Parenteral liposome formulations

Vineland, NJ) or over-the-counter cosmetic creams promoted for improved hydration (L Oreal, Paris and Dior, Paris). More recently, parenteral liposome formulations of amphotericin B, doxorubicin, and dau-norubicin have been approved and marketed (ABELCET, Elan, the Liposome Co., Inc, Princeton, NJ AmBisome and DaunoXome, Nexstar/Fujisawa, Deerfield Park, IL Amphotec and Doxil, Sequus/ Alza, Menlo Park, CA), with others on the horizon for applications in photodynamic therapy. Although the vast majority of liposome preparations are constructed from phospholipids, other nonphospholipid materials can be used either alone or in mixtures to form bilayer arrays. One such example is Amphotec, which utilizes sodium cholesteryl sulfate as the primary lipid. Other liposome forming materials may include but are not limited to fatty-acid compositions, ionized fatty acids, or fatty acyl amino acids, longchain fatty alcohols plus surfactants, ionized lysophospholipids or combinations, non-ionic or ionic surfactants and amphiphiles, alkyl maltosides, a-tocopherol esters, cholesterol esters, polyoxyethylene alkyl ethers, sorbitan alkyl esters, and polymerized phospholipid compositions. ° ... 

All nystatin preparations are well tolerated by patients. Very occasionally nausea, vomiting and diarrhoea are reported following oral administration and skin irritation following topical application. Commercial development of a parenteral liposomal formulation of nystatin is in progress for the treatment of systemic mycoses and it is anticipated that this will provide similar clinical benefits to those observed with AmBisome. 

Schwendener RA, Schott H. Lipophilic 1-P-D-arabinofuranosylcytosine derivatives in liposomal formulations for oral and parenteral antitleukemic therapy in the murine L1210 leukemia model. J Cancer Res Clin Oncol 1996 122 723. 

Additional naturally occurring lipids may be minor components of oral lipid-based formulations. Terpenes such as peppermint oil (>50% menthol) are fairly hydrophobic but can provide some solvent capacity. Steroids such as cholesterol, while important in topical and in parenteral liposomal products, are not important as oral pharmaceutical adjuvants. Phospholipids (e.g., egg or soybean phosphatidylcholine) an essential component of cell membranes, are considered polar lipids, and have surfactant properties. 

Aseptic Lltration is necessary for parenteral formulations. Because both lipids and the structure of liposomes are unstable at high temperatures, conventional terminal steam sterilization is not suitable for liposome formulations. Thus, the membrane aseptic Lltration is the most reliable method for sterilizing liposome formulations. Since the possibility exists for the membrane being defective, it is advisable to test the integrity of the assembled unit by carrying out a bubble-point test. This test... 

A commercial product based on conventional liposomes has been introduced for the parenteral delivery of the anti-fungal drug, amphotericin B, which is poorly tolerated in conventional formulations. AmBisome, a liposomal formulation of amphotericin B, comprises SUV of diameter 50-100 ran. Two other lipid-based formulations of amphotericin B have also recently been commercially introduced ... 

Normally, reconstituted amphotericin B solutions are administered by slow infusion over a period of six hours (minimum one to two hours) to avoid potentially serious adverse effects. The manufacturers state that during administration the IV infusion solutions should be "protected from light." Photoprotection during administration is not required for ampothericin B cholesteryl sulfate complex, amphotericin B lipid complex, or liposomal formulations of amphotericin B. The administration of amphotericin B in parenteral fat emulsions is no longer an accepted practice. 

Other lipid compositions with synthetic lipids, hydrogenated SPC (HSPC) and PEG-modified phospholipids are often used, especially for liposome formulations intended for parenteral applications use (long circulating or stealth liposomes) (41). Several analytical methods to follow loss of lipids during the preparation steps are available. Radioactively labeled lipids ( H-DPPC, C-DPPC) or cholesterol ( H-cholesterol) or H-cholesteryl hexadecyl ether (NEN Life Science Products, Boston, MA, USA) or lipophilic fluorescence dyes (e.g. lipophilic BODIPy derivatives. Molecular Probes) are added at appropriate amounts to the initial lipid mixtures. 

Table 6 presents currently marketed liposomal formulations for parenteral administration. 

Drugs that are highly lipophilic by their own nature, e.g., taxanes, epothilones, and cyclosporins, can only be used therapeutically by the addition of possibly toxic solubilizing agents (e.g., Cremophor EL) in complex pharmaceutical formulations [97-99]. One of several feasible means of obtaining nontoxic parenterally applicable formulations of such drugs is their incorporation into the bilayer matrix of phospholipid liposomes. 

The antimykotie amphotericine is eneapsulated in liposomes and marketed as Am-Bisome" against severe systemic mycosis. The liposomal encapsulation reduces the toxicity of amphotericine while increasing the half-life of the drug and plasma level peaks [31], For stability reasons, the parenteral formulation is a lyophilized powder whieh has to be reeonstituted by adding the solvent just before administration. 

Solution formulations, however, do not typically have these same constraints, and complexation provides an alternative to the use of non-aqueous solvents or large volumes. A few derivatized CDs (e.g., hydro-xypropyl and sulfobutyl ether) can be safely administered by parenteral routes. This is often where complexation and its improvements in aqueous solubility can be most readily utilized. The derivatized CDs often can be used to replace cosolvents such as ethanol, polyethylene glycol, and lipids, as well as provide an alternative to the use of emulsions and liposomes. The hydroxypropyl and sulfobutyl ether derivatives are stable in solution and can be readily autoclaved, often improving the heat stability of drugs. There are however, reports of complexation of CDs with anti-oxidants and preservatives " with both decreased and increased efficacy. ... 

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