Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
2000-10-12
2002-01-01
Shaver, Paul F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
C556S413000, C556S419000, C556S482000, C530S300000, C530S343000, C530S345000, C424S484000, C424S070120, C424S070140, C424S489000, C424S499000
Reexamination Certificate
active
06335457
ABSTRACT:
The present invention concerns a complex containing biologically assimilable orthosilicic acid, which is under solid form, stable and concentrated, and a process of preparation of said complex.
Silicon is an essential element for life. It has both a structural role being a constituent of the proteins-glycosaminoglycanes complexes found in the connective tissue's matrix, and a metabolic role on growth and osteogenesis (silicon favours the process of mineralisation of the bone). Thus, silicon is compulsory for a normal development of bones and connective tissue.
It was also shown that silicon under the form of orthosilicic acid Si(OH)
4
has a high affinity for Al
3+
ions and enhances their elimination. Thus, it could act against the toxic effects of aluminium on bones and brain, especially in neurologic degenerative diseases such as Alzheimer's disease.
These data suggest that a punctual supply in silicon can be very helpful, during the growing period for instance, or in particular pathologies.
Nevertheless, it is also important to prevent silicon deficiency,: several studies performed on human showed that silicon decreases with aging in skin and arteries walls, essentially because of the decrease of gastro-intestinal absorption of silicon in the course of time.
The main problem with silicon metabolism arises from the difficulty of its assimilation. Although silicon is a very abundant element, it naturally occurs under the form of minerals insoluble in water (crystalline oxides (silicas and silicates) or amorphous (clays, opals, . . . )), which do not represent a source of assimilable silicon for the organism.
Likewise, silicon as it naturally occurs in our food, i.e. essentially under the form of aluminosilicates or silica, is very slightly assimilable. The actual techniques of purification and refining of vegetable products (dietary cereals and fibres are the main source of silicon), which tend to eliminate the parts rich in silicon (the husks), have still reduced this supply.
It seems now admitted that a biologically active form of silicon must be hydrosoluble, and that the solubility depends on the amount of free OH groups (silanol functions) on the silicon atom.
In blood and extravascular liquids, the silicon is physiologically present under hydrated form of orthosilicic acid (Si(OH)
4
), non dissociated at the pH of the organism, and almost completely in its free form.
Moreover, studies have shown that only monomeric or oligomeric (very slightly polimerized) orthosilicic acid is able to pass the intestinal barrier (P. Creach, J. Adrian, Méd. et Nut. 1990, 26(2), 73-90).
The presence on the silicon atom of free OH groups is closely linked to its biological role. Indeed, these functions can make covalent or hydrogen bonds with amides, water, alcohols, ketones, esters, . . . .
Thus, in biological media, bonds with the membrane's phospholipids, proteins, glycosaminoglycanes and polysaccharides can be formed.
So it is necessary to conceive a silicon supply in which silicon is under the form of silicic acid or a form as similar as possible.
Monomeric orthosilicic acid in solution is relatively stable until a concentration of about 10
−4
Mol.l
−1
; but, when the concentration increases, the Si(OH)
4
molecules associate to make oligomers and polymers of orthosilicic acid (formation of siloxane bonds Si—O—Si) to finally make colloidal solutions or silica gels that are weakly soluble or insoluble in water, and which silicon biodisponibility is very weak.
The supply of orthosilicic acid under the form of very diluted stable solutions do not comply with a daily supplementation in silicon and also make impossible its incorporation, in sufficiently high amounts, in nutrients or dietetic, cosmetic or therapeutic compositions.
The already available sources of biologically active and concentrated silicon are organosilicic compounds presenting several free hydroxyl groups, that can be found under the form of solutions or under solid form (EP- 0 289 366 and FR 2 761 074 patents).
Besides, more concentrated solutions of orthosilicic acid are available, in which orthosilicic acid is stabilized by a very acid pH that counteracts the polymerization by hydrolyzing the siloxane bonds Si—O—Si (patent JP 58176115).
The patent WO 95/21124 also proposes concentrated preparations of orthosilicic acid stabilized by a stabilizer. A complex between orthosilicic acid and choline in solution is made, but a good stability can not be obtained without maintaining an acid pH.
Such acid solutions do not provide an optimal assimilation because during ingestion, the pH conditions are not maintained (physiological pH). An important part of the orthosilicic acid polymerizes before being assimilated.
In the scope of a medical study, a topical application of colloidal silicic acid was combined with an oral intake in order to improve aged skin, fragile hair and brittle nails (Lassus A., Journal of International Medical Research 1993, 21, 209-215). However, the biodisponibility of this form is weak because of the presence of many siloxane bonds.
This is why a purpose of the invention is proposing a form of orthosilicic acid which is assimilable, concentrated and stable.
Moreover, to be orally assimilable, orthosilicic acid has to be soluble and chemically stable at the different physiological pH that is to say in acidic, neutral or slightly alkaline medium Thus an other aim of the invention is obtaining a form of orthosilicic acid which is stable at these different pH.
Lastly, an other purpose was to obtain a solid form which can be incorporated in dietetic, cosmetic or therapeutic compositions, and in nutritional supplements, under non aqueous forms: capsules, granules or tablets for oral administration.
These objectives can be reached by complexing orthosilicic acid with a polypeptide which acts as a stabilizer by forming hydrogen bonds with orthosilicic acid. This prevents the formation of siloxane bonds and orthosilicic acid polymerisation.
A stable solid form (powder) of orthosilicic acid is thus obtained which is, after ingestion, solubilized in biological fluids to release a soluble form of assimilable and biologically active orthosilicic acid (monomeric or oligomeric).
Notwithstanding the excellent stability of the concentrated solid form, an important characteristic of the invention is its ability to remain stable during its transit in the gastrointestinal tractus, and this despite the existence of different physiological pH favouring its polymerisation.
This can be explained by the particularly strong interaction existing between the silicon and the polypeptide. When dissolving, the complex between the polypeptidic chain and the hydroxylic functions carried by the silicon atom remains; the cohesion of the complex is linked to the formation of a group of weak bonds (hydrogen bonds) and probably to the structural organisation of the polypeptidic chain.
It is to be noted that in the prospect of preparing a sustained-release form, some peptides having a pharmacological activity have been associated to natural minerals containing silicon or to synthetic minerals made of silicic acid (patent No. BE 778.239). The common characteristic of all these silicon compounds is the formation of a colloidal suspension suitable as a support for the peptides; it is clear that the technical problem treated in this patent has no connection with the present invention.
The subject of the present invention is proposing a complex containing biologically assimilable orthosilicic acid in which orthosilicic acid is complexed with a polypeptide and is under solid, stable and concentrated form.
The subject of the present invention is also to provide a process of preparation of the said complex containing orthosilicic acid, comprising the following steps:
the polypeptide is dissolved in 1 volume of distilled water
the pH is adjusted between 2 and 4
in a proportion comprised between 1/4 and 1 volume, an alcohol soluble in water, preferably ethanol, is added under stirring,
a hydrolyzable precursor of ortho
Gueyne Jean
Seguin Marie-Christine
Exsymol S.A.M.
Lydon James C.
Shaver Paul F.
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