Solid Lipid Systems

High melting point lipids formed into pellets by melt-solidification or extrusion-spheronization, or filled directly into capsules can be used to slow the release of poorly soluble drugs. Waxy lipids that are crystalline at room temperature, such as Compritol® 888 ATO (glyceryl behenate) [71, 72] or high melting ethoxylated lipids such as Gelucire® 50/02 [73] can slow release by a combination of diffusion and erosion mechanisms [74, 75].

Formulation of piroxicam as Gelucire 50/13 microspheres provided rapid release that was ascribable to liquid crystal formation in an aqueous environment [76]. This may result in earlier onset of action, a desirable attribute with this anti-inflammatory agent.

15.3.2.1 Lipid-Polymer Solid Dispersions

Solid dispersion of poorly water soluble drugs in polymer may improve dissolution characteristics [77]. Strategies include crystallization of lipids within solid polymer matrices such as PEG 6000 [78-80]. This has led to the formulation of solid microemulsion preconcentrates that spontaneously form a microemulsion on polymer dissolution [81]. Fine dispersion of the lipid domains results in rapid dissolution and/or dispersion of drug compared to conventional drug suspensions and may accelerate absorption.

Table 15.2 Examples of lipid-based suspension, solutions, and emulsions used in enhancing the oral bioavailability (BA) of poorly water soluble drugs

Compound

Formulation

Study

max

Reference

Danazol

Oil-in-water emulsion of

Oral BA in fed humans

4.9 h for the emulsion vs. 3.1 h for

[65]

monoolein

the capsule

Griseofulvin

Corn oil-in-water emulsion

Oral BA in humans

5.7 h vs. 3.3 h for suspension

[66]

Ontazolast

SBO oil-in-water emulsion

Oral BA in rats

4.6 h vs. 3.3 h for suspension

[67]

Halofantrine

Solutions of peanut oil (LCT)

Oral BA in rats

T approximately 10 h cf. 6 h for max r r J

[68]

suspension

Cinnarizine

Oleic acid solution

Oral BA in beagle dogs

T unchanged cf. tablet max °

[69]

Griseofulvin

Oil suspensions of peanut oil

Oral BA in rats

Oil suspensions the same or slightly

[70]

(LCT), Captex 355 (MCT)

reduced T for lipid formulations

and triacetin (SCT)

compared to suspension

D LL

LU 22 cc U

8 12 16 20 Hours

Hours

Hours

Fig. 15.2 Plasma vs. time profiles after oral administration of poorly water soluble drugs from lipid formulations compared to suspensions. Left hand panel is oral administration of griseofulvin to rats as a corn oil in water emulsion (squares) versus suspension (circles) (Reproduced from [89]). Right hand panel is administration of cinnarizine in oleic acid or an aqueous suspension to beagle dogs (closed and open circles, respectively) (Reproduced from [69])

15.3.2.2 Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLNs) have the potential to encapsulate drugs for oral delivery. Slow erosion of the lipid controls drug release, prolonging plasma residence and "damping down" peak plasma concentrations. In vitro release is slowed, relative to other formulations [82-85].

In vivo studies using SLNs for oral administration (human and animal) are relatively limited. Camptothecin-loaded SLNs altered the drug's oral pharmacokinetics, resulting in two peaks in the plasma profile. The first peak was attributed to rapidly released free drug, the second peak to slower release from the SLN particles. Peak plasma concentration (Cmax) occurred approximately 6 h after administration [86]. Other reports have shown that:

• An SLN-based cyclosporine product exhibited prolonged plasma presence compared to Neoral™ formulation in rats [87] and pigs (Fig. 15.3) [88].

• T for quercetin was increased from 5 to 8 h, accompanied by a fourfold increase max 1 r J

in bioavailability [90].

• Tmax was increased by only 20 min with melatonin-loaded SLNs [91].

• Tmax of buspirone, formulated as SLNs, was not different from a simple solution [92].

• Vinpocetine delivered in six different SLN formulations did not show a difference in Tmax values compared to drug administered in a simple solution [93].

2200

c 1320

Time(hr)

Fig. 15.3 Illustration of plasma profiles for cyclosporine after oral administration in stearic acid SLNs (lower curve) vs. a microemulsifying lipid formulation (Neoral) (upper curve) (reproduced from [87])

TO i c 1320

Time(hr)

Fig. 15.3 Illustration of plasma profiles for cyclosporine after oral administration in stearic acid SLNs (lower curve) vs. a microemulsifying lipid formulation (Neoral) (upper curve) (reproduced from [87])

It would seem therefore that, in many cases, the formulation of poorly soluble drugs in SLN form does not affect absorption characteristics, relative to solution or suspension dosage. Further work is indicated to explain such inconsistent behavior.

SLNs pose a number of challenges that may limit more widespread application.

• Drug may be driven to the particle surface during lipid solidification, resulting in either burst or other nonuniform release [94].

• In vivo degradation of SLNs is not well characterized; hence, interpretation of biopharmaceutical behavior may be difficult.

• The crystalline nature of the lipids themselves can be questionable, as supercooling after processing may occur. Size reduction induces supercooling (as with fat emulsions) [95], again complicating the interpretation of in vitro release and in vivo kinetic data.

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