CryoFESEM

Hexosomes

Cubosomes

Fig. 15.6 Images of cubosomes and hexosomes using cryo-transmission electron microscopy (cryo-TEM) and cryo-field emission scanning electron microscopy (cryo-FESEM)

[113, 114] (e.g. oleyl glycerate), glycerol ethers [115, 116] (selachyl alcohol) and esters [117] (such as GMO), glycolipids [118, 119] (1-O-phytanyl-b-D-xyloside), branched chain alcohols [120] (phytantriol) and nonionic urea surfactants [121, 122] (1-(2-hydroxyethyl)-1-oleyl urea). Many have been investigated, especially GMO as it is widely available and is used in food products [123, 124].

15.3.3.2 Controlled Release from Liquid Crystalline Structures

The tortuous structure of cubic phases and the closed micellar structure of the inverse hexagonal phase have potential for sustaining delivery [125]. The aqueous and lipid domains of the matrix may provide solubilization and sustained release for drugs of widely varying polarity and structure. Wyatt et al. assessed the in vitro release of drugs of varying chemical properties from GMO-based cubic phases [126]. In the presence of simulated gastrointestinal fluids the V2 matrix provided sustained, diffusion-controlled release of aspirin, with 70% released after 24 h, compared to 100% dissolution of the control tablet after 2 h. Such diffusion control has been subsequently confirmed. Clogston and Caffrey studied release rates of hydrophilic compounds, ranging from small molecules to DNA macromolecules, from cubic phases [127].

Release rate may also depend on matrix nanostructure. Release rates of the hydrophobic anticancer drugs paclitaxel and irinotecan were more rapid from cubic than from hexagonal phases. The same patterns were observed with the hydrophilic compounds octreotide, histidine, and glucose [128]. Glucose release depended on

Oleyl glycerate

Glyceryl monooleate

Selachyl alcohol

1-O-phytanyl-P-D-xyloside

1-O-phytanyl-P-D-xyloside

H2N'

1-(2-hydroxyethyl)-1-oleyl urea

Fig. 15.7 Structures of amphiphilic lipids that form liquid crystal phases in excess water (the hydrophobic region of the molecule is shaded )

the lipid in the cubic phase, release kinetics being slower from the smaller channel size in cubic phase assembled from phytantriol than from GMO-assembled cubic phase (see also below) [129]. Chlorpheniramine release from lamellar liquid crystals was faster than from cubic phase material [130].

Inducing transitions between liquid crystalline structures such as cubic and hexagonal phases by temperature changes can reverse the drug release rates from different nanostructures. Figure 15.8 illustrates the reversible change in glucose

Fig. 15.8 In vitro release of glucose as a model hydrophilic drug from liquid crystalline structures using temperature to reversibly induce transitions between the cubic and hexagonal phase structures. Modified from [131]

Fig. 15.8 In vitro release of glucose as a model hydrophilic drug from liquid crystalline structures using temperature to reversibly induce transitions between the cubic and hexagonal phase structures. Modified from [131]

Fig. 15.9 Panel A shows in vitro release profiles for glucose as a model hydrophilic drug from different liquid crystalline phases formed using phytantriol (PHYT), glyceryl monooleate (GMO) and vitamin E acetate (VitEA). Panel B shows plasma concentrations vs. time after oral administration of liquid crystalline systems. Figures modified from Lee et al. [129]

Fig. 15.9 Panel A shows in vitro release profiles for glucose as a model hydrophilic drug from different liquid crystalline phases formed using phytantriol (PHYT), glyceryl monooleate (GMO) and vitamin E acetate (VitEA). Panel B shows plasma concentrations vs. time after oral administration of liquid crystalline systems. Figures modified from Lee et al. [129]

concentration when switching between the cubic phase at 30°C and the hexagonal phase structure at 40°C [131]. The relevance of such behavior for controlling oral administration is not apparent at this time (while speculating on possibilities at body temperature). However, it illustrates the concept of changing release through changes in other stimuli.

The wealth of in vitro release studies reported for lipid-based liquid crystalline systems contrasts with limited reports on in vivo performance. For hydrophilic drugs, two reports are apparent. Lee et al. used glucose as a model hydrophilic compound [129]. Figure 15.9 illustrates in vitro release from different cubic and hexagonal phase structures and correlation with in vivo oral absorption. Release was slowest from the inverse hexagonal phase, with in vivo Tmax delayed significantly compared to the cubic phase.

0 20 40 60 80 100 120

Fig. 15.10 Plasma concentration over time after oral administration of cinnarizine in aqueous suspension, GMO, phytantriol and oleyl glycerate to rats (data taken from [128] and [134])

0 20 40 60 80 100 120

Fig. 15.10 Plasma concentration over time after oral administration of cinnarizine in aqueous suspension, GMO, phytantriol and oleyl glycerate to rats (data taken from [128] and [134])

Insulin loaded into GMO-based cubosomes controlled blood glucose levels for approximately 4 h, a comparable duration to that achieved with IV-administered drug, albeit at a tenfold greater dose [132]. No pharmacokinetic data for insulin were provided, a common feature of reports on particle-assisted oral insulin delivery.

A number of studies used cinnarizine as a model poorly water soluble (hydrophobic) drug administered in liquid crystalline formulations, or in lipidic systems anticipated to form liquid crystalline structures in gastrointestinal fluids. Kossena et al. [133] reported that monolaurin and lauric acid formed a cubic phase in the presence of simulated intestinal fluids. The cubic phase was not stable to dilution but was considered representative of structures formed during digestion of trilaurin, a common component of medium chain triglycerides. Intraduodenal administration of the cubic phase containing cinnariz-ine resulted in a twofold prolongation of Tmax compared to a control suspension formulation, indicating the potential of cubic phases for controlling absorption.

GMO and oleyl glycerate, which form cubic and hexagonal phases, respectively, have also been evaluated as vehicles for cinnarizine. When cinnarizine was dissolved in GMO or oleyl glycerate and administered orally to rats, there was a 1.2- and 14-fold extension in rnax, respectively, compared to drug in simple suspension (Fig. 15.10) [128]. The plasma profile for GMO was somewhat typical for a lipid-based formulation, with a slight increase in Tmax being attributable to delayed gastric emptying. However the dramatic effect with the oleyl glycerate vehicle was unexpected, and was accompanied by a fourfold enhancement in bioavailability. Oleyl glycerate has identical molecular structure to GMO (Fig. 15.7), except that the ester is reversed, in which case lipolysis should liberate oleyl alcohol rather than oleic acid. It was hypothesized (and supported by in vitro digestion experiments) that this might inhibit digestion and contribute to the sustained absorption profile, contrasting with GMO which is known to be readily digested in vivo.

To further probe this effect, a subsequent experiment used phytantriol as the vehicle for delivery of cinnarizine [134]. Phytantriol is inherently indigestible due to a lack of an ester link (Fig. 15.7) but forms cubic phases in excess water [110]. Plasma profiles for cinnarizine when using phytantriol and oleyl glycerate as the vehicle were very similar, viz. prolonged Tmax and greater AUC (Fig. 15.10). Prolonged gastric retention, consequent to poor digestibility is a plausible explanation. In the case of phytantriol, the sustained plasma concentrations were linked to improved gastric retention. Cinnarizine, formulated as an oleic acid emulsion provided profiles similar to those from GMO [135]. An explanation may be that if GMO is readily digested soon after administration, oleic acid would be formed. Oleic acid does not form liquid crystals. Neither did it provide extended plasma profiles, in contrast to oleyl glycerate.

Formulations containing poorly digestible or nondigestible lipids do not typically enhance drug absorption as readily as those comprising digestible components. Yamahira et al. showed that the poorly digestible lipid vehicle N-a-methylbenzyl linoleamide reduced absorption of the lipophilic drug SL-512 in rats, compared to administration in readily digested MCT [136]. Myers et al. also reported reduced oral bioavailability of penclomedine, given intraduodenally in mineral oil, compared to soybean oil, although, an improvement in bioavailability was evident relative to a simple aqueous suspension [137]. Oleyl alcohol has also been noted to significantly reduce the absorption of sulfisoxazole acetyl, dicumarol, and griseofulvin when compared to more digestible lipids [138]. Gastroretention effects have not been tendered as explanation for such findings.

To further probe the relative roles of digestibility and liquid crystal formation, selachyl alcohol was used as a vehicle, being nondigestible, but similar in structure to GMO and oleyl glycerate (Fig. 15.6); it also forms liquid crystalline structures. Selachyl alcohol dramatically extended cinnarizine plasma presence [135] (Tmax approximately 24 h), indicating that liquid crystalline delivery vehicles should incorporate a poorly or nondigestible lipid if sustained absorption is desired. Investigations continue to examine mechanisms of gastric retention. Moreover, it has emerged that GMO possesses mucoadhesive properties [52, 139]. Similarly structured lipids may also possess such properties.

The gastric compartment presents a generally low absorption environment and has limited variability in volume; hence, sink conditions may not pertain with some poorly soluble drugs administered in gastroretentive formulations. The relative roles of slow release and nonsink conditions in determining release kinetics and subsequent absorption from the cinnarizine-containing lipid-based liquid crystalline systems described earlier were not elucidated. Consequently, additional studies were undertaken using dispersed cubosomes loaded with cinnarizine. Drug and lipid load was the same as in the earlier work. The hypothesis was that submicron particles would deliver burst release. Rapid absorption would be expected if drug and/or particles were not retained in the stomach. Figure 15.11 shows that extended cinnarizine plasma profiles were obtained once more with the nondigestible lipid vehicle, while GMO and oleic acid-based systems provided similar pharmacokinet-ics to bulk GMO [135, 140]. This is consistent with Lai who reported a slightly delayed T for simvastatin in GMO cubosomes (1.50 h for cubosomes vs. 0.8 h for

J max v

30 40

Time(hr)

150-

30 40

Time(hr)

Fig. 15.11 Administration of cinnarizine in different particulate vehicles: (a) drug suspension, (b) GMO cubosomes (digestible liquid crystalline lipid), (c) phytantriol cubosomes (nondigestible lipid), (d) oleic acid emulsion (nondigestible, nonliquid crystalline) [140]

a drug suspension) when administered orally to beagles [141]. The findings confirmed that gastroretention, reduced digestibility, and nonsink conditions contribute to the prolonged absorption of cinnarizine from these systems (Fig. 15.11).

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