Nanotechnology is the study and use of structures among 1 nanometer and 100 nanometers in size. Nanotechnology carries different formulations like nanopsonges, nano-erythosomes, nano suspensions, nanoparticles, nanocapsules, nanospheres, nanocrystals, etc.^[1]

Nanosponge technology was used for widely for the delivery of drugs for topical administration, parental administration, and oral administration. It is a targeted delivery of drug for extended period of time. The active ingredients such as emollients, fragrances, essential oils, sunscreens have high capacity to get entrapped in nanosponges. These are porous, non-toxic, insoluble in water and organic solvents and stable at high temperatures up to 300ᵒ C^[2-3]

Hydrogels are hydrophilic polymers which are not soluble in water but in aqueous media it absorbs a large amount of water.

Hydrogel were established in many fields such as regenerative medicine, as food additives, drug delivery and tissue engineering^[4]. Nanosponge incorporated hydrogel were given topically at targeted site the gel which absorbs into the deeper skin and gives cooler sensation at inflammation part^[5].

Advantages of nanosponges^[6,7]

· It provide extended release condition

· Protected from degradation of drug

· It is non-mutagenic, non-irritating, non-toxic and no side effects

· At the pH from 1 to 11 the formulations are stable

· The formulations are cost effective

· Dosing frequency can be reduced

· Better patient compliance.

· Act as a absorbent and remove toxic and venom substance from the body

Disadvantages of nanosponges^[2,8]

· Large molecules cannot encapsulated into nanosponges

· Dose dumping

· May retard the release

· Depend only upon loading capacity

Applications of nanosponges:

Nanosponges have many applications in the pharmaceutical field. Nanosponges can be loaded in to the different locations such as pellets, tablets, suspensions, granules, suspensions, solid dispersions or topical dosage forms.

1) Cancer^[9]:

When doctors injected the drug in to the cancer patients are ineffective, these is mainly because of the either they can't get to the tumor site or they are attacked by the immune system. These can be overcome by the use of nanosponge to certain extent. Paclitaxel was one of the important drugs formulated as nanosponges. The researchers conducted study in the two different tumor types in animals like slow-growing human breast cancer and fast-acting mouse glioma. In the both cases they got the result that delivery of drug through the nanosponges increased the death of cancer cells and delayed tumor growth.

2) Delivery of protein^[10]:

Bovine serum albumin (BSA) was used as a model protein to study the encapsulating capacity of β-cyclodextrin-based nanosponges. Bovine serum albumin (BSA) protein solution is stored in lyophilized form due to unstable form. The major drawback for the formulation and development of protein is maintains its native form and long-term storage. Stability of the proteins can be increased by nanosponges and also have the ability for controlled delivery, immobilization of enzyme, stabilization and enzyme, encapsulation of protein.

3) For treatment of drug delivery^[10,11]:

Nanosponges are spherical shape and have nanomeric in size so they are used as carriers for water-insoluble drugs. BCS Class II drug having dissolution rate limited bioavailability and these is used to mask the unpleasant flavors, to increase the dissolution rate, solubility and stability. From the inclusion complex the highest solubility and in vitro drug release was observed were prepared from nanosponges and NaHCO₃.

4) For delivery of gases^[12,13]:

For the treatment and diagnostic purposes gas plays an important role in medicine. Due to the inflammation of cancer there is a deficiency of oxygen supply called hypoxia. Cavalli et al who developed the nanosponge formulation for deliver oxygen at the topical application. Nanosponges have the ability to store and releases oxygen slowly over time.

5) Role of nanosponges for treatment of poison in blood^[10,14]:

Instead of using antidotes, nanosponges which have the ability to absorb the toxins from the blood. Nanosponges are delivers to the blood by the injection and they are look like red blood cells. Each nanosponge absorb toxin molecules depends on the number of the toxin molecules.

6) Enzyme immobilization of nanosponges^[14,15]:

For lipases enzyme immobilization is particularly relevant to progress their stability and modulates properties in the case of reaction rates and enantio selectivity. As a result, the demand for new solid chains, proper for this family of enzymes is continuously growing. For this Boscolo et al., statement is Pseudomonas fluorescents lipase have high catalytic performances on a new form of cyclodextrin-based nanosponges.

Factors considering for nanosponge development^[13]:

a) Polymer: It affects the pre-formulation of nanosponges and influences its formulation.

b) Temperature: Increase the temperature decrease the stability of nanosponges by reduction of hydrophobic forces and Van der Waal forces of drug/nanosponges

c) Degree of substitution: The ability of complexation of the nanosponges was affect by the number, position, and type of the substituent of the parent molecule.

d) Method of preparations: Complexation of drug and the nanosponges may cause a change by method of drug loading into the nanosponges; here it can be succeed by the nature or the characteristics of the drug and polymer. Freeze drying was found to be most effective for drug complexation in many cases

Structure of nanosponges:

Nanosponges are nano-sized porous light weight polymeric delivery system with more or less spherical in nature. The cavities of the framework have a tunable polarity. The nanosponges can encapsulates the drug in its core. These are three-dimensional networks of polyester which are degrades naturally. Once the network of polyester breaks down it release the drug molecules. ^[16-17]

Fig 1: Structure of nanosponges

Formulation aspects of nanosponges,^[18]:

A. The drug: Selection of suitable drug should be based on following characteristics. Conventional single dose of drug should be low, drugs have biological half life between 2 – 8 hours.

B. Polymer: The main step on the development of the nanosponges is selection of appropriate polymers. The wild used polymers are ethyl cellulose, poly venyl alcohol, Eudragit, Chitosan, Poly (Valerolactoneallylvalerolactone), Alkyloxycarbonyl Cyclodextrins, 2-hydropropyl β-cyclodextrine, Hyper cross linked Polystyrene.

C. Cross linking agent: cross linking agent is used for rigidisation of polymer they are Diarylcarbonates, Carbonyldiimidazoles, Dichloromethane, Disocyanates, Carboxylic acid dianhydrides

D. Stabilizing agent: Poly Venyl Alcohol, PVP

Methods of nanosponge prepration:

Nanosponges can be prepared by following methods

· Quassi emulsion solvent diffusion method^[8,10]:

In this method both the organic and aqueous phases are using for the preparation of the nanosponges. Different proportions of organic and aqueous phases are taking. Polyvinyl alcohol is used as the aqueous phase and organic phase include drug and polymer. The drug and polymer was dissolved in the particular organic solvent then this phase slowly added to aqueous phases containing polyvinyl alcohol. The above mixture stirred for two or more hours at 1000 rpm. Then by the filtration the nanosponges was collected, washed, dried and stored in the vacuum desiccators.

Fig 2: Emulsion solvent diffusion method

· Ultrasound-assisted synthesis^[11]

In this method, by the reaction between the polymers with the cross-linkers in the absence of solvent and under the sonication the nanosponges were preparing. Spherical and uniform in the sized nanosponges are obtained by this method which is smaller than 5 microns. In this method cross-linkers are di-phenyl carbonate or pyromellitic anhydride are mixed with polymer at particular molar ratio in the flask. This flask containing mixture is heated to 90°C in ultrasound bath which was filled with water, after this mixture was cooled. To remove the excess of non-reacted polymer the mixture is washed with water. The mixture is purified by prolonged Soxhlet extraction using ethanol.

· Solvent method^[9]:

In this method a polar solution of polymer was added to the excess quantity of crosslinker, here the temperature should maintain at the 10°C for 48 hours. Then the mixture cool down to room temperature and add the excess quantity of water. By the addition of water nanosponges were developed, then it collected by the filteration under vaccum. The mixture is purified by prolonged Soxhlet extraction using ethanol.

· Hyper cross-linked method^[20]:

In a round bottom flask 100 ml of anhydrous DMF was taken and to this add 17.42 g of anhydrous β-cyclodextrin then stirred for complete dissolution. To this mixture add 9.96 g of carbonyldiimidazole then kept the solution for reaction at 100◦C for 4hours. After the condensation polymerization is over, a hyper-cross-linked cyclodextrin is developed in RBF. To remove excess of DMF an excess of deionized water should added to above mixture. Finally, unreacted reagents were completely eliminates by Soxhlet extraction with ethanol.

Fig 3: Cyclodextrin nanosponges

Evaluation of nanosponges^{[21, 22]}:

· Solubility studies: Solubility and bioavailability of the drug can determine by the technique is inclusion complexes.

· Microscopic study: Scanning electron microscopy (SEM) and transmission electron microscopy (TEM)

· Particle size and poly-dispersity: Particles size (90Plus particle size determining software), Size distribution profile of nanoparticles (Dynamic light scattering (DLS))

· To determine the formation of a complex between drug and nanosponges: Thin layer chromatography (TLC)

· The interaction between nanosponges and the drug in the solid state: Infrared spectroscopy

· Loading efficiency: UV spectrophotometer

· Stability of the colloidal dispersion and the difference of potential between two layers (dispersion medium and immobile layer): Zeta potential determination

· Extent of interaction between and drug molecule: Single crystal X-ray structure analysis nanosponge

· To measure surface charge: Laser doppler anemometry, Zeta potential meter

Mechanism of drug release^[15]:

The nanosponges are open structure and drug had the ability to move out of the particles into the vehicle until equilibrium is reached. In topical delivery, once the product containing nanosponge with drug is applied to the skin, the drug which is already present in the vehicle will be absorbed into the skin. These will decrease the concentration of drug in the vehicle and reaches to the equilibrium. At the time flow of the drug from the sponge particle into the vehicle will starts into the skin and vehicle is either dried or absorbed. This will provides prolonged release of drug to the stratum corneum of the skin.

Fig 4: Mechanism of drug release

Table 1: Examples of nanosponges currently under research^{[8, 23]}

Drug	Nanosponge vehicle	Indication
Camptothecin	β-cyclodextrin	Cancer
Paclitaxel	β -cyclodextrin	Cancer
Econazole nitrate	Ethyl cellulose Polyvinyl alcohol	Fungal infections
Dexamethasone	β -cyclodextrin	Brain tumors
Tamoxifen	β -cyclodextrin	Breast cancer
Temozolamide	β-cyclodextrin Poly (valerolactoneallyl-valerolactone)	Inflammation Breast cancer Cardiovascular disease
Antisense oligonucleotide	Sodium alginate Poly L-lysine	Cancer therapy

CONCLUSION:

Nanosponges can be formulated into different dosage forms they are parenterals, aerosols, topical, capsules and tablets due to its size and shapes. For effective drug delivery the drug has to reaches target site instead of circulating through the body. This can be possible when the drug is converted in to topical dosage forms. Hence, this stated that nanosponge drug delivery systems ideal platform form for topical use and prolonged delivery systems.

REFERENCES:

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7. Shrishail M Ghurghure et al. Nanosponges: A novel approach for targeted drug delivery system. International Journal of Chemistry Studies. 2018; 2(6): 15-23

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12. Francesco Trotta, Roberta Cavall. Characterization and applications of new hyper-cross-linked cyclodextrins. Composite Interfaces. 2009; (16)39–48

13. Shastrulagari Shivani, Kranthi Kumar Poladi. Nanosponges – novel emerging drug delivery system: a review. International Journal of Pharmaceutical Science and Research. 2015; 6(2): 529-540.

14. Selvamuthukumar Subramanian, Anandam. Nanosponges: A novel class of drug delivery system review. Journal of Pharmacy and Pharmaceutical Science. 2012; 15(1):103-111

15. Riyaz Ali M. Osmani, Shailesh Thirumaleshwar, et al. Nanosponges: the spanking accession in drug delivery- an updated comprehensive review. Pelagia Research Library. 2014; 5(6):7-21

16. Bindiya Patel, Om Bagade et al. An assessment on preparations, characterization, and poles apart appliances of nanosponge. International Journal of Pharm Tech Research. 2014; 6(6): 1898-1907

17. Honey Tiwari, Alok Mahor et al. A review on nanosponges. World Journal of Pharmacy and Pharmaceutical Sciences. 2014; 3(11): 219-233

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21. Francesco Trotta, Marco Zanetti. Cyclodextrin based nanosponges as drug carriers. Beilstein Journal of Organic Chemistry. 2012; 8: 2091–2099.

22. Anuradha Salunkhe, Seemadevi Kadam et al. Nanosponges: a modern formulation approach in drug delivery system. World Journal of Pharmacy and Pharmaceutical Sciences. 2018; 7(2): 575-592

23. Boscolo B, Trotta F. High catalytic performances of Pseudomonas fluorescence lipase adsorbed on a new type of cyclodextrin-based nanosponges. Drug Development and Industrial Pharmacy. 2010; 62: 155-161.

Received on 11.01.2020 Modified on 08.03.2020

Research J. Pharm. and Tech. 2021; 14(1):527-530.

DOI: 10.5958/0974-360X.2021.00096.2

8. Nagasamy Venkatesh et al. Nanosponges: a review. International Journal of Applied Pharmaceutics. 2018; 10(4), 1-5.

13. Shastrulagari Shivani, Kranthi Kumar Poladi. Nanosponges – novel emerging drug delivery system: a review. International Journal of Pharmaceutical Science and Research. 2015; 6(2): 529-540.

15. Riyaz Ali M. Osmani, Shailesh Thirumaleshwar, et al. Nanosponges: the spanking accession in drug delivery- an updated comprehensive review. Pelagia Research Library. 2014; 5(6):7-21

8. Nagasamy Venkateshet al. Nanosponges: a review. International Journal of Applied Pharmaceutics. 2018; 10(4), 1-5.