Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 369

high loading level and its high stability during storage and blood
circulation are required. However, due to the combination of needs
for nano-liposomes and high dose of doxorubicin (~50 mg/m 2 ) to
achieve the sufficiently high loading (to be in the range of intra-
liposome drug concentration, which is in the range of hundreds of
mM) is not an easy task. When the loading is poor, so will be the
drug/lipid ratio. This means that either therapeutic levels of drug
cannot be reached or therapeutic use of such liposomes will require
administering very large amounts of lipids. In addition, when
the loading is inefficient there is a great loss of the active agent
during the loading and a need to remove unloaded drug. Therefore,
the use of liposomes as a vehicle becomes inefficient as well as
uneconomical. The major requirements of drug loading into nano-
liposomes are (1) to achieve a high level of loading of active agent
in the liposome and to make this loading stable during handling
and storage, irrespective of the nature of the agent and (2) to fit the
release rate of the loaded active agent to specific therapeutic aims of
the liposome formulation.
A careful analysis of the currently available loading approaches
reveals clearly that the remote loading approach is the best, and
in many cases the only, way to achieve the desired intraliposome
drug concentration (usually defined as drug to lipid mole ratio)
(Barenholz, 2003).
12.4.6.2 Drug classification
In 1985, we looked for a simple way to classify drugs by their physico-
chemical features in a way that will enable the formulator to predict
which loading approach to use or, specifically, if a drug is suited for
a remote loading approach. At that time, with very little available
information, we came up with an oversimplified approach and
classified all agents into three categories based on their oil/buff er
and octanol/buff er partition coefficients ( K p ). Category I, molecules
having high oil/buff er K p , are considered lipophilic; these molecules
do not fit liposomes as their carrier. Category II, molecules having low
oil/buff er partition coefficient and medium to high octanol/buff er
K p , are amphipathic. Category III, molecules of very low values in
both partition coefficients, by definition, are defined as being water
soluble. For some of the molecules, those which are amphipathic
weak acids or bases, the classification between group II and III is pH