ReviewNanosuspensions of poorly water-soluble drugs prepared by bottom-up technologies
Graphical abstract
Nanosuspension could be prepared by precipitation–ultrasonication method. Anti-solvent precipitation is an effect way to make nano-sized particles; ultrasonication could control the process of nucleation and crystallization effectively. Spray drying or freeze drying could make dry nanoparticles that could store a longer time.
Introduction
In recent years, active chemical entities have been increasingly studied, although most of them are poorly soluble or insoluble in water (Al-Qadi et al., 2011). More than 40% of the potential drugs are poorly soluble in water, which, although important, are thus excluded from further study (Gebremedhin et al., 2014). It is estimated that annually about $65 billion is spent on treatment of disease worldwide due to the poor bioavailability of drugs, with little curative effect. In particular, some drugs have also been proven to exert severe or even fatal effects. The low bioavailability of poorly soluble drugs prepared by traditional methods for oral or intravenous administration greatly limits their application (Zhu et al., 2014). To overcome this limitation, preparation workers use methods such as using mixed solvents, adopting inclusion technology and micronization, or converting into intravenous emulsion (Merisko-Liversidge and Liversidge, 2011). However, these methods have certain drawbacks: the mixed solvent method requires drugs with particular physical and chemical properties, capable of being dissolved in some organic solvents; the inclusion technology requires drugs of suitable molecular size; and the micronization method does not increase bioavailability significantly (Tran et al., 2015).
In fact, exploiting the density and solid state is beneficial in producing drug–polymer complexes of large unit volume, especially in preparing pharmaceuticals in large doses (Sievens-Figueroa et al., 2012). However, molecular complexation approaches have often failed, as complex materials with large mole ratio are used (Rabinow, 2004). A high loading dose is used to reduce the administration volume, which is important in the case of small-volume intramuscular and ophthalmic injections (Deng et al., 2014).
Furthermore, in order to increase the solubility of insoluble drugs, conventional preparation methods often require large amounts of cosolvent, although this could result in a toxic effect (Jeon et al., 2000). Subsequently, an increasing number of experimental animals were used in studies investigating the optimal, safe dose (Alhassan et al., 2014).
Therefore, researchers abroad have developed a new kind of preparation nanosuspension to improve the bioavailability of poorly soluble drugs (George and Ghosh, 2013). Nanosuspension is a kind of pure particle–drug system that is composed of submicron colloidal dispersions, with a surfactant as the suspension agent (Kuntsche and Bunjes, 2007). Nanosuspensions can be used to prepare water-insoluble but oil-soluble drugs, although lipid systems such as liposome and emulsion preparations can also be used (Mengersen and Bunjes, 2012). In comparison to the lipid systems, nanosuspensions can also successfully formulate drug preparations that are poorly soluble in both water and oil. Nanosuspensions helps prevent the dissolution of the drug before preparation, as it must be maintained under the optimum crystallization conditions and at sufficiently small sizes (Yao et al., 2012).
Therefore, nanosuspensions have several benefits in disease treatment. For instance, intravenous administration of drugs can reduce toxicity and increase the curative effect; further, pulmonary drug delivery can increase lung-deep penetration of the medication (Wu et al., 2011). Nanosuspensions also reduce the size of solid drugs to improve their solubility, especially in the case of poorly soluble oral drugs. The solid state is superior to the liquid state, and small size can increase the physical stability of sedimentation. Therefore, nanosuspensions differ significantly from drug carriers such as colloidal polymer nanoparticles (Wu et al., 2011).
This dosage form has also shown other advantages such as the production of biological adhesion and improvements in chemical stability (Otsuka et al., 2012). In 2000, nanosuspensions were made commercially available in the pharmaceutical market with its special features of increased saturation velocity, increased adhesiveness to surfaces/cell membranes, and increased dissolution velocity (Müller et al., 2011).
Section snippets
Precipitation–ultrasonication method
In recent years, ultrasound has emerged as an effective method of controlling the process of nucleation and crystallization. Further, ultrasound irradiation helps intensify mass transfer and accelerate molecular diffusion (Zeng and Weber, 2014). As shown in Fig. 1, ultrasonic power inputs of 200, 300, 400, and 580 W were selected and applied for 15 min. The crystal size decreased with an increase in the ultrasonic power input. However, the particle size did not change significantly between 400
Particle size and particle size distribution
Physicochemical properties such as particle size, size distribution, morphology, crystalline state of the drug, zeta potential, in vitro release, and plasma stability were evaluated (Nikolov et al., 2013). Methods such as laser diffraction (LD), dynamic light scattering (DLS), field-flow fractionation, single-particle tracking analysis, scanning ion occlusion sensing, and light and electron microscopy were found to be suitable for particle size determination (Menz et al., 2012).
Dynamic light
Drug properties and nanosuspension production
Nanosuspension was developed to prevent the needless exposure of organs other than the targeted one and reduce the cost of treatment, thus increasing bioavailability and reducing dose (Wei et al., 2014). Nanosuspensions offer an easy, simple, and cost-effective solution to all of these issues (Joshi et al., 2014). Nanosuspension can also be considered relevant to the pharmaceutical industry because it overcomes the limitations of other drug delivery systems such as polymer toxicity, low
Stability of nanosuspension
The instability of nanoparticles may be induced in three ways: first, aggregation without sufficient surface protection such as steric and static stabilizations; second, recrystallization from an amorphous to crystalline state to lower lattice energy (Zhu, 2013); and third, Ostwald ripening driven by the solubility difference between different-sized particles based on the Kelvin equation (Lai et al., 2013).
Aggregation is considered a more significant factor affecting stability during storage.
Spray drying
In pharmaceutical research, freeze drying with a cryoprotectant spray has been used to stabilize powders of proteins (Sato et al., 2015). In spray freeze drying, the nanosuspension is atomized and frozen in a cryogenic fluid (Cho et al., 2015). The solidified state is preferred to an aqueous nanosuspension, as aggregation and other instability factors are significantly decreased under the former (Schaefer and Lee, 2015). Liquid nanosuspensions are further transformed into dry products to reduce
Oral delivery
As is known, oral suspensions are preferred because they are easily dissolved, easily swallowed by the elderly and young alike, and more palatable. Compared with other traditional medicinal suspension agents, it has a higher Cmax value and superior pharmacokinetics. For instance, danazol, with a nanoparticulate dispersion of 169 nm, has a higher Cmax value and a higher bioavailability than its conventional form (Li et al., 2015).
Nanoparticle loading of drugs has also been proven to reduce their
Challenges and future perspectives
Despite its many advantages, the bottom-up approach has some limitations. The solubility of the drug is slightly higher than other insoluble drugs. Low concentrations will impede the formation of the crystal nucleus and high concentrations will hamper drug delivery in animal models; the repeatability is poor (Bousnina et al., 2015). For the anti-solvent precipitation technique, although a simple setup, the anti-solvent must be miscible with water and mixing conditions cannot be accurately
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No: 81302711) and the Outstanding Young Scientist Research Award Fund of Shandong Province (No: BS2012YY023).
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