Development and optimization of a new processing approach for manufacturing topical liposomes-in-hydrogel drug formulations by dual asymmetric centrifugation

Abstract

Objectives: The objective of the present study was to utilize dual asymmetric centrifugation (DAC) as a novel processing approach for the production of liposomes-in-hydrogel formulations. Materials and Methods:Lipid films of phosphatidylcholine, with and without chloramphenicol (CAM), were hydrated and homogenized by DAC to produce liposomes in the form of vesicular phospholipid gels with a diameter in the size range of 200-300 nm suitable for drug delivery to the skin. Different homogenization processing parameters were investigated along with the effect of adding propylene glycol (PG) to the formulations prior to homogenization. The produced liposomes were incorporated into a hydrogel made of 2.5 % (v/v) soluble β-1,3/1,6-glucan (SBG) and mixed by DAC to achieve a homogenous liposomes-inhydrogel-formulation suitable for topical application.Results and Discussion: CAM-containing liposomes with a vesicle diameter of 282 ± 30 nm and polydispersity index (PI) of 0.13 ± 0.02 were successfully produced by DAC after 50 minutes centrifugation at 3500 rpm, and homogenously (< 4 % content variation) incorporated into the SBG hydrogel. Addition of PG decreased the necessary centrifugation time to 2 minutes and 55 seconds, producing liposomes of 230 ± 51 nm and PI of 0.25 ± 0.04. All formulations had an entrapment efficiency of approximately 50%. Conclusions:We managed to develop a relatively fast and reproducible new method for the production of liposomes-in-hydrogel formulation by DAC.

Dual Centrifugation - A Novel “in-vial” Liposome Processing Technique

“…Similarly, the morphology of the liposome vesicles was affected by the lipid composition, with more lamellas formed in more rigid lipid formulations [10]. The same effect was observed when propylene glycol was added to the lipid mixtures (PG-Lip) [18]. PG obviously reduces the lipid interactions in the lipid bilayers and makes the membranes more flexible than the conventional liposome formulation without PG (C-Lip).…”

“…PG obviously reduces the lipid interactions in the lipid bilayers and makes the membranes more flexible than the conventional liposome formulation without PG (C-Lip). This gave a significant shorter DC processing time required to reach the aimed liposome sizes of 200-300 nm, the optimal liposome size for topical drug deposition [27], with a processing time of 3 minutes with PG vs. 50 minutes without PG [18]. In these experiments, the standard deviation of the vesicle sizes, and the PI values were higher for the PG-Lip formulation because of the reduced processing time.…”

“…In general, entrapping water-soluble drugs into VPGs does not seem to affect the liposome vesicle sizes [10,15,18]. The water-soluble fluorescence dye calcein has been used in several studies to investigate the entrapment efficiency of water-soluble drugs into DC-manufactured liposomes [15,16,21].…”

“…Also more lipophilic drugs, such as chloramphenicol (CAM), have been entrapped into liposomes by DC-homogenization and EE values close to 50% were found [18,19]. When comparing this value with EE values obtained with the conventional liposome production techniques, probe sonication and filter extrusion, when using the same lipids and CAM-to-lipid ratio, a 70% increase in EE was achieved by using DC, even though the resulting liposomes were smaller (282 ± 30 nm) compared to those getting from sonication (836 nm) or extrusion (667 nm).…”

“…However, the average sizes of liposomes made by homogenization of highly concentrated lipid mixtures are small, but seldom below 100 nm with PI values > 0.2 (PCS (Photon Correlation Spectroscopy), intensity weighted 1 ) [10,[16][17][18][19][20][21]. At a first glance, this appears somewhat confusing, since it is known that the liposome diameters clearly depend on the energy by which the highly concentrated lipid-water mixture has been treated and thus, liposomes made by HPH would have been expected to be very small.…”