Research and Development of a New Safe Form of Drugs - Aerosols: Measurement, Dosimetry, and Health Effects - page 280

solubility ratio of one of the pharmacons. For example, in complex AG: mezapam 20:1 the solubility
ratios are 10.8, 46.8, and 17.5 for the irst, second, and third modes, respectively. Therefore, mecha-
nochemical activation of the solid component of the mixture produces optimal conditions for the
synthesis. The complexes are powders consisting of vitreous particles sized 2-50 μm.
No traces typical of the crystalline phase of pharmacons can be found in the x-ray photographs
and thermograms of complexes, indicating that pharmacon molecules have undergone molecular
dispersion into the polysaccharide matrix, that is, complexation has taken place. The stability of
intermolecular complexes of AG with pharmacons increases in the series sibazon < IM < mezapam
< azaleptin. Complexation proceeds mainly due to the intermolecular hydrogen bonds and Coulomb
interaction at the ionization of pharmacon molecules. The investigation by the NMR-relaxation
method showed that mobility of the pharmacon molecules dramatically decreases in solutions,
which is evidence of complex existence (Fielding, 2000).
The study of pharmacological properties of the complexes produced the following main results.
The basic activity of indomethacin within the complexes remains high at the doses of pharmacon
reduced by 10 (complex 10:1) and 20 (complex 20:1) times. Destructive mucosal involvement of
the stomach halves. The basic activity of sibazone within the complexes holds at the dose reduced
by 10 times. Besides, the anxiolythic effect of pharmacon increases.
For complexes of AG with mezapam the standard antianxious activity was observed at the phar-
macon doses reduced by 20 times. The complexation effect for the complex of AG with azaleptin is
manifested in the halved dose and ampliication of the sedative component.
As was discussed earlier in the part about glycyrrhizic acid complexes, pharmacological prop-
erties of anticoagulant drug warfarin in the WF:GA complex were not as desired. Therefore, the
obtained results of examination of WF: GA complex prompted us to replace the complexing agent
and we selected AG. We assumed that a complexing agent with such a structure should interact dif-
ferently with warfarin.
The WF:AG complex was synthesized in a similar way and with the same component ratio, 1:10,
as the complex with GA. This component ratio had previously been determined as effective for
other pharmacons with AG (Tolstikova et al., 2009).
The same scheme was used in order to secure the accuracy of the experiment. No increase in
PT was observed in 6 h after a single intragastric administration, just as in the previous experi-
ment. However, in 24 h after the experiment start (one administration), some signiicant differences
were observed. PT increased by more than two times, compared to the control (phys. solution), and
amounted to 30.03 s. Although this indicator is lower than that of the comparator agent (42 s) in a
2 mg/kg dose, it still may be considered suficient for the manifestation of the effect of increase in
hemopexis time (Figure 11.23).
We can suppose that this 28.5% difference between WF and WF:AG may be beneicial in the
reduction of hemorrhages during the dose selection period, that is, we can reduce undesirable side
effect of warfarin therapy. Moreover, the eficacy of WF and WF:AG is the same in 48 h after a
single administration (Figure 11.24).
Thus, it may be said that while the dissolubility of the WF:AG clathrate is lower than that of the
WF:GA clathrate, the structure of clathrates with AG allows preserving the anticoagulative poten-
tial of warfarin and increase its solubility in water.
Thus, the study of pharmacological properties shows that the results for AG complexes agree
well with those for complexes with terpenoids (glycyrrhizic acid, stevioside, rebaudioside). In both
cases complexation results in enhanced basic activity, reduced dose, appearance of new properties
of pharmacons.
Therefore, the discovered effect of complexation of drugs by plant carbohydrate-containing
metabolites allows reducing the toxicity and the effective dose (by 5-100 times), and to improve the
pharmacological properties, which may lead to the increase in safety of the therapy of many socially
signiicant diseases. Besides, this method may lower the pharmacoeconomical production expenses
and make the course of treatment cheaper for the patients.