INTRODUCTION:

In the beginning, only one standard drug delivery system was approved for the nanosponges drug delivery system, but it can be administered by oral, topical and Parenteral route in the 21st century. It is the modern category of materials and made up tiny particle with a narrow cavity of few nanometre. As an important carrier of enzymes, vaccines, antibiotics and proteins. It can also be used.

The composition of the nanosponge technology has been stuck and leads to reducing side effects, improving stability, versatility of formulation, improving elegance. Nanosponge are encapsulating types of nanoparticles in which encapsulated to drug molecules and its core.¹

The small particle is capable of carrying out both hydrophilic and hydrophobic drugs and increasing the solubility of the water compound. Polyester is a biodegradable polymer but inside the body and it breaks down. They are three-dimensional scaffolds (backbone) or polyester networks and are naturally able to degrade. It is combined with a solution called cross-linker with small molecules such as tiny grappling hooks to join together various polymers more easily. Cavities have been filled with the impact of spherical shaped particles where drug molecules have to be processe.²

Fig 1. Structure of a nanosponges showing a cavity of drug loading.

Advantage^1,2

· Reduce dose frequency.

· Better compliance for patients.

· Improve the aqueous solubility of poor compliance with water-soluble drugs.

· They are non-toxic, non-mutagenic, and non-irritant.

· Minimize adverse reactions.

· Increase the stability of formulation and formulation flexibility.

· Specific drug distribution to the targeted site. These are free flowing, highly compatible with wide variety of ingredients.

· Cost effective.

· It help to removed toxin and venom substance from the body

Disadvantage^1,2

· Dosage dump.

· They have the ability to encapsulate tiny molecules that are not appropriate for large molecules.

· Used for small molecules only.

· The release may be delayed.

Mechanism of drug release from nanosponge¹:

Since the structure of the nanosponge has been opened (they do not have any continuous membrane in the vicinity of the nanosponge). The active substance is added in encapsulated form to the vehicle. The encapsulated active material will travel freely through the vehicle from the particles until the vehicle is saturated and balance is achieved. As soon as the substance is added to the skin, the vehicle containing the active component becomes unsaturated, causing the balance to be disrupted. Thus, once the vehicle is either absorbed or dried, the active flow from the nanosponge particle into the vehicle from it and to the skin will start and after that, the nanosponge particles maintained on the skin surface, i.e. the stratum, the corneum and the release of the active material, continue to stay on the skin for a long time.

Fig2. Mechanism of Topical use of drug release from nanosponge

Mechanism of Parenteral use of drug release from nanosponges:

In the presence of a non-ionizing light source, such as broadband light, lasers, and LEDs in the visible or infrared spectrum, when inserted by the nanosponge formulation within the rat vein. In order to alter the biological activity of cells, NIR light converts luminous energy to metabolic energy. Then, the release of the drug into the tumor cell and the development of cancer cells. Lymphocyte and t-cell invasion of cancer cells. Tumor ablation is an invasive procedure used in the treatment of liver, kidney, bone and lung tumor ablation and thermal energy is used to cytotoxic levels of heart or cool tissue (less than -40^○C or more than 60^○C). Then, after time, the death of tumor cells. In the B, in the presence of nanosponge uptake and then, formulation to bind the receptors and cell death, the drug loaded into nanosponge was obtained.

Carrier used in preparation of nanosponges:³

Polymers:

Hyper cross linked Polystyrenes, Cyclodextrins and its derivatives like Methyl β-Cyclodextrin, Alkyloxy-carbonyl Cyclodextrins, 2-Hydroxy Propyl β-Cyclodextrins, Copolymers like Poly (valerolactone – allylvalerolactone) and Poly (valerolactone-oxepanedione) and Ethyl Cellulose and Poly vinyl acetate (PVA).

Copolymer:

Poly (Valero lactone-allyl Valero lactone), Poly (valerolactone-allylvalerolactone oxepanedione). Ethyl cellulose and polyvinyl alcohol.

Cross linkers:

Diphenyl carbonate, Di-arylcarbonates, Di-Isocyanates, Pyromellitic anhydride, Carbonyl-imidazole, Epi-chloridrine, Glutraldehyde, carboxylic acid di-anhydrides2, 2- bis (acrylamidos), Acetic acid and Dichloromethane.

Method of Preparation^{1,
4, 5, 6, 7}

1. Solvent method

2. Hyper cross linker in solvents

3. Ultrasound assisted synthesis

4. Loading of drug into nanosponges

1. Solvent method:

Mix the polymer with a suitable solvent, in particular like as dimethylformamide dimethylsulfoxide, a polar aprotic solvent. Then apply this mixture to the cross-excess linker's amount, preferably 4 to 16 in the crosslinker/polymer molar ratio. The reaction is carried out at a temperature varying from 10 °C to a solvent reflux temperature ranging from 1 to 48h. Cross-linkers that are favoured.

Polymer is mixed with a suitable solvent like polar aprotic solvent.

This mixture is added to quantity of the cross linker preferably in cross linker /polymer molar ratio of 1:4.

Action is carried at temperature ranging from 10^○C to the reflex temperature of the solvent, for time ranging from 1-8 hours.

After completion of the reaction, the solution is cooled at room temperature and the product is added to large excess of distilled water.

This recovery of the product is done by filtration under vacuum.

2. Hyper cross-linked b - Cyclodextrin:

Nanosponges were prepared from β-cyclodextrins as nanoporous materials used as carriers for drug delivery. Nanosponges are recently developed hyper-cross-linked cyclodextrin polymers nano structured to form 3-dimensional networks. A roughly spherical structure, about the size of a protein, with channels and pores inside. They have been obtained by reacting cyclodextrin with a cross-linker such as diisocianates, diarylcarbonates and carbonyl diimidazoles, carboxylic acid dianhydrides and 2, 2-bis (acrylamido) acetic acid. The surface charge density, porosity and pore sizes of sponges can be controlled to attach different molecules. In the neutral or acidic forms, nanosponges can be synthesized in one-step or two-step processes depending on the physico-chemical properties of the drug to be loaded. If the drug is normally an inert non-polar substance, it is called porogen, which produces the porous structure. Porogen drug is stuck with oneste, which does not impact and activated by polymerization, even stable to free radicals.

Fig 4. Structure of hyper cross linked b- cyclodextrins.

3. Ultrasound assisted synthesis:

In this method, the nanosponge has been obtained by reacting polymers with the cross linker in the absence of the solvents and sonication. It is obtained by this method, it will be spherical and uniform size. The mix of the polymers and cross linkers in a particular molar ratio in the flask and place the flask in ultrasound bath and filters with water. It is heated at 90^○C. Sonicated the mixture 5 hours. Then allow the mixture to cool and breaking the product and wash the product with water to remove the polymers. The prolonged soxhlet extraction with ethanol and dry obtained the products.

4. Loading of drug into nanosponges:

Suspend the nanosponge in water and sonicated to avoid the presence of aggregates and then centrifuge the suspension to obtained the colloidal fraction. Separate supernatant and dry the sample by freeze drying. The amount of drug and maintain the suspension under the stirring for specific time required for complexation. After complexation, Separate the undissolved drug from complex drug by centrifugation. Then obtained of the solid crystal of nanosponge by solvent evaporation or freeze drying and formed nanosponge.

Evaluation of Nanosponge:

Particle size determination:^8,9

Free-flowing powders with fine aesthetic qualities can be obtained by controlling the size of particles during polymerization. The particle size study of loaded and unloaded nanosponge and microsponges can be done by laser light diffractometry or Malvern Zeta sizer. The cumulative percentage of drug release from nano and microsponges of different particle sizes will be plotted against time for study.

Drug Content or Entrapment Efficiency (%):¹⁰

50 mg of the prepared drug Nanosponges were suspended in 50 ml of methanol using the emulsion solvent diffusion method using the required polymer and subjected to ultracentrifugation for 40 minutes. The spectrophotometric percentage of the integrated drug was calculated at precise nm. The number of the free drug was detected after centrifugation in the supernatant and the aqueous suspension. Then formula,

Entrapment efficiency = Total drug (assay) – Free drug / Total drug ×100

Scanning Electron Microscopy (SEM) analysis:¹⁰

For the determination of particle surface features and size, SEM analysis is important. The scanning electron microscopy was conducted at an acceleration voltage of 15KV. A condensed aqueous suspension was distributed into a machine cell receiver and vacuum-dried. A 20 mm thickened cathodic evaporator gold layer linked to a monitor representing the images was shaded in the study.

Zeta potential:^10,11

Zeta potential of any system under investigation is a measured of the surface charge.

Loading efficiency:^10,11

The loading efficiency of nanosponges can be determined by the quantitative estimation of drug loaded into nanosponges by UV spectrophotometer and HPLC methods.

Solubility studies:¹²

The phase solubility method defined by Higuchi and Connors, which explores the effect of a nanosponge on drug solubility, is the most commonly used approach to studying inclusion complexation. Diagrams of phase solubility show the degree of complexity.

Fourier Transform Infrared (FTIR):^12,13

Fourier transform infrared analysis was performed to verify the possibility of the interaction of chemical bonds between drugs and polymers. Samples were scanned within the 400-4000 cm-1 and carbon black reference range. To increase the signal level and decrease some peaks of moisture, the detector was carefully purged with clean, dry helium gas. Changes in the loss of weight can also provide for.

X-ray diffractiometry and single crystal X-ray structure analysis:^12,13

For detecting inclusion complexity in the solid state, powder and X-ray diffractiometry can be used. If the drug molecule is liquid and the liquid does not have its own diffraction pattern and the diffraction pattern of the newly formed material is clearly different from that of the uncomplexed nanosponge. The complex formation has been suggested by this difference in the diffraction pattern. If the drug compound is a solid substance.

Drug release kinetics:^12,13

In order to investigate the mechanism of drug release from the Nanosponge and release data was analyzed using the Zero Order, First Order, Higuchi, Korsemeyer-Peppas, Hixon Crowell, Kopcha and Makoid-Banakar models. The data could be analysed using graph pad prism methods. A non-linear function parameter that provides the closest match between experimental and non-linear observations is calculated by the software.

Thermo-analytical methods:¹³

Thermo-analytical methods determine by the drug material undergoes any alteration prior to the thermal degradation of the nanosponge. The modification of the drug content may be freezing, evaporation, decomposition, oxidation or polymorphic transformation. The modification of the drug substance shows the complex formation.

Porosity:^13,14

Porosity analysis has been performed to check the extent of nanochannels and nanocavities generated. As Helium gas is capable of penetrating inter- and intra-specific material channels, the helium pycnometer is used to measure the porosity of nanosponges. By equation, percent porosity is given

Porosity = Void volume (Vv) / total volume (VT)

Factors Affecting Nanosponge Formulation:

1 Type of Drug

2 Type of Polymer used

3 Temperature

4 Method of preparation nanosponge

5 Degree of substitution

1. Type of Drug:¹⁴

For the drug molecules to be nanosponge incision and non-incision complexes, Bellow should have those characteristics:

1 In water, there is less than 10 mg/ml of drug solubility.

2 The molecular weight of the drug is 100 to 400 gm per mole.

3 The drug molecule structure should be found in no more than five condensed rings.

4 The freezing point of the medication should be less than 250°C.

2. Type of polymer:¹⁴

The kind of polymer that can affect the formation and efficiency of nanosponge used in nanosponge formulation. The size of the nanosponge cavity and the complexity of the drug depend on the polymer that is used in the formulation.

3. Temperature:¹⁵

The Changes in temperature can influence the complexity of drugs/nanosponge. In general, rising temperature decreases the magnitude of the Drug/Nanosponge complex's apparent stability constant may be due to the possible decrease in forces of drug/nanosponge interaction, such as van-der Waal forces and temperature rise hydrophobic forces.

1. Degree of substitution:¹⁶

The number, position, and form of the parent molecule substituent may have a greater impact on the ability of the nanosponges to complex.

2. Method of preparation:¹⁶

The complexity of the drug/nanosponge has been affected by the process of loading the drug into the nanosponge. However, the effectiveness of a method depends on the nature of the drug and polymer, and in certain cases, freeze drying was found to be most effective for drug complexation.

Applications of Nanosponges:^14,15,16

Solubility enhancement:

Wetting and solubility of molecules with very low water solubility can be enhanced by nanosponges. Within the nanosponge structure, the drugs can be molecularly distributed and then released as molecules, preventing the dissolution stage. It is possible to improve the apparent solubility of the compound. Many problems with formulation and bioavailability can be solved by improving a substance solubility and dissolution rate and nanosponges can significantly increase the solubility of the drug. The BCS class II drugs that have very low solubility are given in Table 1 and are the perfect candidates for nanosponges.

Nanosponges for drug delivery:

In nature, the nanosponges are solid and can be formulated as dosage forms of oral, parenteral, topical or inhalation. Complexes may be distributed in a matrix of excipients, thinners, lubricants and anticoagulants appropriate for the preparation of capsules or tablets for oral administration. The complex may be transported simply in sterile water, saline or other aqueous solutions for parenteral administration. They can be incorporated efficiently into topical hydrogel for topical administration.

Topical agents:

A novel technique for the controlled release of extended drug release topical agents and drug form retention on the skin is the nanosponge delivery system. Local anaesthetics, antifungals and antibiotics are included in the category of drugs that can be easily produced as topical nanosponges. When the skin is penetrated by active ingredients, rashes or more serious side effects may occur.

On the other hand, this technology allows an even and continuous rate of release, reducing pain while maintaining output. A broad variety of substances can be mixed into a formulated product, such as gel, lotion, cream, ointment, liquid, or powder.

Cancer Therapy:

An a significant thing in cancer is to direct drugs to a particular site, which decreases the side effect and improves bioavailability. Nanosponges, such as breast cancer, colon cancer, brain cancer, lymph carcinoma, lung cancer, are treated for various cancers using a single dose of injections. A plant alkaloid that is used as the antitumor agent, camptothecin (CAM). Owing to its limited therapeutic usefulness and extreme side effects, it has poor aqueous solubility. Nanosponges based on cyclodextrin (NS) are a new class of cross-linked cyclodextrin derivatives used to target anti-cancer drugs. This is used to improve the solubility of the poorly soluble drug, to protect and monitor the release of labile groups.

Antiviral application:

To target nasal and lung drugs, nanosponges are used. It delivers the antiviral drug to target viruses that may cause RTI (Respiratory tract infection) infection such as influenza virus, rhinovirus, through nanocarriers to the lungs or nasal path. Zidovudine and Saquinavir are examples of nanocarriers used in pharmaceutical goods.

Encapsulation of gases:

The inclusion complexes with three different gases i.e. 1-methylcyclopropene, oxygen and carbon dioxide, were developed using cyclodextrin-based carbonate nanosponge. Oxygen or carbon dioxide complexion can be beneficial for many biomedical applications. The oxygen-filled nanosponge could, in particular, supply oxygen to the hypoxic tissues that are present in different diseases. The Nanosponge was also explored as a powerful gas carrier because of its super porous existence. The composition of nanosponge demonstrates the capacity to store and release oxygen in a regulated manner. They may be a helpful method for the distribution of certain essential gases in the future.

Nanosponges as a carrier for biocatalysts:

Cyclodextrin-based nanosponges have been found to be basically efficient carriers for the adsorption of enzymes, antibodies, proteins, and macromolecules. The creation of nanosponge can maintain its activity, efficiency, extend its operation, activity range of pH and temperature, specifically when enzymes are used, and allow continuous flow processes to be carried out in addition, by adsorbing or encapsulating, proteins and other macromolecules can be transferred to cyclodextrin nanosponges.

Nanosponge in protein drug delivery:

Bovineserumalubin (BSA) protein is unstable in solution form and so stored in lyophilized form. Nanosponge has also been used for enzyme immobilization, protein encapsulation, and subsequent regulated delivery and stabilization. Poly (amidoamino) nanosponge-based swellable cyclodextrin enhanced the stability of proteins such as BSA.

As absorbent in treating poison in blood:

By removing the toxin, nanosponges will extract harmful poisonous substances from our blood. If we integrate nanosponges by injection into the blood instead of using antidotes. Nanosponges will soak up the toxins. The nanosponge appears like a red blood cell in the bloodstream, tricks toxins into destroying it and then consumes it. The number of toxin molecules, each nanosponge can be absorb depends on the toxin.

CONCLUSION:

The goal of this review article of nanosponges have been ability to release the drug in controlled manner to the targeted site. The small size and spherical shape of the delivery system enables various dosage forms such as parentral, aerosol, topical and oral dosage forms to be formulated according to specifications and advanced method. This technology provides ingredient capture and thus, decreases side effects, improves stability, increases beauty, and enhances versatility in formulation. Therefore, by offering a site-specific drug delivery system and extending dose intervals to increase patient compliance. For the solution of various nano-related problems in pharmaceutical energy, nanosponge formulation may be best.

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Received on 10.02.2021 Modified on 20.02.2021

Res. J. Pharma. Dosage Forms and Tech.2021; 13(2):127-133.

DOI: 10.52711/0975-4377.2021.00023

Drug	Administration route	Dosage form	Marketed product	Trade name
Dexamethasone	Dermal	Oinments	Japan	Glymesason
Iodine	Topical	Solution	Japan	Mena-Gargle
Alprostadil	I.V	Injection	Europe,Japan,USA	Prostavastin
Piroxicam	Oral	Capsule	Europe	Brexin