NANOSPONGES: A NEW ERA OF VERSATILE DRUG DELIVERY SYSTEM

Nanotechnology is a multi disciplinary science which is getting considerable attention in development of new chemical entities, diagnosis and treatment of several ailments. Nanomedicine technology has developed many drug delivering systems like nanoparticles, nanoemulsions, nanosuspensions, nanosponges etc., which are associated with many advantages including improved bioavailability. Nanosponges are tiny sponges having size of about a virus and can be filled with variety of drugs. This sponge can circulate around the body until interact with specific target site and stick on surface and start releasing drug in a controlled manner. Nanosponge play vital role in targeting drug delivery in a controlled manner. Both lipophilic and hydrophilic drugs are incorporated in nanosponges. The outer surface is typically porous, allowing controlled release of drug. Important characteristic of these sponges is their solubility in aqueous form and suitable for the drugs with poor solubility. This review is focusing on the preparation methods, applications of nanosponges in the field of drug delivery.


INTRODUCTION
The drug delivery technology has certainly a new interest for drugs by providing them new life through their therapeutic targets. Targeting drug delivery is the major problem which is being faced by the researchers. Target oriented drug improvements in therapeutic efficacy, reduction in side effects and optimized dosing regimen, shall be the leading trends in the area of therapeutics 1 . Targeted drug delivery implies for selective and effective localization of pharmacologically active moiety at preidentified (preselected) target in therapeutic concentration, while restricting its access to non-target normal cellular linings and thus minimizing toxic effects and maximizing therapeutic index of the drug 2 . They provide excellent topical delivery of drugs 3 . These embraces nanotechnology which is applied to pharmacy as nano materials, diagnosing and focusing right place in the body and controlling release of the drug 4 . Nanosponges are about the size of virus which has been backed by naturally degradable polyster. These tiny sponges can circulate around the body they encounter the specific target site and stick on the surface and began to release the drug in a controlled and predictable manner. Owing to their small size and porous nature they can bind poorly-soluble drugs within the matrix and improve their bioavailability. These are solid in nature and it can be formulated as oral, parenteral, topical or inhalational dosage forms. For oral administration, nanosponges may be dispersed in a matrix of excipients, diluents, lubricants and anti-caking agents which is suitable for the preparation of tablets or capsules.  2. Improved stability, increased elegance and enhanced formulation flexibility. 3. These formulations are stable over range of pH 1 to 11. 4. These formulations are stable at the temperature up to 130 0 C. 5. These formulations are compatible with most vehicles and ingredients 7 . 6. These are self sterilizing as their average pore size is 0.25¼m where bacteria cannot penetrate. 7. They increase the bioavailability of drug 8 . 8. These modify the release of drug. 9. They increase the solubility of poorly soluble drug. Disadvantages: 1) Nanosponges include only small molecules 9 .

METHODS OF PREPARATION
It is one of the important criteria for the formation of product obtained activity in β-cyclodextrin, titanium oxide.

Solvent method
The solvent required is mixed with the polymer mainly in a polar aprotic solvent, for example dimethyl formide, dimethyl sulfoxide then add this mixture to cross linker in a exceed quantity, the ratio for cross linker/ molar ratio is preferred as 4 to 16 10 . The reaction is completed and solution is allow to cool at room temperature. Finally product is dried under vaccum and grinded in a mechanical mill to obtain homogeneous powder 11 .

Ultrasound assisted synthesis
Nanosponges are obtained by reacting polymer with cross linkers without adding or without using solvent and sonification is maintained. The polymer is mix with a cross linkers in a balanced ratio in a flask. The flask is placed in a molar ratio in an ultrasound bath field with water and temperature maintained at 90 ºC, the mixture is sonicated for 5 hrs 12 . The product is dried under vaccum at 25ºC until its further use is utilized 13 .

Loading of drug into nanosponges
Nanosponges obtained should be pretreated to maintain mean particle size blow 500nm. Nanosponges are suspended in water and were sonicated to avoid presence of aggregates and particles and got centrifuged to obtain colloidal fraction, then supernatant is separated and dried sample by freezing by drying 14 . 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 15 . Factors influence nanosponge formation 1. Type of polymer Type of polymer used can influence the formation as well as the performance of Nanosponges. For complexation, the cavity size of nanosponge should be suitable to accommodate a drug molecule of particular size 16 .

Type of drugs
Drug molecules to be complexed with nanosponges should have certain characteristics mentioned below 17 • Molecular weight between 100 and 400 • Drug molecule consists of less than five condensed rings • Solubility in water is less than 10mg/ml • Melting point of the substance is below 250°C 3. Temperature Temperature changes can affect drug/nanosponge complexation. In general, increasing in the temperature decreases the magnitude of the apparent stability constant of the drug/ nanosponge complex may be due to a result of possible reduction of drug/ nanosponge interaction forces, such as Van-der Waal forces and hydrophobic forces with rise of temperature 18 . Physicochemical characterization of nanosponge 1. Particle size determination Free-flowing powders with fine aesthetic attributes will possible to obtain by controlling the size of particles during polymerization. Particle size analysis of loaded and unloaded nanosponges will performed by laser light diffractometry or Malvern Zeta sizer. Particles larger than 30 m can impart gritty feeling and hence particles of sizes between 10 and 25 m are preferred to use in final topical formulation 19 .

Determination of loading efficiency and production yield
The prepared nanosponge loading efficiency is determined by subtracting the un-entrapped drug from the total amount of drug. The drug entrapment efficiency will be determined by separating unentrapped drug estimated by any suitable method of analysis 20 . The method used for separation of unentrapped drug by gel filtration, dialysis and ultra centrifugation 21 .

Porosity
Porosity study is performed to check the extent of nanochannels and nanocavities formed. Porosity of nanosponges is assessed with a helium pycnometer, since helium gas is able to penetrate inter-and intraparticular channels of materials. The true volume of material isdetermined by the helium displacement method. Owing to their porous nature, nanosponges exhibit higher porosity compared to the parent polymer used to fabricate the system 22 .

Swelling and water uptake
For swellable polymers like polyamidoamine nanosponges, water uptake can be determined by soaking the prepared nanosponges in aqueous solvent 23 . Swelling and water uptake can be calculated using equations:

Resiliency (Viscoelastic properties)
Resiliency of sponges can be modified to produce beadlets that is softer or firmer according to the needs of the final formulation. Increased crosslinking tends to slow down the rate of release. Hence resiliency of sponges will be studied and optimized as per the requirement by considering the release as a function of cross-linking with time 24 .

Zeta Potential
Zeta potential is a measure of surface charge. The surface charge of nanosponges can be determined by using Zeta sizer 25 .

In vitro release studies
Dissolution profile of Nanosponge can be studied by use of the dissolution apparatus usp XXIII with a modified basket consisted of 5m stainless steel mesh. Speed of the rotation is 150 rpm. Samples from the dissolution medium can be analyzed by a suitable analytical method 26 .

Permeation studies
The diffusion studies of the prepared nanosponge can be carrying out in Franz diffusion cell for studying the dissolution release of nanosponge through a cellophane membrane. Nanosponge sample (0.5g) can taken in cellophane membrane and the diffusion studies were carried out at 37±1°C using 250 ml of phosphate buffer (pH 7.4) as the dissolution medium. 5ml of each sample can withdrawn periodically at 1, 2, 3, 4, 5, 6, 7 and 8 hrs and each sample will replaced with equal volume of fresh dissolution medium 27 .

APPLICATIONS OF NANOSPONGES 1. Nanosponges for drug delivery
Because of their nonporous structure, nanosponges can advantageously carry water insoluble drugs (Biopharmaceutical Classification System class-II drugs). These complexes can be used to increase the dissolution rate, solubility and stability of drugs, to mask unpleasant flavors and to convert liquid substances to solids 28 .

Nanosponges as chemical sensors
Nanosponges which are the type of "metal oxides" act as a chemical sensors which is used in highly sensitive detection of hydrogen using nanosponge titania. Nanosponge structure intially have no point of contact so there is less hinderance to electron transport and it results in higher 3D interconnect nanosponges titania which is sensitive to H 2 gas 29 .

Nanpsponge for oral delivery
In oral application it forms the nanosponge system consist of pores which increase the rate of solubilization of poorly water soluble drugs which get entrapped the drug in pores. The surface area is increased due to nanosize form and increase rate of solubilization 30 . 4. Solubility enhancement β-cyclodextrin based nanosponges of itraconazole have enhance solubility of poorly soluble drug. The solubility increased by 50 folds compared to ternary dispersion system e.g. -copolyvidonum 30 .

Nanosponges as a carrier for biocatalysts and release of enzymes, proteins, vaccines and Antibodies
It includes the process applied in industry which correlates with operational condition. Reactions which are not specific give rise to low yields and require high temperatures and pressures which consume large amount of energy and cooling water in down-stream process. This are the drawbacks can be removed by using enzymes as biocatalysts as this operate under high reaction speed, mild condition 31 .

Antiviral application
Nanosponges used in nasal, pulmonary route of administration. It provide specificity to deliver antiviral drug on RNA to lungs or nasal route through nanocarriers for targeting virus which may cause infection to RTI such as influenza virus, rhinovirus. Drugs used as nanocarrriers are-Zidovudine, Saquinavir 32 .

Cancer
Targeting drug to specific site avoiding the obstacle created by immune system. Different cancer cells had been treated by nanosponges like breast cancer or fast acting glioma type with help of single dose of injections 33 .

Oxygen Delivery System
Characterized by using α, β and ϒ cyclodextrins and this are suspended in water and get saturated with water. A silicone form of membrane can also be used for oxygen permeation with the help of nanosponge/ hydrogel system 30 .

CONCLUSION
Nanosponges are tiny mesh-like structures that may revolutionize the treatment of many diseases and this technology is five times more effective at delivering drugs for cancer than conventional methods. Because of their small size and spherical shape nanosponges can be developed as different dosage forms like parenteral, aerosol, topical, tablets and capsules. Nanosponge are nano sized colloidal carrier so they easily penetrate through skin. The nanosponges have the ability to include either lipophilic or hydrophilic drugs and release them in a controlled and predictable manner at the target site. The nanosponges have the ability to incorporate many drugs and release them in a controlled and predictable manner at the target site. Topical nanosponge can be more patient compliant and provide sufficient patient benefits by reducing repeated doses and side effects. Nanosponge can be effectively incorporated into topical drug delivery system for retention of dosage form on skin. Hence present study concludes that nanosponges may play an important role for the treatment of different diseases.