Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar
Yıl: 2022 Cilt: 47 Sayı: 2 Sayfa Aralığı: 265 - 280 Metin Dili: Türkçe DOI: 10.55262/fabadeczacilik.1134604 İndeks Tarihi: 22-09-2022
Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar
Öz: Diyabet, bozulmuş glikoz metabolizması ile ilişkili kronik bir hastalıktır ve genellikle kontrolsüz hiperglisemi veya sürekli yüksek kan şekeri seviyeleri ile kendini göstermektedir. Uluslararası Diyabet Federasyonu verilerine göre küresel sağlık harcamalarının %10’unun (966 milyar Amerikan Doları) diyabete harcandığı belirtilmiştir. Türkiye’de ise diyabet prevalansı %15 olarak Avrupa ülkeleri içinde en hızlı artışı göstermektedir. Tip 2 diyabet, anormal insülin sekresyonu veya kronik insülin direnci ile ilişkilidir ve glikoz alım hücrelerinin insülin etkisine karşı duyarsızlaşmasına neden olur. Son yıllarda Tip 2 diyabet tedavisinde inkretin bazlı tedaviler öne çıkmıştır. İnkretin bazlı tedavilerde yaygın kullanılan exendin-4, GLP-1 reseptörlerine yüksek afinitede bağlanarak vücutta glikoz bağımlı insülin salgılanmasını, gastrik boşalmanın geciktirilmesini, glukagon salımının ve iştahın baskılanmasını sağlamaktadır. Exendin-4, hücre proliferasyonunu artırmakta ve β-hücrelerinde apoptotik yolları inhibe etmektedir. Exendin-4’ün ticari ürünleri parenteral yolla günde iki kez uygulanan Byetta® ve haftada bir kez uygulanan uzun etkili Byderuon™’dur. Parenteral yolla uygulamanın hasta uyuncunda problemler ve enjeksiyonda ağrı hissi gibi sakıncalarının bulunması araştırmacıları oral, pulmoner, transdermal, oküler, nazal, vajinal, rektal yollar gibi alternatif veriliş yolları üzerine yöneltmiştir. Bu derlemede, exendin-4’ün özellikleri, etki mekanizması, terapötik etkinliği ve exendin-4’ün alternatif veriliş yollarına yönelik yeni yaklaşımlar ve yapılan çalışmalar verilmiş ve tartışılmıştır
Anahtar Kelime: Exendin-4 Used in the Treatment of Type 2 Diabetes and Current Approaches for Alternative Administration Routes of Exendin-4
Öz: Diabetes is a chronic disease due to impaired glucose metabolism and usually presents with uncontrolled hyperglycemia or persistently high blood sugar levels. According to the tenth edition of the international Diabetes Federation, 10% of global health expenditures ($ 966 billion) are spent on diabetes. i n turkey, the prevalence of diabetes is 15%, showing the fastest increase among european countries. type 2 diabetes is associated with abnormal insulin secretion or chronic insulin resistance, causing desensitization of the glucose uptake cells to insulin activity. incretin-based therapies have come to the fore in the treatment of type 2 diabetes in recent years. exendin-4, which is widely used in incretin-based therapies, binds to GlP-1 receptors with high affinity, causing glucose-dependent insulin secretion in the body, delaying gastric emptying, suppressing glucagon release and appetite. Also, exendin-4 increases cell proliferation and inhibits apoptotic pathways in β-cells. commercial products of exendin-4 are Byetta® which is administered twice daily and long-acting Byderuon™ which is administered once weekly via parenteral route. The presence of drawbacks of parenteral administration such as problems in patient compliance and feeling of pain due to injection led researchers to search alternative administration routes such as oral, pulmonary, transdermal, ocular, nasal, vaginal and rectal routes. in this review, exendin-4’s properties, mechanism of action, therapeutic efficacy, new approaches and studies on alternative delivery routes of exendin-4 are mentioned.
Anahtar Kelime: Belge Türü: Makale Makale Türü: Derleme Erişim Türü: Erişime Açık
- Agu, R. U., Ugwoke, M. I., Armand, M., Kinget, R., & Verbeke, N. (2001). The lung as a route for syste- mic delivery of therapeutic proteins and peptides, Respiratory Research, 2(4), 1-12. doi: 10.1186/rr58
- Ahn, S., Lee, I. H., Lee, E., Kim, H., Kim, Y. C., and Jon, S. (2013). Oral delivery of an anti-diabetic peptide drug via conjugation and complexation with low molecular weight chitosan, Journal of Control- led Release, 170(2), 226-232. doi: 10.1016/j.jcon- rel.2013.05.031
- Al Bakri, W., Donovan, M. D., Cueto, M., Wu, Y., Orekie, C., Yang, Z. (2018). Overview of intranasally delivered peptides: key considerations for pharmaceutical deve- lopment, Expert Opinion on Drug Delivery, 15(10), 991–1005. doi: 10.1080/17425247.2018.1517742
- Arslan, Ş. A., & Tirnaksiz, F. (2013). Self-Emulsifying Drug Delivery Systems, FABAD Journal of Phar- maceutical Sciences, 38(1), 55-64.
- Bachhav, Y. G., & Kalia, Y. N. (2011). Development and validation of a rapid high performance liqu- id chromatography method for the quantification of exenatide, Biomedical Chromatography, 25(7), 838-842. doi: 10.1002/bmc.1526
- Bain, S. C., and Stephens, J. W. (2008). Exe- natide and pancreatitis: an update, Expert Opinion on Drug Safety, 7(6), 643-644. doi: 10.1517/14740330802432003
- Bertsch, T., & McKeirnan, K. (2018). ITCA 650. Cli- nical Diabetes: A Publication of the American Diabetes Association, 36(3), 265. doi: 10.2337/ cd18-0039
- Bolhassani, A. (2019). Improvements in chemical car- riers of proteins and peptides. Cell Biology Inter- national, 43(4), 437-452. doi: 10.1002/cbin.11108.
- Boztaş, C. U., Inan, E. A., & Altan, V. M. (2017). Ef- fects of incretin mimetic drugs on diabetic cardio- vascular functions, FABAD Journal of Pharmace- utical Sciences, 42(2), 151.
- Cai, Y., Wei, L., Ma, L., Huang, X., Tao, A., Liu, Z., & Yuan, W. (2013). Long-acting preparations of exe- natide, Drug Design Development and Therapy, 7, 963–970. doi: 10.2147/DDDT.S46970
- Çelebi, N., Editör: Zırh-Gürsoy, A. (2014), Nanofar- masötikler ve uygulamaları, (Bölüm 7) Nanojeller, İstanbul (Türkiye): Aktif Matbaa ve Reklam Hiz- metleri San.Tic.Ltd.Şti.
- Celik-Tekeli, M., Celebi, N., Tekeli, M. Y., Aktas, Y. (2021). Evaluation of the hypoglycemic effect of exendin-4’s new oral self-nanoemulsifying system in rats, European Journal of Pharmaceutical Sci- ences: official journal of the European Federation for Pharmaceutical Sciences, 158, 105644. doi: 10.1016/j.ejps.2020.105644.
- Chakraborti, C. K. (2010). Exenatide: a new promising antidiabetic agent, Indian Journal Of Pharmace- utical Sciences, 72(1), 1–11. doi: 10.4103/0250- 474X.62228.
- Chauhan, I., Yasir, M., Verma, M., & Singh, A. P. (2020). Nanostructured lipid carriers: A ground- breaking approach for transdermal drug deli- very. Advanced Pharmaceutical Bulletin, 10(2), 150. doi: 10.34172/apb.2020.021.
- Chen, Y. E., & Drucker, D.J. (1997). Tissue-specific expression of unique mRNAs that encode proglu- cagon-derived peptides or exendin 4 in the lizard, The Journal of Biological Chemistry, 272(7), 4108- 4115. doi: 10.1074/jbc.272.7.4108.
- Chen, W., Tian, R., Xu, C., Yung, B. C., Wang, G., Liu, Y., Ni, Q., Zhang, Y., Zhou, Z., Wang, J., Niu, G., Ma, Y., Fu, L., Chen, X. (2017). Microneedle-ar- ray patches loaded with dual mineralized protein/ peptide particles for type 2 diabetes therapy. Na- ture communications, 8(1), 1-11. doi: 10.1038/ s41467-017-01764-1
- Chuang, E. Y., Nguyen, G. T., Su, F. Y., Lin, K. J., Chen, C. T., Mi, F. L., Yen, T. C., Juang, J. H., & Sung, H. W. (2013). Combination therapy via oral co-administration of insulin- and exendin-4- loaded nanoparticles to treat type 2 diabetic rats undergoing OGTT, Biomaterials, 34(32), 7994– 8001. doi:10.1016/j.biomaterials.2013.07.021
- Couvreur, P., Barratt, G., Fattal, E., Legrand, P., & Va- uthier, C. (2002). Nanocapsule technology: a revi- ew, Critical Reviews in Therapeutic Drug Carrier Systems, 19(2), 99–134. doi:10.1615/critrevtherd- rugcarriersyst.v19.i2.10
- Date, A. A., Desai, N., Dixit, R., & Nagarsenker, M. (2010). Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances, Nanomedicine (London, England), 5(10), 1595–1616.doi: 10.2217/nnm.10.126.
- Eissa, N. G., Elsabahy, M., & Allam, A. (2021). En- gineering of smart nanoconstructs for delivery of glucagon-like peptide-1 analogs. Internatio- nal Journal of Pharmaceutics, 597, 120317. doi: 10.1016/j.ijpharm.2021.120317.
- Ensign, L. M., Cone, R., & Hanes, J. (2012). Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers, Advanced Drug Delivery Reviews, 64(6), 557–570. doi: 10.1016/j. addr.2011.12.009
- Fakhraei Lahiji, S., Jang, Y., Huh, I., Yang, H., Jang, M., & Jung, H. (2018). Exendin-4-encapsulated dissolving microneedle arrays for efficient treat- ment of type 2 diabetes, Scientific Reports, 8(1), 1170. doi: 10.1038/s41598-018-19789-x
- FDA. (2018), BYDUREON® (exenatide exten- ded-release) for injectable suspension, https:// www.accessdata.fda.gov/drugsatfda_docs/ label/2018/022200s026lbl.pdf., Erişim tarihi: 10 Kasım 2021.
- FDA. (2021), Proposal To Refuse To Approve a New Drug Application for ITCA 650 (Exenatide in DU- ROS Device);Opportunity for a Hearing, https:// www.govinfo.gov/content/pkg/FR-2021-09-02/ pdf/2021-18928.pdf. Erişim tarihi: 27 Mart 2022.
- Freiberg, S., & Zhu, X. X. (2004). Polymer microsp- heres for controlled drug release, International Journal of Pharmaceutics, 282(1-2), 1–18. doi: 10.1016/j.ijpharm.2004.04.013
- Gao, W., & Jusko, W. J. (2012). Target-mediated pharmacokinetic and pharmacodynamic mo- del of exendin-4 in rats, monkeys, and humans, Drug Metabolism and Disposition: The Biological Fate of Chemicals, 40(5), 990–997. doi: 10.1124/ dmd.111.042291
- Gedulin, B. R., Smith, P. A., Jodka, C. M., Chen, K., Bhavsar, S., Nielsen, L. L., Parkes, D. G., & Young, A. A. (2008). Pharmacokinetics and pharmacodynamics of exenatide following al- ternate routes of administration, International Journal of Pharmaceutics, 356(1-2), 231–238. doi: 10.1016/j.ijpharm.2008.01.015
- Gursoy, R.N., & Benita, S. (2004). Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs, Biomedicine & Phar- macotherapy, 58(3), 173-182. doi: 10.1016/j.biop- ha.2004.02.001
- Homan Gökçe, E., Özer, Ö. Editör: Zırh-Gürsoy, A. (2014), Nanofarmasötikler ve uygulamaları, (Bö- lüm 6) Katı Lipit Nanopartiküller, İstanbul (Türki- ye): Aktif Matbaa ve Reklam Hizmetleri San.Tic. Ltd.Şti.
- Ibraheem, D., Elaissari, A., & Fessi, H. (2014). Ad- ministration strategies for proteins and peptides, International Journal of Pharmaceutics, 477(1-2), 578–589.doi: 10.1016/j.ijpharm.2014.10.059
- International Diabetes Federation. (2021), IDF Dia- betes Atlas (10th edition), https://www.diabetesat- las.org, Erişim Tarihi: 10 Kasım 2021.
- Jin, C. H., Chae, S. Y., Son, S., Kim, T. H., Um, K. A., Youn, Y. S., Lee, S., & Lee, K. C. (2009). A new orally available glucagon-like peptide-1 receptor agonist, biotinylated exendin-4, displays imp- roved hypoglycemic effects in db/db mice, Jour- nal of Controlled Release : official journal of the Controlled Release Society, 133(3), 172–177. doi: 10.1016/j.jconrel.2008.09.091
- Jun, H. S., Bae, G., Ko, Y. T., & Oh, Y. S. (2015). Cytotoxicity and biological efficacy of exendin- 4-encapsulated solid lipid nanoparticles in INS-1 cells, Journal of Nanomaterials, doi: 10.1155/2015/753569
- Kayaalp, O. (2009). Rasyonel tedavi yönünden tıbbi farmakoloji. 12. Baskı, Pelikan Yayıncılık, Ankara, 1039-1066.
- Katzung, B. G. (2017). Basic & clinical pharmacology, 14th ed., McGraw Hill.
- Kim, J. Y., Lee, H., Oh, K. S., Kweon, S., Jeon, O. C., Byun, Y., Kim, K., Kwon, I. C., Kim, S. Y., & Yuk, S. H. (2013). Multilayer nanoparticles for sustai- ned delivery of exenatide to treat type 2 diabetes mellitus, Biomaterials, 34(33), 8444–8449. doi: 10.1016/j.biomaterials.2013.07.040
- Kim, H., Lee, J., Kim, T. H., Lee, E. S., Oh, K. T., Lee, D. H., Park, E. S., Bae, Y. H., Lee, K. C., & Youn, Y. S. (2011). Albumin-coated porous hollow poly(lactic-co-glycolic acid) microparticles bound with palmityl-acylated exendin-4 as a long-acting inhalation delivery system for the treatment of diabetes, Pharmaceutical Research, 28(8), 2008– 2019. doi: 10.1007/s11095-011-0427-4.
- Kim, W., & Egan, J. M. (2008). The role of incretins in glucose homeostasis and diabetes treatment, Pharmacological Reviews, 60(4), 470-512. doi: 10.1124/pr.108.000604
- Kwak, H. H., Shim, W. S., Hwang, S., Son, M. K., Kim, Y. J., Kim, T. H., Yoon, Z. H., Youn, H. J., Lee, G. I., Kang, S. H., & Shim, C. K. (2009). Pharmacokine- tics and efficacy of a biweekly dosage formulation of exenatide in Zucker diabetic fatty (ZDF) rats, Pharmaceutical Research, 26(11), 2504–2512. doi: 10.1007/s11095-009-9966-3
- Lee, C., Choi, J. S., Kim, I., Oh, K. T., Lee, E. S., Park, E. S., Lee, K. C., & Youn, Y. S. (2013). Long-acting inhalable chitosan-coated poly(lactic-co-glycolic acid) nanoparticles containing hydrophobically modified exendin-4 for treating type 2 diabetes, International Journal of Nanomedicine, 8, 2975– 2983. doi: 10.2147/IJN.S48197
- Lee, J., Lee, C., Kim, I., Moon, H. R., Kim, T. H., Oh, K. T., Lee, E. S., Lee, K. C., & Youn, Y. S. (2012). Preparation and evaluation of palmitic acid-con- jugated exendin-4 with delayed absorption and prolonged circulation for longer hypoglycemia, International Journal of Pharmaceutics, 424(1-2), 50–57. doi: 10.1016/j.ijpharm.2011.12.050
- Lee, Y. S., & Jun, H. S. (2014). Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells, Metabolism: Clinical and Experimental, 63(1), 9–19. doi: 10.1016/j.metabol.2013.09.010
- Levetan, C. (2007). Oral antidiabetic agents in type 2 diabetes. Current medical research and opinion, 23(4), 945–952. doi: 10.1185/030079907x178766
- Li, X., Wang, C., Liang, R., Sun, F., Shi, Y., Wang, A., Liu, W., Sun, K., & Li, Y. (2015). The glucose-lo- wering potential of exenatide delivered orally via goblet cell-targeting nanoparticles, Pharmaceu- tical Research, 32(3), 1017–1027. doi: 10.1007/ s11095-014-1513-1
- Li, Y., He, J., Lyu, X., Yuan, Y., Wang, G., & Zhao, B. (2018). Chitosan-based thermosensitive hydrogel for nasal delivery of exenatide: Effect of magne- sium chloride. International Journal of Phar- maceutics, 553(1-2), 375-385. doi: 10.1016/j.ijp- harm.2018.10.071
- Lim, S. M., Eom, H. N., Jiang, H. H., Sohn, M., & Lee, K. C. (2015). Evaluation of PEGylated exen- din-4 released from poly (lactic-co-glycolic acid) microspheres for antidiabetic therapy, Journal of Pharmaceutical Sciences, 104(1), 72–80. doi: 10.1002/jps.24238.
- Liu, S., Wu, D., Quan, Y. S., Kamiyama, F., Kusamo- ri, K., Katsumi, H., Sakane, T., & Yamamoto, A. (2016). Improvement of transdermal delivery of exendin-4 using novel tip-loaded microneedle arrays fabricated from hyaluronic acid, Molecular Pharmaceutics, 13(1), 272–279. doi: 10.1021/acs. molpharmaceut.5b00765
- Long, L. Y., Zhang, J., Yang, Z., Guo, Y., Hu, X., & Wang, Y. (2020). Transdermal delivery of pep- tide and protein drugs: strategies, advantages and disadvantages, Journal of Drug Delivery Science and Technology, 102007. doi:10.1016/j. jddst.2020.102007.
- Luna, B., & Feinglos, M. N. (2001). Oral agents in the management of type 2 diabetes mellitus. Ameri- can Family Physician, 63(9), 1747–1756.
- Malone, J., Trautmann, M., Wilhelm, K., Taylor, K., & Kendall, D.M. (2009). Exenatide once weekly for the treatment of type 2 diabetes, Expert Opinion on Investigational Drugs, 18(3), 359-367. doi: 10.1517/13543780902766802
- Marín-Peñalver, J. J., Martín-Timón, I., Sevillano- Collantes, C., Del Cañizo-Gómez, F.J. (2016) Up- date on the treatment of type 2 diabetes mellitus, World Journal of Diabetes, 7(17), 354-95. doi: 10.4239/wjd.v7.i17.354.
- Millotti, G., Vetter, A., Leithner, K., Sarti, F., Shahnaz Bano, G., Augustijns, P., & Bernkop-Schnürch, A. (2014). Development of thiolated poly (acrylic acid) microparticles for the nasal administration of exenatide, Drug Development and Industrial Pharmacy, 40(12), 1677-1682. doi:10.3109/03639 045.2013.842578
- Nguyen, H. N., Wey, S. P., Juang, J. H., Sonaje, K., Ho, Y. C., Chuang, E. Y., Hsu, C. W., Yen, T. C., Lin, K. J., & Sung, H. W. (2011). The glucose-lowe- ring potential of exendin-4 orally delivered via a pH-sensitive nanoparticle vehicle and effects on subsequent insulin secretion in vivo, Biomateri- als, 32(10), 2673–2682. doi: 10.1016/j.biomateri- als.2010.12.044
- Numanoğlu, U., & Tarımcı, N. (2006). Katı Lipid Na- nopartiküllerin (Slntm) Özellikleri, Farmasötik ve Kozmetik Alandaki Uygulamaları, Ankara Eczacı- lık Fakültesi Dergisi, 35(3), 211-235.
- Oh, K. S., Kim, J. Y., Yoon, B. D., Lee, M., Kim, H., Kim, M., Seo, J. H., & Yuk, S. H. (2014). Sol-gel transition of nanoparticles/polymer mixtures for sustained delivery of exenatide to treat type 2 di- abetes mellitus, European Journal of Pharmace- utics and Biopharmaceutics, 88(3), 664-669. doi: 10.1016/j.ejpb.2014.08.004
- Pouton, C.W. (1997). Formulation of self-emulsifying drug delivery systems, Advanced Drug Deli- very Reviews, 25(1), 47-58. doi: 10.1016/S0169- 409X(96)00490-5
- Prausnitz, M. R., & Langer, R. (2008). Transdermal drug delivery, Nature Biotechnology, 26(11), 1261–1268. doi: 10.1038/nbt.1504.
- Punthakee, Z., Goldenberg, R., & Katz, P. (2018). De- finition, classification and diagnosis of diabetes, prediabetes and metabolic syndrome, Canadian Journal of Diabetes, 42, S10-S15. doi: 10.1016/j. jcjd.2017.10.003
- Renukuntla, J., Vadlapudi, A. D., Patel, A., Boddu, S. H., & Mitra, A. K. (2013). Approaches for enhan- cing oral bioavailability of peptides and proteins, International Journal of Pharmaceutics, 447(1-2), 75–93. doi: 10.1016/j.ijpharm.2013.02.030
- Saeedi, P., Petersohn, I., Salpea, P., Malanda, B., Karu- ranga, S., Unwin, N., Colagiuri, S., Guariguata, L., Motala, A. A., Ogurtsova, K., Shaw, J. E., Bright, D., Williams, R., & IDF Diabetes Atlas Committee (2019). Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition, Diabetes Research and clinical practice, 157, 107843. doi: 10.1016/j.diabres.2019.107843.
- Saralidze, K., Koole, L.H., Knetsch, M.L.W. (2010) Polymeric Microspheres for Medical Applications, Materials (Basel), 7;3(6):3537–3564. doi: 10.3390/ ma3063537.
- Shrestha, N., Bouttefeux, O., Vanvarenberg, K., Lund- quist, P., Cunarro, J., Tovar, S., Khodus, G., An- dersson, E., Keita, A.V., Dieguez, C. G., Artursson, P., Préat, V., Beloqui, A. (2018). The stimulation of GLP-1 secretion and delivery of GLP-1 ago- nists via nanostructured lipid carriers. Nanosca- le, 10(2), 603-613. doi: 10.1039/C7NR07736J
- Song, Y., Shi, Y., Zhang, L., Hu, H., Zhang, C., Yin, M., Chu, L., Yan, X., Zhao, M., Zhang, X., Mu, H., & Sun, K. (2019). Synthesis of CSK-DEX-PLGA Na- noparticles for the Oral Delivery of Exenatide to Improve Its Mucus Penetration and Intestinal Ab- sorption, Molecular Pharmaceutics, 16(2), 518– 532. doi: 10.1021/acs.molpharmaceut.8b00809.
- Soudry-Kochavi, L., Naraykin, N., Nassar, T., & Be- nita, S. (2015). Improved oral absorption of exe- natide using an original nanoencapsulation and microencapsulation approach, Journal of Cont- rolled Release, 217, 202-210. doi: 10.1016/j.jcon- rel.2015.09.012.
- Suzuki, K., Kim, K. S., & Bae, Y. H. (2019). Long- term oral administration of Exendin-4 to control type 2 diabetes in a rat model, Journal of Cont- rolled Release, 294, 259–267. doi:10.1016/j.jcon- rel.2018.12.028
- Tan, M. L., Choong, P. F., & Dass, C. R. (2010). Re- cent developments in liposomes, microparticles and nanoparticles for protein and peptide drug delivery, Peptides, 31(1), 184–193. doi: 10.1016/j. peptides.2009.10.002.
- T.C. Çalışma ve Sosyal Güvenlik Bakanlığı. (2021), SGK 2020 Yılında İlaç İçin 48,6 Milyar Lira Kay- nak Aktardı, https://www.csgb.gov.tr/haberler/ sgk-2020-yilinda-ilac-icin-48-6-milyar-lira- kaynak-aktardi/, Erişim Tarihi: 10 Kasım 2021.
- Tucker Jr, T. A., Turley, S., Bollinger, K., Beck, J., & Hrometz, S. L. (2013). Comparing the GLP-1 Re- ceptor Agonists: Byetta®, Victoza® and once-we- ekly Bydureon™, Pharmacy and Wellness Revi- ew, 4(1), 16-20.
- Türkiye Endokrinoloji ve Metabolizma Der- neği (TEMD). (2019), Diabetes mellitus ve komplikasyonlarının tanı, tedavi ve izlem kı- lavuzu. https://temd.org.tr/admin/uploads/ tbl_kilavuz/20190819095854-2019tbl_kilavuzb- 48da47363.pdf, (Erişim Tarihi: 12.11.2021).
- Ükinç, K., Gürlek, A., & Umsan, A. (2007). Yeni an- tidiyabetik ilaçlar, Hacettepe Tıp Dergisi, 38(3), 113-120.
- Wang, M., Zhang, Y., Sun, B., Sun, Y., Gong, X., Wu, Y., Zhang, X., Kong, W., & Chen, Y. (2014). Per- meability of exendin-4-loaded chitosan nanopar- ticles across MDCK cell monolayers and rat small intestine, Biological and Pharmaceutical Bulletin, 37(5), 740-747. doi: 10.1248/bpb.b13-00591
- World Health Organization (WHO). (2006), Definiti- on and diagnosis of diabetes mellitus and interme- diate hyperglycaemia: report of a WHO/IDF con- sultation, https://www.who.int/diabetes/publica- tions/Definition%20and%20diagnosis%20of%20 diabetes_new.pdf (Erişim Tarihi: 12.11.2021).
- Xu, Y., Van Hul, M., Suriano, F., Préat, V., Cani, P. D., & Beloqui, A. (2020). Novel strategy for oral peptide delivery in incretin-based diabe- tes treatment, Gut, 69(5), 911-919. doi: 10.1136/ gutjnl-2019-319146
- Yap, M., & Misuan, N. (2019). Exendin-4 from He- loderma suspectum venom: From discovery to its latest application as type II diabetes combatant, Basic & Clinical Pharmacology & Toxicology, 124(5), 513–527. doi: 10.1111/bcpt.13169.
- Yang, H. J., Park, I. S., & Na, K. (2009). Biocompatible microspheres based on acetylated polysaccharide prepared from water-in-oil-in-water (W1/O/W2) double-emulsion method for delivery of type II di- abetic drug (exenatide), Colloids and Surfaces A: Physicochemical and Engineering Aspects, 340(1- 3), 115-120. doi: 10.1016/j.colsurfa.2009.03.015
- Zhang, H., Meng, J., Zhou, S., Liu, Y., Qu, D., Wang, L., Li, X., Wang, N., Luo, X., & Ma, X. (2016). Intrana- sal delivery of exendin-4 confers neuroprotective effect against cerebral ischemia in mice. The AAPS Journal, 18(2), 385–394. doi: 10.1208/s12248-015- 9854-1
- Zırh-Gürsoy, A. Editör: Zırh-Gürsoy, A. (2002), Kontrollü Salım Sistemleri, (Bölüm 5) Lipozom- lar, Kontrollü Salım Sistemleri Derneği Yayını, İstanbul (Türkiye): Elma Bilgisayar Basım ve Am- balaj San.Tic.Ltd.Şti.
| APA | celik tekeli m, Aktas Y, Celebi N (2022). Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar. , 265 - 280. 10.55262/fabadeczacilik.1134604 |
| Chicago | celik tekeli merve,Aktas Yesim,Celebi Nevin Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar. (2022): 265 - 280. 10.55262/fabadeczacilik.1134604 |
| MLA | celik tekeli merve,Aktas Yesim,Celebi Nevin Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar. , 2022, ss.265 - 280. 10.55262/fabadeczacilik.1134604 |
| AMA | celik tekeli m,Aktas Y,Celebi N Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar. . 2022; 265 - 280. 10.55262/fabadeczacilik.1134604 |
| Vancouver | celik tekeli m,Aktas Y,Celebi N Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar. . 2022; 265 - 280. 10.55262/fabadeczacilik.1134604 |
| IEEE | celik tekeli m,Aktas Y,Celebi N "Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar." , ss.265 - 280, 2022. 10.55262/fabadeczacilik.1134604 |
| ISNAD | celik tekeli, merve vd. "Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar". (2022), 265-280. https://doi.org/10.55262/fabadeczacilik.1134604 |
| APA | celik tekeli m, Aktas Y, Celebi N (2022). Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar. FABAD Journal of Pharmaceutical Sciences, 47(2), 265 - 280. 10.55262/fabadeczacilik.1134604 |
| Chicago | celik tekeli merve,Aktas Yesim,Celebi Nevin Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar. FABAD Journal of Pharmaceutical Sciences 47, no.2 (2022): 265 - 280. 10.55262/fabadeczacilik.1134604 |
| MLA | celik tekeli merve,Aktas Yesim,Celebi Nevin Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar. FABAD Journal of Pharmaceutical Sciences, vol.47, no.2, 2022, ss.265 - 280. 10.55262/fabadeczacilik.1134604 |
| AMA | celik tekeli m,Aktas Y,Celebi N Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar. FABAD Journal of Pharmaceutical Sciences. 2022; 47(2): 265 - 280. 10.55262/fabadeczacilik.1134604 |
| Vancouver | celik tekeli m,Aktas Y,Celebi N Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar. FABAD Journal of Pharmaceutical Sciences. 2022; 47(2): 265 - 280. 10.55262/fabadeczacilik.1134604 |
| IEEE | celik tekeli m,Aktas Y,Celebi N "Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar." FABAD Journal of Pharmaceutical Sciences, 47, ss.265 - 280, 2022. 10.55262/fabadeczacilik.1134604 |
| ISNAD | celik tekeli, merve vd. "Tip 2 Diyabet Tedavisinde Kullanılan Exendin-4 ve Exendin-4’ün Alternatif Uygulama Yolları İçin Güncel Yaklaşımlar". FABAD Journal of Pharmaceutical Sciences 47/2 (2022), 265-280. https://doi.org/10.55262/fabadeczacilik.1134604 |
