Muco-adhesive buccal tablets of candesartan cilexetil for oral delivery: preparation, in-vitro and ex-vivo evaluation
Candesartan cilexetil (CC) is an angiotensin II-receptor blocker (ARB). The antihypertensive effect of CC 4-16 mg/day was as great as that of other once-daily dosage regimens. Candesartan cilexetil has high first-pass metabolism and low oral bioavailability. The bioavailability of such drugs may be significantly improved if delivered through the buccal route; hence mucosal delivery is one of the alternative methods of systemic drug delivery. This study’s objective was to develop mucoadhesive buccal tablets of candesartan cilexetil using carbopol-934P, hydroxyl propyl methyl cellulose (HPMC), Eudragit RLPO, and sodium carboxy methyl cellulose (Na-CMC) as mucoadhesive polymers. Prepared CC buccal tablet formulations were evaluated for an optimized system based on physicochemical properties, ex-vivo residence time, in-vitro, and ex vivo permeation studies. The evaluation parameters of the tablets were within the acceptable Pharmacopoeial limits. However, the swelling and bio-adhesive time were increased with increasing polymer concentrations. The in-vitro release research shown that buccal tablets with sodium carboxy methyl cellulose (Na-CMC) exhibited a higher release than all other formulations and have been considered as optimized CC formulation. The release mechanism from kinetic methods suggests that the drug release follows zero-order kinetics with a diffusion mechanism. Further, in-vivo research in animal fashions is required to prove the bioavailability performance of the formulation.
Keywords: Candesartan cilexetil, mucoadhesive buccal tablets, first-pass metabolism, bioavailability.
2. Laffleur F, Bernkop-Schnürch A. Strategies for improving mucosal drug delivery. Nanomedicine. 2013 Dec; 8(12):2061-75.
3. Doodipala R. A review of novel formulation strategies to enhance oral delivery of zaleplon. J Bioequvi avail. 2016; 8(5): 211-213.
4. Chinna Reddy Palem, Ramesh Gannu, Narender D, Vamshi Vishnu Yamsani, and Madhusudan Rao Yamsani. Transmucosal Delivery of Domperidone from Bilayered Buccal Patches: In Vitro, Ex Vivo and In Vivo Characterization. Arch Pharm Res. 2011; 34(10):1701-1710.
5. Narendar D, Thirupathi G. Neuroprotective effect of ropinirole loaded lipid nanoparticles hydrogel for Parkinson’s disease: preparation, in vitro, ex vivo, pharmacokinetic and pharmacodynamic evaluation. Pharmaceutics, 2020; 12(5):448.
6. Dudhipala N, Narala A, Bomma R. Recent Updates in the Formulation Strategies to Enhance the Bioavailability of Drugs Administered via Intranasal Route. J Bioequiv Availab 8: 204-207. doi: 10.4172/jbb.
7. Banala N, Peddapalli H, Dudhipala N, Chinnala KM. Transmucosal Delivery of Duloxetine Hydrochloride for Prolonged Release: Preparation, in vitro, ex vivo Characteri-zation and in vitro-ex vivo Correlation. International Journal of Pharmaceutical Sciences and Nanotechnology. 2018 Sep 30; 11(5):4249-58.
8. Donthi MR, Dudipala N, Komalla DR, Suram D, Banala N. Design and evaluation of floating multi unit mini tablets (mumts) muco adhesive drug delivery system of famotidine to treat upper gastro intestinal ulcers. Journal of Pharmacovigilance. 2015 Oct 12.
9. Chopparapu C, Palem CR, Yamsani MR. Development of Promethazine mucoadhesive tablets for buccal delivery: in-vitro, ex-vivo and in-vivo characterization. American Jr PharmTech Res. 2012; 2(1):1697-705.
10. Chinna Reddy Palem, Narendar D, Sunil Kumar Battu, Satyanarayana Goda, and Madhusudan Rao Yamsani. Combined dosage form of pioglitazone and felodipine as mucoadhesive pellets via hot melt extrusion for improved buccal delivery with application of quality by design approach. J Drug Del Sci Tech. 2015; 30:209-219.
11. Zhang Z, Gao F, Bu H, Xiao J, Li Y. Solid lipid nanoparticles loading candesartan cilexetil enhance oral bioavailability: in vitro characteristics and absorption mechanism in rats. Nanomedicine: Nanotechnology, Biology and Medicine. 2012 Jul 1; 8(5):740-7.
12. Easthope SE, Jarvis B. Candesartan cilexetil. Drugs. 2002 Jun 1; 62(8):1253-87.
13. Gurunath S, Shailesh S, Narender D, Sandhya G, Baswaraj KN. Strongly enhanced dissolution rate of candesartan cilexetil solid dispersion tablets by incorporation of superdisintegrants. J. Pharm. Res. 2011; 4:4190-4.
14. Samanthula KS, Satla SR, Bairi AG. Development, In-Vitro and Ex-Vivo Evaluation of Muco-adhesive Buccal patches of Candesartan cilexetil. Research Journal of Pharmacy and Technology. 2019; 12(6):3038-44.
15. Donthi MR, Dudhipala NR, Komalla DR, Suram D, Banala N. Preparation and evaluation of fixed combination of ketoprofen enteric coated and famotidine floating mini tablets by single unit encapsulation system. Journal of Bioequivalence & Bioavailability. 2015; 7(6):279.
16. Swamy SK, Reddy LN, Goud BA. Development and in vitro evaluation of bioadhesive buccal tablets of hydralazine hydrochloride. Int. J. Pharm. Educ. Res. 2014; 1:8-16.
17. Reddy AB, Reddy ND. Development of multiple-unit floating drug delivery system of clarithromycin: formulation, in vitro dissolution by modified dissolution apparatus, in vivo radiographic studies in human volunteers. Drug research. 2017 Jul; 67(07):412-8.
18. Reddy, N.D., Chinna R. P., Sunil, R., & & Madhusudan, R. Y. Development of floating matrix tablets of Ofloxacin and Ornidazole in combined dosage form: in vitro and in vivo evaluation in healthy human volunteers. Int J Drug Deli, 2012; 4:462-469.
19. Ramana MV, Nagada C, Himaja M. Design and evaluation of mucoadhesive buccal drug delivery systems containing metoprolol tartrate. Indian Journal of Pharmaceutical Sciences. 2007; 69(4): 515-518.
20. Narendar D, K. Someshwar, N. Arjun and Y. Madhusudan Rao. Quality by design approach for development and optimization of Quetiapine Fumarate effervescent floating matrix tablets for improved oral delivery. J Pharm Investigation., 2016; 46(3):253-263.
21. Rajitha R, Narendar D, Arjun N, Mahipal D and Nagaraj B. Colon delivery of naproxen: preparation, characterization and in vivo evaluation. IJPSN, 2016; 9(3):1-10.
22. Alekya T, Narendar D, Mahipal D, Arjun N, Nagaraj B. Design and evaluation of chronomodulated drug delivery of tramadol hydrochloride. Drug research. 2018 Mar; 68(03):174-80.
23. Gowthamarajan K, Jawahar N, Wake P, Jain K, Sood S. Development of buccal tablets for curcumin using Anacardium occidentale gum. Carbohydrate Polymers. 2012 May 16; 88(4):1177-83.
24. Arjun N, Narendar D, Sunitha K, Harika K, Madhusudan Rao Y and Nagaraj B. Development, evaluation and influence of formulation and process variables on in vitro performance of oral elementary osmotic device of atenolol. Int J Pharm Invest, 2016; 6(4):1-9.
25. Çelik B. Risperidone mucoadhesive buccal tablets: formulation design, optimization and evaluation. Drug Design, Development and Therapy. 2017; 11:3355.
26. Narendar D, Arjun N, Karthik Yadav J and Ramesh Bomma. Amoxycillin Trihydrate Floating-Bioadhesive Drug Delivery System for Eradication of Helicobacter pylori: Preparation, In Vitro and Ex Vivo Evaluation. J bioequ avail. 2016; 8(3):118-124.
27. Jain AC, Aungst BJ, Adeyeye MC. Development and in vivo evaluation of buccal tablets prepared using danazol–sulfobutylether 7 β‐cyclodextrin (SBE 7) complexes. Journal of pharmaceutical sciences. 2002 Jul; 91(7):1659-68.
28. Chinna Reddy Palem, Narendar D, Sunil Kumar Battu, Michael A. Repka and Madhusudan Rao Yamsani. Development, Optimization and in vivo Characterization of Domperidone Controlled Release Hot Melt Extruded Films for Buccal Delivery. Drug Dev Ind Pharm, 2016; 42(3):473-484.
29. El-Nahas AE, Allam AN, El-Kamel AH. Mucoadhesive buccal tablets containing silymarin Eudragit-loaded nanoparticles: formulation, characterisation and ex vivo permeation. Journal of Microencapsulation. 2017 Jul 4; 34(5):463-74.
30. Narendar D, Riyaz PMD, Ahmed AY, Nagaraj B. Effect of lipid and edge activator concentration on development of Aceclofenac loaded transfersomes gel for transdermal application: in vitro and ex vivo skin permeation. Dru Dev Ind Pharm. 2020; 46(8):1334-1344.
31. Dudhipala, Narendar, Ahmed Adel Ali Youssef, and Nagaraj Banala. Colloidal lipid nanodispersion enriched hydrogel of antifungal agent for management of fungal infections: comparative in-vitro, ex-vivo and in-vivo evaluation for oral and topical application. Chemistry and Physics of Lipids (2020): 104981.
32. Ahmed AAY, Narendar D, Mujumdar S. Ciprofloxacin Loaded Nanostructured Lipid Carriers Incorporated into In-Situ Gels to Improve Management of Bacterial Endophthalmitis. Pharmaceutics, 2020; 12(6):572.
33. Narendar D and Kishan V. Candesartan cilexetil nanoparticles for improved oral bioavailability. Ther deli, 2017; 8(2):79-88.
34. Geçer A, Yıldız N, Çalımlı A, Turan B. Trimethyl chitosan nanoparticles enhances dissolution of the poorly water soluble drug candesartan-cilexetil. Macromolecular research. 2010 Oct 1; 18(10):986-91.
35. Dudhipala N, Veerabrahma K. Candesartan cilexetil loaded solid lipid nanoparticles for oral delivery: characterization, pharmacokinetic and pharmacodynamic evaluation. Drug delivery. 2016 Feb 12; 23(2):395-404.
36. Ettireddy S, Dudhipala N. Influence of β-Cyclodextrin and Hydroxypropyl-β-Cyclodextrin on Enhancement of Solubility and Dissolution of Isradipine. Int J Pharma Sci and Nanotech. 2017; 10(3):3752-7.
37. Palem CR, Reddy ND, Satyanarayana G, Varsha BP. Development and optimization of Atorvastatin calcium-cyclodextrin inclusion complexed oral disintegrating tablets for enhancement of solubility, dissolution, pharmacokinetic and pharmacodynamic activity by central composite design. Int J Pharm Sci Nanotech 2016; 9(2): 1-11.
38. Butreddy A, Narendar D. Enhancement of solubility and dissolution rate of trandolapril sustained release matrix tablets by liquisolid compact approach. Asian J Pharm 2015; 9 (4): 290-297.
39. Dudipala R, Palem CR, Reddy S, Rao YM. Pharaceutical development and clinical pharmacokinetic evaluation of gastroretentive floating matrix tablets of levofloxacin. Int J Pharma Sci and Nanotech, 2011; 4(3):1461-1467.
40. Veerabrahma K. Development of olmesartan medoxomil lipid-based nanoparticles and nanosuspension: preparation, characterization and comparative pharmacokinetic evaluation. Artificial cells, nanomedicine, and biotechnology. 2018 Feb; 46(1):126.
41. Kishan V, Sandeep V, Narendar D, Arjun N. Lacidipine loaded solid lipid nanoparticles for oral delivery: preparation, characterization and in vivo evaluation. International Journal of Pharmaceutical Sciences and Nanotechnology. 2016 Nov 30; 9(6):3524-30.
42. Narendar D, Veerabrahma K. Improved anti-hyperlipidemic activity of Rosuvastatin Calcium via lipid nanoparticles: Pharmacokinetic and pharmacodynamic evaluation. European Journal of Pharmaceutics and Biopharmaceutics. 2017 Jan 1; 110:47-57.
43. Narendar D, Ahmed A AyA Amelioration of ketoconazole in lipid nanoparticles for enhanced antifungal activity and bioavailability through oral administration for management of fungal infections. Chemistry and Physics of Lipids 2020; 232:104953.
44. Banala, N, Tirumalesh C, Suram, D. Dudhipala, N. Zotepine loaded lipid nanoparticles for oral delivery: preparation, characterization, and in vivo pharmacokinetic studies. Fut J Pharm Sci, 2020; 6(1):37.
45. Vamshi Krishna M, Vijay Kumar B, Narendar Dudhipala. In-situ Intestinal Absorption and Pharmacokinetic Investigations of Carvedilol Loaded Supersaturated Self-Emulsifying Drug System. Pharm Nanotechnol. 2020 May 17. doi: 10.2174/2211738508666200517121637.
46. Pitta S, Dudhipala N, Narala A and Veerabrahma K. Development and evaluation of zolmitriptan transfersomes by Box-Behnken design for improved bioavailability by nasal delivery. Drug Dev Ind Pharm. 2018; 44(3):484-492.
47. Tirumalesh C, Suram, D.; Dudhipala, N.; Banala, N. Enhanced pharmacokinetic activity of Zotepine via nanostructured lipid carrier system in Wistar rats for oral application. Pharm. Nanotechnol. 2020; 8(2):158-160.
48. Karri V, Butreddy A, Narender R. Fabrication of Efavirenz Freeze Dried Nanocrystals: Formulation, Physicochemical Characterization, In Vitro and Ex Vivo Evaluation. Advanced Science, Engineering and Medicine. 2015; 7(5):385-392.
49. Nagaraj K, D. Narendar and V. Kishan. Development of olmesartan medoxomil optimized nanosuspension using the Box–Behnken design to improve oral bioavailability. Drug Dev Ind Pharm, 2017; 43(7):1186-1196.
50. Esim O, Savaser A, Ozkan CK, Bayrak Z, Tas C, Ozkan Y. Effect of polymer type on characteristics of buccal tablets using factorial design. Saudi Pharmaceutical Journal. 2018 Jan 1; 26(1):53-63.
51. Mahipalreddy D, Narendar D, Devendhar K, Dinesh S, Kiran S, Nagaraj B. Preparation and evaluation of ketoprofen enteric coated mini tablets for prevention of chronic inflammatory disease. J Pharm Drug Deliv Res. 2015; 4(2).
52. Boyapally H, Nukala RK, Bhujbal P, Douroumis D. Controlled release from directly compressible theophylline buccal tablets. Colloids and Surfaces B: Biointerfaces. 2010 Jun 1; 77(2):227-33.
53. Koradia H, Chaudhari K. Formulation of unidirectional buccal tablet of Mirtazapine: an in vitro and ex vivo evaluation. Journal of Drug Delivery Science and Technology. 2018 Feb 1; 43:233-42.
54. Shruthi K, Narendar D, Arjun N, Kishan V. Development and Antimicrobial Evaluation of Binary Ethosomal Topical Gel of Terbinafine Hydrochloride for the Treatment of Onychomycosis. Int. J. Pharm. Sci. Nanotechnol. 2018; 11:3998-4005.
55. Nagaraj B, Anusha K, Narendar D, Sushma P. Formulation and evaluation of microemulsion-based transdermal delivery of duloxetine hydrochloride. International Journal of Pharmaceutical Sciences and Nanotechnology. 2020 Jan 31; 13(1):4773-82.
56. Shivanand K, Raju SA, Nizamuddin S, Jayakar B. In vivo bioavailability studies of sumatriptan succinate buccal tablets. DARU: Journal of Faculty of Pharmacy, Tehran University of Medical Sciences. 2011; 19(3):224.
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