Novel oral or nasal compositions

Abstract

Disclosed are compositions for the oral or nasal cavity. The compositions comprise a biologically active agent, a matrix forming agent comprising beta-glucan, and a bulking agent. The compositions can also comprise additional excipients, such as antioxidants, preservatives, taste or flavor enhancers, pH adjusting agents, plasticizers, and sweeteners. Also disclosed are methods of manufacturing the compositions.

Description

[0001] This application is a divisional application of Chinese invention patent application No. 202180024747.9, entitled "Novel Composition for Mouth or Nose", filed on April 6, 2021 (PCT application No. PCT / SE2021 / 050304). Technical Field

[0002] This invention relates to compositions for use in the oral cavity or nasal cavity and methods for preparing such compositions, the compositions comprising a bioactive agent, a matrix forming agent comprising cereal β-glucan, and a filler. Background Technology

[0003] Delivering pharmaceutical active agents to the oral and nasal cavities is often an ideal route of administration and first-line bypass metabolism for achieving rapid therapeutic onset and avoiding metabolic activity in the gastrointestinal system. Numerous solid dosage forms, such as lozenges, sublingual tablets, chewing gum, oral patches, or sachets, have been developed to provide patients with adherent formulations based on oral treatment. These solid dosage forms typically contain active agents, fillers, binders, lubricants, and other components that support mucosal adhesion, palatability, adherence, and active agent release.

[0004] Suppliers and developers of smokeless tobacco and nicotine products have developed numerous products configured for oral or nasal delivery of nicotine. Tobacco products include, for example, chewing tobacco for oral or nasal use, wet smokeless tobacco, snuff, and dry snuff. Non-tobacco products rely on pure nicotine extracted from tobacco or synthetic nicotine formulated with suitable additives into the exemplified oral or nasal dosage forms. For oral use, non-tobacco dosage forms may, for example, rely on fiber-filling materials and matrix-forming agents that act as binders. Nicotine (3-(1-methyl-2-pyrrolyl)pyridine) is a volatile compound that is readily degraded under the influence of heat, oxygen, and light. For this reason, finding suitable non-tobacco dosage forms that counteract degradation during their manufacturing process, provide suitable nicotine storage stability, allow for an ideal nicotine release rate in the oral cavity, and ensure user compliance is a technical challenge. For these reasons, developers of nicotine dosage forms are seeking new agents to replace tobacco, but with the support of extended shelf life, ideal release profiles, and high consumer compliance.

[0005] WO 2010 / 011445 discloses an oral plant fiber product suitable for delivering active agents such as nicotine. The introduction of alginate as a matrix forming agent provides the product with ideal release characteristics and appropriate stabilization for susceptible active agents.

[0006] WO 2010 / 104464 discloses alginate particles for oral use encapsulated in a bag and containing active agents such as nicotine.

[0007] WO 2015 / 051308 and US 2015 / 0098996 disclose tobacco or nicotine tablets having at least 40% by weight of water-soluble fiber, primarily maltodextrin, and less than 15% water. However, neither discloses anything regarding the shelf life of nicotine or the release characteristics of nicotine in the oral cavity.

[0008] EP1622627 describes a pharmaceutical composition comprising cereal beta-glucan and a pharmaceutical agent, suggested for oral delivery of agents such as local anesthetics. However, no such product has been manufactured or actually tested in this literature, therefore it cannot be determined whether cereal beta-glucan is a suitable excipient for delivering susceptible active agents into the oral or nasal cavity.

[0009] US2010 / 158988 describes oral-use dry, soluble films or coatings based on cereal beta-glucan, which may contain up to 10% by weight of filler. However, these films have not shown any suitability as nicotine products suitable for delivery of nicotine to the mouth or nasal cavity. EP1790687 describes similar dry films that may contain nicotine, but does not teach nicotine formulations with similar consumer compliance to conventional tobacco products.

[0010] WO2010091649 relates to tobacco-free nicotine products for oral use, and thus describes pH values. However, it does not disclose how the stability and release of nicotine can be affected by purposefully selected supportive agents.

[0011] CN10707494 discloses a chewing gum comprising a gum matrix, β-glucan, a sweetener, and cellulose lecithin as an active agent.

[0012] CN104784197 discloses a composition specifically for delivering the active agent epigallocatechin gallate, which contains β-glucan.

[0013] US6499490 discloses a tobacco alternative sheet comprising β-glucan and tobacco leaf extract. Summary of the Invention

[0014] One object of the present invention is to provide a composition suitable for delivering a bioactive agent into the oral cavity or nasal cavity, which allows for the stability of the active agent throughout the manufacturing and storage process, while allowing for a suitable release profile of the active agent.

[0015] Another object of the present invention is a composition that provides a controlled release rate of the active agent and a suitable duration of said release rate.

[0016] Another object of the present invention is to provide a composition that promotes the stabilization of active agents that are easily degraded during storage, thereby obtaining a stable product with a long shelf life even in compositions with high water content.

[0017] Another object of the present invention is to provide a composition with high compliance to the oral or nasal mucosa to avoid local irritation and side effects caused by repeated or prolonged exposure.

[0018] Another object of the present invention is to provide compositions suitable for delivering nicotine into the oral cavity or nasal cavity, thereby meeting user expectations for compliance with comparable conventional tobacco products or pharmaceutical products.

[0019] In general, the present invention relates to compositions for use in the oral cavity or nasal cavity, the compositions comprising a bioactive agent, a matrix forming agent comprising β-glucan, and a filler.

[0020] In the general context of this invention, a matrix forming agent, together with a filler, can provide a cohesive, homogeneous composition containing a bioactive agent and contributing to the stabilization of such susceptible agents, while also contributing to a controlled and desirable release profile of the active agent upon contact with the oral or nasal cavity. The stabilization effect and release profile can, in part, result from interactions or synergies with the filler (e.g., between the matrix forming agent and the fibers of the filler). Therefore, in the compositions of this invention, the interaction between the active agent and the matrix forming agent can be used to modulate and control the release rate.

[0021] The matrix forming agent of the present invention is also used to bind a bioactive agent in a controlled manner in a composition. For example, when the active agent is nicotine, the matrix forming agent can be selected such that the controlled amount of nicotine is free, unbound nicotine, and the controlled amount of nicotine is gradually and controllably released from the matrix forming agent. For example, by increasing the amount of the matrix forming agent in the composition of the present invention, more nicotine is bound and gradually released. Therefore, compositions can be developed to provide users with a satisfactory initial dose of nicotine administered orally or nasally, and to provide nicotine gradually released from the composition over a predetermined period of time. For nicotine products, the matrix forming agent can be used to meet different user compliance requirements.

[0022] In one aspect, the compositions of the present invention contain less than 50% by weight of a matrix forming agent, such as less than 40% by weight, less than 30% by weight, less than 20% by weight, or 0.1% by weight to 10% by weight, or 0.5% by weight to 5% by weight.

[0023] In other respects, the compositions of the present invention contain more than 50% by weight of a matrix forming agent, for example, 50% to 90% by weight, or 50% to 70% by weight.

[0024] Furthermore, in this general context, the filler will primarily contribute to the volume and shape of the composition, for example, allowing for user compliance in different parts of the oral cavity and / or facilitating the manufacture, handling, and application of the composition. In embodiments, the filler may also positively interact with the matrix-forming agent to stabilize the reagent and induce desired release characteristics.

[0025] The β-glucan in the composition can be obtained from various sources, including cereals and yeast, and contains at least 30% β(1-3)(1-4)glucan, preferably 70% to 99% or almost 100% β(1-3)(1-4)glucan. The β-glucan is preferably obtained from cereals, more preferably from oats. 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-Román et al.).

[0026] In one aspect, the compositions of the present invention comprise a matrix forming agent containing at least 50% by weight of β-glucan. The compositions of the present invention may comprise a matrix forming agent that also comprises at least one additional food- or pharmaceutical-grade pharmaceutically acceptable gum or gel-forming polysaccharide, preferably selected from alginate and suitable salts thereof, xanthan gum, carrageenan, methylcellulose, gelatin, amylopectin, guar gum, gum arabic, and similar polysaccharides, preferably the additional gum being an alginate, more preferably sodium alginate.

[0027] The filler in the compositions 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 it may be natural or modified using bioprocesses or chemical methods. In a preferred aspect, the fibrous material is plant fiber; more preferably, the filler comprises natural or modified cellulose fibers; most preferably, at least one microcrystalline cellulose.

[0028] In various embodiments, the plant fibers contained in the filler may be derived from tea, coffee, tobacco, cocoa, corn, bamboo, oats, barley, rye, beets, vanilla, buckwheat, potatoes, tomatoes, eggplants, cauliflower, apples, yerba mate, or cellulose fibers and the like from various sources. The plant fibers may be natural or modified using various biological or chemical methods. Tobacco fibers may be processed according to various conventional techniques used for whiteness and / or nitrosamine reduction.

[0029] Microcrystalline cellulose (MCC) suitable as a filler can be selected from AVICEL.® Grade PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, VIVACEL ® Levels 101, 102, 12, 20, EMOCEL ® Levels 50M and 90M, HiCel ® Levels, such as HiCel ® 90M, etc., and mixtures thereof. For embodiments of the compositions of the present invention in which water-soluble microcrystalline cellulose is required, colloidal microcrystalline cellulose grades, such as various grades of TABULOSE, are useful. ® .

[0030] For embodiments of the present invention requiring water-soluble microcrystalline cellulose, such as powder compositions for nasal use, a suitable colloidal microcrystalline cellulose grade is one with Cas No. 51395-75-6, such as various brands of Tabulaose. ® The preferred colloidal gelled MCC is traded under the name FEIYUN XW591.

[0031] In embodiments of the compositions of the present invention, the filler comprises a polyol, preferably one or more selected from mannitol, xylitol, sorbitol, maltitol and / or isomaltitol, lactitol and erythritol. Suitably, the compositions of the present invention comprise plant fiber material and 5% to 70% by weight of a polyol, preferably with the filler comprising mannitol and at least one microcrystalline cellulose.

[0032] In embodiments of the invention relating to powder compositions for use in the nasal cavity, the filler may comprise a mucosal adhesive selected from at least one of cellulose derivatives, starch derivatives, and polyvinylpyrrolidone, preferably at least one of sodium glycolate starch and cross-linked polyvinylpyrrolidone. In such embodiments, the filler may comprise guar gum or starch. Suitable starches are corn starch, pregelatinized starch, hydroxypropyl starch, and modified or unmodified starches.

[0033] In embodiments of the invention relating to powder compositions for use in the nasal cavity, the composition comprises powder particles having a controlled average size (diameter), for example, 0.01 mm to 2 mm, or 0.05 mm to 0.5 mm, or 0.02 mm to 0.2 mm, or 0.01 mm to 0.1 mm. For this composition, the powder particle size is optimized to avoid aerosolization and the risk of accidental powder distribution into the lungs when the particle size is close to <10 μm, as well as to avoid poor compliance and the distribution of large particles larger than approximately several millimeters.

[0034] Bioactive agents can be therapeutic or non-therapeutic substances that are not typically considered pharmaceuticals, such as naturopathic preparations, stimulants, or nutritional supplements. Examples of therapeutic bioactive substances that can be administered alone or in combination with the compositions of the present invention include: urinary incontinence agents; antihistamines, analgesics, anti-inflammatory drugs, antiemetics, antiepileptics, vasodilators, antitussives and expectorants, antispasmodics, hormones, diuretics, antihypertensives, bronchodilators, anti-inflammatory steroids, antibiotics, sedatives, central nervous system active substances, cannabinoids such as Δ9-tetrahydrocannabinol (THC) or cannabidiol (CBD), decongestants, laxatives, and antacids. Typically, the compositions can be used as drug delivery dosage forms for patients with complications such as coma, severe migraine, acute stroke, or gastrointestinal obstruction that prevent them from accepting conventionally swallowed tablets. Examples of suitable non-therapeutic agents are caffeine, alcohol powder, ethanol, vitamin B12, vitamin C, vitamin E, and bioperin. ® It contains coenzyme Q10, selenium, glutathione, alpha-lipoic acid, folic acid, ginseng, pollen extract, antioxidants, minerals, acetaminophen, acetylsalicylic acid, Russian root and rose root, etc.

[0035] In embodiments of the invention, the composition has a pH of at least 6.5, preferably 8 to 9, and the bioactive agent is nicotine or cannabinoid, such as THC.

[0036] In this embodiment, the bioactive agent is nicotine. The term nicotine includes synthetic nicotine and nicotine extracts derived from tobacco plants such as the genus *Nicotiana* or other plant sources, and includes nicotine or nicotine derivatives in any solid or liquid form, such as amorphous, crystalline, polymorphic physical forms, or chemical forms such as isomers and enantiomers, and any pharmaceutically acceptable salts, complexes, or solvates thereof. The term nicotine as used herein also includes nicotine bases and / or their salts, such as nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine hydrogen tartrate, nicotine sulfate, nicotine zinc chloride (monohydrate), and nicotine salicylate.

[0037] Calculated as free base, nicotine is typically present at a concentration of about 0.1 wt% to about 5 wt%, for example, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 2 wt%, about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 0.75 wt%, about 0.2 wt% to about 0.5 wt%, or about 0.2 wt% to about 0.4 wt%. Nicotine or its salts used with the compositions of the present invention preferably have high purity, for example, 99.5% purity.

[0038] The antioxidant in the compositions of the present invention is an antioxidant effective at a pH of at least 6.5, for example, 8 to 9. Preferably, the antioxidant is a complex-bound antioxidant; more preferably, the antioxidant is selected from at least one of the alkali metal and / or alkaline earth metal salts of ascorbic acid, calcium citrate, calcium lactate, calcium maleate, calcium tartrate, calcium disodium EDTA, calcium phosphate, and ammonium citrate; even more preferably, the antioxidant is an ascorbate salt selected from sodium ascorbate phosphate, potassium ascorbate, calcium ascorbate, calcium ascorbate phosphate, and magnesium ascorbate. Most preferably, the antioxidant is calcium ascorbate. This type of antioxidant is generally preferred when the bioactive agent is nicotine. However, other types of active agents may require supplementation or different antioxidant or antioxidant systems to achieve suitable storage stability.

[0039] The compositions of the present invention further comprise at least one excipient selected from plasticizers, pH adjusters, preservatives, flavor or taste enhancers, colorants, and sweeteners.

[0040] Plasticizers can be, for example, polyethylene glycol, propylene glycol, glycerin, and sorbitol. A preferred plasticizer is sorbitol, optionally combined with a portion of glycerin.

[0041] pH adjusters are capable of maintaining a pH of at least 6.5 in the composition and include carbonates, including monocarbonates, bicarbonates, and sesquicarbonates, as well as other alkali metal salts of physiologically acceptable acids, such as acetates, glycine salts, gluconates, borates, glycerophosphates, or weak organic acids such as citric acid, phosphates, metal hydroxides such as sodium hydroxide and potassium hydroxide, and mixtures thereof. Suitable examples of pH adjusters are sodium bicarbonate and sodium carbonate, and mixtures thereof. It is preferred that the composition is produced at a relatively high pH, ​​for example, pH 8 to 9, but the pH adjuster should be able to maintain a pH > 6.5 throughout storage and use.

[0042] Preservatives can be selected from reagents approved in the food and pharmaceutical industries, such as sorbic acid, sorbates, benzoic acid, lactic acid, and physiologically acceptable salts. Potassium sorbate is a preferred preservative.

[0043] Flavor enhancers include ammonium chloride, essential oils (including distillates, solvent extracts, or cold-pressed extracts of chopped flowers, leaves, peels, or pulped whole fruits containing a mixture of alcohols, esters, aldehydes, and lactones), or flavorings (including diluted solutions of essential oils or mixtures of synthetic chemical blends) to match desired flavors from, for example, bergamot, eucalyptus, orange, mandarin orange, citrus, lemon, peppermint, mint, menthol, licorice, wintergreen, tobacco, coffee, vanilla, lime, apple, peach, and mixtures thereof. Other examples include: brewed and spirit products (e.g., cognac, whiskey, rum, gin, sherry, port, and wine), eucalyptus, licorice, and menthol, both artificial and natural flavorings.

[0044] The colorant can be selected from dyes containing light-absorbing chemical groups, including dyes such as indigo carmine, amaranth, erythrosine, carbon black, titanium dioxide, and any mixture thereof.

[0045] Sweeteners can be natural sweeteners that do not ferment in the mouth, or artificial sweeteners such as aspartame, acesulfame potassium, saccharin, cyclamate, stevia extract and other similar agents.

[0046] In some aspects of the invention, the composition is a powder composition suitable for delivery into the nasal cavity and comprises: less than 50%, preferably 0.5% to 5% by weight, of a defined matrix forming agent, and less than 20% by weight, preferably 1% to 15% by weight, of water. The particle size of such a composition ranges from 0.01 mm to 5 mm, or preferably 0.05 mm to 2 mm. In embodiments of such compositions, 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 also comprise active agents, fillers, and excipients as defined above. In one embodiment suitable for nasal use, the composition comprises nicotine, β-glucan as a matrix forming agent, a filler comprising at least a portion of water-soluble cellulose, less than 20% by weight of water, a pH adjuster, an antioxidant, and one or more other excipients selected from preservatives, flavor / taste enhancers, and sweeteners. In one embodiment suitable for nasal use, the composition is a powder with a particle size of less than about 2 mm and contains nicotine, β-glucan as a matrix forming agent, a filler containing at least partially water-soluble cellulose, less than 20% by weight of water, a pH adjuster, an antioxidant, and one or more other excipients selected from preservatives, flavor enhancers, and sweeteners. In another embodiment suitable for nasal use, the composition is a powder with a particle size of 0.01 mm to 5 mm and contains nicotine, β-glucan as a matrix forming agent, a filler containing at least partially water-soluble cellulose, 1% to 15% by weight of water, sodium bicarbonate as a pH adjuster, calcium ascorbate as an antioxidant, and one or more other excipients selected from preservatives, flavor enhancers, and sweeteners.

[0047] In various aspects of the invention, the composition is adapted to be delivered to the oral cavity by contact with a mucosa. Such compositions contain less than 50%, preferably 0.1% to 10% by weight, more preferably 0.5% to 5% by weight of a matrix forming agent as defined above, and at least 30% by weight of water, preferably 40% to 60% by weight. Such compositions may also contain activators, fillers, and excipients as defined above. In embodiments, the composition contains at least 40% by weight of a filler, which preferably comprises microcrystalline cellulose. Suitably, such compositions can be provided as conventional tobacco products, such as snuff products in which a prescribed amount of the composition is packaged in a pouch. In one embodiment of such a composition, it contains nicotine, β-glucan as a matrix forming agent, a filler comprising microcrystalline cellulose, at least 30% by weight of water, a pH adjuster, an antioxidant, and one or more other excipients selected from preservatives, flavor / flavor enhancers, and sweeteners. In one embodiment of such a composition, it comprises nicotine, β-glucan as a matrix forming agent, a filler comprising microcrystalline cellulose and optionally mannitol and / or other plant fibers, 40% to 60% water, a pH adjuster, an antioxidant, and other excipients selected from one or more of preservatives, flavor / flavor enhancers, and sweeteners. In another embodiment of such a composition, it comprises nicotine, a matrix forming agent comprising β-glucan and one or more additional pharmaceutically / nutritionally acceptable gums as defined above, a filler comprising microcrystalline cellulose and optionally mannitol and / or other plant fibers, 40% to 60% water, a pH adjuster, an antioxidant, and other excipients selected from one or more of preservatives, flavor / flavor enhancers, and sweeteners.

[0048] In several aspects of the invention, the composition is suitable for delivery to the oral cavity as a lozenge or tablet that gradually dissolves upon contact with saliva. The composition contains at least 50% of a matrix-forming agent as defined above, and contains less than 30% by weight of water, preferably from 1% to 30% by weight. Such compositions may also contain an active agent, a filler, and an excipient as defined above. In some embodiments, the filler may comprise microcrystalline cellulose, and in some embodiments, the lozenge may have a coating comprising an active agent, preferably containing nicotine designed to provide an initial rapid-acting dose for use before establishing a gradual release.

[0049] In other aspects of the invention, the compositions comprise more than 50% of a matrix forming agent and are configured to form a membrane suitable for transmucosa delivery of the active agent. The membrane composition has a thickness of 0.01 mm to 7 mm and optionally includes a plasticizer. In one embodiment, these compositions comprise 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.

[0050] The composition and amount of fillers and other excipients mentioned can vary depending on the desired properties of the final product (e.g., to achieve attractiveness for the mouth or nose).

[0051] These and other implementation methods will be illustrated more fully by example in the following detailed description.

[0052] In another general aspect, the present invention relates to a method of manufacturing a composition for oral and nasal cavities. The method comprises: dry mixing a filler, at least one matrix forming agent, and an antioxidant; mixing the dry mixture with a first aqueous solution containing a pH adjuster; adding a second aqueous solution containing at least one of a preservative, a flavor or taste enhancer, and a sweetener; adding a third aqueous solution containing one or more bioactive agents; and finally mixing all the components added to the mixture with an appropriate amount of water.

[0053] In one embodiment of the method, the filler from the first step is dry-mixed with the matrix forming agent and the antioxidant.

[0054] In one embodiment of the method, the filler in the first step is dry-mixed with an antioxidant, and the third aqueous solution contains a matrix forming agent and one or more bioactive agents.

[0055] In an alternative, the method can be configured to produce a nasal powder composition by one or more further processing steps of the resulting mixture, such as spray drying into a powder having a particle size of less than 1 mm and containing less than 20% by weight of water, for example, 1% to 15% by weight of water.

[0056] In another alternative, the method can be configured to produce a composition for oral use by one or more further processing steps of the resulting mixture, said one or more further processing steps using at least one of bagging, forming tablets or tablets, extrusion, stamping, casting, molding, injection molding, compounding, spinning, film forming, dilution into a spray form, shaping, and mixing with chewing gum base. Detailed Implementation

[0057] Table 1 below further illustrates examples of oral or nasal compositions containing suitable excipients.

[0058] Element use Quantity (by weight) water humidify 2%-70% Sodium chloride smell <15% microcrystalline cellulose filler 5%-95% Sodium bicarbonate / sodium carbonate pH adjuster <2% β-glucan >70% purity Matrix forming agent <5% ammonium chloride Flavor <2% Potassium sorbate preservative <0.2% Xylitol sweeteners <5% Acesulfame K / stevia sweeteners <0.5% Menthol / Spearmint / Lemon / Other Flavor <5% Calcium ascorbate antioxidants <5% nicotine Surfactant <20%

[0059] Table 1

[0060] Example 1

[0061] Table 2 shows specific examples of compositional products manufactured using the method described.

[0062] Element use Quantity (by weight) water humidify 45.93 microcrystalline cellulose filler 42.10 Sodium chloride smell 5.22 spices smell and taste 1.86 Xylitol Sweeteners / fillers 1.74 nicotine Surfactant 0.89 98% pure oat beta-glucan from Xi'an Retalin Biotechnology, China Matrix forming agent 0.70 Calcium ascorbate antioxidants 0.70 ammonium chloride smell 0.35 Sodium bicarbonate pH adjuster 0.26 Potassium sorbate preservative 0.2 Acesulfame K sweeteners 0.07

[0063] Table 2

[0064] The nicotine stability of the compositions in Table 2 was tested. These compositions are odorless, have a pH of approximately 8.5, and are suitable for packaging in sachets as a snuff-type product for oral use. An 80 g sample of the compositions in Table 2 was compared with a commercially available tobacco-based snuff product over 9 weeks at 40°C and 75% relative humidity (equivalent to 10 months at 25°C and unadjusted relative humidity).

[0065] The compositions in Table 2 Commercially available products Moisture content (by weight) 45.93 41.9 Initial nicotine dose (mg) 1.1 1.0 Nicotine levels (mg) after 9 weeks 1.1 0.74

[0066] Table 3

[0067] Table 3 shows that the β-glucan and antioxidants in the compositions of the present invention lead to a significant increase in nicotine stability. Previous tests on compositions similar to those in Table 2 but without any antioxidants showed nicotine stability comparable to commercially available tobacco products. This result indicates that the β-glucan-containing matrix forming agent in the compositions of the present invention has a nicotine retention capacity comparable to that of natural tobacco fibers. In summary, the combination of a β-glucan-containing matrix forming agent and a chelating antioxidant provides effective long-term nicotine stability.

[0068] Example 2

[0069] Element use Quantity (by weight) Xylitol filler 31.0 Guar gum / Gum arabic Matrix forming agent 31.0 Maltodextrin Matrix forming agent 31.0 magnesium stearate lubricant 1.0 nicotine Surfactant 0.4 98% pure oat beta-glucan from Xi'an Retalin Biotechnology, China Matrix forming agent 0.7 Acesulfame K sweeteners 0.3 Sodium bicarbonate pH adjuster 0.4 Fennel oil Fragrance 0.2 Honey flavoring / menthol / peppermint Fragrance 4

[0070] Table 4

[0071] Table 4 shows examples of lozenges or water-soluble tablets containing β-glucan as a matrix forming agent.

[0072] The tablets or lozenges are made by dry-mixing all the ingredients in Table 4, transferring the resulting product to a conventional tablet forming machine, and subjecting it to high pressure to form tablets / lozenges. The tablets are then spray-coated and dried in a coating tank to obtain a coating with the desired flavor, containing sweeteners, flavorings, and similar agents. The coating may optionally contain nicotine to provide an initial dose.

[0073] Example 3

[0074] The product according to the present invention and Table 1 contains 0.89% by weight nicotine, about 41% by weight water, and 1% or 2% β-glucan as a matrix forming agent. The product is made using the two alternative methods described above. In process 1, β-glucan is dry-mixed with a filler in a first step, and a nicotine solution is added in a third step. The product of process 1 contains 1% by weight β-glucan. In process 2, 1% or 2% by weight β-glucan is added to a nicotine-containing solution in a third step. The product of process 2 contains 1% or 2% by weight β-glucan. These products were packaged in conventional snuff bags and benchmarked against two commercially available tobacco-free nicotine products, CP1 and CP2, which respectively contain microcrystalline cellulose as a filler but no β-glucan as a matrix forming agent. The stability and nicotine release of the product of the present invention, CP1, and CP2 were investigated. Regarding stability testing, all products were placed in a heating cabinet at 40°C and 75% humidity for 9 weeks (representing 7 months at room temperature).

[0075] Initial nicotine content (by weight) Nicotine levels after 7 months % Nicotine loss Products of Process 1 0.89 0.75 20 CP1 1 0.74 26 CP2 0.61 0.46 25

[0076] Table 5

[0077] initial pH pH value after 7 months % pH decrease Products of Process 1 7.6 7.4 3 CP1 8.4 7.9 6 CP2 8.3 8 4

[0078] Table 6

[0079] Initial moisture content (by weight) Moisture content (by weight) after 7 months %change Products of Process 1 41.2 43.9 +7 CP1 41.9 39.8 -5 CP2 45.3 47.9 +6

[0080] Table 7

[0081] The results in Tables 5 to 7 indicate that the products of this invention containing a matrix forming agent using β-glucan exhibit significantly better stabilization of both nicotine and pH during storage than CP1 or CP2. Variations in moisture content between products may be due to different fillers.

[0082] To test the nicotine release capacity of the compositions of the present invention, sachets containing the product were manufactured using processes 1 and 2 as described above and compared with CP1. These products were tested orally by respondents, and after a specified time, the nicotine was removed and disposed of. The used sachets were chopped and placed in 100 ml glass bottles and sonicated for 5 minutes with 5 ml of Milli-Q water. Subsequently, 100 ml of 0.05 M potassium hydroxide solution was added, the sample was shaken, and then sonicated for 60 minutes. The sample was shaken on a shaking table overnight and then sonicated again for 30 minutes the next day. The sample was then centrifuged and diluted to the desired level, an internal standard was added, and the sample was analyzed by LC / MS / MS. The average results of the three tests are shown in Table 8 below.

[0083] Initial nicotine content (mg / g) Nicotine content (mg / g) after 38 minutes Nicotine release (mg / g) Nicotine bound to matrix forming agents The product of process 1 contains 1% by weight of β-glucan. 8.1 2.8 5.3(65%) 44% The product from process 2 contains 1% by weight of β-glucan. 8.1 4.4 3.7(45%) 55% The product of process 2 contains 2% by weight β-glucan. 8.1 5.1 3.0(37%) 63% CP1 8.9 5.7 3.2(36%) N / A

[0084] Table 8

[0085] Table 8 shows that the amount of matrix-forming agent in the compositions of the present invention can be used to control the nicotine release rate. For example, doubling the amount of β-glucan from 1% by weight to 2% by weight over a period of 38 minutes will produce an additional 18% of nicotine bound to the matrix-forming agent. Furthermore, the method of manufacturing the composition can be used to control the amount of nicotine bound to the β-glucan of the matrix-forming agent. The results in Table 8 indicate that when nicotine is added together with the matrix-forming agent as the third and final step in the manufacturing process, a higher amount of bound nicotine is obtained.

[0086] In summary, the present invention relates to the following technical solutions:

[0087] 1. A composition for use in the oral cavity or nasal cavity, comprising a bioactive agent, a filler, and a matrix forming agent comprising β-glucan.

[0088] 2. The composition according to claim 1, having a pH of at least 6.5, wherein the bioactive agent is nicotine or cannabinoid.

[0089] 3. The composition according to any one of the preceding items, wherein the β-glucan comprises at least 30% β(1-3)β(1-4)glucan, preferably 70% to 100% β(1-3)β(1-4)glucan, preferably the β-glucan is a cereal β-glucan, preferably obtained from oats.

[0090] 4. The composition according to any one of the preceding claims, wherein the matrix forming agent comprises at least one additional pharmaceutically acceptable gum, preferably selected from alginate and its salts, xanthan gum, carrageenan, methylcellulose, gel polysaccharide and amylopectin, preferably the additional gum being an alginate, more preferably sodium alginate.

[0091] 5. The composition according to item 3 or 4, wherein the matrix forming agent comprises at least 50% by weight of cereal β-glucan.

[0092] 6. The composition according to any one of the preceding claims, comprising an antioxidant that is effective at a pH of at least 6.5, preferably at a pH of 8 to 9, preferably said antioxidant is a complexing antioxidant, preferably selected from at least one of alkali metal and / or alkaline earth metal salts of ascorbic acid, calcium citrate, calcium lactate, calcium maleate, calcium tartrate, calcium disodium EDTA, calcium phosphate, and ammonium citrate, more preferably said antioxidant is calcium ascorbate.

[0093] 7. The composition according to any one of the preceding items, wherein the filler comprises a fibrous material, preferably a plant fiber, more preferably a natural or modified cellulose fiber, and most preferably at least one microcrystalline cellulose.

[0094] 8. The composition according to 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.

[0095] 9. The composition according to claim 8, wherein the filler comprises plant fiber material and 5% to 70% by weight of polyol, preferably the filler comprises mannitol and at least one microcrystalline cellulose.

[0096] 10. The composition according to any one of the preceding claims, comprising at least one excipient selected from preservatives, flavor or taste enhancers, pH adjusters, plasticizers and sweeteners.

[0097] 11. The composition according to any one of the preceding items, comprising less than 50% by weight, preferably less than 40% by weight, of the matrix forming agent.

[0098] 12. The powder composition according to any one of the preceding items, which is suitable for delivery into the nasal cavity, contains less than 20% by weight, preferably from 1% to 15% by weight, of water.

[0099] 13. The composition according to item 12, wherein the size of the powder particles is from 0.01 mm to 2 mm.

[0100] 14. The composition according to item 12 or 13, wherein the filler comprises water-soluble cellulose, preferably water-soluble microcrystalline cellulose, more preferably a combination of water-soluble and water-insoluble microcrystalline cellulose.

[0101] 15. The composition according to any one of claims 1 to 11, which is suitable for contact with oral mucosa, comprises at least 30% by weight of water and a filler containing microcrystalline cellulose.

[0102] 16. The composition according to claim 15, comprising 40% to 60% by weight of water.

[0103] 17. The composition according to any one of claims 1 to 10, suitable for use in the oral cavity as an invoice or tablet, comprising 1% to 30% by weight of water and a filler comprising at least one of microcrystalline cellulose, plant fiber and polyol, preferably comprising at least 50% by weight of the matrix forming agent.

[0104] 18. The composition according to any one of claims 1 to 10, configured to deliver an active agent through a membrane into a film of thickness from 0.01 mm to 7 mm, comprising at least 50% by weight of the matrix forming agent and optionally a plasticizer.

[0105] 19. The composition according to claim 18, comprising 0.1% to 20% by weight, preferably 5% to 10% by weight, of a filler, preferably microcrystalline cellulose and a plasticizer, preferably the plasticizer being selected from at least one of sorbitol and glycerol.

[0106] 20. A method for manufacturing the composition according to any one of items 1 to 19, comprising:

[0107] (i) a dry-mix filler, at least one matrix forming agent and an antioxidant;

[0108] (ii) Mix the dried mixture with a first aqueous solution containing a pH adjuster;

[0109] (iii) Add a second aqueous solution containing at least one of a preservative, a flavor or taste enhancer, and a sweetener;

[0110] (iv) Add a third aqueous solution containing one or more bioactive agents and mix all the ingredients added to the mixture with an appropriate amount of water.

[0111] 21. The method according to item 20, wherein the filler is dry-mixed with the matrix forming agent and the antioxidant.

[0112] 22. The method according to 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 bioactive agents.

[0113] 23. The method according to any one of items 20 to 22, configured to produce a nasal powder composition by one or more further processing steps of the resulting mixture, including drying it into a powder containing less than 15% by weight of water with a particle size of less than 2 mm.

[0114] 24. The method according to any one of claims 20 to 23, configured to produce a composition for oral use by one or more further processing methods of the resulting mixture, said one or more further processing methods using at least one of bagging, forming tablets or tablets, extrusion, stamping, casting, molding, injection molding, compounding, spinning, film forming, and mixing with chewing gum base.

Claims

1. A composition for use in the oral cavity, comprising: a. Bioactive agents; b. Less than 50% by weight of matrix forming agents containing β-glucan; c. Filler; The bioactive agent mentioned therein is nicotine.

2. The composition according to claim 1, wherein, The β-glucan contains at least 30% β(1-3)β(1-4)glucan, preferably 70% to 100% β(1-3)β(1-4)glucan, and preferably the β-glucan is a cereal β-glucan, preferably obtained from oats.

3. The composition according to any one of the preceding claims, wherein, The matrix forming agent comprises at least one other pharmaceutically acceptable gum, preferably selected from alginate and its salts, xanthan gum, carrageenan, methylcellulose, gel polysaccharides and amylopectin, preferably the other gum being alginate, more preferably sodium alginate.

4. The composition according to claim 2 or 3, wherein, The matrix forming agent contains at least 50% by weight of cereal β-glucan.

5. The composition according to any one of the preceding claims, comprising an antioxidant that is effective at a pH of at least 6.5, preferably at a pH of 8 to 9, preferably said antioxidant is a complexing antioxidant, preferably selected from at least one of alkali metal and / or alkaline earth metal salts of ascorbic acid, calcium citrate, calcium lactate, calcium maleate, calcium tartrate, calcium disodium EDTA, calcium phosphate, and ammonium citrate, more preferably said antioxidant is calcium ascorbate.

6. The composition according to any one of the preceding claims, wherein, The filler comprises a fibrous material, preferably a plant fiber, more preferably a natural or modified cellulose fiber, and most preferably at least one microcrystalline cellulose.

7. The composition according to any one of the preceding claims, wherein, The filler comprises a polyol, preferably one or more polyols selected from mannitol, xylitol, sorbitol, maltitol and / or isomaltitol, lactitol and erythritol.

8. The composition according to claim 7, wherein, The filler comprises plant fiber material and 5% to 70% by weight of polyol, preferably mannitol and at least one microcrystalline cellulose.

9. The composition according to any one of the preceding claims, comprising at least one excipient selected from preservatives, flavor or taste enhancers, pH adjusters, plasticizers and sweeteners.

10. The composition according to any one of the preceding claims, comprising less than 40% by weight of the matrix forming agent.

11. The composition according to any one of claims 1 to 10, which is suitable for contact with oral mucosa, comprises at least 30% by weight of water and a filler containing microcrystalline cellulose.

12. The composition according to claim 11, comprising 40% to 60% by weight of water.

13. The composition according to any one of claims 1 to 9, suitable for use in the oral cavity as an invoice or tablet, comprising 1% to 30% by weight of water and a filler comprising at least one of microcrystalline cellulose, plant fiber and polyol, preferably comprising at least 50% by weight of the matrix forming agent.

14. The composition according to any one of claims 1 to 9, configured as a membrane with a thickness of 0.01 mm to 7 mm suitable for transmural delivery of the active agent, comprising at least 50% by weight of the matrix forming agent and optionally a plasticizer.

15. The composition according to claim 14, comprising 0.1% to 20% by weight, preferably 5% to 10% by weight, of a filler, preferably microcrystalline cellulose and a plasticizer, preferably the plasticizer being selected from at least one of sorbitol and glycerol.

16. A method for manufacturing the composition according to any one of claims 1 to 15, comprising: (i) Dry-mix the filler, the matrix forming agent containing β-glucan, and optionally, the antioxidant; (ii) Mix the dried mixture with a first aqueous solution containing a pH adjuster; (iii) Add a second aqueous solution containing at least one of a preservative, a flavor or taste enhancer, and a sweetener; (iv) Add a third aqueous solution containing nicotine to obtain a mixture, and mix the resulting mixture with an appropriate amount of water.

17. A method for manufacturing the composition according to any one of claims 1 to 15, comprising: (i) Dry-mix the filler and, optionally, the antioxidant; (ii) Mix the dried mixture with a first aqueous solution containing a pH adjuster; (iii) Add a second aqueous solution containing at least one of a preservative, a flavor or taste enhancer, and a sweetener; (iv) Add a third aqueous solution to obtain a mixture, wherein the third aqueous solution contains a matrix forming agent and the nicotine, the matrix forming agent containing β-glucan, and mix the resulting mixture with an appropriate amount of water.

18. The method according to any one of claims 16 to 17, configured to produce a composition for oral use by one or more further processing methods of the resulting mixture, said one or more further processing methods using at least one of filling in a pouch, forming a tablet or tablet, extruding, stamping, casting, molding, injection molding, compounding, spinning, film forming, and mixing with a chewing gum base.

19. A sachet product comprising the oral composition according to any one of claims 1 to 15.

20. A method for testing the nicotine-releasing capacity of a composition, comprising: a. Chop the used sachets into small pieces, put them into a 100 ml glass bottle, and sonicate them with 5 ml of Milli-Q water for 5 minutes. b. Then, add 100 ml of 0.05 M potassium hydroxide solution, shake the sample, and then sonicate for 60 minutes; c. Shake the sample on a vibration table overnight, and then treat it with ultrasound for another 30 minutes the next day; and d. The sample was then centrifuged and diluted to the required level, an internal standard was added, and the sample was analyzed by LC / MS / MS.