Review
Nanosuspensions of poorly water-soluble drugs prepared by bottom-up technologies

https://doi.org/10.1016/j.ijpharm.2015.09.021Get rights and content

Abstract

In recent years, nanosuspension has been considered effective in the delivery of water-soluble drugs. One of the main challenges to effective drug delivery is designing an appropriate nanosuspension preparation approach with low energy input and erosion contamination, such as the bottom-up method. This review focuses on bottom-up technologies for preparation of nanosuspensions. The features and advantages of drug nanosuspension, including bottom-up methods as well as the corresponding characterization techniques, solidification methods, and drug delivery dosage forms, are discussed in detail. Certain limitations of commercial nanosuspension products are also reviewed.

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.

  1. Download : Download high-res image (171KB)
  2. Download : Download full-size image

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).

References (162)

  • M.M. Can et al.

    Effect of milling time on the synthesis of magnetite nanoparticles by wet milling

    Mat. Sci. Eng. B Solid

    (2010)
  • A.M. Cerdeira et al.

    Miconazole nanosuspensions: influence of formulation variables on particle size reduction and physical stability

    Int. J. Pharm.

    (2010)
  • A.M. Cerdeira et al.

    Formulation and drying of miconazole and itraconazole nanosuspensions

    Int. J. Pharm.

    (2013)
  • H.K. Chan et al.

    Production methods for nanodrug particles using the bottom-up approach

    Adv. Drug Deliv. Rev.

    (2011)
  • K. Chaudhury et al.

    Mitigation of endometriosis using regenerative cerium oxide nanoparticles

    Nanomed. Nanotechnol.

    (2013)
  • H.-Y. Cho et al.

    Effect of spray-drying process on physical properties of sodium chloride/maltodextrin complexes

    Powder Technol.

    (2015)
  • S.F. Chow et al.

    Assessment of the relative performance of a confined impinging jets mixer and a multi-inlet vortex mixer for curcumin nanoparticle production

    Eur. J. Pharm. Biopharm.

    (2014)
  • P. Couvreur

    Nanoparticles in drug delivery: past, present and future

    Adv. Drug Deliv. Rev.

    (2013)
  • S.M. D’Addio et al.

    Controlling drug nanoparticle formation by rapid precipitation

    Adv. Drug Deliv. Rev.

    (2011)
  • S.M. D’Addio et al.

    Effects of block copolymer properties on nanocarrier protection from in vivo clearance

    J. Controlled Release

    (2012)
  • F. Danhier et al.

    Nanosuspension for the delivery of a poorly soluble anti-cancer kinase inhibitor

    Eur. J. Pharm. Biopharm.

    (2014)
  • Y. Deng et al.

    Encapsulation of antigen-loaded silica nanoparticles into microparticles for intradermal powder injection

    Eur. J. Pharm. Biopharm.

    (2014)
  • M. Dinarvand et al.

    Oral delivery of nanoparticles containing anticancer SN38 and hSET1 antisense for dual therapy of colon cancer

    Int. J. Biol. Macromol.

    (2015)
  • C. Dong et al.

    Synthesis of magnetic chitosan nanoparticle and its adsorption property for humic acid from aqueous solution

    Colloids Surf. A

    (2014)
  • J.A. Eldridge et al.

    Nanoparticle ζ-potential measurements using tunable resistive pulse sensing with variable pressure

    J. Colloid Interface Sci.

    (2014)
  • R. Fanciullino et al.

    Challenges, expectations and limits for nanoparticles-based therapeutics in cancer: a focus on nano-albumin-bound drugs

    Crit. Rev. Oncol. Hematol.

    (2013)
  • M. Forati-Nezhad et al.

    Affecting the morphology of silver deposition on carbon nanotube surface: from nanoparticles to dendritic (tree-like) nanostructures

    Mater. Sci. Eng. C Mater.

    (2015)
  • D. Francis et al.

    Ion milling coupled field emission scanning electron microscopy reveals current misunderstanding of morphology of polymeric nanoparticles

    Eur. J. Pharm. Biopharm.

    (2015)
  • J.A. Gallego-Urrea et al.

    Applications of particle-tracking analysis to the determination of size distributions and concentrations of nanoparticles in environmental, biological and food samples

    TRAC Trends Anal. Chem.

    (2011)
  • L. Gan et al.

    Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers

    Drug Discovery Today

    (2013)
  • H.S. Ganapathy et al.

    Polymeric nanoparticles from macroscopic crystalline monomers by facile solid-state polymerization in supercritical CO2

    J. Colloid Interface Sci.

    (2009)
  • L. Gao et al.

    Preparation of a chemically stable quercetin formulation using nanosuspension technology

    Int. J. Pharm.

    (2011)
  • S. Gebremedhin et al.

    Gene delivery to carcinoma cells via novel non-viral vectors: nanoparticle tracking analysis and suicide gene therapy

    Eur. J. Pharm. Biopharm.

    (2014)
  • M. George et al.

    Identifying the correlation between drug/stabilizer properties and critical quality attributes (CQAs) of nanosuspension formulation prepared by wet media milling technology

    Eur. J. Pharm. Biopharm.

    (2013)
  • P. Georgiev et al.

    Implementing atomic force microscopy (AFM) for studying kinetics of gold nanoparticle’s growth

    Colloids Surf. A

    (2013)
  • Y. Gokce et al.

    Ultrasonication of chitosan nanoparticle suspension: influence on particle size

    Colloids Surf. A

    (2014)
  • H. Grohganz et al.

    The influence of lysozyme on mannitol polymorphism in freeze-dried and spray-dried formulations depends on the selection of the drying process

    Int. J. Pharm.

    (2013)
  • H. Gupta et al.

    Sparfloxacin-loaded PLGA nanoparticles for sustained ocular drug delivery

    Nanomed. Nanotechnol.

    (2010)
  • J. Hao et al.

    Fabrication of a composite system combining solid lipid nanoparticles and thermosensitive hydrogel for challenging ophthalmic drug delivery

    Colloids Surf. B

    (2014)
  • V.P. Heljo et al.

    The effect of freeze-drying parameters and formulation composition on IgG stability during drying

    Eur. J. Pharm. Biopharm.

    (2013)
  • R. Herrero-Vanrell et al.

    Nano and microtechnologies for ophthalmic administration, an overview

    J. Drug Deliv. Sci. Technol.

    (2013)
  • S. Hirn et al.

    Particle size-dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration

    Eur. J. Pharm. Biopharm.

    (2011)
  • M.R. Housaindokht et al.

    Study the effect of HLB of surfactant on particle size distribution of hematite nanoparticles prepared via the reverse microemulsion

    Solid State Sci.

    (2012)
  • S. Huang et al.

    Tumor targeting and microenvironment-responsive nanoparticles for gene delivery

    Biomaterials

    (2013)
  • M. Iijima et al.

    Free-standing, roll-able, and transparent silicone polymer film prepared by using nanoparticles as cross-linking agents

    Adv. Powder Technol.

    (2013)
  • K. Jannoo et al.

    Electron beam assisted synthesis of silver nanoparticle in chitosan stabilizer: preparation, stability and inhibition of building fungi studies

    Radiat. Phys. Chem.

    (2015)
  • H.-J. Jeon et al.

    Effect of solvent on the preparation of surfactant-free poly(-lactide-co-glycolide) nanoparticles and norfloxacin release characteristics

    Int. J. Pharm.

    (2000)
  • N. Ji et al.

    Effects of heat moisture treatment on the physicochemical properties of starch nanoparticles

    Carbohydr. Polym.

    (2015)
  • G. Joshi et al.

    Enhanced bioavailability and intestinal uptake of Gemcitabine HCl loaded PLGA nanoparticles after oral delivery

    Eur. J. Pharm. Biopharm.

    (2014)
  • S. Kamiya et al.

    The physicochemical interactive mechanism between nanoparticles and raffinose during freeze-drying

    Int. J. Pharm.

    (2014)
  • Cited by (123)

    • Nanocrystals in cosmetics and cosmeceuticals by topical delivery

      2023, Colloids and Surfaces B: Biointerfaces
    View all citing articles on Scopus
    View full text