Solubilisierung stark lipophiler Arzneistoffe in lipidhaltige ...

Summary of the Work
Solubilization of Highly Lipophilic Drugs in Mixed Micellar Systems
and its Influence upon Drug Absorption Process
Summary
It is well known that lipid containing mixed micelles show many beneficial features as
pharmaceutical carrier systems, especially because of their ability to improve drug
absorption in general and the aqueous solubility of lipophilic compounds in particular.
This in turn implies their use as very promising carrier systems for highly lipophilic drugs.
However, it is less known about the factors which may influence the incorporation of
such drugs within the structure of such systems and thus may affect drug solubility in
them. The same applies also to the factors, which may affect the delivery process of
highly lipophilic drugs carried by these vehicles at biological membranes, especially the
mucosal membrane of the gastrointestinal Tract. Therefore, these factors were subject
of investigation throughout the present thesis work.
Surface active agents used to develop the micellar systems were chosen among the frequently
used surfactants for pharmaceutical purposes. Systematical solubilization tests
were conducted to select one representative of each of the main three surfactant groups,
the anionics, the cationics and the nonionics, for further experimentation. Lipids added
to form binary and ternary mixed micellar systems were saturated and unsaturated Soya
lecithins (P90H and P90G respectively) as well as stearic acid (SS) and oleic acid (OS).
The most important used surfactants were Brij® 35 (Br35), sodium glycodeoxycholate
(NaGDC) and hexadecyltrimethylamonium bromide (HTAB). Testosterone and its
propionate, enanthate and undecanoate esters (T, TP, TE, and TU) were used as model
drugs to investigate the solubilization and absorption of highly lipophilic drugs.
First, the solubilization of lipids in simple surfactant systems and in binary
(lipid+surfactant) systems was tested. The solubilization of the unsaturated lipids (P90G
and OS) in the studied micellar systems was distinctly higher than it was for their
saturated analogues (P90H and SS), regardless of the used surfactant. In the case of
HTAB or Br35, added P90G and OS in order to form ternary systems were found to
have no significant interactive influence on their mutual solubilization values. In contrast,
the addition of one lipid to the micellar system of sodium glycodeoxycholate (NaGDC)
decreased considerably its solubilizing capacity for the other added lipid.
Based on the results of first experiment series the solubilization of the drugs was
investigated in micellar systems (drug/surfactant) and in binary mixed micellar systems
(drug/lipid+surfactant). Among the studied surfactants, the highest solubilization results
of testosterone and its esters were achieved in the micellar and the developed mixed
micellar systems of HTAB. With the exception of one case, which is the solubilization of
testosterone in the micellar systems of HTAB, a marked improvement in the
solubilization of the studied steroids was achieved using the mixed micellar systems in
comparison with their lipid free analogues. This was ascribed mainly to an increased
lipophilicity in the interior of aggregates as well as to the growth in aggregate sizes
following the lipid addition. Moreover, the double bonds of the added unsaturated lipids
were accounted for a facilitated embedding of the steroid molecules within the
aggregates by reducing the adhesion of the hydrocarbon chains or the Laplace pressure
inside the aggregates, and by interacting with the polar functions of embedded steroids.
The optimized binary systems showed the best solubilizing capacities toward the tested
model drugs, as compared to their corresponding ternary mixed micellar systems. These
optimized binary Systems were mixtures of OS with HTAB or Br35 as well as the mixture
of P90G with NaGDC.
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