Marinella Regina Visser

Strongly enhanced dissolution rate of fenofibrate solid dispersion tablets by incorporation of superdisintegrants

In this study, it was shown that the incorporation of superdisintegrants in solid dispersion tablets containing a high drug load can strongly enhance the dissolution rate of the highly lipophilic drug fenofibrate. In addition, the dissolution rate was more increased when the superdisintegrant was incorporated in the drug containing solid dispersions than when it was physically mixed with the solid dispersions. The dissolution rate enhancement strongly depended on the type of superdisintegrants and increased in the order Polyplasdone XL-10<Polyplasdone XL<<Ac-Di-Sol approximately Primojel. The dissolution behavior also depended on the type of hydrophilic carriers. Solid dispersion tablets based on inulin 4 kDa, polyethylene glycol 20K and polyvinylpyrrolidone K30 showed a much faster dissolution than those based on mannitol and hydroxypropyl-beta-cyclodextrin. Finally, inulin 4 kDa-based solid dispersion tablets showed excellent storage stability, while polyethylene glycol 20K-and polyvinylpyrrolidone K30-based solid dispersion tablets did not.

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

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 30min, while a tablet with the same composition, but manufactured as physical mixture, released only 6% after 2h. In a subsequent single-dose study in dogs (200mg of TMC240), plasma concentrations of TMC240 remained below the lower limit of quantification (<1.00ng/mL) in all animals (n=3 per tested formulation), except in one dog receiving the inulin solid dispersion tablet (C(max)=1.8ng/mL, AUC(0-7 h)=3.0ngh/mL). In the latter treatment group, ritonavir co-administration (10mg/kg b.i.d.) increased TMC240 exposure more than 30-fold (mean AUC(0-7 h)=108ngh/mL; F(rel)=3588%). Exposure was also 16-fold higher than after TMC240 administration as PEG400 suspension in the presence of ritonavir (AUC(0-7 h)=6.7ngh/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.

Surface-active derivative of inulin (Inutec® SP1) is a superior carrier for solid dispersions with a high drug load.

The aim of this study was to compare the applicability of inulin, its surface-active derivative (Inutec® SP1), and polyvinylpyrrolidone (PVP) as carriers in high drug load solid dispersions (SDs) for improving the dissolution rate of a range of lipophilic drugs (diazepam, fenofibrate, ritonavir, and efavirenz). The SDs were prepared by spray freeze-drying. Scanning electron microscopy showed that the obtained samples were highly porous spherical particles. Modulated differential scanning calorimetry showed that the drugs incorporated in these carriers were fully or partially amorphous. The solubility of the drugs in solutions of the different carriers was increased in an order: inulin 2.3 kDa < PVP K30  ≪ Inutec® SP1. The dissolution behavior of SD tablets was evaluated. Inutec® SP1-based SD tablets showed the best performance followed by PVP- and inulin-based SD tablets. The superior dissolution behavior of the drugs from Inutec® SP1-based SDs could be ascribed to its surface-active nature. In addition, Inutec® SP1-based SD tablets gave good physical stability at 20 °C/45% relative humidity (RH) and 40 °C/75% RH for 3 months.

Pore formation in tablets compressed from binary mixtures as a result of deformation and relaxation of particles

This paper describes the internal structure of tablets compressed from binary mixtures of sodium chloride and pregelatinised starch. The minimum particle diameter of pregelatinised starch inside tablets compressed from mixtures was calculated from the difference between the initial pore size distribution and the pore size distribution after removal of the starch particles by burning. Subsequently, the tablets were carefully crushed. These powders, consisting of almost only sodium chloride particles, were measured by laser diffraction. It was found that the diameter of the sodium chloride particles hardly changed, whereas the minimum diameter of starch particles strongly decreased during the compaction process. As an effect of the difference in yield pressure, the harder sodium chloride particles cause deformation of the softer starch particles, resulting in a change in particle shape. The pore size distribution of tablets compressed from mixtures of sodium chloride and starch is typically that of viscoelastic materials; the larger pores (>5 microm) change, while the small pores stay constant in number and size. The median pore diameter in tablets compressed from the mixtures is higher than the median pore diameter in tablets compressed from the pure materials. This paper shows that the formation of large pores was the result of the extra porosity expansion of tablets compressed from binary mixtures of sodium chloride and pregelatinised starch.

Influenza antigen-sparing by immune stimulation with Gram-positive enhancer matrix (GEM) particles

Gram-positive enhancer matrix (GEM) particles, produced from non-genetically modified Lactococcus lactis bacteria have an inherent immunostimulatory activity. It was investigated whether co-administration of GEM particles can reduce the amount of influenza subunit vaccine (HA) necessary to protect mice from viral infection. Decreasing HA amounts of 5, 1, 0.2 and 0.04μg admixed with GEM particles were tested in intramuscular immunizations. Combinations of GEM and seasonal HA (A/Wisconsin/67/2005 [H3N2]) induced significantly higher systemic and better Th1/Th2-type balanced immune responses than HA alone. Addition of GEM to 0.04μg HA resulted in similar HI titers as 1-5μg non-adjuvanted HA. To test the protective efficacy of the adjuvanted combination, mice were immunized with influenza subunit vaccine A/PR/8/34 (H1N1) and then challenged with live virus (A/PR/8/34). Mice immunized with 1μg HA+GEM showed undetectable virus titers in the lungs 5 days after challenge, whereas mice immunized with 1μg HA alone showed detectable levels of virus in the lungs. Interestingly, mice vaccinated with the 0.04μg HA+GEM vaccine demonstrated reduced lung virus titers and a reduction in weight that was similar as that in mice vaccinated with 1μg non-adjuvanted HA. These results indicate that the use of GEM as immunostimulant allows for a strong reduction in the antigen dose as compared to the benchmark vaccine by using GEM particles. Thus, addition of GEM can strongly potentiate immunogenicity of influenza subunit vaccine both quantitatively and qualitatively.

Development of a dry, stable and inhalable acyl–homoserine–lactone–acylase powder formulation for the treatment of pulmonary Pseudomonas aeruginosa infections

In the lungs of cystic fibrosis (CF) patients, Pseudomonas aeruginosa commonly causes chronic infections. It has been shown that the P. aeruginosa quorum sensing (QS) system controls the expression of virulence factors during invasion and infection to host cells. PvdQ is an acyl-homoserine lactone (AHL) acylase able to degrade the signal molecule of P. aeruginosa QS. The role of PvdQ in inhibiting the QS and its successive virulence determinants has been established in in vitro as well as in in vivo, the latter in a Caenorabdhitis elegans model. For the treatment of pulmonary P. aeruginosa infections, we propose that PvdQ can be best administered directly to the lungs of the patients as a dry powder because this is expected to give specific advantages in delivery as compared to nebulizing. Therefore in this study we investigated the production of a PvdQ powder by spray-freeze drying using mannitol, trehalose and inulin as excipient. The activity of PvdQ in the powder was determined immediately after production and after subsequent storage during 4 weeks at 20°C and 55°C. We found that the enzymatic activity of PvdQ is fully maintained during spray-freeze drying using mannitol, trehalose or inulin as excipient. However, mannitol was not able to stabilize the protein during storage, while PvdQ incorporated in trehalose or inulin was fully stabilized even during storage at 55°C for at least 4 weeks. The poor stabilizing capacities of mannitol during storage could be related to its crystalline nature while the excellent stabilizing capacities of trehalose and inulin during storage could be related to their amorphous nature. The trehalose and inulin-based particles consisted of porous spheres with a volume average aerodynamical diameter of ∼1.8 μm implying that they are suitable for pulmonary delivery. This is the first study in which an AHL-degrading enzyme is processed into spray-freeze-dried powder suitable for inhalation.

Effect of drug-carrier interaction on the dissolution behavior of solid dispersion tablets.

The objective of this study was to compare the dissolution behavior of tablets prepared from solid dispersions with and without drug-carrier interactions. Diazepam and nifedipine were used as model drugs. Two types of carriers were used; polyvinylpyrrolidone (PVP K12, K30 and K60) and saccharides (inulin 1.8 kDa, 4 kDa and 6.5 kDa). Solid dispersions with various drug loads were prepared by lyophilization. It was found that the drug solubility in aqueous PVP solutions was significantly increased indicating the presence of drug-carrier interaction while the drug solubility was not affected by the saccharides indicating absence of drug-carrier interaction. X-ray powder diffraction and modulated differential scanning calorimetry revealed that all solid dispersions were fully amorphous. Dissolution behavior of solid dispersion tablets based on either the PVPs or saccharides was governed by both dissolution of the carrier and drug load. It was shown that a fast drug dissolution of solid dispersions with a high drug load could be obtained with carrier that showed interaction with the drug.

Gastro-intestinal delivery of influenza subunit vaccine formulation adjuvanted with Gram-positive enhancer matrix (GEM) particles

In this study, a liquid formulation of influenza subunit vaccine admixed with Gram-positive enhancer matrix (GEM) particles as adjuvant was delivered to upper and lower parts of intestinal tract. The aim was to determine the most effective immunization site in the intestines. Mice were vaccinated with a liquid formulation of GEM and influenza subunit vaccine orally and rectally. The oral administration of the vaccine with GEM particles induced a better systemic and mucosal immune response than oral (vaccine only) and rectal (with and without adjuvant) immunizations. Rectal administration elicited high IgG1 responses but little IgG2a, indicating a Th2 dominated immune response. In contrast, the oral immunization with GEM particles elicited a balanced IgG1 and IgG2a response. In conclusion, our results demonstrate that GEM-adjuvanted influenza vaccine should be targeted to the upper part of the intestinal tract.