Increased dissolution and oral absorption of itraconazole/Soluplus extrudate compared with itraconazole nanosuspension

Zhang, Keru; Yu, Hailing; Luo, Qing; Yang, Shenshen; Xia, Lin; Zhang, Yu; Tian, Bin; Tang, Xing

doi:10.1016/j.ejpb.2013.03.002

Cited by 99 publications

(58 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…14) Kalivoda et al also showed a significant increase in the dissolution rate of fenofibrate by Soluplus ® -based SD compared with commercial capsules. 15) It was revealed that the polymer serves not only as a functional carrier but also an inhibitor of drug molecular precipitation.…”

Section: 13)mentioning

confidence: 96%

Preparation of Solid Dispersion of Dronedarone Hydrochloride with Soluplus® by Hot Melt Extrusion Technique for Enhanced Drug Release

Han

Jung

Jang

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

In order to enhance the dissolution rate of dronedarone hydrochloride (DRN), a novel soluplus ® (polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer)-based solid dispersion (SD) was formulated using a hot melt extrusion technique. The physical characteristics determined using scanning electron microscopy and X-ray powder diffraction, revealed that the active compound was molecularly dispersed in the amphiphilic polymer in a stable amorphous form. The dissolution rate of DRN from the tablet dosage form of SD extrudate consisted of the drug and Soluplus ® in a weight ratio of 1 : 1, and was obviously more rapid and higher than that of the intact drug and marketed product (Multaq ® , Sanofi, U.S.A.) at pH 1.2, 4.0 and 6.8. This suggests that Soluplus ® -based SD formula can be a promising approach for enhancing the dissolution and oral absorption of DRN with a simple preparation process.Key words dronedarone hydrochloride; Soluplus ® ; hot melt extrusion; dissolution Dronedarone hydrochloride (Fig. 1, DRN), an antiarrhythmic agent, has been recently prescribed to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter.1,2) In a clinical study, DRN effectively reduced hospitalization due to cardiovascular events or death due to any cause by 24.2% when compared to the placebo group.2) However, the oral absorption of DRN is quite challenging owing to its pH-dependent aqueous solubility; solubility in a weak acidic environment (pH 3 to 5) is about 1 to 2 mg/mL, but the solubility is remarkably decreased to one hundredth of a point in gastric fluid (pH 1.2) and/or intestinal fluid (pH 6.8).3) To improve oral absorption of the antiarrhythmic agent, the originator (Sanofi, U.S.A.) formulated an oral dosage form (Multaq ® tablet, 400 mg as base) based on the solid dispersion (SD) system using conventional solvent method, with a triblock copolymer of polypropylene glycol and polyethylene glycol.3) In the SD formula, the drug may be dispersed within the hydrophilic carrier at a molecular level in the amorphous state, and the formula provides a large surface, which enhances the dissolution rate of the poorly water-soluble molecule. [4][5][6] However, the oral absorption of the marketed product is still unsatisfactory. The absolute bioavailability (BA) of DRN was about 4% without food, while the BA was approximately 15% when administered with a high fat meal. 7)Hot melt extrusion (HME) is a promising preparation tool to prepare SD formulations for improved drug dissolution and oral BA.8) The mixture of active pharmaceutical ingredients (APIs) and hydrophilic carriers was melted at an elevated temperature and mixed homogeneously at a molecular level, resulting in an amorphous state of API dispersed in the carrier.9,10) The process to prepare extrudates by HME is relatively economic and does not require complicated processes used in the preparation of conventional solvents. Polyethyleneglycol (PEG)-polyvinyl caprolactam-polyvinyl a...

show abstract

Section: 13)mentioning

confidence: 96%

Preparation of Solid Dispersion of Dronedarone Hydrochloride with Soluplus® by Hot Melt Extrusion Technique for Enhanced Drug Release

Han

Jung

Jang

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

show abstract

“…Soluplus has been proven to possess the potential to increase the solubility and bioavailability of a number of poorly water-soluble compounds, such as itraconazole [28] , osthole [29] , fenofibrate [30] and sorafenib [31] . In the current study, the Soluplus-based micelle system was applied for the first time to scopoletin.…”

Section: Discussionmentioning

confidence: 99%

Soluplus micelles for improving the oral bioavailability of scopoletin and their hypouricemic effect in vivo

Zeng

Liu

et al. 2017

Acta Pharmacol Sin

View full text Add to dashboard Cite

Scopoletin is an active coumarin possessing a variety of pharmacological activities, including anti-hyperuricemic effect, but with poor solubility. To improve its oral bioavailability, we attempted to encapsulate scopoletin into Soluplus micelles (Soluplus-based scopoletin micelles, Sco-Ms) and evaluated the hypouricemic action of Sco-Ms. Sco-Ms were prepared using a thin-film hydration method. Sco-Ms displayed near spherical shapes with an average size of 59.4±2.4 nm (PDI=0.08±0.02). The encapsulation efficiency of scopoletin was 87.3%±1.5% with a loading capacity of 5.5%±0.1%. Sco-Ms were further characterized using transmission electron microscopy, powder X-ray diffraction, Fourier transform infrared techniques and scanning electron microscopy. After oral administration in rats, Sco-Ms exhibited significantly improved absorption in each intestinal segment compared to free scopoletin, with the duodenum and jejunum being the main absorption regions. In rats administered Sco-Ms (at an equivalent dose of free scopoletin of 100 mg/kg, po), the AUC 0-∞ and C max of Sco-Ms were 4.38-and 8.43-fold, respectively, as large as those obtained following administration of free scopoletin. After oral administration in rats, Sco-Ms did not alter the tissue distributions of scopoletin, but significantly increased the scopoletin levels in the liver. In potassium oxonate-induced hyperuricemic mice, oral administration of Sco-Ms (at an equivalent dose of free scopoletin of 300 mg/kg) reduced the serum uric acid concentration to the normal level. The results suggest that Soluplus-based micelle system greatly improves the bioavailability of poorly water-soluble drugs, such as scopoletin, and represents a promising strategy for their oral delivery.

show abstract

“…HME has been successfully applied to enhance solubility of poorly soluble API through formation of solid dispersion of API in a polymeric (or lipid) carrier matrix (3,(6)(7)(8)(9). Based on the molecular state of the API in the carrier phase, solid dispersions prepared by HME can be categorized as crystalline solid dispersions, amorphous solid dispersions, and solid solutions (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…HME is recently being used in healthcare industry to manufacture medical devices, amorphous solid dispersion (ASD) to enhance bioavailability of poorly soluble API, targeted release drug delivery systems, implants, bioadhesive films, taste masked products (2)(3)(4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

2015

View full text Add to dashboard Cite

Abstract. The objective of the study was to develop an amorphous solid dispersion (ASD) for an insoluble compound X by hot melt extrusion (HME) process. The focus was to identify material-sparing approaches to develop bioavailable and stable ASD including scale up of HME process using minimal drug. Mixtures of compound X and polymers with and without surfactants or pH modifiers were evaluated by hot stage microscopy (HSM), polarized light microscopy (PLM), and modulated differential scanning calorimetry (mDSC), which enabled systematic selection of ASD components. Formulation blends of compound X with PVP K12 and PVP VA64 polymers were extruded through a 9-mm twin screw mini-extruder. Physical characterization of extrudates by PLM, XRPD, and mDSC indicated formation of single-phase ASD's. Accelerated stability testing was performed that allowed rapid selection of stable ASD's and suitable packaging configurations. Dissolution testing by a discriminating two-step non-sink dissolution method showed 70-80% drug release from prototype ASD's, which was around twofold higher compared to crystalline tablet formulations. The in vivo pharmacokinetic study in dogs showed that bioavailability from ASD of compound X with PVP VA64 was four times higher compared to crystalline tablet formulations. The HME process was scaled up from lab scale to clinical scale using volumetric scale up approach and scale-independent-specific energy parameter. The present study demonstrated systematic development of ASD dosage form and scale up of HME process to clinical scale using minimal drug (∼500 g), which allowed successful clinical batch manufacture of enabled formulation within 7 months.

show abstract

Increased dissolution and oral absorption of itraconazole/Soluplus extrudate compared with itraconazole nanosuspension

Cited by 99 publications

References 35 publications

Preparation of Solid Dispersion of Dronedarone Hydrochloride with Soluplus® by Hot Melt Extrusion Technique for Enhanced Drug Release

Preparation of Solid Dispersion of Dronedarone Hydrochloride with Soluplus® by Hot Melt Extrusion Technique for Enhanced Drug Release

Soluplus micelles for improving the oral bioavailability of scopoletin and their hypouricemic effect in vivo

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

Contact Info

Product

Resources

About