Preparation and physicochemical evaluation of a new tacrolimus tablet formulation for sublingual administration

Abstract

The aim of this study was to develop a new fast-disintegrating tablet formulation containing 1 mg tacrolimus for sublingual application. First, solid dispersions containing tacrolimus (2.5%, 5% and 10% w/w) incorporated in Ac-Di-Sol(®) and carriers (inulin 1.8 kDa and 4 kDa, and polyvinylpyrrolidone (PVP) K30) were prepared by freeze drying. Subsequently, a tablet formulation composed of a mixture of the solid dispersions, Ac-Di-Sol(®), mannitol, Avicel(®) PH-101 and sodium stearyl fumarate was optimized concerning drug load in the solid dispersions and the type of carrier. Tablet weight was kept constant at 75 mg by adjusting the amount of Avicel(®) PH-101. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) results indicated the absence of the drug in the crystalline state, which was confirmed by the scanning electron microscopy (SEM). These results suggest that tacrolimus incorporated in all of the solid dispersions was fully amorphous. Dissolution of the tablets containing solid dispersions with a low drug load highly depends on the type of carrier and increased in the order: PVP K30 < inulin 4 kDa < inulin 1.8 kDa. Solid dispersions with a drug load of 10% w/w incorporated in the carriers yielded optimal formulations. In addition, the physicochemical characteristics and the dissolution behavior of the tablet formulation containing inulin 1.8 kDa-based solid dispersions with a drug load of 10% w/w did not change after storage at 20°C/45%RH for 6 months indicating excellent storage stability.

Sublingual Administration of Tacrolimus: Current Trends and Available Evidence

“…Properties of effective sublingually administered medications include high lipophilicity, small to moderate molecular weight, good solubility in salivary secretion, and favorable oil‐to‐water coefficients . Although tacrolimus is a larger molecule with erratic solubility, it is highly lipophilic with a favorable oil‐to‐water coefficient, making it an acceptable candidate for sublingual administration, and a novel sublingual‐specific formulation of tacrolimus was even reported in the literature …”

“…15 Although tacrolimus is a larger molecule with erratic solubility, it is highly lipophilic with a favorable oil-to-water coefficient, making it an acceptable candidate for sublingual administration, and a novel sublingual-specific formulation of tacrolimus was even reported in the literature. 16 With regard to brand versus generic differences, the first generic formulation of tacrolimus capsules became available in August 2009. Although some in vitro studies found differences in rates of dissolution between the different generic formulations compared with the brand formulation, all studies included in this review used brand name Prograf (Astellas Pharma, Tokyo, Japan), limiting the applicability of study data to generic formulations.…”

Rectal and sublingual administration of tacrolimus: a single‐dose pharmacokinetic study in healthy volunteers

“…It is not precluded, however, that repetitive and/or escalated dosing or other formulations of tacrolimus (e.g. intravenous solution or solid dispersions ) could result in significant drug exposure after sublingual exposure. This is in line with the finding that one in three subjects experienced local paraesthesia after sublingual dosing.…”

Development and pharmacokinetic evaluation of once-daily sustained-released matrix capsules of nifedipine using solid dispersion technique

“…However, the highly crystalline and poorly soluble characterizations of NFD result in lower oral bioavailability (Sawada et al, 2004). Application of solid dispersions composed of hydrophilic carrier in which a lipophilic drug is incorporated is a proven technique to improve the poor water solubility of drug (Huang et al, 2011;Srinarong et al, 2012). Furthermore, many studies have been reported that the solid dispersion technique was used to enhance oral bioavailability of poor water soluble drugs (Boghra et al, 2011;Tran et al, 2011).…”