it has now been found that nanosponges having improved properties in comparison with the prior art material disclosed in wo 03 / 085002 may be obtained by reacting natural cyclodextrins with an organic dicarbonate in the absence of a solvent and under sonication . the nanosponges obtainable according to the present invention may be distinguished from the previously known material in a number of characteristics , namely in the particle shape which is substantially spherical as well as in the uniformity of particle size . the nanosponges of the invention , in view of said structural features , may be used for applications previously not disclosed for this kind of material , for example as carriers for the aerosol administration of pharmaceutical active ingredients . given their characteristics the nanosponges of the invention are useful for solving the intrinsic problems of the active ingredient such as the poor hydrosolubility , instability , degradation , protection and toxicity . the nanosponges of the invention could also carry simultaneously both lipophilic molecules in the hydrophobic cavity of the cyclodextrin and hydrophilic molecules in the spaces between the single cyclodextrins . nanosponges have colloidal dimensions and form clear and opalescent suspensions in water . following the process of synthesis developed for their preparation , the nanosponges solidify into particles whose morphology is found to be spherical following observations at the optical microscope . this characteristic of the synthesised nanosponges , together with suitable values of density , allow for their possible application also as carriers for the inhalation route in addition to oral administration . the synthesis of nanosponges using organic carbonates in solution at high temperatures is a known process which involves the use of solvents such as dmf , butanone , pyridine or dmso in which both reagents are soluble . the reaction is carried out at temperatures higher than 130 - 140 ° c . and leads to the formation of a reticulate which has proved to be active in the complexing of numerous organic molecules . the product which is the object of the invention is obtained by a reaction between a natural cyclodextrin ( i . e . α , β or γ - cyclodextrin , preferably β - cyclodextrin ) and a dicarbonate , preferably diphenyl carbonate ( dpc ) in the absence of a solvent operating at various temperatures between the ambient temperature and 90 ° c . under sonication . the product obtainable in these conditions shows under the optical microscope a peculiar morphology : it is made up of spheroidal particles with regular dimensions smaller than 5 microns , as shown by way of an example in fig1 . the spherical shape of the individual particles is an essential condition for the polymer to be used for very advanced and innovative pharmaceutical applications . the nanosponges produced with the assistance of ultrasounds according to the present invention can bind to numerous organic compounds such as pcb , chlorinated and aromatic organic solvents , phthalates , pops ( persistant organic pollutants ) and pah ( persistant aromatic hydrocarbons ) and can therefore be used as decontaminating agents , similarly to what is disclosed in u . s . pat . no . 5 , 425 , 881 , wo 03 / 085002 and de 10008508 , e . g . for the treatment of environmental matrices such as air , water , soil and surfaces . the nanosponges of the invention may also be used in the following fields and applications : in analytical chemistry as stationary phases for chromatography ; as excipients for preparing tablets , pellets , granules with sizes between 0 . 5 mm and 20 mm and powder , also for inhalation administration ; in the extraction of vegetable and / or animal active ingredients ; in magnetised form for complexing of active ingredients ; removal of organic and inorganic radioactive substances and in particular radioactive elementary iodine . in individual systems of protection against chemical attack and agents ; in deodorising processes of liquid and / or gaseous effluents . the nanosponges of the invention may be regenerated by simple thermal desorption , extraction with solvents and / or use of microwaves and ultrasounds . 4 . 54 g ( 0 . 001 mols ) of anhydrous β - cd and 0 . 856 g ( 0 . 004 mols ) of diphenyl carbonate are mixed in a 250 ml flask . the flask is placed in an ultrasound bath filled with water and heated to 90 ° c . the mixture is sonicated for 5 h . the reaction mixture is left to cool and the product obtained is broken up roughly . numerous needle - shaped crystals of phenol can be seen on the clear surface and the neck of the flask and part of the phenol developed contributes to agglomerating the product . the product is washed with water in order to remove the non - reacted cyclodextrin and then is washed in soxhlet with ethanol to remove the phenol developed and the residual dpc . the product obtained is a fine white powder insoluble in water . observations at the optical microscope ( fig1 ) show the perfect spherical shape of the particles and their average diameter smaller than 5 microns and the low rate of polydispersity . moreover the microspherical nanosponges have a high degree of crystallinity at low values of θ as can be seen from the x - ray analysis of the sample as in example 3 ( fig2 ). 100 ml of dmf , 4 . 54 g ( 0 . 001 mols ) of anhydrous β - cd and 0 . 856 g ( 0 . 004 mols ) of diphenyl carbonate are placed in a 250 ml flask . the flask is placed in an ultrasound bath filled with water and heated to 90 ° c . the mixture is sonicated for 5 h . the reaction mixture is allowed to cool and is concentrated to a small volume in the rotavapor . at the end excess water is added , with filtering and washing with water for a long period and the product obtained is dried . the product obtained is a fine white powder insoluble in water . 4 . 54 g ( 0 . 001 mols ) of anyhdrous β - cd and 0 . 428 g ( 0 . 002 mols ) of diphenyl carbonate are mixed in a 250 ml flask . the flask is placed in an ultrasound bath filled with water and heated to 90 ° c . the mixture is sonicated for 5 h . the reaction mixture is left to cool and the product obtained is broken up roughly . numerous needle - shaped crystals of phenol can be seen on the clear surface and the neck of the flask and part of the phenol developed contributes to agglomerating the product . the product is washed with water in order to remove the non - reacted cyclodextrin then is cleansed of the phenol developed by evaporation in a nitrogen flow at 130 ° c . the product obtained is a fine white powder not soluble in water and common organic solvents . 20 g ( 0 . 0176 mols ) of anhydrous β - cd and 7 . 54 g ( 0 . 0352 mols ) of diphenyl carbonate are mixed in a 100 ml beaker . the beaker is placed in an oil bath bain - marie and heated to 90 ° c . the mixture is sonicated for 4 h at 19 khz using an ultrasound probe capable of supplying a maximum power of 250 w at 19 khz . the reaction mixture is left to cool and the product obtained is broken up roughly . numerous needle - shaped crystals of phenol can be seen on the clear surface of the beaker and part of the phenol developed contributes to agglomerating the product . the product is washed with water in order to remove the non - reacted cyclodextrin and then is washed in soxhlet with acetone to remove the phenol developed and the residual dpc . the product obtained is a fine white powder not soluble in water and common organic solvents . 20 g ( 0 . 0176 mols ) of anhydrousβ - cd and 11 . 30 g ( 0 . 0528 mols ) of diphenyl carbonate are mixed in a 100 ml beaker . the beaker is placed in an oil bath bain - marie and heated to 90 ° c . the mixture is sonicated for 4 h at 19 khz using an ultrasound probe capable of supplying a maximum power of 250 w at 19 khz . the reaction mixture is left to cool and the product obtained is broken up roughly . numerous needle - shaped crystals of phenol can be seen on the clear surface of the beaker and part of the phenol developed contributes to agglomerating the product . the product is washed with water in order to remove the non - reacted cyclodextrin and then is washed in soxhlet with acetone to remove the phenol developed and the residual dpc . the product obtained is a fine white powder not soluble in water and common organic solvents . 10 g ( 0 . 0088 mols ) of anhydrous β - cd and 9 . 416 g ( 0 . 044 mols ) of diphenyl carbonate are mixed in a 100 ml beaker . the mixture is sonicated for 5 h at 19 khz at ambient temperature using an ultrasound probe capable of supplying a maximum power of 250 w at 19 khz . the reaction mixture is left to cool and the product obtained is broken up roughly . numerous needle - shaped crystals of phenol can be seen on the clear surface of the beaker and part of the phenol developed contributes to agglomerating the product . the product is washed with water in order to remove the non - reacted cyclodextrin and then is washed in soxhlet with acetone to remove the phenol developed and the residual dpc . the product obtained is a fine white powder not soluble in water and common organic solvents . 0 . 25 g of polymer are added to 10 ml of water contaminated with 19 ppm of chlorobenzene , as in example 1 . various samples are taken in time and each sample was analysed by uv - vis spectroscopy . the concentration of chlorobenzene was found to be 8 . 2 ppm after 30 minutes and 3 . 1 ppm after 180 minutes . 2 g of polymer are added to 50 ml of water contaminated with a mixture of chlorobenzene ( 820 ppb ), 4 - chlorotoluene ( 830 ppb ), 2 , 6 - dichlorotoluene ( 770 ppb ), 1 , 3 , 5 - trichlorobenzene ( 540 ppb ) and hexachlorobenzene ( 225 ppb ), as in example 3 . several samples are taken in time and each sample is analysed by gas chromatography - mass spectrometry . the total concentration of organics after 50 minutes is 180 ppb with an abatement of 94 % approximately . considering the individual constituents a high efficiency is obtained for the more chlorinated compounds for which abatement higher than 97 % is obtained . 2 g of polymer are added to 50 ml of water contaminated with 316 ppb of pcb ( commercial mixture aroclor 1242 ), as in example 4 . several samples are taken in time and each sample is analysed by gas chromatography - mass spectrometry . the total concentration of pcb after 50 minutes was 32 ppb with an abatement of 90 % approximately . 100 mg of nanosponges are added to 3 ml of water containing 20 mg of flurbiprofen , as in example 3 . this is left to be magnetically stirred for a night at ambient temperature . at the end it is filtered and the solid phase recovered and lyophilised . the nanosponges incorporate 10 mg of flurbiprofen / 100 mg . the lyophilised substance is subjected to release tests in a ph 7 . 4 buffer , while stirring and at a temperature of 3 ° c . fig3 gives the results obtained where the progressive and constant release of the active ingredient considered can be seen clearly . 50 mg of nanosponges are added to 3 ml of water containing 3 mg of doxorubicin , as in example 3 . this is left to be magnetically stirred for a night at ambient temperature . at the end it is filtered and the solid phase recovered and lyophilised . the lyophilised substance incorporates 1 % in weight of doxorubicin . the lyophilised substance is subjected to tests of release in two different aqueous buffers . fig4 gives the results obtained where the progressive and constant release of the active ingredient considered can be seen clearly . it should be noted that the release depends largely on the ph used . with decidedly acid ph ( gastric environment ) the kinetics of release is slow . at ph 7 . 4 the release is considerable with faster release kinetics . this experiment proves that the nanosponges are able to carry active ingredients , passing unchanged through the gastric environment of the human stomach and releasing the active ingredients in the intestine . the nanosponges are therefore configured as carriers of active ingredients . the results of controlled and prolonged release in time are of particular importance considering the poor haemolytic activity of the nanosponges used as described in greater detail in example 12 . to determine haemolytic activity 250 μl of blood , obtained from donors , are added in a set of test tubes to increasing quantities of nano - cd and then brought to 1 ml with pbs 10 mm ph = 7 . 4 sterile buffer . the quantities of nano - cd considered are : 0 . 5 mg , 1 . 0 mg , 1 . 5 mg , 2 . 0 mg , 2 . 5 mg , 5 . 0 mg , 7 . 5 mg , 10 . 0 mg , 15 . 0 mg , 20 . 0 mg and 25 . 0 mg . to this set of test tubes 1 test tube is added containing 250 μl of blood and 750 μl of pbs 10 mm ph = 7 . 4 sterile buffer used as a control and a test tube containing 250 μl of blood and 750 μl of pbs 10 mm ph = 7 . 4 sterile buffer to which excess ammonium chloride is added to obtain total haemolysis of the red globules present . the test tubes are then incubated for 90 minutes at a temperature of 37 ° c . after 90 minutes centrifuging is carried out at 2000 rpm for 10 minutes ; 250 μl of the surnatant are taken and placed in a quartz cuvette containing 2 . 5 ml of a 10 mm ph 7 . 4 sterile phosphate buffer . as a reference the sample of blood is used and in which total haemolysis is caused by adding ammonium chloride . all the samples are then analysed at the spectrophotometer ( lambda 2 , perkin elmer ) at the wavelength of 543 nm . the percentage of haemolysis is calculated from the absorbance due to the presence of haemoglobin in the surnatant . 100 % haemolysis corresponds to 543 nm absorbance of the fully haemolysed sample ( reference ). no haemolytic activity occurs up to the concentration of 6 mg / ml .
a description is given of substantially spherical nanosponges which can be obtained by crosslinking cyclodextrins and their by - products with organic carbonates as crosslinkers and ultrasounds without a solvent .