Research paper
Inulin solid dispersion technology to improve the absorption of the BCS Class IV drug TMC240

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Abstract

TMC240 is a very poorly soluble and poorly permeating HIV protease inhibitor. In order to enhance its oral bioavailability, a fast dissolving inulin-based solid dispersion tablet was developed. During the dissolution test in water (0.5% or 1.0% SLS), this tablet released at least 80% of TMC240 within 30 min, while a tablet with the same composition, but manufactured as physical mixture, released only 6% after 2 h. In a subsequent single-dose study in dogs (200 mg of TMC240), plasma concentrations of TMC240 remained below the lower limit of quantification (<1.00 ng/mL) in all animals (n = 3 per tested formulation), except in one dog receiving the inulin solid dispersion tablet (Cmax = 1.8 ng/mL, AUC0-7 h = 3.0 ng h/mL). In the latter treatment group, ritonavir co-administration (10 mg/kg b.i.d.) increased TMC240 exposure more than 30-fold (mean AUC0-7 h = 108 ng h/mL; Frel = 3588%). Exposure was also 16-fold higher than after TMC240 administration as PEG400 suspension in the presence of ritonavir (AUC0-7 h = 6.7 ng h/mL). The current data demonstrate that a solid dispersion of TMC240 in an inulin matrix allows considerable improvement in the release of poorly water-soluble TMC240, both in vitro in the presence of a surfactant and in vivo upon oral administration.

Introduction

Many new drugs can be categorized as Class II or IV drugs according to the Biopharmaceutics Classification System Guidance (BCSG) [1], [2], [3]. Class II drugs are poorly water soluble but once dissolved, they rapidly pass biological membranes like the gastro-intestinal wall. As a consequence, Class II drugs slowly dissolve in the aqueous environment of the gastro-intestinal tract after oral administration and result in a poor bioavailability, while increasing the dissolution rate will also improve bioavailability [4], [5].

Application of solid dispersions is one of the strategies to increase the dissolution rate of Class II drugs [6], [7]. Solid dispersions consist of two (or more) component systems in which the drug is dispersed monomolecularly or as small particles in a hydrophilic matrix. Increased dissolution rate can be attributed to a strongly enhanced surface area of the drug for dissolution [8], to an improved wetting of the drug [7] and to an enhanced solubility due to small size of the drug particles (Ostwald–Freundlich equation) and if applicable to the amorphous state of the drug [9], [10].

Many studies on the application of solid dispersions for the improved dissolution behavior of lipophilic drugs have been published (reviewed in e.g. [6], [7], [8], [11]). In most of these studies, either polyvinylpyrrolidone or polyethylene glycol was used as matrix material. Recently, we published on the application of sugar glass-based solid dispersions. In previous studies, we have investigated the dissolution behavior of tablets prepared from these solid dispersions [12]: it was found that in many cases, the release rate of the drug from tablets prepared from these solid dispersions was much higher than from tablets prepared from physical mixtures of the sugar and the drug. However, when small sugars like sucrose or trehalose were used and the drug load exceeded a certain threshold, the release of the drug was very slow [12]. This phenomenon was attributed to the extremely fast dissolution of the sugar which resulted in a very high concentration of drug in the near vicinity of the dissolving tablet, resulting in the formation of large drug crystals which slowly dissolve. Due to its oligomeric nature, the oligofructose inulin 4 kDa dissolves slower than sucrose and trehalose. Therefore, it was subsequently investigated whether for a given drug load, the use of inulin instead of sucrose or trehalose as matrix material allowed to lower the drug concentration in the near vicinity of the dissolving tablet and, hence, lower the risk of crystallization. Whereas replacing the sucrose or trehalose in the solid dispersion tablets by inulin indeed allowed to increase the drug load threshold, above which drug release again decreases due to crystallization [12], increasing the molecular weight of inulin from 4 kDa to 7 kDa was not successful because in that case drug release became limited by slower dissolution of the matrix [13]. Therefore, inulin 4 kDa is currently used as matrix material for formulation studies. The surfactant sodium laurylsulphate (SLS) and superdisintregrant Primojel® (sodium starch glycolate) are added to overcome the limitations with regard to drug load [14], [15]: the high surfactant concentration in the near vicinity of the dissolving tablet allows to increase the local drug solubility and limit the risks of its crystallization, this also due to the faster disintegration of the tablet itself. Fast in vitro release of active ingredients from inulin-4 kDa-based solid dispersion tablets, containing high drug loads and either SLS or Primojel®, has been confirmed for several poorly water soluble Class II active ingredients, including diazepam [12], [13], [14], nifedipine [13], cyclosporine A [16], fenofibrate [15] and Δ9-tetrahydrocannabinol [17].

Class IV drugs pose an even bigger challenge as their absorption is not only limited by their slow dissolution in the aqueous environment of the gastro-intestinal tract, but also by their low permeation capacity, so that too low levels of dissolved drug in the intestine per definition will lead to poor bioavailability [1], [2], [3]. This is the case for TMC240 (Tibotec BVBA, Belgium), an experimental HIV-1 protease inhibitor (PI) with a broad-spectrum activity against a panel of highly PI cross-resistant viruses. Its structure is shown in Fig. 1. It is a structural analogue of a series of compounds that were designed to be active against multidrug-resistant viruses [18]. The compound is practically insoluble in water (2.07 mg/L) and has a low permeability (as also further confirmed in the results section of this paper). Permeation through the gastro-intestinal wall can be enhanced by the use of glycoprotein-P inhibitors, such as the protease inhibitor ritonavir, which can boost the plasma concentration levels of protease inhibitors in a number of ways: in the case of P-glycoprotein, it inhibits the protein efflux channels that take part in the active transport of protease inhibitors out of cells [19]. Ritonavir may also enhance drug exposure by hepatic and intestinal inhibition of CYP3A4 metabolism [19]. Ritonavir is commonly used in combination with currently marketed PIs in the treatment of HIV-infections.

In order to enhance absorption of TMC240, two strategies were studied: the use of the inulin solid dispersion technology to improve its dissolution behavior and the combined administration with ritonavir to improve its permeation over the intestinal wall. Therefore, inulin solid dispersion tablets were formulated and studied for their in vitro dissolution properties, as well as for their in vivo pharmacokinetics in dogs in the presence and absence of ritonavir, thereby comparing with physical mixture tablets of identical composition and with a liquid PEG400 suspension of TMC240.

Section snippets

Materials

The HIV protease inhibitor TMC240 was supplied by Tibotec BVBA, Mechelen, Belgium and has been established to be stable under crystalline form (Tibotec, internal data on file). Inulin 4 kDa (further designated as inulin) was provided by Sensus, Roosendaal, The Netherlands. Primojel®, SLS and dimethyl sulfoxide (DMSO) were obtained from Avebe (Veendam), Bufa B.V. (Uitgeest) and Sigma–Aldrich Chemie B.V. (Zwijndrecht), respectively, in The Netherlands. Polyethylene glycol 400 (PEG400) was

Solubility of TMC240

Because the dissolution behavior of the tablets was determined in pure water and in 0.5% and 1.0% w/v SLS, the solubility of TMC240 in these media was determined. As expected, the TMC240 solubility increased with increasing SLS concentration. The TMC240 solubility was 2.07 ± 0.08, 5.10 ± 0.52 and 11.75 ± 0.36 mg/L in pure water, 0.5% and 1.0% w/v SLS, respectively.

Production of TMC240 solid dispersion tablets

Application of the described technique allowed producing TMC240 as an inulin-based solid dispersion. The thermogram of pure TMC240 showed a

Discussion

The dissolution data in this study confirmed that the HIV protease inhibitor TMC240 is poorly water soluble. Furthermore, the solubility-enhancing effects of SLS were limited, i.e. the solubility of TMC240 is only increased about 2.5-fold by the addition of 0.5% SLS. This increase is usually much higher for lipophilic drugs, e.g. for fenofibrate, this increase is 2000-fold [20]. These data therefore show that TMC240 is not only poorly water soluble but will also have a low permeability. In

Acknowledgements

We thank Suzy Huijghebaert (HuginCR, B-1310La Hulpe, Belgium) for her assistance in preparing the manuscript.

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