International Journal of Pharma Research & Review, Dec 2013; 2(12):30-39 Review Article

Nanosuspension -A Novel Approaches in Drug Delivery System

*Chaudhari

Shilpa P, Kamble Shrenik C, Mahajan Ritesh A, Jagdale Sachin, Ratnaparkhi Mukesh P

Department of Pharmaceutics, Marathwada Mitra Mandals College of Pharmacy, Thergaon (Kalewadi). Pune, India 411033. ABSTRACT The interest in the preparation and application of nanometer-sized materials is increasing due to their tremendous potential as a drug delivery system with wide range of applications. Recently, nanoscale systems have received much interest as a way to resolve solubility issues because of their costeffectiveness and technical simplicity compared to liposomes and other colloidal drug carriers. Nanosuspensions have proven to be a better alternative over other approaches currently available for improving bioavailability of number of drugs with low solubility. Nanosuspensions have been extensively developed for a wide range of drugs (poorly soluble) and have been evaluated for in vitro and in vivo applications by various routes: parenteral, oral, pulmonary, topical. They have also been used for drug targeting. This review describes the different methods of preparation for pharmaceutical nanosuspensions production, formulations and pharmaceutical applications in drug delivery as well as the marketed products, and their application that are being reported and patented. In fact, the number of products based on nanosuspension in the market and under clinical study is higher than that of other nanotechnology-based applications. A surprisingly large proportion of new drug candidates emerging from drug discovery programs are water insoluble and therefore poorly bioavailable, leading to abandoned development efforts. Keywords: Bioavailability, colloidal dispersion, homogenization, nanosuspension drug delivery, solubility Received 13 August 2013 Received in revised form 02 Sept 2013 Accepted 06 Sept 2013

*Address for correspondence: Dr. Shilpa P. Chaudhari Associate Professor, Marathwada Mitra Mandals, College of Pharmacy, Sr. No. 4/17, sector 34, PCNTDA, Thergaon, Pune-33, Maharashtra, India. E-mail: shilpapchaudhari78@yahoo.com

INTRODUCTION A nanosuspension is a submicron colloidal dispersion of drug particles which are stabilized by surfactants. A pharmaceutical nanosuspension is defined as very finely dispersed solid drug particles in an aqueous vehicle for either oral or topical use or for parenteral and pulmonary administration. The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 200 to 600 nm [1, 2]. In nanosuspension technology, the drug is maintained in the required crystalline state with reduced particle size, leading to an increased dissolution rate and therefore improved bioavailability. An increase in the dissolution rate of micronized particles

(particle size < 10 m) is related to an increase in the surface area and consequently the dissolution velocity. Nanosized particles can increase solution velocity and saturation solubility because of the vapor pressure effect [3]. In addition, the diffusional distance on the surface of drug nanoparticles is decreased, thus leading to an increased concentration gradient. The increases in surface area and concentration gradient lead to a much more pronounced increase in the dissolution velocity as compared to a micronized product. Furthermore, the saturation solubility is increased as well. Another possible explanation for the increased saturation solubility is the creation of high

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International Journal of Pharma Research & Review, Dec 2013; 2(12):30-39 energy surfaces when disrupting the more or less ideal drug microcrystals to nanoparticles. Nanosuspensions consist of the poorly water-soluble drug without any matrix material suspended in dispersion [4]. These can be used to enhance the solubility of drugs that are poorly soluble in water. As a result of increased solubility, the rate of flooding of the active compound increases and the maximum plasma level is reached faster. This approach is useful for molecules with poor solubility, poor permeability, or both, which poses a significant challenge for the formulators. The reduced particle size renders the possibility of intravenous administration of poorly soluble drugs without any blockade of the blood capillaries. The suspensions can also be lyophilized into a solid matrix. Apart from these advantages, it also has the advantages of liquid formulations over others [5]. In the present review, we are mainly focusing on the different methods of preparation associated merits, demerits and its pharmaceutical application as drug delivery system. The advantages of the nanosuspensions over current conventional deliveries were given below (Table 1). In nanosuspension technology, the drug is maintained in the required crystalline state with reduced particle size leading to an increased dissolution rate and therefore improved bioavailability [6].

Table 1: Advantage of Nanosuspensions over Conventional Formulations Route of administration Oral Ocular Intravenous Intramuscular Inhalations Disadvantages of conventional Formulations Slow onset of action/ poor Absorption Lacrimal wash off/ low bioavailability Poor dissolution/ non specific Action Low patient compliance due to pain Low bioavailability due to low Solubility Benefit of nanosuspensions Rapid onset of action/ improved solubility so improved bioavailability Higher bioavailability/ dose consistency Rapid dissolution/ tissue targeting Reduced tissue irritation Rapid dissolution/ high bioavailability/ dose regulation

The stability of the particles obtained in the nanosuspension is attributed to their uniform particle size which is created by various manufacturing processes. The absence of particles with large differences in their size in nanosuspensions prevents the existence of different saturation solubilities and concentration gradients, consequently preventing the Ostwald ripening effect. Molecules diffuse from the higher concentration area around small particles which have higher saturation solubility to an area around larger particles possessing a lower drug concentration. This leads to the formation of a supersaturated solution around the large particles and consequently to drug crystallization and growth of the large particles. PREPARATION OF NANOSUSPENSION For the preparation of nanosuspension, mostly two methods namely Bottom up

technology and Top down technology are used, as (Fig.1) [7]. Bottom up technology is an assembling method to form nanoparticles from precipitation, microemulsion, melt emulsification method and top down technology involves the disintegration of larger particles into nanoparticles, examples of which are highpressure homogenization and milling methods [8, 9]. 1. Precipitation Method Precipitation method is a general method used to prepare submicron particles of poorly soluble drugs [1012]. In this method, drug is dissolved in solvent and then solution is mixed with solvent to which drug is insoluble in the presence of surfactant. Rapid addition of solution to such solvent (generally water) leads to rapid super saturation of drug in the solution, and formation of ultrafine

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International Journal of Pharma Research & Review, Dec 2013; 2(12):30-39 amorphous or crystalline drug. This method involves nuclei formation and crystal growth which are mainly dependent on temperature. High nucleation rate and low crystal growth rate are primary requirements for preparing a stable suspension with minimum particle size [13]. 2. High-Pressure Homogenization This technique involve the following three steps: First, drug powders are dispersed in a stabilizer solution to form presuspension; after that, presuspension is homogenized by high pressure homogenizer at a low pressure sometimes for premilling; and finally homogenized at a high pressure for 10 to 25 cycles until the nanosuspensions are formed with desired size [6].

Bottom Up process-form nanoparticles from precipitation, microemulsion, melt emulsification method

Nanosuspensions

Top down process- nano particles obtained by high-pressure homogenization and milling methods
Figure 1: Approaches for Preparation of Nanosuspension 3. Lipid emulsion/microemulsion template Lipid emulsions as templates are applicable for drugs that are soluble in either volatile organic solvents or partially water miscible solvents. This technique follows an organic solvent or mixture solvent loaded with the drug dispersed in an aqueous phase containing suitable surfactants to form an emulsion. The organic phase is then evaporated under reduced pressure to make drug particles precipitate instantaneously to form the nanosuspension which is stabilized by surfactants. Another way to produce nanosuspensions is to use an emulsion which is formed by the conventional method using a partially water miscible solvent as the dispersed phase. Nanosuspensions are obtained by just diluting the emulsion. Moreover, microemulsions as templates can produce nanosuspensions. Microemulsions are thermodynamically stable and isotropically clear dispersions of two immiscible liquids such as oil and water stabilized by an interfacial film of surfactant and cosurfactant. The drug can be either loaded into the internal phase or the pre-formed microemulsion can be saturated with the drug by intimate mixing. Suitable dilution of the microemulsion yields the drug nanosuspension [14]. 3.1 Melt emulsification method In this method drug is dispersed in the aqueous solution of stabilizer and heated above the melting point of the drug and homogenized to give an emulsion. During this process, the sample holder was enwrapped with a heating tape fitted with temperature controller and the temperature of emulsion was maintained above the melting point of the drug. The emulsion was then cooled down either slowly to room temperature or on an icebath. The main advantage of melt emulsification technique relative to the solvent diffusion method is total avoidance of organic solvents during the production process. 4. Milling techniques 4.1. Media milling Liversidge et al. had a patent on nanocrystal technology [15]. In this technique, drugs are subjected to media milling for nanoparticle production. Effect of impaction between the milling media and drugs gives essential energy for disintegration of the

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International Journal of Pharma Research & Review, Dec 2013; 2(12):30-39 microparticulate system into nanoparticles. In this process, the chamber of milling is charged with the milling media involving drug, stabilizer, and water or suitable buffer, which is rotated at a very high shear rate to generate suspension. Residue left behind in the finished product is a major problem of this method [16]. 4.2. Dry co-grinding Recently, nanosuspensions can be obtained by dry milling techniques [17, 18]. Dry cogrinding can be carried out easily and economically and can be conducted without organic solvents. The cogrinding technique can reduce particles to the submicron level and a stable amorphous solid can be obtained. 5. Supercritical fluid method Supercritical fluid technology can be used to produce nanoparticles from drug solutions. The various methods attempted are rapid expansion of supercritical solution process (RESS), supercritical anti-solvent process and precipitation with compressed antisolvent process (PCA).The RESS involves expansion of the drug solution in supercritical fluid through a nozzle, which leads to loss of solvent power of the supercritical fluid resulting in precipitation of the drug as fine particles. The disadvantages of the above methods are use of hazardous solvents and use of high proportions of surfactants and stabilizers as compared with other techniques, particle nucleation overgrowth due to transient high super saturation, which may also result in the development of an amorphous form or another undesired polymorph. 6. Microprecipitation High-pressure homogenization (Nanoedge) Nanoedge is a combination of microprecipitation and high-pressure homogenization techniques. Method includes precipitation of friable materials followed by fragmentation under high shear and/or thermal energy [19, 20]. The preparation method of nanoedge is shown in Figure 2.

Figure 2: Method for preparation of nanoedge 7. Nanojet technology This technique is also called opposite stream technology, uses a chamber where a stream of suspension is divided into two or more parts, both streams colloid with each other at high pressure. The high shear force produced during the process results in particle size reduction. Dearns had prepared nanosuspensions of atovaquone using the microfluidization process. The major disadvantage of this technique is the high number of passes through the microfluidizer and that the product obtained contains a relatively larger fraction of microparticles. Advantages and disadvantages of various preparation techniques of nanosuspension The following table (Table 2) shows the advantages and disadvantages of various preparation techniques used in nanosuspension.

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International Journal of Pharma Research & Review, Dec 2013; 2(12):30-39 Table 2: Advantages and Disadvantages of Various Preparation Techniques of Nanosuspension Method 1.Precipitation [13] Advantages Disadvantages

2.High-Pressure Homogenization [6]

3.Lipid emulsion/ microemulsion template [14] 4.Milling [16, 17]

5. Microprecipitation-high pressure homogenization

Low need of energy, stable Narrowly applying space, products and simple process wide size distribution and potential toxicity of non-aqueous solvent Widely applying regions, ease of Pretreatment of micronized scale-up and little batch to batch drug particles and variation, narrow size distribution presuspending materials in the final product, allowing before subjecting it to aseptic production of homogenization nanosuspensions for parenteral administration and flexibility in handling the drug quantity Low need of energy, stable high concentration products, simple process, undesired surfactants and small size of particles and residual solvents uniform particle distribution widely applying regions, ease of potential erosion of material scale-up and little batch to from the milling pearls batch variation, narrow size distribution in the final product much smaller, more uniform and The manufacturing more stable compared to that by process is complicated the microprecipitation; less mechanical force and energy compared with the high-pressure homogenization by Photon Correlation Spectroscopy (PCS), laser diffraction and coulter current multisizer. Particle charge (Zeta Potential) [22]: The particle charge is of importance in the study of the stability of the suspensions. Usually the zeta potential of more than 40mV will be considered to be required for the stabilisation of the dispersions. For electrostatically stabilized nanosuspension a minimum zeta potential of 30mV is required and in case of combined steric and electrostatic stabilization it should be a minimum of 20mV zeta potential is required. Crystalline State and Particle Morphology: It is of importance as there are chances of the polymorphism during the storage of the nanosuspensions. Hence it is necessary to study the crystal morphology of the drug in suspension. Differential Scanning 34

CHARACTERIZATION TECHNIQUES The particle size, particle size distribution, and zeta potential affect the safety, efficacy, and stability of nanodrug delivery systems as well as dissolution performance is also altered by solid state of nanoparticles. Thus, characterization of nanoparticles plays a great role in forecasting in vitro and in vivo performance of nanodrug delivery systems. In vivo pharmacokinetic performance and biological function of nanosuspension strongly depends on its particle size and distribution, particle charge (zeta potential), crystalline state, and particle morphology. Particle size and size distribution [21]: It is the most important parameter in the evaluation of the suspensions as it is having the direct effect on the solubility and dissolution rate and the physical stability of the formulation. The mean particle size and the width of particle size can be determined Shilpa P Chaudhari et.al, IJPRR 2013; 2(12)

International Journal of Pharma Research & Review, Dec 2013; 2(12):30-39 Calorimetry (DSC) is most commonly used for such studies. Saturation solubility and dissolution velocity Nanosuspension increases the dissolution velocity and saturation solubility. Size reduction leads to increase in the dissolution pressure. An increase in solubility that occurs with relatively low particle size reduction may be mainly due to a change in surface tension leading to increased saturation solubility. By using postproduction processing, nanosuspensions are prepared into various dosage forms. The available marketed drugs in the form of nanosuspensions along with their routes of administration are mentioned below (Table 3) [23].

Table 3: Available Marketed Drugs in the Form of Nanosuspension With Their Route of Administration Route Oral Drug Paliperidone Palmitate Megasterol Acetate Insulin Fenofebrate Cytokine Inhibitor Paclitaxel Thymectacin Emend Calcium Phosphate Budesonide Busulfan Silver Use Antischizophrenia Steroid Hormone Diabetes Lipid Lowring Crohns Disease Anticancer Anticancer Antiemetic Mucosal Vaccin Adjuvant for Herpes Asthama Anticancer Eczema Company Johnson & Johnson Par. Pharmaceuticals Biosante Sky Pharma Elan Nano Systems Amirican Bioscience Elan Nano Systems Elan Nano Systems Biosante Elan Nano Systems Sky Pharma Nucryst

Parenteral Intravenous

Pulmonary Intrathecal Topical

The technologies and patents which are based on the various nanosuspension processes are shown in Table 4. Table 4: Overview of the Technologies and Patents/Patent Applications On Which The Various Homogenization Processes Are Based Formulations and Method Patents/patent application examples 1] Nanosuspensions prepared by WO 2003045353 Supercritical fluid method [24]. A1 2] Nanosuspensions prepared by US 20110124702 Microfluidization Process [25]. A1 3] Nanosuspensions Prepared by US 5858410 A Milling technique [26]. Description They dispersed solid therapeutically active compound in a solvent to high pressure in a supersonic fluid flow through a nozzle to form nanoparticles. The method was optimized through microfluidization process with water soluble polymeric excipients without surfactants. They tried one pure active insoluble compound introduced into water, and/or organic solvent. Then increased saturation solubility and increased rate of dissolution of compound compared with powders of the active compound prepared using an ultrasonic probe. They dissolved pharmaceutically-active

4] Submicron particle suspensions US 6884436 B2

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International Journal of Pharma Research & Review, Dec 2013; 2(12):30-39 by Precipitation method [27]. compound in the water-miscible organic solvent to form a first solution and mixed first solution with the second solvent to precipitate the pharmaceutically-active compound and seeded the first solution or the second solvent or the presuspension. WO 2007038524 Suitable liquids are combined with A2 solutions of guests, both with and without suitable liquids, in an interface region. EP 2310009 A2 Nanosuspensions of a benzimidazole derivative as having maximum therapeutic efficacy for a treatment regimen by adjusting particles size(s) based on pharmacokinetic parameters. gradient between gastrointestinal tract lumen and blood and the increased dissolution velocity of the drug. Aqueous nanosuspensions can be used directly in a liquid dosage form and a dry dosage form such as tablet or hard gelatin capsule with pellets. The aqueous nanosuspension can be used directly in the granulation process or as a wetting agent for preparing the extrusion mass pellets [31]. 3. Ophthalmic Drug Delivery For delivery of poorly soluble drug in culdesac suspensions and ointments are recommended. Suspensions have advantages of prolonged residual time in culdesac and avoidance of higher tonicity produced by water soluble drugs. The ocular bioavailability of suspensions depends on the dissolution rate of the drug in lachrymal fluid [32]. 4. Pulmonary Drug Delivery For pulmonary delivery, nanosuspensions can be nebulized through mechanical or ultrasonic nebulizers. Due to the presence of many small particles, all aerosol droplets contain drug nanoparticles. Budesonide corticosteroid has been successfully prepared in the form of nanosuspension for pulmonary delivery. Aqueous suspensions of the drug can be easily nebulized and given by pulmonary route as the particle size is very small. Different types of nebulizers are available for the administration of liquid formulations. Some of the drugs successfully tried with pulmonary route are budesonide, ketotifen, ibuprofen, indomethacin, nifedipine, 36

5] Cocrystals Cocrystallization

prepared by methods [28].

6] Parenteral and oral formulations by Microemulsion Template Technique [29].

Pharmaceutical Applications of Nanosuspensions in Drug Delivery: 1. Parenteral Administration Nanosuspensions can be administered via different parenteral administration routes ranging from intra-articular via intraperitonal to intravenous injection. For administration by the parenteral route, the drug either has to be solubilized or has particle/globule size below 5 m to avoid capillary blockage. The current approaches for parenteral delivery include salt formation, solubilization using co-solvents, micellar solutions, complexation with cyclodextrin and recently liposomes. However, there are limitations on the use of these approaches because of the limitations on their solubilization capacity and parenteral acceptability. liposomes are much more tolerable and versatile in terms of parenteral delivery. However, they often suffer from problems such as physical instability, high manufacturing cost and difficulties in scale-up. Nanosuspensions would be able to solve the problems mentioned above. In addition, nanosuspensions have been found to increase the efficacy of parenterally administered drugs [30]. 2. Oral administration Nanosizing of drugs can lead to a dramatic increase in their oral absorption and subsequent bioavailability. Improved bioavailability can be explained by the adhesiveness of drug nanoparticles to the mucosa, the increased saturation solubility leading to an increased concentration Shilpa P Chaudhari et.al, IJPRR 2013; 2(12)

International Journal of Pharma Research & Review, Dec 2013; 2(12):30-39 itraconazole, interleukin-2, p53 gene, leuprolide, doxorubicin, etc [33]. 5. Targeted Drug Delivery Nanosuspensions are suitable for targeting particular organs because of their surface properties. Along with this, it is easy to alter in vivo behavior by changing the stabilizer. The drug will be taken up by the mononuclear phagocytic system which allows region-specific delivery. This can be used for targeting antifungal, antimycobacterial, or antileishmanial drugs to macrophages if the pathogens persist intracellularly. Kayser formulated an aphidicolin nanosuspension that improved the drug targeting to macrophages which were Leishmania infected. He stated that the drug in the form of nanosuspension had EC of 0.003g/ml, whereas the conventional form had 0.16 g/ ml. Scholer et al. described an enhanced drug targeting to brain in the treatment of toxoplasmic encephalitis using an atovaquone nanosuspension [34]. 6. Topical formulations Drug nanoparticles can be incorporated into creams and water-free ointments. The nanocrystalline form leads to an increased saturation solubility of the drug in the topical dosage form, thus enhancing the diffusion of the drug into the skin. 7. Bioavailability enhancement. The poor oral bioavailability of the drug may be due to poor solubility, poor permeability or poor stability in the gastrointestinal tract (GIT). Nanosuspensions resolve the problem of poor bioavailability by solving the twin problems of poor solubility and poor permeability across the membrane. Bioavailability of poorly soluble oleanolic acid, a hepatoprotective agent, was improved using a nanosuspension formulation. The therapeutic effect was significantly enhanced, which indicated higher bioavailability. This was due to the faster dissolution (90% in 20 min) of the Lyophilized nanosuspension powder when compared with the dissolution from a coarse powder (15% in 20 min). 8. Mucoadhesion of the nanoparticles Nanoparticles orally administered in the form of a suspension diffuse into the liquid media and rapidly encounter the mucosal Shilpa P Chaudhari et.al, IJPRR 2013; 2(12) surface. The particles are immobilized at the intestinal surface by an adhesion mechanism referred to as "bioadhesion." From this moment on, the concentrated suspension acts as a reservoir of particles and an adsorption process takes place very rapidly. The direct contact of the particles with the intestinal cells through a bioadhesive phase is the first step before particle absorption. The adhesiveness of the nanosuspensions not only helps to improve bioavailability but also improves targeting of the parasites persisting in the GIT. CONCLUSION Nanosuspension is distinctive and commercially feasible approach to solve the problem of hydrophobic drug such as poor solubility and poor bioavailability. For large-scale production of nanosuspensions, media milling and high-pressure homogenization technology have been successfully used. Striking characteristics, like improvement of dissolution velocity, increased saturation solubility, improved bioadhesivity, versatility in surface modification, and ease of postproduction processing, have widened the applications of nanosuspensions for various routes of administration. The applications of nanosuspensions in oral and parental routes have been very well established. However, their delivery through buccal, nasal, and topical delivery is yet to be done. REFERENCES

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