Classical Lipid Based Formulations Used in Oral Drug Delivery

Lipid-based formulations range from simple lipid solutions to more complex systems incorporating triglycerides, partially digested triglycerides, semisynthetic ester glycerides, lipophilic and hydrophilic surfactants and cosolvents [59, 60]. The formulation can influence digestibility, dispersion and solubilization of the lipid vehicle in vivo, in turn influencing drug absorption. Pouton has proposed a lipid classification scheme to provide insight on lipid behavior on oral dosage (Table 15.1) [59].

• Type I formulations comprise drug dissolved in dietary glycerides or vegetable oils and bioavailability is highly dependent on digestion [60]. Lipolysis of the lipid results in dispersion and solubilization of the drug through mixed micellar systems.

• Type II formulations are self-emulsifying systems (SEDDS), combining lipid and water insoluble surfactant(s), which are self-emulsified by gentle agitation [61]. The hydrophobic nature of the surfactant and physicochemical properties of the lipid dictate the type and capacity of the formed solubilized entity.

• Type III formulations contain greater quantities of hydrophilic and/or hydrophobic surfactants to enhance dispersion. They are less dependent on digestion to provide reduced particle size. Type IIIB systems are commonly described as self-microemulsifying drug delivery systems (SMEDDS) [62], which may be capable of promoting drug absorption independent of digestion [61].

• Type IV formulations do not contain lipids but comprise a combination of drug, surfactant, and cosolvent. They often provide highly solubilized drug in the formulation [59]. They are predisposed to drug precipitation in GI fluids, forming fine suspensions or amorphous particles that readily dissolve [60].

Table 15.1 The classification of lipid-based formulations proposed by Pouton [59]

Type I

Type II

Type IIIA

Type IIIB

Type IV

Hydrophobic composition

High

-►

Low

Lipid: TG, DG, MG (%)

100

40-80

40-80

<20

-

Water insoluble surfactants

-

20-60

-

-

0-20

HLB<12 (%)

Water soluble surfactants

-

-

20-40

20-50

30-80

HLB>12 (%)

Hydrophilic cosolvents (%)

-

-

0^10

20-50

0-50

Particle size on dispersion (nm)

Coarse

100-250

100-250

50-100

<100

Importance of digestion

Crucial

-►

Not recognized as essential but

may occur

Effect of aqueous dilution

Not important

-►

Loss of solvent capacity

Lipid-based formulations commonly utilize lipids that are liquids at room temperature; hence, they are not designated as matrix or erosion controlled release systems. Rapid dispersion in the GIT, assisted by digestion or the high interfacial activity in the formulation can engender short diffusional distances and rapid release [63, 64]. Thus in the absence of physiological effects that might delay gastric emptying or absorption, these formulations will not constrain but may even increase the rate of drug availability for absorption. Consequently, there are reports of both rapid and delayed absorption from lipid-based formulations as listed in Table 15.2.

Simple lipid formulations often exhibit a delayed Tmax relative to other presentations for poorly water soluble drugs. Figure 15.2 illustrates the relative systemic exposure for griseofulvin when administered in lipid emulsion compared to a lipid or aqueous suspension. In addition to the greatly increased exposure from the emulsion, a delayed T is also evident.

J max

Conversely, plasma profiles may be unchanged compared to a conventional tablet or simple suspension. For example, although the bioavailability of cinnarizine was improved fourfold in beagles when dosed as an oleic acid solution, compared to a tablet [69], there was no delay in reaching Tmax. Delayed absorption, reflected in greater Tmax values may reflect the time taken for lipid digestion and drug transport. Such delay is probably not clinically relevant in most cases but the increased exposure (bioavailability) can clearly be beneficial.

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