EA046569B1 - COMPOSITION OF SILICIC ACID AND ITS APPLICATION - Google Patents

Description

Field of technology to which the invention relates

The invention relates to a silicon additive, including stabilized silicic acid, and to its use as a medicine or dietary supplement. The invention also relates to a dosage form comprising stabilized silicic acid for use as a medicine.

BACKGROUND OF THE INVENTION

The mineral silicon is present in drinks and water in the form of orthosilicic acid (OSA). OSA is chemically stable in low concentrations, i.e. <10 ^-3 M (Iler, 1979). At higher concentrations, polycondensation of OSA occurs, leading to the formation of oligomers and polymers. Absorption studies in humans indicate that only OSA is bioavailable, while its polycondensed forms are not absorbed (Jugdaohsingh et al., 2000). The limited persistence of OSA and its rapid conversion to non-bioavailable species, which is highly dependent on pH, are problematic for optimal nutrition, in addition to the fact that other minerals and nutrients can cause polycondensation.

Orthosilicic acid can be stabilized by a stabilizer suitably selected from the group of quaternary ammonium compounds and amino acids, amino acid sources, or combinations thereof. One of the well-known stabilizers is choline. In practice, some oligomerization is observed. However, this oligomerization does not convert orthosilicic acid into silicon dioxide, but rather into oligomers, which in the gastrointestinal tract can be converted (particularly by hydrolysis) into orthosilicic acid. Orthosilicic acid and its oligomers - which are in a form or can be converted into a form that can be absorbed from the gastrointestinal tract into the systemic circulation - are hereinafter referred to as stabilized silicic acid.

The present Applicant has invented and developed both liquid and solid stabilized silicic acid compositions into commercially available products. Liquid compositions are disclosed in EP 0743922, and a variant of a solid composition obtained by extrusion-spheronization technology is disclosed in EP 1551763. These products have been tested in a number of clinical trials, which have found positive results in bone, cartilage, hair, nails and skin. It was found that after oral administration of stabilized silicic acid, the ingested silicon compound is found in the blood and urine mainly in the form of orthosilicic acid.

When developing effective products, consumer satisfaction is almost as important as direct bioavailability. If the consumer does not take the product as frequently as intended, a therapeutically effective concentration in the body may not be achieved and therefore beneficial effects on bones, cartilage, hair, nails and skin will not occur. In this regard, stabilization of orthosilicic acid with a quaternary ammonium compound such as choline is technologically cumbersome. Indeed, such compounds impart an unpleasant odor and a very bitter fishy taste to the liquid composition, making it difficult for the consumer to swallow. The solid composition does not have this disadvantage, but it has a very low effective concentration of silicon. As a result of extrusion-spheronization, many granules are formed, which are packed into a capsule. It generally includes a large mass of carrier material such as microcrystalline cellulose. As a consequence, the capsule size required for a clinically effective dose is very large. Such large capsules are not preferred.

It would therefore be desirable to provide another stabilized silicic acid composition that is food grade and/or pharmaceutically effective (and converts any oligomers to an absorbable form of orthosilicic acid) and leads to good consumer or patient acceptance. However, this is not easy, since stabilized OSA is a technologically difficult product. First of all, it is very hygroscopic, given the presence of a quaternary ammonium compound such as choline. Second, the liquid form of concentrated stabilized OSA, which forms the basis of both liquid and solid compositions, is active at a pH of approximately 1 to prevent polycondensation.

The essence of the invention

It is therefore an object of the invention to provide another stabilized silicic acid composition which results in mucosal absorption into the gastrointestinal tract, optionally after partial hydrolysis, and which is also effective in obtaining consumer or patient acceptance.

Another object of the invention is a method for preparing such a composition.

Another object of the invention is a method for preventing, inhibiting and treating diseases associated with bone loss and cartilage degeneration, loss of hair and nail quality and skin aging in diseases, which is clinically effective and beneficial for obtaining good perception, as well as a composition for use in this way.

Another object of the invention is a stabilized silicic acid composition for use as a medicine, more particularly as a medicine for the prevention,

- 1 046569 inhibition and treatment of bone loss, cartilage degeneration, loss of hair and nail quality and skin aging in diseases.

According to a first aspect, the invention relates to a capsule for oral administration, including a capsule shell, and filled with an acidic liquid composition with a pH in the range of 0-2.5, containing choline compound stabilized silicic acid, and in which the capsule shell includes hydroxyalkyl alkyl cellulose.

Preferably, the stabilized silicic acid in the capsule comprises substantially silicic acid monomers and/or oligomers, preferably orthosilicic acid and/or oligomers thereof.

Preferably, the liquid composition in the capsule has a pH in the range of 0.5-2.0, preferably 0.81.3.

Preferably, the silicic acid in the capsule is stabilized by a choline compound which is present in a concentration of at least 20% by weight of the liquid composition.

Preferably, the capsule composition comprises water in an amount of at most 30% by weight, preferably water in an amount of at most 20% by weight, preferably water in an amount of at most 15% by weight.

Preferably, the capsule composition has a viscosity in the range of 0.08.10 ³ -2.0.10 ³ mPa-s.

Preferably, the capsule composition also includes a rheological additive.

Preferably, the rheological additive is selected from amorphous silicon, phosphoric acid and/or its salts and triglycerides, in particular amorphous silicon such as fumed silica.

Preferably, the capsule liquid composition contains a diluent in an amount of at most 20% by weight and more preferably at most 10% by weight or is free of diluents.

Preferably, in hydroxyalkyl alkylcellulose, the alkyl is one or more of the C'i-C-galkyls.

Preferably, the capsule shell also includes hydroxyalkylcellulose, or hydroxyalkylcellulose and hydroxyalkylcellulose derivatives selected from the group consisting of hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, hydroxyethylcellulose ether, hydroxypropylcellulose ether, hydroxyethylmethylcellulose ether zy, hydroxyethylethylcellulose ether, hydroxypropylmethylcellulose ether, and also mixtures thereof.

According to a second aspect, the invention provides an oral capsule product comprising at least one inner capsule contained within an outer capsule, wherein said capsule is present as an inner capsule and the outer capsule also contains a pharmaceutically acceptable or nutritionally acceptable composition.

Preferably, in the capsule product, the pharmaceutically acceptable or nutritionally acceptable composition is a liquid hydrophobic composition and, for example, includes an oil.

Preferably, the pharmaceutical and/or nutritional capsule product has a suitable composition comprising a nutritional and/or pharmaceutically active ingredient.

According to a third aspect, the invention relates to a method for producing a capsule as defined in any of the preceding paragraphs, comprising the steps of producing an acidic liquid composition of stabilized silicic acid;

filling the capsule shell with the liquid composition and sealing the capsule shell to obtain said capsule.

According to a fourth aspect, the invention relates to a dietary supplement as a source of silicon, comprising a capsule in any of the preceding paragraphs or a capsule product in any of the preceding paragraphs.

According to a fifth aspect, the invention relates to the use of the above capsule or capsule product as a medicinal product as a source of silicon. Preferably as a medicament for the prevention, inhibition or treatment of bone loss, cartilage degeneration, loss of hair and nail quality and skin aging in diseases.

In other aspects, the invention relates to the use of the silicon supplement of the invention in the prevention, inhibition or treatment of bone loss, cartilage degeneration, loss of hair and nail quality and skin aging in diseases and/or as a dietary supplement.

And according to another aspect, the invention provides a capsule product comprising at least one first inner capsule contained in a second outer capsule, wherein the capsule of the invention is present as the first capsule, and wherein the outer capsule also contains a nutritional and/or pharmaceutically acceptable composition.

In experiments leading to the invention, it was unexpectedly found that stabilized silicic acid is stable in capsules comprising a capsule shell of a polysaccharide or a polysaccharide derivative. This is very surprising since such capsules are usually not stable in combination with a liquid composition including water, see Chiwele et al. (2000). Indeed, capsules

- 2 046569 are designed so that they open in an aqueous acidic environment such as the stomach.

In a preferred embodiment, the liquid composition has a pH in the range of 0-2.5, preferably 0.5-2.0, such as 0.8-1.3. Experimental data show the unexpectedly high stability of such a liquid composition in capsules comprising a capsule shell of a polysaccharide or a polysaccharide derivative, and the same composition has been found to leak in gelatin capsules. Both below and above this range there is a higher risk of polycondensation of the liquid composition.

In another preferred embodiment, the stabilized silicic acid composition includes a quaternary ammonium compound as a stabilizer. Particularly good results are observed with a choline derivative such as choline chloride. However, the presence of other choline compounds, such as choline acetate and choline bitartrate, choline hydroxide, cannot be excluded. The quaternary ammonium compound has a charge that is believed to have a positive effect on the stability of silicic acid. In addition, the use of a charged compound can make a good contribution to the observed stability of the capsule in accordance with the present invention. Preferably, the stabilizer is present in an amount of at least 15% by weight of the liquid composition. The amount of stabilizer in the present invention is determined on the basis of a quaternary ammonium ion without a counterion, thus choline rather than choline chloride.

In another preferred embodiment, particularly suitable in combination with the use of a quaternary ammonium compound, the stabilized silicic acid comprises water. Surprisingly, it was found that little water migration occurs between the composition and the capsule shell. If water migrates from the capsule shell into the stabilized silicic acid composition, the capsule may become brittle. This does not happen as observed in the 3-month and 9-month experiments. If water migrates into the capsule shell, the capsule shell will begin to decompose, which does not happen as observed in experiments. In a preferred embodiment, water is present in the stabilized silicic acid in an amount corresponding to at most 30% by weight of the composition. In a more preferred embodiment, water is present in the liquid composition in an amount of at most 20% by weight water, for example at most 15% by weight water.

Preferably, in the invention, the stabilized silicic acid comprises substantially oligomers and/or monomers of orthosilicic acid. Oligomers are, for example, oligomers comprising less than 1000 monomers, preferably less than 100 monomers per molecule. More preferably, the oligomers are such that at least 80% and preferably at least 90% of the silicon atoms are linked to at most 3 other silicon atoms via a silicon-oxygen-silicon bond. The term essentially as used herein suitably refers to at least 95% by weight, preferably at least 98% by weight, more preferably at least 99% by weight.

In another embodiment, the composition has a viscosity in the range of 0.08.10 ³ - 2.0.103 mPa-s. Viscosity below the specified minimum of 80 mPa-s will tend to leak out of the capsules, while viscosity above the specified maximum will cause the capsules to fill incorrectly. Viscosity herein is measured using a Brookfield viscometer and a thermostated water bath, 25°C.

In the practice of the present invention, the viscosity is modified by adding a rheological additive. An additive is a compound that is added to a composition, suitably in solid form, and then dissolved therein or finely dispersed therein. A fine dispersion is, especially in the present context, a dispersion of particles with an average size of at most 1 μm. Such fine dispersions are also known as colloidal solutions or colloidal suspensions. In this embodiment, the additive is suitably added in an amount of up to 10% by weight, for example 3-6% by weight. The additive is suitably selected from the group consisting of hydroxypropyl methylcellulose (HPMC) and other cellulose derivatives, silica particles, more preferably amorphous silica particles, phosphoric acid and its salts, triglycerides, xanthan gum and other gums, stearates such as aluminum and magnesium stearates.

Suitable amorphous silica particles are, for example, highly dispersed silica particles. Preferably, the silica particles have a hydrophilic surface rather than a surface treated to make them hydrophobic. Phosphoric acid or a salt thereof may well be added in the form of a hypophosphate salt, such as dibasic calcium phosphate, which will then be reacted with the acid present in the composition to form phosphoric acid. Phosphoric acid may be present as orthophosphoric acid, but it is possible that polymerization occurs. Triglycerides are respectively triglycerides of fatty acids. More preferably, the triglycerides are fatty acid triglycerides with a chain length in the range of 6-14 carbon atoms - also known as medium chain triglycerides. A rheological additive is added to the composition after obtaining stabilized silicic acid. In addition to the rheological additive, the liquid composition may additionally contain a diluent.

- 3 046569

In another embodiment, the liquid composition may include a diluent. It has been found advantageous that the use of such a diluent does not cause the pH of the liquid composition to change beyond a minimum. Diluents are suitably selected from the group consisting of glycerin, polyethylene glycol, polypropylene glycol. In addition, they do not interfere with the stability of the liquid composition. The weight content of one or more diluents in the liquid composition can reach up to 80 wt.%. However, it is preferable that the diluent is present in an amount of at most 20% by weight. More preferably, the acidic liquid composition includes a diluent in an amount of at most 10% by weight, or even no diluent. If the amount of diluents is less than 20 wt.% and preferably less than 10 wt.%, or if the liquid composition does not include diluents, the liquid composition preferably includes a rheological additive described herein above. The advantage of filling the capsule with an undiluted liquid composition is that the greatest size reduction is achieved while the stability of the stabilized silicic acid is not compromised.

The capsule shell material, the polysaccharide or polysaccharide derivative, is preferably selected from the group consisting of cellulose, a cellulose derivative including alkylcellulose, carboxyalkylcellulose, hydroxyalkylcellulose, hydroxyalkylalkylcellulose, carboxyalkylalkylcellulose and derivatives thereof, starch, modified starch such as starch ethers and oxidized starches, hydroxymethyl starches, hydroxyalkylated starches and succinate starches, pullulan, dextran and/or combinations thereof.

More preferred polysaccharide derivative materials are selected from the group consisting of hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses. Alkyl is one or more Cl-C4 alkyls and is preferably linear alkyl. The most preferred optional polysaccharide derivative is selected from the group consisting of hydroxyethylcellulose and hydroxyethylmethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, hydroxyethylcellulose ether, hydroxypropylcellulose ether, hydroxyethylmethylcellulose ether, hydroxyethylethylcellulose ether, hydroxypropylmethylcellulose ether vines and their derivatives, as well as their mixtures. Good results are obtained with hydroxypropyl methylcellulose (HPMC) or derivatives. The presence of a hydroxyl group on the cellulose unit substituent may contribute to the stability of the liquid composition.

The use of other celluloses and their derivatives is not excluded. Examples include methylcellulose, ethylcellulose, cellulose acetyl phthalate, sodium carboxymethylcellulose, methylcellulose ether, as well as mixtures thereof and mixtures with hydroxyalkylcellulose or hydroxyalkylalkylcellulose described above.

The polysaccharide derivatives are preferably acid-modified cellulose, alkylcellulose, hydroxyalkylcellulose or hydroxyalkylalkylcellulose, the acid modification preferably leading to one or more of the phthalate, succinate, acetate, maleate, trimellitate compounds. Thus, acid modification leads to the formation of esters when the hydroxyl group of cellulose reacts with the acid used. Preferred is the acid modification of hydroxyalkylcelluloses or hydroxyalkylalkylcelluloses. The term alkyl is defined herein as ^-^-alkyl. Specific examples of such celluloses are given above.

As is known in the art, a capsule typically includes more than one portion. Typically, a capsule is used in two parts, usually called a capsule body and a capsule cap. The term capsule shell actually refers to the shell of a portion of a capsule, such as the capsule body shell. The capsule body will then be filled with an acidic liquid composition. Once filled, the capsule cap, usually including the shell, is mounted onto the cap. After this, the capsule body and the capsule lid are hermetically connected to each other. However, the invention is not limited to conventional capsule manufacturing and assembly methods and can, for example, also be applied to one-piece capsules including a filling opening, which are then sealed without prior assembly to a second capsule part. The filling of capsules in the method of the present invention can be carried out in a known manner. Preferably, filling occurs at a temperature in the range of 20-40°C, for example at room temperature, and most preferably without performing a heating step of the composition and/or a cooling step of the composition. The shell capsule is preferably a so-called hard capsule.

The capsule shell preferably contains a polysaccharide or polysaccharide derivative material (and/or the preferred examples thereof above) in an amount of from 90 to 99% by weight of the finished capsule shell. The capsule shell may also contain a gelling agent known in the art, for example selected from the group consisting of alginic acid and its salts (eg, sodium, potassium and calcium salts), agar, carrageenan, locust bean gum and gellan gum. The choice of gelling agent has not been established as critical. The capsule shell typically contains an enteric polymer and a film former. Both may be HPMC and/or its derivatives.

- 4 046569

An enteric polymer is, for example, a polymer containing acid groups. An HPMC derivative such as acid-modified hydroxyalkylcellulose is then used. Examples of acids include maleic acid (anhydride), succinic acid, acetic acid, phthalic acid, trimellitic acid. The preferred derivatives are hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose phthalate, and are believed to be a very suitable choice among other acid-modified HPMC derivatives. Preferably, any acidic groups are carboxyl groups. The film former is selected, for example, from HPMC, methylcellulose, gellan gum, carrageenan and mixtures thereof and preferably includes at least HPMC. In general, when the film former is HPMC or methylcellulose, the ratio of enteric polymer to film former is in the range of 1.5-3.5, for example 2.0-2.5.

Optionally, the capsule shell is coated to modify its dissolution properties, such as an enteric coating, to make the capsule resistant to stomach acid. Commonly used coatings are anionic polymethacrylates (copolymers of methacrylic acid and methyl methacrylate or ethyl acrylate (Eudragit®), cellulose-based polymers such as cellulose acetate phthalate (Aquateric®) or polyvinyl derivatives such as polyvinyl acetate phthalate (Coateric®).

In yet another embodiment, the capsule shell is sealed using a solution of a polysaccharide, such as hydroxypropyl methylcellulose, in alcohol.

In yet another embodiment, the capsule shell has a size of at most 0. More preferably, the capsule shell has a size of at most 1. The inventors believe, without wishing to be limited to this, that the stability of stabilized orthosilicic acid in capsules decreases with increasing capsule size. Capsules of size type 01 or smaller (eg type 2-5) are very suitable. Filled capsules are accordingly packed in primary packaging, which protects the capsules from moisture. Preferred packaging materials are aluminum/aluminum (ALU/ALU) blisters or high-density polyethylene (HDPE) strips or bottles with a magnetic induction aluminum seal and desiccant sachet. In the case, as discussed hereinafter, where an inner capsule and an outer capsule are present, the size refers to the inner capsule. In such an embodiment, the most suitable size of the inner capsule is at most 1. The outer capsule can be of any desired size.

According to a preferred embodiment of the invention, the capsule of the invention is present as an inner capsule in an outer capsule which also contains a nutritional and/or pharmaceutically acceptable composition. The nutritional and/or pharmaceutically acceptable composition (present in the outer capsule) is suitably a liquid, but in another embodiment is a solid, such as a powder or extruded particles. The presence of a dispersion, emulsion, cream, gel or other so-called semi-solid composition as a food and/or pharmaceutically acceptable composition is not excluded. The term nutritional and/or pharmaceutically acceptable composition as used herein refers to a composition or formulation that meets the standards established for use in a particular application as known to one skilled in the art. In addition, the composition must be compatible with the inner capsule so as to prevent leakage and/or premature opening of the inner capsule. In an embodiment wherein said composition is or includes a liquid, said composition preferably includes a hydrophobic liquid such as an oil. In the embodiment in which said composition is or includes a solid, the solid essentially comprises a food grade and/or pharmaceutically acceptable excipient, as is known to one skilled in the art. In one more preferred embodiment, said composition is substantially or completely free of water, with essentially in this case referring to a value of at most 5% by weight, more preferably at most 2% by weight. In a preferred embodiment, the acidic liquid composition contained in the first capsule includes a diluent in an amount of at most 20 wt.% and more preferably at most 10 wt.% and is preferably free of diluent.

The composition of such a capsule product, which includes a first inner capsule within a second outer capsule, is considered to offer highly advantageous options. First, the second outer capsule and the food and/or pharmaceutically acceptable composition therein provide additional encapsulation for the stabilized silicic acid, making it less susceptible to moisture loss. This is beneficial for shelf life. In addition, it becomes suitable for applications with less primary packaging requirements.

Secondly, the second outer capsule can be selected to achieve a predetermined release, for example a slow release capsule. In this way, it is possible to ensure that stabilized silicic acid is not released in the stomach, but only in the intestines or even in the colon. This is believed to enhance absorption. In the present description, the inner and/or outer capsule, and in particular the inner capsule, can be provided with enterosol

- 5 046569 thick coating.

Third, stabilized silicic acid can be combined with another food or pharmaceutical ingredient. One suitable food ingredient is, for example, an oil such as omega-3 oil and/or fish oil. The latter oils typically contain relevant nutritional polyunsaturated fatty acids. Three types of polyunsaturated fatty acid involved in human physiology are α-linolenic acid, eicosanpentaenoic acid and docosahexaenoic acid. As adjuvant drugs, anti-osteoporosis agents, osteoporosis agents, for example alendronate, zoledronic acid, risedronate, ibandronate, raloxifene, denosumab, and also selected vitamins such as vitamin E, vitamin K can be used. It will be understood that many combination treatments are possible. In addition, an additional ingredient may be selected, for example, from polysaccharides, amino acids, peptides, vitamins and minerals, or other therapeutically active compounds, including antioxidants and compounds that stimulate the synthesis of connective tissue components.

It is noted, for completeness, that the outer capsule may be either a soft or hard capsule, and may be based on one or more suitable capsule materials, such as gelatin, polysaccharide and polysaccharide derivatives, such as starch, modified starch, cellulose and its derivatives. The outer capsule is usually at least one size larger than the inner capsule, but may be two or more sizes larger. The number of inner capsules per outer capsule may be one or more than one, depending on the relative size of the inner and outer capsules. The number of inner capsules per outer capsule is, for example, 1-10, and more preferably 1-5.

The capsule can be used as a pharmaceutical and as a nutritional agent, i.e. food supplement. It is primarily intended for use in humans, although use in animals is not excluded. It is believed that the stabilized silicic acid will only be released from the capsule by opening the capsule. Therefore, the capsule is also highly suitable for patients with digestive limitations who are unable to completely remove any solid carrier from the active ingredient (ie stabilized silicic acid). It is further believed that it is advantageous that the liquid composition remains in its predetermined form until it is released from the capsule. When patients mix drops of the liquid formulation into a drink or dilute the drops with water, there is a risk that the amount of OSA (and or its oligomers) will decrease due to changes in pH and concomitant polycondensation.

Specific indications for the liquid composition as a medicinal product include bone loss, cartilage degeneration, loss of hair and nail quality, and skin aging and disease. The drug is believed to be particularly suitable for suppressing these indications, although at the same time a preventive effect by maintaining an adequate silicon concentration is also observed. Treatment in the context of the invention is understood as supporting at least partial regeneration of bones, cartilage, hair and nail quality. Specific diseases include osteopenia, osteoporosis, osteoarthritis, rheumatology and dermatology.

The pharmaceutical or nutritional agent is most preferably administered at a dose of 5-20 mg of silicon per day, preferably 10 mg of silicon per day, preferably for at least 6 months, more preferably for at least 12 months.

Although the composition of the present invention is highly suitable for any type of patient population, beneficial effects are expected especially for patient populations of childhood and adolescence (up to 20 years, most preferably in the age group 10-16 years) and elderly patients aged at least 50 years. such as those aged at least 65 years. Preliminary research confirms that perceptions are elevated in these groups.

According to another preferred aspect, the invention relates to an acidic liquid composition of stabilized silicic acid, also comprising a rheological additive selected from the group consisting of amorphous silica, phosphoric acid and triglycerides. Preferably, the rheological additive is added in an amount of at most 10% by weight of the liquid composition.

More preferably, the rheological additive is an amorphous silica such as fumed silica. Such highly dispersed silica mainly comprises particles with an average particle size of approximately 100 nanometers. These basic particles may accordingly clump together into aggregates. Aggregates can combine into agglomerates, and the bond between the aggregates is less strong than the bond between the main particles in the aggregates. As a consequence, highly dispersed silica is easily dispersed and can also be dissolved in the acidic liquid composition. It is observed that the viscosity of the acidic liquid composition can be effectively controlled by such a rheological additive. In addition, it is observed that the rheological additive does not adversely affect the stability of the stabilized silicic acid.

More preferably, the stabilized silicic acid includes a quaternary ammonium compound such as choline for stabilization. In addition, the stabilized silicic acid may include water. In the most preferred embodiment, the acidic liquid composition of the present

- 6 046569 aspect includes 2.5-4.0 vol.% silicon, 45-60 wt.% choline compound and 15-30 wt.% water, as well as 2-8% highly dispersed silicon dioxide. The amount of choline compound herein is based on the choline ion without a counterion. The preferred counterion is choline, but other counterions may be present instead or preferably other than choline. The amount of silicon is the amount of elemental silicon measured using atomic absorption spectrometry (AAS).

It is noted that preferred embodiments discussed in connection with one aspect also apply correspondingly to another aspect of the invention even though not discussed in detail in the foregoing.

It is further noted that the term stabilized silicic acid refers to a form of silicic acid that is stabilized from polymerization (also known as polycondensation) to silica (ie, fully polycondensed). Therefore, silicic acid is in monomeric form and/or oligomeric form, so that hydrolysis of the oligomer into monomers occurs in the gastrointestinal tract, especially due to the acidic environment existing therein. It is possible that the stabilized silicic acid in the present invention is in the so-called colloidal form. One known method of achieving stabilization is to use a stabilizer, for example a quaternary ammonium compound, with choline being the most preferred.

The term polysaccharide is well known in the art. It is defined as a saccharide compound with six or more repeating units. It is defined (according to the USPTO) as saccharide radicals linked to each other by glycosidic bonds. Typical polysaccharides are glucose, starch, glycogen, chitin.

The term polysaccharide derivative is defined as a polysaccharide in which at least a portion of the repeating units are chemically modified by at least one modifier. Typical modifiers are chain alkyl and substituted chain alkyls such as hydroxyalkyl and carboxyalkyl. In the present specification, alkyl is preferably lower alkyl such as methyl, ethyl, propyl, butyl. The term cellulose derivative is used as appropriate as substituted variants of cellulose.

The term derivative of HPMC or other individual cellulose in connection with this application refers to modified HPMC, for example, by modification with an organic acid, in order to improve processing properties. Such a derivative may also be in the form of a salt or in the form of a conjugate base.

Brief description of the figures

These and other aspects of the invention will be further illustrated by reference to the drawing, which schematically shows the dissolution of HPMC capsules filled with a liquid mixture of choline-stabilized orthosilicic acid and glycerol.

Examples

Preparative example 1.

Choline chloride is treated with cold hydrochloric acid. Silicon tetrachloride (PU) is added to the resulting solution of choline hydrochloride (the ratio of SiCl ₄ to choline chloride is 1 mol per 1-5 mol). The resulting solution is hydrolyzed by adding water (ice/ice water) while cooling in the temperature range from -10 to -30°C. The solution is neutralized by adding sodium hydroxide and maintaining the temperature below 0°C. The final pH is 1-1.5. The pH value is measured with a pH analyzer commercially available from Stratos, type MS A405, Knick, equipped with a Memosens pH electrode with an Ag/AgCl ₂ reference system and liquid KCl electrolyte.

After cleaning with activated carbon, the precipitate along with the activated carbon is removed by filtration. The water concentration is reduced by distillation in vacuum until a preparation is obtained containing 2.5-4 vol.% silicon, 65-80 wt.% choline chloride and 15-30 wt.% water. The precipitate that forms during distillation is removed by filtration. Solid HPMC capsules are filled, using a pipette, with a liquid preparation containing concentrated stabilized orthosilicic acid. Very small HPMC capsules (type 3) can be used to contain 190 mg of liquid drug. The filled capsules are sealed using a solution of HPMC (pharmacoate 603) in ethanol.

Preparative example 2.

Choline chloride is treated with cold hydrochloric acid. Silicon tetrachloride (PU) is added to the resulting solution of choline hydrochloride (the ratio of SiCl ₄ to choline chloride is 1 mol per 1-5 mol). The resulting solution is hydrolyzed by adding water (ice/ice water) while cooling in the temperature range from -10 to -30°C. The solution is neutralized by adding sodium hydroxide and maintaining the temperature below 0°C. The final pH is 1-1.5 when measured with the pH detector described above. After cleaning with activated carbon, the precipitate along with the activated carbon is removed by filtration. The water concentration is reduced by distillation in vacuum until a preparation is obtained containing 2.5-4 vol.% silicon, 65-80 wt.% choline chloride and 15-30 wt.% water. The precipitate that forms during

- 7 046569 distillation time, removed by filtration. 5% silicon dioxide (Aerosil®) is added to a liquid preparation containing concentrated stabilized orthosilicic acid to increase the viscosity from 56 to 93 mPa-s. The resulting mixture is encapsulated into hard HPMC capsules. Very small HPMC capsules (type 3) can be used to contain 190 mg of the drug. The filled capsules are sealed using a solution of HPMC (pharmacoate 603) in ethanol.

Preparative example 3.

Choline chloride is treated with cold hydrochloric acid. Silicon tetrachloride (1U) is added to the resulting solution of choline hydrochloride (the ratio of SiCl ₄ to choline chloride is 1 mol per 1-5 mol). The resulting solution is hydrolyzed by adding water (ice/ice water) while cooling in the temperature range from -10 to -30°C. The solution is neutralized by adding sodium hydroxide and maintaining the temperature below 0°C. The final pH is 1-1.5. After cleaning with activated carbon, the precipitate along with the activated carbon is removed by filtration. The water concentration is reduced by distillation in vacuum until a preparation is obtained containing 2.5-4 vol.% silicon, 65-80 wt.% choline chloride and 15-30 wt.% water. The precipitate that forms during distillation is removed by filtration. The liquid preparation of stabilized orthosilicic acid is diluted with glycerol and the resulting mixture is encapsulated into solid HPMC capsules using a standard method. HPMC capsules (maximum size type 1) are filled to contain 0.66 mg of liquid mixture. The filled capsules are sealed using a solution of HPMC (pharmacoate 603) in ethanol.

Preparative example 4.

Choline chloride is treated with cold hydrochloric acid. Silicon tetrachloride (1U) is added to the resulting solution of choline hydrochloride (the ratio of SiCl ₄ to choline chloride is 1 mol per 1-5 mol). The resulting solution is hydrolyzed by adding water (ice/ice water) while cooling in the temperature range from -10 to -30°C. The solution is neutralized by adding sodium hydroxide and maintaining the temperature below 0°C. The final pH is 1-1.5 when measured with the pH detector described above. After cleaning with activated carbon, the precipitate along with the activated carbon is removed by filtration. The water concentration is reduced by distillation in vacuum until a preparation is obtained containing 2.5-4 vol.% silicon, 65-80 wt.% choline chloride and 15-30 wt.% water. The precipitate that forms during distillation is removed by filtration. 5% silicon dioxide (Aerosil®) is added to a liquid preparation containing concentrated stabilized orthosilicic acid to increase the viscosity from 56 to 93 mPa-s. The resulting mixture is encapsulated in hard HPMC capsules type 3, which contain 195 mg of the drug. The filled capsules are sealed using a solution of HPMC (pharmacoate 603) in ethanol. Using a two-position encapsulator, type 3 sealed capsules containing concentrated stabilized orthosilicic acid are placed into OO HPMC bodies that are filled with 400 mg of purified fish oil (48% EPA and 21% DHA in triglyceride form) and then seal the filled open bodies with OO type closures . The resulting capsule-within-capsules are sealed using a solution of HPMC (pharmacoate 603) in ethanol.

Example 1 of defining characteristics.

Capsules filled with a stabilized silicic acid composition prepared according to Example 3 were subjected to a disintegration test. Use O HPMC extended type capsules supplied by Capsugel. The disintegration test is performed at various water concentrations and is performed according to standard Pharma Tests DTC-70 and DIST-3. For this purpose, the capsules are first incubated for 24 hours in the dissolution system and then 12 hours in the disintegration system (36 hours in total). The capsules are completely intact after incubation, i.e. there are no signs of disintegration. The results are given in table. 1.

Table 1. Incubation time of HPMC capsules filled with mixtures of stabilized silicic acid with glycerol, obtained according to example 3

Composition of the preparation of choline-stabilized orthosilicic acid Incubation A of HPMC capsules Dissolution system (Pharma Test DTC-70), 37°C, 200 rpm, 24 hours Incubation in HPMC capsules Disintegration system (Pharma Test DIST-3), 37°C, 12 hours Number of intact capsules 3% Si, 74% choline chloride, 23% water, pH 1 10 of 10 10 of 10 2% Si, 50% choline chloride, 15% water, 33% glycerol pH 1 10 of 10 10 of 10 1.5% Si, 38% choline chloride, 10.5% water, 50% glycerol pH 1 10 of 10 10 of 10

Example 2 of defining characteristics.

Capsules filled according to example 1 are subjected to chemical analysis. Capsules for this purpose are capsules packaged in HDPE bottles with a magnetic induction aluminum seal and a desiccant sachet and stored at room temperature for 12

- 8,046,569 months. Capsules are tested using ETAAS and colorimetry, as well as visually to determine friability. ETAAS is a measurement method also called electrothermal atomic absorption spectrometry. It is used to measure the amount of elemental silicon (analytical error 10%). Colorimetric experiments are performed according to the molybdenum blue method. This method is specific for orthosilicic (monomeric) acid, i.e. The test measures the amount of silicon in the form of orthosilicic acid (analytical error 10%).

The results are given in table. 2 and 3. It follows from them that the concentration of both elemental silicon and silicic acid remains stable. Also, capsules in aluminum/aluminium blisters stored at high relative humidity show no signs of polycondensation after 12 months, as confirmed by stable concentrations of orthosilicic acid (Table 3).

Table 2. Chemical Stability of Type 3 HPMC Capsules Filled with Choline Stabilized Orthosilicic Acid Packaged in HDPE Vial with Magnetic Induction Aluminum Seal

Composition/Packaging 190 mg choline-stabilized orthosilicic acid (100%); Primary packaging type: HDPE bottle with magnetic induction aluminum seal 25°C/40% RH Original After 12 months ETAAS (mg Si/caps) 5.1 5.4 Colorimetry (mg Si/caps) 5.1 5.3 Fragility (number damaged capsules/100 capsules) 0/100 0/100

Table 3. Chemical stability of Type 3 HPMC capsules filled with choline-stabilized orthosilicic acid packaged in ALU/ALU blisters

Composition/Packaging 190 mg choline-stabilized orthosilicic acid (100%); type of primary packaging: ALU/ALU blister 25 °C /60% RH 30°C /70% RH Original After 12 months Original After 12 months ETAAS (mg Si/caps) 5.1 4.9 5.1 5.0 Colorimetry (mg Si/caps) 5.1 5.2 5.1 5.4 Fragility (number damaged capsules/100 capsules) 0/100 0/100 0/100 0/100

Example 3 of defining characteristics.

The 2000 capsules obtained according to the preparative example are kept in vacuum (at a pressure of 20 kPa (200 mbar)) for 2 hours at room temperature. It was found that none of the capsules leaked and the capsule weight did not change (<0.03%). The capsules were stored in a sealed alu/alu bag and the leak test was repeated after 1 month. Of the 2000 capsules stored, not a single one leaked, and the capsule weight did not change (<0.03%).

Example 4 of defining characteristics.

The dissolution of the filled capsules obtained according to preparative example 3 is carried out in a buffer solution, which is a physiological saline solution. The results are shown in the drawing. These results show that the stabilized silicic acid is released from the capsule in a solvent environment very quickly and completely without polycondensation.

Example 5 of defining characteristics.

Capsules obtained according to Preparative Example 3 are incubated at different temperatures and different relative humidity. Capsules are tested using ETAAS and colorimetry, as well as visually to determine friability. ETAAS is a measurement method also called electrothermal atomic absorption spectrometry. It is used to measure the amount of elemental silicon (analytical error 10%). Colorimetric experiments are performed according to the molybdenum blue method. This method is specific for orthosilicic (monomeric) acid, i.e. The test measures the amount of silicon in the form of orthosilicic acid (analytical error 10%).

The results are given in table. 4 and 5. From these tables it is clear that both the physical integrity of the capsules and the stability of choline-stabilized orthosilicic acid are good. Neither the capsule shell becomes brittle nor is polycondensation of the stabilized silicic acid observed.

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Table 4. Chemical and physical stability of HPMC capsules type 1 filled with a liquid mixture of choline-stabilized orthosilicic acid and glycerol prepared according to Preparative Example 3

Composition A 285 mg glycerol (60%) 190 mg choline stabilized orthosilicic acid (40%) 25°C/40% RH 25°C/60% RH Original In 3 months Original In 3 months Chemical stability ETAAS (mg Si/caps) 4.9 4.7 4.9 4.7 Colorimetry (mg Si/caps) 4.8 4.8 4.9 4.8 Fragility (number damaged capsules/100 capsules) 0/100 0/100 0/100 0/100

Table 5. Chemical and physical stability of HPMC capsules type 1 filled with a liquid mixture of choline-stabilized orthosilicic acid and glycerol prepared according to Preparative Example 3

Composition B 125 mg glycerol (39.7%) 190 mg choline stabilized orthosilicic acid (60.3%) 25°C/40% RH 25°C/60% RH Original In 3 months Original In 3 months Chemical stability ETAAS (mg Si/caps) 4.8 4.6 4.8 4.6 Colorimetry (mg Si/caps) 5 5 5 5 Fragility (number damaged capsules/100 capsules) 0/100 0/100 0/100 0/100

Example 6 of defining characteristics.

Compositions A and B described in Characterization Example 5 were subjected to compression testing on a TA XT Plus Texture analyzer (10% analytical error). The results are given in table. 6 and 7.

Table 6. Compression test performed with composition A

25°C/40% RH 25°C/60% RH Original In 3 months Original In 3 months Peak Force (N) 13.7 13.2 13.7 12.8 Positive peak area (N.c) 78.8 77.0 78.8 75.0

Table 7. Compression test performed with composition B

25 °C 40% RH 25°C/60% RH Original In 3 months Original In 3 months Peak Force (N) 12.1 12.8 12.1 13.2 Positive peak area (N.c) 71.0 75.0 71.0 76.0

Example 7 of defining characteristics.

The tests performed for characterization in Example 5 were repeated, but the composition was now encapsulated in larger capsules, i.e. type O rather than type 1. In addition, the test is performed over a longer period, i.e. 9 months, not 3 months.

Table 8. Long-term chemical and physical stability of HPMC type O capsules filled with a liquid mixture of choline-stabilized orthosilicic acid and glycerol

Composition C 460 mg glycerol (69.7%) 200 mg choline-stabilized orthosilicic acid (30.3%) 25°C/60% RH Original After 9 months ETAAS (mg Si/caps) 5.3 5.5 Colorimetry (mg Si/caps) 4.9 4.8 Fragility (number of damaged capsules/100 capsules) 0/100 0/100

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Table 9. Long-term chemical and physical stability of HPMC type O capsules filled with a liquid mixture of choline-stabilized orthosilicic acid and glycerol

Composition D 130 mg glycerol (39.4%) 200 mg choline stabilized orthosilicic acid (60.6%) 25°C/60% RH Original After 9 months ETAAS (mg Si/caps) 5.4 5.8 Colorimetry (mg Si/caps) 5.5 5.5 Fragility (number damaged capsules/100 capsules) 0/100 0/100

An example for comparison.

Mixtures of liquid choline-stabilized orthosilicic acid with glycerol, prepared according to the protocol described in Example 3, are used directly to fill soft and hard gelatin capsules. Capsules are stored at room temperature in a packaging container (HDPE bottle). Soft gelatin capsules are stored for 1 week, after which the condition of the capsules is assessed. Hard capsules are stored for 3 months, after which the condition of the capsules is assessed. The results are given in table. 1 and 2. Water was found to migrate between the respective gelatin shell, stabilized silicic acid mixture and air in the packaging container, resulting in deformed and leaking capsules. The stability problem cannot be solved by using a specific primary packaging material.

Table 10. Stability of soft gelatin capsules filled with ch-OSA-containing polyol blends. For each composition, 4 capsules are stored for 1 week at room temperature and in a temperature-controlled stability chamber with a relative humidity of 25°C, 60% RH). Capsules are checked visually after 1 week

Composition Room temperature 25°C, 60%RH 100% ch-OSA (pH 1.0) 4 out of 4 capsules are very soft and damaged (partially dissolved, destroyed and swollen). 4 out of 4 capsules are very soft and damaged (partially dissolved, destroyed and swollen). 67 ch-OSA 33% glycerin 4 out of 4 capsules are very soft and damaged (partially dissolved, destroyed and swollen). 4 out of 4 capsules are very soft and damaged (partially dissolved, destroyed and swollen). 67% ch-OSA 33% PEG 600 4 out of 4 capsules are very soft and damaged (partially dissolved, destroyed and swollen). 4 out of 4 capsules are very soft and damaged (partially dissolved, destroyed and swollen). Reference sample: 100% soybean oil 4 out of 4 capsules are intact 4 out of 4 capsules are intact

Table 11. Stability of hard gelatin capsules filled with ch-OSA-containing polyol blends. For each composition, 5 capsules are stored for 3 months at room temperature in an open Petri dish or packaged in an HPDE vial. Capsules are checked visually after 3 months

Composition Petri dish HDPE bottle 100% ch-OSA (pH 1.0) 5 out of 5 capsules are damaged and deformed. 5 out of 5 capsules are damaged and deformed. 67% ch-OSA 33% glycerin 4 out of 5 capsules are damaged and deformed. 4 out of 5 capsules are damaged and deformed. 67% ch-OSA 33% PEG 600 5 out of 5 capsules are damaged and deformed. 4 out of 5 capsules are damaged and deformed. Reference sample: 100% soybean oil 5 out of 5 capsules are intact. 5 out of 5 capsules are intact.

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Claims (9)

References Iler 1979, The chemistry of silica, John Wiley & Sons, NY. Jugdaohsingh et al., 2000, Oligomeric but not monomeric silica prevents aluminum absorption in humans. Am. J. Clin. Nutr., 71, 944. Calomme et al., 1997, Supplementation of calves with stabilized orthosilicic acid. Effect on the Si, Ca, Mg, and P concentrations in serum and the collagen concentration in skin and cartilage. Biol. Trace Elem. Res., 56, 153. Calomme et al., 2006, Partial prevention of long-term femoral bone loss in aged ovariectomized rats supplemented with choline-stabilized orthosilicic acid. Calcif. Tissue Int., 78, 227. Spector et al., 2008, Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial. BMC Musculoskeletal Disorders, 9, 85. Barel et al., 2005, Effect of oral intake of choline-stabilized orthosilicic acid on skin, nails and hair in women with photodamaged skin. Arch. Dermatol. Res., 297, 147. Wickett et al., 2007, Effect of oral intake of choline-stabilized orthosilicic acid on hair tensile strength and morphology in women with fine hair. Arch. Dermatol. Res., 299, 499. Geusens P, Pavelka K, Rovensky J, Vanhoof J, Demeester N, Calomme M, Vanden Berghe D., (2017). A 12-week randomized, double-blind, placebo-controlled multicenter study of choline-stabilized orthosilicic acid in patients with symptomatic knee osteoarthritis, BMC Musculoskeletal Disorders, 18: 2 DOI 10.1186/sl2891-016-1370-7. Chiwele et al., 2000, The Shell dissolution of various empty hard capsules, Chem. Pharm. Bull., 48, 951. Rabadiya et al., 2013, A review: capsule shell material from gelatin to non animal origin material, International Journal of Pharmaceutical Research and Bio-Science, 2, 42. Scientific opinion of the Panel on Food Additives and Nutrient Sources added to Food. choline-stabilized orthosilicic acid added for nutritional purposes to feed supplements, The EFSA Journal (2009), 948, 1-23. CLAIM 1. A capsule for oral administration, including a capsule shell and filled with an acidic liquid composition with a pH in the range of 0-2.5 containing choline compound stabilized silicic acid, and in which the capsule shell includes hydroxyalkyl alkyl cellulose. 2. A capsule according to claim 1, wherein the stabilized silicic acid essentially comprises silicic acid monomers and/or oligomers, preferably orthosilicic acid and/or oligomers thereof. 3. Capsule according to claim 1 or 2, wherein the liquid composition has a pH in the range of 0.5-2.0, preferably 0.8-1.3. 4. A capsule as claimed in any one of the preceding claims, wherein the silicic acid is stabilized by a choline compound which is present in a concentration of at least 20% by weight of the liquid composition. 5. A capsule as claimed in any one of the preceding claims, wherein the composition comprises water in an amount of at most 30% by weight, preferably water in an amount of at most 20% by weight, more preferably water in an amount of at most 15% by weight. 6. Capsule according to any of the preceding paragraphs, in which the composition has a viscosity in the range of 0.08.103-2.0.10 ³ mPa-s. 7. A capsule according to any of the preceding claims, wherein the composition further includes a rheological additive. 8. Capsule according to claim 7, in which the rheological additive is selected from amorphous silicon, phosphoric acid and/or its salts and triglycerides, in particular from amorphous silicon, such as highly dispersed silicon dioxide. 9. A capsule according to any one of the preceding claims, especially according to claim 7, wherein the liquid composition further contains a diluent in an amount of at most 20% by weight and preferably at most 10% by weight or is free of diluents. -