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«Dissertation Zur Erlangung des Doktorgrades der Naturwissenschaften Der Fakultät für Mathematik, Informatik und Naturwissenschaften der ...»

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This retention could be minimized by using either a diluted drug solution or PVP as crystallization inhibitor [18, 25]. Moreover, PVP may also act as binder during compaction leading to an increase of the liquid load factor [18].

The release rate of a drug from a dosage form is dependent on its disintegration and the dissolution rate of the drug. Therefore, it is very important for liquisolid systems with enhanced drug release to ensure that disintegration is not the rate-limiting step and drug dissolution is not hindered by a slow disintegration of the dosage form. It was found that the release rate increases by addition of superdisintegrants such as sodium starch glycolate or croscarmellose sodium to the liquisolid formulation [6, 16, 20].

Liquisolid Technology 16 Another formulation parameter that may be optimized is the ratio of carrier to coating material (R). An increase in the R-value results in an enhanced release rate if microcrystalline cellulose and colloidal silica are used as carrier and coating materials, respectively. Liquisolid compacts with high R-values contain high amounts of microcrystalline cellulose, low quantities of colloidal silica, and low liquid/powder ratios.

This is associated with enhanced wicking, disintegration and thus, enhanced drug release. In contrast, if high amounts of colloidal silica are used, which means that the R-value is low, the liquisolid compact is overloaded with liquid formulation due to a high liquid load factor. In such cases, even though drug diffusion out of the primary particles may be rapid, oversaturation might occur resulting in local precipitation/ recrystallization of the drug and thus decreased release rates [18, 29]. Moreover, as colloidal silica is a hydrophobic material high amounts of it can cause retardation of drug release. Therefore, Spireas et al. recommend a minimum R-value of 20 [29]. In the case of liquisolid sustained release compacts lower R-values may be used [34, 35] (see below).

Liquisolid Technology 17

1.3.3 Stability of liquisolid systems with enhanced drug release

To obtain information on the stability of liquisolid systems, the effects of storage on the release profile and the crushing strength of liquisolid compacts were investigated.

Stability studies of liquisolid systems containing polythiazide (40 °C/ 42 and 75 % R.H., 12 weeks) [32], hydrocortisone (ambient conditions, 10 months) [1], carbamazepine (25 °C/ 75 % R.H., 6 months) [18], indomethacin (25 °C/ 75 % R.H., 12 months) [28], piroxicam (25 °C/ 75 % R.H., 6 and 9 months, respectively) [4, 31], or naproxen (20 °C/ 76 % R.H., 4 weeks) [30] showed that storage at different conditions neither had an effect on the hardness nor on the release profiles of liquisolid compacts. This indicates that the technology is a promising technique to enhance the release rate without having any physical stability issues.

Liquisolid Technology 18

1.4 Liquisolid formulations for sustained drug release

Numerous methods have been described to produce sustained release formulations, among which the liquisolid technology is a quite new and promising technology resulting in a sustained release pattern with zero order kinetics [8, 12]. So far, only few drugs have been formulated as liquisolid systems with prolonged drug release. In Table 4 the fomulations of these drugs with the respective liquid vehicle, carrier and coating material as well as the additional retarding agent (matrix forming material) are listed.

Table 4: Formulations of liquisolid systems with sustained drug release (abbreviations are listed at the end of the table)

–  –  –

1.4.1 Mechanisms of sustained drug release from liquisolid systems With X-ray crystallography and DSC measurements it could be confirmed, that sustained drug release from these liquisolid compacts is not caused by a change in crystallinity or by complex formation of the drug during the manufacturing process of the sustained release liquisolid formulations [36, 37]. Liquisolid formulations with sustained drug release may contain hydrophobic carriers such as Eudragit® RL or RS instead of hydrophilic carriers, the latter being used for fast release liquisolid formulations [37, 38]. Hydrophobic carriers may lead to poor wetting properties of the compacts resulting in slow disintegration and thus, prolonged drug release.

Furthermore, the liquid vehicle may affect drug release. A comparison of drug release from conventional matrix tablets (direct compression) and liquisolid compacts, both containing Eudragit® RS or RL as matrix forming material, showed that the retardation effect of liquisolid compacts with polysorbate 80 as liquid vehicle is much more pronounced than that of conventional matrix tablets [37, 38]. This confirms the important role of the liquid vehicle in sustaining drug release from liquisolid matrix systems. It was shown that the liquid vehicle polysorbate 80 may act as a plasticizer [40] and thus, decreases the glass transition temperature of the polymer Eudragit® RS.

Accordingly, with liquisolid compacts the coalescence of the polymer particles occurs at lower temperatures than with conventional matrix tablets. This more pronounced coalescence of polymer particles of liquisolid compacts leads to a matrix with lower porosity and higher tortuosity. Consequently, the drug is surrounded by a fine network of the hydrophobic polymer resulting in a sustained release of the drug [41, 42].

Moreover, it has been shown that the addition of hydroxypropyl methylcellulose (HPMC) increases the retardation effect of liquisolid compacts [1, 13]. HPMC is commonly used for the preparation of hydrophilic matrix systems. Depending on its molecular weight the polymer either swells in contact with water and forms a hydrated matrix layer through which the drug has to diffuse or erodes resulting in a zero order drug release kinetic [43]. In the case of HPMC it was also found that a stronger retardation effect was observed with liquisolid compacts as compared to directly compressed tablets (conventional formulation) [38].

Liquisolid Technology 20 1.4.2 Optimization of liquisolid formulations with sustained drug release In contrast to liquisolid compacts with immediate drug release liquisolid sustained release formulations may be optimized by selection of low R-values, suspensions with a high percentage of undissolved drug and by avoidance of disintegrants.

If the R-value is low, which means that the applied amount of silica is high, the liquisolid compacts are overloaded with liquid formulation due to a high liquid load factor. In such cases oversaturation might occur resulting in local precipitation of the drug and thus, decreased release rates [18, 29]. Moreover, the higher the percentages of undissolved drug in the liquid formulation the slower the release rate. This is especially important for poorly soluble drugs, as the dissolution rate of these drugs is low. In addition, as drug release from a tablet is dependent on the disintegration of the tablet and the subsequent dissolution of the drug, the absence of disintegrants, which prevents disintegration, will slow down drug release.

–  –  –

1.5 In vivo evaluation of immediate release liquisolid systems The liquisolid technology is a promising approach for the enhancement of drug release of poorly soluble drugs as described in subchapter 1.3. However, the improved bioavailability to be expected from liquisolid systems has not been investigated in detail.

Khaled et al. studied the absorption characteristics of hydrochlorothiazide liquisolid compacts in comparison with commercial tablets in beagle dogs [10]. Significant differences in the area under the plasma concentration-time curve, the peak plasma concentration, and the absolute bioavailability of the liquisolid and the commercial tablets were observed. However, for the mean residence time, the mean absorption time, and the rate of absorption no significant differences were found. The absolute bioavailability of the drug from liquisolid compacts was 15 % higher than that from the commercial formulation.

Fahmy et al. investigated the in vitro and in vivo performance of famotidine liquisolid compacts in comparison with directly compressed tablets and commercial famotidine tablets, respectively [19]. The dissolution rate of famotidine in 0.1 N HCl was shown to be enhanced with the liquisolid compacts compared to directly compressed tablets.

The in vivo evaluation of famotidine liquisolid compacts was compared to that of commercial famotidine tablets using six healthy male volunteers aged between 20 and

40. It was found that there were no significant differences between the mean peak plasma concentrations (cmax), the mean times of peak plasma concentrations (tmax), or the mean area under the plasma concentration-time curve (AUC). Unfortunately, the in vivo evaluation of the directly compressed tablets was not determined in this study and thus, an improved bioavailability of liquisolid compacts compared to directly compressed tablets could not be shown.

Tayel et al. measured drug release of the poorly soluble antiepileptic drug carbamazepine from liquisolid compacts and commercial tablets [44]. It was observed that drug release from liquisolid compacts and that from commercial tablets is comparable. Furthermore, an oral dose of carbamazepine administered to mice led to Liquisolid Technology 22 less protection against an electroshock-induced convulsion with liquisolid compacts compared to the commercial product. This lower pharmacological activity of liquisolid compacts is probably due to the high drug concentration in the liquid vehicle and thus a precipitation of carbamazepine in the silica pores.

El-Houssieny et al. investigated the bioavailability and biological activity (glucose tolerance in rabbits) of repaglinide formulated as liquisolid compacts and commercial tablets, respectively [9]. It was found that the relative bioavailability of repaglinide from the liquisolid compacts was significantly higher than that from the commercial tablets.

The increase in insulin blood level was more pronounced with the liquisolid compacts than with the commercial tablets indicating a higher bioavailability from the liquisolid compacts. Moreover, liquisolid compacts of repaglinide decreased blood glucose levels significantly more than the commercial tablets.

These partially contrary results of bioavailability of liquisolid formulations show that still more in vivo data is needed to confirm the superiority of liquisolid compacts. The varying bioavailability of the above mentioned liquisolid formulations may be explained by a different percentage of dissolved drug in the liquid vehicle. However, in most of the studies an improved bioavailability from liquisolid formulations was observed compared to the commercial tablets.

Liquisolid Technology 23

1.6 Comparison between liquisolid systems and alternative technologies

The liquisolid technology can be used both for the enhancement and the retardation of drug release. It is a promising technique because of the simple manufacturing process, low production costs, and the possibility of industrial production due to good flow and compaction properties of the liquisolid formulations.

Within the next two subchapters the liquisolid technology is compared to alternative technologies and their advantages and disadvantages are pointed out.

1.6.1 Technologies for the enhancement of drug release

Release enhancement of poorly soluble drugs may be achieved by an increase of the drug surface area, the drug solubility, or by formulating the drug in its dissolved state.

Several methodologies such as micronization, adsorption onto high surface area carriers, co-grinding, formulation of inclusion complexes, solid dispersions, and lipid based formulations (e.g. SEDDS) are used for enhancement of drug release [45-47].

A simple method for increasing the surface area of the drug is micronization [48].

However, in practice the effect of micronization is often disappointing, especially if the drugs are encapsulated or tableted. Micronized drugs have the tendency to aggregate as a result of their hydrophobicity and electrostatic charge, thus, reducing their available surface area [49, 50].

Adsorption of poorly soluble drugs on hydrophilic silica aerogels was found to enhance drug dissolution [51, 52]. This can be explained by both an increase in the specific surface area of the drug adsorbed to the aerogel and an at least partial amorphisation of the drug. However, drug adsorption is dependent on the selected drug and sometimes only low drug loads are achieved. Another disadvantage of this technique is the complex manufacturing process: Silica aerogels are loaded with drugs by adsorption from their solutions in supercritical carbon dioxide [52, 53].

Liquisolid Technology 24 Co-grinding of poorly soluble drugs with different excipients may also result in an amorphisation of the drug and thus improved dissolution characteristics [54].

Crospovidone [55, 56], polyvinylpyrrolidone [56], and different types of silica [57, 58] are suitable for that purpose. Co-grinding is another straight forward procedure to achieve drug release enhancement.

Complexes of a lipophilic drug with cyclodextrin, commonly known as inclusion complexes, can be easily formulated by mixing the drug with the carrier [59]. The most commonly used carrier β-cyclodextrin acts as a solubilizer and stabilizer consisting of a truncated cone type structure with an outer hydrophilic and an inner hydrophobic surface [60-63]. However, the maximum possible drug load of these systems is relatively low and the inclusion complexation only works with drugs that fit into the cavities of the cyclodextrin molecule.

Solid dispersions consist of one or more active ingredients dispersed in a readily soluble solid hydrophilic matrix prepared by a melting (fusion) or solvent method [64].

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