol Ther. 2022;60(7):317-26. [Crossref]  [PubMed]  [PMC] 
  15. De Caro V, Ajovalasit A, Sutera FM, Murgia D, Sabatino MA, Dispenza C. Development and characterization of an amorphous solid dispersion of furosemide in the form of a sublingual bioadhesive film to enhance bioavailability. Pharmaceutics. 2017;9(3):22. [Crossref]  [PubMed]  [PMC] 
  16. Pawar YB, Shete G, Popat D, Bansal AK. Phase behavior and oral bioavailability of amorphous Curcumin. Eur J Pharm Sci. 2012;47(1):56-64. [Crossref]  [PubMed] 
  17. Meiron OE, Bar-David E, Aflalo ED, Shechter A, Stepensky D, Berman A, et al. Solubility and bioavailability of stabilized amorphous calcium carbonate. J Bone Miner Res. 2011;26(2):364-72. [Crossref]  [PubMed] 
  18. Cho KH, Jee JP, Yang DA, Kim ST, Kang D, Kim DY, et al. Improved dissolution and oral bioavailability of celecoxib by a dry elixir system. J Nanosci Nanotechnol. 2018;18(2):1482-6. [Crossref]  [PubMed] 
  19. Li L, Yin XH, Diao KS. Improving the solubility and bioavailability of pemafibrate via a new polymorph form II. ACS Omega. 2020;5(40):26245-52. [Crossref]  [PubMed]  [PMC] 
  20. Barmpalexis P, Grypioti A, Vardaka E, Karagianni A, Kachrimanis K. Development of a novel amorphous agomelatine formulation with improved storage stability and enhanced bioavailability. J Pharm Sci. 2018;107(1):257-66. [Crossref]  [PubMed] 
  21. Ren S, Jiao L, Yang S, Zhang L, Song J, Yu H, et al. A novel co-crystal of bexarotene and ligustrazine improves pharmacokinetics and tissue distribution of bexarotene in SD rats. Pharmaceutics. 2020;12(10):906. [Crossref]  [PubMed]  [PMC] 
  22. Santos OM, Freitas JT, Cazedey EC, de Araújo MB, Doriguetto AC. Structure, solubility and stability of orbifloxacin crystal forms: hemihydrate versus anhydrate. Molecules. 2016;21(3):328. [Crossref]  [PubMed]  [PMC] 
  23. Wiergowska G, Stasiłowicz A, Miklaszewski A, Lewandowska K, Cielecka-Piontek J. Structural polymorphism of sorafenib tosylate as a key factor in its solubility differentiation. Pharmaceutics. 2021;13(3):384. [Crossref]  [PubMed]  [PMC] 
  24. Ahuja S, Scypinski S. Handbook of Modern Pharmaceutical Analysis. 2nd ed. Amsterdam: Academic Press; 2010.
  25. Amézqueta S, Subirats X, Fuguet E, Rosés M, Ràfols C. Octanol-water partition constant. Liquid-Phase Extraction. 2020;183-208. [Crossref] 
  26. Ahmad I, Kuznetsov AE, Pirzada AS, Alsharif KF, Daglia M, Khan H. Computational pharmacology and computational chemistry of 4-hydroxyisoleucine: Physicochemical, pharmacokinetic, and DFT-based approaches. Front Chem. 2023;11:1145974. [Crossref]  [PubMed]  [PMC] 
  27. Wang Y, Chen J, Yang Y, Gao S, Wang Z, Liu Y, et al. Oil-water partition coefficient preparation and detection in the dihydroartemisinin self-emulsifying drug delivery system. BMC Biotechnol. 2022;22(1):16. [Crossref]  [PubMed]  [PMC] 
  28. Vaddi HK, Ho PC, Chan YW, Chan SY. Terpenes in ethanol: haloperidol permeation and partition through human skin and stratum corneum changes. J Control Release. 2002;81(1-2):121-33. [Crossref]  [PubMed] 
  29. Abioye AO, Issah S, Kola-Mustapha AT. Ex vivo skin permeation and retention studies on chitosan-ibuprofen-gellan ternary nanogel prepared by in situ ionic gelation technique--a tool for controlled transdermal delivery of ibuprofen. Int J Pharm. 2015;490(1-2):112-30. [Crossref]  [PubMed] 
  30. Borbás E, Balogh A, Bocz K, Müller J, Kiserdei É, Vigh T, et al. In vitro dissolution-permeation evaluation of an electrospun cyclodextrin-based formulation of aripiprazole using μFlux?. Int J Pharm. 2015;491(1-2):180-9. [Crossref]  [PubMed] 
  31. Avachat AM, Parpani SS. Formulation and development of bicontinuous nanostructured liquid crystalline particles of efavirenz. Colloids Surf B Biointerfaces. 2015;126:87-97. [Crossref]  [PubMed] 
  32. Devhare L, Kore P. A recent review on bioavailability and solubility enhancement of poorly soluble drugs by physical and chemical modifications. Research Chronicle in Health Sciences. 2016;2(5):299-308. [Link] 
  33. Bhalani DV, Nutan B, Kumar A, Singh Chandel AK. Bioavailability enhancement techniques for poorly aqueous soluble drugs and therapeutics. Biomedicines. 2022;10(9):2055. [Crossref]  [PubMed]  [PMC] 
  34. Samineni R, Chimakurthy J, Konidala S. Emerging role of biopharmaceutical classification and biopharmaceutical drug disposition system in dosage form development: a systematic review. Turk J Pharm Sci. 2022;19(6):706-13. [Crossref]  [PubMed]  [PMC] 
  35. ?alamúnová P, Saloň I, Ruphuy G, Kroupová J, Balouch M, Hanu? J, et al. Evaluation of β-glucan particles as dual-function carriers for poorly soluble drugs. Eur J Pharm Biopharm. 2021;168:15-25. [Crossref]  [PubMed] 
  36. Trastullo R, Dolci LS, Passerini N, Albertini B. Development of flexible and dispersible oral formulations containing praziquantel for potential schistosomiasis treatment of pre-school age children. Int J Pharm. 2015;495(1):536-50. [Crossref]  [PubMed] 
  37. Meng F, Ferreira R, Zhang F. Effect of surfactant level on properties of celecoxib amorphous solid dispersions. Journal of Drug Delivery Science and Technology. 2019;49:301-7. [Crossref] 
  38. Jambhekar S, Casella R, Maher T. The physicochemical characteristics and bioavailability of indomethacin from beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, and hydroxypropyl-beta-cyclodextrin complexes. Int J Pharm. 2004;270(1-2):149-66. [Crossref]  [PubMed] 
  39. Neau SH, Howard MA, Claudius JS, Howard DR. The effect of the aqueous solubility of xanthine derivatives on the release mechanism from ethylcellulose matrix tablets. Int J Pharm. 1999;179(1):97-105. [Crossref]  [PubMed] 
  40. Liversidge GG, Cundy KC. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. International Journal of Pharmaceutics. 1995;125:91-7. [Crossref] 
  41. Sanches BMA, Ferreira EI. Is prodrug design an approach to increase water solubility? Int J Pharm. 2019;568:118498. [Crossref]  [PubMed] 
  42. Özdemir Z, Karakurt A. İlaç metabolizması ve farmasötik kimyada önemi [Drug metabolism and its ımportance in pharmaceutical chemistry]. Annals of Health Sciences Research. 2016;5(2):35-46. [Crossref] 
  43. Najjar A, Najjar A, Karaman R. Newly developed prodrugs and prodrugs in development; an ınsight of the recent years. Molecules. 2020;25(4):884. [Crossref]  [PubMed]  [PMC] 
  44. Ates-Alagoz Z, Adejare A. Prodrugs. In: Adejare A, ed. Remington. 23th ed. Philadelphia: Academic Press; 2021. p.169-86. [Crossref] 
  45. Wang X, Borges CA, Ning X, Rafi M, Zhang J, Park B, et al. A trimethoprim conjugate of thiomaltose has enhanced antibacterial efficacy in vivo. Bioconjug Chem. 2018;29(5):1729-35. Erratum in: Bioconjug Chem. 2018;29(11):3935. [Crossref]  [PubMed]  [PMC] 
  46. Meibom D, Albrecht-Küpper B, Diedrichs N, Hübsch W, Kast R, Krämer T, et al. Neladenoson bialanate hydrochloride: a prodrug of a partial adenosine a1 receptor agonist for the chronic treatment of heart diseases. ChemMedChem. 2017;12(10):728-37. [Crossref]  [PubMed] 
  47. Liu T, Yuan X, Jia T, Liu C, Ni Z, Qin Z, et al. Polymeric prodrug of bufalin for increasing solubility and stability: Synthesis and anticancer study in vitro and in vivo. Int J Pharm. 2016;506(1-2):382-93. [Crossref]  [PubMed] 
  48. Ayalew L, Acuna J, Urfano SF, Morfin C, Sablan A, Oh M, et al. Conjugation of Paclitaxel to Hybrid Peptide Carrier and Biological Evaluation in Jurkat and A549 Cancer Cell Lines. ACS Med Chem Lett. 2017;8(8):814-9. [Crossref]  [PubMed]  [PMC] 
  49. Patil S, Lis LG, Schumacher RJ, Norris BJ, Morgan ML, Cuellar RA, et al. Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts. J Med Chem. 2015;58(23):9334-44. [Crossref]  [PubMed]  [PMC] 
  50. Saal C, Becker A. Pharmaceutical salts: a summary on doses of salt formers from the Orange Book. Eur J Pharm Sci. 2013;49(4):614-23. [Crossref]  [PubMed] 
  51. Bharate SS. Recent developments in pharmaceutical salts: FDA approvals from 2015 to 2019. Drug Discov Today. 2021;26(2):384-98. [Crossref]  [PubMed] 
  52. Bharate SS. Modulation of biopharmaceutical properties of acidic drugs using cationic counterions: A critical analysis of FDA-approved pharmaceutical salts. Int J Pharm. 2021;607:120993. [Crossref]  [PubMed] 
  53. Liu L, Zou D, Zhang Y, Zhang Q, Feng Y, Guo Y, et al. Pharmaceutical salts/cocrystals of enoxacin with dicarboxylic acids: Enhancing in vitro antibacterial activity of enoxacin by improving the solubility and permeability. Eur J Pharm Biopharm. 2020;154:62-73. [Crossref]  [PubMed] 
  54. Surov AO, Manin AN, Voronin AP, Drozd KV, Simagina AA, Churakov AV, et al. Pharmaceutical salts of ciprofloxacin with dicarboxylic acids. Eur J Pharm Sci. 2015;77:112-21. [Crossref]  [PubMed] 
  55. Joshi M, Roy Choudhury A. Salts of Amoxapine with Improved Solubility for Enhanced Pharmaceutical Applicability. ACS Omega. 2018;3(2):2406-16. [Crossref]  [PubMed]  [PMC] 
  56. Liu L, An Q, Zhang Y, Sun W, Li J, Feng Y, et al. Improving the solubility, hygroscopicity and permeability of enrofloxacin by forming 1: 2 pharmaceutical salt cocrystal with neutral and anionic co-existing p-nitrobenzoic acid. Journal of Drug Delivery Science and Technology. 2022;76:103732. [Crossref] 
  57. Suresh A, Gonde S, Mondal PK, Sahoo J, Chopra D. Improving solubility and intrinsic dissolution rate of ofloxacin API through salt formation via mechanochemical synthesis with diphenic acid. Journal of Molecular Structure. 2020;1221:128806. [Crossref] 
  58. Park C, Meghani NM, Shin Y, Oh E, Park JB, Cui JH, et al. Investigation of crystallization and salt formation of poorly water-soluble telmisartan for enhanced solubility. Pharmaceutics. 2019;11(3):102. [Crossref]  [PubMed]  [PMC] 

.: 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