Novel compositions for oral or nasal use

Abstract

A composition for use in the oral or nasal cavity is disclosed. The composition includes a biologically active substance, a matrix-forming agent including β-glucan, and a filler. The composition can further include additional additives such as antioxidants, preservatives, taste or flavor enhancers, pH adjusters, plasticizers, and sweeteners. Methods for producing the composition are also disclosed.

Description

[Technical Field]

[0001] The present invention relates to compositions for use in the oral or nasal cavity comprising a biologically active substance, a matrix-forming agent comprising cereal β-glucan, and a filler, and to methods of making said compositions. [Background technology]

[0002] The delivery of pharmaceutically active substances to the oral cavity and nasal cavity is generally a desirable administration route to obtain a rapid therapeutic onset and avoid the metabolic activity and first-pass metabolism of the gastrointestinal system.A number of solid dosage forms, such as lozenges, sublingual tablets, chewing gums, buccal patches or pouches, have been developed to obtain a suitable dosage form for patients in response to treatment through the oral cavity.Such solid dosage forms typically include active substances, fillers, binders, lubricants, and other ingredients that support mucoadhesion, palatability, compliance, and the release of active substances.

[0003] Suppliers and developers of smokeless tobacco and nicotine products have developed numerous products designed to deliver nicotine through the oral or nasal cavity. Tobacco products include, for example, chewing tobacco, moist smokeless tobacco, snus, and dry snuff, which are used orally or nasally. Non-tobacco products rely on pure nicotine extracted from tobacco or synthetic nicotine formulated with additives suitable for oral or nasal dosage forms, as exemplified. Non-tobacco dosage forms for oral use may rely, for example, on fibrous filler materials and matrix-forming agents that act as binders. Nicotine (3-(1-methyl-2-pyrrolidinyl)pyridine) is a volatile compound that is susceptible to decomposition under the influence of heat, oxygen, and light. Therefore, it is a technical challenge to find a suitable non-tobacco dosage form that allows a desirable release rate of nicotine in the oral cavity while counteracting its degradation during its manufacture, providing adequate storage stability of nicotine, and providing a user-friendly product. For these reasons, developers of nicotine dosage forms are looking for new agents that can replace tobacco but that also support a long shelf life, a desirable release profile, and high consumer compliance.

[0004] WO2010 / 011445 discloses a vegetable fiber product for oral use suitable for the delivery of active substances such as nicotine. The incorporation of alginate as a matrix-forming agent provides the product with desirable release characteristics and adequate stabilization of the liable active substance.

[0005] WO2010 / 104464 discloses particles of alginate containing an active substance such as nicotine enclosed in a pouch for use in the oral cavity.

[0006] WO2015 / 051308 and US2015 / 0098996 disclose tobacco or nicotine lozenges containing at least 40% by weight of water-soluble fiber, primarily maltodextrin, and less than 15% water, but do not disclose anything about the shelf life of the nicotine or the release characteristics of the nicotine in the oral cavity.

[0007] EP 1622627 describes a pharmaceutical composition containing cereal β-glucan and a pharmaceutical agent, which is proposed for use in the oral cavity to deliver drugs such as local anesthetics. However, since no such product was manufactured or actually tested in this document, it is not possible to conclude whether cereal β-glucan is a suitable additive for the delivery of liable active substances to the oral or nasal cavity.

[0008] US2010 / 158988 describes an orally consumable dry dissolvable film or coating based on cereal beta-glucan, which may contain up to 10% (by weight) of a filler. However, the film does not demonstrate any indication as a nicotine product suitable for delivering nicotine to the oral or nasal cavity. EP1790687 describes a similar dry film that may contain nicotine, but does not teach a nicotine dosage form with consumer compliance similar to that of conventional tobacco products.

[0009] WO2010091649 relates to tobacco-free nicotine products for oral use and therefore describes pH values, but does not disclose how to affect the stability and release of nicotine using purposefully selected support agents.

[0010] CN10707494 discloses a chewing gum comprising a gum matrix, β-glucan, a sweetener, and cellulose lecithin as an active substance.

[0011] CN104784197 discloses a composition specific for delivering the active substance epigallocatechin gallate, which contains β-glucan.

[0012] US6499490 discloses a tobacco substitute sheet material comprising β-glucan and leaf tobacco extract. Summary of the Invention [Problem to be solved by the invention]

[0013] It is an object of the present invention to provide a composition suitable for delivering a biologically active agent to the oral or nasal cavity that allows for a suitable release profile of the agent while allowing for stability of the active agent throughout manufacture and storage.

[0014] It is also an object of the present invention to provide a composition that supports a controlled release rate of an active substance and an appropriate duration of the release rate.

[0015] It is also an object of the present invention to provide a composition that promotes stabilization of active substances that are susceptible to degradation during storage, resulting in a stable product with a long shelf life, even in compositions with a relatively high moisture content.

[0016] It is also an object of the present invention to provide a composition that has high compliance with the mucous membranes of the oral or nasal cavity to avoid local irritation and side effects due to repeated or prolonged exposure.

[0017] It is yet another object of the present invention to provide a composition suitable for delivering nicotine to the oral or nasal cavity, thereby meeting user expectations of parity and compliance with conventional tobacco products or pharmaceuticals. [Means for solving the problem]

[0018] In a general aspect, the present invention relates to a composition for use in the oral or nasal cavity comprising a biologically active substance, a matrix-forming agent comprising β-glucan, and a filler.

[0019] In the present invention, the matrix-forming agent, together with the filler, can provide a cohesive and homogeneous composition that encapsulates the biologically active substance and contributes to a controllable and desirable release profile of the active substance upon contact with the oral or nasal cavity, while exerting a stabilizing effect on susceptible drugs. In one aspect, the stabilizing effect and release profile can be caused by an interaction or synergism with the filler (e.g., between the matrix-forming agent and the filler fibers). Thus, in the compositions of the present invention, the interaction between the active substance and the matrix-forming agent can be utilized to adjust and control the release rate.

[0020] The matrix-forming agent of the present invention can also be used to bind biologically active substances in a controlled manner in the composition.For example, when the active substance is nicotine, the matrix-forming agent can be selected so that a controlled amount of nicotine is liberated, and unbound nicotine and a controlled amount of nicotine are gradually and controllably released from the matrix-forming agent.For example, by increasing the amount of matrix-forming agent in the composition of the present invention, more nicotine is bound and gradually released.Therefore, the composition can be developed to provide the user with a satisfactory initial dose of nicotine administered to the oral cavity or nasal cavity, and gradually release nicotine from the composition over a predetermined period of time.For nicotine products, the matrix-forming agent can be used to meet various requirements for user compliance.

[0021] In one embodiment, the composition of the invention comprises less than 50% (by weight) of matrix-forming agent, such as less than 40% (by weight) or less than 30% (by weight) and less than 20% (by weight), or between 0.1 and 10% (by weight), or between 0.5 and 5% (by weight) of matrix-forming agent.

[0022] In other embodiments, the compositions of the present invention comprise more than 50% (by weight) of matrix-forming agent, for example 50-90% (by weight) or 50-70% (by weight) of matrix-forming agent.

[0023] Also, as used herein, fillers primarily contribute to the bulk and shape of the composition, for example, to allow user compliance in different parts of the oral cavity, and / or aid in convenient manufacturing, handling, and administration of the composition. Fillers may also, in embodiments, actively interact with the matrix-forming agent to stabilize the drug(s) and induce desirable release characteristics.

[0024] The β-glucan of the composition can be obtained from a variety of sources, including cereals and yeast, and contains at least 30% β(1-3)β(1-4) glucan, preferably 70-99% or nearly 100% β(1-3)β(1-4) glucan. The β-glucan is preferably obtained from a cereal, more preferably from oat. Cereal β-glucan can be purified to a suitable high grade by methods outlined, for example, in Journal of Food Science, 2017, 82(9) (G Maheshwari et al.) and Chemical Engineering and Processing, 2014, 84, pp. 90-97 (O Benito-Roman et al.).

[0025] In one aspect, the compositions of the present invention comprise a matrix-forming agent comprising at least 50% (by weight) β-glucan. The compositions of the present invention may further comprise a matrix-forming agent comprising at least one additional pharmaceutically acceptable gum or gel-forming polysaccharide of food or pharmaceutical grade, preferably selected from alginate and suitable salts thereof, xanthan, carrageenan, methylcellulose, cudran, pullulan, guar gum, gum arabic, and similar polysaccharides; preferably, the additional gum is a salt of alginate, more preferably sodium alginate.

[0026] The filler of the composition of the present invention comprises a fibrous material, which may be of natural or synthetic origin. The fiber is preferably derived from plants, algae, or fungi, and may be natural or modified by bioprocessing or chemical methods. In a preferred embodiment, the fibrous material is a plant fiber, and more preferably, the filler comprises natural or modified cellulose fiber, and most preferably comprises at least one type of microcrystalline cellulose.

[0027] In various embodiments, the plant fiber included in the filler can be derived from various sources, such as tea, coffee, tobacco, cocoa, corn, bamboo, oats, barley, rye, sugar beet, herbs, buckwheat, potato, tomato, eggplant, cauliflower, apple, yerba mate, or one of a variety of cellulose fibers, and the like. The plant fiber can be natural or modified by various biological or chemical methods. Tobacco fiber can be processed according to various conventional techniques for whiteness and / or nitrosamine reduction.

[0028] Microcrystalline cellulose (MCC) suitable as a filler can be selected from AVICEL® grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, VIVACEL® grades 101, 102, 12, 20; EMOCEL® grades 50M and 90M, HiCel® grades such as HiCel® 90M, and mixtures thereof. For embodiments of the compositions of the present invention in which water-soluble microcrystalline cellulose is desired, various grades of colloidal microcrystalline cellulose, such as TABULOSE®, are useful.

[0029] For embodiments of the compositions of the invention in which water-soluble microcrystalline cellulose is desired, such as powdered compositions for use in the nasal cavity, a suitable grade of colloidal microcrystalline cellulose is the grade having Cas No. 51395-75-6, e.g., various brands of TABULOSE®. A preferred such colloidal gelling MCC has the trade name FEIYUN XW591.

[0030] In an embodiment of the composition of the invention, the filler comprises a polyol, preferably one or more polyols selected from mannitol, xylitol, sorbitol, maltitol and / or isomaltitol, lactitol and erythritol. Suitably, the composition of the invention comprises a plant fibre material and 5 to 70% (by weight) of a polyol, and preferably the filler comprises mannitol and at least one microcrystalline cellulose.

[0031] In embodiments of the present invention relating to powder compositions for use in the nasal cavity, the filler can include a mucoadhesive selected from at least one of cellulose derivatives, starch derivatives, and polyvinylpyrrolidone, and preferably the mucoadhesive is selected from at least one of sodium starch glycolate and cross-linked polyvinylpyrrolidone. In such embodiments, the filler can include guar gum or starch. Suitable starches include corn starch, pregelatinized starch, hydroxypropyl starch, and modified or unmodified starches.

[0032] In embodiments of the invention directed to powder compositions for use in the nasal cavity, the compositions comprise powder particles having a controlled average size (diameter), such as 0.01-2 mm, or 0.05-0.5 mm, or 0.02-0.2 mm, or 0.01-0.1 mm. The compositions are optimized for powder particle size, taking into consideration that particles approaching <10 μm avoid the risk of aerosolization and inadvertent powder distribution into the lungs, and particles larger than a few mm avoid poor compliance and distribution.

[0033] The biologically active substance may be a therapeutic or non-therapeutic substance not generally considered a pharmaceutical, such as a naturopathic preparation, a stimulant, or a dietary supplement. Examples of therapeutic biologically active substances that can be administered alone or in combination by the compositions of the present invention include urinary incontinence agents; antihistamines, analgesics, anti-inflammatory drugs, antiemetics, antiepileptic drugs, vasodilators, antitussives and expectorants, antispasmodics, hormones, diuretics, antihypotensives, bronchodilators, anti-inflammatory steroids, antibiotics, sedatives, CNS active substances, cannabinoids, such as Δ9-tetrahydrocannabinol (THC) or cannabidiol (CBD), decongestants, laxatives, and antacids. In general, the compositions are useful as drug delivery dosage forms for patients suffering from complications that lead to the inability to administer conventional swallowing tables, such as loss of consciousness, severe migraine, acute stroke, or gastrointestinal obstruction. Examples of suitable non-therapeutic agents include caffeine, alcohol powder, ethanol, vitamin B12, vitamin C, vitamin E, Bioperin®, coenzyme Q10, selenium, glutathione, alpha lipoic acid, folic acid, ginseng, pollen extract, antioxidants, minerals, paracetamol, acetylsalicylic acid, russian root, and rose root.

[0034] In an embodiment of the invention, the composition has a pH of at least 6.5, preferably a pH of 8-9, and the biologically active substance is nicotine or a cannabinoid, such as THC.

[0035] In some embodiments, the biologically active substance is nicotine. The term nicotine includes synthetic nicotine and nicotine extracts from tobacco plants, such as Nicotiana tabacum or other plant sources, and includes nicotine or nicotine derivatives in any solid or liquid form, such as a physical form, for example, amorphous, crystalline, polymorphic, or chemical form, such as isomers and enantiomers, as well as any pharmaceutically acceptable salts, complexes, or solvates thereof. The term nicotine herein also includes nicotine base and / or its salts, such as nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine ditartrate, nicotine sulfate, nicotine zinc chloride (monohydrate), and nicotine salicylate.

[0036] Nicotine is typically present at a concentration of about 0.1% (by weight) to about 5% (by weight), e.g., about 0.1% (by weight) to about 4% (by weight), about 0.1% (by weight) to about 3% (by weight), about 0.1% (by weight) to about 2% (by weight), about 0.1% (by weight) to about 1% (by weight), about 0.1% (by weight) to about 0.75% (by weight), about 0.2% (by weight) to about 0.5% (by weight), or about 0.2% (by weight) to about 0.4% (by weight), calculated as the free base. Nicotine or a salt thereof used with the compositions of the present invention is preferably highly pure, e.g., 99.5% pure.

[0037] The antioxidant of the present compositions is an antioxidant effective at a pH of at least 6.5, e.g., 8-9. Preferably, the antioxidant is a complex-binding antioxidant. More preferably, the antioxidant is selected from at least one of alkali and / or alkaline earth metal salts of ascorbate, calcium citrate, calcium lactate, calcium maleate, calcium tartrate, Ca-di-Na-EDTA, calcium phosphate, and ammonium citrate. Even more preferably, the antioxidant is an ascorbate salt selected from sodium ascorbyl phosphate, potassium ascorbate, calcium ascorbate, calcium ascorbyl phosphate, and magnesium ascorbate. Most preferably, the antioxidant is calcium ascorbate. This type of antioxidant is generally preferred when the biologically active substance is nicotine. However, other types of active substances may require complementary or different antioxidants or antioxidant systems to achieve adequate storage stability.

[0038] The composition according to the present invention further comprises at least one additive selected from plasticizers, pH adjusters, preservatives, taste or flavor enhancers, colorants and sweeteners.

[0039] Plasticizers can be, for example, polyethylene glycol, propylene glycol, glycerol and sorbitol. A preferred plasticizer is sorbitol, optionally with a portion of glycerol.

[0040] The pH adjuster can maintain a pH of at least 6.5 in the composition, and examples include carbonates, including monocarbonates, bicarbonates, and sesquicarbonates, as well as weak organic acids such as acetate, glycinate, gluconate, borate, glycerophosphate, or citric acid, other alkali / alkali metal salts of physiologically acceptable acids such as phosphates, metal hydroxides such as sodium hydroxide and potassium hydroxide, and mixtures thereof. Examples of suitable pH adjusters are sodium bicarbonate and sodium carbonate, and mixtures thereof. While a higher pH (e.g., pH 8-9) is preferred during the composition's manufacture, the pH adjuster must be capable of maintaining a pH > 6.5 throughout storage and consumption.

[0041] Preservatives can be selected from agents approved in the food and pharmaceutical industries, such as sorbic acid, sorbates, benzoic acid lactic acid and physiologically acceptable salts, etc. A preferred preservative is potassium sorbate.

[0042] Flavor or flavor enhancers include ammonium chloride; essential oils, including those obtained by distillation, solvent extraction, or cold pressing of chopped flowers, leaves, peels, or pulped whole fruits, containing a mixture of alcohols, esters, aldehydes, and lactones; or essences, including either a diluted solution of essential oils or a mixture of synthetic chemical blends that match the desired flavor, such as bergamot, eucalyptus, orange, mandarin, citrus, lemon, peppermint, mint, menthol, licorice, wintergreen, tobacco, coffee, vanilla, lime, apple, peach, and mixtures thereof. Further examples include breweries and alcoholic beverages, such as cognac, whiskey, rum, gin, sherry, port, and wine; and the artificial and natural flavors of eucalyptus, licorice, and menthol.

[0043] The colorant may be selected from dyes containing chemical groups that absorb light, including dyes such as indigo carmine, amaranth, erythrosine, carbon black, titanium dioxide, and any mixtures thereof.

[0044] Sweeteners can be natural sweeteners that are not fermentable in the mouth, or artificial sweeteners such as aspartame, acesulfame K, saccharin, cyclamate, stevia extract and other similar agents.

[0045] In an aspect of the present invention, the composition is a powder composition adapted for delivery to the nasal cavity, comprising less than 50%, preferably 0.5-5%, by weight of a matrix-forming agent as defined above, and less than 20% by weight of water, preferably 1-15% by weight. The powder particles of such compositions have a size range of 0.01-5 mm, or preferably 0.05-2 mm. In an embodiment of such a composition, the filler comprises water-soluble cellulose, preferably water-soluble microcrystalline cellulose, more preferably a combination of water-soluble and water-insoluble microcrystalline cellulose. Such compositions may further comprise an active substance, filler, and additives as defined above. In one embodiment suitable for nasal use, the composition comprises nicotine, a beta-glucan as a matrix-forming agent, a filler comprising at least partially water-soluble cellulose, less than 20% by weight of water, a pH adjuster, an antioxidant, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners. In one embodiment suitable for nasal use, the composition is a powder having particles less than about 2 mm in size and comprises nicotine, β-glucan as a matrix-forming agent, a filler comprising at least partially water-soluble cellulose, less than 20% (by weight) water, a pH adjuster, an antioxidant, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners. In another embodiment suitable for nasal use, the composition is a powder having particles in the range of 0.01-5 mm in size and comprises nicotine, β-glucan as a matrix-forming agent, a filler comprising at least partially water-soluble cellulose, 1-15% (by weight) water, sodium bicarbonate as a pH adjuster, calcium ascorbate as an antioxidant, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners.

[0046] In an embodiment of the present invention, the composition is adapted for delivery to the oral cavity by contact with the mucosa. Such compositions comprise less than 50%, preferably 0.1-10% (by weight), more preferably 0.5-5% (by weight) of a matrix-forming agent as defined above, and at least 30% (by weight) of water, preferably 40-60% (by weight). Such compositions may further comprise an active substance, a filler, and additives as defined above. In an embodiment, the composition comprises at least 40% (by weight) of a filler, preferably comprising microcrystalline cellulose. Suitably, such compositions may be presented as a conventional tobacco product, such as a snus product, in which a defined amount of the composition is packaged in a pouch. One embodiment of such a composition comprises nicotine, β-glucan as a matrix forming agent, a filler comprising microcrystalline cellulose, at least 30% (w) of water, a pH adjuster, an antioxidant, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners; one embodiment of such a composition comprises nicotine, β-glucan as a matrix forming agent, a filler comprising microcrystalline cellulose and optionally mannitol and / or other vegetable fibers, 40-60% (wt) of water, a pH adjuster, an antioxidant, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners. One embodiment of such a composition comprises nicotine, a matrix-forming agent comprising β-glucan and one or more other additional pharmaceutically / nutritional acceptable gums as defined above, a filler comprising microcrystalline cellulose and optionally mannitol and / or other vegetable fibers, 40-60% (by weight) water, a pH adjuster, an antioxidant, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners.

[0047] In an embodiment of the present invention, the composition is adapted for delivery to the oral cavity as a lozenge or tablet that dissolves gradually upon contact with saliva. The composition comprises at least 50% matrix-forming agent, as defined above, containing less than 30% water by weight, preferably 1-30% water by weight. Such compositions may further comprise an active agent, a filler, and additives, as defined above. In certain embodiments, the filler may comprise microcrystalline cellulose, and in certain embodiments, the lozenge may have a coating containing an active agent, preferably nicotine, designed to provide an initial rapid-dose application before sustained release is established.

[0048] In another aspect of the invention, compositions comprise greater than 50% matrix-forming agent and are configured as films suitable for transmucosal delivery of active agents. The film compositions have a thickness of 0.01 to 7 mm and optionally contain a plasticizer. In one embodiment, these compositions contain 0.05 to 20% (by weight), preferably 5 to 10% (by weight), of a filler, preferably microcrystalline cellulose and a plasticizer, preferably selected from at least one of sorbitol and glycerol.

[0049] The components and amounts of fillers and other specified additives may vary depending on the desired properties of the final product, for example, to obtain attractiveness for oral or nasal use.

[0050] These and other embodiments are more fully illustrated in the detailed description that follows.

[0051] In another general aspect, the present invention relates to a method for making a composition for use in the oral and nasal cavities, comprising dry-blending a filler with at least one of a matrix-forming agent and an antioxidant; mixing the dry blend with a first aqueous solution containing a pH adjuster; adding a second aqueous solution containing at least one of a preservative, a taste or flavor enhancer, and a sweetener; adding a third aqueous solution containing one or more biologically active substances; and finally blending all added ingredients with an appropriate amount of water to form a mixture.

[0052] In one embodiment of the method, the filler in the first step is dry mixed with the matrix forming agent and antioxidant.

[0053] In one embodiment of the method, the filler in the first step is dry mixed with an antioxidant, and the third aqueous solution comprises a matrix-forming agent and one or more biologically active substances.

[0054] In one alternative, the method can be configured to produce a powder composition for nasal use containing less than 20% water (by weight), for example 1-15% water (by weight), by one or more further processing steps of the resulting mixture, for example spray drying to a powder with a particle size of about 1 mm or less.

[0055] In another alternative, the method may be configured to produce a composition for use in the oral cavity by one or more further processing steps of the resulting mixture using at least one of filling into pouches, tableting or lozenge forming, extrusion, punching, casting, molding, injection molding, knead-spinning, filming, dilution into a sprayable dosage form, and forming and mixing with a chewing gum base. DETAILED DESCRIPTION OF THE INVENTION

[0056] Table 1 below provides further examples of oral or nasal compositions containing suitable additives. [Table 1]

[0057] Example 1

[0058] Specific examples of product compositions prepared according to the methods outlined are shown in Table 2. [Table 2]

[0059] The unflavored compositions of Table 2, which may have a pH of about 8.5 and are suitable for packaging in pouches as snus-type products for oral use, were tested for nicotine stability. 80g samples of the compositions of Table 2 and a commercially available tobacco-based snus product were compared at 40°C and 75% relative humidity for 9 weeks (equivalent to 10 months at 25°C without adjusting for relative humidity). [Table 3]

[0060] Table 3 demonstrates that the β-glucan and antioxidant of the compositions of the present invention provide a significant increase in nicotine stability. Previous studies using compositions similar to those in Table 2 but without antioxidants have demonstrated nicotine stability equivalent to that of commercially available tobacco-based products. The results indicate that the matrix-forming agent containing β-glucan of the compositions of the present invention has nicotine preservation capabilities equivalent to those of natural tobacco fiber. In conclusion, the combination of a matrix-forming agent containing β-glucan and a chelating antioxidant provides effective long-term nicotine stability.

[0061] Example 2 [Table 4]

[0062] Table 4 shows examples of lozenges or water-soluble tablets containing β-glucan as a matrix-forming agent.

[0063] Lozenges or tablets are made by dry blending all of the ingredients in Table 4, and the resulting product is transferred to a conventional tablet press, subjected to high pressure, and formed into tablets / lozenges. Tablets are spray coated and dried in a coating pan to obtain a desirable flavor coating, including sweeteners, flavorings, and similar agents. The coating may optionally include (optionally1), containing nicotine to provide an initial dose.

[0064] Example 3

[0065] A product according to the present invention and Table 1 contains 0.89% (by weight) nicotine, approximately 41% (by weight) water, and 1 or 2% β-glucan as a matrix former. The products were made using the two alternative methods outlined above. In Step 1, β-glucan is dry-mixed with the filler in the first step, and a solution of nicotine is added in the third step. The product according to Step 1 contains 1% (by weight) β-glucan. In Step 2, 1 or 2% (by weight) β-glucan is added to a solution containing nicotine in the third step. The product according to Step 2 contains 1% or 2% (by weight) β-glucan. The product was packaged in a conventional snus pouch and benchmarked against two commercially available tobacco-free nicotine products (CP1 and CP2, respectively) that contain microcrystalline cellulose as a filler but no β-glucan as a matrix former. The products according to the present invention, CP1 and CP2, were tested for stability and nicotine release. For stability testing, all products were placed in a heating cabinet at 40°C and 75% humidity for 9 weeks (equivalent to 7 months at room temperature). [Table 5] [Table 6] [Table 7]

[0066] The results in Tables 5-7 show that products according to the invention that include a matrix-forming agent that includes beta-glucan stabilize both nicotine and pH during storage significantly better than either CP1 or CP2. The variation in moisture content between the products can be attributed to the different fillers.

[0067] To test the nicotine release capacity of the compositions according to the present invention, pouches containing the product were prepared as outlined above in Steps 1 and 2 and compared with CP1. The products were orally tested by the participants, removed after the prescribed period, and processed for residual nicotine. The consumed pouches were shredded into 100 ml glass bottles and exposed to ultrasound for 5 minutes with 5 ml of Milli-Q water. 100 ml of 0.05 M potassium hydroxide solution was then added, the samples were shaken, and then exposed to ultrasound for 60 minutes. The samples were shaken overnight on a vibrating table and exposed to ultrasound for an additional 30 minutes the following day. The samples were then centrifuged, diluted to the desired level, an internal standard was added, and the samples were then analyzed by LC / MS / MS. The average results of the three tests are shown in Table 8 below. [Table 8]

[0068] Table 8 demonstrates that the amount of matrix former in the compositions of the present invention can be used to control the release rate of nicotine. For example, doubling the amount of beta-glucan from 1 to 2% (by weight) results in an 18% increase in nicotine bound to the matrix former over a 38-minute period. Additionally, the method of manufacturing the compositions can be used to control the amount of nicotine bound to the beta-glucan of the matrix former. The results in Table 8 demonstrate that adding nicotine with the matrix former as the third and final step in the manufacturing process results in a higher amount of bound nicotine. <Additional Notes> The present disclosure includes the following aspects. <Section 1> A composition for use in the oral or nasal cavity comprising a biologically active substance, a matrix-forming agent comprising β-glucan, and a filler. <Section 2> Item 1. The composition according to item 1, wherein the pH is at least 6.5 and the biologically active substance is nicotine or a cannabinoid. <Section 3> 5. The composition of any preceding claim, wherein the β-glucan comprises at least 30% β(1-3)β(1-4) glucan, preferably 70-100% β(1-3)β(1-4) glucan, and the β-glucan is preferably a cereal β-glucan, preferably obtained from oat. <Section 4> 5. The composition of any of the preceding clauses, wherein the matrix-forming agent comprises at least one additional pharmaceutically acceptable gum, preferably selected from alginate and its salts, xanthan, carrageenan, methylcellulose, curdlan and pullulan, and preferably the additional gum is a salt of alginate, more preferably sodium alginate. <Section 5> Item 3 or Item 4, wherein the matrix-forming agent comprises at least 50% (by weight) of cereal β-glucan. <Section 6> Item 10. The composition of any one of the preceding items, further comprising an antioxidant effective at a pH of at least 6.5, preferably effective at a pH of 8-9, preferably wherein the antioxidant is a complex-binding antioxidant, preferably selected from at least one of alkali and / or alkaline earth metal salts of ascorbate, calcium citrate, calcium lactate, calcium maleate, calcium tartrate, Ca-diNa-EDTA, calcium phosphate, and ammonium citrate, more preferably wherein the antioxidant is calcium ascorbate. <Section 7> Item 11. The composition of any one of the preceding items, wherein the filler comprises a fibrous material, preferably wherein the fibrous material is a plant fiber, more preferably wherein the filler comprises natural or modified cellulose fibers, and most preferably comprises at least one microcrystalline cellulose. <Section 8> Item 11. The composition of any one of the preceding items, wherein the filler comprises a polyol, preferably one or more polyols selected from mannitol, xylitol, sorbitol, maltitol and / or isomaltitol, lactitol and erythritol. <Section 9> Item 9. The composition according to item 8, comprising a filler comprising a plant fiber material and 5 to 70% (by weight) of a polyol, preferably the filler comprising mannitol and at least one type of microcrystalline cellulose. <Section 10> Item 11. The composition of any one of the preceding items, further comprising at least one additive selected from preservatives, taste or flavor enhancers, pH adjusters, plasticizers and sweeteners. <Section 11> Item 11. The composition of any one of the preceding items, comprising less than 50% (by weight), preferably less than 40% (by weight) of said matrix-forming agent. <Section 12> Item 10. A powder composition according to any one of the preceding items, adapted for delivery to the nasal cavity and comprising less than 20% water (by weight), preferably 1-15% water (by weight). <Section 13> Item 13. The composition according to item 12, wherein the powder particles have a particle size of 0.01 to 2 mm. <Section 14> Item 14. The composition according to item 12 or 13, wherein the filler comprises a water-soluble cellulose, preferably a water-soluble microcrystalline cellulose, more preferably a combination of water-soluble and water-insoluble microcrystalline cellulose. <Section 15> Item 12. The composition according to any one of items 1 to 11, which is adapted to contact the mucous membrane of the oral cavity and comprises at least 30% (by weight) water and a filler comprising microcrystalline cellulose. <Section 16> Item 16. The composition according to item 15, comprising 40 to 60% (by weight) of water. <Section 17> Item 11. The composition according to any one of items 1 to 10, which is adapted to be used in the oral cavity as a lozenge or tablet and comprises 1 to 30% (by weight) water and a filler comprising at least one of microcrystalline cellulose, plant fiber, and polyol, and preferably the composition comprises at least 50% (by weight) of the matrix-forming agent. <Section 18> Item 11. The composition according to any one of items 1 to 10, which is configured as a film having a thickness of 0.01 to 7 mm suitable for transmucosal delivery of an active substance, and which comprises at least 50% (by weight) of the matrix-forming agent and optionally a plasticizer. <Section 19> Item 19. The composition according to Item 18, comprising 0.1 to 20% (by weight), preferably 5 to 10% (by weight) of a filler, preferably the filler is microcrystalline cellulose and a plasticizer, preferably the plasticizer is selected from at least one of sorbitol and glycerol. <Section 20> A method for producing the composition according to any one of items 1 to 19, (i) dry-blending a filler with at least one of a matrix-forming agent and an antioxidant; (ii) mixing the dry mixture with a first aqueous solution containing a pH adjuster; (iii) adding a second aqueous solution comprising at least one of a preservative, a taste or flavor enhancer, and a sweetener; (iv) adding a third aqueous solution containing one or more biologically active substances and mixing all added ingredients with an appropriate amount of water to form a mixture. <Section 21> 21. The method of claim 20, wherein the filler is dry mixed with the matrix forming agent and the antioxidant. <Section 22> 21. The method of claim 20, comprising dry-mixing the filler and the antioxidant, wherein the third aqueous solution comprises the matrix-forming agent and the one or more biologically active substances. <Section 23> 23. The method according to any one of items 20 to 22, which is configured to produce a powder composition for nasal use by one or more further processing steps of the obtained mixture, comprising drying to a powder with a particle size of less than 2 mm containing less than 15% water (by weight). <Section 24> 24. The method according to any one of items 20 to 23, wherein the method comprises further processing the resulting mixture by one or more methods, using at least one of filling into a pouch, forming a tablet or lozenge, extrusion, punching, casting, molding, injection molding, knead-spinning, film-forming, and mixing with a chewing gum base, to produce a composition for use in the oral cavity.

Claims

1. 1. A composition packaged in a pouch for use in the oral cavity, comprising a biologically active substance, a matrix-forming agent comprising β-glucan, and a filler, wherein the composition has a pH of at least 6.5, and the biologically active substance is nicotine.

2. 2. The composition of claim 1, wherein the β-glucan comprises at least 30% β(1-3)β(1-4) glucan.

3. 3. The composition of claim 1 or claim 2, wherein the matrix-forming agent comprises at least one additional pharmaceutically acceptable gum.

4. 4. The composition of claim 2 or claim 3, wherein the matrix-forming agent comprises at least 50% (by weight) of cereal β-glucan.

5. The composition of any one of claims 1 to 4, comprising an antioxidant that is effective at a pH of at least 6.

5.

6. The composition of any one of claims 1 to 5, wherein the filler comprises a fibrous material.

7. The composition of any one of claims 1 to 6, wherein the filler comprises a polyol.

8. The composition of any one of claims 1 to 7, comprising less than 50% (by weight) of the matrix-forming agent.

9. 9. A composition according to any one of claims 1 to 8, adapted for contact with the mucous membranes of the oral cavity, comprising at least 30% (by weight) water and a filler comprising microcrystalline cellulose, and comprising 40 to 60% (by weight) water.

10. A composition described in any one of claims 1 to 9, further comprising at least one additive selected from a preservative, a taste or flavor enhancer, a pH adjuster, a plasticizer, and a sweetener.

11. 11. A method for making the composition of claim 10, comprising: (i) dry-mixing a filler, the matrix-forming agent comprising β-glucan, and an antioxidant; (ii) mixing the dry mixture with a first aqueous solution containing a pH adjuster; (iii) adding a second aqueous solution comprising at least one of a preservative, a taste or flavor enhancer, and a sweetener; (iv) adding a third aqueous solution containing nicotine, and mixing all added ingredients into a mixture with an appropriate amount of water.

12. 12. The method of claim 11, comprising dry blending the filler and the antioxidant, and the third aqueous solution comprising the matrix forming agent and the nicotine.

13. 13. The method of claim 11 or claim 12, configured to produce a composition for use in the oral cavity by one or more further processing methods of the resulting mixture, with filling into a pouch.

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