Pawar Pravin, Yadav Adhikrao, Gharge Varsha*
Gourishankar Institute of Pharmaceutical Education and Research, Limb, Satara, India-41501
Nanosuspensions it is a colloidal dispersions of nanosized drug particles stabilized by various surfactants. They can define as a biphasic system consisting of pure drug particles dispersed in an aqueous vehicle in which the diameter of the suspended particle is less than 1μm in size. Nanosuspension are the most of the rapidly developing field of nanotechnology with various applications in drug delivery, medical and research as that of other medical sciences and develop new therapeutics. Now day a new generation of Nanosuspension (NS) consisting of a mixture of two phases in that one it is a solid and another is liquid. Nanosuspension technology solved the problem of drugs which are poorly aqueous soluble and less bioavailability. Stability and bioavailability of the drugs can be improved by the Nanosuspension technology, also the Nanosuspension improves drug loading and firmly incorporates the drug during storage. The present review gives highlight on the different techniques for preparation and characterization of Nanosuspension as Particle Size, Zeta Potential, Entrapment Efficiency, Stability Study and the importance of NLC in pharmaceutical applications.
Nanotechnology is the preparation of the nanosized structures cotaining the drugs.1 The defination of nanotechnology is study and structures in the size range of 1-100nm2,3. In the nanotechnology other important drug delivery system it will be developed that is Nanoparticles, SLNs, Nanosuspension, NLCs, Nanoemulsion, Nanocrystals, LDCs etc.4,5, 6 This review focused on the NS for drug delivery and targeting application.
There are many conventional methods for increasing the solubility of poorly soluble drugs, which include micronization, solubilization using co‐solvents, salt form, surfactant dispersions, precipitation technique, and oily solution. Other techniques are like liposomes, emulsions, microemulsion, solid dispersion and inclusion complexation using cyclodextrins7-13 Nanosuspensions are colloidal dispersions of nanosized drug particles stabilized by surfactants. They can also be defined as a biphasic system consisting of pure drug particles dispersed in an aqueous vehicle in which the diameter of the suspended particle is less than 1μm in size. The Nanosuspensions can also be lyophilized or spray dried and the nanoparticles of a Nanosuspension can also be incorporated in a solid matrix14-19.
STRUCTURE OF NANOSUSPENSION:
Figure No 1: Structure of Nanosuspension
With the help of this technique, the drugs are dispersed in water and the fineness of dispersed particles force them to dissolve more quickly owing to their higher dissolution pressure and leads to an increased saturation solubility. 20 In nanoformulation it is not only necessary that the drug particles be rendered into nanosize domains, but they must also be stabilized and formulated rigorously to retain the nature and properties of the nanoparticles
1. Simple technology
2. Low-cost process regarding the milling itself
3. Large-scale production possible to some extent
1. Potential erosion from the milling material leading to product contamination.
2. Duration of the process not being very production friendly.
3. Potential growth of germs in the water phase when milling for a long time.
4. Time and costs associated with the separation procedure of the milling material from the drug nanoparticle suspension, especially when producing parenteral sterile products.21-24
Table no 1: shows list of excipients used in NLCs preparation25. 26
Wet the drug particles thoroughly, prevent Ostwald’s ripening and agglomeration of Nanosuspensions, providing steric or ionic barrier
Lecithins, poloxamers, polysorbate, Cellulosics, povidones
Influence phase behavior when micro emulsions Are used to formulate nanosuspensions
Bile salts, dipotassium glycerrhizinate, transcutol, glycofurol, Ethanol, isopropanol
Pharmaceutically acceptable less hazardous Solvent for preparation of formulation.
Methanol, ethanol, chloroform, isopropanol, ethyl acetate, ethyl Formate, butyl lactate, triacetin, propylene carbonate, benzyl alcohol
According to the requirement of the route of Administration or the properties of the drug moiety
Buffers, salts, polyols, osmogens, cryoprotectant etc
2. DIFFERENT TECHNIQUES FOR PREPARATION OF NANOSTRUCTURED LIPID CARRIER:
1. High pressure homogenization (HPH)
1. Hot homogenization
2. Cold homogenization
2. Ultrasonication or high speed homogenization
4. Solvent Evaporation Technique
5. Supercritical fluid technology
6. Double emulsion technique
7. Solvent emulsification-diffusion method
8. Precipitation Technique
9. Film Ultrasound Dispersion
10. Melting dispersion method
11. Solvent injection (or solvent displacement) technique
1. High pressure homogenization (HPH)27-33:
High pressure homogenization technique used for the formulation of NS. High pressure homogenizers push a liquid with high pressure (100–2000 bar) through a narrow gap. The fluid accelerates on a small distance to high velocity (over 1000 Km/h). Very high Shear stress and cavitation forces disrupt the particles down to the submicron range. Generally 5-10% lipid content is used but up to 40% lipid content has also been investigated. High pressure homogenization is of two types-hot homogenization and cold homogenization. In this two, a formulation step gives the drug incorporation into the bulk lipid by dissolving or dispersing the drug in the lipid melt or liquid lipid.
1. Hot homogenization34-38:
In this method, homogenization occurs at temperatures upper than melting point of lipid. Drug loaded lipid melt is dispersed in hot aqueous surfactants phase (isothermal) by mixing device (Ultra-Turrax) and leads to the formation of pre-emulsions. Because of the reduced viscosity at high temperatures, particle size becomes lesser mainly. This technique is illustrated in Figure 2 Hot homogenization has three basic problems. The first is temperature-dependent degradation of the drug, the second is the drug penetrates into the aqueous phase during homogenization and the third is complexity of the crystallization step of the nano-emulsion leading to several modifications and/or super cooled melts.
2. Cold homogenization39,40:
Like the hot homogenization method, the drug is dissolved in the lipid melt, and then rapidly cooled by liquid nitrogen or dry ice. Milling leads to formation of nanoparticles in the range of 50-100 nm which are dispersible in a cold surfactant phase that form a pre-suspension. PHP is done at ambient temperature that leads to break the nanoparticles to NS. Cold homogenization technique has been expanded to resolve the problems of the hot homogenization technique Schematic diagram of this method is given in Figure 2.
FIGURE 2: Hot homogenization and cold homogenization method.
2. Ultrasonication or high speed homogenization41-43
NS were also developed by high speed stirring or sonication. A most advantages are that, equipment whatever use here is very common in every lab. The problem of this method is broader particle size distribution ranging into micrometer range. This lead physical instability likes particle growth upon storage. Potential metal contamination due to ultrasonication is also a big problem in this method. So for making a stable formulation, studies have been performed by various research groups that high speed stirring and ultrasonication are used combined and performed at high temperature. Schematic diagram of this method is given in Figure 4
Figure 3: Ultasonication
This method is based on the dilution of microemulsions. As micro-emulsions are two-phase systems composed of an inner and outer phase (e.g. o/w microemulsions). They are made by stirring an optically transparent mixture at 65-70°C, which typically composed of a low melting fatty acid (e.g. stearic acid), an emulsifier (e.g. polysorbate 20), co-emulsifiers (e.g. butanol) and water. The hot microemulsion is dispersed in cold water (2-3°C) under stirring. NS dispersion can be used as granulation fluid for transferring in to solid product (tablets, pellets) by granulation process, but in case of low particle content too much of water needs to be removed. High-temperature gradients facilitate rapid lipid crystallization and prevent aggregation.
4. Solvent Evaporation Technique47, 48:
This is a method analogous to the production of NS solvent evaporation in o/w emulsions via precipitation. In the solvent emulsification-evaporation the lipid is dissolved in a water-immiscible organic solvent (e.g. toluene, chloroform) which is then emulsified in an aqueous phase before evaporation of the solvent under condition of reduced pressure. The lipid precipitates upon evaporation of the solvent thus forming nanoparticles.
Firstly, an organic phase has produced containing the lipid material dissolved in a water-immiscible organic solvent, and then the drug is dissolved or dispersed in that solution. This organic phase is emulsified in an o/w surfactant containing aqueous phase by mechanical stirring. Subsequent quick removal of solvent by evaporation from the obtained o/w emulsion under mechanical stirring or reduced pressure nanoparticle dispersion is formed by precipitation of the lipid in the aqueous medium. The solvent evaporation step must be quickly in order to avoid particle aggregation.
This method is suitable for the incorporation of highly thermolabile drugs due to avoidance of heat during the preparation but presence of solvent residues in the final dispersion may create problems due to regulatory concern. Limited solubility of lipids in organic materials generally leads to dilute dispersions and need to concentrate by means of another process such as ultra-filtration, evaporation or lyophilization. On the other hand small particle size around 100 nm with narrow size distribution can be achieved by this method. This procedure has schematically depicted in Fig no.4.
FIGURE 4: Solvent Evaporation Technique.
5. Supercritical fluid technology49:
This is a novel technique which recently applied for the production of NS. A fluid is qualifiedas supercritical when its pressure and temperature exceed their respective critical value. Above the critical temperature, it is not possible to liquefy a gas by increasing the pressure. The supercritical fluid has unique thermo-physical properties. As the pressure is raised, the density of the gas increases without significant increase in viscosity while the ability of the fluid to dissolve compounds also increases. A gas may have little to no ability to dissolve a compound under ambient condition can completely dissolve the compound under high pressure in supercritical range. Therefore, its solvation power is altered by careful control of changes in temperature and pressure. Many gases like, CO2, ammonia, ethane and CH2FCF3 were tried, but CO2 is the best option for SCF technique because, it is generally regarded as safe, easily accessible critical point [31.5ºC, 75.8 bar), does not causes the oxidation of drug material, leaves no traces behind after the process, is inexpensive, noninflammable, environmentally acceptable an easy to recycle or to dispose off. In the SCF phase or this technique generally use organic solvents (e.g. DMSO, DMFA) because they are fully miscible in SCF-CO2. This technology comprises several processes for nanoparticles production such as rapid expansion of supercritical solution (RESS), particles from gas saturated solution(PGSS), gas/supercritical anti-solvent (GAS/SAS), aerosol solvent extraction solvent (ASES), solution enhanced dispersion by supercritical fluid (SEDS),supercritical fluid extraction of emulsions (SFEE). Mainly SAS and PGSS were used for SLN preparation
6. Double Emulsion Technique50:
In double emulsion technique used for preparation NS. In this the drug (mainly hydrophilic drugs) was dissolved in aqueous solution, and then was emulsified in melted polymer. This primary emulsion was stabilized by adding stabilizer (e.g. gelatin, poloxamer-407). Then this stabilized primary emulsion was dispersed in aqueous phase containing hydrophilic emulsifier (e.g. PVA). Thereafter, the double emulsion was stirred and was isolated by filtration. Double emulsion technique avoids the necessity to melt the lipid for the preparation of peptide-loaded lipid nanoparticles and the surface of the nanoparticles could be modified in order to sterically stabilize them by means of the incorporation of a polymer /-PEG derivative. Sterical stabilization significantly improved the resistance of these colloidal systems in the gastrointestinal fluids. This technique is mainly used to encapsulate hydrophilic drug (peptides).
7. Solvent emulsification-diffusion method51:
NS can also be produced by solvent emulsification-diffusion technique. The mean particle size depends upon polymer concentration in the organic phase and the emulsifier used. Particles with average diameters of 30-100 nm can be obtained by this technique. Avoidance of heat during the preparation is the most important advantage of this technique. Here, the polymer matrix is dissolved in water-immiscible organic solvent followed by solidification in an aqueous phase. The solvent is evaporated under reduced pressure resulting in nanoparticles dispersion NS.
8. Precipitation Technique52:
NS can also be produced by a precipitation method which is characterized by the need for solvents. The polymer will be dissolved in an organic solvent (e.g. methanol, ethanol, chloroform) and the solution will be solidified in an aqueous phase. After evaporation of the organic solvent the polymer will be precipitated forming NS.
9. Film Ultrasound Dispersion53,54:
The polymer and the drug were put into suitable organic solutions, after decompression, rotation and evaporation of the organic solutions, a polymer film is formed, then the aqueous solution which includes the emulsions was added. Using the ultrasound with the probe to diffuser at last, the NS with the little and uniform particle size is formed.
10. Solvent injection (or solvent displacement) technique55:
Technique in which a solvent that distributes very rapidly in water (DMSO, ethanol) is used . First the lipid is dissolved in the solvent and then it is quickly injected into an aqueous solution of surfactants through an injection needle. The solvent migrates rapidly in the water and lipid particles precipitate in the aqueous solution. As shown in Figure 6 schematic overview of Solvent injection method. Particle size depends on the velocity of distribution processes. Higher velocity results in smaller particles. The more lipophilic solvents give larger particles which may become an issue. The method offers advantages such as low temperatures, low shear stress, easy handling and fast production process without technically sophisticated equipment (e.g. high-pressure homogeniser). However, the main disadvantage is the use of organic solvents.
Figure 5: Solvent Evaporation Technique.
CHARACTERIZATION OF NLCs:
Measurement of particle size and zeta potential56, 57
Photon correlation spectroscopy (PCS) and laser diffraction (LD) are the most powerful techniques for routine measurements of particle size. PCS (also known as dynamic light scattering) measures the fluctuation of the intensity of the scattered light which is caused by particle movement. This method covers a size range from a few nanometers to about 3 microns. PCS is a good tool to characterize nanoparticles, but it is not able to detect larger micro particles. Electron Microscopy provides, in contrast to PCS and LD, direct information on the particle shape. The physical stability of optimized NS dispersed is generally more than 12 months. ZP measurements allow predictions about the storage stability of colloidal dispersion.
Dynamic light scattering (DLS):
DLS also known as PCS records the variation in the intensity of the scattered light on the microsecond time scale.
Static light scattering (SLS):
SLS is an ensemble method in which the light scattered from a solution of particles is collected and fit into fundamental primary variable
It measures the attenuation of the scattered sound waves as a means of determining size through the fitting of physically relevant equations.
Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) provide a way to directly observe nanoparticles and physical characterization of nanoparticles. TEM has a smaller size limit of detection, is a good validation for other methods and one must be cognizant of the statistically small sample size and the effect that vacuum can have on the particles
Differential scanning calorimetry (DSC)59:
DSC and powder X-ray diffractometry (PXRD) is performed for the determination of the degree of crystallinity of the particle dispersion. The rate of crystallinity using DSC is estimated by comparison of the melting enthalpy/g of the bulk material with the melting enthalpy/g of the dispersion.
X-Ray Diffraction and Differential Scanning Calorimetry (Dsc)60:
The geometric scattering of radiation from crystal planes within a solid allow the presence or absence of the former to be determined thus permitting the degree of crystallinity to be assessed. DSC can be used to determine the nature and speciation of crystallinity within nanoparticles through the measurement of glass and melting point temperatures and their associated enthalpies.
Dynamic light scattering (DLS)61:
DLS, also known as PCS or quasi-elastic light scattering (QELS) records the variation in the intensity of scattered light on the microsecond time scale. This variation results from interference of light scattered by individual particles under the influence of Brownian motion, and is quantified by compilation of an autocorrelation function. The advantages of the method are the speed of analysis, lack of required calibration and sensitivity to sub micrometer particles.
Storage stability of Nanosuspension62,63:
The physical properties of NS during prolonged storage can be determined by monitoring changes in zeta potential, particle size, drug content, appearance and viscosity as the function of time.
External parameters such as temperature and light appear to be of primary importance for long – term stability. The zeta potential should be in general, remain higher than -60mV for a dispersion to remain physically stable.
4 oC - Most favorable storage temperature.
20 oC - Long term storage did not result in drug loaded NS aggregation or loss of drug.
50 oC - A rapid growth of particle size was observed.
The controlled or sustained release of the drugs from NS can result in the prolonged half-life and retarded enzymatic attack in systematic circulation. The drug release behavior from NS is dependent upon the production temperature, emulsifier composition, and oil percentage incorporated in the lipid matrix. The drug amount in the outer shell of the nanoparticles and on the particulate surface is released in a burst manner, while the drug incorporated into the particulate core is released in a prolonged way.
APPLICATIONS OF NLCs
Figure 6: Application of NLCs in different area.
The smart nanosuspension as the new generation offer much more flexibility in drug loading, modulation of release and improved performance in producing final dosage forms such as creams, tablets, capsules and injectables. The aim has been to developed therapeutic nanotechnology under taking, particularly for targetted drug therapy. The effort to develop alternative routes and to treat other diseases with NLCs should be continued to extend their applications.
I solicit my deep sense of appreciation and love to my wonderful Father and Mother consider my self-privilege to have seen an entity of almighty in them. I consider myself as luckiest person being my sister Rupali always there besides me during my ups and downs in my life and also thank to my teacher who will guide me for writing this review article. I am immensely thankful to G.I.P.E.R Limb Satara for their providing all facilities required for my work.
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