Enhanced In Vivo Absorption of Itraconazole via Stabilization of Supersaturation Following Acidic-to-Neutral pH Transition

Miller, Dave A.; DiNunzio, James; Yang, Wei; McGinity, James W.; Williams, Robert O.

doi:10.1080/03639040801929273

Cited by 139 publications

(109 citation statements)

References 40 publications

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“…Both formulations showed significant reductions in die pressure at the lower processing temperature evaluated. APIs with miscibility in a polymer can also contribute a plasticizing effect on a formulation (48,49 in softening temperature was observed, allowing for HME processing at temperatures around 150°C. Given the plasticization effect of GRIS (T g =~89°C, Tm=~220°C; (31)), as observed by a decrease in T g in MDSC experiments, a higher drug loading could allow for further reduction in viscosity of high molecular weight polymer grades to enable extrusion processing.…”

Section: Discussionmentioning

confidence: 99%

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

et al. 2015

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Abstract. Thermal processing technologies continue to gain interest in pharmaceutical manufacturing. However, the types and grades of polymers that can be utilized in common thermal processing technologies, such as hot-melt extrusion (HME), are often limited by thermal or rheological factors. The objectives of the present study were to compare and contrast two thermal processing methods, HME and KinetiSol® Dispersing (KSD), and investigate the influence of polymer type, polymer molecular weight, and drug loading on the ability to produce amorphous solid dispersions (ASDs) containing the model compound griseofulvin (GRIS). Dispersions were analyzed by a variety of imaging, solid-state, thermal, and solution-state techniques. Dispersions were prepared by both HME and KSD using polyvinylpyrrolidone (PVP) K17 or hydroxypropyl methylcellulose (HPMC) E5. Dispersions were only prepared by KSD using higher molecular weight grades of HPMC and PVP, as these could not be extruded under the conditions selected. Powder X-ray diffraction (PXRD) analysis showed that dispersions prepared by HME were amorphous at 10% and 20% drug load; however, it showed significant crystallinity at 40% drug load. PXRD analysis of KSD samples showed all formulations and drug loads to be amorphous with the exception of trace crystallinity seen in PVP K17 and PVP K30 samples at 40% drug load. These results were further supported by other analytical techniques. KSD produced amorphous dispersions at higher drug loads than could be prepared by HME, as well as with higher molecular weight polymers that were not processable by HME, due to its higher rate of shear and torque output.

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Section: Discussionmentioning

confidence: 99%

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

et al. 2015

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“…The dissolution of pharmaceutical excipients with pH-dependent ionizing properties can be variable across the gastrointestinal pH range (44). For example, dissolution rate and apparent solubility of weakly basic drugs in gastric pH and weakly acidic drugs in intestinal pH would be higher due to the ionization at those pH conditions (6,7,45). Anionic and cationic polymers are prone to those same ionization effects, which allow for differing dissolution rates across the gastrointestinal tract.…”

Section: Introductionmentioning

confidence: 99%

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1)

Brough

Miller²,

Keen³

et al. 2015

AAPS PharmSciTech

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Abstract. Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentrationenhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole.

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“…They demonstrated that amorphous compositions of ITZ with these polymers provided improved bioavailability due to the increased period of time in the supersaturated state of ITZ in rat small intestine. Miller et al demonstrated that METHOCEL™ E50 and Eudragit L100-55 produced substantially greater in vivo absorption than immediate release formulations owing to improved supersaturation of ITZ in the small intestine (14). The absorption variability with Eudragit L 100-55 was 140% which reduced to 32% by addition of 20% Carbopol 974P to the Eudragit L 100-55 matrix, although both formulations had equivalent area under the dissolution curve (15).…”

Section: Introductionmentioning

confidence: 99%

In Vitro Characterization of a Novel Polymeric System for Preparation of Amorphous Solid Drug Dispersions

Mahmoudi

Upadhye

Ferrizzi

et al. 2014

AAPS J

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Abstract. Preparation of amorphous solid dispersions using polymers is a commonly used formulation strategy for enhancing the solubility of poorly water-soluble drugs. However, often a single polymer may not bring about a significant enhancement in solubility or amorphous stability of a poorly water-soluble drug. This study describes application of a unique and novel binary polymeric blend in preparation of solid dispersions. The objective of this study was to investigate amorphous solid dispersions of glipizide, a BCS class II model drug, in a binary polymeric system of polyvinyl acetate phthalate (PVAP) and hypromellose (hydroxypropyl methylcellulose, HPMC). The solid dispersions were prepared using two different solvent methods: rotary evaporation (rotavap) and fluid bed drug layering on sugar spheres. The performance and physical stability of the dispersions were evaluated with non-sink dissolution testing, powder X-ray diffraction (PXRD), and modulated differential scanning calorimetry (mDSC). PXRD analysis demonstrated an amorphous state for glipizide, and mDSC showed no evidence of phase separation. Non-sink dissolution testing in pH 7.5 phosphate buffer indicated more than twofold increase in apparent solubility of the drug with PVAP-HPMC system. The glipizide solid dispersions demonstrated a high glass transition temperature (T g ) and acceptable chemical and physical stability during the stability period irrespective of the manufacturing process. In conclusion, the polymeric blend of PVAP-HPMC offers a unique formulation approach for developing amorphous solid dispersions with the flexibility towards the use of these polymers in different ratios and combined quantities depending on drug properties.KEY WORDS: amorphous solid dispersions; fluid bed drug layering; hypromellose (hydroxypropyl methylcellulose, HPMC); polyvinyl acetate phthalate (PVAP); solubility enhancement; sugar spheres (Suglets).

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Enhanced In Vivo Absorption of Itraconazole via Stabilization of Supersaturation Following Acidic-to-Neutral pH Transition

Cited by 139 publications

References 40 publications

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1)

In Vitro Characterization of a Novel Polymeric System for Preparation of Amorphous Solid Drug Dispersions

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