Novel compositions for oral or nasal use

Abstract

The present specification discloses a composition for use in the oral or nasal cavity, comprising a biologically active substance, a matrix-forming agent comprising alginate and suitable salts thereof, a filler, and at least one antioxidant that is an effective composite binder. The composition may further comprise additional additives such as preservatives, taste or flavor enhancers, pH adjusters, plasticizers, and sweeteners. The present specification also discloses a method for producing the composition.

Description

[Technical Field]

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

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

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

[0004] There are several disclosures of products suitable for delivering active substances to the oral cavity, such as WO2005 / 048080, WO0054777; US Patent Application Publication No. 200307315; WO2010 / 0104464, which disclose matrix-forming agents and antioxidants. Antioxidants. WO2007 / 104574; U.S. Patent Application Publication No. 2005226823; U.S. Patent Application Publication No. 2013186418 disclose various orally useful nicotine compositions containing antioxidants, but do not disclose matrix-forming agents. WO2013 / 143891 discloses an alginate-based nicotine-containing oral film without specifically inducing nicotine stabilization. WO2019 / 224323 discloses another alginate-based oral film containing antioxidants for delivering drugs other than nicotine.

[0005] WO 2010 / 011445 discloses a plant fiber product for oral use suitable for delivering active substances such as nicotine. The incorporation of alginate as a matrix-forming agent provides the product with desirable release characteristics and adequate stabilization of susceptible active substances. WO 2010 / 104464 discloses alginate particles containing an active substance such as nicotine encapsulated in a pouch for oral use. WO 2010 / 0104464 indicates that the alginate matrix may form an oxygen barrier, and the addition of antioxidants may not be required. However, certain highly susceptible active substances require additional protection from degradation during long-term storage, especially in systems with high water content. Therefore, there is a need for an additionally stabilized composition that relies on an alginate matrix and includes an effective antioxidant along with alginic acid throughout the desired pH range. Summary of the Invention [Means for solving the problem]

[0006] It is an object of the present invention to provide a composition suitable for delivering a biologically active substance to the oral or nasal cavity, which allows for a suitable release profile of the biologically active substance while allowing for stability of the active substance throughout manufacture and storage.

[0007] It is also an object of the present invention to provide a composition that supports a controlled release rate of an active substance and an appropriate duration of the controlled release rate.

[0008] It is also an object of the present invention to provide a composition that promotes stabilization of active substances that are susceptible to degradation during storage, resulting in a stable product with a long shelf life, even in compositions with a relatively high moisture content.

[0009] It is also an object of the present invention to provide a composition that has high compliance with the mucous membranes of the oral nasal cavity to avoid local irritation and side effects due to repeated or prolonged exposure.

[0010] It is yet another object of the present invention to provide a composition suitable for delivering nicotine to the oral or nasal cavity, thereby meeting user expectations of compliance with comparable and conventional tobacco or nicotine products or pharmaceuticals.

[0011] Another object of the present invention is to provide a manufacturing method that controls both the bound and unbound nicotine in the matrix-forming agent to provide an initial consumer-satisfying nicotine dose with a gradual nicotine release comparable to that from conventional tobacco fiber, while also providing suitable stabilization of both the bound and unbound nicotine throughout storage, as well as the high moisture content product composition.

[0012] In a general aspect, the present invention relates to a composition for use in the oral or nasal cavity, the composition having a pH of at least 6.5 and comprising an active agent selected from nicotine and a cannabinoid, a matrix-forming agent comprising alginate and suitable salts thereof, a filler, and an antioxidant which is a composite binder effective at a pH of at least 6.5 and comprises at least one ammonium citrate or salt thereof.

[0013] Herein, the matrix-forming agent, together with the filler, can provide a coherent, homogeneous composition that encapsulates the biologically active substance and contributes to exerting a liable stabilizing effect on such agents, while contributing to a controllable and desirable release profile of the active substance upon contact with the oral or nasal cavity. The stabilizing effect may or may not be caused by, for example, a synergistic effect at the filler between the filler matrix and the fibers. In the compositions of the present invention, the affinity between the active substance and the matrix-forming agent can be employed to adjust and control the release rate.

[0014] The matrix-forming agent of the present invention can also be used in the composition to release nicotine in a controlled manner.For example, when the active substance is nicotine, the matrix-forming agent can be selected so that a controlled amount of nicotine is liberated, and unbound nicotine and a controlled amount of nicotine are gradually and controllably released from the matrix-forming agent.For example, by increasing the amount of matrix-forming agent in the composition of the present invention, more nicotine is bound and gradually released.Therefore, the composition of the present invention can be developed to provide users with a satisfactory initial dose of nicotine administered to the oral cavity or nasal cavity, and gradually release nicotine from the composition over a predetermined period.For nicotine products, the matrix-forming agent can be used to meet various requirements for user compliance.

[0015] Antioxidants include, for example, ammonium citrate, which is effective at pH 8-9 to complex with metal ions in compositions with high pH and contributes to stabilizing the composition throughout manufacturing and storage. The ammonium citrate is selected from dibasic ammonium citrate (ammonium hydrogen citrate), tribasic ammonium citrate (ammonium tribasic citrate), and ammonium citrate salts such as ammonium iron citrate, and most preferably, the ammonium citrate is selected from tribasic ammonium citrate (ammonium tribasic citrate).

[0016] The antioxidant is contained in the composition of the present invention in an amount of less than 5% (by weight), preferably 0.1 to 5% (by weight), and most preferably 0.5 to 1% (by weight). The antioxidant may further include at least one of alkali and / or alkaline earth metal salts of ascorbate, calcium citrate, calcium lactate, calcium maleate, calcium tartrate, Ca-diNa-EDTA, calcium phosphate, and calcium phosphate.

[0017] In one embodiment, the composition of the invention comprises less than 50% (by weight) of matrix-forming agent, such as less than 40% (by weight) or less than 30% (by weight) and less than 20% (by weight), or between 1 and 10% (by weight), or between 0.5 and 5% (by weight) of matrix-forming agent.

[0018] In another embodiment, the composition of the present invention comprises more than 50% (by weight) of matrix-forming agent, for example 50-90% (by weight) or 50-70% (by weight) of matrix-forming agent.

[0019] Also, as used herein, fillers primarily contribute to the bulk and shape of the composition, for example, to allow user compliance in different parts of the oral cavity, and / or aid in convenient manufacturing, handling, and administration of the composition. Fillers may also, in embodiments, actively interact with the matrix-forming agent to stabilize the drug(s) and induce desirable release characteristics.

[0020] Generally, alginates suitable for the present invention are alginates of monovalent cations that are soluble in cold water and have low viscosity. Those skilled in the art can select alginates with different viscosities, solubility, and molecular weights to modify dissolution in water and also in the oral or nasal cavity. Pronatal® alginate LFR 5 / 60 is an example of a low-viscosity alginate, and Protanal® LF 10 / 60 (FMC BioPolymer) is an example of a high-viscosity alginate. It may be preferable to mix alginates with different viscosities to obtain a suitable dissolution and release profile. Alginates of divalent cations, such as Ca, generally have low solubility and can be used in the compositions of the present invention, preferably in combination with one or more alginates of monovalent cations to support a specific release profile of the active substance.

[0021] In one embodiment, the matrix-forming agent in the composition of the present invention comprises at least 50% (by weight) of alginate or a salt thereof, for example 50 to 90% (by weight) of alginate or a salt thereof.

[0022] The compositions of the present invention may further comprise a matrix-forming agent comprising at least one additional pharmaceutically acceptable gum or gel-forming polysaccharide, preferably of food or pharmaceutical grade, selected from beta-glucans, including various grades of β(1-3)β(1-4) glucan, xanthan, carrageenan, methylcellulose, curdlan, pullulan, maltodextrin, guar gum, gum arabic, and similar polysaccharides, and, where applicable, suitable salts thereof.

[0023] The filler of the composition of the present invention comprises a fibrous material, which may be of natural or synthetic origin. The fiber is preferably derived from plants, algae, or fungi, and may be natural or modified by bioprocessing or chemical methods. In a preferred embodiment, the fibrous material is plant fiber, and more preferably, the filler comprises natural or modified cellulose fiber, most preferably at least one type of microcrystalline cellulose. Many chemically modified celluloses may be included in the filler of the composition, such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose brands.

[0024] In various embodiments, the plant fiber included in the filler may be derived from various sources, such as tea, coffee, tobacco, cocoa, corn, bamboo, oats, barley, rye, sugar beet, herbs, buckwheat, potato, tomato, eggplant (aubergine), cauliflower, apple, yerba mate, or one of a variety of cellulosic fiber sources, and the like. Plant fibers may be natural or modified by various biological or chemical methods. Tobacco fiber may be processed according to various conventional techniques for whiteness and / or nitrosamine reduction.

[0025] Suitable microcrystalline cellulose (MCC) can be selected from AVICEL® grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302; VIVACEL® grades 101, 102, 12, and 20; EMOCEL® grades 50M and 90M; HiCel® grades, such as HiCel® 90M, and mixtures thereof. For embodiments of the compositions of the present invention in which water-soluble microcrystalline cellulose is desired, such as powdered compositions for use in the nasal cavity, a suitable grade of colloidal microcrystalline cellulose is the grade having Cas No. 51395-75-6, e.g., various brands of TABULOSE®. A preferred such colloidal gelling MCC has the trade name FEIYUN XW591.

[0026] In an embodiment of the composition of the present invention, the filler comprises a polyol, preferably a polyol selected from one or more of mannitol, xylitol, sorbitol, maltitol and / or isomaltitol, lactitol, and erythritol. Preferably, the composition of the present invention comprises a plant fiber material and a filler comprising 5 to 70% (by weight) of a polyol. In one example, the filler comprises mannitol and at least one microcrystalline cellulose. In another example of the present invention for use in lozenges or tablets, the filler may be a polyol as defined above.

[0027] In embodiments of the present invention relating to powder compositions for use in the nasal cavity, the filler can include a mucoadhesive selected from at least one of cellulose derivatives, starch derivatives, and polyvinylpyrrolidone, and preferably the mucoadhesive is selected from at least one of sodium starch glycolate and cross-linked polyvinylpyrrolidone. In such embodiments, the filler can include guar gum or starch. Suitable starches include corn starch, pregelatinized starch, hydroxypropyl starch, and modified or unmodified starches.

[0028] In embodiments of the invention directed to powder compositions for use in the nasal cavity, the compositions comprise powder particles having a controlled average size (diameter), such as 0.01-2 mm, or 0.05-0.5 mm, or 0.02-0.2 mm, or 0.01-0.1 mm. The compositions are optimized for powder particle size, taking into consideration that particles approaching <10 μm avoid the risk of aerosolization and inadvertent powder distribution into the lungs, and particles larger than a few mm avoid poor compliance and distribution.

[0029] Generally, the compositions of the present invention are useful for active substances that may be therapeutic or non-therapeutic substances not traditionally considered pharmaceuticals, such as naturopathic medicines, stimulants, or dietary supplements. Examples of therapeutic biologically active substances suitable for administration alone or in combination via the compositions of the present invention include urinary incontinence agents, antihistamines, analgesics, anti-inflammatory agents, antiemetics, antiepileptics, vasodilators, antitussives and expectorants, antispasmodics, hormones, diuretics, antihypotensives, bronchodilators, anti-inflammatory steroids, antibiotics, sedatives, CNS active substances, decongestants, laxatives, and antacids. Generally, the compositions are useful as drug delivery dosage forms for patients suffering from complications that make swallowing impossible, such as unconsciousness, severe migraines, acute stroke, or gastrointestinal obstruction. Examples of suitable non-therapeutic agents include caffeine, alcohol powder, ethanol, vitamin B12, vitamin C, vitamin E, Bioperin®, coenzyme Q10, selenium, glutathione, alpha lipoic acid, folic acid, ginseng, pollen extract, antioxidants, minerals, paracetamol, acetylsalicylic acid, russian root, and rose root.

[0030] In one embodiment, the biologically active substance is nicotine or a cannabinoid such as Δ-tetrahydrocannabinol (THC) or cannabidiol (CBD). The term nicotine includes synthetic nicotine and nicotine extracts from tobacco plants, such as Nicotiana, or other plant sources, and includes nicotine or nicotine derivatives in any solid or liquid form, such as physical forms, e.g., amorphous, crystalline, polymorphic, or chemical forms, e.g., isomers and enantiomers, and any pharmaceutically acceptable salts, complexes, or solvates thereof. Nicotine forms herein include nicotine base and / or salts of nicotine, such as nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine ditartrate, nicotine sulfate, nicotine zinc chloride (monohydrate), and nicotine salicylate.

[0031] Nicotine is typically present at a concentration of about 0.1% (wt) to about 5% w / w, calculated as the free base, e.g., about 0.1% (wt) to about 4% (wt), about 0.1% to about 3% (wt), about 0.1% (wt) to about 2% w / w, 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 a salt thereof used with the compositions of the present invention is preferably highly pure, e.g., 99.5% pure.

[0032] The composition according to the present invention further comprises at least one additive selected from plasticizers, pH adjusters, preservatives, taste or flavor enhancers, colorants and sweeteners.

[0033] The plasticizer is chosen, for example, from polyethylene glycol, propylene glycol, glycerol and sorbitol. A preferred plasticizer is sorbitol, optionally with a portion of glycerol.

[0034] The pH adjuster can maintain a pH of at least 6.5 in the composition, and examples include carbonates, including monocarbonates, bicarbonates, and sesquicarbonates, as well as weak organic acids such as acetate, glycinate, gluconate, borate, glycerophosphate, or citric acid, other alkali / alkali metal salts of physiologically acceptable acids such as phosphates, metal hydroxides such as sodium hydroxide and potassium hydroxide, and mixtures thereof. Examples of suitable pH adjusters are sodium bicarbonate and sodium carbonate, and mixtures thereof. While a higher pH (e.g., pH 8-9) is preferred during the composition's manufacture, the pH adjuster must be capable of maintaining a pH > 6.5 throughout storage and consumption.

[0035] Preservatives can be selected from agents approved in the food and pharmaceutical industries, such as sorbic acid, sorbates, benzoic acid lactic acid and physiologically acceptable salts, etc. A preferred preservative is potassium sorbate.

[0036] Flavor or flavor enhancers include ammonium chloride; essential oils, including those obtained by distillation, solvent extraction, or cold pressing of chopped flowers, leaves, peels, or pulped whole fruits, containing a mixture of alcohols, esters, aldehydes, and lactones; or essences, including either a diluted solution of essential oils or a mixture of synthetic chemical blends that match the desired flavor, such as bergamot, eucalyptus, orange, mandarin, citrus, lemon, peppermint, mint, menthol, licorice, wintergreen, tobacco, coffee, vanilla, lime, apple, peach, and mixtures thereof. Further examples include breweries and alcoholic beverages, such as cognac, whiskey, rum, gin, sherry, port, and wine; and the artificial and natural flavors of eucalyptus, licorice, and menthol.

[0037] The colorant may be selected from dyes containing chemical groups that absorb light, including dyes such as indigo carmine, amaranth, erythrosine, carbon black, titanium dioxide, and any mixtures thereof.

[0038] The sweetener or texture-improving agent may be a natural sweetener such as a sugar alcohol, including mannitol, xylitol, sorbitol, maltitol, and / or isomalt, a sugar that is preferably not fermented in the mouth, or an artificial sweetener such as aspartame, acesulfame K, saccharin, cyclamic acid, stevia extract, and other similar agents.

[0039] In one aspect, the composition comprises less than 50% matrix-forming agent, is compatible with delivery to the nasal cavity, and comprises less than 20% water (by weight), preferably 1-15% water (by weight). The powder particles have a particle size of 0.01-2 mm. In an embodiment of this aspect, the filler comprises water-soluble cellulose, preferably water-soluble microcrystalline cellulose, more preferably a combination of water-soluble and water-insoluble microcrystalline cellulose.

[0040] In one embodiment, the composition comprises less than 50% matrix-forming agent, is adapted for contact with the mucous membrane of the oral cavity, and comprises at least 30% (by weight) water, preferably at least 40% (by weight) water. Preferably, the filler is selected from at least one of microcrystalline cellulose and vegetable fiber. Preferably, the composition comprises 40-60% (by weight) water. Such high-water content compositions are particularly useful as traditional snus products, providing high user compliance by being easy to form into doses or use in pouches.

[0041] In another embodiment, the composition comprises less than 50% matrix-forming agent and is adapted for contact with the mucous membrane of the oral cavity, the composition comprising less than 40% (by weight) water, the filler is also selected from at least one of microcrystalline cellulose and plant fiber, and preferably the composition comprises 1-30% (by weight) water.

[0042] In another aspect, the compositions comprise greater than 50% matrix-forming agent and are configured as films suitable for transmucosal delivery of an active agent. The film compositions have a thickness of 0.01 mm to 7 mm, preferably 0.01 mm to 3 mm, and optionally contain a plasticizer. In one embodiment, these compositions contain 0.05 to 20% (by weight), preferably 5 to 10% (by weight), of a filler, preferably microcrystalline cellulose and a plasticizer, preferably selected from at least one of sorbitol and glycerol.

[0043] The components and amounts of fillers and other specified additives may vary depending on the desired properties of the final product, for example, to obtain attractiveness for oral or nasal use.

[0044] In one embodiment suitable for oral use, the composition comprises nicotine, alginic acid and suitable salts thereof as matrix forming agents, a filler comprising microcrystalline cellulose, at least 40% (by weight) water, a pH adjuster, an antioxidant comprising ammonium citrate, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners.

[0045] In another embodiment suitable for oral use, the composition comprises nicotine, alginate and suitable salts thereof as matrix-forming agents, fillers including microcrystalline cellulose and optionally additional vegetable fiber, 40-60% (by weight) water, a pH adjuster, an antioxidant including ammonium citrate, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners.

[0046] In another embodiment suitable for oral use, the composition comprises nicotine, a matrix-forming agent comprising alginate and suitable salts thereof and one or more other additional pharmaceutically acceptable gums, a filler comprising microcrystalline cellulose, a polyol, preferably mannitol, and optionally additional vegetable fibers, 40-60% (by weight) water, a pH adjuster, an antioxidant comprising ammonium citrate, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners.

[0047] In another embodiment suitable for oral use, the composition comprises nicotine, 0.5 to 10% (by weight) of alginate and suitable salts thereof as matrix-forming agents, 40 to 90% (by weight) of a filler comprising microcrystalline cellulose and optionally additional vegetable fiber, 40 to 60% (by weight) of water, sodium bicarbonate as a pH adjuster, 0.1 to 5% (by weight) of ammonium citrate as an antioxidant, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners.

[0048] In another embodiment suitable for oral use, the composition comprises nicotine, less than 40% (by weight) of alginate and suitable salts thereof as matrix-forming agents, a filler comprising microcrystalline cellulose and optionally vegetable fiber, 40-60% (by weight) of water, sodium bicarbonate as a pH adjuster, ammonium citrate as an antioxidant, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners.

[0049] In yet another embodiment, the composition comprises 0.5-1.5% (by weight) nicotine; 0.5-1% (by weight) antioxidant including ammonium citrate, preferably triamnium citrate; 0.5-10% (by weight) matrix forming agent; 40-50% filler; 40-50% (by weight) water; and one or more other additives selected from pH adjusters, preservatives, taste / flavor enhancers, and sweeteners.

[0050] In an embodiment of the invention suitable as a slowly dissolving tablet lozenge in the oral cavity, the composition comprises nicotine; 1-30% (by weight) water; 50-90% (by weight) matrix forming agents, including alginate and optionally further matrix forming agents as defined; an antioxidant, including ammonium citrate; and 1-40% (by weight) filler.

[0051] In one embodiment suitable for nasal use, the composition comprises nicotine, alginate and suitable salts thereof as matrix-forming agents, a filler comprising at least partially water-soluble cellulose, less than 20% (by weight) water, a pH adjuster, an antioxidant comprising ammonium citrate, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners.

[0052] In one embodiment suitable for nasal use, the composition is a powder of particles having a particle size of less than about 2 mm, comprising nicotine, alginate and suitable salts thereof as matrix-forming agents, a filler comprising at least partially water-soluble cellulose, less than 20% (by weight) water, a pH adjuster, a chelating antioxidant, and one or more other additives selected from preservatives, taste / flavor enhancers, and sweeteners.

[0053] In another embodiment suitable for nasal use, the composition is a powder of particles having a particle size of 0.01 mm to 2 mm, comprising nicotine, alginate and suitable salts thereof as matrix-forming agents, a filler comprising at least partially water-soluble cellulose, 1 to 15% (by weight) water, sodium bicarbonate as a pH adjuster, a chelating antioxidant, preferably ammonium citrate as the antioxidant, and one or more other additives selected from preservatives, taste / flavor enhancers and sweeteners.

[0054] These and other embodiments are more fully illustrated in the detailed description that follows.

[0055] In another general aspect, the present invention relates to a method for making a composition for use in the oral and nasal cavities, comprising dry-blending a filler with at least one of a matrix-forming agent and an antioxidant, and optionally a taste or flavor enhancer; mixing the dry blend with a first aqueous solution containing a pH adjuster; adding a second aqueous solution containing at least one of a preservative, a taste or flavor enhancer, and a sweetener; adding a third aqueous solution containing nicotine; and finally mixing all the added ingredients with an appropriate amount of water, for example at least 30% (by weight) of water, into a mixture.

[0056] In one embodiment of the method, in a first step the filler is dry mixed with the matrix forming agent, the antioxidant, and optionally a taste or flavor enhancer.

[0057] In one embodiment of the method, the filler in the first step is dry mixed with an antioxidant and optionally a taste or flavor enhancer, and the third aqueous solution comprises the matrix-forming agent nicotine.

[0058] In one alternative, the method may be configured to produce a powder composition for nasal use by using one or more further processing steps of the resulting mixture, including drying, e.g. spray drying, using less than 20% (by weight) water, e.g. 1-15% (by weight) water, to a powder with a particle size of less than 1 mm.

[0059] In another alternative, the method may be configured to produce a composition for use in the oral cavity by one or more further processing steps of the resulting mixture using at least one of the processes of filling into pouches, tableting or lozenge forming, extrusion, punching, casting, molding, injection molding, knead-spinning, film, dilution into a sprayable dosage form, and forming and mixing with a chewing gum base. DETAILED DESCRIPTION OF THE INVENTION

[0060] As used herein in both a general and exemplary context, weight percent (wt) % means weight percent of the total composition.

[0061] Table 1 below provides further examples of oral or nasal compositions containing suitable additives. [Table 1]

[0062] Specific examples of compositional products made using the methods outlined are shown in Table 2. [Table 2]

[0063] Example 1 The unflavored compositions of Table 2, containing approximately 1% nicotine and having a pH of 8.5, suitable for packaging in pouches as snus-type products for oral use, were tested for nicotine stability. 80 g samples of the compositions of Table 2 and a sample of a commercially available tobacco-based snus product were compared at 40° C. and 75% relative humidity over a 9-week period (equivalent to 10 months at 25° C., see Table 3). For the compositions shown in Table 3, equivalent amounts of different chelating and non-complexing antioxidants were compared with the commercially available products. [Table 3]

[0064] Table 3 demonstrates that the sodium alginate and antioxidants of the compositions of the present invention provide a significant increase in nicotine stability. The results indicate that the matrix-forming agent containing sodium alginate in the compositions of the present invention has a nicotine preservation capacity equivalent to that of natural tobacco fiber. This example also demonstrates the positive effect of ammonium citrate compared to calcium ascorbate. The adverse effect of the non-complexing antioxidant BHT (butylhydroxytoluene) can also be seen in Table 3. In conclusion, the combination of a matrix-forming agent containing alginate and a complex-bound antioxidant provides effective long-term nicotine stability.

[0065] Example 2 Products containing approximately 1% (by weight) nicotine were made according to Table 2 using the two exemplary methods outlined above. In Step 1, sodium alginate is dry-blended with MCC filler in the first step, and a solution of nicotine is added in the third step. The Step 1 product contains 0.7% (by weight) sodium alginate. In Step 2, sodium alginate is added to a nicotine-containing solution as the third step. The Step 2 product contains 0.7% sodium alginate. The products were packaged in traditional snus pouches and evaluated with CP1, a commercially available tobacco-free nicotine product that contains microcrystalline cellulose as a filler but no sodium alginate as a matrix-forming agent. The products made according to the present invention and CP1 were tested for stability and nicotine release.

[0066] To test the nicotine release capabilities of the compositions of the present invention, pouches containing the products were prepared as outlined above in Steps 1 and 2 and compared with CP1. The products were orally tested by the subjects and removed after the specified time period and processed for residual nicotine. The consumed pouches were shredded into 100 mL glass bottles and exposed to ultrasound for 5 minutes with 5 mL of Milli-Q water. 100 mL of 0.05 M potassium hydroxide solution was then added, the samples were shaken, and then exposed to ultrasound for 60 minutes. The samples were shaken overnight on a vibrating table and exposed to ultrasound for an additional 30 minutes the following day. The samples were then centrifuged, diluted to the desired level, an internal standard was added, and the samples were then analyzed by LC / MS / MS. The average results of the three tests are shown in Table 4 below. [Table 4]

[0067] Table 4 demonstrates that the amount of matrix former in the compositions of the present invention can be used to control the release rate of nicotine. Alternative methods of manufacturing the compositions can be used to control the amount of nicotine bound to the alginate of the matrix former. The results in Table 8 demonstrate that higher amounts of bound nicotine are obtained when nicotine is added together with the matrix former as the third and final step in the manufacturing process.

[0068] Example 3 To further evaluate the stabilizing effect of the antioxidants of the present invention, products containing approximately 1% (by weight) nicotine were made according to the recipe in Table 2 and step 1 of Example 2. These products were made with and without ammonium citrate antioxidant and compared to the same commercial product (CP1) as in Example 2-1. For stability testing, all products were placed in a heating cabinet at 40°C and 75% humidity for 9 weeks (equivalent to 7 months at room temperature). The results of testing for nicotine loss, pH, and moisture content are shown in Tables 5-7 below. [Table 5] [Table 6] [Table 7]

[0069] The results in Tables 5-7 demonstrate the stabilizing ability of compositions of the present invention containing ammonium citrate antioxidant. <Additional Notes> The present disclosure includes the following aspects. <Item 1> A composition for use in the oral or nasal cavity, the composition having a pH of at least 6.5 and comprising an active agent selected from nicotine and a cannabinoid, a matrix-forming agent comprising alginate and suitable salts thereof, a filler, and an antioxidant which is a composite binder effective at a pH of at least 6.5 and comprises at least one ammonium citrate or salt thereof. <Item 2> 10. The composition of claim 1, wherein the matrix-forming agent comprises at least one additional pharmaceutically acceptable gum, preferably selected from β-glucan, xanthan, carrageenan, methylcellulose, curdlan, and pullulan. <Item 3> The composition according to <Item 1> or <Item 2>, wherein the matrix-forming agent comprises at least 50% (by weight) of alginate and a suitable salt thereof. <Item 4> 10. The composition of any one of the preceding items, comprising 5 to 95% (by weight) of a filler comprising at least one plant fiber, more preferably wherein the filler comprises natural or modified cellulose fiber, and most preferably comprises at least one microcrystalline cellulose. <Item 5> The composition according to <Item 4>, wherein the filler further comprises a polyol, preferably a polyol selected from one or more of mannitol, xylitol, sorbitol, maltitol and / or isomaltitol, lactitol, and erythritol. <Item 6> 10. The composition of any one of the preceding items, comprising at least one additive selected from a preservative, a taste or flavor enhancer, a pH adjuster, a plasticizer, and a sweetener. <Item 7> 10. The composition of any one of the preceding items, comprising less than 50% (by weight), preferably less than 40% (by weight) of said matrix-forming agent. <Item 8> 10. A powder composition according to any one of the preceding items, adapted for delivery to the nasal cavity and comprising less than 20% water (by weight), preferably 1-15% water (by weight). <Item 9> The composition according to <Item 8>, wherein the powder particles have a particle size of 0.01 to 2 mm. <Item 10> The composition according to <Item 8> or <Item 9>, wherein the filler comprises water-soluble cellulose, preferably water-soluble microcrystalline cellulose, more preferably a combination of water-soluble microcrystalline cellulose and water-insoluble microcrystalline cellulose. <Item 11> The composition according to any one of <Item 1> to <Item 7>, which is adapted to come into contact with the mucous membrane of the oral cavity and comprises at least 30% (by weight), preferably at least 40% (by weight) water, and a filler comprising at least one of microcrystalline cellulose and other plant fibers. <Item 12> The composition according to <Item 11>, which contains 40 to 60% (by weight) of water. <Item 13> The composition according to any one of <Item 1> to <Item 7>, which is adapted to come into contact with the mucous membrane of the oral cavity and comprises less than 40% (by weight) water and a filler selected from at least one of microcrystalline cellulose and other plant fibers, and preferably the composition comprises 1 to 40% (by weight) water. <Item 14> The composition according to any one of <Item 1> to <Item 6>, which is configured as a film having a thickness of 0.01 mm to 7 mm suitable for transmucosal delivery of an active substance, and which comprises at least 50% (by weight) of the matrix-forming agent and optionally a plasticizer. <Item 15> The composition according to <Item 14>, comprising 0.1 to 20% (by weight), preferably 5 to 10% (by weight) of a filler, preferably the filler is microcrystalline cellulose and a plasticizer, preferably the plasticizer is selected from at least one of sorbitol and glycerol. <Item 16> 10. The composition of any one of the preceding items, wherein the alginate is sodium alginate. <Item 17> A method for producing the composition according to any one of <Item 1> to <Item 16>, (i) dry blending a filler with at least one of said matrix forming agent, antioxidant, and optionally at least one taste or flavor enhancer; (ii) mixing the dry mixture with a first aqueous solution containing a pH adjuster; (iii) adding a second aqueous solution comprising at least one of a preservative, a taste or flavor enhancer, and a sweetener; (iv) adding a third aqueous solution containing an active substance and mixing all added ingredients with an appropriate amount of water into a mixture; A method comprising: <Item 18> 18. The method according to <Item 17>, wherein the filler is dry mixed with the matrix-forming agent, the antioxidant, and optionally at least one taste or flavor enhancer. <Item 19> 18. The method according to claim 17, further comprising dry-mixing the filler, the antioxidant, and optionally at least one taste or flavor enhancer, wherein the third aqueous solution comprises the matrix-forming agent and the active substance. <Item 20> The method according to any one of <Item 17> to <Item 19>, which is configured to produce a powder composition for nasal use by one or more further processing steps of the obtained mixture, comprising drying to a powder having a particle size of less than 2 mm containing less than 15% water (by weight). <Item 21> The method according to any one of <Item 17> to <Item 19>, wherein the composition for use in the oral cavity is produced by one or more further processing methods of the resulting mixture using at least one of filling into a pouch, forming a tablet or lozenge, extrusion, punching, casting, molding, injection molding, knead-spinning, film formation, and mixing with a chewing gum base.

Claims

1. A composition for use in the oral or nasal cavity, the composition having a pH of at least 6.5 and comprising an active substance, nicotine, a matrix-forming agent comprising alginate and salts thereof, a filler, and an antioxidant which is a composite binder effective at a pH of at least 6.5 and comprises at least one ammonium citrate or salt thereof.

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

3. The composition of claim 2, wherein the at least one additional pharmaceutically acceptable gum is selected from beta-glucan, xanthan, carrageenan, methylcellulose, curdlan, and pullulan.

4. The composition of any one of claims 1 to 3, wherein the matrix-forming agent comprises at least 50% (by weight) of alginate and its salts.

5. The composition according to any one of claims 1 to 4, comprising 5 to 95% (by weight) of a filler comprising at least one vegetable fiber.

6. The composition described in claim 5, wherein the filler comprises natural or modified cellulose fibers.

7. The composition of claim 5, wherein the filler comprises at least one type of microcrystalline cellulose.

8. The composition of any one of claims 5 to 7, wherein the filler further comprises a polyol.

9. The composition of claim 8, wherein the polyol is selected from one or more of mannitol, xylitol, sorbitol, maltitol and / or isomaltitol, lactitol and erythritol.

10. The composition according to any one of claims 1 to 9, further comprising at least one additive selected from a preservative, a taste or flavour enhancer, a pH adjuster, a plasticiser and a sweetener.

11. The composition of any one of claims 1 to 10, comprising less than 50% (by weight) of the matrix-forming agent.

12. The composition of claim 11, comprising less than 40% (by weight) of the matrix forming agent.

13. A composition according to any one of claims 1 to 12, adapted for delivery to the nasal cavity and comprising less than 20% water (by weight).

14. The composition of claim 13, comprising 1 to 15% (by weight) water.

15. The composition of claim 13 or claim 14, wherein the composition is a powder composition and comprises powder particles having a particle size of 0.01 to 2 mm.

16. The composition of any one of claims 13 to 15, wherein the filler comprises a water-soluble cellulose.

17. The composition of claim 16, wherein the filler comprises water-soluble microcrystalline cellulose.

18. The composition of claim 16, wherein the filler comprises a combination of water-soluble microcrystalline cellulose and water-insoluble microcrystalline cellulose.

19. 13. The composition of any one of claims 1 to 12, adapted for contact with the mucous membranes of the oral cavity, comprising at least 30% (by weight) water and a filler comprising at least one of microcrystalline cellulose and other vegetable fibers.

20. The composition of claim 19, comprising at least 40% (by weight) water.

21. 21. The composition of claim 19 or claim 20, comprising 40 to 60% (by weight) water.

22. 13. The composition of any one of claims 1 to 12, adapted for contact with the mucous membranes of the oral cavity, comprising less than 40% (by weight) water and a filler selected from at least one of microcrystalline cellulose and other vegetable fibers.

23. 11. The composition of any one of claims 1 to 10, configured as a film having a thickness of 0.01 mm to 7 mm suitable for transmucosal delivery of an active agent, and comprising at least 50% (by weight) of the matrix-forming agent.

24. The composition of claim 23, wherein the composition further comprises a plasticizer.

25. 25. The composition of claim 23 or claim 24, comprising 0.1 to 20% (by weight) of a filler.

26. The composition of claim 25, comprising 5 to 10% (by weight) of a filler.

27. ​​A composition described in any one of claims 24 to 26, wherein the plasticizer is selected from at least one of sorbitol and glycerol.

28. The composition of any one of claims 1 to 27, wherein the alginate is sodium alginate.

29. A method for producing a composition according to any one of claims 1 to 28, comprising the steps of: (i) dry blending a filler with at least one of the matrix forming agent and the antioxidant; (ii) mixing the dry blend with a first aqueous solution containing a pH adjuster; (iii) adding a second aqueous solution comprising at least one of a preservative, a taste or flavor enhancer, and a sweetener; (iv) adding a third aqueous solution containing an active substance and mixing all added ingredients with an appropriate amount of water into a mixture; A method comprising:

30. 30. The method of claim 29, wherein the filler is dry mixed with the matrix forming agent and the antioxidant.

31. 30. The method of claim 29, comprising dry blending the filler and the antioxidant, and wherein the third aqueous solution comprises the matrix-forming agent and an active agent.

32. A method according to any one of claims 29 to 31, configured to produce a powder composition for nasal use by one or more further processing steps of the obtained mixture, including drying to a powder of particle size less than 2 mm containing less than 15% water (by weight).

33. 32. A method according to any one of claims 29 to 31, adapted to produce a composition for use in the oral cavity by one or more further processing methods of the resulting mixture using at least one of filling into pouches, tablet or lozenge forming, extrusion, punching, casting, moulding, injection moulding, knead spinning, film forming and mixing with a chewing gum base.

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