INTRODUCTION:

Targeting the drug to the specific place in the body has been create a problem to the medical researchers, how to addministerd in right place and how to control its release and overdose¹. Nanotechnology is potentially the most important process in the industrial area. Nanotechnology process cotain the various of formulations like nanoparticles, nanocapsules, nanospheres, nanosuspensions, nanocrystals, nano erythosomes etc².

Nanotechnology contain mainly nanomaterials are defined as materials they have dimension in the range between 1-100 nm^3,4,5. Nanosponges was firstly developed for drug addministerd in topical drug delivery system. Nanosponges are tiny sponges with a size of about a average diameter below 1μm⁶. Nanosponges are tiny sponges with a size of about a virus, which can be filled with a different variety of drugs⁷. Nanosponges are insoluble in water and organic solvents, as compare to other nanopartical. They have porous, non-toxic and stable at high temperatures up to 3000C. The nanosponges are solid in nature and can be administered by oral, parenteral, topical or inhalational dosage forms⁸. Nanosponge is a modern dosage form of material and it is formulated through tiny particles with a narrow cavity of few nanometers. These narrow cavities are filled with differenttypes of substances. These tiny particles are have capacity to able to carry both hydrophilic and lipophilic drug substance and they increase the stability and solubility of poorly water-soluble drug substance or molecules⁹.

A novel nanostructured material can be obtained by reacting polyesters (cyclodextrins) with appropriate crosslinking agents, known as nanosponges¹⁰

Fig. Formation of Nanosponges

Nanosponges are solid in nature. They have safe for oral, topical or parentral routes; since they have best carrier for drug delivery¹¹. The tiny shape of nanosponges usefull for pulmonary and venous delivery of nanosponges¹². For oral delivery, the misture may be dispersed in a matrix of excipients (diluents, lubricants and anti-caking agents). For parenteral delivery, the mixture may be simply carried a sterile water, saline or other aqueous solutions. For topical delivery they can be effectively incarporated into topical hydrogel¹³. Nanosponges are encapsulating process of nanoparticles which encapsulates the drug partical within its core. A nanosponge can circulate in the body until they reach the specific target site, bind to the surface and release the drug in a predictable manner¹⁴

Advantages of nanosponge^15,16,17,18

· Increase aqueous solubility of the less water-soluble drug.

· Nanosponges drug delivery system are non-irritating, nonmutagenic and non-toxic.

· Nanosponges drug delivery system have less side effect.

· Increase stability, elegance and flexibility of the formulation.

· Reduce frequency of dosing.

· Provides extended release up to 12 hrs.

· Reduce the degradation of active ingredient.

· To mask the bitter taste.

Disadvantages¹⁹

· Nanosponges contain only small molecules.

· Depend only upon loading capacities of drug molecules.

Characteristic Features of Nanosponges^20,21,22

· Nanosponge are nontoxic, porous, insoluble in most organic solvents and stable up to 300 °C.

· They are stable at the pH range of 1-11.

· Nanosponges provide a range of dimensions (1 μm or less).

· They can bind to different target sites because of they have capacity to link with different functional groups.

· Nanosponges are virus size can be formulate by changing the crosslinker to polymer ratio.

· Deliver the drug molecule at the targeted site

· Nanosponge improved stability, elegance and formulation flexibility.

· Drug is protected from degradation.

· Nanosponge have less side effect since small quatities of the drug are contact with healthy tissue.

· Nanosponge have major advantage control release, they produce a control realese of drug.

Types of Nanosponges²³

COMPOSITION AND STRUCTURE OF NANOSPONGES^24,25,26

A. Polymer

The polymer have different type and it affect the formation as well as theperformance of nanosponge. Polymer have a ability to cross-linked due to its functional and active grouop present. The selection of polymer is depend of drug release and how much quantity drug enclose. Cyclodextrines and its derivatives like alkyloxycarbonyl cyclodextrins, hyper cross linked polystyrenes, methyl β-cyclodextrin, hydroxy propyl β-cyclodextrins.

B. Copolymer:

When two or more than two different monomers unite polymerize to togather, the resultant product is calleda copolymer and the process known as copolymerization. The properties of manufactured product will be change by using co-polymerization to meet specific needs, for example, to reducecrystallinity, modify glass transition temperature, and control wetting properties or to improve solubility. It is a process of improving mechanical properties. like Poly (valerolactone allyl valerolactone) Pyromellitic anhydride, Ethyl Cellulose, PVA, 2,2-bis (acrylamide) Acetic acid, Carboxylic acid dianhydrides, Glutaraldehyde Poly(valerolactone allyl valerolactone oxepane dione), Epichloridrine.

C. Crosslinking agent:

Selection of crosslinking agent depends on the structure of polymer and the drug to be encapsulate.

Carbonyl Diimidazole, diarylcarbonates, dichloromethane. diisocyanates, diphenyl carbonate, gluteraldehyde, diisocyanates, diphenyl carbonate, pyromellitic anhydride, carboxylic acid dianhydrides, epichloridine, 2,2-bis (acrylamido) acetic acid.

C. Drug substance:

Drug molecules to be formulated as nanosponges should have following characteristics.

· Molecular weight in range between 100 and 400 Daltons.

· Drug molecule contain less than five condensed rings.

· Drug have Solubility in water less than 10 mg/ml.

· Drug have Melting point below the 250⁰C.

Biopharmaceutical classification system class II drugs: ²⁷

Category of drug	List of drug
Antianxiety drugs	Lorazepam
Antiarrhythmic agents	Amiodarone hydrochloride
Antibiotics	Azithromycin, Ciprofloxacin, Erythromycin, Ofloxacin, Sulfamethoxazole
Anticoagulant	Warfarin
Anticonvulsants	Carbamazepine, Clonazepam, Felbamate, Oxycarbazepine, Primidone
Antidiabetic and Antihyperlipidemic drugs	Atorvastatin, Fenofibrate, Glibenclamide, Glipizide, Lovastatin, Troglitazone
Antiepileptic drugs	Phenytoin
Antifungal agents	Econazole nitrate, Griseofulvin, Itraconazole, Ketoconazole, Lansoprazole,Vericonazole
Antihistamines	Terfenadine
Antihypertensive drugs	Felodipine, Nicardipine, Nifedipine, Nisoldipine
Antineoplastic agents	Camptothecin, Docetaxel, Etoposide, Exemestane, Flutamide, Irinotecan,Paclitaxel, Raloxifene, Tamoxifen, Temozolamide, Topotecan
Antipsychotic drugs	Chlorpromazine Hydrochloride
Antiretrovirals	Indinavir, Nelfinavir, Ritonavir, Saquinavir
Antiulcer drugs	Lansoprazole, Omeprazole
Antioxidants	Resveratrol
Anthelmintics	Albendazole, Mebendazole, Praziquantel
Cardiac drugs	Carvedilol, Digoxin, Talinolol
Diuretics	Chlorthalidone, Spironolactone
Gastroprokinetic agent	Cisapride
Immunosupressants	Cyclosporine, Sirolimus, Tacrolimus
NSAIDs	Dapsone, Diclofenac, Diflunisal, Etodolac, Etoricoxib, Flurbiprofen, Ibuprofen,Indomethacin, Ketoprofen, Mefenamic acid, Naproxen, Nimesulide, Oxaprozin,Piroxicam
Steroids	Danazol, Dexamethazone

METHODOLOGY FOR PREPARATION OF THE NANOSPONGES:

SOLVENT DIFFUSION METHODS^28,29

1.Quassi emulsion solvent diffusion:

Prepration of inner phase. Consist of polymer dissolve in suitable solvent.

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Drug added in to solution and dissolved under ultrasonication at 35⁰C.

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Inner phase is add into the polyvinyl alcohol solution in water.

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Stirred the mixture for 60 min, then the mixture is filtered.

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Prepared nanosponges are dried in a air heated oven at 40⁰ C for 12 h

2. Emulsion solvent diffusion method:

Preparation of disperse and continousphase.

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Continous phase contain copolymer.

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Disperse phase contain drug and polymer.

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Disperse phase is slowly added in the continous phase and

Stirred for 2-3 hrs at 1000rpm.

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Filtered the prepared nanosponge, washed and thendried in air at room temperature or in vacuum oven to 40⁰C for 24 hrs.

Ultrasound assisted synthesis³⁰

Polymer is added in cross linker in balanced ratio in a flask.

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Then flask is placed in an ultrasound bath filled with water.

The temp is maintained at range 90⁰C

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Sonicate the mixture for 5 hrs

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Non reacted polymer removed out, then wash out the product with water

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Ethanol use for product purificationis by soxhlet extraction process.

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Allow the product to dried under vaccum at 25⁰C.

Quasi-emulsion solvent diffusion³¹

Disperse phase is prepare by dissolving eudragit RS100 in suitable solvent.

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Then, drug can be added in solution and dissolved under ultrasonication at 35⁰C.

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The disperse phase was added into the polyvinyl alcohol solution in water as a continuous phase.

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The mixture is filtered after 60min of stirring to separate the nanospnges.

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The naosponges are dried in an air-heated oven at 40⁰C for 12 hrs.

Characterization of Nanosponges:

Solubility study:

The phase solubility method is the most widely used approach to study inclusion complexation described by Higuchi and Connors, who studied the effect of a nanosponge on the solubility of drug. The degree of complexation indicate through Phase solubility diagrams³².

Porosity:

For the checking of the extent of nanochannels and nanocavities formed the porosity study is performed. For the assess porosity study of nanosponges Helium pycnometer is used, since helium gas isable to penetrate inter- and intra-particular channels of materials. Following equation is used for to calculate percent of porosity³³.

Percentage of Porosity: Bulk volume-Tab Volume/Bulk Volume 100

Particle size and polydispersity index Determination:

Particle size:

Partical size is determined by laser light Diffractometry or zeta seizer. Particle size range from 10-30μm can be usefull for topical drug delivery.

The polydispersity index (PDI):

Polydispersity index is measure byusing dynamic light scattering Instruments.PDI is an index of width and variation with particle size distributes. Monodisperse samples they have a lower PDI value, and the higher value of PDI indicates a wider particle size distribution and the polydisperse nature of the sample. Following equation is use for calculate the PDI.

PDI=Δd/davg where. Δd=width of distribution

The Range of Polydispersity index in the form of a table as below:

Polydispersity index Type of dispersion:

0-0.05 Monodisperse standard

0.05-0.08 Nearly monodisperse

0.08-0.7 Mid-range polydispersity

> 0.7 Very polydisperse

Determination of production yield:

The production yield (PY) can be determined by dividing initial weight of raw materials and final weight of nanosponges³⁴.

Production Yield = Practical mass of nanosponges / Theoretical mass × 100.

Drug entrapment efficiency:

Centrifugation method is used for drug entrapment efficiency, at the 1300 rpm for 20 min. After centrifugation, the supernatant layer was removed &diluted with appropriate solvent

% DEE =Wt of initial drug added in the formulation-wt of free into formulation / Wt of initial drug added in the formulation × 100

Loading efficiency:

The loading efficiency (%) of Nanosponge can be determined by following equation³⁵.

Loading Efficiency = Actual drug content/Theoretical drug content × 100.

Zeta potential:

Zeta potential is use for measuring of surface charge. It can be measured by using electrode in the particle size equipment. Zeta sizer is use for the determine the surface charge of Nanosponge.

Drug content:

In 100 ml of volumetric flask 50 ml of methanol is taken and it add a formulation, allow to stand for 2hr. the volume is make up upto 100 ml by using methanol. 1ml of the above solution was diluted to 10 ml with6.8 pH phosphate buffer. The drug content was determined by measuring the absorbance using UV Visible spectrophotometer³⁶.

Microscopic studies:

Scanning electron microscopy and Transmission electron microscopy are usedto study the morphology and surface topography.

X-ray diffractometry:

X-ray diffractometry is used for detection of inclusion complexation in the solid state.

Infrared spectroscopy:

Infrared spectroscopy is used for determination of the interaction between nanosponges and the drug molecules in the solid state.

Thin layer chromatography:

Identifying the complex formation between the drugand nanosponge is carried out by using thin layer chromatography.

Raman spectroscopy:

Molecular structures determine by using raman spectroscopy.

APPLICATIONS OF NANOSPONGES:

Nanosponges have following applications in the pharmaceutical field.

Nanosponges as Solubility Enhancer:

Nanosponge is the best carrier system for low soluble molecules, which entrap the molecule into its core and provide improved solubility as well as the bioavailability of lipophilic drugs. Nanosponges are widely used for improving the solubility and dissolution rate of poorly soluble drugs as well as providing controlled release profile³⁷.

Nanosponges in Drug Delivery:

Nanosponge have a nanoporous structure, hencethey perfectly carry water insoluble drugs and/or molecule (BCS Class-II drugs). Nanosponge are useful for increase the dissolution rate, solubility and stability of BCS class II drugs. Some drugs having low solubility and they are successfully delivered by loading into the nanosponges. Due to their solid nature and they can be formulated as oral, parenteral, topical or inhalation dosage forms³⁸.

Nanosponge in protein drug delivery:

Nanosponge are useful in enzyme immobilization, protein encapsulation and subsequent controlled delivery and stabilization Bovineserumalubin (BSA) protein is unstable in solution form so they are stored in lyophilized form. The stability of proteins like BSA are increase by Swellablecyclodextrin based poly (amidoamino) nanosponge’s³⁹

Nanosponges as a Carrier for Delivery of Gases:

The gases play a key role in medicine, they are useful to treatment purpose in diagnostic. Hypoxia (deficiency of adequate oxygen supply) through inflammation to cancer is related to various pathologies. The delivery oxygen in appropriate form and doses in clinical practice is Sometimes difficult. Cavalli et al. developed Nanosponge formulations in that oxygen delivery system for topical application which having the ability to store and to release oxygen slowly over time⁴⁰

Topical drug delivery system:

Local anesthetics, antifungals and antibiotics are some the category of the drug substances that can be easily formulated as topical nanosponges. In this context, nanosponges can be prepared by different methods like emulsion solvent diffusion method, etc⁴¹

In Antiviral Therapy:

Nanosponge are useful in the ocular, nasal and pulmonary administration routes. Were the many antiviral drug are given through nanosponge in the oral, parentral, and other drug delivery system. There are some drugs which are formulated in nano delivery systems are zidovudine, saquinavir, interferon-α, acyclovir, nelfinavir etc⁴²

Modulating Drug Release:

The conventional, commercially available drug have major drawback it is a frequent administration. Hence, a drug loaded into the nanosponge is retained and released slowly over time. Vyas et al. has been studied that the hydrophilic cyclodextrin nanosponges are to change the drug release rate, to increase the drug absorption across biological barriers, as a potent drug carrier in immediate release formulations. Hydrophobic cyclodextrin nanosponges are use as a sustained release carriers for water soluble drugs, contain peptide and protein drugs and it was best carriers for the anticancer drug such as doxorubicin, and also they protect the drug through stomach during its passage time. At pH 1.1 this drug is released very slowly, whereas release is faster if pH is raised to 7.4⁴³

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Received on 29.05.2020 Modified on 03.07.2020

Res. J. Pharma. Dosage Forms and Tech.2020; 12(4):261-266.

DOI: 10.5958/0975-4377.2020.00043.9