pH-sensitive chitosan/alginate core-shell nanoparticles for efficient and safe oral insulin delivery
Introduction
Sharp rise in prevalence of diabetes includes rapid population growth, aging, increase in obesity, physical inactivity and urbanization [1], [2] and finally reducing the quality of life. External insulin being the only effective treatment of diabetes demands success in terms of good patient compliance. Oral insulin is advantageous, with a very similar mechanism of action as of endogenous insulin enabling long-term glycemic control in diabetic patients [3], [4]. However, physicochemical barriers of gastrointestinal (GI) tract hampers the bioavailability of oral insulin [5]. Recently, polymeric nanoparticles have gained a lot of attention in oral insulin delivery [5] to improve insulin bioavailability in animal system without producing any systemic toxicity. Nanoparticles of both natural and synthetic biodegradable polymers, lipids and polysaccharides have been extensively studied over last few decades. Among them, chitosan (CS) and alginate (ALG) are most extensively studied in pharmaceutical research for controlled drug delivery. The CS, a linear polymer having (1-4)-linked 2-amino-2-deoxy-β-d-glucopyranose units on its structure, is a biodegradable, biocompatible, non-toxic and non-immunogenic mucoadhesive polymer, which offers certain advantages over other natural polymers in formulating nanoparticles for oral administration of drug molecules [6]. Cationic nature of CS (due to protonation of amine groups in acidic pH) facilitates effective encapsulation of biomolecules like proteins and drugs and prolongs the drug resident time in the GI tract [7]. Apart from the endowment of positive charge on the surfaces of nanoparticles, CS also elevates the contact time with intestinal epithelium enhancing permeation through tight junction of epithelial cells via paracellular transport [8]. Most importantly, CS is digested by chitosanase enzymes secreted by microorganisms at the intestine after oral ingestion [6].
ALG is another water-soluble natural linear polysaccharide, containing varying amounts of 1,4-linked β-d-mannuronic acid (M) and α-l-guluronic acid (G) residues, extracted from brown seaweed. It is a very popular pH-responsive polymer due to its shrinkage in lower pH [9], enabling encapsulated drug retention in the stomach while protecting it against enzymatic deactivation. Properties of biodegradability, biocompatibility, low toxicity, low immunogenicity and good mucoadhesion [10], [11] facilitate its application in oral drug delivery. Micro- or nanoparticles of ALG can be formed either by physical or chemical crosslinking for the sustained drug release. As some crosslinkers are toxic in nature, physical crosslinking is usually preferred over chemical crosslinking [12]. Calcium, a divalent cation used for crosslinking of ALG, is reported to maintain the biological efficiency of the drug molecules [13], [14]. Again, CS/ALG nanoparticles were reported to be efficient in protecting insulin from the aggressive environment of the stomach and sustained insulin release was observed under intestinal milieu [15]. Furthermore, pH-sensitive, mucoadhesive CS/ALG nanoparticles showed significant hypoglycemic effects in rat model too [16].
Therefore, the main objective of our present investigation is to develop insulin-loaded core-shell CS/ALG nanoparticles with comparatively smaller size than those reported previously [15] to improve the insulin bioavailability after its oral administration. In the earlier report [15], no in vivo systemic toxicity was studied after oral delivery of insulin through these CS/ALG nanoparticles. In the present article, all these systemic toxicity were studied in detail in mice model.
Section snippets
Materials
CS having MW of 365 and 222 kDa and the degree of deacetylation (DDA) of 86% was obtained from Himedia, India. Sodium nitrite, glacial acetic acid and tris(hydroxymethyl)aminomethane were purchased from Merck, India. Low-viscosity, low-G (α-l-guluronic acid) ALG (β-d-mannuronic acid (M)/α-l-guluronic acid (G) content 64.5%/35.5%) was purchased from Loba Chemie, India. The molecular weight of alginate is 1.03 × 105 g/mol. Alloxan monohydrate and insulin (Bovine insulin, 27USP units per mg) was
Results and discussion
The molecular weight and the degree of deacetylation (DDA) of CS and depolymerized CS are shown in Table 1. It is noticed that the molecular weight of CS and the β-d-mannuronic acid (M) and α-l-guluronic acid (G) ratio of ALG played a pivotal role in controlling the physical properties of the nanoparticles and also influenced the conditions of interaction between the polymers and insulin during the nanoparticle formation [15].
Conclusions
The present investigation concludes a successful preparation and characterization of insulin-loaded CS/ALG nanoparticles in in vitro and in vivo systems. These spherical nanoparticles showed excellent insulin encapsulation capacity with pH-sensitive sustained release of insulin. Furthermore, in vivo experiments indicated significant intestinal absorption of insulin, showing pronounced hypoglycemic effects with improved insulin bioavailability in diabetic mice. The acute toxicity study
Acknowledgement
We are highly grateful to the Department of Science and Technology, Government of West Bengal, for their financial support for this work and the project entitled ‘Synthesis of derivatives of chitosan and their IPNs for oral insulin delivery’ (Sanction No. 428 (sanc.)/ST/P/S&T/2G-7/2011).
References (29)
- et al.
Lancet
(2010) - et al.
J. Control. Rel.
(2006) - et al.
Int. J. Pharm.
(2001) - et al.
Prog. Polym. Sci.
(2012) - et al.
Biomaterials
(2005) - et al.
J. Control. Rel.
(2006) - et al.
Biomaterials
(1996) - et al.
Biomaterials
(2005) - et al.
Mater. Sci. Eng. C
(2013) - et al.
J. Pharm. Sci.
(1993)
J. Control. Rel.
Carbohydr. Polym.
Int. J. Pharm.
J. Saudi Chem. Soc.
Cited by (252)
Chitosan and sodium alginate nanocarrier system: Controlling the release of rapeseed-derived peptides and improving their therapeutic efficiency of anti-diabetes
2024, International Journal of Biological MacromoleculesOral peptide therapeutics for diabetes treatment: State-of-the-art and future perspectives
2024, Acta Pharmaceutica Sinica BInjectable systems for long-lasting insulin therapy
2023, Advanced Drug Delivery ReviewsAlginate/chitosan/diallyl disulfide nanoparticles: Synthesis, characterization and their anti-inflammatory efficacy on TPA-induced acute mouse ear inflammation
2023, Carbohydrate Polymer Technologies and Applications