Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods

Peltonen, Leena; Hirvonen, Jouni

doi:10.1111/j.2042-7158.2010.01022.x

Cited by 321 publications

(210 citation statements)

References 86 publications

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“…Excipients in dispersing agents are known to be important for reducing particle size and improving storage stability because they are adsorbed onto particle surfaces and inhibit crystal growth and aggregations in suspension phases. 15,22) Therefore, effective dispersing agents to obtain the proposed nanosuspension formulation were screened using 11 different test compounds and wet media milling methods using a mixer mill (10 mg/batch) and a rotation/revolution mixer (0.5 g/batch). Furthermore, the crystalline properties and in vitro dissolution rates were evaluated for the nanosuspensions of two poorly water-soluble compounds, cilostazol and danazol, and their oral absorptions in rats at high doses were compared with those of microsuspensions.…”

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confidence: 99%

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and in Vitro/in Vivo Evaluation of Nanosized Poorly Water-Soluble Compounds

Komasaka¹,

Fujimura

Tagawa

et al. 2014

Chem. Pharm. Bull.

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The present study aimed to develop a practical method for preparing nanosuspension formulations of poorly water-soluble compounds for enhancing oral absorption in toxicology studies in the discovery stage. To obtain a suitable nanosuspension formulation for the intended purpose, formulations were optimized with a focus on the following characteristics: i) containing a high drug concentration, ii) consisting of commonly used excipient types in proper quantities for toxicology studies, iii) having long-term stability, and iv) having versatility for use with diverse compounds. Test compounds were milled with various excipients by wet media milling methods using a mixer mill (10 mg/batch) and a rotation/revolution mixer (0.5 g/batch). As a result, 100 mg/mL nanosuspensions of all 11 test compounds could be prepared with an optimized dispersing agent, 0.5% hydroxypropyl methylcellulose (HPMC) (3 cP)-0.5% Tween 80. Notably, it was found that the molecular weight of HPMC influenced not only particle size but also the stability of nanosuspensions and they were stable for 4 weeks at 5°C. The nanosuspensions increased in vitro dissolution rates and provided 3.9 and 3.0 times higher C max and 4.4 and 1.6 times higher area under the concentration-time curve from 0-24 h (AUC 0-24 h ) in rats (oral dose of 300 mg/kg) for cilostazol and danazol, respectively. In conclusion, applying a wet media milling method with the combination of HPMC of a small molecular weight and Tween 80 as a dispersing agent, nanosuspensions can be practically prepared and conveniently utilized for enhancing the oral absorption of poorly water-soluble compounds in toxicology studies in the discovery stage.Key words nanosuspension; toxicology study; wet media milling; mixer mill; rotation revolution mixer; oral absorptionThe proportion of poorly water-soluble compounds among drug candidates in the discovery stage has been increasing for the past decade.1,2) Because of the poor solubility of these compounds, sufficient oral absorption is not observed in animal studies, and the evaluation of pharmacological and toxicological profiles of drug candidates has therefore become more challenging. In particular, this problem frequently occurs in toxicology studies that require high oral absorption and is now a common problem in pharmaceutical companies.3)The application of formulation technologies such as solubilizing excipients, 4) solid dispersions, 5,6) and nanosuspensions 7,8) is an attractive strategy for improving oral absorption of poorly water-soluble compounds. However, the use of solubilizing excipients and solid dispersions for toxicology studies in the discovery stage is practically limited because of toxicities of excipients and amount of drug substances for formulation studies, respectively. On the other hand, nanosuspensions have the potential to solve these problems. Because nanosuspensions can be prepared as highly drug-loaded formulations with small quantities of excipients, adverse effects caused by excipients can be avoided. 9) In addition, n...

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mentioning

confidence: 99%

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and in Vitro/in Vivo Evaluation of Nanosized Poorly Water-Soluble Compounds

Komasaka¹,

Fujimura

Tagawa

et al. 2014

Chem. Pharm. Bull.

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“…In addition, design and optimization of any wet media milling process entails a good understanding of the breakage kinetics and its controlling process parameters (24). While process parameters of the wet stirred media milling, the most commonly used process for preparing drug nanosuspensions, have been widely studied (24,42,43) and the process has been intensified via a novel model-guided approach (44), no such investigation for the vibratory milling exists.…”

Section: Introductionmentioning

confidence: 99%

An Intensified Vibratory Milling Process for Enhancing the Breakage Kinetics during the Preparation of Drug Nanosuspensions

Zhang

Davé

et al. 2015

AAPS PharmSciTech

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Abstract. As a drug-sparing approach in early development, vibratory milling has been used for the preparation of nanosuspensions of poorly water-soluble drugs. The aim of this study was to intensify this process through a systematic increase in vibration intensity and bead loading with the optimal bead size for faster production. Griseofulvin, a poorly water-soluble drug, was wet-milled using yttrium-stabilized zirconia beads with sizes ranging from 50 to 1500 μm at low power density (0.87 W/g). Then, this process was intensified with the optimal bead size by sequentially increasing vibration intensity and bead loading. Additional experiments with several bead sizes were performed at high power density (16 W/g), and the results were compared to those from wet stirred media milling. Laser diffraction, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and dissolution tests were used for characterization. Results for the low power density indicated 800 μm as the optimal bead size which led to a median size of 545 nm with more than 10% of the drug particles greater than 1.8 μm albeit the fastest breakage. An increase in either vibration intensity or bead loading resulted in faster breakage. The most intensified process led to 90% of the particles being smaller than 300 nm. At the high power intensity, 400 μm beads were optimal, which enhanced griseofulvin dissolution significantly and signified the importance of bead size in view of the power density. Only the optimally intensified vibratory milling led to a comparable nanosuspension to that prepared by the stirred media milling.

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“…Since the beginning of the 1990s, Elan Pharma International Ltd. (San Francisco, CA, USA) has proven the significance of nanocrystals over the microcrystals to improve the oral absorption of poorly watersoluble drug. The drug nanocrystals are the crystals with a size in the nanometer range, typically below 500 nm (13,14). According to Noyes-Whitney equation, the dissolution is a function of surface area, so formulating nanocrystals will benefit to enhance the oral bioavailability, where absorption is dissolution rate limited.…”

Section: Introductionmentioning

confidence: 99%

Ultra Rapidly Dissolving Repaglinide Nanosized Crystals Prepared via Bottom-Up and Top-Down Approach: Influence of Food on Pharmacokinetics Behavior

2014

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Abstract. The present work was undertaken with the objectives of improving the dissolution velocity, related oral bioavailability, and minimizing the fasted/fed state variability of repaglinide, a poorly watersoluble anti-diabetic active by exploring the principles of nanotechnology. Nanocrystal formulations were prepared by both top-down and bottom-up approaches. These approaches were compared in light of their ability to provide the formulation stability in terms of particle size. Soluplus® was used as a stabilizer and Kolliphor™ E-TPGS was used as an oral absorption enhancer. In vitro dissolution profiles were investigated in distilled water, fasted and fed state simulated gastric fluid, and compared with the pure repaglinide. In vivo pharmacokinetics was performed in both the fasted and fed state using Wistar rats. Oral hypoglycemic activity was also assessed in streptozotocin-induced diabetic rats. Nanocrystals TD-A and TD-B showed 19.86 and 25.67-fold increase in saturation solubility, respectively, when compared with pure repaglinide. Almost 10 (TD-A) and 15 (TD-B)-fold enhancement in the oral bioavailability of nanocrystals was observed regardless of the fasted/fed state compared to pure repaglinide. Nanocrystal formulations also demonstrated significant (p<0.001) hypoglycemic activity with faster onset (less than 30 min) and prolonged duration (up to 8 h) compared to pure repaglinide (after 60 min; up to 4 h, respectively).

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Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods

Cited by 321 publications

References 86 publications

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and <i>in Vitro</i>/<i>in Vivo</i> Evaluation of Nanosized Poorly Water-Soluble Compounds

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and <i>in Vitro</i>/<i>in Vivo</i> Evaluation of Nanosized Poorly Water-Soluble Compounds

An Intensified Vibratory Milling Process for Enhancing the Breakage Kinetics during the Preparation of Drug Nanosuspensions

Ultra Rapidly Dissolving Repaglinide Nanosized Crystals Prepared via Bottom-Up and Top-Down Approach: Influence of Food on Pharmacokinetics Behavior

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