The sponge particles have the open structure and until the equilibrium is reached the action is free to move in and out from the particles and into the vehicle. Once the finished product is applied to the skin, In case of topical delivery the active that is already in the vehicle will be absorbed into the skin, depleting the vehicle which will become unsaturated hence disturbing the equilibrium. This will start the flow of the action from a sponge particle into the vehicle and from it to the skin until the vehicle is either absorbed or dried. Even after that the sponge particles that are retained on the surface of stratum corneum will continue to gradually release the active to the skin thus providing prolonged release over time.⁶

Method of Preparation:

The nano sponges made from the hyper cross-linked β-cyclodextrins:

The nano sponges are made from the materials that makes the non-porous molecules that are carriers called cyclodextrins for the release of drug. These cyclodextrins are the hyper-cross-linking agents that forms the numerous networks in the nano networks or can be even the spherical shaped with many networks of the protein channels, pores etc. With the specific surface charge density, pore sizes and porosity, these cross linkers stabilizes the sponge based on the molecules contained in them. At different acidic and even neutral pH the cross linkers help to retain the Nano sponges.

The Emulsion solvent method:

Ethyl cellulose and polyvinyl alcohol are the main polymers used in this method in varying proportions. By adding ethyl cellulose the dispersed phase is formed and the available drug which is dissolved in the 20ml of dichloromethane. The drop wise addition of the continuous phase is prepared by dissolving the polyvinyl alcohol in 150ml of distilled water. Then the mixture is allowed to stir at 1000rpm for 2 hours. Then obtained nanosponges are collected, filtered and dried in the oven for around one day and stored in the desiccators.

Solvent used method:

Above used polymer can be used along with some suitable polar aprotic solvent such as dimethyl sulfoxide, dimethylformamide and mix proportionally. To this mixture then cross-linkers available are added with the ratio of 4: 16. The temperature is maintained from 10°C for the reaction of the polymers for two days. Most of the carbonyl cross linkers [Carbonyl diimidazole and Dimethyl carbonate] are used. The product kept to cool at room temperature after the reaction is complete then add the mixture with the distilled water for recovering and filtered under air oven the purification is done with the help of soxhlet apparatus added with ethanol for the further extraction. Again go for drying under vacuum and powdered mechanically to get the homogeneous white powder.

Ultrasound-assisted synthesis:

In this method the nano sponges can be obtained by using the polymers with the carbonyl cross linkers in the absence of the solvent and kept for sonication. These Nano sponges that are developed will have uniform spherical dimension. Mix the polymer and the cross-linker in sufficient quantity and is taken in the flask. Fill the flask with water and heats it to 90°C for ultrasonication. For continuous sonication the mixture is kept for five hours. After that the mixture is cooled and washed the product with the distilled water and allowed to purify it by using soxhlet extractor using ethanol. After obtaining the final is dried at 25˚C and whitish powder is collected and store from humidity.^7-10

Loading of Drug into Nanosponges:

For delivery of drug the nanosponges are pre-treated to obtain the mean particle size below 500nm. The nanosponges were suspended in the aqueous phase and sonicated to avoid the aggregation of the particles and to obtain the colloidal fraction the suspension is centrifuged. From the suspension the supernatant was separated and then dried by freeze dryer. By dispersing into the aqueous suspension the nanosponges were prepared and the excess amount of drug was added and maintained the suspension under the constant stirring for the specific time till it forms the complex. The uncomplexed [undissolved] drug was separated from the complexed drug by centrifugation after the complexation. Then by solvent evaporation or by freeze drying the solid crystals of nanosponges was obtained. In complexation with the drug the crystal structure of the nanosponge plays the very important role. The paracrystalline nanosponges have greater loading capacities than crystalline nanosponges in some studies it has been revealed. The drug loading occurs as an inclusion complex in crystalline forms while the drug loading occurs as a mechanical mixture in case of poorly crystalline nanosponges.^11-12

Factors Influence Nanosponge Formation:

a] Type of polymer:

The type of polymer used can influence the performance as well as the formation of Nanosponges. For the complexation, the cavity size of the nanosponge should be suitable to accommodate the drug molecule of the particular size.

b] Type of drugs:

The drug molecules to be complexed with the nanosponges should have certain characteristics which are mentioned below:

i] Solubility in water should be less than 10mg/ml.

ii] Molecular weight of drug should be in between 100 to 400 Daltons.

iii] Drug molecule consists of less than five condensed rings.

iv] Melting point of the substance should be less than 250°C.

c] Temperature:

The drug/nanosponge complexation are affected due to Temperature changes. The increasing in the temperature decreases the magnitude of the apparent stability constant of a drug/nanosponge complex may be due to the result of the possible reduction of the drug/ nanosponge interaction forces, such as the van-der Waal forces and hydrophobic forces with rise of the temperature.

d] The method of preparation:

The method of loading a drug into the nanosponge can affect the drug/nanosponge complexation. However, the effectiveness of the method depends on the nature of the drug and polymer, the freeze drying in many cases was found to be most effective for drug complexation.

e] The degree of substitution:

The complexation ability of the nanosponge may be greatly affected by position, type and number of the substituent on the parent molecule.^13-14

Evaluation of Nanosponges:

Particle Size and Polydispersity:

By Dynamic Light Scattering Instrument (DLSI) equipped with particle sizing software the particle size can be determined. From this the mean diameter and the PDI [Polydispersity Index] can be determined. The polydispersity Index is an index width or the spread or variation within the particle size distribution. The mono-dispersed samples have the lower polydispersity Index value, whereas higher value of the polydispersity Index indicates the wider particle size distribution and the samples poly-dispersed nature. By Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM) and Freeze Fracture Electron Microscopy (FFEM), the particle size can also be determined.

Microscopy Studies:

To study the morphology, surface topography and microscopic aspects of the drug, nanosponges and the product [drug/ nanosponges complex] the SEM [Scanning Electron Microscopy] and TEM [Transmission Electron Microscopy] can be used. The difference in the crystallization state of the raw materials and the product seen under the electron microscope indicates the formation of the inclusion complexes even if there is the clear difference in the crystallization state of the raw material and the product obtained by the co-precipitation.

Zeta Potential:

The zeta potential is the measure of the surface charge. By using additional electrode in the particle size equipment the zeta potential can be measured. Also the zeta potential meter, laser doppler anemometry, can be used.

Solubility Studies:

the phase solubility method described by Higuchi and Connors is the most widely used approach to study the inclusion complex which examines the effect of the nanosponge on the solubility of the drug. The phase solubility diagrams indicate the degree of the complexation. The changes in solubility of the guest are plotted in the solubility studies as the function of the cyclodextrins concentration if the solubility of the potential guest increases with the increasing cyclodextrin concentration; the complex formation in the solution is indicated. To evaluate the drug pH solubilization profile the solubility studies were performed and to assess the effect of the multi-component complexation on the solubility of drug.

Thin Layer Chromatography:

The Rf values of the drug molecule diminish to the considerable extent in TLC [Thin Layer Chromatography] and this helps in identifying the complex formation between the nanosponges and drug. The Inclusion complexation between the guest and the host molecules is the reversible process. The complex may separate completely in guest and host molecules during the chromatographic process consequently and only the spots of the guest and the host molecules are found on the Thin Layer Chromatography plate.

Infra-Red Spectroscopy:

To estimate the interaction between the nanosponges and the drug molecules in the solid state the Infra-Red spectroscopy is used. The Infrared spectral studies give the information regarding the involvement of the hydrogen in different functional groups. This generally shifts the absorbance bands to a lower frequency increases the intensity and widens the band caused by the stretching vibration of the group involved in the formation of the hydrogen bonds. The hydrogen bond at the hydroxyl group causes the largest shift of the stretching vibration band.

Analytical Methods:

Whether the drug substance undergoes some change before the thermal degradation of the nanosponges is determined by thermoanalytical methods. The change of the drug substance may be evaporation, melting and decomposition.

Single Crystal X-ray Structure Analysis:

To determine the detailed inclusion structure and mode of interaction this method is used. The interaction between the host and guest molecules can be identified and the precise geometrical relationship can be established. This obtained information from the analysis leads to know about the formation of the inclusion complexes.

X-ray Diffractometry and Single Crystal X-ray Structure Analysis:

To detect inclusion complexation in the solid state the powder x-ray diffractometry can be used. The diffraction pattern of the newly formed substance clearly differs from that of the uncomplexed nanosponges when the drug molecule is liquid [since the liquid has no diffraction pattern of their own]. This difference of the diffraction pattern indicates the complex formation. 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, when the drug compound is a solid substance.

The diffraction pattern of the physical mixture is often the sum of those of the each component, while the diffraction pattern of the complexes are apparently different from each constituent and lead to the “new” solid phase with the different diffractograms. In determining the chemical decomposition and complex formation the diffraction peaks for the mixture of compounds are useful. A complex formation of the drug with the nanosponges alters the diffraction patterns and also changes the crystalline nature of drug. The complex formation leads to the sharpening of the existing peaks appearance of the few new peaks and shifting of certain peaks.

Loading Efficiency and Production Yield:

By the quantitative estimation of the drug loaded into nanosponges the loading efficiency [%] of the nanosponges can be determined by UV spectrophotometer, HPLC methods and calculations according to the following equation:

Loading Efficiency=Actual drug content in the nanosponge/Theoretical drug content × 100

By accurately calculating the initial weight of the raw materials and the final weight of the nanosponge obtained, the production yield of the nanosponges can be determined.

Photo-degradation Study:

Under UV lamp the photo-degradation of the drug loaded nanosponge complex is performed. At the distance of 10cm from the lamp, the samples are kept for 1hour, with stirring under dark, simultaneously by HPLC the samples are quantitatively analyzed.

Resiliency:

To produce beadlets that are softer or former according to the need of final formulation the resiliency [viscoelastic properties] of the sponges can be modified. The increased crosslinking tends to slow down the release rate. By considering release as the function of cross-linking with time, hence the resiliency of the sponges will be studied and optimized as per the requirement.

True Density:

By using an ultra-pycnometer under helium gas the true density of the nanosponges can be determined.

Drug Release Kinetics:

From nanosponge to investigate the mechanism of drug release, the release data could be analyzed using Zero order, First order, Peppas, Higuchi, Hixon-Crowell, Kopcha and Makoid-Banakar etc. models. Using graph pad prism software the data can be analyzed. The software estimates the parameters of the non-linear function that provides the closest fit between the non-linear function and experimental observations.

In-vitro Drug Release:

Using Franz Diffusion Cell the drug release from the nanosponges can be measured across the dialysis membrane. The dialysis membrane which is soaked in receptor medium for 8 hours is used as the barrier between the donor and the receptor compartment. The 01 gram Nanosponge is placed on the surface of membrane in the donor compartment that is sealed from the atmosphere with aluminum foil. With specific volume of the phosphate buffer of suitable pH [6.8 skin pH] the receptor compartment is filled. The solution of receptor side compartment is kept at 37±0.5^oC during the experiment and stirred at 100rpm with teflon-coated magnetic stirring bars. At designated time intervals the aliquots are collected from the receptor compartment and replaced by the same volume of fresh receptor solution to maintain the constant volume and sink condition. By using UV-spectrophotometer the sample is analyzed. In many cases, even the USP type II dissolution apparatus can be used depending upon the formulation.^15-16

Advantages of Nanosponges:

1. Nanosponges Increase the formulation stability and enhance the flexibility of the formulation.

2. The nanosponges complexes are stable over the wide range of pH and the temperature of 130°C

3. Nanosponges Increase aqueous solubility of the poorly water-soluble drug.

4. The bacteria cannot penetrate the nanosponges because of their tiny pore size [0.25µm] and they act like the self-sterilizer.

5. In a predictable fashion the nanosponges can release the drug molecules.

6. The nanosponges drug delivery system are nonmutagenic, non-toxic and non-irritating.

7. The nanosponges drug delivery system minimize side effect.

8. They have better patient compliance.

9. Nanosponges help to remove the venom and toxic substance from the body.^17-19

Disadvantages of Nanosponges:

1. The dose dumping may occur at times

2. The nanosponges have the capacity of encapsulating small molecules, not suitable for larger molecules.²⁰

Application of Nanosponges:

The nanosponges due to their versatility and biocompatibility, in the field of pharmacy they have many applications. In the preparation of capsules, tablets, granules, pellets, solid dispersions, suspensions, or topical dosage forms they can be used as excipients. The nanosponges can act as the multifunctional carriers for enhancing product performance and elegancy, extended release, irritation is reduced, improved physical, thermal, and the chemical stability of the product. Following are some of the application of nanosponges which shows versatility of nanosponges.²¹

In the solubility enhancement:

The nanosponges improved the solubility of the drug more than 27-fold. When the copolyvidonum was added as the supporting component to the nanosponge formulation this exceeded to 55-fold. By increasing the wetting of the drug, and/or by decreasing the crystallinity of the drug the nanosponges solubilize the drug by possibly masking the hydrophobic groups of itraconazole.²²

As the carrier for delivery of gases:

In medicine for diagnostic or the treatment purposes the gases play an important role. The deficiency of more oxygen supply named as hypoxia is related to the various pathologies from inflammation to that of the cancer. So, it is sometime difficult to deliver the oxygen gas in appropriate form and dosage in the clinical practice. The nanosponges formulations as oxygen delivery systems for topical application was developed by Cavalli et al., which have the ability to store and to release the oxygen slowly over time.²³

In anticancer therapy:

The nanosponges carrying the anticancer drugs effectively slows the tumor growth. The researcher at Vanderbilt University have developed nanosponges which can be used as the delivery system for anticancer drugs to tumors. They claim that this method is 3 to 5 times more effective at reducing the tumor growth than direct injection of the drugs. The tiny nanosponges are filled with the drug load and expose at the targeting peptide that binds to the radiation-induced cell surface receptors on the tumor. When the sponges encounter tumors cells they stick to the surface and are triggered to release their cargo. The studies so far have been carried out in the animals with the paclitaxel as the sponge load. The researchers have recorded the response of 2 different tumors types in the animal studies that are slow-growing human breast cancer and the fast acting mouse glioma-to single injections. The particle holds the anticancer drug that it gradually releases as it decomposes. With the ball and stick representation the peptides linkers are shown. Although only 2 in about 3 dozen are attached to the surface of the actual particles. To the surface of the irradiated cancer cells the linkers are specially configured to bind. In both cases, they found that the delivery through nanosponges increased the death of the cancer cells and delayed tumors growth compared with the other chemotherapy approaches. The camptothecin the plant alkaloid and the potent antitumor agent, because of its lactone ring instability, poor aqueous solubility, and serious side effects has the limited therapeutic utility. The cyclodextrins-based nanosponges are the novel class of cross-linked derivatives of the cyclodextrin. To increase the solubility of poorly soluble actives, to control the release and to protect the labile groups, they have been used.^24-25

In enzyme immobilization:

For lipases the issue of enzyme immobilization is particularly useful because it improves their stability and modulates the properties such as reaction rates and enantioselectivity. As the consequence, the demand for the new solid supports suitable for this family of enzymes is constantly growing on. The high catalytic performances of pseudomonas fluorescens lipase adsorbed on a new type of the cyclodextrin-based nanosponges was reported by Boscolo et al.^7,26

In drug delivery:

The nanosponges because of their nanoporous structure can advantageously carry water-insoluble drugs and/or agents [BCS Class-II drugs]. To increase the dissolution rate, stability and solubility of the drugs, to convert the liquid substances to solids and to mask unpleasant flavours these complexes can be used. The β-Cyclodextrin-based nanosponges are reported to deliver the drug to the target site three to five times more effectively than the direct injection. The drugs which are particularly critical for the formulation in terms of their solubility can be delivered successfully by loading it into the nanosponges. The nanosponges are solid in nature and can be formulated as parenteral, oral, inhalation or topical dosage forms. The complexes may be dispersed for the oral administration in the matrix of excipients, lubricants, diluents and anticaking agents suitable for the preparation of the tablets or capsules. The complex may be simply carried in sterile water, saline, or other aqueous solutions for the parenteral administration. For the topical administration they can be effectively incorporated into the topical hydrogel.^7,27-29

As a protective agent from light or degradation:

In the formation of nanosponges the gamma-oryzanol was encapsulated showing the good protection from the photodegradation. With the gamma oryzanol-loaded nanosponges a O/W emulsion and a gel were formulated. The gamma-oryzanol is the ferulic acid ester mixture which has recently attracted a great interest as the natural antioxidant and usually employed to stabilize the pharmaceutical raw materials and food, moreover as the sunscreen in cosmetics industry. Because of its high instability and photodegradation its application is limited.³⁰

As a sustained delivery system:

Due to its efficacy in the treatment of herpes simplex virus infections the drug acyclovir is used widely as an antiviral agent. Hence neither the oral nor the parenteral administration of the currently available formulations of the drug acyclovir is able to result in to suitable concentrations of the agent reaching at target sites. In the GIT [gastrointestinal tract] the absorption of acyclovir is incomplete and slow, its pharmacokinetics following the oral medication has the high variable. The in vitro release profiles of the acyclovir from the 2 types of nanosponges showed the sustained release of the drug from the 2 types of nanosponges indicating the encapsulation of the acyclovir within the nanostructures. The percentages of the acyclovir released from the Carb- nanosponges and nanosponges after three hours in vitro were approximately 22% and 70%, respectively. For either formulation the Initial burst effect was not observed which proved that the drug was not weakly adsorbed onto the surfaces of nanosponges.^11,31

Biopharmaceutical Classification System Class II drugs:

Drugs which are particularly critical for formulation in terms of their solubility can be successfully delivered by loading into the nanosponges. List of some BCS Class II dugs which can be developed as nanosponges are given in Table 2.³²

Table 2: Biopharmaceutical Classification System Class II drugs

Sr. No	Category of Drug	List of Drugs
01	Steroids	Danazol, Dexamethazone
02	NSAIDs	Diflunisal, Dapsone, Etodolac, Diclofenac, Etoricoxib, Ibuprofen, Piroxicam Indomethacin, Mefenamic acid, Ketoprofen, Flurbiprofen, Naproxen, Oxaprozin, Nimesulide,
03	Gastroprokinetic agent	Cisapride
04	Immunosupressants	Tacrolimus, Cyclosporine, Sirolimus,
05	Cardiac drugs	Digoxin, Carvedilol, Talinolol
06	Anthelmintics	Praziquantel, Albendazole, Mebendazole,
07	Diuretics	Spironolactone, Chlorthalidone
08	Antipsychotic drugs	Chlorpromazine Hydrochloride
09	Antiulcer drugs	Omeprazole, Lansoprazole,
10	Antioxidants	Resveratrol
11	Antiretrovirals	Nelfinavir, Indinavir, Saquinavir, Ritonavir
12	Antihypertensive drugs	Nicardipine, Felodipine, Nisoldipine, Nifedipine
13	Anticonvulsants	Clonazepam, Carbamazepine, Primidone, Felbamate, Oxycarbazepine,
14	Antihistamines	Terfenadine
15	Antineoplastic agents	Docetaxel, Camptothecin, Exemestane, Etoposide, Irinotecan, Flutamide
16	Antibiotics	Sulfamethoxazole, Azithromycin, Ofloxacin, Erythromycin, Ciprofloxacin,
17	Antiarrhythmic agents	Amiodarone hydrochloride
18	Anticoagulant	Warfarin
19	Antiarrhythmic agents	Amiodarone hydrochloride
20	Antianxiety drugs	Lorazepam

Table 3: Drugs formulated as nanosponges ^33-40

Sr. No	Drug	Therapeutic Benefit	Nanosponge Vehicle
01	Camptothecin	Cancer	β‑cyclodextrin
02	Tamoxifen	Breast cancer	β‑cyclodextrin
03	Paclitaxel	Cancer	β‑cyclodextrin
04	Econazole nitrate	Antifungal	Ethyl cellulose, Polyvinyl alcohol
05	Antisense	Cancer therapy	Sodium alginate
06	Dexamethasone	Brain tumor	β‑cyclodextrin
07	oligonucleotides	Viral infection Pathologic disorder	Poly L‑lysine
08	Resveratrol	Inflammation Cardiovascular disease Dermatitis Gonorrhea Fever Hyperlipidemia	β‑cyclodextrin
09	Itraconazole	Antifungal	β‑cyclodextrin Copolyvidonum

Table 4: Patent reports on nanosponges ^41-45

Sr. No	Patent/App. No.	Title	Applicant
01	CA2692493A1	Cyclodextrin based nanosponges as a vehicle for antitumoral drugs	Vander Tumiatti, S.A.S, Francessco Trotta, Vander Tumiatti, Roberta Cavalli, Carlo Maria Roggero, Barbar Mognetti, Giovan
02	WO2006002814A1	Ultra-sound-assisted synthesis of cyclodextrin-based nanosponges	Francesco Trotta, Wander Tumiatti, Orfeo Zerbinati, Carlo Roggero, Roberto Vallero
03	W02012147069A1	Method of preparing dextrin nanosponges	Universita DegliStudi Di Torino, Sea Marconi, Technologies Di
04	DE10008508A1 (2001)	New polycarbonate with cyclodextrin units, used ex: as a chromatographic stationary phase, catalyst, drug delivery system, extractant or moulding material, especially for removing organic compounds from water.	Bayer Ag
05	W02003041095A1 (2003)	Process of composites preparation between particulate materials and cyclodextrin and/or their derivatives.	Alberto Bocanegra Diaz
06	EP0502194A1 (1992)	Cyclodextrin polymer and cyclodextrin film formed	Toppan Printing co. Ltd.
07	W02003085002A1 (2003)	Cross-linked polymers based on cyclodextrin for removing polluting agents	Sea Marconi Technologies Diw.

CONCLUSION:

The nanosponges have the ability to release the drug in a controlled manner to the targeted site. They are also capable of carrying both hydrophilic and lipophilic molecules. Because of their spherical shape and small size nanosponges can be developed as different dosage forms like topical, parenteral, capsules, tablets, aerosol. The nanosponges enable the insoluble drugs and protect the active moieties from the physicochemical degradation and controlled release. The nanosponges are nano sized colloidal carrier so they can easily penetrate through the skin. Due to their small size and porous nature, they can bind the poorly- soluble drugs within the matrix and improve the bioavailability of poorly- soluble drugs and they also increase the solubility of poorly soluble drugs.

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Received on 27.03.2020 Modified on 09.05.2020

Research J. Pharm. and Tech 2021; 14(3):1797-1804.

DOI: 10.5958/0974-360X.2021.00319.X

Polymers	Apolar solvents	Cross-linkers
Cyclodextrins and its derivatives like Alkyloxycarbonyl-Cyclodextrins, Methyl β- Cyclodextrin,	Dimethyl formamide	Diarylcarbonates,
2-Hydroxy Propyl β-Cyclodextrins and Copolymers like Poly (valerolactone -allylvalerolactone),	Ethanol, Dimethylacetamide.	Diphenyl Carbonate, Di-Isocyanates, Carbonyl-di-Imidazoles,
Poly (valerolactone-allyl valerolactone oxe pane-dione),		Pyromellitic anhydride, Epichloridrine, Glutarldehyde,
Ethyl Cellulose, PVA and Hyper cross linked Polystyrenes,		Carboxylic acid dianhydrides,
		2,2-bis (acrylamido) Acetic acid and Dichloromethan