In contrast, the Dissocubes® technology employs piston-gap homogenizers. The technology was developed by Müller and colleagues (, ) and later. DissoCubes are part of Nanosuspension preparation. In which piston–gap high- pressure homogenization occurs. The main advantages of this technology. Employing piston-gap homogenizers, Müller and coworkers developed the Dissocubes technology (now belonging to Skyepharma plc) and the.
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To receive news and publication updates for Journal of Nanomaterials, enter your email address in the box below. This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Poor aqueous solubility of some drug molecules is a major problem in drug formulation. Drug nanosuspensions emerged as one solution to dissocubee such hydrophobic drugs.
Scaling down to nanoparticles enhances drug aqueous solubility and bioavailability by disdocubes drug surface area that comes into contact with biological media. These nanoparticles are capable of accumulating in targeted areas such as cancer tissues and infarct zones with minimal damage to healthy tissues. Nanosuspensions are often prepared by commercially available methods such as high pressure homogenization, media milling, emulsification, and melt emulsification. Solidification and surface modification methods are post-processing techniques used to add particular properties for advanced therapies.
In this review, we firstly describe preparation methods for nanosuspensions. Secondly, we highlight typical characterization techniques. Finally, we describe several practical application of applications for drug delivery technologyy and different administration routes such as parenteral, pulmonary, oral, and ocular.
Lipophilic compounds have poor aqueous solubility and imperfect dissolution profile which causes their low bioavailability.
Bioavailability is percentage of the drug which reaches the systemic circulation [ 3 ]. Therefore, formulating new poorly water soluble molecules to obtain an adequate bioavailability has become a serious and challenging scientific, industrial, and medical issue. Grease ball molecules are highly lipophilic with high due to no interactions with water. Their poor solubility in water is caused by the strong intermolecular bonding and high lattice energy in solid state.
Poorly water soluble molecules are typically formulated using various excipients dissocubex the aim of improving dissolution rate and storage stability. Excipients increase drug dissolution rate by increasing active drug surface area in contact with tfchnology dissolution medium [ 7 ]. The use of excipients in formulations of poorly soluble drugs has been demonstrated to increase dissolution rate.
However, limitations such as toxicity of surfactants dissocubds are often used in high doses to keep drug in the dispersed state and limited drug loading have disaocubes identified [ 24 ]. Micronization is another approach used to increase drug solubility. Colloid mills or jet mills are examples of the micronization technique. The obtained particle size varies in the range from 0. Transferring micron size drug particles into nanoscale was the next development stage [ 2627 ]. The dussocubes of this technique is the requirement for the drug to be soluble in at least one solvent and that solvent needs to be technopogy with a nonsolvent [ 29 ].
It is now well established that nanosizing increases drug saturation solubility and dissolution rate [ 33 ].
Nanosuspension: An approach to enhance solubility of drugs
Furthermore, nanosuspensions reduce drug administration doses, side effects, and cost of therapy [ 34 ]. PEGylated nanoparticles are colloidal structures with a cargo space for drugs, segregated from the environment by hydrophilic PEG corona that prevents recognition by macrophages and enables long-term circulation upon intravenous i.
Passive targeting is based on pathophysiological characteristics unique to solid tumours: Nanosuspensions have been demonstrated to have a number of advantages compared to traditional forms of drug delivery. These advantages are summarised below: BCS allocates drugs to one of 4 classes: Table 1 shows examples of drugs which belong to the different biopharmaceutical classes [ 3940 ].
The media milling technique was developed by Liversidge et al. In this method high-shear media mills or pearl mills are used to produce nanosuspension. The media mill consists of a milling chamber, a milling shaft, and a recirculation chamber Figure 1. The milling media or balls are framed in ceramic-sintered aluminium oxide or highly cross-linked polystyrene resin.
The milling chamber is fed with an aqueous suspension of the drug, stabilizer, and the milling media or pearls rotate at a very high shear rate. This procedure can be carried out under controlled temperature. The friction and collisions among drug particles and pearls generate nanoparticles. Ease of scale-up and little batch-to-batch variation are the advantages of media milling. Disadvantage of this method is the erosion of pearls which leads to contamination of the final product and subsequently problems upon administration [ 47 ].
Table 2 shows examples of marketed nanosuspensions that have been produced by media milling technique [ 4849 ]. High pressure homogenization is a commonly employed method for producing nanosuspensions of poorly soluble drugs [ 50 — 55 ].
This method involves forcing a suspension, which contains drug and stabilisers, through a valve with a small orifice technolpgy pressure. High pressure homogenization is often classified into two groups: This causes an increase in the dynamic pressure with simultaneous reduction in the static pressure which reduces the boiling point of water to room temperature.
Tecbnology, at room temperature water starts boiling creating gas bubbles. When the suspension departs the gap and the pressure returns to atmospheric level, the gas bubbles implode.
This phenomenon is called cavitation. The combined forces of cavitation, high shear, and collisions lead to fracture of the drug microparticles into nanosized particles [ 56 ]. Homogenization pressure, number of homogenization cycles, hardness of drugs, dissocubex temperature when thermosensitive drugs are processed are factors that influence the physical characteristics such as particle size of the resulting nanosuspensions.
Tecnnology contamination due to the erosion is less pronounced in this technique than in media milling. High pressure homogenization is considered as a safe technique for producing nanosuspensions.
The main drawback of this method is the need for pretreatment to obtain microparticles before starting the homogenization process and the many cycles of homogenization [ 5960 ].
For dissoocubes purposes such as dispersing drug nanocrystals in low molecular weight PEG or in oil, liquid nanosuspensions are teechnology in nonaqueous media or media with reduced texhnology content.
Because of the high boiling point and low vapour pressure of oily fatty acids and oils, the drop in pressure is not sufficient for cavitation and thus the latter is not a determining factor in this process.
Table 3 shows examples of drugs processed by high pressure homogenization and corresponding references. The technology consists of two processes: Generally, this technique includes mixing of two different solutions. The drug is dissolved in an organic solvent which is miscible with water and forms the organic phase.
The stabilisers are dissolved in the aqueous phase in which the drug is insoluble. Mixing these two solutions causes precipitation of drug particles. The last step of the process is high pressure homogenization [ 76 ]. This method uses dissoucbes water-miscible and volatile organic solvent such as butyl lactate, benzyl alcohol, triacetin, and ethyl acetate as the disscoubes phase [ 7879 ].
The emulsion is prepared by dispersing the drug loaded in a mixture of solvents or an organic solvent and forming emulsion with water by high pressure homogenisation or other techniques.
Nanosuspension: An approach to enhance solubility of drugs
Dilution leads to formation of nanosuspensions by diffusion of the internal phase into the external phase when droplets convert into solid particles. The size of the emulsion droplets determines the particle size.
The use of organic solvents such as ethyl acetate, ethanol, methanol, and chloroform and the presence of residual solvents in the final products are major drawbacks of this technology due to potential environmental hazards dissocubed human safety issues [ 78 ]. Acyclovir nanosuspensions have been produced by emulsion diffusion method [ 80 ]. Melt dissocybes method has been used to prepare solid lipid nanoparticles [ 8182 ]. The first step in melt emulsification involves dispersing the drug in aqueous solution with stabiliser.
Secondly, the nanosuspension is heated above the melting point of the drug and homogenised with a high-speed homogeniser to produce an emulsion. During this procedure the temperature must be controlled and maintained above the melting point of the drug. The final step of the melt emulsification method is cooling off the emulsion to a suitable temperature, either at room temperature or in an ice bath. Factors affecting particle size include drug and stabiliser concentrations, type of stabiliser, and cooling condition.
Solvent-free prepared nanosuspensions are particularly important from toxicity point of view. Therefore, the advantage of this method over solvent diffusion method is avoidance of organic solvents. The most important characteristics of nanosuspensions are particle size and polydispersity index PI: Particles size of nanosuspensions critically determines the following characteristics of nanosuspensions [ 56 ]: Increased solubility with reduction of particles size is also demonstrated by Ostwald-Freundlich equation 2 [ 4185 ]: Figure 2 shows surface area as a function of particle size [ 86 ].
It has been experimentally demonstrated that particle size affects drug saturation solubility and dissolution rate.
In vivo studies of Wang et al. In addition, from a perspective of practical application, drug particles have to be within specific size ranges. In this technique, the Brownian motion movement in random direction of particles is measured as a function of time.
Larger particles move with lower velocity than smaller particles. In addition, larger particles may settle out of the measurement zone.
Laser Diffraction LD is typically used to measure particle size range of 0. This technique can also be used to detect and quantify particle size ranges during the production procedure [ 5688 ].
Other techniques routinely used for measuring particle size are optical and electron microscopy. Furthermore, the Coulter Counter analysis can be used to determine the absolute number of particles per unit volume for different particle sizes [ 88 ].
Details are available in [ 98 ]. The high energy amorphous form of drugs is thermodynamically unstable and changes to a crystalline form during storage. The amorphous form is preferred due to superior dissolution characteristics and consequently higher bioavailability of the drugs [ 99 ]. Transformation from amorphous to crystalline forms over storage is one of the issues that should be considered when formulating nanosuspensions. XRPD is sometimes considered to be the most appropriate method for evaluating drug crystalline structure, since each crystal has a specific diffraction pattern [ ].
However, it should be taken into consideration that there is a slight difference in the crystal structure of the same drug as observed by Tian et al. Terahertz spectroscopy is a relatively new analytical method used to evaluate crystalline form of drugs where each crystalline polymorph form exhibits specific terahertz absorption spectrum [ — ].