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    • 专利摘要:
    The present invention relates to a soluble silica composition comprising: a mesoporous silica having a specific surface area of at least 100 m²/g; and a salt, said salt consisting of a cation and an anion, wherein said salt is selected from the list of alkali metal salts, alkaline earth metal salts or a mixture thereof; wherein the weight ratio of cation of said salt to mesoporous silica is between 0.1:100 and 300:100. The present invention further relates to a method of solubilizing silica. The present invention also relates to the use of soluble silica compositions.
    公开号:BE1028282B1
    申请号:E20215274
    申请日:2021-04-08
    公开日:2022-02-04
    发明作者:Ivan Coste-Manière；Frederik Monsuur；Nicolas Mannu
    申请人:Silinnov Scrl；
    IPC主号:
    专利说明:

    SOLUBLE MESOPOROUS SILICA COMPOSITION, MESOPOROUS SILICA SOLUBILIZATION METHOD AND USE THEREOF FIELD OF THE INVENTION The present invention relates to mesoporous silica, in particular the solubilization of mesoporous silica. The invention further relates to the technical field of nutraceuticals for providing a bioabsorbable source of silicon to humans or animals as well as drug delivery systems for delivering active ingredients to humans or animals in a manner controlled.
    BACKGROUND Mesoporous silica, and nanoparticles of mesoporous silica (NSM) in particular, have been intensively studied as a biomaterial over the past decade due to its many promising benefits. Mesoporous silica materials exhibit superior capacity for drug loading and provide controlled release of bioactive compounds if functionalized, compared to amorphous colloidal silica, such as fumed silica. Mesoporous silica is of particular interest because of its high specific surface area, uniform and fine-tunable pore size, high pore volume, and easy functionalization. However, silica is known to be very stable; making it difficult to dissolve or degrade. For food and pharmaceutical applications in particular, questions regarding the biodegradability and clearance of silica materials remain. Food and pharmaceutical products should not —accumulate in the body to prevent severe and unpredictable side effects. Non-degradable nanoparticles smaller than 5.5 nm are often assumed to be eliminated by the kidneys. This will be called renal clearance. It is impossible to make the same assumption for nanoparticles of larger particle size.
    A known method for modifying the properties of mesoporous silica is functionalization.
    Namely, the introduction of elements, atoms or molecules into the silica network.
    However, functionalized mesoporous silica has several drawbacks.
    It requires specialized knowledge and reagents.
    She often uses energy-intensive methods such as heat treatments.
    It is difficult to target changes of a single property, the adaptation of the silica network in a mesoporous silica will affect many properties such as porosity, pore volume, surface area, dissolution rate, etc.
    It is thus difficult to adapt a property without affecting the other properties.
    As a result, each functionalized mesoporous silica is only effective for a narrow and specific use.
    The present invention aims to solve at least some of the problems and disadvantages mentioned above.
    The object of the invention is to provide a method which eliminates these disadvantages.
    The present invention aims to solve at least one of the disadvantages mentioned above.
    SUMMARY OF THE INVENTION The present invention and embodiments thereof serve to provide a solution to one or more of the aforementioned disadvantages.
    To this end, the present invention relates to a soluble silica composition according to claim 1. Preferred embodiments of the device are shown in any one of claims 2 to 11. The incorporation of cations into a silica network is known to destabilize said network.
    The inventors have surprisingly discovered that the rate of dissolution of a mesoporous silica having a sufficiently high surface area can be significantly increased by providing alkaline and alkaline earth cations in the solution medium rather than in the silica network.
    It is thus not necessary to functionalize the mesoporous silica with cations; by incorporating said cations into the silica network.
    Instead, the combination of a mesoporous silica with a sufficiently high surface area and a salt that readily dissociates into the required alkaline and alkaline earth cations once brought into solution is sufficient. This avoids the need for functionalization of the mesoporous silica. Furthermore, it allows the dissolution rate to be adjusted without affecting properties such as pore size distribution, particle size or even the structure of the silica network.
    In a second aspect, the present invention relates to a method according to claim 12. In a preferred embodiment, the present invention comprises a method according to claim 13.
    It is particularly advantageous to increase the rate of dissolution of the particles of mesoporous silica in the human or animal body. This ensures the clearance of said mesoporous silica from the body. Furthermore, the dissolution rate can be fine-tuned to control the release of silicon and/or bioavailable pharmaceutically active ingredients that can be loaded onto said mesoporous silica.
    In a third aspect, the present invention relates to a use according to claim 14. In a preferred embodiment, the present invention relates to a use according to claim 15.
    DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a soluble silica composition, a method for solubilizing silica and the use of soluble silica compositions.
    Unless otherwise defined, all terms used in the disclosure of the invention, including technical and scientific terms, have the meaning commonly understood by one skilled in the art to which this invention belongs. Definitions of terms are included for information purposes to better appreciate the teaching of the present invention.
    As used herein, the following terms have the following meanings: The terms "a", "an", "the" and "the" as used herein refer to both the singular and the plural, unless the context clearly indicates otherwise. By way of example, “a Compartment” means one or more Compartments.
    "About" as used herein in reference to a measurable value such as a parameter, quantity, duration and the like, is intended to encompass variations of +/-20% or less, preferably +/-10 % or less, more preferably +/-5% or less, still more preferably +/-1% or less, and still more preferably +/-0.1% or less relative to the value specified, insofar as such variations are applicable to the invention disclosed. However, it is understood that the value to which the "about" modifier refers is itself specifically disclosed.
    "Include", "comprising" and "comprises" and "consist of" as used herein are synonymous with "include", "including", "include" or "contain", "containing", "contains" and are inclusive or open-ended terms that specify the presence of the following, for example, a component, and do not exclude or preclude the presence of additional components, features, elements, members, steps not listed, known in the art or disclosed here.
    Further, the terms first, second and third and others in the description and in the claims, are used to distinguish between like items and not necessarily to describe sequential or chronological order unless otherwise specified. It is understood that the terms so used are interchangeable in appropriate circumstances and that the embodiments of the invention described herein are capable of functioning in sequences other than those described or illustrated herein.
    Citation of numeric ranges by bounds includes all numbers and fractions subsumed within that range, as well as the quoted bounds. The term "% by weight", "percent by weight", "percent by weight", here and throughout the description, unless otherwise defined, refers to the relative weight of the respective component based on the total weight of the formulation.
    While the terms "one or more" or "at least one", such as one or more or at least one member(s) of a group of members, are clear per se, by way of further example, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any of = 3, > 4, = 5, = 6 or = 7 etc of said members, and up to all of said members.
    Unless otherwise defined, all terms used in the disclosure of the invention, including technical and scientific terms, have the meaning commonly understood by one skilled in the art to which this invention belongs. Definitions of terms used in the specification are included as a guide to better appreciate the teaching of the present invention. Terms or definitions used herein are provided solely to aid in the understanding of the invention. Reference throughout this specification to "an embodiment" means that a particular feature, structure or feature described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the terms "in one embodiment" at various places throughout this specification do not necessarily all refer to the same embodiment, but may. Further, particular features, structures or features may be combined in any suitable manner, as would be apparent to those skilled in the art from this disclosure, in one or more embodiments. Further, although some embodiments described herein include some, but not other features included in other embodiments, combinations of features from different embodiments are intended to be within the scope of the invention, and to form various embodiments, as would be understood by those skilled in the art. For example, in the following claims, any of the claimed embodiments may be used in any combination.
    A "clogged mesoporous silica" as used herein refers to a mesoporous silica comprising a surfactant within at least some of its mesopores. An "obstructed mesoporous silica" is not restricted to a mesoporous silica in which all or nearly all of the mesopores are obstructed. Without being bound by theory, it is believed that the surfactant comprised within the mesoporous silica partially clogs these mesopores. That is, the mesopores are at least partly clogged or otherwise unavailable. It should be noted that this "clogging" does not require that all pores, or even all mesopores, be unavailable. Plus, the pores don't need to be permanently blocked.
    In a first aspect, the invention provides a soluble silica composition comprising:
    at. a mesoporous silica having a specific surface area of at least 100 m2/g; and B. a salt, said salt consisting of a cation and an anion, wherein said salt is selected from the list of alkali metal salts, alkaline earth metal salts or a mixture thereof; wherein the weight ratio of cation of said salt to mesoporous silica is between 0.1:100 and 300:100. The inventors have observed that, unexpectedly, a mesoporous silica having a sufficiently high surface dissolves much more quickly in the presence of alkali or alkaline-earth metal ions. In other words, the inventors have discovered that alkali and alkaline-earth metal ions catalyze the dissolution of mesoporous silica in aqueous media.
    The inventors have surprisingly found that supplying alkali or alkaline earth metal salts works well to provide a sufficiently high concentration of cations to provide rapid degradation and dissolution of mesoporous silica in aqueous media. This is a significant advantage over mesoporous silica which is functionalized, for example with alkali or alkaline earth metals. It eliminates the need for functionalization process steps requiring less reagents and energy, allows the ratio of salt to cation to be adjusted to existing mesoporous silica, on demand and in situ if desired, does not affect not the other properties of mesoporous silica unlike functionalization.
    Furthermore and very surprisingly, the inventors have discovered that the mixture of mesoporous silica thus obtained shows surprisingly high dissolution rates in terms of dissolution of silica in aqueous environments, thus releasing high amounts of silicic acid Si( OH)4 in reasonably short times - thus providing an efficient source of bioavailable silicon.
    In another preferred embodiment, the salts are selected from the list of magnesium salts, calcium salts, potassium salts, sodium salts or a mixture thereof. Although great differences exist depending on the anion, these salts are soluble and have high dissolution rates in the aqueous media themselves. In addition, magnesium, calcium, potassium and sodium ions are well tolerated by the human and animal body, unlike, for example, lithium and beryllium ions which cause several undesirable side effects.
    In a preferred embodiment, the salts are alkaline earth metal salts. Alkaline earth metal salts have a greater impact on the dissolution rate for a similar concentration of alkaline earth metal ions. Without being bound by theory, it is believed that a higher net electrical charge and lower ionic radius are correlated with a higher dissolution rate of mesoporous silica. In a further preferred embodiment the alkaline earth metal salts are calcium and magnesium salts or mixtures thereof, most preferably the salts are magnesium salts. Magnesium showed the best solubilization results for mesoporous silica. In addition, it is well tolerated by the human and animal body.
    In a preferred embodiment, the present invention provides a mixture of mesoporous silica according to the first aspect of the invention, whereby said salt is food grade. This is advantageous to allow consumption of the obtained silica by humans and/or animals. This provides a safe and bioavailable source of silicon. It may also provide a safe method for delivering active ingredients, particularly drugs and more preferably drugs having low dissolution rates themselves, to the human or animal body through an oral dosage form. In a further preferred embodiment, said salt is pharmaceutically acceptable. Pharmaceutically acceptable salts are understood to be salts that can be administered to the body directly rather than through the digestive tract. The pharmaceutically acceptable salts are thus suitable for at least one method of direct administration, for example as addition to IV fluids, injection into muscle, or subcutaneous or intradermal injection.
    In a preferred embodiment the salt has a water solubility at 20°C of at least 1 g/l, more preferably the salt has a water solubility at 20°C of at least 5 g/l, more preferably the salt has a water solubility at 20°C of at least 10 g/l, more preferably the salt has a water solubility at 20°C of at least 50 g/l, more preferably the salt has a water solubility at 20°C of at least 100 g/l, more preferably the salt has a water solubility at 20°C of at least 500 g/l, more preferably the salt has a water solubility at 20°C of at least 1000 g/l, more preferably the salt has a water solubility at 20°C of at least 1500 g/l.
    In a preferred embodiment, a mixture of salts is used. A mixture of salts can advantageously be used to obtain an improved dissolution rate or a precisely refined dissolution profile of a mesoporous silica. For example the rate of dissolution of different magnesium salts can be improved compared to any of these individual magnesium salts, since the use of said mixture of different magnesium salts allows an increase in the concentration at the balance of magnesium ions in solution. A desired dissolution profile can be obtained by mixing different cations or mixing salts having different dissolution profiles.
    In a preferred embodiment, said salt is an organic salt. In a more preferred embodiment said salt is an acetate, citrate, tartrate, formate, benzoate, gluconate, sorbate or a mixture thereof, more preferably said salt is an acetate, a citrate, tartrate, formate, sorbate or a mixture thereof. Organic salts can be used to reduce the salty taste compared to inorganic salts. Preferred organic salts are well known and available for food grade and pharmaceutical grade products.
    In another preferred embodiment, said salt is an inorganic salt. In a more preferred embodiment said salt is a chloride, bromide or iodide salt. Chloride, bromide and iodide salts generally have high solubility and dissociation rates in aqueous media.
    In a preferred embodiment, the mesoporous silica has a surface area of at least 150 m2/g, more preferably the mesoporous silica has a surface area of at least 200 m2/g, more preferably the mesoporous silica has a specific surface area of at least 250 m2/g, more preferably the mesoporous silica has a specific surface area of at least 300 m2/g, more preferably the mesoporous silica has a specific surface area of at least 350 m2 /g, more preferably the mesoporous silica has a surface area of at least 400 m2/g, more preferably the mesoporous silica has a surface area of at least 450 m2/g, more preferably the mesoporous silica has a specific surface area of at least 500 m2/g, more preferably the mesoporous silica has a specific surface area of at least 550 m2/g, more preferably said mesoporous silica has a specific surface area of at least 600 m2 /g, so and more preferably the mesoporous silica has a surface area of at least 650 m2/g, more preferably the mesoporous silica has a surface area of at least 700 m2/g, most preferably the mesoporous silica has a surface area of specific of at least 750 m2/g.
    The specific surface as used here is calculated from the sorption isotherms of nitrogen at the temperature of liquid nitrogen (77 K) by the theory of Brunauer, Emmett and Teller (BET). A sufficiently high specific surface area is required for the cations in solution to have a significant effect on the degradation and dissolution of mesoporous silica. Those skilled in the art know that the specific surface area is related to the pore size distribution, and thus to the median pore size as well as the pore volume. In a preferred embodiment, the mesoporous silica has a median pore size dp50 between 0.1 and 30 nm, preferably between 0.1 and 20 nm, more preferably between 0.1 and 10 nm, more preferably preferably between 0.2 and 8 nm, most preferably between 0.5 and 5 nm. These preferred median pore sizes have proven to be the most suitable for high dissolution rates while retaining all of the traditional properties expected of mesoporous silica materials. In a preferred embodiment, the mesoporous silica has a median particle size between 1 and 1000 µm, more preferably the mesoporous silica has a median particle size between 1 and 800 µm, more preferably the mesoporous silica has a median particle size between 1 and 600 µm, more preferably the mesoporous silica has a median particle size between 1 and 400 µm, more preferably the mesoporous silica has a median particle size between 1 and 200 µm, more preferably the mesoporous silica has a median particle size between 1 and 100 µm, more preferably the mesoporous silica has a median particle size between 1 and 80 µm, more preferably the mesoporous silica has a particle size median particle size between 1 and 60 µm, more preferably the mesoporous silica has a median particle size between 1 and 50 µm, more preferably the mesoporous silica mesoporous silica has a median particle size between 1 and 40 µm, most preferably mesoporous silica has a median particle size between 1 and 30 µm.
    In a preferred embodiment the weight ratio of the cation of said salt to mesoporous silica is at least 1:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at least 5: 100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at least 10:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at least 20: 100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at least 30:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at least 40: 100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at least 50:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at least 60: 100, more preferably the weight ratio of the cation said salt to mesoporous silica is at least 70:100, more preferably the weight ratio of cation of said salt to mesoporous silica is at least 80:100, more preferably the weight ratio of cation said salt to mesoporous silica is at least 90:100, more preferably the weight ratio of cation of said salt to mesoporous silica is at least 1:1.
    In a preferred embodiment the weight ratio of the cation of said salt to mesoporous silica is at most 200:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at most 190: 100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at most 180:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at most 170: 100, more preferably the weight ratio of the cation of said salt to mesoporous silica is at most 160:100, most preferably the weight ratio of the cation of said salt to mesoporous silica is at most 150 :100.
    In a preferred embodiment, the weight ratio of the cation of said salt to mesoporous silica is between 1:100 and 200:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 5 :100 and 200:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 10:100 and 200:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 20:100 and 200:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 30:100 and 200:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 40:100 and 200:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 50:100 and 200:100, more preferably the weight ratio of the cation of said mesoporous silica salt is if kills between 60:100 and 200:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 70:100 and 200:100, more preferably the weight ratio of the cation of said salt to the mesoporous silica is between 80:100 and 200:100, more preferably the weight ratio of the cation of said salt to the mesoporous silica is between 90:100 and 200:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 100:100 and 200:100. In another preferred embodiment, the weight ratio of the cation of said salt to mesoporous silica is between 10:100 and 190:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 10:100 to 180:100, more preferably the weight ratio of cation of said salt to mesoporous silica is between 10:100 and 170:100, more preferably the weight ratio of cation of said salt to silica mesoporous silica is between 10:100 and 150:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 20:100 and 150:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 30:100 and 150:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 50:100 and 150:100, more preferably the ratio of weight of cation of said mesoporous silica salt is between 70:100 and 150:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 80:100 and 150:100, more preferably the weight ratio of the cation of said salt to mesoporous silica is between 90:100 and 150:100, most preferably the weight ratio of the cation of said salt to mesoporous silica is between 100:100 and 150:100.
    These ratios are measured by the weight of the salt cation. Take as an example a mixture of 100 g of mesoporous silica and 100 g of NaCl. 100 g of NaCl contains 39.34 g of Na* and 60.66 g of Cl. The ratio of salt cation to mesoporous silica of this example blend is thus 39.34:100. In the case of a mixture of salts, the weight ratio of the cation of said salt refers to the ratio by weight of the combined cations of said mixture of salts, not a ratio with respect to each salt of said mixture individually.
    In a preferred embodiment, said soluble silica composition further comprises a pharmaceutically active principle. In a more preferred embodiment, said pharmaceutically active principle is comprised within the pores of said mesoporous silica. The soluble silica composition according to the present invention can advantageously be used as a drug delivery system.
    In a second aspect, the invention provides a method for increasing the rate of dissolution of mesoporous silica in an aqueous medium, said method comprising the steps of: - providing a mesoporous silica having a specific surface area of at least 100 m2 /g; — provision of a salt, said salt consisting of a cation and an anion, wherein said salt is selected from the list of alkali metal salts, alkaline earth metal salts or a mixture thereof -ci in a ratio by weight of the cation of said salt to the mesoporous silica lying between 0.1:100 and 300:100; and — adding the mesoporous silica and the salt to the aqueous medium.
    The method according to the present advantage is advantageous since it does not require special reagents, knowledge and processes to functionalize the mesoporous silica to be dissolved. This substantially facilitates execution as well as precise refinement on an industrial scale. This allows the dissolution rate and profile to be adjusted in situ and on demand by adjusting the salt to silica ratio and/or the choice or mixture of salts. This makes it possible to adjust the dissolution rate of silica without adjusting the mechanical properties of mesoporous silica, especially pore size, pore size distribution, silica network structure, particle size, mechanical strength and so on. Advantageously the present method can utilize a wide selection of commercially available mesoporous silica products having sufficiently high surface areas.
    Aqueous medium as defined here refers to any mixture in which the solvent is water, and in particular includes human and animal bodies which consist of a very large amount of water. In a preferred embodiment, the aqueous medium to which the mesoporous silica and the salt are added is a human or animal body.
    In a preferred embodiment, the mesoporous silica and the salt are added in a short time, i.e. the silica and the salt are added in a short time and preferably in the same way and/or at the same place. A short time interval is at most 1 hour, preferably less than 30 minutes, more preferably less than 15 minutes, more preferably less than 10 minutes, more preferably less than 5 minutes , more preferably less than 3 minutes, more preferably less than 2 minutes, more preferably less than 1 minute, more preferably less than 30 seconds, most preferably the salt and silica are added to the aqueous medium — simultaneously.
    This is particularly advantageous if the silica and the salt are added to very large quantities of aqueous medium, to aqueous medium which is in circulation as well as to human and animal bodies. In these situations, the dissolved cation concentration is greatly diluted or the cation concentration is suppressed or buffered; resulting in a low equilibrium cation concentration. However, high temporary and local concentrations are sufficient to degrade mesoporous silica, in particular when the equilibrium constant of orthosilicic acid, which is the degradation product of mesoporous silica, is also kept low.
    In a preferred embodiment of the second aspect, the mesoporous silica is provided with an active ingredient. In a further preferred embodiment, the mesoporous silica is loaded with an active ingredient using processing methods suitable for granular and particulate materials, such as fluidized bed mixing or spraying the active ingredient onto said silica particles mesoporous. More preferably, the active ingredient is at least partially loaded into the pores of the mesoporous silica. This can make it possible to obtain a controlled release of the active principle. It can also help in the gradual dissolution of active ingredients that are traditionally difficult to dissolve. In another preferred embodiment, the silica is sprayed onto the active principle. The silica envelope can advantageously act as a barrier between the active principle and the aqueous medium, in particular the human or animal body. In combination with the cations according to the present invention, the silica shell can be dissolved at a controlled rate; thus releasing the active ingredient at a controlled rate.
    In a third aspect, the present invention relates to the use of a soluble silica composition according to the first aspect in food or animal feed, pharmaceuticals, cosmetics and in agriculture.
    In another embodiment of the third aspect, the present invention relates to the use of a method according to the second aspect in food or animal feed, pharmaceuticals, cosmetics and in agriculture.
    In a preferred embodiment, the present invention relates to the use of a soluble silica composition according to the first aspect in a drug delivery system, preferably a subcutaneous or intradermal drug delivery system or a form oral dosage.
    In another preferred embodiment, the present invention relates to the use of a method according to the second aspect in a drug delivery system, preferably a subcutaneous or intradermal drug delivery system or an oral dosage form. .
    In a further aspect, the present invention provides an oral dosage form comprising a soluble silica composition according to the first aspect of the invention. Preferably said oral dosage form is a solid oral dosage form such as a tablet or powder, and more preferably said solid oral dosage form is a tablet.
    In a preferred embodiment, the present invention provides an oral dosage form according to the second aspect of the invention, comprising said soluble silica composition in an amount of at least 1% by weight, based on the total weight of said form. oral dosage, preferably at least 25% by weight, more preferably at least 30% by weight, more preferably at least 35% by weight, more preferably at least 40% by weight, more preferably at least 45 wt%, more preferably at least 50 wt%, more preferably at least 55 wt%, more preferably at least 60% by weight, more preferably at least 65% by weight, more preferably at least 70% by weight, more preferably at least 75% by weight, more preferably by at least 80% by weight, more preferably at least 85% by weight, so more preferably at least 90 wt%, more preferably at least 95 wt%, more preferably at least 96 wt%, more preferably at least 97 wt% weight, more preferably at least 98% by weight, more preferably at least 99% by weight.
    A higher percentage of the silica according to the invention makes it possible to obtain a higher concentration of silicon in the gastrointestinal tract of the subject, and thus makes it possible to obtain better absorption in the human or animal body.
    The oral dosage form may optionally further comprise one or more active ingredients, allowing the oral dosage form to function as an oral drug delivery system.
    Advantageously, the active principles can be loaded into the pores of the mesoporous silica.
    This is beneficial if the dissolution rate of the active ingredient is low.
    In another embodiment of the third aspect of the invention, the present invention can be used to increase the amount of silicon in beverages.
    In a preferred embodiment, the beverage may be potable water, more preferably mineral water.
    This allows mineral water to act as a source of silicon in addition to being a source of minerals and water.
    In another embodiment, a mixture of soluble silica can be added to concentrates, such as soft drink concentrates before dilution.
    Advantageously the present invention allows the dissolution of mesoporous silica in the beverage, thereby providing silicon in the form of bioavailable orthosilicic acid rather than as the polymer species SiO2 which has very low bioavailability.
    The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended to limit the scope of the invention, nor should they be construed as such. The present invention will now be described in more detail, with reference to examples which are not limiting.
    EXAMPLES Materials and Methods Table 1 shows the properties of a series of mesoporous silica materials - used in these examples. Table 2 shows the properties of a series of salts used in these examples. Table 1: Material Properties of Mesoporous Silica Silica Surface Size | Volume Size of | BET specific mesoporous adsorption | pore pore | particle | of oil (m2/9) median | (g/ml) (um) (9/1009) (nm) ow 2 [039 GSE as [ms [et [Es a os [a [et [Es NE OSI107 190 16.0 - | 250 ea
    Table 2: Properties of salts % of | Ray ; Metals Ionic Weight Solubility Salts Molar Formula | (alkaline or | cation in water (g/mol) | alkaline earth (pm)) Dicitrate of x | | Ci2HisCa3018 e | 0.96 9/1 to tricalcium 570.49 21.0 114; ‚ | 4H20 23°C tetrahydrate Acetate de | | Ca(CH3COO)2 e | 4869/l to calcium 176.18 22.8 114; H20 0 °C hydrate Acetate of | == Mg(CH3COO)2 e | 1,200 g/l at magnesium 214.45 11.3; ‚ | 4H20 15°C tetrahydrate Sodium CH3COONa &e acetate 136.08 | 20.6 116 / ‚ 3H20 trihydrate Acetate from 2,530 g/l to CH3COOK 98.14 39.8 152 potassium 20°C Chloride from 7459/l to CaCl2 110.98 | 36.11 114 calcium 20°C Chloride 542 g/l at == MgCl2 95.21 25.53 magnesium 20°C Carbonate 13 mg/| to CaCO3 100.09 | 40.04 114 Calcium 25°C Carbonate; 106 mg/l at MgCO3 84.31 28.83 == 20°C magnesium The degradation behavior of mesoporous silicas was examined in 900 ml of ultra-pure water at 37 + 0.5°C with stirring at 75 rpm on a dissolution device (Sotax AT Xtend) and characterized by ICP-OES (5110 VDV from Agilent) to evaluate the quantity of degraded silica after 8 hours as a function of the quantity of salts introduced into the dissolution media at t0 .
    Examples 1-5 A series of dissolution tests were carried out on OSI100, OSI101, OSI102, OSI103 and OSI104 in combination with tricalcium dicitrate tetrahydrate as the calcium salt in ultrapure water. These experiments were performed with a constant amount of silicon dioxide (100 mg), a constant amount of water (900 ml) and the amount of tricalcium dicitrate tetrahydrate as the calcium salt was varied.
    Figure 1 shows the proportion of dissolved silicon after 8 h as a function of the quantity of elemental calcium (in mg) introduced into the aqueous medium for the mesoporous silicas OSI100 (example 1) and OSI103 (example 4).
    Figure 2 shows the proportion of dissolved silicon after 8 h as a function of the — quantity of elemental calcium (in mg) introduced into the media for the mesoporous silicas OSI101 (example 2), OSI102 (example 3) and OSI104 (example 5) . The mesoporous silicas evaluated show a very significant increase in dissolved silicon with the increase in the ratio of calcium to silicon.
    The increase in dissolved silicon is most pronounced for OSI100.
    Examples 5-6 The mesoporous silica OSI100 having the highest dissolution properties in water in the presence of elemental calcium was used to compare its solubility in the presence of two calcium salts: tricalcium dicitrate tetrahydrate (example 5) and acetate of hydrated calcium (Example 6). These two salts were chosen to evaluate the effect of salt solubility on the degradation of mesoporous silica. Calcium acetate hydrate has a solubility in water that is significantly higher than that of tricalcium dicitrate tetrahydrate.
    Figure 3 shows the proportion of dissolved silicon after 8 h for OSI100 as a function of the quantity of calcium cation introduced into the media for tricalcium dicitrate tetrahydrate (example 5) and for calcium acetate hydrate (example 6). The experiments were performed with a constant amount of silicon dioxide (100 mg) in a constant amount of water (900 ml) as previously described.
    The dissolution of OSI100 increased significantly when calcium was introduced in the acetate form compared to the dicitrate form of tricalcium.
    The significant increase is thought to be related to the higher solubility of calcium acetate compared to the dicitrate form of tricalcium.
    The amount of dissolved silica appears to be related to the amount of Ca** in solution.
    Examples 7-10 The influence of the nature of the cation on the dissolution of a mesoporous silica was studied. The dissolution tests were carried out with a constant quantity of silica (100 mg) in the presence of different quantities of acetate salts. All of these acetate salts are completely soluble in the concentration range used and full solubility is reached after a few minutes. The following cations, derived from their acetate salt, were selected: sodium (example 7), potassium (example 8), calcium (example 9) and magnesium (example 10). The properties of these acetate salts are indicated in table 2. Figure 5 shows the evolution of the quantity of silicon dissolved after 8 h in water as a function of the quantity of the various cations (in moles) added at the beginning of the dissolution test.
    Divalent cations (Ca * and Mg *) are a better solubilizer for mesoporous silica than monovalent (Na* and K+) as can be seen in Figure 5. Approximately 82% of the silicon is dissolved after 8 h with 0.37 mmol of Mg *. To reach the same order of magnitude of silicon dissolved with Ca”*, 0.90 mmol are necessary. For approximately 0.90 mmol of Na*, 42% silicon is dissolved and approximately 30% with K*. This is believed to be due to the difference in valence and ionic radius of the cations, where a divalent and smaller ionic radius is preferred for higher dissolution rates.
    Examples 11-18 The dissolution of OST100 to OSI107 in the presence of calcium acetate and magnesium acetate was tested quantitatively. 100 mg of each silica material was supplied in seven different beakers containing 900 ml of water. A first mixture contained only water and silica and served as a reference. A second, third and fourth mixture additionally contained magnesium acetate so that the weight of magnesium was equal to 50 mg, 100 mg and 150 mg respectively. A fifth, sixth and seventh mixture contained water, mesoporous silica and calcium acetate so that the weight of calcium was equal to 50 mg, 100 mg and 150 mg respectively.
    The degradation in the beakers of the mesoporous silicas was visually inspected at regular intervals.
    The reference blends showed little degradation.
    At each interval and for each silica material, higher amounts of cation showed greater or equal degradation of the silica material.
    Furthermore, at each interval and for each silica material before complete degradation, magnesium showed higher degradation than calcium.
    It is clear that the method according to the invention, and its applications, are not limited to the examples presented.
    Examples 19-23 The dissolution of OSI100 was tested in 900 ml of mineral water comprising varying amounts of cations.
    The total dissolved silicon content in water was measured before the addition of 100 mg of OSI100 (t0) and measured again after 8 hours.
    The compositions of mineral water at tO as well as the total amount of silicon after 8 hours are shown in Table 3. The elements calcium, magnesium, potassium and sodium are present in the form of their respective cation in mineral water.
    Table 3: Examples 19-25 ensen) | AA Tamo) 2 [38 [OE Tensen [e 10 [B [B [6
    权利要求:
    Claims (15)
    [1]
    1. A soluble silica composition comprising: a. a mesoporous silica having a specific surface area of at least 100 m2/g; and B. a salt, said salt consisting of a cation and an anion, wherein said salt is selected from the list of alkali metal salts, alkaline earth metal salts or a mixture thereof; wherein the weight ratio of cation of said salt to mesoporous silica is between 0.1:100 and 300:100.
    [2]
    2. Soluble silica composition according to claim 1, wherein the salt is selected from the list of magnesium salts, calcium salts, potassium salts, sodium salts or a mixture thereof.
    [3]
    3. A soluble silica composition according to claim 1 or 2, wherein said salt is edible, more preferably said salt is pharmaceutically acceptable.
    [4]
    4. Soluble silica composition according to any one of claims 1 to 3, wherein said salt has a solubility in water at 20°C of at least 1 g/l, preferably at least 10 g/l. l, more preferably at least 100 g/l, most preferably at least 1000 g/l.
    [5]
    5. Soluble silica composition according to any one of claims 1 to 4, wherein said mesoporous silica has a specific surface area of at least 250 m2/g, preferably said mesoporous silica has a specific surface area of at least 500 m2 /g.
    [6]
    6. Soluble silica composition according to any one of claims 1 to 5, wherein said mesoporous silica has a median pore size dp50 between 0.1 and 30 nm, preferably between 0.1 and 20 nm, more preferably between 0.1 and 10 nm.
    [7]
    7. Soluble silica composition according to any one of claims 1 to 6, wherein said mesoporous silica has a median particle size between 1 and 1000 µm, preferably between 1 and 100 µm, more preferably between 1 and 50 µm. um.
    [8]
    8. Soluble silica composition according to any one of claims 1 to 7, wherein the weight ratio of the cation of said salt to the mesoporous silica is between 1:100 and 200:100, preferably the weight ratio of the cation said mesoporous silica salt is between 10:100 and 200:100, more preferably between 50:100 and 150:100.
    [9]
    9. Soluble silica composition according to any one of claims 1 to 9, wherein said salt is a magnesium or calcium salt, preferably a magnesium salt.
    [10]
    10. Soluble silica composition according to any one of claims 1 to 10, wherein said salt is an organic salt, preferably said salt is an acetate, a citrate, a tartrate, a formate, a benzoate, a gluconate, a sorbate or a mixture thereof.
    [11]
    11. A soluble silica composition according to any one of claims 1 to 11, wherein said soluble silica composition further comprises a pharmaceutically active ingredient.
    [12]
    12. Method for increasing the rate of dissolution of mesoporous silica in an aqueous medium, said method comprising the steps of: - providing a mesoporous silica having a specific surface of at least 100 m2/g; - provision of a salt, said salt consisting of a cation and an anion, wherein said salt is selected from the list of alkali metal salts, alkaline earth metal salts or a mixture thereof -ci in a ratio by weight of the cation of said salt to the mesoporous silica lying between 0.1:100 and 300:100; and - adding mesoporous silica and salt to the aqueous medium.
    [13]
    13. A method for increasing the dissolution rate of mesoporous silica according to claim 12, wherein the aqueous medium is a human or animal body.
    [14]
    14. Use of a soluble silica composition according to any one of claims 1 to 11 in food or animal feed, pharmaceuticals, cosmetics and in agriculture.
    [15]
    15. Use of a soluble silica composition according to any one of claims 1 to 11 in a drug delivery system, preferably a subcutaneous or intradermal drug delivery system or an oral dosage form.
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    同族专利:
    公开号 | 公开日
    WO2021069074A1|2021-04-15|
    WO2021069108A1|2021-04-15|
    BE1028282A1|2021-12-03|
    引用文献:
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    US20060018966A1|2003-07-22|2006-01-26|Lin Victor S|Antimicrobial mesoporous silica nanoparticles|
    WO2010139987A2|2009-06-02|2010-12-09|Intrinsiq Materials Global Limited|Mesoporous materials|
    WO2014013044A1|2012-07-20|2014-01-23|Formac Pharmaceuticals Nv|Dry granulates of mesoporous silica powders|
    WO2019175100A1|2018-03-11|2019-09-19|Nanologica Ab|Porous silica particles for use in compressed pharmaceutical dosage form|
    EP2526954B1|2011-05-26|2014-08-13|Dexsil Labs|Liquid biological composition comprising a bioavailable silicon complex, method for producing same and use thereof|
    EA201600412A1|2013-11-26|2016-10-31|Мерк Патент Гмбх|METHOD OF MANUFACTURING INORGANIC MATERIAL IN THE FORM OF PARTICLES|
    BE1023538B1|2016-04-22|2017-04-26|Sil'innov Scrl|Mesoporous silicas and their synthesis process|
    GB201803363D0|2018-03-01|2018-04-18|Sigrid Therapeutics Ab|New materials and uses thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/EP2019/077458|WO2021069074A1|2019-10-10|2019-10-10|Silica with ultra-fast dissolution properties|
    PCT/EP2020/065084|WO2021069108A1|2019-10-10|2020-05-29|Silica with ultra-fast dissolution properties|
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