CENSURA ADMINISTRATIVA E INFLUENZA IDEOLOGICA

In the first testing round pastes with different taste masked praziquantel formulations or flavors were evaluated. According to their properties they were incorporated into the three paste bases. The concentration of praziquantel was 2.5% in all pastes. The

Eudragit E microspheres (see Chapter 2.2.3) could only be included in a PEG base because Eudragit E is soluble in miglyol and swellable in water. The praziquantel-β-cyclodextrin-complex obtained by solvent method (see Chapter 3.2.2) and the hand made lipid particles with Precirol ATO 5 (see Chapter 4.2.2) were both incorporated into water and miglyol pastes. These bases were chosen because they showed the best results in the placebo tests, and to compare the taste masked formulations in two bases. Besides, β-cyclodextrin is partially water soluble and thus further inclu-sion complex formation of β-cyclodextrin with free praziquantel could happen in the aqueous paste. In addition, water based pastes with only flavor as taste masking agent were tested to study the effect of the simple addition of a flavor: artificial beef flavor and malt extract were used for this issue. Other taste masked formulations from another group were also tested, including hot melt coating with PEG 8000 and granulation with Marcoat/HPMC or Kollicoat SR30D as taste masking agents.

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Figure 5.1: Acceptance tests of taste masked praziquantel pastes; indicated are taste masking agent and paste base; PZQ amount 2.5%; number of cats: 6; mean±stdev

Results of these acceptance tests with taste masked praziquantel or a flavor are shown in Fig. 5.1. The pastes were applied to six cats whereby the first four formu-lations were tested on a group of six cats and the last four formuformu-lations were tested on another group of six cats. As can be seen the formulations based on water were accepted best. Both taste masking agents which were tested in water and miglyol, β-cyclodextrin and Precirol, showed clearly better values in water. Both formulations reached the same average of 1.67 with a standard deviation of 1.03 in water whereas their values for miglyol were rather low: 1.00 for β-cyclodextrin and 0.83 for Precirol.

In all cases slight salivation was recorded for 33% of the cats. Excitation was only needed for the oily pastes (33% for β-cyclodextrin and 50% for Precirol); the aqueous pastes were taken by the cats more willingly so that no animation was required. This is another indicator that the aqueous pastes are superior in acceptance compared to the pastes based on miglyol.

Surprisingly, the flavor pastes reached good results, too: the malt extract equaled the average of β-cyclodextrin and Precirol and the beef flavor paste was also accepted quite good by the cats (average 1.33). Similarly, salivation occurred in 33% and stim-ulation was necessary in 33% of all cases for the beef flavor and 17% for malt. This is slightly astonishing because the pastes containing flavor should smell much better and thus should be taken more willingly by the cats than those without, even if they do not taste better in the end. However, 17% means that only one cat out of six needed to be animated to take the paste so this variation does not seem to be significant.

For comparison a worst-case paste was also tested: praziquantel is partially sol-uble in PEG and, because only dissolved substances elicit taste (Szejtli & Szente, 2005;

Nanda et al., 2002), this base was chosen as a negative control to experience the reac-tion of cats to dissolved and unmasked praziquantel. Reacreac-tions were unambiguous:

nearly all cats (eleven out of twelve) were rated a zero accompanied with severe sali-vation (see Fig. 5.2).

Figure 5.2: Salivating cat after administration of negative control

As can be seen the Eudragit E microspheres containing praziquantel which were also tested in a PEG base are nearly equaling the "worst case scenario". The average acceptance is 0.17±0.41 which means that 5 cats were rated with failed acceptance (0 points) and only one cat showed poor accep-tance (1 point). Severe salivation was recorded for 5 cats (83%) and excitation was needed for one half of the cats. The rea-son for this failed acceptance might be the good solubility of praziquantel in PEG which leads to drug leaking out of the microspheres into the base. This is possible because the active ingredient is not entirely coated with Eudragit E, but only sus-pended homogeneously in the microsphere matrix and thus can diffuse into the surrounding paste. As a result the con-centration of dissolved praziquantel might be at its solubility limit as it is in the negative control paste. This and the reason that cats prefer other paste bases to PEG led to the very bad result. Therefore, this method was not tested any further.

Taste masked formulations of praziquantel from another group included hot melt coating with PEG 8000 tested in a PEG paste and granulation with Marcoat/

HPMC or Kollicoat SR30D which were incorporated in an oily paste. All these taste masking methods did not reach satisfying results (data not shown). Consequently, these methods were abandoned for further development of the paste.

The four water based pastes (β-cyclodextrin, Precirol, malt extract and beef fla-vor) were further tested with the other six cats which had not been used for the

respective pastes in the first tests. β-cyclodextrin showed the same acceptance level as before but with a lesser deviation whereas the level rose for the flavored pastes and Precirol. The malt and beef flavor were accepted much better and showed an average of 2.17 and 2.00, respectively. The acceptance level for Precirol also showed a slight increase (1.83).

To optimize the acceptance of the pastes combinations of the best taste masked formulations with a flavor was tested in the next acceptance round.