Wakure et al., IJPSR, 2022; Vol. 12(10): 5570-5583.

E-ISSN: 0975-8232; P-ISSN: 2320-5148

IJPSR (2021), Volume 12, Issue 10 (Research Article)

Received on 15 July 2021; received in revised form, 25 August 2021; accepted, 28 August 2021; published 01 October 2021

NANOSPONGES AS NOVEL CARRIER FOR TOPICAL DELIVERY OF LULICONAZOLE -AN

ANTIFUNGAL DRUG
B. S. Wakure *, M. A. Salunke, P. T. Mane, S. R. Awale, R. D. Shinde and S. S. Eklinge
Vilasrao Deshmukh Foundation, Group of Institutions, VDF School of Pharmacy, Latur - 413531,
Maharashtra, India.
Keywords: ABSTRACT: The main goal of this work is to formulate nanosponges
Nanosponges; Luliconazole, and access its suitability to deliver Luliconazole for topical application, to
Antifungal activity, Topical improve its therapeutic effect, better dispersion and good storage.
nanosponge gels Nanosponges are water-soluble, which does not mean that molecules are
Correspondence to Author: chemically decomposed in water but that nanosponge particles are mixed
Dr. B. S. Wakure with water and used as a carrier fluid. Compared with traditional drug
Principal, delivery methods, nanosponges have several advantages. Using polyvinyl
Vilasrao Deshmukh Foundation, alcohol as a surfactant, a nanosponge with ethyl cellulose as a polymer
Group of Institutions, VDF School of was prepared by the emulsion solvent diffusion method. An optimized
Pharmacy, Latur - 413531, batch of nanosponges with high entrapment efficiency was used to
Maharashtra, India.
formulate the gel with Carbopol 940. The prepared gel was evaluated for
E-mail: [email protected] pH value, viscosity, spreadability, in vitro diffusion study, skin irritation
test and in-vitro antifungal activity. The nanosponge system is non-toxic,
non-irritating, non-allergenic, and non-mutagenic. Nanosponge gel as a
local drug delivery system has a huge potential, with better antifungal
activity and stability. These small sponges loaded with luliconazole
proved to be better scaffold for topical application.
INTRODUCTION: The development of a wide increase the solubility of poorly water-soluble
range of nanotechnology has begun to change the molecules 2. Nanosponge is a virus sized, naturally
basis of disease diagnosis, treatment and degradable scaffold like structure.
prevention. Various nano-devices had a significant
impact on medical technology, greatly improving
the efficacy of many existing drugs and enabling
the construction of brand-new treatment methods.
Nanosponge is a new type of material with a cavity
of a few nanometers in size, in which various
substances can be encapsulated 1. These particles
can carry lipophilic and hydrophilic substances and
QUICK RESPONSE CODE
DOI:
10.13040/IJPSR.0975-8232.12(10).5570-83

FIG. 1: AN ARTIST’S PERCEPTION OF A

This article can be accessed online on NANOSPONGE TARGETING A BREAST CANCER
www.ijpsr.com CELL (PEPTIDE LINKERS ARE SHOWN AS BALL
AND STICK MODEL) (CREDIT: HARTH
DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.12(10).5570-83 LABORATORY)

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The long polymer strands are mixed in solution anhydride, Carbonyl diimidazoles, Epichloridrine,
with small molecules called cross-linking, which Glutaraldehyde, 2, 2-bis (acrylamido) Acetic acid,
have affinity for certain parts of polymer 3. They and dichloromethane.
have completely changed the treatment of various
diseases and early trials have shown that this Drug Molecule Compatibility Properties:
technology is five times more effective than
 The drug molecules formulated into
traditional methods in targeting drugs to breast
nanosponges should have certain
cancer cells 4. The artistic perception of
characteristics.
nanosponges is shown in Fig. 1.
 The molecular weight is between 100 and
Drug Release Mechanism of Nanosponges: 400 Daltons.
Sponge atoms have an open arrangement and active
materials can freely enter and exit the particles and  The drug molecule consists of less than 5
enter the carrier until equilibrium is reached. In the fused rings.
case of topical administration, once the finished  The solubility in water is less than 10
product is applied to the target tissue, the active mg/ml.
substance already in the carrier will be absorbed
 The melting point of the substance is below
into into it, depleting the carrier that will become
250 °C 3.
unsaturated, thus disturbing the balance. This will
allow the active substance to flow from the sponge Preparation of Nanosponges:
particles into the carrier and from it to the target Solvent Method: The polymer is mixed with a
tissue, until the carrier dries or is absorbed. Even suitable solvent, especially in polar aprotic solvents
after that, the sponge particles remaining on the such as dimethylformamide, dimethyl sulfoxide.
surface of the tissue will continue to gradually This mixture is then added to an excess of cross-
release the active substance to the tissue, providing linkers, preferably with a crosslinker/polymer
a prolonged release over time 3. molar ratio of 1:4. The reaction is carried out at a
temperature from 100 °C to the reflux temperature
Chemicals Used for the Synthesis of Nano- of the solvent and the time is 1 to 48 h. The
sponges:
preferred cross-linking agents are carbonyl
Polymer: The type of polymer used will affect the
compounds (dimethyl carbonate and carbonyl
formation and performance of the nanosponge. For
diimidazole). After the reaction is complete, let the
complexation, the cavity size of the nanosponge
solution cool at room temperature, then add the
should be suitable for accommodating drug
product to a large amount of excess double-distilled
molecules of a specific size. The ability of the
water, vacuum filter to recover the product, and
polymer to crosslink depends on functional groups
then extend the Soxhlet purification 2.
and reactive groups to be substituted. The choice of
the polymer depends on the desired release and the Emulsion Solvent Diffusion Method: Nano-
drug to be encapsulated 5. Ex- Hyper crosslinked sponges can be prepared using ethyl cellulose and
polystyrenes, cyclodextrin and its derivatives like polyvinyl alcohol in different concentrations.
Alkyloxy carbonyl cyclodextrin, Methyl β- Different ratios of drug to the polymer are used to
Cyclodextrin, 2-Hydroxy Propyl β-Cyclodextrins. improve drug loading and obtain tailored release.
The dispersed phase containing the drug and
Co-polymers: Poly (Valerol-actone-allylvalerol-
polymer dissolved in 20 ml of dichloromethane is
actone), Poly (Valerolactone-allylvalerolactone
slowly added to a certain amount of polyvinyl
oxepanedione), ethylcellulose, polyvinyl alcohol.
alcohol in 100 ml of aqueous external phase, and a
Cross-linkers: The choice of crosslinking agent magnetic or mechanical stirrer is used at a stirring
depends on the structure of the polymer and the speed of 1000-1500 rpm for 3-5 h. The formed
drug to be formulated. Ex: Carbonyl diimidazoles, nanosponges are collected by filtration and dried in
Carboxylic acid dianhydrides, Diphenyl Carbonate, an oven at 40 °C for 24 h and packaged in a
Diaryl carbonates, Diisocyanates, Pyromellitic container 3.

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Ultrasound-assisted Synthesis: In this method, the The polymerization process leads to formation of a
polymer reacts with the cross-linking agent under reservoir-type system that opens on the surface
solvent-free and ultrasonic treatment. Here, the through pores 3.
polymer and cross-linking agents are mixed in the
flask. Place the flask in an ultrasonic bath filled Loading of drug into Nanosponges: Nanosponges
with water, heat it to 90 ºC and sonicate it for 5 h. used for drug delivery should be pre-treated to
Let it cool and wash with water to remove obtain an average particle size below 500 nm. The
unreacted polymer. Purification was performed by nanosponge is suspended in water and sonicated to
prolonged Soxhlet extraction with ethanol. Dry the avoid aggregates and then the suspension is
product under vacuum and store at 25 ºC 6. centrifuged to obtain a colloidal part. The
supernatant is separated and the sample is dried by
Quasi-Emulsion Solvent Diffusion: Nanosponges freeze-drying. Prepare an aqueous suspension of
can also be prepared by the quasi-emulsion solvent nanosponges, disperse the excess drug, and keep
diffusion method using different polymer amounts. the suspension compounded for a specific time
To prepare the internal phase, eudragit RS100 is under continuous stirring. After compounding, the
dissolved in a suitable solvent. Then, the drug can undissolved drug is separated from the complexed
be added to the solution and dissolved under drug by centrifugation. Then, solid crystals of
ultrasound at 35 °C. Pour the inner phase into the nanosponges are obtained by solvent evaporation or
PVA aqueous solution (outer phase) and stir for 1 h freeze-drying.
and then filter the mixture to separate the
nanosponges. The nanosponge is dried in a 40 ºC Factors Influencing the Formation of
air heating oven for 12 h 7. Nanosponge 3, 8:
Polymer and Cross-linkers: The type of polymer
From Hyper Cross-Linked Β-Cyclodextrin: used will affect the formulation and performance of
Here, β-cyclodextrin can be used as a vehicle for the nanosponge. A high-efficiency efficiency cross-
drug delivery. Nanosponges can be obtained by linking transforms the molecular nanocavity into a
reacting cyclodextrin with a crosslinking agent. 3-dimensional nanoporous structure.
Due to the formation of this 3D network, it can be a
roughly spherical structure approximately the size Hydrophilic Nanosponges: They are formed by
of a protein, with channels and pores inside. using epichlorohydrin as a cross-linking agent.
Cyclodextrin reacts with crosslinking agents such Hydrophilic nanosponges can change the drug
as diisocyanate, dicarbonate, etc. The size of the release rate and enhance the absorption of drugs
sponge is controlled according to porosity and across biological barriers, and can also be used as
surface charge density to connect different effective drug carriers even in immediate-release
molecules. Nanosponges can be synthesized in formulations.
neutral or acidic form. The average diameter of the
The Hydrophobic Nanosponge: They can be
nanosponge is less than 1µm, but fractions of size
synthesized using diphenyl carbonate, pyromellitic
less than 500 nm can be selected. They are used to
anhydride, diisocyanate and carbonyl diimidazole
increase the water solubility of poorly water-
as a cross-linking agent. They are used as
soluble drugs. They are composed of solid particles
sustained-release carriers for water-soluble drugs
and transformed into crystalline form 8.
(including peptide and protein drugs).
Polymerization: A non-polar drug solution is
Complexation Temperature: The stability
prepared in the monomer and an aqueous phase, constant of the composite depends on temperature
which usually contains a surfactant and a
changes. The stability constant and temperature rise
dispersing agent, is added to it to promote are negatively correlated. At elevated temperatures,
suspension.
the apparent stability constant decreases due to the
Once the monomer is activated by catalysis or decrease of the drug/nanosponge interaction force.
elevated temperature to establish a suspension of Therefore, thorough temperature control should be
discrete droplets of the desired size. maintained when preparing nanosponges.

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Degree of Substitution: The number, type and X-ray Diffraction and Single Crystal X-ray
position of the substituents on the polymer Structure -Analysis: X-ray diffraction can be used
molecule affect the complexing ability of the to detect inclusion complexes in the solid-state.
nanosponge. The type of substitution is important When the drug molecule is liquid, it does not show
because β-CD derivatives can be obtained in its own diffraction, so the diffraction pattern of the
various forms, which have different functional newly formed substance is obviously different from
groups on the surface of cyclodextrin derivatives. that of the uncomplexed nanosponge. The
When combined with the help of cross-linking, difference in the diffraction patterns indicates the
different functional groups will produce different formation of clathrates. When the drug substance is
types of composite materials (β-CD nanosponges, solid in nature, a comparison must be made
CD- carbamate nanosponges, CD-carbonate between the diffractogram of the hypothetical
nanosponges Etc.). The higher the number of complex and the diffractogram of the mixture of
substitutions and the degree of cross-linking the drug and polymer molecules. The formation of the
more the number of substituents, the greater the inclusion compound between the drug and the
possibility of higher cross-linking. nanosponge changes the diffraction pattern and
changes the drug's crystalline nature. The
Due to the greater interconnection between the sharpening of existing peaks and the appearance of
polymers forming the network, a higher cross- a few new peaks lead to the formation of clathrates
linking, will produce highly porous nanosponges. 5, 10
.
The position of substitution depends on the
production conditions. Since the functional groups Microscopy Studies: Scanning electron
on the parent compound occupy some different microscopy (SEM) and Transmission electron
positions, changes in the production process will microscopy (TEM) can be used to study the
produce materials with different physical and microscopic aspects of drugs, nanosponges, and
chemical properties. products (drug/nanosponge composites). The
difference in the crystalline state of the raw
Characterization of Nanosponges: materials and products observed under the electron
Particle Size and Polydispersity Index: The microscope indicates the formation of clathrates
particle size can be determined by dynamic light (inclusion complexes) 6.
scattering using the 90 Plus particle size analyzer or
laser diffractometer or Malvern Zeta particle size Drug Release Kinetics: In order to study the
analyzer equipped with MAS OPTION particle size mechanism of drug release, we analyzed the drug
analysis software. From this, the average diameter release data using zero-order, first-order, and
and polydispersity index can be determined 9 and Higuchi Kosemeyer-Peppas, Hixon Crowell,
value of polydispersity index is given in Table 1. Kopcha and Makoid-banaker models. The data can
be analyzed using graph pad prism software. The
TABLE 1: POLYDISPERSITY INDEX
software estimates the parameters of non-linear
Polydispersity Index Type of Dispersion
0-0.05 Monodispersed standard functions and provides a close fit between
0.05-0.08 Nearly monodisperse experimental observations and non-linear functions
6
0.08-0.7 Midrange polydispersity .
>0.7 Very polydisperse
Thermoanalytical Methods: The thermal analysis
Resiliency: Depending on the needs of the final method determines whether the API has undergone
formulation, the resilience (viscoelasticity) of the some changes before the nanosponge is thermally
sponge can be modified to produce softer or degraded. The change of the drug substance may be
stronger beads. Increased cross-linking tends to melting, evaporation, decomposition, oxidation or
slow down the release rate. Therefore, by polymorphic transformation. Changes in the drug
considering the release as a function of cross- substance indicate the formation of complexes. The
linking over time, the elasticity of the sponge will thermogram obtained by differential thermal
be studied and optimized according to requirements analysis and differential scanning calorimetry can
9
. be observed for the broadening, movement and

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appearance of new peaks or the disappearance of The phase solubility diagram indicates the degree
some peaks. Changes in weight loss can also of complexation. An Erlenmeyer flask is used in
provide supporting evidence for the formation of this method. Drugs containing different percentages
inclusion complexes 11. of nanosponge aqueous solution were added to the
flask.
Infrared Spectroscopy: The interaction between
nanosponges and solid drug molecules can be The Erlenmeyer flask was stirred on a mechanical
detected by infrared spectroscopy. After the shaker at room temperature until a steady state was
composite is formed, the nanosponge band reached, and the suspension was filtered by
changes. If the fraction of guest molecules wrapped centrifugation using a 3000 Dalton molecular filter
in the complex is less than 25% of the band, it can (MICRON YN 30, Millipore Corporation, Bed ford
be allocated to the included part of the guest MA 1730 USA). The solution was analyzed and the
molecule, which is easily concealed by the spectral drug concentration is determined by high-
band of the nanosponge. Infrared spectroscopy is performance liquid chromatography 11.
suitable for drugs with characteristic bands such as
carbonyl or sulfonyl. This spectroscopic study Zeta Potential: Zeta potential is used to measure
revealed information about the participation of surface charge by using additional electrodes in the
hydrogen in various functional groups. This usually particle size measuring device. In this process, take
shifts the absorption band to a lower frequency, out the sample containing the nanosponge, dilute it
increases the strength, and widens the absorption with 0.1 mol/L KCl and put it in the electrophoresis
band caused by the stretching vibration of the cell and apply a 15V/cm electric field. Thus, the
groups participating in the formation of hydrogen average hydrodynamic diameter and polydispersity
bonds. The hydrogen bond at the hydroxyl group index are determined after averaging the total
causes the maximum displacement of the stretching measured values 11.
vibration band 11.
Dissolution Test: The dissolution profile of
Thin Layer Chromatography: In thin-layer nanosponges can be studied using the dissolution
chromatography, the Rf value of the drug molecule device USP XXIII, which has a modified basket
is reduced to a considerable extent, which helps to composed of 5m stainless steel mesh and a rotation
determine the complex formation between the drug speed of 150 rpm. When selecting the dissolution
and the nanosponge. medium, consider the solubility of the active
substance to ensure sink conditions. The sample
Loading Efficiency and Production Yield: The from the dissolution medium can be analyzed by a
loading efficiency (%) of the nanosponge can be suitable analytical method.
calculated according to the following formula.
Applications of Nanosponges:
Loading efficiency = Actual drug contents in NS/Theoretical Solubility Enhancement: Nanosponges can
drug content × 100 improve the wettability and solubility of molecules
After determining the accurate initial weight of the with poor solubility in water. The drug can be
raw materials and the final weight of the resulting molecularly dispersed in the nanosponge structure
nanosponge, the production yield of the and then released as a molecule, avoiding the
nanosponge can be calculated by the following dissolution step.
formula. Therefore, the apparent solubility of the drug can
be increased. Many formulations and bio-
Production yield = Practical mass of NS/Theoretical mass
(Polymer + drug) × 100
availability problems can be solved by improving
the solubility and dissolution of substances and
Solubility Studies: Higuchi and Connors describe nanosponges can greatly improve the solubility of
a method for studying inclusion complexation, that drugs 9. Table 2 provides BCS class II drugs with
is, a phase solubility method for detecting the very low solubility, which are ideal candidates for
solubility of drugs in nanosponges. nanosponges

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TABLE 2: BIOPHARMACEUTICAL CLASSIFICATION SYSTEM CLASS II DRUGS

S. no. Category Drugs
1 Antihypertensive Felodipine, Nicardipine, Nifedipine, Nisoldipine
2 Antibiotics Azithromycin, Ciprofloxacin, Erythromycin, Ofloxacin,
3 Antiarrhythmic agents Amiodaronehydro chloride
4 Antifungal agents Econazolenitrate, Griseofulvin, Itraconazole, Ketoconazole
5 Antidiabetic and Atorvastatin, Fenofibrate, Glibenclamide, Glipizide, Lovastatin, Troglitazone
Antihyperlipidemic
6 NSAIDs Dapsone, Diclofenac, Diflunisal, Etodolac, Etoricoxib, Flurbiprofen,
Ibuprofen, Indomethacin, Ketoprofen, Mefenamicacid, Naproxen, Nimesulide,
Oxaprozin, Piroxicam
7 Cardiac drugs Carvedilol, Digoxin, Talinolol
8 Anticoagulant Warfarin
9 Anticonvulsants Carbamazepine, Clonazepam, Felbamate, Oxycarbazepine, Primidone.
10 Antipsychotic drugs Chlorpromazine Hydrochloride Antiretrovirals Indinavir, Nelfinavir,
Ritonavir, Saquinavir
11 Antianxiety drugs Lorazepam
12 Antiepileptic drugs and Steroids Phenytoin, Danazol, Dexamethasone
13 Immuno suppressants Cyclosporine, Sirolimus, Tacrolimus
14 Antiulcer drugs Lansoprazole, Omeprazole
15 Antioxidants Resveratrol
16 Diuretics Chlorthalidone, Spironolactone
17 Antineoplastic agents Camptothecin, Docetaxel, Etoposide, Exemestane, Flutamide, Irinotecan,
Paclitaxel, Raloxifene, Tamoxifen, Temozolomide
18 Miscellaneous Atovaquone, Melarsoprol, Phenazopyridine, Ziprasidone

Nanosponges for Drug Delivery: Nanosponges Nanosponges Serve as the Carrier of

are solid in nature and can be formulated into oral, Biocatalysts and the Delivery and Release of
parenteral, topical or inhalation dosage forms. Enzymes, Proteins, Vaccines and Antibodies:
Many systems for carrying enzymes and proteins
For oral administration, the complex can be have been developed, such as nanoparticles and
dispersed in a matrix suitable for the preparation of microparticles, liposomes and hydrogels. The
capsules or tablets with excipients, diluents, carrier in a specific system can protect proteins
lubricants, and anti-caking agents. For parenteral from decomposition, change their
administration, the complex can simply be carried pharmacokinetics and improve their in-vivo
in sterile water, saline or other aqueous solutions. stability. Now, it has been found that nanosponges
For topical administration, they can be effectively based on cyclodextrin are particularly suitable for
incorporated into topical hydrogels 12. adsorbing proteins, enzymes, antibodies and
macromolecules.
Topical Agents: The nanosponge delivery system
is a unique technology used to control the release Especially when enzymes are used, they can
of topical drugs that extend drug release and maintain their activity, efficiency, extend their
retention of drug form on the skin. operation and extend the active pH and temperature
range and allow continuous flow processes. In
Local anesthetics, antifungals, and antibiotics
addition, proteins and other macromolecules can be
belong to the category of drugs that can be easily
carried by adsorbing or encapsulating them in
formulated into topical nanosponges. When the
cyclodextrin nanosponges 13.
active ingredient penetrates into the skin, a rash or
more serious side effects may occur. Nanosponges as a Carrier for Delivery of Gases:
Gas plays an important role in medicine, whether it
In contrast, this technology allows for a uniform
is used for diagnostic or therapeutic purposes. The
and sustained release rate, reducing irritation while
lack of an adequate supply of oxygen, called
maintaining efficiency. A variety of substances can
hypoxia, is associated with various pathologies,
be incorporated into the formulated product, such
from inflammation to cancer. In clinical practice, it
as gels, lotions, creams, ointments, liquids, or
is sometimes difficult to deliver oxygen in an
powders 10.

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appropriate form and dose. Cavalli et al. develop Removal of Organic Pollutants from Water: β-
nanosponge formula as an oxygen delivery system cyclodextrin nanosponges are completely insoluble
for topical application, with the ability to store and in water and have the characteristics of
release oxygen slowly over time 11. encapsulating organic pollutants in water. Ceramic
porous filters can be impregnated with these
Nanosponges AS Protective Agent against Photo nanosponges to form organic/inorganic hybrid filter
Degradation: Sapino et al. reported that γ- modules. These hybrid filter modules have been
Oryzanol (a mixture of ferulic acid esters) is an tested to purify water, employing a variety of water
antioxidant, usually used to stabilize food and pollutants effectively. It has been determined that
pharmaceutical raw materials and also used as a polycyclic aromatic hydrocarbons (PAH) can be
sunscreen in the cosmetics industry. Due to its high removed very effectively (over 95%). It can also
instability and photodegradability, its application is remove representatives of pollutant groups such as
limited. Nanosponges are prepared by trihalomethanes (THM), monoaromatic hydro-
encapsulating γ-Oryzanol and show good carbons (BTX) and pesticides (simazine). Table 3
protection from photodegradation. The enlist various research studies done on the
nanosponges loaded with gamma oryzanol can be formulation of nanosponges of various drugs for
formulated as gels and O/W emulsions 2. the desirable characteristics.
TABLE 3: VARIOUS EXAMPLES OF NANOSPONGES
Drug Nanosponge Vehicle Category of drug Study
Itraconazole Beta cyclodextrin and Antifungal Solubility
copolyvidonum
Voriconazole Ethyl cellulose, Poly methyl Antifungal Drug release
methacrylate (PMMA), PluronicF-
68.
Miconazole Beta cyclodextrin, Di- Antifungal Drug release
Nitrate phenylcarbonate
Celecoxib Beta cyclodextrin, N,N methylene NSAID Solubility
diacylamine
Erlotinib Beta cyclodextrin Tyrosine kinase inhibitor Solubility, bioavailability and
(Anticancer) In-vitro
cytotoxicity
Econazole Nitrate Ethyl cellulose, PVA Antifungal Irritation study, Adsorption
Isoniazid Ethyl cellulose, PVA Anti-tubercular Drug release
Cephalexin Ethyl cellulose, PVA Antibiotic Drug release and stability
Norfloxacin Beta cyclodextrin and Diphenyl Antibiotic Bioavailability
carbonate
L-Dopa Beta cyclodextrin Parkinson’s Disease Drug release
Fenofibrate Maize starch, SDS Fibrate Solubility and Bioavailability
Nifedipine Beta cyclodextrin Calcium-channel blocker Solubility
Glipizide Beta cyclodextrin Sulfonylurea Drug release
Ibuprofen Ethylcellulose and PVA NSAID Drug release
Resveratrol Cyclodextrin Antioxidant Stability, cytotoxicity and
permeation
Paclitaxel Beta cyclodextrin Antineoplastic Bioavailability
Camptothecin Beta cyclodextrin Antineoplastic Stability and solubility
Tamoxifen Beta cyclodextrin Antiestrogen Solubility
Temozolomide Poly(valerolactineallylvalerolactone) Antitumor Drug release
and poly
(Valerolactoneallylvalerolactoneoxe
panedione)
Dexamethasone Beta cyclodextrin Antitumor Drug release
γ-Oryzanol Beta cyclodextrin Anti-oxidant Stability
Telmisartan Carbonated cross-linkers Antihypertensive Dissolution rate
Lysozyme Cyclodextrin-based poly Enzyme Solubility and drug release
(amidoamine)
Nelfinavir Mesylate Beta cyclodextrin Antiviral Solubility and drug release

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Formulation of Luliconazole Loaded Nano- improve the entry of sedative atoms encapsulated
sponges: Topical drug administration refers to the by ineffective solvents. One of the fascinating
application of a drug-containing preparation to the elements is the possibility of nanosponges. For this
skin or mucosal surface to directly treat skin reason, the frame must be connected to the
diseases or the skin manifestations of systemic commonly used skin carrier. For example, the gel
diseases, with the purpose of limiting the keeps in mind that the ultimate goal is to have
pharmacological or other effects of the drug to the proper semi-solid consistency. Therefore, this
surface of the skin or within the skin 14. The method was chosen to combine the nanosponge
combination of active ingredients and base technology with the principle of transdermal drug
provides opportunities for a wide range of topical delivery to improve the systemic and local
formulations, such as gels, creams, foams, administration of luliconazole, thereby effectively
ointments, lotions, etc., which are suitable for transferring the drug to the skin 17.
various types of drug delivery and therapeutic
terms, and are used to perform topical formulations Material: The following materials are used with
on the base. AR/LR grades or the best grades available,
provided by the manufacturer without further
The classification is based on their physical purification or investigation. The drug luliconazole
properties or their intended use or their used was a gift sample from Mankind Pharma Ltd
composition, in which therapeutically active in Delhi. Ethylcellulose, DMSO Carbopol 940,
ingredients are incorporated. The outcome of HMPC, polyvinyl alcohol, sodium alginate, gum
topical dermatological drug treatment is arabic, methylparaben, and propylparaben were
significantly affected by choice of carrier or purchased from Scientific Chemicals, Latur. All
delivery system. Examples of the most common reagents and solvents used in the research are of
dosage forms for topical dosage forms include pharmacopeial grade and analytical grade.
solutions, suspensions, emulsions (such as lotions),
semi-solids (ointments, creams, pastes, gels), solids Preparation of Ethyl Cellulose Nanosponges:
such as powders and aerosols, sprays 4, 15. Porous The ethyl cellulose-based nanosponge is prepared
polymer delivery systems, in which small spherical by the emulsion solvent diffusion method using
particles with large porous surfaces are called polymer and a crosslinking agent. For each ratio,
nanosponges, are used to passively target cosmetics the dispersed phase with polymer, cross-linking
to the skin to avoid systemic absorption. agent (PVA) is accurately weighed and dissolved in
Nanosponges can encapsulate a variety of the solvent DMSO. Finally, the homogenized ethyl
substances. cellulose and DMSO are placed in an Erlenmeyer
flask. The mixture was added to the water phase
They have the ability to solubilize poorly soluble and then continuously stirred on a magnetic stirrer
drugs and extend the release of drugs by increasing at 1000 rpm for three hours. The reaction mixture
their bioavailability. Due to the internal was cooled, and the required nanosponges were
hydrophobic cavity and external hydrophilic collected through a filtration process, and the
branches, both hydrophilic and lipophilic drug nanosponges were purified by acetone and kept in
molecules can be loaded into the nanosponge 16. an oven for drying at 40°C. for 12 h. After
Now, targeted drug delivery has always been a purification, store the nanosponges at 250°C for
long-term problem for medical researchers. How to further use.
deliver the drug to the body at the right place at the
right time, how to control the release of the drug, Preparation of Luliconazole-loaded
its effect on the body, its therapeutic effect, safety, Nanosponges: Luliconazole was loaded into ethyl
how to control the release to prevent overdose cellulose nanosponges by solvent evaporation
effects. The use of nanotechnology has solved these technology. The solvents used are acetone and
problems with the aid of nanosponges. This ethanol. Mix the ethylcellulose nanosponge with a
nanosponge can easily target specifically targeted suitable solvent (organic phase) in 100ml.
cells or tissues 17. For feasible and useful Preferably, the mixture is added to the excess
treatments, different methods have been used to cross-linking agent in a ratio of 4:16. i.e Dissolve

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4000 mg luliconazole drug in 100 ml solvent. The nanosponges and disperse them in distilled water
reaction proceeds at 100 °C until the solvent is by ultrasonic treatment to form a nano-suspension.
refluxed for 1-48 h. The solution was cooled at Disperse 250 mg of gelling agent in 5 ml of
room temperature, and distilled water was added. distilled water and allow for swelling overnight.
Filter the mixture. The product was recovered by Use different gelling agents, such as Carbopol940,
filtration and dried in an oven at 40 °C. gum arabic, HPMC, sodium alginate. Stir
continuously in a magnetic stirrer for 1-2 h and add
Formulation of Topical Gel Containing the weighed other excipients to the previously
Luliconazole Loaded Nanosponges: The dried soaked Carbopo l940. Triethanolamine was used to
drug-encapsulated nanosponges were collected and adjust the pH. Transfer the gel to a graduated
transfer the required amount of drug equivalent to cylinder and makeup to 20 ml with distilled water.
the nanosponges, that is, 0.2 gm, into a 250 ml
volumetric flask containing 100 ml of ethanol to TABLE 4: FORMULA FOR NANOSPONGES
remove free unencapsulated drugs by dissolving in Ingredients NS1 NS2 NS3 NS4
Ratio 1:1 1:2 1:3 1:4
ethanol. The drug-encapsulated nanosponge is Ethyl cellulose (mg) 60 120 180 240
separated from the free drug by membrane DMSO (ml) 20 20 20 20
filtration. Collect the remaining drug-loaded %PVA(in 100 ml) 0.5 0.5 0.5 0.5

TABLE 5: COMPOSITION OF LULICONAZOLE NANOSPONGES GELS CONTAINING VARIOUS POLYMERS

Ingredients NS1 NS2 NS3 NS4 NS5 NS6
Nanosponges(gm) 0.2 0.2 0.2 0.2 0.2 0.2
Sod.alginate(gm) 1 - - - 0.5 -
HPMC K-15(gm) - 1 - - 0.5 0.5
Acacia(gm) - - 1 - - 0.5
Carbopol934(gm) - - - 1 - -
MethylParaben(mg) 0.1 0.1 0.1 0.1 0.1 0.1
PropylParaben(mg) 0.05 0.05 0.05 0.05 0.05 0.05
DMSO(ml) 10 10 10 10 10 10
Water(ml) 20 20 20 20 20 20

Evaluation of Nanosponges: Actual Drug Content: An accurately weighed

Physical Appearance: The physical appearance of equal amount (10 mg) of the nanosponge
the prepared nanosponge was observed with naked containing the drug was continuously stirred for
eyes. A white spongy powder was observed. The one hour in 100 ml of phosphate buffer pH 7.4
spherical appearance of the nanosponge depends on solution. Use an ultraviolet spectrophotometer to
the viscosity of the ethylcellulose solution. analyze further the filtered sample at 296 nm next
to the blank. Estimation of drug content for all
Production Yield: The production yield was batches was done using the following expressions:
determined by the following formula.
Actual Drug content (%) = Nact/Nms × 100
Production yield = Practicle mass of nanosponges /
Theoretical mass (drug + polymer) × 100 Where Nact = actual luliconazole content in the
weighed quantity of nanosponges, Nms = weighed
Drug Entrapment Efficiency: Accurately weigh quantity of nanosponges and ‘N’ is the theoretical
10 mg of nanosponge and suspend it in 100 ml of
Luliconazole content in nanosponges.
phosphate pH 6.8 buffer solution. After that, the
solution was filtered through filter paper, an Swelling and Water uptake: The prepared
appropriate dilution was made from the filtrate, and nanosponge was immersed in an aqueous solvent to
the absorbance was measured at 296 nm using a determine the swelling and water absorption rate.
(Shimadzu UV1800) dual-beam UV spectro- Swelling index and water uptake were calculated
photometer. The entrapment efficiency is using the equation.
determined by the following formula,
Swelling index = (Mass of Hydrogel after 72 h)/(Initial mass
Entrapment efficiency = (Total drug-free drug)/(Total drug ) of polymer) × 100
× 100

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Water uptake = (Mass of Hydrogel after 72 h)/(Initial mass of receptor compartment is filled with phosphate-
polymer) × 100 buffered saline (PBS) of pH 7.4. The cut-out
Infrared Spectroscopy: The FTIR spectrum of dialysis membrane was used for the study. The
luliconazole nanosponge formulation batches was entire device was placed on a thermostatic
recorded in the wavelength range of 4000 to 400 magnetic stirrer, and the temperature was
cm-1. The characteristics of IR absorption peaks of maintained at 37 °C during the entire study. The
luliconazole were studied. study lasted for 6 h. regular. The sample was taken
out and analyzed by spectrophotometry at 296 nm.
Particle Size: The average particle size analysis
was performed with the help of a zeta sizer Skin Irritation Test: In this study, all experiments
(Malvern) to evaluate the effect of polymer were performed with the permission of the Animal
concentration on particle size. Ethics Committee (CPCSEA), and all animal care
and handling guidelines were followed. The
Evaluation of Topical Nanosponges Loaded Gel: permission of the ethics committee has been
Evaluation parameter for gel is pH, viscosity, drug obtained. Perform the skin irritation test according
content, skin irritation test, in-vitro dissolution test to the procedure. Skin irritation studies on 10
spreadability. healthy rats. With the help of sharp surgical
scissors and chemical depilatory, the hair on the
Physical Evaluation: Homogeneity and clarity are back were physically removed. Then the skin was
observed. A digital pH meter was used to measure washed properly one day prior to use. The animals
the pH of the formulation. First, adjust the pH of were divided into 2 experimental groups with 5
the water to 7 pH and then measure the pH of the animals in each group.
prepared gel.
Group 1: Control and 0.8% formalin solution,
Viscosity: Viscosity of prepared gel was measured Group 2: Control and medicated gel (with drug).
using Brook field viscometer (HBDVE) at different The latter observed for any sensitivity after 24hrs,
RPM and noted. 48 h, 72 h and the reaction if any graded as: Score
Erythema scale: 0 No reaction, 1 Slight, patchy
Drug Content: Dissolve 1gm of gel which was erythema, 2 Slight but confluent or moderate but
quantity equivalent to dose, that is, 2% of the drug patchy erythema, 3 Moderate erythema, 4 Severe
in 100 ml of phosphate buffer PH 7.4 and measure erythema with or without edema.
the absorbance at λmax 296 nm.
Antifungal Activity (Zone of Inhibition): Weigh
Calculate the drug content based on the slope and 16.25 g of Sabouraud's dextrose agar and transfer it
intercept obtained from the linear equation, that is, to a 500 ml Erlenmeyer flask and 250 ml of
y = mx + C for the pure drug. purified water, and heat to completely dissolve it.
Spreadability Test: Weigh 1 gm of gel and place Sterilize in an autoclave at 121 °C and 15 pounds
it on a spreadable device with a glass slide on the of pressure for 15 min about 20 min. Then cool at
lower side and another glass slide on the upper room temperature, disperse the fungal strain
side, and the weight is tied to the upper glass slide. (Candida albicans) in the culture medium, then
After placing the gel on the download slide, place pour the culture medium into three petri dishes, let
the upper slide on the download slide and calculate it cool for a while at room temperature, until it
the time required to slide the two slides from the forms solidification at room temperature and then
gel. And use the formula to calculate the each petri dish is drilled with a 6 mm sterile steel
spreadability, (Length of slide = 7.5 cm): S = hole, and the calculated concentration of standard
M*L/TS = spreadability, M = weight tied to upper drug (luliconazole), gel preparation (NS1) and
slide, L = length of glass slide. T=Time taken to placebo gel are placed in the hole and incubated in
separate two slides (sec). the petri dish at 37 °C for 72 h. Then observe the
zone of inhibition and calculate the radius of the
In-vitro Drug Release Study: The in-vitro study of zone of inhibition.
the gel was performed on a dialysis membrane. The

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Infrared Spectroscopy: The FTIR spectrum of wide range of 67.35 to 75.65%. It can be seen that
luliconazole nanosponge Formulation batch NS4 the NS1 and NS4 batches have good production
was recorded in the wavelength range of 4000 to yields (72.42% and 75.65%). The conclusion is that
400 cm-1. The characteristics of IR absorption the ethyl cellulose concentration and cross-linking
peaks of luliconazole were studied. time affect the yield of nanosponges. Due to
changes in polymer concentration, yields may vary.
Stability Study: A stability study of the The % Entrapment efficiency of batches NS1 to
formulation giving the maximum dissolution rate NS4 is in the range of 64.83 to 79.16%. The
was conducted to indicate that the optimized highest % entrapment efficiencies shown in batches
batch's visual physical or chemical stability was NS1 and NS4 were 72.40% and 79.16%,
assessed at 40 ± 20 ºC / 75 ± 5% RH according to respectively. The conclusion is that the
ICH guidelines. The optimized batch of concentration of ethyl cellulose increases and then
nanosponges loaded with luliconazole was the % entrapment efficiency increases. The
packaged in aluminum strips and stored for three prepared nanosponge were immersed in an aqueous
months. After 90 days, the physical appearance and solvent to determine the swelling and water
drug encapsulation efficiency of the samples were absorption rate. Swelling index and water uptake
analyzed. were calculated using the equation. An accurately
weighed equal amount (10 mg) of the nanosponge
RESULT AND DISCUSSION:
containing the drug was continuously stirred for
Evaluation of Nanosponges of Luliconazole: The
one hour in 100 ml of phosphate buffer pH 7.4
physical appearance of the prepared nanosponge
solution. A (UV1800) UV dual-beam
was observed with naked eyes. All the batches
spectrophotometer was used to further analyze the
observed are spongy white powder. It was observed
filtered sample at 296 nm next to the blank.
that the % yield of batches NS1 to NS4 was in a
TABLE 6: ACTUAL DRUG CONTENT, PRODUCTION YIELD, ENTRAPMENT EFFICIENCY, WELLING INDEX
AND WATER UPTAKE FLUCONAZOLE NANOSPONGES
Formulation Code Production Yield Entrapment Actual drug % Swelling index Water
efficiency content uptake
NS1 72.42 72.40 17.43 75 96
NS2 67.35 64.83 28.67 80 108.69
NS3 70.99 69.92 48.654 74.35 129.26
NS4 75.65 79.16 35.112 73.91 114.28

Evaluation of Gel: Physical appearance i.e., clarity Viscosity was measured by HBDVE Brook field
and homogeneity, was observed visually. viscometer.
TABLE 7: VISCOSITY OF DIFFERENT FORMULATIONS
Formulation Code Torque RPM Viscosity
97.50 60 22014
NS1 99.2 100 12154
94 150 10052
96 200 11026
94 60 19672
95 100 17653
NS2 95 150 15638
88 200 12656
94 60 11754
91 100 13620
NS3 91 150 14854
88 200 12058
98 60 18254
94 100 16185
NS4 91 150 14210
88 200 12052
97 60 11495

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96 100 13072
NS5 92 150 13668
88 200 12114
96 60 14192
92 100 15415
NS6 91 150 14543
88 200 12252

TABLE 8: CLARITY AND HOMOGENICITY OF THE A diffusion rate study was performed to evaluate
FORMULATIONS the diffusion characteristics of luliconazole from
Formulation code Clarity Homogenicity
the prepared nanosponge hydrogel. Table 10 shows
NS1 + Good
the release profiles of all batches. Diffusion studies
NS2 ++ Good
of all formulations showed that the drug release
NS3 ++ Good
percentage was found to be between 57.21 and
NS4 +++ Good
NS5 +++ Good
85.65% in a given time period. According to the
NS6 ++ Good data, NS4 shows the highest drug release compared
+turbid, ++clear, +++veryclear to any other batches and NS1 batch shows the
lowest drug release, so NS4 is considered to be the
TABLE 9: ACTUAL DRUG CONTENT, SPRE- best formulation based on its kinetic release
ADABILITY AND PH characteristics because the polymer uses
Formulation Actual drug Spreadability pH
ethylcellulose. During the diffusion experiment,
code content
maintaining the temperature and stirring speed is
NS1 88.32 5.922 7.0
important for consistent and accurate measurement
NS2 89.26 6.128 7.1
NS3 74.43 6.266 7.3
of the diffusion rate. This can be maintained
NS4 94.58 6.368 7.2
throughout the diffusion study, and the solubility of
NS5 90.65 6.185 7.0 the drug will not be a deciding factor leading to the
NS6 91.46 6.230 6.9 delay of drug release in the formulation study.

TABLE 10: % DRUG RELEASE OF VARIOUS FORMULATIONS

Time (h) Formulation code
NS1 NS2 NS3 NS4 NS5 NS6
1 4.87±0.01 4.62±0.02 4.72±0.01 7.43±0.021 5.76±0.02 5.94±0.01
2 5.26±0.03 6.43±0.01 6.88±0.02 11.24±0.04 7.85±0.03 8.90±0.02
3 15.48±0.01 11.02±0.02 14.68±0.02 22.96±0.01 16.84±0.01 15.43±0.03
4 18.42±0.03 17.68±0.01 25.44±0.02 32.14±0.04 28.65±0.01 28.42±0.02
5 24.54±0.02 22.88±0.02 28.68±0.03 38.24±0.02 36.06±0.02 32.32±0.01
6 32.11±0.01 29.18±0.03 34.36±0.02 51.02±0.01 40.39±0.01 44.17±0.03
7 41.12±0.03 34.84±0.02 42.12±0.03 59.42±0.02 51.02±0.01 55.12±0.01
8 44.20±0.01 41.21±0.01 44.42±0.02 66.42±0.04 54.66±0.03 57.94±0.01
9 51.34±0.02 48.44±0.04 51.27±0.01 69.76±0.01 61.54±0.03 62.92±0.01
10 52.12±0.01 54.14±0.03 53.16±0.03 77.21±0.02 65.63±0.01 67.1±0.01
11 55.24±0.01 56.64±0.03 58.94±0.01 82.75±0.01 67.90±0.04 71.33±0.02
12 57.21±0.02 61.62±0.01 62.07±0.02 85.65±0.02 68.96±0.01 75.76±0.03

TABLE 11: SKINIRRITATIO NTEST

Formulation Presence of edema 24 h. Presence of edema 48 h. Presence of edema 72 h
Control 0 0 0
Aqueous formalin solution 2 3 3
Medicated Gel 0 0 0

Skin Irritation Test: It was performed by using in- Therefore, it can be concluded that the formulation
vitro skin irritation test method. The formulation has no possibility of skin irritation and is safe for
did not show any signs of skin irritation, such as topical application.
redness or any change in the skin.

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Zone of Inhibition: In this study, the fungus used Candida albicans and luliconazole nanosponges
was Candida albicans. The optimized batch NS4 proved as a better scaffold for topical application.
was studied. TABLE 12: ZONE OF INHIBITION
S. no Formulation Zone of inhibition
It was observed that the inhibition zone of NS4 was (mm2)
7.2 mm 2, the placebo gel was 0 mm2 and the pure 1 Placebo gel 0
drug luliconazole was 6.8 mm2. This indicates that 2 Pure drug (luliconazole) 6.8
the luliconazole gel is effective against the fungus 3 Formulation batch NS4 7.2

ZONE OF IN HIBITION NS4 BATCH ZONE OF INHIBITION PLACEBO GEL

ZONE OF INHIBITION FORMULATION OF PURE DRUG

FIG. 2: ZONE OF INHIBITION

Stability Studies: The results of stability studies CONCLUSION: From all the above observations
showed that no significant changes in physical and results, it can be concluded that all
appearance, entrapment efficiency and in-vitro drug formulations exhibit satisfactory organoleptic
release studies. properties. The nanosponge loaded with
luliconazole was prepared by a hyper-crosslinking
Stability studies also showed that there was no method and the entrapment efficiency, physical
change in the drug release profile. This indicates properties, yield, swelling index and water uptake,
that the selected batch NS4 is stable and drug content and particle size of the nanosponge
reproducible. were tested. The results obtained from the research
TABLE 13: STABILITY TEST STUDY OF confirmed that the maximum entrapment efficiency
NANOSPONGES GEL was found to be 79.16% in the formulation code
Parameters Before stability After stability testing NS4, and the formula was optimized. Therefore,
testing particle size and morphology studies were
Color White White Translucent
Translucent performed on the optimized formulation. It was
Visual Clear and Clear and homogenous found that the average diameter of the optimized
appearance homogenous formula was 175.3 nm.
% Drug release 84.60%% 84.45%

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The prepared nanogels were evaluated for its 4. Dasht Bozorg B: Transdermal and dermatological
formulations for delivery of pharma- and cosmeceuticals
viscosity, in-vitro drug diffusion study and in-vivo into healthy and diseased skin. Pro Quest Dissertations and
animal study of nanosponge gel and the results Theses 2020.
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ACKNOWLEDGEMENT: This work was 11. Srinivas P and Sreeja K: Formulation and evaluation of
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responsible for the content and writing of this Pharmacy 2013; 39.
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How to cite this article:

Wakure BS, Salunke SA, Mane PT, Awale SR, Shinde RD and Eklinge SS: Nanosponges as novel carrier for topical delivery of
luliconazole -an antifungal drug. Int J Pharm Sci & Res 2021; 12(10): 5570-83. doi: 10.13040/IJPSR.0975-8232.12(10).5570-83.
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