(681a) Thermal Processing for the Delivery of Water-Insoluble Drugs: Hot-Melt Extrusion and Kinetisol® Dispersing

Thermal Processing for the Delivery of Water-Insoluble Drugs:  Hot-Melt Extrusion and Kinetisol® Dispersing

Robert O. Williams III, Bo Lang, James W. McGinity and Dave A. Miller

INTRODUCTION

With the advances of combinational chemistry and high throughput screening, an increasing number of pharmacologically active compounds have been identified and developed (Lipinski, 2002). A significant proportion of these drug candidates are poorly water-soluble, thereby exhibiting limited absorption. Therefore, advanced pharmaceutical formulation and processing technologies are required to overcome solubility limitations and to enable delivery of these poorly water-soluble drugs.

Amorphous solid dispersion systems are a promising method to improve the wetting and dissolution profile of poorly water-soluble drugs (Serajuddin, 1999). The use of amorphous solid dispersions to enhance the dissolution rate of a drug substance has been employed with several new pharmaceutical products based on oral bioavailability improvement.  Formation of amorphous compositions breaks the crystal lattice; therefore, the barrier of drug molecule dissociation is significantly reduced. Moreover, the use of polymeric carriers helps improve the wetting and dissolution properties of hydrophobic drugs with a high partition coefficient (Craig, 2002).

 Hot-melt extrusion and Kinetisol® Dispersing are two thermal processing technologies more recently reported for producing amorphous solid dispersions and enhancing the wetting, dissolution and absorption of poorly water-soluble drugs. In the present study, we investigated the two thermal technologies for the production of amorphous solid dispersion systems with drug substances exhibiting different physic-chemical properties.

HOT-MELT EXTRUSION OF ITRACONAZOLE AMORPHOUS SOLID DISPERSIONS

            Itraconazole (ITZ) is a broad spectrum systemic antifungal drug exhibiting limited aqueous solubility. Being a weak base, the solubility of ITZ is pH-dependent. At neutral pH values, the de-protonated ITZ showed extremely low solubility. The LogP value of ITZ is 6.5, indicating the highly lipophilic nature of the drug substance. In order to improve the dissolution property of ITZ, amorphous solid dispersion systems have been developed using hot-melt extrusion technology. A series of preformulation studies were performed to select the most suitable polymeric carrier, drug loading, and processing temperature of the hot-melt extrusion process. Drug-polymer miscibility was evaluated using modulated differential scanning calorimetry (mDSC). Results suggested that both Eudragit® L100-55 and HPMCAS LF exhibited good miscibility with ITZ. The glass transition temperatures of binary dispersions were analyzed for drug loading selection. In order to prevent any potential re-crystallization, the glass transition temperature of the amorphous solid dispersion should be at least 50ºC above the storage temperature. It was observed that the glass transition temperature could be maintained above 90ºC when the drug-to-polymer ratio is 1:2. Therefore, this ratio was kept in the following studies. The precipitation inhibition effect of Eudragit® L100-55 and HPMCAS LF was also evaluated in an in vitro assay. Results showed that HPMCAS LF prolonged the period of ITZ supersaturation to a greater extent as compared with Eudragit® L100-55. Therefore, HPMCAS LF was selected as the polymeric carrier. In order to minimize the thermal degradation of drug and polymeric carrier, thermogravimetric analysis (TGA) was performed. HPMCAS LF started to degrade at about 160ºC; therefore, the extrusion temperature was controlled at 150ºC that was below the onset degradation temperature of the polymer.  Hot-melt extrusion was performed on ITZ-HPMCAS system with Vitamin E TPGS as the additive. X-ray powder diffraction (XRD) and DSC studies confirmed the formation of amorphous solid dispersion systems. Dissolution results in fasted state simulated intestinal fluid (FaSSIF) suggested that the ITZ-HPMCAS-Vitamin E TPGS formulation exhibited a significantly improved supersaturation profile as compared with the amorphous solid dispersion without Vitamin E TPGS. As a BSC class II compound, a high degree of drug supersaturation at neutral pH environment helps overcome the dissolution hurdle, which may further enhance the oral absorption of ITZ.

KINETISOL® PROCESSING OF DS901

            Kinetisol® Dispersing is a new fusion-based process that was recently developed to rapidly form solid dispersions by imparting high shear and friction forces without external heat input.  It enables rapid processing of heat labile drugs and polymers, since these materials are subjected to elevated temperatures for only a few seconds.  No solvent or plasticizers are required, although plasticizers have been shown to function as pore formers to increase drug release rates.  The absence of a plasticizer has been demonstrated to enhance solid-state stability by producing solid dispersions with higher glass transition temperatures.  DS901 is a poorly water-soluble compound with a solubility of less than about 2 µg/mL. Its solubility is pH-independent. The melting point of DS901 is 295ºC, raising challenges for the use of hot-melt extrusion. Kinetisol® Dispersing technology was used to produce amorphous solid dispersions of DS901. Amorphous compositions contain DS901, dioctyl sodium sulfosuccinate (DSS) along with four different polymeric carrier systems including HPMCAS LF (a), HPMCAS MF (b), Soluplus® in combination with Eudragit® L100-55 (c), and Eudragit® L100-55 (d). Molecular dispersions of DS901 were obtained. During the Kinetisol® process, all of the compositions were exposed to a temperature of above 100ºC for less than 5 seconds. Dissolution results showed that the HPMCAS LF composition exhibited the most promising drug release profile. The lead composition was further tested in an in vivo study using Sprague-Dawley rats. The peak blood level of the Kinetisol® composition was 20-times higher than that of the pure DS901 crystalline drug substance.

KINETISOL® PROCESSING OF MELOXICAM

            Melocixam is a non-steroidal anti-inflammatory drug with limited aqueous solubility. The solubility in hydrochloric acid solution is 0.9 µg/mL. In water, the solubility of melocixam is 12 µg/mL. The melting point of the drug is 270ºC; moreover, meloxicam is thermally labile, causing extreme difficulty for use of hot-melt extrusion processing. As an alternative approach, Kinetisol® Dispersing was investigated for producing amorphous solid dispersion systems of melocixam (Hughey et al., 2011). Polymer screening was performed on povidone, copovidone, and Soluplus®. Results suggested that Soluplus® was the most suitable polymeric carrier for melocixam. Kinetisol® was conducted at a temperature of less than 110ºC. An amorphous solid dispersion of meloxicam was formed with minimal degradation. The potency was greater than 97%. As a control group, hot-melt extrusion was also performed at 175ºC. Significant thermal degradation of meloxicam was observed and only 88% potency was achieved. Non-sink dissolution testing was performed in different media (i.e., 0.1N HCl and purified water). Results showed that the Kinetisol® composition exhibited a markedly increased dissolution profile as compared with the pure drug substance and a commercial meloxicam tablet formulation.

CONCLUSIONS

            As demonstrated in the present studies, thermal processes including hot-melt extrusion and Kinetisol® are feasible for producing amorphous solid dispersion systems to improve the wetting and dissolution properties of poorly water-soluble drugs. Regarding thermally labile drugs and high melting point drugs, Kinetisol® Dispersing is a promising process for rendering amorphous compositions while minimizing thermal degradation of drug substances. The use of hot-melt extrusion and Kinetisol® Dispersing enables the formation of amorphous systems of drugs within a wide window of physic-chemical properties.

Keywords:  Hot-melt extrusion; Kinetisol® Dispersing; itraconazole; Meloxicam

REFERENCES

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HUGHEY, J. R., KEEN, J. M., BROUGH, C., SAEGER, S. & MCGINITY, J. W. 2011. Thermal processing of a poorly water-soluble drug substance exhibiting a high melting point: The utility of KinetiSol (R) Dispersing. International Journal of Pharmaceutics, 419, 222-230.

LIPINSKI, C. A. 2002. Poor aqueous solubility – an industry wide problem in drug discovery. American Pharmaceutical Review, 5, 82-85.

SERAJUDDIN, A. T. 1999. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci, 88, 1058-66.