Chronological Delivery of Antihypertensive Drugs in Bilayered Core-in-Cup Buccoadhesive Tablets: In Vitro and In Vivo Evaluation


Hypertension shows circadian blood pressure rhythms (day–night pattern) that urge the delivery of antihypertensive drugs at the right time in the desired levels. Thus, a bilayered core-in-cup buccoadhesive tablet was formulated that immediately releases olmesartan, to give a burst effect, and controls azelnidipine release, to prolong its therapeutic effect. The main challenge was the poor bioavailability of azelnidipine due to its poor aqueous solubility and first-pass effect. Hence, liquisolid compact buccoadhesive tablets were prepared to enhance solubility, dissolution profiles, and bypass the oral route. Two factorial designs were conducted to study the type and concentration effect of the mucoadhesive polymers on the dissolution and mucoadhesion of olmesartan and azelnidipine. Characterization studies were conducted regarding drug content, surface pH, water uptake, mucoadhesive strength, in vitro release, and ex vivo permeability. The core-in-cup olmesartan/azelnidipine buccoadhesive tablet showed similar release profile to the statistically optimized formulae of each drug. In vitro dissolution study showed enhanced release of azelnidipine than the directly compressed tablets, to comply with the regulatory standards of controlled release systems. In vivo pharmacokinetic study of olmesartan and azelnidipine conducted on human volunteers against Rezaltas® 10/8 mg tablet showed percentage relative bioavailability of 106.12 and 470.82%, respectively.

Graphical Abstract

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. 1.

    Modi D, Amaliyar P, Kalal Y, Gangadia B, Chaudhry S, Sanghvi K, et al. Novel approach in compressed-coated tablet dosage form: core-in-cup (in lay) tablet with geometrically altered drug delivery concept. Bri Bio Bull. 2013;1(1):90–102.

    Google Scholar 

  2. 2.

    Burnier M. Medication adherence and persistence as the cornerstone of effective antihypertensive therapy. Am J Hypertens. 2006;19(11):1190–6.

    PubMed  Google Scholar 

  3. 3.

    Kjeldsen SE, Aksnes TA, de la Sierra A, Ruilope LM. Amlodipine and valsartan: calcium channel blockers/angiotensin II receptor blockers combination for hypertension. Therapy. 2007;4(1):31–40.

    CAS  Google Scholar 

  4. 4.

    Prabhakar D, Sreekanth J, Jayaveera K. Development and evaluation of transdermal patches of azelnidipine. Int J Pharm Pharm Sci. 2013;5:805.

    CAS  Google Scholar 

  5. 5.

    Wellington K, Scott LJ. Azelnidipine. Drugs. 2003;63(23):2613–21.

    CAS  PubMed  Google Scholar 

  6. 6.

    Han Y, Pan Y, Lv J, Guo W, Wang J. Powder grinding preparation of co-amorphous β-azelnidipine and maleic acid combination: molecular interactions and physicochemical properties. Powder Technol. 2016;291:110–20.

    CAS  Google Scholar 

  7. 7.

    Hamsanandini J, Parthiban S, Vikneswari A, Tamiz MT. Dissolution enhancement techniques of poorly soluble drugs by liquisolid compacts. Int J Res Pharm Nano Sci. 2014;3(4):298–304.

    CAS  Google Scholar 

  8. 8.

    Shivanand K, Raju SA, Jaykar B. Mucoadhessive bilayered buccal tablets of tizanidine hydrochloride. Int J Pharm Tech Res. 2010;2(3):1861–9.

    CAS  Google Scholar 

  9. 9.

    Jadhav TS, Thombre NA, Kshirsagar SJ. Pulsatile drug delivery system using core-in-cup approach: a review. Pharm Biol Eval. 2016;3(3):288–304.

    Google Scholar 

  10. 10.

    British Pharmacopeia. 2015.

  11. 11.

    Basalious EB, El-Sebaie W, El-Gazayerly O. Application of pharmaceutical QbD for enhancement of the solubility and dissolution of a class II BCS drug using polymeric surfactants and crystallization inhibitors: development of controlled-release tablets. AAPS PharmSci Tech. 2011:9646–66.

  12. 12.

    Patel JK, Patel NK. Validated stability-indicating RP-HPLC method for the simultaneous determinat ion of azelnidipine and olmesartan in their combined dosage form. Sci Pharm. 2014;82(1):541–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Singh R, Sharma D, Garg R. Review on mucoadhesive drug delivery system with special emphasis on buccal route: an important tool in designing of novel controlled drug delivery system for the effective delivery of pharmaceuticals. J Dev Drugs. 2017;6(1):1–12.

    Google Scholar 

  14. 14.

    Tangri P, Jawla S, Jakhmola V, Mishra R. Highlights of mucoadhesive drug delivery systems: a review. Indo Glob J Pharm. 2017;7(2):112–25.

    CAS  Google Scholar 

  15. 15.

    European Medicines Agency. Guideline on quality of oral modified release products. 2012.

  16. 16.

    Shah M, Pathak K. Development and statistical optimization of solid lipid nanoparticles of simvastatin by using 23 full-factorial design. AAPS PharmSciTech. 2010;11(2):489–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Singh B, Mehta G, Kumar R, Bhatia A, Ahuja N, Katare O. Design, development and optimization of nimesulide-loaded liposomal systems for topical application. Curr Drug Deliv. 2005;2(2):143–53.

    CAS  PubMed  Google Scholar 

  18. 18.

    Swarupa A, Sharma JVC, Vishnu Priya P, Shyamala. A review on liquisolid technology. Int J Pharm Sci Rev Res. 2015;5(3):207–11.

    Google Scholar 

  19. 19.

    Draganoiu E, Rajabi-Siahboomi AR, Tiwari SB. Handbook of pharmaceutical excipients. 6th ed. London: Pharmaceutical Press; 2009.

    Google Scholar 

  20. 20.

    Darekar SS, Khadabadi SS, Shahi SR. Formulation and evaluation of bilayer buccal tablet of sumatriptan succinate. Int J Pharm Pharm Sci. 2014;6(6):469–75.

    Google Scholar 

  21. 21.

    Patil GB, Patil ND, Deshmukh PK, Patil PO, Bari SB. Nanostructured lipid carriers as a potential vehicle for carvedilol delivery: application of factorial design approach. Artificial Cells, Nanomedicine, and Biotechnology. 2016;44(1):12–9.

    CAS  PubMed  Google Scholar 

  22. 22.

    Parodi B, Russo E, Caviglioli G, Cafaggi S, Bignardi G. Development and characterization of a buccoadhesive dosage form of oxycodone hydrochloride. Drug Dev Ind Pharm. 1996;22(5):445–50.

    CAS  Google Scholar 

  23. 23.

    Çelik B. Risperidone mucoadhesive buccal tablets: formulation design, optimization and evaluation. Drug Des Devel Ther. 2017;11:3355–65.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Olorunsola EO, Akpan GA, Adikwu MU. Evaluation of chitosan-microcrystalline cellulose blends as direct compression excipients. J Drug Deliv. 2017;2017:1–8.

    Google Scholar 

  25. 25.

    Kassem MAA, ElMeshad AN, Fares AR. Enhanced bioavailability of buspirone hydrochloride via cup and corebuccal tablets: formulation and in vitro/in vivo evaluation. Int J Pharm. 2014;463(1):68–80.

    CAS  PubMed  Google Scholar 

  26. 26.

    Langoth N, Kalbe J, Bernkop-Schnürch A. Development of buccal drug delivery systems based on a thiolated polymer. Int J Pharm. 2003;252(1–2):141–8.

    CAS  PubMed  Google Scholar 

  27. 27.

    Jenkins S, Liversidge GG. Nanoparticulate azelnidipine formulations. 2010; US20100221327 A1. p.1–24.

  28. 28.

    Moore JW. Mathematical comparison of dissolution profiles. Pharm Technol. 1996;20:64–75.

    Google Scholar 

  29. 29.

    FDA. Guidance for industry: dissolution testing of immediate release solid oral dosage forms. 1997.

  30. 30.

    Higuchi T. Mechanisms of sustained action medication,theoretical analysis of the rate of release of solid drugs dispersed in solid matrices. J Pharm Sci. 1963;52(1):1145–9.

    CAS  Google Scholar 

  31. 31.

    Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanism of solute release from porous hydrophilic polymers. Int J Pharm. 1983;72(10):1189–91.

    CAS  Google Scholar 

  32. 32.

    Dash S, Murthy PN, Nath L, Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm. 2010;67(3):217–23.

    CAS  Google Scholar 

  33. 33.

    El-Samaligy M, Yahia S, Basalious E. Formulation and evaluation of diclofenac sodium buccoadhesive discs. Int J Pharm. 2004;286(1–2):27–39.

    CAS  PubMed  Google Scholar 

  34. 34.

    FDA. Guidance for industry, bioavailability and bioequivalence studies submitted in NDAs or INDs—general considerations 2014.

  35. 35.

    FDA. Guidance of industry, food-effect bioavailability and bioequivalence studies. 2002.

  36. 36.

    Ramesh A, Neelima B, Pallapothu L, Ashok Kumar A. A novel method for the simultaneous determination of azelnidipine and olmesartan in human plasma by using liquid chromatography-electro spray ionization tandem mass spectrometry and application to a pharmacokinetic study. Int J Pharm. 2017;7(3):111–24.

    Google Scholar 

  37. 37.

    Perioli L, Ambrogi V, Giovagnoli S, Blasi P, Mancini A, Ricci M, et al. Influence of compression force on the behavior of mucoadhesive buccal tablets. AAPS Pharm SciTech. 2008;9(1):274–81.

    CAS  Google Scholar 

  38. 38.

    Elshafeey AH, Kamel AO, Awad GAS. Ammonium methacrylate units polymer content and their effect on acyclovir colloidal nanoparticles properties and bioavailability in human volunteers. Colloids Surf B. 2010;75(2):398–404.

    CAS  Google Scholar 

  39. 39.

    Maryadele, O’Neil J. The Merck index. 14th ed. Whitehouse Station: Merck & Co., Inc.; 2006.

    Google Scholar 

  40. 40.

    Sruthy PN, Anoop KR. Formulation and evaluation of olmesartan medoxomil floating tablets. Int J Pharm Pharm Sci. 2013;5(3):691–6.

    CAS  Google Scholar 

  41. 41.

    Kapavarapu S, Bhandaru VR, Chintala R. Structural identification and characterization of potential impurities of azelnidipine. Int J Pharm Res Scholars. 2016;5(1–2):202–17.

    CAS  Google Scholar 

  42. 42.

    Damian F, Blaton N, Naesens L, Balzarini J, Kinget R, Augustijns P, et al. Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. Eur J Pharm Sci. 2000;10(4):311–22.

    CAS  PubMed  Google Scholar 

  43. 43.

    Aditya G, Gudas GK, Bingi M, Debnath S, Rajesham VV. Design and evaluation of controlled release mucoadhesive buccal tablets of lisinopril. Int J Curr Pharm Res. 2010;2(4):24–7.

    CAS  Google Scholar 

  44. 44.

    Patel VM, Prajapati BG, Patel MM. Formulation, evaluation, and comparison of bilayered and multilayered mucoadhesive buccal devices of propranololhydrochloride. AAPS PharmSciTech. 2007;8(1):147–54.

    Google Scholar 

  45. 45.

    Ali MF, Bakalisa S. Mucoadhesive polymers for food formulations. Procedia Food Sci. 2011;1(1):68–75.

    CAS  Google Scholar 

  46. 46.

    Costa P, Lobo JMS. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Srivalli KMR, Lakshmi PK, Balasubramaniam J. Design of a novel bilayered gastric mucoadhesive system for localized and unidirectional release of lamotrigine. Saudi Pharm J. 2013;21(1):45–52.

    Google Scholar 

  48. 48.

    Raju KN, Velmurugan S, Deepika B, Vinushitha S. Formulation and in vitro evaluation of buccal tablets of metoprolol tartrate. Int J Pharm Pharm Sci. 2011;3(2):239–46.

    Google Scholar 

  49. 49.

    Habib BS, Abd El Rehim RT, Nour SA. Feasibility of optimizing trimetazidine dihydrochloride release from controlled porosity osmotic pump tablets of directly compressed cores. J Adv Res. 2014;5(1):347–56.

    CAS  PubMed  Google Scholar 

  50. 50.

    Chen J, Qiu L, Hu M, Jin Y, Han J. Preparation, characterization and in vitro evaluation of solid dispersions containing docetaxel. Drug Dev Ind Pharm. 2008;34(6):588–94.

    CAS  PubMed  Google Scholar 

  51. 51.

    Delaney SP, Nethercott MJ, Mays CJ, Winquist NT, Arthur D, Calahan JL, et al. Characterization of synthesized and commercial forms of magnesium stearate using differential scanning calorimetry, thermogravimetric analysis, powder X-ray diffraction, and solid-state NMR spectroscopy. J Pharm Sci. 2017;106(1):338–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Xie Y, Li G, Yuan X, Cai Z, Rong R. Preparation and in vitro evaluation of solid dispersions of total flavones of Hippophae rhamnoides L. AAPS PharmSciTech. 2009;10(2):631–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Rojas J, Lopez A, Guisao S, Ortiz C. Evaluation of several microcrystalline celluloses obtained from agricultural by-products. Journal of Advanced Pharmaceutical Technology & Research. 2011;2(3):144–50.

    CAS  Google Scholar 

  54. 54.

    Roberts SNC, Williams AC, Grimsey IM, Booth SW. Quantitative analysis of mannitol polymorphs. X-ray powder diffractometry—exploring preferred orientation effects. J Pharm Biomed Anal. 2002;28(6):1149–59.

    Google Scholar 

  55. 55.

    Mogilevskaya E, Akopova T, Zelenetskii A, Ozerin A. The crystal structure of chitin and chitosan. Polymer Science Series A. 2006;48(2):116–23.

    Google Scholar 

  56. 56.

    Dondeti P, Zia H, Needham TE. Bioadhesive and formulation parameters affecting nasal absorption. Int J Pharm. 1996;127(2):115–33.

    CAS  Google Scholar 

  57. 57.

    Wang J, Sakai S, Deguchi Y, Bi D, Tabata Y, Morimoto K. Aminated gelatin as a nasal absorption enhancer for peptide drugs: evaluation of absorption enhancing effect and nasal mucosa perturbation in rats. J Pharm Pharmacol. 2002;54(2):181–8.

    CAS  PubMed  Google Scholar 

  58. 58.

    Mohanty D, Gurulatha C, Bakshi V, Mavya B. Novel aproaches on buccal mucoadhesive drug delivery system. Indo Am J Pharm Res. 2018;5(4):2131–45.

    CAS  Google Scholar 

  59. 59.

    Illum L, Jørgensen H, Bisgaard H, Krogsgaard O, Rossing N. Bioadhesive microspheres as a potential nasal drug delivery system. Int J Pharm. 1987;39(3):189–99.

    CAS  Google Scholar 

  60. 60.

    Nakamura K, Maitani Y, Lowman AM, Takayama K, Peppas NA, Nagai T. Uptake and release of budesonide from mucoadhesive, pH-sensitive copolymers and their application to nasal delivery. Journal of Controlled Release: official journal of the Controlled Release Society. 1999;61(3):329–35.

    CAS  Google Scholar 

  61. 61.

    Lee JW, Park JH, Robinson JR. Bioadhesive-based dosage forms: the next generation. J Pharm Sci. 2000;89(7):850–66.

    CAS  PubMed  Google Scholar 

  62. 62.

    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 Pharm J. 2018;26(1):53–63.

    CAS  PubMed  Google Scholar 

  63. 63.

    Chatterjee B, Amalina N, Sengupta P, Mandal UK. Mucoadhesive polymers and their mode of action: a recent update. J Appl Pharm Sci. 2017;7(5):195–203.

    CAS  Google Scholar 

  64. 64.

    Singh MK, Prajapati SK, Mahor A, Rajput N, Singh R. Formulation and in-vitro evaluation of microcrystalline chitosan based buccoadhesive bilayered tablets of repaglinide. Int J Pharm Biol Sci Arch. 2011;2(4):1282–90.

    Google Scholar 

  65. 65.

    Bertram Ulrike BR. In situ gelling, bioadhesive nasal inserts for extended drug delivery: in vitro characterization of a new nasal dosage form. Eur J Pharm Sci. 2006;27(1):62–71.

    CAS  PubMed  Google Scholar 

  66. 66.

    Madgulkar A, Kadam S, Pokharkar V. Studies on formulation development of mucoadhesive sustained release itraconazole tablet using response surface methodology. AAPS Pharm SciTech. 2008;9(3):998–1005.

    CAS  Google Scholar 

  67. 67.

    Cook SL, Woods S, Methven L, Parker JK, Khutoryanskiy VV. Mucoadhesive polysaccharides modulate sodium retention, release and taste perception. Food Chem. 2018;1(240):482–9.

    Google Scholar 

  68. 68.

    Madsen F, Eberth K, Smart JD. A rheological examination of the mucoadhesive/mucus interaction: the effect of mucoadhesive type and concentration. Journal of Controlled Release: official journal of the Controlled Release Society. 1998;50(1):167–78.

    CAS  Google Scholar 

  69. 69.

    Shirizadeh B, Maghsoodi M, Alami-Milani M, Salatin S, Jelvehgari M. Tailored hydrogel microbeads of sodium carboxymethylcellulose as a carrier to deliver mefenamic acid: transmucosal administration. J Nat Pharm Prod. 2017;12(4):1–10.

    Google Scholar 

  70. 70.

    Akbari J, Saeedi M, Morteza-Semnani K, Zarrabi B, Rostamkalaei SS, Kelidari HR. The effect of Plantago major seed mucilage combined with carbopol on the release profile and bioadhesive properties of propranolol HCl buccoadhesive tablets. Pharm Biomed Res. 2016;2(2):84–100.

    Google Scholar 

  71. 71.

    Sasidhar RLC, Vidyadhara S, Maheswari GV, Deepti B, Srinivasa BP. Solubility and dissolution rate enhancement of olmesartan medoxomil by complexation and development of mouth dissolving tablets. Adv Biol Res. 2013;7(2):32–41.

    CAS  Google Scholar 

  72. 72.

    Tile MK, Pawar AY. Solubility and dissolution rate enhancement of olmesartan medoxomil by chitosan base co-crystal approach. Int J Pharma Bio Sci. 2015;5(2):400–11.

    CAS  Google Scholar 

  73. 73.

    Abdelkader H, Abdalla OY, Salem H. Formulation ofcontrolled-release baclofen matrix tablets: influence of some hydrophilic polymers on the release rate and in-vitro evaluation. AAPS Pharm Sci Tech. 2007;8(4):156–66.

    Google Scholar 

  74. 74.

    Saha AK, Ray SD. Effect of cross-linked biodegradable polymers on sustained release of sodium diclofenac-loaded microspheres. Braz J Pharm Sci. 2013;49(4):874–88.

    Google Scholar 

  75. 75.

    Yadav VK, Gupta AB, Kumar R, Yadav JS, Kumar B. Mucoadhesive polymers: means of improving the mucoadhesive properties of drug delivery system. J Chem Pharm Res. 2010;2(5):418–32.

    CAS  Google Scholar 

  76. 76.

    Agarwal S, Murthy RSR. Effect of different polymer concentration on drug release rate and physicochemical properties of mucoadhesive gastroretentive tablets. Indian J Pharm Sci. 2015;77(6):705–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Alhalmil A, Altowairi M, Saeed O, Alzubaidi N, Almoiliqy M, Abdulmalik W. Sustained release matrix system: an overview. World J Pharm Pharm Sci. 2018;7(6):1470–86.

    Google Scholar 

  78. 78.

    Yvonne P, Thomas R. Controlling drug delivery. 1st. London: Fastrack, Pharmaceutical Press; 2010.

    Google Scholar 

  79. 79.

    Fahmy RH, Kassem MA. Enhancement of famotidine dissolution rate through liquisolid tablets formulation: in vitro and in vivo evaluation. Eur J Pharm Biopharm. 2008;69(3):993–1003.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Charman SA, Charman WN. Oral modified-release delivery systems. In: Modified-release drug delivery technology. California: Marcel Dekker Inc; 2003. p. 1–7.

    Google Scholar 

  81. 81.

    Zhang X, Xing H, Zhao Y, Ma Z. Pharmaceutical dispersion techniques for dissolution and bioavailability enhancement of poorly water-soluble drugs. Pharmaceutics. 2018;10(24):1–33.

    Google Scholar 

  82. 82.

    Rodriguez C, Bruneau N, Barra J, Alfonso D, Doelker E, Wise D. Drug release from swelling-controlled systems. 2000.

    Google Scholar 

  83. 83.

    Vigoreaux V, Ghaly ES. Fickian and relaxational contribution quantification of drug release in a swellable hydrophillic polymer matrix. Drug Dev Ind Pharm. 1994;20(16):2519–26.

    CAS  Google Scholar 

  84. 84.

    Farid RM, Etman MA, Nada AH, Ebian AR. Formulation and in vitro evaluation of salbutamol sulphate in situ gelling nasal inserts. AAPS Pharm SciTech. 2013;14(2):712–8.

    CAS  Google Scholar 

  85. 85.

    Prajapati ST, Joshi HA, Pate CN. Preparation and characterization of self-microemulsifying drug delivery system of olmesartan medoxomil for bioavailability improvement. J Pharm. 2013:1–9.

  86. 86.

    Aspden T, Illum L, Skaugrud Ø. Chitosan as a nasal delivery system: evaluation of insulin absorption enhancement and effect on nasal membrane integrity using rat models. Eur J Pharm Sci. 1996;4(1):23–31.

    CAS  Google Scholar 

  87. 87.

    Fernandez-Urrusuno R, Calvo P, Remunan-Lopez C, Vila-Jato JL, Alonso MJ. Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharm Res. 1999;16(10):1576–81.

    CAS  PubMed  Google Scholar 

  88. 88.

    Oechslein CR, Fricker G, Kissel T. Nasal delivery of octreotide: absorption enhancement by particulate carrier systems. Int J Pharm. 1996;139(1):25–32.

    CAS  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Sara Nageeb El-Helaly.

Ethics declarations

This study design was approved by the Cairo University Research Ethics Committee (serial number of the protocol: PI 1189) and conducted with respect to the world medical association’s code of ethics of Declaration of Helsinki 2013.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material


(DOCX 1301 kb)


(DOC 1534 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rashad, A.A., Nageeb El-Helaly, S., Abd El Rehim, R.T. et al. Chronological Delivery of Antihypertensive Drugs in Bilayered Core-in-Cup Buccoadhesive Tablets: In Vitro and In Vivo Evaluation. AAPS PharmSciTech 21, 21 (2020).

Download citation


  • azelnidipine
  • olmesartan
  • liquisolid compacts
  • core-in-cup
  • buccoadhesive tablets