Journal of

Medical Pharmaceutical www.jmpas.com

And Allied Sciences ISSN NO. 2320 - 7418

RESEARCH ARTICLE
Correspondence
A. R. Thakre
Department of Pharmaceutics,
Priyadarshini J. L. College of
Pharmacy, Maharashtra, India.
Nanosponges: A Novel Email Id:
Approach of Drug Delivery
anupthakre13@gmail.com
Keywords
System Nanosponges, topical
application, polymers,
A. R. Thakre*, Y. N. Gholse, R. H. Kasliwal targeted drug delivery,
controlled drug delivery.
Department of Pharmaceutics, Priyadarshini J. L.
College of Pharmacy, Maharashtra, India Received
07 June 2016
Reviewed
10 June 2016
Accepted
12 June 2016

ABSTRACT
Targeted drug delivery to specific sites is the significant problem which is being faced by the
researchers. The development of new colloidal carrier called nanosponges has the potential to
solve these problems. Nanosponge is a novel and emerging technology which offers controlled
drug delivery for topical use. In this review article, application of nanosponges, its preparation
methods by Emulsion solvent diffusion method, and by using hyper crosslinked cyclodextrin and
evaluation have been discussed. Nanosponge play vital role in targeting drug delivery in a
controlled manner. Both lipophilic and hydrophilic drugs are incorporated in nanosponge. The
outer surface is typically porous, allowing controlled release of drug. They enhanced solubility,
bioavailability reduce side effects and modify drug release. Nanosponge drug delivery system
has emerged as one of the most promising fields in life science used in chemotherapy nowadays.

Journal of Medical Pharmaceutical and Allied Sciences (June_2016); 78-92 78

INTRODUCTION

Targeting the delivery of drugs has long been a up in the body, the drug can be released on a
problem for medical researchers - how to get known schedule [2]. The nanosponges are
them to the right place in the body and how to encapsulating type of nanoparticles which
control the release of the drug to prevent encapsulates the drug molecules within its core.
overdoses. The developments of new and By the method of associating with drugs, the
complex molecules called nanosponges have the nanoparticles can be classified into
potential to solve these problems. Nanosponges encapsulating nanoparticles, complexing
are a new class of materials and made of nanoparticles and conjugating nanoparticles.
microscopic particles with few nanometers wide The first type is represented by nanosponges
cavities, in which a large variety of substances and nanocapsules. Nanosponges such as alginate
can be encapsulated. These particles are capable nanosponge, which are spongelike nanoparticles
of carrying both lipophilic and hydrophilic containing many holes that carry the drug
substances and of improving the solubility of molecules. Nanocapsules such as poly(isobutyl-
poorly water soluble molecules. [1] cyanoacrylate) (IBCA) are also encapsulating
Nanosponges are tiny mesh-like structures that nanoparticles. They can entrap drug molecules
may revolutionise the treatment of many in their aqueous core. The second category is
diseases and early trials suggest this technology Complexing nanoparticle, which attracts the
is up to five times more effective at delivering molecules by electrostatic charges.
drugs for breast cancer than conventional
The third type is Conjugating nanoparticle,
methods. [2] The nanosponge is about the size
which links to drugs through covalent bonds. [3]
of a virus with a backbone (a scaffold
These nanosponges represent a novel class of
structure) of naturally degradable polyester. The
nanoparticles usually obtained by natural
long length polyester strands are mixed in
derivatives. As compared to the other
solution with small molecules called cross-
nanoparticles, they are insoluble both in water
linkers that have an affinity for certain portions
and organic solvents, porous, non toxic and
of the polyester. They cross link segments of
stable at high temperatures up to 300C.
the polyester to form a spherical shape that has
many pockets (or cavities) where drugs can be They are able to capture, transport and
stored. The polyester is predictably selectively release a huge variety of substances
biodegradable, which means that when it breaks because of their 3D structure containing cavities

Journal of Medical Pharmaceutical and Allied Sciences (June_2016); 78-92 79

of nanometric size and tunable polarity. loading capacity of nanosponges depends
Furthermore, nanosponges show a remarkable mainly on degree of crystallisation.
advantage in comparison with the common Paracrystalline nanosponges can show different
nanoparticles: indeed, they can be easily loading capacities. The nanosponges can be
regenerated by different treatments, such as synthesized to be of specific size and to release
washing with eco-compatible solvents, stripping drugs over time by varying the proportion of
with moderately inert hot gases, mild heating, or cross linker to polymer. The engineering
changing pH or ionic strength. For all these capacity of nanosponge is due to the relatively
characteristics, nanosponges have been already simple chemistry of its polyesters and cross-
employed in different applied fields, such as linking peptides, compared to many other
cosmetic and pharmaceutical sectors. [4] nanoscale drug delivery systems. [2] These
nanosponges can be magnetized when they are
Nanosponges can be used as a vessel for
prepared in the presence of compounds having
pharmaceutical principles to improve aqueous
magnetic properties. [5] The tiny shape of
solubility of lipophilic drugs, to protect
nanosponges enables the pulmonary and venous
degradable molecules and to formulate drug
delivery of nanosponges. [1]
delivery systems for various administration
routes besides the oral one. The simple ADVANTAGES OF NANOSPONGES [13,
chemistry of polymers and cross linkers does 14]
not pose many problems in the preparation and
This technology offers entrapment of
this technology can be easily ramp up to
ingredients and reduces side effects.
commercial production levels. Nanosponges are
Improved stability, increased elegance
water soluble but does not breakup chemically
and enhanced formulation flexibility.
in water. They mix with water and use as a
These formulations are stable over
transport fluid. They can be used to mask
unpleasant flavours, to convert liquid substances range of pH 1 to 11.

to solids. The chemical linkers enable the These formulations are stable at the

nanosponges to bind preferentially to the target temperature up to 1300C.

site. The main disadvantage of these These formulations are compatible

nanosponges is their ability to include only with most vehicles and ingredients.
small molecules. The nanosponges could be
either paracrystalline or in crystalline form. The

Journal of Medical Pharmaceutical and Allied Sciences (June_2016); 78-92 80

 These are self sterilizing as their These modify the release of drug.
average pore size is 0.25m where They increase the solubility of poorly
bacteria cannot penetrate. soluble drug.
These formulations are free flowing They increase the bioavailability of drug.
and can be cost effective.
The list of polymers and crosslinking agents used for the synthesis of nanosponges are presented in
Table-1.

Table 1. Chemicals used for the synthesis of nanosponges

Polymers Hyper cross linked Polystyrenes, Cyclodextrines and its derivatives like
Methyl -Cyclodextrin,Alkyloxycarbonyl Cyclodextrins, 2-Hydroxy
Propyl -Cyclodextrins and Copolymers like Poly(valerolactone-
allylvalerolactone) & Poly(valerolactone-allylvalerolactoneoxepanedione)
and Ethyl Cellulose & PVA

Crosslinkers Diphenyl Carbonate, Diarylcarbonates, Diisocyanates, Pyromellitic

anhydride,Carbonyldiimidazoles, Epichloridrine, Glutarldehyde,
Carboxylic acid dianhydrides, 2,2-is(acrylamido) Acetic acid and
Dichloromethane

Journal of Medical Pharmaceutical and Allied Sciences (June_2016); 78-92 81

Drugs which are particularly critical for formulation in terms of their solubility can be successfully
delivered by loading into the nanosponges. List of some BCS Class II dugs which can be developed as
nanosponges are given in Table 2.

Table 2. Biopharmaceutical Classification System Class II drugs [6]

Drug Category List of Drugs

Antianxiety drugs Lorazepam

Antiarrhythmic agents Amiodarone hydrochloride

Antibiotics Azithromycin, Ciprofloxacin, Erythromycin,

Ofloxacin, Sulfamethoxazole

Anticoagulant Warfarin

Anticonvulsants Carbamazepine, Clonazepam, Felbamate,

Oxycarbazepine, Primidone

Antidiabetic and Atorvastatin, Fenofibrate, Glibenclamide,

Glipizide, Lovastatin, Troglitazone
Antihyperlipidemic drugs

Antiepileptic drugs Phenytoin Econazole nitrate, Griseofulvin, Itraconazole,

Ketoconazole, Lansoprazole,Vericonazole
Antifungal agents

Antihistamines Terfenadine

Antihypertensive drugs Felodipine, Nicardipine, Nifedipine, Nisoldipine

Antineoplastic agents Camptothecin, Docetaxel, Etoposide,

Exemestane, Flutamide, Irinotecan,

Journal of Medical Pharmaceutical and Allied Sciences (June_2016); 78-92 82

 Paclitaxel, Raloxifene, Tamoxifen,
Temozolamide, Topotecan

Antioxidants Resveratrol

Antipsychotic drugs Chlorpromazine Hydrochloride

Antiretrovirals Indinavir, Nelfinavir, Ritonavir, Saquinavir

Lansoprazole, Omeprazole

Antiulcer drugs

Anthelmintics Albendazole, Mebendazole, Praziquantel

Cardiac drugs Carvedilol, Digoxin, Talinolol

Chlorthalidone, Spironolactone

Diuretics

Gastroprokinetic agent Cisapride

Immunosupressants Cyclosporine, Sirolimus, Tacrolimus

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NSAIDs Dapsone, Diclofenac, Diflunisal, Etodolac,
Etoricoxib, Flurbiprofen, Ibuprofen, Piroxicam
Indomethacin, Ketoprofen, Mefenamic acid,
Naproxen, Nimesulide, Oxaprozin,

Steroids Danazol, Dexamethazone,

Miscellaneous Melarsoprol, Phenazopyridine, Ziprasidone,

Table 3. Examples of nanosponges

Drug Nanosponge Indication Study In vitro / in Reference

vehicle vivo

/
Mathematical

Model

Paclitaxel -cyclodextrin Cancer Bio- Sprague

availability 9
Dawley rats
10
MCF7 cell line

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Camptothecin -cyclodextrin Cancer Haemolytic Diluted blood
11
activity
HT-29 cell line
12
Cytotoxicty

Tamoxifen -Cyclodextrin Breast Cytotoxicty MCF-7 cell

5
cancer line

Econazole Ethyl cellulose Antifungal Irritation study Rat

nitrate 7,8
Polyvinyl
alcohol

PREPARATION OF NANOSPONGE
b. Nanosponge prepared from hyper
a. Emulsion solvent diffusion method
crosslinked cyclodextrin
Nanosponges prepared by using different
In the melt method, the crosslinker is
proportion of ethyl cellulose and
melted along with CDs. All ingredients are
polyvinyl alcohol. The dispersed phase
finely homogenized and placed in a 250
containing ethyl cellulose and drug was
ml flask heated at 100 C and the reaction
dissolved in 20ml dichloromethane and
is carried out for 5 hrs under magnetic
slowly added to a definite amount of
stirring. The reaction mixture is allowed
polyvinyl alcohol in 150ml of aqueous
to cool and the obtained product is
continuous phase. The reaction mixture
broken down followed by repeated
was stirred at 1000rpm for 2 hrs. The
washing with suitable solvents to remove
nanosponges formed were collected by
unreacted excipients and byproducts.
filtration and dried in oven at 400 c for 24
In the solvent method, the melting step is
hrs.The dried nanosponges were stored in
eliminated and the crosslinker is
vacuum desiccators to ensure the
solubilise in solvents like
removal of residual solvent.[15]
dimethylformamide or dimethylsulfoxide
(DMF/DMSO). The polymer is generally
mixed with a suitable solvent, particularly

Journal of Medical Pharmaceutical and Allied Sciences (June_2016); 78-92 85

a polar aprotic solvent, followed by be plotted against time to study effect of
addition of this mixture to an excess particle size on drug release. Particles
quantity of the crosslinker. Optimization larger than 30 m can impart gritty feeling
of the process is performed by varying the and hence particles of sizes between 10
crosslinker/polymer molar ratio. The and 25 m are preferred to use in final
reaction is carried out at temperatures topical formulation. [1, 8]
ranging from 10 C to the reflux
temperature of the solvent, for 1 to 48 2. Determination of loading efficiency
hrs. Preferred crosslinkers for this and production yield The prepared
reaction are the carbonyl compounds nanosponge loading efficiency is
diphenyl carbonate (DPC), dimethyl determined by subtracting the un-
carbonate (DMC) or carbonyldiimidazole entrapped drug from the total amount of
(CDI).The product is obtained by adding drug. The drug entrapment efficiency will
the cooled solution to a large excess of be determined by separating un-
bidistilled water. Recovery of the product entrapped drug estimated by any suitable
is done by filtration under vacuum and method of analysis. The method used for
the product is further purified by separation of un-entrapped drug by gel
prolonged Soxhlet extraction. [16, 17] filtration, dialysis and ultra
centrifugation. The loading efficiency is
PHYSICOCHEMICAL CHARACTERIZATION calculated as [23]:
OF NANOSPONGE
Loading efficiency=Actual drug
1. Particle size determination Free-
content in nanosponge/Theoretical drug
flowing powders with fine aesthetic
content100
attributes will possible to obtain by
The production yield of the nanosponge
controlling the size of particles during
can be determined by calculating
polymerization. Particle size analysis of
accurately the initial weight of the raw
loaded and unloaded nanosponges will
materials and the last weight of the
performed by laser light diffractometry or
nanosponge obtained .
Malvern Zeta sizer. Cumulative
Production yield=Practical mass of
percentage drug release from
nanosponge/Theoretical
nanosponges of different particle size will
mass(drug+polymer)100

Journal of Medical Pharmaceutical and Allied Sciences (June_2016); 78-92 86

3. Porosity 5. Resiliency (Viscoelastic properties)
Porosity study is performed to check the Resiliency of sponges can be modified to
extent of nanochannels and nanocavities produce beadlets that is softer or firmer
formed. Porosity of nanosponges is assessed according to the needs of the final
with a helium pycnometer, since helium gas formulation. Increased crosslinking tends to
is able to penetrate inter- and intra-particular slow down the rate of release. Hence
channels of materials. The true volume of resiliency of sponges will be studied and
material is determined by the helium optimized as per the requirement by
displacement method. Owing to their porous considering the release as a function of
nature, nanosponges exhibit higher porosity cross-linking.
compared to the parent polymer used to
6. In vitro release studies Dissolution
fabricate the system. Percent porosity is
profile of Nanosponge can be studied by use
given by equation [24]
of the dissolution apparatus usp xxiii with a
%Porosity=Bulk modified basket consisted of 5m stainless
volumeTrue volume/Bulk steel mesh. Speed of the rotation is 150 rpm.
volume100 The dissolution medium is selected while
considering solubility of actives to ensure
4. Swelling and water uptake For swellable
sink conditions. Samples from the
polymers like polyamidoamine
dissolution medium can be analyzed by a
nanosponges, water uptake can be
suitable analytical method studied by use of
determined by soaking the prepared
the dissolution apparatus USP xxiii with a
nanosponges in aqueous solvent. Swelling
modified basket consisted of 5m stainless
and water uptake can be calculated using
steel mesh. Speed of the rotation is 150 rpm.
equations [24]
The dissolution medium is selected while
% Swelling=Marking of cylinder at considering solubility of actives to ensure
aspecified time point/Initial marking before sink conditions. Samples from the
soaking100 dissolution medium can be analyzed by a
suitable analytical method. [19]
% Water uptake=Mass of hydrogel
after 72 hrs/Initial mass of dry polymer100 7. Permeation studies The diffusion studies
of the prepared nanosponge can be carrying

Journal of Medical Pharmaceutical and Allied Sciences (June_2016); 78-92 87

out in Franz diffusion cell for studying the wide variety of substances can be
dissolution release of nanosponge through a incorporated into a formulated product
cellophane membrane. Nanosponge sample such as gel, lotion, cream, ointment,
(0.5g) can taken in cellophane membrane liquid, or powder [20]. Econazole nitrate,
and the diffusion studies were carried out at an antifungal used topically to relive the
37 1 using 250 ml of phosphate buffer symptoms of superficial candidasis,
(pH 7.4) as the dissolution medium. 5ml of dermatophytosis, versicolor and skin
each sample can withdrawn periodically at infections available in cream, ointment,
1, 2, 3, 4, 5, 6, 7 and 8 hrs and each sample lotion and solution. Adsorption is not
will replaced with equal volume of fresh significant when econazole nitrate is
dissolution medium. Then the samples can applied to skin and required high
analyzed for the drug content by using concentration of active agents to be
[25]
phosphate buffer as blank. incorporated for effective therapy. Thus,
econazole nitrates Nanosponge were
fabricated by emulsion solvent diffusion
APPLICATIONS OF NANOSPONGE
method, and these Nanosponges were
Topical agents loaded in hydrogel as a local depot for
Nanosponge delivery system is a unique sustained drug release. [21]
technology for the controlled release of Enhanced solubility The nanosponge

topical agents of prolonged drug release system has pores,that increase the rate of

and retention of drug form on skin. Local solubilisation of poorly soluble drug by

anesthetics, antifungal and antibiotics are entrapping such drugs in pores. Due to
among the category of the drugs that can nano size surface area significantly
be easily formulated as topical increased and increase rate of
nanosponges. Rashes or more serious solubilisation1. BS class-2 drugs having
side effects can occur when active low solubility, and a dissolution rate

ingredients penetrate the skin. In limited poor bioavailability. However,

contrast, this technology allows an even when formulated with Nanosponge they

and sustained rate of release, reducing demonstrate enhanced solubilisation

irritation while maintaining efficiency. A efficiency, with desired drug release
characteristics. [21]

Journal of Medical Pharmaceutical and Allied Sciences (June_2016); 78-92 88

Nanosponge as chemical sensors nature they can bind poorly- soluble
Nanosponges which are the type of metal drugs within the matrix and improve
oxides act as a chemical sensors which is their bioavailability of drug and they also
used in highly sensitive detection of increase the solubility of poorly soluble
hydrogen using nanosponge titania. drugs. The nanosponges have the ability
Nanosponge structure intially have no to incorporate many drugs and release
point of contact so there is less them in a controlled and predictable
hinderance to electron transport and it manner at the target site. Topical
results in higher 3D interconnect nanosponge can be more patient
nanosponges titania which is sensitive to compliant and provide sufficient patient
H2 gas.[22] benefits by reducing repeated doses and
Chemotherapy The tiny sponges are side effects. Nanosponge can be
filled with drug and expose a targeting effectively incorporated into topical drug
peptide that bind to radation induced cell delivery system for retention of dosage
surface receptor on tumor. When the form on skin. Nanosponges are tiny mesh-
sponge encounter tumur cell they stick to like structures that may revolutionise the
surface and triggered to release cargo. treatment of many diseases and this
One of the important drug formulated as technology is five times more effective at
nanosponge is paclitaxel, the active delivering drugs for cancer than
ingredient in the anti-cancer therapy conventional methods. These are self
Taxol. [2l, 22] Biomedical applications sterilizing as their average pore size is
Nanosponge can be used for 0.25m where bacteria cannot penetrate.
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