• P. ANITHA Department of Pharmaceutics, JNTUA, Anantapuramu, AP, India, 2Department of Chemical Engineering, JNTUA, Anantapuramu, AP, India
  • S. V. SATYANARAYANA Department of Pharmaceutics, JNTUA, Anantapuramu, AP, India, 2Department of Chemical Engineering, JNTUA, Anantapuramu, AP, India


Objective: The objective of the present work was to develop an optimized dosage form for treating comorbidity in combination and evaluate it for its pharmacodynamic performance in male Wistar albino rats.

Methods: Transdermal proniosomal gel for Combination of Glibenclamide (GLB) and Atenolol (ATN) was developed and optimized by Box Behnken design. This optimized combinational proniosomal gel (OCPG), which was selected by a point prediction method, was evaluated for its ex vivo, skin irritation studies and pharmacodynamic activities of both drugs in rats in comparison with its oral therapy.

Results: The ex-vivo permeation behavior through different skins was studied and the findings were also confirmed by the values of the steady-state flux (Jss). The OCPG observed an increase of more than twice in the cumulative amount of impregnated drugs compared to pure drug films. The study on skin irritation revealed the non-irritability of the developed OCPG applied. OCPG significantly showed sustained hypoglycemic activity in rats (p<0.001), when compared to orally treat animals up to 24 h. Systolic blood pressure (SBP) lowering effect of OCPG was found to be significant (p<0.02), when compared to orally treat rats up to 24 h. However, the reduction was slow and sustained in the case of OPCG where a significant response was observed in the performed studies.

Conclusion: Overall, the results show that controlled release GLB and ATN proniosomes offer a useful and promising transdermal delivery system. Henceforth this may be an achievement in treating the diabetic hypertensive patient.

Keywords: Combination therapy, Atenolol, Glibenclamide, Proniosomes, Pharmacodynamic study


1. Ahad A, Al-Saleh AA, Akhtar N, Al-Mohizea AM, Al-Jenoobi FI. Transdermal delivery of antidiabetic drugs: formulation and delivery strategies. Drug Discovery Today 2015;20:1217–27.
2. Amos A, Mc Carty D, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabetic Med 1987;14:S1–85.
3. Libby P, Nathan DM, Abraham K, Judith E Fradkin, Steven M Haffner, Willa Hsueh, et al. Report of the national heart, lung and blood institute: national institute of diabetes and digestive and kidney diseases working group on cardiovascular complications of DM. Circulation 2005;111:3489-93.
4. Paul B, Sapra B, Maheswari S, Goyle RK. Role of losartan therapy in the management of diabetic hypertension. J Asso Physicians India 2000;48:514-7.
5. Satman I, Yilmaz T. Population-based study of diabetes and risk characteristics in turkey. Diabetes Care 2002;25:1551-6.
6. Varadarajan Baskar, Desikan Kamala Kannan, Martin R Holland, Baldev M Singh. The prevalence of hypertension and the utilization of antihypertensive therapy in a district diabettes population. Diabetes Care 2002;25:2107-8.
7. Baskar V, Kamala Kannan D, Holland MR, Singh BM. Does the ethnic origin have an independent impact on hypertension and diabetic complications? Diabetes Obes Metab 2006;8:214-9.
8. Chae DW, Son M, Kim Y, Son H, Jang SB, Seo JM, et al. Pharmacokinetics of a telmisartan/rosuvastatin fixed-dose combination: a single-dose, randomized, open-label, 2-period crossover study in healthy Korean subjects. Int J Clin Pharmacol Ther 2015;53:883-9.
9. Pourkavoos N. Unique risks, benefits, and challenges of developing drug-drug combination products in a pharmaceutical industrial setting. Comb Prod Ther 2012;2:1-31.
10. Mominur Rahman MD, Fahadul Islam, Abdur Rahman, Tanjin Ahmed, Mohammad Borhan Uddin, Sharif Mohammad Shaheen, et al. Present and future prospect of combination drugs therapy. World J Pharm Res 2020;9:1625-38.
11. Mouradian MM, Heuser IJ, Baronti F, Chase TN. Modi?cation of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson's disease. Ann Neurol 1990;27:18–23.
12. Shah Hirva, Patel Jenisha. Bicelle: a lipid nanostructure for transdermal delivery. J Crit Rev 2016;3:18-22.
13. Umeda T, Naomi S, Iwaoka T. Timing for the administration of an antihypertensive drug in the treatment of essential hypertension. Hypertension 1994;23:I211-4.
14. Ikegami H, Shima K, Tanaka A, Tahara Y, Hirota M, Kumahara Y. Interindividual variation in the absorption of glibenclamide in man. Acta Endocrinol 1986;111:528–32.
15. Darshan Kaur, Aparajita Raina, Nirmal Singh. Formulation and evaluation of carbopol 940 based glibenclamide transdermal gel. Int J Pharm Pharm 2014;6:435-40.
16. Yamamoto T, Katakabe K, Akiyoshi K, Kan K, Asano T, Okumura M. Topical application of the hypoglycemic agent glibenclamide and changes in blood glucose, plasma insulin (IRI) levels and plasma concentration of glibenclamide in normal rat. Diabetes Res Clin Pract 1990;8:19–22.
17. Heel RC, Brogden RN, Speight TM, Avery GS. Atenolol: a review of its pharmacological properties and therapeutic efficacy in angina pectoris and hypertension. Drugs 1979;17:425–60.
18. Barrett AM, Carter J, Fitzgerald JD, Hull R, Count D. A new type of cardioselective adrenoceptor blocking drug. Br J Pharmacol 1973;48:340.
19. Perrett S, Golding M, Williams WP. A simple method for the preparation of liposomes for pharmaceutical applications: characterization of the liposomes. J Pharm Pharmacol 1991;43:154-61.
20. Vora B, Khopade AJ, Jain NK. Proniosome based transdermal delivery of levonorgestrel for effective contraception. J Controlled Release 1998;54:149-65.
21. Alia badawi, Mohamed A Elnabarawi, Randa Tag A Elrehem, Bassem A Fayed. Formulation and evaluation of dispersed permethrin proniosomes in powder and micro emulsion-based hydrogel bases for the treatment of scabies. Int J Pharm Pharm Sci 2016;8:221-9.
22. Xi H, Yang Y, Zhao D, Fang L, Sun L, Mu L, et al. Transdermal patches for site-specific delivery of anastrozole: in vitro and local tissue disposition evaluation. Int J Pharm 2010;391:73-8.
23. Prabu SL, Prakash TNS, Thiyagarajan S, Amritha, Manibhrathi R, Priyadharsini N. Design and evaluation of matrix diffusion controlled transdermal patches of dexibuprofen. J Appl Res 2012;12:38-46.
24. Ankit Acharya, Kiran Kumar GB, Mohammed Gulzar Ahmed, Saroj Paudel. Novel approach to increase the bioavailability of candesartan cilexetil by proniosomal gel formulation: in vitro and in vivo evaluation. Int J Pharm Pharm Sci 2016;8:241-6.
25. Ahad A, Aqil M, Kohli K, Sultana Y, Mujeeb M, Ali A. Interactions between novel terpenes and main components of rat and human skin: the mechanistic view for transdermal delivery of propranolol hydrochloride. Curr Drug Delivery 2011;8:13–24.
26. Mi-Kyeong Kim, Hong Zhao, Chi-Ho Lee, Dae-Duk Kim. Formulation of a reservoir-type testosterone transdermal delivery system. Int J Pharm 2001;219:51–9.
27. Posina Anitha, Sundarapandiyan Ramkanth, Mohamed TS Saleem, Kommireddy Umasankari, Boddu Praveen Reddy, Madhusudhana Chetty. Preparation, in vitro and in vivo characterization of transdermal patch containing glibenclamide and atenolol: a combinational approach. Pak J Pharm Sci 2011;24:155-63.
28. Soujanya C, Ravi Prakash P. Formulation and evaluation of proniosomal gel-based transdermal delivery of atorvastatin calcium by box–behnken design. Asian J Pharm Clin Res 2019;12:335-43.
29. Ahmed OAA, Ahmed TA, Abdel-naim AB, Khedr A, Banjar ZM, Afouna MI. Enhancement of in vitro skin transport and in vivo hypoglycemic efficacy of glimepiride transdermal patches. Trop J Pharm Res 2014;13:1207-13.
30. Hesham M Tawfeek, Ahmed AH Abdellatif, Jelan A Abdel-Aleem, Yasser A Hassand, Dina Fathalla. Transfersomal gel nanocarriers for enhancement the permeation of lornoxicam. J Drug Del Sci Tech 2020;56:1-10.
31. Draize JH, Woodard, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Ex Ther 1944;82:377-90.
32. Xu L, Pan J, Chen Q, Yu Q, Chen H, Xu H, et al. In vivo evaluation of the safety of triptolide-loaded hydrogel-thickened microemulsion. Food Chem Toxicol 2008;46:3792–9.
33. Khanderao R Jadhav, Ashish Y Pawar, Ashwini A Bachhav, Satish A Ahire. Proniosome: a novel non-ionic provesicles as a potential drug carrier. Asian J Pharm 2016;10:S210-22.
34. Liu S, Jin MN, Quan YS, Kamiyama F, Kusamori K, Katsumi H, et al. Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin. Eur J Pharm Biopharm 2014;86:267-76.
35. Anitha P, Ramkanth S, Satyanarayana SV. Development and validation of a new analytical RP-HPLC method for simultaneous determination of glibenclamide and atenolol in bulk. Int J Res Pharm Sci 2019;10:2433-45.
36. Aqil M, Sultana Y, Ali A, Dubey K, Najmi AK, Pillai KK. Transdermal drug delivery systems of a beta-blocker: design, in vitro, and in vivo characterization. Drug Delivery 2004;11:27–31.
37. Amol Shete, Priyanka Thorat, Rajendra Doijad, Sachin Sajane. Formulation and in vitro, in vivo evaluation of proniosomal gel of neomycin sulphate. Int J Appl Pharm 2019;11:156-63.
38. Sharda Sambharkar, Sarvesh Paliwal, Swapnil Sharma, Bishambar Singh. Formulation of risperidone loaded proniosomes for effective transdermal delivery: an in vitro and in vivo study. Bull Fac Pharm (Cairo Univ) 2017;55:239-47.
39. Sridevi S, Chary MG, Krishna DR, Prakash Diwan V. Pharmacodynamic evaluation of transdermal drug delivery system of glibenclamide in rats. Indian J Pharm 2000;32:309-12.
40. Yuqing Li, Yuhui Wei, Fan Zhang, Dan Wang, Xinan Wu. Changes in the pharmacokinetics of glibenclamide in rats with streptozotocin-induced diabetes mellitus. Acta Pharm Sin B 2012;2:198-204.
41. Mutalik S, Udupa N. Glibenclamide transdermal patches: physicochemical, pharmacodynamic, and pharmacokinetic evaluations. J Pharm Sci 2004;93:1577-93.
42. Bhosale SS, Avachat AM. Design and development of ethosomal transdermal drug delivery system of valsartan with preclinical assessment in wistar albino rats. J Liposome Res 2013;23:119-25.
43. Yoko Kubota, Keizo Umegaki, Satomi Kagota, Naoko Tanaka, Kazuki Nakamura, Masaru Kunitomo, et al. Evaluation of blood pressure measured by tail-cuff methods (without Heating) in spontaneously hypertensive rats. Bio-Pharm Bull 2006;29:1756-8.
44. Ahad A, Aqil M, Ali A. Investigation of antihypertensive activity of Carbopol valsartan transdermal gel containing 1,8-cineole. Int J Biol Macromol 2014;64:144-9.
45. Sabareesh M, Yanadaiah JP, Chandra Sekhar KB. A novel vesicular approach for transdermal administration of enalapril maleate loaded nano proniosomal gel: formulation, ex vivo evaluation and in vivo antihypertensive study. Int J Appl Pharm 2020;12:190-202.
46. Imam SS, Aquil M, Akhtar M, Sultana Y, Ali A. Formulation by design-based proniosomes for accentuated transdermal delivery of risperidone: in vitro characterization and in vivo pharmacokinetic study. Drug Delivery 2015;22:1059–70.
47. Alsarra IA, Bosela AA, Ahmed SM, Mahrous GM. Proniosomes as a drug carrier for transdermal delivery of ketorolac. Eur J Pharm Biopharm 2005;59:485–90.
48. Ahmed M Samy, Afaf A Ramadan, Amal SM, Abu El-Enin, Yasmin IM Mortagi. Formulation and optimization of itraconazole proniosomes using box Behnken design. Int J Appl Pharm 2018;10:41-51.
49. Mohammed Ashif Khan, Jayamanti Pandit, Yasmin Sultana, Sarwat Sultana, Asgar Ali, Mohammed Aqil, et al. Novel carbopol-based transfersomal gel of 5-fluorouracil for skin cancer treatment: in vitro characterization and in vivo study. Drug Del 2014;22:1–8.
50. Vijayan V, Ravindra Reddy K, Sakthivel S, Swetha C. Optimization and characterization of Repaglinide biodegradable polymeric nanoparticle loaded transdermal patchs: in vitro and in vivo studies. Colloids Surf B 2013;111:150–5.
51. Abdul Ahad, Abdul Mohsen A Al-Saleh, Abdullah M Al-Mohizea, Fahad I Al-Jenoobi, Mohammad Raish, Alaa Eldeen B Yassin, et al. Pharmacodynamic study of eprosartan mesylate-loaded transfersomes carbopol gel under dermaroller1 on rats with methylprednisolone acetate-induced hypertension. Bio-Pharm 2017;89:177–84.
30 Views | 13 Downloads
How to Cite
Original Article(s)