Oral dosage forms for the transmucosal administration of bioavailable micronutrients

Abstract

An oral dosage form for placement in the oral vestibule, under or on the tongue for the absorption of micronutrients, comprising a carrier matrix and an active ingredient composition, characterized in that the active ingredient composition comprises at least one form selected from (a) a nano-micronized form with a mean particle size of 50 to 1000 nm; (b) a liposomal form with a mean vesicle size of 50 to 500 nm based on phospholipids; (c) a nano-liposomal form comprising liposomes containing active substances, wherein the liposomes themselves are nano-micronized.

Description

[0001] The present invention relates to oral dosage forms for placement in the buccal vestibule, under the tongue (sublingual), or on the tongue for absorption of an active ingredient composition by humans. In particular, the invention relates to dosage forms designed as an oral pouch or as an orally disintegrating film (strip) containing vitamins, minerals, plant extracts, and functional excipients. These are in a galenically modified form to ensure significantly increased bioavailability and accelerated absorption (kinetics).

[0002] In modern nutritional science, sports medicine and supplementation, there is a steadily growing need for dosage forms that ensure high and reliable bioavailability of micronutrients while also enabling convenient, discreet and flexible application.

[0003] Classic oral dosage forms for dietary supplements are tablets, capsules, coated tablets, or powders that must be swallowed with liquid. However, these conventional forms are subject to significant physiological limitations that restrict their effectiveness: • First-pass effect: After ingestion and absorption in the small intestine, the active ingredients pass directly to the liver via the portal vein. There, many substances (e.g., certain vitamins, hormones, plant compounds such as curcumin or resveratrol) are metabolized to a considerable extent before they even reach the systemic circulation. This leads to a drastic reduction in the amount of the active ingredient actually available. • Gastrointestinal barriers: The variability of the pH value in the stomach (highly acidic) can destroy acid-sensitive active ingredients or alter their chemical structure. Furthermore, digestive enzymes in the stomach and small intestine break down proteins and complex molecules. • Delayed kinetics: The disintegration of the tablet, the release of the active ingredient, and the subsequent absorption in the intestine all take time. The maximum plasma concentration (peak) is often not reached for standard tablets until 60 to 120 minutes or even later. This is insufficient for applications requiring a rapid onset of action (e.g., energy boost before exercise, cognitive focus). • Variability of absorption: The filling state of the stomach and the composition of the food can massively influence the absorption rate, leading to unpredictable plasma levels.

[0004] As an alternative to swallowed medications, sublingual sprays, drops, or orally disintegrating tablets are available. These aim for absorption via the oral mucosa to bypass the first-pass effect. The oral mucosa is highly vascularized and allows direct access to the systemic circulation via the jugular vein. However, these liquid or rapidly disintegrating forms have the disadvantage that the contact time (retention time) with the mucosa is often too short. A significant portion of the liquid is inevitably transported to the stomach by the swallowing reflex, thus partially negating the benefit of transmucosal absorption. Furthermore, the dosage of sprays is often imprecise.

[0005] Oral pouches are also known from the state of the art, which originally come from the tobacco sector (snus, nicotine pouches), but are increasingly being adapted for other applications.

[0006] EP 4 111 870 A1 discloses an oral pouch containing caffeine and taurine, designed to act as an "energy pouch." The patent describes the delivery of stimulants and the mechanical properties and arrangement of the nonwoven fabric (compacting, embossing) for controlling the release kinetics. While the bypass of gastric acid is mentioned, it lacks a explanation of how poorly soluble or more complex molecules (other than the highly water-soluble substances caffeine and taurine) can be efficiently transported through the mucosa. The described granules are of a conventional nature.

[0007] German patent DE 10 2023 002 534 A1 discloses oral pouches that are free of nicotine, CBD, and tobacco and contain various mixtures of vitamins (B vitamins, vitamin C), caffeine, plant extracts (ginkgo, ashwagandha), or amino acids. The disclosed pouches are intended to enable the delivery of specific combinations of active ingredients while adhering to regulatory requirements (WADA Prohibited List, anti-doping status). Galenic measures for actively increasing bioavailability beyond the mere selection of the pouch dosage form, such as particle size reduction or encapsulation, are not disclosed in detail.

[0008] US 2021 / 0177738 A1 describes oral products with high moisture content and fillers that may contain botanical materials. Here, too, the macroscopic product properties are paramount, not the microscopic formulation of the active ingredients for permeation enhancement.

[0009] A general problem with the use of pouches for dietary supplements is that the oral mucosa presents an effective barrier. Many vitamins (especially fat-soluble ones like vitamins D3, E, and K2) and plant compounds are hydrophobic and dissolve poorly in aqueous saliva. Others are too large in molecular weight to passively diffuse through the epithelium. Simply placing standard vitamin powders in a pouch therefore often fails to achieve the desired increase in bioavailability, as the active ingredient is released but does not penetrate the mucosa sufficiently and is ultimately swallowed.

[0010] The present invention therefore aims to provide an oral dosage form of the type mentioned above that overcomes the disadvantages of the prior art. In particular, a dosage form is to be created that: a) enables a significantly increased bioavailability of micronutrients, going beyond simply avoiding the first-pass effect; b) ensures an accelerated influx (kinetics) of the active substances into the bloodstream; c) also makes it possible to efficiently administer poorly water-soluble (lipophilic) active substances transmucosally; d) is physiologically harmless and its components can be completely and safely digested in the event of accidental ingestion.

[0011] This problem is solved according to the invention by providing an oral dosage form for placement in the oral vestibule, under or on the tongue for the absorption of micronutrients, comprising a carrier matrix and an active ingredient composition, characterized in that the active ingredient composition comprises at least one form selected from: (a) a nano-micronized form with a mean particle size of 50 to 1000 nm; (b) a liposomal form with a mean vesicle size of 50 to 500 nm based on phospholipids; (c) a nano-liposomal form comprising liposomes containing active substances, wherein the liposomes themselves are nano-micronized.

[0012] The essential aspect of the invention is that the active ingredient composition is present in a galenically modified form to maximize solubility and permeability. The common inventive concept lies in the combination of this specific active ingredient formulation with a carrier matrix optimized for transmucosal absorption, which is designed either as a permeable pouch or as an orally disintegrating film (strip).

[0013] This specific selection of dosage forms at the nanoscopic level massively increases the effective surface area of ​​the active ingredients (nano-micronization) or ensures their solubility and transportability in the aqueous environment through encapsulation (liposomes). This makes it possible to optimally utilize the short residence time in the mouth (typically 5 to 15 minutes for pouches, seconds to minutes for strips) for drug delivery.

[0014] The present invention utilizes advanced galenic methods to modify the physicochemical properties of the micronutrients so that they can overcome the oral mucosal barrier.

[0015] A. Nano-micronization: In this process, vitamins, minerals, or plant extracts, which are normally present as coarse crystals or powders with particle sizes in the micrometer range (typically 50–500 µm), are reduced to an average particle size of 50 to 1000 nm, preferably 100 to 500 nm. According to the Noyes-Whitney equation, the reduction in particle size leads to an exponential increase in the specific surface area. This increases the solubility rate in the salivary film. Since only dissolved substances can pass through the mucosa, the solubility rate is often the rate-limiting step. Nanoparticles also possess a higher saturation solubility and, due to their small size, can more easily penetrate the paracellular spaces of the epithelium or be absorbed by endocytosis.

[0016] Nano-micronization can be carried out using various methods (“top-down” or “bottom-up”): • Wet milling (media milling / bead milling): In this process, a suspension of the active ingredient in a carrier liquid (e.g., water, ethanol, or oil) is milled with grinding beads (e.g., made of zirconium oxide) in a stirred ball mill under high shear forces until the desired nanosize is achieved. The suspension can then be dried (e.g., spray-dried) to obtain a powder for the sachet. • High-pressure homogenization: A coarse suspension is forced through a narrow gap under extremely high pressure (up to 1500 bar). Cavitation, shear, and collision break down the particles. • Spray drying of nanosuspensions: A previously prepared nanosuspension is sprayed in a hot gas stream to obtain fine, nanostructured solid particles.

[0017] This technology is particularly suitable for poorly water-soluble vitamins (e.g., vitamin D3, E) and minerals (e.g., magnesium oxide, zinc oxide) in order to significantly increase their bioavailability.

[0018] B. Liposomal Form: Lipophilic (fat-soluble) active ingredients are enclosed in vesicles consisting of one or more phospholipid bilayers. According to the invention, the average size of these vesicles is between 50 and 500 nm. Due to their amphiphilic character (hydrophilic head, lipophilic tail of the phospholipids), liposomes are able to transport both water- and fat-soluble substances. In the context of the present invention, they primarily serve to solubilize lipophilic active ingredients (such as omega-3 fatty acids, curcumin, vitamin K2) in the aqueous environment of saliva and to protect them from oxidation or enzymatic degradation. Crucially, however, they interact with the oral mucosa: The phospholipids of the liposome membrane are very similar to the lipids of human cell membranes.This allows the liposomes to fuse with the epithelial cells of the mucous membrane or facilitates lipid exchange, thereby delivering the active ingredient directly into the cell.

[0019] Suitable manufacturing processes according to the invention include, for example: • Thin-film hydration method: Phospholipids and the lipophilic active ingredient are dissolved in an organic solvent. The solvent is evaporated, resulting in a thin lipid film. This film is then rehydrated with an aqueous phase, forming multilamellar vesicles. Subsequent extrusion through polycarbonate filters or ultrasonic treatment (sonication) reduces these vesicles to unilamellar vesicles of the desired size (50–500 nm). • Ethanol injection: An ethanolic solution of the lipids / active ingredients is rapidly injected into an aqueous phase, resulting in the spontaneous formation of small unilamellar vesicles. • High-pressure homogenization: Here too, liposomes can be standardized in size by shearing and pressure.

[0020] Phospholipids preferably used are phosphatidylcholine from soy, sunflowers or rapeseed (lecithin).

[0021] C. Nano-Liposomal Form This represents a further development of the invention and the preferred embodiment of the present invention, in which already formed, drug-loaded liposomes are subjected to a further process step of micronization (e.g., high-pressure homogenization) to achieve an extremely homogeneous distribution and particle size in the lower nano range (e.g., <100 nm). These “nano-liposomes” exhibit even higher stability and penetration capability than conventional liposomes. In detail, the production of the “nano-liposomes” preferably takes place in two stages: First, standard liposomes (size 200–500 nm) are loaded with the drug. In a second step, this liposome suspension is subjected to high-pressure microfluidization. Here, the suspension is forced through interaction chambers with a defined geometry under pressures of up to 2000 bar.The extreme shear forces and impact energies lead to fragmentation and immediate reformation of the lipid bilayers into extremely small, monodisperse vesicles (SUVs – Small Unilamellar Vesicles). These nanoliposomes are characterized by a particularly favorable surface-to-volume ratio, which maximizes the contact area with the mucosa and accelerates fusion with cell membranes. Furthermore, due to their small size, these particles can more easily penetrate the deep crypts of the oral mucosa, where they are protected from removal by saliva. embodiments of the support matrix

[0022] The active ingredient composition according to the invention can be in two preferred embodiments, both of which aim to deliver the active ingredients specifically to the oral mucosa:

[0023] 1. Oral Pouch In this embodiment, the carrier matrix is ​​a saliva-permeable pouch shell enclosing a powdered or granulated filling of the active ingredients. This form is particularly suitable for delayed release (slow release) over a period of 5 to 30 minutes. A crucial aspect is product safety. Since the pouch is used in the oral cavity, there is a theoretical risk of accidental ingestion (e.g., during sports, laughing, or coughing). The present invention therefore provides pouch shells that are not only saliva-permeable and mechanically stable, but also completely biocompatible and digestible or biodegradable in the gastrointestinal tract without leaving toxic residues. In addition to the cellulose fibers known from the prior art (e.g., viscose, lyocell), which are excreted as dietary fiber, the following easily digestible alternatives are suitable according to the invention: • Alginate fleeces or films: Alginate is obtained from brown algae. Nonwovens or perforated films made of calcium alginate are stable in the neutral environment of the mouth, but dissolve in the acidic environment of the stomach or through ion exchange in the intestines and are metabolized as a harmless dietary fiber. • Corn starch fabric (PLA): Polylactides (PLA) based on fermented corn starch can be spun into fine nonwovens. PLA is biocompatible and hydrolyzes in the body to lactic acid, a natural metabolic product. • Pullulan films: Pullulan is a water-soluble polysaccharide obtained through fermentation. It forms thin, transparent, edible films that are impermeable to oxygen (protecting the active ingredients) but soluble in water. By cross-linking or combining it with other polymers, the dissolution time in the mouth can be adjusted so that the sachet remains stable for 10-15 minutes but dissolves immediately in the stomach. • Hemp or cotton fibers: In unbleached organic quality. These natural fibers are mechanically very stable, tasteless, and, if swallowed, can be considered harmless plant fibers. • Combinations / hybrids: E.g. a cellulose fleece coated with a thin layer of alginate or pectin to control the pore size.

[0024] All materials mentioned are food-grade and free from synthetic plastics (such as PP, PE), microplastics or bleaching agents.

[0025] 2. Orally Disintegrating Film (Vitamin Strip / Oral Thin Film) In this embodiment, the active ingredient composition is directly embedded in a thin, film-forming polymer matrix that dissolves upon contact with saliva in the mouth. This form is particularly suitable for rapid release and applications where a lower dosage is sufficient or discreet administration is desired. The strips typically dissolve completely within seconds to a few minutes, releasing the active ingredients for direct absorption through the oral mucosa.

[0026] Properties and materials: The matrix of the strips consists of hydrophilic polymers that quickly decompose or dissolve in water (saliva). Suitable materials according to the invention are: • Pullulan: A microbial polysaccharide with excellent film-forming properties, transparent and extremely fast dissolving. It is tasteless and protects sensitive active ingredients from oxidation. • Hydroxypropylmethylcellulose (HPMC): A cellulose derivative frequently used in pharmaceutical films. The dissolution rate can be controlled by varying the molecular weight. • Starch (e.g. cornstarch, potato starch) and modified starches: These are inexpensive and easily digestible. • Pectin: A plant polysaccharide (e.g. from apples or citrus fruits) that also has good film-forming properties. • Sodium alginate: As with the pouch material, but formulated here as a soluble matrix.

[0027] Additionally, the strips contain plasticizers (e.g. glycerin, sorbitol, propylene glycol) to ensure the film's flexibility and break resistance, as well as sweeteners and flavorings for taste masking.

[0028] Production of the strips: The strips are preferably manufactured using the "solvent casting" process: 1. The active ingredients (in nano-micronized or liposomal form), bioenhancers and enzymes are dispersed or dissolved in an aqueous solution of the polymers and plasticizers. 2. The viscous mass is degassed to remove air bubbles. 3. The mixture is spread as a thin film onto a carrier film using a squeegee. 4. The film is dried in a controlled manner in a drying tunnel to remove the solvent (water). 5. The dried film is cut into the desired size (e.g. 2x3 cm) and packaged.

[0029] The technologies according to the invention (nano, liposomal, bioenhancer, enzymes) are also used in the strips to ensure that the active ingredients are efficiently absorbed during the short contact time in the mouth.

[0030] To further increase the absorption of the (nano / liposomal) active ingredients, a preferred embodiment of the invention provides for the addition of absorption enhancers. These substances modulate the barrier function of the mucosa or inhibit mechanisms that hinder drug transport.

[0031] How absorption enhancers work: • Increased membrane fluidity: Certain substances can be incorporated into the lipid bilayer of epithelial cells, making them more permeable. • Inhibition of efflux pumps: Transporters such as P-glycoprotein (P-gp) actively pump foreign substances out of the cell. Inhibition of these pumps increases the intracellular concentration of the drug. • Inhibition of metabolizing enzymes: Enzymes such as CYP3A4 in the intestinal wall or liver (and to a lesser extent in the oral mucosa) break down active substances. Their inhibition prolongs the half-life. • Thermogenesis / blood flow: Increased blood flow to the mucous membrane accelerates the removal of absorbed substances into the blood, thus maintaining the concentration gradient.

[0032] Inventive absorption amplifiers: • Piperine: An alkaloid from black pepper (Piper nigrum). It is the most potent known natural bioenhancer. It inhibits P-glycoprotein and CYP enzymes and increases the bioavailability of substances such as curcumin, coenzyme Q10, and vitamins by up to 2000%. An extract with a piperine content of >90% is preferred, in amounts of 0.5 to 25 mg per sachet. • Capsaicin: From chili peppers (Capsicum). It massively promotes local blood flow to the mucous membrane (vasodilation) and thus increases the absorption rate. • Gingerols / Shogaols: From ginger. They promote permeability and stimulate saliva production. • Quercetin and resveratrol: These plant polyphenols can also inhibit efflux pumps and act synergistically with other active ingredients. • Naringin: A flavonoid from grapefruit, known for inhibiting CYP3A4. • Lysophosphatidylcholine: A naturally occurring phospholipid (e.g., from lecithin through enzymatic cleavage) that acts as a strong permeation mediator by temporarily loosening the membrane structure.

[0033] Another innovative aspect of the present invention is the addition of enzymes to the drug matrix. These enzymes fulfill two functions: Firstly, they support the release of the active ingredients from the matrix in the pouch. Secondly, they can modify the mucus layer on the oral mucosa. Mucus consists of glycoproteins (mucins) that form a viscous network and can hinder the diffusion of particles. Proteolytic enzymes can locally reduce the viscosity of this mucus, thereby facilitating and accelerating diffusion to the epithelial surface.

[0034] Suitable enzymes and their extraction: • Bromelain: A mixture of proteolytic enzymes from the stem of the pineapple (Ananas comosus). Extraction: Aqueous extraction from the fruit stems, followed by purification (ultrafiltration) and freeze-drying. It is anti-inflammatory and well-tolerated by mucous membranes. • Papain: A cysteine ​​protease from the latex of the green papaya tree (Carica papaya). Extraction: Incisions are made in the unripe fruit, the latex is collected, dried, and purified. It has protein-splitting properties. • Fungal amylases and lipases: These enzymes break down carbohydrates and fats, respectively. They aid in the dissolution of the carrier matrix in the pouch. Production: Biotechnologically through fermentation of fungal cultures such as Aspergillus oryzae or Rhizopus species on nutrient media (e.g., rice, soy), followed by extraction and purification. • Serrapeptase: A potent proteolytic enzyme, originally from silkworms. Production: Today, it is mostly obtained through the fermentation of Serratia bacteria (e.g., Serratia marcescens E-15). It has a strong mucolytic effect and can significantly improve permeation through the mucus layer. • Nattokinase: A fibrinolytic enzyme from fermented soybeans (natto). Production: Fermentation with Bacillus subtilis var. natto.

[0035] While each of the aforementioned technologies (nano, liposomal, bioenhancer, enzyme) offers advantages on its own, the core of the invention lies in providing a combination that leads to a surprising, synergistic effect. In a particularly preferred embodiment, the oral pouch or orally disintegrating film therefore comprises an active ingredient matrix that combines the five aforementioned technologies: • Sachet application: Keeps the active ingredients at the site of absorption (retention time) and prevents immediate swallowing. • Nano-micronization: Maximizes the dissolution rate of hydrophilic components. • Liposomal encapsulation: Protects and solubilizes the lipophilic components and enables membrane fusion. • Enzymes: Reduce the viscosity of the mucus barrier on the mucous membrane, allowing the nanoparticles and liposomes to diffuse more quickly to the epithelial surface. • Absorption enhancers (e.g., piperine): Open the cellular gates (increase membrane fluidity, inhibit efflux) as soon as the active substances reach the epithelial surface.

[0036] This combination results in absorption kinetics that significantly surpass those of conventional dosage forms. Internal tests have shown that the combination of these factors can increase bioavailability by a factor of 2.5 compared to the calculated sum of the individual effects. Application examples and formulations

[0037] The following formulation examples illustrate the invention without limiting it to these applications. The invention can be adapted modularly to various fields of application (indications). The quantities given refer to the filling of a single pouch (total weight typically 400 to 1000 mg). For the strip formulation, the quantities can be reduced proportionally (e.g., to 1 / 2 to 1 / 10 of the pouch dose), since the strips typically have a lower total weight (e.g., 50–200 mg).

[0038] In a particularly preferred embodiment of the invention as a pouch, the filled pouch has a total weight of exactly 1.0 gram (1000 mg). This standardization to 1 gram is technically and application-oriented advantageous for several reasons: Firstly, it enables precise dosing and scalability of the active ingredients in relation to the matrix. Secondly, this weight represents an optimal volume that can be comfortably placed in the oral vestibule without being perceived as a bothersome foreign body (oral sensation), while still providing sufficient surface area for transmucosal absorption. Furthermore, a standard weight of 1000 mg significantly simplifies the setup of filling machines in industrial production.

[0039] To achieve this target weight of 1000 mg per pouch and to ensure homogeneous distribution of the active ingredients, each pouch contains, in addition to the active ingredients listed below, a matrix of inactive excipients (fillers). This filler matrix preferably consists of: cellulose powder (as the main filler), maltitol (as a filler and sweetener), potassium sorbate (as a preservative), sodium bicarbonate (for pH regulation), sucralose (as a sweetener), sodium alginate (as a binder and for texturizing), vegetable oil (as a carrier for lipophilic components), propylene glycol (PG, as a humectant), and flavorings for taste.

[0040] The following recipe examples illustrate the invention without limiting it to: The following examples list the compositions of active ingredient complexes, which are supplemented to a total weight of 1000 mg each by the above-mentioned filler matrix: 1. FLOW EVERYDAY • Algae Oil (algae oil concentrate, 70% DHA+EPA): 480 mg (in phospholipid-enriched, lecithin-supported liposomal dispersion) • Magnesium (magnesium bisglycinate chelate): 30 mg (equivalent to 4.2 mg elemental Mg) • Zinc (zinc bisglycinate chelate): 6 mg (equivalent to 1.2 mg elemental Zn) • Bromelain (2400 GDU / g): 10 mg • Piperine (BioPerine®): 5 mg • Vitamin D3 (cholecalciferol): 0.5 mg (800 IU) (microencapsulated, liposomal compatible) • Vitamin K2 (MenaQ7® MK-7, trans): 0.1 mg (100 µg) • L-5-MTHF (Metafolin® / L-5-Methylfolate Calcium): 0.2 mg (200 µg) • Methylcobalamin (Vitamin B12): 0.02 mg (20 µg) • Pyridoxal 5-phosphate (B6): 0.9 mg • L-Selenomethionine: 0.045 mg (45 µg) • Potassium iodide (iodine): 0.197 mg (150 µg l) 2. FLOW ENERGY • Panax Ginseng extract (standardized to 20% ginsenosides): 200 mg • Rhodiola rosea extract (3% rosavins / ≥1% salidrosides): 150 mg • CoQ10 (ubiquinone): 60 mg (liposomal, ubiquinone microdispersion) • Calcium pantothenate (B5): 50 mg • Cayenne powder (2% capsaicinoids): 20 mg • Bromelain (2400 GDU / g): 15 mg • Piperine (BioPerine®): 8 mg • Thiamine HCI (B1): 12 mg • Amylase (3000 SKB / g): 10 mg • Methylcobalamin (B12): 0.1 mg (100 µg) 3. FLOW FOCUS • Alpha-GPC (L-alpha-glycerylphosphorylcholine, 40-50% choline): 200 mg (granules) • L-Theanine: 80 mg • L-Tyrosine: 60 mg • Bacopa Monnieri extract (50% bacosides, full spectrum): 50 mg • Lion's Mane (Hericium erinaceus, fruiting body extract, 30% polysaccharides): 40 mg • Phosphatidylserine (from sunflowers, 20% phosphatidylserine): 15 mg (liposomal compatible) • Niacinamide (nicotinamide, non-flush): 30 mg • Protease (60,000 HUT / g): 5 mg • Piperine (BioPerine®): 8 mg 4. FLOW METABOLISM • Green tea extract (decaffeinated, 50% EGCG): 250 mg • Green coffee bean extract (45% chlorogenic acid, decaffeinated): 150 mg • L-Carnitine L-Tartrate (68% L-Carnitine): 50 mg • Cayenne powder (2% capsaicinoids): 20 mg • Lipase (10,000 FIP / g): 30 mg • Coleus Forskohlii Extract (10% Forskolin): 20 mg • Piperine (BioPerine®): 10 mg • Chromium picolinate (12% Cr): 0.6 mg (approx. 72 µg Cr) 5. FLOW RECOVERY • Montmorency tart cherry extract (5% anthocyanins): 200 mg • Ashwagandha (KSM-66, 5% withanolides): 200 mg • L-Theanine: 20 mg • Magnesium bisglycinate (14% elemental): 12 mg elemental • Taurine: 10 mg • Apigenin (98%): 6 mg • Papain (6000 USP / mg): 5 mg • Piperine: 10 mg 6. FLOW PUMP • Beetroot extract (standardized to 10% nitrates): 250 mg • Pine bark extract (Pinus pinaster, 95% OPC): 120 mg • Agmatine sulfate (98%): 60 mg • Vitamin C (ascorbic acid, microencapsulated / liposomal compatible): 40 mg • L-Norvaline: 30 mg • Hesperidin (90%): 20 mg • Bromelain (2400 GDU / g): 20 mg • Piperine: 8 mg

[0041] Another object of the present invention is the use of an active ingredient composition in an oral dosage form according to the invention for dietary supplementation.

[0042] With regard to all relative or percentage weight-related quantities mentioned above or below, it must be noted that these must be selected within the context of the preparations according to the invention in such a way that, in total, they always add up to 100% or 100% by weight in the preparation according to the invention, including all components, ingredients, additives, constituents, or excipients. This, however, is self-evident to those skilled in the art.

[0043] Furthermore, it should be noted that the person skilled in the art may deviate from the following numerical, range, weight and quantity specifications depending on the application or the specific case, without departing from the scope of the present invention.

[0044] It is also self-evident that embodiments, designs, advantages and the like, which are listed below for the purpose of avoiding repetition only with regard to one aspect of the invention, also apply accordingly to the other aspects of the invention. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature

[0000] EP 4 111 870 A1

[0006] DE 10 2023 002 534 A1

[0007] US 2021 / 0177738 A1

[0008]

Claims

An oral dosage form for placement in the oral vestibule, under or on the tongue for the absorption of micronutrients, comprising a carrier matrix and an active ingredient composition, characterized in that the active ingredient composition comprises at least one form selected from (a) a nano-micronized form with a mean particle size of 50 to 1000 nm; (b) a liposomal form with a mean vesicle size of 50 to 500 nm based on phospholipids; (c) a nano-liposomal form comprising liposomes containing active ingredients, wherein the liposomes themselves are nano-micronized. Oral dosage form according to claim 1, characterized in that the carrier matrix is ​​designed as an oral pouch, comprising a saliva-permeable pouch shell enclosing the active ingredient composition as a filling, and the pouch shell is preferably formed from a material selected from the group consisting of cellulose fibers, alginate, maize starch (polylactide / PLA), pullulan, hemp fibers, cotton fibers or combinations thereof, wherein the material is physiologically safe, non-toxic and completely digestible or biodegradable in the gastrointestinal tract. Oral dosage form according to claim 1, characterized in that the carrier matrix is ​​designed as an orally disintegrating film (strip), wherein the active ingredient composition is embedded in a film-forming polymer matrix which dissolves upon contact with saliva. Oral dosage form according to claim 3, characterized in that the film-forming polymer matrix comprises at least one polymer selected from the group consisting of pullulan, hydroxypropyl methylcellulose (HPMC), starch, modified starch, pectin, sodium alginate and gelatin. Oral dosage form according to one of the preceding claims, characterized in that the active ingredient composition additionally contains at least one absorption enhancer selected from the group consisting of piperine (extract from Piper nigrum), capsaicin, gingerols, shogaols, quercetin, resveratrol, naringin and lysophosphatidylcholine, particularly preferably an extract of black pepper with a piperine content of at least 90%, preferably 95%. Oral dosage form according to one of the preceding claims, characterized in that the active ingredient composition additionally contains at least one enzyme selected from the group consisting of bromelain, papain, fungal amylases, fungal lipases, serrapeptase and nattokinase. An oral dosage form according to any of the preceding claims, characterized in that the active ingredient composition comprises a synergistic combination of: (i) vitamins or minerals in nano-micronized form according to claim 1(a); (ii) lipophilic active ingredients in liposomal form according to claim 1(b); (iii) an absorption enhancer according to claim 5; and (iv) an enzyme according to claim 6. Oral dosage form according to one of the preceding claims, characterized in that the nano-micronized form is produced by wet milling (media milling), high-pressure homogenization, controlled precipitation or spray drying of a nanosuspension. Oral dosage form according to one of the preceding claims, characterized in that the liposomal form is produced by thin-layer hydration, ethanol injection or high-pressure homogenization and contains as a lipophilic active ingredient omega-3 fatty acids, vitamin D3, vitamin K2, vitamin E, curcumin, coenzyme Q10, cannabinoids or combinations thereof. Use of an active ingredient composition in an oral dosage form, as described in any one of claims 1 to 9, for dietary supplementation.