WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Jagadeesh. World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 5.210

Volume 5, Issue 2, 1365-1380 Review Article ISSN 2278 – 4357

REVIEW OF NANOCAPSULES
Anexure
Perumalla Jagadeesh*, S.Dasthagiri, G. Nethravani

Department of Pharmaceutics, JNTUA-Oil Technological ResearchInstitute,

Ananthapuramu.

Article Received on ABSTRACT

15 Dec 2015,
Nanotechnology is the science of small. Nano derives from the Greek
Revised on 05 Jan 2016, word “Nano” which means dwarf small. Nano capsules are vesicular
Accepted on 30 Jan 2016
systems in which the drug is confined to a cavity consisting of an inner
liquid core surrounded by a polymeric membrane. Nano capsules
*Correspondence for
Author having various advantages and disadvantages. Preparation of Nano
Perumallajagadeesh capsules can be used as a two types of polymers 1) Natural polymers
Department of 2) Synthetic polymers. Nano capsules are prepared by different method
Pharmaceutics, JNTUA-Oil
those are a) Solvent evaporation b) Nano precipitation c)
Technological
emulsification/Solvent diffusion d) Salting out e) Dialysis f) Super
ResearchInstitute,
Ananthapuramu. critical fluid technology. Different characterization and evaluation tests
are performed to Nano capsules.
KEYWORDS: Natural polymers, Synthetic polymers, Super critical fluid technology,
Salting out, Dialysis method.

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.

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Application of nanotechnology in pharmaceutical field

NANO NANO
EMUSION
SUSPENSIONS

NANO TECHNOLOGY

NANO
PARTICLES

NANO CAPSULES NANO SPHERE

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 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.

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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 havings direct effect on heart
and vascular function.

POLYMERS USED IN PREPARATION OF NANO PARTICLES

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.

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Natural polymers
The most commonly used natural polymers in preparation of polymeric Nano-particles are
1) Chitosan
2) Gelatin
3) Sodium alginate
4) Albumin

There are many synthetic polymers like

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.

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Nano precipitation method

Emulsion-diffusion method

Double emulsification method

Preparation of
Nano capsules

Emulsion-coarcervation method

Polymer-coating method

Layer-by-layer method

1) 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.Ethonol, 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
mmethod
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

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frequently they cannot etheless give good results. Regarding water/oil surfactants, sorbitan
ester and phospholipids are preferred. Suggested composion 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

Slow injection (drop wise

and moderate stirring)

Aqueous Solvent
Organic phase
phase elimination
phase
Fig 1: Nano precipitation method

Example of drugs used for preparation of nanoprecipitation method

Usnic acid, Indomethacin(ingredient),

pereiraetal(2006) Pohlmann et.al.(2002),

Nano precipitation method

Atovaquone(In) cauchetier et
Diclofenac schaffazick et al(2003) (Ref)
al(2003)

Melatonin schaffazick et
al(2008)

2) EMULSION-DIFFUSION METHOD
Preparation of nanocapsules by the emulsion-diffusion method allows both liphophilic and
hydrophilic active substance nanoencapsulation. In this method of preparation required three
phases those are organic phase and aqueous phase and dilution phase. The objective is the

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nano encapsulation of a liphophilic active substance, oil and an organic solvent partially
miscible with water which should be water saturated. In this organic medium act as solvent
for the different components of the organic phase. Inorganic phase can also include an active
substance solvent (or) oil solvent. The aqueous phase comprises the aqueous dispersion of a
stabilizing agent that is prepared using solvent-saturated water while the dilution phase is
usually water. Polymers commonly used are biodegradable polyesters, especially PCL, PLA
and Eudragit. Poly (hydroxyl butyrate-co-hydroxyvalerate) (PHBHV) may also be used.
Inner phase contains the oil in addition to the active substance and solvent. In regarding to the
external phase, the solvent used is water and poly(vinyl alcohol) (PVA) is preferred as the
stabilizing agent. Other stabilizing agents such as poloxamer and ionic emulsifiers have been
used. Suggested composition for preparation of nanocapsules by emulsion-diffusion method.

Material Suggested composition

Active substance 10-50 mg
Polymer 1.0-2.0 % of inner phase solvent
Oil 205-5.0 % of inner phase solvent
Inner phase solvent 10 ml
Stabilizer agent 2.0-5.0 % of external phase solvent
External phase solvent 40 ml
Dilution phase 200 ml

Dilution
phase
Organic Emulsification Diffusion
phase (high shear (Moderate
+Aqueous mixer) stirring)
phase

Solvent elimination
moderate magnetic
agitation, evaporation
by vacuum, tangential
Fig 2: Emulsion-diffusion method ultra filtration.

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Example of drugs used in emulsification diffusion method

Hinokitiol Indomethacin (In)

Joo et al (2008) Limayem et

al(2004)

Emulsification &
diffusion method

Sudan 111 Eugenol

Quintanar et
Choietal(2009)
al(1998 b)

3) DOUBLE EMULSIFICATION METHOD

Double emulsions are complex hetero disperse systems called “Emulsion of Emulsion”.
Double emulsion can be classified two types.
1) Water-oil-Water emulsion (w/o/w)
2) Oil-water-Oil emulsion (o/w/o)

Double emulsion are usually prepared in a double step emulsification process hear using two
surfactants: hydrophobic one designed to stabilize the interface of the w/o internal emulsion
and a hydrophilic one to stabilize the external interface of the oil globules for w/o/w
emulsion. Preparation of nanocapsules by double emulsion method. Specifically of the w/o/w
types is followed with the principle of emulsion-diffusion method and nano precipitation
method. In this method primary w/o emulsion the oil is changed by an organic phase
containing a solvent that is totally (or) partially miscible in water the film formed polymer
and a w/o surfactant. Hear water containing a stabilizing agent is added to the system to
obtain the water in organic in water emulsion. Water is frequently added to the double
emulsion in order to achieve full solvent diffusion. Hear surfactant play a dual role in
emulsion as a film former and a barrier to the drug release at the internal interface and a steric
stabilizer on the external interface. In laboratory scale nanocapsule prepared by double
emulsion size about 150-200nm.

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In this preparation inner aqueous phase is composed only for the active substance in some
cases forming complexes and water. In the organic phase ethyl acetate, Methylene chloride
and dichloromethane have been used as solvent and biodegradable polyesters such as PCL,
PLA and PLGA have been normally used composition of nanocapsules by double-emulsion
method

Material Suggested composition

Inner aqueous phase Variable (0.5-25 mg)
Active substance
Water 0.15-0.5 ml
Organic phase 5-10 % of organic phase solvent
Polymer
w/o surfactant 5-7 % of organic phase solvent
Solvent 1.5-5 ml
External aqueous phase 1-5 % of external aqueous phase
Stabilizer agent solvent
Water 2-5 ml
Dilution phase(optional) 1-5 % of dilution phase solvent
Stabilizer agent
Water 50-100 ml

Dilution
phase

Organic Emulsification Emulsification Recuperation

phase o/w (Ultracentrifug
(Sonication)
+Aqueous (Sonication) ation)
phase

Fig 3: Double emulsification method

Example of drugs used in double emulsification method

Bovine serum albumin

Lu et al (1999)
Luatal(1999) (2000)

Penicillin G Insulin ,Zhuetal (2005),

Lamprent et al (2000) Bilatietal (2005 a)

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Double emulsification
method (liquid core)

Tetanustoxid lysozyme
Ciprofloxacin.HCl
,Insulin
Jeong et al (2005 a)
Bilatietal (2005 a)

3) EMULSION –CO ACCERVATION METHOD

The emulsion-co accervation process is mainly presented as a basically for nanocapsules
preparation from naturally occurring polymeric materials. In the preparation of nanocapsules
used as a sodium alginate and gelatin been used through synthetic polymeric material. The
procedure involves the o/w emulsification of an organic phase with an aqueous phase by
mechanical stirring (or) ultrasound co accervation process is performed by using either
electrolytes as done by with a sodium alginate- calcium chloride system by the addition of a
water miscible non-solvent (or) a dehydration agent done by with a gelatin-isopropanol-
sodium sulfate system (or) by temperature modification as done by with the application of
triblock terpolymer in gold nanocapsule synthesis.

Nanocapsule formation by the emulsion-co accervation method uses the emulsion as a

template phase and the formation of a co accervate phase that causes polymer precipitataion
from the continuous emulsion phase to form a film on the template formation the
nanocapsules. Additionally, it can be stabilized by physical intermolecular (or) covalent
cross-linking which can be achieved by altering temperature (or) PH (or) by a cross-linking
agent.
Cross linking agent (or)
Dehydratant agent

Organic Co-accervation
Emulsification
phase (Moderate
(Sonication)
+Aqueous stirring)
phase

Purification
(Water washing, filtration
through 0.45µg)
Fig 4: Emulsion –co accervation method

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Drugs used for emulsion-co accervation method:-

Tumeric oil(In)
Triamcinolone acetonide
Lertsuttiwong et al
(In)
(2008 a (Ref))
Krause and Rohdewald
(Ref)

Emulsion co
accervation method

5) POLYMER-COATING METHOD
Polymer coating method can be achieved by adsorbing the polymer on to the preformed
uncoated nanocapsules when the latter are incubated in polymer dispersion under
predetermined stirring and time condition. In this polymer coating method have been
modified in order to add a layer of polymer to the external aqueous medium and allow to
simultaneous later formation due to the precipitation of the charged polymer and to the
diffusion of the solvent.

In the preparation of nanocapsules by polymer-coating method in which the first step is to

prepare the nano emulsion template and then coat it by polymer deposion on the water/oil
nano emulsion surface.

The polymers are added in the continuous phase and their precipitation onto the nano
emulsion droplets is triggered by solvent evaporation as opposed to the emulsion-
coacervation method. In the preparation mainly used Chitosan and PEG Chitosan.

The nanocapsule formation mechanism is mediated by the ionic interaction between the
negatively charged phospholipids and the positively charged Chitosan molecule. The layered
formed polymer used by them is poly (methyl methacrylate) (PMMA), poly (methacrylate)
(PMA) and PCL.

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Coating
agent
Oil phase Emulsification
+Aqueous w/o Emulsification
phase (Sonication) o/w
(Sonication)

Stabilization
(spraydrying,ly
ophilization)
Fig 5: Polymer-coating method

Drug used for polymer-coating method

Calcitonin(A.I) Tetanus toxoid

Prego et al(2006) Vila et al(2002)

Polymer-coating method

Indomethacin (In)
Calvo et al (1997)

6) LAYER-BY-LAYER METHOD
The layer-by-layer assembly process developed for colloidal particle preparation makes it
possible to obtain vesicular particles called polyelectrolyte capsules. This method requires a
colloidal template onto which is adsorbed a polymer layer either washed (or) by decreasing
polymer solubility by drop-wise addition of a miscible solvent.

As reported in different research works the layer-by-layer method makes used of polycations
such as polylysine, Chitosan, gelatin-B, poly(ally amine) (PAA), poly(ethyleneimine) (PEI),
aminidextran and protamine sulfate. The polyanion are sodium alginate , poly (styrene
sulfonate) (PSS),poly(acrylic acid), dextran sulfate carboxy methylcellulose, haluronic acid,
gelatin-A, chondroitin and heparin.

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Drug used for layer-by-layer method:

Layer-by-layer method

ARTEMISININ

Chen et al. (2009)

CHARACTERIZATION (OR) EVALUATION OF NANOCAPSULES

1) DETERMINATION OF THE PH OF NANOCAPSULE
Nano capsules formulation pH was measured using a digital pH meter at room temperature.
Nano capsules dispersion pH values fall within a range of 3.0-7.5.

2) MEAN NANO CAPSULES

The mean particle size of nanocapsules prepared from performed polymers are in general
between 250-500nm. In double emulsification method has concluded that particle size
depends on the internal and external surfactants that determine droplet size, the interaction at
the interface and the structural conformation of the nano capsules wall.

3) DETERMINATION OF DRUG CONTENT:-

Drug content was determined by dissolving 1ml of prepared nanocapsules in 20ml of
acetonitrile. Appropriate quantity of sample was then subjected to the UV Spectrophotometer
at 232nm. The absorbance for each sample was measured and compared with the standard.

4) PARTICLE SIZE DISTRIBUTATION AND PARTICLE CHARGE/ZETA

POTENTIAL
Particle size distribution is an important aspect during the formulations of nano systems.
Nano capsules were characterized for their particle size distribution and zeta potential using
Malvern zetasizer.

5) STRUCTURAL CHARACTERIZATION
Structural characterization can be done by using field emission scanning electron microscopy
(FE-SEM) and transmission electron microscopy (TEM) to determine the various attributes
like shape, size and surface morphology. Micrographs of the nano capsules were obtained

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using a Phillips Cm 200 operated at 20-200 kv while the Fe-SEM was carried out using
Hitachi S-4800 FE-SEM equipped with energy dispersion spectrometer (EDS).

6) IN-VITRO DRUG RELEASE

In vitro dissolution studies were carried out using USP type 11 dissolution apparatus. The
study was carried out in 100 ml of buffer (PH 3.0). the nano capsules suspension was placed
in dialysis membrane and dipped in dissolution medium which was kept inert
thermostatically at 37±0.50C. The stirring rate was maintained at 100 rpm. At predetermined
time intervals 5ml of sample were withdrawn and assessed for drug release spectrophoto
metrically. After each withdrawal 5 ml of fresh dissolution medium was added to dissolution
jar.

APPLICATIONS
Nano capsules have been proposed as drug delivery system for several drugs by different
routes of administration such as oral, ocular (or) Parenteral. Drug-loaded nano capsules were
used to improve the stability of the drug either in biological fluids (or) simply in the
formulation.

ORAL ROUTE
 Indomethacin an anti-inflammatory drug has been successfully encapsulated in the poly
alkylcyanoacrylate nano capsules with the aim of reducing its side effect on the gastric
and intestinal mucosa.
 Diclofenac and Indomethacin two major non-steroidal anti-inflammatory agents, have
been encapsulated in poly(lactic acid) nano capsules obtained by nano precipitation with
the aim of reducing their side effects on the gastric mucosa.
 Insulin-loaded nano capsules yielded promising pharmacological results.
 Anti infectionus agents such as Atovaquone and Rifabulin, two compounds active against
the opportunituistic parasite Toxoplasma gondil, were successufully entrapped in poly
(lactide) nano capsules formed by nano precipitation.

PARENTERAL ROUTE
 As far as the parenteral route is concerned, nano capsules could be useful for the
formulation of poorly soluble drugs and for controlling the drug distribution according to
properties of the carrier.

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 Nano capsules prepared by interfacial polymerization of the iso butyl cyano acrylate
monomers were retained longer at the injection site after intra muscular administration
that the other types of carriers such as emulsion (or) liposomes.
 An antimalarial drug Halofantrine was entrapped with the aim of obtaining a well-
tolerated injectable form for the treatment of this sever intravascular disease.
OCULAR DELIVERY:-
 Betaxolol-loaded poly (iso butyl cyano acrylate) nano capsules made by interfacial
polymerization were prepared for the treatment of glaucoma.
 Ganciclovir encapsulation in poly (ethyl ayano acrylate) nano capsules made by
interfacial polymerization provided a sustained release of the drug over four days.
 Ganciclovir is an antiviral drug used for the treatment of cytomegalovirus infections.

CONCLUSION
The main goal of this review was to describe the different preparation techniques available
for production of polymeric nanoparticals. The drug loaded Nano sphere (or) nanocapsules
now can be produced by simple, safe and reproducible technique available.

Nano particle preparation methods have been marked by THREE aspects

1. Need for lees toxic reagents.
2. Simplification of the procedure to allow economic scale up.
3. Optimization to improve yield and entrapment efficiency.

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