Polymer hydrogels and use thereof

[0001] The present invention relates to polymer hydrogels, methods for their preparation and use. Polymer hydrogels are cross-linked hydrophilic polymers that are able to absorb large amounts of water. In particular, crosslinked polymer hydrogels capable of absorbing an amount of water exceeding 10 times their dry weight is defined as "superabsorbents". Some of these materials are capable of absorbing even over 1 liter of water per gram of dry polymer.

[0002] Cross-linking connections or cross-linking nodes, i.e. physical or chemical bonds between macromolecular chains forming a polymer hydrogel network guarantee the structural integrity of the polymer-liquid system, on the one hand preventing the complete dissolution of the polymer, and on the other hand allowing the retention of the aqueous phase in molecular meshes.

[0003] Superabsorbent polymer hydrogels, which are currently available on the market, are characterized not only by their outstanding absorption properties, but also by their biocompatibility, which is probably due to the high water content, and above all the possibility of adapting their absorption properties to an external stimulus. Consequently, such polymer hydrogels can be used as intelligent materials, for example for the production of sensors or actuators for many industrial applications. In addition to the usual applications as absorbent cores in the field of personal care absorbent products, there are newer and more innovative applications such as, for example, in the field of biomedicine for the development of controlled release drug formulations, artificial muscles, sensors etc. and in agriculture and horticulture, for example in devices for the controlled release of water and nutrients in sterile soils.

[0004] However, currently available superabsorbent polymer hydrogels are almost exclusively acrylic based products and are therefore not biodegradable.

[0005] Given the growing interest in environmental issues, in recent years a significant portion of activity has focused on the development of superabsorbent materials based on biodegradable polymers and properties similar to traditional superabsorbent polyacrylics. [0006] Examples of biodegradable polymers used to obtain superabsorbent polymer hydrogels are starch and cellulose derivatives.

[0007] In 1990, Anbergen and Oppermann [1] proposed a method for the synthesis of superabsorbent material made entirely of cellulose derivatives. They especially used hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose (CMCNa), chemically cross-linked in alkaline solution with divinyl sulfone. However, the absorption properties of such materials are not good when compared to superabsorbent materials based on acrylic.

[0008] In 1996, Esposito et al. [2], studying the synthetic process proposed by Anbergen and Opperman, developed a method of increasing the gel's absorption properties, mainly affecting the physical properties of the material. The basic idea was to induce microporosity in

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The polymer structure so as to promote water absorption and retention using capillarity. Said microporosity was induced during the drying step, which was carried out through the inversion phase in the non-solvent for the polymer, and the absorption properties of the material thus obtained were significantly better than those for an air-dried gel.

[0009] CMCNa can be chemically crosslinked with any reagent that is bifunctional with respect to cellulose. In addition to the divinyl sulfone used in the synthetic process according to Anbergen and Opperman, epichlorohydrin, formaldehyde and various diepoxides are also used as crosslinking agents. However, such compounds are highly toxic in unreacted states [3]. Some carbodiimides are known among unconventional crosslinkers. The use of carbodiimides for cross-linking carboxymethyl cellulose (CMC) in the form of salts or not in the form of salts has been particularly described [4]. Carbodiimides induce the formation of ester bonds between cellulose macromolecules without participating in the bonds themselves, instead causing the formation of a urea derivative with very low toxicity [5]. A superabsorbent polymer hydrogel obtained by cross-linking sodium carboxymethylcellulose and hydroxyethylcellulose with a carbodiimide as a cross-linking agent is disclosed in International Patent Application WO 2006/070337 [6].

[0010] However, the disadvantage of carbodiimide used as crosslinker in WO 2006/070337 is the very high price. In addition, during the crosslinking reaction with CMCNa, this substance changes into a slightly toxic urea derivative, which must be removed during the rinsing step, which further increases the cost and complexity of the manufacturing process. These disadvantages are extremely disadvantageous, especially for those applications that require large scale polymer hydrogel production and consequently involve high costs both for the purchase of starting materials and for the removal of toxic substances that are produced during synthesis.

[0011] WO 99/26670 discloses a method for preparing a polymer foam, which foam is defined as a porous polymer matrix. The foam is created by freezing the soluble polymer solution, removing the solvent and optionally treating the polymer to form a foam.

[0012] Furthermore, the formation of substances with a certain degree of toxicity, although very low, is a key factor in excluding the use of such polymers in biomedical and pharmaceutical applications.

Summary of the invention [0013] It is an object of the present invention to provide polymer hydrogels that do not have the abovementioned disadvantages associated with the use of carbodiimide as a crosslinker.

[0014] Thus, the present invention provides a polymer hydrogel obtained by a method comprising the steps of:

(a) providing an aqueous solution containing citric acid and carboxymethyl cellulose, and (b) heating the solution to remove water and cross-linking carboxymethyl cellulose with citric acid, thereby forming a polymer hydrogel;

wherein said polymer hydrogel has a swelling ratio in distilled water of

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EP 2 532 685 B1 at least 50.

[0015] The invention partly relates to the finding that cross-linking of soluble cellulose derivatives with citric acid (3-carboxy-3-hydroxy-1,5-pentanedioic acid; hereinafter referred to as "CA") results in the formation of polymer hydrogels and superabsorbent polymer hydrogels. CA occurs naturally, is non-toxic and is available on the market at a low price. Although CA has been reported as a crosslinker for polymers such as cellulose, hydroxypropyl methylcellulose and starch in textile and food applications [7-11], in these applications CA is used to crosslink and further stabilize insoluble fibers to provide fabrics with better resistance and mechanical properties. However, the use of CA for cross-linking carboxymethylcellulose or other soluble hydrophilic polymers for preparing polymer hydrogels and superabsorbent polymer hydrogels has not yet been disclosed.

[0016] In one embodiment, the aqueous solution further comprises a nonionic polymer, e.g., hydroxyethyl cellulose.

Brief description of the figures [0017]

Figure 1 illustrates the proposed mechanism for cross-linking the polymer with citric acid.

Figure 2 is a graph of cumulative food intake versus time for rats administered orally with the polymer hydrogel of the invention and rats treated with vehicle only.

Detailed description of the invention [0018] The present invention provides polymer hydrogels obtained by using the methods described herein.

[0019] The method for preparing the polymer hydrogel of the present invention comprises the step of cross-linking an aqueous solution containing carboxymethylcellulose with citric acid, resulting in a polymer hydrogel. In one embodiment, the aqueous solution further comprises a nonionic polymer, e.g., hydroxyethyl cellulose.

[0020] The crosslinking reaction is preferably carried out at an elevated temperature, for example at a temperature higher than room temperature (25 ° C). The reaction may be carried out, for example, at a temperature from about 30 ° C to about 150 ° C, preferably from about 50 ° C to about 120 ° C. In one embodiment, although the crosslinking reaction is performed at an elevated temperature, the reaction solution is concentrated by removing water. Water removal can be carried out, for example, by evaporation. In one embodiment, some of the water is removed. In another embodiment, substantially all of the water is removed, thereby producing a dry precipitate. The reaction mixture is optionally maintained at an elevated temperature for a period of time after the water has been removed to dryness.

[0021] The expression "nonionic polymer" as used herein refers to a hydrophilic polymer which

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EP 2 532 685 B1 does not contain monomeric functional groups that can be ionized, such as acidic or basic groups. Such a polymer in an aqueous solution will not be charged. Examples of suitable nonionic polymers for use in the present method are polyallyl alcohol, polyvinyl alcohol, starches such as corn starch and hydroxypropyl starch, alkyl celluloses such as C-C alkyl celluloses, including methyl cellulose, ethyl cellulose and n-propyl cellulose; substituted alkyl celluloses, including hydroxy-C-alkyl alkyl celluloses and hydroxy-C₁-C₆-alkyl-C₁-C₆-alkyl cellulose, such as hydroxyethyl cellulose, hydroxy-n-propyl cellulose, hydroxy-n-butyl cellulose, hydroxypropyl methyl cellulose and ethyl hydroxyethyl cellulose.

[0022] The method may further comprise the steps of purifying the polymer hydrogel, for example by washing the polymer hydrogel in a polar solvent such as water, an organic polar solvent, for example an alcohol such as methanol or ethanol, or a combination thereof. A polymer hydrogel immersed in a polar solvent swells and releases any component, such as by-products or unreacted polycarboxylic acid, which has not been incorporated into the polymer network. Water is preferred as the polar solvent, distilled water is even more preferred. The volume of water needed during this step to achieve the maximum degree of gel swelling is approximately 10 to 20 times more than the initial volume of the gel itself. Given the substantial amounts of water that will be used during this stage on an industrial scale, as well as the washings removed and / or recycled, the importance of avoiding the presence of any toxic by-products in the synthesis process becomes evident. The washing step of the polymer hydrogel can be repeated more than once, optionally changing the polar solvent used. For example, the polymer hydrogel may be washed with methanol or ethanol followed by distilled water, these two steps optionally being repeated one or more times.

[0023] The method may further comprise drying the polymer hydrogel. The drying step is carried out by immersing the fully swollen polymer hydrogel in a non-solvent for cellulose in a process known as phase inversion. Suitable non-solvent substances for cellulose include, for example, acetone and ethanol. Drying of the polymer hydrogel by phase inversion results in a final microporous structure that improves the absorption properties of the polymer hydrogel through capillarity. In addition, if the pores are interconnected or open, i.e. the micropores communicate with each other, the gel absorption / desorption kinetics will also be better. When the swollen gel is completely or partially immersed in the non-solvent substance, the gel undergoes phase inversion with the excretion of water until the gel precipitates as a glassy solid in the form of white particles. To obtain a dried gel in a short time, different rinses in the non-solvent substance may be necessary. For example, when the swollen polymer hydrogel is immersed in acetone as a non-solvent, a water / acetone mixture is formed, which increases the water content as the hydrogel polymer dries; at a certain acetone / water concentration, e.g. about 55% in acetone, water is no longer able to leave the polymer hydrogel, and therefore fresh acetone must be used for the polymer hydrogel in the drying process. The higher the acetone / water ratio during drying, the faster the drying process.

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EP 2 532 685 B1

The pore size is affected by the speed of the drying process and the initial dimensions of the polymer hydrogel particles: larger particles and a faster process seem to increase the pore size; preferred are the dimensions of psoyróntwhewticzparkorcesisebsekcaolmi mesikervoi, depnotn. iTehweapżoplyomryerwhytdyrmogzeal kwraesshiiengwietietelkpomścaiywbyekraezpuejaątesdilnmeordeztihaałannoienckea, poiplatironnea, llyco_sk^chat^andtkⁿat^gj^ande^ngin^ts^hfrom^es^pand^olas^ror^sp^aboutc^lvj^eandⁿand^t from^ed^mabout^pln^loabout^sś^ec^dble^{. F}from^aboutand^rtr^efrom^xs^andm^ms^pin^leand^, n^thia^e in^afterabout^ld^ss^m.^{er hydrogel can be washed with methanol or ethanol}^[0[00²2⁴3^]]^hyT^dh^re^aboutm^thate^lt^eho^pd^aboutc^land^mn^ef^rat^aboutrtⁱⁿher ⁱⁿin^ecl^dat^Ld^ate^gdⁱⁿry^sing^alabout^andf^fromt^kh^atep^mol^abouts^frommⁿe^andrh^abouts^sd^atro^sg^frome^andl^Æ. Tⁱⁿheⁱⁿdⁿry^sin^mgs^pt^re^aboutp^cand^es^sc^eand^,r ri^te^andd^kiabout^mut ^jb^ands^kthem^axism^ate^srs^fromand^andnⁿg^eptohweiefutlrlzyesmw, ollieonfilpizoalycmeraerluhby dorosgueslziannaiecewll uploiesceun.oTnesoslvpeonst, oab yp rosceussz aknioawnmoswa npah assteosinovwearsościna. mSueit, awblekcoemllublionsaecja luⁿb^hein^solvk^eaboutⁿm^tsbⁱⁿin^cand^luc^dji^e, from^forabout^ep^xand^ands^mand^pn^ls^em^{, ace}p^tabout^aboutin^ADYZ^andeⁿj^dee^tt^hand^andpⁿe^aboutm^l.Drabout^ssⁱⁿat^gs^tfrom^hand^en^pia^olys^mat^eb^rs^ht^sand^dn^rc^aboutj^gand^{el b}n^se^phb^andę^sestriveⁱⁿc^vand^{e rs}r^andabout^aboutfromⁿp^rat^ess^atfrom^lc^tsfrom^andandⁿln^andik^fiandⁿe^andm^l_.

Pre-generationalism, erstwhile and honest companion, cf. tmheo mżnicar oopsouressz acćomwmsuunbicsattaenwcijtihnoineebaęndoąthcerj, trhoez apbusozrcpztiaoln / idkeiesomrp, taionakisnteętpicnsie os^aboutat^fts^hfrom^eay^gelpⁱⁿabout^andin^ll and^be^etr^andfrom^me^pm^ro,^vel^dof^andloam^sandⁱⁿthat^Eland^l.Æ^IN, ^habout^esⁿat^ands^cand^aboutÆ^mpin^letep^lye^aboutc^rat^pal^rat^tib^{and lly}st^saboutⁱⁿs^olin^flaxay^geand^lc^andh^sko^mm^erb^sand^en^dacⁱⁿPH^{it's a}dLⁿand^hein^sos^le^vl^ethem^nt,in^thabout^ewa^gen^land me^atkⁿc^dh^ek^rgabout^aboutl^ese^pk^haś^sl^eadⁱⁿabout^vin^ersp^andaboutⁿzoⁱⁿs^itt^how^tabout^hś^ec^eand^xps^atat^lb^ss^andtⁿan^aboutc^fjⁱⁿand ^andn^thesee^{r, u}bⁿę^td^loam and^thc^eabove^ger^labout^pfrom^rp^eat^cs^ipfrom^itc^andfrom^theseand^sln^andandⁿki^te^hm^ef.^orABOUT^ms^aboutat^fs^andbehind^vin^trand^ee^ouin^ssp^aboutand^le^idcu^ace m^whabout^andfrom^theseon prozfetipmreo.wFaodrzeaxćamwplete, wmhpeenr athtuerszweolwleynn after the posting of mjjndnd.ogwel written by mybmlieżresendiui n3a0c-e4t5o ° nCe _after^mfrom^ixabout^ts^att^rand^eoh^isś^fc^aboutand^rmsu^eb^dsⁱⁿthis^hn^cc^hji ⁱⁿn^cand^re^eab^sę^ed^sandⁱⁿceⁱⁿj^andr^theseabout^rfrom^cp^aboutatⁿs^tfrom^ecⁿfrom^tand^andl^sthan^tk^hand^ee^pm^about.^lyP^mr^efrom^re^hm^Jewyt^rs^ogand^Elabout^ds^rat^es^sfrom^;about^andn^t s^ach^es^rd^thisroⁱⁿfrom^ande^cl ^ep^thisaboutⁿl^em^/ine^andro^thesein^r s^Whatm^ncabout^efromⁿn^-and then used as such or it can be milled to form hydrogel particles pdoulimrinegrodwryeingo, tohephoedicals ethj ewdierylkinogś cpir.ocess. Pore ​​dimensions are affected by the rate of the drying process and the_[0ⁱⁿ0^it2^ia5^l] ^dIN^{im e}inⁿn^sis^aboutm^ns p^aboutr^ffrom^ts^hk^ela^pd^aboutfrom^lye^mein^rs^hk^sabout^dn^rand^aboutn^gand^eand^l,^pr^andabout^rfrom^tictw^leabout^sr^{: l}in^arabout^gd^en^r s^pafrom^rand^tiin^clee^sra^anp^dol^andthem^fae^sr^thesen^re^pj^rabout^aboutn^cabout^esin^sy^thesekⁿabout^dgovernment^thisysⁱⁿtn^cand^re^eap^sabout^ed^ts^ht^eand^afterand^ren celfufeloctz, ęre, sultkinogrzinysthtneiheijgherhsyodrrpotikosnyanlkdi lwocaetelur lroezteęntionlucbapacihtyy.roxyalkylalkylcellulose, and most preferably h [y0r2o4k] syeTlyelelsoel. _[0^about0^r2^about6^v]^enS^dthis^rysⁱⁿat^gn^.k^Tand ^hin^eand^sehim^din^rye^ingeach^mr^eb^tabout^hk^abouts^ds^sm^caeⁿyou^blo^ec^ate^sl^eat^dlo^andfrom^ls^heand^ep^,aboutⁱⁿl^cm^aboute^mr^babout^andin^onn^thioeⁿj^,about^aboutn^raboutⁱⁿin^cs^aboutc^mh ^bmⁱⁿabout^andg^thioandⁿmⁱⁿand^ande^thś^tc^hll of^ens^aboututⁿin^saltfrom^vand^ekⁿr^te^ds^rye^ingfrom okdoryłiong1,: o1v0enddor yoinkgo, łło a1c0o: 1m, biknoartizoynsthneiereofdtooekliomłoina1te: 5andyoreoskidoualal 5tr: a1c.esWofknornzsyoslvtneynct.hOvperznydkrwainki _st^aboutabout^ats^tat^andn^te^andk^thesein^mand^pg^eabout^rain^heres^rethem^abouts^ft^e.in^gand^.ę^andk^ps^pfrom^rs^oxn^themthat^ate1^l:^s1,³⁰p^-r⁴from⁵s^°k^Cla^atdⁿabout^tiin^ltabout^heabout^rd^esiabout^dk^atabout^andL^labout^Well2^nsd^aboutabout^{lv e}aboutⁿk^t about^isBovine^What5^m. ^pIN^{let e}s^lyzc^refrom^meg^aboutabout^veln^dand^.e^thk^eorⁱⁿzy^ands^st^hn^es^dIn an embodiment, the ionic polymer is carboxymethylcellulose, the non-ionic polymer is hymdroexprythylcellulose, hyperhydroxylcellulose, cellulose, fatty acid, low-fat, very low-fat^("0^H2^E7^C] ^")IN^. a preferred embodiment of the method according to the invention which results in formation ^su1^p0:^e1^r,^andp^bre^sf^aboute^rr^band^atb^jl^ands^cfr^sabout^cm^h and^hb^sabout^dat^rt^about1^from:5^Elt^andabout^pand^aboutb^labout^themut^e5^r:^about1ⁱⁿ..AND^sn^cp^hre^aboutfer^sre^fromd^parte^em^gb^aboutabout^lndi^emeⁱⁿnt^ss^s,^aboutth^ke^theminⁱⁿg^sh^kt^andra^fromtⁿand^ikand^atsg^pre^ęand^ct^fromeⁿr ^andt^ehⁿand^andn^and1⁽:1^S,^Rfo⁾r^, e^cxa^Lm^kopⁱⁿle^and,^thesestfęrożmenaibeopurte2ktuorsaobroautw5.roInztaworzcrzc uwlaorldynpyrmefewrryendoesmi bcodnimaejmntn, itehje2io% n icwpaoglyomweyrcihs wcarobdonxiyemseiethnyiucedlloul omsea, zwithhewnoodny-^ands^aboutjⁿś^andc^cand^afterin^lye^mhim^err^andabout^sfrom^ht^sin^dabout^roru^xyin^etabout^hd^yln^ce^eg^lluabout^loand^seloam^,about^andśⁿÆ^dś^thro^edⁱⁿk^eand^gs^hand^te^rc^andand in^thioI⁽c^andeⁿg^andabout^{c: n}in^aboutsⁿn^andaboutⁿs^cand ⁾m^isut^andd^bfrom^abouts^utabout³k^:1about^.about 1% and about 5% by weight in opdonliyemsiernhiyuddroogemlsahsayvpinrgekauprasrotircau.la Wrly nhinghiesjswzeyllmingorpaitsioie (, SwR) y, rtahżeetontiael p "prerecukrusrosrocro" noczenatrcazmeolitolysi^isaxis^aboutabout^f in^atand^ln^ee^acej^tand²k^%op^br^seⁱⁿto^er^gs^habout^tr^rs^ed^feabout^rretw^dabout^thisgovernment^te^hn^eiaⁱⁿp^andabout^ghlim^thise^fr^tabout^hin^e eⁱⁿj^ands^thesee^rc^aboutand^fh^ths^eDr.^sabout^tfrom^ande^rtl^andand^ngafter^andl^qthem^WEUr^atabout^sin^ss^aboutc^lh^at,^{t io}nⁿand^, p^andrⁿfrom^ds^tk^hL^ead^amin^aboutn^atandⁿe^tk^aboutt^fabout^tr^hs^ein these embodiments, "precursor mass" means the mass of CMCNa used or the combined masses zapsotlyomsoewr haynderoggoelCpMolCymNear ni eHtwEoCrk., Rfoorzetxwaómrpwleo, dinncyerztaiwn iemrabokdoimrzeynsttsnitehes "owrebigththo _inC_andM_himC_inN_sand_cat_hs_ined_sabout_thisr _sth_ate_nc_kabout_atm_db_aboutin_med_andin_syei_ingh_aboutt_ds_sabout_.f CMCNa and HEC used. The aqueous solution preferably includes sorbitol in [0028] The swelling index (SR) is a measure of the ability of a polymer hydrogel to absorb water. StRhrouzgyhsskwuejellinsgi ęmepaospurezmeze nptsoamt tiaheryeqpuililbzrniuiemn (iuasinwg, sfotar enxiea mrpólw, nao Swargtoi riu (stomiculture^-and⁵k) ro Sartorius with sensitivity 10^-5) and is calculated using the following formula:

<img file="PL2532685T3_D0001.tif" />

with W_s is the mass of the polymer hydrogel after immersion in distilled water for 24 _g^ofd^tfrom^hand^eny^afterand^lyIN^med^rhabout^sfrom^dn^rand^aboutc^gfrom^eand^lbm^efand^ors^eę ^themhy^md^er^rabout^sfrom^andeⁿlu^{, th}p^eol^pthem^olye^mro^ein^r e^hg^Jewabout^rop^gr^efrom^le^hd^avfrom^andandⁿn^gat^br^efrom^enn^pe^rm^ev,^andp^atr^sfrom^{ly d}c^rfrom^es^dmⁱⁿh^abouts^rdr^eabout^rfrom^thisEl^rep^mol^aboutthem^vee^androⁿin^s_s

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EP 2 532 685 B1 was previously dried to remove any residual water.

[0029] According to the preparation method in this embodiment, the crosslinking reaction is preferably carried out at a temperature between about 60 ° C and 120 ° C. Differentiating the temperature during this stage of the process will allow increasing or reducing the degree of crosslinking of the polymer network. A crosslinking temperature of about 80 ° C is preferred.

[0030] One particularly preferred embodiment of the method comprises the following steps: Step 1, the hydrophilic polymer (s), carboxylic acid and optionally the molecular spacer is dissolved in water at room temperature; Step 2, water is removed from the solution at 40 ° C in two days; Step 3, the product of Step 2 is heated to 80 ° C for 10 hours to induce a crosslinking reaction and form a polymer hydrogel; Step 4, the polymer hydrogel is rinsed three times with water for 24 hours; Step 5, the washed polymer hydrogel is immersed in acetone for 24 hours to remove water; Step 6, the polymer hydrogel is further dried in an oven at 45 ° C for 5 hours and Step 7, the dried polymer hydrogel was ground to provide polymer hydrogel particles.

[0031] The polymer hydrogels of the invention have swelling ratios of at least about 50. In preferred embodiments, the polymer hydrogels of the invention have SR of at least about 60, about 70, about 80, about 90 or about 100. For example, in some embodiments of the polymer hydrogels of the invention have SR from about 50 to about 100, from about 60 to about 100, from about 70 to about 100, from about 80 to about 100, or from about 90 to about 100. In some embodiments, the invention includes polymer hydrogels with SR to 150, 200, 250, 300, 330 or 350.

[0032] In some embodiments, the polymer hydrogels of the invention can absorb an amount of one or more body fluids, such as blood, blood plasma, urine, intestinal fluid or gastric fluid, which is at least 10, 20, 30, 40, 50 , 60, 70, 80, 90 or 100 as much as their dry matter. The ability of polymer hydrogels to absorb body fluids can be tested using conventional methods, including testing with body fluid samples obtained from one or more individuals or with simulated body fluids such as simulated urine or gastric fluid. In some preferred embodiments, polymer hydrogels can absorb significant amounts of fluid obtained by combining one volume of simulated body fluid (SGF) with eight volumes of water. SGF can be obtained using procedures for USP test solutions that are known in the art. In some embodiments, the polymer hydrogels of the invention can absorb at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more times as much of this SGF / water mixture as their dry weight.

[0033] The polymer hydrogels of the invention contain cross-linked polymers with different hydration sizes. For example, polymer hydrogels may be provided in a hydrated state ranging from a substantially dry or anhydrous state, such as a state in which from about 0% to about 5% by weight of the polymer hydrogel is water or an aqueous fluid, to conditions containing a significant amount of water or an aqueous fluid , including to a state in which the polymer hydrogel has absorbed the maximum amount of water or aqueous fluid.

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[0034] The polymer hydrogels of the invention can be used in methods of treating obesity, lowering calorie or food intake, or achieving or maintaining satiety. The methods include the step of administering an effective amount of the polymer hydrogel of the invention to the stomach of the subject, preferably by causing the polymer hydrogel to be ingested by the subject, such as a mammal, including a human. Such polymer hydrogels can be used to occupy the stomach volume, for example by increasing the bolus volume of the food, without adding caloric content of the food. The polymer hydrogel may be consumed by the subject before eating or in combination with food, for example as a mixture of the polymer hydrogel with food. After ingestion and contact with gastric fluid or a combination of gastric fluid or water, the polymer hydrogel swells. The polymer hydrogel can be consumed alone or in a mixture with liquid or dry food in a dry, partially swollen or completely swollen state, but is preferably consumed in a hydrated state that is significantly below its fluid capacity, more preferably the polymer hydrogel is consumed in anhydrous state. Thus, the volume of the stomach occupied by the polymer hydrogel may be significantly greater than the volume of the polymer hydrogel consumed by the subject. The polymer hydrogels of the invention may also occupy volume and / or exert pressure on the wall of the small intestine by movement from the stomach to the small intestine and swelling. The polymer hydrogel will preferably remain swollen in the small intestine for a sufficient period of time to inhibit the subject's consumption of food before it contracts enough to be expelled from the body. In general, the time required by the subject to eat and to move digested food through the small intestine will generally be sufficient to inhibit food intake by an individual. Such shrinkage can occur, for example, by degradation by loss of cross-linking, fluid release and a decrease in volume sufficient for excretion from the body. Preferred polymers for use in this method exhibit pH-dependent swelling, with greater swelling being observed at higher pH than at lower pH. Thus, such a polymer will not significantly swell in the stomach as long as food and / or water are present to raise the pH of the stomach content and travel to the small intestine. When ingested with food, the polymer hydrogel will initially swell in the stomach, then shrink when the stomach is emptied of food and the pH drops, and then move from the stomach to the small intestine. In an environment of a higher pH of the small intestine, the polymer hydrogel will swell, taking up volume in the small intestine and / or exerting pressure on the wall of the small intestine.

[0035] The polymer hydrogel can optionally be administered in combination with a pH modifying agent, which is a pH modifying agent of the polymer hydrogel microenvironment, thereby modifying its ability to absorb liquids. For example, for polymer hydrogels containing anionic polymer, agents that increase the pH of the microenvironment may increase the swelling potential of polymer hydrogels. Suitable pH modifying agents for use with the polymer hydrogels of the invention include buffering agents, H blockers₂ proton pump inhibitors, antacids, proteins, nutritional cocktails and combinations thereof. Suitable buffering and neutralizing agents include ammonium bicarbonate, sodium bicarbonate, calcium carbonate, calcium hydroxide, aluminum hydroxide,

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Aluminum carbonate, magnesium carbonate, magnesium hydroxide, potassium bicarbonate, potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide and combinations thereof. Suitable H blockers₂ include cimetidine, ranitidine, famotidine, nizatidine and combinations thereof. Suitable proton pump inhibitors include omeprazole, lansoprazole, ezorneprazole, pantoprazole, abeprazole and combinations thereof.

[0036] The present polymer hydrogels can also be used to remove water from the gastrointestinal tract, for example as a treatment for subjects suffering from kidney disease, including chronic and acute kidney disease, especially those undergoing kidney dialysis. Polymer hydrogels may further be used to modify the fluid content of the gastrointestinal tract of an individual in need thereof, for example for the treatment of constipation.

[0037] The polymer hydrogels and superabsorbent polymer hydrogels of the present invention can be used as absorbent materials in the following areas, which are given as a non-limiting example:

- dietary supplements (for example fillers in dietary supplements for hypocaloric diets, capable of causing a feeling of long-lasting satiety, kept in the stomach for a limited period of time or as water and low molecular weight supplementation compounds, such as mineral salts or vitamins, for incorporation in beverages in dry or swollen form);

- in agricultural products (for example in devices for the controlled release of water and / or nutrients and / or phytochemicals, especially for cultivation in dry, desert and in all cases where frequent irrigation is impossible; such products, mixed in dry form with the soil in the areas surrounding the roots of plants, absorb water during irrigation and are able to retain it, release it slowly in some cases, together with nutrients and photochemicals useful for growing);

- in absorbent products for personal and household hygiene (such as, for example, absorbent pads in baby diapers, sanitary napkins and the like);

- in the field of toys and gadgets (as, for example, in products that have the ability to significantly change their size after contact with water or an aqueous solution);

- in the field of biomedicine (for example in biomedical and / or medical devices, such as absorbent dressings for the treatment of highly runny wounds, such as ulcers and / or burns, or in slow release polymer films suitable for slow release fluids adapted for use in ophthalmology) ;

- in the field of body fluid management, i.e. to control the amount of fluid in the body, for example in products with the ability to promote the removal of fluid from the body, such as for example for edema, CHF (chronic heart failure), dialysis.

[0038] The above-mentioned products containing the polymer hydrogel of the present invention as the absorbent material are also within the scope of the invention.

[0039] The invention further encompasses the use of any of the polymer hydrogels in medicine

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EP 2 532 685 B1 according to the invention. Such uses include the use of polymer hydrogels for the preparation of medicaments for the treatment of obesity or any medical disorder or disease in which calorie restriction is a therapeutic, palliative or prophylactic benefit.

Examples [0040] The materials and processes of the present invention will be better understood in connection with the following examples, which are intended only to illustrate and not limit the scope of the invention. Various changes and modifications of the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including without limitation those of the chemical structures, derivatives, formulations and / or methods of the invention may be made without departing from the scope of the appended claims.

Example 1

Cross-linking with citric acid carboxymethyl cellulose / hydroxyethyl cellulose mixtures

Materials [0041] CMCNa (MW 700 kDa, DS 0.9, food grade), HEC (MW 250kDa, food grade) were purchased from Eigenmann e Veronelli SpA Milano and citric acid was supplied by Dal Cin SpA Sesto San Giovanni Milano and used as received

Synthesis of polymer hydrogels [0042] Polymer hydrogel samples were obtained by reacting CMCNa and HEC in water with citric acid as a crosslinker according to the following procedure. First, the polymer at a total concentration of 2% by weight in water, using a mixture of CMCNa and HEC, at a weight ratio of 3/1 was dissolved in distilled water by gently stirring at room temperature to obtain a clear solution. Poor cross-linking efficiency was reported if only CMCNa was used, due to electrostatic repulsion between polyelectrolyte chains and the high degree of substitution of hydroxyl groups on C6, the most reactive position [13]. Dissolution of CMCNa at the concentration used is slow; therefore, HEC was first added to water until a clear solution was obtained after 5 min with a slight increase in viscosity; then CMCNa was added and mixed until a clear solution was obtained (24h), with a significant increase in viscosity. Finally, CA was added at various concentrations (1.75%, 2.75%, 3.75%, 10% and 20% w / w polymer) to obtain samples with different degrees of crosslinking. This final solution was used to cast samples 10 mm thick. All samples were first pre-dried at 30 ° C for 24 h to remove absorbed water, and then kept at 80 ° C for the crosslinking reaction (24h with intermediate control).

[0043] In addition, samples containing pure HEC or samples of pure CMCNa were also obtained ₁-l₀in

P^dFROM^at/^e29^b0^ot0^h/AND^thisG^t

Ef sPub2s5tit3u2tio6n8o5f hBy1d puffed up eto wCaAte, r tpilol, satfęprprumcinz, gaocdlenaier sozlutdioonwładsnoiebtatianekymnkatkatta _from^andand^ds^dthis^es^dabout^,andinⁿand^dn^te^hed^sla^tirm^rinand^gesⁱⁿfrom^andand^sn^kin^epH^thisEⁿC^t/^loamC^laM^cC^leN^arand^s.^{olution was obtained (24h), with a significant increase of viscosity. finally,}[0w0it4h4v] arWiousszydsetgkrieesporóf cbrkoissa-nlinaklizngo.wTahnisofinzal spoolumtioncaw apsoumseiadrtóowmoFldT10IRm.mTtwhoicrkzseanmieplebse.zAwllosdanmikpaleswwyno^pabout^rp^er^-from^de^rifrom^edm^andabout^t n³and⁰this^{° C}ro^fin^oran²and⁴e^hc^th^aboutand^rr^eand^mkt^aboute^vr^eys^andt^bs^sc^aboutfrom^rn^be^eg^dabout^wad^tl^eand^ranⁿe^dg^tabout^herⁿoz^kc^eand^pand^tg^andn^tut⁸t⁰e^°g^Cabout^fop^rand^ths^em^cand^roin^SS-about^lb^nks^andfromⁿand^ggovernment^ree^ack^tand^andrⁿbecause⁽²n⁴s^hluⁱⁿp^ithrzy 1 [7030843c] m^-M¹ o [1re4o] .v er, samples containing neat HEC or neat CMCNa samples cross-linked with CA were also prepared _IN[0_s0_k4_and4_from]_ScoreAND_pll_ęs_cand_fromm_np_ele_ns_iawere analyzed by FT IR measurements. Anhydride formation was detected by monitoring its char [0S0w4e5ll] ingPoamtioiary equilibrium swelling for all samples was carried out in distilled water using a Sartorius micro balance (sensitivity 10^-5 ). The swelling index was measured in a ratio of non-concentrate (1k0^-p⁵rszendsiitivpioty) i.cThhzeasnwuerlzliengnirua twio waosdmzieadsuersetdylboywwaeniegjhinag soakmołpole2s4behf.orWe sakndażanftiekr pthęecirzinmiemneiarsi (oSnR) _d^andeⁿfi^dn^isand in^tij^le^ledsiⁱⁿę ^andn^theseand^rs^ft^aboutę^rp^andat^bI^aboutc^atabout^t_:^{24 h. The swelling ratio (SR) is defined as the following:}

SR = (W_s-Wd) / Wd _pⁱⁿgovernment^hs^erc^efrom^INyms ^andIN^{s th}s^eaboutⁱⁿn^eiand^gc^hfrom^t and^ofm^thand^es^sęⁱⁿn^aboutand^llepⁿEc^pfrom^aboutn^lyand^mow^ee^rg^habout^Jewh^rs^aboutd^gr^eabout^lfrom^andeⁿl^dat ^INunder_l^andand^sm^te^heroⁱⁿin^ee^gg^habout^thisand^f IN^thed ^dabout^rfrom^en^dand^sc^andfrom^mand^pm^leand^[s¹ę^5]dried sample [1D5if] f.erential Scanning Calorimeter _R^[about⁰⁰from⁴n⁶c^]that^ANDs ^dk^andand^ffl^eabout^rr^esⁿm^thiae^ltr^ss^cakⁿandⁿn^andandⁿn^ghim^cain^ls^{orimeter (Mettler-Toledo 822 Mettler DSC) was used for thermal analysis. The} [0¹⁰4^0°6^C] ^tD^aboutabout¹⁰and^°n^Cand^;l⁽and⁴from⁾s^ht^ee^andr^tm^ingaln^fre^ohmj¹and⁰s^°t^Caxis^thisin²and⁰⁰n^°about^C;r⁽⁵from⁾n^andand^sc^otin^hes^rmk ^andl^tabout²ry⁰m^0°e^Ct^;r ⁽⁶s⁾each^Whatn^aboutin^lg^ngthat^uns^til(M^roe^aboutt^mbackground^tr^e-^mT^pabout^ele^rad^tabout^ure8^.2^AND2^{ne e}M^me^ptytler DSC). The scanning temperature range and heating speed were 10-200 ° C and 5 ° C / min, respectively. [0F0o4u7rie] rZTarasntosfsoormwaedn yInmfr acreydklSempectterormscaolpnyym was: (1) heating 10-100 ° C; (2) isotherm at 100 ° C for 3 minutes; (3) cooling from 100 ° C to 10 ° C; (4) heating from 10 ° C to 200 ° C; (5) isotherm at 200 ° C; (6) srcehfl No. at a resolution of 4 cm^-1,

Fourier transform infrared spectroscopy [0048] All FT IR spectra were recorded on a JASCO FT IR 660 plus spectrometer equipped with a kraftszewntewdewuitrhztahdezdeenhieyddraot iponobleieardaingiatoparónbaenkhymdreidtoed. ąA ocosmłapblieotneedgeogrcaadłaktoiowiska, tsetgaortinogdbaitcaiabo (uAtT1R60, ° aCn, gis. aotbtseenruveadted toⁱⁿthis^tl^here^sf^ele^cc^abouttⁿand^dn^sc^ce^and).^n.Film samples were used directly on a crystal sampling device mAebtovdeą10A0T ° RC aprpzoyssrioblzeddzeieglrcazdoaśticoin4pecamk ^-about¹f, CpMrCzyNa30is0destkeacnteadc.hB, owth CzaMkCreNsaieanadbHsEorCbsahnocwji aotdhe4r0m0a0l sctambi^-l¹itydboelo6w00 ^c[^m00^-15^.1] A film of polymer hydrogel obtained using a 3: 1 ratio of CMCNa / HEC and 3.75% by weight of polymer of citric Results and discussion [0049] A DSC thermogram of pure citric acid revealed a peak at about 60 ° C, attributable to the water loss process associated with dehydration leading to anhydride. The second scan shows complete decjradation, starting at around 160 ° C.

[0050] DSC analysis of pure CMCNa and HEC in the form of powders indicates that they are still in polymers

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Some water is absorbed. Above 100 ° C a peak of possible CMCNa degradation was detected. Both CMCNa and HEC exhibit thermal stability below 100 ° C.

[0051] The polymer hydrogel film obtained using a 3: 1 ratio of CMCNa / HEC and citric acid in an amount of 3.75% by weight of the polymer was analyzed by DSC after drying the sample at 30 ° C for 24 h and then reducing to powder. A large endothermic peak is associated with the evaporation of water produced by the drying process. A small exothermic peak associated with the esterification is superimposed on the former. In the second heating cycle, vitrification is observed (T_g= 38 ° C) cross-linked cellulose mixture.

[0052] After this initial DSC test, samples of various polymer hydrogels were prepared according to the following procedures. After mixing the reagents in water, the reaction vessel was kept at 30 ° C for 24 h in dry conditions to remove water. Then, the temperature was raised above

60 ° C, according to the results of the first DSC analysis, to obtain citric acid anhydride. Above this temperature-limiting, citric anhydride is available for cross-linking with cellulose OH groups. Various reaction conditions were tried to optimize the synthetic procedure, such as temperature and CA concentration, as summarized in Table 1. Two different reaction temperatures of the crosslinking process, 80 ° C and 120 ° C, were tested. However, a temperature of 80 ° C was chosen to prevent the risk of degradation or limit the reaction rate. In addition, very high concentrations (10% and 20% by weight) of CA were initially used to amplify the FT IR signals associated with each step of the chemical reaction. First, pure CMCNa and HEC were crosslinked with CA to test its reactivity with each of the polymers.

Table 1

<td>Reaction determination</td><td>Output Polymer</td><td>Citric acid concentration (% w / w polymer)</td>

<td>A10</td><td>CMCNa</td><td> 10</td>

<td>A20</td><td>CMCNa</td><td> 20</td>

<td>B10</td><td>HEC</td><td> 10</td>

<td>B20</td><td>HEC</td><td> 20</td>

<td>C10</td><td>CMCNa / HEC (3/1)</td><td> 10</td>

<td>C20</td><td>CMCNa / HEC (3/1)</td><td> 20</td>

[0053] FT IR spectra of citric acid were recorded from the reaction mixture A10 before heating and from the reaction mixture A10 after 5 h of heating. A strong C = O band concentrated at 1715 cm can be observed in the CA spectrum^-1 from carboxylic acid. The FT IR spectrum of sample A10 shows a strong absorption band at 1590 cm^-1, characteristic of cellulose [16]. After heating, the absorbance band is still observed at about 1590cm^-1 and in addition a new band appears at 1738 cm^-1. anhydrides

1 show two stretched bands in the carbonyl region at about 1758 cm^-1 and 1828 cm^-1. The band at higher frequency is more intense in acyclic anhydrides, while cyclic anhydrides show a stronger C = O stretched band at a lower frequency than the stretched band

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EP 2 532 685 B1 at a higher frequency [14]. New peak observed at 1738 cm^-1 can be attributed to the characteristic stretched band of the carbonyl group at a lower frequency, associated with anhydride formation, the intermediate reaction necessary for the reaction of CA with cellulose hydroxyl groups. In contrast, a carbonyl peak predicted at a higher frequency is not detected, probably due to its low intensity.

[0054] FT IR spectra of citric acid were recorded from the B10 reaction mixture before heating and from the B10 reaction mixture after 6.5 hours of heating. The HEC spectrum again shows a band at 1590 cm^-1before and after heating, while absorbance from the carbonyl group at 1738 cm^-1 appears only after heating at 80 ° C, as observed for sample A10.

[0055] Although FT IR analysis is generally considered a qualitative technique, a literature study by Coma and colleagues showed that infrared spectroscopy can be used as a first approximation to determine the crosslinking speed in crosslinked cellulose derivatives [9]. Starting from this, the development of various reactions eventually leading to crosslinking at 80 ° C was monitored by recording FT IR spectra at different reaction times.

[0056] Area under the absorbance peak at 1738 cm^-1 (A) representing the carbonyl group was compared to the area under the reference absorbance peak at 1592 cm^-1 (A), which is unchanging in all specters. Anhydride development was evaluated as the ratio of A₁/AND₂ as a function of reaction time. Both FTIR spectra of CMCNa polymer, when the reaction is carried out at 80 ° C with 20% CA or 10% CA, show a similar tendency: the anhydride band, which is absent before heating, reaches a maximum almost immediately after the first hour, successively drops to a minimum of 3 h, then rising again reaches a second maximum after 5 h. Finally, the slower process lowers the bandwidth to zero after 24 h. It is noteworthy that in the 20% CA reaction spectrum, the second maximum matches the value (A / A = 0.10) higher than that observed in the 10% CA reaction (A / A = 0.04).

η [0057] It is believed that the peak around 1738 cm^-1 results from a drying process involving free CA followed by the first condensation of this anhydride with OH cellulose, leading to the rapid disappearance of the C = O anhydride groups. Then, the carboxylate groups now attached to the polymer are able to re-form the anhydride, leading to an increase in peak at 1738 cm^-1 . The second reaction of this anhydride, responsible for cross-linking, results in the consumption of a new anhydride group and, consequently, a lower peak at 1738 cm^-1. This second reaction is slower because it includes groups attached to large macromolecules and therefore encounters greater steric hindrance, as has also been reported for other cellulose cross-linking processes [17]. This possible reaction mechanism was confirmed by swelling measurements.

[0058] FTIR spectra were also recorded for the HEC polymer reaction when the reaction was performed at 80 ° C with 20% CA or 10% CA. At 10%, the anhydride band intensity increases from 0 to 098 when the reaction time increases from 0h to 6.5h, but decreases to 0 when the reaction time reaches 24h. The 20% CA reaction shows the exact same tendency to provide a value maximum, 0.079, at 5h.

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Assuming that the crosslinking mechanism is the same as described for CMCNa, the drying and esterification reactions seem to overlap in this case. Therefore, in the FTIR spectrum, the HEC polymer shows a single peak. The latter result agrees with the conclusion of Xie and colleagues [18]. They studied the degree of substitution, as an assessment of cross-linking esterification, on starch heat-reacted with CA at different reaction times, and found a maximum after a few hours.

[0059] To clarify the data observed in all FTIR spectra recorded after 24 hours, we assumed that in all cases the polymer is unstable when it is kept in the oven for 24 hours because there are unspecified secondary reactions that modify the structure of the polymer, which also includes ester functions. In the work of Xie and co-workers [18], it was assumed that the degree of substitution reached its maximum, and then decreased because of the dissociation of substituents from starch when the reaction time was longer than 7 hours.

[0060] Finally, to complete this study, a mixture of CMCNa and HEC polymers was crosslinked. CMCNa has carboxylic acid functional groups in its structure, which increases the process of volume variability in solution. The initial approach to conducting the reaction failed. It is likely that these reaction systems are too complex with many different reaction centers. The FT IR spectra of the C10 reaction recorded before, after 8 h and after 13 h of heating were compared. The C20 reaction sample shows similar spectra. In addition, it is worth noting that when mixtures of polymers (C10 and C20) are used, a wide signal occurs at about 1715 cm^-1, especially when a higher CA concentration is used in the reaction. In fact, due to the fact that at 20% CA the signal from CA at 1715 cm^-1 is very wide and η

superimposed on the polymer signal at 1590 cm^-1 , no clear band is detected. However, a band of around 1715cm should be indicated^-1 before heating. The C10 reaction mixture before heating shows a band around 1715 cm^-1 , covering the absorbance area previously monitored for other reactions (A10, A20, B10, B20); consequently, it is difficult to explicitly assign it to a carbonyl group. However, two other spectra indicate that this band shifts to higher wave numbers during the crosslinking reaction. Particularly after 8 h, the FT IR spectrum shows a wide band in the range of 1711 cm^-1 - 1736 cm^-1 and after 13h this band looks more clearly like the narrow absorbance band at

1737 cm^-1, which is typical for carbonyl groups. C20 reaction spectra provide similar results. Although quantitative analysis of carbonyl groups is not possible when samples C10 and C20 are crosslinked, an assessment of the carbonyl peak similar to those observed for pure polymer reactions can be assumed.

[0061] Crosslinking kinetics were also monitored, examining the swelling method during the reaction process. The swelling index was calculated as a function of reaction time for: (a) CMCNa with 10% or 20% CA concentration; (b) HEC with 10% or 20% CA concentration; (c) mixtures of CMCNa and HEC (3/1) with 10% or 20% concentration of CA; (d) mixtures of CMCNa and HEC (3/1) with 1.75%, 2.75% or 3.75% CA concentration.

[0062] The results obtained show that the swelling of CMCNa cross-linked with 10% citric acid is higher than HEC with the same concentration of citric acid after 24 h. When 20% citric acid was added to the celluloses, the swelling curve shapes were similar to that of HEC and CMCNa. In this case, as far as

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As the cross-linking progresses, the swelling of the HEC-based samples decreases faster than the CMCNa samples, indicating a higher reaction rate between CA and HEC. This is probably because HEC is less sterically unavailable than CMCNa and may react faster than CMCNa chains. In addition, in each repeating unit, HEC has more OH groups than CMCNa (3 vs 2).

[0063] The maximum swelling of the CMCNa / CA sample is observed at the beginning of gelation, after 3 h, when the second esterification reaction begins, the one leading to crosslinking. Then, as the cross-linking process progresses, the corresponding equilibrium water sorption decreases, which is confirmed by the results of the FTIR analysis.

[0064] The same reaction mechanism can be assumed for pure HEC cross-linked CA. However, in this case, the general behavior is slightly different, which is a consequence of the absence of carboxyl groups bound to the polymer. The results of swelling experiments must be interpreted taking into account that CA introduces highly hydrophilic carboxyl groups that are responsible for the formation of the polyelectrolyte network. Therefore, water sorption is significantly increased when carboxyl groups are first attached to HEC chains and then to the gelled network. This effect cannot be appreciated in CMCNa polymer hydrogels, because a large number of -COOH groups, those attached to CMCNa chains, are already bound to the network at the beginning of gelation. A similar trend is observed for mixtures of HEC and CMCNa. [0065] Practical polymer hydrogels showing a high swelling ratio were obtained with a reduced concentration of citric acid (1.75%, 2.75%, 3.75% by weight of the polymer). With a citric acid concentration of 3.75%, the swelling ratio can reach 900. This swollen polymer hydrogel is characterized by adequate rigidity and is able to maintain the same shape as the synthesis vessel. Polymer hydrogels previously synthesized [13] using divinyl sulfone, a toxic reagent, as a crosslinker and with the same ratio between CMCNa and HEC had a maximum swelling ratio of 200. In this case, a higher swelling ratio is obtained by using an environmentally friendly crosslinking agent . At concentrations lower than 1.75% CA, weak crosslinking is observed, associated with insufficient mechanical properties.

Conclusions [0066] This work shows for the first time that CA can be successfully used as a crosslinker for CMCNa / HEC mixtures. As shown in Figure 1, an esterification mechanism based on the formation of anhydride intermediates was proposed to explain the reaction of cellulose polymers with CA.

[0067] The crosslinking reaction for the CMCNa / HEC system was observed by DSC or FTIR analysis. The course of the various cross-linking reactions was monitored using FT IR spectra recorded at different reaction times using excess citric acid. The swelling ratio, monitored at different reaction times, confirmed the reaction path deduced from FTIR analysis. Using low CA concentrations, a swelling ratio (900) was obtained that was optimal for practical applications. The polymer hydrogel obtained by the method described in this Example 1 has the great advantage of reducing base costs and production and bypassing any toxic product

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Indirect during its synthesis process.

Example 2

Carboxymethylcellulose citric acid crosslinking and carboxymethylcellulose / hydroxyethylcellulose mixtures in the presence of sorbitol

Materials and methods [0068] All materials used were provided by Aldrich Italia and used without any additional modification. The devices used for the characteristics, in addition to standard laboratory glassware, cabinets and countertops for standard synthesis, were the JEOL JSOL JSM-6500F scanning electron microscope, exact weight 10^-5g Sartorius, Isco mixer and ARES rheometer.

[0069] Polymer hydrogels were obtained by cross-linking an aqueous solution of sodium carboxymethylcellulose (CMCNa) and hydroxyethylcellulose (HEC) using citric acid (CA) as a crosslinker and sorbitol as a molecular spacer. The gel composition is given by the nominal amount of reagents in the stock solution. The parameters used to define said composition are as follows:

(i) weight concentration of the precursor (%) = total mass of polymers in solution (e.g. CMCNa + HEC) (g) x 100 / weight of water (g);

(ii) weight ratio CMCNa to HEC = mass CMCNa (g) in solution / mass HEC in solution (g);

(iii) weight concentration of crosslinker (CA) (%) = mass of CA in solution (g) x 100 / mass of precursors in solution (g); and (iv) weight concentrations of the molecular spacer (e.g. sorbitol) (%) = weight of molecular spacer (g) x 100 / weight of water (g).

[0070] Laboratory tests have shown that the polymer concentration less than 2% and the CA concentration less than 1% do not result in gel crosslinking or lead to gel synthesis with very poor mechanical properties. On the other hand, CA concentrations higher than about 5% significantly increase the degree of crosslinking and polymer stabilization, but excessively reduce the absorption properties of the superabsorbent gel.

[0071] Because CMCNa is an ionic polymer, it is possible to achieve the desired absorption properties by adjusting the weight ratio of sodium carboxymethyl cellulose (CMCNa) to hydroxyethyl cellulose (HEC). It has been observed that the weight ratio CMCNa / HEC between 0/1 and 5/1, preferably between 1/1 and 3/1, allows the synthesis of a polymer hydrogel with optimal absorption properties.

[0072] The following are examples of the synthesis of various polymer hydrogels of the invention differing in weight percent (w / w%) of citric acid and the composition of the polymer precursor.

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[0073] Preparation of polymer hydrogel A: in a beaker containing distilled water, sorbitol was added at a concentration of 4% by weight based on the weight of distilled water and mixed until complete dissolution took place within a few minutes. The CMCNa and HEC polymers were added at a total concentration of 2% by weight based on the weight of distilled water, with a 3/1 weight ratio of CMCNa / HEC. Stirring was continued until all the polymer had dissolved and a clear solution was obtained. At this stage, 1% by weight citric acid based on the weight of the precursor was added to the solution whose viscosity increased significantly. The solution thus obtained was poured into a vessel and dried at 48 ° C for 48 hours. During this process, macromolecules are stabilized into a polymer network, which is the backbone of the polymer hydrogel. At the end of the cross-linking process, the polymer hydrogel was washed with distilled water for 24 hours at room temperature. During this phase, the polymer hydrogel swelled, thereby eliminating impurities. In order to obtain the maximum degree of swelling and eliminate all impurities, at least 3 rinses with distilled water were carried out during the 24-hour washing step. At the end of this washing step, the polymer hydrogel was dried by phase inversion in acetone as a non-solvent, until a glassy, ​​white precipitate was obtained. Then, the pellet was placed in an oven at 45 ° C for about 3 hours to remove any trace residues of acetone.

[0074] Preparation of polymer hydrogel B: Polymer hydrogel B was obtained in the same way as polymer hydrogel A, except that the polymer is produced only from CMCNa and that the concentration

The CMCNa is 2% by weight based on the weight of distilled water.

[0075] Preparation of polymer hydrogel C: Polymer hydrogel C was prepared like polymer hydrogel B, except that the concentration of citric acid is 2% by weight based on the weight of CMCNa.

[0076] Preparation of polymer hydrogel D: Polymer hydrogel D was prepared as polymer hydrogel B, except that the concentration of citric acid is 0.5% by weight based on the weight of CMCNa.

Absorption measurements [0077] To test the absorption properties of the polymer hydrogels obtained as described above, they were subjected to absorption measurements in distilled water. Absorption measurements consist essentially of placing the dry sample obtained from the drying step in distilled water so that it swells until it reaches equilibrium.

[0078] The gel absorption properties are evaluated based on its swelling index (SR), defined according to the formula depicted above. In order to minimize the impact of experimental errors, each test was performed on three samples from each gel, and then the average value from the results of the three measurements was taken as the actual value.

[0079] Three dry samples were taken from each of the test gels, each having a different weight and size. After the masses were noted, the samples were swelled with a large amount of distilled water at room temperature. After equilibration after 24 hours, the samples were weighed again to determine the indicator

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Swelling.

Results [0080] Table 2 below lists some of the results obtained, in terms of swelling ratio, variation in reagent concentrations and cross-linking times (6 hours, 13 hours, 18 hours, 24 hours).

Table 2

<td>A sample</td><td>CMCNa</td><td>HEC</td><td>CA</td><td>sorbitol</td><td colspan="4">crosslinking time / swelling ratio</td>

<td> -</td><td> 75%</td><td> 25%</td><td> -</td><td> -</td><td>6 hours</td><td>13 hours</td><td>18 hours</td><td>24 hours</td>

<td>gi6</td><td colspan="2"> 2%</td><td> 1%</td><td> 4%</td><td>No.</td><td> 50</td><td> 30</td><td> 20</td>

<td>gi7</td><td colspan="2"> 4%</td><td> 1%</td><td> 4%</td><td>No.</td><td> 25</td><td> 10</td><td> 5</td>

<td colspan="9">nr = no crosslinking</td>

[0081] An increase in polymer concentration has been shown to have a negative effect on the swelling properties of the final product and it has also been shown that crosslinking time has a significant effect on the absorption properties.

[0082] Thus, further experiments were carried out maintaining a constant polymer concentration of 2% and varying the citric acid concentration. The results are shown in Table 3.

Table 3

<td>A sample</td><td>CMCNa</td><td>HEC</td><td>CA</td><td>sorbitol</td><td colspan="4">crosslinking time / swelling ratio</td>

<td> -</td><td> 75%</td><td> 25%</td><td> -</td><td> -</td><td>6 hours</td><td>13 hours</td><td>18 hours</td><td>24 hours</td>

<td>g21</td><td colspan="2"> 2%</td><td> 2%</td><td> 4%</td><td> 40</td><td> 25</td><td> 20</td><td> 10</td>

<td>g22</td><td colspan="2"> 2%</td><td> 1%</td><td> 4%</td><td>No.</td><td> 50</td><td> 30</td><td> 20</td>

<td>g23</td><td colspan="2"> 2%</td><td> 0,5 %</td><td> 4%</td><td>No.</td><td>No.</td><td> 50</td><td> 30</td>

<td colspan="9">nr = no crosslinking</td>

[0083] Table 3 shows that the sample with the best swelling ratio is the sample designated g22, which has a 1% citric acid (CA) concentration.

[0084] Thus, further experiments were carried out by completely removing HEC from the solution. This should give a more hydrophilic polymer hydrogel, thus leading to an increase in the swelling rate. Table 4 shows some of the results obtained.

Table 4

<td>A sample</td><td>CMCNa</td><td>HEC</td><td>CA</td><td>sorbitol</td><td colspan="4">crosslinking time / swelling ratio</td>

<td></td><td> 100%</td><td> 0%</td><td> -</td><td> -</td><td>6 hours</td><td>13 hours</td><td>18 hours</td><td>24 hours</td>

<td>g30</td><td colspan="2"> 2%</td><td> 2%</td><td> 4%</td><td>No.</td><td> 85</td><td> 55</td><td> 30</td>

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<td>g3i</td><td> 2%</td><td> 1%</td><td> 4%</td><td>No.</td><td> 100</td><td> 75</td><td> 40</td>

<td>G32</td><td> 2%</td><td> 0,5%</td><td> 4%</td><td>No.</td><td>No.</td><td> 70</td><td> 50</td>

<td colspan="8">nr = no crosslinking</td>

[0085] The highest swelling ratio is related to a crosslinking time of 13 hours and a citric acid concentration of 1%. It should also be noted that higher concentrations of citric acid, along with shorter crosslinking times, led to equally satisfactory swelling rates, although the reaction is very fast and more difficult to control.

[0086] Finally, the possibility of increasing the swelling ratio by forming pores in the material was evaluated, which could stimulate absorption. To this end, the sample g31, crosslinked for 12 hours, was swelled in distilled water for 24 hours, and then dried by phase inversion in acetone. A swelling index of 200 was obtained with this technique.

Example 3

Swelling of polymer hydrogel in simulated gastric fluid (SGF) and mixtures

SGF / water [0087] This example shows the evaluation of a superabsorbent polymer hydrogel referred to as polymer hydrogel B in Example 2 in in vitro swelling and disintegration experiments at various media at 37 ° C.

Swelling kinetics (100% SGF) at 37 ° C [0088] 100 mg of dried polymer hydrogel was immersed in simulated gastric fluid ("SGF") or a mixture of SGF and water, and allowed to swell until equilibrium was reached. SGF was prepared according to the procedures for USP test solutions. The swelling index in each fluid was determined at different time points. The results are set out in Tables 5 and 6.

Table 5. Swelling of dry polymer hydrogel B in 100% SGF at 37 ° C.

Weights were recorded at 15, 30, 60 and 90 min.

<td>Swelling time, min</td><td>Swelling indicator, g / g</td>

<td> 15</td><td> 15,4</td>

<td> 30</td><td> 15,6</td>

<td> 60</td><td> 16,2</td>

<td> 90</td><td> 15,1</td>

Table 6. Swelling of dry polymer hydrogel B in a mixture of SCTF and water (1: 8) at 37 ° C. Weights were recorded at 15, 30, 60 and 90 min.

<td>Swelling time, min</td><td>Swelling indicator, g / g</td>

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<td> 15</td><td> 78,8</td>

<td> 30</td><td> 84,6</td>

<td> 60</td><td> 88,6</td>

<td> 90</td><td> 79,3</td>

Disintegration kinetics (with the addition of SGF) at 37 ° C [0089] To simulate the effect of digestion on the hydrated polymer hydrogel, to the swollen polymer hydrogel described above (Table 6, SGF / water) after 60 minutes, 100% SGF was added slowly to cause the gel particles to break down. The swelling ratio was monitored as a function of cumulative volume of SGF added. The results are set out in Table 7.

Table 7

<td>SGF added (ml)</td><td>Swelling ratio (g / g)</td>

<td> 0</td><td> 88,6</td>

<td> 8</td><td> 23,1</td>

<td> 30</td><td> 22,6</td>

<td> 50</td><td> 23,1</td>

<td> 75</td><td> 17,1</td>

Swelling (in 1: 8 SGF / water), decay (in SGF) and re-swelling (in simulated intestinal fluid) kinetics [0090] Experiments were carried out by monitoring the swelling ratio over a full swelling cycle in 1: 8 SGF / water, decay in SGF and re-swelling (then degrading) in simulated intestinal fluid (SIF), all at 37 ° C. The experiments and results carried out are shown in Table 8 for re-swelling / degradation kinetics. PH values ​​are given when available.

Table 8. Swelling kinetics in SGF / water, degradation in SGF and re-swelling in SIF

<td rowspan="2">experiments ment #</td><td>60 min swelling in SGF / water</td><td>Disintegration in 70-ml SGF</td><td colspan="4">Re-swelling / degradation in SIF</td>

<td>Indicator swelling</td><td>Indicator swelling</td><td>30 minutes</td><td>45 min</td><td>90min</td><td>120 min</td>

<td> 1</td><td>95.5 pH 4.82</td><td>20.7 pH 1.76</td><td></td><td> 71,2</td><td> 87,3</td><td></td>

<td> 2</td><td> 95,3</td><td>19.5 pH 1.75</td><td> 72,6</td><td></td><td></td><td> 80,5</td>

Conclusions:

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[0091] This polymer hydrogel swells in simulated gastric fluids (pH 1.5) approximately 15 times and in a simulated gastric fluid / water mixture (pH 3) approximately 85 times. This indicates the presence of a pH / swelling correlation for the polymer hydrogel, where at pH below 3 (CMC pKa is ~ 3.1) the swelling of the polymer hydrogel will be limited due to the lack of the Donnan effect. The polymer may also swell at the increased pH of the simulated intestinal fluid.

Example 4

Effect of polymer hydrogel on dietary behavior in rats [0092] A series of experiments was performed to evaluate the effect of polymer hydrogel B in laboratory animals. One of the objectives of this study was to determine the effect of polymer B hydrogel on food consumption in rats. The study was performed in male Sprague Dawley rats by acute administration of pre-swollen polymer B hydrogel orally by gavage.

[0093] A total of 22 male Sprague-Dawley rats were randomized into two weight-matched groups prior to administration of the polymer hydrogel or carrier (polymer hydrogel B was pre-swollen in water, 100 mg in 10 ml water). Every 5 minutes for 40 hours after dosing, food and water intake (digital scale) as well as motor activity (breaking of subsequent beams) were monitored online. Data for food and water consumption were collected using MaNi FeedWin, an online computerized feeding system, using weighing cells. Two primary food intake (digital scale) and number of licks were monitored. All data were entered into Excel sheets and then subjected to appropriate statistical analyzes. Results are presented as mean ± SEM, unless otherwise stated. Statistical evaluation of data is performed using one-way or two-way analysis of variance (ANOVA).

Results and conclusions [0094] Figure 2, a graph of cumulative food intake versus time, is a typical test result. There was no difference between the groups at the basic level. Gavage administration of 8 ml polymer hydrogel B caused satiety in rats, which led to a significant decrease in food intake. As shown by the yellow line, this polymer hydrogel induced a significant decrease in food intake, which lasted for 2 hours. These data suggest that polymer hydrogel B may induce satiety in animals and lead to reduced food consumption.

Reference literature [0095] [1] AnbergenU, Opperman W, Polymer, 31, 1854 (1990) [2] Esposito F et al., J Appl Polym Sci, 60, 2403 (1996) [3] Denn WL, Ferguson GN, US 3,589,364, 1971 [4] Sachetto JP et al., ES 484964, 1978

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EP 2 532 685 B1 [5] Choi YS et al., Biomaterials, 20, 409 (1999) [6] International Patent Application WO 2006/070337 [7] Glusker JP. Acc. Chem. Res. 1980; 13: 345-352 [8] Wang CC et al., Applied Catalysis A: General 2005; 293: 171-179 [9] Coma V et al., Carbohydrate Polymers 2003; 51: 265-271 [10] Xie XS et al., Food Research International 2006; 39: 332-341 [11] Yang CQ et al., J. Appl. Polym. Sci. 1998; 70: 2711-2718 [12] Flory PJ, Principles of Polymer Chemistry, Ithaca, NY: Cornell University Press, 1953 [13] Sannino A. et al., Polymer 2005; 46: 4676 [14] Silverstein RM, et al. Spectrometric Identification of Organic Compounds, Wiley, 1991, pp. 120-130.

[15] Peppas NA, Polymer hydrogels in Medicine and Pharmacy; CRC Press, Boca Raton, Florida, 1987, p. 29 [16] Chen CC and Wang CC, J. Sol-Gel Sci. Technol. 2006, 40: 31.

[17] Xie XS and Liu Q, Starch 2004, 56: 364 [18] Khutoyanskaya OV et al., Macromol. Chem. Phys. 2005, 206: 1497 [0096] The following embodiments are disclosed:

1. A method of obtaining a polymer hydrogel, comprising the steps of:

(a) providing an aqueous solution containing a hydrophilic polymer and a polycarboxylic acid or anhydride thereof, wherein said polycarboxylic acid is C-C dicarboxylic acid, tricarboxylic acid or tetracarboxylic acid, and (b) maintaining the solution of step (a) under conditions suitable for polymer crosslinking hydrophilic polycarboxylic acid; thereby forming a polymer hydrogel.

2. The method of item 1, wherein the polymer hydrogel has a swelling index of at least about 10.

3. The method of item 2, wherein the polymer hydrogel has a swelling index of at least about 50.

4. The method of item 3, wherein the polymer hydrogel has a swelling index of at least about 100.

5. The method of item 1, wherein the hydrophilic polymer is selected from the group consisting of polyallyl alcohol, polyvinyl alcohol and polysaccharides.

6. The method of item 5, wherein the hydrophilic polymer is selected from the group consisting of substituted celluloses, substituted dextrans, substituted starches, glycosaminoglycans and polyuronic acids.

7. The method of item 6, wherein the hydrophilic polymer is selected from the group consisting of C₁-C₆alkyl cellulose, hydroxy-C-alkyl alkyl cellulose and hydroxy-C-C alkyl-C-alkyl alkyl cellulose.

8. The method of item 6, wherein the hydrophilic polymer is selected from the group consisting of

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Methylcellulose, ethylcellulose, n-propylcellulose, hydroxyethylcellulose, hydroxy-n-propylcellulose, hydroxy-n-butylcellulose, hydroxypropylmethylcellulose, ethyloxyethylcellulose, diethyl ethylcellulose, carboxymethylcellulose duct, carboxymethylcellulose, chondroitin sulfate, heparan sulfate, polyglucuronic acid, polymanuronic acid, polygalacturonic acid and polyarabinic acid.

9. The method of item 1, wherein the aqueous solution contains at least two hydrophilic polymers.

10. The method of item 9, wherein the aqueous solution comprises an ionic polymer and a nonionic polymer.

11. The method of item 10, wherein the ionic polymer is selected from the group consisting of alginate, dextran sulfate, carboxymethyl cellulose, hyaluronic acid, polyglucuronic acid, polymanuronic acid, polygalacturonic acid, polyarabinic acid; chondroitin sulfate, dextran phosphate, chitosan and dimethylaminodextran.

12. The method of item 10, wherein the non-ionic polymer is selected from the group consisting of polyallyl alcohol, polyvinyl alcohol, methyl cellulose, ethyl cellulose, n-propyl cellulose, hydroxyethyl cellulose, hydroxy-n-propyl cellulose, hydroxy-n-butyl cellulose, hydroxypropyl methyl cellulose.

13. The method of item 10, wherein the ionic polymer is carboxymethyl cellulose and the non-ionic polymer is hydroxyethyl cellulose.

14. The method of item 13, wherein the polycarboxylic acid is citric acid.

15. The method of item 14, wherein the polycarboxylic acid is selected from the group consisting of malonic acid, malic acid, maleic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, corkic acid, azelaic acid, sebacic acid, phthalic acid, acid o-phthalic acid, isophthalic acid, m-phthalic acid, terephthalic acid, citric acid, isocytic acid, aconitic acid, propane-1,2,3-tricarboxylic acid, pyromellitic acid, 2,3,3 ', 4'-biphenyl tetracarboxylic acid, 3,3', 4,4'-tetracarboxydiphenylether, 2,3 ', 3,4'-tetracarboxydiphenylether, 3,3', 4,4'- benzophenone tetracarboxylic, 2,3,6,7-tetracarboxynaphthalene, 1,4,5,7-tetracarboxynaphthalene, 1,4,5,6-tetracarboxynaphthalene, 3,3 ', 4,4'-tetracarboxydiphenylmethane, 2,2-bis (3.4 -dicarboxyphenyl) propane, butanetetracarboxylic acid and cyclopentanetetracarboxylic acid.

16. The method of item 1, wherein the polycarboxylic acid is citric acid.

17. The method of item 1, wherein the aqueous solution further comprises a molecular spacer.

18. The method of item 17, wherein the molecular spacer is selected from the group consisting of monosaccharides, disaccharides and sugar alcohols.

19. The method of item 18, wherein the molecular spacer is selected from the group consisting of sucrose, sorbitol, plant glycerol, mannitol, trehalose, lactose, maltose, erythritol, xylitol, lactitol, maltitol, arabitol, glycerol, isomalt and cellobiose.

twenty. Method according to item 1, wherein in step (b) the solution is kept at elevated temperature.

21. The method of item 20, wherein the solution is maintained at a temperature from about 60 ° C to about 120 ° C.

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22. The method of item 20, wherein in step (b) the water is partially or completely evaporated.

23. The method of item 1, further comprising the step (c) of washing the polymer hydrogel with water, a polar organic solvent or a combination thereof, resulting in the production of the washed polymer hydrogel.

24. The method of item 23, further comprising the step of (d) drying the washed polymer hydrogel.

25. The method of item 24, wherein step (d) comprises immersing the washed polymer hydrogel in a non-cellulose solvent.

26. The method of item 27, wherein step (d) further comprises drying the washed polymer hydrogel in an oven.

27. A method of obtaining a polymer hydrogel, comprising the steps of (a) providing an aqueous solution of precursor polymers, said precursor polymers consisting of carboxymethylcellulose and hydroxyethylcellulose, citric acid and a molecular spacer, and (b) heating of the aqueous solution, which causes water evaporation and cross-linking of carboxymethylcellulose cellulose citric acid, thereby forming a material in the form of a polymer hydrogel.

28. The method of item 27, wherein the molecular spacer is sorbitol.

29. The method of item 28, wherein the weight ratio of carboxymethyl cellulose to hydroxyethyl cellulose is about 3; the total weight ratio of carboxymethyl cellulose and hydroxyethyl cellulose to water in the solution of step (a) is at least about 2%, the weight ratio of sorbitol to water in the solution of step (a) is about 4% and the weight ratio of citric acid to precursor polymers is from about 1 % to about 5%.

thirty. A method for preparing a polymer hydrogel, comprising the steps of (a) providing an aqueous solution of carboxymethyl cellulose, citric acid and a molecular spacer, and (b) heating the aqueous solution, thereby causing water evaporation and crosslinking of the carboxymethyl cellulose to form a polymer hydrogel.

31. The method of item 30, wherein the molecular spacer is sorbitol.

32. The method of item 31, wherein the weight ratio of sorbitol to water in the solution of step (a) is about 4% and the weight ratio of citric acid to carboxymethyl cellulose is from about 1% to about 5%.

33. Polymer hydrogel obtained by the method of item 1.

34. Polymer hydrogel obtained by the method of item 27.

35. The polymer hydrogel according to any of items 33 or 34, wherein said polymer hydrogel has a swelling index of at least about 10.

36. Polymer hydrogel containing ionic polymer and polycarboxylic acid selected from C acids₄C₁₂-dicarboxylic, tricarboxylic and tetracarboxylic acids, wherein said

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Polycarboxylic acid cross-links the ionic polymer.

37. The polymer hydrogel of item 36, wherein the ionic polymer is carboxymethylcellulose and the polycarboxylic acid is citric acid.

38. The polymer hydrogel of item 37, wherein the weight ratio of citric acid to carboxymethyl cellulose is from about 1% to about 5%.

39. The polymer hydrogel of item 37, having a swelling index of at least 10.

40. The polymer hydrogel of item 39, having a swelling index of at least 50.

41. The polymer hydrogel of item 40, having a swelling index of at least 100.

42. Polymer hydrogel containing:

(a) an ionic polymer;

(b) a non-ionic polymer and (c) a polycarboxylic acid selected from C -C-dicarboxylic acids, tricarboxylic acids and tetracarboxylic acids, said polycarboxylic acid cross-linking the ionic polymer and the non-ionic polymer.

43. The polymer hydrogel of item 42, wherein the ionic polymer is carboxymethyl cellulose, the non-ionic polymer is hydroxyethyl cellulose and the polycarboxylic acid is citric acid.

44. The polymer hydrogel of item 43, wherein the weight ratio of carboxymethylcellulose to hydroxyethylcellulose is from about 1: 5 to 5: 1 and citric acid is present in an amount of 1% to 5% by weight based on the combined weight of carboxymethylcellulose and hydroxyethylcellulose.

45. The polymer hydrogel of item 44, wherein the weight ratio of carboxymethyl cellulose to hydroxyethyl cellulose is from about 2 to about 5.

46. The polymer hydrogel of item 45, wherein the weight ratio of carboxymethyl cellulose to hydroxyethyl cellulose is about 3.

47. The polymer hydrogel of item 42, having a swelling index of at least about 10.

48. The polymer hydrogel of item 47, having a swelling index of at least about 50.

49. The polymer hydrogel of item 48, having a swelling index of at least about 100.

50. A manufactured article containing a polymer hydrogel according to any of items 33, 36 or 42.

51. The object of manufacture according to item 50, wherein said object of manufacture is selected from the group consisting of devices and pharmaceuticals for eliminating water or aqueous solutions from the body, devices for the controlled release of water, nutrients or phytopharmaceuticals in agriculture, personal hygiene absorbent products and households, toys and devices adapted to change its size when in contact with water or aqueous solutions, biomedical devices and polymer films capable of slowly releasing fluids in ophthalmology.

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