Sains Malaysiana 50(6)(2021): 1755-1765

http://doi.org/10.17576/jsm-2021-5006-21

Physicochemical Properties and Glucose-Lowering Effect of an Insulin - Aloe vera Buccal Delivery System

(Sifat Fizikokimia dan Kesan Penurunan Glukosa daripada Sistem Penghantaran Bukal Insulin - Aloe vera)

HENG HUAY CHIN¹, KHURRAM REHMAN³, PEI-YUEN NG^1,4 & MOHD HANIF ZULFAKAR^1,2*

¹Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 53000 Kuala Lumpur, Federal Territory, Malaysia

²Centre for Drug Delivery Technology, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 53000 Kuala Lumpur, Federal Territory, Malaysia

³Department of Pharmacy, Forman Christian College, Ferozpur Road, 54600, Lahore, Pakistan

⁴Centre for Drug & Herbal Development, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 53000 Kuala Lumpur, Federal Territory, Malaysia

Received: 13 October 2020/Accepted: 5 November 2020

ABSTRACT

Subcutaneous insulin injection is one of the therapies in the treatment of diabetes mellitus. However, problems such as pain at the injection site and lipodystrophy present a challenge that will influence patient compliance. This study aims to develop and characterise buccal film formulations containing insulin, utilising the glucose-lowering and pharmaceutical properties of Aloe vera. Characterisation tests such as morphology, rheological measurement, pH value, mechanical properties, and permeation test were performed on the optimal formulation. Assessment of the glucose-lowering efficacy was performed using alloxan-induced diabetic rabbits. Composition of the final film formulation included 3% w/w sodium carboxymethyl cellulose, 40% v/v glycerol, 70% v/v Aloe vera, 0.5% w/v mannitol, 0.125% w/v aspartame, 0.125% v/v Tween 80 and 15.3 mg insulin. The drug content has been determined to be 56.77 ± 8.55%. The formulation shows a low variation in weight and thickness measurements and acceptable physicochemical properties, in addition to sustained drug release for 6 h. The final film formulation that combined insulin and Aloe vera was effective enough to reduce blood glucose levels compared to the negative control (p > 0.05), despite fluctuation in the blood glucose levels throughout the study, and did not show any enhancement in reduction compared to the insulin-only film. In conclusion, the developed buccal film formulation has the potential to be used as a vessel for the delivery of insulin. Nevertheless, further studies are required to ensure the stability of the insulin via buccal route and stabilisation of insulin within the formulation.

Keywords: Aloe vera; buccal drug delivery; diabetes; insulin

ABSTRAK

Suntikan subkutaneus insulin merupakan salah satu terapi untuk rawatan diabetes melitus. Namun begitu, masalah berkaitan penyuntikan seperti sakit pada tempat suntikan dan lipodistrofi menjadi satu cabaran yang akan mempengaruhi pematuhan pesakit. Tujuan kajian ini adalah untuk membangun dan mencirikan formulasi filem bukal yang mengandungi insulin, memanfaatkan kesan penurunan aras glukos dan ciri farmaseutik Aloe vera. Pencirian seperti morfologi, pengukuran reologi, nilai pH, sifat mekanik dan ujian penembusan dijalankan pada formulasi filem optimum. Penilaian kadar penurunan glukosa darah dijalankan dengan menggunakan model arnab yang diaruh aloksan sebagai model untuk diabetes. Komposisi filem bukal terpilih terdiri daripada 3% b/b SCMC, 40% i/i gliserol, 70% i/i gel Aloe vera, 0.5% b/i manitol, 0.125% b/i aspartam, 0.125% i/i polisorbat 80 dan 15.3 mg insulin. Peratus kandungan insulin adalah 56.77 ± 8.55%.  Formulasi ini menunjukkan variasi berat dan ketebalan filem yang rendah dan sifat fizikokimia yang memuaskan, di samping menunjukkan pelepasan dadah secara tertahan untuk tempoh enam jam. Filem terpilih yang menggabungkan insulin dan Aloe vera didapati berkesan dalam mengurangkan aras glukosa darah arnab berbanding kumpulan kawalan negatif (p >0.05), sungguhpun berlaku turun naik aras glukosa sepanjang tempoh kajian dan tidak menunjukkan penurunan dipertingkat berbanding filem insulin. Kesimpulannya, filem bukal yang dibangunkan mempunyai potensi untuk digunakan sebagai jasad penghantar insulin. Namun yang demikian, kajian lanjut diperlukan untuk menentukan kestabilan insulin yang dihantar melalui tapakjalan ini dan penstabilan insulin di dalam formulasi yang dibangunkan.

Kata kunci: Aloe vera; diabetes; insulin; penghantaran bukal dadah

REFERENCES

Abo-Youssef, A.M.H. & Messiha, B.A.S. 2013. Beneficial effects of Aloe vera in treatment of diabetes: Comparative in vivo and in vitro studies. Bulletin of Faculty of Pharmacy, Cairo University 51(1): 7-11.

Abruzzo, A., Bigucci, F., Cerchiara, T., Cruciani, F., Vitali, B. & Luppi B. 2012. Mucoadhesive chitosan/gelatin films for buccal delivery of propranolol hydrochloride. Carbohydrate Polymers 87(1): 581-588.

Ahmad, N., Mohd Amin, M.C.I., Ismail, I. & Buang, F. 2016. Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles. Expert Opinion on Drug Delivery 13(5): 621-632.

Ahmad, N., Amin, M.C.I.M., Mahali, S.M., Ismail, I. & Chuang, V.T.G. 2014. Biocompatible and mucoadhesive bacterial cellulose-g-poly(acrylic acid) hydrogels for oral protein delivery. Molecular Pharmaceutics 11(11): 4130-4142.

Ajabnoor, M.A. 1990. Effect of aloes on blood glucose levels in normal and alloxan diabetic mice. Journal of Ethnopharmacology 28(2): 215-220.

Alibolandi, M., Alabdollah, F., Sadeghi, F., Mohammadi, M., Abnous, K., Ramezani, M. &  Hadizadeh, F. 2016. Dextran-b-poly(lactide-co-glycolide) polymersome for oral delivery of insulin: in vitro and in vivo evaluation. Journal of Controlled Release 227: 58-70.

Baligar, S., Muglikar, S. & Kale, R. 2013. Salivary pH: A diagnostic biomarker. Journal of Indian Society of Periodontology 17(4): 461-465.

Behra, J.S., Mattsson, J., Cayre, O.J., Robles, E.S., Tang, H. & Hunter, T.N. 2019. Characterization of sodium carboxymethyl cellulose aqueous solutions to support complex product formulation: A rheology and light scattering study. ACS Applied Polymer Materials 1(3): 344-358.

Boudreau,  M.D. &  Beland, F.A. 2006. An evaluation of the biological and toxicological properties of Aloe barbadensis(Miller), Aloe vera. Journal of Environmental Science and Health, Part C Environmental Carcinogenesis and Ecotoxicology Review 24(1): 103-54.

Can, A., Akev, N., Ozsoy, N., Bolkent, S., Arda, B.P., Yanardag, R. & Okyar, A. 2004. Effect of Aloe veraleaf gel and pulp extracts on the liver in type-II diabetic rat models. Biological & Pharmaceutical Bulletin 27(5): 694-698.

Choi, S. & Chung, M.H.A. 2003. A review on the relationship between Aloe vera components and their biologic effects. Seminars in Integrative Medicine 1(1): 53-62.

Dixit, R.P. & Puthli, S.P. 2009. Oral strip technology: Overview and future potential. Journal of Controlled Release 139(2): 94-107.

Fonte, P., Araújo, F., Silva, C., Pereira, C., Reis, S., Santos, H.A. & Sarmento, B. 2015. Polymer-based nanoparticles for oral insulin delivery: Revisited approaches. Biotechnology Advances 33(6): 1342-1354.

Hussain, Z., Katas, H., Amin, M.C.I.M., Kumulosasi, E. & Sahudin, S. 2013. Antidermatitic perspective of hydrocortisone as chitosan nanocarriers: An ex vivo and in vivo assessment using an NC/Nga mouse model. Journal of Pharmaceutical Sciences 102(3): 1063-1075.

International Diabetes Foundation. 2019. Diabetes Atlas. http://www.worlddiabetesfoundation.org. Accessed on 30 August 2020.

Ismail, R. & Csóka, I. 2017. Novel strategies in the oral delivery of antidiabetic peptide drugs - Insulin, GLP 1 and its analogs. European Journal of Pharmaceutics and Biopharmaceutics 115: 257-267.

Koner, J.S., Rajabi-Siahboomi, A., Bowen, J., Perrie, Y., Kirby, D. & Mohammed, A.R.A. 2015. Holistic multi evidence approach to study the fragmentation behaviour of crystalline mannitol. Scientific Reports 5(1): 1-12.

Lopez, C.G., Rogers, S.E., Colby, R.H., Graham, P. & Cabral, J.T. 2015. Structure of sodium carboxymethyl cellulose aqueous solutions: A sans and rheology study. Journal of Polymer Science Part B: Polymer Physics 53(7): 492-501.

Wasilewska, K. & Winnicka, K. 2019. How to assess orodispersible film quality? A review of applied methods and their modifications. Acta Pharmaceutica 69(2): 155-176.

Xu, H., Huang, K., Zhu, Y., Gao, Q., Wu, Q., Tian, W., Sheng, Xi., Chen,  Z. & Gao, Z. 2002. Hypoglycaemic effect of a novel insulin buccal formulation on rabbits. Pharmacological Research 46(5): 459-467.

Xu, Y.,  Zhang, X.,  Wang,  N., Pei, X., Guo, Y., Wang, J.,  Barth, S.,  Yu, F.,  Lee, S.J.,  He, H. & Yang, V.C. 2020. Cell-penetrating peptide enhanced insulin buccal absorption. International Journal of Pharmaceutics 584(119469): 1-9.

Zulfakar, M.H., Ng, P.Y. & Heng, H.C. 2018. Pharmaceutical applications of Aloe vera. Indonesian Journal of Pharmacy 29(3): 101-116.

Zulfakar, M.H., Goh, J.Y. & Rehman, K. 2016. Development and mechanical characterization of eugenol-cetalkonium chloride sustained release mucoadhesive oral film. Polymer Composites 37(11): 3200-3209.

*Corresponding author; email: hanifzulfakar@ukm.edu.my