International Journal of Innovative Pharmaceutical ...ijipsr.com/sites/default/files/articles/IJIPSRMN-66.pdf · CATEGORY EXAMPLES Nanotubes Nanowires Nanocrystals Nanobots Other

REVIEW ARTICLE Ramkrishna et.al / IJIPSR / 3 (4), 2015, 340-357

Department of Pharmaceutics ISSN (online) 2347-2154

Available online: www.ijipsr.com April Issue 340

NANOPARTICLES A PROMISING PHARMACEUTICAL

CARRIER: A COMPLETE REVIEW

1Ramkrishna Sen

*

University Department of Pharmaceutical Sciences, Utkal University, Bhubaneswar, Odisha –

751004, INDIA

Corresponding Author

Ramkrishna Sen

Research Scholar,

University Department of Pharmaceutical Sciences,

Utkal University

Bhubaneswar, Odisha, INDIA

Email: [email protected]

Phone: +91-8763836123

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

For the past few decades, there has been a considerable research interest in the area of drug

delivery using nanoparticles. Nanoparticles have been used as a physical approach to alter and

improve the pharmacokinetic and pharmacodynamic properties of various types of drug

molecules. They have been used to protect the drug entity in the systemic circulation, restrict

access of the drug to the chosen sites and to deliver the drug at a controlled and sustained rate to

the intended site of action. Various polymers have been used in the formulation of nanoparticles

for drug delivery research to increase therapeutic benefit, while minimizing side effects. These

nanoparticles have the capability to reverse multidrug resistance a major problem in

chemotherapy. In addition, studies are still required to determine the potential of nanotherapy

and some up to date idea on nanoparticle delivery system. This review is summarizing the

fundamentals of nanoparticles, nanoparticulate drug delivery system, and their applications.

Keywords: Nanoparticles, Classification, Drug delivery systems, Application in drug delivery.




INTRODUCTION

Nanoparticles are sub-nanosized colloidal structures composed of synthetic or semi-synthetic

polymers. 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 method of preparation, nanoparticles, nanospheres or nanocapsules

can be obtained. Nanocapsules are systems in which the drug is confined to a cavity surrounded

by a unique polymer membrane, while nanospheres are matrix systems in which the drug is

physically and uniformly dispersed. In recent years, biodegradable polymeric nanoparticles,

particularly those coated with hydrophilic polymer such as poly(ethylene glycol) (PEG),

polyethylene oxide, have been used as potential drug delivery devices because of their ability to

circulate for a prolonged period time target a particular organ, as carriers of DNA in gene therapy,

and their ability to deliver proteins, peptides and genes. The major goals in designing

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 [1, 2].

Fig.1: FESEM (Field-emission scanning electron microscopy) photograph of the

nanoparticles [3]

TYPES OF NANOPARTICLES

According to structural organization biodegradable polymeric nanoparticles are classified as

Nanocapsules and Nanospheres. The drug molecules are either entrapped inside or adsorbed on

the surface.




Fig 2: Types of polymeric nanoparticles - nanocapsules and nanospheres

NANOPARTICLE CLASSIFICATION

Table 1: Category of nanoparticles with examples

CATEGORY EXAMPLES

Nanotubes

Nanowires

Nanocrystals

Nanobots

Other nanoparticles

carbon, (fullerenes)

metals, oxides, semiconductors, sulfides, nitrides

semiconductors, metals, quantum dots insulators, magnetic materials

biochip, nubots

ceramic oxides, metals

NANOTUBE

Carbon nanotubes are allotropes of carbon with a cylindrical nanostructure. These cylindrical

carbon molecules have novel properties which make them potentially useful in many applications

in nanotechnology, electronics, optics, and other fields of materials science, as well as potential

uses in architectural fields. They exhibit extraordinary strength and unique electrical properties,

and are efficient thermal conductors. The diameter of a nanotube is on the order of a few

nanometers (approximately 1/50,000th of the width of a human hair), while they can be up to 18

centimeters in length (as of 2010). Nanotubes are categorized as single-walled nanotubes

(SWNTs) and multi-walled nanotubes (MWNTs). Nanotubes naturally align themselves into

"ropes" held together by Vander Waals forces [4].

NANOWIRE

A nanowire is a nanostructure, with the diameter of the order of a nanometer (10−9 meters).

Alternatively, nanowires can be defined as structures that have a thickness or diameter

constrained to tens of nanometers or less and an unconstrained length. Many different types of




nanowires exist, including metallic (e.g., Ni, Pt, Au), insulating (e.g., SiO2, TiO2) and

semiconducting (e.g., Si, InP, GaN, etc.). Molecular nanowires are composed of repeating

molecular units either organic or inorganic [4].

NANOCRYSTALS

Nanocrystal is any nanomaterial with at least one dimension ≤ 100nm and that is single

crystalline. Any particle which exhibits regions of crystallinity should be termed nanoparticle or

nanocluster based on dimensions. These materials are of huge technological interest since many

of their electrical and thermodynamic properties show strong size dependence and can therefore

be controlled through careful manufacturing processes. Crystalline nanoparticles made with

zeolite are used as a filter to turn crude oil onto diesel fuel at an ExxonMobil oil refinery in

Louisiana, a method cheaper than the conventional way. A layer of crystalline nanoparticles is

used in a new type of solar panel named SolarPly made by Nanosolar [4].

NANOBOTS

Nanorobotics is the technology of creating robots at or close to the microscopic scale of a

nanometer (10−9 meters). Nanorobotics refers to the still largely hypothetical nanotechnology

engineering discipline of designing and building nanorobots, devices ranging in size from 0.1-10

micrometers and constructed of nanoscale or molecular components. Potential applications for

nanorobotics in medicine include early diagnosis and targeted drug-delivery for cancer,

biomedical instrumentation surgery, pharmacokinetics monitoring of diabetes, and health care. In

such plans, future medical nanotechnology is expected to employ nanorobots injected into the

patient to perform work at a cellular level [4].

OTHER NANOPARTICLES

A quantum dot is a semiconductor whose excitons are confined in all three spatial dimensions. As

a result, they have properties that are between those of bulk semiconductors and those of discrete

molecules. Researchers have studied quantum dots in transistors, solar cells, LEDs, and diode

lasers. They have also investigated quantum dots as agent’s for medical imaging and hope to use

them as qubits. In layman's terms, quantum dots are semiconductors whose conducting

characteristics are closely related to the size and shape of the individual crystal. The main

advantages in using quantum dots is that because of the high level of control possible over the

size of the crystals produced, it is possible to have very precise control over the conductive

properties of the material [4].




PROPERTIES OF NANOPARTICLES

NANOPARTICLE SIZE

Nanoparticles are of great interest in drug delivery because of the comparable size of the

components in the human cells. If one has to go hand in hand with nature in treating the diseases

one needs to use the same scale, whether it is correcting a faulty gene, killing leprosy bacteria

sitting inside the body cells, killing a cancer cell, blocking the multiplication of viral genome,

repairing the cellular metabolism, or preventing wrinkles. Size matching is important in carrying

out any activity. It appears that nature, in making the biological systems, has extensively used

nanometer scale. The basic unit of the biological processes is the cell and the biochemical

reactions inside it. With the advent of nanoparticles it is now possible to selectively influence the

cellular processes at their natural scales.

NANOPARTICLE SURFACE

When nanoparticles are administered intravenously they are cleared by phagocytes from the

circulation [5]. Surface hydrophobicity of nanoparticles determines the amount of adsorbed blood

components, mainly proteins (opsonins). Binding of these opsonins onto the surface of

nanoparticles called opsonization acts as a bridge between nanoparticles and phagocytes. To

increase the success in drug targeting by nanoparticles, it is necessary to minimize the

opsonization and to prolong the circulation of nanoparticles in vivo. This can be achieved by

(i) Surface coating of nanoparticles with hydrophilic polymers or surfactants.

(ii) Formulation of nanoparticles with biodegradable copolymers with hydrophilic segments such

as polyethylene glycol (PEG), polyethylene oxide, polyoxamer, poloxamine etc.

In many studies show that PEG conformation at the nanoparticle surface is of great importance

for the opsonin repelling function of the PEG layer. PEG surfaces in brush-like and intermediate

configurations reduced phagocytosis [6, 7]. The zeta potential of a nanoparticle is commonly used

to characterize the surface charge property of nanoparticles [8]. It reflects the electrical potential

of particles and is influenced by the composition of the particle and the medium in which it is

dispersed. Nanoparticles with a zeta potential above (+/-) 30 mV have been shown to be stable in

suspension, as the surface charge prevents aggregation of the particles [9].

PREPARATION OF NANOPARTICLES

Nanoparticles can be prepared mostly by three methods:




DISPERSION OF PREFORMED POLYMERS

Dispersion of preformed polymers is a common technique used to prepare biodegradable

nanoparticles from poly (lactic acid) (PLA); poly (D, L-glycolide), PLG; poly (D, L-lactideco-

glycolide) (PLGA) and poly (cyanoacrylate) (PCA).

SOLVENT EVAPORATION METHOD

In solvent evaporation method, the polymer is dissolved in an organic solvent such as

dichloromethane, chloroform or ethyl acetate which is also used as the solvent for dissolving the

hydrophobic drug. The mixture of polymer and drug solution is then emulsified in an aqueous

solution containing a surfactant or emulsifying agent to make an oil in water (o/w) emulsion.

After the formation of stable emulsion, the organic solvent is evaporated either by reducing the

pressure or by continuous stirring. Particle size was found to be influenced by the type and

concentrations of stabilizer, homogenizer speed and polymer concentration [10]. In order to get

small particle size, a high-speed homogenization or ultrasonication may be used [11].

SPONTANEOUS EMULSIFICATION OR SOLVENT DIFFUSION METHOD

This method is modified version of solvent evaporation method. In this method, the water

miscible solvent along with a small amount of the water immiscible organic solvent is used as an

oil phase. Due to the spontaneous diffusion of solvents an interfacial turbulence is created

between the two phases leading to the formation of small particles. As the concentration of water

miscible solvent increases, a decrease in the size of particle can be achieved. Both solvent

evaporation and solvent diffusion methods can be used for hydrophobic or hydrophilic drugs. In

the case of hydrophilic drug, a multiple w/o/w emulsion needs to be formed with the drug

dissolved in the internal aqueous phase [12].

POLYMERIZATION METHOD

In this method, monomers are polymerized to form nanoparticles in an aqueous solution. Drug is

incorporated by being dissolved in the polymerization medium or by adsorption onto the

nanoparticles after polymerization completed. The nanoparticle suspension is then purified to

remove various stabilizers and surfactants employed for polymerization by ultracentrifugation and

resuspending the particles in an isotonic surfactant-free medium. This technique has been reported

for making polybutylcyanoacrylate or poly (alkylcyanoacrylate) nanoparticles [13, 14].

Nanocapsule formation and their particle size depends on the concentration of the surfactants and

stabilizers used [15].




COACERVATION OR IONIC GELATION METHOD

Most of the research has been aimed on the preparation of nanoparticles using biodegradable

hydrophilic polymers such as chitosan, sodium alginate and gelatin. 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 (PEOPPO) and the other is a polyanion sodium

tripolyphosphate. In this method, the 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 [16, 17].

PRODUCTION OF NANOPARTICLES USING SUPERCRITICAL FLUID

TECHNOLOGY

Conventional methods such as solvent extraction-evaporation, solvent diffusion and organic phase

separation methods require the use of organic solvents which are hazardous to the environment as

well as to physiological systems. So, the supercritical fluid technology has been investigated as an

alternative to prepare biodegradable micro and nanoparticles. Supercritical fluids are

environmentally safe. A supercritical fluid can be generally defined as a solvent at a temperature

above its critical temperature, at which the fluid remains a single phase regardless of pressure.

The most common processing techniques involving supercritical fluids are supercritical anti-

solvent and rapid expansion of critical solution.

The process of supercritical anti-solvent employs a liquid solvent, eg methanol, which is

completely miscible with the supercritical fluid, to dissolve the solute to be micronized, at the

process conditions, because the solute is insoluble in the supercritical fluid, the extract of the

liquid solvent by supercritical fluid leads to the instantaneous precipitation of the solute, resulting

the formation of nanoparticles. Rapid expansion of critical solution differs from the SAS process

in that its solute is dissolved in a supercritical fluid (such as supercritical methanol) and then the

solution is rapidly expanded through a small nozzle into a region lower pressure, Thus the solvent

power of supercritical fluids dramatically decreases and the solute eventually precipitates. This

technique is clean because the precipitate is basically solvent free. Rapid expansion of critical

solution and its modified process have been used for the product of polymeric nanoparticles [18-

20].




POLYMERS USED IN PREPARATION OF NANOPARTICLES

The polymers should be compatible with the body in the terms of adaptability (non-toxicity) and

non-antigenicity and should be biodegradable and biocompatible.

Table 2: Polymers used in preparation of nanoparticles [21-27]

EQUIPMENTS USED IN PREPARATION OF NANOPARTICLES

Homogenizer

Ultra Sonicator

Mills

Spray Milling

Supercritical Fluid Technology

Electrospray

Ultracentrifugation

Nanofiltration

DRUG LOADING

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:

Incorporating at the time of nanoparticles production (incorporation method). Absorbing the drug

after formation of nanoparticles by incubating the carrier with a concentrated drug solution

(adsorption or absorption technique). Drug loading and entrapment efficiency very much depend

on the solid-state drug solubility in matrix material or polymer, which is related to the polymer

composition, the molecular weight, the drug polymer interaction and the presence of functional

groups. 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 [28-31].

DRUG RELEASE

Drug release depends on following factors:

Solubility of drug.

Desorption of the surface bound or adsorbed drug.

Drug diffusion through the nanoparticle matrix.

Nanoparticle matrix erosion or degradation.

Natural polymers Chitosan, Sodium alginate, Gelatin, Albumin, Lectins, Legumin

Natural polysaccharides Alginate, Dextran, Chitosan, agarose

Synthetic polymers

Polylactides(PLA), Polyglycolides(PGA), Poly(lactide co-glycolides)

(PLGA), Polyanhydrides, Polyorthoesters, Poly(methyl methacrylate),

Poly(vinyl alcohol), Poly(acrylic acid), Poly acrylamide, Poly(ethylene

glycol), Poly(methacrylic acid), Polycyanoacrylates, Polycaprolactone, Poly

glutamic acid, Poly malic acid, Poly(N-vinyl pyrrolidone)




Combination of diffusion or erosion process.

Thus solubility, diffusion, erosion and biodegradation of the matrix materials govern the release

process. In the case of nanospheres, where the drug is uniformly distributed, the release occurs by

diffusion or erosion of the matrix under sink conditions. It is evident that the method of

incorporation has an effect on release profile. If the drug is loaded by incorporation method, the

system has a relatively small burst effect and better sustained release characteristics. If the

nanoparticle is coated by polymer, the release is then controlled by diffusion of the drug from the

core across the polymeric membrane. The release rate can also be affected by ionic interaction

between the drug and addition of auxillary ingredients [32-33].

Different methods of evaluation for release of drugs:

Side-by-side diffusion cells.

Dialysis bag diffusion technique.

Reverse dialysis bag technique.

Agitation followed by ultracentrifugation or centrifugation.

Ultra-filtration or centrifugal ultra-filtration techniques.

CHARACTERIZATION OF NANOPARTICLES

Drug release is affected by particle size. Smaller particles have larger surface area, so, most of the

drug associated would be at or near the particle surface, leading to fast drug release. Larger

particles have large cores which allow more drugs to be encapsulated and slowly diffuse out.

Smaller particles also have greater risk of aggregation of particles during storage and

transportation of nanoparticle dispersion. It is always a challenge to formulate nanoparticles with

the smallest size possible but maximum stability [34, 35].

PARTICLE SIZE

Photon correlation spectroscopy (PCS): For smaller particle.

Laser diffractrometry: For larger particle.

Electron microscopy (EM): Required coating of conductive material such as gold & limited to dry

sample.

Transmission electron microscopy (TEM): Easier method & Permits differentiation among

nanocapsule & nanoparticle.

Atomic force microscope: High-resolution microscope.

Laser force microscope: High-resolution microscope.

Scanning electron microscope: High-resolution microscope.




DENSITY

Helium or air using a gas pycnometer.

Density gradient centrifugation.

MOLECULAR WEIGHT

Gel permeation chromatography using refractive index detector.

STRUCTURE & CRYSTALLINITY

X-ray diffraction.

Differential scanning calorimetry.

Differential thermal analysis.

Thermogravimetry.

SPECIFIC SURFACE AREA

Sorptometer.

SURFACE CHARGE & ELECTRONIC MOBILITY

Surface charge of particle can be determined by measuring particle velocity in electrical field.

Laser Doppler Anemometry tech. for determination of Nanoparticles velocities.

Surface charge is also measured as electrical mobility.

Charged composition critically decides bio-distribution of nanoparticle.

Zeta potential can also be obtain by measuring the electronic mobility.

SURFACE HYDROPHOBICITY

Important influence on interaction of nanoparticles with biological environment.

Several methods have been used

1. Hydrophobic interaction chromatography.

2. Two phase partition.

3. Contact angle measurement.

IN VITRO RELEASE

Diffusion cell

Recently introduce modified Ultra-filtration tech.

Media used: phosphate buffer

NANOPARTICLE YIELD

%yield = Actual weight of product

Total weight of excipient & Drug

DRUG ENTRAPMENT EFFICIENCY




Drug entrapment % = Mass of drug in nanoparticle

Mass of drug used in formulation

APPLICATION OF NANOPARTICULATE DELIVERY SYSTEMS

In healthcare or medical science nanoparticles and nanoformulations have already been applied as

drug delivery systems with great success and nanoparticulate drug delivery systems have still

greater potential for many applications.

Targeted drug delivery.

Alternative drug and vaccine delivery mechanisms (e.g. inhalation, oral in place of

injection).

Bone growth promoters.

Cancer treatments.

Biocompatible coatings for implants.

Sunscreens / cosmetics.

Biolabeling and detection.

Carriers for drugs with low water solubility.

Fungicides.

MRI contrast agents.

New dental composites.

Biological binding agents.

Antiviral, antibacterial, anti-spore non-chemical creams.

Powders (using surface tension energy on the nanoscale to destroy biological particles).

LIST OF THE SELECTED DRUGS AS NANO DRUG DELIVERY SYSTEM

Table 3

Name of the drug Purpose Ref.

Clonazepam To determine the drug loading capacity & drug release. 36

Morphine To study antinociceptive activity and blood brain delivery. 37

Phenformin For targeting both cancer cells and cancer stem cells 38

Adriamycin To enhance effective delivery of Adriamycin. 39

Dexamethasone To increase the amount of drug release with respect to pure drug. 40

Tamoxifen To increase the local concentration of tamoxifen in estrogen receptor

positive breast cancer cells.

41

Cisplatin For the treatment of non-small cell lung carcinoma 42

Cyclosporin A To form stable suspention of submicron particles of Cyclosporin A. 43

Praziquantel To study the effect of formulation variables on size distribution. 44

Paclitaxel For lung-targeted delivery 45

Aspirin Capable of releasing the drug in a slow sustained manner. 46

X 100




Docetaxel For effective delivery of drug to solid tumors. 47

Vinorelbine For treating non-small cell lung cancer 48

Estradiol To increase oral bioavailability of Estradiol. 49

Cyproterone To improve skin penetration of the poorly absorbed drug cyproterone. 50

Curcumin For coating curcumin onto a metal stent by electrophoretic deposition

thereby avoiding problem with restenosis after percutaneous coronary

intervention.

51

Gemcitabine

triphosphate

For lung cancer and pancreatic cancer therapy 52

Ropivacaine To decrease the systemic toxicity of ropivacaine. 53

Doxorubicin To improve oral bioavailability of Doxorubicin. 54

Didanosine For sustained release of Didanosine. 55

Lamivudine Increased bioavailability of lamivudine is observed when tested in AIDS

patients.

56

Simvastatin To enhance effective delivery of poorly water soluble drug simvastatin. 57

Amphotericin B To improve oral bioavailability and to show reduced nephrotoxicity

compared to intravenous fungizone.

58

Rifampicin To formulate Rifampicin for aerosol delivery in a dry powder,Which is

suited for self stability, effective dispersibility and extended release with

local lung and systemic drug delivery.

59

Curcumin To enhance the transport of curcumin to brain and to enhance the delivery

system to cross the BBB.

60

SOME CLINICALLY USED NANOFORMULATIONS [61, 62]

Table 4

API Brand name Company

Methotrexate MTX-HAS (Albumin-methotrexate) -

L-asparaginase Oncaspar (PEG-L-asparaginase) Enzon Pharmaceuticals Inc., NJ,

USA

Paclitaxel Abraxane (Albumin-paclitaxel) Abraxis BioScience, LosAngeles,

CA, USA; Astra Zeneca, London,

UK

Paclitaxel Genexol-PM (PEG-poly(l -lactic acid)) Samyang

Doxorubicin Daunoxome Gilead sciences

Cisplatin NC-6004 (PEG-poly(glutamic acid)) Nano carrier

SN-38 NK012 (PEG-poly(glutamic acid)) Nippon Kayaku

Camptothecin CRLX101 (PEG-cyclodextrin) Cerulean Pharma

Doxorubicin SP1049C (Pluronic F127 and L61) Supratek Pharma

Amphotericin B Ambisome Gilead sciences

Amphotericin B Amphotec Alza

Amphotericin B Abelect Elan

Sirolimus Rapamune Elan/Wyeth

siRNA (Targeting

moiety:

Transferrin)

CALAA-01 Cyclodextrin-basedpolymeric

NP)

Calando Pharma

Docetaxel

(Targeting

moiety: Peptide)

BIND-014 (PEGylated PLGA nanoparticle) BIND Biosciences




Aprepitatnt Emend Elan/Merck

Fenofibrate Tricor Elan/Abbot

Fenofibrate Triglide First Horizon Pharmaceuticals

CONCLUSION

The use of nanotechnology in developing nanocarriers for drug delivery is bringing lots of

aspiration and interest in the field of drug delivery research. Nanoparticles have been recognized

as extremely useful carrier systems for targeted drug delivery. Nanoparticles as drug delivery

systems are designed to improve the pharmacological and therapeutic properties of conventional

drugs. The incorporation of drug molecules into nanoparticles can protect a drug against

degradation as well as offers possibilities of targeting and controlled release. They can reduce the

toxicity and other adverse side effects in normal tissues by accumulating drugs in target sites. The

major applications of nanoparticles in medicine are diagnosis and target therapy, however, their

wider use is still the future. Many nanoparticle based formulations are already in the market and

many are under the clinical trials to get the approval. Thus, nanoparticle drug delivery systems

may change the entire drug therapy strategy and bring it to a new height in near future.

ACKNOWLEDGEMENT

The author is highly thankful to the University Department of Pharmaceutical Sciences, Utkal

University, Odisha for their kind support.

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