Ispaghula mucilage-gellan mucoadhesive beads of metformin HCl: Development by response surface methodology
Introduction
Gellan gum (GG) is an anionic polysaccharide, produced as fermentation product by pure culture of Psedomonus eloda (Vijan et al., 2012, Ahuja et al., 2010). It is composed of the tetrasaccharide, (1 → 4)-l-rhamnose-α (1 → 3)-d-glucose-β-(1 → 4)-d-glucorunic acid-β-(1 → 4)-d-glucose as a repeating unit in the molar ratio of 2:1:1 (Emeje et al., 2010, Jana et al., 2013). It undergoes ionotropic-gelation in the presence of di- or tri-valent metal cations. The mechanism of ionotropic-gelation property of GG in presence of multivalent metal cations involves the formation of double helical junction zones followed by aggregation of double helical segments to form three-dimensional network by complexation with multivalent metal cations and hydrogen bonding with water (Hamcerencu, Desbrieres, Khoukh, Popa, & Riess, 2008). They have been used in the formulation of multiple-unit particulates like microspheres, beads, etc. (Babu et al., 2010, Narker et al., 2010, Maiti et al., 2011). They are found stable in the stomach pH (acidic) than intestinal pH (alkaline) due to comparatively rapid swelling in alkaline pH than acidic pH (Babu et al., 2010). In the intestinal environment, where the concentration of monovalent ions (e.g., Na+, K+) is higher and exceeds the concentration of multivalent metal cations (e.g., Ca2+, Al3+). Therefore, these ionotropic-gels tend to lose their stability over the term due to diffusion leading to exchange of multivalent metal cations for monovalent ones, which results faster and premature release of encapsulated drugs from ionotropically-gelled GG particulates in intestinal pH. Moreover, the drug encapsulation in these systems is low. To overcome these limitations, modifications of ionotropically-gelled GG-based particulates have been investigated (Maiti et al., 2011, Kulkarni et al., 2011, Kulkarni et al., 2013). Blending of other natural polymers with GG in the development of ionotropically-gelled GG-based particulates for drug delivery was also reported (Ahuja et al., 2010, Prajapati et al., 2013, Nayak et al., 2014b). However, development of ionotropically-gelled GG-based beads made of GG and ispaghula (Plantago ovata F.) husk mucilage (IHM) blends for controlled drug release is not reported till date.
IHM is hydrophilic in nature, which contains a high amount of highly branched neutral arabinoxylan and non-reducing terminal sugar residues (Nayak, Pal, & Santra, 2013c). It is widely used as excipients in various drug delivery applications (Prajapati et al., 2006, Singh, 2007, Shirsand et al., 2009, Deveswaran et al., 2010, Nayak et al., 2013c). Our research group has already reported the utility of isolated IHM as mucoadhesive polymer-blend with sodium alginate in the development of mucoadhesive beads through ionotropic-gelation technique (Nayak et al., 2013c). In the current study, we made an attempt to develop metformin HCl-loaded mucoadhesive beads for oral use using IHM-GG polymer-blend through ionotropic-gelation.
Metformin HCl is an orally administered biguanide, which is widely used in the management of non-insulin dependent diabetes mellitus (type-II) (Basak et al., 2008, Boldhane and Kuchekar, 2009). Its biological half-life is 1.5–1.6 h (Nayak, Pal, Pradhan, & Hasnain, 2013b). It shows dose-dependent and saturable transport with absorption window in the upper intestine (Kumar & Ahuja, 2012). Its bioavailability is reported to be improved by gastric-retention (Sharma & Bhattyacharya, 2008). Therefore, it would be valuable to develop mucoadhesive beads of metformin HCl using IHM-GG blend, which might facilitate mucoadhesion on the mucous membrane. As a result of this, the gastric residence of the developed beads could be prolonged to release the encapsulated metformin HCl at a controlled manner over a longer period to maximize the therapeutic benefit.
The successful development of pharmaceutical formulations requires careful consideration of a number of formulation parameters influencing the performance of the formulation. Many experiments fail their purpose because they are not properly thought out or designed and even the best data analysis cannot compensate for a lack of planning (Nayak et al., 2013c). The statistical experimental design allows simultaneous investigation of the effects of several process variables, as well as their actual significance on the considered response and possible inter-relationship among them, giving maximum information with the fewest number of trial experiments (Shah and Pathak, 2010, Malakar and Nayak, 2012, Guru et al., 2013). For this purpose, optimization by response surface methodology (RSM) utilizing polynomial equations has been widely used (Ahuja et al., 2010, Nayak and Pal, 2011). The RSM is used to understand a model as fully as possible the effect of factors and their levels, over the whole of the experimental domain, and to predict the response inside the domain (Nayak, Pal, & Das, 2013a). This methodology requires minimum experimentation and time, thus providing to be far more effective and also cost-effective than the conventional methods of optimization (Malakar, Nayak, & Pal, 2012). Therefore, a computer-aided optimization method using RSM based on 32 factorial (2 factors and 3 levels) design was employed to investigate the effects of two independent variables (factors), i.e., polymer-blend ratio (GG to IHM ratio) and cross-linker (CaCl2) concentration on the properties of ionotropically-gelled IHM-GG mucoadhesive beads containing metformin HCl relating to drug encapsulation and drug release. Swelling and mucoadhesion behaviors of the optimized beads in different physiological pH were studied and analyzed. Furthermore, the pharmacodynamic activity of the optimized beads was assessed in alloxan-induced diabetic rats.
Section snippets
Materials
Metformin HCl (Abhilash Chemicals Pvt. Ltd., India), deacetylated gellan gum (GG) (SRL India Ltd., India), calcium chloride (Merck Ltd., India) were used. IHM was isolated from ispaghula (Plantago ovata F.) husk (Shree Baidyanath Ayurved Bhawan Pvt. Ltd., India). The procedure of IHM isolation has been described in previously published paper by our research group (Nayak et al., 2013c). All other chemicals and reagents were commercially available and of analytical grade.
Preparation of ionotropically-gelled IHM-GG beads containing metformin HCl
The ionotropically-gelled
Optimization of ionotropically-gelled IHM-GG beads containing metformin HCl
According to the trial plan of the 32 factorial design, 9 trial formulations of IHM-GG beads containing metformin HCl were prepared through Ca2+-ion induced ionic gelation technique. Overview of matrix of the design including two independent variables (factors) (i.e., GG to IHM ratio, X1 and concentration of CaCl2 as cross-linker, X2) investigated responses (i.e., DEE and R10h) is presented in Table 1. The values of investigated responses measured for all trial formulations were fitted in the 32
Conclusion
IHM-GG mucoadhesive beads containing metformin HCl for oral drug delivery was developed through Ca2+-ion cross-linked ionotropic-gelation technique and optimized by response surface methodology based on 32 factorial design. The optimized ionotropically-gelled IHM-GG beads containing metformin HCl demonstrated high drug encapsulation efficiency, good mucoadhesivity with the goat intestinal mucosal membrane, pH-dependent swelling and suitable controlled drug release pattern over prolonged period.
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