DE2303247A1 - PROCESS FOR MANUFACTURING MIXTURES OF SUBSTANCE FOR MEDICAL OR FOOD PURPOSES - Google Patents

Description

DR.-ING. BY KREISLER DR.-ING. SCHÖNWALD DR.-ING. TH. MEYER DR. FUES DIPL.-CHEf /. ÄLEK VON KREISLER DIPL.-CHEM. CAROLA KELLER DR.-ING. KLÖPSCH DIPL.-ING. RARE

COLOGNE 1, DEiCHMANNHAUS

Cologne, January 23, 1973 AvK / Ax

Roelof Wilke Liebenberg, Pierneef Park, Johannesburg, Transvaal (South African R epublic).

Process for the production of mixtures of substances for medical or food use

The invention "relates to the production of mixtures of substances for medical purposes and for food, in particular monomolecular dispersions or monomolecular Layers of medically active substances, e.g. sterol and steroid glycosides.

Sterol and steroid glycosides are pharmacological and biological importance in medicine and, in the case of non-toxic glycosides, are used in the food industry used. The intermolecular binding forces in crystalline or amorphous glycoside aggregates make the removal of individual molecules before any biological utilization very difficult, if not impossible. For maximum utilization and effectiveness, these glycosides must or should therefore be in monomolecularly dispersed -gated forms can be brought. It is therefore important to break up molecular aggregates of sterol or steroid glycosides and in a medium as isolated units or in closed monomolecular layers to distribute. This does not, of course, include producing true solutions.

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The invention relates to the production of a mixture of substances for medical purposes or for food by a process in which an active ingredient, e.g. steryl or steroid glycoside, in monomolecularly dispersed form either essentially as single molecules or as monomolecular layers on one or more adsorbents and / or absorbents or dispersed in an emulsion »In a preferred one Embodiment of the invention becomes the active ingredient dissolved in a suitable solvent and then an absorbent or adsorbent or an emulsion added in a predetermined amount, after which the solvent is evaporated if necessary »

Maximum carrier effectiveness for solids is achieved - ■ by covering the surface of all solid particles with a monomolecular layer of the glycoside used will. If the particle dimensions and density of a such adsorbent or carrier and the adsorbed area of the glycoside molecule are known, the weight ratio from carrier to glycoside can be calculated using the following formula:

g glycoside / g carrier = _χ S _χ Ι _χ 1

Mean therein

"Molecular Weight" means the molecular weight of the adsorbed

Glycoside

JR = 6.022 χ 10 ²⁵ (number of molecules in 1 g-molecule) S = surface of an adsorbent or carrier part

medium size in cm V = volume of an adsorbent or carrier part - chens of medium size in cm

d = density of the adsorbent or carrier in g / cm A = area of t adsorbed glycoside molecule that is in contact with the adsorbent or carrier,

2
in cm.

The effective surface area of the glycoside molecules (ie, the adsorbed area of the molecule, term A in the equation above) is determined by measuring the surface area from scale models of these compounds. For example, ß-sitosteryl- or cholesteryl-ß-glucosides have an approximate ß-surface area of 200 % ^Z (200 χ 1θ " ¹⁶ cm). Its single hexose unit has an approximate flat ß-surface area of 60 3 (60 χ 10 ~ ^{16 cm)} cm ² ) Depending on the adsorbent or carrier material, the following ratios apply:

a) A full side of a glycoside molecule, both the Both aglycon and sugar components are adsorbed or together

b) only one side of the sugar component is adsorbed or

c) is only one side of the sterol or steroid aglycone adsorbed.

If there is no experimental data indicating the nature of glycoside adsorption describe, are available, it is assumed that the whole glycoside, i. the sugar component and that Aglycon, are adsorbed on the carrier surface.

Absorbents are also suitable carriers. In this case, the available surface area is quite significant greater, though difficult, if not impossible, the effective surface area of these carrier absorbents to calculate or even to estimate. These absorbents need to be detached from the digestive juices or be decomposed.

Emulsions are suitable dispersants. Oil-in-water emulsions are preferred. The hydrophobic one protrudes here Aglycon part in the oil droplet and causes vertical packing of the steroid molecule, while the hydrophilic sugar component With its cross-sectional area, a space on the surface of the oil droplet thus takes up

309832/1164.

in contact with the water phase is (approximately 60 S ~ 60 χ 10 cm for a single glucose or hexose) o Ss is to be noted that in the case of dispersions of monomolekulären layers in the emulsions of the sugar components of the Glykosidmoleküle with any surfactant emulsifiers for the Production and stabilization of the emulsion are used for the available surface of the micelle (oil droplets) must compete. In addition, glycoside molecules are dispersed inside the oil droplet (micelle), and these molecules take the place of all the molecules that are withdrawn from the surface of the oil droplet. there are no longer any steryl or steroid glycoside molecules in the oil droplet.

The glycosides can be prevented from forming homomolecular aggregates by interacting with other substances dissolved or precipitated and the mixture then either as such or together with a carrier quickly evaporated or dried. Since the glycosides are relatively heat-resistant up to 160 to 200 C, it is also possible to dissolve them in a molten substance. The hard product obtained on cooling can then ground and used in any suitable manner alone or in combination with other substances.

In this way, the non-glycoside substances act as Diluents, solvents (solid solutions), cosolvents or emulsifiers and contribute to the easier absorption of the individual glycoside molecules.

example 1 Production of ß-sitosteryl-ß-D-glucoside on talc

Theoretical: Talc is a hydrous magnesium silicate that comes in irregularly shaped and flaky flaky aggregates occurs. Due to its - hydrophobic / organophilic Nature, talc is an ideal carrier for steryl and steroid glycosides, as the strongly polar sugar

3 0 9 8 3 2/1 1 8 n

component is not absorbed too much, if at all, talc has a density of 2.8.

Other dimensions that have been specified or calculated are i

Talc, leaflet size 3 to 5 Vl high, maximum length

Total ß-area of 1 sitosteryl glucoside molecule:

200 χ 10 ~ ¹⁶ cm ²

Molecular weight of sitosteryl glucoside 576 For particles of maximum size:

Particle volume i (5xl35xi35x10 ~ ¹² ) cm ⁵ = 9.11 ^ xIO " ⁰ cm ⁵

Particle surface areaί (5 x'i35 x 4) + (135 x 135 x 2) 10 ~ ⁸ cm ⁵ 3.915 x 10 ~ ⁴ cm ² .

Glucoside weight required for coverage as a monomolecular layer: 7.34 x 10 "" * g / g.

Particles of average size (assumed size about 50 JU square and 3fl high): (An actual electron microscopic examination of the talc used confirmed that the average Particle size is 22.5 to 50u square.)

Particle volume 7.5 χ 10 cm

Particle surface area 5.6 10 ~ ⁵ cm ²

Required Glucoside Weight

for coverage in monomolecular.

Layer 1.275 x 10 ~ ⁴ g / g

In the case of talc particles of average size, 170 g of talc thus require 21.67 mg of ß-3itosteryl-ß-glucoside Achieving maximum coverage with a monomolecular layer.

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Manufacture of the product

ß-sitosteryl glucoside 20 mg

Talc 170 g

Ethanol 160 ml

Gelatin capsules 1000

The ß-sitosteryl-ß-glucoside is dissolved in ethanol which is heated under reflux. The hot solution is added to the talc powder and the resulting slurry is evaporated at elevated temperature with constant stirring. The powder obtained is ground again and filled into gelatin capsules (No. ₀ 2, Parke, Davis &Co.); Each capsule contains. · ■

ß-sitosteryl-ß-glucoside 0.02 mg

Talc '17Q mg

a) The amount of ß-sitosteryl-ß-glucoside per capsule can be between 0.010 and 0.0217 mg »It was found that smaller amounts have less effect. Larger amounts than 0.0217 mg cause the formation of glucoside aggregates and therefore worsen the utilization of the glucoside used.

b) It was found that the calculated surface of a Adsorbent is often smaller than the experimentally determined area,

c) Instead of ß-sitosteryl-ß-glucoside any other steryl or steroid glycosides can be used, provided that changes in the surface of the molecule are appropriately taken into account.

d) Instead of talc, any other pharmaceutically acceptable materials, e.g. chemically pure Silicic acid "Aerosil", the different gravel igurs, Chalk, cellulose, starch and the like can be used as a carrier or adsorbent »To achieve maximum utilization of the glycoside must surface size and volume of the individual carrier particles of

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average size can be calculated, determined or estimated in order to determine the effective weight limit of the glycoside to be adsorbed _e

e) An enlargement of the surface can be achieved by absorption , which have porous supports. These carriers must be able to disintegrate after ingestion in order to release the absorbed glycoside molecules.

f) The treated carrier, adsorbent or absorbent can be in tablets, suspensions, Emulsions or other forms of preparation can be incorporated using suitable additives.

g) To increase or supplement the activity of the steryl or steroid glycosides can contain other pharmaceutically active compounds at any stage prior to the process Completion of the final product to be incorporated.

Example 2

Production of cholesteryl-ß-glucoside on silica (Aerosil) «,

Theoretical: Aerosil is a powdered silica that is used as an extender, lubricant or adsorbent is used. The product consists of spherical particles with a diameter of 4 to 25 microns and one Density of about 2.4. Silicates are stronger adsorbents than magnesium silicates, so they are adsorbed Glycoside molecules are less easily released than talc and related silicates.

Molecular weight of cholesteryl-ß-gluco3id: 548 Surface of 1 cholesterylglucoside- _{Λ (} - molecule: 200 χ 10 cm

Assumed average particle diameter of "Aerosil": "14 mu

Volume of 1 Aerosil particle:

4.189 x 7.5 x 7.5 χ 7.5 χ 10 ~ ¹⁸ cm ³ = 1.44 x 10 " ¹⁵ cm ³

8 3 2/1164

Surface of 1 aerosil particle:

12.57 x 7.5 x 7.5 x 10 ~ ¹² cm ² = 6.16 χ 1 (T ¹⁰ cm ² Required amount of glycoside by weight for

Covering as a monomolecular layer 8.11 χ 10 g / g 50 g Aerosil can absorb 4-05 mg

The actual electron microscopic examination of the "Aerosil" silica used gave an average result Particle diameter of 1.6 µm.

Manufacture of the product

Cholesteryl-ß-glucoside - 400 mg

Silicic acid ^M Aerosil "· 50 g ·

Ethanol · · 750 ml gelatin capsules 1000

The cholesteryl-ß-glucoside is dissolved in ethanol, which is heated on a reflux condenser. The hot solution will added to the silica powder, and the slurry formed is at elevated temperature under constant Stir evaporated. The powder obtained is filled into gelatin capsules after grinding again. Each capsule contains i.

Cholesteryl glucoside ■ 0.40 mg

Silicic acid "Aerosil ¹ '50 mg

a) The amount of cholesteryl glucoside per capsule can be between 0.01 and 0.40 mg «

b) During the biological or pharmacological activity of ß-sitosteryl and cholesteryl glucosides on a molecular basis in humans can so far As yet unexplained differences in effects occur in different species of animals, insects, etc. Further the optimal effective amounts of other Sireryl- or steroid glycosides of those determined for the glucosides of β-sitosterol and cholesterol (0.1 "to 2.5 mg per single dose), be different.

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Example 3

Production of ß-sitosteryl-ß-mal t osid on corn starch Theoretical: Starch is a digestible α-polyglucoside * Corn starch has an approximate mean grain diameter of 13.9 μ, a density of around 1.5 and a surface area of 0.29 m / g (2.9 x 10 ^ cm). The molecular weight of ß-sitosteryl maltoside is 738 with an approximate size of the ß-area of 2.60 χ ^10-14 "cm ² .

Required maltoside weight per g starch when covered as a monomolecular layer:

1) Based on the surface =

738 ^ 9 _1O 17 _ ./■ " ₁₀ -4 '■

6.022 χ 1 (r ^p 2.6

2) On the basis of diameter and density 1.36 10 g

Manufacture of the product

ß-sitosteryl-ß-maltoside 10 mg

Ethanol as needed

Corn starch flour 100 g

A slurry is made with ethanol and starch and heated ^{to 60 ° G.} The ß-sitosteryl maltoside dissolved in 50 ml of boiling ethanol is added to the slurry with thorough stirring. The slurry is then evaporated at an elevated temperature with constant stirring. The product obtained, after re-grinding, is incorporated into capsules, tablets or other pharmaceutical forms using suitable auxiliaries.

Example 4
Production of ß-sitosteryl-ß-glucoside in an oil-in

Vasser emulsion

Theoretical: The steryl or steroid glycoside is used in dissolved in a suitable solvent. The solution then becomes the emulsion or the emulsion oil, if necessary together with suitable surface-active compounds

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and emulsion stabilizing additives added. The individual Glycosidmoleküle "remain in the oil and the oil droplets ^of: separately emulsion.

In the emulsion, the polar sugar components of the glycoside molecules settle on the surface of the oil droplets from where they are available for absorption. By removing a glycoside molecule from the surface of the oil droplet biological absorption o.dglo creates space for a new glycoside sugar component on the surface of the Oil droplets created This process repeats itself, until the glycoside supply in the oil droplet is exhausted.

Manufacture of the product

ß-Sito & teryl-ß-glucoside ethanol

Acaeiae gum

Pulvis Tragacanthae Compositus (PuIv.Trag.Co.) Sunflower oil ^Γ Benzoic acid

water

The Aeaeiae-Gummi and PuIv.Trag.Co. are with the sunflower oil " rubbed in. The mixture is heated to 60 ° C. With thorough mixing, a boiling solution of the glucoside becomes After adding 100 ml of water, the mixture is homogenized, with a primary emulsion is formed. This emulsion is then made up to volume with water in which the benzoic acid has been dissolved filled up. . ..

Example 5

Production of a ß-sitosteryl-ß-glucoside solution in ß-sitosterol on talc as a carrier

Theoretical; When a steryl or steroid glycoside is mixed with an excess of its aglycon (1: 500 and more) the glycoside loses its identity (thin-film

100 mg ml 25th ml 40 G 10 G 120 ml 1 G 1000

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Chromatography) o The glycoside forms a loose complex with the aglycon, and in this state the glycoside is prevented from attaching to other identical molecules tie.

Manufacture of the product

ß-sitosteryl glucoside. 20 mg

ß-sitosterol 10 g

Ethanol 160 ml

Talc 170 g

Gelatin capsules- 1000

The ß-sitosterol and the ß-sitosteryl glucoside are in the atb ^ nol, which is heated to reflux, dissolved. The rest of the., Borrowed procedural measures are the same as in example 1 described

a) The activity of the product obtained here does not depend on the formation of the monomolecular layer of the Glueosids or glycosides on the support, rather than from the monomolecular dispersion of the glycoside in the aglycon.

b) Steryl or steroid glycosides form complexes (molecular or solvation) with excesses of the corresponding aglycones or with related sterols and Steroids.

c) Steryl or steroid glycosides can be used in excess The carbohydrates used are mixed, with results similar to those described under (a) and (b) have been obtained.

d) Steryl or steroid glycosides can be mixed with the most varied pharmacologically harmless substances are mixed, e.g. with bioflavonoids, ascorbic acid, chelidonic acid, Inositol and lecithins, with the monomolecular availability of these glycosides

s'-et is _f ? r. The activity of the glycosides "depends on the 3098 3 2/116 /»

._ -j 2 -

Formation of dispersions, as under (a), (b) and (o) described.

e) The remarks (a), (d), (e), (f) and (g) in example 1 also apply in this case.

The extremely valuable properties of ß-sitosteryl-ß-D-glucoside have already been described in British patent application 1,298,047.

3098 3

Claims (4)

Patent claims 1) Process for the production of mixtures of substances for medical purposes or food purposes, thereby characterized in that the active compound is a sterol or steroid glycoside in monomolecularly dispersed State dispersed or dissolves in a pharmaceutically acceptable compound and the dispersion or solution of an adsorbent serving as a carrier, absorbent or one serving as a carrier Emulsion is added in a predetermined amount, which the available surface of the carrier for the as Single molecules or as monomolecular layers to be adsorbed or absorbent active compound The basis is. 2) Method according to claim 1, characterized in that ß-Sitosteryl-ß-D-glycoside used as an active ingredient will. 5) .A method according to claim 1 and 2, characterized in that that pharmaceutically acceptable compounds are used as carriers. 4) Method according to claim 1 to 3, characterized in that an aglycone as pharmaceutically acceptable Compound in which the steroid or steroid glycoside is dispersed or dissolved is used. 309832/1