US20140037958A1

US20140037958A1 - Silicic acid condensates having a low cross-linkage rate

Info

Publication number: US20140037958A1
Application number: US13/981,599
Authority: US
Inventors: Thomas Gerber
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-01-31
Filing date: 2012-01-31
Publication date: 2014-02-06
Also published as: CA2829491A1; ES2821395T3; US20180344895A1; EP2670705A1; WO2012104320A1; US20140031452A1; EP2670706B1; EP2670705B1; EP2670706A1; CA2829491C; US10064974B2; CA2828759C; CA2828759A1; WO2012104310A1; ES2754053T3; US10842909B2

Abstract

A material or biomaterial comprising silicic acid condensates with a low degree of crosslinking and methods of producing the same are subject matter of the present invention. A method of producing silicic acid structures having a low degree of crosslinking is disclosed, in which a sol is prepared, with further condensation being prevented if certain cross-linkages of the silicic acid are achieved, and wherein, preferably, structures with a size of 0.5-1000 nm are produced, e.g., polyhedral structures or aggregates of the same. Further condensation can be prevented by a chemical reaction of OH groups of the silicic acid condensates, e.g., by esterification or silylation. In one embodiment, the material primarily includes silicon dioxide (SiO₂), in particular silicon dioxide that, because of its modification, e.g., by esterification, is nanostructured and has a low degree of crosslinking. The material may be used for therapeutic purposes in the field of medicine or for cosmetic purposes, and, herein, it may enter into direct contact with biological tissues in the body. In this, said material enters into chemical, physical and biological interactions with the corresponding biological systems. In this context, it can be degraded and can supply the silicic acid needed in the metabolism. It may also have a supportive or shielding effect. It may be present in the form of granules, microparticles, fibers and as woven or fleece fabrics produced from those, or as a layer on implants or wound dressings. This material may be used as a medical device or as a nutritional supplement.

Description

A material or biomaterial comprising silicic acid condensates with a low degree of crosslinking and methods of producing the same are subject matter of the present invention. A method of producing silicic acid structures having a low degree of crosslinking is disclosed, in which a sol is prepared, with further condensation being prevented if certain cross-linkages of the silicic acid are achieved, and wherein, preferably, structures with a size of 0.5-1000 nm are produced, e.g., polyhedral structures or aggregates of the same. Further condensation can be prevented by a chemical reaction of OH groups of the silicic acid condensates, e.g., by esterification or silylation. In one embodiment, the material primarily includes silicon dioxide (SiO₂), in particular silicon dioxide that, because of its modification, e.g., by esterification, is nanostructured and has a low degree of crosslinking. The material may be used for therapeutic purposes in the field of medicine or for cosmetic purposes, and, herein, it may enter into direct contact with biological tissues in the body. In this, said material enters into chemical, physical and biological interactions with the corresponding biological systems. In this context, it can be degraded and can supply the silicic acid needed in the metabolism. It may also have a supportive or shielding effect. It may be present in the form of granules, microparticles, fibers and as woven or fleece fabrics produced from those, or as a layer on implants or wound dressings. This material may be used as a medical device or as a nutritional supplement.
Since the 1970s in the last century, it has been known that silicon is an important trace element for the synthesis of bones and collagen (see, for example, M. Carlisle; Silicon: An Essential Element for the Chick; Science, 10 Nov. 1972, vol. 178. no. 4061, pp. 619-621). The precise biochemical processes are still unknown. In the metabolism, silicon primarily occurs as silicon dioxide. It is also not known in which structure the silicon dioxide best participates in the metabolism. Silicon dioxide occurs as a crystalline compound (e.g., quartz, cristobalite), as glass and as an amorphous substance. In the crystal and in glass, silicon dioxide is determined by almost complete crosslinking of the SiO_4/2tetrahedrons. However, amorphous silicon dioxide, with silica gel as the main representative, has a network that is not continuous and is characterized by more or less internal surface area with open bonds (usually SiOH).
With respect to degradation of silicon dioxide, the solubility of silicon dioxide in water in the range of the physiological pH is of interest. For amorphous SiO₂, its solubility is approx. 150 ppm at pH 7. When it comes in contact with living tissue, it goes into solution more rapidly than in a buffered solution at pH 7.4. The reason for this is unknown (Iler, The Chemistry of Silica, 1979, John Wiley &Sons).
For wound dressing, the patent US 005741509A describes a mixture of silicon medium with “fumed silica.” “Fumed silica” consists of nonporous SiO₂particles with a density of 2.2 g/cm³and a size between 5 and 50 nm (Wikipedia). This density, which is identical to that of silica glass, as well as the lack of porosity, shows that these are completely crosslinked SiO₂structures.
The patent US 2004/0235574 A1 also describes a mixture of silicon medium with “fumed silica” where antibacterial active ingredients are additionally added.
The patent U.S. Pat. No. 7,074,981 B2 describes a wound dressing in which an absorbent or an adsorbent in the form of silica gel is used. According to the state of the art, an absorbent or adsorbent made of silica gel is a xerogel, which is usually made of a sodium water glass solution, where the crosslinking of SiO₂structures typical of a xerogel takes place. (Under “Adsorption” in Wikipedia: “Silica gel is a chemically inert, nontoxic, polar and dimensionally stable (<400° C. or 750° F.) amorphous form of SiO₂. It is prepared by the reaction between sodium silicate and acetic acid, which is followed by a series of after-treatment processes such as aging, pickling, etc. These after-treatment methods result in various pore size distributions.”)
The patent DE 196 09 551 C1 relates to biodegradable fibers, including those made of SiO₂, their production and use as reinforcing fibers. This describes the production of a spinnable sol. The method and the application described here are based on the thesis by Monika Kursawe in 1995. This thesis is in turn based on the original synthesis procedures by Sakka in 1982 (S. Sakka, K. Kamiya: J. Non-Cryst. Solids 48, 1982, 31). Sakka describes a method in which gel fibers are spun and then used to produce glass fibers in a subsequent step. The starting material is tetraethyl orthosilicate (TEOS), and a spinnable sol is produced by hydrolysis and condensation. Sakka had already demonstrated that, due to the thixotropic properties of the sols, spinnable sols are obtained only in a limited range of the composition (TEOS, H₂O, solvent (usually ethanol) and catalyst). The molar ratio of water to TEOS in particular must be around r_w=2.
In the dissertation “Development of a method for producing degradable silica gel fibers for medical technology” (Monika Kursawe, 1999), a further enlargement of the 1995 thesis by Kursawe, it is stated that the most important difference between the method described in her thesis and the method by Sakka is that aging of the sol after condensation was introduced, and that nitric acid was used as the catalyst instead of hydrochloric acid. In the dissertation, the method is then optimized, so that high-quality silica gel fibers can be produced in large quantities. This process is based on the easily modified synthesis procedure by Sakka, as described in the thesis.
The patent DE 37 80 954 T2 describes a method for producing silicon dioxide glass fibers, where Sakka's basic method has been modified here again.
The patent DE 10 2007 061 873 A1 describes the production of a silica sol material and the use of same as a biologically resorbable material. The patent DE 19609551 C1 is cited as prior art. In differentiation from this patent, it is stated that the fibers here do not achieve optimal results in cytotoxicity tests after spinning, although there may be various causes for this and they are not associated with the main process steps. The second delineation, namely that according to DE 10 2007 061 873 A1, there is a formation of a “solid phase” which necessitates a filtration of the sol, but this is not discussed in relation to the main process steps either. The main claim 1 of the patent DE 10 2007 061 873 A1 essentially describes the synthesis instruction given by M. Kusawe in her dissertation (1999) and also published in her 1995 thesis. M. Kusawe divides the production of the spinnable sol into “hydrolysis,” “condensation” and “aging.” According to Kusawe, the “condensation” is characterized in that ethanol is withdrawn from the sol. This corresponds to claim 1 b) of the patent DE 10 2007 061 873 A1. In her standard approach, the “aging” in Kusawe takes place at 5° C. This in turn corresponds to claims 1 c) and 1 d). In the example of the patent DE 10 2007 061 873 A1, the aging is performed at 4° C. In the other essential parameters, this example also corresponds to Kusawe's standard approach (e.g., water/TEOS molar ratio of 1.75; in
Kusawe 1.8). The processes for producing spinnable sols according to the patents DE 196 09 551 C1 and DE 10 22007 061 873 A1 in their essential steps do not go beyond the level of knowledge in the thesis by Kusawe in 1995. The thesis also heavily relies on the findings by Sakka in 1982 (S. Sakka, K. Kamiya; Journal of Non-Crystalline Solids 48, 1982, 31).
The object of the present invention is to optimize the structure of silicic acid condensation products so that there can be a controlled degradation during in vivo use, andso that these silicic acid condensation products may be present in certain application forms such as granules, microparticles, fibers or as layers on implants or wound dressings. Synthesis processes should also be made available for this purpose.
According to the invention this object is achieved in that the condensation of the silicic acid in aqueous or alcoholic solution is controlled so that defined polyhedral structures are formed and these polyhedral structures are preserved in the following process steps such as removal of the solvent. The goal is to create silicic acid structures which have a low degree of crosslinking and are characterized in that they are not incorporated into a continuous network such as the silica glass network. The lowest degree of crosslinking is represented by a polyhedron comprised of SiO₂tetrahedrons where five-membered, six-membered and seven-membered rings form a three-dimensional structure with a diameter of approx. 0.5 nm. Such structures are described for example in: B. Himmel, Th. Gerber and H. Burger: WAXS and SAXSinvestigations of structure formation in alcoholic SiO₂solutions, Journal of Non-Crystalline Solids, Amsterdam, 119 (1990), 1-13; B. Himmel, Th. Gerber and H. Burger: X-ray diffraction investigations of silica gel structures, Journal of Non-Crystalline Solids, Amsterdam, 91 (1987), 122-136; B. Himmel, Th. Gerber, W. Heyer and W. Blau: X-ray diffraction analysis of SiO₂structure, Journal of Material Science, Chapman and Hall Ltd., London, 22 (1987), 1374-1378; Th. Gerber and B. Himmel: The structure of silica glass in dependence on the fictive temperature, Journal of Non-Crystalline Solids, Amsterdam, 92 (1987), 407-417; Th. Gerber and B. Himmel: The structure of silica glass, Journal of Non-Crystalline Solids, Amsterdam, 83 (1986), 324-334; B. Himmel, Th. Gerber and H.-G. Neumann: X-ray diffraction investigations of differently prepared amorphous silicas, Physica Status Solidi (a), 88 (1985), K127-K130).
One starting material for production of silicic acid condensation products is tetraethyl orthosilicate (TEOS). Silicic acid is obtained with water in the presence of a catalyst, where the molar ratio of water to TEOS must be at least 4 in order to achieve complete hydrolysis by the starting point. The resulting monosilicic acid condenses out, forming polyhedral structures of approx. 0.5 nm to 1 nm or so-called primary particles, which then develop fractal clusters in a cluster-cluster aggregation. These clusters grow due to the aggregation process, resulting in gelation at a certain cluster size. In other words, the clusters fill up the container due to their packing and/or the resulting percolation network (Th. Gerber, B. Himmel and C. Hubert: WAXS and SAXS investigation of structure formation of gels from sodium water glass, Journal of Non-Crystalline Solids (1994), vol. 175, p. 160-168 and B. Knoblich, Th. Gerber.). C. F. Brinker and G. W. Scherer describe gelation in a separate chapter in “Sol-gel-science: the physics and chemistry of sol-gel processing” (Academic Press, San Diego; 1990). Gelation is characterized by an extreme increase in viscosity.
These or similar structures can be created on the basis of sodium water glass solutions. The sodium ions here are preferably removed from the solution using an ion exchanger. The remaining silicic acid here is already present as a condensation product. These are polyhedral structures with a size of approx. 0.5 nm, again called primary particles, which then form fractal clusters by aggregation as a function of pH, these clusters in turn leading to gelation (B. Knoblich, Th. Gerber: Aggregation in SiO₂sols from sodium silicate solutions, Journal of Non-Crystalline Solids 283 (2001), 109-113).
The aggregation clusters (solid structure, metal oxide) of the alcogel (solvent, alcohol) and/or of the hydrogel (solvent, water) are destroyed in drying due to the capillary forces in effect and the condensation of the inside surface taking place (2Si_surface−OH→Si_bulk−O−M_bulk+H₂O). A xerogel is formed, its internal surface area being, e.g., in the case of SiO₂, in the range of 25-700 m²/g, and its density being in the range of 1.0 g/cm³. The defined polyhedral structures in the primary particles undergo crosslinking during drying, forming a continuous network having the large internal surface area described above. The crosslinking of the silicon dioxide is increased.
This process is prevented in the production of aerogels. There are fundamentally two different methods for accomplishing this according to the state of the art.
First, hypercritical drying methods are used. The effect of the capillary forces is prevented in this way, because the liquid/gas phase transition is bypassed by a corresponding temperature-pressure regime. As solvents, herein alcohols (methanol, ethanol, propanol) or liquid CO₂is used, which must replace the original solvent, usually H₂O, through exchange processes (S. S. Kistler, Phys. Chem. 36 (1932), 52-64; EP 171722; DE 1811353; US 3,672,833; DE 39 24 244 Al; PCT/EP 94/02822). These methods are very expensive due to the autoclaves used.
On the other hand, there are methods in the state of the art which allow a subcritical drying of aerogels. The core point of the method according to PCT/US 94/05105 is a modification of the contact angle between the solvent and the scaffold of solid structure, This reduces the capillary pressure and nearly preserves the structure of the moist gel. The contact angle is obtained by a modification of the inner surface of the scaffold of solid structure in the moist gel. To this end, a reaction of the internal surface area with R_xSiX_yoccurs, wherein R is an organic group and X is a halogen. In this method it is necessary to replace the solvent several times. In the patent DE 19538333 A1 a modification of the internal surface of the moist gel is implemented with Si_surfaceO−Z where Z is any group that should prevent condensation of the internal surface in drying.
The methods used for production of aerogels are not used in the context of the present invention. In particular, no gelation occurs.
The object of the present invention is to produce materials having a defined degree of crosslinking of the silicic acid. Products such as microparticles, fibers or layers can be produced from these.
According to the invention, this object is achieved by preventing further condensation when certain degrees of crosslinking of the silicic acid are obtained, in particular when the desired size of the silica gel clusters has been obtained by condensation, wherein the desired size of the silica gel clusters is preferably in the range of approx. 0.5 nm up to approx. 1000 nm, more preferably from 0.5 nm to 20 nm, more preferably up to 10 nm, up to 5 nm, up to 4 nm, up to 3 nm, up to 2 nm or up to 1 nm.
According to the invention, in one embodiment, this object is achieved by preventing further condensation when certain degrees of crosslinking of the silicic acid are obtained. In contrast with the production of aerogel, this occurs even before gelation.
The polyhedrons in the primary particles of polysilicic acid described above or small aggregates of same (see above), which can also referred to as primary particles within the scope of this invention, have a very low degree of crosslinking. This is preserved by replacing the water present by an organic solvent after their formation. The solvent may be in particular an alcohol having 1 to 10 carbon atoms, for example, methanol, ethanol, propanol, butanol, pentanol, hexanol, etc. or phenol as an aryl group, optionally substituted to a degree that is compatible with use according to the present invention; in particular this solvent is ethanol or phenol, preferably ethanol. In the Si_{primary particle}OH groups present at the surface of the primary particles, the proton is replaced by an organic group such as an alkyl or aryl group, preferably one having 1 to 10 carbon atoms, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. or phenyl as the aryl group, optionally being substituted to a degree that is compatible with the inventive use, this group being in particular ethyl or phenyl, preferably ethyl. Thus an esterification is performed. The hydrolysis/esterification is an equilibrium reaction which is shifted in the direction of esterification. This may occur, for example, by withdrawing water in the presence of a catalyst. The water can be eliminated by distilling off the water-solvent (e.g., ethanol) mixture, and by removing the water in the distillate by a molecular sieve, and returning the solvent (e.g., ethanol).
The degree of esterification in the materials obtained according to the invention is preferably approx. 50% to approx. 95%, more preferably approx. 60% to approx. 80% or approx. 70% to approx. 75%.
The size of the silica gel clusters/aggregates obtained by condensation is preferably in the range of approx. 0.5 nm to 1000 nm, in particular approx. 0.5 nm to approx. 20 nm or up to approx. 10 nm, up to approx. 4 nm, up to approx. 2 nm or up to approx. 1 nm. Gelation is thus prevented by the inventive method.
The esterified primary particles (and/or the aggregates of same) in alcoholic solution without water are now stable. They can be processed further. If they are, e.g., spray dried, the alcohol escapes from the droplets, forming microparticles (original droplets) having a dense packing of primary particles without any further crosslinking.
If secondary structures such as microparticles or fibers are to be produced from the esterified primary particles, then the degree of esterification should be between approx.
60% and 95%, so that a bonding of the primary particles via silanol bridges can take place, but crosslinking of the SiO₂structure is prevented.
For a medical application, the organic groups such as ethyl groups may subsequently be removed again by hydrolysis or by treatment in an oxygen plasma. Vicinal SiOH groups may then also be condensed, but no continuously crosslinked structure such as that in xerogel is formed.
The crosslinking of the SiO₂structures can be documented with the help of small angle x-ray scattering (SAXS) and wide small angle x-ray scattering (WAXS) (B. Himmel, Th. Gerber and H. Burger: WAXS and SAXS investigations of structure formation in alcoholic SiO₂solutions, Journal of Non-Crystalline Solids, Amsterdam, 119 (1990), 1-13; B. Himmel, Th. Gerber and H. Burger: X-ray diffraction investigations of silica gel structures, Journal of Non-Crystalline Solids, Amsterdam, 91 (1987)122-136; B. Himmel, Th. Gerber, W. Heyer and W. Blau: X-ray diffraction analysis of SiO₂structure, Journal of Material Science, Chapman and Hall Ltd., London, 22 (1987), 1374-1378; Th. Gerber and B. Himmel: The structure of silica glass in dependence on the fictive temperature, Journal of Non-Crystalline Solids, Amsterdam, 92 (1987), 407-417; Th. Gerber and B. Himmel: The structure of silica glass, Journal of Non-Crystalline Solids, Amsterdam, 83 (1986), 324-334; B. Himmel, Th. Gerber and H.-G. Neumann: X-ray diffraction investigations of differently prepared amorphous silicas, Physica Status Solidi (a), 88 (1985), K127-K130).
It is an important finding that can be utilized to control the synthesis processes that the position of the main maximum of the WAXS scattering curve of different SiO₂structures is a measure of the degree of crosslinking. The lowest crosslinking (of a complete polyhedron) has a maximum at approx. 16.4 nm⁻¹. Complete crosslinking, such as that which occurs in silica glass, has a maximum at approx. 14.7 nm⁻¹. This is utilized in the examples.
The degree of crosslinking of the inventive material is preferably one that would lead to a main maximum of a WAXS scattering curve of more than 14.7 nm⁻¹and less than 16.4 nm⁻¹. The main maximum is preferably between 15.5 nm⁻¹and less than 16.4 nm⁻¹, e.g., approx. 16.0 nm⁻¹.
Then, a spinnable solution can be prepared from the esterified primary particles (and/or aggregates of same). To do so, enough alcohol is removed that the viscosity is in the range of approx. 0.6-0.8 Pas, preferably approx. 0.7 Pas. The solution is then forced through nozzles at a pressure of approx. 9-11 bar, preferably approx. 10 bar. In a spinning tower, the fibers dry in a temperature-controlled air stream and are captured on a grating. Similar as in the microparticles, the esterified primary particles are present in the form of a dense packing in the fibers. The ethyl groups can also be removed again here.
The esterified primary particles (and/or aggregates of same) in alcoholic solution can also be used to produce layers on implants or wound dressings. Known coating methods such as dip coating, spin coating or spray coating may be used for this purpose. The decisive point here is again that the layer is constructed by a packing of the primary particles wherein no continuous network like that in a xerogel is formed in drying.
The esterification is preferably facilitated by a catalyst, in particular an acid or a base or an ion exchanger. An organic acid (e.g., formic acid, acetic acid, maleic acid, oxalic acid) is preferably used, but inorganic acids such as HCl may also be used. The catalyst is preferably tissue compatible in the quantities contained in the product. Orientation for the selection of a catalyst is provided by C. F. Brinker and G. W. Scherer in Sol-Gel Science: The physics and chemistry of sol-gel processing, chapter 2.3.1 “Effects of catalysts” (Academic Press, San Diego, 1990).
In the process steps described so far the catalyst is still present in the biomaterial at the end of the process, but this might have an influence on the biological efficacy. However, the catalyst may also be removed so that the resulting material does not contain any significant amounts of catalyst or even none at all. First, this can be prevented by using organic acids as the catalyst for hydrolysis and for esterification. Since acetic acid and formic acid themselves undergo esterification easily, oxalic acid is preferred here. The acid can be removed easily by an oxygen plasma treatment. Secondly, an ion exchanger, e.g., sulfonated polystyrene may be used as the catalyst. The advantage is that the ion exchanger (polystyrene beads) can easily be removed from the finished solution.
The process described here can also be performed when the aggregation of the primary particles has begun. If a few primary particles have been bonded by a condensation reaction and if the esterification and the drying processes described above are performed then, the result is a dense packing of these aggregates which do not undergo further crosslinking.
The degree of crosslinking of the silicic acid can be increased in a controlled manner in an aqueous solution before esterification. The sol with the primary particles is adjusted to a pH between 7 and 9, preferably approx. pH 7 to approx. 7.4, approx. pH 8 or approx. pH 9. As the isoelectric point of the silicic acid is approx. pH 2, the particles have a strong negative charge and therefore cannot aggregated. However, the nanoparticles grow by Ostwald aging. Since the silicic acid in the nanoparticles forms a network, the degree of crosslinking becomes greater with the growth in particle size. The process is stopped and preserved by replacing the solvent water and performing esterification.
Then, the various dosage forms (granules, microparticles, fibers, layers) can be produced using these primary particles which are now larger and more crosslinked.
Silylation of the internal surface of the silicic acid condensates described above instead of esterification is another possibility for preventing further crosslinking of the silicic acid. The following reaction is preferably performed:
Si_surface 0H+(C₂H₅)₃SiCl→Si_surfaceOSi(C₂H₅)₃+HCl.
Acetone is the preferred organic solvent here, but another ketone (e.g., propanone) can also be used. The synthesis procedures for the different dosage forms described above (granules, microparticles, fibers, layers) can also be used here subsequently.
Using the silicic acid structures with a low degree of crosslinking described herein to improve wound healing, it is advantageous to utilize a suitable support material. Wound dressings according to the state of the art are recommended here. Absorbable materials should preferably be used because the SiO₂is released on absorption of the support.
The invention preferably provides a method for creating silicic acid structures having a low degree of crosslinking, comprising:
a) preparing a sol,
b) replacing the water contained in the sol by a water-soluble organic solvent,
c) after eliminating the water in the sol by using an organic solvent, replacing the hydrogen atoms of the Si_surfaceOH groups present on the internal surface of the silicic acid clusters are replaced by a chemical group Z which has the ability to prevent further condensation (2Si_surface 0H=Si_bulkO−Si_bulk+H₂O) and does not undergo polymerization itself. This group Z preferably has an organic residue R facing the surface.
In this method, the sol can be produced by hydrolysis of tetraethyl orthosilicate (TEOS), preferably using an r_wvalue (molar ratio of water to TEOS) of 4. The preferred solvent for use is ethanol. The catalyst for the hydrolysis reaction is preferably an organic acid, especially oxalic acid. The water can be replaced by an organic solvent, preferably ethanol, when the desired size of the silica gel clusters has been obtained by condensation, wherein the size is in the preferred range of approx. 0.5 nm up to 1000 nm, in particular approx. 0.5 nm to approx. 20 nm or 1 to 10 nm.
The sol can also be produced by ion exchange of a sodium water glass solution, wherein the water is replaced by an organic solvent, preferably ethanol, when the desired size of the silica gel clusters has been obtained by condensation, wherein the preferred size is in the range of approx. 0.5 nm up to 1000 nm, in particular approx. 1 nm to approx. 10 nm or 2 to 5 nm.
The internal surface of the silicic acid clusters and/or OH groups thereof can be esterified to yield Si_surfaceOR, wherein R is an organic group such as an alkyl or aryl group, preferably having 1 to 10 carbon atoms, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. or phenyl as an aryl group, optionally substituted to a degree that is compatible with the inventive application; in particular, this group is ethyl or phenyl, preferably ethyl. The esterification herein is preferably implemented by removing the water formed in esterification in the presence of an acid, preferably an organic acid, most preferably oxalic acid. Preferably a degree of esterification of 50% or more is obtained, in particular 60% or more or 70% or more.
Alternatively, the internal surface in the sol may be silylated to form Si_surfaceOSiR_xand/or Si_surfaceR, wherein R is an organic group such as an alkyl or aryl group, preferably with 1 to 10 carbon atoms, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. or phenyl as an aryl group, optionally substituted to a degree that is compatible with the inventive use; in particular, this group is ethyl or phenyl, preferably ethyl. The following reaction is preferably utilized herein:
Si_surfaceOH+(C₂H₅)₃SiClI→Si_surfaceOSi(C₂H₅)₃+HCl.
The degree of silylation preferably is 50% or more. Other process steps are preferably also performed as in the esterification.
The solvent is preferably removed in the processes of the invention.
A spray drying process is preferably used in the processes of the invention.
The water contained in the sol is preferably replaced by an organic solvent in the processes of the invention when the silica gel clusters have a size of 0.5 to 4 nm. The organic solvent is preferably ethanol. Esterification is performed, and the esterified sol is preferably boiled down until the solids content (SiO₂) in the sol is preferably in the range of 3 to 25 wt %. This sol is preferably spray dried, wherein the spray drying parameters are preferably selected so as to form hollow microparticles.
The solvent is preferably removed in the processes of the invention until the viscosity of the sol is in the range of 0.1 Pas to 10 Pas, preferably in the range of 0.3 Pas to 0.7 Pas. This sol may be spun into fibers by known methods.
The water contained in the sol is preferably replaced by an organic solvent in the processes of the invention when the silica gel clusters have a size of 0.5 to 4 nm. The organic solvent preferably is ethanol. Esterification is performed, and the esterified sol is preferably boiled down until the sol has a viscosity preferably in the range of 0.3 Pas to 0.7 Pas. This sol is preferably spun to form gel fibers by known methods.
A solids content (SiO₂) in the sol which is in the range of 3 to 25 wt % is preferably obtained in the process of the invention by removing or adding solvent. This sol is preferably used for known coating methods such as dip coating, spin coating or spray coating.
Preferably, a catalyst, in particular an organic acid, preferably oxalic acid, is used in the processes of the invention. Alternatively the catalyst used may be an acidic ion exchanger, preferably sulfonated polystyrene R—SO₃H.
In the processes of the invention, the sol is preferably subjected to an aging process before the surface is preserved as described above, wherein the solvent is water or a mixture of water and organic solvent and a pH>7 is set.
The organic components are preferably oxidized in the processes of the invention, preferably using an oxygen plasma. In particular, this takes place after esterification/silylation.
In one embodiment, the silicic acid structures with a low degree of crosslinking that are produced in the processes of the invention (preferably after esterification/silylation) are added to an aqueous solution of polymer, wherein that the polymer content in the solution preferably is between 2 and 15 wt %, and the amount of SiO₂with respect to the polymer/water solution is preferably in the range of 2 up to 40 wt %, wherein the solution containing the homogeneously mixed silicic acid structures is poured into a mold and freeze dried. Herein, the water-soluble polymer may be polyvinyl pyrrolidone. Collagen may also be used instead of the water-soluble polymer.
The subject matter of the invention is also a material obtainable by this method. Materials according to the invention may also be referred to as biomaterials.
A material formed by SiO₂polyhedral structures having a size of 0.5 nm to 4 nm and having SiOH, SiOR or SiR groups at the surface, wherein R is an organic group such a an alkyl or aryl group, preferably with 1 to 10 carbon atoms, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. or phenyl as an aryl group, optionally substituted to a degree that is compatible with the use of the invention, is also subject matter of the invention, wherein, in particular, said group is methyl, ethyl or phenyl, preferably ethyl. The size of these structures is stable.
The material may be present in the form of granules. The material may also be in the form of microparticles, preferably hollow microparticles and/or preferably having a diameter in the range of 2 μm to 100 μm. The material may also be present in the form of fibers, preferably with a diameter in the range of 1 μm to 50 μm. The material may also be in the form of a layer on implants or wound dressings.
The material of the invention may be embedded in a support material, preferably using an organic membrane, an organic fleece or an organic sponge, wherein a biodegradable organic material is preferably employed. In particular a gelatin sponge or a sponge of polyvinyl pyrrolidone may be used as support.
The subject matter of the present invention is also the use of the inventive material (biomaterial) for medical devices, in particular for those having a supporting or shielding function and/or those that can at the same time, through degradation, serve as a supplier of the silicon dioxide that supports tissue regeneration. Within the context of the present invention, the term medical device is to be used as interchangeable with medical or pharmaceutical composition or medicament, because the classification depends on national law, which however does not change the substance of the invention.
The subject matter of the present invention also includes the use of the inventive material (biomaterial) as a nutritional supplement.
The present invention is illustrated and explained in the following examples, but they do not restrict its scope in any way. Publications cited in this patent application are herewith fully incorporated herein through this reference.

LEGENDS

FIG. 1 shows a photographic illustration of the fleece made of silica fibers according to example 1.

FIG. 2 shows a scanning electron micrograph of a gel fiber according to example 1.

FIG. 3 documents an x-ray diffraction analysis of the silica gel fibers according to example 1, untreated and after various temperature treatments.

FIG. 4 shows a scanning electron micrograph of the microparticles produced in example 2.

FIG. 5 shows the x-ray diffraction of the microparticles produced in example 2 through 5 with a degree of esterification of approx. 50% (bottom curve), approx. 75% (middle curve) and approx. 90% (top curve).

FIG. 6 shows, in different magnifications, scanning electron micrographs of a polyvinyl pyrrolidone sponge with microparticles bound into it. A: scale=200 μm, B: scale=40 μm.

FIG. 7 shows scanning electron micrographs of a gelatin sponge with microparticles bound into it in two different magnifications. A: scale=40 μm, B: scale=9 μm.

EXAMPLES

Example 1

For 20 minutes, 100 g TEOS, 35 g H₂O, 3 g oxalic acid and 800 g ethanol are mixed with a magnetic stirrer in a vessel. During this period of time, the TEOS is hydrolyzed. Then the water is removed by azeotropic distillation, wherein the ethanol is returned back to the vessel after removing the water through a molecular sieve. This process is performed for 2 hours.
Then the ethanol reflux is stopped and the solvents are removed by distillation until the viscosity determined in situ is between 0.5 and 0.7 Pas.
The sol esterified in this way is forced through a nozzle system of seven nozzles at 11 bar, wherein these nozzles each have a diameter of 0.2 mm.
The fibers are spun in a 3-meter-tall tower (stainless steel tube with a diameter of 30 cm) in a stream of air at a temperature of 60° C. The gel fibers are captured on a screen by means of a turbulent air stream across the spinning direction at a temperature of 150° C. to form a fleece-type fabric.
FIG. 1 shows a photographic image of the gel fleece. The interior of the fibers appears to be homogeneous in the scanning electron micrograph (FIG. 2). However, the x-ray diffraction analyses (FIG. 3) document that the fibers are determined by a packing of approx. 0.5 to 1 nm particles. This is shown by the peak at approx. 5 nm⁻¹. The peak at 16.4 nm⁻¹of the untreated sample (main maximums of the WAXS scattering curve) documents a low degree of crosslinking of the SiO₂polyhedral structures. Only the high temperature treatment leads to better crosslinking, until a complete network typical of silica glass is formed starting at a temperature of approx. 650° C. or higher. The peak at approx. 5 nm⁻¹has then disappeared.
This example documents that gel fibers containing SiO₂polyhedral structures with the lowest possible degree of crosslinking are obtained by the method described here.

Example 2

For 20 minutes, 100 g TEOS, 35 g H₂O, 3 g oxalic acid and 800 g ethanol are stirred with a magnetic stirrer in a vessel. During this period of time, the TEOS is hydrolyzed. Then the water is removed by azeotropic distillation, wherein ethanol is returned back to the vessel after removing the water through a molecular sieve. This process is performed for 1 hour.
Then the ethanol reflux is stopped and solvent is removed by distillation until 220 g of the batch remains (the SiO₂portion here amounts to approx. 28 g).
The batch is then spray dried using a Büchli 290 with inert loop.
FIG. 4 shows the resulting microparticles in a scanning electron micrograph. The x-ray diffraction in FIG. 5 (curve with a degree of esterification of approx. 50%, determined by IR spectroscopy) shows the typical peak at approx. 5 nm⁻¹.

Example 3

For 20 minutes 100 g TEOS, 35 g H₂O, 3 g oxalic acid and 800 g ethanol are stirred with a magnetic stirrer in a vessel. During this period of time, the TEOS is hydrolyzed. Then the water is removed by azeotropic distillation, wherein ethanol is returned back to the vessel after removing the water through a molecular sieve. This process is performed for 2 hours.
Then the ethanol reflux is stopped and solvent is removed by distillation until 220 g of the batch remains (the SiO₂portion here amounts to approx. 28 g).
The batch is then spray dried using a Büchli 290 with inert loop.
FIG. 5 shows the x-ray diffraction of the resulting microparticles (curve with a degree of esterification of approx. 75%, determined by IR spectroscopy).

Example 4

For 20 minutes 100 g TEOS, 35 g H₂O, 3 g oxalic acid and 800 g ethanol are stirred with a magnetic stirrer in a vessel. During this period of time, the TEOS is hydrolyzed. Then the water is removed by azeotropic distillation, wherein ethanol is returned back to the vessel after removing the water through a molecular sieve. This process is performed for 4 hours.
Then the ethanol reflux is stopped and solvent is removed by distillation until 220 g of the batch remains (the SiO₂portion here amounts to approx. 28 g).
The batch is then spray dried using a Büchli 290 with inert loop.
FIG. 5 shows the x-ray diffraction of the resulting microparticles (curve with a degree of esterification of approx. 90%, determined by IR spectroscopy).

Example 5

7 g polyvinyl pyrrolidone is dissolved in 100 g H₂O. The microparticles produced in example 4 are treated in an oxygen plasma for 1 hour, so the ethyl groups and residues of the catalyst (oxalic acid) are removed. Then 3 g of these microparticles are added to the solution and distributed homogenously. Next the material is placed in dishes, so that the level of the liquid is 5 mm high. The mixture of H₂O and polyvinyl pyrrolidone and the microparticles is frozen and freeze dried, forming a polyvinyl pyrrolidone sponge with the microparticles bound into it, as shown in the scanning electron micrograph in FIGS. 6A and B.

Example 6

7 g gelatin is dissolved in 100 g H₂O. The microparticles produced in example 4 are treated in an oxygen plasma for 1 hour, so the ethyl groups and residues of the catalyst (oxalic acid) are removed. Then 3 g of these microparticles are added to the solution and distributed homogenously. Next the material is placed in dishes so that the level of liquid is 5 mm high. The mixture of H₂O and gelatin and the microparticles is frozen and freeze dried resulting in a gelatin sponge with microparticles bound into it as shown in the scanning electron micrograph in FIGS. 7A and B.

Claims

1. A method for producing silicic acid structures having a low degree of crosslinking, comprising producing a sol, and comprising preventing further condensation before gelation when a certain crosslinking of the silicic acid is obtained, wherein, preferably, structures 0.5-1000 nm in size are produced.

2. A method for producing silicic acid structures having a low degree of crosslinking, preferably according to claim 1, comprising controlling the condensation of silicic acid in aqueous or alcoholic solution so that defined polyhedral structures are formed, and preserving these polyhedral structures in the following method steps such as removal of the solvent, so that silicic acid structures with a low degree of crosslinking are produced which are not incorporated into a continuous network, wherein the polyhedral structures are preferably essentially SiO₂tetrahedrons, wherein five-membered, six-membered and/or seven-membered rings form a three-dimensional structure with a diameter of approx. 0.5 nm.

3. The method according to claim 1, wherein further condensation is prevented by esterifying or silylating OH groups of the silicic acid structures, preferably by esterifying them.

4. A method for producing silicic acid structures having a low degree of crosslinking, according to claim 1, comprising

a) producing a sol,

b) replacing the water contained in the sol by a water-soluble organic solvent,

c) after eliminating the water with an organic solvent, replacing the hydrogen atoms of the Si_surfaceOH groups present on the internal surface of the silicic acid clusters in the sol by a chemical group Z which has the property of preventing further condensation and does not itself undergo polymerization, wherein said group Z preferably has an organic residue R, wherein the reaction of group Z with the Si_surfaceOH groups preferably is an esterification reaction.

5. The method according to claim 1,

wherein the sol is created by hydrolysis of tetraethyl orthosilicate (TEOS),

wherein an r_wvalue (molar rate of water to TEOS) of 4is preferably used,

and/or wherein ethanol is preferably used as a solvent,

and/or wherein an organic acid, preferably oxalic acid, is preferably used as the catalyst for the hydrolysis,

and/or wherein the water is preferably replaced by an organic solvent, preferably ethanol, when the desired size of the silica gel cluster has been reached by condensation, wherein the desired size preferably is in the range of 0.5 nm to 1000 nm.

6. The method according to claim 1, wherein the sol is produced by ion exchange of sodium water glass solution, wherein preferably the water is replaced by an organic solvent, preferably ethanol, when the desired size of the silica gel clusters has been reached by condensation, wherein the desired size preferably is in the range of 0.5 nm to 1000 nm, more preferably 1 nm to 1000 nm.

7. The method according to claim 1, wherein the internal surface of the silicic acid clusters is esterified to Si_surfaceOR wherein R is an organic residue,

wherein R preferably is an alkyl or aryl group, preferably with 1 to 10 carbon atoms, selected from the group comprising methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. or phenyl as an aryl group, optionally substituted to a degree that is compatible with the use of the invention, wherein R in particular is ethyl or phenyl, preferably ethyl, and/or

wherein the esterification is preferably implemented by removing the water formed in the esterification in the presence of an acid, preferably an organic acid, more preferably oxalic acid, and/or

wherein a degree of esterification greater than 50% preferably is achieved.

8. The method according to claim 1, wherein the internal surface in the sol is silylated to Si_surfaceOSiR_xor Si_surfaceR, wherein R is an organic residue, preferably methyl, ethyl or phenyl,

wherein the following reaction is preferably used:

Si_surfaceOH+(C₂H₅)₃SiClI→Si_surfaceOSi(C₂H₅)₃+HCl

and/or wherein the degree of silylation preferably is greater than 50%.

9. The method according to claim 1, wherein a catalyst is used, wherein the catalyst that is used is selected from the group comprising an organic acid, more preferably oxalic acid, and an acetic ion exchanger, preferably sulfonated polystyrene R—SO₃H.

10. The method according to claim 1, wherein the sol is subject to an aging process before the surface is preserved by the reaction of the group Z with the Si_surfaceOH groups, wherein the solvent is water or a mixture of water and organic solvent and the pH is adjusted to 7 or more.

11. The method according to claim 1, wherein the organic components are oxidized, preferably using an oxygen plasma.

12. The method according to claim 1, wherein the solvent is removed.

13. The method according to claim 12, wherein a spray drying process is used.

14. The method according to claim 1, wherein the water contained in the sol is replaced by an organic solvent when the silica gel clusters have a size of 0.5 to 4 nm,

wherein the solvent preferably is ethanol, and

wherein, preferably, an esterification is performed, wherein the esterified sol is preferably boiled down to the extent that the solids content (SiO₂) in the sol is in the range of 3 to 25 wt %, and/or

wherein the sol preferably is spray dried, wherein the spray parameters are preferably selected so that hollow microparticles are formed.

15. The method according to claim 1, wherein the solvent is removed so that the viscosity of the sol is in the range of 0.1 Pas to 10 Pas, preferably in the range of 0.3 Pas to 0.7 Pas, and wherein said sol is preferably spun to form fibers.

16. The method according to claim 1, wherein the water contained in the sol is replaced by an organic solvent when the silica gel clusters have a size of 0.5 to 4 nm, wherein the solvent preferably is ethanol, wherein an esterification is performed with the ethyl group, and wherein the esterified sol is preferably boiled down so that said sol has a viscosity in the range of 0.3 Pas to 0.7 Pas, and wherein said sol is preferably spun to gel fibers.

17. The method according to claim 1, wherein a solids content (SiO₂) in the sol which is in the range of 3 to 25 wt % is obtained by adding or removing solvent, wherein said sol is preferably used for known coating methods such as dip coating, spin coating or spray coating.

18. The method according to claim 1, wherein the silicic acid structures having a low degree of crosslinking are added to an aqueous solution of a polymer selected from a group comprising polyvinyl pyrrolidone and collagen,

wherein, preferably, the polymer content in the solution is between 2 wt % and 15 wt %, and/or

wherein, preferably, the amount of SiO₂with respect to the polymer/water solution is in the range of 2 wt % to 40 wt %, and/or

wherein, preferably, the solution with the homogeneously mixed silicic acid structures is poured into a mold and freeze dried.

19. A biomaterial obtainable by a method according to claim 1, which is preferably composed of silicic acid structures having a size of 0.5 nm to 1000 nm, more preferably of 0.5 nm to 4 nm, and/or comprises said structures.

20. A biomaterial, preferably according to claim 19, which is composed of SiO₂polyhedral structures having a size of 0.5 nm to 4 nm, which have SiOH, SiOR and/or SiR groups on the surface, wherein R is an organic residue, preferably an alkyl or aryl group with 1 to 10 carbon atoms selected from the group comprising methyl, ethyl or phenyl.

21. The biomaterial according to claim 19, having a form selected from the group consisting of

granules,

microparticles, preferably hollow microparticles, preferably with a diameter in the range of 2 μm to 100 μm,

fibers, preferably with a diameter in a range of 1 μm to 50 μm,

layer, where the layer preferably is a layer on an implant or a wound dressing.

22. The biomaterial according to claim 19, which is embedded in a support material, wherein the support material preferably is an organic membrane, an organic fleece or an organic sponge and/or wherein the support material preferably is a biodegradable organic material,

wherein, preferably, a gelatin sponge or a sponge of polyvinyl pyrrolidone is used as the support.

23. The biomaterial according to claim 9 for use as a medical device, which has a supporting or shielding function, and, preferably, can, through its degradation, at the same time serve to supply silicon dioxide that supports tissue regeneration.

24. The biomaterial according to claim 19 for use in the treatment of wounds or scars or for cosmetic applications, in particular as a cream or ointment.

25. A medical device or a nutritional supplement comprising the biomaterial according to claim 19.