Research paper
Two galactomannans and scleroglucan as matrices for drug delivery: Preparation and release studies

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Abstract

Two galactomannans, Guar gum and Locust bean gum, have been used as matrices for tablets to study the release of model molecules. As a comparison, matrices obtained with another polysaccharide, Scleroglucan, have been tested. Despite the different conformations that the polymers assume in aqueous solution (flexible coils for Guar gum and Locust bean gum; triple helix for Scleroglucan), when prepared as tablets, they show (in distilled water and at 37 °C) very similar release profiles of guest molecules (i.e. theophylline, vitamin B12 and myoglobin) of different steric hindrance. Furthermore, the polymers were chemically crosslinked with glutaraldehyde to obtain a network suitable as a matrix for modified drug release. The delivery of the model molecules from the Guar gum and Locust bean gum gels, and from tablets prepared from the freeze-dried hydrogels of the three polymers was evaluated, and a comparison with the tablets prepared with the not-crosslinked polymers was carried out. Experimental data showed how the presence in the matrix of a well-defined network, by introducing a spacer among the macromolecular chains, always increased the rate of delivery of the tested molecules in comparison to the release profiles obtained when no crosslinker was present. Release data from the tablets were analyzed according to a mathematical model able to determine the relative importance of drug dissolution and drug diffusion on the overall release kinetics. Good agreement was found between the simulated and the experimental data.

Introduction

Galactomannans are neutral polysaccharides that occur in the endosperm of the seeds of leguminous plants. They consist of a β-(1  4)-d-mannose (M) backbone to which galactose (G) units are attached α-(1  6). The various galactomannans show a different mannose/galactose ratio, a different substitution pattern of side-chain units and different molecular weights [1], [2], [3], [4], [5]. In the present work two galactomannans, Guar gum (GG) and Locust bean gum (LBG) (Fig. 1b and c), have been considered for their possible use as matrices for modified drug delivery. Furthermore, another neutral polysaccharide, Scleroglucan [6], [7], [8] (Sclg) (Fig. 1a), has been tested and chosen for a comparison.

The primary structure of this last polymer exhibits a backbone built up by β-(1  3) linked β-d-glucopyranose (glcp) units with single glcp side chains linked β-(1  6) to every third residue in the main chain. GG has a mannose/galactose ratio (M/G) of about 2 while LBG has a M/G ratio of about 4; in aqueous solutions both polysaccharides assume a flexible coil conformation as it can be evidenced, for example, by the value of the Mark–Houwink–Sakurada exponent α = 0.74 ± 0.01 [9], [10]. On the other side Sclg, in aqueous solution, assumes a very stable triple helix conformation and, with a value of α = 1.7 [11], it represents one of the most stiff systems present in nature; accordingly, Sclg exhibits a rigid rod-behaviour in a wide range of pH and temperatures.

Furthermore, Sclg was extensively studied for its peculiar properties, notably rheological properties [12], and has been also proposed for biomedical applications [13], [14], [15], [16], [17]; and it is found, as viscousing agent, in some preparations for topical uses that are actually in the market.

Scleroglucan is also used in the oil industry, for food quality improvements, and in cosmetic formulations [18], [19], [20].

In the present work, the three polymers have been used as carriers for the delivery of three model molecules with different size, specifically theophylline (TPH), vitamin B12 (Vit. B12) and myoglobin (MGB). The release profiles in water from tablets prepared with GG, LBG and Sclg, loaded with the guest molecules, were evaluated. Crosslinked systems, obtained by crosslinking reactions of the mentioned polysaccharides with glutaraldehyde (Ga), were also studied (GG/Ga, LBG/Ga, and Sclg/Ga) [21], [22].

According to the chemical structure of the repeating units of GG and LBG and to the fact that the reaction of Ga occurs only with the vicinal diols, the network formed in the presence of GG will be more crosslinked than that obtained with LBG due to the fact that the degree of branching is higher in the former polymer. No direct comparison can be made for the Sclg that, though bearing vicinal diols, has a different repeating unit and in particular a different conformational state.

In fact, also from the macroscopic point of view, the macromolecular networks gave gels capable to maintain their shape in a “test-tube inverting method” (i.e., self-sustaining gels) [23] in the case of GG and LBG while, in the case of Sclg, only an increase in viscosity leading to a connectivity not extended to the whole sample (i.e., microgels) was obtained. For this reason the releases from the gels of the model molecules were studied only for the GG and LBG systems while the release of TPH and MGB was monitored for all the three crosslinked polymers after the preparation of tablets.

It is very important to study the behaviour of these systems as it is well-known that the polysaccharidic matrices can play an important role in the design of drug release formulations since the bioavailability of many drugs is deeply dependent on the performance of the carrier system [24], [25], [26].

It is therefore, very useful to know how, and to which extent, such type of matrices can be capable to modulate the release of guest molecules; in particular, in the present work, a comparison among the behaviours of matrices prepared with the plain polymers and those prepared after the crosslinking reaction is reported. Furthermore, the influence of the dimension of the model molecule on the release profiles has been evaluated; the influence of the different hydration, between gels and tablets, has also been considered.

Finally, release data have been studied by means of a recently developed semi-empirical mathematical model [27] aimed to yield some insight about the relative importance of the phenomena ruling release kinetics. In particular, this model assumes that tablet composition, drug dissolution and diffusion through the swelled polymer layer surrounding the tablet dry core, are key factors for the delivery process.

Section snippets

Materials

All polymers, Sclg, GG and LBG, were purchased from Carbomer (U.S.A.). Sclg was provided with a degree of polymerization DP = 800 (MW ∼1.5 × 106); GG had a molecular weight, MW ∼1.2 × 106; and LBG a MW ∼1.8 × 106.

TPH and Ga were Carlo Erba products (Italy), Vit. B12 and MGB were purchased from Fluka (Germany). All other products and reagents were of analytical grade. For the preparation of the samples distilled water was always used.

Polymer purification

A given amount of polymer (GG, LBG or Sclg) was dissolved in distilled

Water uptake experiments

In Fig. 2a water uptake of tablets prepared with only GG, LBG and with GG/Ga and LBG/Ga is reported. It is evident how the matrix prepared with only GG showed a lower swelling capacity while, in the case of the tablets prepared from the hydrogel GG/Ga, a remarkably higher amount of water was uptaken. The same data, reported as a function of the square root of time (Fig. 2b), indicated that the phenomenon, at least macroscopically, could be satisfactory described according to a Fickian process.

Conclusions

From the experimental data it can be concluded that the GG and Sclg polymers, when crosslinked with Ga and used for the preparation of tablets, increase the rate of release of small guest molecules because the chemical reaction with Ga introduces meshes with a size larger than those present in the simply entangled systems. Such effect is almost undetectable in the case of LBG where the degree of crosslinking is remarkably lower in comparison to the other two polymers. Furthermore, the GG

Acknowledgement

This work was carried out with the financial support of MIUR.

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