The History And Purpose Of Nanotechnology Biology Essay

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Nanotechnology has a long development and application history. However, the most important scientific advancements have only taken place in the last two decades. In the filed of pharmaceutics, the term "Nanoparticle" has been loosely applied to structures less than 1μm in diameter. They are produced by either mechanical or chemical means and characterized by conventional analytical methods such as microscopy or light scattering.

Heterogeneous catalysts were among the first examples, developed in the early 19th century7-8. Danazol particles have been milled to a median diameter of 169 nm9. The Danazol nanosuspension showed enhanced oral bioavailability (82.3 ± 10.1%) that was similar to that of a danazol-2-hydroxypropyl-β-cyclodextrin dispersion (106.7±12.3%), and far superior to that of the conventional drug suspension (5.1±1.9%). Homogenization (microfluidization) was applied to atovaquone to obtain particles in the 100-3000 nm range10. Fine particles were produced by dissolution of drug in a high-melting organic material, such as a lipid. When heated above its melting point, the liquid will comminute into a fine emulsion by piston-gap homogenization. Cooling of the melt to room temperature form solid particles of the lipid entrained with the drug11.

In some cases, micronisation of raw material was required before homogenization in order to obtain the desired final particle size. Muller and co-authors have suggested jet milling or milling as a size reduction step prior to piston-gap homogenization12. The need for prior processing to homogenization may be attributed to the density, hardness and particle size of the starting input material. Muller and coworkers have produced drug nanoparticles (DISSOCUBES) by piston- gap homogenization13. The first United States (US) approval of a product produced incorporating the NanoCrystal® technology happened in August 2000. The product, Wyeth's first solid-dose formulation of the immunosuppressant Rapamune® (sirolimus) received marketing approval from the U.S. Food and Drug Administration (FDA). Rapamune was previously available only as an oral solution in bottles or sachets. The oral solution required refrigeration storage and had to be mixed with water or orange juice prior to administration. The new tablet developed with NanoCrystal® technology provides patients with more convenient administration and storage than Rapamune oral solution. The development of a NanoCrystal® dispersion of sirolimus provided a drug product with enhanced bioavailability and improved stability.

Antiemetic drug, Emend® (Aprepitant, MK 869) was approved by the FDA in March 2003 and launched in the United States by Merck in April 2003. Whereas the first commercial product that utilized NanoCrystal® technology (Rapamune) was a reformulation of a marketed product, Emend was an NCE that was developed as a NanoCrystal® formulation (May 2005)14. Tricor® (Fenofibrate tablet for hypercholesterolemia) was the next product developed by Abbott laboratories. The doses of 48 mg and 145mg are given as a tablet for treatment. The product is successor for Fenofibrate after patent expiry. The nanoparticle technology in this case served for patent life time extension of Fenofibrate with improved product performance.

Another product containing Fenofibrate nanoparticles is Triglide®. The product is used for the treatment of hypercholesterolemia, produced by Skye Pharma based on the IDD-P® technology and marketed by sciele Pharma Inc. (Atlanta, USA).

Megace ES® (ES stands for enhanced solubility) is introduced by Par Pharmaceutical companies Inc. (NY, USA). It is an aqueous suspension of Megestrol acetate (a synthetic progestin, antianorexic) with a dose of 625mg / 5 mL. The name Megace ES® was licensed from Bristol Myers Squibb (New York). The megestrol acetate nanosuspension reduces the fed and fast variability similar to Tricor. The product in nanosuspension demonstrated that aqueous nanosuspension can be produced with adequate physical stability for a product shelf life using this technology.

A list of other products on the market and candidates in clinical trials are summarized in Tables 2.1 and 2.2 respectively15-16.

Table 2.1. Overview of Nanoparticle Technology Based Marketed Products

Trade Name

Drug

Indication

Drug Delivery Company

Innovator Company

Status

Rapamune®

Rapamycin, Sirolimus

Immunosuppressant

Elan Nanosystems

Wyeth

Marketed

Emend®

Aprepitant

Anti-emetic

Elan Nanosystems

Merck &Co.

Marketed

Tricor®

Fenofibrate

Hypercholesterolemia

Abbott Laboratories

Abbott Laboratories

Marketed

Megace ES®

Megestrol

Anti anorexic

Elan Nanosystems

Par Pharmaceuticals

Marketed

Triglide®

Fenofibrate

Hypercholesterolemia

IDD-P Skyepharma

Sciele Pharma Inc.

Marketed

Avinza®

Morphine sulphate

Phychostimulant drug

Elan Nanosystems

King Pharmaceuticals

Marketed

Focalin

Dexmethyl-Phenidate HCl

Elan Nanosystems

Novartis

Marketed

Ritalin

Methyl Phenidate HCl

Elan Nanosystems

Novartis

Marketed

Zanaflex CapusulesTM

Tizanidine HCl

Muscle relaxant

Elan Nanosystems

Acorda

Marketed

Table 2.2 Overview of Drug Candidates in Clinical Studies

Trade Name

Indication

Drug Delivery Company

Innovator Company

Route of Administration

Status

Fenofibrate

Lipid lowering

Skye pharma

Undisclosed

oral

Phase-1

Insulin

Diabetes

BioSante

Self developed

oral

Phase-I

Calcium Phosphate

Mucosal vaccine adjuvant for herpes

BioSante

Self developed

oral

Phase-I

Megesstol Acetate

AIDS related weight loss

Elan Nanosystems

Par pharmaceuticals Inc.

oral

Phase-II

Panzem® NCD (2-methoxy estradiol)

Ovarian cancer

Elan Nanosystems

EntreMed

oral

Phase-II

Penzem®NCD

Recurrant glibolatoma multiforme

Elan Nanosystems

EntreMed

oral

Phase-II

Penzem®and Tamozolomide

Anti-cancer

Elan Nanosystems

EntreMed

oral

Phase-II

Panzem®NCD with and without sanitinib Maleate

Renal cell carcinoma

Elan Nanosystems

EntreMed

oral

Phase-II

Panzem®NCD

Prostate cancer

Elan Nanosystems

EntreMed

oral

Phase-II

Fenofibrate

Sleep apnea syndrome

Elan Nanosystems

Solvay Pharmaceuticals

oral

Phase-II

Undisclosed

Anti infective

Baxter Nanoedge

Undisclosed

oral

Phase-II

Cytokine inhibitor

Crohn's disease

Elan Nanosystems

Cytokine Pharmasciences

oral

Phase-II

2.2 FORMULATION THEORY

The basic principle of micronisation and nanonisation is the increase in surface area leading to enhancement in dissolution rate according to Noyes-Whitney equation17. Poor water solubility correlates with slow dissolution rate and decreasing particle size increases the surface area with concomitant increase in the dissolution rate.

Dissolution kinetics is the primary driving force behind the improved pharmacokinetics properties of nanoparticle formulations of poorly water soluble compounds. Dissolution rate of a drug is a function of its particle size and intrinsic solubility. For poorly water soluble drugs, surface area of the drug particles drives dissolution. As described by the Nernst-Brunner and Levich modification of Noyes-Whitney model the rate of drug dissolution is directly proportional to surface area;

dx/dt = (A x D/δ) x (C-X/V) …………………….. (1)

Where X is the amount of drug in solution, t is time, A is the effective surface area, D is the diffusion coefficient of the drug, δ is the effective diffusion boundary layer, C is the saturation solubility of the drug, and V is the volume of dissolution medium.

Saturation solubility is a compound specific constant that depends on temperature. This is applicable for powders of sizes handled in daily life but it is different for drug nanoparticles. The dissolution pressure is a function of the curvature of the surface that means it is much stronger for a curved surface of nanoparticles. Below a size of approximately 1 - 2μm, the dissolution pressure increases distinctly leading to an increase in the saturation solubility. In addition, the diffusional distance on the surface of drug nanoparticles is decreased, thus leading to an increased concentration gradient. The increase in surface area and increase in concentration gradient lead to a much more pronounced increase in the dissolution velocity compared to a micronized product. In addition, saturation solubility is increased as well. Saturation solubility and dissolution velocity are important parameters affecting the bioavailability of orally administered drugs. From this it can be seen that nanoparticles have the potential to overcome these limiting steps.

Increased solubility near the particle surface results in enhancement of concentration gradient between the surface and the bulk solution. This high gradient, by Fick's law, must lead to an increased mass flux away from the particle surface. As the particle size decreases, its surface area to volume ratio increases inversely, and this further lead to an increased dissolution rate. Under sink conditions when the drug concentration in the surrounding medium approaches zero, rapid dissolution of drug may theoretically occur.

2.3 Properties of Nanoparticles

Nanoparticles have unique properties as compared to micro and macro particles, the Salient features include the following

Small particle size

Increased surface area

Increased dissolution rate

Increased saturation solubility

Deep access to cells and organelles

Variable optical and magnetic properties

2.4 Pharmaceutical Benefits: The pharmaceutical benefits of nanoparticles include;

Improved formulation performance such as enhanced saturation solubility and

dissolution velocity.

Reproducibility of oral absorption and improved oral bioavailability

Increase patient compliance via reducing the number of oral units to be taken18-19

Ideal system for oral drugs having low dissolution velocity as rate limiting step

for absorption. (BCS Class-II compounds)

2.5 Nanotoxicology Concerns

In the last 3-4 years there is an increasing concern about toxicity of nanosized particles. This is majorly due to change in the physico-chemical properties of nanosized drug. When the particle size is reduced to nano range the change in properties may also give potentially new toxic features to the drug. Therefore nanotoxicology plays an increasingly important role in developing safe nanocarriers20. Literature indicates, the particles below 100 nm are of major toxicological concern (e.g. FDA, European Cosmetic Regulation21. The properties of particles < 100nm are also different from larger nanoparticles (e.g. 200-800 nm). The larger nanoparticles are internalized by macrophages causing effects inside the cell where as the particles < 150 can internalized by any cell via pinocytosis resulting in higher toxicity risk. Considering these factors, nanoparticles of poorly soluble compounds can be relatively safe. In most of the products, particle size of drug is above 100 nm and most importantly they are all biodegradable (after addition of water, the drug particles dissolve in the gastrointestinal tract). Nevertheless, it is important to investigate potential cytotoxic effects of a biodegradable nanoparticle with in the life time which may still be sufficient to irritate the immune system. However, considering the above aspects, the larger nanoparticles (> 200 nm) are safe with best tolerability, proven also by the number of products in the market.

2.6 Overview of Existing Technologies to Produce Drug Nanoparticles

There are several techniques used to produce drug nanoparticles. The existing technologies can be broadly divided into two: 'bottom up' and 'top down' technologies. The bottom-up technologies involves controlled precipitation /crystallization by adding a suitable non-solvent. The top down technologies are milling or homogenization methods. However the combination techniques, a pretreatment step followed by size reduction are also being used. In some instances Solvent evaporation and supercritical fluid technologies are also used but they are less industrially relevant at present.

2.6.1 Bottom-up-Precipitation Methods

Precipitation has been applied for many years for the preparation of small particles, particularly in the development of photographic films22-23, and within the last decade in the preparation of sub-micron particles for drug delivery.

Examples for precipitation techniques are the hydrosols24-29 developed by Sucker (company Sandoz, presently Novartis) and the product Nanomorph by Soliqs/Abbott (previously Knoll/BASF).

In this process, the drug is dissolved in an organic solvent and this solution is subsequently added to a non-solvent. This results in high super saturation, rapid nucleation and the formation of many small nuclei30. After removing the solvent, the suspension may be filtered and lyophilized. Addition of the solvent to the non-solvent is necessary to yield a very fine product by passing the Ostwald Mier area fast31. The mixing processes may vary considerably. Through careful control of this addition process it is possible to obtain a particle with a narrow size distribution. In the case of Nanomorph, amorphous nanocrystals of drug are produced to enhance dissolution velocity and solubility.

Simple precipitation methods, however, have numerous limitations; it is very difficult to control nucleation and crystal growth to obtain a narrow size distribution. Often a metastable solid, usually amorphous, is formed which is converted to more stable crystalline forms33-34. Furthermore, non-aqueous solvents utilized in the precipitation process must be reduced to toxicologically acceptable levels in the end product and due to the fact is many of the poorly soluble drugs are poorly soluble aqueous as well as in organic media. To sum up, the bottom up techniques is not widely used for production of drug nanocrystals. Instead, top down technologies that includes homogenization and milling techniques are more frequently used.

2.6.2 Top-down technologies

The two top down technology frequently used for producing drug nanoparticles include;

1. High pressure homogenization methods

2. Milling Methods

2.6.2.1 High Pressure Homogenization methods

One of the disintegration method used for size reduction is high-pressure homogenization. The two-homogenization principles/homogenizer types applied are;

1. Microfluidisation (Microfluidics, Inc.)

2. Piston-gap homogenizers (e.g. APV Gaulin, Avestin, etc.)

2.6.2.2 Microfluidisation for Production of Drug Nanoparticle

Microfluidisation works on a jet stream principle, where the suspension is accelerated and passes with a high velocity in a specially designed homogenization chamber. In the 'Z' type chamber, the suspension changes the direction of its flow a few times leading to particle collision and shear forces. In the second type of chamber, the 'Y'-type, the suspension stream is divided into two streams, which then collide frontally.

A disadvantage of the technology is that often a number of passes through the microfluidiser is required to obtain particles in the sub-micron range resulting in increased process time. In addition, the product obtained by microfluidisation may contain a relatively large fraction of microparticles (especially in the case of hard drugs) thus losing the special benefits of a real homogeneous drug nanoparticulate suspension.

2.6.3 Piston-gap Technologies

Using Microfluidisation principle, an alternative drug nanoparticle technology based on piston-gap homogenizers was developed in the middle of the 1990s. Homogenization can be performed in water (DISSO CUBES) or alternatively in non-aqueous media or water reduced media (NANOPURE). There is also a combination process of precipitation followed by a second high-energy step, e.g. homogenization (NANOEDGE). The result is a suspension of drug nanoparticles in a liquid, the so-called nanosuspension.

Reduction of particle size generally depends on high-energy input, which results in enormous impact forces. Piston gap homogenization generally produces high turbulent energy by cavitation. In a piston-gap homogenizer, the starting suspension or slurry is pumped through a narrow gap at high pressure (15,000-30,000 psi). In this homogenizer type, the dispersion (emulsion or suspension) passes a very thin gap with an extremely high velocity. In APV LAB 40, the diameter of the cylinder is about 3 cm, it narrows to about roughly 25 mm (varies with applied pressure). The major limitation of the high pressure homogenization process is that nanoparticulate dispersion of low solid content (usually < 10% w/w) is produced which is difficult for manufacture of solid intermediates required for capsule filling or tabletting.

2.6.4 Milling Methods

Conventional milling and precipitation processes generally result in particles much greater than 1μm. Milling techniques were later refined to enable milling of solid drug particles to sub-micron range. Ball mills are already known from the first half of the 20th century for the production of fine suspensions. The suspension comprising of drug and stabilizers along with milling media are charged into the grinding chamber. The reduction of particle size occurs due to the shear forces of impact, generated by the movement of the milling media. In comparison to high pressure homogenization, it is a low energy milling process. Smaller or larger milling beads can be used as milling media. The pearls or beads consist of ceramics (cerium or yttrium stabilized zirconium dioxide), stainless steel, glass or highly cross linked polystyrene resin-coated beads. Contamination from the milling material during the milling process is a common problem of this technology. To overcome this problem, the milling beads are often coated35-36.

In the bead milling process, the drug suspension is passed through a milling container containing milling beads of sizes ranging from 0.2 to 3 mm. These beads may be composed of glass, zirconium salts, ceramics, plastics (e.g., cross-linked polystyrene) or special polymers such as hard polystyrene derivatives. The drug concentration in the suspension can range from 5 - 40% w/v. Stabilizers such as polymers and/or surfactants are used to aid the dispersion of particles. To be effective the stabilizers must be capable of wetting the drug particles and providing steric and ionic barrier. In the absence of stabilizers, the high surface energy of the nanometer-sized particles would tend to agglomerate the drug crystals. The concentration of polymeric stabilizers can range from 1 - 10% w/v and the concentration of surfactants is generally < 1 % w/v. If required other excipients such as buffers, salts, diluents like sugar can be added to the dispersion to enhance stability and further processing.

During the process, milling chamber is charged with milling or grinding media. The milling chamber has a rotor fitted with disks that can be accelerated at the desired speed (500 - 5000 RPM). The rotation of the disk accelerates the milling media radially. The product flows axially through the milling chamber where the shear forces generated and/or forces generated during impaction of the milling media with the drug provides the energy input to fracture the drug crystals into nanometer-sized particles. The temperature inside the milling chamber is controlled by circulating coolant through the outer jacket. The process can be performed either in a batch mode or in a recirculation mode. The milled product is subsequently separated from the milling media using a separation system.

Scaling up with bead mills is easy and convenient. The batch size can be increased above the void volume (volume in between the hexagonal packaging of the beads) using the mill in a recirculation mode. The suspension is contained in a product container and continuously pumped through the mill in a circular motion. This increases the batch size with concomitant increase in the milling time because the required exposure time of the drug particles per unit mass to the milling material remains unchanged.

Surfactants or stabilizers have to be added for the physical stability of the produced nanosuspensions. In the manufacturing process the drug substance is dispersed by high speed stirring or homogenizer in a surfactant/ stabilizer solution to yield a macrosuspension. The choice of surfactants and stabilizers depends not only on the physical principles (electrostatic Vs steric stabilization) and the route of administration. In general, steric stabilization is recommended as the first choice because it is less susceptible to electrolytes in the gut or blood. Electrolytes reduce the zeta potential and subsequently impair the physical stability, especially of ionic surfactants. In many cases an optimal approach is the combination of a steric stabilizer with an ionic surfactant, i.e, the combination of steric and electrostatic stabilization. There is a wide choice of various charged surfactants in case of drug nanocrystals for oral administration. There are a number of bead mils available on the market, ranging from laboratory-scale to industrial-scale volumes. The ability for large-scale production is essential prerequisite for the introduction of product into market. To sum up, of all the technologies available, bead milling offers a convenient process for production of nanoparticle dispersion at high concentrations for solid dosage form processing that offers ease of scale-up to enable commercial manufacturing37.

Table 2.3 Advantages and Disadvantages of Milling Methods

Technology

Advantages

Disadvantages

Precipitation

Fine drug dispersion

desired particle size

Stabilization is needed

organic residual solvent

not universally applicable, only drugs with certain properties are possible (eg, soluble in at least one solvent)

Milling

low energy required

residue from milling media

4 FDA approved drugs using this technology

Process can be scaled up

Homogenization

applicable universally

high energy technique

Process can be scaled up

Technical experience needed

fast method (several minutes possibly)

water free production possible

2.7 Conversion of Nanosuspension in to Solid Intermediate for Encapsulation or Tableting

For production of solid intermediate, the water has to be removed from the suspension to obtain a dry powder. Nanosuspension can be dried using drying operations such as fluid bed coating / granulation, spray drying and freeze drying. Freeze drying is considered as a complex and cost-intensive process leading to a highly sensitive product. The main challenge is to preserve the re-dispersibility of the nanoparticles up on reconstitution with water and gastric fluids. The re-dispersants must be incorporated in the nanosuspensions prior or during the drying step. Commonly used re-dispersants are sugars such as lactose, sucrose and mannitol38. Generally, re-dispersibility depends on the choice of re-dispersants, choice of surfactants and polymeric stabilizers. The loading capacity of the solid intermediate with drug nanoparticles can be adjusted by varying the concentrations of excipients. The objectives of solid nanoparticle system is releasing the drug nanoparticles after administration in the gastrointestinal tract (GI) as fine non-aggregated suspension and increase the physical stability for long term storage of the product. Spray drying is especially suitable for drugs that are insensitive to high temperatures. Depending on the spray conditions and formulation, the resulting products can easily be filled into hard gelatin capsules or blended with extra granular excipients and compressed in to tablets. In the case drugs which are acid liable, the capsule or tablet can be coated with enteric polymers to protect the drug from gastric fluids.

An alternative way to convert nanosuspension in to solid intermediate is the suspension layering on to sugar beads or lactose. The binders that are necessary for this process can also be added before the milling process resulting in the improved nanosuspension properties. The suspensions were layered at a predetermined spray rate on to a water soluble inert carrier using a top spray fluid bed process. The granules were dried as they moved upward, small droplets and low viscosity of the spray medium ensured that distribution was uniform resulting in granules with a narrow size distribution.

2.8 Characterization of Nanoparticles

There are various techniques for detecting, measuring and characterizing nanoparticles. There is no single method that can be selected as the "best" for analysis. Most often the method is chosen to balance the restriction of the type of sample, the information required, time constraints and the cost of analysis. Following methods are used to characterize the nanoparticles.

2.9 Particle Size and Size Distribution

Nanoparticle size and the range of distribution is measured by following techniques

2.9.1 Spectroscopy

The particle size characterization of nanosuspensions is performed to obtain information about the average particle size of the system and particle size distribution and about changes in particle size on storage (e.g. crystal grows and agglomeration). As nanosuspensions consist of submicron particles, the appropriate method used to evaluate particle size distribution is photon correlation spectroscopy. PCS or dynamic light scattering analyses scattered laser light from particles diffusing in a low viscosity dispersion medium (e.g. water). PCS analyze the fluctuation velocity of the scattered light rather than the total intensity of the scattered light. The detected intensity signals (photons) are used to measure the correlation function. The diffusion coefficient D of the particles is obtained from the decay of this correlation function. Applying the Stokes-Einstein equation, the mean particle size (called z-average) can be calculated. In addition a polydispersity index (PI) is obtained as a measure for the width of the distribution. The value of PI is 0 in case a monodisperse particle population. Incase of narrow distribution the PI values are around 0.10 - 0.20, values of 0.5 and higher indicate a very broad distributions. From the values of z-average and PI, even small increases of nanocrystals size with time can be detected. The extent of increase in the size of the particle is a measure for the extent of instability. Therefore PCS is considered as a sensitive instrument to detect instabilities during long-term storage39.

Laser Diffractometry was developed around 1980 and found very fast and is used as a routine method in many laboratories. The measurement range using this method is between 10nm and 8750μm. LD measurements are essential for characterization of drug nanoparticles. The instrument is used for quantifying the percentage of micro particles present, which is not possible by PCS measurements. LD analyses the Fraunhofer diffraction patterns generated by particles in a laser beam. The first instruments were based on the Fraunhofer theory which is only valid for particle sizes being 10 times larger than the wavelength of the light used for generating the diffraction pattern. For particle sizes below approximately 6.3 μm (in case of using a helium neon laser, wavelength 632.8 nm), the Mie theory needs to be applied to obtain correct particle sizes. The Mie theory requires the knowledge of the real refractive index of the particles and the imaginary refractive index (absorbance of the light by the particles). Unfortunately for most of the pharmaceutical solids the refractive indices is not known. However, laser diffractometry is frequently used as the second characterization method for nanosuspensions, because of its "simplicity"40-41.

2.9.2 Microscopy

Microscopy based techniques can be used to study a wide range of materials with a broad distribution of particle sizes, ranging from the nanometer to the millimeter scale. Instruments used for microscopy based techniques include optical light microscopes, scanning electron microscopes (SEM) transmission electron microscopes (TEM) and Atomic force microscopes (AFM). The choice of the instrument for evaluation is determined by the size range of the particles being studied, magnification, and resolution. However, the cost of analysis is also observed to increase as the size of the particles decreases due to requirements of higher magnification, improved resolution, greater reliability and reproducibility. The cost of size analysis also depends upon the system being studied, as it dictates the techniques of specimen preparation and image analysis. Optical microscopes tend to be more affordable, and comparatively easier to operate and maintain than electron microscopes, but are more limited in magnification and resolution42-43.

2.9.3 Morphology

2.9.3.1 Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry is used to determine the nature of crystallinity with in nanoparticles by measuring the glass transition temperature, melting point and their associated enthalpies. This method along with XRPD is used in determination of the extent of which multiple phases exists in the interior and their interaction with the drug.

2.9.3.2 X-Ray Powder Diffraction (XRPD)

XRPD is used to study single crystal or polycrystalline materials. A beam of x-rays is passed through a sample and the way the beam is scattered by the atoms in the path of the x-ray is studied. The x-rays scattered constructively interfere with each other. This interference can be looked at using Bragg's Law to determine various characteristics of the crystal or polycrystalline material44.

2.9.4 Interparticular Interactions

The interactions occurring between nanoparticles are measured by the Surface charge density (zeta potential). The particle charge is one of the important factors in determining the physical stability of nanosuspensions. The higher particles are equally charged, the higher is the electrostatic repulsion between the particles and the higher is the physical stability. Typically the particle charge is quantified as zeta potential, which is measured e.g. via the electrophoretic mobility of the particles in an electrical field45.

2.10 Applications of Drug Nanoparticles

The particle size reduction and the resulting increased surface area, curvature, saturation solubility and consequently increased dissolution velocity are important factors in improving the bioavailability of poorly soluble drugs.

Solubility enhancement of drug nanoparticles plays an important factor for drugs with narrow therapeutic window, the increased solubility and dissolution velocity in these cases lead to improved drug absorption and acceptable bioavailability.

Drug nanoparticles with enhanced solubility may also reduce the fed and fast variability. The drug which normally requires food to get soluble will be bioequivalent in nanoparticles in both fed and fasted states.

Furthermore, the drug nanoparticles faster onset of action. This provides an advantage for drugs which need to produce fast onset of action (eg. Naproxen).

The drug nanoparticles allow for smaller doses and thus decrease the side effects in comparison to larger dose of poorly soluble drugs, to achieve reasonable blood levels.

Based on the understanding that reduction in particle size can enhance dissolution rate, we wished to evaluate the effect of particle size on solubility, dissolution and bioavailability enhancement for two poorly soluble drugs (Candesartan cilexetil and a novel Camptothecin analog). In this study, a media milling process was evaluated for production of nanosuspensions of these poorly soluble drugs. The drug nanoparticles were evaluated for solubility and dissolution enhancement. Solid-state changes were also evaluated before and after particle size reduction. Conversion of nanosuspension into solid intermediate was evaluated using spray drying and spray granulation process. The recovery of particles from the powder was accessed following drying process. The dissolution characteristics of the nanoparticles were investigated to study the impact of particle size on drug dissolution. Systemic exposure studies of drug nanoparticles were evaluated in male Wistar rats to assess the rate and extent of drug absorption.

2.11 Drug Candidate Selection Criteria

For this investigational study, two poorly soluble drugs, Candesartan cilexetil - a non-peptide angiotensin II type 1 (AT1) receptor antagonist used in the treatment of hypertension and, a novel Camptothecin analog [5-Substituted (2 Hydroxy ethoxy) Camptothecin] - a topoisomerase inhibitor that has shown potential in the treatment of solid tumors, were selected as model drugs. Both drugs exhibit poor wettability and low aqueous solubility.

2.12 Objective of the Investigation

The objective of the present investigation is to develop a solid oral dosage form for the selected drug candidates by formulating them as drug nanoparticles to enhance solubility, dissolution rate and concomitantly bioavailability.

2.13 Scope

There is a large potential for nanoparticle enabled drug delivery systems because of their unique advantages over other types of delivery systems. The benefits of nanoparticle technology based drug delivery include lower drug toxicity, improved bioavailability and reduced cost of treatment. The nanoparticle formulation approach is very useful and invaluable in all stages of the drug product development. In developing new chemical entities (NCEs), the technology can be of great value when it is used as a screening tool during preclinical efficacy and / or safety studies in the early development phase. During later drug product development, robust nanoparticle formulations can be post processed into various types of patient friendly dosage forms that provide maximal drug exposure. For marketed products requiring life-cycle extension opportunities, nanoparticle formulation strategies may provide a means to develop a new drug-delivery platform incorporating the existing drug, thus creating new avenues for addressing unmet medical needs.

2.14 Plan of Work

The objective of the present work is to develop a solid oral dosage form for poorly soluble drug candidates, Candesartan cilexetil and Camptothecin analog by formulating them as drug nanoparticles to enhance solubility, dissolution rate and concomitantly bioavailability. In order to meet the objective, the work was planned in the following sequential order.

To evaluate formulations incorporating the selected stabilizer and surfactant at varying concentrations using an in-house fabricated laboratory scale (capacity 250 mL) bead mill and subsequently scale-up the selected formulation using a Netzsch Bead Mill.

To evaluate the saturation solubility and dissolution rate of nanoparticle formulations to study the impact of particle size.

To evaluate the systemic exposure of nanoparticle formulation in male Wistar rats to study potential increase in rate and extent of drug absorption.

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