Liposome retention

Yerushalmi N, et al. Hyaluronic acid-modified bioadhesive liposomes as local drug depots effects of cellular and fluid dynamics on liposome retention at target sites. Arch Biochem Biophys. 1998 349 21-6. 

EP 274 714 (Daiichi Seiyaku appl. 18.12.1987 J-prior. 18.12.1987). liposomes with increased retention ... 

Several groups investigated the use of liposomes for the intra-pulmonary delivery. Farr et al. (1985) showed that the deposition of aerosolized liposomes in the human lung depends on the aerosol particle size. Short-term retention profiles for MLVs and SUVs deposited in the lung were indicative of clearance via the mucociliary transport mechanism. 

Kim et al. (1987) showed that the prolonged retention time of Ara-C in the peritoneal cavity after intraperitoneal administration of the drug in liposomal form as discussed above resulted in better therapeutic effects on intraperitoneally inoculated L1210 cells, as compared to the free drug. The activity of intraperitoneally administered cDDP on Ehrlich ascites carcinoma in mice was increased after encapsulation in neutral liposomes (Sur et al., 1983). The in vivo studies revealed improved antitumor activity and a lower toxicity sifter administration of cDDP liposomes compared to free drug. 

Gregoriadis, G. (1988a). Fate of injected liposomes Observations on entrapped solute retention, vesicle clearance and tissue distribution in vivo, in Liposomes as Drug Carriers Recent Trends and Progress (G. Gregoriadis, ed.), John Wiley and Sons, Chichester, pp. 3-18. 

Hunt, C. A., Rustum, Y. M., Mayhew, E., and Papahadjopoulos, D. (1979). Retention of cytosine arabinoside in mouse lung following intravenous administration in liposomes of different size, Drug Metabol. Dispos., 7, 124-128. 

Taillardat-Bertschinger, A., Marca-Martinet, C. A., Carrupt, P. A., Reist, M., Caron, G., Fruttero, R., Testa, B. Molecular factors influencing retention on immobilized artiflcial membranes (1AM) compared to partitioning in liposomes and n-octanol. Pharm. Res. 2002, 79, 129-Til. 

Figure 3. Retention of immunoliposomes in lung. Immunoliposomes (200 /ig lipid) labeled with lxlIn-DTPA-SA were injected iv. The percent initial accumulation in lung was calculated at indicated time intervals. Bar is S.D. (n=3) Data taken with permission from reference 14. Key , 34A-liposomes (PC chol GMx=10 5 l), Ab lipid= 1 11 (w/w), 297 nm in average diameter A, 34A-liposomes (PC chol GM.=10 5 1), Ab lipid=l 37 (w/w), 292 nm in average diameter , 34A-liposomes (PC chol PS=10 5 1), Ab lipid=l 8 (w/w), 253 nm in average diameter A, 34A-liposomes (PC chol PS=10 5 1), Ab lipid=l 31 (w/w), 255 nm in average diameter.

A method where phospholipids are entrapped in the pores of resin beads, in the forms of multilamellar vesicles, has been described [313-319,376]. In some ways, the idea is similar to that of IAM chromatography, even though the resin is modified differently. The retention indices correlate very well with the partition coefficients measured in liposome-water systems (described below). 

Osterherg, T. Svensson, M. Lundahl, P, Chromatographic retention of drug molecules on immohilized liposomes prepared from egg phospholipids and from chemically pure phospholipids, Eur. J. Pharm. Sci. 12, 427 139 (2001). 

Talsma, H., van Steenberg, M.J., and Crommelin, D.J.A. (1991) The cryopreservation of liposomes 3. Almost complete retention of a water-soluble marker in small liposomes in a cryoprotectant containing dispersion after a freezing/thawing cycle. Int. J. Pharm. 77, 119-126. 

Crowe and Crowe [3.39] proved that it is sufficient for certain liposomes, e. g. egg phosphatidyl-choline (DPPC), to be vitrified by trehalose or dextran during freezing and freeze drying. In trehalose the retention rate was almost 100 %, and in dextran more than 80 %. This did not apply to egg PC-liposomes Dextran as CPA alone led to an almost total loss of the CF-indicator, but addition of dextran into a trehalose solution (Fig. 3.20) also reduced the retention rate of CF substantially, e. g. from 90 % in a pure trehalose to approx. 45 % if trehalose and dextran were in equal amounts in the solution. Since T of dextran is approx. -10 °C and Tg- of trehalose is -30 to -32 °C, dextran should form a glass phase at much higher temperatures than trehalose. Therefore the stabilization of egg- PC with trehalose cannot be related with the vitrification. Crowe showd with IR spectroscopy that egg-PC freeze dried with 2 g trehalose/g lipid had almost the identical spectrographic characteristics as the hydrous lipid Trehalose molecules replaced the water molecules, and hydrogen... 

Fig. 3.21. Retention rate of liposome-encapsulated hemoglobin as a function of the time elapsed after the reconstitution of the freeze dried LEH, with different trehalose concentrations as CPA. 1, no trehalose 2, 10 mM 3, 50 mM 4, 150 mM 5, 300 mM trehalose (Fig. 2 from [3.43]).

Studies with the freeze dried DPPC liposomes in trehalose solution showed, that not Tg )f the amorphous sugar is the critical temperature during storage, but the bilayer transition emperature Tm. for the lyposomes determines the short term stability of the formulation. With trehalose as lyoprotectant and a low residual water content, Tm proved to be 10 to 30 °C below the onset of T . 30 min heating above Tm but well below T% decreased the retention of CF after rehydration. Tm< after the heating was reduced from 40 to 80 °C to below 25 °C. 

Freeze dried liposomes loaded with doxorubicin (DXR) have been stored for 6 months at temperatures between -20 and +50 °C. Up to 30 °C, no sign of degradation was found, but at 40 to 50 °C - well below T of the dried cake - the total DXR content and the retention of the drug after dehydration decreased, while the size of the liposomes increased jo a certain extent. The stability with RM below 1 % has been better than with 2.5-3.5 %. 

In summary [3.65], with an optimized formulation and freeze drying protocol, liposomes loaded with water-soluble CF or DXR can be freeze dried with a 90 % retention upon rehydration. The cake is stable for at least 6 months at temperatures up to 30 °C. 

Although monolayers at the gas-water interface are useful to study adsorption phenomena of e.g. proteins at membranes they are not a very good model, since they represent only one half of a biological membrane. Attempts have therefore been made to extend this concept of polymer monolayers to bilayers and particularly to liposomes. It was to prove, whether the monomers (Table I.) could form bilayers and whether a polyreaction within these bi-layers was possible under retention of the structure and the orientation of the molecules. 

Mixtures of proteins, natural and polymerizable lipids can be transferred into liposomes and polymerized hereafter. Initial experiments have shown that even very complex proteins such as F F.-ATPase can be incorporated in polymeric liposomes by this method under retention of the activity of the protein (76). 

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