Micellar system for the transport of active ingredients

Description

Field of the invention

[0001] The invention relates to active ingredient compositions comprising artificially produced, self-agglomerating, stable micelles with good transport properties for an incorporated active ingredient, as well as a production process for such micelles. background

[0002] Active ingredient compositions containing a single type of micelle are known per se. WO 2008 / 034273 discloses micelles containing active ingredients and gum arabic; WO 2008 / 138155 discloses micelles containing root resins and optionally gum arabic; and WO 2010 / 022525 discloses micellar compositions containing one or more active ingredients, glycerol fatty acid esters, and optionally gum arabic, root resin, or cyclodextrin. The Vitana-X product line describes micellar compositions with improved bioavailability of selected active ingredients.

[0003] From CA 2922959 A1, active ingredient compositions containing two types of micelles are known, which may contain glycerol esters and / or polyelectrolytes.

[0004] Providing drug formulations with high concentrations of diverse active ingredients remains a challenge. Providing drug formulations with a targeted and defined release profile also remains a challenge.

[0005] The aim of the present invention is therefore to provide active ingredient compositions that absorb a large amount of active ingredient and can preferably be administered orally. The aim of the present invention is also to provide active ingredient compositions that release the active ingredient at a predetermined location (directed) and / or over a predetermined time (release profile). Description of the invention

[0006] This goal was achieved by providing active ingredient compositions containing micelles, as well as processes for producing corresponding micelles and active ingredient compositions.

[0007] Active ingredient compositions according to the invention contain at least two types of micelles, each type of micelle comprising, in addition to at least one active ingredient, at least one oligo- and / or polysaccharide (hereinafter generally referred to as polyelectrolytes) and / or at least one glycerol ester selected from glycerol esters of fatty acids and wood resins. The invention will be explained in more detail below in its various embodiments. Micelles

[0008] The term "micelles" is well known. Micelles according to the present invention have a core – which primarily contains the active ingredient – and a simple or complex shell, which contains excipients from the group of polyelectrolytes and / or glycerol esters. Additional components can be present in the core or the shell. If the shell contains polyelectrolytes and glycerol esters, it is referred to as a "first type of micelle" or "complex micelle." If the shell contains polyelectrolytes or glycerol esters, it is referred to as a "second type of micelle" or "simple micelle."

[0009] The mean geometric diameter of micelles according to the invention is 5 nm - 100 nm, particularly preferably 10 nm - 30 nm (optical measurement, expressed as the d 90 value, i.e., in the quantile of 5 - 95, independent of the size distribution). This is thus significantly smaller than the dimensions of most human cells and smaller than the geometric-optical diameter of most viruses. Without wishing to be bound by any theory, it is assumed that these relatively small dimensions of the micelles, compared to human tissue cells, favor the absence of an immune reaction. The nanoscale micelles efficiently circumvent the immune system's response.

[0010] The ratio of the two types of micelles to each other can vary widely and depends, for example, on the choice of active ingredient. Suitable ratios of the first type of micelle to the second type of micelle are in the range of 1:99 to 99:1 (n / n), preferably 10:90 to 90:10, such as 2:1 to 1:2. The first type of micelle contains, in addition to the active ingredient, at least one polyelectrolyte and at least one glycerol ester. This type of micelle forms complex structures, roughly described as a two-shell micelle. The second type of micelle contains, in addition to the active ingredient, at least one polyelectrolyte or at least one glycerol ester.

[0011] This type of micelle forms comparatively simpler structures, which can be roughly described as a single-shell micelle. It is understood that the active ingredient composition can contain various micelles of the first type and / or various micelles of the second type. The composition shown in Example 1 contains micelles (i), (ii), and (iv) of the first type ("complex micelles") and micelles (iii) of the second type ("simple micelles"). The active ingredient compositions containing micelles can be in the form of micellar phases or micellar dispersions. Micellar phases and micellar dispersions differ only in the solvent content, preferably water or an aqueous solution.

[0012] Unless the context indicates otherwise, the terms active ingredient and active substances, glycerol esters and polyelectrolyte and polyelectrolytes shall include both the singular and the plural (at least two).

[0013] In micelle-containing dispersions, the micelles are typically dispersed in an aqueous phase. Accordingly, the active ingredient composition according to the invention can be present as a liquid formulation with a comparatively high water content. In this embodiment, the active ingredient composition contains at least two different types of micelles in an aqueous phase. In this embodiment, the water content in the active ingredient composition is typically > 10 wt.%.

[0014] The active ingredient composition according to the invention can be present as a solid dosage form with a comparatively low water content. In this embodiment, the water content in the active ingredient composition is typically <10 wt.%. Such solid dosage forms are obtainable by removing water from the liquid formulations, e.g., by evaporation. For example, coated tablets or capsules are available. Such solid dosage forms are also obtainable by removing water from the liquid formulations, e.g., by freeze-drying. For example, powders or tablets are available. Excipients (polyelectrolytes, glycerol esters)

[0015] Suitable fatty acid esters are low-molecular-weight, amphiphilic esters with one to three fatty acids, each with the same or varying carbon chain length, which can be either saturated or unsaturated and linked to each other by glycerol or, more generally, a C3 chain. The fatty acids are preferably C18 chains, although other carbon chain lengths are also effective and common.

[0016] Preferred fatty acid esters are mono- and diglycerides of fatty acids, i.e. mono- and diesters of glycerol with fatty acids. Mono- and diglycerides of naturally occurring fatty acids, such as edible fatty acids, are preferred. Mono- and diglycerides of edible fatty acids are marketed in the EU as food additives under the number E 471 and further esterified with various acids as E 472a-f and are generally approved for use in food without a maximum limit (quantum satis). During esterification to E 472, depending on the letter, acetic acid (E 472a), lactic acid (E 472b), citric acid (E 472c), tartaric acid (E 472d), mono- and diacetyltartaric acid (E 472e) or mixed acetic and tartaric acid (E 472f) are used.

[0017] Glycerol esters of wood resins are also approved in the EU as food additives under the number E 445. E 445 is fat-soluble and has a higher density than water. The main component of wood resins is resin acids. E 445 is produced by esterifying resin acids with glycerol. The resin used is the resin of the pine tree (Pinus palustris). Esterification with additional acids, as disclosed above for the fatty acid glycerides, is less preferred but also included.

[0018] Resin acids have alicyclic structures and, in addition to the carboxyl group, often contain additional functional groups such as hydroxyl, keto, or aldehyde groups. They are essentially diterpene and triterpene acids.

[0019] In addition to the glycerol esters of fatty acids and resin acids (including other substances that occur in natural mixtures), or instead of such glycerol esters, at least one polyelectrolyte may be present. This at least one polyelectrolyte is selected from oligosaccharides or polysaccharides with polyelectrolyte characteristics, such as gum arabic, cyclodextrins, glycans, glycogens, glycolipids, and mixtures thereof, but especially gum arabic and / or cyclodextrins. Preferred polysaccharides for release in the small intestine are gum arabic and fractions of gum arabic.

[0020] Polyelectrolytes are water-soluble compounds with long chain lengths (polymers) that carry anionic (polyacids) or cationic (polybases) dissociable groups.

[0021] Compounds with polyelectrolyte character according to the present invention are polyelectrolytes and compounds with a plurality, such as 15 or more, ionic and / or polar groups.

[0022] A preferred polyelectrolyte is a natural polysaccharide with linear (1-3)-linked β(D)-galactopyranoside groups in the main chain, which also contains carboxyl groups due to oxidation of the sugar side chains. These carboxyl groups, when deprotonated, act as negative charge carriers of the polyelectrolyte and are crucial for the interaction between polysaccharides and also with the active ingredients, any glycerol esters, any excipients, and the solvent, especially water or aqueous solutions. The carboxylate groups are also influenced by the amounts of mono- and divalent cations as well as the pH of the surrounding solvent. The amounts of polyelectrolyte, glycerol ester, active ingredient, and water, as well as their pH, determine the ionic strength, which in turn influences micelle formation.

[0023] The polyelectrolyte is preferably a polysaccharide with variable chain length and a variable number of negative charges in the side chains. Typical molecular weights of the polymers are up to 1 million, especially 300,000–800,000.

[0024] The interactions between polyelectrolyte, glycerol ester and active ingredient occur mainly via hydrogen bonding, dipole forces and Van der Waals interactions, e.g. between active ingredients and side chains of the polyelectrolyte.

[0025] The main components of gum arabic are polydisperse polyelectrolyte mixtures of copolymers, particularly acidic alkaline earth and alkali salts of arabic acid (polyarabic acid), a branched polysaccharide consisting of L-arabinose, D-galactose, L-rhamnose, and D-glucuronic acid in a ratio of 3:3:1:1. Other components of gum arabic include polygalactose (poly-β-(1-6)-galactopyranose) with multi-branched sugar chains, particularly 1-4-D-galacturonic acid side chains, as well as their alkali metal and alkaline earth metal salts.

[0026] Cyclodextrins belong to the cyclic oligosaccharides. Based on the number of glucose molecules they contain, they are classified as alpha-cyclodextrin (6 glucose molecules), beta-cyclodextrin (7 glucose molecules), gamma-cyclodextrin (8 glucose molecules), and delta-cyclodextrin (9 glucose molecules). Alpha-cyclodextrin is currently the preferred type.

[0027] Polyhydric alcohols, such as glycerol E422 in particular, can also be added as an excipient, e.g. to adjust the viscosity.

[0028] The micelles described here are composed of variable proportions of the excipients polyelectrolytes and / or glycerol esters. A polyelectrolyte is particularly advantageous for targeted release. Since this is preferably selected from natural polysaccharides with polyelectrolyte characteristics, it does not trigger any immune reactions. This advantageous property is due to the nanoscale as well as the specific, natural molecular components and—for the natural product gum arabic—the highly relevant carbohydrate structures of the polyelectrolyte arabic acid as the main component of gum arabic. The approximate relative molar mass of arabic acid is M r = 3 10 5 to 1.1 10 6 .

[0029] Without wishing to be bound by any theory, it is assumed that the active ingredient composition defined here is based on the special structure of the micelles and thus leads to beneficial pharmacological effects. The following statements regarding micelle transport are based on the current state of knowledge and are not intended to limit the invention in any way: The micelles can be transported into the organism orally via the gastrointestinal tract or by other means. Oral administration is the most common. Micelles can also be administered topically, intravenously, or—by inhaling a mist of microdroplets generated by a spray system—via the respiratory tract.

[0030] If the micelles are manufactured with a fraction of gum arabic that contains a high proportion of D-galacturonic acids in the side chains of arabic acid, these are predominantly in a protonated form at gastric pH. This results in virtually no local, electrically negative charge at pH 1 to pH 2, which promotes the safe and stable inclusion of the active ingredients together with suitable excipients and their safe transport into the intestine.

[0031] In addition, no enzymatic digestion of the arabic acid in gum arabic is possible in the stomach, since the stomach and small intestine lack the specific enzymes for the substantial degradation of the micelle-forming polyelectrolytes.

[0032] The protonated polyelectrolyte, together with low molecular weight (active) substances, takes on a spherical shape in the stomach, which encloses the (active) substances, which additionally sterically prevents enzymatic attack on the micelle.

[0033] Micelles whose total charge tends toward zero towards the outside assume a thermodynamically favored spherical shape. Counterions, such as neutralizing alkali ions and virtually neutralizing alkaline earth ions, also play a role in charge shielding.

[0034] The protonation of galacturonic acid, the oxidized product of galactose, in the branched side chains of arabic acid is virtually complete at pH values below 2, as is known to be measured in the stomach. The pK a value of free α-D-galacturonic acid is approximately 2.9. The pK a values of the various galacturonic acid residues bound in arabic acid depend on the local environment and are strongly influenced by the local dielectric constant, the potential for hydrogen bonding, i.e., the local steric environment, and also the local ionic strength.

[0035] In the aqueous phase of the duodenum, the pH value increases rapidly from approximately 8.2 to approximately 6.6 due to alkaline pancreatic secretions and bicarbonates. The bile acid present there, as well as the proteolytic enzymes trypsin and chymotrypsin, do not lead to any enzymatic degradation of the micelles or the components enclosed therein.

[0036] In the duodenum, dietary fats, present in the form of triglycerides, are emulsified by bile acids. The triglycerides are enzymatically broken down by lipase into monoglycerides and fatty acids, which form micelles. These micelles are transported into the intestinal epithelial cells of the small intestine. Within the cells, they are assembled in the endoplasmic reticulum of the intestinal epithelial cells together with cholesterol and lipoproteins to form chylomicrons, which ultimately enter the bloodstream via the lymphatic vessels.

[0037] The lowest pH values are found immediately upon entry into the short duodenum, the uppermost part of the small intestine. At the transition from the short duodenum to the next section of the small intestine, pH values of approximately 6.6 prevail. Locally, slightly different pH values prevail in each section of the small intestine, i.e., slightly acidic values around pH 6.5.

[0038] Upon entering the upper portion of the large intestine, the pH drops to approximately 5.5. This pH reduction is caused by the short-chain fatty acids produced by the intestinal bacteria. These acidic bacterial products are absorbed along the length of the large intestine, causing a slight pH increase in the large intestine until its end.

[0039] The polyelectrolyte micelles release their active ingredients primarily in the small intestine or are introduced into cells, where they are broken down into their components. The deprotonation associated with the pH increase in the small intestine causes a partial unfolding of the negatively charged arabic acid side chains through charge repulsion forces, which partially releases the loosely bound substances from the micelles.

[0040] Depending on the type of micelle, polyelectrolyte and / or glycerol ester, any excipients and the active ingredients (active ingredients), the transfer of the micelle into the intestinal epithelium occurs over the entire length of the small intestine and allows the efficient transport of the low-molecular-weight, active substances into the bloodstream.

[0041] In parallel, or alternatively, the micellized active ingredients can be transported into the bloodstream via the intestinal epithelial cells. This is believed to be enabled by the docking of the micelles' diverse sugar components to the equally diverse carbohydrate functions of membrane-bound proteins. This is considered the first step in overcoming the cell membrane barrier and transporting the micelles' active ingredients into the cytoplasm.

[0042] The mucous membranes between the intestinal lumen and the intestinal epithelial cells protect the cells from enzymatic digestion. The micelles must traverse these mucous membranes by diffusion.

[0043] It is assumed that the lateral molecular forces resulting from the binding of micelles to the carbohydrate functional sites act on the initially intact cell membrane, then locally weakening or opening it, thereby allowing the active ingredients to enter the cell or the micelles to enter the endothelial cells, where the micelles release their contents. While the majority of carbohydrates are absorbed in the duodenum and the subsequent jejunum, the enzymes responsible for this cannot hydrolytically break down the micelle-forming arabic acid, as is the case with certain other long-chain carbohydrates. Gum arabic from micelles, whose active ingredient was released and absorbed in the small intestine, can only be degraded in the large intestine with the help of bacteria, since the enzymes provided by human cells cannot digest this polysaccharide.Gum arabic is therefore considered a soluble fiber, which in larger quantities increases the water content of the undigested contents in the large intestine.

[0044] The formation of stable micelles is improved by the appropriate choice of glycerol esters and / or polyelectrolytes. The choice of glycerol esters and, in particular, polyelectrolytes depends on the respective active ingredients and the properties of the gum arabic fraction, as well as the solvent.

[0045] Active ingredients with dipole moment or charge can be better incorporated into compositions rich in polyelectrolyte, in particular in compositions containing > 50% polyelectrolyte based on the total amount of polyelectrolyte and glycerol ester, preferably > 75% polyelectrolyte. PH value

[0046] By adjusting the pH, the incorporable amount of ionic active ingredients in the deprotonated state can also be optimized for the preferred, charged (carbonylate group-containing) polysaccharides. This means that the active ingredient and polysaccharide are preferably both predominantly protonated or deprotonated. For example, ascorbic acid (pKa = 4.25) can be better incorporated at a low pH into a composition with a high gum arabic content or consisting of gum arabic (pKa of arabic acid = 4.4 to 4.93).

[0047] For micellar compositions containing polyelectrolytes, the pH is preferably lower than the pK a of the side chains, such as pH < 4, especially < 3.5, and especially preferably approximately 3.2. At pH values of 3.2, the polymer side chains are predominantly uncharged, and the electrostatic Coulomb interaction within and between the polyelectrolyte molecules decreases progressively. As the pH increases, deprotonation of the carboxylic acid groups in the side chains occurs, which facilitates or even enables the release of the active ingredients ("uncoiling" or "defolding" of the spherical particles).

[0048] The pH value is preferably adjusted using natural acids such as citric acid, malic acid, etc. Additional components and parameters

[0049] A low content of proteins and glycoproteins can influence micelle formation. Proteins and glycoproteins found as accompanying substances in natural starting materials, such as polysaccharides, are preferred. For example, the small amounts of plant proteins contained in gum arabic improve the micelle formation of non-polar substances or even enable it in the first place. The protein content of the polysaccharide by mass is generally less than 5%, but usually at least 0.5%, preferably 1.5-2.5%.

[0050] Micelle formation may therefore depend on the active ingredients and / or the (usually low) content of plant proteins in the acacia species from which the gum arabic was obtained. The typically present one to two percent by mass of such proteins has proven particularly advantageous in stabilizing emulsions of fat-soluble active ingredients through micellization.

[0051] For the inclusion of different active ingredients of different polarity and molecular structure into the micelles, the thermodynamic aspects of the interaction of the individual substances involved in micelle formation are relevant, in particular the solvent water, the polyelectrolyte and / or the glycerol ester.

[0052] The sum of the changes in energetic and entropic components defines the free energy difference and thus the extent of micelle formation, as well as the thermodynamic stability of the micelles. The free energy change ΔG must be negative (ΔG = ΔH - TΔS).

[0053] The energetic components (ΔH) include the interactions of the hydrated protons or the alkali or alkaline earth ions with the basic carboxylate residues of arabic acid, as well as the interactions of the polar moieties and sub-regions of the polyelectrolytes, the glycerol esters, and, if applicable, the excipients with the active ingredients. Excipients include, for example, the plant proteins contained in natural gum arabic, but can also be other substances with emulsifying and / or dispersing properties.

[0054] Apolar parts of the glycerol esters and / or excipients interact preferentially with apolar active ingredients, since arabic acid - even in the uncharged state - does not contain any apolar molecular fragments.

[0055] The entropic fractions (ΔS) depend primarily on the number of free molecules. The free molecules also include the fractions of the solvent molecules involved in the reaction, such as water, as well as the polyelectrolytes and / or glycerol esters, any excipients, and the active ingredients.

[0056] In addition, entropic contributions from conformational changes in the polyelectrolyte can be important. It is assumed that the electrostatic field near the negatively charged carboxylate residues of bound glucuronic acid, in particular, induces local ordering of the polar water molecules, in addition to polarization and hydrogen bonding, resulting in a strong local decrease in the local dielectric constant relative to free water. Near these carboxylate residues, or more generally near charged residues of the polyelectrolyte, the various hydrated cations and polarizable molecules move under the influence of the local electric field of the charged polyelectrolyte.

[0057] The pKa values of the polyelectrolytes, together with the chosen pH conditions and the cations in the liquid phase, are essential for the global charge state of the molecular aggregates.

[0058] In free solution without ions, the size of the molecules, the temperature, the nature of the solvent and the dipole forces with their polarizing effect on the neighboring particles essentially determine the diffusion of all mixing partners.

[0059] For polyelectrolytes, it is assumed that their conformational change from a quasi-linear state to a quasi-spherical state, or the formation of aggregates to form micelles, is accompanied by the initial partial neutralization or shielding of the negative charge of the carboxylate groups in the side chains (glucuronic acid) by protons or cations, followed by the formation of intramolecular hydrogen bonds and, if necessary, hydrogen bonds with the active ingredients and / or with the glycerol esters. The conformational change from quasi-linear to quasi-spherical also causes the partial freezing of degrees of freedom of rotation in the main chain and, to some extent, in the numerous branched side chains of the polyelectrolyte. These processes are associated with a negative entropy change because the mobility of the particles is restricted.This negative entropy change is compensated by the predominantly negative enthalpy changes during the formation of new hydrogen bonds, so that the total free energy of all processes combined becomes negative. This is especially true if pressure and temperature are kept constant during formation.

[0060] The kinetics of protonation of carboxylates are rapid and diffusion-controlled. Conformational changes of the side chains are also rapid processes, whereas the conformational change of the long main chain of arabic acid takes more time.

[0061] If several polyelectrolytes, such as arabic acid chains or molecules with many polar groups, are involved in the formation of a micelle, the scope and extent of possible interactions among all substances involved increase.

[0062] The classification of polarity is based on the definition of the difference in electronegativity of the atoms involved in the chemical bond according to Pauling. Δ EN = difference in electronegativity) Table 1: ( Difference of EN values (Δ EN ) for the classification of the polarity of a bond D EN Binding type Character of the bond 0 nonpolar bond Electron pairs are used by both atomic nuclei with exactly the same intensity. No partial charge imbalance occurs. (no dipole) 0.1-0.4 weakly polar bond One atomic nucleus places slightly more strain on the electron pair than the other. Slight partial charge imbalance (symbolized by δ+. δ-) (weak dipole) 0.4-1.7 strongly polar bond One atomic nucleus places significantly more strain on the electron pair than the other. Thus, the partial charge distribution is strongly asymmetric. (strong dipole) > 1.7 Ionic bond There are no shared electron pairs. An atomic nucleus requires both electrons (ion formation; complete charge separation)

[0063] The interaction in polyelectrolytes, such as arabic acid, is long-range and occurs when positively charged ions are located between two negatively charged particles, thus inducing micelle formation or cluster formation of the polyelectrolytes. The same applies to molecules with many polar groups, such as cyclodextrins. As soon as a sufficient number of oppositely polar charge carriers are present, micelle formation occurs rapidly. Micelle formation involves multiply charged counterions, dipole-dipole forces, quadrupole interactions with the polyelectrolyte, hydrogen bond formation, and cation-π interactions of double bonds. The entire process can be described as the associative behavior of polyelectrolyte solutions.

[0064] The cluster-like micelle formation leaves behind quasi-empty spaces in the solvent, which are only occupied by molecules of the solvent but do not contain any ions, since these preferentially reside near the oppositely charged parts of the polyelectrolyte or dipoles.

[0065] While the above description primarily highlights essential aspects using arabic acid as an example, these also apply to other polyelectrolytes, in particular cyclodextrins, glycans, glycogens, glycolipids, and mixtures thereof. However, gum arabic and / or cyclodextrins are especially preferred.

[0066] The weight ratio of glycerol ester to polyelectrolyte can vary widely depending on the desired properties. Typically, more polysaccharide is used for an ionic / dipolar active ingredient compared to an apolar / uncharged active ingredient.

[0067] The ratio of the excipients, glycerol ester : polysaccharide, standardized to a sum of 100%, can vary from 1% : 99% to 99% : 1%, preferably from 10% : 90% to 90% : 10%, more preferably from 20% : 80% to 80% : 20%, in particular 25 ± 2% : 75 ± 2% or 50 ± 2% : 50 ± 2% or 75 ± 2% : 25 ± 2%, such as 25% : 75% or 50% : 50% or 75% : 25%. Active ingredients

[0068] The micelle-containing active ingredient compositions according to the invention can protect a wide variety of different active ingredients and transport them to the desired absorption or destination site. Virtually any active ingredient can be used as the active ingredient. However, due to their tolerability, active ingredients of natural origin or nature-identical synthetic substances, as well as substances whose biological-biochemical mode of action is identical to that of natural substances, are preferred.

[0069] The active ingredients can be ionic, polar, slightly polar or apolar and they can be salts, small molecules, monomeric natural products, oligomers, small peptides, proteins, oligonucleotides or polynucleotides.

[0070] A list of possible active substances that can be used individually or as a mixture of substances within a class of substances (in bold below) or as a mixture of substances from two or more of these classes of substances is attached below: amino acids, How Essential amino acids, e.g. Tryptophan (Hydroxytryptophan), L-Phenylalanine, L-Methionine, L-Lysine and / or conditionally essential amino acids, e.g. Glutamine, L-glutamic acid, L-cysteine, and / or L-ornithine and / or N-acetylcysteine; Natural fatty acids, such as essential fatty acids, e.g. linoleic acid, linolenic acid, omega-3 fatty acids, and / or mixtures of natural fatty acids: corn germ oil, wheat germ oil, and / or phospholipids and / or phosphatidylserine; Acids / bases,i.e. protonated and / or deprotonated known active ingredients with pharmacological activity, but other than natural fatty acids, amino acids or pH adjusting excipients; Peptides and oligopeptides, such as peptides and oligopeptides of human, plant or animal origin; Proteins, such as insulin, transferrin, ceruloplasmin, hemopexin, globulins, albumins, antibodies, e.g. monoclonal antibodies (biologics); DNA, RNA, such as oligonucleotides and / or polynucleotides of human, animal, bacterial or viral origin; Essential ionic substances, such as Chloride, sulfate, phosphate, iodide, carbonate, hydrogen carbonate, borate, (each with a physiologically acceptable cation, e.g. the corresponding Na salts), boric acid; Antioxidants, such as vitamin C and its salts, e.g. ascorbyl palmitate, ascorbyl stearate, vitamin E and its salts, e.g. tocopherols, tocopherol acetate, a-(R+)-lipoic acid and its racemate, glutathione, thiolactic acid, L-cysteine, carotenoids, e.g. lycopene, beta-carotene, lutein; Redox-active substances, such as reducing agents / oxidizing agents; Natural substances from plants: Polyphenols (resveratrol, flavonoids) curcumin, bromelain, papain, olibanum, artemisinin, Natural substances from other living organisms, microbes, algae, fungi and manufactured mixtures / extracts such as astaxanthin, lutein, zeaxanthin, choline, lecithin, canthaxanthin arbustin; Vitamins and modified vitamins, such as vitamin A (retinol), provitamin A, vitamin B complex and its derivatives, e.g. B1 (thiamine, B2 (riboflavin), B3 (niacin, nicotinamide, nicotinic acid), B4 (adenine, choline), B5 (pantothenic acid), B6 (pyridoxine), B7 (biotin), B8 (adenosine phosphate), B9 (folic acid), B11 (folic acid), B12 (cobalamin, methylcobalamin, cyanocobalamin, cobalamin, B15 (pangamic acid) B17 (amygdalin), vitamin C (ascorbic acid) and its salts, e.g. with Na, Mg, Ca, vitamin D, especially D3 (cholecalciferol), vitamin E (tocopherol), vitamins K, K1, K2, K3 vitamin P group (bioflavonoids), para-aminobenzoic acid (PABA); Essential minerals,such as sodium, potassium, magnesium, calcium, selenium, selenoproteins, selenite, selenate, iron, zinc, copper, manganese, cobalt, tin, chromium, nickel, vanadium, molybdenum, silicon, iodine, etc.; Natural substances, such as vitamin-like natural substances, polymeric natural substances, oligomeric natural substances, and monomers of natural substances, e.g. all sugars, inulin, beta-glucan, coenzyme Q10, L-carnitine, carnosine, creatine, taurine, orotic acid, choline, inositol; enzymes, such as amylases, pepsin, trypsin, chymotrypsin, cathepsin, chymosin, di-saccharidases (saccharase, malatase, lactase) lipases, proteases, peptidases, elastases, hydrolases, isomerases, ligases, lyases, oxidoreductases, transferases, superoxide dismutase, glutathione peroxidase, catalase; Hormones, like melatonin; neurotransmitters, such as serotonin; and substances from the above classes of substances labelled with radioactive isotopes and / or substances of these substances labelled with stable isotopes.

[0071] In one embodiment, the active ingredient composition according to the invention comprises various active ingredients, such as various natural substances. In this embodiment, the first type of micelles comprises a first active ingredient, and the second type of micelles comprises a second active ingredient. An example is the combination of at least two, preferably all four, of the following active ingredients: curcumin, olibanum, artemisinin, and vitamin C. The presence of vitamin C—in addition to its positive pharmaceutical effect—is also preferred for stabilization purposes due to its antioxidant effect.

[0072] The weight ratio of active ingredients to polysaccharide and / or glycerol ester can vary widely. In one embodiment, the loading of the micelles with one or more active ingredients is between 0.1% (w / w) and 90% (w / w). In another embodiment, the ratio is in the range of 4:1 to 1:4, preferably from 3:1 to 1:3, such as 2:1 to 1:2 (w / w). Production

[0073] The invention also relates to various processes for producing active ingredient compositions containing micelles.

[0074] A process for preparing a micellar phase or a micelle-containing dispersion comprising the following steps: Mixing all components and stirring them at a first temperature at which at least the polyelectrolytes and the glycerol esters are liquid for a predeterminable time, adding water, the water being heated to a second temperature corresponding to the first temperature minus a maximum of 15°C, and stirring at the second temperature for a predeterminable time to form the micellar phase or the micelle-containing dispersion.

[0075] A preferred method for preparing micelles containing active ingredient and polyelectrolyte comprises: a first step, in which at least one polysaccharide and optionally at least one glycerol ester are dried by mixing (in particular with stirring) and the at least one polysaccharide is then melted at a first temperature or dissolved by adding at least one glycerol ester, a second stepin which the active ingredient is added at the first temperature by mixing (in particular by stirring) and the micelle formation is prepared by waiting until the composition, which has become cloudy due to the addition of the active ingredient, becomes clear again, a third step, in which solvent, in particular water or an aqueous solution, preferably of a predetermined pH value, is added to the clear composition from the second step by mixing (in particular while stirring), whereupon self-regulating spherical shapes ("micelles") form.

[0076] A preferred polyelectrolyte for this process is a polysaccharide with carboxyl groups in side chains.

[0077] Also in this process, the water or aqueous solution added in the third step preferably has a second temperature which corresponds to the first temperature, ie the temperature of the composition from the second step, minus a maximum of 15°C.

[0078] Whether a micellar phase or a micelle-containing dispersion is obtained depends solely on the amount of water added. To produce a micellar phase, only the amount of water needed to form the micelles is added; typically, approximately 0.1% water by weight, based on the weight of the active ingredients and the polyelectrolyte and / or the glycerol ester, is sufficient. Furthermore, the water is largely evaporated due to the elevated temperature after the micelles have formed, resulting in a nearly dry micellar phase. This can be made fluid by moderately increasing the temperature (to approximately 40-50°C, such as 45°C), allowing it to be filled into capsules, for example.

[0079] For the preparation of a micelle-containing dispersion, a water quantity of approximately 20 to approximately 50 wt.% based on the weight of the micelles in the micelle-containing dispersion, in particular 30 to 40 wt.%, has been found to be preferred.

[0080] The process for producing a micellar phase or a micelle-containing dispersion can be carried out at ambient pressure. However, it has proven advantageous to carry out the production in a closed container and to allow a slight overpressure. Such an overpressure, generally < 5 bar, especially < 1 bar, reduces foam formation, shortens the production time, and often also improves homogeneity.

[0081] The composition according to the invention is produced by simply mixing two or more micellar phases and / or micellar dispersions, wherein the ionic strength, pH value and micelle size are advantageously of the same order of magnitude (i.e. + / - 10 of the respective parameter).

[0082] Drying in the first step is usually carried out by heating, optionally and preferably under vacuum. The polyelectrolyte-glycerol ester composition in the first step should be selected such that more polyelectrolyte is used for an ionic / dipolar active ingredient compared to an apolar / uncharged active ingredient. The temperature and gas pressure should preferably be selected such that the polyelectrolytes and glycerol esters are completely liquefied and at a constant temperature. In the second step, the composition is preferably degassed after addition of the active ingredient.

[0083] The water or aqueous solution added in the third step is preferably adjusted to a predetermined pH value. Preferably, the water or aqueous solution is adjusted to a second temperature corresponding to the first temperature, i.e., the temperature of the composition from the second step, minus a maximum of 15°C.

[0084] For micellar compositions containing polysaccharides, the pH is preferably lower than the pK a of the side chains, such as pH < 4, especially < 3.5, and especially preferably approximately 3.2. At pH values of 3.2, the polymer side chains are mostly uncharged, and the electrostatic Coulomb interaction within and between the polyelectrolyte molecules decreases progressively. As the pH increases, deprotonation of the carboxylic acid groups in the side chains occurs, which facilitates or even enables the release of the active ingredients.

[0085] It is assumed that micelle formation occurs upon addition of the solvent to energetically minimize the composition and that the polyelectrolytes and, if applicable, the glycerol esters thermodynamically stabilize the active ingredients in an ordered shell and seal them off from the surrounding solvent.

[0086] In a preferred embodiment of the manufacturing process, the temperature is kept approximately constant in all process steps, i.e. + / - 5°C or less.

[0087] If the active ingredient is sensitive to oxidation, the second and third stages can be carried out under inert gas.

[0088] The gas pressure above the reaction mixture can preferably vary between 0.5 bar and 2 bar. A typical gas pressure is between 0.8 and 1 bar. The temperature of the reaction mixture varies between 0°C and 100°C, typically 30°C to 95°C depending on the active ingredient. The type of gas or gas mixture, if used, is adapted to the substances involved in micelle formation and sometimes exerts a protective effect, particularly on the active ingredients. Common gases are inert gases such as N2 and Ar, but also CO2.

[0089] The following applies to the above-mentioned procedures: A micellar phase can be prepared by adding a quantity of water just sufficient for micelle formation, in particular approximately 0.1 wt.%. A micelle-containing dispersion can be prepared by adding a quantity of water of approximately 20 to approximately 50 wt.% based on the weight of the micelles, in particular 30 to 40 wt.%. The time required for mixing and stirring all components, or in steps 1 and 2, can be determined by determining the quality of the micelles after different lengths of time and extrapolating the times if necessary. The time required for micelle formation can be determined visually. The composition according to the invention can be produced by simply mixing two or more micellar phases and / or micellar dispersions, paying attention to the aforementioned parameters. Examples

[0090] The invention will now be explained by means of some Examples explained in more detail: Example 1: (Active ingredient combination + solubilization or micellization excipients):

[0091] Individual compositions were prepared from (i) 60 g curcumin, 60 g gum arabic and 40 g glycerol esters of wood resins (E 445) (ii) 30 g olibanum, 30 g gum arabic and 10 g glycerol esters of wood resins (E 445) (iii) 100 g vitamin C and 100 g gum arabic (iv) 20 g artemisinin, 100 g gum arabic and 50 g glycerol esters of wood resins (E 445)

[0092] The individual compositions were prepared by initially mixing all components and heating them to 105°C for 1 hour while stirring. A sufficient amount of water at 95°C was then added to each individual composition, allowing micelle formation. The individual compositions were then combined and mixed. The mixture was then diluted with water at 95°C to an active ingredient content of 21%. The reaction mixture was mixed for 5 minutes at 92°C, degassed at this temperature, and filtered to remove larger non-micellar structures. 1000 g of a stable dispersion was obtained.

[0093] This concentrated composition with 21% active ingredient combination was subsequently diluted to 1% active ingredient combination, 2.5% active ingredient combination, 5% active ingredient combination, and 10% active ingredient combination. The visual assessment (summary of the assessment of multiple samples) is shown in Table 2. Table 2: dilution assessment 1% clear / transparent, fast dissolving; 5 FTU 2,5% clear / transparent - opaque, fast dissolving; >5 FTU - 10 FTU 5% (preferred) clear / transparent - opaque, fast dissolving; <2 FTU - 5 FTU 10% clear-cloudy / opaque, fast dissolving; <5 FTU - 5 FTU FTU: Formacine turbidity units, measured at 860 nm, cf. ISO 7027.

[0094] Curcumin or (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-hepta-1,6-diene-3,5-dione is the main component of turmeric root extract, which contains curcumin as well as its derivatives (curcuminoids), typically in the following composition: curcumin (60%), demethoxycurcumin (25%), and bisdemethoxycurcumin (15%). The curcuminoids may be present together with sesquiterpenes such as turmerone (up to 30%), ar-turmerone (up to 25%), atlantone and zingiberene (up to 25%), and monoterpenes (cymene, 1,8-cineole, phellandrene, sabinene, and borneol).

[0095] Olibanum (Frankincense) is typically composed of: Approx. 15 to 16% resin acids, such as boswellic acids, lupanic acids and tirucallenic acids, at least 1% each of 3-O-acetyl-11-keto-β-boswellic acid (AKBA) and 11-keto-β-boswellic acid (KBA) Approx. 5-9% essential oils, such as alpha-thujene, beto-myrcene, p-cymene and methyl eugenol and up to 20% mucilage.

[0096] A fraction without mucilage is preferred. Ascorbic acid and its derivatives / precursors (vitamin C), L-(+)-ascorbic acid, (5R)-5-[(1S)-1,2-dihydroxyethyl], 3,4-dihydroxy-5-hydrofuran-2-one (IUPAC), 3-oxo-L-gulonic acid γ-lactone Artemisinin (3R,5aS,6R,8aS,9R,125,12aR)-Octahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one

[0097] In addition to or instead of the plant extracts used above, which contain a plurality of ingredients, the main ingredients (one or more) can also be used.

[0098] For the compositions listed above, especially those with 5% active ingredient mixture, anti-viral, anti-fungal and anti-bacterial effects were found in initial tests.

[0099] Example 2: Example 1 was repeated, but artemisinin extract was replaced with artemisinin isolate (HPLC purity > 99%). Antiviral, antifungal, and antibacterial effects were also observed in initial trials.

[0100] While preferred embodiments of the invention are described in this application, it is to be clearly understood that the invention is not limited thereto and may be embodied in other ways within the scope of the following claims.

Claims

1. Active ingredient composition containing micelles, wherein the micelle-containing active ingredient composition comprises at least two different types of micelles, preferably in an aqueous phase; and each type of micelle has a core - which predominantly contains the active ingredient - and a simple or complex shell - which contains auxiliary substances from the group of polyelectrolytes and / or glycerol esters - ; and each type of micelle has an optically determined mean geometric diameter d90 of 5 - 100 nm; and the first type of complex micelles: • contains at least one active substance, and • at least one polyelectrolyte selected from oligosaccharides and / or polysaccharides, and • contains at least one glycerol ester selected from fatty acid glycerol esters and / or glycerol esters of root resins; the second type of simple micelles: • contains at least one active substance, and either • at least one polyelectrolyte selected from oligosaccharides and / or polysaccharides, or • contains at least one glycerol ester selected from fatty acid glycerol esters and / or glycerol esters of root resins.

2. Active ingredient composition containing micelles according to claim 1, characterised in that • in each type of micelles, the active ingredient and the at least one glycerol ester and / or the at least one polyelectrolyte have similar physical-chemical properties; and / or • the ratio of first type to second type is in the range 1:99 to 99:1 (n / n) preferably 10:90 to 90:10, such as 2:1 to 1:2.

3. Active ingredient composition containing micelles according to claim 1 or 2, wherein micelles containing polar or ionic active ingredients contain > 50% by weight of polyelectrolyte, based on the total amount of polyelectrolyte and glycerol ester.

4. Active ingredient composition containing micelles according to one of the preceding claims, characterised in that the pH value • is below the pKa value of the polyelectrolyte, and • is below the pKa value of an active ingredient in deprotonated ionic form.

5. Active ingredient composition containing micelles according to one of the preceding claims, characterised in that the at least one polyelectrolyte is selected from the group comprising gum arabic, a fraction of gum arabic, in particular a fraction with an increased galacturonic acid content, cyclodextrin, glycans, glycogenes, glycolipids or a mixture of one or more of the said polyelectrolytes, but in particular gum arabic, cyclodextrins or a mixture thereof.

6. Active ingredient composition containing micelles according to one of the preceding claims, characterised in that • the polyelectrolyte is gum arabic or a fraction thereof, in particular with a pKa value of the side chains of 4.4 to 4.93, and • the pH is < 4, in particular < 3.5, especially preferably approx. 3.2.

7. Active ingredient composition containing micelles according to one of the preceding claims, characterised in that the at least one glycerol ester is selected from the group consisting of monoglycerides of fatty acids, diglycerides of fatty acids, monoglycerides of fatty acids and at least one further acid, diglycerides of fatty acids and a further acid, monoglycerides of root resins, diglycerides of root resins, monoglycerides of root resins and at least one further acid, diglycerides of root resins and a further acid and mixtures of one or more of the said glycerol esters, in particular monoglycerides of fatty acids, diglycerides of fatty acids, monoglycerides of fatty acids and at least one further acid, diglycerides of fatty acids and a further acid, the fatty acids preferably being natural fatty acids, and monoglycerides of root resins, diglycerides of root resins and mixtures of one or more of the said glycerol esters.

8. Active ingredient composition containing micelles according to one of the preceding claims, characterised in that the optically determined mean geometric diameter of the micelles d90is 10 nm - 30 nm.

9. Active ingredient composition containing micelles, according to one of the preceding claims, characterised in that the weight ratios of active ingredient(s) to the sum of polyelectrolyte and / or glycerol ester are in the range from 4:1 to 1:4.

10. active ingredient composition containing micelles according to one of the preceding claims, characterised in that the active ingredient(s) are selected from • from the group comprising oligopeptides, polypeptides, proteins (in particular proteins with less than 30 amino acids), and antibodies; or • selected from the group consisting of oligonucleotides and polynucleotides; or • from the group consisting of curcumin, olibanum, artemisinin and vitamin C and in particular containing or consisting of curcumin, olibanum, vitamin C and optionally artemisinin.

11. active ingredient composition containing micelles according to one of the preceding claims • for the treatment of viral, bacterial or fungal infections, especially viral infections; or • for the treatment of proliferative diseases, especially cancer.

12. Process for the preparation of a composition according to claim 1, comprising (A) Preparation of a type of micelles in the form of a micellar phase or a micellar dispersion comprising: a first step in which at least one polysaccharide and optionally at least one glycerol ester are dried with mixing and the at least one polysaccharide is subsequently melted at a first temperature or dissolved by addition of at least one glycerol ester, a second step in which the active ingredient is added at the first temperature and the micelle formation is prepared by waiting until the composition that has become cloudy due to the addition of the active ingredient becomes clear again, a third step in which solvent, in particular water or an aqueous solution, preferably of predetermined pH, is added to the clear composition from the second step with mixing, whereupon self-regulating spherical moulds are formed in the form of a micellar phase or micellar dispersion; and (B) mixing of two or more of these micellar phases and / or micellar dispersions.

13. The method according to claim 12, characterised in that in the first step (A), the drying is carried out by heating, optionally and preferably under vacuum, and / or the temperature and the gas pressure are selected such that the polyelectrolytes and / or glycerol esters are completely liquefied and at a constant temperature, and / or in the second step (A), the composition is degassed after addition of the active ingredient, and / or water or aqueous solution added in the third step (A) is previously adjusted to a specific pH value such that in deprotonated form the ionic active ingredient and polysaccharide are both predominantly protonated or deprotonated and / or the temperature of the water or aqueous solution is adjusted to a second temperature which corresponds to the first temperature, i.e. the temperature of the composition from the second step, minus a maximum of 15°C; and / or in step (B), the ionic strength, pH value and micelle size of said micellar phases and / or of said micellar dispersions are + / - 10 of the respective parameter.

14. A solid dosage form comprising a micelle-containing active ingredient composition according to any one of claims 1-11.

15. The solid dosage form according to claim 14, selected from coated tablets or capsules.