**3. Microemulsion templates**

Another precursor which can be used for SLN preparation is the microemulsion.

Microemulsions are clear, thermodynamically stable, isotropic liquid mixtures of oil, water and surfactant, frequently in combination with a cosurfactant. The aqueous phase may contain salt(s) and/or other ingredients, and the "oil" may actually be a complex mixture of different hydrocarbons and olefins.

The concept of microemulsion was first introduced by Hoar and Schulman in 1943 [17]; they prepared the first microemulsion by dispersing oil in an aqueous surfactant solution and adding an alcohol as a cosurfactant, leading to a transparent, stable formulation.

The existence of this theoretical structure was later confirmed by the use of various technolo‐ gies, and today we can adopt the definition given by Attwood [18]: "a microemulsion is a system of water, oil, and amphiphilic compounds (surfactant and cosurfactant) which is a transparent, single optically isotropic, and thermodynamically stable liquid".

microemulsion can be prepared, too, in order to encapsulate hydrophilic drugs within SLN [21,22]. SLN with reduced mean particle size and narrow size distribution can be obtained

Techniques for the Preparation of Solid Lipid Nano and Microparticles

http://dx.doi.org/10.5772/58405

57

The lipids employed can be triglycerides, fatty acids, fatty alcohols. Surfactants can be chosen among bile salts, phospholipids, polysorbates and cosurfactants among short chain alcohols and glycols (butanol, hexanol, hexanediol, propylene glycol), short chain fatty acids (butyric

Dilution of the microemulsion can be performed with a volume of water 10 to 200 compared

Recently, Mumper and Jay [23,24] patented a microemulsion based method to produce SLN. The technique is simple, reproducible, and easy to scale-up. In particular for the production of SLN the authors start from an O/W microemulsions: an emulsifying wax is melted (37-55 °C) and water is then added at the same temperature under minimal stirring to form an homogeneous milky slurry. Upon the addition of defined amounts of a suitable pharmaceut‐ ically-acceptable polymeric surfactant in water, a clear and stable liquid matrix O/W microe‐ mulsion is formed. SLN are precipitated from this O/W microemulsion by cooling of the

The matrix material may be selected from a variety of excipients including for examples waxes, such as emulsifying wax (Polysorbate 60, PEG-150 Stearate and Steareth-20), the polymeric surfactants can be chosen among the Brij®-type, polyethylene glycol derivatives of fatty acids such as PEG-400 monostearate, and phospholipids such as phosphatidylcholine (lecithin).

An advantage of this invention is that the described nanoparticle system can be formulated at mild operating temperatures, rapidly, reproducibly and cost-effectively from the microemul‐ sion precursor in an one-step process and contained in a manufacturing vessel, vial or

Moreover all ingredients are potentially biocompatible, well-defined and uniform solid nanoparticles (50 to 300 nm) may be reproducibly made, no organic solvents were used during the preparation, very high entrapment efficiencies are achievable [25], especially for waterinsoluble drugs, and cell-specific ligands can easily be incorporated on the surface of the

Recently, a new method was developed to prepare-in a controlled way-SLN by coacervation. This method allows the incorporation of drugs, without using very complex equipment or dangerous solvents, and is therefore inexpensive for laboratory and industrial application. It is based on the interaction between a micellar solution of a fatty acid alkaline salt (soap) and

after dilution in cool (2-10° C) water of the hot microemulsion.

undiluted O/W microemulsion to room temperature or to 4 °C.

to microemulsion volume.

container.

nanoparticles [26].

**4. Coacervation method**

**3.2. Microemulsion cooling technique**

acid, hexanoic acid), phosphoric acid alkyl esters and benzyl alcohol [20].

The main difference between emulsions and microemulsions lies in the size — and shape of the particles dispersed in the continuous phase: these are at least an order of magnitude smaller in the case of microemulsions (10 – 200 nm) than those of conventional emulsions (1 – 20 μm). Also, whereas emulsions consist of roughly spherical droplets of one phase dispersed into the other, microemulsions are dynamic systems, constantly evolving between various structures ranging from droplet-like swollen micelles to bicontinuous structures.

Microemulsions are formed when and only when the interfacial tension at the oil/water interface is brought to a very low level and when the interfacial layer is kept highly flexible and fluid.

These two conditions are usually met by a careful and precise choice of the components and of their respective proportions, and by the use of a "cosurfactant" which brings flexibility to the oil/water interface [17].

This situation leads to a thermodynamically optimised structure, which is stable — as opposed to conventional emulsions — and does not require high input of energy (i.e. through agitation) to be formed. In contrast to ordinary emulsions, microemulsions form upon simple mixing of the components and do not require the high shear conditions generally used in the formation of ordinary emulsions.

Because the size of the particles is much smaller than the wavelength of visible light, microe‐ mulsions are transparent and their structure cannot be observed through an optical micro‐ scope.

The three basic types of microemulsions are direct (O/W), reversed (W/O) and multiple (W/O/W and O/W/O).

Hot microemulsion can be used as template for SLN production: in this case the oil phase is made up of the solid lipid, liquefied above its melting point; SLN can be obtained through dilution of the hot microemulsion in cold water (microemulsion dilution technique) or by simple cooling of the hot microemulsion itself (microemulsion cooling technique).

Because of their unique solubilisation properties, microemulsions have attracted increasing attention as potential drug delivery systems for poorly water soluble active pharmaceutical ingredients (API) [19]; also the good solubilisation properties of hot microemulsion precursor allows an advantageous drug loading within SLN for many drugs, especially for poorly water soluble drugs.

#### **3.1. Microemulsion dilution technique**

Gasco [20] was the first researcher to use a microemulsion template for the preparation of SLN. Lipids are heated above their melting point and an aqueous phase containing surfactants and cosurfactants is added at the same temperature in order to form a clear O/W microemulsion under stirring; lipophilic drug can be dissolved in the hot microemulsion. Multiple W/O/W microemulsion can be prepared, too, in order to encapsulate hydrophilic drugs within SLN [21,22]. SLN with reduced mean particle size and narrow size distribution can be obtained after dilution in cool (2-10° C) water of the hot microemulsion.

The lipids employed can be triglycerides, fatty acids, fatty alcohols. Surfactants can be chosen among bile salts, phospholipids, polysorbates and cosurfactants among short chain alcohols and glycols (butanol, hexanol, hexanediol, propylene glycol), short chain fatty acids (butyric acid, hexanoic acid), phosphoric acid alkyl esters and benzyl alcohol [20].

Dilution of the microemulsion can be performed with a volume of water 10 to 200 compared to microemulsion volume.

#### **3.2. Microemulsion cooling technique**

system of water, oil, and amphiphilic compounds (surfactant and cosurfactant) which is a

The main difference between emulsions and microemulsions lies in the size — and shape of the particles dispersed in the continuous phase: these are at least an order of magnitude smaller in the case of microemulsions (10 – 200 nm) than those of conventional emulsions (1 – 20 μm). Also, whereas emulsions consist of roughly spherical droplets of one phase dispersed into the other, microemulsions are dynamic systems, constantly evolving between various

Microemulsions are formed when and only when the interfacial tension at the oil/water interface is brought to a very low level and when the interfacial layer is kept highly flexible

These two conditions are usually met by a careful and precise choice of the components and of their respective proportions, and by the use of a "cosurfactant" which brings flexibility to

This situation leads to a thermodynamically optimised structure, which is stable — as opposed to conventional emulsions — and does not require high input of energy (i.e. through agitation) to be formed. In contrast to ordinary emulsions, microemulsions form upon simple mixing of the components and do not require the high shear conditions generally used in the formation

Because the size of the particles is much smaller than the wavelength of visible light, microe‐ mulsions are transparent and their structure cannot be observed through an optical micro‐

The three basic types of microemulsions are direct (O/W), reversed (W/O) and multiple

Hot microemulsion can be used as template for SLN production: in this case the oil phase is made up of the solid lipid, liquefied above its melting point; SLN can be obtained through dilution of the hot microemulsion in cold water (microemulsion dilution technique) or by

Because of their unique solubilisation properties, microemulsions have attracted increasing attention as potential drug delivery systems for poorly water soluble active pharmaceutical ingredients (API) [19]; also the good solubilisation properties of hot microemulsion precursor allows an advantageous drug loading within SLN for many drugs, especially for poorly water

Gasco [20] was the first researcher to use a microemulsion template for the preparation of SLN. Lipids are heated above their melting point and an aqueous phase containing surfactants and cosurfactants is added at the same temperature in order to form a clear O/W microemulsion under stirring; lipophilic drug can be dissolved in the hot microemulsion. Multiple W/O/W

simple cooling of the hot microemulsion itself (microemulsion cooling technique).

transparent, single optically isotropic, and thermodynamically stable liquid".

structures ranging from droplet-like swollen micelles to bicontinuous structures.

and fluid.

scope.

the oil/water interface [17].

56 Application of Nanotechnology in Drug Delivery

of ordinary emulsions.

(W/O/W and O/W/O).

soluble drugs.

**3.1. Microemulsion dilution technique**

Recently, Mumper and Jay [23,24] patented a microemulsion based method to produce SLN. The technique is simple, reproducible, and easy to scale-up. In particular for the production of SLN the authors start from an O/W microemulsions: an emulsifying wax is melted (37-55 °C) and water is then added at the same temperature under minimal stirring to form an homogeneous milky slurry. Upon the addition of defined amounts of a suitable pharmaceut‐ ically-acceptable polymeric surfactant in water, a clear and stable liquid matrix O/W microe‐ mulsion is formed. SLN are precipitated from this O/W microemulsion by cooling of the undiluted O/W microemulsion to room temperature or to 4 °C.

The matrix material may be selected from a variety of excipients including for examples waxes, such as emulsifying wax (Polysorbate 60, PEG-150 Stearate and Steareth-20), the polymeric surfactants can be chosen among the Brij®-type, polyethylene glycol derivatives of fatty acids such as PEG-400 monostearate, and phospholipids such as phosphatidylcholine (lecithin).

An advantage of this invention is that the described nanoparticle system can be formulated at mild operating temperatures, rapidly, reproducibly and cost-effectively from the microemul‐ sion precursor in an one-step process and contained in a manufacturing vessel, vial or container.

Moreover all ingredients are potentially biocompatible, well-defined and uniform solid nanoparticles (50 to 300 nm) may be reproducibly made, no organic solvents were used during the preparation, very high entrapment efficiencies are achievable [25], especially for waterinsoluble drugs, and cell-specific ligands can easily be incorporated on the surface of the nanoparticles [26].
