Preparation, characterization and in-vitro evaluation of theophylline loaded microemulsion formulations

Abstract

Theophylline is widely used as a bronchodilator drug in asthma and chronic obstructive lung disease because it is effective and inexpensive. Theophylline blood concentrations should be monitored since its therapeutic index is narrow, its optimum blood levels range from 10 to 20 μg/mL; its serious side effects take place over 20 μg/mL; its efficacy falls below 10 μg/mL blood concentrations. The aim of the present study is to formulate and characterize oil-in-water microemulsion systems for oral delivery of theophylline. Microemulsion formulations represent an interesting delivery vehicle for poorly water-soluble drugs, allowing for improving their solubility and dissolution properties. A simple and reliable UV-Spectrophotometric method was developed and validated for the determination of theophylline in the concentration range of 25- 150 μg/mL. In vitro drug release profile showed that after 1 hour, 40% of the drug released through the formulation in Simulated Intestinal Fluid at pH 6.8 as a release medium and the microemulsion formulations released more than 75% of the drug during the 5 hours study period. The globule size of drug-loaded formulations was in the range of 203.6 ± 0.2 nm. Results confirmed that the proposed microemulsion formulation containing theophylline could improve and control the drug release profile in comparison to the conventional dosage form.

Keywords

• Asthma Therapy,Controlled Release,Drug Delivery System,Microemulsion,Theophylline

References

1. [1] Undem BJ, Lichtenstein LM. Drugs used in the treatment of asthma. In: Hardman JG, Limbird LE, editors. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw -Hill; (2001). p. 733-754. ISBN:9780071354691
2. [2] Kayaalp SO. Rasyonel Tedavi Yönünden Tıbbi Farmakoloji. 11th ed. Ankara: Hacettepe-Taş Kitapçılık; (2005). p. 594-611. ISBN:9789759534158
3. [3] Kobzik L, Schoen FJ. The Lung. In: Cotran RS, Robbins SL, Kumar V, editors. Robbins pathologic basis of disease. 5th ed. United States of America: W. B. Saunders Company; (1994). p. 673-734. ISBN:9780721650326
4. [4] D’Amato G, Vitale C, Molino A, Stanziola A, Sanduzzi A, Vatrella A, Mormile M, Lanza M, Calabrese G, Antonicelli L, D’Amato M. Asthma-related deaths. Multidiscip Respir Med. (2016);11(37):1-5. https://doi.org/10.1186/s40248-016-0073-0
5. [5] Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, Gibson P, Ohta K, O’Byrne P, Pedersen SE, Pizzichini E, Sullivan SD, Wenzel SE, Zar HJ. Global strategy for asthma management and prevention: Gina executive summary. Eur Respir J. (2008); 31(1), 143-178. https://doi.org/10.1183/09031936.00138707
6. [6] Global initiative for asthma. Global srategy for asthma management and prevention. (2008). Retrieved April 15, 2009 from http://www.ginasthma.org
7. [7] Wilson AJ, Gibson PG, Coughlan J. Long acting beta-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev. (2003); (3): 1-26. https://doi.org/10.1002/14651858.CD001281
8. [8] Ukena D, Harnest U, Sakalauskas R, Magyar P, Vetter N, Steffen H, Leichtl S, Rathgeb F, Keller A, Steinijans VW. Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J. (1997); 10(12): 2754-2760. https://doi.org/10.1183/09031936.97.10122754

9. [9] Lim S, Jatakanon A, Gordon D, Macdonald C, Chung KF, Barnes PJ. Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice. Thorax. (2000); 55(10): 837-841. https://doi.org/10.1136/thorax.55.10.837
10. [10] Baumann TW. Some thoughts on the physiology of caffeine in coffee - and a glimpse of metabolite profiling. Braz J Plant Physiol. (2006); 18(1): 243-251. https://doi.org/10.1590/S1677-04202006000100017
11. [11] Scheindlin S. A new look at the xanthine alkaloids. Mol Interv. (2007); 7(5): 236-242. https://doi.org/10.1124/mi.7.5.1
12. [12] Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm Res. (1995); 12: 1561-1572. https://doi.org/10.1023/a:1016268311867
13. [13] Liandong H, Yang J, Liu W, Li L. Preparation and evaluation of Ibuprofen-loaded microemulsion form improvement of oral bioavailability. Drug Deliv. (2011); 18(1): 90-5. https://doi.org/10.3109/10717544.2010.522613
14. [14] Baker RC, Florence AT, Tadros TF, Wood RM. Investigations into the formation and characterization of microemulsions. J Colloid Interface Sci. (1984); 100: 311-331. https://doi.org/10.1016/0021-9797(84)90438-7
15. [15] International Conference on Harmonization (ICH) Q2 (R1) Validation of analytical procedures: text and methodology. In: Brussels, Belgium: International Conference on Harmonisation. 1996.
16. [16] The United States Pharmacopeia: USP 29. Rockville, MD. (2006) [17] Figueiredo KA, Neves JKO, Silva JAD, Freitas RMD, Carvalho ALM. Phenobarbital loaded microemulsion: development, kinetic release and quality control. Braz J Pharm Sci. (2016); 52(2): 251-264. https://doi.org/10.1590/S1984-82502016000200003
17. [18] Ozturk AA, Güven UM. Cefaclor monohydrate loaded microemulsion formulation for topical application: Characterization with new developed UPLC method and stability study. J Pharm Res. (2019); 23 (3): 426-440. https://doi.org/10.12991/jrp.2019.150
18. [19] Okur NU, Apaydin S, Yavasoglu NU, Yavasoglu, A, Karasulu HY. Evaluation of skin permeation and anti-inflammatory and analgesic effects of new naproxen microemulsion formulations. Int J Pharm. (2011); 416(1): 136-144. https://doi.org/10.1016/j.ijpharm.2011.06.026
19. [20] Piao HM, Balakrishnan P, Cho HJ, Kim H, Kim YS, Chung SJ, Shim CK, Kim DD. Preparation and evaluation of fexofenadine microemulsions for intranasal delivery. Int J Pharm. (2010); 395(1- 2): 309-316. https://doi.org/10.1016/j.ijpharm.2010.05.041
20. [21] Shah RM, Malherbe F, Eldridge D, Palombo EA, Harding IH. Physicochemical characterization of solid lipid nanoparticles (SLNs) prepared by a novel microemulsion technique. J Colloid Interface Sci. (2014); 428: 286-294. https://doi.org/10.1016/j.jcis.2014.04.057
21. [22] Güven UM, Berkman MS, Yazan Y. Development and validation of UPLC method for the determination of olopatadine hydrochloride in polymeric nanoparticles. Acta Pharm Sci. (2019); 57 (1): 7-18. https://doi.org/10.23893/1307-2080.APS.05701
22. [23] Okur NU, Caglar ES, Yozgatli, V. Development and validation of an HPLC method for voriconazole active substance in bulk and its pharmaceutical formulation. Marmara Pharm J. (2016); 20(2): 79-85. https://doi.org/ 10.12991/mpj.20162076793
23. [24] Bhadra S, Das SC, Roy S, Arefeen S, Rouf ASS. Development and validation of RP-HPLC method for quantitative estimation of vinpocetine in pure and pharmaceutical dosage forms. Chromatogr Res Int. (2011); ID 801656. https://doi.org/10.4061/2011/801656
24. [25] Sintov AC, Brandys-Sitton R. Facilitated skin penetration of lidocaine: combination of a short-term iontophoresis and microemulsion formulation. Int J Pharm. (2006); 316(1-2): 58-67. https://doi.org/10.1016/j.ijpharm.2006.02.034
25. [26] Arevalo MI, Escribano E, Calpena A, Domenech J, Queralt J. Rapid skin anesthesia using a new topical amethocaine formulation: a preclinical study. Anesth Analg. (2004); 98(5): 1407-1412. https://doi.org/10.1213/01.ANE.0000107936.69436.5B
26. [27] Hathout RM, Woodman TJ, Mansour S, Mortada ND, Geneidi AS, Guy RH. Microemulsion formulations for the transdermal delivery of testosterone. Eur J Pharm Sci. (2010); 40(3): 188-196. https://doi.org/10.1016/j.ejps.2010.03.008
27. [28] Cao M, Ren L, Chen G. Formulation optimization and ex vivo and in vivo evaluation of celecoxib microemulsion-based gel for transdermal delivery. AAPS J. (2017); 18(6): 1960-1971. https://doi.org/10.1208/s12249-016-0667-z
28. [29] Gurpreet K, Singh SK. Review of nanoemulsion formulation and characterization techniques. Indian J Pharm Sci. (2018); 80(5): 781- 789. https://doi.org/10.4172/pharmaceutical-sciences.1000422
29. [30] Momoh MA, Franklin KC, Agbo CP, Ugwu CE, Adedokun MO, Anthony OC, Chidozie OM, Okorie AN. Microemulsion-based approach for oral delivery of insulin: formulation design and characterization. Heliyon. (2020); 6(3): e03650. https://doi.org/10.1016/j.heliyon.2020.e03650
30. [31] Ustundag Okur N, Caglar ES, Arpa MD, Karasulu HY. Preparation and evaluation of novel microemulsion-based hydrogels for dermal delivery of benzocaine. Pharm Dev Technol. (2017); 22(4): 500-510. https://doi.org/10.3109/10837450.2015.1131716
31. [32] Li X, Nie SF, Kong J, Li N, Ju CY, Pan W. A controlled-release ocular delivery system for ibuprofen based on nanostructured lipid carriers. Int J Pharm. (2008); 363(1-2): 177-182. https://doi.org/10.1016/j.ijpharm.2008.07.017