International Journal of Drug Delivery Technology
Volume 14, Issue 3

Design Strategies for Improving Oral Bioavailability of Tizanidine: Solid Dispersion Approach

Manisha Saini1, Suresh Kumar1,2*, Vikas Jhawat1, Rameshwar Dass3

1Department of Pharmacy, School of Healthcare and Allied Sciences, GD Goenka University, Gurugram, Haryana, India.

2School of Pharmacy, Pragjyotishpur University, Guwahati, Assam, India.

3Guru Gobind Singh College of Pharmacy, Yamunanagar, Haryana, India. 

Received: 20th February, 2024; Revised: 27th March, 2024; Accepted: 15th August, 2024; Available Online: 25th September, 2024 

ABSTRACT

Tizanidine is a poorly soluble drug that helps relax muscles and lower mild blood pressure. Solid dispersion of tinidazole may improve the solubility of the drug. The method involved mixing tizanidine with Soluplus in different amounts using a simple tumbling method for 15 minutes. The mixtures were then stored in a desiccator. These mixtures, in different ratios (5:5, 4:6, 3:7, 2:8), were dissolved in ethanol. Tablets were made using a tablet machine with direct compression. The tablets were tested for thickness, breakability, hardness, drug content, disintegration time, wetting time, how fast the drug was released, and stability. The optimized batch (F9) showed that the drug followed a steady release pattern, with an R2 value of 0.984. Stability studies, done under specific conditions (40°C ± 2°C/75% ± 5%RH), showed no chemical or physical changes and no noteworthy drop in drug content. The pharmacokinetic study revealed that the height concentration (Cmax) was 97.53 ng/ mL, and the drug’s half-life was 1.75 hours. The formulation was optimized using a design that tested different combinations of two factors: the amount of crospovidone (superdisintegrant) and camphor (subliming agent). The goal was to improve disintegration time and friability.

Keywords: Tizanidine, Solid dispersion, Soluplus, Antihypertensive, Pharmacokinetic profile, Dissolution kinetics. International Journal of Drug Delivery Technology (2024); DOI: 10.25258/ijddt.14.3.65

How to cite this article: Saini M, Kumar S, Jhawat V, Dass R. Design Strategies for Improving Oral Bioavailability of Tizanidine: Solid Dispersion Approach. International Journal of Drug Delivery Technology. 2024;14(3):1708-1715.

REFERENCES

  1. Leiphart JW, Dills CV, Levy RM. Alpha-2-adrenergic receptor subtype specificity of intrathecally administered tizanidine used for analgesia for neuropathic pain. J of Neurosurgery. 2004;101(4):641-7. org/10.3171/jns.2004.101.4.0641
  2. Zhu LL, Wang YH, Zhou Tizanidine: Advances in pharmacology & therapeutics and drug formulations. Journal of Pain Research. 2024;1257-71. Doi.org/10.2147/JPR.S461032.
  3. Mohsen AM, El-Hashemy HA, Salama A, Darwish AB. Formulation of tizanidine hydrochloride–loaded pro vesicular system for improved oral delivery and therapeutic activity employing a 23 full factorial Drug Delivery Translational Research. 2023;13(2):580-92. Doi.org/10.1007/s13346-022-01217-3
  4. Sinha S, Thapa S, Singh S, Dutt R, Verma R, Pandey P, Mittal V, Rahman MH, Kaushik D. Development of biocompatible nanoparticles of tizanidine hydrochloride in orodispersible films: In-vitro characterization, Ex-vivo permeation, and cytotoxic study on carcinoma Current Drug Delivery. 2022;19(10):1061-72. Doi.org/10.2174/1567201819666220321111338
  5. Malanga G, Reiter RD, Garay Update on tizanidine for muscle spasticity and emerging indications. Expert Opinion on Pharmacotherapy. 2008;9(12):2209-15. Doi. org/10.1517/14656566.9.12.2209
  6. Pardhi E, Vasave R, Srivastava V, Yadav R, Mehra NK. Nanocrystals technologies in biomedical science: Bench to beside the Drug Discovery Today. 2024:103913. Doi.org/10.1016/j. drudis.2024.103913
  7. Kumar N, Dureja H, Chandra Enhancement of drug dissolution of erlotinib tablets by micronization technique using pharmaceutical experimental design. Journal of Pharmaceutical Research International. 2021;33(51):70-8. Doi.org/10.9734/ jpri/2021/v33i51A33470
  8. Semalty A. Cyclodextrin and phospholipid complexation in solubility and dissolution enhancement: a critical and meta- Expert Opinion on Drug Delivery. 2014;11(8):1255-72. Doi.org/10.1517/17425247.2014.916271
  9. Bhalani DV, Nutan B, Kumar A, Singh Bioavailabilityenhancement techniques for poorly aqueous soluble drugs and therapeutics. Biomedicines 2022;10(9):2055. Doi.org/10.3390/ biomedicines10092055
  10. Serajuddin AT. Salt formation to improve drug solubility. Adv Drug Delivery 2007;59(7): 603-16. Doi.org/10.1016/j. addr.2007.05.010
  11. Hermans A, Milsmann J, Li H, Jede C, Moir A, Hens B, Morgado J, Wu T, Cohen M. Challenges and strategies for solubility measurements and dissolution method development for amorphous solid dispersion AAPSJ. 2022;25(1):11. Doi.org/10.1208/s12248-022-00760-8
  12. Nakkala RK, Maddiboyina B, Bolisetti SC, Roy H. Duloxetine hydrochloride enteric-coated pellets in capsules with delayed release: formulation and Smart Sci. 2023;11(3):434-Doi.org/10.1080/23080477.2023.2191496
  13. Pandi P, Bulusu R, Kommineni N, Khan W, Singh Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations and marketed products. Intenational Journal of Pharmaceutics. 2020;586:119560. Doi.org/10.1016/j.ijpharm.2020.119560
  14. Maddiboyina B, Nakkala RK, Kokkilagadda VK. Preparation and evaluation of esomeprazole enteric coated tablets. IJPPR. 2020;18(1):16–30.
  15. Zhang X, Xing H, Zhao Y, Ma Z. Pharmaceutical dispersion techniques for dissolution and bioavailability enhancement of poorly water-soluble Pharmaceutics. 2018; 10(3):74. Doi. org/10.3390/pharmaceutics10030074
  16. Sood S, Maddiboyina B, Rawat P, Garg AK, Foudah AI, Alam A, Aldawsari HM, Riadi Y, Singh S, Kesharwani P. Enhancing the solubility of nitazoxanide with solid dispersions technique: formulation, evaluation, and cytotoxicity J Biomater Sci Polym Ed. 2021 Mar;32(4):477-87. Doi: 10.1080/09205063.2020.1844506
  17. Wang X, Zhang L, Ma D, Tang X, Zhang Y, Yin T, Gou J, Wang Y, He H. Characterizing and exploring the differences in dissolution and stability between crystalline solid dispersion and amorphous solid dispersion. AAPS PharmSciTech. 2020; 21:1-15. org/10.1208/s12249-020-01802-0Maddiboyina B, Jhawat V, Nakkala RK, Desu PK, Gandhi
  18. Design expert assisted formulation, characterization and optimization of microemulsion based solid lipid nanoparticles of repaglinide. Prog Biomater. 2021;10(4):309-20. DOI: 10.1007/ s40204-021-00174-3
  19. Giri BR, Kwon J, Vo AQ, Bhagurkar AM, Bandari S, Kim Hot-melt extruded amorphous solid dispersion for solubility, stability, and bioavailability enhancement of telmisartan. Pharmaceuticals. 2021;14(1):73. Doi.org/10.3390/ph14010073
  20. Sharma U, Saroha KA. Review of hydrotropic solubilization techniques for enhancing the bioavailability of poorly soluble drugs. International Journal of Toxicology. 2024;43(1):63-71. org/10.1177/10915818231216414
  21. Vasam M, Maddiboyina B, Talluri C, et al. Formulation, characterization, and Taguchi design study of eplerenone lipid- based solid dispersions integrated with Gelucire. BioNanoSci. 2023;13:576–587. Doi.org/10.1007/s12668-023-01102-4
  22. Ainurofiq A, Putro DS, Ramadhani DA, Putra GM, Santo LD. A review on solubility enhancement methods for poorly water-soluble drugs. Journal of Pharmaceutical Sciences. 2021;10(1):137-47. Doi.org/10.4103/jrptps.JRPTPS_134_19
  23. Maddiboyina B, Nakkala RK, Sivaraman Biomass-derivedmesoporous carbon nanomaterials for drug delivery and imaging applications. In: Biomass‐Derived Carbon Mater. 2022. p. 129–46. Doi.org/10.1002/9783527832903.ch6
  24. Ghatmale R, Pathan VT. Formulation and evaluation of sublingual tablet of edoxaban by solid dispersion method. International Journal of Pharmaceutical Sciences Review and Research. 2023;1(2):115-28. Doi.org/10.5281/zenodo.8019467
  25. Mohapatra D, Kumar DN, Shreya S, Pandey V, Dubey PK, Agrawal AK, Sahu AN. Quality by design-based development and optimization of fourth-generation ternary solid dispersion of standardized Piper longum extract for melanoma therapy. Drug Delivery Translational. Research. 2023;13(12):3094-31. org/10.1007/s13346-023-01375-y
  26. Sohn JS, Choi JS. Development and evaluation of febuxostat solid dispersion through screening Saudi Pharmaceutical Journal. 2023;31(9):101724. Doi.org/10.1016/j.jsps.2023.101724
  27. Maddiboyina B, Shanmugapriya J, Rasala S, Sivaraman G. In bioinspired nanomaterials: synthesis and emerging Materials Research Forum LLC. 2021;111:63-95. DOI: https://doi. org/10.21741/9781644901571-3
  28. Eisa AM, El-Megrab NA, El-Nahas HM. Formulation and evaluation of fast dissolving tablets of haloperidol solid dispersion. Saudi Pharmaceutical 2022;30(11):1589-02. Doi.org/10.1016/j.jsps.2022.09.002
  29. Roy, B. Maddiboyina, SA. Rahaman, PK. Singh, AK. Tripathi, SK. Srivastava, R. Chaubey, VK. Theendra, KR. Sankula, Implementation and effect estimation by Taguchi orthogonal array design for Metoprolol Sustained Release Tablets. Smart Sci., 11 (2023) 649–660. Doi.org/10.1080/23080477.2023.2236778
  30. Maddina BY, Asthana GS, Asthana A. A review of current scenario of spirulina drug delivery systems. World J Pharm 2016;4:86-9.
  31. Maddiboyina B, Jhawat V, Sivaraman G, Sunnapu O, Nakkala KR, Naik HM, Gulia M. Formulation development and characterization of controlled release core-in-cup matrix tablets of venlafaxine HCl. Curr Drug Ther. 2020;15(5):503-11. Doi.org/10.2174/1574885515666200331104440
  32. Attia MS, Elshahat A, Hamdy A, Fathi AM, Emad-Eldin M, Ghazy FES, Chopra H, Ibrahim Soluplus® as a solubilizing excipient for poorly water-soluble drugs: recent advances in formulation strategies and pharmaceutical product features. Journal of Drug Delivery Science and Technology. 2023:104519. Doi.org/10.1016/j.jddst.2023.104519
  33. Singh C, Yashwant, Gupta AK, Garg Formulation Development and Evaluation of Divalproex Sodium Extended-release Tablets. International Journal of Drug Delivery Technology. 2022;12(4):1769-1773.DOI: 10.25258/ijddt.12.4.46