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Pelagia Research Library

Der Pharmacia Sinica, 2014, 5(6):7-21

ISSN: 0976-8688
CODEN (USA): PSHIBD

Nanosponges: The spanking accession in drug delivery- An updated

comprehensive review
Riyaz Ali M. Osmani*, Shailesh Thirumaleshwar, Rohit R. Bhosale and
Parthasarathi K. Kulkarni
Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagar,
Mysore (Karnataka), India
_____________________________________________________________________________________________
ABSTRACT
The drug delivery technology landscape has become highly competitive and rapidly evolving as more and more
developments in delivery systems are being integrated to optimize the efficacy and cost effectiveness of therapy. In
addition new classes of pharmaceuticals, biopharmaceuticals are fuelling rapid evolution of drug delivery
technology. These new drugs typically cannot be effectively delivered by conventional means. Hence, benefits from
targeted, localized delivery of therapeutic agents are other driving forces for the current market. Nanosponge
technology has been introduced to facilitate controlled release of drugs over the time in order to reduce systemic
toxicity and severe reactions. Nanosponges consist of nanoporous particles that can suspend or entrap a wide
variety of substances, and then be incorporated into a dosage form. They release their active components on a time
mode and also in response to other stimuli (rubbing, temperature, pH etc.), that are used mostly for topical and
recently for other routes of administration. Nanosponge delivery system (NDS) provides increased efficacy with
enhanced safety, extended product stability, improved formulation flexibility, reduced side effects and superior
aesthetic properties in an efficient and novel manner. Adding up they are non-irritating, non-mutagenic, nonallergenic and non-toxic. In short nanosponges encompass many favourable characteristics which make them a
versatile drug delivery vehicle. The present review explores current standing of nanosponges in drug delivery in
great detail.
Keywords: Biodegradable polymers, Drug delivery, Low solubility, Nanosponges, Tumour targeting.
_____________________________________________________________________________________________
INTRODUCTION
Nanotechnology is the science and technology of precisely manipulating the structure of matter at the molecular
level. It is the use and manipulation of matter at a tiny scale. Nanotechnology deals with the creation of useful
materials, device and systems and systems through control of matter on the nanometer length scale and exploitation
of novel phenomena and properties at that length scale. With advancements in nano science and technology, a large
number of materials and improved products may be available with a change in the physical properties when their
sizes are shrunk. Nanotechnology-based delivery systems can also protect drugs from degradation. These properties
can help reduce the number of doses required, make treatment a better experience and reduce treatment expenses. A
number of nano-based systems allow delivery of insoluble drugs, allowing the use of previously rejected drugs or
drugs which are difficult to administer e.g. paclitaxel. At present these systems are generally used for existing, fully
developed off-patent drugs, the so called low-hanging fruit of nanotechnology-based delivery. Nanotechnology
should not be viewed as a single technique that only affects specific areas. It is more of a catch-all term for a
science which is benefiting a whole array of areas, from the environment, to healthcare, to hundreds of commercial
products [1, 2].

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The area of drug delivery technology is evolving rapidly and becoming highly competitive day by day. The
developments in the delivery systems are being utilized to optimize the efficacy and the cost effectiveness of
therapy. The major challenges faced by drug development industry are:
Sustained release technology for reducing irritation of a wide range of APIs thereby increasing patient/client
compliance and results.
Enhanced formulation stability ensuring long term product efficacy and extended shelf life.
Also targeting the drug delivery has long been a problem for medical researchers perhaps how to get them to the
right place in the body and how to control the release of the drug to prevent overdose [3]. The development of new
and complex molecules called nanosponges has the potential to solve these problems [4].
Nanosponges are a new class of materials, made of microscopic particles with few nanometers wide cavities, in
which a large variety of substances can be encapsulated. These particles are capable of carrying both lipophilic and
hydrophilic substances and of improving the solubility of poor water soluble molecules [5]. Nanosponges are tiny
mesh-like structures that may revolutionise the treatment of many diseases and early trials suggest this technology is
up to five times more effective at delivering drugs for breast cancer than conventional methods. The nanosponge is
about the size of a virus having with an average diameter below 4m and with a backbone (a scaffold structure) of
naturally degradable polyester. The long length polyester strands are mixed in solution with small molecules called
cross-linkers that have an affinity for certain portions of the polyester. They cross link segments of the polyester to
form a spherical shape that has many pockets (or cavities) where drugs can be stored. The polyester is predictably
biodegradable, which means that when it breaks up in the body, the drug can be released on a known schedule [6].
By the method of associating with drugs, the nanoparticles can be classified into encapsulating nanoparticles,
complexing nanoparticles and conjugating nanoparticles. The nanosponges are encapsulating type of nanoparticles
which encapsulates the drug molecules within its core. Nanosponges such as alginate nanosponge, which are sponge
like nanoparticles containing many holes that carry the drug molecules. Nanocapsules such as poly(isobutylcyanoacrylate) (IBCA) are also encapsulating nanoparticles. They can entrap drug molecules in their aqueous core.
The second category is complexing nanoparticles, which attracts the molecules by electrostatic charges. The third
type is conjugating nanoparticles, which links to drugs through covalent bonds [7]. These nanosponges represent a
novel class of nanoparticles usually obtained by natural derivatives. As compared to the other nanoparticles, they are
insoluble both in water and organic solvents, porous, non toxic and stable at high temperatures up to 300C. They
are able to capture, transport and selectively release a huge variety of substances because of their 3D structure
containing cavities of nanometric size and tunable polarity.
Furthermore, nanosponges show a remarkable advantage in comparison with the common nanoparticles: indeed,
they can be easily regenerated by different treatments, such as washing with eco-compatible solvents, stripping with
moderately inert hot gases, mild heating, or changing pH or ionic strength. For all these characteristics, nanosponges
have been already employed in different applied fields, such as cosmetic and pharmaceutical sectors [8].
Nanosponges can be used as a vessel for pharmaceutical principles to improve aqueous solubility of lipophilic drugs,
to protect degradable molecules and to formulate drug delivery systems for various administration routes besides the
oral one. The simple chemistry of polymers and cross linkers does not pose any problem in the preparation and this
technology can be easily ramp up to commercial production levels. Nanosponges are water soluble but does not
breakup chemically in water. They mix with water and use as a transport fluid. They can be used to mask unpleasant
flavours, to convert liquid substances to solids. The chemical linkers enable the nanosponges to bind preferentially
to the target site. The main disadvantage of these nanosponges is their ability to include only small molecules. As
the nanoscale materials are small enough to be effective in attaching to or passing through cell membranes. The
nanosponge can be engineered to be of specific size and to release drugs over time- not just in the burst mode
common with other delivery methods [7].
The nanosponges could be either paracrystalline or in crystalline form. The loading capacity of nanosponges
depends mainly on degree of crystallisation. Paracrystalline nanosponges can show different loading capacities. The
nanosponges can be synthesized to be of specific size and to release drugs over time by varying the proportion of
cross linker to polymer. The engineering capacity of nanosponge is due to the relatively simple chemistry of its
polyesters and cross-linking peptides, compared to many other nanoscale drug delivery systems [6]. These
nanosponges can be magnetized when they are prepared in the presence of compounds having magnetic properties
[9]. The tiny shape of nanosponges enables the pulmonary and venous delivery of nanosponges [5].

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2. Boons of Nanosponges
1. Targeted site specific drug delivery.
2. Can be used to mask unpleasant flavours and to convert liquid substances to solids [10].
3. Less harmful side effects (since smaller quantities of the drug have contact with healthy tissue).
4. Nanosponge particles are soluble in water, so the hydrophobic drugs can be encapsulated within the nanosponge,
after mixing with a chemical called an adjuvant reagent.
5. Particles can be made smaller or larger by varying the proportion of cross-linker to the polymer.
6. Production through fairly simple chemistry called "click chemistry" (methods for making the nanosponge
particles and for attaching the linkers).
7. Easy scale-up for commercial production.
8. The drug profiles can be tailored from fast, medium to slow release, preventing over or under-dosing of the
therapy [11].
9. The material used in this system can provide a protective barrier that shields the drug from premature destruction
within the body [12].
10. Improved stability, increased elegance and enhanced formulation flexibility.
11. Nanosponges systems are non-irritating, non-mutagenic, non-allergenic and non-toxic.
12. These are self sterilizing as their average pore size is 0.25m, where bacteria cannot penetrate [13].
13. Extended release - continuous action up to 12 h.
14. Biodegradable [14].
3. Materials Used for Preparation
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
Crosslinkers

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), Ethyl Cellulose and PVA
Diphenyl Carbonate, Diarylcarbonates, Diisocyanates, Pyromellitic anhydride, Carbonyldiimidazoles, Epichloridrine,
Glutarldehyde, Carboxylic acid dianhydrides, 2,2-bis(acrylamido) acetic acid and Dichloromethane

4. Preparation of Nanosponges
Nanosponges are prepared by means of following methods:
4.1. Emulsion Solvent Diffusion Method
Nanosponges can be prepared by using different proportions of ethyl cellulose and polyvinyl alcohol. The dispersed
phase containing ethyl cellulose and drug was dissolved in 20ml dichloromethane and slowly added to a definite
amount of polyvinyl alcohol in 150ml of aqueous continuous phase. The reaction mixture was stirred at 1000 rpm
for 2 hrs. The nanosponges formed were collected by filtration and dried in an oven at 400c for 24 hrs. The dried
nanosponges were stored in vacuum desiccators to ensure the removal of residual solvent [15].
4.2. From Hypercross-linked -Cyclodextrins
Nanosponges can be obtained by cross linking with different types of cyclodextrins (CDs) with a carbonyl or a
dicarboxylate compound as a cross linker [11]. The ratio of CDs can be varied during preparation to improve the
drug loading and to obtain a tailored release profile [16-18].
-cyclodextrin nanosponges were prepared as reported in the patent by Trotta and Tumiatti [19], 100 ml of Dimethyl
Formamaide (DMF) was placed in a round bottomed flask and 17.42g of anhydrous -CD was added to achieve
complete dissolution. Then 9.96 g of carbonyl di-imidazole (61.42mmol) was added and the solution was allowed
react for 4 hrs at 100oc. Once condensation polymerization was completed, the transparent block of hyper cross
linked cyclodextrin was roughly ground and an excess of de-ionised water added to remove DMF. Finally residual
by-products or unreacted reagents were completely removed by Soxhlet extraction with ethanol. The white powder
thus obtained was dried overnight in an oven at 60oc and subsequently grinded in a mortar. The fine powder
obtained was dispersed in water. The colloidal part that remained suspended in water was recovered and lyophilised.
The obtained nanosponges are sub-micron in dimension and with a spherical shape.
4.3. Solvent Method
Mix the polymer with a suitable solvent, in particular in a polar aprotic solvent such as dimethylformamide (DMF),
dimethylsulfoxide (DMSO). Then add this mixture to excess quantity of the cross-linker, preferably in
crosslinker/polymer molar ratio of 4 to 16. Carry out the reaction at temperature ranging from 10C to the reflux
temperature of the solvent, for time ranging from 1 to 48 hrs. Preferred cross linkers are carbonyl compounds

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(dimethyl carbonate and carbonyl diimidazole) [9]. After completion of the reaction, allow the solution to cool at
room temperature, then add the product to large excess of distilled water and recover the product by filtration under
vacuum and subsequently purify by prolonged Soxhlet extraction with ethanol. Dry the product under vacuum and
grind in a mechanical mill to obtain homogeneous powder [10].
4.4. Ultrasound-Assisted Synthesis
Nanosponges can be obtained by reacting polymers with cross-linkers in the absence of solvent and under
sonication. The obtained nanosponges will be spherical, uniform in size and smaller than 5 microns [5]. In this
method di-phenyl carbonate or pyromellitic anhydride is used as cross-linker. An amount of anhydrous CD was put
to react in melted di-phenyl carbonate at 90oc for at least 5 hrs. Then, the solid was ground in a mortar and Soxhlet
extracted with ethanol to remove either impurities or unreacted diphenyl carbonate. After purification nanosponges
were stored at 25oc until further use [5, 10].
5. Factors Influencing Nanosponges Formation
5.1. Type of Polymer
Type of polymer used can influence the formation as well as the performance of nanosponges. For complexation, the
cavity size of nanosponges should be suitable to accommodate a drug molecule of particular size [20].
5.2. Type of Drug
Drug molecules to be complexed with nanosponges should have certain characteristics as mentioned below [20].
Molecular weight of drug should be in between 100 to 400 Daltons.
The structure of the drug molecule should contain not more than five condensed rings.
Solubility in water should be less than 10 mg/ml.
Melting point of the substance should be less than 250C.
5.3. Temperature
Temperature changes can affect drug/nanosponges complexation. In general, increase in the temperature decreases
the magnitude of the apparent stability constant of the drug/nanosponges complex which may be due to a result of
possible reduction of drug/nanosponges interaction forces, such as van-der Waal forces and hydrophobic forces with
rise of temperature [21].
5.4. Method of Preparation
The method of loading drug into the nanosponges can affect drug/nanosponge complexation. However, the
effectiveness of a method depends on the nature of the drug and polymer, in many cases freeze drying was found to
be most effective method for drug complexation [21].
5.5. Degree of Substitution
The complexation ability of the nanosponges may be greatly affected by type, number and position of the substituent
on the parent molecule [21].
6. Loading of Drug into Nanosponge
Nanosponges for drug delivery should be pre-treated to obtain a mean particle size below 500 nm. Nanosponges are
suspended in water and sonicated to avoid the presence of aggregates and then suspension centrifuged to obtain the
colloidal fraction. Supernatant separated and sample is dried by freeze drying [10].
Other way, aqueous suspension of nanosponge is prepared and excess amount of drug is dispersed in it with constant
stirring for specific time required for complexation. After complexation, the uncomplexed (undissolved) drug from
complexed drug separated by centrifugation. Then solid crystals of nanosponges are obtained by solvent evaporation
or by freeze drying [9,10]. The crystal structure of nanosponges plays a very important role in complexation with
drug. A study revealed that paracrystalline nanosponges showed different loading capacities when compared to
crystalline nanosponges. The drug loading is greater in crystalline nanosponges than paracrystalline one. In poorly
crystalline nanosponges, the drug loading occurs as a mechanical mixture rather than inclusion complex [22].
7. Characterization of Nanosponges
Inclusion complexes formed between the drug and nanosponges can be characterized by following methods:
7.1. Solubility Studies
The most widely used approach to study inclusion complexation is the phase solubility method described by Higuchi
and Connors, which examines the effect of a nanosponge, on the solubility of drug. Phase solubility diagrams
indicate the degree of complexation [9, 21]. In the solubility studies changes in solubility of the guest are plotted as

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a function of the cyclodextrin concentration, if the solubility of a potential guest increases with increasing
cyclodextrin concentration; complex formation in solution is indicated [23,24]. Solubility studies were performed to
evaluate the drug pH solubilization profile and to assess the effect of multi-component complexation on drug
solubility [25-27].
7.2. Particle Size and Polydispersity
The particle size can be determined by Dynamic Light Scattering Instrument (DLSI) equipped with particle sizing
software. From this the mean diameter and Polydispersity Index (PDI) can be determined [22]. PDI is an index of
width or spread or variation within the particle size distribution. Monodisperse samples have a lower PDI value,
whereas higher value of PDI indicates a wider particle size distribution and the polydisperse nature of the sample.
PDI can be calculated by the following equation:
PDI = d/davg
Where, d is the width of distribution denoted as SD and davg is the average particle size denoted as MV (nm) in
particle size data sheet. The types of dispersions with PDI values are depicted in Table 2 [28].
Table 2: Polydispersity index.
Polydispersity Index
0-0.05
0.05-0.08
0.08-0.7
> 0.7

Type of Dispersion
monodisperse standard
nearly monodisperse
mid range polydispersity
very polydisperse

The particle size can also be determined by Scanning Electron Microscopy (SEM), Transmission Electron
Microscopy (TEM), Atomic Force Microscopy (AFM) and Freeze Fracture Electron Microscopy (FFEM) [29].
7.3. Zeta Potential
Zeta potential is a measure of surface charge. It can be measured by using additional electrode in the particle size
equipment [22]. Also, laser doppler anemometry, zeta potential meter can be used [29].
7.4. Microscopy Studies
Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) can be used to study the
morphology, surface topography and microscopic aspects of the drug, nanosponges and the product
(drug/nanosponges complex). The difference in crystallization state of the raw materials and the product seen under
electron microscope indicates formation of the inclusion complexes, even if there is a clear difference in
crystallization state of the raw material and the product obtained by co-precipitation [22, 30, 31].
7.5. Thin Layer Chromatography
In Thin Layer Chromatography (TLC), the Rf values of a drug molecule diminishes to considerable extent and this
helps in identifying the complex formation between the drug and nanosponges [26, 32]. Inclusion complexation
between guest and host molecules is a reversible process. Consequently, the complex may separate completely in
guest and host molecules during the chromatographic process and only the spots of the guest and host molecules are
found on the TLC-plate [23].
7.6. Infra-Red Spectroscopy
Infra-Red spectroscopy is used to estimate the interaction between nanosponges and the drug molecules in the solid
state. Nanosponge bands often change only slightly upon complex formation and if the fraction of the guest
molecules encapsulated in the complex is less than 25%, bands which could be assigned to the included part of the
guest molecules are easily masked by the bands of the spectrum of nanosponges [33, 34]. The technique is not
generally suitable to detect the inclusion complexes and is less clarifying than other methods. The application of the
Infra-red spectroscopy is limited to the drugs having some characteristic bands, such as carbonyl or sulphonyl
groups. Infrared spectral studies give information regarding the involvement of hydrogen in various functional
groups. This generally shifts the absorbance bands to the lower frequency, increases the intensity and widens the
band caused by stretching vibration of the group involved in the formation of the hydrogen bonds. Hydrogen bond at
the hydroxyl group causes the largest shift of the stretching vibration band [26].
7.7. Thermo-analytical Methods
Thermo-analytical methods determine whether drug substance undergoes some change before the thermal
degradation of the nanosponges. The change of the drug substance may be melting, evaporation, decomposition,

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oxidation or polymorphic transition. The change of the drug substance indicates the complex formation [35, 36]. The
thermogram obtained by Differential Thermal Analysis (DTA) and Differential Scanning Calorimetry (DSC) can be
observed for broadening, shifting and appearance of new peaks or disappearance of certain peaks. Changes in the
weight loss also can provide supporting evidence for the formation of inclusion complexes. The nature of the drug
and cyclodextrin used and method of preparation of complex have been found to influence the above finding
considerably. If the interaction between the drug and the excipient is weak, the shift in the endothermic peak is very
small [26].
7.8. X-ray Diffractometry and Single Crystal X-ray Structure Analysis
Powder X-ray diffractometry can be used to detect inclusion complexation in the solid state. When the drug
molecule is liquid (since liquid have no diffraction pattern of their own) the diffraction pattern of a newly formed
substance clearly differs from that of uncomplexed nanosponges. This difference of diffraction pattern indicates the
complex formation. When the drug compound is a solid substance, a comparison has to be made between the
diffractogram of the assumed complex and that of the mechanical mixture of the drug and polymer molecules.
A diffraction pattern of a physical mixture is often the sum of those of each component, while the diffraction pattern
of complexes are apparently different from each constituent and lead to a new solid phase with different
diffractograms. Diffraction peaks for a mixture of compounds are useful in determining the chemical decomposition
and complex formation.
The complex formation of drug with nanosponges alters the diffraction patterns and also changes the crystalline
nature of the drug. The complex formation leads to the sharpening of the existing peaks, appearance of a few new
peaks and shifting of certain peaks [26].
7.9. Single Crystal X-ray Structure Analysis
This method used to determine the detailed inclusion structure and mode of interaction. The interaction between the
host and guest molecules can be identified and the precise geometrical relationship can be established. This
information obtained during the analysis lead to know about the formation of inclusion complexes [26, 37, 38].
7.10. Loading Efficiency and Production Yield
The loading efficiency (%) of nanosponges can be determined by the quantitative estimation of drug loaded into
nanosponges by UV spectrophotometer, HPLC methods and calculations according to the following equation:
Loading Efficiency = Actual drug content in nanosponge/ Theoretical drug content 100
The production yield of the nanosponges can be determined by calculating accurately the initial weight of the raw
materials and the final weight of the nanosponge obtained [39, 40].
7.11. Photo-degradation Study
The photo-degradation of drug loaded nanosponge complex is performed under UV lamp. The samples are kept at
distance of 10 cm from the lamp for 1 hr, with stirring under dark; simultaneously the samples are quantitatively
analyzed by HPLC [41].
7.12. In-vitro Drug Release
Drug release from the nanosponges can be measured across the dialysis membrane using Franz Diffusion cell. The
dialysis membrane soaked in receptor medium for 8 hrs is used as a barrier between the donor and receptor
compartment. A one gram nanosponge is placed on the membrane surface in the donor compartment that is sealed
from the atmosphere with aluminium foil. The receptor compartment is filled with specific volume of phosphate
buffer of suitable pH (6.8 skin pH). During the experiment, the solution of receptor side compartment is kept at
370.5oc and stirred at 100 rpm with Teflon-coated magnetic stirring bars. Aliquots are collected from the receptor
compartment at designated time intervals and replaced by the same volume of fresh receptor solution to maintain
sink condition and constant volume. The sample is analysed using UV spectrophotometer [15]. Even, USP type II
dissolution apparatus can be used in many cases depending upon the formulation [29].
7.13. Drug Release Kinetics
To investigate the mechanism of drug release from nanosponge the release data could be analysed using Zero order,
First order, Higuchi, Peppas, Hixon-Crowell, Kopcha and Makoid-Banakar etc. models. The data can be analysed
using graph pad prism software. The software estimates the parameters of a non-linear function that provides the
closest fit between experimental observations and non-linear function [42]. The mathematical expressions that
describe the dissolution curves are summarized in Table 3 [15].

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Table 3: Mathematical expressions of dissolution curves
Model
Zero order
Higuchi model
Korsemeyerpeppas model
Kopcha model
Makoid-bankar model

Equation
Qt = Q0 + K0 t
Qt = Q0 + KH t1/2
Qt = KKPtn
Qt= At1/2 + Bt
Qt= KMBtn e(-et)

7.14. Resiliency
Resiliency (viscoelastic properties) of sponges can be modified to produce beadlets that are softer or firmer
according to the need of final formulation. Increased crosslinking tends to slow down the rate of release. Hence
resiliency of sponges will be studied and optimized as per the requirement by considering release as a function of
cross-linking with time [43].
7.15. True Density
True density of nanosponges can be determined using an ultra-pycnometer under helium gas [43].
8. Mechanism of Drug Release
The sponge particles have an open structure and the active is free to move in and out from the particles and into the
vehicle until equilibrium is reached. In case of topical delivery, once the finished product is applied to the skin, the
active that is already in the vehicle will be absorbed into the skin, depleting the vehicle, which will become
unsaturated, therefore disturbing the equilibrium. This will start a flow of the active from the sponge particle into the
vehicle and from it to the skin until the vehicle is either dried or absorbed (Figure 1). Even after that the sponge
particles retained on the surface of stratum corneum will continue to gradually release the active to the skin,
providing prolonged release over time [44].

Figure 1: Drug release mechanism in topical delivery

9. Factors Affecting Drug Release from Nanosponges

Physical and chemical properties of entrapped actives.
Physical properties of sponge system like pore diameter, pore volume, resiliency etc.
Properties of vehicle in which the sponges are finally dispersed.
Particle size, pore characteristics, compositions can be considered as imperative parameters.
External triggers like pressure, temperature and solubility of actives.
Pressure: Pressure or rubbing can release active ingredient from microsponges onto skin.
Temperature: Some entrapped actives can be too viscous at room temperature to flow spontaneously from sponges
onto the skin but increased skin or environment temperature can result in increased flow rate and ultimately drug
release.
Solubility: Sponges loaded with water-soluble ingredients like antiperspirants and antiseptics release the
ingredient in the presence of water [20].
10. Applications
10.1. Nanosponges for Drug Delivery
Because of their nanoporous structure, nanosponges can advantageously carry water insoluble drugs and/or agents
(BCS Class-II drugs). These complexes can be used to increase the dissolution rate, solubility and stability of drugs,

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to mask unpleasant flavours and to convert liquid substances to solids. -cyclodextrin based nanosponges are
reported to deliver the drug to the target site three to five times more effectively than direct injection [6]. 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 drugs that could be developed as nanosponges is given in Table 4
[45].
Table 4: Biopharmaceutical Classification System Class-II drugs
Category
Antianxiety agents
Antiarrhythmic
agents
Antibiotics
Anticoagulant
Anticonvulsants
Antidiabetics
Antiepileptic
Antifungal agents
Antihelmintics
Antihistamine
Antihyperlipidemics
Antihypertensive
Antineoplastic agents

Antioxidants
Antipsychotics
Antiretrovirals
Antiulcer agents
Cardiac drugs
Diuretics
Gastro-prokinetic agent
Immunosuppressants
NSAIDs

Drugs
Lorazepam
Amiodarone hydrochloride
Azithromycin, Ciprofloxacin, Erythromycin, Ofloxacin, Sulfamethoxazole
Warfarin, Felbamate, Carbamazepine, Clonazepam, Oxycarbazepine
Primidone
Glibenclamide, Glipizide, Troglitazon
Phenytoin
Econazole, Griseofulvin, Itraconazole, Ketokonazole, Lansoprazol, Voriconazole
Albendazole, Mebendazole, Praziquantel
Terfenadine
Lovastatin, Atorvastatin, Fenofibrate
Felodipine, Nicardipine, Nifedipine, Nisoldipine
Camptothecin, Docetaxel, Etoposide, Exemestane, Flutamide, Irinotecan, Paclitaxel, Raloxifene, Tamoxifen,
Temozolamide, Topotecan
Resveratrol
Chlorpromazine hydrochloride
Indinavir, Nelfinavir, Ritonavir, Saquinavir
Lansoprazole, Omeprazole
Carvedilol, Digoxin, Talinolol
Chlorthalidone, Spironolactone
Cisapride
Cyclosporine, Sirolimus, Tacrolimus,
Dapsone, Diclofenac, Diflunisal, Etodolac, Etoricoxib, Flubiprofen, Ibuprofen, Indomethacin, Ketoprofen,
Mefenamic acid, Naproxen, Nimesulide, Oxaprozin, Piroxicam
Danazol, Dexamethazone
Atovaquone, Melarsoprol, Phenazopyridine, Ziprasidone

Steroids
Miscellaneous

The nanosponges are solid in nature and can be formulated as oral, parenteral, topical or inhalation dosage forms.
For the oral administration, the complexes may be dispersed in a matrix of excipients, diluents, lubricants and anticaking agents suitable for the preparation of capsules or tablets [9]. For the parenteral administration the complex
may be simply carried in sterile water, saline or other aqueous solutions. For topical administration they can be
effectively incorporated into topical hydrogel [15]. The nanosponge technology used in formulation of some drugs is
mentioned in the Table 5.
Table 5: Examples of drug nanosponges formulated

Drug

Nanosponge Vehicle

Indication

Tamoxifen

-cyclodextrin

Breast cancer

Dexamethasone

-cyclodextrin

Brain tumours

Econazole nitrate

Ethyl cellulose
Polyvinyl alcohol

Fungal infections

Itraconazole

-Cyclodextrin
copolyvidonum

Paclitaxel

-cyclodextrin

Cancer

Camptothecin

-cyclodextrin

Cancer

-cyclodextrin

Inflammation,
Cardiovascular
diseases,
Dermatitis,
Gonorrhoea,

Resveratrol

and

Fungal infections

Cytotoxicity
Drug release
Experiment

In-vitro/
In-vivo/
Mathematical Model
MCF-7 cell line
Dialysis bag
technique in-vitro

Irritation study

Rat

15

Higuchi Model

17

MCF-7 cell line

Sprague Dawley rats
Diluted blood

41
46
22

HT-29 cell line

HCPC-I cell line
Rabbit buccal
mucosa

47

Study

Saturation
solubility
Study
Cytotoxicity
Bioavailability
Haemolytic
activity
Cytotoxicity
Cytotoxicity
Accumulation of
drug
in
the
buccal
mucosa of rabbit

Reference
9
10

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Fever
and
Hyperlipidemia

Ex-vivo
Permeation study

48

Pig skin

Temozolamide

Antisense
Oligonucleotides

Poly
(valerolactoneallylvalerolactone)
and
poly
(valerolactoneallylvalerolactone
-oxepanedione)

Brain tumours

Sodium alginate
Poly L-lysine

Cancer therapy,
Viral infections,
Pathologic disorders

Drug
study

release

49
Pharmacokinetic
Studies
In-vitro release

Acyclovir

Voriconazole

-cyclodextrin

Ethyl cellulose
Polyvinyl alcohol

Viral infections

Fungal infections

Cellular uptake
Cytotoxicity
Antiviral activity
Antifungal
activity
In-vitro
In-vivo

Bovine
serum
albumin (BSA)

-cyclodextrin

In-vitro and in
-vivo studies

Viral,
malignant,
autoimmune
diseases

In-vitro release

Mice
50
Multicompartment
rotating cells with dialysis
membrane
Vero cells
Vero cells

51

HSV-1 MRC

Against Candida albicans

Male Wistar rats
Dialysis bag

52

53

10.2. Nanosponges as Biocatalysts Carrier

Nanosponges act as carriers in the delivery of enzymes, proteins, vaccines and antibodies. Many industrial processes
involving chemical transformation are associated with operational disadvantages. Non-specific reactions lead to low
yields, and the frequent need to operate at high temperatures and pressures requires consumption of large amounts of
energy, and very large amounts of cooling water in the down-stream process. All these drawbacks can be eliminated
or significantly reduced by using enzymes as biocatalysts. These enzymes operate under mild reaction conditions,
have higher action speed, and are highly specific. They have a beneficial effect on environment because they reduce
energy consumption and reduce production of pollutants. Developments in genetic engineering have increased the
stability, economy, specificity of enzymes and number of their industrial applications is continually increasing day
by day. Examples of industrially useful enzymes include alpha amylase, trypsin, cellulose and pectinase for fruit
juice clarification processes, ligninase to breakdown lignin, lipase in the detergent industry and biodiesel production
etc. The catalytic activity of enzymes depends mainly on the correct orientation of the active site [20].
Proteins, peptides, enzymes and derivatives thereof also can be used in the biomedical and therapeutic field.
Proteolytic enzymes can be used to treat cancer or type I mucopolysaccharidosis, while DNA and oligonucleotides
are used in gene therapy. The administration of these molecules presents various problems and limitations. Most
protein drugs are poorly absorbed through the biological membranes due to the some factors such as large molecular
size, hydrophilic nature, degree of ionization, high surface charge, chemical and enzymatic instability and low
permeability through mucous membranes. Following intravenous administration, protein molecules may be rapidly
cleared from blood, bind to plasma proteins, and sensitive towards proteolytic enzymes. With oral administration
bioavailability is the problem. Various approaches exist for therapeutic use, such as increasing the dose or using
absorption promoters, which can cause toxicity problems [20, 53].
A number of systems for carrying enzymes and proteins have been developed, such as nano and microparticles,
liposomes and hydrogels. Carriage in a particular system can protect proteins from breakdown, modify their
pharmacokinetics and improve their stability in-vivo. Now, it has been found that cyclodextrin based nanosponges
are particularly suitable carrier to adsorb proteins, enzymes, antibodies and macromolecules. In particular when
enzymes are used, it is possible to maintain their activity, efficiency, prolong their operation and extends the pH and
temperature range of activity and allows the conduct of continuous flow processes. Moreover, proteins and other
macromolecules can be carried by adsorbing or encapsulating them in cyclodextrin nanosponges [20].
10.3. For Protein Delivery
Bovine serum albumin (BSA) protein in solution is not stable; hence it is stored in lyophilized state. However
proteins can reversibly denatured on lyophilisation and adopts conformation markedly different from native
structure. Major drawback in protein formulation and development is to maintain its native structure during

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processing and long term storage. In the nanosponges based approach proteins like BSA are encapsulated in
swellable cyclodextrin based poly(amidoamine) nanosponges to increase the stability of proteins [53].
10.4. In Anti-cancer Therapy
Nanosponges carrying anticancer drugs effectively slow tumour growth, researcher at Vanderbilt University have
developed nanosponges which can be used as delivery system for anticancer drugs to tumours. They claim that the
method is three to five times more effective at reducing tumour growth than direct injection of the drugs. The tiny
nanosponges are filled with a drug load and expose at targeting peptide that binds to radiation-induced cell surface
receptors on the tumour. When the sponges encounter tumour cells they stick to the surface and are triggered to
release their cargo. Benefits of targeted drug delivery include more effective treatment at the same dose and fewer
side-effects. Studies so far have been carried out in animals with paclitaxel as the sponge load. The researchers have
recorded the response of two different tumour types in animal studies: slow-growing human breast cancer and fastacting mouse glioma- to single injections. The particle holds an anticancer drug that it releases gradually as it
decomposes. Peptides linkers are shown with the ball and stick representation, although only two are shown in the
illustration in Figure 2, about three dozen are attached to the surface of actual particles. The linkers are specially
configured to bind to the surface of irradiated cancer cells. In both cases, they found that the delivery through
nanosponges increased the death of cancer cells and delayed tumour growth compared with other chemotherapy
approaches [54].

Figure 2: Nanosponge particle attaching to human breast cancer cells

Camptothecin, a plant alkaloid and a potent antitumor agent, has a limited therapeutic utility because of its poor
aqueous solubility, lactone ring instability and serious side effects. Cyclodextrins based nanosponges are a novel
class of cross-linked derivatives of cyclodextrin. They have been used to increase the solubility of poorly soluble
actives, to protect the labile groups and control the release [22].
10.5. In Anti-mycotic Therapy
Econazole nitrate, an antifungal agent used topically to relive the symptoms of superficial candidiasis,
dermatophytosis and skin infections available in cream, ointment, lotion and solution. Adsorption is not significant
when econazole nitrate is applied to skin and required high concentration of active agents to be incorporated for
effective therapy. Thus econazole nitrate nanosponges were fabricated by emulsion solvent diffusion method and
these nanosponges were loaded in hydrogel as a local depot for sustained drug release [15]. Itraconazole is a BCS
class-II drug that has a dissolution rate limited poor bioavailability, hence to enhance the solubility of it (eventually
for high bioavailability) in a work nanosponges of -cyclodextrin cross-linked with carbonate bonds were prepared
and loaded with itraconazole, where enhanced solubility is reported [17].
10.6. In Anti-viral Therapy
Nanosponges can be useful in the ocular, nasal and pulmonary administration routes. The selective delivery of
antiviral drugs or small interfering RNA (siRNA) to the nasal epithelia and lungs can be accomplished by

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nanocarriers in order to target viruses that infect the RTI such as respiratory sinctial virus, influenza virus and
rhinovirus. They can also be used for Human Immunodeficiency Virus (HIV), Hepatitis-B Virus (HBV) and Herpes
Simplex Virus (HSV). The drugs which are formulated in nano delivery systems are zidovudine, saquinavir,
interferon-, acyclovir, nelfinavir etc. [48].
10.7. Other Applications
10.7.1. Biomedical Applications
Cyclodextrin based carbonate nanosponges were used to form inclusion complexes with three different gases i.e.
methylcyclopropene, oxygen and carbon dioxide. The complexation of oxygen or carbon dioxide could be useful for
many biomedical applications. In particular the oxygen filled nanosponges could supply oxygen to the hypoxic
tissues which are present in various diseases [55,56]. Nanosponges can selectively soak up biomarkers for the
diagnosis. One study concluded that nanosponges can harvest rare cancer marker from blood [57].
10.7.2. Analytical Applications
The microporous hypercross-linked nanosponges have been used in selective preparation of inorganic electrolytes
by size exclusion chromatography. The three dimensional nanosponges will play important role in the
fractionalization of peptides for proteomic applications [58].
10.7.3. For Hydrogen Storage
Hydrogen is considered as an alternative energy for the future, but one of the problems to be solved before it
achieves the versatility of other fuel sources as oil is how to store it. Recent studies claim to find materials that could
act as sponges that absorb hydrogen and store it until ready to use. But until now had not found a material with the
capability to store hydrogen under the necessary pressure and temperature. A team of scientists from the Universities
of Newcastle and Liverpool have discovered a new class of materials which composed of long carbon chains linked
by metal atoms. To crystallize, these molecules form cavities that are less than a nanometer, which are connected by
windows that are even smaller than a molecule of hydrogen. While these cavities are filled, hydrogen fits through
the windows, because the carbon chains are flexible. But once filled the cavities, the chains lose their flexibility,
thus closing the windows. Consequently, it can be loading the high-pressure hydrogen gas, and when pressure levels
drop, forming a sort of molecular size seal. Although so far the materials created by this team of scientists do not
have enough capacity for most applications that use fuel cells, their work represents a new approach to the problem,
and nanosponges could potentially have a key role in the hydrogen storage system in future [59-61].
10.7.4. In Agriculture
Plants that grow more have a better appearance, what counts is not just the climate, but technology. This is so for
functionalized nanosponges (FNS), an agricultural invention that allows plants to grow more and improve their
appearance by feeding them with an optimal dosage of micro-nutrients and active ingredients that are necessary for
healthy growth. Another notable advantage is that nanosponges allow a significant reduction in the use of herbicides
and fertilizers, thereby increasing productivity and improving both the environmental and cultivation quality levels.
Nutritive substances (such as iron and zinc), or active ingredients, are encapsulated in the nano-cavities during the
synthesis process. The nutritive substances incorporated in the nanosponges are dosed and fed to the plants in a very
precise manner, drop by drop, thereby optimising photosynthesis. The significant reduction in the use of fertilizers
makes their cultivation similar to that of organic products, although production levels are much higher. This means
lower production costs and access to healthier food for many more people. For example, FNSs with iron solve one of
the most common problems with plants, ironchlorosis (yellowing of leaves), thereby allowing a more efficient
photosynthesis conversions and higher plant growth rate. One of the major advantages of this innovative product is
the possibility of making ad-hoc formulations for diverse applications [13, 55].
10.7.5. In Floriculture
Nanosponges have been recently developed and proposed for delivering nutrients, preservative and anti-ethylene
compounds in order to improve cut off flower life [12, 60].
10.7.6. In Food Industry
Nanosponges are useful for masking, reduction and elimination of bitter components from fruit juices and other
dietary products by selective combination of polymer and cross-linker [55].
10.7.7. For Water Purification
Cyclodextrin nanosponges can be used for the removal of organic pollutants from water. -cyclodextrin
nanosponges are completely insoluble in water, have the property of encapsulating organic pollutants from water.
Ceramic porous filters can be impregnated with these nanosponges resulting in hybrid organic/inorganic filter
modules. These hybrid filter modules were tested for the effective purification of water, employing a variety of

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water pollutants. It has been established that polycyclic aromatic hydrocarbons (PAHs) can be removed very
efficiently (>95%). Representatives of the pollutant group of trihalogen methanes (THMs), monoaromatic
hydrocarbons (BTX), and pesticides (simazine) can also be removed (>80%) [62]. Cyclodextrin nanosponges can
strongly bind organic molecules and remove them from water even at very low concentrations [12, 19].
10.7.8. For Oil Cleaning
Nanotechnology allows for the creation of new materials with unique and enhanced properties, and has specific
implications for the electronics and biomedical industries. One of the latest nanotech discoveries came through
researchers at Rice University and Penn State. They found that adding boron to carbon during nanotube construction
creates spongy blocks that have amazing oil absorbing properties. The nanosponges are extremely hydrophobic,
giving it the natural tendency to float on water and not absorb it even when submerged. It is also ferromagnetic,
meaning it can be controlled or retrieved using a magnet. The density of the material is extremely low, making the
available volume for oil uptake very high. Not only can it soak up over 100 times its weight in oil as it floats on the
water, but it can store the oil for later retrieval. The oil can then be squeezed out or burned off, allowing the sponge
to be reused. The researchers also tested the sponge robustness and reusability in the lab, where it maintained
elasticity even after 10,000 compressions. Safe to say, this material has tremendous power as an agent for surface oil
cleanup [12, 63].
10.7.9. As Chemical Sensors
Metal oxide nanosponges as chemical sensors used in highly sensitive detection of hydrogen using nanosponge
titania. In a nanosponge structure, however there are no contact points, consequently there is much less hindrance to
electron transport and results in higher sensor stability. 3-dimensionally (3D) interconnected nanosponge titania
(NST) is highly sensitive to H2 gas. 3D interconnected metal oxide nanostructure is a promising class of sensor
material through which the ultra-high chemical sensitivity of nanostructures can be harnessed in practical devices
[64].
10.7.10. As Novel Flame Retardants
A novel flame retardant in tumescent system, aimed to improve the fire stability of ethylene vinyl acetate copolymer
(EVA), has been prepared by melt blending of the copolymer and a complex of cyclodextrin nanospongephosphorus compounds. As compared to traditional systems, this complex is stable in processing conditions, has the
advantage that nanosponges act as both carbon sources and foam forming agents while the phosphorus compounds
are able to directly generate phosphoric acid in-situ. In this context, cyclodextrin nanosponges undergo dehydration
in presence of the acid source, generating water vapour and char, and thus protecting the copolymer against
combustion [12, 65].
10.8. Against Pore Forming Toxins and Superbug Infections
Detoxification treatments such as toxin-targeted anti-virulence therapy offer ways to cleanse the body of virulence
factors that are caused by bacterial infections, venomous injuries and biological weaponry. Because detoxification
platforms existing such as antisera, monoclonal antibodies, small-molecule inhibitors and molecularly imprinted
polymers act by targeting the molecular structures of toxins; customized treatments are required for different
diseases. Researchers at the University of California, San Diego prepared biomimetic toxin nanosponges that
functions as a toxin decoy in-vivo. The nanosponges are consists of a polymeric nanoparticle core surrounded by red
blood cell (RBC) membranes, absorbs membrane damaging toxins and diverts them away from their cellular targets,
combating drug-resistant infections (Figure 3), such as those caused by methicillin-resistant Staphylococcus
aureus (MRSA). One red blood cell membrane can be used as a cloak for more than 3,000 of these stealthy
nanosponges. Once the nanosponges are fully loaded with toxins, they are safely disposed of by the liver. As
reported in a mouse model, the nanosponges markedly reduced the toxicity of staphylococcal alpha-haemolysin (a
toxin) and thus improved the survival rate of toxin-challenged mice. This biologically inspired toxin nanosponge
presents a detoxification treatment that can potentially treat a variety of injuries and diseases caused by poreforming toxins [66].
10.9. Micropatterning of Mammalian Cell
Developing artificial scaffolding structures in-vitro in order to mimic physiological-relevant situations in-vivo is
critical in many biological and medical arenas including bone and cartilage generation, biomaterials, small-scale
biomedical devices, tissue engineering, as well as the development of nanofabrication methods. Group of
researchers, using simple physical principles (photolithography) and chemical techniques (liquid vapour deposition)
build non-cytotoxic scaffolds with a nanometer resolution using silicon substrates as the backbone. This method
merges an optics-based approach with chemical restructuring to modify the surface properties. Through this
nanofabrication-based approach, they developed hydrophobic oxidized silicon nanosponges and then probed cellular
responses-examining cytoskeletal and morphological changes in living cells through a combination of fluorescence

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microscopy and scanning electron microscopy-via culturing Chinese hamster ovary cells, HIG-82 fibroblasts and
Madin-Darby canine kidney cells on these silicon nanosponges. This study has demonstrated the potential
applications of using these silicon-based nanosponges for influencing cellular behaviours at desired locations with a
micro or nanometer level [67].

Figure 3: Rendering of biomimetic nanosponges attracting bloodstream-borne toxins

CONCLUSION
With demand for innovative and highly efficient pharmaceutical and cosmetic products, the market holds
considerable potential for nanosponge technology based formulations and the versatility they offer. As formulators
consider new and creative ways to deliver actives, they can realize the full capabilities of these unique assets
providing enhanced safety, improved stability, reduced side effects, enhanced multi-functionality and improved
ingredient compatibility. Complemented by novel development approaches and creative formulation techniques,
nanosponge delivery systems can be a promising strategy for a new generation of pharmaceuticals and
cosmeceuticals. Nanosponges have many distinct advantages over existing conventional topical dosage forms for the
treatment of topical diseases; in addition it is a one of its kind technology for the controlled release by means of oral
as well as targeted drug delivery. So microsponge drug delivery system has got a lot of potential and is a very
emerging field which is needed to be explored further in the future with most research emphasis.
12. Future Perspectives
Nanosponge drug delivery system holds a promising opportunity in various pharmaceutical applications in the
upcoming future due to its unique characteristics; which makes it supple to design and develop novel product forms.
The actual challenge in future is the progression of the delivery systems for oral peptide and other susceptible
biomers. The use of bioerodible and biodegradable polymers for drug delivery is enabling it for the safe delivery of
the actives via diverse routes. As these porous systems have also been studied for drug delivery through pulmonary
route; which depicted that these system has effective drug release even in the scarce of the dissolution fluid, thus
colon targeted delivery may be able to expand like such as never before. Nanosponge particles can also be implied
in cell culture media, leading to a new loom in stem cell culture, cellular regeneration in the body and cytology.
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