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77| P a g e International Standard Serial Number (ISSN): 2319-8141

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International Journal of Universal Pharmacy and Bio Sciences 5(6): November-December 2016

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.96***

ICV 5.13***

Pharmaceutical Sciences REVIEW ARTICLE …………!!!

NANOCAPSULE: REVIEW ARTICLE

S. M. Sonawane1*

, A.B.Darekar2, R.B. Saudagar

3

1*Department of Pharmaceutics, R. G. Sapkal College of Pharmacy, Anjaneri,

Nashik-422213, Maharashtra, India. 2Department of Pharmaceutics, R. G. Sapkal College of Pharmacy, Anjaneri,

Nashik-422213, Maharashtra, India. 3Department of Pharmaceutical Chemistry, R. G. Sapkal College of Pharmacy, Anjaneri,

Nashik- 422213, Maharashtra, India.

KEYWORDS:

Natural polymers,

Synthetic polymers,

Super critical fluid

technology, Saltingout,

Dialysis method.

For Correspondence:

Saurabh M. Sonawane*

Address:

Department of

Pharmaceutics, R. G.

Sapkal College of

Pharmacy, Anjaneri,

Nashik-422213,

Maharashtra, India.

ABSTRACT

Nanotechnology is the science of small. Nano derives from the Greek

word “Nano” which means dwarf small. Nano capsules are vesicular

systems in which the drug is confined to a cavity consisting of an inner

liquid core surrounded by a polymeric membrane. Nano capsules having

various advantages and disadvantages. Preparation of Nano capsules can

be used as a two types of polymers 1) Natural polymers 2) Synthetic

polymers. Nano capsules are prepared by different method those are a)

Solvent evaporation b) Nano precipitation c) emulsification/Solvent

diffusion d) Salting out e) Dialysis f) Super critical fluid technology.

Different characterization and evaluation tests are performed to Nano

capsules.

78 | P a g e International Standard Serial Number (ISSN): 2319-8141


INTRODUCTION:

Nanotechnology is the science of small Nano derives from the Greek word “Nano” which means

dwarf small. It comprises Nano technological development on the nanometer scale, usually 0.1 to

100nm. Nano materials have found many important applications in biomedical, pharmaceutical,

electronic and molecular diagnostic fields. The polymeric nanoparticals (PNPs) are prepared from

biocompatible and biodegradable polymers in size between 10-1000nm.Where the drug is

dissolved, entrapped, encapsulated (or) attached to a nanoparticals matrix. A nanocapsule is a

nanoscale shell made from a nontoxic polymer. They are vesicular systems made of a polymeric

membrane which encapsulates an inner liquid core at the nanoscale. Nanocapsules have many uses,

including promising medical applications for drug delivery, food enhancement, neutraceuticals, and

for self-healing materials. The benefits of encapsulation methods are for protection of these

substances to protect in the adverse environment, for controlled release, and for precision targeting.

Nanocapsules can potentially be used as MRI guided nanorobots or nanobots, although challenges

remain. Nanocapsule structure consists of nanovesicular system that is formed in a core-shell

arrangement. The shell of a typical nanocapsule is made of a polymeric membrane or coating. The

type of polymers used is of biodegradable polyester, as nanocapsules are often used in biological

systems. Poly-e-caprolactone (PCL), poly(lactide) (PLA), and poly(lactide-co-glicolide) (PLGA)

are typical polymers used in nanocapsule formation Other polymers include

thiolatedpoly(methacrylic acid) and poly(N-vinyl Pyrrolidone) As synthetic polymers have proven

to be more pure and reproducible when compared naturally occurring polymers, they are often

preferred for the construction nanocapsules. However, some natural occurring polymers such

as chitosan, gelatin, sodium alginate, and albumin are used in some drug delivering nano

capsules. Other nano capsule shells include liposomes, along with polysaccharides and saccharides.

Polysaccharides and saccharides are used due to their non-toxicity and biodegradability. They are

attractive to use as they resemble biological membranes.

The core of a nanocapsule is composed of an oil surfactant that is specifically selected to coordinate

with the selected drug within the polymeric membrane. The specific oil used must be highly soluble

with the drug, and non-toxic when used in a biological environment. The oil-drug emulsion must

have low solubility with the polymer membrane to ensure that the drug will be carried throughout

the system properly and be released at the proper time and location. When the proper emulsion is

obtained, the drug should be uniformly dispersed throughout the entire internal cavity of the

polymeric membrane.

https://en.wikipedia.org/wiki/Polymer

https://en.wikipedia.org/wiki/Nanorobotics

https://en.wikipedia.org/wiki/Chitosan

https://en.wikipedia.org/wiki/Gelatin

https://en.wikipedia.org/wiki/Sodium_alginate

https://en.wikipedia.org/wiki/Albumin

https://en.wikipedia.org/wiki/Liposome

https://en.wikipedia.org/wiki/Polysaccharide

https://en.wikipedia.org/wiki/Saccharides



Structure:

The typical size of the nanocapsule used for various applications ranges from 10-1000 nm.

However, depending on the preparation and use of the nanocapsule, the size will be more

specific.Nanocapsule structure consists of nanovesicular system that is formed in a core-shell

arrangement. The shell of a typical nanocapsule is made of a polymeric membrane or coating. The

type of polymers used is of biodegradable polyester, as nanocapsules are often used in biological

systems. Poly-e-caprolactone (PCL), poly(lactide) (PLA), and poly(lactide-co-glicolide) (PLGA)

are typical polymers used in nanocapsule formation Other polymers include

thiolatedpoly(methacrylic acid) and poly(N-vinyl Pyrrolidone). As synthetic polymers have proven

to be more pure and reproducible when compared naturally occurring polymers, they are often

preferred for the construction nanocapsules. However, some natural occurring polymers such

as chitosan, gelatin, sodium alginate, and albumin are used in some drug delivering nanocapsules.

Other nanocapsule shells include liposomes, along with polysaccharides and saccharides.

Polysaccharides and saccharides are used due to their non-toxicity and biodegradability. They are

attractive to use as they resemble biological membranes.

The core of a nanocapsule is composed of an oil surfactant that is specifically selected to coordinate

with the selected drug within the polymeric membrane. The specific oil used must be highly soluble

with the drug, and non-toxic when used in a biological environment. The oil-drug emulsion must

have low solubility with the polymer membrane to ensure that the drug will be carried throughout

the system properly and be released at the proper time and location. When the proper emulsion is

obtained, the drug should be uniformly dispersed throughout the entire internal cavity of the

polymeric membrane.

Fig: Structure of Nano capsules

https://en.wikipedia.org/wiki/Chitosan

https://en.wikipedia.org/wiki/Gelatin

https://en.wikipedia.org/wiki/Sodium_alginate

https://en.wikipedia.org/wiki/Albumin

https://en.wikipedia.org/wiki/Liposome

https://en.wikipedia.org/wiki/Polysaccharide

https://en.wikipedia.org/wiki/Saccharides



Figure . a) Chemical reactions, self-assembly and schematic structures of various nanocapsules,

b) procedure for encapsulating drug and iron oxide into nanocapsules and events triggered

by magnetic heating: volume shrinkage, core collapse, heat conduction, and drug release.(10-12)

POLYMERS USED IN PREPARATION OF NANO PARTICLES (1,2,14)

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

(non-antigen city) and should be biodegradable and biocompatible.



Natural polymers

The most commonly used natural polymers in preparation of polymeric Nano-particles are

1) Chitosan

2) Gelatin

3) Sodium alginate

4) Albumin

Synthetic polymers

1) Polylactides(PLA)

2) Polyanhydrides

3) Polyglycolides(PGA)

4) Poly orthoesters

5) Poly lactide co-glycolides(PLGA)

6) Poly glutamic acid

7) Poly cyanoacrylates

8) Poly malic acid

9) Poly carolactone

10) Poly methacrylic acid

11) Poly(N-Vinyl pyrrolidone)

12) Poly(ethylene glycol)

13) Poly (methyl methacrylate)

14) Poly acrylamide

15) Poly (vinyl alcohol)

16) Poly (acrylic acid

MECHANISMS OF DRUG RELEASE

The polymeric drug carries deliver the drug at the tissue site by any one of the three general physic-

chemical mechanisms.

1) By the swelling of the polymer Nano particles by hydration followed by release through

diffusion.

2) By an enzymatic reaction resulting in rupture (or) cleavage (or) degradation of the polymer at

site of delivery, there by releasing the drug from the entrapped inner core.

3) Dissociation of the drug from the polymer and its de adsorption (or) release from the swelled

Nano particles.

Various methods for preparation of nanocapsules:

1.Polymerization method



2.Arc-discharge method

3.Emulsion polymerization

4.Encapsulation of nanocapsules

5.Nano precipitation method

6.Emulsion-diffusion method

7.Double emulsification method

8.Emulsion-coarcervation method

9 Polymer-coating method

10.Layer-by-layer method

Preparation method of nanocapsules:

Nanocapsules composition:

Nanocapsules comprise of an oily or an aqueous core, which is surrounded by a thin polymer

membrane. Two technologies have been utilized for obtaining such nanocapsules: the interfacial

polymerization for monomer and the interfacial nano deposition method for preformed polymer.

The development tin technologies in pharmaceutical research field has been spread widely in

designing of the tumor targeting nano-scale vectors, capable of delivering radionuclides. Among

them, the lipid nanocapsules(LNCs) as a nanovector-based formulation with biomimetic properties

shows to be an applicable therapeutic option for HCC (Hepatocellular carcinoma) treatment. It is

composed of a liquid lipid core, which is surrounded by a shell of tension active. LNCs results in

the encapsulation of a lipophilic composite of radioactive Rhenium-188.The capsules are

constructed in several steps layer bilayer:

1. In capsule preparation, the positively or negatively surface charged polymer addition comprises

the first actual step.

2. Second step utilizes layer by layer self-assembling to form an ultrathin polymer film. Each new

layer has the opposite charge to that of previous layer. The polymer coating is thrown by

electrostatic gravities. They create shells of well ordered polyelectrolyte complex layers. This will

result in capsule walls with 4 to 20 layers with a thickness of 8-50 nm. The completed capsules will

possess precise properties. Additional functions are often taken on by their surfaces for instance to

provide connections for antibodies to dock.

It is optional that in the case of demand, the core of the capsule can be removed or various

substances can fill the empty capsule shells.

Researchers suggest a number of approaches for preparing nanocapsules, but mostly four different

approaches are utilized, namely: methods of interfacial polymerization or interfacial precipitation or

interfacial nano deposition, and self-assembly methods. For designing the optimized drug carrier



systems, each procedure offers its advantages and disadvantages. Nanocapsules can also be

prepared according to the nano precipitation method. The preparation of nanocapsules involving the

organic phase which constitutes solvent, polymer, oil, and drug is penetrated into the pores of an

ultrafiltration membrane via the filtrate side and then it is pressed. The aqueous phase containing

water and surfactant circulates inside the membrane module, and removes the nano capsules

forming at the pore outlets.

NANO PRECIPITATION METHOD:

Nano precipitation method is also called solvent displacement (or) interfacial deposition. In this

method Nano capsule synthesis need both solvent and non-solvent phases. The solvent phase

essentially consisting of a solution in a solvent (or) in a mixture of solvents (i.e.Ethanol, Acetone,

Hexane, Methylene chloride(or) dioxane) of a film-forming substance such as a polymer (synthetic,

semi-synthetic(or)natural occurring polymer).The active substance(oil) a liphophilic tension active

and active substance solvent (or) oil solvent. If there are needed. In this preparation solvent phase

used as a organic medium and non-solvent phase used as a water. This method of preparation

commonly used polymers are biodegradable polyesters, especially poly-e-caprolactone (PCL), poly

lactide (PLA) and poly(lactide-co-glicolide) (PLGA). Eudragit can also be used as many other

polymers such as poly(alkylcyanoacrylate)(PACA).In this method of preparation of can be used as

solvents, non-solvents ,polymers, oils, surfactants and stabilizer agents used in this method.

In the nanopreparation method, the nanocapsules are obtained as a colloidal suspension formed

when the organic phase is added slowly and with moderate stirring to the aqueous phase. Besides

the liphophilic active substance, the nanocapsule core is composed by a water/oil surfactants and oil

chooser having as criterion the highest possible drug solubility absence of toxicity, low solubility of

oil in the polymer and vice-versa and the absence of risk of polymer degradation. Although other

oils such as benzyl benzoate, benzyl alcohol, oleic acid, ethyloleate, argon oil , sunflower seed oil

and soya bean oil have not been used frequently they cannot the less give good results. Regarding

water/oil surfactants, sorbitan ester and phospholipids are preferred. Suggested composition for

preparation of Nano capsule by the Nano precipitation method.

Material Suggested composition

Active substance 10-25mg

Polymer 0.2-0.5% of solvent

Oil 1.0-5.0% of solvent

W/O Surfactant 0.2-0.5% of solvent

Solvent 25 ml

Stabilizer agent 0.2-0.5% of non-solvent

Non-solvent 50ml



Fig 2: Nano precipitation method

Example of drugs used for preparation of nano precipitation method

1.Usnic acid, pereiraetal

2.Indomethacin(ingredient),Pohlmann

3. Diclofenac schaffazick

4. Atovaquone(In) cauchetier

5. Melatonin schaffazick

Nanocapsules in Targeting Drug Delivery System:

The possibility of silencing miRNA was investigated using nuclease-resistant locked nucleic acid

(LNA) conjugated-lipid nanocapsules (LNCs) as miRNA-targeted nanomedicines in U87MG

glioblastoma (GBM) cells. Treatment of LNA-LNC complexes with U87MG cell in an in vitro

model showed that marked reduction of miR-21 expression and it was assessed by RTqPCR [9].

The isoflavonegenistein (GEN) is a natural product and can be used in skin cancer treatment.

But it has limited clinical use due to its high lipophilicity and chemical instability. Therefore, GEN

loaded-PLA nanocapsules (GEN-NC) were developed by interfacial deposition of preformed

polymer and were incorporated into semi-solid formulations and permeation experiments were

performed using porcine ear skin.

Permeation experiments showed that higher amount of GEN reaches deeper layers of the skin. This

study indicated that GEN-NC semi-solid gel formulation might be effective for skin cancer

treatment. The anti-glioma effect of trans-resveratrol-loaded lipid-core nanocapsules (RSV-LNC)

was investigated based on in vitro (C6 glioma cell line) and in vivo (brain-implanted C6 cells)

models of the disease. The in vitro study indicated that RSV-LNC decreased the viability of C6

glioma cells to a higher extent than resveratrol in solution.

In the in vivo studies, when RSV-LNC (5 mg/kg/day, i.p.) treated with brain implanted C6 tumors

cells for 10 days exhibited a marked decrease in tumor size. This study suggested that RSV-LNC

nano formulation could be effective in the treatment of gliomas. The plitidepsin-polyamino acid

nano capsules were prepared using solvent displacement technique. The nano capsules showed an

Organic phase Aqueous phase Solvent

elimination



average size of 200nm, a negative zeta potential and a large capacity for the encapsulation of

plitidepsin. In vivo studies indicated that plitidepsin-polyamino acid nanocapsules provided the

drug with a prolonged blood circulation and reduced toxicity in cancer-induced mice model. This

study showed that plitidepsin- polyamino acid nanocapsules might be useful in nano-oncological

therapy.

The antiproliferative effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNC) was

investigated in C6 and U138-MG glioma cells. IndOH-LNC reduced the cell viability by inducing

apoptotic cell death in C6 and U138-MG glioma cell lines. IndOH-LNC also induced G0/G1 and/or

G2/M phase arrest and IndOH-LNC promoted glioblastomamultiforme (GBM) cell differentiation

and downregulation of nestin and CD133. This study suggested that indomethacin-loaded lipid-core

nanocapsules (IndOH-LNC) could be effective in controlling of gliomagrowth. [6,7,8]



Application of nanotechnology in pharmaceutical field(1,2,14)

Nano suspensions

They are colloidal dispersion of Nano sized drug particles that are produced by suitable method and

stabilizer.

Nano Emulsion

Nano emulsion can be defined as oil/Water emulsions with mean droplet diameters ranging from

50-1000nm. Usually, the average droplets size in between 100 -500nm.

NANO TECHNOLOGY

NANO CAPSULES NANO SPHERE

NANO

SUSPENSIONS

NANO

EMULSION

NANO

PARTICLES



Nano particles

Nano particles are defined as solid, sub-micron-sized drug carriers that may (or) may not be

biodegradable. The term Nano particle is a collective name for both Nano spheres and Nano

capsules.

Nano spheres

Nano spheres have a matrix type of structure. Drug may be absorbed at the sphere surface (or)

Encapsulated within the particles.

Nano capsules

Nano capsules are vesicular systems in which the drug is confined to a cavity consisting of an inner

liquid core surrounded by a polymeric membrane. In this case the active substances are usually

dissolved in the inner core but may also be adsorbed to the capsule surface.[4,5,6,7,8,]

ADVANTAGES OF POLYMERIC NANO PARTICLES

1) Polymeric Nano particles can be easily incorporated into other activities related to drug delivery.

such as tissue engineering.

2) Increases the stability of any volatile pharmaceutical agent, easily and cheaply fabricated in large

quantities by a multitude of method.

3) Delivers a higher concentration of pharmaceutical agent to a desired location.

4) Increases the stability of any volatile pharmaceutical agents, easily and cheaply fabricated in

large quantities by a multitude of methods.

5) The choice of polymer and the ability to modify drug release from polymeric Nano particle have

made ideal candidates for cancer therapy, delivery of vaccines, contraceptives and delivery to

targeted antibiotics.

6) Particle size and surface characteristics of Nano particles can be easily manipulated to active

both passive and active drug targeting after parenteral administration.

7) The system can be used for various routes of administration including oral, nasal, parenteral,

intra-ocular etc.,

8) Faster dissolution generally equates with greater bioavailability.

9) Smaller drug doses.

10) Reduction in fed/fasted variability.

11) Less toxicity

DISADVANTAGES OF NANO PARTICLES

1) Extensive use of poly vinyl alcohol as a detergent issues with toxicity.

2) Limited targeting abilities.



3) Discontinuation of therapy is not possible.

4) Alveolar inflammation.

5) Cytotoxicity.

6) Pulmonary inflammation and pulmonary carcinogenicity.

7) The disturbance of autonomic imbalance by Nano particles having direct effect on heart and

vascular function. (14)

Characterization of nanocapsules (4,5,15)

1.Particle size

2.Surface properties of the nanocapsules

3.Fluorescence quenching

Evaluation studies

X-Ray Diffraction (XRD) studies:

Phase analysis of the products is performed by powder XRD on a Rigaku D/max-2000

diffractometer with graphite monochromatized Cu Kα (λ = 0.154 056 nm) at a voltage of 50 kV and

a current of 250 mA. The XRD pattern shows the phase composition of prepared products.

Scanning Electron Microscopy (SEM)

The architecture of the hierarchical branching aggregates, characterized from nanocapsules, may be

of flocculent structure, small clusters, big clusters and big branches step by step at different scales,

which confirms the self-similar attributes of the structure. It is characterized by a Philips XL-30

scanning electron microscope (SEM) which shows at a high magnification the clear morphology of

small clusters. The clusters are composed of flocculent structure formed by the small particles

adhered together .A low-magnification SEM image may reveal the coral-like architecture that

contains hierarchical branching characteristics along the axial and lengthwise directions.

Differential Scanning Calorimetry (DSC)

DSC analysis is conducted in both open samples (no lid) and closed samples (pan capped

possessing a small hole in the center). Both methods have similar thermal behavior as per the

observations reported.

Transmission Electron Microscopy (TEM)

The transport of particularly insulin-loaded nano capsules across the epithelium can be assessed by

transmission electron microscopy after their oral administration to experimental rats when they are

subjected to in vitro and in vivo studies. TEM observations indicate the intestinal absorption of

biodegradable nano capsules leading to the transport of insulin across the epithelium mucosa.



High-Resolution Transmission Electron Microscopy (HRTEM)

The detailed morphology of the corresponding nano capsules examined by means of high-

resolution transmission electron microscopy clearly shows the shell/core structure of the nano

capsules. The morphology of nano capsules constructing the aggregates is tested from the low-

magnification TEM images.

X-Ray Photoelectron Spectroscopy (XPS)

X-ray photoelectron spectroscopy measurements are performed on an ESCALAB-250 with a

monochromatic x-ray source (an aluminium Kα line of 1486.6 eV energy and 150 W) to describe

the valency of surface aluminium atoms present on the nano capsules at a depth of 1.6 nm. The

XPS technique is highly specific to the solid surface due to the narrow range of photoelectrons that

are excited. The excited energy of the photoelectrons emitting from the sample is determined by

using a concentric hemispherical analyzer (CHA) which demonstrates a spectrum with a serial

levels of the photoelectron peaks. The binding energies of the peaks are characteristic to each

element. The peak areas are utilized (with equivalent sensitivity factors) to demonstrate the

composition of the surface materials. The shape of each peak and binding energy can be slightly

varied by the emitting atom of chemical state. XPS technique provides the chemical bonding

information as well.

Superconducting Quantum Interference Device (SQUID)

The magnetic properties of nano capsules are measured by using Quantum Design MPMS-7s or

MPMS-5ssuperconducting quantum interference device. SQUIDs are the most sensitive detectors

in detecting the tiny changes in magnetic flux, which take an account to the wide spectrum of

application potential of SQUID devices.

Multi Angle Laser Light Scattering (MALLS)

Vaults have a capsule-like structure with a very thin shell (approximately 2 nanometers)

surrounding a large internal cavity. The vault particle in a nano capsule has an incredible potential

for compound encapsulation, protection, and delivery. Vault conformation in solution is probed

using the multiangle laser light scattering to determine conditions that can stimulate the inter

conversion of opened and closed conformers. These studies enable the control of entrapment and

release of encapsulated materials. Vaults containing binding sites for the toxic metals have

importance in environmental and medical detoxification.

FT-IR analysis

The presence of characteristic peaks is confirmed by using the FTIR analysis. The peaks indicate

the characteristic functional groups of compound



Applications of Nano particulate Delivery Systems:

1. Tumor targeting using nano particulate delivery systems.

2. Reversion of multidrug resistance in tumour cells.

3. Nanoparticles for oral delivery of peptides and proteins.

4. Targeting of nanoparticles to epithelial cells in the GI tract using ligands.

5. Nanoparticles for gene delivery.

6. Nanoparticles for drug delivery into the brain.

7. Nanocapsules for drug delivery

8. Nanocapsules for oral delivery of peptides and proteins

9. Treatment of hormone dependent breast cancer

10. MRI-guided nanorobotic systems for therapeutic and diagnostic applications

11. Nuclear nano capsules treatment for cancer by using radioactive materials

Application Drug Mode of Preparation

Agrochemicals Abamectin-nanocapsules Emulsion polymerization

Cypermethrinnanocapsules Microemulsion polymerization

Pyrethrum Nanocapsules Microemulsion polymerization

Anti-inflammatory

drugs

Diclofenac sodium Sol-gel method

Indomethacin loaded nanocapsules Interfacial polymerization

Antiseptics Monodisperse polymer nanocapsule Precipitation

Cosmetics Hinokitiol-loaded poly (epsilon-caprolactone)

Nanocapsules

Emulsion-diffusion method

Diabetes Insulin loaded Biodegradable poly

(isobutylcyanoacrylate)

Nanocapsules

Interfacial polymerization

Nanocapsules for

cancer

Artemisinin Nanoencapsulation method

Camptothecin (CPT) and doxorubicin Sol-gel method

Cisplatin Repeated freezing and thawing of a

concentrated solution of Cisplatin

in the presence of negatively

charged phospholipids.

Nanocapsule for

Topical use

Chlorhexidine Interfacial Polymerization method



CONCLUSION:

One of the greatest challenges in drug delivery system is to maximize the effectiveness of the active

agent while reducing its systemic adverse effects. Many drugs present poor physicochemical

properties (low solubility, lack of biological stability) that limit their therapeutic applications. All

these issues may be overcome by designing adequate drug delivery systems; nanocarriers

(nanocapsules) are particularly suitable for this purpose. Drug encapsulated nanocapsule can be

used for targeted-drug release especially in the field of neuroscience and cancer biology.

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