Liposome encapsulated amphiphilic drug compositions

Details Liposome encapsulated amphiphilic drug compositions Liposome encapsulated amphiphilic drug compositions

1998-11-19

2000-11-21

Kishore, Gollamudi S.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

424 121, 424 9321, 424 951, 424417, 424 943, 264 41, 264 43, A61K 9127

Patent

active

061499374

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the entrapment of amphiphilic compounds, as uncharged or ionic species, into liposomes, with or without extraliposomal crystals or ions in the suspension; and to a method allowing the prediction of the permeation of these compounds through cell membranes.
Amphiphilic compounds are molecules which possess both a hydrophilic and a hydrophobic part. For example, phospholipids are amphiphilic compounds which comprise two hydrophobic fatty acid chains and a hydrophilic phosphocholine group. In the present invention an example of such compound is tin(II) dioxinate. Amphiphilic compounds may also be represented by uncharged hydrophobic and ionic hydrophilic forms of molecules whose proportions depend upon the pH. The pK of such compounds is defined as the pH at which equal concentrations of both the uncharged and charged forms of the molecule are found. Four such compounds will be specifically described in the present invention, namely morphine, bupivacaine, oxine and clonidine.


STATE OF THE ART

Liposomes are vesicles consisting of a double layer of phospholipids in an aqueous solution, with their hydrophilic portions in contact with water and their hydrophobic portions inside the bilayers.
The liposomal encapsulation of amphiphilic compounds into phospholipid mono- and bi-layers has been poorly practised because this type of molecule has generally been considered to be unstable inside phospholipid vesicles (Reference 1).
In order to predict the feasibility and the stability of the association of pharmaceutical compounds with liposomes, the partition coefficient between water and an organic solvent, such as octanol (Poct), has been considered (Reference 1) as is described in Table 1.


TABLE 1 ______________________________________ Classification of the behaviour of compounds in liposomes based upon their partition coefficient between water and octanol (Reference 1). Log Poctanol -0.3 0 1.7 4 5 ______________________________________ Hydrophilic Amphiphilic Hydrophobic ______________________________________
Hydrophilic compounds with a negative log octanol/water partition coefficient (Log Poct<-0.3) are entrapped within the inner aqueous compartments of phospholipid vesicles and their stability and release depend upon the respective sizes and the electric charges of the compound and the pores of the lipid layers. Lipid soluble drugs have a high octanol/water partition coefficient (Log Poct>5) and are almost completely trapped inside the lipid layers. Their stability inside the lipid layers may be so high that they are not released anymore from the lipid layers once entrapped (Reference 2). Amphiphilic compounds have an intermediate partition coefficient (-0.3<Log Poct<5) and are readily partitioned between liposomal lipid and water phases depending on the pH of hydration of the vesicles referred to the compound's pK. Amphiphilic compounds were shown to be trapped into the liposomal bilayers only if they formed a complex with the lipid layers acyl chains (Reference 3).
The partition coefficients of most pharmaceutical compounds are within the -0.3 to 5 logarithmic range, thus being amphiphilic (Reference 4). This classification only offers empirical and often erroneous information on their liposomal encapsulation, thereby restricting their currently developed entrapment processes. Indeed, as a consequence of using the partition coefficient of the neutral species as the unique predictive data, amphiphilic compounds have been entrapped into liposomes after insertion of the sole neutral, apolar, hydrophobic species into the preliposomal lipid film. This method has been claimed in several patents or patent applications (References 5 to 9). No entrapment assays into the phospholipid bilayers have been performed using the ionic species of amphiphilic compounds inserted into the preliposomal lipid film, these species being considered as hydrophilic since they are water soluble, and thus unable to be inserted into phospholipid layers (Referenc

REFERENCES:
patent: 5244678 (1993-09-01), Legros et al.
J. Boogaerts et al.; ACTA Anaesthesiologica Belgica, vol. 46 No. 1, 19-24 (1995).
G.J. Grant et al., Regional Anesthesia, vol. 19 No. 4, 264-269 (1994).
J.G. Boogaerts et al., British Journal of Anaesthesia, vol. 75 No. 1, 319-325 (1995).
V. Umbrain et al., British Journal of Anaesthesia, vol. 75, 311-318 (1995).
C.J. Grant et al., Anesthesia & Analgesia, vol. 78, S138 (1994).

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