Doxil

Adrimedac (medac) I Adriblastina (Farmitalia Doxil (Sequus)... 

Several liposome-based drugs have been approved for clinical application [64]. One of the clinically approved liposomes is Doxil, a PEGylated liposome containing doxorubicin (DOX), which is used for the treatment of a number of diseases [65]. As shown in this case, in the field of liposome drug development, PEG is widely used to protect the liposome from recognition by opsonins, thereby reducing liposome clearance. 

Many drugs are administered as parenterals for speed of action because the patient is unable to take oral medication or because the drug is a macromolecule such as a protein that is unable to be orally absorbed intact due to stability and permeability issues. The U.S. Pharmacopoeia defines parenteral articles as preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal. They include intravenous, intramuscular, or subcutaneous injections. Intravenous injections are classified as small volume (<100 mL per container) or large volume (>100 mL per container) injections. The majority of parenteral dosage forms are supplied as ready-to-use solutions or reconstituted into solutions prior to administration. Suspension formulations may also be used,101 although their use is more limited to a subcutaneous (i.e., Novolin Penfill NOVO Nordisk) or intramuscular (i.e., Sandostatin LAR Depot Novartis) injection. Intravenous use of disperse systems is possible but limited (i.e., Doxil Injection Ortho Biotec). 

Pegulated liposomal doxorubicin (Doxil) Liposome encapsulated doxorubicin Ovarian Phase II data... 

Amphipathic Weak Base Loading into Preformed Liposomes Having a Transmembrane Ammonium Ion Gradient From the Bench to Approved Doxil... 

Doxil , of which I had the pleasure of being one of the inventors (1-12), serves as an example of successful passive targeting to tumors in animals and humans (1,3,4,13). The ammonium sulfate (AS) transmembrane inside high/outside low gradient-driven loading is also the basis for doxorubicin (DOX) loading for Targeted Doxil (14), which soon will be tested in clinical trials. 

Doxil, the first liposomal drug that was approved by the Food and Drug Administration, in 1995, is a good example of the successful application of a transmembrane inner liposome high/outer liposome low ammonium ion gradient for remote loading of an amphipathic weak base, the anticancer... 

THE DOXIL EXAMPLE FOR REMOTE LOADING OF AMPHIPATHIC WEAK BASE INTO LIPOSOMES... 

The octanol/buffer represents a partition coefficient between two bulk phases it is less affected by the structure of the analyte and therefore it cannot be used to predict the exact value of liposome membrane-to-buffer Xp, which is also affected by the geometry of the analyte (41 4). However, it is accepted and established that the octanol-to-buffer can help to predict transmembrane passive diffusion (40). In the case of liposomes such as Doxil, in which the internal aqueous phase (intraliposome aqueous phase) is different from the external liposome aqueous medium due to large differences in the composition and pH of these two aqueous phases, there are two different liposome membrane-to-aqueous phase partition coefficients this is referred to as asymmetry in the membrane-to-aqueous media partition coefficient. 

EXPERIMENTAL DEMONSTRATION OF DOX REMOTE LOADING TO FORM DOXIL... 

Removal of nonentrapped doxorubicin (in the case of Doxil this step was omitted as loading is approaching 100%)... 

All studies on the application of Doxil were done in collaboration with Professor Alberto Gabizon, Oncology, Shaare Zedek Hospital, Jerusalem, Israel (3-5,8). 

Burstein HJ, Ramirez MJ, Petros WP, et al. Phase I study of Doxil and vinorelbine in metastatic breast cancer. Ann Oncol 1999 10 1113. 

Judson I, Radford JA, Harris M, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL(R)/CAELYX(R)) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma, a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2001 37 870. 

Chanan-Khan A, Szebeni J, Savay S, et al. Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil) possible role in hypersensitivity reactions. Ann Oncol 2003 14 1430. 

Recently, this method was adapted to label two commercially available liposomal formulations doxorubicin encapsulated in polyethylene glycol (PEG)-coated liposomes (Caelyx /Doxil ) (14) and daunorubicin encapsulated in small distearoyl-phosphatidyl-choline/cholesterol liposomes (Daunoxome ) (15). Although no DTPA was encapsulated in these liposomes, the labeling efficiency was typically between 70% and 80% and the radiolabeled preparations were stable in vivo during the time course of the experiment (four hours). Most likely, the lipophilic In-oxine avidly associates with the lipid bilayer and encapsulation of DTPA might not be necessary when the experimental observation period does not exceed four to six hours. 

Figure 3 Planar scintigraphic images acquired at various times of a normal rat intravenously injected with Tc-Doxil (17MBq) Tc, 2 mg doxorubicin, and 16 mg total lipid labeled using Tc-iV,iV-bis(2-mercaptoethyl)-Af, Af diethyl-ethylenediamine method. Abbreviations-. H, heart L, liver K, kidney B, bowel.

Bao A, Goins B, Klipper R, Negrete G, Phillips WT. Direct Tc labeling of pegylated liposomal doxorubicin (Doxil) for pharmacokinetic and non-invasive imaging studies. J Pharmacol Exp Ther 2004 308 419. 

Skubitz KM. Phase II trial of pegylated-liposomal doxirubicin (Doxil) in sarcoma. Cancer Investig 2003 21 167. 

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