Pharmaceutical Manufacturing Handbook: Production and

1260 NANOTECHNOLOGY IN PHARMACEUTICAL MANUFACTURING
preparation, characteristics, and applications of nanosized liposomes are presented
as well as some modifi ed liposomes and recent progress.
Although various methods of manufacturing liposomes are reported, three types
are usually involved: hydration of lipid fi lm, interface aggregation of lipid molecules
by emulsion - like process, and lipid solutions dispersing into nonsolvents by an
injection - like process or controlled mixture. Practical methods are thin - fi lm hydration
[65] , reverse - phase evaporation [66] , ethanol injection [67] , polyol dilution [68] ,
double emulsions [69] , proliposome method [70] , and high - pressure homogenization
[71] . Liposomes may have various morphologies related to manufacturing methods,
mainly multilamellar vesicles (MLVs), large unilamellar vesicles (LUVs), and small
unilamellar vesicles (SUVs). Liposomes can be further processed by sonication,
detergent depletion, membrane fi ltration [72] , and lyophilization [73] to make them
fi ner and more uniform or stable. For example, MLVs are sonicated to SUVs.
The composition of liposomes is a key factor in their manufacturing. Phospholipids
are major components of liposomes. In terms of resources, phospholipids are
classifi ed as natural, semisynthetic, and wholly synthetic phospholipids. Natural
phospholipids also have different resources (e.g., soybean, egg yolk). In terms of
polar head groups, phospholipids are classifi ed as phosphatidylcholine (PC), phosphatidylethanolamine
(PE), phosphatidylserine (PS), phosphatidylinositol (PI),
phosphatidylglycerol (PG), and phosphatidic acid (PA), where PC and PE are the
most used. Different polar head groups result in varied surface charged liposomes
that then infl uence the stability and in vivo distribution. Because PS, PI, PG, and PA
have negative charges, the liposomes containing them are negatively charged. Sometimes,
other lipids such as N,N′ - dioleoyl - N,N′ - dimethylammonium chloride
(DODAC) and stearylamine are mixed with phospholipids to prepare positively
charged liposomes. Cholesterol is commonly used with phospholipids because cholesterol
can make liposomal membranes stronger [50] . The mole percentage of
cholesterol in the liposomal composition is commonly not more than 50%. Lecithin
(an often used term in the lipid fi eld) as a phospholipid from natural resources (e.g.,
soybean lecithin and egg lecithin) is often used to manufacture liposomes, which is
actually a mixture composed of various kinds of phospholipids though PC dominates.
The long - chain fatty acids constituting phospholipids also have many types,
such as lauric (C12), myristic (C14), palmitic (C16), and stearic (C18). In general,
unsaturated fatty acids occur in natural phospholipids. Dimyristoyl phosphatidylcholine
(DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine
(DSPC), and dipalmitoyl phosphatidylethanolamine (DPPE) are the most
common synthetic phospholipids. The length of the lipid chain infl uences the gel –
liquid crystalline phase transition temperature ( Tc ) of phospholipids, wherein longer
chained lipids lead to higher Tc . For example, DPPC has a Tc of 41 ° C while DSPC
has a Tc of 54 ° C [50] .
Drug entrapment is an important parameter in manufacturing liposomes which
is infl uenced by many factors: the types, molecular weights, and physicochemical
properties of drugs; the types, sizes, and compositions of liposomes; and the manufacturing
methods. In addition, entrapped drugs may leak during storage. Drugs may
be entrapped in one of two parts of liposomes, the inner phase or bilayers, depending
on the physicochemical property of the drugs. Water - soluble drugs prefer the
aqueous inner phase while lipophilic drugs prefer the hydrophobic environment of
bilayers. Macromolecules such as peptides and proteins can adsorb onto bilayers,