Design of Dry Nanosuspension with Highly Spontaneous Dispersible Characteristics to Develop Solubilized Formulation for Poorly Water-Soluble Drugs

Niwa, Toshiyuki; Miura, Satoru; Danjo, Kazumi

doi:10.1007/s11095-011-0465-y

Cited by 33 publications

(7 citation statements)

References 31 publications

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“…11 This combination allowed for fast recovery of drug NCs from NC-aggregated particles. 12,13 However, despite their effectiveness as dispersants, surfactants could pose several challenges, such as aggregation of drug nanoparticles in suspensions during milling/storage and low drug loading capacity (most ,20%, seldom .50%). 14,15 For example, van Eerdenbrugh et al combined microcrystalline cellulose and d-α-tocopheryl polyethylene glycol 1000 succinate to use as dispersants for redispersible itraconazole NCs.…”

Section: Introductionmentioning

confidence: 99%

Novel nanocrystal-based solid dispersion with high drug loading, enhanced dissolution, and bioavailability of andrographolide

Ma¹,

Yang²,

Xie³

et al. 2018

IJN

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ObjectiveThe current study sought to design a quickly dissolving, high drug loading nanocrystal-based solid dispersion (NC-SD) in order to improve the dissolution of poorly soluble drugs.MethodsThe NC-SD was prepared by means of combination of homogenization and spray-drying. Polymer hydroxypropylmethylcellulose (HPMC) was used as baseline dispersant for NC-SD of the model drug – andrographolide (AG). Three superdisintegrants cohomogenized with HPMC were used as codispersant for AG-NC-SD and compared to common water-soluble dispersants – mannitol and lactose. The dissolution characterization and oral bioavailability of AG-NC-SD were evaluated.ResultsThe AG-NC-SD with the higher concentration of HPMC exhibited fast dissolution due to the enhanced wettability of HPMC. The water-soluble codispersants (mannitol and lactose) did not completely prevent AG-NC from aggregation during spray-drying. To achieve much faster AG release, cohomogenized superdisintegrants at a level of 20% must be used along with 25% HPMC. Compared with water-soluble dispersants like mannitol and lactose, superdisintegrants with high swelling capacity were much more effective dispersants for enhancing fast redispersion/dissolution of AG-NC-SD via a swelling-triggered erosion/disintegration mechanism. Surfactant-free AG-NC-SD with 15% cohomogenized sodium carboxymethyl starch combined with 15% HPMC and 10% lactose enhanced the dissolution further, without comprising drug loading, exhibited a barely compromised dissolution rate compared to precursor NC suspensions (f2>50), and possessed drug loading up to 67.83%±1.26%. The pharmacokinetics results also demonstrated that the AG-NC-SD significantly improved the bioavailability in vivo of AG (P<0.05), compared with to the coarse AG.ConclusionThis study illustrates that a quickly dissolving, high drug load, surfactant-free NC-SD can be prepared by using a superdisintegrant as codispersant, and provides a feasible strategy to improve the oral bioavailability of poorly soluble drugs.

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Section: Introductionmentioning

confidence: 99%

Novel nanocrystal-based solid dispersion with high drug loading, enhanced dissolution, and bioavailability of andrographolide

Ma¹,

Yang²,

Xie³

et al. 2018

IJN

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“…In addition, long-term stability of nanoparticles in suspension phases is required so that the nanosuspension formulations can be used for repeated dosing in toxicology studies. Although solidification techniques such as freeze-drying and spray-drying of nanosuspensions have been developed to avoid instability of nanoparticles in suspension phases, 12,13) they are not favorable for toxicology studies because they normally require additional large quantities of excipients to redisperse the nanoparticles in water. In addition, nanosuspension formulations should be versatile for multiple compounds because many drug candidates are subjected to toxicology studies in the discovery stage.…”

mentioning

confidence: 99%

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

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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“…111 Drying manufactured NPs for storage is also a practical way by which nanotechnologists reduce agglomeration risks and stabilize nanomedicine properties for eventual reconstitution. 120,121 Methods include spray freeze-drying or drying onto lactose surfaces. 122,123 Nanosilica and other nanostructures can survive drying.…”

Section: Dilutionin Nanoscience: Possible Relevance Tohomeopathic Manmentioning

confidence: 99%

Enhancement of adaptive biological effects by nanotechnology preparation methods in homeopathic medicines

Bell

Schwartz

2015

Homeopathy

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Multiple studies have demonstrated that traditional homeopathic manufacturing reagents and processes can generate remedy source and silica nanoparticles (NPs). Homeopathically-made NPs would initiate adaptive changes in an organism as a complex adaptive system (CAS) or network. Adaptive changes would emerge from several different endogenous amplification processes that respond to exogenous danger or threat signals that manufactured nanomaterials convey, including (1) stochastic resonance (SR) in sensory neural systems and (2) time-dependent sensitization (TDS)/oscillation. SR is nonlinear coherent amplification of a weak signal by the superposition of a larger magnitude white noise containing within it the same frequencies of the weak signal. TDS is progressive response magnitude amplification and oscillatory reversal in response direction to a given low dose at physiological limits with the passage of time. Hormesis is an overarching adaptive phenomenon that reflects the observed nonlinear adaptive dose-response relationship. Remedies would act as enhanced micro- and nanoscale forms of their source material via direct local ligand-receptor interactions at very low potencies and/or by triggering systemic adaptive network dynamical effects via their NP-based electromagnetic, optical, and quantum mechanical properties at higher potencies. Manufacturing parameters including dilution modify sizes, shapes, and surface charges of nanoparticles, thereby causing differences in physico-chemical properties and biological effects. Based on surface area, size, shape, and charge, nanoparticles adsorb a complex pattern of serum proteins, forming a protein corona on contact that constitutes a unique biological identity. The protein corona may capture individualized dysfunctional biological mediator information of the organism onto the surfaces of the salient, i.e., resonant, remedy nanostructures. SR would amplify this weak signal from the salient remedy NPs with protein corona adsorbed, leading to sensitized nonlinear dynamical modulation of gene expression and associated changes in biological signaling pathways. When the system reaches its physiological limits during a homeopathic aggravation or the natural disease state, the amplified remedy signal triggers a nonlinear reversal in dynamical direction back towards health.

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Design of Dry Nanosuspension with Highly Spontaneous Dispersible Characteristics to Develop Solubilized Formulation for Poorly Water-Soluble Drugs

Abstract: The present technique with combination of wet nano-milling and spray-drying processes would be a novel approach to develop the pharmaceutical products with poorly water-soluble and oral-absorbable drugs.

Cited by 33 publications

References 31 publications

Novel nanocrystal-based solid dispersion with high drug loading, enhanced dissolution, and bioavailability of andrographolide

Novel nanocrystal-based solid dispersion with high drug loading, enhanced dissolution, and bioavailability of andrographolide

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

Enhancement of adaptive biological effects by nanotechnology preparation methods in homeopathic medicines

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