Fig. 1. A representative photograph of nanoparticles

Table 2. PROCESS USED FOR THE PREPARATION OF NANOPARTICLES

PROCESS	PARTICLE SIZE
Single emulsion	(Particle size depends on the size of dispersion used)
Double emulsion	100-1000 nm
Spray drying	>200 nm
Gas- antisolvent precipitation	400-600 nm
Nanoprecipitation	>100
High pressure homogenisation	>300
Wet milling	>100
Microprecipitation- homogenisation	>100
High gravity reactive precipitation	>100

These methods are still the most widely used today, yet each has its disadvantages. Oral delivery via tablets or capsules is largely inefficient due to exposure of the pharmaceutical agent to the metabolic processes of the body. Therefore, a larger than necessary dose is often required and the maximum effectiveness of the drug is limited. Traditional intravenous (IV) administration is much more problematic. Specificity for IV injectable drugs is often low, necessitating large amounts of a drug be injected into a patient, creating a high concentration of the drug in the blood stream that could potentially lead to toxic side effects. Nanoparticle drug delivery, utilizing degradable and absorbable polymers, provides a more efficient, less risky solution to many drug delivery challenges. ^10,11

DEFINATION:

Nanoparticles are defined as particulate dispersions or solid particles with a size in the range of 10-1000nm. The drug is dissolved, entrapped, encapsulated or attached to a nanoparticle matrix. Depending upon the methods of preparation of nanoparticles, nanospheres or nanocapsules can be obtained.¹² The devices and systems produced by chemical and/or physical processes having specific properties. Representative of nanoparticles as seen in Figure 1.

BACKGROUND OF NANOTECHNOLOGY:

Yet, utilising science at the nanoscale is not new. In the 4^thCentury A.D., the Romans applied gold and silver nanoparticles to colour glass cups. The resulting artefacts were red in transmitted light and green in reflected light a sophistication not reproduced again until medieval times. There are many scientists today, who would argue they have been conducting research in the realms of the nanoscale since well before 1990. Nanotechnology mainly ‘concerned with materials and systems, whose structures and components exhibit novel and significantly improved physical, chemical and biological properties, phenomena and processes due to their nanoscale size. It is actively being pursued in many technical fields including aerospace, information management (computers), communications, electronics, materials sciences and medicine.¹³

According to researchers at the University of North Carolina, nanoparticles might enable a more targeted and effective delivery of anti-cancer drugs than current treatments and have the potential to reduce side effects associated with chemotherapy. The nanoparticles are designed at the molecular level to attack specific kinds of cancer without harming healthy cells; this is one example for the application of nanotechnology. They are many more that can change the life of human beings.

OBJECTIVES:

The main objectives of nano-drug delivery are the targeting of diseased cells and the release of drugs into specific portions of the body. By making use of the special properties of dendrimers, nanoshells, and nanotubes, we can destroy diseased cells without severe side effects and without causing harm to healthy cells within the body. The designing of nanodevices, nanomachines, nanoparticles as a delivery system are to control particle size, surface properties and release of pharmacologically active agents in order to achieve the site-specific action of the drug at the therapeutically optimal rate and dose regimen. ¹⁴

ADVANTAGES OF NANOPARTICLES: ^15,16

· Better drug utilization.

· Specific site of drug release.

· Greater patient convenience and/ or better patient compliance.

· Enhancement of therapeutic effectiveness of drug.

· Easy handling of Nanoparticles prepared in the powder form.

· Good control over size and size distribution.

· Good protection on the encapsulated drug.

· Longer clearance times increased therapeutic efficacy of drugs.

· Limiting side effects.

· Retention of drug at the active site.

· Reduces size of drug nanoparticles, allowing for greater dissolution of the drug in water and improved bioavailability.

· Significantly increases drug solubility in the supercritical solvent, improving productivity.

· Particle size and surface characteristics of nanoparticles can be easily manipulated to achieve both passive and active drug targeting after parenteral administration.

· Nanoparticles control and sustain release of the drug during the transportation and at the site of localization.

· Controlled release and particle degradation characteristics can be readily modulated by the choice of matrix constituents.

· Nanoparticles can be used by various routes of administration including oral, nasal, parenteral, intra-ocular etc.

FIG. 2. Proposed mechanism of particle formation at (a) low monomer Concentration and (b) high monomer concentration.

DISADVANTAGES OF NANOPARTICLES:

· Extensive use of poly vinyl alcohol as a detergent issue with toxicity.

· Limited targeted abilities.

· Discontinuation of therapy is not possible, when administration of drugs by intravenously.

· Expensive.

LIMITATIONS OF NANOPARTICLES:¹⁷

Their small size and large surface area can lead to particle particle aggregation, making physical handling of nanoparticles difficult in liquid and dry forms. In addition, small particles size and large surface area readily result in limited drug loading and burst release. These practical problems have to be overcome before nanoparticles can be used clinically or made commercially available.

POLYMERS USED IN PREPARATION OF NANOPARTICLES: ^18-22

In recent years, biodegradable polymeric nanoparticles have attracted considerable attention as potential drug delivery devices. Polymers applications in drug targeting to particular organs/tissues and their ability to deliver proteins and peptides through a oral route of administration. In spite of development of various synthetic, semi synthetic and natural polymers still enjoy their popularity in drug delivery. A polymer used in controlled drug delivery formulations, must be chemically inert, non-toxic and free of leachable impurities. It must also have an appropriate physical structure with minimal undesired aging and be readily processable.²³

The main advantage of these degradable polymers is that they are broken down into biologically acceptable molecules that are metabolized and removed from the body via normal metabolic pathways. However, biodegradable materials do produce degradation by products that must be tolerated with little or no adverse reactions within the biological environment.²⁴ some of the polymers are listed in Table 1.

PREPARATION OF NANOPARTICLES: ^35-37

Numerous methods are exist for the manufacture of nanoparticles allowing extensive modulation of their structure, composition and physicochemical properties. The choice of preparation methods essentially depends on the raw materials intended to be used and on the solubility characteristic of active compound to be associated with the particles. Regarding raw materials, criteria such as biocompatibility, the degradation behavior, choice of administrative route, desired release profile of drugs. Processes used for the preparation of polymeric nanoparticles summaries in Table 2. and mechanism of nanoparticle formation showed in figure 2.

EMULSION SOLVENT EVAPORATION:³⁸

This technique is based on a patent of Vanderhoff et al. The polymer is dissolved generally in a chlorinated solvent and emulsified in an aqueous phase containing surfactant. The most common surfactants used for this type of preparation are polysorbate, poloxamers and sodium dodecyl sulphates. Emulsification can be achieved by mechanical stirring, sonication or microfluidisation (high pressure homogenization through narrow channels). The organic solvent is then removed and pressure is reduced under these conditions, the organic diffuses in to aqueous phase and progressively evaporated.

SALTING OUT: ³⁹

The salting out techniques was introduced and patented by Blindschaedler et. al.® and Ibrahim et al.® In this method toxic solvents are avoided. Here acetone is used which can be easily removed by cross flow filtration in the final stage. The preparation methods consist of adding under mechanical stirring, an electrolyte saturated solution containing a hydrocolloid generally a PVA, as stabilizing and viscosity increasing agent to an acetone solution of polymer. This PVA is compatible with several electrolytes. The saturated aqueous solution prevents acetone from diffusing in to water by a salting out process after the preparation of O/W emulsion, sufficient water or aqueous solution of PEG is added to allow the complete diffusion of acetone in to the aqueous phase, thus inducing the formation of nanospheres.

Table 3. METHODS FOR CHARACTERIZATION OF NANOPARTICLES

PARAMETERS	METHODS
Particle size	Photon correlation spectrometry Transmission electron micro mission Scanning electron microscopy Scanned probe microscopy SEM combined with energy dispersive X- ray Spectrometry Franuhofer diffraction Dark field optical microscopy Dynamic light scattering Ultrasonic spectroscopy Turbidimetry Freeze fracture electron microscopy Atomic force microscopy
Molecular weight	Gel permeation chromatography
Density	Helium compression pycnometry
Crystallinity	X- ray diffraction Differential Scanning colorimetry
Surface charge	Electrophoresis Laser Doppler anemometry Zeta potential measurement
Hydrophobicity	Hydrophobic interaction chromatography Contact angle measurement
Surface properties	Static secondary ion mass spectrometry
Surface Element analysis	X- ray Photoelectron spectroscopy for chemical analysis( ESCA) Nuclear magnetic resonance Fourier transform infra red spectroscopy
Protein absorption	Two dimentional polyacrylamide gel electrophoresis.

Table 4. SUMMARY OF THERAPEUTIC APPLICATIONS OF NANOPARTICLES

APPLICATION	PURPOSE
Cancer therapy 53-55	Targeting, reduced toxicity, enhanced uptake of antitumor agents, improved in vitro and in vivo stability.
Intracellular Drug delivery	Target reticuloendothelial system for intracellular targeting infections
Prolonged systemic	Prolonged systemic drug effects
Per oral absorption	Enhanced bioavailability, protection from gastrointestinal enzymes
Ocular delivery	Improved retention of drug or reduced washout
DNA delivery	Enhanced delivery and significantly higher expression levels
Oligonucleotide delivery	Enhanced delivery of oligonucleotide
Tuberculosis	Reduced drug requirement and Multiple drug resistance
Infectious diseases	Nano vaccines in Malaria
HIV/AIDS ⁵⁶	Dendrimer nanotechnology is more effective.
Other application	Crosses blood brain barrier
	Improved absorption and permeation
	Enzyme immunoassays
	Radio imaging
	Oral delivery of peptides.
	Carriers of antigens and vaccines
	Carriers of diagnostic and therapeutic ⁵⁷
	Radioisotopes carriers of florescence for optical imaging
	Carriers of MRI contrast
	Carriers of infrared absorbers

SOLVENT DISPLACEMENT: ^40,41

This techniques was first described and patented by Fessi et al. in this process, polymer drug and optionally a lipophilic stabilizer (Phospho lipids) are dissolved in a semi polar water miscible solvent, such as acetone or ethanol. The solution is then poured under magnetic stirring in to a non solvent (usually water containing surfactant), which leads to preparation of nanospheres.

EMULSIFICATION DIFFUSION:⁴²

This method is a modification of salting out procedure. It was first described and patented by Leroux et al., wherein large amount of salts in aqueous phase are avoided to eliminate the problem of compatibility. Here, partially water soluble solvent is used, which is previously saturated in water to ensure the thermodynamic equilibrium. ( Saturated solution is the solution in which the excess amount of solute is added in solvent at study temperature and shaken with continuous stirring for few hours or container is kept for 24 hours for saturation) Polymer is dissolved in the water saturated solvent containing stabilizer and the organic phase is emulsified under agitation. The subsequent addition of water leads to diffusion in to the external phase, which in turn forms nanoparticles.

EMULSION POLYMERIZATION METHOD:

In this method, monomers are polymerized to form nanoparticles in an aqueous solution. Drug is incorporated either by being dissolved in the polymerization medium or by adsorption on to the nanoparticles after polymerization completed. The nanoparticle suspension is then purified to remove various stabilizers and surfactants employed for polymerization by ultracentrifugation and re-suspending the particles in an isotonic surfactant free medium. This technique has been reported for making polybutylcyanoacrylate or poly (alkylcyanoacrylate) nanoparticles. Nanocapsule formation and their particle size depend on the concentration of the surfactants and stabilizers used.

COACERVATION OR IONIC GELATION METHOD:⁴³

Much research has been focused on the preparation of nanoparticles using biodegradable hydrophilic polymers such as chitosan, gelatin and sodium alginate. Calvo and co-workers developed a method for preparing hydrophilic chitosan nanoparticles by ionic gelation. The method involves a mixture of two aqueous phases, of which one is the polymer chitosan, a di-block co-polymer ethylene oxide or propylene oxide (PEO-PPO) and the other is a polyanion sodium tripolyphosphate. In this method, positively charged amino group of chitosan interacts with negative charged tripolyphosphate to form coacervates with a size in the range of nanometer. Coacervates are formed as a result of electrostatic interaction between two aqueous phases, whereas, ionic gelation involves the material undergoing transition from liquid to gel due to ionic interaction conditions at room temperature.

AEROSOL FLOW REACTOR METHOD:

In this continuous particle preparation method, each of the generated droplets converts into one particle on drying. The aerosol flow reactor method has previously been used for the manufacture of micron sized drug particles. The experimental set-up was modified with an atomiser producing nanosized droplets and a collection device capable of separating nanosized particles from the carrier gas.

INTERFACIAL POLYMERISATION:⁴⁴

This involves polymerization of alkyl cyanoacrylates in an organic solvent containing water swollen micells binding to the formation of a polymer wall at the solvent in case of poly (alkyl cyanoacrylates) nanoparticles.

DESOLVATION: ⁴⁵

This solution of the polymer and drug to be entrapped are poured in to water, resulting in the spontaneous formation of nanoparticles of size between 90-200 nm. Polyacrylic nanoparticles can be prepared by dissolving relatively hydrophilic copolymer such as Eudragit R (RS) or Eudragit R (RL) in water miscible solvents such as acetone and ethanol.

CHARACTERISATION OF NANOPARTICLES: ^46,-50

Particle size and Particle size distribution are the most important characteristics of nanoparticle systems. They determine the in vivo distribution, biological fate, toxicity and the targeting ability of nanoparticle systems. In addition, they can also influence the drug loading, drug release and stability of nanoparticles.

SURFACE PROPERTIES OF NANOPARTICLES:

Surface charge of nanoparticles was determined by zeta potential measurement on a Malvern Zetasizer 2000 HS (Malvern, UK) with a flow measurement cell connected to a Mettler DL 25 (Mettler-Toledo, Giessen, Germany) auto-titrator via a circulating system. Within the 250 ml sample container at the titrator, 5–10 ml of nanoparticle samples were diluted with demineralized water to a final volume of 200 ml. The pH was adjusted to 3 by using HCl (1 N) before titration to pH 10 with NaOH (0.1 N). Measurements of the zeta-potential were carried out at 0.5 pH increments at 25 °C. The instrument was calibrated routinely with a 50 mV latex standard.

PARTICLE SIZE DETERMINATION:

Particle size determination was performed with two different methods, dynamic light scattering and scanning electron microscopy; a new sizing method was evaluated. The applied new analytical tool was an asymmetric flow fluid-flow fractionation unit with a multiangle light scattering detector.

DYNAMIC LIGHT SCATTERING (DLS):

DLS is also often referred as photon correlation spectroscopy (PCS) or quasielastic light scattering (QELS). In DLS experiments, the Brownian motion of the analytes within the dispersion medium is detected. More precisely, this is done by measuring the angular distribution of time-dependent scattered light intensity due to density and/or concentration fluctuations. From these fluctuations an auto correlation function is derived, which is inverted to determine the diffusion coefficient of the analyzed sample. The diffusion coefficient in turn represents the velocity of the analyte’s Brownian motion. The size of the analyte is now calculated based on the measured velocity with respect to two further factors having significant impact on this calculation; medium viscosity and temperature.

SCANNING ELECTRON MICROSCOPY (SEM):

Gelatin nanoparticles were analyzed by SEM to characterize the surface morphology of dry, non-dispersed nanoparticles. The pictures were taken with a field emission scanning electron microscope (JSM-6500 F, Jeol, Ebersberg, Germany) at 5.0 kV and a working distance of 9.7 mm. For sample preparation gelatin nanoparticles were dispersed in acetone at a concentration of 20 µg/mL and applied on a specifically polished sample grid. The samples were vacuum-dried over 12 hours and finally metallized with a 2 nm gold layer before microscopically analysis.

PHOTON CORRELATION SPECTROSCOPY:

Particle size was determined by photon correlation spectroscopy (PCS) on an ALV 5000 (Laser Vertriebsgesell- schaft mbH, Langen, Germany) at a scattering angle of 90° (sampling time 200 sec). Autocorrelation was performed using the “contin” method. For PCS measurements, all samples were diluted 50 fold in demineralized water, resulting in comparable viscosities. Hence, no corrections for the effect of the additives were necessary.

ATOMIC FORCE MICROSCOPY:

The size and surface morphology of the PLGA particles was analyzed by AFM Nanoscope IV Bioscope™ (Digital Instruments, Veeco) in tapping mode. Scanning was performed at a scan speed of 0.5 Hz with a resolution of 512 pixels. The tip loading force was minimized to avoid structural changes of the sample. Methods for characterization of nanoparticles summaries in Table 3.

DRUG LOADING: ⁵¹

Ideally, a successful nanoparticulate system should have a high drug loading capacity thereby reduce the quantity of matrix materials for administration. Drug loading can be done by two methods:

1. Incorporation method: Incorporating at the time of nanoparticles production.

2. Adsorption / Absorption technique: Absorbing the drug after formation of nanoparticles by incubating the carrier with a concentrated drug solution.

Drug loading and entrapment efficiency very much depend on the solid-state drug solubility in matrix material or polymer (solid dissolution or dispersion), which is related to the polymer composition, the molecular weight, the drug polymer interaction and the presence of end functional groups (ester or carboxyl). The PEG moiety has no or little effect on drug loading. The macromolecule or protein shows greatest loading efficiency, when it is loaded at or near its isoelectric point, when it has minimum solubility and maximum adsorption. For small molecules, studies show the use of ionic interaction between the drug and matrix materials can be a very effective way to increase the drug loading.

DRUG RELEASE:

To develop a successful nanoparticulate system, both drug release and polymer biodegradation are important consideration factors. In general, drug release rate depends on:

1. Solubility of drug.

2. Desorption of the surface bound/ adsorbed drug.

3. Drug diffusion through the nanoparticle matrix.

4. Nanoparticle matrix Erosion/degradation.

5. Combination of erosion/diffusion process.

APPLICATIONS OF NANOPARTICLES IN DRUG DELIVERY SYSTEM:⁵²

Anticancer therapy:

Conventional anticancer treatments are nonspecific to target killing of tumor cells, may induce severe systemic toxicity, and produce drug resistant phenotypic growth. An exciting potential use of nanotechnology in cancer treatments is the exploration of tumor-specific thermal scalpels to heat and burn tumors. O'Neal et al. (2004) observed in mice that selective photothermal ablation of tumor using near infrared-absorbing polyethylene-coated gold nanoshells of 130 nm inhibited tumor growth and enhanced survival of animals for up to 90 days compared with controls.

Gene therapy:

Attempts to cure genetic diseases by transfer of somatic cells transfected with normal genes gained popularity in the last two decades. In gene therapy a normal gene is inserted in place of an abnormal disease-causing gene using a carrier molecule. Conventional uses of viral vectors are associated with adverse immunologic, inflammatory reactions, and diseases in the host. In this regard Gopalan et al. (2004) found NP-based gene therapy to be effective in systemic gene treatment of lung cancer using a novel tumor suppressor gene. Chitosan, a polymer long used in gene therapy, was reported to have increased transfection efficiency and decreased cytotoxicity (Mansouri et al. 2006).

Imaging and diagnosis:

Molecular imaging is an important discipline in biology and medicine with ability to detect, quantify, and display molecular and cellular changes that happen in vitro and in vivo. Nanoparticle based probes have high levels of brightness, photostability, and absorption coefficients across a wide spectral range (Niemeyer 2001). Their abilities to monitor ultrastructural interactions on a continue make them ideal for applications in biology and disease. Furthermore, the potential for coating the NPs with antibodies, collagen, and other micromolecules makes them biocompatible for detection and diagnosis.

Drug delivery:

Site-specific-targeted drug delivery is important in the therapeutic modulation of effective drug dose and disease control. Targeted encapsulated drug delivery using NPs is more effective for improved bioavailability, minimal side effects, decreased toxicity to other organs, and is less costly. NP-based drug delivery is feasible in hydrophobic and hydrophilic states through variable routes of administration, including oral, vascular, and inhalation. Summaries in Table 4.

STABILITY OF NANOPARTICLES:

Nanoparticles, due to their small size degrade faster than larger micro spheres. The degradation pathways vary from polymer to polymer. However, the common pathways are erosion of polymer backbone and cleavage of the ester.

OPORTUNITIES AND CHALLENGES:^58,59

There are many technological challenges to be met, in developing the following techniques:

· Nano-drug delivery system that delivers large but highly localized quantities of drugs to specific areas to be released in controlled ways.

· Controlled release profiles, especially for sensitive drugs.

· Materials for nanoparticles that is biocompatible and biodegradable.

· Architectures/ structures, such as biomimetic polymers, nanotubes.

· Technologies for self assembly.

· Functions( active drug targeting, on command delivery, intelligent drug release devices/ bioresponsive triggered system, Self regulated delivery system, system interacting with body, smart delivery).

· Virus like systems for intracellular delivery.

· Nanoparticles to improve devices such as implantable devices/ nanochips for nanoparticles release, or multireservoir drug delivery chips.

· Nanoparticles for tissue engineering.

· Cells and genes targeting systems.

CONCLUSION:

Nanoparticles are one of the promising drug delivery system, which can be potential use in controlling and targeting drug delivery systems. It is a frontier area of future scientific and technological development. Significant efforts have been made on surface engineering of nanoparticles carriers to overcome various biological barriers and target to specific tissues sites. Nanoparticles are used for parenteral, oral, ocular and transdermal applications as well as used in cosmetics and hair care technologies, sustained release formulations and as a carriers for radio nucleotides in nuclear medicines.⁶⁰

The technology of nanoparticles being now quite well mastered, the main objectives is the improvement of their targeting properties following intravenous administration. Several strategies have been developed to achieve this goal, relying on the considerable progress made in the field of nanoparticles characterization and the growing understanding of their in vivo behavior. The strategy that is actually gaining a wide spreads interest is based on the design of nanoparticles with tailored surface characteristics. Moreover, the achievement of pharmaceutical nanoparticles formulation for human use depends on the successful exploitation of multidisciplinary knowledge.

REFERENCES :

1. Leroux J.C, Allémann E., De Jaeghere F., Biodegradable nanoparticles from sustained release formulations to improved site specific drug delivery, J.Control. Rel., 1996, 39,339-350.

2. Gurny R., Leroux J.C., Allémann E. and Doelker E. Nanoparticles for site specific drug delivery A new approach in pharmaceutical technology. Seminar of the Swiss Polymer Group, ETHZ, Zurich, Switzerland 1996.

3. Williams J., Lansdown R., Sweitzer R., et.al.,“Nanoparticle drug delivery system for intravenous delivery of topoisomerase inhibitors” J. Control. Rel., 2003, 91, 167-172.

4. Leroux J.C., Allemann, E., Da Jaeghere F., et.al., “Biodegradable nanoparticles From sustained release formulations to improved site specific drug delivery” J. Control. Rel., 1996, 39, 339-350.

5. Soppimath K.; Aminabhavi T.; Kulkarni A., Rudzinski W., “Biodegradable polymeric nanoparticles as drug delivery devices” J. Control. Rel. 2001, 70, 1-20.

6. Brannon-Peppas L. “Recent advances on the use of biodegradable microparticles and nanoparticles in controlled drug delivery” Int. J. Pharma., 1995, 116, 1-9.

7. Labhasetwar V., Song C.; Levy R. J. “Nanoparticle drug delivery system for restinosis” Adv. Drug Deli. Rev., 1997, 24, 63-85.

8. http://www.azonano.com

9. http://www.wikipedia.org

10. http://www.nanotech-now.com

11. Moghimi S.M., Adv. Drug Deli. Rev., 1995, 16, 183-193.

12. Matsumoto J., Nakada Y., Sakurai K., “Preparation of nanoparticles consisted of poly(L-lactide), poly(ethylene glycol), poly(L-lactide) and their evaluation in vitro” Int. J. Pharma. 1999, 185, 93-101

13. Couvreur P., Dubernet C., and Puisieux F., Controlled drug delivery with nanoparticles: current possibilities and future trends. Eur. J. Biopharm., 1995, 41, 2-13.

14. Kreuter J., Nanoparticles in Colloidal drug delivery systems. Kreuter (Eds.) Marvel Dekker, New York, 1994, 219-342.

15. Muller R. H., Radtke M., and Wissing S. A.. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv. Drug Deli. Rev., 2002, 54:131-155.

16. Panyam J., Labhasetwar V., Biodegradable nanoparticles for drug and gene delivery to cells and tissues, Adv. Drug Deli. Rev.,2003, 55, 329-347.

17. Mengi S.A., and Deshpande S.G., Jain N.K., Controlled and novel drug delivery, CBS publishers and distributors, 1997, 93.

18. Gurny R, Allémann E. and Doelker E., Nanocarriers: potential applications and limitations, Farm. Vest. 1995, 46,161-162.

19. Allémann E, Leroux J. and Gurny R., Polymeric nano and microparticles for the oral delivery of peptides and peptidomimetics, Adv. Drug Deli. Rev 1998, 34,171-189.

20. Alonso M.J., Nanoparticulate drug carrier technology, in Microparticulate systems for the delivery of proteins and vaccines, Cohen S. and Bernstein H. (Eds.) Marvel Dekker, New York, 1996, 203-242.

21. Jones M.C and Leroux J.C., Polymeric micelles - A new generation of colloidal drug carriers., Eur. J. Pharm. Biopharm. 1999, 48,101-111.

22. Kreuter J., Davis S. S., Wilson C. G., Polybutylcyanoacrylate nanoparticles for the delivery of norcholesterol. Int. J. Pharma.,1983, 16, 105- 113.

23. Kulkarni R.K., Pani L.K., J. Biomed. Mater. Res., 1967, 1, 11.

24. Kost J., Langer R. “Responsive polymeric delivery systems” Adv. Drug Deli.Rev., 2001, 46, 125-148.

25. Saltzman W. M., Olbricht W. L. “Building drug delivery into tissue engineering” Drug Discovery, 2002, 1, 177-186.

26. Rouge N., Leroux J.C., Cole E.T., Doelker E., Prevention of the sticking tendency of floating minitablets filled into hard gelatin capsule. Eur. J. Pharm. Biopharm., 1997, 43,165-171.

27. Chawla J. S., Amiji M. M., “Biodegradable poly(e-caprolactone) nanoparticles for tumor-targeted delivery of tamifoxen” Int. J. Pharma., 2002, 249, 127-138.

28. De Jaeghere F., Allémann E., Doelker E., Design of poly(ethylene oxide)-surface modified nanoparticles: critical pharmaceutical aspects, Pharm. Res., 1999, 16,859-866.

29. Allémann E., Leroux J.C. and Gurny R ,. Biodegradable nanoparticles of poly(lactic acid) and poly(lactic-co-glycolic acid), Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, New York, 1998,2 (3), 163-193.

30. Das S.K., Tucker I.G., Hill D.J., Ganguly N., Evaluation of poly(isobutylcyanoacrylate) nanoparticles for mucoadhesive ocular drug delivery, effect formulation variables on physicochemical characteristics of Nanoparticles; Pharm. Res., 1999, 12, 534-540.

31. Ammoury N., Fessi H., Devissaguet J.P., et.al., Effect on cerebral blood flow of orally administered indomethacin-loaded poly (isobutylcyanoacrylate) and poly (DL-lactide) nanocapsules. J. Pharm. Pharmacol., 1990, 42 558-561.

32. Al Khouri Fallouh N., Roblot T.L., Fessi H. et.al., Development of a new process for the manufacture of polyisobutyl-cyanoacrylate nanocapsules., Int. J. Pharm., 1986,28, 125-132.

33. Damge C., Michel C., Aprahamian M., New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as drug carrier, Diabetes, 1988,37, 246-251.

34. Couvreur P., Kante B., Grislain L., et.al., Toxicity of polyalkylcyanoacrylate nanoparticles, Doxorubicin loaded nanoparticles, J. Pharm. Sci., 1982, 71, 790-793.

35. De Jaeghere F., Allémann E., Leroux J.C, et.al., PLA-PEG nanoparticles: preparation and cell interaction studies., 24th Int. Symposium on Controlled Release of Bioactive Materials, Stockholm, Sweden, 1997.

36. Muller R.H., Colloidal carriers for controlled drug delivery and targeting, CRC Press, Boca Raton, 1991.

37. Bhave S., Sewak P., Saxena J., Eastern pharmacist, 1989, 32, 17.

38. Sahoo S., Labhasetwar V., Nanotech approaches to drug delivery and imaging, Drug Discovery Today, 2003, 8, 1112-1120.

39. Lamprecht A., Ubrich N., Pérez M. H., Biodegradable monodispersed nanoparticles prepared by pressure homogenization-emulsification., Int. J. Pharm., 1999, 184, 97-105.

40. Allemann E., Gurny R., Doelker E., Drug-loaded nanoparticles preparation methods and drug targeting issues. Eur. J. Pharm. Biopharm., 1993, 9, 173-191.

41. Fessi H., Dubrasquet M., Devissaguet J.H, et.al., Pharmacokinetic evaluation of indomethacin nanocapsules., Drug Des. Del.,1989, 4, 295-302.

42. Allémann E., Doelker E. and Gurny R., New approach for the preparation of nanoparticles by an emulsification-diffusion method. Eur. J. Pharm. Biopharm., 1995, 40,14-18

43. Coester C.,Langer K., Kreuter J., Gelatin nanoparticles by two step desolvation - a new preparation method, surface modifications and cell uptake., J. Microencapsulation, 2000, 17,187-193.

44. Bodmeier R., McGinity J. W., “Solvent selection in the preparation of poly(D,L-lactide) microspheres prepared by the solvent evaporation method” Int. J. Pharma., 1988, 43, 179–186.

45. Calvo P., et.al., Pharm. Res., 13, 1996, 311-315.

46. Langer K., Zimmer A., Kreuter J.,et.al. Characterisation of polybutylcyanoacrylate nanoparticles: I. Quantification of PBCA polymer and dextrans., Int. J. Pharm., 1994, 110, 21 – 27.

47. Mehnert W. and Mader K., Solid lipid nanoparticles: production, characterization and Applications, Adv. Drug Deli. Rev., 2001, 47:165-196.

48. Magenheim B. and Benita S., Nanoparticle characterization: a comprehensive physicochemical approach. Pharma Sciences, 1991, 1, 221-241.

49. Krause K. P.and Müller R. H., Production and characterisation of highly concentrated nanosuspensions by high pressure homogenization, Int. J. Pharm., 2001, 214, 21-24.

50. http://www.nanobio.com/

51. Allémann E., Gurny R. and Doelker E., In vitro extended-release properties of drug-loaded poly(D,L-lactic acid) nanoparticles produced by a salting-out procedure, Pharm. Res., 1993, 10,1732-1737.

52. Govendar T., Riley T., IIIUm L., PLA-PEG nanoparticles for site specific delivery: drug incorporation studies, J. Control. Rel., 2000, 64, 269-347.

53. Mukherji G., Murthy RSR and Miglani B.D., Int. J. Pharm., 1989, 50, 15.

54. Michaelis M., Vogel J.U., et.al., Cytotoxicity of aphidicolin and its derivatives against neuroblastoma cells in vitro: synergism with doxorubicin and vincristine., Anticancer Drugs, 2000, 11 (6), 479-485.

55. Couvreur P., Kante B., Lenaerts V., et.al. Tissue distribution of anticancer drugs associated to polyalkylcyanoacrylate nanoparticles. J. Pharm. Sci., 1980, 69,199-202.

56. Singla A. K., Garg A., and Aggarwal D. Paclitaxel and its formulations. Int. J. Pharm., 2002, 235:179-192.

57. Barratt G. Colloidal drug carriers: achievements and perspectives, Cell. Mol. Life Sc., 2003, 60:21-37.

58. http://www.infectioncontroltoday.com/

59. http://www.pharmacast.com/

60. http://www.usmedicine.com/

Received on 13.08.2009

Accepted on 12.09.2009

Research Journal of Pharmaceutical Dosage Forms and Technology. 1(2): Sept.-Oct. 2009, 80-86