NANOSPONGES – NOVEL EMERGING DRUG DELIVERY SYSTEM

NANOSPONGES – NOVEL EMERGING DRUG DELIVERY SYSTEM

Tarun Kumar Satpathy ^{* 1}, Neelesh Chaubey ¹, B. Usha Sri ² and Venkata R. Naidu ³

College of Pharmacy ¹, Sri Satya Sai University of Technology and Medical Sciences, Sehore - 466001, Madhya Pradesh, India.

Vijaya College of Pharmacy ², Hyderabad - 501511, Telangana, India.

Intas Pharmaceutical Ltd. ³, Ahmedabad - 382440, Gujarat, India.

ABSTRACT: The contemporary development in the drug delivery system is a seamless process. Any delivery system targeting a molecule to a particular site is always been appreciated. This requirement can be fulfilled through a specialized drug delivery system that can easily target the drug at the site of action without compromising its efficacy and quality. Few new drugs typically cannot be effectually delivered by conventional dosage form. Hence, benefits from targeted, localized delivery of therapeutic agents are other driving forces for the current scenario. Nanosponge technology has been introduced to assist the release of drug in a controlled manner over time to reduce systemic toxicity and severe reactions. Nanosponges are tiny sponges with a size of about a virus (250 nm^-1 μm), which consist of cavities that can be filled with a wide variety of hydrophilic as well as hydrophobic drugs, which can be further incorporated into a pharmaceutical dosage form such as oral, parenteral, topical or inhalation. The sighting of nanosponge has become a noteworthy step in overcoming certain problems such as drug toxicity, poor bioavailability, physiochemical in-stability, and patient non-acceptability.

Nanosponges,

Targeted drug delivery, Solubility enhancement, Polymers, Crosslinkers

INTRODUCTION: Authentic targeted drug delivery systems have been a fantasy for always in the past and today as well. But it has been mainly unsatisfied by the difficult chemistry that is involved in the new development systems. Targeting drug delivery has long been problematic for medical investigators, i.e., how to get them to the right place in the body and how to control the release of the drug to prevent overdoses.

The recent development of a novel molecule called nanosponges has the probable capability to solve this problem. An advance version of nano-particulate systems is entitled to nanosponges. These are designed with a hyper cross-linked polymer-based colloidal structure. Nanosponges are spongy polymeric delivery systems that are minor sphere-shaped particles with great porous external.

These do not really sponge-like structured shape, more like a network of molecules in three-dimensional structures. Nanosponges are very small, with a size of about a virus having a diameter below 1 µ. These are fused in solution along with tiny molecules coined as cross-linkers that helps to break different parts of the polymer together. The net effect is to form spherically shaped particles filled with cavities where drug molecules can be stored. It is also possible to control the size of nanosponge particles. By varying the proportion of cross-linker to polymer, the nanosponge particles can be made larger or smaller ^{1, 2, 3}.

FIG. 1: THEORETICAL IMAGE OF NANOSPONGE

TABLE 1: ADVANTAGES AND DISADVANTAGES OF NANOSPONGES ^{4, 5, 6}

Characteristics of Drugs Suitable For Nanosponges: ^{7, 8, 9, 10}

• Dug candidates should have a molecular weight in between 100 to 400 Daltons.
• Drug molecule having a maximum five condensed rings is more preferred.
• Solubility in water should be less than 10 mg/ml, BCS class II drugs most commonly used.
• Melting point of the substance should be below 250 °C.

TABLE 2: CONSTITUENTS OF NANOSPONGES ¹¹

Method of Preparation: ^{12, 13, 14, 15}

FIG. 2: EMULSION SOLVENT DIFFUSION METHOD

FIG. 3: ULTRASOUND ASSISTED SYNTHESIS

FIG. 4: SOLVENT METHOD

FIG. 5: FROM HYPERCROSS-LINKED Β-CYCLODEXTRINS

FIG. 6: LOADING OF DRUG INTO NANOSPONGES ¹⁶

Effort Engaged for Nanosponges Ground Work by Various Arenas: E. G. Chadwick et al., the discovery paves the way for a more economical production method for porous silicon. The related surface pore structure is examined in detail using scanning electron microscopy and transmission electron microscopy techniques while the internal pore structure is explored using focused ion beam milling and ultramicrotome cross-sections.

Analysis of the etched samples indicates a disordered pore structure with pore diameters ranging up to 15 nm on porous silicon particles ranging up to 5 μm in size. Crystallographic orientation did not appear to affect the surface pore opening diameter. Internal pore data indicated pore depths of up to 1 μm dependent on the particle size and etching conditions applied ¹⁷.

Eskandari Sabzi et al., develop an application of β-cyclodextrin-based nanosponges with the tiny mesh-like structure as porous three-dimensional nanocatalyst in the one-pot three-component condensations of various aromatic aldehydes with activated methylene compounds such as dimedone, thiobarbituric acid, 4-hydroxycoumarin, 4-hydroxy -6-methyl-2-pyrone and nucleophiles including indole and amines. This nanosponge catalyst afforded the privileged N- containing organic scaffolds as key intermediates in pharmaceutical chemistry in very short reaction times ¹⁸.

Mina Jafari Nasab et al., were prepared β-Cyclodextrin- epichlorohydrin nanosponge polymer, from the stepwise polymerization of β-cyclodextrin with epichlorohydrin under basic conditions and characterized by FT-IR spectroscopy, thermogravimetric analysis, scanning electron microscopy and Brunauer–Emmett–Teller. An efficient synthesis of spiro [indoline-3, 4′-pyrano [2, 3-c] pyrazole] and pyranopyrazole derivatives is described using β-CD/EP as a stationary micro-vessel and basic heterogeneous catalyst via a four-component reaction under solvent-free conditions ¹⁹.

Barbara Mognetti et al., were proposed the use of β-cyclodextrin based nanosponges to deliver paclitaxel as an alternative to classical formulation in Cremophor EL. Nanosponges dissolved and encapsulated paclitaxel up to 2 mg/ml. The paclitaxel-loaded nanosponges formed a water-stable colloidal system avoiding the re-crystallization of paclitaxel. The in-vitro release studies showed an almost complete release in 2 h without an initial burst effect. Delivery of paclitaxel via nanosponges increased the amount of paclitaxel entering cancer cells and lowers paclitaxel IC₅₀, therefore enhancing its pharmacological effect ²⁰.

Anny Leudjo Taka et al., were reported the synthesis and characterization of a novel bio nanosponge filter for applications in water treatment. Firstly the oxidized multi-walled carbon nanotubes (MWCNTs) were chlorinated using oxalyl chloride and then phosphorylated via an amidation reaction. The phosphorylated carbon nanotube (pMWCNT) obtained was polymerized with β-cyclodextrin (βCD) using hexamethylene-diisocyanate (HMDI) as a linker. The resulting polymer (pMWCNT-βCD) was decorated by a sol-gel method with TiO₂ and Ag nanoparticles to obtain a biopolymer nanocomposite, pMWCNT-βCD/TiO2-Ag. For a better evaluation of the target material, CD polymer and pMWCNT-CD polymer were also synthesized for comparison purposes ²¹.

Francesco Trotta et al., were synthesized Cyclodextrin based carbonate nanosponges starting from native β-cylodextrin and active carbonyl compounds i.e. carbonildiimidazole. In this work they were used to form inclusion complexes with three different gases i.e. 1-methylcyclopropene, oxygen and carbon dioxide. The encapsulation of gases were proved by direct reaction to known adduct (1-methylcyclopropene), by gravimetric analysis (CO₂) and by oxymeter (Oxygen).

The complexetion of oxygen or carbon dioxide could be useful for many biomedical applications. In particular the oxygen-filled nanosponges could supply oxygen to the hypoxic tissues which are present in various diseases. 1-methylcyclopropene included in β-cyclodextrin nanosponges showed superior antiethylenic performances in long lasting cut flowers in comparison with marketed products ²².

Sharad S. Darandale et al., were studying significance of lipid composition on free propofol concentration in aqueous phase and associated pain on injection. Three different nanoformulations, namely long-chain triglyceride (LCT)/medium-chain glyceride (MCG)-based nanoemulsion (ProNano), MCG-based self-nanoemulsifying formulation (PSNE), and lipid-free nano-formulation (PNS) were accessed for the same. In-vitro and in-vivo performances of developed formulations were compared with Diprivan®. ProNano showed minimum free propofol concentration (0.13%) and hence lower pain on injection (rat paw-lick test, 6 ± 2 s) compared to Diprivan®, PSNE, and PNS (0.21%, 0.23% and 0.51% free propofol, respectively, and rat paw-lick test; 12 ± 3, 14 ± 2, and 22 ± 3 s, respectively) ²³.

Swaminathan et al., were synthesized new swellable cyclodextrin-based poly (amidoamine) nanosponges, named PAA-NS10 and PAA-NS11, by cross-linking β-cyclodextrin with either 2, 2-bisacrylamidoacetic acid or with polyamidoamine segments deriving from 2, 2-bisacrylamidoacetic acid and 2-methylpiperazine, respectively. Water uptake studies showed a tremendous swelling capacity of both nanosponges, forming hydrogels. Time-dependent swelling experiments in various aqueous media showed that the nanosponge hydrogels were stable over a period of at least 72 h maintaining their integrity. Thermal analysis showed that the two nanosponges were stable up to 250 and 300 °C, respectively. Both PAA-NS10 and PAA-NS11 were converted to aqueous nano-suspensions using the high-pressure homo-genization technique. In-vitro BSA release studies were carried out showing a prolonged release of albumin from the two swollen BSA loaded β-CD PAA-NS over a period of 24 h ²⁴.

Roberta Cavalli et al., were prepared nanosponges from β-cyclodextrins as nanoporous materials for possible use as carriers for drug delivery. The structure of β-cyclodextrin-based nanosponges was principally investigated by FT-IR, DSC and RX analyses. Sizes, morphology, and toxicity were also examined. The capacity of the nanosponges to incorporate molecules within their structure was evaluated using drugs with different structures and solubilities. The nanosponges were found capable of carrying both lipophilic and hydrophilic drugs and of improving the solubility of poorly water-soluble molecules ²⁵.

Crupi et al., were prepared cyclodextrin nanosponges (CDNS), which are a very promising class of cross-linked polymers, swollen in aqueous solution give rise to cyclodextrin-based hydrogel in different states-gel or liquid suspension-depending on the hydration level of the system. The spectral de-convolution analysis gives evidence of the existence of a characteristic cross-over hydration level associated with the rearrangement of water molecules in more cooperative, bulk-like networks as a consequence of saturation sites of water confinement of nanosponges. These interpretations are further confirmed by the inspection of the estimated collective intensities ²⁶.

Usman Zubair et al., synthesized microporous carbon spheres with pore size ranges from 5 to 11 Å from hyper-cross-linked polymer β-cyclodextrin. Sulphur is incorporated in the micropores by solution impregnation followed by melt infusion. The resultant carbon sulphur (C/S) composite is wrapped in reduced graphene oxide (rGO) to provide conductive pathways to access the sulphur in micropores and to protect the surface-adhered sulphur. The cathode material obtained from rGO wrapping delivers an initial discharge capacity of 1103 mA h g^-1 at 0.1 ºC, maintaining a capacity of 626 mA h g^-1 at 0.2 ºC with a capacity loss of 0.2% per cycle for more than 100 cycles ²⁷.

Monica Vercelli et al. were evaluated the effects of innovative Si-applications on. Soilless-grown Cucumis sativus L. and Cucurbita pepo L. Crop growth, powdery mildew incidence, and abiotic stress resistance. Two experiments were carried out in a non-heated glasshouse on benches. Two new Si treatments (Si–Nano-sponge complex, and one experimental fertilizer) were compared with the traditional K₂SiO₃. Topas®EC 10 was used as a control fungicide treatment. Biometric parameters and incidence and severity of powdery mildew were measured. Cucumis sativus plants showed a severe powdery mildew infection, and no significant effect of the Si treatments was found. Cucurbita pepo plants were initially grown under lower disease pressure conditions, and the positive effect of Si treatments was found ²⁸.

Jaishree et al. were synthesized nanosponges are some of the materials used for cancer detection. Using specific crosslinkers, such as specific antibodies against cancer cells individual cancer cells can be located. With the aid of a novel set of lipid-coated, targeted quantum dots a method for quantifying multiple specific biomarkers on the surfaces of individual cancer cells was also developed. This approach to quantitative biomarker detection stands to improve the histopathology methods used to diagnosis pancreatic and other cancers and enable the development of methods to spot cancer cells circulating in the bloodstream ²⁹.

Weiwei Gao et al., have formulated nanoparticles which offered a unique set of properties for drug delivery including high drug loading capacity, combinatorial delivery, controlled and sustained drug release, prolonged stability and lifetime, and targeted delivery. To further enhance the therapeutic index, especially for localized applications, nanoparticles have been increasingly combined with hydrogels to form a hybrid biomaterial system for controlled drug delivery. Integrating therapeutic nanoparticles with hydrogel technologies creates a unique and robust hybrid biomaterial system that enables effective localized drug delivery ³⁰.

Ludovica Seglie et al., were investigated the influence of different degrees of cross-linking of β-cyclodextrin-based nanosponges (β-CD-NSs) on the activity of the incorporated 1-methyl-cyclopropene (1-MCP) to extend the postharvest longevity of carnation cut flowers. The polymeric β-CD-NSs were synthesized from cyclodextrins at three varying reticulations, β-CD-NS 1:2, β-CD-NS 1:4, and β-CD-NS 1:8. In particular, the lowest suspended concentration (0.25 μL L−1) of the β-CD-NS 1:8 complex proved best for maintaining cut flower ornamental quality. The potential for the formulated 1-MCP-loaded β-CD-NS suspension to induce prolonged vase life was demonstrated. Its use could yield benefits, such as a reduction in total dose and frequency of administration ³¹.

Castiglione et al., were studied the effect of the macrocycle size on the gel-to-sol evolution of cyclodextrin-based hydrogel is here investigated by using Fourier transform infrared absorption in attenuated total reflectance geometry (FTIR-ATR). Different types of nanosponges obtained by polymerization of α- and β-cyclodextrin (CDNS) with an activated derivative of ethylenediamine-tetraacetic acid have been progressively hydrated in order to follow the evolution of these systems from a gel state to a liquid suspension. The in a deep analysis of the high-frequency vibrational dynamics of the hydrogel during its gel-sol evolution revealed that the microscopic origin of this phenomenon is strictly connected to different hydrogen bond environments in which water molecules confined in the pores of nanosponges can arrange ³².

Mitra Naghdi et al., were studied regarding the major challenge of contamination for human health and environment since their concentrations are increasing. Contaminants occur in air, soil and aquatic media, then finally end up in drinking water. Contaminants cause many health issues to living organisms, by disruption of endocrine systems and feminization of male fish, for instance. They discussed methods to remove contaminants using nanomaterials, such as nanoparticles, nanotubes, and nanostructured membranes. New processes based on nanostructured materials such as TiO₂ nano-wires or nanofiltration membranes can achieve up to 95 % removal of contaminants ³³.

Vahini Raja et al., were designed a novel Co₃O₄/NiO nanosponges for the photocatalytic degradation of organic contaminants were synthesized by a simple precipitation technique. The formation of sponge-like nanostructures was clearly evident through the TEM analysis. The photocatalytic efficiency was tested against rhodamine B (RhB) and congo red (CR) dye solutions. Co₃O₄/NiO nanosponges showed excellently and enhanced photocatalytic efficacy compared to those of Co₃O₄, NiO nanoparticles, and standards like TiO₂ and ZnO. The trapping experiment revealed that the reactive oxygen species (ROS) identified was $OH radical. These findings certainly open up a new way for synthesizing a morphology dependent photocatalyst ³⁴.

Castiglione et al., studied the crosslinking and inclusion/release properties of cyclodextrin nanosponges (CDNS). CDNS shows the swelling capability and a hydrophilicity/hydrophobicity balance that can be dramatically modified by the type and quantity of cross-linking agents. The vibrational properties of CDNS thus synthesized have been investigated by Fourier transform infrared spectroscopy in attenuated total reflectance geometry and Raman spectroscopy in the dry state at room temperature. The quantitative analysis of the O–H stretching region (3,000–3,800 cm^-1) allowed us to obtain structural information on the role played by primary and secondary OH groups in the hydrogen bond network of the polymer. Also, the contribution of interstitial and intra-cavity crystallization water molecules is reported. The observed relaxation parameters point out that the ester formation occurs mainly at the primary OH groups of CDs, also supporting the interpretation of vibrational spectra ³⁵.

A. Pavlova et al., were synthesized hydrophilic ionic nanosponges with quaternary pyridinium groups on the basis of 4-vinylpyridine and its polymer. Their synthesis relies on the use of bior poly-functional agents alkylating pyridine in dilute solutions in a thermodynamically good solvent. Individual intra-molecularly cross-linked soluble macromolecules with molecular masses from 6000 to 400000 are prepared at various degrees of dilution. 1, 4-Bis (halomethyl) benzenes, p-vinylbenzyl chloride, and poly (vinylbenzyl chloride) are used as N-alkylating agents. The shapes and sizes of macromolecules are determined via the methods of diffusion, sedimentation, viscometry, dynamic light scattering, atomic force microscopy, and transmission electron microscopy ³⁶.

Singireddy Anandam et al., were prepared cyclodextrin nanosponges by doing polymerization of cyclodextrins with suitable polyfunctional agents, which leads to highly cross-linked porous structures, referred to as cyclodextrin nanosponges. The conventional heating approach for the synthesis of nanosponges can lead to nonuniform reaction conditions caused by sharp thermal gradients in the bulk solution. A facile method for the synthesis of cyclodextrin nanosponges by microwave irradiation with a significant reduction in reaction time is used. Response surface methodology and Box–Behnken design were used for the optimization of the process parameters including microwave power level (A), reaction time (B), and stirring speed (C). Two dependent variables, practical yield, and particle size were measured as responses ³⁷.

Fabrizio Caldera et al., were prepared for the β-CD nanosponges using apple polyphenols. Rutin, phloridzin, and chlorogenic acid are some of the most important and characteristic polyphenols found in apples and their by-products (cider, apple juice, apple pomace, etc.). Despite their antioxidant power, their low stability under light or heating conditions restricts the use of this kind of molecules as nutraceuticals. To deal with this issue, encapsulation seems to be an alternative solution. Based on the obtained results, it can be concluded that β-cyclodextrin nanosponges (β-CD NS) are promising agents for the encapsulation of polyphenols. Using these encapsulating agents, other polyphenols from apple and its by-products could be encapsulated in order to enhance their bioavailability ³⁸.

Pravin K. Shende et al., were formulated β-cyclodextrin nanosponges with acetylsalicylic acid (ASA), a non-steroidal anti-inflammatory drug. The selected drug was formulated into inclusion complexes by grinding and precipitation with β-cyclodextrin and freeze-drying with pyromellitic dianhydride (PMDA) cross-linked β-cyclodextrin nanosponges. The in-vitro and in-vivo studies indicated a slow and prolonged ASA release from PMDA cross-linked β-cyclodextrin nanosponges over a long period ³⁹.

Li et al., were synthesized a new class of organic nanoporous polymers using cyclodextrins as basic building blocks. These processable nanoporous polymers were named 'nanosponges' because they have nanometer-size pores (distribution 0.7-1.2 nm) and exhibit superior ability to absorb organic molecules in water. The significant potential of the study is that hazardous organic contaminants may be reduced to parts-per-trillion levels in water by these polymers, as measured by ion-trap mass spectroscopy and UV-visible spectroscopy ⁴⁰.

Sapino et al., were prepared and characterized a nanosponges based stable formulation, which increases the stability and effectiveness of antioxidants is based on the inclusion in supra-molecular structures (nanoparticles, cyclodextrins, liposomes, etc.). In this work, they have studied the inclusion of gamma-oryzanol (GO) in β-cyclodextrin-based nanosponges, which in the last few years have been chosen for their ability to encapsulate a great variety of substances to decrease their side-effects and to protect them from degradation. The inclusion complex was prepared in 1:1 w/w ratio and characterized by DSC, XRPD and membrane diffusion runs. The photo-degradation of GO upon either UVA or UVB irradiation was found to be slowed down by inclusion in nanosponges ⁴¹.

Shankar Swaminathan et al., were developed nanosponges (NS) with a class of hyper-branched polymers, nano-structured to form three dimensional meshwork; obtained by reacting cyclodextrins with a crosslinker like diphenyl carbonate. Two distinct forms viz. crystalline and para-crystalline of NS were identified and extensively characterized by the use of high-resolution transmission electron microscopy (HR-TEM), X-ray powder diffraction (XRPD), scanning electron microscope, atomic force microscope, optical microscope, and Fourier transform infrared attenuated total reflectance spectroscopy (FTIR-ATR). The crystallinity of NS was found to be an important factor in solubilization, in-vitro kinetics, and encapsulation behavior and can be tuned to give a tailored drug release profile or formulation characteristics ⁴².

Monica R. P. Rao et al., were synthesized a Cyclodextrin based Gabapentin nanosponges and the nanosponge–drug complexes were characterized by FTIR, DSC and PXRD as well as evaluated for taste and saturation solubility. The complexes were coated on espheres by a suspension layering technique followed by coating with ethyl cellulose and eudragit RS-100. The complexes showed partial entrapment of drug nanocavities. A significant decrease in solubility (25%) was observed in the complexes than the pure drug in different media. The microspheres of nanosponge complexes showed the desired controlled release profile for 12 h. Nanosponges effectively masked the taste of Gabapentin and the coating polymers provided controlled release of the drug and enhanced taste-masking ⁴³.

Nirosha Manyam et al., were studied to enhance Trimethoprim solubility by preparing Trimethoprim nanosponges loaded extended-release tablets to delay the drug release at the urinary tract. From the evaluation, it was concluded that nanosponge loaded extended-release tablets of trimethoprim showed delayed drug release up to 10 h with enhanced solubility and dissolution.

Hence, the nanosponge technique will be a challenging approach for enhancing the solubility of poorly soluble drugs ⁴⁴. Subhash Chandra Bose et al., were prepared Lansoprazole loaded nanosponges by Emulsion solvent diffusion method using ethylcellulose, PVA and pluronic F-68 and dichloromethane as a solvent. The drug release from nanosponges was found to extend up to 12 h. The optimized nanosponges were formulated into the enteric-coated tablet and evaluated for weight variation, hardness, friability and dissolution studies.

In-vitro release of drug from enteric-coated tablet follows zero-order and showed controlled release behavior for a period of 24 h. The data obtained in this study suggest that nanosponges of lansoprazole are promising for controlled drug delivery, which can reduce dosing frequency ⁴⁵.

Dr. Prathima Srinivas et al., were formulated the controlled release Voriconazole Nanosponges for topical and oral delivery. Nanosponges using three different polymers ethylcellulose, Poly (methyl methacrylate), and pluronic F-68 (poloxamer 188) were prepared successfully using PVA as surfactant by emulsion solvent evaporation method.

The polymers studied were found to be the efficient carriers for voriconazole nanosponges showing diffusion-controlled release. The nanosponge systems have been found to have good potential for prolonged drug release ⁴⁶. Patil Bhagyashree Subhash et al., produced controlled release Artesunate Nanosponges for topical and oral delivery. Nanosponges using three different polymers ethylcellulose, Poly (methyl methacrylate) and Pluronic F-68 (poloxamer 188) were prepared successfully using PVA as surfactant by emulsion solvent evaporation method. These small sponges can circulate around the body until they encounter the target site and stick on the surface and began to release the drug in a controlled and predictable manner, which is more effective for a particular given dosage ⁴⁷.

Monica R. P. Rao et al., were evaluated nanosponges loaded with efavirenz by a solvent evaporation method, and the nanosponge with higher drug loading capacity was selected for further studies. Binary and ternary complexes with EFA, NS, and PVP K30 were prepared. The saturation solubility was found to be 17-fold higher with ternary complex in distilled water and about 4-fold in simulated gastric fluid. In-vitro dissolution was improved 3 folds with a ternary complex. Ternary nanosponge complexes were found to have a 2-fold increase in the oral bioavailability of efavirenz as compared to plain drug ⁴⁸.

Barbara Mognetti et al., were developed paclitaxel-loaded nanosponges, a water-stable colloidal system avoiding the recrystallization of paclitaxel. The in-vitro release studies showed an almost complete release in 2 h without an initial burst effect. The study demonstrates that the delivery of paclitaxel via nanosponges increased the amount of paclitaxel entering cancer cells and lowers paclitaxel IC₅₀, therefore enhancing its pharma-cological effect. β-cyclodextrin based nanosponges can, therefore, be considered an alternative system to solubilize and deliver the paclitaxel ⁴⁹.

Shankar Swaminathan et al., were worked to enhance the solubility of Itraconazole so that the bioavailability problems are solved. A solid dispersion technique has been used for drug incorporation. The effect of a ternary component copolyvidonum on the solubility of itraconazole has been studied. Phase solubility studies have been carried out with a rationale of comparing the solubilization efficiency of nanosponges, copoly-vidonum and combination. It was found that the solubility of itraconazole was enhanced by more than 50-folds with a ternary solid dispersion system. Using copolyvidonum in conjunction with nanosponges helps to increase the solubilization efficiency of nanosponges as evident from the phase solubility studies ⁵⁰.

Singireddy Anandam et al., were studied to enhance the dissolution rate and stability of poorly water-soluble drug quercetin by complexation with cyclodextrin-based nano-sponges. The particle sizes of plain and quercetin-loaded nanosponges are between 40 and 100 nm with low polydispersity indices. Zeta potential is sufficiently high to obtain a stable colloidal nanosuspension.

The dissolution of the quercetin nanosponges was significantly higher compared with the pure drug. The stability of encapsulated quercetin nanosponge was tracked in a simulated intestinal fluid. A marked improvement in the photostability was also observed ⁵¹.

Andreea Alexandra Olteanu et al., formulated nano-sponge complexes and hecomplexing properties of the polymers were investigated against repaglinide (a hypoglycemic agent, practically insoluble in water). Solubility studies were performed according to the method reported by Higuchi and Connors, and the phase solubility diagrams were plotted. The repaglinide-nano-sponges complexes were prepared, lyophilized and the resulted inclusion complexes were characterized by FT-IR and NMR. The solubility profile and the loading capacity of the cyclodextrin based polymers were also determined ⁵².

Swaminathan et al., were synthesized new swellable cyclodextrin-based poly (amidoamine) nanosponges, named PAA-NS10 and PAA-NS11, by crosslinking β-cyclodextrin with either 2, 2-bisacrylamidoacetic acid or with polyamidoamine segments deriving from 2, 2-bisacrylamidoacetic acid and 2-methylpiperazine, respectively.

Both PAA-NS10 and PAA-NS11 were converted to aqueous nano-suspensions using the High-Pressure Homogenization technique. In-vitro BSA release studies were carried out showing a prolonged release of albumin from the two swollen BSA loaded β-CD PAA-NS over a period of 24 h ⁵³. Roberta Cavalli et al., were prepared nanosponges from β-cyclodextrins as nanoporous materials for possible use as carriers for drug delivery. The structure of β-cyclodextrin-based nanosponges was principally investigated by FT-IR, DSC and RX analyses. Sizes, morphology, and toxicity were also examined. The capacity of the nanosponges to incorporate molecules within their structure was evaluated using drugs with different structures and solubilities. The nanosponges were found capable of carrying both lipophilic and hydrophilic drugs and of improving the solubility of poorly water-soluble molecules ⁵⁴.

S. Darandale et al., were formulated the complex of curcumin with β-cyclodextrin nanosponge obtained with dimethyl carbonate as a crosslinker. The particle size of loaded nanosponge was found to be 487.3 nm with a minimum polydispersibility index (0.476). The loaded NS have shown more solubilization efficiency (20.89 μg/ml) in comparison with plain curcumin (0.4 μg/ml) and β-CD complex (5.88 μg/ml). The zeta potential was sufficiently high (−27 mV) which indicates the formation of a stable colloidal nanosuspension. The in-vitro drug release of curcumin was controlled over a prolonged period of time ⁵⁵.

Monica Rao et al., were prepared β-Cyclodextrin (β-CD) based nanosponges (NSs) cross-linking β-CD with carbonate bonds, which were porous as well as nanosized. Telmisartan was incorporated by the solvent evaporation method. Saturation solubility and in-vitro dissolution study of the β-CD complex of TEL was compared with plain TEL and NS complexes of TEL. It was found that solubility of TEL was increased by 8.53-fold in distilled water; 3.35-fold in 0.1 N HCl and 4.66-fold in phosphate buffer pH 6.8 by incorporating NaHCO₃ in drug–NS complex than TEL. It was found that the NaHCO₃ in NS based complex synergistically enhanced the dissolution of TEL by modulating microenvironmental pH and by changing the amorphization of the drug. The highest solubility and in-vitro drug release were observed in the inclusion complex prepared from NS and NaHCO₃. An increase of 54.4% in AUC was seen in the case of the ternary NS complex whereas the β-CD ternary complex exhibited an increase of 79.65 % ⁵⁶.

Khalid A. Ansari et al., were worked to increase the solubility, stability, and permeation of resveratrol by complexation with cyclodextrin-based nanosponges (NS). Nanosponges are developed using hyper-cross-linked cyclodextrin polymers nanostructured to form three-dimensional networks; they are obtained by reacting cyclodextrin with a cross-linker such as carbonyl-diimidazole.

The in-vitro release and stability of resveratrol complex were increased compared with the plain drug. Cytotoxic studies on HCPC-I cell showed that resveratrol formulations were more cytotoxic than plain resveratrol. The permeation study indicates that the resveratrol NS formulation showed good permeation in pigskin. The accumulation study in rabbit mucosa showed better accumulation of resveratrol NS formulation than plain drug ⁵⁷.

Monica R. P. Rao et al., were studied to enhance solubility and dissolution of rilpivirine using beta-cyclodextrin-based nanosponges. These nano-sponges are biocompatible nanoporous particles having high loading capacity to form supra-molecular inclusion and non-inclusion complexes with hydrophilic and lipophilic drugs for solubility enhancement. Beta-cyclodextrin was crosslinked with carbonyl diimidazole and pyromellitic-dianhydride to prepare nanosponges. The nano-sponges were loaded with rilpivirine by a solvent evaporation method. Solubility enhancement was evident in bio-relevant media.

A 3-fold increase in dissolution with ternary complexes was observed. Animal studies revealed a nearly 2-fold increase in oral bioavailability of rilpivirine. It was inferred that electronic interactions, hydrogen bonding, and van der Waals forces are involved in the supra-molecular interactions ⁵⁸.

Upendra Nagaich et al., were formulated the nanosponges of peppermint oil, and herbal approach to reduce the side effects of chemicals as sun protecting factors. Nanosponges were evaluated for particle size, surface morphology, and in-vitro sun protection efficiency. 2³ factorial designs were used to optimize the formulation for peppermint oil loaded nanosponges. Sun protection factor was calculated and it was found to be 5.28713 ± 0.722, concluded that nanosponges formulated can be efficiently used as a sun-protecting agent with no or fewer side effects ⁵⁹.

TABLE 3: DIFFERENT PHARMACEUTICAL DOSAGE FORMULATION ^{4, 6, 16, 60, 61, 62}

Factors Influences Nanosponges Formulation: ^{8, 13, 63, 64}

• Type of polymer.
• Type of drugs.
• Temperature
• Method of preparation.
• Degree of substitution.

Evaluation of Nanosponges: ^{2, 7, 9, 61}

• Particle size determination.
• Determination of loading efficiency.
• Swelling and water uptake.
• Resiliency (Viscoelastic properties).
• Compatibility Studies.
• Zeta potential.
• Thermo-analytical methods.
• Solubility studies.
• Drug release kinetics.
• Thin-layer chromatography.
• Infra-red spectroscopy.
• In-vitro release studies.
• Permeation studies.
• Microscopy studies.
• Photodegradation study.
• X-ray diffraction study.

CONCLUSION: Nanosponges have the capability to include both lipophilic and hydrophilic drugs. Nanosponges can release them in a precise and expectable manner at the target site. By controlling the ratio of polymer to cross-linker the particle size and release rate of nanosponge formulation can be modulated. Nanosponges facilitate the uses of insoluble molecules and can protect the active moieties from external physiochemical degradation. Because of their small size and spherical shape nanosponges can be developed in various dosage forms like parenteral, topical, aerosol, tablets and capsules.

ACKNOWLEDGEMENT: The author would like to acknowledge the support from his family and colleagues from INTAS Pharmaceuticals, Ahmedabad.

CONFLICTS OF INTEREST: There are no conflicts of interest.

REFERENCES:

1. Bhowmik H, Venkatesh DN, Kuila A and Kumar KH: Nanosponges: A review. International Journal of Applied Pharmaceutics 2018; 10(4): 1-5.
2. Ting LK: A mini review: recent trends on nanosponge. Rapports De Pharmacie 2016; 3: 289-94.
3. Jilsha G and Viswanad V: Nanosponges: A novel approach of drug delivery system. Int J Pharm Sci Rev Res 2013; 19(2): 119-23.
4. Salunkhe A, Kadam S, Magar S and Dangare K: Nanosponges: A modern formulation approach in drug delivery system. World Journal of Pharmacy and Pharmaceutical Sciences 2018; 7(2): 575-92.
5. Bezawada S, Charanjitha, Reddy VN and Naveen A: Nanosponges -a concise review for emerging trends, International Journal of Pharmaceutical Research and Biomedical Analysis 2014; 3(1): 1-6.
6. Targe BM, Patil MP, Jahagirdar AC and Khandekar BD: Nanosponges - an emerging drug delivery system. International Journal of Institutional Pharmacy and Life Sciences 2015; 5(6): 160-74.
7. Osmani RAM, Thirumaleshwar S, Bhosale RR and Kulkarni PK: Nanosponges: The spanking accession in drug delivery- an updated comprehensive review, Pelagia Research Library. Der Pharmacia Sinica 2014; 5(6): 7-21.
8. Singh D, Soni GC and Prajapati SK: Recent advances in nanosponges as drug delivery system: a review article. European Journal of Pharmaceutical and Medical Research 2016; 3(10): 364-71.
9. Gursalkar T, Bajaj A and Jain D: Cyclodextrin based nanosponges for pharmaceutical use: a review. Acta Pharm 2013; 63: 335-58.
10. Kumar MH: Nanosponge: an innovative drug carrier system - a review. Pharmaceut Reg Affairs 2012; 1: 4.
11. Kaur G, Aggarwal G and Harikumar S: Nanosponge: New colloidal drug delivery system for topical delivery. Indo Global Journal of Pharma Sciences 2015; 5(1): 53-57.
12. Adeoye O and Cabral-Marques H: Cyclodextrin Nanosystems in oral drug delivery: a mini review. International Journal of Pharmaceutics 2017; 531(2): 521-31.
13. Osmani RA, Kulkarni P, Manjunatha S, Gowda V, Hani U, Vaghela R and Bhosale R: Cyclodextrin Nanosponges in Drug Delivery and Nanotherapeutics. Environmental Nanotechnology 2018: 279-42.
14. Arshad K, Khan A, Bhargav E, Reddy K and Sowmya C: Nanosponges: a new approach for drug targeting. International Journal of Advances in Pharmaceutical Research 2016; 7(3): 381-96.
15. Pawar AY, Naik A and Jadhav KR: Nanosponges: A novel drug delivery system. Asian Journal of Pharmaceutics 2016; 10 (4): S456.
16. Indira B, Bolisetti S, Samrat, Reddy SM and Reddy NS: Nanosponges: a new era in drug delivery: review. Journal of Pharmacy Research 2012; 5(12): 5293-96.
17. EG Chadwick, S Beloshapkin and DA Tanner: Microstructural characterization of metallurgical grade porous silicon nanosponge particles. Journal of Materials Science 2012; 47(5): 2396-04.
18. Sabzi NE and Kiasat AR: β-Cyclodextrin based nanosponge as a biodegradable porous three-dimensional nanocatalyst in the one-pot synthesis of n-containing organic scaffolds. Catalysis Letters 2018: 1-11.
19. Nasab MJ, Kiasat AR and Zarasvandi R: β-Cyclodextrin nanosponge polymer: a basic and eco-friendly heterogeneous catalyst for the one-pot four-component synthesis of pyranopyrazole derivatives under solvent-free conditions, Reaction Kinetics. Mechanisms and Catalysis 2018; 124(2): 767-78.
20. Mognetti B, Barberis A, Marino S, Berta G, De Francia S, F Trotta and Cavalli R: In-vitro enhancement of anticancer activity of paclitaxel by a cremophor free cyclodextrin-based nanosponge formulation. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2012; 74(1-4): 201-10.
21. Taka AL, Pillay K and Mbianda XY: Synthesis and characterization of a novel bio nanosponge filter (pMWCNT-CD/TiO2-Ag) as potential adsorbent for water purification. International Conference on Pure and Applied Chemistry. Emerging Trends in Chemical Sciences 2016: 313-43.
22. Trotta F, Cavalli R, Martina K, Biasizzo M, Vitillo J, Bordiga S, Vavia P and Ansari K: Cyclodextrin nanosponges as effective gas carriers, Journal of Inclusion Phenomena and Macrocyclic Chemistry 2011; 71(1-2): 189-94.
23. Darandale SS, Shevalkar GB and Vavia PR: Effect of lipid composition in propofol formulations: decisive component in reducing the free propofol content and improving pharmacodynamic profiles. AAPS Pharm Sci Tech 2017; 18(2): 441-50.
24. Swaminathan S, Cavalli R, Trotta F, Ferruti P, Ranucci E, Gerges I, Manfredi A, Marinotto D and PR Vavia: In-vitro release modulation and conformational stabilization of a model protein using swellable polyamidoamine nanosponges of β-cyclodextrin. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2010; 68(1-2): 183-91.
25. Cavalli R, Trotta F and Tumiatti W: Cyclodextrin-based nanosponges for drug delivery. Journal of Inclusion Phenomena and Macrocyclic Chem 2006; 56(1-2): 209-13.
26. Crupi V, Fontana A, Majolino D, Mele A, Melone L, Punta C, Rossi B, Rossi F, Trotta F and Venuti V: Hydrogen-bond dynamics of water confined in cyclodextrin nanosponges hydrogel. Journal of Inclusion Phenomena and Macrocyclic Chem 2014; 80(1-2): 69-75.
27. Zubair U, Anceschi A, Caldera F, Alidoost M, Amici J, Francia C, Zanetti M, Trotta F, Bodoardo S and Penazzi N: Dual confinement of sulphur with rGO-wrapped microporous carbon from β-cyclodextrinnanosponges as a cathode material for Li–S batteries. Journal of Solid State Electrochemistry 2017; 21(12): 3411-20.
28. Vercelli M, Minuto A, Minuto G, Contartese V, Devecchi M and Larcher F: The effects of innovative silicon applications on growth and powdery mildew control in soilless-grown cucumber (Cucumis sativus) and zucchini (Cucurbita pepo L.). Acta Physiologiae Plantarum 2017; 39: 129.
29. Jaishree V and Gupta PD: Nanotechnology: A revolution in cancer diagnosis. Indian Journal of Clinical Bio-chemistry 2012; 27(3): 214-20.
30. Gao W, Zhang Y, Zhang Q and Zhang L: Nanoparticle-hydrogel: a hybrid biomaterial system for localized drug delivery. Annals of Biomed Eng 2016; 44(6): 2049-61.
31. Seglie L, Martina K, Devecchi M, Roggero C, Trotta F and Scariot V: β-cyclodextrin-based nanosponges as carriers for 1-MCP in extending the postharvest longevity of carnation cut flowers: an evaluation of different degrees of cross-linking. Plant Growth Regul 2011; 65(3): 505-11.
32. Castiglione F, Crupi V, Majolino D, Mele A, Melone L, Panzeri W, Punta C, Rossi B, Trotta F and Venuti V: Gel-sol evolution of cyclodextrin-based nanosponges: role of the macrocycle size. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2014; 80(1-2): 77-83.
33. Naghdi M, Taheran M, Sarma S, Brar SK, Ramirez AA and Verma M: Nanotechnology to remove contaminants. Nanoscience in Food and Agriculture 2016; 1: 101-28.
34. Raja V, Puvaneswaran SK and Swaminathan K: Unique and hierarchically structured novel Co₃O₄/NiO nano-sponges with superior photocatalytic activity against organic contaminants. Frontiers of Materials Science 2017; 11(4): 375-84.
35. Castiglione F, Crupi V, Majolino D, Mele A, Panzeri W, Rossi B, Trotta F and Venuti V: Vibrational dynamics and hydrogen bond properties of β-CD nanosponges: an FTIR-ATR, Raman and solid-state NMR spectroscopic study. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2013; 75(3-4): 247-54.
36. Pavlova LA, Davankov VA, Timofeeva GI, Il’inJr MM, Blagodatskikh IV, Sinitsyna OV, Matveev VV and Chalykh AE: Nanosponges as products of N-alkylation of 4-vinylpyridine and poly (4-vinylpyridines) in dilute solutions. Polymer Science Series 2013; 55(10): 603-13.
37. Anandam S and Selvamuthukumar S: Optimization of microwave-assisted synthesis of cyclodextrin nanosponges using response surface methodology. Journal of Porous Materials 2014; 21(6): 1015-23.
38. Caldera F, Trotta F, Berrueta LÁ and Gallo B: Encapsulation of apple polyphenols in β-CD nanosponges. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2014; 80(1-2): 85-92.
39. Shende PK, Trotta F, Gaud RS, Deshmukh K, Cavalli R and Biasizzo M: Influence of different techniques on formulation and comparative characterization of inclusion complexes of ASA with β-cyclodextrin and inclusion complexes of ASA with PMDA cross-linked β-cyclodextrin nanosponges 2012; 74(1-4): 447-54.
40. Li D and Ma M: Nanosponges for water purification. Clean Products and Processes 2000; 2(2): 112-16.
41. Sapino S, Carlotti ME, Cavalli R, Ugazio E, Berlier G, Gastaldi L and Morel S: Photochemical and antioxidant properties of gamma-oryzanol in beta-cyclodextrin-based nanosponges. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2013; 75(1-2): 69-76.
42. Swaminathan S, Vavia PR, Trotta F, Cavalli R, Tumbiolo S, Bertinetti L and Coluccia S: Structural evidence of differential forms of nanosponges of beta-cyclodextrin and its effect on solubilization of a model drug. Journal of Inclusion Pheno and Macro Chem 2013; 76(1-2): 201-11.
43. Rao MRP and RC Bhingole: Nanosponge-based pediatric-controlled release dry suspension of Gabapentin for reconstitution, Drug Development and Industrial Pharmacy 2015; 41(12): 2029-36.
44. Manyam N, Budideti RKK and Mogili S: Formulation and in-vitro Evaluation of Nanosponge Loaded Extended Release Tablets of Trimethoprim. UPI Journal of Pharmaceutical Medical and Health Sciences 2018; 1(1): 78-86.
45. Penjuri SCB, Ravouru N, Damineni S, Sailakshmi BNS and Poreddy SR: Formulation and evaluation of lansoprazole loaded nanosponges. Turk J Pharm Sci 2016; 13(3): 304-10.
46. Srinivas P and Sreeja K: Formulation and evaluation of voriconazole loaded nanosponges for oral and topical delivery. International Journal of Drug Development and Research 2013; 5(1).
47. Subhash PB and Mohite SK: Formulation design & development of artesunate nanosponge. European Journal of Pharma and Medical Research 2016; 3(5): 206-11.
48. Rao MRP and Shirsath C: Enhancement of bioavailability of non- nucleoside reverse transciptase inhibitor using nanosponges. AAPS Phar Sci Tech 2017; 18(5): 1728-38.
49. Mognetti B, Barberis A, Marino S, Berta G, De Francia S, Trotta F and Cavalli R: In-vitro enhancement of anticancer activity of paclitaxel by a cremophor free cyclodextrin-based nanosponge formulation. Journal of Inclusion Phenomena and Macrocyclic Chem 2012; 74(1-4): 201-10.
50. Swaminathan S, Vavia P, Trotta F and Torne S: Formulation of betacyclodextrin based nanosponges of itraconazole. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2007; 57(1-4): 89-94.
51. Anandam S and Selvamuthukumar S: Fabrication of cyclodextrin nanosponges for quercetin delivery: physicochemical characterization, photostability and antioxidant effects. Journal of Materials Science 2014; 49(23): 8140-53.
52. Olteanu AA, Corina-Cristina A, Radu C and Crina-Maria CMM: Effect of β-cyclodextrins based nanosponges on the solubility of lipophilic pharmacological active substances (repaglinide). Journal of Inclusion Phenomena and Macrocyclic Chemistry 2014; 80(1-2): 17-24.
53. Swaminathan S, Cavalli R, Trotta F, Ferruti P, Ranucci E, Gerges I, Manfredi A, Marinotto D and Vavia PR: In-vitro release modulation and conformational stabilization of a model protein using swellable polyamidoamine nanosponges of β-cyclodextrin. Journal of Inclusion Phenomena and Macrocyclic Chem 2010; 68(1-2): 183-91.
54. Cavalli R, Trotta F and Tumiatti W: Cyclodextrin-based nanosponges for drug delivery. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2006; 56(1-2): 209-13.
55. Darandale SS and Vavia PR: Cyclodextrin-based nanosponges of curcumin: formulation and physicochemical characterization. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2013; 75(3-4): 315-22.
56. Rao M, Bajaj A, Khole I, Munjapara G and Trotta F: In-vitro and in-vivo evaluation of β-cyclodextrin-based nanosponges of telmisartan. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2013; 77(1-4): 135-45.
57. Ansari KA, Vavia PR, Trotta F and Cavalli R: Cyclodextrin-based nanosponges for delivery of resveratrol: in-vitro characterisation, stability, cytotoxicity and permeation study. AAPS Pharm Sci Tech 2011; 12(1): 279-86.
58. Rao MRP, Chaudhari J, Trotta F and Caldera F: investigation of cyclodextrin-based nanosponges for solubility and bioavailability enhancement of rilpivirine, AAPS Pharm Sci Tech 2018; 19(5): 2358-69.
59. Nagaich U, Gulati N and Chauhan S: Fabrication and in vitrocharacterization of peppermint oil nanosponges as sun protecting agent. SPER J Pharm Res 2016; 1(1): 8-10.
60. Trotta F, Zanetti M and Cavalli R: Cyclodextrin-based nanosponges as drug carriers. Beilstein J Org Chem 2012; 8: 2091-99.
61. Tamkhane V and Sharma PH: Nanosponge - a novel drug delivery system. Journal of Current Pharma Research 2014; 4(3): 1186-93.
62. Dhavala PB and Tenneti VSVK: An interesting nanosponge as a nanocarrier for novel drug delivery: a review. International Journal of Pharmaceutical and Medical Research 2017; 5(2).
63. Vyas A, Saraf S and Saraf S: Cyclodextrin based novel drug delivery systems. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2008; 62(1-2): 23-42.
64. Patel P and Deshpande A: Patent review on cyclodextrin based nanosponges prepared by different methods: physicochemical characterization, factors influencing formation and applications. World Journal of Pharmaceutical Sciences 2014: 2321-86.
    

    ---

    How to cite this article:

    Satpathy TK, Chaubey N, Usha SB and VR Naidu: Nanosponges – novel emerging drug delivery system. Int J Pharm Sci & Res 2020; 11(7): 3087-00. doi: 10.13040/IJPSR.0975-8232.11(7).3087-00.

    ---

    All © 2013 are reserved by the International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---