Development of liposomal topical gel of bexarotene for effective management of cutaneous t-cell lymphoma: Formulation to preclinical assessment

Abstract

Background and Aims: The objective of this work was to formulate liposomal gel formulation of bexarotene for Cutaneous T-cell Lymphoma (CTCL). Low solubility and high log P value make the drug a poor candidate for its penetrability and absorp- tion through the transdermal route. When bexarotene is incorporated into liposomal formulation, its solubility and perme- ability can enhance. Methods: In the present investigation, the liposomes of bexarotene were prepared by thin film-hydration method and opti- mized for different critical processing parameters such as the amount of lipid and the time of stirring. Checkpoint batches were prepared to validate the mathematical model. Results: The final optimized liposome formulation, which has more than 85% entrapment efficiency and vesicle size of 625 nm, was prepared. The optimized liposomes were loaded (equivalent to 1% w/w bexarotene) into the carbopol gel (1.5% w/w) and, evaluated for physico-chemical parameters. In vitro drug permeation and deposition of promised liposomal gel were performed through rat skin. The skin irritation studies of the liposomal gel were examined on rats, in vivo. MTT assay was performed to determine the cytotoxicity and cell apoptosis on CTCL specified cell line (Hut-78) by bexarotene liposomal gel. The optimized liposomes of bexarotene (FL1) were found to be spherical having a vesicle size of 639 nm with PDI 0.115 and a zeta potential value of -19.3 mV. The promised liposomal gel (LG5) evaluations were found in the limit. The LG5 was shown 31% bexarotene deposition in the skin. The experiment revealed a significant decrease (p<0.005) in the number of viable cells following MTT assay. Conclusion: The liposomal gel formulation of bexarotene improved the treatment and management of CTCL.

Keywords

• Bexarotene
• Liposome
• Topical Gel
• Lymphoma
• MTT assay
• UV skin irritation studies

References

1. Agarwal, R., Katare, O. P., & Vyas, S. P. (2001). Preparation and in- vitro evaluation of liposomal/niosomal delivery systems for an- tipsoriatic drug dithranol. International Journal of Pharmacy, 228 (1-2), 43–52. doi: 10.1016/s0378-5173(01)00810-9.
2. Akbari, A., Akbarzadeh, A., Tehrani, M. R., Cohan, R. A., Chiani, M., & Mehrabi, M. R. (2020). Development and characterization of nanoliposomal hydroxyurea against BT-474 breast cancer cells. Advanced Pharmaceutical Bulletin, 10(1), 39-45. doi: 10.15171/ apb.2020.005
3. Bavarsad, N., Kouchak, M., Mohamadipour, P., & Sadeghi-Nejad,
4. B. (2016). Preparation and physicochemical characterization of topical chitosan-based film containing griseofulvin-loaded liposomes. Journal of Advanced Pharmaceutical Technology & Re- search, 7(3), 91–98. doi: 10.4103/2231-4040.184591.
5. Bhatia, A., Bhushan, S., Singh, B., & Katare, O. P. (2009). Studies on tamoxifen encapsulated in lipid vesicles: Effect on the growth of human breast cancer MCF-7 cells. Journal of Liposome Research, 19(3),169-172. doi: 10.1080/08982100802518574.
6. Chen, L., Wang, Y., Zhang, J., Hao, L., Guo, H., … Lou, H. (2014). Bexarotene nanocrystal oral and parenteral formulation develop- ment, characterization and pharmacokinetic evaluation. Europe- an Journal of Pharmaceutics and Biopharmaceutics, 87(1),160-169. doi: 10.1016/j.ejpb.2013.12.005
7. Dicko, A., Kwak, S., Frazier, A. A., Mayer, L. D., & Liboiron, B. D. (2010). Biophysical characterization of a liposomal formulation of cyta- rabine and daunorubicin. International Journal of Pharmaceutics, 391(1-2),248–259. doi: 10.1016/j.ijpharm.2010.02.014
8. Fathalla, D., Youssef, E. M. K., Soliman, G. M. (2020). Liposomal and ethosomal gels for the topical delivery of anthralin: preparation, comparative evaluation and clinical assessment in psoriatic patients. Pharmaceutics, 12(5), 446-470. doi: 10.3390/pharmaceutics12050446

9. Garg, V., Singh, H., Bhatia, A., Raza, K., Singh, S. K., … Singh, B. (2017). Systematic development of transethosomal gel system of piroxicam: formulation optimization, in-vitro evaluation and ex vivo assessment. AAPS PharmSciTech, 18(1), 58-71. doi: 10.1208/s12249-016-0489-z
10. Hashemi, M., Karami-Tehrani, F., & Ghavami, S. (2004). Cytotoxicity effect of cladribine on the MCF-7 human breast cancer cell line. Iranian Biomedical Journal, 8(1), 7-12.
11. Jangde, R., & Singh, D. (2016). Preparation and optimization of quercetin-loaded liposomes for wound healing, using response surface methodology. Artificial Cells, Nanomedicine, and Biotech- nology, 44(2), 635–641. doi: 10.3109/21691401.2014.975238
12. Jewett, P.I., Lazovich, D., Wehelie, H., Boull, C., & Vogel, R. I. (2020). Sun exposure and protection behaviors in urban and rural long- term melanoma survivors. Archives of Dermatological Research 312(6), 413-420. doi: 10.1007/s00403-019-02023-7
13. Madan, J., Baruah, B., Nagaraju, M., Abdalla, M. O., Yates, C., … Turner, T. (2012). Molecular cycloencapsulation augments solu- bility and improves therapeutic index of brominated noscapine in prostate cancer cells. Molecular Pharmaceutics, 9(5), 1470-1480. doi: 10.1021/mp300063v.
14. Madan, J., Gundala, S. R., Baruah, B., Nagaraju, M., Yates, C., … Turn- er, T. (2014). Cyclodextrin complexes of reduced bromonoscapine in guar gum microspheres enhance colonic drug delivery. Molec- ular Pharmaceutics, 11(12), 4339-4349. doi: 10.1021/mp500408n.
15. Manosroi, A., Kongkaneramit, L., & Manosroi, J. (2004). Characterization of amphotericin B liposome formulations. Drug Development and In- dustrial Pharmacy, 30(5), 535–543. doi: 10.1081/DDC-120037484
16. Minh, H. P. T., Phuong, L. L., Thanh, H. N., Anh, S. H., & Thanh, T. B. (2015). Development and evaluation antitumor activity of PE- Gylated liposomal doxorubicin on tumor-bearing BALB/c-Foxn- 1nu mice model. Journal of Applied Pharmaceutical Science, 5(9), 001-006. doi:10.7324/JAPS.2015.50901
17. Olsen, E. A. (2015). Evaluation, diagnosis, and staging of cuta- neous lymphoma. Dermatologic Clinics, 33(4), 643–654. doi: 10.1016/j.det.2015.06.001
18. Priprem, A., Damrongrungruang, T., Limsitthichaikoon, S., Kham- paenjiraroch, B., Nukulkit, C., … Thapphasaraphong, S. (2018). Topical niosome gel containing an anthocyanin complex: a potential oral wound healing in rats. AAPS PharmSciTech, 19(4), 1681-1692. doi: 10.1208/s12249-018-0966-7
19. Raimondi, S., Suppa, M., & Gandini, S. (2020). Melanoma Epide- miology and Sun Exposure. Acta Dermato-Venereologica, 100(11), adv00136. doi: 10.2340/00015555-3491.
20. Saka R, Jain H, Kommineni N, Chella N, & Khan W. (2020). En- hanced penetration and improved therapeutic efficacy of bex- arotene via topical liposomal gel in imiquimod induced psoriatic plaque model in BALB/c mice. Journal of Drug Delivery Science and Technology, 58, 101691. doi: 10.1016/j.jddst.2020.101691
21. Sharma, N., & Verma, S. (2017). Current and future prospective of liposomes as drug delivery vehicles for the effective treatment of cancer. International Journal of Green Pharmacy, 11(3), S377-384. doi:10.22377/ijgp.v11i03.1145
22. Singh, B., Mehta. G., Kumar, R., Bhatia, A., Ahuja, N., & Katare, O. P. (2005). Design, development and optimization of nimesulide- loaded liposomal systems for topical application. Current Drug Delivery, 2(2),143-153. doi : 10.2174/1567201053585985
23. Surini, S., Leonyza, A., & Suh, C. W. (2020). Formulation and in-vitro penetration study of recombinant human epidermal growth factor-loaded transfersomal emulgel. Advanced Pharmaceutical Bulletin, 10(4), 586-594. doi: 10.34172/apb.2020.070.
24. Yu, J., Chen, Z., Yin, Y. Z., Tang, C., Hu, E., … Zheng, S. (2019). Improving Topical Skin delivery of monocrotaline via liposome gel- based nanosystems. Current Drug Delivery, 16(10), 940-950. doi: 10.2174/1567201816666191029125300.
25. Zinzani, P. L., Bonthapally, V., Huebner, D., Lutes, R., Chi, A., & Pileri, S. (2016). Panoptic clinical review of the current and future treat- ment of relapsed/refractory T-cell lymphomas: Cutaneous T-cell lymphomas. Critical Reviews in Oncology/Hematology, 99(6), 228– 240. doi: 10.1016/j.critrevonc.2015.12.018.