Antifungal Treatments

Itraconazole is a synthetic triazole antifungal agent which exhibits activity against histoplasmosis, blastomycosis, and onychomycosis (51,52). The compound is a poorly water-soluble weak base, and thus is extremely

Table 4 Pharmacokinetic Parameters of CGP 70726 Incorporated in Eudragit L100-55 pH-Sensitive Particles after Oral Administration to Dogs; Mean 6 SEM (n = 4)

Cmax - SEM

AUC 0-8 h - SEM

Formulation

(^mol/L)

Tmax (h)

(^mol-h/L)

Fasted State

Nanoparticles

1.62 - 0.04

2

5.83-0.77a

Microparticles

1.59 - 0.32

2

7.83 -1.55

Fed State

Nanoparticles

0.86 - 0.21

1

2.00 - 0.50

Microparticles

0.88 - 0.33

2

4.40-1.38

a Statistically different (Student test, P<0.01).

a Statistically different (Student test, P<0.01).

insoluble at neutral pH (1 ng/mL) with increasing solubility in acid (4 mg/ mL at pH 1). Itraconazole is very lipophilic (calculated log P = 6.2), and therefore shows excellent biological membrane permeability (53). These physiochemical parameters place itraconazole amongst the group of poorly soluble, readily permeable BCS class II compounds (1).

The leading commercial solid oral dosage form of itraconazole is Sporanox® capsules produced by Janssen Pharmaceutica. This formulation is a solid dispersion system produced by film coating sugar spheres with an organic solution of itraconazole and HPMC. By this process, a readily soluble, amorphous dispersion of itraconazole in HPMC is formed as a film on the surfaces of small spherical particulate substrates. These film coated pellets are then filled into hard gelatin capsules to produce a single unit, multiparticulate dosage form with substantially improved bioavailability over the crystalline drug (51).

In a recent study by Six et al. a clinical study was conducted to evaluate different solid dispersion formulations produced by hot-melt extrusion against Sporanox capsules (52). Amorphous solid dispersions containing itraconazole where produced with the following polymer carrier systems: (i) HPMC, (ii) Eudragit E 100 and (iii) Eudragit E 100-polyvinylpyrollidone-covinylacetate (PVPVA 64) in a 70:30 (w/w) ratio. All solid dispersion formulations evaluated in this study contained 40% (w/w) itraconazole in an amorphous state. In vitro dissolution testing was conducted with the three extrudate formulations and Sporanox in simulated gastric fluid. The results demonstrated that the Eudragit E 100 and Eudragit E 100-PVPVA formulations showed instantaneous dissolution of itraconazole with 80% release within the first 10 min while the HPMC extrudate and Sporanox formulations showed much slower dissolution rates with 80% release in 2 h.

The in vivo study with these formulations was conducted with healthy human volunteers. The pharmacokinetic parameters from this study are shown in Table 5. The relative bioavailabilities of the extrudate formulations with respect to Sporonox capsules were 102.9%, 77.0%, and 68.1% for the HPMC, Eudragit E 100, and Eudragit E 100-PVPVA 64 formulations, respectively. Interestingly, these in vivo results are the converse of the in vitro dissolution data. The authors proposed that this could be attributed the lack of polymer stabilization of supersaturated itraconazole in GI fluids by the rapidly dissolving formulations versus the more slowly dissolving HPMC-based formulations where the polymer remained in close proximity to dissolving itraconazole and thereby more effectively maintaining supersaturation. Drug absorption was similar to Sporonox in all cases, but was most similar in the case of the HPMC extrudate formulation. Despite the lack of improved in vivo performance the authors argued that the extrusion formulations were more attractive solid dispersion formulations than Sporonox capsules by citing the economic and environmental benefits of the continuous and solvent-free hot-melt extrusion process.

Table 5 Pharmacokinetic Parameters (±SD) of Itraconazole and Hydroxyitraconazole after Oral Administration of Four Different Formulations in Healthy Humans

Sporanox HPMC Eudragit El00 Eudragit E100-PVPVA64

Itraconazole

AUCo-72 (ng-h/ml) 1365.5 + 619.9 1405.6±778.2 1054.0±583.9 928.9±355.7

Cmax (ng/ml) 115.8±51.2 118.8 + 53.7 77.3±39.9 76.6±23.4

Hydroxyitraconazole

AUCo-72 (ng-h/ml) 3552.0±2241.8 4033±2631.7 3109.6± 1970.3 2625.6± 1401.2

Cmax (ng/ml) 217.6± 106.7 231.0± 104.6 172.6±89.6 164.7 + 51.5

Therefore, this study demonstrated a safe and efficient means of producing amorphous solid dispersion formulations of itraconazole with similar bioavailability to Sporanox. Moreover, these authors also found that a carrier system with slower dissolution properties could stabilize supersaturated concentrations of itraconazole to extend elevated drug levels in the intestinal lumen beyond that of rapidly dissolving carrier systems and thus increasing drug absorption. The Sporanox and HPMC extrudate formulations evaluated in this study demonstrate the benefit of solid dispersion systems that deliver a more soluble form of a poorly soluble drug in a modified release carrier to not only improve the dissolution properties of the drug, but also to optimally deliver a soluble form of the drug in the GI tract.

Albendazole is a drug with a wide spectrum of antihelminthic activity used to treat a variety of worm infestations. The poor water-solubility of albendazole limits oral bioavailability of the drug and leads to substantial inter-subject absorption variability (54,55). Similar to itraconazole, alben-dazole is more soluble in acidic media than in media of neutral pH. Consequently, the intestinal absorption of albendazole has been observed to be substantially lower in animal models with low gastric acidity than with those of high gastric acidity (56).

In a study conducted by Kohri et al. solid dispersion systems were investigated as a means of overcoming the poor solubility of albendazole in neutral pH environments to improve intestinal absorption (57). Amorphous solid dispersions were produced by a solvent evaporation method with carrier systems containing HPMC, HP-55, or a combination of HPMC and HP-55. A pH shift dissolution test method was used as an in vitro simulation of the transition from the stomach to the small intestine that the drug would undergo in vivo. The results of this dissolution study are shown in Figure 7.

This dissolution testing method revealed that for each formulation, with the exception of the HP-55 only formulation, albendazole dissolved rapidly in the pH 1.2 medium. Precipitation of dissolved albendazole occurred rapidly following the pH shift; however, the solid dispersion formulations, particularly those containing HP-55, maintained high drug concentrations at pH 6.5. The combination HPMC and HP-55 formulation showed the greatest inhibition of recrystallization following the pH shift, and hence was selected for in vivo evaluation. In vivo studies were conducted with two groups of rabbits, one group having normal gastric acidity and the other having low gastric acidity. A physical mixture of crystalline albendazole with lactose was used a as a reference. The plasma concentration versus time data for these two groups are shown in Figure 8.

For both groups, the Cmax and AUC values were higher with the solid dispersion formulation than the physical mixture. The bioavailability of the solid dispersion formulation in the normal gastric acidity was almost 100%,

Figure 7 Dissolution behavior of albendazole from solid dispersions in media of pH 1.2-6.5: ■, physical mixture; •, solid dispersion with hydroxy-propylmethylcellulose and hydroxypropyl methylcel-lulose phthalate; O, solid dispersion with hydroxy-propyl methylcellulose; □, solid dispersion with hydroxypropyl methylcellulose phthalate.

Figure 7 Dissolution behavior of albendazole from solid dispersions in media of pH 1.2-6.5: ■, physical mixture; •, solid dispersion with hydroxy-propylmethylcellulose and hydroxypropyl methylcel-lulose phthalate; O, solid dispersion with hydroxy-propyl methylcellulose; □, solid dispersion with hydroxypropyl methylcellulose phthalate.

and in the reduced gastric acidity group the bioavailability of the solid dispersion formulation was 3.2 times that of the physical mixture. With the normal gastric acidity group, albendazole dissolved rapidly from both formulations; however, the presence of the polymers in the solid dispersion

Figure 8 Mean plasma concentrations of albendazole sulphoxide after oral administration of physical mixture (A,0) and solid dispersion (s,®) to normal acidity rabbits (A) and to low acidity rabbits (B) at a dose of 5 mg/kg. Each point represents the mean — standard error of results from five rabbits.

Figure 8 Mean plasma concentrations of albendazole sulphoxide after oral administration of physical mixture (A,0) and solid dispersion (s,®) to normal acidity rabbits (A) and to low acidity rabbits (B) at a dose of 5 mg/kg. Each point represents the mean — standard error of results from five rabbits.

formulation most likely prevented precipitation in the neutral pH environment of the small intestine, thus promoting greater drug absorption. With the low gastric acidity group, the authors approximated that drug dissolution with the solid dispersion formulation was four times that of the physical mixture. The enhanced solubilization of albendazole in a neutral pH environment coupled with the stabilizing effect of the polymers was proposed as the reason for improved drug absorption with the solid dispersion formulation for the low-gastric acidity group. Thus, the amorphous solid dispersion formulation proved to be a more effective delivery system for albendazole as the combination of a more soluble form of the drug with a polymeric carrier system that acted to stabilize supersaturated drug concentrations provided for extensive drug absorption that was less affected by pH than the crystalline drug formulation. Since the pH of the GI tract can vary substantially on both an intra and interpatient basis, the solid dispersion formulation would provide more effective treatment of albendazole overall considering the reduced pH dependency of drug absorption.

Griseofulvin is another antibiotic drug whose therapeutic efficacy has shown improvement when formulated as a solid dispersion. Griseofulvin is a systemic anti-fungal agent that is indicated for the treatment of fungal infections that commonly cause ringworm infestations of the hair, skin, and nails (58). Griseofulvin is poorly water-soluble, exhibits high biological membrane permeability, and is a relatively high dose drug (125-250 mg); and thus is classified as a BCS class II drug (59). Griseofulvin is a commonly mentioned drug in pharmaceutical papers that focus on solid dispersion technologies because it is one of the original drugs to be marketed as a solid dispersion formulation (Gris-PEG, Novartis).

Recently, Wong et al. demonstrated a crystalline solid dispersion of griseofulvin in poloxamer 407 produced by spray drying from an organic solution (60). The authors utilized both DSC and XRD to determine that spray drying did not alter the crystalline morphology of griseofulvin spray died alone or in combination with poloxamer 407. In vitro dissolution testing revealed that the griseofulvin-poloxamer 407 spray dried formulation exhibited a dramatically improved dissolution rate with 50% of drug released in 15 min, as compared to 18% and 7% for spray dried griseofulvin alone and the bulk drug, respectively. Since drug morphology was not altered by the spray drying process, this improvement was not due to improved apparent solubility, and thus was attributed to increased surface area due to the spray drying process and improved wettability by intimate mixing of the drug with poloxamer. In vivo absorption studies were conducted in rats with the bulk drug, spray dried griseofulvin, and spray dried griseofulvin-poloxamer 407 formulations dosed in capsules. Figure 9 illustrates the plasma concentration of griseofulvin versus time for each formulation.

Figure 9 Mean griseofulvin plasma concentration-time profile following oral administration to rats (± S.D., n — 4). (•) Control; (□) Spray-dried; (s) Spraydried + Poloxamer 407.

Figure 9 Mean griseofulvin plasma concentration-time profile following oral administration to rats (± S.D., n — 4). (•) Control; (□) Spray-dried; (s) Spraydried + Poloxamer 407.

This study revealed that the spray dried griseofulvin-poloxamer 407 formulation provided the greatest drug absorption with significantly greater Cmax and AUC values than the two non-dispersion formulations. Also, the absolute bioavailability of the griseofulvin-poloxamer solid dispersion formulation was determined to be approximately two-fold greater than the non-dispersion formulations. This study thus demonstrated that intimately mixing particles of griseofulvin with a polymeric surfactant greatly improved the wettability of the particles which resulted in an accelerated dissolution rate and ultimately doubled the in vivo absorption over the bulk drug.

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