Solid dispersion of gum arabic and at least one lipid-soluble active ingredient

Abstract

The present invention relates to a solid solution made of gum arabic and at least one fat-soluble active ingredient, having particles less than 100 μm in size, wherein the weight ratio of gum arabic to fat-soluble active ingredient is between 5:1 and 200:1, which can be obtained by drying an aqueous solution of gum arabic to obtain a particulate dry product, combining this dry product with a solution or dispersion of the fat-soluble active ingredient in an anhydrous solvent in which gum arabic is insoluble, homogenizing with mixing in the solution, further grinding the dry product to a particle size less than 100 μm, and removing the solvent at a temperature less than 70° C. The present invention further relates to a method for preparing the solid solution and to an aqueous suspension containing it.

Description

Technical Field

[0001] The present invention contains particles having a size of less than 100 μm, and the weight ratio of gum arabic to a lipophilic active substance is 5:1 to 200:1. It relates to a composition of gum arabic and at least one lipophilic active substance solid dispersions , as well as such solid dispersions and a method for preparing the same and an aqueous suspension containing the same.

Background Art

[0002] Oral administration of lipophilic active ingredients often causes problems because the active substances are not absorbed into the body from the aqueous environment found in the intestine and on the mucosa. Even when administered via a lipophilic carrier, the uptake rate is often below expectations.

[0003] For this reason, it has been proposed to administer the active ingredient by binding it to micelles in order to improve absorption into the body. Micelles can encapsulate and transport lipophilic substances in an aqueous environment because they are formed from substances having a lipophilic end and a hydrophilic end. Examples related to this include not only various detergents, polysorbates, poloxamers, but also a number of natural substances, such as various natural resins, and furthermore gum arabic.

[0004] Patent Document 1 describes the use of poloxamer for solubilization of an active ingredient containing insulin. The basic suitability of resins for these purposes is also mentioned.

[0005] Patent Document 2 describes a gum arabic-based composition in the form of micelles to which an active ingredient is bound, and the composition is obtained from a warm aqueous solution. The composition is liquid and contains micelles having a diameter in the range of 2 to 300 nm.

[0006] Common to all these approaches is that they do not fundamentally improve the absorption of each active substance into the body.

Prior Art Documents

[0007] [Patent Document 1] International Publication No. 2007 / 104173 [Patent Document 2] International Publication No. 2008 / 034273 [Overview of the project]

[0008] The object of the present invention is to provide an active substance that can more efficiently absorb lipid-soluble active substances into the body. At the same time, a method for preparing this active substance is provided, and examples of its administration are given.

[0009] The size of the particles formed from gum arabic and the active ingredient affects the administration method and the distribution of the active ingredient. On the other hand, particle size is governed and determined by the manufacturing method and, furthermore, by the ratio of gum arabic to the active ingredient.

[0010] Gum arabic exhibits suspension and emulsion stabilization effects. Gum arabic forms a protective colloidal coating around lipid-soluble substances and consists of gum arabic and lipid-soluble active ingredients. solid dispersions It can be used to form [a substance], promoting its transport and absorption into living organisms.

[0011] Therefore, the present invention comprises gum arabic and at least one lipid-soluble active ingredient. solid dispersions The product contains particles smaller than 100 μm in size, has a weight ratio of gum arabic to lipid-soluble active ingredient of 20:1 to 200:1, and can be obtained by drying an aqueous solution of gum arabic to obtain a fine-particle dry product, mixing the dry product with a solution of the lipid-soluble active ingredient in an anhydrous solvent in which gum arabic does not dissolve, homogenizing while mixing in the solution to further fragment the dry product into particles smaller than 100 μm, and removing the solvent at a temperature below the decomposition temperature of gum arabic, particularly below 70°C. solid dispersionsRegarding.

[0012] Furthermore, the present invention comprises gum arabic and at least one lipid-soluble active ingredient. solid dispersions The present invention relates to a method for preparing a gum arabic, characterized by comprising the steps of: drying an aqueous solution of gum arabic to obtain a fine particle dry product; mixing the fine particle dry product with an aqueous solution or dispersion of an lipid-soluble active ingredient in a solvent in which gum arabic is insoluble, in a weight ratio of gum arabic to lipid-soluble active ingredient of 20:1 to 200:1; homogenizing the solution while mixing and further fragmenting the dry product into particles of less than 100 μm; and removing the solvent at a temperature of 70°C or lower, preferably 40°C or lower, particularly at room temperature.

[0013] It is essential to understand that the mentioned particle size defines the maximum threshold. Therefore, "particles smaller than 100 μm" means that the particles are overwhelmingly much smaller than 100 μm. It should not be considered to represent the average particle size of the statistical distribution. This applies to both the lower and upper thresholds.

[0014] Furthermore, it is essential that the manufacturing method is carried out at a temperature of 70°C or lower, preferably 40°C or lower, and especially at room temperature. The required fineness cannot be achieved from a solution or melt. Gum arabic can be dissolved in the presence of a small amount of water at a temperature of 40°C to 60°C. The solubility of gum arabic in water is approximately 500 g / l.

[0015] As proposed by the present invention, comprising gum arabic and an active ingredient solid dispersions These exist in the form of micelles in aqueous media. Micelles, as transporters for fatty active ingredients, have been used for decades to solubilize water-insoluble substances. Ultimately, the cleaning effect of surfactants is based on micelle formation.

[0016] Micelles are aggregates of surfactant molecules. In an aqueous environment, their interior consists of the lipophilic groups of individual surfactant molecules, and the hydrophilic groups are located on the surface. These hydrophilic groups can accumulate water and lead to the formation of an emulsion.

[0017] In its simplest form, a micelle is spherical and self-organizes spontaneously. The remaining residues inside do not contact the surrounding aqueous phase. The diameter of the micelle is defined by the spatial requirements of the lipophilic core and the surrounding hydrophilic shell. Micelles can be considered as droplets in their respective environments.

[0018] When surfactant molecules are supplied in excess, the diameter of the aggregate increases significantly, exceeding a value far more than 10 times the smallest possible diameter. For this reason, it is essential to keep the ratio of gum arabic to the active substance within the claimed range in the present invention, thereby restricting the particle size of the micelles formed.

[0019] In micelles, individual surfactant molecules in an aqueous environment can always escape from the micelle to the surrounding phase, and conversely, free surfactant molecules can aggregate with the active ingredient to form new micelles, so a constant exchange is taking place. This equilibrium between the micelles, free surfactant, and active ingredient molecules enables the movement of the active ingredient into and through the membrane via a permeable membrane.

[0020] Therefore, the transport effect of the particles of the present invention of gum arabic and the lipophilic active ingredient is based on the active ingredient being transported from the micelle to the site of movement in an aqueous environment and released there. The release allows the active ingredient to enter the cell through the membrane.

[0021] Gum arabic is obtained from the sap of various acacias (e.g., Acacia senegal, Acacia seyal) and consists mainly of the acidic alkali salts and alkaline earth salts of arabic acid (poly arabic acid). Poly arabic acid consists of L - arabinose, D - galactose, L - rhamnose and D - glucuronic acid in a ratio of 3:3:1:1 and is a branched polysaccharide with a molecular weight in the range of 200,000 - 350,000 g / mol depending on the measurement method applied.

[0022] In food industry applications, gum arabic is used as a thickener, emulsifier and stabilizer. It is also used in the beverage industry, confectionery, pharmaceuticals, cosmetics and engineering sectors.

[0023] The present invention basically provides for the use of all grades of gum arabic. A prerequisite related to this is that a certain particle size already exists prior to the treatment of the present invention, which is achieved particularly in the case of spray drying from an aqueous solution. However, the particle size after spray drying is still too coarse and thus not yet suitable for the purposes proposed by the present invention. Good quality gum arabic powder obtained by spray drying is commercially available with a bulk density of 600 kg / m 3 and an internal specific surface area of 150 m 2 / g or more. The capillary action of this water - resistant powder can be utilized for encapsulating lipophilic active ingredients. Then, the particles proposed by the present invention are formed by further grinding.

[0024] Therefore, the gum arabic powder used is preferably an amorphous structure with many capillaries and a large internal surface area. A large internal surface area is an important requirement for "sucking up" the active ingredient solution, or properly dispersing it and distributing it as uniformly as possible. At the same time, good water solubility is essential, which is usually ensured by the product obtained by spray drying. This enables the production of high - concentration solutions or suspensions with a relatively low viscosity.

[0025] As proposed in this invention, the preparation method is carried out in the absence of water. solid dispersions It is anhydrous. This is essential not only for ensuring the stability of the product but also for the usefulness of the aqueous suspensions and solutions obtained therefrom.

[0026] The method proposed by the present invention and the resulting " solid dispersions This process is suitable for stabilizing these micelles over several years. In this process, even if the active ingredient is in liquid form, the resulting particles (micelles) are solid and can be obtained as a dry powder, which can be easily incorporated as a "semi-finished product" into any galenical form (cream, serum, lotion, gel, drink, shot). The powder can be easily suspended in small amounts of water or aqueous solution, and a complete emulsion is formed only when the solubility limit is exceeded.

[0027] By using different active ingredient modules, a variety of effects can be produced simply, economically, and without significant development effort. The effects of such active ingredient complexes are achieved more rapidly than with conventional "carrier systems."

[0028] According to the present invention, gum arabic and the active ingredient are used in a weight ratio of 5:1 to 200:1, particularly 10:1 to 100:1. The weight ratio is an important factor because if the proportion of gum arabic is too high, the particle size may increase, which is undesirable for effective distribution.

[0029] As already shown, particle size is essentially important. solid dispersions All particles should preferably be substantially 100 μm or smaller in size, and more preferably 80% of the particles should be 60 μm or smaller. Similarly, in order to achieve a homogeneous product, the minimum particle size should also be restricted so that 80% of the particles are 1 μm or larger, and especially 90% of the particles are 1 μm or larger. As a result, the average particle size appears to be approximately 40 μm.

[0030] As far as the incorporation of active ingredients into a solution is concerned, the particle size and inner surface area of ​​the gum arabic matrix material used are extremely important. The solution must be absorbed and distributed completely and as uniformly as possible within the matrix material. In this regard, it should be ensured that the solvent of the active ingredient does not dissolve the gum arabic and therefore does not alter its structure.

[0031] A suitable solvent is one that dissolves each lipophilic active ingredient and forms a solution of the highest possible concentration. The solvent is preferably anhydrous, and another criterion is that its boiling point is as low as possible and that it can be removed from the product. Examples of suitable solvents include ethers and alcohols, particularly ethanol. Anhydrous alcohol (100%) is especially preferred. The presence of water in the matrix material mixed with the active ingredients must be avoided.

[0032] The present invention proposes solid dispersions The primary prerequisite for the preparation is the homogenization and further fragmentation of the matrix material impregnated with the active ingredient. Essentially, any method that ensures the appropriate particle size can be used for this purpose, but the use of cutters and homogenizers that exhibit high shear force is particularly preferred for these purposes.

[0033] The solvent of the active ingredient is removed during homogenization or the final step of the manufacturing process. In the case of highly volatile solvents such as alcohols, a large amount of the solvent has already evaporated during homogenization and further fragmentation, and the remaining residue is evaporated at a temperature of 70°C or lower, preferably 40°C or lower, especially at room temperature, or removed by vacuum.

[0034] Following this procedure, a stable powder consisting of gum arabic and the active ingredient is formed. This powder can be easily suspended in a small amount of water and is soluble in larger amounts of water. The aqueous suspension or solution is also stable without aggregation.

[0035] The present invention is sealed in gum arabic. solid dispersions Preferably, it contains only one lipid-soluble active ingredient. Nevertheless, the present invention may, on the one hand, be obtained by a manufacturing process that simultaneously incorporates several lipid-soluble active ingredients into gum arabic particles, or a mixture of several active ingredients mixed together. solid dispersions It's important to understand that this also includes [something else]. The same applies to manufacturing methods.

[0036] The present invention proposes solid dispersions It can be sold in powder form, but suspended in water. solid dispersions It is primarily useful as a starting material for preparing suspensions containing 2.5 to 40.0% by mass of [the substance]. Suspensions of this nature may further contain common food-grade additives such as preservatives, stabilizers, pH adjusters, sweeteners, and flavorings.

[0037] Furthermore, water-soluble vitamins, provitamins, dietary supplements, and nutritional supplements may be added in normal amounts. These normal amounts range from 30% to 300% of the recommended daily intake. The total content of these additives is typically 0.5% to 2.5% by mass of the aqueous suspension.

[0038] In this type of aqueous suspension, it should be understood that some of the added particles, consisting of gum arabic and lipid-soluble active ingredients, dissolve in the solution depending on the concentration. In a 5% aqueous suspension, some of the gum arabic containing the active ingredients is present primarily in granular form, while some is present in the form of a film or sponge.

[0039] As provided by the method of the present invention, all active ingredients suitable for incorporation in a soluble form into fine particle gum arabic can be used as essentially lipid-soluble active ingredients. Examples include coenzyme Q10, coenzyme Q10H2, vitamin A, vitamin D, vitamin E (tocopherol), vitamin K, B group lipid-soluble vitamins, curcumin, chalcone, flavan-3-ol, flavanone, flavone, flavonol, isoflavone, flavanonol, essential fatty acids, growth factors, immunoglobulins, immunomodulatory factors, hormones (progesterone, testosterone, estrone, estradiol, androstenedione, etc.), and numerous lipid-soluble drugs (analgesics, anti-inflammatory agents, antibiotic preparations). [Examples]

[0040] Coenzyme Q10 (ubiquinone) was used as the active ingredient. The procedure involved mixing 100 g of gum arabic powder obtained by spray drying with 2.0 g of ubiquinone suspended in 10 ml of anhydrous alcohol, homogenizing it with a cutter (Robocoupe) for 90 seconds, and fragmenting it to achieve a particle size of 100 μm or less. The ubiquinone in the resulting gum arabic was solid dispersions The fine powder was left to stand at room temperature in the dark until the alcohol evaporated. The powder stabilizes when stored in a cool, dark place.

[0041] The 51 g of powder obtained in this way was added to 946.5 g of distilled water along with 0.5 g of citric acid (pH adjuster), 1 g of ascorbic acid (stabilizer), and 1 g of potassium sorbate (preservative), resulting in a suspension that remained stable for several months. This suspension can be consumed immediately and is suitable for immediate oral intake of ubiquinone.

[0042] Other substances such as water-soluble vitamins, provitamins, nutritional supplements, nutrients, sweeteners, and flavorings can be added to the suspension obtained in this manner. The addition of vitamins, turmeric extract (curcumin), and passion fruit extract (chrysin) has been found to be particularly suitable. These and other additives can assist in the escorting process.

[0043] Sodium bicarbonate (approximately 4 g / l) may be added as a release agent. It has been found that this additive promotes the dissolution of the powder and, when combined with vitamin C, also produces effervescence.

Claims

1. A solid dispersion of gum arabic and at least one lipid-soluble active ingredient, having particles with a size of less than 100 μm, and having a weight ratio of gum arabic to lipid-soluble active ingredient of 5:1 to 200:

1. The process of drying an aqueous solution of gum arabic to produce finely powdered dried products. Mix the dried product with a solution or dispersion of the lipid-soluble active ingredient in an anhydrous solvent in which gum arabic is insoluble. Homogenizing the dried product while mixing it in the aforementioned solution, and further fragmenting the dried product into particles with a size of less than 100 μm, and Remove the aforementioned solvent at a temperature of 70°C or lower. A solid dispersion obtained by [method].

2. The solid dispersion according to claim 1, characterized in that the particles, each comprising gum arabic and at least one lipid-soluble active ingredient, form micelles.

3. The solid dispersion according to claim 1 or 2, characterized in that the weight ratio of gum arabic to the lipid-soluble active ingredient is in the range of 50:1 to 100:

1.

4. The solid dispersion according to any one of claims 1 to 3, characterized in that 80% of the particles have a size of 60 μm or less.

5. The solid dispersion according to claim 4, characterized in that 80% of the particles have a size of 40 μm or less.

6. The solid dispersion according to any one of claims 1 to 5, characterized in that the dried fine particles are spray-dried gum arabic.

7. The solid dispersion according to any one of claims 1 to 6, characterized in that the solvent of the solution or dispersion of the lipid-soluble active ingredient is an anhydrous alcohol.

8. A method for preparing a solid dispersion of gum arabic and at least one lipid-soluble active ingredient, A process of drying an aqueous solution of gum arabic to produce fine particle dried products. A step of adding to the dried fine particles a solution or dispersion of the lipid-soluble active ingredient in an anhydrous solvent in which gum arabic is insoluble, in a weight ratio of gum arabic to lipid-soluble active ingredient in the range of 20:1 to 200:

1. A step of homogenizing the dried product while mixing it in the aforementioned solution, and further fragmenting the dried product into particles smaller than 100 μm, and A step of removing the solvent at a temperature of 70°C or lower. A method characterized by including

9. The method according to claim 8, characterized in that spray-dried gum arabic is used as the dried product.

10. The method according to claim 8 or 9, characterized by further fragmentation using a cutter or sonicator.

11. The method according to any one of claims 8 to 10, characterized in that further fragmentation is performed under high shear until 80% of the particles have a size of 60 μm or less.

12. The method according to claim 11, characterized in that further fragmentation is performed until 80% of the particles have a size of 40 μm or less.

13. The method according to any one of claims 8 to 12, characterized in that a weight ratio of gum arabic to a lipid-soluble active ingredient of 50:1 to 100:1 is used.

14. The method according to any one of claims 8 to 13, characterized in that an anhydrous alcohol is used as the solvent.

15. An aqueous suspension containing 2.0 to 40.0% by mass of the solid dispersion according to any one of claims 1 to 7.

16. The aqueous suspension according to claim 15, characterized in that the suspension further contains 0.05 to 1.0% by mass of a combination of ordinary food-grade preservatives, stabilizers, pH adjusters, sweeteners and / or flavorings.

17. The aqueous suspension according to claim 15 or 16, characterized in that the suspension further contains a total of 0.5 to 2.5% by mass of water-soluble vitamins, provitamins, nutrients and / or nutritional supplements.

18. The solid dispersion according to any one of claims 1 to 7, characterized in that the active ingredient or one of the active ingredients is coenzyme Q10 and / or curcumin.

19. The method according to any one of claims 8 to 13, characterized in that the active ingredient or one of the active ingredients is coenzyme Q10 and / or curcumin.

20. The aqueous suspension according to any one of claims 15 to 17, characterized in that the active ingredient or one of the active ingredients is coenzyme Q10 and / or curcumin.

21. The solid dispersion according to any one of claims 1 to 7, wherein the lipid-soluble active ingredient is selected from coenzyme Q10, coenzyme Q10H2, vitamin A, vitamin D, vitamin E (tocopherol), vitamin K, lipid-soluble vitamins of the B group, curcumin, chalcone, flavan-3-ol, flavanone, flavone, flavonol, isoflavone, flavanonol, essential fatty acids, growth factors, immunoglobulins, immunomodulatory factors, hormones, and lipid-soluble drugs.

22. The solid dispersion according to claim 21, wherein the lipid-soluble active ingredient is coenzyme Q10 or coenzyme Q10H2.

23. The solid dispersion according to claim 1, wherein the anhydrous solvent is an ether or an alcohol.

24. The method according to claim 8, wherein the lipid-soluble active ingredient is selected from coenzyme Q10, coenzyme Q10H2, vitamin A, vitamin D, vitamin E (tocopherol), vitamin K, B group lipid-soluble vitamins, curcumin, chalcone, flavan-3-ol, flavanone, flavone, flavonol, isoflavone, flavanonol, essential fatty acids, growth factors, immunoglobulins, immunomodulatory factors, hormones, and lipid-soluble drugs.

25. The method according to claim 24, wherein the lipid-soluble active ingredient is coenzyme Q10 or coenzyme Q10H2.

26. The method according to claim 8, wherein the anhydrous solvent is an ether or an alcohol.