Gelucires

One excipient that has stimulated interest in lipid-based solid dispersion formulations is Gelucire 44/14 (Gattefosse Corp., St. Priest, France). This self-emulsifying excipient that exists as a waxy semi-solid at ambient room temperature is a mixture of glyceryl and PEG 1500 esters of long-chain fatty acids and is listed in the European Pharmacopoeia as laurylmacrogolglycerides and in the United States Pharmacopoeia as lauroylpolyoxyglycerides. The suffixes, 44 and 14, in the excipient trade name refer to its melting point and hydrophilic-lipophilic balance (HLB), respectively. Serajuddin et al. (28) compared properties of different formulations of the poorly water-soluble drug, REV5901, which were prepared by dissolving the drug in molten PEG1000, PEG1450, PEG8000, or Gelucire 44/14; the molten formulations were filled into size 0 hard gelatin capsules in amounts that contained 100 mg of REV5901 and 550 mg of the excipient. Upon congealing of the formulations at ambient room temperature, the incorporated drug existed as either a molecular dispersion (solution) or in the amorphous state within the excipient matrix. REV5901 is a weakly basic drug with a pKa value of 3.6 and a maximum solubility of 0.95 mg/mL at pH 1 and 37°C; the aqueous solubility at pH 6.8 was less than 2 ^g/mL (29). Although sink conditions existed in the 900 mL volume of simulated gastric fluid USP (without enzyme) used for dissolution testing of the drug capsules, dissolution from all of the PEG-based solid dispersions was incomplete, whereas Gelucire 44/14 provided complete dissolution (Fig. 6). The results of this study demonstrate the potential value of surface active excipients for enhancing dissolution of poorly water-soluble drugs. When the dissolution study was repeated in water (pH ~6) in which the drug was practically insoluble, the Gelucire 44/14-based solid dispersion completely released the drug in the dissolution medium, forming a milky dispersion of the free drug as fine, metastable oily globules. In contrast, no such release of drug in water by any of the PEG formulations was observed. From this study, it was concluded that, relative to a simple PEG dispersion, a poorly water-soluble drug formulated in a surface-active excipient (e.g., Gelucire 44/14) would either dissolve completely in aqueous media or be

Figure 6 Relative dissolution rates of REV5901 from solid dispersion formulations of various polyethylene glycols and Gelucire 44/14 in 0.1 M HCl. Each capsule contained 100 mg of drug in a total fill weight of 550 mg. Capsules were prepared by filling with the molten formulations. Abbreviation: PEG, polyethylene glycol. Source: From Ref. 28.

Figure 6 Relative dissolution rates of REV5901 from solid dispersion formulations of various polyethylene glycols and Gelucire 44/14 in 0.1 M HCl. Each capsule contained 100 mg of drug in a total fill weight of 550 mg. Capsules were prepared by filling with the molten formulations. Abbreviation: PEG, polyethylene glycol. Source: From Ref. 28.

released in a finely divided particulate state, thus increasing its dissolution rate and bioavailability. Clinical testing of a Gelucire 44/14 solid dispersion formulation of REV5901 in normal fasted volunteers revealed substantially improved bioavailability relative to a conventional tablet formulation prepared from micronized drug and containing a wetting agent (30).

Aungst et al. (31) observed that the bioavailability in dogs of a PEG-based formulation of the poorly water-soluble HIV protease inhibitor, DMP323, decreased 10-fold when the dose was increased from 100 to 350mg. In contrast, bioavailability from a Gelucire 44/14 solid dispersion was relatively unaffected by the delivered dose of DMP323 (69% and 50% after doses of 85 mg and 350mg, respectively). The bioavailability of another HIV protease inhibitor, ritonavir, was also substantially enhanced, relative to a conventional formulation, by using a solid dispersion formulation prepared from a mixture of Gelucire 50/13, polysorbate 80 and polyoxyl 35 castor oil (32).

Barker et al. (33) reported an increase in a-tocopherol (vitamin E) bioavailability from a Gelucire 44/14 solid dispersion formulation, which was attributed to the formation of fine emulsion droplets containing the vitamin following dispersion of the formulation in the aqueous contents of the GIT (Fig. 7).

Gelucire 44/14 has also been extensively used in combination with other surfactants and solubilizing agents to enhance the performance of solid dispersions. For example, Vippagunta et al. (34) observed higher dissolution rate of crystalline nifedipine from solid dispersion in a mixture of Gelucire 44/14 and Pluronic F68 as compared to the neat crystalline drug substance milled to the same particle size.

Time afw dosing (hours)

Figure 7 Comparison of mean plasma concentration versus time profiles of a-tocopherol after oral administration of a commercial product or in a formulation containing Gelucire 44/14 to six healthy male volunteers in the fasted state. Two capsules, each containing 300 IU of a-tocopherol, were given to each subject in a cross-over study design. Source: From Ref. 33.

Time afw dosing (hours)

Figure 7 Comparison of mean plasma concentration versus time profiles of a-tocopherol after oral administration of a commercial product or in a formulation containing Gelucire 44/14 to six healthy male volunteers in the fasted state. Two capsules, each containing 300 IU of a-tocopherol, were given to each subject in a cross-over study design. Source: From Ref. 33.

He et al. (35) used Gelucire 44/14 in combination with N,N-dimethyl acetamide (DMA) to enhance solubility, stability, and bioavailability of a poorly water-soluble antiviral agent that was chemically unstable and poorly soluble in aqueous media. It was, however, soluble and stable in DMA and incorporating Gelucire 44/14 resulted in a stable, semi-solid formulation that could be easily filled into soft gelatin capsules. Solid dispersion formulations of flurbiprofen (36) and piroxicam (37) prepared in a mixture of Gelucire 44/14 and Labrasol (caprylocaproyl macrogolglycerides) demonstrated an improved dissolution rate in vitro and a corresponding higher bioavailability as compared to conventional formulations (38,39).

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