Gastroretentive extended release of metformin from methacrylamide-g-gellan and tamarind seed gum composite matrix

Highlights

• The optimized tablet exhibited buoyancy lag time of 2.83 min.

• It showed to remain buoyant over a 10 h period.

• It exhibited significant mucoadhesion.

• The tablets showed to extend drug release over a period of 10 h.

• Dissolution similarity factor f₂ = 71.58.

Abstract

Formulation of a gastroretentive extended release tablet of metformin based on polymethacrylamide-g-gellan (Pmaa-g-GG)-tamarind seed gum (TSG) composite matrix is the main purpose of this study. Tablets were prepared employing wet granulation method taking amount of Pmaa-g-GG, TSG and NaHCO₃ (SBC, buoyancy contributor) as independent formulation variables. The tablets were then evaluated for in vitro drug release, buoyancy, ex vivo mucoadhesion, swelling and surface morphology. Compatibility between drug and excipients was checked by DSC, FTIR and XRD analysis. Buoyancy-lag-time, mucoadhesive strength, % drug release and release-rate constant were statistically analyzed using Design-Expert software (version 9.0.4.1) and the formulation was then numerically optimized to obtain USP-reference release profile. The optimized formulation showed excellent buoyancy over a 10 h period with buoyancy lag time of 2.76 min, significant mucoadhesion and drug release over a period of 10 h with f₂ = 71.58. Kinetic modeling unveiled anomalous non-Fickian transport based drug release mechanism.

Introduction

Metformin HCl (MFH) is an orally administered biguanide widely used in the management of type-2 diabetes. It is slowly and incompletely absorbed from the stomach and proximal small intestine. The absolute bioavailability is reported to be 50–60% with relatively short plasma elimination half-life of approximately 2 h (Pentikainen, Neuvonen, & Penttila, 1979). This has raised the interest in developing extended-release formulations of metformin (Vijan, Kaity, Biswas, Isaac, & Ghosh, 2012). A significant problem associated with extended release device is that after a short gastric transit period of less than 6 h, the device leaves the upper gastrointestinal tract and the drug release occurs in non-absorbing distal segments of the gastrointestinal tract resulting a short absorption phase accompanied by lesser bioavailability (Chavanpatil, Jain, Chaudhari, Shear, & Vavia, 2005). Therefore, due to its narrow absorption window, it would be beneficial to develop gastroretentive device through which the gastric residence could be prolonged to release the drug at the absorbing site in a controlled manner for the entire period of drug release from the extended release products to maximize the bioavailability as well as therapeutic benefit.

Use of various natural polysaccharides as rate modulator in extended release drug delivery device is a current trend because of their biocompatibility, low cost, free availability and biodegradability (Efentakis & Kouttis, 2001). Gellan, an anionic deacylated exocellular polysaccharide produced by a pure culture of Pseudomonas elodea with a tetrasaccharide repeating unit of one α-l-rhamnose, one β-d-glucuronic acid and two β-d-glucose residues, has been used in several types of dosage forms such as stomach-specific controlled release beads (Narkar, Sher, & Pawar, 2010), interpenetrating hydrogel microsphere (Agnihotri & Aminabhavi, 2005), etc. However, rapid solubility in water, substantial swelling and rapid erosion of gellan are some of the limitations to make it an ideal matrix material for extended release. One of the powerful methods to modify the various physical, chemical and functional properties of polysaccharides is graft co-polymerization in which polymers are grafted onto polysaccharides backbone. Graft co-polymerization introduces hydrophobicity and steric bulkiness which considerably protect the matrix and carbohydrate backbone from rapid dissolution and erosion, and provides extended release of drugs. Recently, we have reported synthesis and characterization of methacrylamide grafted gellan (Nandi, Patra, Priyadarshini, Kaity, & Ghosh, 2015), which possesses significant hydrophobicity and capacity to form a rigid erosion proof matrix. However, the matrix is less continuous due to poor gelation. On the other hand, native natural hydrophilic polysaccharides are capable of forming intensively continuous matrix due to high degree of swelling that ensures drug release in more sustained manner but advance erosion is their main limiting factor. Incorporation of natural hydrophilic polysaccharide into hydrophobic matrix of graft-copolymer is another approach to improve desired functional properties like swelling, drug release kinetic and stability (Ahuja, Yadav, & Kumar, 2010). The composite matrix resulted from intimate physical blending of hydrophobic graft-copolymer and hydrophilic natural gum yields a continuous soft erosion proof hydrated matrix after absorbing water from gastrointestinal fluid, followed by extended drug release over a significantly long period of time.

Tamarind seed gum (TSG) is an excellent natural hydrophilic polysaccharide obtained from the endosperm of Tamarindus indica Linn; family Leguminosae (Gidley et al., 1991). It is widely used as a thickening, emulsifying, mucoadhesive and gelling agent in various pharmaceutical formulations due to possessing of high thermal and chemical stability, non-carcinogenicity, biocompatibility, mucoadhesivity and non-toxicity (Nayak, Pal, & Santra, 2014). Numerous oral sustained release gastroretentive drug delivery systems viz., buoyant systems (Nayak, Pal, & Malakar, 2013), mucoadhesive systems (Pal & Nayak, 2012), expandable or swellable systems (Klausner, Lavy, Friedman, & Hoffman, 2003), etc. have been reported. Recently, the combined floatation–mucoadhesion approaches for gastroretention have gained importance as these devices exhibit a better gastroretention by virtue of their buoyancy and bio-adhesion properties (Malakar & Nayak, 2013). SBC has been widely reported as buoyancy contributor in different buoyant systems (Fukuda, Peppas, & McGinity, 2006). Further, TSG has been reported as excellent natural mucoadhesive (Nayak et al., 2014). Therefore, incorporation of TSG in the matrix of polymethacrylamide-g-gellan would impart sustained release as well as mucoadhesion property which can be combined with buoyancy to achieve better gastroretention.

In our present attempt, a novel buoyant-mucoadhesive extended release tablet formulation of metformin based on a hydrophobic polymethacrylamide-g-gellan copolymer and hydrophilic TSG composite matrix has been developed, which is not reported earlier. In this study, SBC and TSG have been used as buoyancy contributor and release modulator-cum-mucoadhesive, respectively. A 2³ full factorial design was adopted to evaluate the influence of independent factors on the responses using Design-Expert software (version 9.0.4.1, Stat-Ease Inc., Minneapolis, USA). Tablets were evaluated for in vitro drug release, buoyancy, ex vivo mucoadhesion, swelling kinetic and surface morphology. Finally, the formulation was numerically optimized.