Review Article ISSN: 0974-6943
Devesh Ashvin Bhatt et al. / Journal of Pharmacy Research 2010, 3(8),1748-1751
Available online through www.jpronline.info Nanotechnology: A promising Drug Delivery for Poorly Water Soluble Drugs Devesh Ashvin Bhatt*, A. M. Pethe SVKM’s, NMIMS, School of Pharmacy and Technology Management Shirpur, Dist. Dhule, M.S., India. Pin- 425405
Received on: 16-04-2010; Revised on: 12-06-2010; Accepted on:13-07-2010 ABSTRACT Today the world is really facing a huge problem of poorly water soluble drugs. Many methods are there for increasing the solubility, but nanotechnology is one of the most prominent and latest technology. It deals with the nanoparticles (having high surface area) which are useful for increasing the solubility of poorly water soluble drugs. So the main objective is to increase the solubility of poorly water soluble drugs by various various techniques related to nanotechnology. The study methodology includes different processes for production of nanoparticles which are as follows: Wet milling, high pressure homogenization, emulsification, Precipitation with a compressed fluid antisolvent (PCA), Rapid expansion from a liquefied-gas solution (RESS), Spray freezing into liquid (SFL), Evaporative precipitation into aqueous solution (EPAS).Commercialized nanotechnology for the better solubility of poorly water soluble drugs: 1) Dissocubes 2) Nanocrystal tech 3) Nanomorph tech 4) Nanoedge tech 5) Nanopure tech 6) Crititech tech 7) Nanochelate tech. Key words: Nanotechnology, nanoparticles, different processes.
INTRODUCTION Bioavailability is defined as the rate and the extent to which the ingredients or active moiety is absorbed from the drug product and becomes available at the site of action.
the nanoscale increases dissolution velocity and saturation solubility, which leads to improvement in vivo drug performance. They are shown in figure 1. Nanosuspensions increases drug loading which can be significant for injectable products. They also eliminate the possibility of ostwald ripening i.e. the growth of larger particles at the expense of smaller ones and so facilitating physical long term stability.3
As per the definition of bioavailability, a drug with poor bioavailability is one with poor aqueous solubility, slow dissolution rate in biological fluids, poor stability of dissolved drug at physiological pH, poor permeation through biomembrane, extensive presystemetic metabolism. Bioavailability of poorly PROCESSES FOR PRODUCTION OF NANOPARTCILES water soluble drugs is a major problem. There are three major approaches to Nanoparticles can be produced by either dispersion- based (which overcome the bioavailability problems. involves breaking larger micrometer particles into nanoparticles) or precipita1) Pharmaceutics approach: This involves modification of formulation, manu- tion based processes (which involves nucleation of particles from the molecular facturing processes or physiochemical properties of the drug without changing state). Various processes such as wet milling, high pressure homogenization, emulsification, precipitation, rapid expansion and spray freezing can be used to chemical structures. produce drug nanopartciles.4 2) Pharmacokinetic approach: In this, pharmacokinetics of drug is altered by modifying its chemical structure .e.g. for weak acids and bases the water solubil- 1) Wet milling: ity can be enhanced by forming a salt with a suitable counter-ion (e.g. hydroWet milling is an attrition based process in which the drug suspension chloride salt of propranolol, potassium salt of ibuprofen) is subjected using a pearl mill in the presence of milling media. The impaction of 3) Biological approach: In this, route of drug administration may be changed a drug particle with milling media generates enough energy to convert the drug crystals into nanoparticles. The grinding media consists of glass, zirconium such as parenteral form instead of oral form. oxide stabilized with zirconium silicate or highly cross linked polystyrene resin Rate dissolution and its solubility are very important factors in third in a spherical form (0.4-3.0 mn diameter). Temperature is less than 40 *C and approach. The second approach of chemical modification has number of draw- pressure is as high as 20 psi.5 backs such as being very expensive, time consuming, requires repetition of chemical studies, risk of precipitation and adverse effects. So generally only Limitation: Products can become contaminated because of abrasion occurring pharmaceutics approach is considered there.A technology of an atomic or mo- on grinding beads, which is intolerable for parenterally administered drugs. lecular scale, concerned with dimensions of less than 100 nanometers is known Example: By formulating Danazol, a poorly bioavailable gonadotropin inhibias nanotechnology.1-2 tor, as a nanocrystal suspension, the absolute bioavailability increased to 82.3% when compared with 5.2% of a commercial danazol suspension.6 NANOPARTICLES Nanoparticles are solid colloidal particles ranging in size from 1 to 1000nm that are used as drug delivery agents. The reduction of drug particles to
2) High pressure homogenization:
*Corresponding author.
High-pressure homogenization is based on the principle of cavitation i.e., the formation, growth, and implosive collapse of vapor bubbles in a liquid. In this process, a drug presuspension (containing drug in the micrometer range) is prepared by subjecting the drug to air jet milling in the presence of an aqueous surfactant solution. The presuspension is subjected to high-pressure homogenization in which it passes a very small homogenizer gap of 25 mm. Cavitation forces are created, which are sufficiently high to disintegrate drug micro par-
Devesh A Bhatt, 18, Vikas Tenements, Nr. Zydus Cadilla High School, Jivraj Park,Ahmedabad- 380051,Gujarat. Tel.: 09823605535, 09510097166 E-mail:
[email protected]
Journal of Pharmacy Research Vol.3.Issue 8.August 2010
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Devesh Ashvin Bhatt et al. / Journal of Pharmacy Research 2010, 3(8),1748-1751 ticles to nanoparticles as the suspension leaves the gap and normal air pressure is reached again. The homogenization pressure and number of homogenization cycles are key parameters in optimizing the process. The homogenization pressures generally range from 100 to 1500 bar and the number of homogenization cycles could be 3, 5, or 10 depending upon the drug’s hardness, the desired mean particle size, and the product’s required homogeneity.7 Limitation: Sometimes pressure used is so high that in some cases, the crystal structure is changed which leads to increased amorphous fraction. The variation in crystallinity can result in instability and also poses quality control problems.8-10 3) Emulsification technology: Emulsification also can be used to prepare nanoparticle suspensions. In this method, the drug solution in an organic solvent is dispersed in the aqueous phase containing surfactant. This step is followed by the evaporation of organic solvent under reduced pressure, which results in the precipitation of drug particles to form a nanoparticle suspension which is stabilized by the added surfactant. Alternatively, the nanoparticle suspension can be obtained by diluting an emulsion prepared by conventional methods, which results in the complete diffusion of the internal phase into the external phase leading to nanoparticle suspension. By forming drug nanosuspensions using emulsification technology, the mitotane anticancer drug dissolution rate was increased by five-fold compared with commercial products.11-14 4) Precipitation with a compressed fluid antisolvent (PCA): In the PCA process, supercritical carbon dioxide is mixed with organic solvents containing drug compounds. The solvent expands into supercritical carbon dioxide, thus increasing the concentration of the solute in the solution, making it supersaturated, and causing the solute to precipitate or crystallize out of solution. Microparticles and nanoparticles are formed after drug precipitation by mass transfer because of organic solvent extraction into carbon dioxide and the diffusion of carbon dioxide into the droplets. High mass-transfer rate is important to minimize particle agglomeration and reduce drying time. Moreover, the drug in organic solvent interacts with the compressed fluid carbon dioxide antisolvent in the mixing chamber before dispersion and then flows through a restricted orifice into a particle-formation vessel. The high frictional surface forces that are generated cause the solution to disintegrate into droplets.15-20 5) Rapid expansion from a liquefied-gas solution (RESS): In an RESS process, a solution or dispersion of phospholipids or other suitable surfactant in the supercritical fluid is formed. Then, rapid nucleation of drug is induced in the supercritical fluid containing surfactant. This process allows rapid, intimate contact of the drug dissolved in supercritical fluid and the surfactant which inhibits the growth of the newly formed particles. This process was used to prepare nanoparticles of cyclosporine in the size range of 500–700 nm.21-22 6) Spray freezing into liquid (SFL): In this process, an aqueous, organic, or aqueous–organic cosolvent solution; aqueous–organic emulsion; or drug suspension is atomized into a cryogenic liquid such as liquid nitrogen to produce frozen nanoparticles which are subsequently lyophilized to obtain free-flowing powder. The rapid freezing rate caused by the low temperature of liquid nitrogen and the high degree of atomization resulting from the impingement occurring between drug solution and cryogenic liquid leads to the formation of amorphous nanoparticles. Apart from liquid nitrogen, the drug solution also can be atomized into compressed fluid carbon dioxide, helium, propane, or other cryogenic liquids such as argon or hydrofluoroethers. Highly potent danazol nanoparticles contained in larger structured aggregates were produced by the SFL process. The SFL powders exhibited significantly enhanced dissolution rates.23-29
Figure 1: Scanning electron micrographs of control fibrin clot and fibrin targeted paramagnetic nanaoparticles bound to clot surface.
7) Evaporative precipitation into aqueous solution (EPAS): In this process, the drug solution in a low boiling liquid organic solvent is heated under pressure to a temperature above the solvent’s normal boiling point and then atomized into a heated aqueous solution containing stabilizing surfactant. The surfactant also can be added to organic solvent along with an aqueous solution to inhibit crystallization and growth of nucleating drug particles. The EPAS process was used to produce a nanoparticle suspension of cyclosporine A and danazol, which showed high dissolution rates. Nanoparticle suspensions produced by the EPAS process can be incorporated into a parenteral dosage form or can be dried to produce solid oral dosage forms. In a recent study, danazol particles formed by both EPAS and SFL processes produced amorphous powders with high glass transition temperature and low contact angle values. The dissolution rates were faster for the SFL particles, although both techniques enhanced dissolution rates of the active ingredient.3033
COMMERCIALIZED NANOTECHNOLOGY Various nanotechnologies already have been commercialized to help deliver poorly water-soluble drugs into the body. A review of some of these technologies will follow. 1) Dissocubes: Dissocubes technology is based on piston–gap high-pressure homogenization. The main advantages of this technology are ease of scale-up, little batch-to-batch variation, and aseptic production for parenteral administration. 2) Nanocrystal technology: Nanocrystal technology can be used to formulate and improve compound activity and final product characteristics of poorly water-soluble compounds. The nanocrystal technology can be incorporated into all parenteral and oral dosage forms, including solid, liquid, fast-melt, pulsed-release, and controlled-release dosage forms. Nanocrystal particles are produced by milling the drug substance using a proprietary wet-milling technique. The Nanocrystal drug particles are stabilized against agglomeration by surface adsorption of selected generally regarded as safe (GRAS) stabilizers. The result is an aqueous dispersion of the drug substance that behaves like a solution—a nanocrystal colloidal dispersion that can be processed into finished dosage forms for all routes of administration. For example, the Rapamune immunosuppressant tablet developed with nanocrystal technology is designed to give patients more convenient administration and storage than the oral solution. Nanocrystal technology is an enabling technology for evaluating new chemical entities that exhibit poor water solubility. In addition, it is a valuable tool for optimizing the performance of established drugs.34-36
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Devesh Ashvin Bhatt et al. / Journal of Pharmacy Research 2010, 3(8),1748-1751 3) Nanomorph technology: Nanomorph technology converts drug substances with low water solubility from a coarse crystalline state into amorphous nanoparticles. Nanomorph technology is based on a dissolution–precipitation concept that operates using water-miscible solvents for dissolution, followed by precipitation by aqueous polymer solutions. In this technology, the drug suspension in solvent is fed into a chamber, where it is rapidly mixed with another solvent. Immediately, the drug substance suspension is converted into a true molecular solution. The admixture of an aqueous polymer solution induces precipitation of the drug substance. The polymer keeps the drug substance particles in their nanoparticulate state and prevents them from aggregation or growth. Water redispersable dry powders can be obtained from the nanosized dispersion by conventional methods (e.g., spray drying). Nanomorph formulations can be incorporated into the whole range of standard galenic application forms.37-39 4) Nanoedge technology: Nanoedge technology is a formulation toolbox for poorly watersoluble drugs. It is a useful technology for active ingredients that have high melting points and high octanol-water partition coefficients, log P. It is based on direct homogenization, micro precipitation, and lipid emulsions. In micro precipitation, the drug first is dissolved in a water-miscible solvent to form a solution. Then, the solution is mixed with a second solvent to form a presuspension and energy is added to the presuspension to form particles having an average effective particle size of 400 nm to 2 µm. The energy-addition step involves adding energy through sonication, homogenization, countercurrent flow homogenization, micro fluidization, or other methods of providing impact, shear, or cavitation forces. A drug suspension resulting from these processes may be administered directly as an injectable solution, provided water-for-injection is used in the formulation and an appropriate means for solution sterilization is applied. Nanoedge technology facilitates small particle sizes (
