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

TECHNICAL FIELD

[0001] The present invention relates to a composition for the oral or nasal cavity comprising a biologically active agent, a matrix forming agent comprising cereal beta-glucan and a filler, and a method of preparing the composition. BACKGROUND

[0002] Delivery of pharmaceutically active agents to the oral and nasal cavity is often the desired route of administration and first bypass metabolism to obtain a rapid onset of therapeutic effect and to avoid metabolic activities of the gastrointestinal system. Many solid dosage forms such as lozenges, sublingual tablets, chewing gums, oral patches or sachets have been developed to obtain a compliance dosage form for the patient according to the therapy by the oral cavity. Such solid dosage forms usually comprise the active agent, a filler, a binder, a lubricant and other ingredients to support the mucoadhesion, palatability, compliance and release of the active agent.

[0003] Suppliers and developers of smokeless tobacco and nicotine products have developed many products configured to deliver nicotine through the oral or nasal cavity. Tobacco products include for example oral or nasal chewing tobacco, moist 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 form. For the oral cavity, non-tobacco dosage forms can for example rely on a fibrous filler material and a matrix forming agent acting as a binder. Nicotine (3-(1-methyl-2-pyrrolidinyl)pyridine) is a volatile compound which is prone to degradation under the influence of heat, oxygen and light. For this reason, it is a technical challenge to find a suitable non-tobacco dosage form as a product which counteracts the degradation during its manufacturing process, provides suitable nicotine storage stability while allowing an ideal release rate of nicotine in the oral cavity and has compliance for the user. For these reasons, developers of nicotine dosage forms are looking for new agents to replace tobacco but support an extended shelf life, an ideal release profile and high compliance for the consumer.

[0004] WO 2010 / 011445 discloses an oral plant fiber product suitable for delivering an active agent such as nicotine. The introduction of alginate as a matrix forming agent provides the product with ideal release properties and proper stabilization of the susceptible active agent.

[0005] WO 2010 / 104464 discloses alginate particles for the oral cavity comprising an active agent such as nicotine encapsulated in a pouch.

[0006] WO 2015 / 051308 and US 2015 / 0098996 disclose tobacco or nicotine lozenges having at least 40% by weight of water-soluble fibers mainly maltodextrin and less than 15% water. However, nothing is disclosed about the shelf life of nicotine or the release properties of nicotine in the oral cavity.

[0007] EP1622627 describes pharmaceutical compositions comprising cereal beta-glucan and a pharmaceutical agent, suggested for the delivery of pharmaceutical agents such as local anesthetics in the oral cavity. However, no such products were manufactured or actually tested in this document, and therefore it cannot be concluded whether cereal beta-glucan is a suitable excipient for the delivery of susceptible active agents to the oral or nasal cavity.

[0008] US2010 / 158988 describes dry, dissolvable films or coatings for oral use based on cereal beta-glucan, which can comprise up to 10% by weight of a filler. However, these films do not show any suitability as nicotine products suitable for the delivery of nicotine to the oral or nasal cavity. EP1790687 describes similar dry films that can comprise nicotine, but does not teach nicotine dosage forms with similar consumer compliance as traditional tobacco products.

[0009] WO2010091649 relates to a tobacco-free nicotine product for oral use, thereby describing the pH value. However, it is not disclosed how the stability and release of nicotine can be influenced by purposefully selected supporting agents.

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

[0011] CN104784197 discloses a composition specifically for the delivery of the active agent epigallocatechin gallate, comprising beta-glucan.

[0012] US6499490 discloses a tobacco substitute sheet comprising beta-glucan and tobacco leaf extract. SUMMARY

[0013] It is an object of the present invention to provide a composition suitable for the delivery of a biologically active agent to the oral 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.

[0014] It is a further object of the present invention to provide a composition that supports a controlled release rate of the active agent and a suitable duration of said release rate.

[0015] It is a further object of the present invention to provide a composition that facilitates the stabilization of active agents that are susceptible to degradation during storage, thereby obtaining a stable product with a long shelf life also in compositions with a higher water content.

[0016] It is another object of the present invention to provide compositions with high compliance to the oral or nasal mucosa 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 compositions suitable for delivering nicotine to the oral or nasal cavity to meet the user's expectations of comparable compliance to conventional tobacco products or pharmaceutical products.

[0018] In general, the present invention relates to compositions for the oral or nasal cavity comprising a bioactive agent, a matrix forming agent comprising beta-glucan, and a filler.

[0019] In the general context of the present invention, the matrix forming agent is capable of providing a cohesive homogeneous composition together with the filler, which comprises the bioactive agent and contributes to exert a stabilizing effect on such agent susceptible to be affected, while contributing to a controlled desirable release profile of the active agent upon contact with the oral or nasal cavity. The stabilizing effect and the release profile can be caused, in one aspect, by the interaction or synergy with the filler (e.g. between the fibers of the matrix forming agent and the filler). Thus, in the compositions of the present invention, the interaction between the active agent and the matrix forming agent can be used to modulate and control the release rate.

[0020] The matrix forming agent of the present invention is also used to bind the bioactive agent in the composition in a controlled manner. For example, when the active agent is nicotine, the matrix forming agent can be selected such that a controlled amount of nicotine is free, unbound nicotine, and a controlled amount of nicotine is gradually and controllably released from the matrix forming agent. For example, by increasing the amount of matrix forming agent in the compositions of the present invention, more nicotine is bound and gradually released. Thus, compositions can be developed to provide a satisfactory initial dose of nicotine to the user upon application to the oral or nasal cavity, and to provide nicotine gradually released from the composition over a predetermined length of time. For nicotine products, the matrix forming agent can be used to meet different requirements of user compliance.

[0021] In one aspect, the compositions of the present invention comprise less than 50% by weight of the matrix forming agent, for example less than 40% or less than 30% and less than 20%, or 0.1% to 10% by weight, or 0.5% to 5% by weight.

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

[0023] In addition, in this general context, the bulking agent will primarily contribute to the volume and shape of the composition, for example allowing user compliance in different parts of the oral cavity and / or facilitating easy manufacture, handling and application of the composition. In embodiments, the bulking agent can also positively interact with the matrix forming agent to stabilize the agent and induce desirable release characteristics.

[0024] The beta-glucan of the composition can be obtained from various sources, including cereals and yeast, and comprises at least 30% beta(1-3)beta(1-4) glucan, preferably 70% to 99% or almost 100% beta(1-3)beta(1-4) glucan. The beta-glucan is preferably obtained from cereals, more preferably from oats. Cereal beta-glucan can be refined to an appropriate high grade by methods outlined in, for example, Journal of Food Science, 2017, 82(9) (G Maheshwari et al.) and Chemical Engineering and Processing, 2014, 84, pages 90-97 (O Benito-Roman et al.).

[0025] In one aspect, the composition of the invention comprises a matrix forming agent comprising at least 50% by weight of beta-glucan. The composition of the invention can comprise a matrix forming agent further comprising at least one additional food or pharmaceutical grade pharmaceutically acceptable gum or gel forming polysaccharide, preferably selected from the group consisting of alginic acid and suitable salts thereof, xanthan gum, carrageenan, methylcellulose, curdlan, pullulan, guar gum, gum arabic and similar polysaccharides, preferably the additional gum is alginic acid salt, more preferably sodium alginate.

[0026] The bulking agent of the composition of the invention comprises a fibrous material, which can be of natural or synthetic origin. The fibre is preferably derived from a plant, an alga or a fungus, and it can be natural or modified with biological or chemical processes. In a preferred aspect, the fibrous material is a plant fibre, more preferably the bulking agent comprises natural or modified cellulose fibres, most preferably at least one microcrystalline cellulose.

[0027] In various embodiments, the plant fibres comprised in the bulking agent can be derived from tea, coffee, tobacco, cocoa, corn, bamboo, oat, barley, rye, sugar beet, vanilla, buckwheat, potato, tomato, eggplant, cauliflower, apple, mate or cellulose fibres from various sources and the like. The plant fibres can be natural or modified with various biological or chemical processes. The tobacco fibres can be processed according to various conventional techniques for whiteness and / or reduction of nitrosamines.

[0028] The microcrystalline cellulose (MCC) suitable for the bulking agent can be selected from grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, grades 101, 102, 12, 20, grades 50M and 90M, grades, for example 90M and the like, and mixtures thereof. For embodiments of the composition of the application wherein water-soluble microcrystalline cellulose is required, the colloidal microcrystalline cellulose grades are useful, for example the various grades of

[0029] For embodiments of the composition of the application wherein water-soluble microcrystalline cellulose is required, for example powder compositions for the nasal cavity, suitable colloidal microcrystalline cellulose grades are grades with Cas No. 51395-75-6, for example the various brands of The preferred such colloidal gelified MCC is known under the trade name FEIYUN XW591.

[0030] In embodiments of the composition of the application, the filler comprises a polyol, preferably a polyol selected from one or more of mannitol, xylitol, sorbitol, maltitol and / or isomaltitol, lactitol and erythritol. Suitably, the composition of the application comprises a plant fibre material and 5 to 70 wt% of a polyol, preferably the filler comprises mannitol and at least one microcrystalline cellulose.

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

[0032] In embodiments of the application relating to powder compositions for the nasal cavity, the composition comprises powder particles having a controlled average size (diameter) of, 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 taking into account the avoidance of aerosolization and the risk of accidental distribution of the powder to the lungs when the particle size is close to <10 pm, as well as the avoidance of insufficient compliance and distribution of large particles with a size exceeding about a few millimetres.

[0033] The biologically active agent can be a therapeutic or non-therapeutic substance not generally considered a drug, such as a natural remedy formulation, a stimulant or a nutraceutical. Examples of therapeutic biologically active substances that can be administered alone or in combination by the compositions of the present application include: urinary incontinence agents; antihistamines, analgesics, anti-inflammatory agents, anti-emetics, anti-epileptics, vasodilators, antitussives and expectorants, antispastics, hormones, diuretics, hypotensives, 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 a drug delivery dosage form for patients suffering from complications that result in an inability to accept conventional swallowable tablets, such as coma, severe migraine, acute stroke or gastrointestinal obstruction. Examples of suitable non-therapeutic agents are caffeine, alcohol powder, ethanol, vitamin B12, vitamin C, vitamin E, Coenzyme Q10, selenium, glutathione, alpha-lipoic acid, folic acid, ginseng, pollen extract, antioxidants, minerals, paracetamol, acetylsalicylic acid, Russian and rose roots and the like.

[0034] In embodiments of the application, the composition has a pH of at least 6.5, preferably a pH of 8 to 9, and the biologically active agent is nicotine or a cannabinoid, such as THC.

[0035] In embodiments, the biologically active agent is nicotine. The term nicotine includes synthetic nicotine and nicotine extract from tobacco plants such as Nicotiana species or other plant sources, and includes nicotine or nicotine derivatives in any solid or liquid form, such as amorphous, crystalline, polymorphic and the like physical forms, or chemical forms 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 salts thereof, such as nicotine hydrochloride, nicotine dihydrochloride, nicotine monobitartrate, nicotine bitartrate, nicotine sulphate, nicotine zinc chloride (monohydrate) and nicotine salicylate.

[0036] Nicotine is typically present at a concentration of about 0.1 wt% to about 5 wt%, such as 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% calculated as the free base. Nicotine or salts thereof for use with the compositions of the present application preferably have a high purity, such as 99.5% purity.

[0037] The antioxidant of the composition 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 complexing binding antioxidant, more preferably the antioxidant is selected from at least one of the group consisting of alkali and / or alkaline earth metal salts of ascorbic acid, calcium citrate, calcium lactate, calcium maleate, calcium tartrate, calcium disodium ethylenediaminetetraacetate, calcium phosphate and ammonium citrate, more preferably the antioxidant is an ascorbate salt selected from sodium ascorbylphosphate, potassium ascorbate, calcium ascorbate, calcium ascorbylphosphate, magnesium ascorbate. Most preferably the antioxidant is calcium ascorbate. This type of antioxidant is generally preferred when the biologically active agent is nicotine. However, other types of active agents can require supplemental or different antioxidants or antioxidant systems to achieve suitable storage stability.

[0038] The composition of the present invention further comprises at least one excipient selected from the group consisting of plasticizers, pH adjusting agents, preservatives, taste or flavour enhancers, colouring agents and sweetening agents.

[0039] The plasticizer can be, for example, polyethylene glycol, propylene glycol, glycerol and sorbitol. The preferred plasticizer is sorbitol, optionally together with a proportion of glycerol.

[0040] The pH adjusting agent is capable of maintaining a pH of at least 6.5 in the composition and examples can be carbonates, including mono-, bi- and hemi-carbonates, and other alkali metal salts of physiologically acceptable acids, for example acetate, glycolate, gluconate, borate, glycerophosphate, or weak organic acids such as citric acid, phosphates, metal hydroxides such as sodium and potassium hydroxide, and mixtures thereof. Examples of suitable pH adjusting agents are sodium bicarbonate and sodium carbonate and mixtures thereof. It is preferred that the pH is higher at the time of production of the composition, for example pH 8 to 9, but the pH adjusting agent should be capable of maintaining a pH > 6.5 throughout storage and use.

[0041] The preservative can be selected from agents approved in the food and pharmaceutical industries, for example sorbic acid, sorbates, benzoic acid, lactic acid and physiologically acceptable salts. The preferred preservative is potassium sorbate.

[0042] Taste or flavour enhancers include ammonium chloride, essential oils (including distillates, solvent extracts or cold-pressed materials of chopped flowers, leaves, fruit peels or pulped whole fruits containing mixtures of alcohols, esters, aldehydes and lactones) or essences (including dilute solutions of essential oils or mixtures of synthetic chemical blends) to match the desired flavour from, for example, bergamot, eucalyptus, orange, tangerine, mandarin, lemon, peppermint, mint, menthol, liquorice, wintergreen, tobacco, coffee, vanilla, lime, apple, peach and mixtures thereof. Other examples include: artificial and natural flavours of spirits and liquors (for example cognac, whiskey, rum, gin, sherry, port and wine), eucalyptus, liquorice and menthol.

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

[0044] The sweetener can be a natural sweetener that does not ferment in the mouth, or an artificial sweetener, such as aspartame, acesulfame, saccharin, cyclamate, stevia extract, and other similar agents.

[0045] In some aspects of the application, the composition is a powder composition suitable for delivery to the nasal cavity and comprises: less than 50%, preferably 0.5% to 5% by weight of the defined matrix forming agent, and less than 20% by weight of water, preferably 1% to 15% by weight of water. The size of the powder particles of such a composition ranges from 0.01 mm to 5 mm, or preferably from 0.05 mm to 2 mm. In embodiments of such a composition, 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. Such a composition can further comprise an active agent as defined above, a filler and excipients. In one embodiment suitable for nasal use, the composition comprises nicotine, 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 adjusting agent, an antioxidant, and further excipients selected from one or more of a preservative, a taste / flavour enhancer and a sweetener. In one embodiment suitable for nasal use, the composition is a powder having a particle size of less than about 2 mm, and comprises nicotine, 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 adjusting agent, an antioxidant, and further excipients selected from one or more of a preservative, a taste / flavour enhancer and a sweetener. In another embodiment suitable for nasal use, the composition is a powder having a particle size of 0.01 mm to 5 mm, and comprises nicotine, beta-glucan as a matrix forming agent, a filler comprising at least partially water-soluble cellulose, 1% to 15% by weight of water, sodium bicarbonate as a pH adjusting agent, calcium ascorbate as an antioxidant, and further excipients selected from one or more of a preservative, a taste / flavour enhancer and a sweetener.

[0046] In aspects of the application, the composition is suitable for delivery to the oral cavity by contact with the mucosa. Such compositions comprise less than 50%, preferably 0.1 to 10%, more preferably 0.5 to 5% by weight of a matrix former as defined above, and comprise at least 30% by weight of water, preferably 40 to 60% by weight of water. Such compositions can also comprise an active agent as defined above, a filler and excipients. In embodiments, the composition comprises at least 40% by weight of a filler, which preferably comprises microcrystalline cellulose. Suitably, such compositions can be provided as conventional tobacco products, for example snus products in which a defined amount of the composition is packaged in a pouch. In one embodiment of such a composition, it comprises nicotine, a beta-glucan as matrix former, a filler comprising microcrystalline cellulose, at least 30% by weight of water, a pH adjusting agent, an antioxidant and further excipients selected from one or more of a preservative, a taste / flavour enhancer and a sweetener. In one embodiment of such a composition, it comprises nicotine, a beta-glucan as matrix former, a filler comprising microcrystalline cellulose and optionally mannitol and / or other plant fibres, 40 to 60% by weight of water, a pH adjusting agent, an antioxidant and further excipients selected from one or more of a preservative, a taste / flavour enhancer and a sweetener. In one embodiment of such a composition, it comprises nicotine, a matrix former comprising a beta-glucan and one or more further pharmaceutically / nutrically acceptable gums as defined above, a filler comprising microcrystalline cellulose and optionally mannitol and / or other plant fibres, 40 to 60% by weight of water, a pH adjusting agent, an antioxidant and further excipients selected from one or more of a preservative, a taste / flavour enhancer and a sweetener.

[0047] In aspects of the application, the composition is suitable for delivery to the oral cavity as a lozenge or tablet which dissolves gradually on contact with saliva. The composition comprises at least 50% of a matrix former as defined above, which comprises less than 30% by weight of water, preferably 1 to 30% by weight of water. Such compositions can also comprise an active agent as defined above, a filler and excipients. In certain embodiments, the filler can comprise microcrystalline cellulose, and in certain embodiments, the lozenge can have a coating comprising an active agent, preferably comprising nicotine designed to provide an initial immediate dose for use before a gradual release is established.

[0048] In other aspects of the application, the composition comprises more than 50% of a matrix forming agent and is configured as a film suitable for transmucosal delivery of the active agent. The film composition has a thickness of 0.01 mm to 7 mm and optionally comprises a plasticizer. In one embodiment, these compositions comprise 0.05% to 20% by weight, preferably 5% to 10% by weight of a filler, preferably the filler is microcrystalline cellulose and the plasticizer, preferably the plasticizer is selected from at least one of sorbitol and glycerol.

[0049] The composition and amount of the filler and other mentioned excipients can vary depending on the desired properties of the final product, for example in order to obtain an attractive appearance for the mouth or nose.

[0050] These and other embodiments will be more fully illustrated in the following detailed description.

[0051] In another general aspect, the application relates to a method of manufacturing a composition for the mouth and nose. 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 comprising a pH adjusting agent; adding a second aqueous solution comprising at least one of a preservative, a taste or flavor enhancer and a sweetener; adding a third aqueous solution comprising one or more bioactive agents; and finally mixing all the ingredients added to the mixture with a suitable amount of water.

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

[0053] In one embodiment of the method, the filler is dry mixed with the antioxidant in the first step, and the third aqueous solution comprises the matrix forming agent and one or more bioactive agents.

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

[0055] In another alternative, the method can be configured to produce a composition for the mouth by one or more further processing steps to the resulting mixture using at least one of bagging, forming tablets or lozenges, extruding, stamping, casting, molding, injection molding, mixing, spinning, film forming, diluting into a spray form, shaping and mixing with a chewing gum base. DETAILED DESCRIPTION

[0056] Table 1 below further illustrates examples of mouth or nose compositions comprising suitable excipients.

[0057] Ingredient Purpose Amount (% by weight) Water Humidification 2％-70％ Sodium chloride Taste <15％ Microcrystalline cellulose Filling agent 5％-95％ Sodium bicarbonate / sodium carbonate pH adjuster <2％ Beta-glucan > 70% purity Matrix former <5％ Ammonium chloride Flavor <2％ Potassium sorbate Preservative <0.2％ Xylitol Sweetener <5％ Acesulfame / Stevia Sweetener <0.5％ Menthol / spearmint / lemon / others Flavor <5％ Calcium ascorbate Antioxidant <5％ Nicotine Active agent <20％

[0058] Table 1

[0059] Example 1

[0060] Table 2 shows specific examples of the composition products manufactured using the described method.

[0061]

[0062] Table 2

[0063] The nicotine stability of the compositions of Table 2, which have no flavour and a pH of about 8.5, suitable for packaging in a pouch for use in the mouth as a snus-type product, was tested against a commercially available tobacco-based snus product. Samples of 80g of the compositions of Table 2 and the tobacco-based snus product were compared over 9 weeks at 40°C and 75% relative humidity (equivalent to 10 months at 25°C, unadjusted relative humidity).

[0064] Composition of Table 2 Commercial product Water content % by weight 45.93 41.9 Initial nicotine amount (mg) 1.1 1.0 Nicotine amount after 9 weeks (mg) 1.1 0.74

[0065] Table 3

[0066] Table 3 shows that the beta-glucan and antioxidant of the compositions of the application result in a significant increase in nicotine stability. Previous testing of a composition similar to Table 2 but without any antioxidant showed nicotine stability comparable to a commercially available tobacco-based product. This result shows that the matrix-forming agent comprising beta-glucan of the compositions of the application has a comparable ability to preserve nicotine to that of natural tobacco fibres. In summary, the combination of a matrix-forming agent comprising beta-glucan and a chelating binding antioxidant provides effective long-term stability of nicotine.

[0067] Example 2

[0068]

[0069] Table 4

[0070] Table 4 shows examples of lozenges or water-soluble tablets comprising beta-glucan as a matrix-forming agent.

[0071] The lozenges or tablets are made by dry mixing all the ingredients in Table 4, transferring the resultant product to a conventional tablet-forming machine and subjecting it to high pressure to form the tablets / lozenges. The tablets are spray-coated and dried in a coating tank to obtain a coating of the desired taste, which comprises sweeteners, flavourings and similar agents. The coating can optionally comprise nicotine to provide an initial dose.

[0072] Example 3

[0073] The products according to the application and Table 1 have 0.89 wt% nicotine, about 41 wt% water, 1% or 2% beta-glucan as a matrix former. The products were made with the two alternative processes described above. In process 1, the beta-glucan was dry mixed with the filler in the first step and the nicotine solution was added in the third step. The product of process 1 contained 1 wt% beta-glucan. In process 2, 1 wt% or 2 wt% beta-glucan was added to the solution containing nicotine in the third step. The product of process 2 contained 1 wt% or 2 wt% beta-glucan. The products were packed in regular snus pouches and benchmarked against two commercially available tobacco-free nicotine products CP1 and CP2, which contained microcrystalline cellulose as filler but no beta-glucan as matrix former. The stability and nicotine release of the products of the application, CP1 and CP2 were investigated. For the stability test, the products were put in a heated cabinet at 40°C, 75% humidity for 9 weeks (representing 7 months at room temperature).

[0074] Initial nicotine amount % by weight Nicotine amount after 7 months % nicotine loss Product of process 1 0.89 0.75 20 CP1 1 0.74 26 CP2 0.61 0.46 25

[0075] Table 5

[0076] Initial pH pH value after 7 months % pH reduction Product of process 1 7.6 7.4 3 CP1 8.4 7.9 6 CP2 8.3 8 4

[0077] Table 6

[0078] Initial water content % by weight Water content % by weight after 7 months % change Product of process 1 41.2 43.9 +7 CP1 41.9 39.8 -5 CP2 45.3 47.9 +6

[0079] Table 7

[0080] The results in Tables 5 to 7 show that the products of the application containing a matrix former using beta-glucan are significantly better stabilized against both nicotine and pH during storage than CP1 or CP2. The change in water content between the products can be caused by the different fillers.

[0081] To test the nicotine release capacity of the compositions of the application, pouches containing the products were made with process 1 and process 2 as described above and compared to CP1. The products were tested in the mouth by the panelists, removed after a specified time and the remaining nicotine was treated. The used pouches were cut up and put in 100 ml glass bottles and treated with ultrasound for 5 minutes with 5 ml Milli-Q water. Thereafter, 100 ml of a 0.05 M potassium hydroxide solution was added, the sample was shaken and then treated with ultrasound for 60 minutes. The sample was shaken on a shaker overnight and treated with ultrasound for another 30 minutes the next day. Thereafter the sample was 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 three tests are shown in Table 8 below.

[0082]

[0083] Table 8

[0084] Table 8 shows that the amount of matrix forming agent in the composition of the present application can be used to control the rate of release of nicotine. For example, doubling the amount of beta glucan from 1 wt% to 2 wt% resulted in an 18% increase in the amount of nicotine bound to the matrix forming agent over a 38 minute period. Furthermore, the method of manufacturing the composition can be used to control the amount of nicotine bound to the beta-glucan of the matrix forming agent. The results of Table 8 show that a higher amount of bound nicotine is obtained when the nicotine is added with the matrix forming agent as the third, i.e. last step in the manufacturing process.

Claims

1. A pouch product comprising a composition for use in the oral cavity, the composition comprising a bioactive agent, a bulking agent, and a matrix forming agent comprising beta-glucan, wherein the composition has a pH of at least 6.5, wherein, The biologically active agent is nicotine, and wherein the composition comprises at least 30% by weight water.

2. The pouch product comprising the composition according to claim 1, wherein, The beta-glucan comprises at least 30% beta (1-3) beta (1-4) glucan.

3. The pouch product comprising the composition of claim 1, wherein, The beta-glucan comprises 70% to 100% beta (1-3) beta (1-4) glucan.

4. The pouch product comprising the composition according to claim 2 or 3, wherein, The beta-glucan is a cereal beta-glucan.

5. The pouch product comprising the composition of claim 4, wherein, The beta-glucan is obtained from oats.

6. The pouch product comprising the composition according to any of claims 1-3 and 5, wherein, The matrix forming agent comprises at least one additional pharmaceutically acceptable gum.

7. The pouch product containing the composition according to claim 4, wherein, The matrix forming agent comprises at least one additional pharmaceutically acceptable gum.

8. The pouch product containing the composition according to claim 6, wherein, The additional pharmaceutically acceptable gum is selected from the group consisting of alginic acid and salts thereof, xanthan gum, carrageenan, methylcellulose, curdlan and pullulan.

9. The pouch product containing the composition according to claim 6, wherein, The additional pharmaceutically acceptable gum is an alginic acid salt.

10. The pouch product comprising the composition of claim 6, wherein, The additional pharmaceutically acceptable gum is sodium alginate.

11. The pouch product comprising the composition of claim 7, wherein, The additional pharmaceutically acceptable gum is selected from the group consisting of alginic acid and salts thereof, xanthan gum, carrageenan, methylcellulose, curdlan and pullulan.

12. The pouch product comprising the composition of claim 7, wherein, The additional pharmaceutically acceptable gum is an alginic acid salt.

13. The pouch product comprising the composition of claim 7, wherein, The additional pharmaceutically acceptable gum is sodium alginate.

14. The pouch product comprising the composition of claim 2, wherein, The matrix forming agent comprises at least 50% by weight cereal beta-glucan.

15. The pouch product comprising the composition of any one of claims 1-3, 5, and 7-14, comprising an antioxidant effective at a pH of at least 6.

5.

16. The pouch product comprising the composition of claim 4, comprising an antioxidant effective at a pH of at least 6.

5.

17. The pouch product comprising the composition of claim 6, comprising an antioxidant effective at a pH of at least 6.

5.

18. The pouch product comprising the composition of claim 15, comprising an antioxidant effective at a pH of 8 to 9.

19. The pouch product comprising the composition of claim 15, wherein the antioxidant is a chelate binding antioxidant.

20. The pouch product comprising the composition of claim 15, wherein the antioxidant is selected from at least one of an alkali and / or alkaline earth salt of ascorbic acid, calcium citrate, calcium lactate, calcium maleate, calcium tartrate, calcium disodium edetate, calcium phosphate, and ammonium citrate.

21. The pouch product comprising the composition of claim 15, wherein the antioxidant is calcium ascorbate.

22. The pouch product comprising the composition of claim 16 or 17, comprising an antioxidant effective at a pH of 8 to 9.

23. The pouch product comprising the composition of claim 16 or 17, wherein the antioxidant is a chelate binding antioxidant.

24. The pouch product comprising the composition of any one of claims 16-17, wherein the antioxidant is selected from at least one of an alkali and / or alkaline earth salt of ascorbic acid, calcium citrate, calcium lactate, calcium maleate, calcium tartrate, calcium disodium edetate, calcium phosphate, and ammonium citrate.

25. The pouch product comprising the composition of any one of claims 16-17, wherein the antioxidant is calcium ascorbate.

26. The pouch product comprising the composition of any of claims 1-3, 5, 7-14, and 16-21, wherein, The filler comprises a fibrous material.

27. The pouch product comprising the composition of claim 4, wherein, The filler comprises a fibrous material.

28. The pouch product comprising the composition of claim 6, wherein, The filler comprises a fibrous material.

29. The pouch product comprising the composition of claim 15, wherein, The filler comprises a fibrous material.

30. The pouch product comprising the composition of claim 22, wherein, The filler comprises a fibrous material.

31. The pouch product comprising the composition of claim 23, wherein, The filler comprises a fibrous material.

32. The pouch product comprising the composition of claim 24, wherein, The filler comprises a fibrous material.

33. The pouch product containing the composition of claim 25, wherein, The filler comprises a fibrous material. The filler comprises a fibrous material.

34. The pouched product comprising a composition of claim 26, wherein the fibrous material is a plant fiber.

35. The pouched product comprising a composition of claim 26, wherein the filler comprises a natural or modified cellulose fiber.

36. The pouched product comprising a composition of claim 26, wherein the filler comprises at least one microcrystalline cellulose.

37. The pouched product comprising a composition of any one of claims 27-33, wherein the fibrous material is a plant fiber.

38. The pouched product comprising a composition of any one of claims 27-33, wherein the filler comprises a natural or modified cellulose fiber.

40. The pouch product comprising the composition of any of claims 1-3, 5, 7-14, 16-21, and 27-36, wherein, 39. The pouched product comprising a composition of any one of claims 27-33, wherein the filler comprises at least one microcrystalline cellulose.

41. The pouch product comprising the composition of claim 4, wherein, The filler comprises a polyol.

42. The pouch product comprising the composition of claim 6, wherein, The filler comprises a polyol.

43. The pouch product comprising the composition of claim 15, wherein, The filler comprises a polyol.

44. The pouch product comprising the composition of claim 22, wherein, The filler comprises a polyol.

45. The pouch product comprising the composition of claim 23, wherein, The filler comprises a polyol.

46. The pouch product comprising the composition of claim 24, wherein, The filler comprises a polyol.

47. The pouch product comprising the composition of claim 25, wherein, The filler comprises a polyol.

48. The pouch product containing the composition of claim 26, wherein, The filler comprises a polyol.

49. The pouch product containing the composition of claim 37, wherein, The filler comprises a polyol.

50. The pouch product containing a composition of claim 38, wherein, The filler comprises a polyol.

51. The pouch product containing a composition of claim 39, wherein, The filler comprises a polyol. The filler comprises a polyol.

52. The pouched product comprising a composition of claim 40, wherein the filler comprises a polyol selected from one or more of mannitol, xylitol, sorbitol, maltitol and / or isomaltitol, lactitol, and erythritol.

54. The pouch product comprising the composition of claim 26, wherein, 53. The pouched product comprising a composition of any one of claims 41-51, wherein the filler comprises a polyol selected from one or more of mannitol, xylitol, sorbitol, maltitol and / or isomaltitol, lactitol, and erythritol.

55. The pouch product comprising the composition of any one of claims 27-33, wherein, The filler comprises a plant fibrous material and 5% to 70% by weight of a polyol. The filler comprises a plant fibrous material and 5% to 70% by weight of a polyol.

56. The pouched product comprising a composition of claim 54, wherein the filler comprises mannitol and at least one microcrystalline cellulose.

57. The pouched product comprising a composition of claim 55, wherein the filler comprises mannitol and at least one microcrystalline cellulose.

58. The pouched product comprising a composition of any one of claims 1-3, 5, 7-14, 16-21, 27-36, 41-52, 54, and 56-57, comprising at least one excipient selected from a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

59. The pouched product comprising a composition of claim 4, comprising at least one excipient selected from a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

60. The pouch product comprising the composition of claim 6, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

61. The pouch product comprising the composition of claim 15, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

62. The pouch product comprising the composition of claim 22, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

63. The pouch product comprising the composition of claim 23, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

64. The pouch product comprising the composition of claim 24, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

65. The pouch product comprising the composition of claim 25, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

66. The pouch product comprising the composition of claim 26, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

67. The pouch product comprising the composition of claim 37, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

68. The pouch product comprising the composition of claim 38, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

69. The pouch product comprising the composition of claim 39, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

70. The pouch product comprising the composition of claim 40, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

71. The pouch product comprising the composition of claim 53, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

72. The pouch product comprising the composition of claim 55, comprising at least one excipient selected from the group consisting of a preservative, a taste or flavor enhancer, a pH adjusting agent, a plasticizer, and a sweetener.

73. The pouch product comprising the composition of any one of claims 1-3, 5, 7-14, 16-21, 27-36, 41-52, 54, 56-57, and 59-72, comprising less than 50% by weight of the matrix former.

74. The pouch product comprising the composition of claim 4, comprising less than 50% by weight of the matrix former.

75. The pouch product comprising a composition of claim 6, comprising less than 50% by weight of the matrix former.

76. The pouch product comprising a composition of claim 15, comprising less than 50% by weight of the matrix former.

77. The pouch product comprising a composition of claim 22, comprising less than 50% by weight of the matrix former.

78. The pouch product comprising a composition of claim 23, comprising less than 50% by weight of the matrix former.

79. The pouch product comprising a composition of claim 24, comprising less than 50% by weight of the matrix former.

80. The pouch product comprising a composition of claim 25, comprising less than 50% by weight of the matrix former.

81. The pouch product comprising a composition of claim 26, comprising less than 50% by weight of the matrix former.

82. The pouch product comprising a composition of claim 37, comprising less than 50% by weight of the matrix former.

83. The pouch product comprising a composition of claim 38, comprising less than 50% by weight of the matrix former.

84. The pouch product comprising a composition of claim 39, comprising less than 50% by weight of the matrix former.

85. The pouch product comprising a composition of claim 40, comprising less than 50% by weight of the matrix former.

86. The pouch product comprising a composition of claim 53, comprising less than 50% by weight of the matrix former.

87. The pouch product comprising a composition of claim 55, comprising less than 50% by weight of the matrix former.

88. The pouch product comprising a composition of claim 58, comprising less than 50% by weight of the matrix former.

89. The pouch product comprising a composition of claim 73, comprising less than 40% by weight of the matrix former.

90. The pouch product comprising a composition of any one of claims 74-88, comprising less than 40% by weight of the matrix former.

91. The pouch product comprising a composition of any one of claims 1-3, 5, 7-14, 16-21, 27-36, 41-52, 54, 56-57, 59-72, and 74-89, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

92. The pouch product comprising a composition of claim 4, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

93. The pouch product comprising a composition of claim 6, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

94. The pouch product comprising a composition of claim 15, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

95. The pouch product comprising the composition of claim 22, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

96. The pouch product comprising the composition of claim 23, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

97. The pouch product comprising the composition of claim 24, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

98. The pouch product comprising the composition of claim 25, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

99. The pouch product comprising the composition of claim 26, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

100. The pouch product comprising the composition of claim 37, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

101. The pouch product comprising the composition of claim 38, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

102. The pouch product comprising the composition of claim 39, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

103. The pouch product comprising the composition of claim 40, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

104. The pouch product comprising the composition of claim 53, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

105. The pouch product comprising the composition of claim 55, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

106. The pouch product comprising the composition of claim 58, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

107. The pouch product comprising the composition of claim 73, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

108. The pouch product comprising the composition of claim 90, adapted for contact with the oral mucosa, the bulking agent comprising microcrystalline cellulose.

109. The pouch product comprising the composition of claim 91, comprising 40% to 60% by weight of water.

110. The pouch product comprising the composition of any one of claims 92-108, comprising 40% to 60% by weight of water.

111. A method of manufacturing the pouch product comprising the composition of any one of claims 1 to 110, comprising: (i) dry mixing a bulking agent, a substrate forming agent comprising beta-glucan, and optionally, an antioxidant; (ii) mixing the dry mixture with a first aqueous solution comprising a pH adjusting agent; (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 comprising nicotine, obtaining a mixture, and mixing the obtained mixture with an appropriate amount of water.

112. A method of manufacturing a pouch product comprising the composition of any one of claims 1 to 110, comprising: (i) dry mixing of the bulking agent and optionally, the antioxidant; (ii) mixing the dry mixture with a first aqueous solution comprising the pH adjusting agent; (iii) adding a second aqueous solution comprising at least one of the preservative, the taste or flavour enhancer, and the sweetener; (iv) adding a third aqueous solution, resulting in a mixture, wherein the third aqueous solution comprises the matrix forming agent and the nicotine, the matrix forming agent comprising beta-glucan, and mixing the resulting mixture with a suitable amount of water.

113. The method of any one of claims 111 to 112, configured to produce a pouch product comprising the composition for the oral cavity by a processing method of bagging the resulting mixture.

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