Hivaids Treatement

Recently, Abbott Labratories introduced a new tablet formulation for Kaletra®, an anti-HIV protease inhibitor, as an alternative to the original soft gelatin capsule (SGC) formulation (45). This new tablet formulation is based on the previously discussed Meltrex technology which utilizes hot-melt extrusion to produce solid dispersion drug formulations. The Kaletra brand contains two insoluble active ingredients, lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV protease that undergoes almost complete metabolism by CYP3A. Ritonavir inhibits CYP3A metabolism of lopinavir, and thus coadministration of these drugs has been demonstrated to increase plasma levels of lopinavir (46). Although the Kaletra SGC formulation proved to be an effective oral antiretroviral drug therapy, the regime required frequent dosing and administration with food. Additionally, the SGC formulation had to be stored in a refrigerated environment. The inconvenience of the SGC formulation, the potential for improved bioavailability/reduced food effect, and presumably reduced manufacturing costs motivated the development of the Meltrex based tablet formulation.

Utilizing the Meltrex system, 33% greater drug loading was achieved in tablets (200mg lopinavir/50mg ritonavir) than in the SGC formulation (133mg lopinavir/33mg ritonavir). The drug contained in the tablet formulation was found to be as readily soluble as drug contained in the SGC formulation, and hence on a dose-normalized basis the tablets were bioequivalent to the SGCs. Therefore, one-third fewer tablets were required to deliver the same therapeutic dose. Also, clinical studies determined that there are no significant differences in Cmax and AUC with the Kaletra tablets between fed and fasted states, thus indicating negligible food effect on the absorption of the actives from the tablet formulations. Therefore, the Meltrex-based tablets provided the added convenience of dosing with or without food. Additionally, the Kaletra tablets were determined to be stable when stored at room conditions, thus offering another advantage over the SGC which must remain refrigerated.

This example of improving a commercial HIV drug therapy by the use of a melt extruded solid dispersion system represents the growing interest of the pharmaceutical industry in solid dispersion technologies as these systems become increasingly more viable. In this example, it was demonstrated that solid dispersion technologies can provide more effective and convenient oral drug therapies which are in many cases simpler to manufacture and more stable than the current alternatives.

Law et al. have also explored solid dispersion systems for improved oral bioavailability of ritonavir with the aim of improving the efficacy of the oral treatment of HIV (47). Amorphous dispersions of ritonavir in PEG at different drug loadings were prepared by a solvent evaporation-fusion method (48) and evaluated for in vitro and in vivo performance. In vitro dissolution studies were conducted in 0.1 N HCl with amorphous ritonavir solid dispersions in PEG at 10%, 20%, and 30% (w/w) drug loading as well as a physical mixture of 10% (w/w) crystalline ritonavir with PEG. The results of this dissolution study are shown below in Figure 5.

This figure illustrates the enhanced dissolution performance of the solid dispersion formulations over the physical mixture and the effect of drug loading on the rate and extent of ritonavir dissolution from the solid



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Time (minutes)

Figure 5 In vitro dissolution in 0.1N HCl of (a) physical mixture containing crystalline ritonavir-PEG at 10:90, and amorphous ritonavir in PEG solid dispersions at concentrations of (b) 10%, (c) 20%, and (d) 30% (w/w). Dissolution was determined by the USP I method (50 rpm, 378C).The data for 20% dispersion is an average of two runs; others are three runs.

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Time (minutes)

Figure 5 In vitro dissolution in 0.1N HCl of (a) physical mixture containing crystalline ritonavir-PEG at 10:90, and amorphous ritonavir in PEG solid dispersions at concentrations of (b) 10%, (c) 20%, and (d) 30% (w/w). Dissolution was determined by the USP I method (50 rpm, 378C).The data for 20% dispersion is an average of two runs; others are three runs.

dispersions. The in vivo performance of these compositions was then evaluated in beagle dogs by oral administration of the solid dispersion formulation in dry capsules. The ritonavir plasma concentration versus time curve from this study is shown in Figure 6.

From Figure 6, it is seen that the extent of in vivo absorption of ritonavir closely follows the in vitro dissolution performance as ritonavir from the solid dispersion formulations is absorbed to a much greater extent than with crystalline ritonavir, and the extent of absorption from the solid dispersions is inversely proportional to drug loading. The 10%, 20%, and 30% (w/w) dispersions showed 22.04-, 17.98-, and 10.98-fold increases in average AUC over the crystalline drug, respectively. From the results of this study, it was concluded that absorption of ritonavir is concurrently improved with improved dissolution rate. Therefore, the enhanced in vivo performance of the solid dispersion formulations was directly attributed to

Figure 6 Mean plasma concentration-time profiles of ritonavir after a single oral dose to beagle dogs. Ritonavir was administered in (a) the crystalline form or the amorphous in PEG solid dispersions at concentrations of (b) 10%, (c) 20%, and (d) 30% (w/w).

higher drug concentrations in digestive fluids when dosed as an amorphous dispersion. Since ritonavir is a substrate and inhibitor of P-glycoprotein (Pgp) intestinal absorption could be limited by Pgp efflux (49). Therefore, improved absorption by supersaturation of digestive fluids may be due to the synergistic effects of an increased concentration gradient to drive absorption and saturation of Pgp resulting in decreased efflux. Irrespective of the mechanism of absorption improvement, this study clearly demonstrated improved absorption, and hence enhanced efficacy of oral ritonavir that is attributable to its delivery as a highly soluble amorphous solid dispersion.

In another similar study, De Jaeghere et al. evaluated pH sensitive micro and nanoparticle solid dispersions for improved absorption of a new HIV-1 protease inhibitor known as GCP 70726 (50). As with the previously described protease inhibitors, GCP 70726 is a poorly water soluble (0.12 mg/mL at pH 6.2) highly lipophilic compound (log P = 4.77). Therefore, poor oral bioavailability of the compound observed in preliminary studies was attributed to limited dissolution of the drug in the lumen of the GI tract. Toward the aim of improving the dissolution properties and oral absorption of GCP 70726, these authors evaluated a solid dispersion formulation consisting of amorphous drug dispersed in a poly(methacrylic acid-co-ethylacrylate) copolymer known as Eudragit® L100-55. This enteric polymer exhibits pH-dependant solubility in which the polymer becomes soluble above pH 5.5 owing to the ionization of carboxylic acid functional groups contained on the polymer. The pH solubility profile of the carrier system thus prevents drug release in the acidic environment of the stomach and promotes dissolution in the more neutral pH environment of the small intestine. The rationale for a solid dispersion system with a pH-dependant release profile is to concentrate the release of the molecularly dispersed drug to the key absorption site, that is, the upper regions of the small intestine. The authors expected that this mode of release would increase the probability of drug absorption by maximizing the exposure of transient supersaturated drug concentrations with the extensive surface area of the small intestine.

The solid dispersions of CGP 70726 in Eudragit L100-55 were produced by two processes: (i) emulsification-diffusion method in which a drug-polymer nanoparticle suspension was produced, rapidly frozen, and freeze-dried to yield a dry powder; (ii) spray drying a methanolic solution of the drug and the polymer to produce dry microparticles. X-ray diffraction confirmed the amorphous nature of the drug in both solid dispersion particle formulations. Particle size analysis revealed that the mean diameter of the particles formed by the emulsification-diffusion method was near 300 nm while the mean diameter of the spray dried particles was near 10 mm. The in vivo performances of the micro and nanoparticle formulations of GCP 70726 were evaluated in a single dose study with beagle dogs in both the fed and fasted states. An aqueous suspension of the crystalline drug was used as a reference; however, the resulting plasma levels were below the limit of quantitation of the analytical method. The pharmacokinetic parameters in the fed and fasted states for the solid dispersion systems are shown in Table 4.

In contrast to the crystalline drug, both groups of solid dispersion particles produced substantial plasma levels of CGP 70726 in both nutritional states; however, it was found that the presence of food reduced drug absorption. The authors suggested that the presence of food increased the gastric pH which caused premature release and partial precipitation of drug in the stomach. Contrary to expectations, the mean AUC of the microparticles was higher than that of the nanoparticles, but this discrepancy was found statistically insignificant. The improved absorption of the solid dispersion particles over the crystalline drug was attributed to rapid dissolution owing to the high specific surface area of the particles and the release of drug in a molecularly dispersed state following dissolution of the polymer carrier. In addition, targeting this rapid drug release to the extensive mucosal membrane surface area in the small intestine provided optimal opportunity for drug absorption. Similarly to previously discussed examples, this solid dispersion formulation was able to improve oral drug absorption by not only improving the dissolution properties of the drug, but also by targeting the delivery of the more soluble drug form to the optimum site for absorption in the GI tract.

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