Process of obtaining insoluble salt gel in the alkaline-earth metal water

FRENCH REPUBLIC.

IP service.

Patent.

Gr. 44.-Cl. 8. [...] 934,81 6

Society said: SHARP and DOH VIE, Incorporated residing in the United States of America.

Demanded 8 October 1946, to 13^{m h 18,} to Paris.

18.-Issued 19 January 19/Published 2 June 19/18.

(Patent application deposited in the United States of America [...] 9 October, on behalf of

M. Herman J. [...]. - Declaration the applicant.)

The invention relates to, gels salts

fear insoluble alkaline-ter & ux

colloidally dispersed in an aqueous medium,

these are thixotropic, i.e. that they

have a rigid consistency at rest and that they

become fluids after stirring or a

stirred short time and can then

casting in the form of a dispersion or addition-

boarding stable liquid and homogeneous, trans-

formation of these gels of the rigid form to the

liquid form is reversible and can be

implementation from one state to the other without any

limiting.

The thixotropic gels according to the invention

are suitable for a variety of applications

and are of a beneficial use in a large

number of industries, for example in the included-

sorts of dyestuffs, pigments and a bouquet-

traits, in the paper industry, and coated-

paper elements, in the finishing of leathers and

other materials; they are also useful for

the preparation of various compositions chi-

irregularities. Therefore, the invention extends,

particular to the thixotropic gels, in the-

which the elements necessary for obtaining the

thixotropic properties are useful per se,

for example for the introduction of elements

metabolic needs, such as the mineral

calcium, iron, magnesium, phosphorus and

8-00528

other, so that these gels may be advantageous alone or in combination with other agents in the form of elements added to the set of the thixotropic gel.

An advantageous feature of the thixotropic gel preparations is that the different operative elements necessary are present in a concentration greater than that generally have these preparations, and sounds a shape remarkably stable.

In tone cases, the thixotropic gels according to the invention contain two essential elements: the primary element the most important of which is an alkaline earth metal salt water insoluble, capable of colloidal dispersion is a mixture of several such salts which, for certain chemical preparations, are those that are non-toxic in doses administered by the selected channel. The second member, present in a minor proportion, is a citrate of a cationic radical alkaline reacting such as some alkali metal or nitrogen, such as ammonia, the derivatives of ammonia, for example the primary aliphatic amines, secondary and tertiary, alkanol amines, quaternary ammonium bases and the like, soluble in water or water containing dissolved at least up to about 5 % nitric acid. The second member can be prepared within] a preparation with the citric acid and alkaline reacting the agent required to form the indicated Ë citrate, or can be used in the form of a citrate already prepared. It is useful for certain compositions in a proportion of not more than 1% and in other, less frequently, in an amount between 10 to 5%, which is often dependent upon all of the solids in alkaline earth metal salts in colloidal dispersion, the citrate Tota decreasing in proportion to the-' layered solids or increasing [...] Unanticipated 5 to all of the solids.

In all cases, the. amount of citrate used is to be sufficient to provide the desired degree of thixotropy to the composition having the constitution final.

_{20 The gels} according to the invention, in which the salt of an alkaline earth metal, water-insoluble and dispersible colloidal medium and citrate of the agent to alkaline reaction are the only components producing the property [...][...] 5^{ue 5} exhibit the [...] in the optimally when the hydrogen ion concentration of the assembly occurs about a pH of about 5.0 to 6.5, thixotropic But the behavior can result in a range of_g 0 pH significantly wider, including those acid and alkali, if is provided as the and in minor proportion in the form of a third component a water soluble agent selected from carbohydrates gg soluble in water and alcohols [...], in particular the [...]. Any carbohydrate, be it a monosaccharide or a polysaccharide, is suitable provided that it is water-soluble, for example the 4_{0 pentoses} such as xylose, ribose or hexoses such as glucose (dextrose), mannose, fructose (levulose), manno-heptose, or disaccharides such as lactose, maltose, sucrose. Among the aliphatic polyhydric alcohols in water soluble 45, suitable for use in particular those which are soluble in the water containing as many hydroxy groups that of carbon atoms in the aliphatic chain, in particular the [...], for example, sorbitol, the 5_{0 mannitol}, the dulcitol. The third constituent in the set [...] the range of ' hydrogen ion concentrations to obtain a good thixotropy for a pH of about 4.0 to 11.5 or even more.

For a particular application, may be added to the thixotropic assembly according to the invention, as described in examples 4 and 5 below, resulting from the use of two components (example 4) or more of these two constituents the third (example 5), other elements compatible with retention of the thixotropic characteristic, these other members added that can be incorporated in the assembly of a higher concentration and a more stable form than those feasible in other [...]. For some applications, in particular, it is possible for example to elements for the treatment of metabolic deficiencies such that one of the vitamins or one of the factors available vitamin, soluble in water or oil, or one of the suitable [...] - [...], proteins, protein hydrolysates and the like, or anti-bacterial agents compatible with all such as sulfanilamide or active derivatives of sulfanilamide and other sulfonamides, antibiotics, water-soluble, or not, such as penicillin, tyrothricine, streptomycin and the like, hormones, antacid substances other than those already contained in the component most important of. the assembly, biological substances such as the vaccines of bacteria, toxoids, virus vaccines and other elements therapeutic or pharmaceutical compatible with all thixotropic. In most cases, the incorporation of the additional pharmaceutical products throughout the thixotropic gel according to the invention is provided by adsorption additional agents on the component alkaline earth metal salt water-insoluble alkali-dispersible of f assembly.

The thixotropic gels according to the invention are prepared ' by a process comprising three essential operations. The first comprises preparing the alkaline earth metal salts insoluble in water, by precipitation in the conditions for their formation to a state colloidally dispersed or dispersible. The second step is to focus these alkaline earth metal salts, and optionally eliminating in part the electrolytes care-' grains in the water remaining after the precipitation in the forming of the alkaline earth metal salts and colloidally water-insoluble to be worn. The third step is to incorporate large or adding the citrate of the agent to alkaline reaction, by forming within the composition or by d -5 the citrate or mixture of citrates desired, both methods generally having the effect of incorporating the citrate to the composition.

Formation alkaline earth metal salts insoluble in water and colloidally dispersible o 1 is obtained by reacting two separate solutions of water-soluble salts.

The first of those solutions that, for clarity, will be called the solution A, is an aqueous solution of a substance such as a 13 salt or salt mixture, whose anion or anions react in aqueous medium with a cation, which is consisting of alkaline earth metal, for the precipitation of the alkaline earth metal salt corresponding, in a O water insoluble. The substance dissolved in the solution A is, for example, a sulfate, a phosphate, a carbonate, a silicate or other water soluble compound] for example an aluminate, a molybdate, a borate, a chromate, a malate 2,5 or another salt, as long as his anion forms a water soluble salt with an alkaline earth metal. The cation of the substance: At dissolved in the solution must then be such that it forms with the anion of ' substance dissolved in the said solution -3 o claim B (defined herein) a water-soluble salt.

The second solutions required, called for clarity the solution B, and for the preparation of the main component of the gel 35 according to the invention, is an aqueous solution of an alkaline earth metal salt water-soluble, or a mixture of interlaced salts, whose anion or anions form a water-soluble salt with the cation or the cations of the salts or selected 4 o of the solution A employed in the particular preparation.

May be employed in each solution B A and all desired concentrations suitable or dissolved substances, the 45 concentration of up to the saturation of the solution. The saturation is generally advantageous for practical applications. A For reacting the solution with the solution B, it is to a certain extent -5oC durable preferably, though not required, the use of equal volumes of each solution. Therefore, the concentration of the substance_AOE296A0AO> dissolved in one of the two must be such that the concentration thereof is quantitative [...] the stoichiometric equivalent of the concentration of the anions in the other solution. The reaction between the two solutions A and B can be performed at a temperature any suitable, preferably below the boiling point of the solutions. But, in general, the particle size of the resulting insoluble salt is set lower as the temperature is lower, and activity [...] is also more favorable, but the result can be improved if the temperature of the mixture of the two solutions is increased from room temperature of the room, about, to the point most favorable which is between 55 and 60 °C about, the quality then decrease as the temperature rises, above this limit. Results are improve are optimum and if the temperature of the mixture is less than the ambient temperature of the premises and as the temperature approaches 0 °C. Each solution can be added to the other, but the particle size becomes insoluble precipitate [...] advantageously lower, if the solution ' B A is added to the solution.

In all cases, advantageously the size the lower or colloidal dispersion are obtained regardless of the solution added to the other, if it uses a sufficient amount of the solution B, to subtract to the reaction a slight excess of ' alkaline earth metal salt water-soluble.

Regardless of the. solution added to the other, the addition is advantageously implemented with agitation, by shaking or stirring, preferably by the latter means, which is to be at least sufficient to produce an intimate mixture of the two solutions suitable. When adding a solution to each other is completed, the salt precipitate [...] -earth, water insoluble, is dispersed homogeneously stable and substantially throughout the mass of the aqueous medium, and there will only be very low sedimentation at rest, varying substantially from zero to about 5% or more, but rarely to 3,0% of the clear liquid [...], which is based on ' conditions of the reaction, in particular the temperature, the sedimentation ia lowest obtained if the precipitation is implemented in temperature limits between 55 and 60° G about, and between the ambient temperature of the premises about to 0° g.

Large The second operation of the process is the concentration of the alkaline earth metal salts precipitates, water-insoluble, optionally accompanied by one partial removal of electrolytes during the interreaction substances dissolved in the two solutions A and B, this concentration may be accomplished by means suitable for the removal of the aqueous solution of the water-soluble salts resulting, in the insoluble precipitate, advantageously by decantation pre all of the supernatant, with or without prior addition of additional water to the supernatant liquid. The concentration is performed (and, optionally, most of the soluble electrolytes is removed) by filtration, by suction under pressure, with or without washing the filtration residue. It is not necessary to remove all electrolytes; it is sufficient to dispose of the waste in an substantially sufficient for the process of concentration. If, for ' reasons relating to the particular composition of the final product, is desired more complete elimination of electrolytes, the filtration residue tablet can be washed for example until a sample washing becomes turbid more than low by adding a silver nitrate solution, if the washing water contains chlorides, or that the sample does not become low disorder that by adding a solution of barium chloride, if the filtrate contains sulfates dissolved. If the final product is to be administered parenterally, the filtration residue can be used without washing, because the electrolytes retained can then promote approach to secured the isotonicity. If the end product must be absorbed orally, further removal electrolytes may be desirable in order to avoid the too salty taste or the effects matched by absorbing elements o^{community has j s-}

In many cases, the concentration may be performed by centrifugation instead of or in addition to the filtration.

Furthermore, depending on the desired concentration of the gel components in the desired end product, excess water required may be removed from the filtration residue, preferably by a hydraulic pressure, with use of suitable bags or other devices for retaining the solid elements. Thus wet gels of alkaline earth metal salts, water-insoluble, containing up to ' 50% and even more elements fully solid.

 future reference, here some instances to which the invention is however not limited:

I.-The Example  solution is prepared by dissolving 120 gr. phosphate disodium USP gr and 18. of sodium carbonate in water^{USP 1.300 cm} 3, and by cooling to 15° g. Is added, stirring, the solution obtained by dissolving 96 B gr. sodium chloride USP and 5 gr. crystal of magnesium chloride in 1.500 cm^{3 water}, and cooling 5° g.. there is formed a fine dispersion, and white disorder colloidally dispersible particles insoluble carbonates of calcium and magnesium and their phosphates. The the reaction mixture allowed to settle overnight and then the small amount of supernatant liquid, which is a clear aqueous solution. This solution is replaced by a substantially equal quantity of fresh water, and is allowed to again rest the reaction mixture overnight. Meanwhile, an additional portion of the electrolytes passes superimposed in fresh water to the precipitate. The second supernatant liquid is removed by decantation, after which the salt insoluble precipitate is filtered by suction and washed Ean until a sample washing has become that low trouble in the addition of a solution of silver nitrate. X ' [...] is applied to the filtration residue long enough to ensure removal as completely as possible the water. Then the filtration residue is introduced into a compression bag and residual water is expressed. in a hydraulic press.

Example 2.-The solution A is prepared by dissolving 80 gr. sodium sulfate, 20 gr. sodium phosphate and 15 gr. potassium carbonate in 2.000 cm^{3 of water and}, by stirring, the solution is added B obtained by dissolving 150 gr. of barium chloride and 25 gr. bromide of strontium in 2.000 cm^{3 of} water. Is heated to 55° G and a fine dispersion of colloidal particles and white disorder sulfates, phosphates or carbonates insoluble barium and strontium, is allowed to settle the reaction mixture overnight as in the example 1. The dispersion precipitated metal salt [...] lino-earth -5 water-insoluble is then substantially free electrolytes by decantation and filtration, and concentrated by a hydraulic compression as in the example 1. Example 3. -A a solution prepared by dissolving 80 i o gr. sodium sulfate USP, of 20 gr. sodium hydroxide USP and 25 gr. sodium silicate (40% solution) 2.000 cm^{3 in water}, and cooled to 15° G, adding a solution obtained by dissolving i5 B of 90 gr. calcium chloride USP, of 25 gr. crystal of magnesium chloride in 2.000 cm^{3 of water and} cooled to 10° g. As a result a fine dispersion of colloidal particles and white disorder, so water-insoluble silicates and hydroxides of calcium and magnesium and calcium sulfate. The the reaction mixture allowed to settle overnight as in the example 1, the dispersion of the precipitated salts and alkaline earth metal, 9,0 insoluble in water, is substantially free of electrolytes, concentrated by decantation and filtration, and more concentrated by hydraulic compression as in the example 1.

3 o The examples 1,2 and 3 have a demonstration of the process for the preparation of the dispersion in suspension alkaline earth metal salts insoluble in water having the desired particle size, and forming the 35 most important portion of the thixotropic gels according to the invention, and the description of these examples comprises the operations of the two essential process for the preparation of thixotropic gels. The third step importantas- [...] aunt is the incorporation to the set of element elicit the thixotropic properties of the gel insoluble mineral salt, i.e. citrate of the agent to alkaline reaction. The third method step h 5 is constituted by the addition to the set of the citrate in the form of alkali metal citrate, ammonium citrate or other citrate of this type (obtained by forming within the composition or by adding the,^{: o} > citrate or mixture of citrates desired) in an amount sufficient to adjust the hydrogen ion concentration of the composition of a value corresponding to at least pH limits of about 5 to 6.

But, to push the tropic [...] behavior of the composition beyond the neutral point and in the alkaline region, even at pH 10 or 11, is added 5% (or less) to about 20% of the carbohydrate a desired [...][...] aliphatic alcohol such as the hexitol, when the alkalinity is set to the desired point, depending on the desired nature of the final preparation.

In the examples previously indicated, it was assumed that the precipitated salts of metals 65 water insoluble alkaline earth ^ was prepared from, for example, carbonate, hydroxide, silicate, sodium silicate, disodium phosphate and potassium carbonate form the yo in the dissolved solution A, but the soluble substances applicable are not limited to these elements.

Π is possible to use the hydroxide or the corresponding salt such as a carbonate, phosphate, silicate or sulfate of another metal, or alkali y5 of the ammonium cation, as well as the salts of an alkali metal or ammonium, whose anions form insoluble precipitates with an alkaline-earth metal cation, as previously described. Also, it was assumed in the 8o previous examples that the dissolved substance in the solution B was a chloride of an alkaline earth metal, but no limitation is provided with respect to the use of chloride. May be employed another 85 water soluble salt of an element in the alkaline-earth metal, for example acetate, nitrate or a similar salt, provided that the anion of the water-soluble salt of the alkaline earth metal forms a water-soluble salt with the go the alkali metal or ammonium cation.

The following examples, given for future reference, have the composition [...] fe side on. stick acid:

H Example. gr^1-2.000. of the dispersion gfi precipitated alkaline earth metal insoluble in water, obtained from the example 1, are added to a blender type [...] carefully and sprayed. Then added 26 gr. of citric acid USP and kneaded [...] in the gel for a period of time of 3,5 minutes. Meanwhile, citric acid is completely dissolved. Creamy consistency is achieved. 13 cm^{3 is then added to a solution of} 20% sodium hydroxide and kneading continues during 20 minutes, the resulting product has a pH of 5.3 and forms a thixotropic gel. This is demonstrated by the fact that, if tapping a reasonable amount of the flowable mass of the mixture and that allowed to stand for one or two minutes, it takes a firm consistency and rigid. If is agitated, it is transformed back into a liquid flowing.

A composition thixotropic of the alkali side is represented by the following example, but not limited thereto.

Example 5. Gr-A 1.000. of the thixotropic gel obtained from the example 4, is added 100 gr. beta-lactose, and the composition is well kneaded during 20 minutes, which provided a complete dissolution of the beta-lactose. There is a net reduction of the viscosity, but a sample of the suspension homogeneous and stable, left to rest for two minutes, takes a firm consistency and rigid, which is easily reduced to the initial fluidity by gentle agitation of the container which contains the. suspension. A modification of the pH of up to 11.0, o^{1 held by} addition of an alkali, does not destroy the thixotropic behavior.

The thixotropic gel of example 4 after the or the example 5 can be used as a final product in the form described by each of the examples, for example as preparation for delivery of the mineral elements that it contains, for actual or preventing metabolic deficiency by a particular mineral element. But the gel according to the invention, as set forth by the examples 4 and 5, can be used as a support or base which may be incorporated with other elements of the ' this type. In this case, the element is added to these elements for obtaining the composition or preparation ' desired may be incorporated or blended with the gel after [...] of the examples 4 and 5, or be incorporated during the operations in which alkaline earth metal salts, water-insoluble, colloidally dispersible, based on the examples 1,2 and 3 for example, are processed in addition to their conversion to thixotropic composition. The method is represented, but not limited to the following example.

Example 6. - 5.000 gr. a dispersion of an alkaline-earth salt water insoluble, produced according to any one of the examples 1,2 and 3, O containing [...] 5% of mineral solids, are well mixed and sprayed at a low velocity into a type mixer Pony, until a thick, heavy paste.

Then added 70 gr. citric acid US P [...] further stirring. The dissolution occurs at the end of 20 minutes. 18 is then added gr. ascorbic acid (vitamin C) and continuing agitation for, 15 minutes. Meanwhile, gr 5. a concentrate 05 vitamin (containing per gram 450,000 one-_AOE296A0AO> tees vitamins-A and 90,000 units of vitamins D) and 5 gr. alpha-tocopherol are progressively and intimately mixed with 500 gr. beta-lactose. The ' lactose 70 vitamin mixture is then added to the mixer Pony to the dough alkaline-earth salt water insoluble and ascorbic acid. The whole is stirred for about 20 minutes and gives a creamy consistency approximately the [...] adhesion of the "cold cream". To this paste optionally added an agent which is the flavor, e.g. lemon oil or another suitable agent, as well as preservative such as the [...] zoic acid or the like. The method further comprises adding to the creamy consistency, by stirring, 37.5 gr. of a solution of 20% sodium [...] of and continuing the kneading has 10 during 5 minutes. [...] The preparation is also formed into a reasonably fluid dispersion, poured into vials, converts to a stiff paste due to its thixotropic properties. Therefore, by a moderate stirring, go the paste is readily converted in a liquid colloidal dispersion, and stable fluid that, at rest, is back in a few minutes in a stiff paste. The finished product has a hydrogen ion concentration pH 5.2. Its density is 1.277. g5 The daily dose of two teaspoons coffee or about 8 cm after the^{3 the product of} example 6 provides gr 1,073. calcium, 0,652 gr.

phosphorus and 0,032 gr. magnesium. It is known that it is not possible to obtain very means by [...] as high a concentration of these minerals essential metabolic in a colloidal dispersion of very low viscosity. If desired, it is even possible to obtain higher concentrations of the content of the mineral elements of a thixotropic gels according to the invention, by expressing, during the hydraulic compression, a larger amount of water D alkaline earth metal salts insoluble in water colloidally dispersible, of the type obtained based on the examples 1,2 and 3. Example 7. - 5.000 gr. salts water insoluble alkaline earth colloidally [...][...], obtained from the one of the examples 1,2 and 3, are well mixed and sprayed at a low velocity into a known mixer until a thick, heavy paste to which is added 7,5 gr. citric acid USP, kneading 15 being extended until dissolved, thereafter adding 150 gr. of a liver extract concentrate (1:20), 100 gr. concentrated yeast, 315 gr. rice bran concentrate, 0.6 gr. hydro-chloride thiamin, 0.3 and 5.0 gr. riboflavin gr. nicotinamide 2 0. The assembly is well kneaded during 40 minutes. Then gradually 30 cm^{3 is added a concentrated solution} (28% NH₃₎ ammonium hydroxide, while continuing the kneading. The pH is a5 4.9. The resulting colloidal suspension can be easily filled into vials and, after-a space of a few minutes, merges into a brownstock thick and rigid, is leaving easily change back to a liquid by 3 [...] o the property given to the composition during, the preparation.

In this particular example, it is not necessary to add separately a carbohydrate particular, because the latter is present in the concentrates 3,5 rice bran and yeast in the form of maltose and sucrose, so that these carbohydrates are Ibis as to the solvents and supports for the natural Vitamins and agents for effecting the 4o [...] property.

This example is that of a thixotropic gel vitamin mineral wherein the vitamins are part of the complex vitamins B. Since it is often desirable to have a pro -45 said containing not only the pure complex factors^{: vitamins} B, but also the s other factors not yet identified and isolated, the concentrated extracts unfractionated fresh liver, and residues of yeast rice (which 5o contain these factors not identified), are combined with the mineral salts in addition to the pure crystallized factors.

Another example of the unusually high concentration of the added substances that may contain the thixotropic gels [...] f > [...]' invention is as follows.

Example 8. -A a mixture of 3,5 [...] gr. of finely pulverized in 30 cm^{3 of} water, is added 10 syrup gr. of grain.

(carbohydrate), 6o Therefore, a thick paste. To this paste by adding a mixture of 0.5 gr, citric acid and 0.6 sodium citrate. The assembly is well, mixed, with virtually no change in the pasty consistency. Then added gr 45 . 65 alkaline earth metal salts insoluble in water colloidally dispersible based on the examples 1,2 and 3 (containing about 28% solids) and the combination is thoroughly kneaded to have a pH of 5.25. No. The mixture is liquid and flows easily.

When allowed to rest for two minutes, is formed into slurry rigid and reversible in the liquid state flowing by shaking or stirring, by. o thixotropic properties 7. 31.8% of [...] It contains' [...], but the proportion of the substance can be increased or decreased if desired.

Preparations after the examples 6 and 7 8o respectively have been obtained with a content of particular vitamins, while the preparation of example 8 after the has been obtained with. a sulfonamide derivative particular, but this that can be used a mine [...] or a combination of suitable vitamins or a sulfonamide, or a suitable combination of sulfonamides, or both, or one of the chemical agents compatible by incorporating the like in a thixotropic gel any 90 according to the invention. Also, another desired product can be incorporated in one of the compositions. While the examples 6,7 and 8 provide the incorporation of chemical elements in some particular points of the 9,5 preparing the compositions, it is possible to insert these elements elsewhere on the preparation, for example as a material soluble or dispersible in one of the solutions A and B. In this case, the elements in question tco thus introduced are absorbed by alkaline earth metal salts dispersed [...], precipitates subsequently! These compositions of thixotropic gels not only for delivering their elements in a high concentration, not yet known, but also ensure a remarkable stability of vitamin elements.

5 Also, while various example 4 to 8 provide the use of alkaline earth metal salts insoluble in particular water, of certain particular citrates and certain particular carbohydrate, O [...] rations in the respective compositions are prepared corresponding thixotropic, some of these elements can be replaced by other examples of these respective agents as previously described. For example, 1,5 it is possible to use ferrous sulfate or ferric same substance in the solution as Soluble Â, if the soluble substances of the anions B form a soluble salt solution with iron, for example the chloride, nitrate or_acetate 20, as long as the anions other substance soluble A solution containing the water soluble salt of iron does not react to precipitate a soluble iron salt.

It is also possible to use an sul fate ferrous g_- 2 as soluble substance in the solution B, if the anion of an alkali metal salt employed as soluble substance in the solution A is to form a precipitate with the water-soluble iron, as in the case of a nitrate, acetate_g 0 is iron sulfate responsive with a phosphate or alkali metal silicate. The copper salts may also be employed in a corresponding manner.

The state liquid or flowable gels [...] -35 Pikes according to the invention can be, called the "ground" state, while the rigid state of the composition may be called the s gel state ". The degree of thixotropy or thixotropic behavior of the compositions according to the invention can ^ be minimized, i.e. to the point where the difference between the "ground" and states _AOE296A0AO> "gel" is no longer that very light, or increased to the maximum, the point where the difference between the two conditions is very enhanced. This can be accomplished by adjusting the concentration of the salts precipitated alkaline earth metal, insoluble in water and easily dispersible, such that they are obtained according to the examples 1,2 or 3, employed in the 5 following operations such as o indicate the examples 4 to 8, or by adjusting the hydrogen ion concentration of the composition thixotropic achieved by adjusting the concentration of citrate or of the agent to alkaline reaction, or the amount of the agent to alkaline reaction 55 added to react with the amount of citrate employed, or by adjusting the amount of carbohydrate or hexitol provided for thixotropic behavior.

Therefore, it is possible to adjust the 6o final content and the degree of activity ' thixotropic composition prepared for filling of any particular conditions, and by some requiring any trial for indicating whether selected quantities of these different-agents 63 are sufficient to obtain desired effects.

Some of the preparations produced with the use of the compositions of the invention can be administered orally, by injection or 70 by external application, according to the particular conditions. When the thixotropic compositions have become-insul ", they pass easily in a fine hypodermic needle so that they can be sold in 7,3 ampoules, in which they may be in a rigid state or the gel state, and picked up following agitation by suction by a hypodermic syringe.

Furthermore, in the liquid form or in the form of gel 80, the thixotropic compositions of the invention can be carefully dried in vacuum, preferably at low temperature, for example between 30° and 40 G.' Starting from this state sec, the composition thixotropic 85 can be restored by an addition of the required amount of water which can, be more or less than that which has been evaporated in the initial composition. Based sec state, the composition can be prepared into qo form of tablets or tablets and used in this form.

Unusual Despite the high mineral content of the thixotropic compositions according to the invention, they are remarkably q5 free from any flavors or gritty and have, in fact, a key smooth and creamy. This is due to the preparation mode, by which the alkaline-earth salts insoluble in water are precipitated in a form physically 100 smooth, with very small particle size, equal to or less than a few microns.

In all cases, the compositions prepared according to the invention show satisfactory stability, contain the various elements at high concentrations uncommon and further provide for absorption.

The thixotropic gels according to the invention, such as shown in the examples 1 to 5, are soluble in hydrochloric acid and diluted nitric, in lactic acid, in phosphorous acid to 50%, but less soluble in the phosphoric acid and citric acid in 75% saturated with Heating. When adding an excess of a concentrated solution of alkali hydroxide in these solutions in citric acid of the thixotropic gel, a precipitate is obtained which overrun white. The thixotropic gels are insoluble in organic solvents such as alcohol, acetone, ether, benzene, chloroform, carbon tetrachloride, andc.

2 0 The thixotropic gels according to the invention are stable and are not affected by sunlight or by the dark, and the effects of temperature changes above. the freezing point and below the boiling point 2,0 are reduced. For example, no syneresis (separation of a clear liquid above the gel at rest) is generally observed at the ambient temperature of the premises, or at temperatures above the freezing point 3o, and any syneresis at room temperature is generally negligible. A slight syneresis occurs during the heating of 37 to 50 °C for example, but, generally, the clear liquid which is 35 above the gel does not exceed 3% of the total volume of the initial gel. The thixotropic gels of the invention can be maintained below the freezing point for a short period of time, but, if they are exposed to the 4 O temperature for a few days or longer, the thixotropic property is frequently irreversibly destroyed.

In the above, the invention has been described in [...]' d of a few modes of implementation particular 45, but this can be imagined to be that variants and providing [...], without departing from the principle.

The present invention is a development of a request for the 5o 4 September 1942 U.S. Patent deposited under the no. 467,532.

II has been found that the absorption and the assimilation of calcium and phosphorus by the body is greatly increased, when these elements are offered with vitamins D in the form of colloidal frozen. In these frozen, the mineral elements and vitamins are [...] D mt dispersed or dissolved in water. The frozen are semi-solid in which the phase fluid is not separated from the solid phase, but trapped therein. There are no separating a richer or leaner portion of the dispersion phase and, therefore, the mineral elements and vitamins form a semi-solid mass, compact, having uniform composition and relatively stable. The frozen are quite concentrated, a teaspoon full may contain 1.5 to 2.0 gr. dicalcium phosphate, for example, with vitamins D, in a pleasing form.

Briefly, the new improved frozen, made of mineral bodies and vitamins provide for absorption elr better uptake by the body, provide a relatively high concentration of active elements, have highly palatable and good stability.

Although the general description above mentions the calcium, phosphorus and vitamins D, is obtained according to the invention of general same constitution, but prepared with other mineral elements and other vitamins, as indicated by the examples below,

Example 1. Product 1: has. 268 gr. crystal dibasic sodium phosphate USP and 45 gr. sodium carbonate monohydrate are dissolved in 2 liters of hot water.

b. 95 gr. calcium chloride USP are dissolved in 2 liters of hot water. The solution b is slowly added, with stirring, to the solution has.

Calcium chloride of the solution b can be replaced by other water-soluble calcium salts such as calcium nitrate, calcium acetate, andc.

Product 2: has. 12,5 gr. fluoride, sodium and 2.0 gr. sodium carbonate monohydrate are dissolved in 300 cm^{3 of} hot water. b. 19 gr. crystal-magnesium chloride USP and 11.5 gr. calcium chloride USP are dissolved in 300 cm^{3 of} hot water. The solution b is slowly added, with stirring, to the solution has.

The magnesium chloride of the solution b can be replaced by other salts of -55 ° 7î 6o 65,7 [...] >

85 9°

[...][...] soluble in water such as magnesium lactate, magnesium nitrate, andc.

100 gr. of the product 2, formed by fluoride and calcium carbonate-magnesium finely dispersed, are then added to the product is also added [...] 2 liters of water to the mixture and, after thorough mixing, the whole is allowed to stand for several days. Furthermore, is decanted the clear solution of sodium chloride which is formed above a precipitate is bulky and adds a new amount of water to wash away remaining sodium chloride.

Finally, the precipitate bulky has [...] endoperidium more or less, is concentrated by another of removed water in a centrifuge apparatus and (or) in a filter-

press.

Resulting The jelly is white, semi-solid and has a consistency similar to that of butter. [...] moderately thick film, the gel is transparent and a microscope reveals no presence of particles, but a film transparent colloidal [...] a uniform composition.

Then freezing is incorporated vitamins D. These vitamins are soluble in fat-based medium, and they are obtainable today as concentrates from fish livers, or in the form of ergosterol irradiated or activated, or in the form of chemically pure crystals. When vitamins D crystallized are used, they are first dissolved in suitable organic solvents such as propylene glycol, the wax dioxide, alcohol, acetone, glycerin, etc In the employment concentrates oily vitamins D, thereof can be directly added and dispersed in the gel, or emulsify them first with water, using emulsification agents such as gums, e.g. gum [...], gum tragacanth, gum arabic, and other agents available emulsification.

Emulsification can be implemented, for example, by mixing a portion of water soluble gum with 4 parts of a concentrate D water-soluble vitamins. Is added to this mixture 2 or 3 parts water by kneading highly until an emulsion. Gums may be substituted by other emulsifying agents such as oleates alkaline earth metal water soluble or oleates alkaline earth metal oil-soluble. Can also be used the agar or extractives Ireland or gelatin or slimy substances, respectively, are the like such as the natural resin or [...].

Finally, the vitamin emulsion prepared by one of the processes described may be treated in a homogenizer, which is a special type of colloid mill, and which further reduces the size of the emulsion particles and contributes to obtaining the required uniformity and stability of the emulsions.

The solutions, colloidal dispersions or emulsion concentrates obtained in this way are then added to the mineral jelly and the whole is thoroughly kneaded for several hours, Je preferably in the absence of air. Being, given that it is possible to obtain solutions, dispersions or emulsions, vitamins D highly concentrated, it is sufficient to add a fraction of 1% freezing to obtain the desired units in vitamins D.

Therefore, a colloidal mineral jelly in which a finely dispersed suspension or dissolution of vitamins D is. uniformly absorbed by the large area colloidal mineral jelly.

The product constitutes a regulating agent of the consequences of an inadequate power supply or an absorber or insufficient uptake of calcium and phosphorus. The product is also a acceptable adjuvant and has still other virtues.

The same product has the property of being easily soluble in dilute hydrochloric acid. H is insoluble in organic solvents such as alcohol, acetone, benzene, toluene, chloroform. H form colloidal dispersions in water. [...] on the surface of the skin or other surface, it is perfectly transparent. In the drying becomes apparent a brittle layer semi-transparent can be easily removed by friction. The color of the jelly is white, it has substantially no taste and has a consistency similar to that of the butter, rigid. Astringent It is slightly.

The jelly is heavy; a teaspoon full contains 12 to 15 grams.

Dried at a temperature of 135° G constant weight, the total mineral residue is about 11 e. 1.000, The dose minimum of three teaspoons coffee per day gives approximately 2.500 USP units of vitamins D, more than 5 1,200 [...]. of elemental calcium and more than 700 [...]. of elemental phosphorus. Furthermore, is obtained and low amounts of magnesium fluoride.

The jelly can be further concentrated by a further centrifugation, by evaporation in a vacuum or filter press.

But ii has been found that, for a number of reasons, the most favorable effects are obtained if the total residue sec, after drying to 135° C, p. 1.000 is about 10.

Finally, the flavor of the frozen can be further improved by the addition of aromatic compounds, e.g. vanilla.

Example 2. Product 1: has. 2.000 gr. sodium phosphate tribasic are dissolved in 20 liters of hot water.

/ >. 850 gr. calcium chloride are dissolved in DSP 20 litres of hot water. The solution b is slowly added, with agitation, to ala solution has.

Product 2: has. 20 gr. crystal of iron chloride are dissolved in a liter of hot water.

b. 24 gr. sodium phosphate tribasic are dissolved in a liter of hot water. The [...]b is slowly added, with stirring, to the solution has.

3 product: has. 4 gr. copper sulfate USP are dissolved in 500 cm^{3 of} hot water.

b. 2,5 gr. potassium carbonate are dissolved in 500 cm USP^{s hot water}. The solution b is slowly added, with stirring, to the solution has.

The products 1,2 and 3, formed by precipitates bulky gel in water, are mixed together. 20 liters of water is added and, with thorough mixing, the whole is allowed to stand for several days. The concentrated then the clear solution sulfates and chloride. sodium and potassium formed fi above a precipitate bulky, and adds a new amount of water for washing away the rest of the sulfates and sodium chloride and potassium. After a rest of several days, the clear solutions of salts above the precipitate are removed again.

The precipitate is then concentrated by centrifugation or in a filter press. Therefore, a jelly made of calcium, phosphorus, iron and copper, present in the 55 form of colloidal dispersions,

The jelly is then combined with vitamins A, j and g. B

The methods for obtaining a colloidal dispersion of these vitamins in the gel, ho and for the adsorption of the dispersion by the jelly, are substantially the same as those disclosed in the example 1.

Solutions, concentrated dispersions or emulsions of these vitamins are thus intimately ho and uniformly dispersed in the gel.. The nature of the vitamins used, in particular their solubility in water or in the fat-based medium,.

and their electric charge, to determine the methods employed in the preparation 70 of adsorbates of the colloidal minerals and vitamins. The choice of methods employed to preparing the products adsorption colloidal minerals and vitamins depends on the form in which these vitamins 70 are available.

The example 2 describes the preparation of a colloidal mineral jelly vitamin containing a number of vitamins greater than 1 and additional minerals, in other words iron and copper. 80 Although it has been found that, in the majority of different samples of adsorbates colloidal vitamin mineral elements prepared, the frozen preservation agents well without the addition of gelatinization, these units 85 improve the stability and uniformity of the experimental series. Application of these agents to the preparation of the products must be part of the invention. Gelatinization agents added to some of the go test products, for stabilizing [...] are pectins, agar, gelatin and other.

It is evident that other minerals and vitamins than those indicated in the examples [...] wind 5 be used in the same manner for obtaining frozen vitamin mineral. Also, Tes proportions of the chemicals used in accordance with the examples may be modified to obtaining the ratio most durable [...] between the different minerals.

The principle of the invention is the production of frozen colloidal or colloidal gels formed by-mineral compounds precipitated from the