Nanosuspensions: A Promising Nanocarrier Drug Delivery System

Atul Phatak*, Pallavi Jorwekar and P.D. Chaudhari

P.E.S. Modern College of Pharmacy, Nigdi, Pune-44

ABSTRACT:

For most of the active pharmaceutical ingredients, poor aqueous solubility and hence low bioavailability and erratic absorption is the common difficulty observed by the formulation development scientist. Nanotechnology drug delivery has gained much interest as a way to improve the solubility problems. Nanosuspension is biphasic system which consists of pure drug particles are dispersed in an aqueous vehicle of particle size less than 1000 nm, and system is stabilized by surfactant. Nanosuspension provide us with useful tool for formulating an poorly water soluble drug may be due to the properties of nanosuspension, their low production cost, ease of manufacture and scale-up. This system helps in dissolution and thus improves bioavailability of poorly water soluble drugs and holds the promise in their aspects of drug delivery. The present article reviews the various methods, manufacturing challenges and their applications as nanocarrier drug delivery system.

KEYWORDS: Nanocarrier, Nanosuspesion, Solubility,Drug Delivery System

INTRODUCTION:

Solubility in different solvents is an intrinsic material characteristic for a defined atom or molecule.²⁶To show a pharmacological activity, the molecules must in general exhibit certain solubility in physiological intestinal fluids to be present in the dissolved state at the site of absorption.³⁵The aqueous solubility is a major indicator for the solubility in the intestinal fluids and its potential contribution to bioavailability issues. ²⁷There are many drugs of various therapeutic categories that fall in BCS class II and class IV as they lack solubility.³² Nanosuspension technology offers novel nanocarrier delivery system solution for these drugs. A pharmaceutical nanosuspension is biphasic systems consisting of nano sized drug particles stabilized by surfactants for either oral and topical use or 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 and 600nm.⁸

Poorly soluble compounds can be usually classified into two types of molecules: “grease ball” and “brick dust” compounds.^1,4 Grease ball molecules represent highly lipophilic compounds with a high log P, whereas brick dust molecules usually are compounds with a high melting point (m.p. >200 ) and a low log P. There are various techniques available to improve the solubility of poorly soluble drugs. Some of the approaches to improve the solubility such as micronisation, solid dispersions, complexation, use of permeation enhancers, salt formation etc.^2,5 These techniques for solubility enhancement have some limitations and hence have limited utility in solubility enhancement. Micronization is not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug⁵.

Nanosuspension of nanoparticles (NPs) offers various advantages over conventional ocular dosage forms, including reduction in the amount of dose, maintenance of drug release over a prolonged period of time, reduction in systemic toxicity of drug, longer residence time of nanoparticles on the corneal surface, higher drug concentrations in the infected tissue, and suitability for poorly water-soluble drugs.^1,17Nanosuspensions as a nanocarrier delivery system have some promising merits: firstly, drugs no longer need to be in the soluble form. It is important for the drug molecules insoluble in oils¹; secondly, the high drug loading can be achieved as a drug exists in the form of pure solids, and can significantly reduce the administration volume of high dose ¹; thirdly, nanosuspensions can increase the physical and chemical stability of drugs as they are actually in the solid state. ¹

2. Physicochemical properties of drug nanosupension(drug nanocrystal):

2.1. Change of dissolution velocity:

For BCS class II drugs dissolution velocity is the rate limiting step. According to the Noyes-Whitney equation dissolution velocity increase due to increase in the surface area from micron size to particles of nanometer size.² Of course, by moving one dimension further to smaller particles, the surface area is further enlarged and consequently, the dissolution velocity is further enhanced. In most cases, a low dissolution velocity is correlated with low saturation solubility.^{6, 31}

2.2 Saturation solubility:

The saturation solubility Cs is a constant depending on the compound, the dissolution medium and the temperature. Below a critical size of 1-2 µm, the saturation solubility is also a function of the particle size. It increases with decreasing particle size below 1000 nm. Therefore, drug nanocrystals possess increased saturation solubility.^{18, 30}

2.3 Internal structure of Nanosuspensions:

The high-energy input during disintegration process causes structural changes inside the drug particles. When the drug particles are exposed to high-pressure homogenization particles are transformed from crystalline state to amorphous state.¹⁸The change in state depends upon the hardness of drug, number of homogenization cycles chemical nature of drug and power density applied by homogenizer.¹⁹

3. Formulation approaches, methods and manufacturing challenges for nanosuspension:

3.1 Strategy:

The preparation of stable nanosuspensions must recognize the thermodynamic forces at work. For a given mass of drug substance, as particle size is reduced, surface area is increased.²⁶ As the surface area is increased in an aqueous medium, significantly increases the surface free energy of the drug system. Therefore in drug crystal lattice structure, strong and stable bonds are produced and the intermolecular hydrogen bonding between the water molecules are disrupted. Instead, they are replaced by a large interfacial area of hydrophilic water molecules in proximity with a hydrophobic drug surface. Such a system will tend to reduce the energetically unfavorable area by particle growth and by aggregation. Ostwald ripening represents one mechanism by which this may occur. By the Ostwald–Freundlich equation, smaller particles have a higher surface energy than larger particles ⁷. This leads to greater dissolution of smaller particles with consequent increasing size of larger particles. As a result, the distribution of the suspension shifts to increasing particle size. To avoid this irreversible agglomeration, formulation strategy is designed to stabilize particle size over time. Utilization of surfactants is an essential part of formulation strategy. In the absence of an appropriate stabilizer, the high surface energy of nano-sized particles can induce agglomeration or aggregation of the drug crystals.³³

3.2 Methods of preparation:

Mainly there are two methods for the preparation of nanosuspensions: ‘Top-down’ and ‘Bottom-up’ technologies.⁶ In Top-down, technology is a disintegration approach from large particles, microparticles to nanoparticles, such as high-pressure homogenization and media milling method.¹⁹ In bottom-up technology involves building of nanostructures atom by atom or molecule by molecule. This can be done in three ways: chemical synthesis, self assembly, and positional assembly.⁶ The different preparation strategies are shown in Figure 1.The Advantages and Disadvantages of Different Nanosuspensions Manufacturing Processes are given in table no.1 A prime challenge for manufacturers is ensuring reproducibility and quality of nanotechnology products.

Figure 1: Schematic representation of different preparation strategies to obtain nanoparticulate Materials³⁷

3.2.1 Top Down Process:

3.2.1.1 Media Milling/nanocrystal:

Media milling or Nanocrystals® is the patented technology of Elan Drug Delivery Systems. This technology was used successfully to market the first nanosuspension product, Rapamune.⁹ In this method the nanosuspensions are produced using high-shear media mills or pearl mills. In order to produce nanocrystalline dispersions by the NanoCrystals^® technology, a milling chamber is charged with milling media, dispersion medium (normally water), stabilizer, and the drug. High shear forces are generated in the milling chamber due to the impact of the milling media, and attrition between the particles and the milling media causes the particles to fracture along weak points. The milling media generally consists of glass, zirconium oxide or highly crosslinked polystyrene resin beads. Challenges in this type of technique include erosion of the milling media and generation of very high surface free energy.² To reduce this surface free energy, the nanoparticles will either have to reagglomerate to decrease the surface area or a formulation has to have a stabilizers to keep them from agglomerating.¹⁶ Therefore, one has to balance out the toxicity associated with the amount and type of these additives with the stability of these systems. Also, cleaning is an issue fine particles potentially remain even after removal of the grinding medium from the suspension. It may required more time required to achieve a desired size range might vary from hours up to several days.¹⁹

3.2.1.2 High-Pressure Homogenization:

High pressure homogenization was first developed and patented by R.H. Muller in the early nineties. This technology, now owned by Sykepharma LLC, is commonly known as Dissocubes^®. The process can be divided into three steps: firstly, drug powders are dispersed in a stabilizer solution to form pre-suspension or macro suspension; then pre-suspension was homogenized by the high-pressure homogenizer at a low pressure for several times through a small aperture as a kind of premilling, and finally was homogenized at a high pressure for 10-25 cycles until the nanosuspensions with the desired size were prepared. The high velocity of the suspension in the small aperture reduces the pressure tremendously, resulting in the formation of bubbles as per Bernoulli’s law.²⁵ When the suspension emerges from the narrow aperture there is a drop in velocity and an increase in pressure to the atmospheric pressure. This causes bubbles to implode and generate high energy shock waves which are mainly responsible for particle size reduction.

According to the liquids used to suspend drug powders, the method is classified into homogenization in water (DissoCubes) or piston-gap homogenization in water, homogenization in water-free media and water mixtures (Nanopure).¹⁹ In Nanopure technology, for oral administration, the drug nanosuspensions themselves are, in most cases, not the final products. For patient's convenience, the drug nanocrystals should be incorporated in traditional dry dosage form, e.g. tablets, pellets and capsules. To homogenize the drug suspension, microfluidizers are also used.¹¹ The microfluidizer is a jet stream homogenizer of two fluid streams collied frontally with high velocity under pressures up to 4000 bar. The dispersion medium is water. Here the particle size reduction can be achieved by high energy impact, cavitation, and shear forces. Manufacturing challenges include larger amounts of energy required to sustain further size reduction.²³ Also, there is a clogging of the piston is a serious problem and scale-up is generally very difficult for this type of operation.¹⁶ Schematic represention of process can be given in Figure 2.

Figure 2: Schematic representation of the high-pressure homogenization process²⁴

3.2.2 Bottom-up Process:

The bottom up approach refers to the building up of the nano-sized particles from their molecular solutions, and is commonly known as precipitation.⁶ This technique is mostly suitable for active pharmaceutical agent which is soluble in non-aqueous water miscible solvent. This process can be carried out at different ambient temperatures, and therefore heat sensitive materials can be processed easily. There are different variations of this approach which are briefly discussed below:

3.2.2.1 Hydrosols or Solvent Anti-solvent:

The Hydrosol technology was developed by Sucker and the intellectual property owned by the company Sandoz, now known as Novartis. Hydrosols consist of the finely precipitated colloidal drug particles in an aqueous medium. In this technique, the drug is dissolved in water miscible organic solvent such as ethanol. The organic solution is then poured slowly into a vessel containing a large amount of water. The stabilizers can be either added to the organic solution of the drug or they can be present in the aqueous phase. Manufacturing challenges include variability of mixing processes which give rise to different particle size distribution. Also spontaneity of crystal growth once the nucleation occurs poses problems for controlling the particle size distribution within a narrow range. Furthermore, non-aqueous solvents utilized in the precipitation process must be reduced to toxicologically acceptable levels in the end product.

3.2.2.2 Amorphous drug nanoparticles (NanoMorph^®):

Amorphous precipitation technology is used by the company Soliqs and the technology is advertised under the tradename NanoMorph^®. Depending on the precipitation methodology, drug nanoparticles can be generated which are in the amorphous state.⁸

3.2.2.3 Emulsion-Solvent Evaporation:

Emulsions are being used as templates for the preparation of drug nanosuspensions. There are three types of methods can be used for the preparation of the drug nanosuspensions by emulsification. In the first method, an organic solvent or mixture of solvents loaded with drug is dispersed in the aqueous phase containing suitable surfactants to form an emulsion or microemulsion. The organic phase is then evaporated under reduced pressure so that the drug particles precipitate instantaneously to form a nanosuspensions stabilized by surfactants. Organic solvents usually included acetone, methylene chloride, chloroform and relatively safer ethyl acetate and ethyl formate etc.

The second method uses partially water-miscible solvents such as butyl lactate, benzyl alcohol, triacetin and ethyl acetate as the dispersed phase.¹ The emulsion or microemulsion is formed by the conventional dispersion method and the drug nanosuspensions are obtained by diluting the emulsion or microemulsion with relatively large amount of water. The dilution causes complete diffusion of the internal phase into the external phase, and leads to instantaneous formation of the nanosuspensions. The manner of diluting the emulsion included high-pressure homogenization or magnetic stirring, the former much more efficient than the latter.

The third method employs some organic solvents such as ethyl acetate (EA), toluene, or dichloromethane (DCM) to dissolve the drug as the internal phase.⁸ This solution was then dispersed into solvent-saturated aqueous solution containing surfactants to form a crude emulsion and subjected to high-pressure homogenization to form an ultrafine emulsion. The extraction of solvents and particle precipitation was carried out in an electrically heated stainless-steel extraction column. Super critical (SC) CO₂ was conversed from the bottom of the extraction column at a certain flow rate, and the emulsion was delivered from the top counter currently using a semi-preparative HPLC pump at a constant flow rate. The ratio of the flow rates of the SC CO₂ to the emulsion was maintained constant. During this process, the organic solvent was extracted quickly by SC CO₂ and the aqueous drug nanosuspensions were formed at the bottom of the column simultaneously.

3.2.2.4. Supercritical Fluid Process:

This new technique obviates the use of toxic organic solvents associated with conventional methods. Carbon dioxide is the most extensively used supercritical fluid (SCF). It has all the desired properties of a suitable pharmaceutical solvent such as nontoxicity, low inflammability, environmentally clean, chemical inertness, cheap, abundant, easy to remove and low critical conditions (pressure and temperature). Two techniques are most commonly used for preparing nanoparticles- Rapid Expansion of Critical Solution (RESS) and Supercritical anti-solvent (SAS). ²⁷

In Rapid Expansion of Critical Solution method, SCF CO₂ is used as a solvent for insoluble drugs. The drug is first solubilized in SCF CO₂ at high pressure in a chamber. The solution is then pumped into an expansion chamber through a nozzle to allow for the rapid expansion of SCF CO₂. Rapid expansion of the SCF causes the drug solubility to decrease rapidly, resulting in a high degree of supersaturation which leads to the formation of nanoparticles. In Supercritical anti-solvent (SAS), solutes are dissolved in methanol which is completely miscible with supercritical fluids.²³The extraction of methanol by the supercritical fluids leads to an instantaneous precipitation of the nanoparticles.¹⁰ A development challenge includes the selection of a polymer as most polymers exhibit little or no solubility in supercritical fluids, thus making the technique less of practical interest.¹⁶

3.2.3. Combined Technique:

Baxter Nanoedge^® which consists of homogenization of freshly prepared particles with a piston gap homogenizer to prepare stable drug nanosuspensions. The basic principles of Nanoedge are the same as that of precipitation and homogenization. A combination of these techniques results in smaller particle size and better stability in a shorter time. In this technique, the precipitated suspension is further homogenized, leading to reduction in particle size and avoiding crystal growth. For an effective production of nanosuspensions using the Nanoedge technology, an evaporation step can be included to provide a solvent-free modified starting material followed by high-pressure homogenization. Because of their small size and shape, particles produced by rapid precipitation are often more friable than the starting material and hence more susceptible to fragmentation. Further, there is a need to remove solvent after homogenization. If solvent impurities remain in the drug-loaded NPs, then these become toxic and may degrade the pharmaceuticals within the polymer matrix.

Microfluidization Reaction Technology (MRT) ⁸ is combination of the “bottom up” and “bottom down” approaches. . In this technology, in Microfluidizer^® reaction chamber pressurized solutions of the drug and its anti solvent are pumped through a coaxial feed system, where streams of these liquids collide with each other at high velocity (up to 300 m/s). Extreme turbulent flow conditions creating an ideal mixing environment leads to homogeneous and rapid nucleation with little time for crystal growth. This approach allows for a greater ability to control the growth rates of nanoparticles to produce uniform, optimally sized nanoparticles in a more efficient, cost-effective manner.

4. Characterization of nanosuspension:

4.1. Mean particle size and particle size distribution:

Accurate determination of mean particle size and particle size distribution is one of the most important characterization tests as the unique characteristics shown by nanosuspensions are due to their size. Particle size distribution determines the physiochemical behavior of the formulation, such as saturation solubility, dissolution velocity, physical stability, etc.The particle size distribution can be determined by photon correlation spectroscopy (PCS), laser diffraction (LD) and coulter counter multisizer.³⁴ PCS measures the particle size in the range of 3nm- 3 μm only. Polydispersivity index governs the physical stability of nanosuspension and should be as low as possible for long-term stability (Should be close to zero). LD measures volume size distribution and measures particles ranging from 0.05- 80μm up to 2000μm.³⁶

4.2. Zeta Potential:

Surface properties, such as charge and surface roughness, play an important role not only in the physical stability of nanosuspensions, but they also have a bearing on the in vivo functioning of the formulation. Zeta potential is an indication of the stability of the suspension. For a stable suspension stabilized only by electrostatic repulsion, a minimum zeta potential of ±30 mV is required whereas in case of a combined electrostatic and steric stabilizer, a zeta potential of ±20 mV would be sufficient.²² The zeta potentials values were commonly assessed by determining the particle electrophoretic mobility using the Zetasizer (Malvern Instruments Ltd., UK).

4.3. Crystal morphology:

Nanosuspensions can undergo a change in the crystalline structure, which may be to an amorphous form or to other polymorphic forms because of high-pressure homogenization.²⁵ Hence it is essential to measure the extent of amorphous drug generated during the nanosuspensions production. The changes in the solid state of the drug particles as well as the extent of the amorphous fraction can be determined by X-ray diffraction analysis and supplemented by differential scanning calorimetry.²⁹

4.4. Saturation solubility and dissolution velocity:

Dissolution of drug is increased due to increase in the surface area of the drug particles from micrometers to the nanometer size. Saturation solubility is compound specific constant depending upon temperature and the properties of dissolution medium. Kelvin equation and the Ostwald-Freundlich equations can explain increase in saturation solubility.⁷

5. Applications of nanosuspension:

Products in nanometer size range offer ‘‘uniqueness’’ because of their altered properties as compared to their macro-counterparts. Improved solubility, permeability, or targetability of nanoparticles seems to be beneficial in the drug delivery area. List of current marketed products are given in Table 2.

5.1 Oral drug delivery:

Oral route is first choice for various drugs due to good patient compliance, readily transportation, and simple manufacture process. But the major problem associated with oral administration is low bioavailability and finally its inadequate efficacy due to poor solubility and incomplete dissolution. Nano-engineering traditional greatly enhance oral bioavailability in some cases.¹² The first nanosuspension product in the market was Rapamune^®, introduced in 2000 by the company Wyeth. Rapamune^® is available on the market as oral solution, and alternatively as tablet. Comparing the oral bioavailabilities of solution and nanocrystal tablet, the bioavailability of the nanocrystals is 21 % higher compared with the solution. The oral single dose of Rapamune^® is 1 or 2 mg, the total tablet weight being 364 mg for 1 mg formulation and 372 mg for the 2 mg formulation, meaning that it contains a very low percentage of its total weight as nanocrystals.³ The second product on the market was Emend^®, introduced in 2001 by the Company Merck. The drug Aprepiptant is for the treatment of emesis (single dose is either 80 or 125 mg). Aprepiptant will only be absorbed in the upper gastrointestinal tract. Particle size reduction leads to rapid in vivo dissolution, fast absorption and increased bioavailability.

5.2 Parenteral drug delivery:

Injections provide fast onset of action, accurate dose, reliable efficacy and avoidance of first-pass metabolism. Nanosuspensions can be administered via different parenteral routes, such as intraarticular, intraperitoneal and intravenous injections. Abraxane™ for Injectable Suspension is an approved, commercialized albumin-bound nanosuspension formulation of the widely used anticancer drug; Paclitaxel (Taxol).It is the albumin-bound solvent free- taxane nanoparticulate formulation that takes advantage of albumin to transport Paclitaxel into tumor cell. Another advantage is that it is administered in 30 minutes, as compared to 3 hours for solvent based Paclitaxel.¹²It could be shown that intraperitoneal administration of a nanosuspension was well tolerated; whereas administration of a macrosuspension leads to irritancy.³ Intraperitoneal administration can be used for local treatment or to obtain a depot with prolonged release into the blood. Producing parenteral products with drug nanocrystals has to meet higher regulatory hurdles and product quality standards distinctly.

5.3 Ophthalmic Drug Delivery:

An exciting challenge for developing suitable drug delivery systems targeted for ocular diseases is one of today’s major focuses of pharmaceutical scientists. Conventionally, most ocular diseases or disorders are treated with water-soluble drugs in aqueous solution while water insoluble drugs in ointments or aqueous suspension.¹ However, there are several disadvantages such as: frequent installation of highly concentrated solutions due to rapid tear turnover and precorneal loss; large volume of the instilled dose (20-50 μl vs. 7-8 μl of the tear film; irritation caused by drug penetration; drug solubility and stability in the eye fluids, difficulty in passing the blood-corneal barrier.²⁸ The nanoparticulate nature of drug allows its prolonged residence time in the cul-de-sac, giving sustained release of the drug.

5.4 Topical drug delivery system:

Drug nanocrystal exhibit the properties like increased penetration into membrane, enhanced permeation and bioadhesiveness thus increasing diffusion through skin. Drug nanocrystal can be formulated into creams and water free emulsions. Diclofenac sodium nanosuspension for transdermal delivery showed increased permeability flux of drug across the skin when tested in animal model.^2,
21

5.5 Pulmonary Drug Delivery:

Pharmaceutical inhalation drug delivery plays a very important role in the health and well being of millions of human throughout many years. But the administration of drug through the lungs is more challenging because more oral deposition of drug. Recent advances in field of nanotechnology helpful in solving the ticky problems related to the drug delivery.³⁷ The application of nanotechnology to the pharmaceutical aerosol collectively known as nano-enabled aerosol with added advantages and effectiveness.¹³ The nanosuspension can be used in all nebulizers. Compare to the conventional aerosols, the nanosuspension aerosols provide advantages like more consistent distribution to the lungs than dry powder formulation and also there is increased adhesiveness of nanosuspension formulation to mucosal surfaces offers prolonged residence time for drug at the absorption site.^{1, 15} Budesonide a poorly water soluble corticosteroid, has been successfully formulated as a naosuspension for pulmonary drug delivery.¹⁴

5.6 Targeted Drug Delivery:

As there is change in drug surface properties and altered in vivo behaviour, nanosuspension can also be used for targeted drug delivery. Their ease of scale up and more versality enable the development of commercial nanosuspension for targeted drug delivery.²⁴ Megace ES is nanocrystal form of megestrol acetate used in breast cancer (Par Pharmaceutical). Targeting of Cryptosporidium parvum in treatment of cryptosporidiosis by using surface modified mucoadhesive nanosuspension of bupravaquone was studied by kayser.²⁰ Because of prolonged residence at infection site, superior targeting was achieved by bupravaquone nanosuspension.

CONCLUSION:

Nanosuspension technology is most promising nanocarrier drug delivery for poorly water soluble drugs, due to its unique characteristics and suitability to formulate the brick dust compounds which are having low solubility in water as well as oil. Nanosuspension serves as a ideal nanocarrier delivery of oral drugs which are having the dissolution velocity as a rate limiting step for absorption and BCS class II and class IV. In addition nanosuspension also plays an important role in other drug delivery systems such as topical, ocular, parenteral, pulmonary and targeted drug delivery.

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Received on 04.08.2011

Accepted on 26.08.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(5): Sept.-Oct. 2011, 176-182

The Methods	Advantages	Disadvantages
Media Milling	Drugs that are poorly soluble in both aqueous and organic media can be easily formulated into nanosuspensions, Ease of scale-up and little batch-to-batch variation, Narrow size distribution of the final nano-sized product, allowing aseptic production of nanosuspensions for parenteral administration and flexibility in handling the drug quantity	potential erosion of material from the milling pearls
High pressure homogenization	Same as Media Milling method	pretreatment of micronized drug particles and presuspending materials before subjecting it to homogenization
Precipitation	low need of energy, stable products and simple process	narrowly applying space, wide size distribution and potential toxicity of non-aqueous solvents
Super Critical fluid process	smooth surface morphology and low surface energy of the nanoparticles prepared as compared to other techniques such as micronization , obviates the use of toxic organic solvents associated with conventional methods	the particle size obtained with this process ranges from 1 to 5 mm, due to aggregation of the fine particles initially generated during the process
Combination technique	greater ability to control the growth rates of nanoparticles to produce uniform, optimally sized nanoparticles in a more efficient, cost-effective manner	the manufacturing process is complicated

API Product	Drug compound	Indication	Company	Technology
RAPAMUNE^®	Sirolimus	Immunosuppresant	Wyeth	Nanocrystal Elan Drug Delivery^®
EMEND^®	Aprepitant	Antiemetic	Merck	Nanocrystal Elan Drug Delivery^®
TriCor^®	Fenofibrate	Treatment of hypercholesterolemia	Abbotte	Nanocrystal Elan Drug Delivery^®
MEGACE^®ES	Megestrol Acetate	Appetite stimulant	PAR Pharmaceutical	Nanocrystal Elan Drug Delivery^®
Triglide^TM	Fenofibrate	Treatment of hypercholesterolemia	First Horizon Pharmaceutical	Nanocrystal Elan Drug Delivery^®