INTRODUCTION:

Nanosponges are colloidal type of carriers which have been developed and proposed for delivery of drug. Nanosponges are tiny mesh like structures. They are spongy porous, spherical, small sized polymeric structures which release the drug in controlled and predictable manner. The average diameter of nanosponge is below 1µm.Nanosponges can enclose various types of molecules by forming inclusion and non-inclusion complexes. These particles are capable for caring both lipophilic and hydrophilic substances.

They are an innovative class of hyper crosslinked polymer based colloidal structures consisting of solid nanoparticles with colloidal and nanosized cavities. They contain inner hydrophobic cavity and external hydrophilic branching. The cross linker gets attached to certain portions of the polyester strand and form a frame structure. The pore size is controlled by using different type of polymer and cross linkers in different proportions. So, they are capable to providing solutions for several formulations related problems. Nanosponges have higher drug loading capacities compared to other nanocarriers. These small sized sponges can circulate around all over the body until interact with specific target site and stick on the surface and start releasing drug in a controlled manner. They are free flowing, self sterilising, cost effective and stable over range of pH 1-11 and temperatures up to 130°C. NSs holds a promising future in various pharmaceutical applications in the coming years like enhanced product performance and elegancy, extended release, reduced irritation, improved thermal, physical and chemical stability of product^1,2.

Advantages of Nanosponges:

· Nanosponge particles are soluble in water, so the hydrophobic drug can be encapsulated within the nanosponge.

· Targeted site-specific drug delivery.

· Less harmful side effects.

· These formulations are stable over range of pH 1 to 11.

· These formulations are stable at the temperature up to 130°C.

· It can be used to mask unpleasant flavours and to convert liquid substances to solid.

· Biodegradable.

· Particles can be made smaller or larger by varying the proportion of cross linker to polymer.

· Predictable release.

· These are self sterilizing as their average pore size is 0.25micron where bacteria cannot penetrate.

· Improved stability, increased elegance and enhanced formulation flexibility.

Disadvantages of nanosponges:

· NSs have ability to include only small molecules.

· They could be either paracrystalline or in crystalline form.

· The loading capacity of NSs depends mainly on degree of crystallization.

· Paracrystalline NSs can show different loading capacities.

Characteristics of nanosponges:

· NSs having high aqueous solubility so that they are used mainly to encapsulate the poor soluble drugs.

· They are capable to carry both lipophilic and hydrophilic drugs.

· They protect the drug from physicochemical degradation.

· NSs can encapsulate various types of molecules by forming inclusion and non-inclusion complexes.

· They are able to remove organic impurities from water.

Classification of nanosponges:

A) By method of associating with drugs.

1) Encapsulating nanoparticles:

The encapsulating nanoparticles are represented by nanosponges. Nanosponges are sponge like nanoparticles containing many holes that carry drug molecules in their aqueous core.

2) Complexing nanoparticles:

They attract the molecules by electrostatic charge.

3) Conjugating nanoparticles: The nanoparticles links to drugs through covalent bonds.

Materials Used:

Table No. 1: Material Required for the Preparation of Nanosponges

Polymers	Hyper cross-linked polystyrene, cyclodextrin and its derivatives like methyl β-cyclodextrin, hydro propyl β-cyclodextrin
Cross linkers	CH-Diphenyl Carbonate, Diarylcarbonate Diisocyanates, Pyromellitic anhydride, Carbonyldiimidazoles, Epicloridrine, Glutaraldehyde, Carboxylic acid dianhydrades,2,2-bis(acrylamido) Acetic acid and Dichloromethane
Copolymer	Ethyl cellulose (EC), Polyvinyl Alcohol (PVA)
Polar a protect solvent	Dimethyl sulfoxide (DMSO), Dimethyl formamide (DMF)

Method of Preparation of Nanosponges:

1] Melt Method:

Nanosponges are prepared by reacting cyclodextrin with a cross-linker. Variety of cross-linkers are available as dimethyl carbonate, diphenyl carbonate, diisocyanates, diaryl carbonates, carbonyl diimidazoles, carboxylic acid anhydrides and 2,2-bis(acrylamido) acetic acid which are widely used. All the ingredients are finely homogenized, placed in a 250ml flask and heated at 100⁰C. The reaction was carried out for several hrs and reactant mixture is mixed uniformly using magnetic stirrer. The mixture was allowed to cool and broken down the product. The obtained product was washed with suitable solvent to remove extra unreacted excipients. E.g., Wrightia tinctoria³, Naproxen, Ibuprofen⁴, Miconazole nitrate etc⁵.

2] Solvent Method:

The solvent required will be a polar aprotic solvent as dimethylforamide, dimethylsulfoxide etc. The polymer is dissolved in the aprotic solvent. The polymer- aprotic solvent mixture is added to cross linker. The cross linker needs to be used in an excess quantity. The ratio for cross linker/molar ratio is preferred as 4 to 16. The reaction is proceed with a solvent reflux temperature and time ranging from 1 to 48 hr. The reaction is completed and solution is allowded to come to room temperature. The formed product is added to excess of double distilled water and filtered through Vacuum filter. Further the product is purified by Soxhlet extraction with ethanol. Finally, product is dried under vacuum and grinded in a mechanical mill to obtain homogeneous powder. e.g., Flurbiprofen⁶, Ciprofloxacin⁷ etc.

3] Ultrasound Assisted Synthesis:

The polymer and cross linkers are allowded to interact in absence of solvent. The ultrasonic waves are the responsible for the interaction. The size obtained by this technique will be spherical and uniform. The polymer to crosslinker used, temperature maintained at water bath and duration of sonication are critical parameters need to be optimized.

4] Loading of drugs Into Nanosponges:

Nanosponges obtained should be pretreated to maintain mean particle size below 500nm. Nanosponges are suspended in water and were sonicated to avoid presence of aggregates and particles and got centrifuged to obtain colloidal fraction, the supernatant is separated and dried sample by freezing by drying. Further proceeding start with preparing aqueous suspension of nanosponges and excess amount of drug is dispensed for maintaining suspension under constant stirring for specific time period for complexation is over the undissolved drug (uncomplexed condition) is separated from complexed drug with the process of centrifugation. This process helps in evolving solid crystals of nanosponges by solvent evaporation or freeze drying. Nanosponges crystal play important part in complexation with drug. Para-crystalline nanosponges revealed different loading capacities when compared to crystalline nanosponges poorly crystalline nanosponges had act drug loading as a mechanical mixture rather than inclusion complex.

Factors influencing Nanosponge formation:

1] Polymers and Crosslinkers:

The formations and the performance of nanosponges depend on the type of polymers and cross linkers used. Nanosponges structures are three dimensional and nano porous. There is a presence of hydrophobic and hydrophilic components which having ability to trap targeted compounds. The rate of drug release which enhance drug absorption across the biological barriers.eg.by using diphenyl carbonate di-isocyanates another cross linker can be formulated and act as a sustained release carriers for water soluble drugs.

2] Types of drugs and medium used for interaction:

Nanosponges have specific characteristics for entrapment into nanocavities. Drug molecules having molecular mass between 100-400 Dalton’s. When the drug is loaded into nanosponges it should have less M.P. The interaction between nanosponges and hydrophilic medium will carry the organic guest molecule into hydrophobic cavities which are trapped in nanosponges. This strong interaction of molecules depends on the polarity, size, hydrophobic EVS and structural properties.

3] Complexation temperature:

The effect of temperature changes stability constant of a complex and these are inversely correlated. Increase in temperature, the magnitude and apparent stability constantly decreases due to nanosponge interaction.

4] Degree of substitution:

Nanosponges having complexing ability, the number and the position of substituents on the polymeric molecules are affected e.g. The substituents cyclodextrene derivative causes beta cyclodextrene beta derivative in the different forms. The presence of different cross-linking agents, functional groups would yield different types of complex materials. The higher no. of substituents having higher cross-linking abilities, which includes the degree of highly pores nanosponge. These effects caused by the position of substituents.

Characterization of Nanosponges:

The characterization techniques as solubility, porosity, microscopy, drug loading, particle size, polydispersity index, zeta potential, drug release, swelling, differential scanning calorimetry etc will be used.

Applications of Nanosponges:

Due to nanosponge versatility and biocompatibility nanosponges have many applications. Nanosponges have wide application in drug delivery as to enhance of solubility of poorly water solubility of drugs, delivery of proteins.

Table no. 1: Different literature examples of Nanosponge formulations developed for various deliveries of drugs.

Drug	Excipient used	Method of preparation		Outcome
Topical Delivery
Itraconazole	Polyvinyl alcohol, ethyl cellulose and dichloromethane		Emulsion solvent diffusion method	Nanosponge formulation loaded with itraconazole resulted in controlled release of drug. The optimized formulation showed high entrapment efficiency and particle size, polydispersity index was found to be excellent⁸.
Lemongrass oil	Ethyl cellulose, PVA, carbopol940		Emulsion solvent evaporation technique	The nanosponge drug delivery was developed for Lemongrass oil. It is a volatile oil that has become one of the most important natural oils in the pharmaceutical industry because of its diverse pharmacologic and clinical effects. Low aqueous solubility, the instability of its major active constituent, skin irritation are major disadvantage of the lemongrass oil. Ethyl cellulose loaded Lemongrass oil nanosponges with a topical hydrogel were successfully developed for improved therapeutic success⁹.
Etodolac	Ethyl cellulose, dichloromethane, Polyvinyl alcohol		Emulsion solvent diffusion method	The work deals with the improvement of solubility of Etodolac; BCS class II drug through development of nanosponge formulation. Nanosponge were prepared by emulsion solvent diffusion method. The results revealed that proportion of Drug 1: Polyvinyl alcohol 3: ethyl cellulose 2 showed nanosized particle, excellent poly dispersibility Index and in vitro release showed significant improvement of the in vitro release than pure Etodolac hydrogel¹⁰.
Fluconazole	Ethyl cellulose, PVA, dichloromethane		Emulsion solvent diffusion method	The polymeric nanosponge based hydrogel system of fluconazole for improved delivery for topical application. Nanosponge was formulated by oil-in-water (o/w) emulsion solvent diffusion method. The nanosponge drug delivery resulted in improved permeation of the fluconazole across skin¹¹.
Tizanidine hydrochloride	βcyclodextrin, diphenyl carbonate, DMSO, triethanolamine, Carbopol 934, propylene glycol		Solvent evaporation method	Tizanidine HCl, central acting skeletal muscle relaxant. It undergoes first pass metabolism and having less BA. Nanosponges were prepared by hyper cross linked β-cyclodextrin method. Formulation and evaluation of nanosponges loaded hydrogel of Tizanidine HCl overcome the limitation of oral bioavailability¹².
butenafine	Ethyl cellulose, dichloromethane, 0.3 % PVA solution		Emulsion solvent evaporation technique	The nano based gel formulation is showed more effective treatment of fungal infections, as drug permeation occurs deeper into skin layer.
Ketoconazole	PVA, ethyl cellulose, methanol (99%), triethanolamine, Carbopol 934		Emulsion solvent evaporation technique	Nanosponge prepared by using various ratios of ethyl cellulose and finally loaded into carbopol 934 gel showed excellent controlled drug release kinetics i.e., zero order and higuchi¹⁴.
Isoniazid	Ethyl cellulose, polyvinyl alcohol, dichloromethane, trimethanolamine, Carbopol 934, carbopol 940, HPMC K4M		Emulsion solvent evaporation method	Nanosponges prepared by emulsion-solvent evaporation method resulted in controlled release for Isoniazid as topical delivery¹⁵.
Flurbiprofen	Dichloromethane, Carbopol		Solvent diffusion method	The development of Flurbiprofen loaded Nanosponges which were found to be self-sterilizing as quasi-emulsion solvent diffusion method. The formulation showed controlled delivery for extended period and claims to reduce frequency of application¹⁶.
Wrightia tinctoria	Olibanum gum, beta-cyclodextrin, dimethyl carbonate, Carbopol		Melt method	Nanosponges based topical gel of Wrightia tinctoria extract showed drug release over 24 h. The sustain drug release is associated with the use of olibanum gum at 1% proportion.
Voriconazole	Pluronic F-68, polymethyl methacrylate, ethyl cellulose, polyvinyl alcohol, dichloromethane, triethanolamine, Carbopol 971P, N-methyl-2-pyrrolidone, microcrystalline cellulose		Emulsion solvent evaporation technique	The optimized nanosponge formulation containing ethyl cellulose, poly (methyl methacrylate) and pluronic F-68 (poloxamer 188) were further prepared as tablets showed controlled drug delivery and it showed diffusion controlled release¹⁷.
Luliconazole	Ethyl cellulose, polyvinyl cellulose, DMSO, Carbopol 940, HMPC, sodium alginate, acacia, methyl paraben, propyl paraben		Emulsion solvent diffusion method	Luliconazole nanosponge hydrogel is developed as dermatological gel and showed improved therapeutic effect, better dispersibility and good more effective than conventional gel¹⁸.
Sertaconazole nitrate	Ethyl cellulose, Polymethyl methacrylate, PVA, Dichloromethane		Emulsion solvent diffusion method	Sertaconazole nitrate is an antifungal drug. The present study concluded that the Sertaconazole nitrate NSs have control release effect for prolonged period of time in th skin. Also it has been reported to show site targeted effect with reduced incidence of side effects and dosing frequency for the treatment of skin disorders like athelete’s foot, dermatophytosis and candidiasis.¹⁹
Benzydamine hydrochloride	Ethyl cellulose, PVA, Dichloromethane		Emulsion solvent diffusion method	Benzydamine hydrochloride nanogel and combination treatment showed an increased state of mucosal repair, thus they can be used for treating mucosal ulcers effectively.²⁰
Oral Delivery Sustained Release
Ciprofloxacin	Ethyl cellulose, polyvinyl alcohol	Solvent evaporation method		Ciprofloxacin is acid labile drug so that it is entrapped with ethyl cellulose. Formulated NSs loaded with Ciprofloxacin nanosponge resulted in sustained release.
Naproxen and Ibuprofen (two different model drugs)	Ethyl cellulose, polyvinyl alcohol	Emulsion solvent diffusion method		Equal proportion of ethyl cellulose to drug develops nanosponges with the desired particle size, Production yield, % drug content, entrapment efficiency. The release kinetics from formulations resulted in sustained release pattern, based on Higuchi model and drug release follows Fickian diffusion and Korsmeyer-Peppas model.
Gliclazide	Eudragit S100, polyvinyl alcohol, dichloromethane, triethyl citrate	Emulsion solvent diffusion method		The GLZ NS was using different drug polymer (Eudragit S100) ratios (1:1 to 1:5). The prepared nanosponge showed increases solubility and dissolution rate for Gliclazide²¹.
Norfloxacin	β-cyclodextrin, diphenyl carbonate	Melt method		β-cyclodextrin was used as base and diphenyl carbonate as crosslinker agent at 1:2 M/M ratio resulted higher encapsulation efficiency and small particle size. The nanosponge showed mucoadhesive property and due to mucoadhesion results in increased norﬂoxacin absorption. It ultimately improves the antibiotic activity²².
Budesonide	Eudragit S-100, polymethyl methacrylate, dibutyl phthalate, PVA	Quasi-emulsion solvent diffusion method		Budesonide is an ideal drug for the local therapy because of low oral bioavailability, quick clearance and toxic metabolites. The nanosponge prepared by Quasi-emulsion solvent diffusion showed prolonged transport of drugs for an extended period of time and it reduces application frequency and enhances bioavailability²³.
Cefadroxil	Diphenyl carbonate, β -cyclodextrin	Solvent diffusion method		The solubility of Cefadroxil is improved by development of nanosponge drug delivery²⁴.
Camptothecin	β-cyclodextrin, Diphenyl carbonate and CAM Milli Q Water	Ultrasound assisted method		The study is aimed at formulation of complexes with three types of β-cyclodextrin Nanosponges with different cross-linking ratio as 1:2 M/M, 1:4 M/M and 1:8 M/M to protect the lactone ring from hydrolysis, increased stability and to prolong the drug release kinetics²⁵.
Resveratrol	Carbonyl diimidazole, β-cyclodextrin, Milli Q water	Solvent diffusion method		The Resveratrol shows increase in solubility, stability and permeation by formulating as cyclodextrin based nanosponge²⁶.
Griseofulvin	β-cyclodextrin, diphenyl carbonate	Ultrasonication method		The developed Griseofulvin loaded nanosponge masks the bitter taste and improve dissolution rate and higher bioavailability²⁷.
Rutin	Ethyl cellulose, polyvinyl alcohol	Emulsion solvent diffusion method		Rutin has antioxidant, anti-inflammatory, anti-allergic and antiviral activity. It has slow and irregular that means poor absorption from GI tract. But Rutin loaded NSs enhanced the drug release when compared to the pure rutin²⁸.
Immediate Release
Clopidogrel Bisulphate	Ethyl cellulose, glutaraldehyde	Emulsion solvent diffusion method		Clopidogrel bisulphate, BCS class Ⅱ drug having poor bioavailability by oral route. The nanosponges of clopidogrel bisulphate showed improved solubility of Clopidogrel bisulphate²⁹.
Enhanced of Bioavailability/ Solubility
Lansoprazole	Ethyl cellulose, PVA, pluronic F-68, dichloromethane	Emulsion solvent diffusion method		The developed nanosponges of Lansoprazole were further formulated as enteric coated tablet. The drug release from coated tablet was extended upto 12 h³⁰.
Losartan	β-cyclodextrin, polyvinyl alcohol, Hydroxypropyl βcyclodextrin	Solvent evaporation method		Losartan is a BCS class II drug, Nanosponge of losartan was prepared by using ethyl cellulose, β-CD and HP-β-CD cyclodextrin. For the optimized nanosponge the entrapment efficiency was found to be more than 95 %³¹.
Simvastatin	Dichloromethane, ethyl cellulose, β -cyclodextrin	Solvent evaporation method		Enhancement of solubility of Simvastatin is achieved through development of nanosponge drug delivery³².
Risedronate Sodium	Eudragit RS 100, Eudragit E 12.5, Ethyl cellulose, potassium hydroxide, methanol, dichloromethane, polyvinyl alcohol	Quasi emulsion solvent diffusion method		The Risedronate Sodium has poor and erratic absorption. The In-Vitro drug dissolution of optimized formulation showed burst release for initial 2 h followed by slow and sustained release up to 24 h. The study revel as better results in improvement of osteoporotic condition³³.
Vaginal Delivery
Miconazole nitrate	D-phenyl carbonate, β CD	Melt method		The nanosponge formulation were developed using β CD as polymer and D-phenyl carbonate as cross linker in 1:1 ratio. Optimized Nanosponge loaded gel showed better results.

CONCLUSION:

Nanosponges are the novel drug delivery. It is a class of biocompatible and versatile drug carriers as they carry both types of drugs such as hydrophilic and lipophilic drugs by forming inclusion and non-inclusion complexes. They are delivered by various routes like oral, topical and parenteral routes^34,35,36. Nanosponges release the drug in controlled and predictable manner to the targeted site, thus it increases the bioavailability of the drug. The particle size and release rate can be modified by controlling the polymer to crosslinker ratio to better fit the application^37,38,39. Nanosponges can be used for improvement of the aqueous solubility of the lipophilic drugs and protect the drugs from physicochemical degradation. They have been found to be promising materials for immediate technological use for drug entrapment and as novel drug carriers⁴⁰.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 24.06.2021 Modified on 14.12.2021

Asian J. Pharm. Tech. 2022; 12(2):129-135.

DOI: 10.52711/2231-5713.2022.00022