BE478537A - - Google Patents

Description

       

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  "Thixotropic gel systems and their preparation process"
The present invention relates to gels of salts of alkaline earth metals ((hereinafter referred to as "alkaline earth salts") 'insoluble in water, forming colloidal dispersions in an aqueous medium, these gels being thixotropic, i.e. that is to say having a firm or fixed consistency when left to stand but becoming, after brief stirring or riddling, fluid and transferable in the form of a liquid, stable and homogeneous dispersion or suspension, gels in which the transformation from the frozen form to the liquid form is reversible and can be brought from one form to another without limitation.



   The thixotropic gels according to the invention offer a wide field of applications and are useful in many industries.

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 such as those for dyes, pigments, colors, paper sizing, leather finishing, and others.



   They are further particularly useful in the pharmaceutical industry for the composition of various species of pharmaceutical and therapeutic preparations. Therefore, the invention especially includes thixotropic gels in which the ingredients necessary to impart the thixotropic characteristics are themselves useful for therapeutic purposes, for example to provide certain metabolic mineral factors, such as calcium, iron, magnesium, phosphorus and the like, so that these gels may be useful either alone or in conjunction with other pharmaceutical or medicinal agents, as ingredients introduced into the thixotropic gel system.



   An advantageous feature of such thixotropic gel preparations resides in the possibility of being able to incorporate the various required and therapeutically active ingredients, called to form part of the composition, in a higher concentration than would ordinarily be possible in preparations known for this purpose. day, as well as in an eminently stable form.



   In all cases, the thixotropic gels according to the invention comprise two essential constituents. The main and most important constituent is an alkaline earth salt which is insoluble in water and capable of giving a colloidal dispersion or a mixture of such salts, which, as far as therapeutic preparations are concerned, are those which do not exhibit of toxicity in the doses administered by the chosen route.

   The second ingredient, that which enters for a lesser percentage, is a citrate of an alkaline reacting cationic radical, for example that of any alkali metal or of a nitrogenous base, for example ammonia, derived from ammonia ;, such as primary, secondary and tertiary alkyl amines and aliphatic amines and

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 quaternary ammonium bases, and the like, which are soluble in water, or in water containing in solution at least about 5% citric acid. The second component can be prepared in situ from the citric acid and the alkaline reacting agent necessary to form the indicated citrate, or can be used in the form of a pre-prepared citrate.



  Its proportion in some compositions may be of a fraction of 1%, and in others - which represent less frequent cases reach 5%, this proportion often being determined by the total of solid substances in the alkaline earth salts. , capable of forming a colloidal dispersion, namely, the lower the total of solid substances, the less citrate is used, while a higher total of solid substances corresponds to a greater proportion of citrate. In all cases, the amount of citrate used must be sufficient to impart the desired degree of thixotropy in the composition which must exhibit the final constitution envisaged.



   The gels according to the invention in which the alkaline earth salt insoluble in water and capable of giving a colloidal dispersion and the citrate of the agent with an alkaline reaction are the only constituents which confer the thixotropic character, manifest. best their thixotropic nature when the concentration of hydrogen ions in the system is between 5.0 and 6.5. However, the thixotropic behavior can be manifested within significantly wider pH limits, extending both on the acid side and on the alkaline side, when a small proportion is incorporated, and as a third component, a soluble agent. water and selected from water-soluble carbohydrates and aliphatic polyhydric alcohols, especially hexitols.

   Any carbohydrate, whether a mono-saccharide or a polysaccharide, is suitable for this purpose, as long as it is soluble in water,

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 e.g. mono-saccharides, such as pentoses, e.g. xylose, ribose, or hexoses, e.g. glucose (dextrose), mannose fructose (levulose), mannoheptose, or bi-saccharides, e.g. lactose, maltose, sucrose . Among the water-soluble aliphatic polyhydric alcohols, those which are especially suitable are those which are soluble in water and which have as many hydroxy groups as there are carbon atoms in the aliphatic chain, particularly the hexitols, for example sorbitol, mannitol, dulcitol.

   Such a third component in the system extends the limit of the concentrations of hydrogen ions in which good thixotropy is obtained, from a pH of about 4.0 to a pH of 11.5 and even higher.



   For any particular desired purpose, the thixotropic system according to the invention, for example that described hereinafter in Examples 4 and 5, whether obtained by the use of the two essential constituents (e.g. Example 4) or by two of these components, plus the third (Example 5 for example), can be added other compatible ingredients to maintain the thixotropic characteristic, these other added ingredients can be incorporated into the system under in a higher concentration and in a more stable form, generally obtained in systems of other types.



  In the therapeutic compositions, in particular, there can be included, for example, ingredients for the treatment of metabolic deficiency, for example any of the known vitamins or vitamin factors, soluble in water or in water. oil, or any of the suitable amino acids, proteins, protein hydrolyzates, and the like, or anti-bacterial agents compatible with the system, such as sulfanilamides and active and non-toxic derivatives of sulfanilamides, and other sulfonamides, antibiotics, soluble or insoluble in water, such as:

   penicillin, tyrothricin, strepto-

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 mycin and the like, hormones, antacid substances other than those already contained in the main constituent of the system, biological preparations, such as bacteria-vaccines, toxoids, viruses'-vaccines, and other therapeutic or pharmaceutical ingredients compatible with the thixotropic system. In most cases, the incorporation of these additional pharmaceutical products into the thixotropic gel system according to the invention is effected by adsorption of the addition agent onto the component of the system represented by the alkaline salt. earthy insoluble in water and forming a colloidal dispersion.



   The thixotropic gels according to the invention are prepared by a process comprising three essential operations. The first consists in preparing the alkaline earth salts which are insoluble in water by precipitation under conditions which control their formation in the form of a colloidal dispersion or capable of giving such a dispersion. The second operation consists in concentrating these alkaline-earth salts, and incidentally involves a partial elimination of the water-soluble electrolytes which remain after the precipitation during the formation of the water-insoluble alkaline-earth salts, capable of giving a colloidal dispersion.

   The third essential operation consists in incorporating or adding the citrate of the alkaline reacting agent, either by in situ formation or by addition in the form of the desired citrate or of a mixture of desired citrates, these two methods being referred to below. generally such as: incorporation of citrate in the composition.



   The formation of alkaline earth salts which are insoluble in water and which can form a colloidal dispersion is carried out by reacting two separate solutions of soluble salts in water. The first of these solutions, which will be designated,

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 for convenience, "solution A", is an aqueous solution of a substance such as a salt or a mixture of salts, the anion or anions of which react in the aqueous medium with a cation, which is an alkaline metal. earthy, to precipitate the corresponding alkaline earth salt, insoluble in water.

   Thus, the substance dissolved in solution A is for example a sulfate, phosphate, carbonate, silicate or other water-soluble compound such as aluminate, molybdate, borate, chromate., Malate and the like, as long as their anion forms , with an alkaline earth metal, a salt insoluble in water. Further, the cation of the dissolved phase of "solution A" should be one with which the anion of the dissolved phase of solution B "(below) forms a water soluble salt.



   The second solution, designated for convenience as "solution B", necessary for the preparation of the main component of the gel system according to the invention, is an aqueous solution of a water-soluble alkaline earth salt, or a mixture. such salts, the anion (s) of which form a water soluble salt, with the cation (s) of the salt (s) chosen for "solution A" with a view to the particular preparation envisaged.



   In each of solutions A and B, the dissolved phases can be present in any desired or suitable concentration, up to a saturated solution. The latter is generally appreciated for practical reasons. In causing solution A to react with solution B it is to some extent advantageous, although not essential, to employ equal volumes of each solution. Therefore, the concentration of the dissolved phase in one of the two solutions should be such that the quantitative concentration of its cations is the stoichiometric equivalent of the concentration of anions in the other solution.

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   The reaction between solutions A and B can be carried out at any suitable temperature, preferably below the boiling point of the solutions. Generally speaking, however, the lower the temperature, the smaller the particle sizes of the resulting insoluble salt and the better the thixotropic activity, although the results improve as the temperature of the mixture of the two solutions becomes better. increases from a temperature approximately equal to ambient temperature, and becomes best between approximately 55 ° C and approximately 6000, to become worse with increasing temperature.

   The results improve, or even are the best, when the temperature of the mixture is lower than the ambient temperature; they are absolutely the best for a temperature approaching 0 C.



   Any of the solutions can be added to the other, but the particle size of the insoluble precipitated salt is advantageously smaller when solution B is added to solution A. In each case, the sizes of part are obtained. - advantageously smaller cells or a better colloidal dispersion capacity, and regardless of the solution which has been introduced into the other, when solution B is used in an amount sufficient to obtain a slight excess of soluble alkaline earth salt in water and not participating in the reaction.



   Whatever solution has been added to the other, the introduction is preferably carried out with agitation, for example shaking or riddling, the latter being preferable, agitation which should be at least sufficient to ensure adequate intimate mixing. of the two solutions.

   Once one solution has been introduced into the other, the water-insoluble alkaline earth salt obtained by precipitation forms a homogeneous and stable dispersion in essentially the whole of the aqueous medium and standing does not give low sedimentation varying from almost 0 to only about 5% or more, but

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 rarely reaches 30% of the clear supernatant liquid, depending on the reaction conditions, mainly the temperature, sedimentation being minimum when the precipitation takes place within temperature limits between 55 and 60 C and between room temperature and 0 C.



   The second essential operation of the process consists in the concentration of the alkaline earth salts insoluble in water, obtained by precipitation, and is incidentally accompanied by the partial elimination of the electrolytes formed during the reciprocal reaction of the dissolved phases of the water. two solutions A and B.



   This concentration can be carried out by suitable means acting to separate the aqueous solution of the soluble salts in water previously obtained from the insoluble precipitate, and advantageously consists in first decanting all the supernatant liquid. , with or without prior addition of additional water, to this liquid. The concentration is carried out (with incidental elimination of the major part of soluble electrolytes) by filtration, either aspirated or pressed, with or without washing of the filter cake. In these concentration operations, the removal of electrolytes does not have to be complete, but only practically sufficient.

   If, for reasons dictated by the particular composition of the final product, it is necessary to remove the electrolytes more completely, the press cake can be washed, for example up to. that a sample of the washing liquid presents only a slight cloudiness after having been added to a solution of silver nitrate, this when this liquid contains certain chlorides, or only a slight cloudiness after addition of a solution of barium chloride, when the filtrate contains dissolved sulphates. When the final product is to be administered parenterally, it is not necessary to wash the filter cake, since in this case the retained electrolytes favor the approximation towards isotony.

   When this product is called for oral administration, elimination more

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 full electrolytes may be beneficial, to avoid overly salty taste or incompatibility with absorption of other incorporated ingredients.



   In many cases, concentration can be achieved by centrifugation alone or in conjunction with filtration.



   In this stage of the process and in accordance with the desired concentration of gel constituents in the intended end product, the additional required amount of water can be removed from the filter cake, preferably by hydraulic pressure, with the use of suitable bags or other means of retaining solid substances. In this way, wet gels of water-insoluble alkaline earth salts containing up to 50%, and even more, of total solid were obtained.



   The invention can be illustrated, without being limited thereto, by the following examples: Example 1 -
Solution A was prepared by dissolving 121 g. of bisodium phosphate USP and 18 g. of sodium carbonate USP in 1500 cc. of water and cooling to 15 C; solution B consisting of 96 g was added thereto with stirring. of Calcium Chloride USP and 5 g. of magnesium chloride crystals dissolved in 1500 cc. of water and cooled to 5 ° C. A cloudy, white, fine dispersion of particles formed, capable of forming a colloidal dispersion of insoluble carbonate and phosphates of calcium and magnesium.

   The reaction mixture was allowed to settle overnight, after which time a small amount of the clear aqueous supernatant solution was decanted, replaced with a substantially equal amount of fresh water, and the mixture was removed. allowed the reaction mixture to stand again overnight, during which time a further quantity of electrolytes migrated to the cool water above the precipitate.



  The second supernatant liquid was then decanted, after which the precipitated in soluble salt was filtered off with suction and washed with

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 water until a sample of the wash water showed only a slight cloudiness after addition of a silver nitrate solution, suction being applied to the filter cake long enough, to suck up all the water practically capable of being removed in this way, after which the filter cake was placed in a squeeze bag and a further quantity of water was squeezed out in a press hydraulic.



  Example 2. -
Solution A was prepared by dissolving 80 g. sodium sulfate, 20 g. of sodium phosphate, and 15 g. of potassium carbonate, in 2000 cc. of water, and thereto was added, with stirring, solution B consisting of 150 g. of baryun chloride and 25 g. of strontium bromide, dissolved in 2000 cc. of water and heated to 55 C, after which a cloudy, white, fine dispersion of colloidal particles of insoluble barium and strontium sulphates, phosphates and carbonates formed.



  The reaction mixture was allowed to settle overnight as in Example 1 and the dispersion formed by the alkaline earth salts. The precipitates, insoluble in water, were then substantially freed of electrolytes by decantation and filtration, and concentrated by hydraulic pressure, as in Example 1.



  Example3 -
Has a soludion prepared by dissolving 80 g. of Sodium Sulphate USP, 20 g. of sodium hydroxide USP and 25 g. of sodium silicate (40% solution) in 2000 cc. of water, and cooled to 15 ° C., a solution B consisting of 90 g was added. Calcium Chloride USP, 25 g. of magnesium chloride crystals, dissolved in 2000 cc. of water and cooled to 10 ° C, after which a cloudy, white and fine dispersion of colloidal particles of silicates and hydroxides of calcium and magnesium and magnesium sulfate, insoluble in water, formed.



  The reaction mixture was left to settle overnight,

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 as in Example 1, and the dispersion of the precipitated alkaline earth salts, insoluble in water, was substantially freed of electrolytes and concentrated by decantation and filtration and then by hydraulic pressure, as in Example 1.



   Examples 1, 2 and 3 above illustrate the process for the preparation of a suspension dispersion of water-insoluble alkali metal salts having the desired particle sizes and forming the main constituent of thixotropic gels according to the invention, the description of these examples comprising the first two essential operations of the process for preparing thixotropic gels. The third essential operation consists in incorporating into the system the ingredient which develops the thixotropic properties. of the insoluble mineral salt gel, namely, the citrate of the agent to. alkaline reaction.

   Thus, the third phase of the process comprises the incorporation, into the system, of a telcitrate, for example an alkali metal citrate or ammonium citrate or other citrate of the type described above (either by in situ formation or by addition of the selected citrate or mixture of citrates) in an amount sufficient to adjust the concentration of hydrogen ions in the system at least to a pH between the limits of about 5.0 to about 6.5 .



   However, to develop the thixotropic behavior of the system up to the neutral point and beyond, that is to say on the alkaline side, even up to a pH of 10 or 11, one adds, during the adjustment of the alkalinity, from 5% or even less, up to about 20%, of the desired and appropriate carbohydrate of an aliphatic polyhydric alcohol, such as excitol, depending on the desired composition of the final preparation envisaged.



   Although in the previous examples it was indicated that the water-insoluble alkaline earth salts were prepared

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 for example from sodium carbonate, sodium hydroxide, sodium silicate, sodium sulfate, bisodium phosphate and potassium carbonate, as the dissolved phase in solutions A, this phase is not limited to these substances.



  The hydroxide or the corresponding salt, such as carbonate, phosphate, silicate or sulfate of any alkali metal or ammonium cation, as well as such salts of any of these alkali metals or ammonium, the anions of which form insoluble precipitates with an alkaline earth cation, as described above. Likewise, and although in the preceding examples, the dissolved phase of solution B consists of a chloride of one of the alkaline earth metals, it is not limited to the use of the chloride.

   Any other water soluble salt of any of the alkaline earth elements, for example acetate, nitrate, and the like, can be employed as long as the anion of the water soluble alkaline earth salt can be employed. Water forms, together with the alkali metal or the ammonium cation, a water soluble salt.



   Below is a non-limiting example of the thixotropic system, on the acid side: Example 4 -
2000 g. of the precipitated and water-insoluble dispersion of alkaline earth metal obtained in Example 1 were placed in a "Pony Mixer" and thoroughly ground, after which 26 g were added. citric acid USP and mixed, until a gel formed, for about 35 minutes, during which time the citric acid was completely dissolved, and a smooth paste was obtained. Then 13 cc was added. of 20% sodium hydroxide solution while continuing to mix for 20 minutes.

   The resulting product had a pH of 5.3 and represented a thixotropic gel, as could be seen by taking a portion of the relatively fluid portion of the mixture and allowing it to stand for one or two minutes after. des-

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 which it has taken on a fixed and firm consistency, only to transform itself after stirring into the former liquid and transferable form.



   Below is a non-limiting example of a thixotropic system on the alkaline side: Example 5.-
At 1000 g. of the thixotropic gel obtained in Example 4, 100 g was added. of beta-lactose and the combination was mixed thoroughly for about 20 minutes, after which the beta-lactose was completely dissolved. A very marked decrease in viscosity was observed, but a sample of the stable and homogeneous suspension, which was allowed to stand for a few minutes, took on a firm and set consistency, which quickly gave way to fluidity. initial then a slight agitation of the mass in its container. Changing the pH to 11.0 by adding alkali did not destroy the thixotropic behavior.



   Although the thixotropic gel described in Example 4 or Example 5 can be used in the form set forth in each of these examples, as a finished product, for example as a pharmaceutical preparation for the administration of the mineral elements which it contains, with a view to treating or preventing a metabolic deficiency of the particular mineral element, the gel according to the invention, as described in Examples 4 and 5, can also be used as a support or a base into which other therapeutically active ingredients of the type mentioned above can be incorporated.

   In this lock, the new ingredient (s) which must be introduced to obtain a desired pharmaceutical composition or preparation, can be incorporated by mixing them with the thixotropic gel provided, for example by one of Examples 4 or 5, or during the stages in which the alkaline earth salts insoluble in water and capable of forming a colloidal dispersion, prepared according to Examples 1, 2 and 3, undergo a subsequent treatment with a view to their conferring.

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 rer the character of a thixotropic system. Such a process can be illustrated, without being limited thereto, by the example below.



    Example, 6¯- '
5000 g. of the water-insoluble alkaline earth salt dispersion produced according to any one of Examples 1, 2 or 3, and containing approximately 35% total solid mineral matter, are thoroughly mixed and ground at low viscosity. tess in a "Pony Mixer" until a thick and dense paste is obtained. 70 g are then added. citric acid USP while stirring continues, and dissolution occurs in about 20 minutes.

   Then 18 g are added. of ascorbic acid (vitamin C) and stirring is continued for about 15 minutes, during which time an intimate mixture of 5 g. a concentrate of vitamins (containing per gram 450,000 units of vitamin A and 90,000 units of vitamin D) and 5 g. alpha tocophenol with 500 g. beta-lactose. This vitamin-lactose mixture is then added to the paste of water-insoluble alkaline earth salt and ascorbic acid contained in the "Pony Mixer" and the whole is stirred for about 20 minutes, to give a smooth paste having approximately the consistency of cold cream.

   It is optionally possible to add to this paste a suitable aromatic agent, for example lemon essence or another aromatic agent, as well as a preservative such as benzoic acid or the like. Then added to this smooth paste, while stirring, 37.50 g. of a 20% solution of sodium hydroxide and mixing is continued for 5 to 10 minutes during which the preparation turns into a moderately fluid dispersion which, after being introduced into bottles, sets into a firm paste due to its thixotropic properties.

   Consequently, a moderate agitation is sufficient to transform this paste easily and at will into a stable and easily transferable liquid colloidal dispersion which, then left to stand, can be transferred back into a few minutes.

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 into a firm dough. The finished product has a hydrogen ion concentration of 5.2 and a specific gravity of 1.277.



   A daily dose of two teaspoons, or about 8 cc. of the product obtained according to Example 6, provides 1, U73 g. calcium, 0.652 g. of phosphorus and 0.032 g. magnesium. To the knowledge of the inventors, such a high concentration of these essential metabolic minerals in a very low viscosity colloidal dispersion is not otherwise achievable. If desired, it is possible to obtain even higher concentrations of the mineral content of any of the thixotropic gels envisaged by the invention, this by expressing more strongly in the phase in which hydraulic pressure is used, so as to remove a still larger quantity of water from the alkaline earth salts which are insoluble in water and which are liable to form a colloidal dispersion of the type obtained in the preceding Examples 1, 2 and 3.



    Example 7 -
5000 g. of alkaline earth salts which are insoluble in water and which can form a colloidal dispersion, obtained by one of Examples 1, 2 or 3, are perfectly mixed and ground at low speed in a "Pony Mixer" until a paste is obtained dense and thick, to which is added 75 g. of citric acid USP, mixing continuing until dissolved, after which 150 g. concentrated liver extract (1: 20), 100 g. of yeast concentrate, 315 g. of rice husk concentrate, 0.6 g. thiamine hydrochloride, 0.3 g. lactoflavin and 5.0 g. nicotinamide (nicotinic acid amide), the whole being thoroughly mixed for about 40 minutes.

   30 cc are then gradually added. of concentrated ammonium hydroxide solution (28% NE}, while continuing to stir. The pH is 4.9. The resulting colloidal suspension can be easily poured into bottles, and, after being left to stand in these

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 for a few minutes, turns into a hard, frozen brown paste, which can easily pass into the liquid and transferable state, given the thixotropic characteristics conferred on the composition during its preparation.



   In this particular example, it was not necessary to separately add a special carbohydrate, as this is found in the concentrates of rice skins and yeast, such as maltose and schacharose, so these The latter carbohydrates fulfilled a dual function, namely that of solvents and supports for the natural vitamin and that of agent promoting thixotropy.



   This example illustrates a thixotropic mineral-vitamin gel, the vitamins of which are part of the vitamin B complex.



    As it is often desired to have a product which contains not only the known pure factors of the vitamin B complex, but also the other factors, which have not yet been particularly identified and isolated, the concentrated and unfractionated extracts of liver fresh, yeast and rice husk (which contain these unidentified factors), were combined, in this example, with the mineral salts, in addition to the pure crystalline factors going into the composition.



   The following is a further illustration of the extremely high concentration of incorporated therapeutically active substances which can be introduced into the thixotropic gels according to the invention: Example 8.



   Has a mixture of 35 g. of finely pulverized phthalylsulfathiazole in 30 cc. of water, 10 g are added. of glucoâe (a carbohydrate) and a thick paste is obtained. A mixture of 0.5 g is added thereto. citric acid and 0.6 g. of sodium citrate, the whole being perfectly mixed, without the pasty consistency being practically modified.

   We then add

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 45 g. of alkaline-earth salts insoluble in water and capable of forming a colloidal dispersion, according to axamples 1, 2 or 3 (containing about 28% of total salt substance) and this combination is mixed intimately, the pH obtained being 5.5 The mixture is liquid and easily transferable; at the end of a few minutes of rest, it turns into a frozen and rigid dough, which can return to the liquid state which can be poured out by shaking. riddling, given its thixotropic nature. This paste contains 31.8% phthalylsulfathiazole, although the content of the latter substance can be increased or reduced according to desired specifications.



   Although Examples 6 and 7 were prepared with some content of individual and specific vitamins, respectively, and Example 8 - with a particular sulfonamide derivative, it should be noted that any vitamin indicated. individual or combination of vitamins, or individual sulfonamide or combination of sulfonamides, or both, or any compatible therapeutic additive agent, may be employed.
 EMI17.1
 by analogous incorporation into a gel ùlixotropiqa3¯> # ùofio # that prepared according to the invention. Likewise, no matter what; The desired compatible 4 "" "'' '' may be optionally incorporated into any of these compositions.

   Although Examples 6, 7 and 8 show the incorporation of therapeutically active ingredients at certain specific stages in the preparation of the compositions, it should be noted that the particular therapeutic ingredient can be incorporated at other stages of the preparation. preparation, for example as a dissolved body or as a dispersoid in any of the solutions A and B described. In this case, any therapeutic ingredient thus incorporated is adsorbed by the alkaline earth salts which subsequently precipitate and form a colloidal dispersion.

   These thixotropic gel compositions not only offer the possibility of

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 flexibility to administer their particular ingredients at a high concentration hitherto unknown in compositions of other types, but with remarkable stability of the ingredients constituted by the incorporated vitamins.



   Likewise, and although the various specific examples, such as 4 to 8, describe the use of certain particular alkaline earth salts, insoluble in water, of certain particular citrates and of certain particular carbohydrates, it It should be noted that, in the respective stages of the preparation of the corresponding thixotropic compositions, any of these various ingredients can be replaced by any other examples of these respective agents, as described above. above.

   For example, ferrous or even ferric sulphate can even be employed as the dissolving body in solution A, in which case the anions of the bodies dissolved in solution B together with iron form a water-soluble salt, such as chlorine. oxide or nitrate or acetate, provided that the anions of any other substance dissolved in solution A which contains the water-soluble iron salt do not react to precipitate a soluble iron salt.



   Ferrous sulphate can also be used as a dissolved body in solution B, in which case the anion of an alkali metal salt used as a dissolved body in solution A will form with iron a precipitate insoluble in water, for example in the case of iron nitrate, acetate or sulphate reacting with an alkali metal phosphate or silicate.



  Copper salts can also be used in a corresponding manner.



   The liquid or transferable state of the thixotropic gels according to the invention can be designated as the “sol” state, and the rigid state of the composition - as the “gel” state. The extent or degree of thixotropy or thixotropic behavior of the

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 compositions coming within the scope of the invention can be modified either to reach a point where it occurs at the minimum, that is to say where the difference between the states of sol and gel, is very slight, or to reach a maximum, that is to say where the difference between these two states is very pronounced, with modifications being obtained by controlling the concentration of precipitated alkaline earth salts which are insoluble in water and easily dispersible, such as those obtained by examples 1, 2 and 3,

   and which are employed in the subsequent steps as shown in Examples 4 to 8, or by adjusting the concentration of hydrogen ions of the thixotropic system by controlling the concentration of citrate or agent alkaline reacting, or by the amount of alkaline reacting agent introduced to react with the amount of citrate employed, or by controlling the amount of carbohydrate or excitol introduced to enhance the behavior thixotropic.

   We can therefore adjust the final content and the degree of thixotropic activity of any preparation, in order to satisfy particular conditions chosen, all with only a small number of preliminary experimental tests in order to see whether Selected amounts of different agents are sufficient for the desired specifications.



   Any therapeutic preparation which can be produced by applying the compositions according to the invention can be administered orally as well as parenterally, or even externally, according to specific needs. When the thixotropic compositions are in the sol state, they pass easily through a fine hypodermic needle, so that they can be offered for sale after having been introduced into ampoules, in which they can acquire the state. frozen or gel and from which they can be removed after shaking, by suctioning into a hypodermic syringe.

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   In addition, in either liquid or gel state, the thixotropic compositions according to the invention can be carefully dried in vacuo, preferably at. low temperature, for example
30 to 40 C. From the dry state, the thixotropic composition can be restored by adding the desired amount of water, which can be less or more than that evaporated from the original composition, or one can, Starting from the dry state, prepare the compositions in the form of pills or lozenges for use in these forms.



   Despite the extremely high content of inorganic elements, thixotropic compositions according to the invention, these are, to. to a remarkable degree, free from the unpleasant gritty sensation and actually providing a smooth, runny and creamy sensation. This is due to their method of preparation and results from the fact that the alkaline earth salts insoluble in water are precipitated in a fairly regular physical form, presenting particles of very small dimensions which range from a submicron to a few microns passing through the intermediate dimensions.



   In any case, the therapeutic compositions prepared according to the invention exhibiting satisfactory stability, contain their various ingredients in an extremely high concentration and allow an increased absorption of the ingredients to the drug from the intestinal tract in the case of an intestinal tract. oral administration.



   The thixotropic gels according to the invention, as illustrated by Examples 1 to 5, are soluble in hydrochlorioic or nitric acids, in lactic acid, in 50% phosphoric acid, while being less soluble in 75% phosphoric acid, and in saturated citric acid solution, after heating. When an excess of a concentrated solution of alkali hyaroxide is added to such citric acid solutions of the thixotropic gel, a large white precipitate forms. Thixotropic gels are insoluble in organic solvents such as

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 as: alcohol, acetone, ether, benzene, chloroform, carbon tetrachloride, and the like.



   The thixotropic gels according to the invention are stable and do not undergo any effects as a result of exposure to sunlight and darkness and only undergo a minimal effect as a result of temperature changes from those located at the bottom. above the freezing point to those below the boiling point. For example, no syneresis (eg separation of a clear liquid above the gel after standing) is usually observed at laboratory temperature and at temperatures above the freezing point, while any syneresis at laboratory temperature is usually negligible.

   Some slight syneresis occurs after reheating, for example at 37 - 50 ° C., but generally the clear liquid above the gel does not exceed 3% of the initial total volume of the gel.



  Although the thixotropic gels according to the invention can be kept below the freezing point for a short time, it should be noted that, if this exposure lasts a few days or more, the thixotropy is often irreversibly destroyed. sible.



   Although the invention described above has been illustrated with reference to some of its particular embodiments, it is understood that it is susceptible of modifications, variants and substitutions, without departing from the spirit of invention.



   It should be noted that the absorption and use of calcium and phosphorus in the body is increased to a considerable extent when these elements are offered with vitamin D in the form of colloidal jellies. In these jellies, mineral substances and vitamin D are dispersed colloidally or dissolved in water. Jellies form semi-solids in which the fluid phase is not free with respect to the solid phase, but is trapped therein. There is no

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 no separation of a richer portion, or a less rich portion, from the dispersant phase and, for this reason, the minerals and vitamins form a compact semi-solid mass, which has a uniform composition and is relative- ment stable.

   The jellies are rather concentrated and one teaspoon can for example contain 1.5 to 2.0 granules of dicalcium phosphate with vitamin D, in the form of a preparation having a pleasant taste.



   In short, the new and improved jellies containing minerals and vitamins ensure greater absorption and better use by the body, a relatively high concentration of active ingredients, very good taste and high stability.



   The following examples show that it is not only possible to prepare products containing calcium, phosphorus and vitamin D, but also products corresponding to the same general description, but prepared with other mineral substances and d. 'other vitamins.



   Example 1. Product 1: (a) 268 grams of sodium phosphate, U.S.P.dibesic crystals. (United States Pharmacopoeia) and 45 grams of sodium carbonate monohydrate are dissolved in 2 liters of hot water.



   (b) 95 grams of calcium chloride U.S.P. are dissolved in 2 liters of hot water. Add solution b) to solution a), slowly and stirring.



   Instead of using calcium chloride for solution b), it can be substituted by other water-soluble calcium salts, such as calcium nitrate, calcium acetate and the like.



   Product 2: (a) 12.5 gr. of sodium fluoride and 2.0 gr. of sodium carbonate monohydrate are dissolved in 300 cc. hot water.

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   (b) 19 gr. of U.S.P. and 11.5 gr. of calcium chloride U.S.P. are dissolved in 300 cc. hot water. Add solution b) to solution a), slowly and stirring
Instead of using magnesium chloride in b), it can be substituted with other water-soluble magnesium salts, such as magnesium lactate, magnesium nitrate and others.



   100 gr. of product 2, consisting of a fine dispersion of fluoride and calcium carbonate ... magnesium, are then added to product 1. 2 liters of water are added to the mixture and, after having mixed thoroughly, the whole is left to stand. during many days.



  Then the clear sodium chloride solution which has formed over a large precipitate is removed by means of a siphon and water is added again to wash off. the remaining amounts of sodium chloride.



   Finally, the voluminous precipitate which has now more or less gelatinized is concentrated by removing a greater quantity of water by means of a centrifuge and / or filter press.



   The jelly thus obtained is white, semi-solid and has a consistency similar to that of butter. When established in a layer of moderate thickness, the jelly is transparent and its microscopic examination does not show particles, but shows a transparent colloidal film of uniform composition.



   The jelly is then combined with vitamin D. This vitamin is soluble in lipoids and is currently obtainable either in the form of concentrates derived from fish livers, or in the form of activated or irradiated ergosterol, or in the form of chemically pure crystals. When use is made of crystalline vitamin D, this is first dissolved in suitable organic solvents, such as propylene glycol, synthetic waxes known under the English name "carbonax", alcohol, acetone, glycerin and the like.

   When using

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 oily concentrates of vitamin D, these can be added directly to and dispersed in the jelly, or they can first be emulsified with water, using emulsifying agents, such as gums, for example karaya gum, tragacanth, gum arabic, or other emulsifying agents. available.



   Emulsification can for example be carried out by thoroughly mixing one part of water-soluble gum with 4 parts of oil-soluble vitamin D concentrate, and adding to this mixture 2 to 3 parts of water while vigorously crushing until an emulsion is obtained. Instead of using gums, other emulsifying agents can be employed, such as water soluble alkali metal oleates or oil soluble alkaline earth metal oleates. In addition, agar-agar, or extracts of Irish moss, or gelatin, or similar mucilaginous substances, such as resin or resinates, may be used.



   Finally, the vitamin emusion, prepared in either of the ways described, can be processed in a homogenizer which is a special type of colloid mill and which further reduces the size of the particles in it. emulsion and helps to make emulsions stable and uniform.



   The concentrated solutions or colloidal exhaustions or dispersions obtained in any one of the ways described above are then added to the mineral jelly and the whole is thoroughly mixed for several hours, preferably away from air. . Since it is possible to obtain solutions, dispersions or emulsions of vitamin D at high concentration, it suffices to add a fraction of one percent to the jelly to obtain the desired units of vitamin D.



   In this way, a colloidal mineral jelly is obtained in which a very finely dispersed solution or suspension

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 of vitamin D is uniformly adsorbed by the large colloidal surface of the mineral jelly.



   The product provides an improved medication usable for the prevention or cure of diseases resulting from insufficient ingestion or insufficient absorption and use of calcium and phosphorus. The product is also a valuable adjuvant in the external treatment of certain pathogenic conditions of bones and teeth. It is also suitable for. external use for the treatment of wounds, burns and other skin conditions.



   The product has the following characteristics: easily soluble in dilute hydrochloric acid; insoluble in organic solvents such as alcohol, acetone, benzene, toluene, chloroform. It forms colloidal dispersions in water. When rubbed on surfaces such as skin or others), it is completely transparent. During drying, a fragile semi-transparent layer becomes visible, which layer is easily rubbed off. The jelly is white in color, practically tasteless and has a consistency similar to butter and rather firm.



  It is slightly astringent.



   The jelly is heavy, a teaspoonful containing 12 to 15 grams.



   When dried at 135 C until the weight remains constant, the total mineral residue is about 11%. The minimum prophylactic dose of three teaspoons per day provides approximately 2,500 U.S.P. of vitamin D, over 1200 milligrams, elemental calcium, and over 700 milligrams of elemental phosphorus. It also provides small amounts of magnesium and fluoride.



   The jelly can be made more concentrated by stronger centrifugation, evaporation in vacuum or treatment in filter-

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 hurry. It has, however, been found that, for various reasons, the most favorable results are obtained when, after drying at 135 ° C., the total dry residue reaches about 10%.



   Finally, the taste of the jelly can be further improved by the addition of flavoring agents, such as vanilla and the like.



   Example 2.



   Product 1: (a) 2000 grades of tribasic sodium phosphate are dissolved in 20 liters of hot water.



   (b) 850 gr. of calcium chloride U.S.P. are dissolved in 20 liters of hot water. Add solution b) to solution a) slowly and while stirring.



     Product 2: (a) 20 grams of iron chloride crystals are dissolved in one liter of hot water.



   (b) 24 grams of tribasic sodium phosphate are dissolved in one liter of hot water. Add solution b) 'to solution a) slowly and while stirring.



   Product 3: (a) 4 gracies of copper sulfate U.S.P. are dissolved in 500 cc of hot water.



   (b) 2.5 grams of potassium carbonate U.S.P. are dissolved in 500 cc. hot water. Add solution b) to solution a) slowly and while stirring.



   Products 1, 2 and 3 are then mixed, which consist of large precipitates in water, similar to jellies.



  20 liters of water are added, and after stirring well, the whole is left to stand for several days. After that the clear solution of sulphates and chlorides of sodium and potassium, which has formed above a voluminous precipitate, is removed by syphoning, and water is again added to remove by washing the remaining quantities of sodium and potassium sulphates and chlorides. After standing for several days, the clear saline solutions above the precipitate are again removed,

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The precipitate is now concentrated using a centrifuge or filter press. A jelly is thus obtained consisting of calcium, phosphorus, iron and copper, existing in the form of colloidal dispersions.



   The jelly is then combined with vitamin A, vitamin B1 and vitamin C.



   The methods applied to obtain a colloidal dispersion of these vitamins in the jelly and their adsorption by the jelly are in substance the same as those described in Example 1.



   Solutions, or dispersions, or concentrated emulsions of these vitamins are therefore intimately and uniformly dispersed in the jelly. The nature of the vitamins used, and especially their solubility in water or lipoids and their electric charge, decide the routes to be followed and the means to be used in preparing adsorption products of colloidal minerals and vitamins. . The choice of methods used to prepare the adsorption products of colloidal minerals and vitamins depends on the forms in which these vitamins are available.



   In Example 2, the preparation of a jelly of colloidal mineral substances and vitamins, containing more than one vitamin and additional mineral substances, in particular iron and copper, was described.



   Although it has been found that in the majority of the many different examples of adsorption products of colloidal minerals and vitamins, prepared according to the indications given above, the jellies keep well without the addition of Gelatinizing agents, the latter, however, improved the stability and uniformity in certain cases. The use of such agents for the preparation of the products according to the invention should therefore be included in the present patent application. As gelatinizing agents which have been added to some of the expedited products.

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 riments for their better stabilization include: pectins, agar, gelatin and others.



   It goes without saying that other minerals and vitamins than those mentioned in the Examples above can be used to produce jellies of colloidal minerals and vitamins. It is also possible to modify the amounts of the chemical substances used in the aforesaid Examples, in order to obtain, from a therapeutic point of view, an optimum ratio between the various mineral substances.



   The essential feature of the invention is the production of colloidal jellies or colloidal gels formed by precipitated mineral compounds, as described, and the dispersion, in these jellies or gels, of vitamins which have been previously emulsified with water by means of different emulsifying agents, or which have been previously dissolved in water or other solvents.



  Of this. In this way, adsorption products of colloidal mineral substances and vitamins are obtained. These products are used to a greater extent by the body than mixtures of minerals and vitamins presented in a form different from that of the products according to 'invention. The latter are concentrated, very tasty and very stable and therefore constitute a distinct improvement, in their respective field of application, over the products known heretofore.



   CLAIMS.

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

1 - Thixotropic gel system, the main constituent of which consists of at least one salt insoluble in water and capable of giving a dispersion in the form of a suspension, chosen from alkaline earth salts insoluble in water and salts of iron insoluble in water, and a secondary constituent of which consists of a citrate, soluble in water, of an alkaline base, this base <Desc / Clms Page number 29> alkaline being chosen from alkali metal bases and nitrated bases. 2 - Thixotropic gel system according to claim 1, wherein the nitrated base is either ammonia or one of the ammonia derivatives capable of forming water-soluble citrates with citric acid. 3 - Thixotropic gel system, the main constituent of which consists of at least one salt insoluble in water and capable of giving a dispersion capable of passing to the state of suspension, chosen from alkaline earth salts insoluble in water and iron salts which are insoluble in water, and a secondary constituent of which consists of a citrate, soluble in water, of an alkaline base, this alkaline base being chosen from alkali metal bases and bases. nitrated, and, as another secondary constituent, a substance capable of extending the pH limits of thixotropy and selected from water-soluble carbohydrates and water-soluble polyhydric aliphatic alcohols . 4 - Thixotropic gel system according to claim 3, in which the nitrated base is ammonia or a derivative of ammonia capable of forming water-soluble citrates with citric acid, and in which the polyhydric alcohol is chosen from water-soluble aliphatic polyhydric alcohols having as many hydroxyl groups as there are carbon atoms in the aliphatic chain. 5 - 'Thixotropic gel system according to claim 3, in. in which the nitrated base is ammonia or one of the ammonia derivatives capable of forming, with citric acid, water-soluble citrates, and in which the polyhydric alcohol is chosen from hexitols. 6 - Thixotropic gel system comprising, in water, and to. title of main solid constituent at least one insoluble salt <Desc / Clms Page number 30> in water and capable of giving a dispersion in the form of a suspension, chosen from alkaline earth salts soluble in water and iron salts insoluble in water and, as secondary solid constituent, a citrate, soluble in water, of an alkaline base chosen from alkali metal bases, ammonia and ammonia derivatives, capable of forming with citric acid soluble citrates in water and, also as a secondary constituent, a water soluble carbohydrate as a substance capable of extending the pH limits of thixotropy, and at least one other substance intimately dispersed in this system. 7. Process for preparing a thixotropic gel system, the main solid constituent of which is formed by at least one salt insoluble in water and capable of giving a dispersion in the form of a suspension, chosen from alkaline earth salts insoluble in water. water and water-insoluble iron salts, this process consisting of: to, precipitate this main solid constituent by bringing together two aqueous solutions, designated respectively as solutions A and B, solution A being a solution of at least one ionizable substance, the cation of which is chosen from metal ions alkali metal or is the ammonium ion and the anion of which is chosen from the radicals which form the compounds insoluble in water with a cation chosen from the alkaline earth metals and iron, while solution B is a solution of at least one member of the class of water soluble salts of alkaline earth metals or of iron, the anion of which forms a soluble salt 0 in water cnoisipami the salts of alkali metals and ammonium; in concentrating this precipitated main constituent; and, in incorporating therein a sufficient amount of a citrate of an alkaline base chosen from alkali metal bases, ammonia and ammonia derivatives, capable of forming, with citric acid, citrates soluble in the water, <Desc / Clms Page number 31> containing 0 to 5% citric acid, in order to impart thixotropic characteristics to the composition, at the concentration of hydrogen ions which is peculiar to it. 8. A process according to claim 7, comprising incorporating the water-soluble citrate of the alkaline base, the hydrogen ion concentration of the composition being adjusted to a pH value of between about 5.0 and 6. , 5 approx. 9. A method according to claim 7, further comprising incorporating a substance capable of extending the pH limits of thixotropy, selected from water-soluble carbohydrates and water-soluble aliphatic polyhydric alcohols, comprising as many hydroxy groups as there are carbon atoms in the aliphatic chain, the concentration of hyclrogen ions in the composition being adjusted to a pH value between approximately 4.0 and approximately 11.0. 10. The method of claim 9 wherein the aliphatic polyhydric alcohol is an exitol. 11. A process for the preparation of a thixotropic gel system, essentially as described in any of the examples above. 12. A method according to any one of claims 7 to 11, wherein at least one additional substance is intimately dispersed in the thixotropic gel system. 13. The method of claim 12, wherein the additional substance is a therapeutic agent. 14. The method of claim 12 or 13, wherein the additional substance is a vitamin. 15. The method of claim 12 or 13, wherein the additional substance is a sulfanilamide or a therapeutically active derivative of sulfanilamide or sulfonamides. 16. A thixotropic gel system, when prepared or produced by the process according to any one of claims 7 to 15.