METHOD TO PRODUCE HYDROGEN

专利摘要:
METHOD FOR PRODUCING HYDROGELS The present invention provides a method for producing a polymer hydrogel comprising the steps of: (1) preparing an aqueous solution of a water-soluble polysaccharide derivative and a polycarboxylic acid; (2) optionally subjecting the solution, for example, to agitation; (3) isolating a compound derived from polysaccharide / carboxylic acid with respect to the solution; and (4) heating the compound derived from polysaccharide / polycarboxylic acid under a temperature of at least about 80 ° C, thereby carrying out the crosslinking of the polysaccharide with polycarboxylic acid. The invention also provides polymer hydrogels produced by the methods of the invention.
公开号:BR112013031209B1
申请号:R112013031209-2
申请日:2012-06-07
公开日:2020-11-24
发明作者:Alessandro Sannino；Christian Demitri；Yishai Zohar；Barry Joseph Hand；Eyal S. Ron
申请人:Gelesis Llc；
IPC主号:

专利说明:

RELATED REQUESTS
[0001] The present application claims the fulfillment of provisional U.S. application No. 61 / 494,298, filed on June 7, 2011 and provisional U.S. application No. 61 / 542., 494, filed on October 3, 2011. All the teachings of the application (s) mentioned above are incorporated in this context by reference. Background of Invention
[0002] Polymer hydrogels are cross-linked hydrophilic polymers that are capable of absorbing and retaining large amounts of water. Some of these materials are capable of absorbing more than 1 kg of water per gram of dry polymer. The cross-links between the macromolecular chains form a network that guarantees the structural integrity of the liquid polymer system and prevents the complete solubilization of the polymer while allowing the retention of the aqueous phase within the molecular mesh. Polymer hydrogels that have a particularly large capacity to retain water are acidified as superabsorbent polymer hydrogels (SAPs). High absorption capacity under load (AUL) is also a common feature of SAPs that in general is not exhibited by polymer hydrogels that have a lower capacity to retain water. In addition, pressure, pH and other environmental conditions can also affect the water retention capacity of a polymeric hydrogel, such as a SAP. Applications of highly absorbent polymer hydrogels include absorbent cores in the field of personal hygiene absorbent products (Masuda, F., Superabsorbent Polymers, Ed. Japan Polymer Society, Kyoritsu Shuppann, (1987)) and as devices for the controlled release of water and nutrients in arid soils.
[0003] Carboxyalkyl cellulose materials and other carboxylalkyl polysaccharides are already known in the art. Carboxyalkyl cellulosic materials can be formed by treating a cellulosic material with a carboxyalkylating agent, such as a chloroalkaneic acid, usually monochloroacetic acid, and an alkali, such as sodium hydroxide in the presence of an alcohol. These carboxyalkyl celluloses are generally soluble in water. Various methods are known for making those carboxyalkyl celluloses insoluble in water insoluble in water. However, these methods are based on a stabilization mechanism that does not include the use of any crosslinking agent; the procedure involves selecting an appropriate range of temperatures and heat treatment time to transform the water-soluble cellulose derivative into a non-water-soluble form. The resulting stabilization appears to be mainly due to physical effects rather than chemical effects. Indeed, under certain pH values, generally from a pH of about 10 and higher, cellulose derivatives become again soluble in water. [Flory, J. P. Principles of Polymer Chemistry; Cornell University: Ithaca, NY, 1953].
[0004] Other methods for the insolubilization of carboxyalkyl cellulose materials include the heat treatment of carboxyalkyl cellulose in the presence of excess carboxyalkylation reagents and by-products of the carboxyalkylation reaction, to provide an insoluble carboxyalkyl cellulose in water that is endowed with water. absorption and retention properties and characteristics. In these cases, the use of accelerators and catalysts to promote stabilization (ie permanent crosslinking), coupled with a non-uniform distribution of the degree of crosslinking, results in an insoluble material that is endowed with a low swelling capacity (Anbergen U ., W. Opperman, Polymer, 31, 1854 (1990), Nijenhuis, K.te, Advances in Polymer Science, 130, (1997)).
[0005] Cellulose-based hydrogels can be obtained through stabilization, be it physical or chemical, of aqueous solutions of cellulosics. Additional natural and / or synthetic polymers have been combined with cellulose to obtain hydrogels composed with specific properties [Chen, H .; Fan, M. Novel thermally sensitive pH-dependent chitosan / hydrogel carboxymethylcellulose. J. Bioact. Compat. Polym. 2008, 23 (1), 38-48. Chang, C .; Lue, A .; Zhang, L. Effects of crosslinking methods on structure and properties of water-based cellulose / PVA. Macromol. Chem. Phys., 2008, 209 (12), 1266-1273] (A. Sannino, M. Madaghiele, F. Conversano, A.Maffezzoli, PA Netti, L. Ambrosio and L. Nicolais' "Cellulose-hyaluronic acid based microporous hydrogel cross-linked through divinyl sulfone (DVS) to modulate equilibrium sorption capacity and network stability ", Biomacromolecules, Vol. 5, No. 1 (2004) 92-96). Physical thermo-reversible gels are usually prepared from aqueous solutions of methylcellulose and / or hydroxypropyl methylcellulose (in a concentration of 1-10% by weight) [Sarkar, N. Thermal gelation properties of methyl and hydroxypropyl methylcellulose. J. Appl. Polym. Sci., 1979, 24 (4), 1073-1087]. The gelling mechanism involves hydrophobic associations between molecules that have the methoxy group. At low temperatures, the polymer chains in the solution are hydrated and simply tangled with each other. As the temperature increases, the macromolecules gradually lose their hydration water, until the polymer-hydrophobic polymer associations occur, thus forming the hydrogel network. The sol-gel transition temperature depends on the degree of substitution of cellulose ethers in the same way as on the addition of salts. A higher degree of substitution of cellulose derivatives provides them with a more hydrophobic character, thereby lowering the transition temperature under which hydrophobic associations occur. A similar effect is obtained by the addition of salts to the polymer solution, since the salts reduce the hydration level of the macromolecules by revoking the presence of water molecules around itself. Both the degree of substitution and the concentration of salt can be appropriately adjusted to obtain specific formulations that gel at 37 ° C and thus potentially useful for biomedical applications [Tate, M.C .; Shear, D.A .; Hoffman, S.W.; Stein, D.G .; LaPlaca, M.C. Biocompatibility of methylcelulose-based constructs designed for intracerebral gelation following experimental traumatic brain injury. Biomaterials, 2001, 22 (10), 1113-1123. Materials, 2009, 2, 370 Chen, C .; Tsai, C .; Chen, W .; Mi, F .; Liang, H .; Chen, S .; Sung, H. Novel living cell sheet harvest system composed of thermoreversible methylcelulose hydrogels. Biomacromolecules, 2006e7 (3), 736-743. Stabenfeldt, S.E .; Garcia, A.J .; LaPlaca, M.C. Thermoreversible laminin- functionalized hydrogel for neural tissue engineering. J. Biomed. Mater. Res., A 2006, 77 (4), 718-725]. Nevertheless, reversible, physically crosslinked hydrogels are available [Te Nijenhuis, K. On the nature of cross-links in thermoreversible gels. Polym. Bull., 2007, 58 (1), 27- 42], and thus must flow under certain conditions (for example, mechanical load) and can degrade in an uncontrollable manner. Because of these drawbacks, physical hydrogels that are based on methylcellulose and hydroxypropylmethylcellulose (HPMC) are not recommended for use in vivo.
[0006] Unlike physical hydrogels that exhibit flow properties, stable and rigid cellulose networks can be prepared by inducing the formation of chemical, irreversible cross-links between the cellulose chains. Either chemical agents or physical treatments (i.e., high energy radiation) can be used to form stable cellulose-based networks. The degree of crosslinking, defined as the number of crosslinking sites per unit volume of the polymer network, affects the diffuse mechanical and degrading properties of the hydrogel, in addition to the absorption thermodynamics, and can be controlled to a certain extent during synthesis . Specific chemical modifications of the cellulose backbone can be carried out before crosslinking, in order to obtain stable hydrogels with certain properties. For example, silylated HPMCs have been developed which are cross-linked through condensation reactions when the pH decreases in water solutions.
[0007] As another example, tyramine-modified sodium carboxymethylcellulose (NaCMC) was synthesized to obtain enzymatically gelable formulations for cell distribution [Ogushi, Y .; Sakai, S .; Kawakami, K. Synthesis of enzymatically-gellable carboxymethylcellulose for biomedical applications. J. Biosci. Bioeng., 2007, 104 (1), 30-33]. The photo-crosslinking of aqueous solutions of cellulose derivatives is likely to be achieved after the appropriate functionalization of the cellulose. However, the use of chemical crosslinker and / or functionalization provides a product that is not suitable for oral administration, especially in significant amounts and chronic use. Summary of the Invention
[0008] The present invention relates to the discovery that water-soluble crosslinking cellulose derivatives, such as carboxymethylcellulose, with low levels of a polycarboxylic acid, such as citric acid (3-carboxy-3-hydroxy-l acid, 5-pentanedioic), hereinafter also referred to as "CA") results in the formation of highly absorbent polymer hydrogels which are endowed with significant water-absorbing properties, mechanical stability and other advantageous characteristics.
[0009] The present invention furthermore relates to improved processes for producing polymer hydrogels, including superabsorbent polymer hydrogels, by crosslinking a soluble polysaccharide derivative, such as a carboxyalkyl polysaccharide, a hydroxyalkyl polysaccharide. or a combination thereof, with a polycarboxylic acid. The invention further relates to polymer hydrogels that are produced using these processes and polymer hydrogels that are endowed with advantageous properties.
[0010] According to one embodiment, the invention provides a method for producing a polymeric hydrogel comprising the steps of (1) preparing an aqueous solution of a water-soluble polysaccharide derivative and a polycarboxylic acid; (2) optionally subjecting the solution to movement, for example, by means of agitation; (3) isolating a polysaccharide derivative / polycarboxylic acid compound from the solution and (4) heating the polysaccharide derivative / polycarboxylic acid compound to a temperature of at least about 80 ° C, thereby providing crosslinking of the polysaccharide with polycarboxylic acid. According to one embodiment, the polysaccharide / polycarboxylic acid derivative compound is granulated before the conduction step (4). According to one embodiment, the polysaccharide / polycarboxylic acid derivative compound is heated in step (4) to a temperature of about 100 ° C or higher.
[0011] The aqueous solution of polysaccharide derivative and polycarboxylic acid is preferably prepared by adipating the polysaccharide derivative and polycarboxylic acid to water and moving, for example, by means of agitation, the resulting mixture for an amount of enough time to create a homogeneous solution.
[0012] The polysaccharide derivative is preferably present in the solution of step (1) in a concentration of at least about 0.25%, by weight, in relation to water, preferably at least about 0.4 % or 0.5%. According to one embodiment, the concentration of the polysaccharide derivative ranges from about 0.25% to about 25% or about 0.25% to about 30%, by weight, in relation to water, preferably between about from 0.4% to about 20% and more preferably from about 0.4% to about 12%. According to certain embodiments, the polysaccharide derivative is present in the solution under the concentration of at least about 4%, for example between about 4% to about 30%, about 4% to about 20%, about 4% to about 10% by weight, in relation to water. According to one embodiment, the polysaccharide derivative is present in the solution of step (1) under a concentration of about 6% by weight, relative to. Water. According to certain embodiments, the polysaccharide concentration is between about 4% to about 8%, between about 4.5% to about 7.5%, between about 5% to about 7%, or between about 5.5% to about 6.5% by weight, in relation to water. According to other embodiments, the concentration of polysaccharide is 0.25% to about 6%, about 0.4% to about 6% or about 0.5% to about 6% by weight, in relation to the water. According to one embodiment, the concentration of the polysaccharide derivative is between about 0.5% to about 1%, 1.5% or 2% by weight, relative to water. According to one embodiment, the solution includes undissolved polysaccharide derivative, that is, the amount of the polysaccharide derivative exceeds its solubility and a suspension or slurry is formed.
[0013] The polycarboxylic acid is preferably present in the solution of step (1) in a concentration of about 0.01% to about 5% or about 0.05 to about 5%, by weight, in relation to to the polysaccharide derivative. Preferably, the acidopolycarboxylic acid is present in a concentration of about 0.3% or less or 0.35% or less, by weight, relative to the polysaccharide derivative. According to one embodiment, the polycarboxylic acid is present in the solution of step (1) in a concentration of about 0.01% to about 0.35%, about 0.05% to about 0.35 %, about 0.1% to about 0.35%, 0.01% to about 0.3%, about 0.05% to about 0.3%, about 0.1% to about 0.3%, about 0.15% to about 0.35%, about 0.15% to about 0.3%, about 0.2% to about 0.35%, about 0 , 25% to about 0.35%, about 0.2% to about 0.3%, or about 0.25% to about 0.3%, by weight, relative to the polysaccharide derivative.
[0014] According to another embodiment, the polycarboxylic acid is present in the step (1) solution, preferably in a concentration of about 0.05 to about 5% (g / g) in relation to the monomeric units of the derivative of polysaccharide. Preferably, the polycarboxylic acid is present in a concentration of about 0.35% (g / g) or 0.3% or less, in relation to the monomer units of the polysaccharide derivative. According to one embodiment, the polycarboxylic acid is present in the solution of step (1) in a concentration of about 0.05% to about 0.3%, about 0.1% to about 0.3 %, 0.2% to about 0.3% or about 0.25% to about 0.3% (g / g) in relation to the monomer units of the polysaccharide derivative.
[0015] According to one embodiment, the aqueous solution consists essentially of the polysaccharide derivative, polycarboxylic acid and water. According to a preferred embodiment, the solution consists essentially of carboxymethylcellulose, citric acid and water.
[0016] According to another embodiment, the solution consists essentially of carboxymethylcellulose, hydroxyethylcellulose, citric acid and water. In accordance with yet another embodiment, the solution consists essentially of hydroxyethylcellulose, citric acid and water. The water is preferably purified water, as well as distilled or deionized water. According to this embodiment, the process is carried out in the substantial absence of any other agent that can affect the pH. According to embodiments, the solution is substantially free of a molecular spagger, as this term is used in WO 2009/021701, including saccharides, polyols and sugar alcohols, such as sorbitol.
[0017] According to another embodiment, the solution comprises a molecular scraper, preferably a polyhydroxylated compound, such as a saccharide, a polyol or a sugar alcohol. According to one embodiment, the molecular spacer is sorbitol. Preferably, a concentration of the molecular scraper ranges from 0% to about 20% by weight, relative to the weight of the water. According to one embodiment, the concentration of the molecular scraper is between about 0.1% to about 20%, by weight, in relation to the weight of the water. According to another embodiment, the concentration of the molecular scraper is between about 4% to about 20% or about 8% to 20%, by weight, in relation to the weight of the water. According to another embodiment, the concentration of the molecular scraper is less than 0.5%, by weight, relative to the weight of the water, for example, less than 0.4%, 0.3%, 0.2% or 0.1%. According to certain embodiments under lower concentrations of polycarboxylic acid, a fraction of the polysaccharide derivative is not cross-linked at the end of the process and can be washed out of the product hydrogel. In this case, the excess polysaccharide derivative serves as a molecular scraper. This can occur, for example, when the polysaccharide and carboxymethylcellulose derivative and the polycarboxylic acid and citric acid, under a concentration of citric acid of about 0.5 or less, about 0.35% or less or about 0, 3% or less, by weight, compared to carboxymethylcellulose.
[0018] The crosslinking reaction is preferably conducted in the substantial absence of a catalyst. According to a preferred embodiment, the cross-linking reaction is carried out in the substantial absence of sodium hypophosphite. Brief Summary of Drawings
[0019] Figure 1 illustrates the crosslinking mechanism of a cellulosic polymer by means of citric acid.
[0020] Figure 2 is a graph showing the theoretical uptake and collapse of an edible polymer hydrogel when it moves through the gastrointestinal tract.
[0021] Figure 3 is a trap of o (Pa) against lo-l (p) from a typical compression experiment as described in Example 5.
[0022] Figure 4 is a trap of -a (a-l / a2) -1 against 1 / a from a typical compression experiment as described in Example 5.
[0023] Figure 5 is a graph showing the degree of crosslinking of carboxymethylcellulose crosslinked by citric acid prepared with two different starting CMC concentrations as a function of the citric acid concentration.
[0024] Figure 6 is a graph showing the degree of crosslinking of carboxymethylcellulose crosslinked by citric acid prepared with different concentrations of starting CMC under 0.3% citric acid.
[0025] Figure 7 is a graph showing the level of media uptake in SGF / water 1: 8 of carboxymethylcellulose prepared with different concentrates of starting CMC under 0.3% citric acid.
[0026] Figure 8 shows the HRMAS NMR spectra of samples C and D of Example 6.
[0027] Figure 9 shows the HRMAS NMR spectra of samples A and B of Example 6.
[0028] Figure 10 shows the HRMAS NMR spectrum of samples C and D of Example 6 with T2 filtering.
[0029] Figure 11 shows the HRMAS NMR spectrum of samples A and B of Example 6 with T2 filtering.
[0030] Figure 12 is a schematic diagram that illustrates the utility apparatus for producing a polymeric hydrogel.
[0031] Figure 13 presents graphs showing the expected dependence of the elastic module, swelling, viscosity module and convenience as a function of the concentration of citric acid as described in Example 9. Detailed Description of the Invention
[0032] The present invention provides polymer hydrogels, methods of preparing polymer hydrogels, methods of using polymer hydrogels and articles of manufacture comprising polymer hydrogels. According to certain embodiments, the invention relates to the discovery that polysaccharide hydrogels, such as chemically cross-linked carboxymethylcellulose with citric acid, having advantageous properties can be prepared using a lower relative amount of polycarboxylic acid than was previously taught in technical.
According to one embodiment, the method of producing the polymer hydrogel comprises the steps of: (1) preparing an aqueous solution of the water-soluble polysaccharide derivative and the polycarboxylic acid; (2) optionally subjecting the solution to agitation; (3) isolating a polysaccharide / polycarboxylic acid derivative compound from a solution; and (4) heating the polysaccharide derivative / polycarboxylic acid compound to a temperature of at least about 80 ° C, or at least about 100 ° C, thereby carrying out the cross-linking of the polysaccharide with the polycarboxylic acid and forming the hydrogel polymeric. According to one embodiment, the polysaccharide / polycarboxylic acid derivative compound is granulated before performing step (4) and optionally sieved to obtain particles of a desired size range. According to one embodiment, the polymeric hydrogel product of step (4) is granulated, for example, by crushing or grinding, and optionally sieved.
[0034] According to a preferred embodiment, the method of the invention includes the steps of (1) preparing an aqueous solution of the water-soluble polysaccharide derivative and the polycarboxylic acid; (2) subjecting the solution to agitation; (3) heating the solution to remove water and produce a polysaccharide / polycarboxylic acid derivative compound; (3a) subjecting the polysaccharide / polycarboxylic acid derivative compound to granulation to produce compound particles; (4) heating the compound particles to a temperature of at least about 80 ° C, thereby cross-linking the polysaccharide derivative with the polycarboxylic acid and forming the polymer hydrogel; (5) washing the polymer hydrogel; (6) drying the polymeric hydrogel and, optionally, (7) granulating the polymeric hydrogel to produce hydrogel particles. The hydrogel particles produced in each or in the two steps (3a) and (7) can be sieved to provide a sample of particles within a specified size range.
The term "polysaccharide derivative / polycarboxylic acid compound" or "compound" as used in this context, refers to a substantially dry material comprising a mixture of the polysaccharide derivative and polycarboxylic acid. According to embodiments in which this compound is produced by means of evaporative drying of an aqueous solution of polysaccharide derivative and polycarboxylic acid, the compound is the substantially dry residue which remains after the removal of free or unbound water. The composition may refer to bound water, and may, for example, be up to 5, 10 or 20% water, by weight.
[0036] Without being limited by theory, it is believed that the preparation of the polymer hydrogels as exposed in this context results by means of covalent cross-linking of the polysaccharide derivative with the polycarboxylic acid. Figure 1 illustrates the cross-linking of a soluble cellulose derivative, such as carboxymethylcellulose, with citric acid. In this mechanism, the C1- carboxyl group of citric acid is activated by forming anhydride under neutral pH and under elevated temperature and in the presence of a very low amount of water, and in the absence of catalyst it reacts with a cellulosic hydroxyl group to form an ester . The carboxyl group C5 is then activated by the formation of anhydride and reacts with a hydroxyl group of another cellulosic polymer chain, thereby forming a covalent chemical crosslinking. The removal of water from the polysaccharide / polycarboxylic acid solution derivative prior to crosslinking and thus will be necessary in order to allow the anhydride forming / esterification reaction to take place. This is done in steps (3) and (4) described above. As illustrated in Example 6 below, failure to remove water in connection with a solution prior to cross-linking results in hydrogels with physical cross-links instead of chemical cross-links.
[0037] The water-soluble polysaccharide derivative is preferably a carboxyalkyl polysaccharide, a hydroxyalkyl polysaccharide or a combination thereof. According to certain embodiments, the water-soluble polysaccharide derivative is a cellulose derivative, such as a hydroxyalkyl cellulose, for example, hydroxyethyl cellulose, or a carboxyalkyl cellulose, including carboxymethyl cellulose, carboxyethyl cellulose, and the like, or else a mixture of them. Preferably the polysaccharide derivative is comprised of carboxymethylcellulose or a salt thereof, as well as the sodium salt. According to certain embodiments, the polysaccharide derivative essentially consists of carboxymethyl cellulose. According to other embodiments, the polysaccharide derivative is comprised of a combination of carboxymethyl cellulose with another polysaccharide derivative, as well as another cellulose derivative, including a hydroxyalkyl cellulose.
[0038] Methods for producing carboxyalkyl cellulose are known to those skilled in the art. Suitably, a cellulosic material such as wood pulp, cotton, cotton linters, and the like is provided. The cellulosic material may be in the form of fibers or fibers which have been fragmented into the particulate form. The cellulosic material is dispersed in an inert solvent, such as an alcohol and a carboxyalkylating agent, and added to the dispersion. Carboxyalkylating agents in general comprise a chloroalkanoic acid, such as monochloroacetic acid and sodium hydroxide. It is possible to carry out the carboxyalkylation of the starting polysaccharide in such a way that a solution of carboxyalkyl cellulose and water is formed directly. That is, the carboxyalkylation process can be carried out in an aqueous medium so that, when carboxyalkyl cellulose is formed, it is solubilized in water. In this way, no recovery step is necessary between the formation of the carboxyalkyl cellulose and the formation of the carboxyalkyl cellulose solution and water.
[0039] Carboxymethylcellulose or its salts preferably has an average degree of substitution between about 0.3 to about 1.5, more preferably between about 0.4 to about 1.2. The degree of substitution refers to the average number of the carboxyl groups that are present in the anhydrous glucose unit of the cellulosic material. Carboxymethylcelluloses that have a medium degree of substitution within the range of about 0.3 to about 1.5 are generally soluble in water. As used in this context, a carboxyalkyl cellulose, such as carboxymethylcellulose, is considered to be "water-soluble" when it dissolves in water to form a true solution.
[0040] Carboxymethyl cellulose is found commercially available in a wide range of molecular weights. Carboxymethyl cellulose, which has a relatively high molecular weight, is preferred for use in the present invention. In a general way, it is more convenient to express the molecular weight of a carboxymethylcellulose in terms of its viscosity in an aqueous solution of 1.0 weight percent. Carboxymethylcelluloses which are suitable for use in the present invention preferably have a viscosity in an aqueous solution of 1.0 weight percent between about 50 centipoise to about 10,000 centipoise, most preferably between about 500 centipoise up to about 10,000 centipoise, and even more preferably between about 1,000 centipoise up to about 2,800 centipoise. According to a preferred embodiment, carboxymethylcellulose has a weighted average molecular weight of 500 to 800 Kd.
[0041] Carboxyalkyl celluloses that are suitable are commercially available from numerous suppliers. As an example of a commercially available carboxyalkyl cellulose, mention may be made of carboxymethylcellulose, commercially available from Ashland / Aqualon Company under the trade name AQUALON ™, Blanose and BONDWELL ™ depending on the geographic region in which it is sold. The polycarboxylic acid is preferably an organic acid that contains two or more carboxyl groups (COOH) and from 2 to 9 carbon atoms in the chain or ring to which the carboxyl groups are linked; carboxyl groups are not included when determining the number of carbon atoms in the chain or ring (for example, 1,2,3 propane tricarboxylic acid will be considered to be a C3 polycarboxylic acid containing three carboxyl groups and 1,2,3 , 4 tetracarboxylic acid butane will be considered to be a C4 acid containing four carboxyl groups). Alternatively, a heteroatom such as an oxygen atom or a sulfur atom, can replace a methylene group in the polycarboxylic acid. More specifically, preferred polycarboxylic acids for use as crosslinking agents in the present invention include aliphatic and alicyclic acids that are either saturated or olefinically unsaturated, with at least three carboxyl groups per molecule or with two carboxyl groups per molecule and a bond double carbon-carbon present in alpha, beta for one or both carboxyl groups. Furthermore, it is preferred that the polycarboxylic acid be provided with a carboxyl group in an aliphatic or alicyclic polycarboxylic acid which is separated from a second carboxyl group by 2 or 3 carbon atoms. Without wishing to be bound by any theory, it is believed that a carboxyl group of polycarboxylic acid can preferably form a 5- or 6-membered cyclic anhydride ring with a neighboring carboxyl group in the polycarboxylic acid molecule. Where two carboxyl groups are separated by a carbon-carbon double bond or are both connected to the same ring, the two carboxyl groups must be in the cis configuration relative to each other to interact in this way.
[0042] Polycarboxylic acids that are suitable include citric acid (also known as 2-hydroxy -1,2,3 propane tricarboxylic acid), tartrate monosuccinic acid, oxidisuccinic acid, also known as 2,2'-oxybis (butanedioic acid) ), thiodisuccinic acid, disuccinic acid, maleic acid, citraconic acid, also known as methylmaleic acid, citric acid, itaconic acid, also known as methylene succinic acid, tricarboxylic acid, also known as 1,2,3 propane tricarboxylic acid, transaconic acid also known as trans-1-propene-1,2,3-tricarboxylic acid, 1,2,3,4-butanotetracarboxylic acid, all-cis-1,2,3,4-cyclopentanotetracarboxylic acid, melitic acid, also known as benzene-hexacarboxylic acid, and oxidisuccinic acid, also known as 2,2'-oxybis (butanedioic acid). A more detailed DESCRIPTION of tartrate monosuccinic acid, tartrate disuccinic acid, and its salts, can be found in Bushe et al., U.S. Pat. No. 4,663,071, which is incorporated in this context by referendum.
[0043] Preferably, the polycarboxylic acid is saturated and contains at least three carboxyl groups per molecule. A preferred polycarboxylic acid is citric acid. Other preferred acids include 1,2,3 propane tricarboxylic acid, and 1,2,3,4 butane tetracarboxylic acid. Citric acid is particularly preferred, as it provides hydrogels with high levels of wettability, absorbency and resilience that are safe and non-irritating to human tissue, and provides stable crosslinking ligands. In addition, citric acid is available in large quantities under relatively low nails, thereby making it commercially viable for use as the crosslinking agent.
[0044] The previously exposed list of specific polycarboxylic acids has only exemplary purposes, and is not intended to be fully inclusive. In an important aspect, the crosslinking agent must be able to react with at least two hydroxyl groups on the cellulose chains located close to two adjacent cellulose molecules. One skilled in the art will recognize that the C2-C9 aliphatic and alicyclic polycarboxylic acid crosslinking agents described above can be caused to react according to a variety of ways to produce the crosslinked polymer hydrogels in this context, such as the free acid form and their salts. Although the free acid form is preferred, all of these forms are understood to be included within the scope of the invention.
[0045] According to one embodiment, the polysaccharide derivative and polycarboxylic acid are the two materials of the food or pharmaceutical class. For example, carboxymethylcellulose and citric acid are both used as food additives and pharmaceutical excipients and are, therefore, available in forms that are suitable for these uses.
[0046] The term "carboxymethylcellulose" (CMC), as used in this context, refers to carboxymethylcellulose (ether of carboxymethyl cellulose) in the form of acid, in the form of a salt or dome a combination of the acid form of a salt. Preferred salt forms include sodium carboxymethylcellulose and potassium carboxymethylcellulose. According to particularly preferred embodiments, carboxymethylcellulose is present in the solution in the form of a sodium salt (NaCMC).
[0047] The aqueous solution of the cellulose derivative and the polycarboxylic acid can be formed at any temperature under which the cellulose derivative is soluble in water. Generally speaking, these temperatures will be within the range of about 10 ° C to about 100 ° C. Preferably, the solution is prepared substantially at room temperature, for example, between 20 ° C and 30 ° C.
[0048] It is preferred to have a solution pH between 5 and 8, more preferably between 6 and 7.
[0049] The polysaccharide / polycarboxylic acid derivative compound isolated from the aqueous solution is suitable for chemical crosslinking to form hydrogels of polymers that are endowed with improved absorption properties due to inter-chain entanglements. Without wishing to be bound by any theory, it is believed that solubilization provides tangles that produce a tighter network and a preferred distribution of carboxyl groups and hydroxyl groups between the polysaccharide derivative and the polycarboxylic acid. The greater tangle of the chains of the polysaccharide derivative thus results in a more uniform crosslinking in the heat treatment, which in turn results in a super absorbent polymeric hydrogel with a significantly improved capacity to capture means and significantly improved mechanical and rheological properties.
The polysaccharide derivative / polycarboxylic acid compound can be isolated from the solution by any method that avoids substantial deterioration in the absorption characteristics of the resulting polymer hydrogel. Examples of such methods include evaporative drying, freeze drying, precipitation, centrifugation, spray drying, critical point drying, and the like.
[0051] Preferably the polysaccharide / polycarboxylic acid derivative compound is isolated by evaporation drying at a temperature within the range of about 10 ° C to about 100 ° C, preferably between about 45 ° C to about 80 ° C. According to certain embodiments, drying is carried out at an initial temperature greater than 80 ° C, for example, from 80 ° C to 100 ° C, to substantially reduce the volume of the solution, then the temperature is reduced below 80 ° C to complete drying. For example, the solution can be dried initially under 85 ° C, and then the temperature can be reduced to 50 ° C to complete drying. Of course, higher temperatures may be employed if the solution is placed under pressure. Lower temperatures may be employed if the solution is placed under a vacuum. According to a preferred embodiment, evaporative drying is carried out under a temperature of about 70 ° C.
[0052] When the solution is subjected to drying by heating, the isolation step of the polysaccharide derivative / polycarboxylic acid compound and the crosslinking step of the compound can be combined in a single step, preferably with a temperature change . For example, the drying step can be carried out under a first temperature and then the temperature can be increased to a second, higher temperature, once the drying has been completed. Alternatively, the solution can be subjected to drying initially at a higher temperature, for example, between about 80 ° C to about 100 ° C and then, before drying is complete, the temperature can be reduced below 80 ° C to complete drying. The temperature can then be increased by more than 80 ° C to start crosslinking. According to one embodiment, drying is carried out at an initial temperature of about 85 ° C, the temperature is reduced to about 50 ° C before drying is completed and then, on completion of drying, the temperature is increased to about 120 ° C.
[0053] Other methods of isolating the compound include precipitation, wherein a precipitating agent (non-solvent), such as methanol, ethanol or acetone is added to the aqueous solution to precipitate the compound from the solution. The compound can then be recovered by means of filtration. If precipitation is used to recover the compound, the compound is optionally washed with water to remove the precipitating agent. Depending on the form in which the compost is recovered, it may be necessary or desirable to change its shape before the crosslinking step. For example, in the event that evaporative drying is employed, the compound can be recovered in the form of a film or sheet. This material in the form of a film or sheet can then be granulated, fragmented, ground or crushed into particles, flakes or granules composed before the crosslinking step. According to one embodiment, the particles of the compound are substantially spherical.
[0054] In the event of using evaporative drying, the compound can be recovered in the form of particles, flakes or granules before the crosslinking step.
[0055] According to one embodiment, the particles of the compound are substantially spherical. According to another embodiment, the particles are substantially irregular in shape.
The compound particles are preferably provided with a maximum sectional diameter or larger dimension within the range between about 5 micrometers to about 2,000 micrometers, preferably within the range between about 100 micrometers to about 1,000 micrometers , and preferably the average sectional diameter of the particle will be between about 300 micrometers to about 800 micrometers.
[0057] Without wishing to be limited by any theory, it is believed that the granulating stage of the compound before crosslinking provides a homogeneous distribution of the crosslinking sites in addition to increasing the evaporation of water before the crosslinking reaction starts. , resulting in a material with high conservation module (G ') and uniform chemical stabilization. This is due to the fact that the thermal gradient in finely granulated particles is more homogeneous than in the bulk structure, resulting in uniform crosslinking kinetics and efficiency. This also eliminates the problem of forming stiffer and weaker areas in the final product, related to higher and lower degrees of crosslinking, respectively. This effect can cause the additional problem of the formation of a residual tension in the mass of hydrogel corresponding to surfaces of different stiffness, which in turn can result in delaminating the material during the capture of the medium, in addition to the decrease in G 'that has already been mentioned. .
[0058] The polysaccharide derivative / polycarboxylic acid compound isolated and heat treated under an elevated temperature to crosslink the polysaccharide derivative. Any combination of temperature and time that achieves a desired degree of crosslinking, without undesirable damage to the polysaccharide derivative, is suitable for use in the present invention. Preferably, the compound is maintained at a temperature of 80 ° C or greater, for example, 100 ° C or greater. According to certain embodiments, the temperature is within the range of about 100 ° C to about 250 ° C, preferably between about 120 ° C to about 200 ° C, and most preferably between about 120 ° C to about 170 ° C. According to a particularly preferred embodiment, the compound is maintained at about 120 ° C. The higher the temperature that is used, the shorter the period of time required to achieve the desired degree of crosslinking. in general, the heat treatment process will extend over a period of time within the range of about 1 minute to about 600 minutes, preferably between about 1 minute to about 240 minutes, and with most preferably between about 5 minutes to about 120 minutes.
[0059] The heat treatment process causes the chains of the polysaccharide derivative to be cross-linked by means of the polycarboxylic acid and become insoluble in water. Desirably, the hot treatment process produces a polymeric hydrogel that is equipped with the ability to absorb aqueous liquids, in particular stomach fluids that are endowed with high salinity and low pH.
Any combination of time and temperature that produces a polymeric hydrogel that is provided with a desired absorbency of an aqueous medium of interest can be used in the present invention. The ability of a polymeric hydrogel to absorb an aqueous medium is indicated by means of its Free Swelling Capacity or its relationship of uptake of the medium to the medium of interest. The term "Free Swelling Capacity" refers to the amount, in grams, of a specified aqueous medium that 1 gram of the dry polymer hydrogel can absorb under 37 ° C in 60 minutes under no load. Preferably, the polymer hydrogel of the invention is provided with a Free Swelling Capacity of at least about 50 grams, more preferably of at least about 70 grams, and even more preferably of at least about 100 grams in a solution water containing about 11% simulated gastric fluid (SGF / water = 1: 8). The procedure for determining the Free Swelling Capacity is set out below in the examples.
The media capture ratio (MUR) is another measure of the polymer hydrogel's ability to absorb water or a specified aqueous solution under a particular temperature. The MUR is obtained by means of balanced swelling measurements (using, for example, a Sartorius micro scale with a sensitivity of 10-5g) and is calculated with the following formula MUR = Ws / Wd, where Ws is the weight of the polymeric hydrogel after immersion in distilled water or until the equilibrium of the specified medium is reached, 24 hours unless otherwise specified. Unless otherwise specified, MUR is determined at room temperature, or about 25 ° C. Wd is the weight of the polymeric hydrogel before immersion, the polymeric hydrogel being previously subjected to drying in order to remove any residual water.
[0062] According to a preferred embodiment, the method for preparing a polymeric hydrogel according to the invention comprises the steps of (a) providing an aqueous solution consisting essentially of: (a) a cellulose derivative, such as carboxymethylcellulose or a salt thereof, or hydroxyethylcellulose or a combination thereof, a polycarboxylic acid, such as citric acid, and water; (b) subjecting to agitation to aqueous solution; (c) evaporating free water from the solution to produce a dry polymer / carboxylic acid compound; (d) grinding the dry compound to form particles of compound; and (e) heating the compound particles to a temperature of at least about 80 ° C or at least about 100 ° C, thereby carrying out the cross-linking of the cellulose derivative and forming a polymeric hydrogel.
[0063] According to certain embodiments, the product of step (e) is milled to produce particles and the particles are optionally sieved. This is particularly desirable in cases where step (e) causes agglomeration of the particles produced in step (d). The particles can be sieved to produce a sample that comprises particles within a desired size range. The particle size can, for example, affect the amount of hydrogel that can fit within a capsule for an oral dosage form. The particle size also affects the rheological properties, such as the elastic module, and the swelling kinetics of the hydrogel. According to one embodiment, the hydrogel consists substantially of particles in the size range from 1 pm to 2000 pm, preferably from 10 pm to 2000 pm, and most preferably from 100 pm to 1000 pm. A hydrogel sample consists substantially of particles in a specified size range when the hydrogel is greater than 50% by mass particles in the specified size range. Preferably, the hydrogel is at least 60%, 70%, 80%, 90% or 95%, by mass particles in the specified size range.
[0064] The cellulose derivative is preferably present in the aqueous solution under a concentration of 4% or greater, preferably between about 4% to about 8%, 5% to about 7%, 5.5% to about 6.5% or about 6% by weight, based on the weight of the water used to prepare the solution. Preferably acidopolycarboxylic acid is present in the solution under a concentration of about 0.5% or less, more preferably, about 0.35% or less or about 0.3% or less, by weight, relative to the weight of the cellulose derivative. Preferably the cellulose and carboxymethylcellulose derivative under a concentration of about 5% to about 7%, more preferably about 5.5% to about 6.5% and more preferably about 6% by weight, in relative to water, and polycarboxylic acid is comprised of citric acid, under a concentration of about 0.15% to about 0.35%, preferably about 0.2% to about 0.35%, 0, 15% to about 0.3% or about 0.3%, by weight, with respect to carboxymethylcellulose.
[0065] The pH of the aqueous solution and preference is maintained between about 5 to about 9, between about 6 to 8, between about 6.5 to about 7.5 or about 5.5 to about 7.
[0066] According to one embodiment of the method of the INVENTION, the aqueous solution is subjected to drying to form the dry compound in the form of a sheet, which is ground to form the compound particles. Preferably, the compound particles are provided with a larger dimension between 10 pm and 1000 pm, more preferably between 100 pm and 1000 pm, with an average dimension between 300 pm and 600 pm. Compound particles are optionally sieved to provide particles in a desired size range. The compound particles are cross-linked under elevated temperature, preferably 80 ° C or higher or 100 ° C or higher. In the preferred embodiments, the resulting particles are cross-linked substantially homogeneously. It is believed that the crosslinking in a particle form creates a fairer external boundary for the particle that improves the elasticity of the particle and still maintains good water absorption capacity in the particle core.
[0067] The time required to crosslink the particles depends on the crosslinking temperature and the concentration of the polycarboxylic acid. For example, under a 0.3% citric acid concentration (w / w vs. carboxymethylcellulose) it takes about 2-10 minutes under 180 ° C or 2-5 hours under 120 ° C to crosslink the carboxymethylcellulose. Under 80 ° C it takes 4 hours with a concentration of citric acid of 2.5% (w / w) or 20 hours with a concentration of citric acid situated at 1% (w / w).
[0068] The steps (b) - (e) of the process can occur in a single operation. The solution of step (a) can be, for example, subjected to spray drying. That is, the solution can be sprayed in a chamber to form droplets that are subjected to drying and cross-linked by means of a stream of hot air. In this embodiment, the solution is fragmented before the formation of the compound is carried out.
[0069] According to one embodiment, the compound is isolated from the aqueous solution by substantially drying the aqueous solution, for example, by heating, as described above.
[0070] In preferred embodiments, the aqueous solution is placed on a tray, as well as a stainless steel, polypropylene or Teflon tray, before the compound is isolated. This increases the surface area of the solution, facilitating the evaporation of water. According to one embodiment, the solution is maintained at an elevated temperature until it begins to form a solid or semi-solid, for example, with the formation of a gel. The gel is then optionally inverted in the tray, and heating is continued until substantial drying. Preferably heating can be conducted in a suitable oven or vacuum oven.
[0071] The compound is granulated, for example, by means of crushing, grinding or fragmenting, to form particles of compound and the particles are kept under high temperature, thus carrying out the cross-linking and producing particles of polymeric hydrogel. Preferably, the crosslinking step (e) is carried out at a temperature of about 80 ° C or higher, or about 100 ° C or higher, more preferably between about 100 ° C to about 160 ° C, and further more preferably, about 115 ° C to about 125 ° C, or about 120 ° C.
[0072] According to preferred embodiments, the compound is substantially dried and ground to form particles of a suitable size. The ground particles are placed in a tray, as well as a stainless steel tray or placed in a rotary oven. This increases the surface area, preferably facilitating the surface crosslinking reaction. According to one embodiment, the particles are maintained at an elevated temperature according to step (e) until the cross-linking is completed. Preferably heating is carried out in a suitable oven or vacuum oven.
[0073] The milled particles are optionally dimensioned, for example, by sieving, before or after the cross-linking step, to obtain particles within the desired size range.
[0074] The methods of the invention may further include the steps of purifying the polymeric hydrogel, for example, by washing the polymeric hydrogel in a polar solvent, such as water, a polar organic solvent, for example, an alcohol, such as methanol or ethanol, or a combination thereof. The hydrogelpolymeric dipped in the polar solvent swells and releases impurities, such as by-products or unreacted citric acid. Water is preferred as the polar solvent, with even more preference being distilled and / or deionized water. The volume of water used in this step is preferably at least the volume for the gel to reach the maximum media uptake degree, or at least approximately 2- to 20-fold greater than the initial volume of the bloated gel itself. The washing step of the polymeric hydrogel can be repeated more than once, optionally changing the polar solvent used. For example, the polymer hydrogel can be washed with methanol or ethanol followed by distilled water, with these two steps being optionally repeated one or more times.
[0075] The polymeric hydrogel can still be dried to remove most or substantially all of the water.
[0076] According to one embodiment, the drying step is carried out by immersing the fully hydrolyzed polymer hydrogel in a non-cellulose solvent, a process known as phase inversion. As this term is used in this context, a "cellulose non-solvent" is a liquid compound that does not dissolve the cellulose derivative and does not swell the hydrogelpolymeric, but is preferably miscible with water. Non-cellulose solvents that are suitable include, for example, acetone, methanol, ethanol, isopropanol and toluene. The drying of the polymeric hydrogel by means of phase inversion provides a final micro-porous structure that improves the absorption properties of the polymeric hydrogel by capillarity. In addition, if the porosity is interconnected or open, that is, the micro pores communicate with each other, the absorption / desorption kinetics of the gel will also be improved. When a gel is completely or partially swollen and dipped into a non-solvent, the gel undergoes a phase inversion with the expulsion of water, until the gel precipitates as a vitreous solid such as white colored particles. Several rinses in the non-solvent may be necessary in order to obtain the dry gel in a short period of time. For example, when the polymer hydrogel is swollen and dipped in acetone as the non-solvent, a water / acetone mixture is formed which increases the water content when the polymer hydrogel dries; under a certain concentration of acetone / water, for example, about 55% in acetone, water is no longer able to leave the polymer hydrogel, and therefore new acetone has to be added to the polymer hydrogel to continue with the drying process . Increasing the acetone / water ratio during drying increases the drying rate. The pore dimensions are affected by the drying speed of a drying process and the initial dimensions of the particles of the polymer hydrogel: the larger particles and a faster process tend to increase the pore dimensions; pore dimensions in the micro scale range are preferred, since the pores in this size range exhibit a strong capillary effect, resulting in a higher water absorption and retention capacity.
[0077] According to other embodiments, the polymeric hydrogel is not subjected to phase inversion drying. In these embodiments, the polymeric hydrogel is subjected to drying by another process, such as air drying, vacuum drying, freeze drying or drying under high temperature, for example, in an oven or by vacuum. These drying methods can be used alone or in combination. According to certain embodiments, these methods are used in combination with the non-solvent drying step described above. For example, the polymeric hydrogel can be subjected to drying in a non-solvent, followed by air drying, freeze drying, oven drying, or a combination of these to eliminate any residual non-solvent traces. Oven drying can be carried out at a temperature of, for example, approximately 30-45 ° C until the water or residual solvent is completely removed. The polymeric hydrogel washed and subjected to drying can then be used as is, or it can be ground to produce particles of polymeric hydrogel of a desired size.
[0078] According to preferred embodiments, the cellulose and carboxymethylcellulose derivative, more preferably carboxymethylcellulose sodium salt. According to another embodiment, the cellulose derivative and hydroxyethylcellulose.
[0079] According to another embodiment, the cellulose derivative is comprised of a combination of carboxymethylcellulose and hydroxyethylcellulose. The weight ratio of carboxymethylcellulose to hydroxyethylcellulose can be between about 1:10 to about 10: 1. Preferably, the weight ratio of carboxymethylcellulose to hydroxyethylcellulose is about 1 or less, more preferably between about 1: 5 to about 1: 2, more preferably about 1: 3.
[0080] A particularly preferred embodiment of the method of the INVENTION comprises the following steps: step 1, the sodium salt of carboxymethylcellulose and the citric acid are dissolved in purified water to produce a solution consisting essentially of about 5% to about 7 %, preferably about 6%, of carboxymethylcellulose, by weight, relative to the weight of water, and citric acid in an amount of about 0.15% to about 0.35% or about 0.15% to about 0.30% by weight, based on the weight of carboxymethylcellulose; step 2, keep the solution at a temperature between about 40 ° C to about 70 ° C or 40 ° C to about 80 ° C, preferably about 70 ° C, to evaporate the water and form a compound of carboxymethylcellulose / substantially dry citric acid; step 3, crushing the compound to form particles of compound; and step 4, keeping the compound particles at a temperature between about 80 ° C to about 150 ° C or about 100 ° C to about 150 ° C, preferably about 120 ° C, for a period of sufficient time to achieve the desired degree of crosslinking and form the polymeric hydrogel. The method may also optionally include step 5, washing the polymeric hydrogel with purified water; and step 6, drying the purified polymer hydrogel under elevated temperature.
[0081] The present invention also provides polymer hydrogels that can be prepared using the methods of the invention. Such polymer hydrogels comprise cross-linked carboxymethylcellulose, hydroxyethylcellulose or a combination of carboxymethylcellulose and hydroxyethylcellulose. According to a preferred embodiment, the polymer hydrogel consists essentially of carboxymethylcellulose cross-linked by citric acid.
[0082] According to another embodiment, the present invention provides polymer hydrogels, including superabsorbent polymer hydrogels, which can be prepared using the methods of the invention. The invention includes articles of manufacture, pharmaceutical compositions, foods, food products and medicinal devices, products for agriculture and horticulture, personal care products that comprise these polymer hydrogels. The invention further includes methods of using the polymer hydrogels of the invention for preparing food and treating obesity.
[0083] According to certain embodiments, the polymer hydrogels produced by the methods described in this context form xerogels that have a higher density than the carboxymethylcellulose xerogels that are produced using other methods, while maintaining significant absorption properties.
[0084] The methods of the invention produce polymer hydrogels that combine both physical and chemical cross-linking and which are endowed with mechanical properties, long-term stability in dry and moist form and good retention and biocompatibility. [Demitri et al., Journal of Applied Polymer Science, Vol. 110, 2453-2460 (2008)]. The polymer hydrogels of the invention exhibit good media capture properties in the free state, high bulk density, and cost effective production. In addition, polymer hydrogels are equipped with fast media capture kinetics in corporeal fluids.
[0085] According to preferred embodiments, the polymer hydrogels of the invention are provided with a means of capturing media in distilled water of at least about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90 or about 100. For example, according to certain embodiments, the polymer hydrogels of the invention are equipped with a media capture ratio in distilled water between about 20 to about from 1000, between about 20 to about 750, between about 20 to about 500, between about 20 to about 250, between about 20 to about 100. According to a certain embodiment, the polymer hydrogels of the invention are equipped with a means of capturing media in distilled water between about 20, 30, 40, 50, 60, 70, 80, 90 or 100 to about 120, 150, 200, 300, 400, 500, 600 , 700, 800, 900, 1000 or greater, or within any range limited by any of these inferred limits values and any of these upper limits.
[0086] According to certain embodiments, the polymer hydrogels of the invention can absorb an amount of one or more bodily fluids, such as blood, blood plasma, urine, intestinal fluid and gastric fluid, which is at least 10, 20 , 30, 40, 50, 60, 70, 80, 90, or 100 times its dry weight. The ability of the polymeric hydrogel to absorb bodily fluids can be tested using conventional means, which include testing with samples of bodily fluids obtained from one or more individuals or with simulated bodily fluids, such as urine or simulated gastric fluid. According to certain preferred embodiments, polymer hydrogels can absorb significant amounts of a fluid prepared by combining a volume of simulated gastric fluid (SGF) with high volumes of water. The SGF can be prepared using USP Test Solutions procedures that are known in the art. According to some embodiments, the polymer hydrogels of the invention have a media capture ratio of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 150 in SGF / water (1 : 8). According to some embodiments, the polymer hydrogels of the invention have a media capture ratio of 10 to 300, from 20 to 250, from 30 to 200, from 50 to 180 or from 50 up to 150 in SGF / water (1: 8). According to preferred embodiments, the hydrogel is equipped with a media capture ratio of 50 or greater in SGF / water (1: 8).
[0087] The polymer hydrogels of the invention include crosslinked polymers which are provided with variable hydration extensions. For example, polymer hydrogels can be provided in a hydration state ranging from a substantially dry or anhydrous state, such as a xerogel or a state in which from about 0% to about 5% or up to about 10% of the polymeric hydrogel, by weight, and water or an aqueous fluid, for states comprising a substantial amount of water or aqueous fluid, including up to a state in which the polymeric hydrogel has absorbed a maximum amount of water or an aqueous fluid.
[0088] According to one embodiment, the polymer hydrogels of the invention are preferably crystalline materials, but amorphous or vitreous when in a substantially dry or xerogel form. According to one embodiment, the polymer hydrogels of the invention have a compacted density greater than about 0.5 g / cm3. According to preferred embodiments, the compacted density is between about 0.55 to about 0.8 g / ml when determined as described in US Pharmacopeia <616>, included in this context by reference. According to a preferred embodiment, the compacted density is about 0.6 g / cm 3 or greater, for example, between about 0.6 g / cm 3 to about 0.8 g / cm 3.
A preferred hydrogel of the invention consists of carboxymethylcellulose cross-linked with citric acid. Preferably the hydrogel has a water content of less than about 10% by weight, a compact density of at least about 0.6 g / ml, an elastic module of at least about 350 Pa, or a ratio of media capture in SGF / water 1: 8 of at least about 50. Most preferably the polymer hydrogel is provided with each of the following properties. According to a particularly preferred embodiment, the polymer hydrogel consists of particles that are substantially in the size range from 100 pm to 1000 pm. According to one embodiment, at least about 95% of the hydrogel, by weight, consists of particles that are in the range of 100 pm to 1000 pm.
[0090] The degree of crosslinking (dc) of a crosslinked polymer is defined as the density in number of juncids that join the polymer chains in a permanent structure. According to this definition the degree of crosslinking is given by:
(eq "1) where o / 2 is the total number of chemical crosslinks and V is the total volume of the polymer.
[0091] The concentration of the elastically effective chain elements, Px = ^ and / ^> corresponds to a concentration of all chemically cross-linked polymer segments (v / V);
where V is the specific volume of the polymer, Mc is the average molecular weight between the crosslinks, and is understood by the moles of the elastically effective chains per unit volume of the network.
[0092] The degree of crosslinking can be assessed by means of uniaxial compression mediums in the swollen hydrogel. In effect, a swollen hydrogel, when subjected to a uniaxial compression load, exhibits a deformation behavior that depends on the elastic response of the deformed chains, on the interaction between fixed loads and on the change of free energy associated with the release of a certain amount of absorbed water. By making the simplifying assumption that no change in volume occurs when compressing the hydrogelink, Flory derived a relationship between the compressive stress and the compression deformation for the case of a swollen crosslinked polymer, based on the assumption of Gaussian statistics and deformation in order to obtain:
where <J = F / A0 is the uniaxial compression stress (where F is the drag force and the initial cross-sectional area of the swollen sample), OC = L / Li with Lr is the effective thickness of the compressed swollen sample and the thickness initial of the swollen sample, R, the universal gas constant, T, the absolute temperature, $ 2sr the volume fraction of polymer in the swollen state under compression which is assumed to be equal to the value for the non-deformed swollen gel, y / o > moles of elastically effective chains per cm3 of dry polymer network and G and the shear module of the swollen network. Example 5 describes the determination of the degree of crosslinking of the citric acid crosslinked CMC samples prepared using the same CMC concentrations and different amounts of citric acid. According to certain embodiments in which a lower concentration of citric acid is used, for example, less than 0.5% or 0.4% citric acid, by weight, relative to carboxymethylcellulose, a fraction of carboxymethylcellulose is not present. involved in the formation of the reticulated network and can be removed by washing from the hydrogel product.
[0093] The hydrogels of the invention are preferably equipped with a simple citric acid to carboxymethyl cellulose bonded and cross-linked from 0.05% to 1% w / w and more preferably a ratio of 0.1% to 0.4 % w / w. Even more preferably, the ratio of citric acid to carboxymethylcellulose is linked in a simple and cross-linked manner and from 0.225% to 0.375% w / w.
[0094] The hydrogels of the invention are preferably endowed with a degree of crosslinking between about 2.5 x 10-5 mol / cm3 to about 5 x 10-5 mol / cm3, more preferably between about 4 x 10-5 mol / cm3 to about 5 x 10-5 mol / cm3.
[0095] The polymer hydrogels of the invention can be used in methods for treating obesity, reducing food or calorie intake or achieving or maintaining satiety. The hydrogels of the invention can also be used to improve glycemic control, to treat or prevent diabetes or to assist in weight management. The methods comprise the step of administering an effective amount of a polymeric hydrogel of the invention to the stomach of a subject, preferably by means of oral administration, for example, when making the subject, as much as a mammal, including a human being, swallow the polymeric hydrogel, optionally in combination with the ingestion of a volume of water. Upon contact with water or aqueous content in the stomach, the polymeric hydrogel is swollen and occupies the stomach volume, decreasing the stomach's capacity for food and / or the rate of food absorption. When ingested in combination with food, the polymeric hydrogel increases the volume of the bolus without increasing the calorie content of the food. The polymeric hydrogel can be ingested by the subject prior to meal or in combination with food, for example, as a mixture of the polymeric hydrogel with food.
[0096] The polymeric hydrogel can be ingested alone, in a mixture with liquid or dry food or as a component of an edible food or matrix, in a dry, partially swollen or fully swollen state, but preferably it is ingested in a state of hydration which is significantly less than its fluid capacity, most preferably the polymeric hydrogel is ingested in a substantially anhydrous state, i.e., about 10% or less of water, by weight. The polymeric hydrogel can be formulated for oral administration in a capsule, sachet or tablet or suspension. When administered in a substantially anhydrous form, the volume of the stomach occupied by the polymeric hydrogel will be significantly greater than the volume of the polymeric hydrogel ingested by the subject. The polymer hydrogels of the invention also occupy volume and / or exert pressure on the wall of the small intestine by moving from within the stomach into the small intestine and capturing media. Preferably, the polymeric hydrogel will remain swollen in the small intestine for a period of time sufficient to inhibit food intake by the subject, before drinking sufficiently to provide excretion from the body. The time sufficient to inhibit the subject's ingestion of food will generally generate the time required for the subject to eat and for the ingested food to pass through the small intestine; such contraction can occur, for example, through degradation through loss of cross-links, release of fluid, and decrease in volume sufficiently for excretion from the body. A schematic illustration of the theoretical behavior of this hydrogel when it passes through the gastrointestinal tract is shown in Figure 2.
[0097] The polymer hydrogels of the invention preferably exhibit pH-dependent media uptake, with greater media uptake observed at a higher pH than at a lower pH. In this way, this polymer will not swell significantly in the stomach unless food and / or water are present to raise the pH of the contents of the stomach and pass into the small intestine. When ingested with food, the polymeric hydrogel preferably swells initially in the stomach, contracts when the stomach is emptied of food and the pH drops and then moves from the stomach to the small intestine. In the higher pH environment of the small intestine the polymer hydrogel will swell again, occupying volume in the small intestine and / or exerting pressure on the wall of the small intestine.
[0098] The polymeric hydrogel can optionally be administered in combination with a pH modifying agent, which is an agent that changes the home-environment pH of the polymeric hydrogel, thereby modifying its ability to absorb fluids. For example, for polymer hydrogels that comprise an anionic polymer, agents that increase the pH of the microenvironment can increase the wettability of the polymeric hydrogel. The pH modifying agents that are suitable for use with the polymer hydrogels of the present invention include buffering agents, H2 blockers, proton pump inhibitors, antacids, proteins, nutritional mixtures, and combinations thereof. Buffering agents and antacids that are suitable include ammonium bicarbonate, sodium bicarbonate, calcium carbonate, calcium hydroxide, aluminum hydroxide, aluminum carbonate, magnesium carbonate, magnesium hydroxide, potassium carbonate, potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide and combinations thereof. H2 blockers that are suitable include cimetidine, ranitidine, famotidine, nizatidine and their combinations. Proton pump inhibitors that are suitable include omeprazole, lansoprazole, esorneprazole, pantoprazole, abeprazole, and combinations thereof.
[0099] The polymeric hydrogel of the invention can be administered to the subject in the form of a tablet or capsule or other formulation that is suitable for oral administration. The tablet or capsule may further include one or more additional agents, such as a pH modifying agent, and / or a pharmaceutically acceptable carrier or excipient. The polymeric hydrogel can also be administered in the form of a component of a food or drink, as described in WO 2010/059725, included in this context by reference in its entirety.
[00100] According to one embodiment, the present invention provides a pharmaceutical composition comprising a polymeric hydrogel of the present invention. The pharmaceutical composition can comprise the polymeric hydrogel in the form of an active agent, optionally in combination with a pharmaceutically acceptable excipient or carrier. For example, the pharmaceutical composition may be intended for oral administration to treat obesity, provide increased satiety, improve glycemic control, treat or prevent diabetes or assist with weight management. According to another embodiment, the pharmaceutical composition comprises the polymeric hydrogel in combination with another active agent. The polymeric hydrogel can serve as a matrix, for example, for the sustained release of the active agent.
[00101] The scope of the present invention includes the use of polymer hydrogels capable of being obtained by means of the invention method in the form of an absorbent material in products that are capable of absorbing water and / or aqueous solupids and / or that are capable of to capture media when brought into contact with water and / or an aqueous solution. The polymer hydrogels of the present invention can be used as absorbent materials in the following fields, which are provided as non-limiting examples: dietary supplements (for example, as bulking agents in dietary supplements for low-calorie diets capable of imparting a sensation of lasting satiety being retained within the stomach for a limited period of time, or as supplements of low molecular weight compounds, such as minerals or vitamins, to be included in drinks in a dry or bloated form); in agricultural products, for example, in devices for controlled release of water and / or nutrients and / or phytochemicals, particularly for cultivation in arid, desert areas and in all cases where it is not possible to carry out frequent irrigation; such products, mixed in a dry form with the soil in the areas surrounding the roots of the plants, absorb water during irrigation and are able to maintain it, releasing it slowly in certain cases, together with nutrients and phytochemicals useful for cultivation; in personal hygiene and household absorbent products, such as, for example, the absorbent core in diapers, feminine and similar pads; on toys and devices, such as, for example, on products that are capable of significantly changing their size once they are brought into contact with water or an aqueous solution; in the biomedical field, for example, in biomedical and / or medical devices, such as absorbent curatives for the treatment of highly exudative wounds, such as ulcers and / or burns, or in slow release polymeric films suitable for slowly releasing fluids adapted for the use in ophthalmology; in the field of corporeal fluid management, for example, to control the amount of fluids in an organism, for example in products capable of promoting the elimination of fluids from the body, such as, for example, in the case of edema, CHF ( congestive heart failure), dialysis; and in household cleaning products.
[00102] The products mentioned above, which contain a polymeric hydrogel of the present invention as the absorbent material, also fall within the scope of the invention.
[00103] The invention further includes the use of any of the polymer hydrogels of the invention in medicine. This use includes the use of a polymeric hydrogel in the preparation of a drug for the treatment of obesity or any medical disorder or illness in which calorie restriction has a therapeutic, palliative or prophylactic benefit. Example 1: Preparation of Acid Reticulated Carboxymethyl Cellulose CitricoMaterialsNaCMC E&V, catalog number 72537 - 7H3SXFA Sigma Citric Acid, catalog number 43309268Purified water Chimica D'Agostino (Bari - Italy) Method
[00104] Purified water (10 kg) was added to a 10 liter Hobart mixer and stirred at 30 rpm. Citric acid (1.8 g) was added to water and dissolved. NaCMC (600 g) was then added to the solution and the resulting mixture was subjected to stirring at room temperature under 60 rpm for 90 minutes and then under 30 rpm for 15 hours. The resulting solution was added to 10 stainless steel support trays (1.030 kg of solution per tray). The trays were placed in a Salvis Thermocenter TC240 oven at 45 ° C for 24 hours. The trays were removed from the oven, the contents were inverted and the trays were placed back in the oven and kept under 45 ° C for 30 hours. After desiccation, the material was crushed by means of a cutting mill (Retsch cutting mill) equipped with a 1 mm sieve. The granulated material was then spread on the trays and cross-linked in the Salvis Thermocenter TC240 oven under 120 ° C for 4 hours. The crosslinked polymer hydrogel thus obtained was washed with purified water for 24 hours to remove unreacted reagents (by changing the washing solution 4 times). The washing stage allows the capture of media from the crosslinked polymer by increasing the relaxation of the network thereby increasing the media capture capacity of the final material obtained after another desiccation step. After washing the material was placed in the trays and inside the oven under 45 ° C to dry. The dry material was then ground and sieved to a particle size from 0.1 mm to 1 mm. Media Capture Relationship (MUR)
[00105] For this example, measurements of capture of balanced media for all samples were performed in a mixture of simulated gastric fluid (SGF) and water (1: 8 v / v) using a Sartorius microbalance (sensitivity of 10 -5). The media capture ratio was measured by weighing samples (sieved between 400 pm and 600 pm) before and after their immersion in SGF / water (1: 8)
[00106] The results indicated that the sample's media capture ratio (MUR) increases with time and reaches its maximum value after 30 minutes. The list of media capture for each sample tested is shown in Table 1 below.
Table 1 Discussion
[00107] The data show dependence on the absorption capacity with a time of up to 30 min. No relevant differences were observed between the samples at 1 h and 2 h. This is a typical behavior exhibited by superabsorbent hydrogels and is due to the Donnan Effect. The presence of fixed charges on the polymeric backbone, typical of polyelectrolyte gels, leads to significant rapid swelling of the polymer in water. This behavior is due to a Donnan balance established between gel and the external solution, whose ionic intensity strongly affects the degree of swelling. In this case, the polymeric hydrogel can be considered as a semipermeable membrane that allows water to enter the end of diluting the fixed charges attached to the backbones of the polymers. Since the loads are fixed and they cannot move in the opposite direction, more water is needed to reach equilibrium, thus allowing the polymer hydrogel to swell.
[00108] The data presented in this context and in Example 8 support the idea that a significant washing effect is the removal of the polymer that has not reacted outside the hydrogel. This unreacted polymer can serve as a molecular spagger during the crosslinking process, serving to increase the distance between crosslinking sites. It is also believed that the wash extends the crosslinked polymer network, increasing the polymer mobility and the absorption kinetics. Example 2: Study of the Effect of the Washing Procedure on the Properties of Carboxymethylcellulose Reticulated by Citric Acid
[00109] The samples were prepared according to the procedure described in Example 1 with the exception of the washing procedure. In this preparation the sample was divided into 4 parts, each of which was washed with distilled water 1, 2, 3 or 4 times. The first 3 washes were performed for 3 hours and the last for 14 hours. The yield of the process was calculated as follows:
Y% = Whidrogel / Wcmcontains the Whidrogei and the weight of the dry material obtained after the process and Wcmc and the weight of the carboxymethylcellulose in the starting mixture. The media capture ratio of each washed sample was determined in SGF / water (1: 8) and the results are shown in Table 2. Table 2
Discussion
[00110] The results indicate that the media capture ratio increases with the number of washes. This is due to a reduction in the degree of crosslinking. The hydrogel network includes both physical tangles and chemical cross-links. Without wishing to be bound by any theory, it is believed that physical entanglements are reduced by washing due to electrostatic repulsion between the chains and the increased mobility of these chains due to the increased volume of the hydrogel. As a direct consequence of this increased absorption capacity, the yield of the process decreases. This is believed to be due to. solubilization of the carboxymethylcellulose that did not react during the washing which reduces the final weight of the product. The reduction in yield can also be related to the losses arising from the additional handling of the material required by the additional washing steps. Example 3: Effect of Crosslinking Time on Properties of Carboxymethylcellulose Reticulated by Citric Acid Method
[00111] Purified water (10 kg) was added to a 10 liter Hobart mixer and subjected to stirring at 30 rpm. Citric acid (1.8 g) was added to water and dissolved. NaCMC (600 g) was then added to the solution and the resulting mixture was subjected to stirring at room temperature under 60 rpm for 90 minutes and then under 30 rpm for 15 hours. The resulting solution was added to 10 stainless steel trays (1.030 kg of solution per tray). The trays were placed 4m in a Salvis Thermocenter TC240 oven under 45 ° C for 24 hours. The trays were removed from the oven, the contents were inverted and the trays were placed back in the oven and kept under 45 ° C for 30 hours. After drying, part of the material was crushed by means of a cutting mill (Retsch cutting mill) equipped with a 1 mm sieve, and a sample was stored as a sheet for control purposes (sample C). The remaining material was then sieved 4 divided into 2 parts according to Table 3. Table 3

[00134] Each of samples A, B and C was divided into three parts. These parts of samples A, B and C were then spread on the tray and cross-linked in the Salvis Thermocenter TC240 oven under 120 ° C for 2, 3 or 4 hours. The resulting cross-linked polymeric hydrogel was washed with distilled water for 24 hours in order to remove unreacted reagents (by changing the washing solution 4 times). After washing, the material was placed in trays inside the oven under 45 ° C until complete desiccation occurred. The dry material was then crushed and sieved for particle size between 100 pm and 1000 pm.
[00135] The ratio of media capture of these samples in SGF / water (1: 8) is shown in Table 4. Table 4

[00137] It is evident that the ability to capture media decreases with the increase in the crosslinking time. However, the main particle size is not the predominant parameter that affects media capture. Example 4: Effect of Particulate Dimension Crosslinking on Properties of Carboxymethylcellulose Crosslinked by Citric Acid Method
[00138] Purified water (10 kg) was added to a 10 liter Hobart mixer and subjected to stirring at 30 rpm. Citric acid (1.8 g) was added to water and dissolved. The solution was then added NaCMC (600 g) and the resulting mixture was stirred at room temperature under 60 rpm for 90 minutes and then under 30 rpm for 15 hours. The resulting solution was added to 10 stainless steel trays (1.030 kg of solution per tray). The trays were placed in a Salvis Thermocenter TC240 oven at 45 ° C for 24 hours. The trays were removed from the oven, the contents were inverted and the trays were placed back in the oven and kept there at 45 ° C for 30 hours. After desiccation, part of the material was crushed by means of a cutting mill (Retsch cutting mill) equipped with a 1 mm sieve, and a small sample was stored as a sheet for control purposes (sample D). The crushed material was then sieved and divided into 3 parts according to Table 5. Table 5

[00141] A-D samples were spread on trays and cross-linked in the Salvis Thermocenter TC240 oven under 120 ° C for 4 hours. The crosslinked polymer hydrogels thus obtained were washed for 24 hours with distilled water to remove unreacted reagents (by changing the washing solution 4 times). After washing, the material was spread on the trays and placed in the oven under 45 ° C to dry. The dry material was then ground and sieved to a particle size ranging from 100 pm to 1000 pm. Discussion
[00142] The media capture ratio (MUR) of the AD samples in SGF: water (1: 8) is shown in Table 6. Table 6

[00143] Samples A, B and C had negligible differences in the capture of media (around 15% that can be attributed to experimental error). Sample D, the cross-linked leaf, demonstrated an increased media capture capacity. Conclusions:
[00144] As shown by the relationship of media capture that is directly related to the density / efficiency of crosslinking, the samples that were crosslinked in the form of particles showed greater crosslinking efficiency due to their homogeneity. The leaf had its top reticulated while its rear side was hardly reticulated, resulting in greater media capture (more than 35%). Example 5 Determination of the Crosslinking Degree of Carboxymethyl Cellulose Cross-linked by Citric Acid Method:
[00145] A swollen hydrogel disk and tested using a uniaxial compression load by means of a rotary rheometer (ARES Rheometric Scientific) equipped with parallel plate tools. The disks were prepared by immersing for 24 h a dry cross-linked sheet of material in distilled water. Then the swollen sheet is cut into round discs 25 mm in diameter by means of a PE punch. The disk is placed on the parallel plates of the rheometer for the compression test with a compression speed of 0.001 mm / s. Assuming that there are no changes in the sample volume during the compression test, Flory derived from a relationship between the compression stress and the compression deformation for the case of a swollen crosslinked polymer, based on the assumption of Gaussian statistics for a related deformation (eq. 3).
[00146] Although this approach is super simplified, due to the assumption of constant volume (in fact a certain amount of water is squeezed out of the swollen sample as a result of the compression), it can be used to understand gel deformation it can be (CX = (where ~ / Q and Z are the high starting sample before and after compression, respectively) and behavior under uniaxial compression in the case of small deformations (cr-41) and can be used for evaluation of the relationship between P and E (see eq. 3.
[00147] The deviation in relation to Gaussian statistics in large strains can be taken into account by the use of a phenomenological expression to describe the behavior of the swollen reticulated network subjected to uniaxial extension. This expression can be derived from the expression of the Mooney-Rivlin deformation energy function for swollen rubbers which takes into account both deformation due to swelling and deformation due to compression. Taking the hypothesis of incompressibility, the following expression relative to tension is uniaxial (referring to the cross-sectional area of the swollen, non-deformed sample) with the extension relation, a, can be derived:
where CT has the same definition as that used in K KEq. (3) and the values of ^ 1 e are proportional to the swelling ratio of the sample. According to Eq. (4), aia-ila2} 1 make a drag of / vs. / based on experimental data should be linear. A drag of o (Pa) versus lo-l (p) from a typical test is shown in Figure 3. A drag of -o (al / a2) -1 versus 1 / aa from a typical experiment is shown in Figure 4.
[00149] The slope of the linear adjustment of the experimental data provides the G value to be used in eq. 3. Using this value, it is possible to evaluate the degree of crosslinking of the swollen hydrogel network. Measurements were made under different concentrations of CMC and different amounts of citric acid, and the results are reported in Figure 5. Five samples were evaluated for each concentration and the trap in Figure 5 and the mean obtained excluding the highest value and the lowest value of the measurement obtained. The results show that the degree of crosslinking increases with the increase in the concentration of citric acid, which is in line with the assumption that citric acid functions as a chemical crosslinker for the polymeric network, through a double anhydrification / esterification mechanism double.
[00150] An assessment of the degree of crosslinking was also performed as a function of the polymer concentration (CMC) in the starting solution, as reported in Figure 6, under a fixed concentration of citric acid (0.3% w / w in regarding CMC).
[00151] It can be seen that the degree of crosslinking increases by increasing the concentration of polymer, under a fixed concentration of crosslinker, although this correlation is not linear. This is because the stabilization reaction takes place in a contracted state, as described above. Thus, under increased polymer concentration, the average distance between two adjacent polymer molecules is lower, and covalent ligands are created between the molecules that potentially can be positioned at a much higher distance once the polymer network is. swollen, thereby preventing the material from swelling to its full potential, and increasing the effective degree of crosslinking, the average distance provided between subsequent crosslinking sites being lower. The non-linear correlation is thus explained as the variation in the average distance between polymer molecules and is related to the volumetric variation of the solid part of the reaction mass.
[00152] According to what has been established previously, it is to be expected that the media uptake capacity of the hydrogel is dependent on the polymer concentration (CMC) in the starting solution. This is confirmed by the graph in Figure 7, where the hydrogel media uptake ratio is reported to be a function of the polymer concentration in the starting solution, under a fixed concentration (0.3% of the polymer) of the crosslinking agent. (Citric acid). The data shown in Figure 7 were obtained from the same samples used for the compression devices. These disk-shaped samples were placed in deionized water for 24 hours and then subjected to drying under 45 ° C for 48 hours. The media uptake ratio was calculated using the weight before and after drying.
[00153] Table 7 compares the properties of the material of this example prepared under a concentration of citric acid of 0.3%, by weight, with respect to carboxymethylcellulose and the material prepared as described in Example 10. Table 7


[00154] It is observed that, except for very low concentration of 0.25% of CMC in the starting solution, where full chemical stabilization of the polymer network is not expected, the level of media uptake decreases with the amount of CMC. This reduction is due to an increased value of the elastic component due to a higher value of the degree of crosslinking. This suggests an appropriate correlation of the CMC concentration used during synthesis as a function of the concentration of the crosslinker, in order to find a range of reagent concentration values capable of providing a superabsorbent behavior of the polymer under conditions closer to actual use. of the material (water, aqueous solutions, gastrointestinal fluids and the like).
[00155] Example 6 Comparison of Structural Properties of Hydrogels Prepared Using Different Methods
[00156] In this example, the properties of hydrogels prepared using the methods of the invention were compared with those of hydrogels prepared as set out in WO 01/87365 example IX, samples 202 and 203.
[00157] Preparation of Samples A and B Materials: Sodium Carboxymethyl Cellulose - Aquaion 7HOF, Pharmaceutical ClassCitric Acid - Carlo Erba, USP Class
[00158] Samples A and B were prepared as described for samples 202 and 203 of Example IX of WO 01/87365. For both samples, a solution of 2% (w / w water) sodium carboxymethyl cellulose and citric acid (0.6% (w / w CMC) for sample A was prepared; 1.0% (w / w CMC) for sample B) in water by mixing until complete dissolution occurs. The solutions were poured into polypropylene trays and kept under 95 ° C for 16 hours. After that, the dried leaves were ground using a Model U5 CoMill Table and the resulting powder was sieved. The fraction between 100 and 1000 gm was collected.
[00159] Sample Preparation C Materials: Sodium sodium carboxymethyl cellulose - Aquaion 7H3SXF, pharmaceutic class Citric acid - Carlo Erba, USP class
[00160] A 6% aqueous solution (w / w water) sodium carboxymethyl cellulose and citric acid (0.3% w / w CMC) was prepared and mixed for 12 hours. The solution was then poured into a polypropylene tray and kept at 45 ° C for 12 hours. The residue was milled with a mill to provide a fine well with a particle size distribution of 100-1000 pm. The well was kept under 120 ° C for 5 hours, and then washed three times with deionized water under a water: well: 80: 1 (v / v) mixture with constant mixing. The powder was then dried for 48 h at 45 ° C. After that, the dry material was ground again using a Model U5 CoMill Frame and the powder was sieved and the fraction between 100 and 1000 pm was then collected.
[00161] DMaterials Sample Preparation: Sodium Carboxymethyl Cellulose-Aquaion 7H3SXF, pharmaceutic classCitric acid - Carlo Erba, USP Sorbitol class (ADEA Sri - food class)
An aqueous solution of 2% (w / w water) sodium carboxymethyl cellulose, sorbitol (4% w / w water) and citric acid (1% w / w CMC), was prepared and mixed for 12 hours. The solution was then poured into a polypropylene tray and kept at 45 ° C for 48 hours. The residue was kept under 80 ° C for 12 hours, and then ground and washed three times with deionized water under a water: well: 80: 1 (v / v) ratio with constant mixing. The well was then subjected to drying for 48 h at 45 ° C. The material was poured into a glass beaker with acetone during 3 desiccation steps of 2 hours each: 1/1, 1/1, 1/10 material to acetone ratio for each step, respectively. After that, the dry material was ground again using a Model U5 CoMill Table. The bread was sieved and the fraction between 100 and 1000 py was collected.
[00163] Characterization of HydrogelsAnalysis of NMR
[00164] Approximately 0.02 g of each hydrogel sample was transferred to a glass bottle and D2O (2 ml) at room temperature. The swollen hydrogels were allowed to settle for at least 24 h before being transferred to the NMR rotor (see ultra). HR-MAS NMR
[00165] 1H NMR spectra of hydrogel systems were recorded on a Bruker Avance spectrometer operating under 500 MHz proton frequency, equipped with a dual 1H / 13C HR MAS (High Resolution Magic Angle Spinning) probe head for semi-solid samples ( Lippens, G. et al., M. Curr. Org. Chem. 1999, 3, 147). The basic principle of this approach can be summarized as follows. Rapid rotation of the sample under the so-called magic angle (54.7 ° with respect to the z-direction of the NMR magnet tray field) averages the dipole - dipole interactions and susceptibility distortions, causing a dramatic improvement or improvement in the spectral resolution (Viel, S .; Ziarelli, F .; Caldarelli, S., Proc. Natl. Acad. Sci. USA 2003, 100, 9696). The hydrogels prepared as described above were transferred to a 4 mm ZrO2 rotor that contained a volume of about 50 pl. All XH spectra were acquired with a rotation rate under 4 kHz to eliminate the dipolar contribution.
[00166] T2 filtration was obtained by using the classic Carr-Purcell-Meiboom-Gill spin-eco pulse sequence with 1 ms of eco-hour.
[00167] The water autodiffusion coefficient was measured using diffusion-ordered correlation spectroscopy (DOSY) experiments, carried out based on the pulsed field gradient spin-echo (PGSE) approach. A pulsed gradient unit capable of producing gradients of magnetic field pulses in the z direction up to 53 G.cm-1.HRMAS-NMR was used: pulse collection with water pre-saturation
[00168] The spectra of the hydrogel samples C and D are illustrated in Figure 8. The correspondents of samples A and B are shown in Figure 9. The spectra were acquired by using the pre-saturation of the intense signal due to residual water 4, 76 ppm. The spectra represent a fingerprint of the polymeric gel. The peaks labeled with * disappeared after a few days. In this way, they may be due to a certain metastable state evolving to balance over time. A striking aspect characterizes these samples. In the spectra of samples A and B, the quartet AB of sodium citrate, indicated in the spectra as "SC", is present. This means that these hydrogels are endowed with an amount of free sodium citrate. For the purpose of a double check for the assignment, the spectra of pure sodium citrate in a standard hydrogel preparation of standard (agarose-carbomer) and in D2O solution are also shown (first and second puffs from the top, respectively ). It is important to note that the free citrate signal is not present in samples C and D (see ultra) .HRMAS-NMR: T2 filtering
[00169] In the general case of swollen, crosslinked polymers, the acquisition of the NMR signal after T2 filtering allows the extraction of magnetization due to: a. low molecular weight fragments of a polydispersed polymer b. The part of the backbone of the polymer with the highest mobility c. Any pending chains or groups moving faster than the backbone; ed. Any small absorbed molecule adsorbed, trapped or encapsulated within the polymer matrix. For samples A, B and C, the spectral signals that survive after T2 filtering are likely due to factors bed.
[00170] Figure 10 shows the superposition of the spectra of samples C and D collected with T2 filtering. As a general comment, sample C shows some peaks that are probably due to metastable states. Peaks labeled with * naturally disappear after the sample is left to stand for 48 h. The spectrum of sample D shows sharp peaks in the spectral region of the glucose backbone, indicating similar chain dynamics. The interpretation of sample C is less clear, probably for the reasons mentioned above. The HRMAS NMR spectra filtered by T2 confirm that samples C and D do not contain free citrate. The signal due to sodium citrate in the reference gel is shown in the top draw of Figure 10 (oval frame). The arrows indicate where, in the spectra of these samples, these signals would be if they were present.
[00171] The results for samples A and B are illustrated in Figure 10. The signal is, in general, less abundant than those observed in samples C and D, indicating slower chain dynamics. Unlike what was observed in samples C and D, samples A and B contain detectable amounts of free citrate. The corresponding NMR signals are in the oval frames in Figure 11. DOSY HRMAS-NMR
[00172] The D coefficient of self-diffusion of water molecules within hydrogels was also measured. In some cases water molecules can interact strongly with the polymeric matrix, thus giving rise to different types of water according to the transport behavior: bulk water and bonding water. If the two types of water are in rapid exchange on the NMR time scale, the observed D and the weighted average population of the D-link and D-bulk, while if the link and free water are in slow exchange on the- NMR time, two different NMR signals are observed and the D-linkage and D-bulk coefficients can be measured (Mele, A .; Castiglione, F. et al J. Incl. Phenom. Macrocyc. Chem., 2011, 69 , 403-409).
[00173] In the present study, the experimental D measured for each sample falls in the range 2.3 to 2.6 x 10-9 m2s-1 'In view of the uncertainty associated with the measurement, it can be concluded that the water within the hydrogels show a self-diffusion coefficient in perfect agreement with that of raw water reported in the literature under the same temperature (Holz, M .; Heil, SR; Sacco, A. Phys. Chem. Chem. Phys., 2000, 2, 4740- 4742). For this reason, no specific water / polymer interactions can be taken into account for these systems. Conclusions
[00174] The HRMAS-NMR methods are suitable for a characterization of the digital printing of hydrogels made of cross-linked polymeric hydrogels by CMC citric acid. Sample C does not show detectable free citric acid / citrate traits, where samples A and B clearly and unambiguously show the NMR signal of citrate. This confirms that in samples A and B the double anhydrification / double esterification reaction is inhibited by the presence of water during the crosslinking stage of these samples, which is associated with the absence of the desiccation and grinding steps before crosslinking.
[00175] Sample C shows faster chain dynamics compared to samples A and B. This is a consequence of the absence of any washing and additional drying steps in the synthesis of these samples. This is related to the faster water absorption than is observed with sample C.
[00176] The water molecules within the polymeric matrices show transport properties close to free, bulk water, thus indicating that no specific interaction of the water molecules with the polymer is present in these hydrogels.
[00177] The data suggest that samples A and B are physically cross-linked in a compact, stable network, compared to the low-crosslinked and highly mobile network structure, chemically stabilized from sample C. Tai as illustrated below, this results in the ability to higher swelling and faster swelling kinetics of sample C compared to samples A and B. Swelling kinetics
[00178] Each of the samples provided a highly viscous, transparent hydrogel, uniform in the treatment with deuterated water, as described above. The two samples B and C showed a decreased ability to absorb water compared to sample A (0.02 g of samples / 1 ml of water).
[00179] During the preparation of the sample, a different swelling behavior was observed from sample C compared to samples A and B. Sample C provided a dense, viscous hydrogel, almost immediately after the addition of water, while samples A and B took much longer to reach a homogeneous, single-phase gel state. Swelling balance
[00180] Measurement measurements were carried out on samples in powder form (particle size distribution 100-1000 micrometers) soaked for 30 minutes in different media (DI water, 0.9% NaCI, SGF / 1: 8 water) ). 0SGF is a simulated gastric fluid. One liter of SGF is obtained by mixing 7 ml of 37% HCl with 2 g of NaCI and 993 ml of water. After dissolving NaCl, 3.2 g of pepsin is added. The results for three aliquots of each sample are reported in Tables 8-10, Table 8

Table 9
Table 10

[00181] The ratio of media uptake in all three media is significantly higher for sample C than for samples A and B. This is due to differences in the molecular structure discussed in the previous chapter, and in particular the difference in the mechanism stabilization of the macromolecular network and increased mobility of macromolecular portions. These properties are in turn associated with the different synthetic processes used for these samples and, in particular, with the desiccation, grinding, washing and second drying processes included in the sample synthesis C. Mechanical properties
[00182] The storage module (G '), the loss module (G ") and the viscosity of the samples were evaluated after soaking three aliquots of each sample in SGF / water 1: 8 for 30 minutes. if a rheometer equipped with parallel plates (25 mm in diameter) for the analyzes, the frequency range was fixed between 1 rad / s to 50 rad / s and the voltage was fixed at 0.5% (value in which the parameters presented a behavior linear in a voltage sweep test: fixed frequency under 1Hz and variable voltage). The values (G'-G "- viscosity) were recorded at 10 rad / s. The results for samples A, B and C are shown in Tables III, respectively. Table 11
Table 12

Table 13

[00183] Higher values for preservation (G ') and dissipation (G' ') modules are in accordance with the lower swelling capacity of samples A and B. Due to the absence of a washing step without subsequent cross-linking, these samples are expected to have a highly stabilized and highly entangled structure, more compact, with secondary binding compared to sample C. This results in greater chemical restriction and, in turn, a lower swelling capacity of samples A and B. The lower chemical mobility associated with the different structure of these samples is also responsible for their greater mechanical properties.
[00184] Differences in the synthesis procedures between samples A and B and sample C result in different hydrogel properties. The main difference refers to the absence of the desiccation, grinding, washing and drying steps for samples A and B. Without this being intended to be limited by any theory, it is believed that this results in the inhibition of the double anhydrification process / double esterification, which requires the elimination of water from the reaction mixture, since water itself is a product of the reaction. This is also believed to result in a different stabilization mechanism for samples A and B compared to sample C and, in turn, different molecular structure and behavior. in terms of swelling kinetics, swelling capacity and mechanical properties.
[00185] Example 7 Preparation of Large Scale Hydrogels
[00186] A process for producing particles of hydrogel on a multi-Kg scale is carried out using the apparatus illustrated schematically in Figure 12. Sodium carboxymethyl cellulose (6% w / w water), citric acid (0.3% w / p sodium carboxymethylcellulose) and water are mixed under temperature and ambient pressure in a low shear mixing vessel (mixer, 1) until a homogeneous ablugation is formed. The solution is transferred to trays in order to maintain a solution depth of about 30 mm. The trays are placed in a forced atmospheric air oven (tray dryer, 2), and dried for 16 to 24 hours at 85 ° C. The temperature is then lowered to 50 ° C until drying is complete. The total drying time is about 60 hours. The resulting residue is in the form of a sheet, which is milled using a coarse mill (3) and a fine mill (4) and sieved (sieve, 5) to provide a sample comprising particles of size between 100 and 1600 pm. The particles are placed in a crosslinking reactor (6) and maintained under 120 ° C and atmospheric pressure for 3 to 10 hours. The resulting hydrogel is transferred to a washing tank (7) and washed under ambient temperature and pressure with an amount of water between 150 and 300 times the weight of the polymer. Free water is removed from the hydrogel by means of filtration (Filter, 8). The hydrogel is placed in trays under a thickness of about 40 mm. The trays are placed in an atmospheric forced air oven (tray dryer, 9) and subjected to drying for 24-30 hours at 85 ° C. The temperature is then lowered to 50 ° C until drying. The total drying time is about 60 hours. The material is dried and ground into particles using a fine mill (10) and mechanically sieved (sieve, 11) to obtain particle fractions between 100 and 1000 pm.
[00187] Using this general process and starting with more than 4 kg of sodium carboxymethylcellulose, the yield was greater than 70% of bread with a particle size range between 100 and 1000 pyr. The sprayed hydrogel product met the product specifications as detailed in Table 14. Table 14 Final Product Specifications


[00188] Example 8 Study of the Effect of the Washing Procedure on the Properties of Carboxymethylcellulose Reticulated by Citric Acid
[00189] Hydrogel samples were prepared according to the procedure described in Example 7.
[00190] 100 g of dry hydrogel was mixed with 5000 g of deionized water for 90 minutes. This wet slurry was passed through a wide mouth stainless steel filter (pore size 500 - 1000 gm). 2.31 Kg of moist hydrogel were collected. The filtrate was saved for future analysis. The wet gel was added again to 5000 g of deionized water for an additional 120 minutes. The material was filtered as before and 2.28 kg of gel was collected. The filtrate was saved for future analysis.
[00191] The filtrate from the two washings was poured into glass drying pans and placed in a forced air oven overnight to dry at 105 ° C. Results: First Wash: Tare: 764.3 gSample weight: 778, 4 gDifferent: 14.1 gSecond Wash: Tare: 764.3 gSample weight: 764.4 gDifferent: 0.1 gObservations:
[00192] It is possible that some gel particles have slid through the filter, since a small number of particles was observed in the first sample of filtrate on drying. No gel particles were observed in the dry residue of the second filtrate. Conclusions: 1) About 15% of the CMC does not react and is washed out of the gel.2) In this experiment, 99.5% of the CMC that did not react is removed by washing afterwards 90 minutes of washing.
[00193] Example 9 Effect of Concentration of Citric Acid on Hydrogel Properties
[00194] Sodium carboxymethylcellulose in aqueous solution was mixed with citric acid under different concentrations. The mixture was dried in the oven (45 ° C) and then ground to form particles of 100 1000 pm. These particles were cross-linked at 120 ° C for 4 hours. The elastic module (Storage) (G '), Loss Module (G "), viscosity (r |), and media capture in SGF / water 1: 8 (recorded after 30 minutes) were determined for the gel particles .
[00195] The results are shown in Table 15, which shows the concentration of NaCMC, by weight, relative to the weight of water and the concentration of citric acid, by weight, relative to the weight of NaCMC. MUR and the media capture ratio in water: 8: 1 simulated gastric fluid, Table 15

[00198] The data previously exposed were analyzed using an Experimental Design Software (JMP, by SAS Institute, Inc). The results are illustrated in Figure 13, which shows that increasing concentration of citric acid results in increased elastic and viscosity modules, but at the expense of swelling capacity. Desirably, what takes into account the desired ranges of elastic modulus, viscosity modulus and swelling capacity, or media capture ratio in SGF / water 1: 8, and raised to the maximum under a concentration of 0.3 citric acid % by weight, relative to the weight of carboxymethylcellulose, with relatively small change between about 0.15% to about 0.35%. Conclusions:
[00199] The results show a strong relationship between the concentrations of NaCMC and citric acid. When optimized for human therapeutic benefit with elastic module similar to chewed food (1000-5000 Pa for unwashed particles and 350-1000 Pa for washed particles) the maximum media capture was located between concentrations of 0.15% citric acid to 0, 3% under 6% NaCMC.
[00200] Example 10
[00201] To validate the results of Example9, the study was repeated using 6% NaCMC with 0.3% CA. The hydrogel was prepared in the manner described in Example 9 and was then washed three times in deionized water and then dried again. The results, which are shown in Table 16, demonstrated good media capture of more than 70 in SGF / water 1: 8 with an elastic module greater than 1000 Pa. Table 17 presents the results of a study of the swelling kinetics of this material in SGF / water 1: 8. The results demonstrate rapid swelling of the hydrogel in this medium. Table 16
Table 17

[00202] Example 11
[00203] Carboxymethylcellulose hydrogels cross-linked by citric acid were prepared in the manner generally described in WO 2009/021701. Aqueous solutions of 2% sodium carboxymethylcellulose (w / w water), 1% citric acid (w / w carboxymethylcellulose) and either no sorbitol or 4% sorbitol (w / w carboxymethylcellulose) were stirred, the solution was poured into a pan, subjected to drying at 30 ° C for 24 hours and then kept under 80 ° C for 24 hours. The resulting hydrogels were washed and dried in acetone, as described in WO 2009/021701.
[00204] The properties of the hydrogel prepared with 4% sorbitol are shown in Table 18. The properties of the hydrogel prepared in the absence of sorbitol could not be determined because this hydrogel dissolves in water during the washing step. Table 18

[00205] These results demonstrate that under low concentrations of carboxymethylcellulose, for example, 2% (w / w water), the production of a stabilized hydrogel requires a physical spagger, such as sorbitol, a higher concentration of citric acid and / or a higher crosslinking temperature.
[00206] It is believed that sorbitol acts as a plasticizer for carboxymethylcellulose, increasing chain mobility and thereby reducing the energy required for crosslinking.
[00207] Example 12
Hydrogels as described in Example 9 were prepared under carboxymethylcellulose concentrations of 2 to 6% by weight, in relation to water and a concentration of 0.1% by weight of citric acid in relation to caboxymethylcellulose. The cross-linking time was either 4 hours or six hours. The hydrogel products were not washed. Hydrogels were characterized by media capture in SGF / water 1: 8, G ', G "er |. The results are shown in Tables 19 and 20, Table 19
Table 20

[00209] The results show that a low concentration of citric acid requires a longer cross-linking time. Increasing the concentration of CMC leads to a stabilized hydrogel compared to a hydrogel prepared with a lower concentration of CMC and a longer cross-linking time.

权利要求:
Claims (18)
[0001]
1. Method for the production of a polymeric hydrogel particle characterized by the fact that it comprises the steps of: (a) preparing an aqueous solution of carboxymethylcellulose in a concentration of about 4% to about 8% by weight in relation to water and an amount of citric acid from 0.15% to 0.35% by weight with respect to the weight of carboxymethylcellulose, provided that said aqueous solution does not include a molecular spagger; (b) agitate the solution; (c) isolate a composite of carboxymethylcellulose / citric acid of the solution; (d) granulate the carboxymethylcellulose / citric acid composite to produce carboxymethylcellulose / citric acid composite particles, (e) heat the particles of the carboxymethylcellulose / citric acid composite to a temperature of at least about 80 ° C, thus crosslinking the carboxymethylcellulose with the citric acid to produce a polymeric hydrogel; (f) washing the polymeric hydrogel with water; (g) drying the washed polymeric hydrogel at elevated temperature; and (h) granulating the dry polymer hydrogel to produce particles of polymer hydrogel.
[0002]
2. Method, according to claim 1, characterized by the fact that citric acid is present in the solution of step (a) at a concentration of about 0.15% to about 0.3% by weight relative to carboxymethylcellulose.
[0003]
3. Method, according to claim 1, characterized by the fact that carboxymethylcellulose is present in the solution of step (a) at a concentration of about 5% to about 7% by weight in relation to water.
[0004]
4. Method, according to claim 1, characterized by the fact that carboxymethylcellulose is present in the solution of step (a) at a concentration of about 6% by weight in relation to water.
[0005]
5. Method, according to claim 4, characterized by the fact that citric acid is present in the solution of step (a) at a concentration of about 0.3% by weight of carboxymethylcellulose.
[0006]
6. Method, according to claim 1, characterized by the fact that the carboxymethylcellulose is in the form of sodium salt.
[0007]
7. Polymeric hydrogel consisting essentially of cross-linked carboxymethylcellulose with citric acid characterized by: (a) an apparent density of at least 0.5 g / cm3; and (b) a media absorption ratio in simulated gastric fluid / water (1: 8) of at least about 50 to 37 ° C.
[0008]
8. Polymeric hydrogel, according to claim 7, characterized by the fact that it is less than about 10% water by weight.
[0009]
9. Polymeric hydrogel, according to claim 7, characterized by the fact that at least about 95% of the hydrogel by weight consists of particles in the size range from 100 pm to 1000 pm.
[0010]
10. Polymeric hydrogel, according to claim 7, characterized by having a ratio of bound citric acid to carboxymethylcellulose from 0.1% to 0.4% w / w.
[0011]
11. Polymeric hydrogel, according to claim 7, characterized by having a ratio of bound citric acid to carboxymethylcellulose from 0.225% to 0.375% w / w.
[0012]
12. Polymeric hydrogel, according to claim 7, characterized by having a degree of crosslinking from about 4 x 10-5 mol / cm3 to about 5 x 10-5 mol / cm3.
[0013]
13. Polymeric hydrogel, according to claim 7, characterized by having an elasticity module of at least about 350 Pa.
[0014]
14. Polymeric hydrogel, according to claim 7, characterized by an apparent density of at least 0.6 g / cm3.
[0015]
15. Polymeric hydrogel, according to claim 7, characterized by having an apparent density from 0.6 g / cm3 to about 0.8 g / cm3.
[0016]
16. Polymeric hydrogel, according to claim 7, characterized by having a media absorption ratio in simulated gastric fluid / water (1: 8) of at least 70 to 37 ° C.
[0017]
17. Polymeric hydrogel, according to claim 7, characterized by having a media absorption ratio in simulated gastric fluid / water (1: 8) of at least 80 to 37 ° C.
[0018]
18. Polymeric hydrogel, according to claim 7, characterized by having a media absorption ratio in simulated gastric fluid / water (1: 8) of at least 90 to 37 ° C.

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法律状态:
2018-01-09| B25A| Requested transfer of rights approved|Owner name: GELESIS LLC (US) |

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-03-24| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-07-21| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-24| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 07/06/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161494298P| true| 2011-06-07|2011-06-07|

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US61/494,298|2011-06-07|

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US201161542494P| true| 2011-10-03|2011-10-03|

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US61/542,494|2011-10-03|

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PCT/US2012/041345|WO2012170682A1|2011-06-07|2012-06-07|Method for producing hydrogels|

---