New composition for oral or nasal use

Abstract

This specification discloses a composition for oral or nasal use comprising: a bioactive agent; a matrix-forming agent comprising alginate or a suitable salt thereof; a filler; and at least one antioxidant as an effective composite binder. The composition may also include additional excipients, such as a preservative, a taste or flavor enhancer, a pH adjuster, a plasticizer, and a sweetener. This specification also discloses a method for preparing the composition.

Description

Technical Field

[0001] The present invention relates to a composition for oral or nasal cavity and a preparation method thereof. The composition comprises a bioactive agent, a matrix forming agent comprising alginate and its salt, a complex binding antioxidant, and a filler. Background Art

[0002] Delivery of pharmaceutically active agents to the oral and nasal cavities is generally an ideal route of administration for obtaining rapid or controlled therapeutic onset and avoiding metabolic activity of the gastrointestinal system and first-pathway metabolism. Many solid dosage forms have been developed, such as lozenges, sublingual tablets, gums, buccal patches, or pouches, to obtain a compliant dosage form for patients based on treatment via the oral cavity. Such solid dosage forms typically include an active agent, a filler, a binder, a lubricant, and other ingredients that support mucoadhesion, palatability, compliance, and release of the active agent.

[0003] Suppliers and developers of smokeless tobacco and nicotine products have developed many products that are configured to deliver nicotine through the oral cavity or nasal cavity. Tobacco products include chewing tobacco, moist smokeless tobacco, moist snuff and dry snuff for example for oral or nasal use. Non-tobacco products rely on pure nicotine extracted from tobacco or are formulated into synthetic nicotine for example for oral or nasal use with suitable additives. For oral cavity, non-tobacco dosage forms can for example rely on fiber filling materials and a matrix forming agent that acts as an adhesive. Nicotine (3-(1-methyl-2-pyrrolidinyl) pyridine) is a volatile compound that is easily degraded under the influence of heat, oxygen and light. Therefore, it is a technical challenge to find a suitable non-tobacco dosage form as a product that counteracts degradation and provides suitable nicotine storage stability during its manufacture, while allowing nicotine to have a desired release rate in the oral cavity and still has compliance to the user.

[0004] There are several disclosures of products suitable for delivering active agents to the oral cavity, such as WO2005048080, WO0054777, US200307315, and WO20100104464, which disclose matrix-forming agents and antioxidants. WO2007104574, US2005226823, and US2013186418 disclose various orally available nicotine compositions containing antioxidants, but do not disclose any matrix-forming agents. WO2013143891 discloses an alginate-based oral film containing nicotine, but does not provide specific guidance on stabilizing the nicotine. WO2019224323 discloses another alginate-based oral film with an antioxidant for delivering agents other than nicotine.

[0005] WO2010 / 011445 discloses a plant fiber product suitable for oral delivery of an active agent (e.g., nicotine). The incorporation of alginate as a matrix forming agent provides the product with desired release characteristics and suitable stability of a variable active agent. WO2010 / 104464 discloses alginate particles comprising an active agent (e.g., nicotine) encapsulated in a pouch for oral cavity. WO2010 / 0104464 shows that an alginate matrix can form an oxygen barrier and does not require the addition of an antioxidant. However, some very active agents that are very easy to work will need further protection to avoid degradation during long-term storage, particularly in systems with high water content. For this reason, it is necessary to rely on another stable composition of the alginate matrix, which is included in an antioxidant effective to alginate within the entire desired pH range. Summary of the Invention

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

[0007] It is another object of the present invention to provide compositions that support a controlled release rate of an active agent and a controlled, suitable duration of the release rate.

[0008] Another object of the present invention is to provide compositions that promote the stabilization of active agents that are susceptible to degradation during storage, in order to obtain stable products with a long shelf life also in compositions with a relatively high water content.

[0009] Another object of the present invention is to provide a composition having high compliance to the oral mucosa to avoid local irritation and side effects caused by repeated or long-term exposure.

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

[0011] Another object of the present invention is to control the nicotine bound to the matrix forming agent and the unbound nicotine through the manufacturing process to provide an initial consumer satisfactory nicotine dose and a gradual nicotine release comparable to that from conventional tobacco fibers, while at the same time achieving suitable stability of the bound and unbound nicotine throughout storage and a high moisture content product composition.

[0012] In a general aspect, the present invention relates to a composition for oral or nasal administration at a pH of at least 6.5, comprising: an active agent selected from nicotine and cannabinoids, a matrix forming agent comprising alginate and suitable salts thereof, a filler, and an antioxidant, said antioxidant being an effective composite adhesive at a pH of at least 6.5, said antioxidant comprising at least one ammonium citrate or a salt thereof.

[0013] In this overall context, the matrix forming agent can provide a cohesive homogeneous composition together with the filler, which surrounds the bioactive agent and helps to stabilize susceptible such agents while also contributing to a controlled and desired release profile of the active agent when in contact with the oral or nasal cavity. The stabilizing effect may or may not be caused by a synergistic effect with the filler, such as between the matrix and the fibers of the filler. In the compositions of the present invention, the affinity between the active agent and the matrix forming agent can be used to regulate and control the release rate.

[0014] Matrix forming agent of the present invention is also used for releasing nicotine in a controlled manner in the composition. For example, when the activating agent is nicotine, the matrix forming agent can be selected so that the nicotine of the controlled amount is free, unbound nicotine, and the nicotine of the controlled amount is gradually and controllably released from the matrix forming agent. For example, by increasing the amount of the matrix forming agent in the composition of the present invention, more nicotine is combined and gradually released. Therefore, the composition of the present invention can be developed to provide a satisfactory initial dose of nicotine applied to the oral cavity or nasal cavity to the user, and within a predetermined time period, the gradual release of nicotine from the composition is provided. For nicotine products, the matrix forming agent can be used to meet the different requirements of user compliance.

[0015] The antioxidant comprises ammonium citrate, which is effective at a pH of 8 to 9, for example, for compounding metal ions in compositions having a high pH, ​​and helps stabilize the composition throughout production and storage. The ammonium citrate is selected from diammonium citrate (ammonium hydrogen citrate), triammonium citrate (triammonium citrate), and ammonium citrate salts (e.g., ferric ammonium citrate). Most preferably, the ammonium citrate is triammonium citrate (triammonium citrate).

[0016] The antioxidant is present 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 also comprise one of an alkali metal salt and / or alkaline earth metal salt of ascorbate, calcium citrate, calcium lactate, calcium maleate, calcium tartrate, calcium disodium EDTA, and calcium phosphate.

[0017] In one aspect, the composition of the invention comprises less than 50 wt% matrix forming agent, such as less than 40 wt% or less than 30 wt% and less than 20 wt%, or 1 to 10 wt%, or 0.5 to 5 wt%.

[0018] In another aspect, the composition of the invention comprises greater than 50 wt% matrix forming agent, such as 50 to 90 wt% or 50 to 70 wt%.

[0019] Additionally, in this overall context, fillers will primarily contribute to the bulk and shape of the composition, for example to allow the user to conform to different parts of the oral cavity and / or to facilitate convenient manufacture, handling, and administration of the composition. In embodiments, fillers may also actively interact with the matrix forming agent to stabilize the agent and induce desired release properties.

[0020] Generally speaking, alginates suitable for use in the present invention are alginates of monovalent cations that are soluble in cold water and have low viscosity. A person skilled in the art will be able to select alginates with different viscosities, solubilities and molecular weights to vary their dissolution in water and in the oral or nasal cavity. Alginate LFR 5 / 60 is an example of a low viscosity alginate, LF 10 / 60 (FMC BioPolymer) is an example of an alginate with higher viscosity. In order to obtain suitable dissolution and release profiles, it may be appropriate to mix alginate with different viscosities. Alginates of divalent cations (e.g., Ca) are generally less soluble and can be used in the compositions of the present invention to support the specific release profile of an active agent, preferably in combination with alginate of one or more monovalent cations.

[0021] In one aspect, the matrix forming agent of the composition of the invention comprises at least 50% by weight of alginate or a salt thereof, such as 50 to 90% by weight of alginate or a salt thereof.

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

[0023] The filler of the present composition comprises a fibrous material, which can be of natural or synthetic origin. The fiber is preferably derived from plants, algae or fungi and can be natural or modified by biological or chemical methods. In preferred aspects, the fibrous material is a plant fiber, more preferably, the filler comprises natural or modified cellulose fibers, most preferably comprises at least one microcrystalline cellulose. It is conceivable that the filler of the composition comprises many chemically modified celluloses, such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.

[0024] In various embodiments, the plant fiber included in the filler can be derived from tea, coffee, tobacco, cocoa, corn, bamboo, oats, barley, rye, beets, herbs, buckwheat, potatoes, tomatoes, eggplant, cauliflower, apples, yerba mate, or various sources of cellulose fibers. The plant fiber can be natural or modified by various biological or chemical methods. Tobacco fiber can be processed according to various conventional techniques for whiteness and / or reduction of nitrosamines.

[0025] Suitable (MCC) can be selected from: Category PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302; Categories 101, 102, 12, 20; Category 50M and 90M; Category, e.g. 90M, etc.; and mixtures thereof. For embodiments of the composition of the present invention where water-soluble microcrystalline cellulose is required (e.g., powder compositions for nasal use), suitable types of colloidal microcrystalline cellulose are those of Cas No. 51395-75-6, such as various brands of A preferred colloidal gelling MCC is commercially available under the name FEIYUN XW591.

[0026] In an embodiment of the present composition, the filler comprises a polyol, preferably, the polyol is selected from one or more of mannitol, xylitol, sorbitol, maltitol and / or isomalt, lactitol and erythritol. Suitably, the composition of the present invention comprises a filler, which comprises a plant fiber material and 5 to 70 % by weight of the polyol. According to an example, the filler comprises mannitol and at least one microcrystalline cellulose. According to other examples of this type of lozenge used according to the present invention or tablets, the filler can be simply defined polyol.

[0027] In an embodiment of the present invention relating to a powdered composition for nasal administration, the filler may comprise a mucoadhesive selected from at least one of a cellulose derivative, a starch derivative, and polyvinylpyrrolidone. Preferably, the mucoadhesive is selected from at least one of sodium starch glycolate and cross-linked polyvinylpyrrolidone. Suitable starches include corn starch, pregelatinized starch, hydroxypropyl starch, and modified or unmodified starch.

[0028] In embodiments of the invention relating to powdered compositions for use in the nasal cavity, the composition comprises powder particles having a controlled average size (diameter) of, for example, 0.01 to 2 mm, or 0.05 to 0.5 mm, or 0.02 to 0.2 mm, or 0.01 to 0.1 mm. Optimization of the powder particle size for the composition allows for avoidance of aerosolization and dangerous unintentional powder distribution to the lungs when the particle size approaches <10 μm, as well as for avoidance of inadequate compliance and distribution for large particle sizes exceeding about a few millimeters.

[0029] Typically, the compositions of the present invention can be used for active agents, which can be therapeutic or non-therapeutic substances that are not generally considered to be drugs, such as naturopathic preparations, stimulants or nutritional supplements. Examples of therapeutic bioactive substances suitable for use alone or in combination with the compositions of the present invention include incontinence agents, antihistamines, analgesics, anti-inflammatory agents, antiemetics, antiepileptics, vasodilators, antitussives and expectorants, antispasmodics, hormones, diuretics, antihypertensives, bronchodilators, anti-inflammatory steroids, antibiotics, sedatives, CNS-active substances, decongestants, laxatives and antacids. Typically, the compositions of the present invention can be used as drug delivery dosage forms for patients with complications such as unconsciousness, severe migraines, acute stroke or gastrointestinal obstruction that result in the inability to accept conventional tablets for swallowing. Examples of suitable non-therapeutic agents are caffeine, powdered alcohol, alcohol, vitamin B12, vitamin C, vitamin E, Coenzyme Q10, selenium, glutathione, alpha-lipoic acid, folic acid, ginseng, pollen extract, antioxidants, minerals, acetaminophen, acetylsalicylic acid, Russian root and rose root, etc.

[0030] In one aspect, bioactivator is nicotine or cannabinoid, for example Δ 9-tetrahydrocannabinol (THC) or cannabidiol (CBD).Term nicotine includes synthetic nicotine and the nicotine extract from tobacco plant such as Nicotiana (Nicotiana) or other plant origin, and includes nicotine or nicotine derivatives in any solid or liquid form, for example, physical forms such as amorphous, crystallization, polymorphic or chemical forms such as isomers and enantiomers, and any pharmaceutically acceptable salt, complex or solvate thereof.Nicotine form herein includes nicotine base and / or nicotine salt, for example nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride (monohydrate) and nicotine salicylate.

[0031] Nicotine is typically present at a concentration of about 0.1% to about 5% by weight, calculated as free base, such as about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.2% to about 0.5%, or about 0.2% to about 0.4%. Nicotine or a salt thereof used with the compositions of the present invention preferably has a high purity, such as 99.5% purity.

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

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

[0034] pH adjusting agents are capable of maintaining a pH of at least 6.5 in the composition, and examples are carbonates, including monocarbonates, bicarbonates, and sesquicarbonates, and other alkali / alkali metal salts of physiologically acceptable acids, such as acetates, glycinates, gluconates, borates, glycerophosphates, or weak organic acids such as citric acid, phosphates, metal hydroxides such as sodium hydroxide and potassium hydroxide, and mixtures thereof. Examples of suitable pH adjusting agents are sodium bicarbonate and sodium carbonate, and mixtures thereof. Preferably, the pH at the time of production of the composition is higher, for example, a pH of 8-9, but the pH adjusting agent should be capable of maintaining a pH>6.5 during storage and consumption.

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

[0036] Taste or flavor enhancers include ammonium chloride, essential oils (including distilled, solvent-extracted, or cold-pressed extracts of chopped flowers, leaves, peels, or pulped whole fruit, which contain mixtures of alcohols, esters, aldehydes, and lactones), or essences (including mixtures of diluted solutions of essential oils or synthetic chemical blends) to match the desired flavor from, for example, bergamot, eucalyptus, orange, tangerine, mandarin, lemon, peppermint, mint, menthol, licorice, wintergreen, tobacco, coffee, vanilla, lime, apple, peach, and mixtures thereof. Other examples include artificial and natural flavors of brews and spirits, such as French brandy, whiskey, rum, gin, sherry, white and red wines, 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 improver can be a sugar alcohol, including mannitol, xylitol, sorbitol, maltitol and / or isomalt; a natural sweetener, such as sugars that are preferably non-fermentable in the mouth; or an artificial sweetener, such as aspartame, acesulfame K, saccharin, cyclamate, stevia extract, and other similar agents.

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

[0040] In one aspect, the composition comprises less than 50% matrix-forming agent, is suitable for contact with the oral mucosa, 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 plant fiber. Preferably, the composition comprises 40 to 60% by weight water. Such high-water content compositions are particularly useful as conventional snus products, offering high user compliance through ease of dosage or use in pouches.

[0041] In another aspect, wherein the composition comprises less than 50% of a matrix forming agent and is suitable for contact with the mucous membranes of the oral cavity, the composition comprises less than 40% by weight of water. The filler is further selected from at least one of microcrystalline cellulose and plant fiber. Preferably, the composition comprises 1 to 30% by weight of water.

[0042] In another aspect, the composition comprises more than 50% matrix forming agent and is constructed as a film suitable for transmucosal delivery of an active agent. The film composition has a thickness of 0.01 to 7 mm, preferably 0.01 to 3 mm, and optionally comprises a plasticizer. In one embodiment, these compositions comprise 0.05 to 20 wt %, preferably 5 to 10 wt % of a filler, preferably a filler is microcrystalline cellulose and a plasticizer, preferably, the plasticizer is selected from at least one of sorbitol and glycerol.

[0043] The composition and amounts of fillers and other designated excipients may vary depending on the desired properties of the final product, such as to achieve oral or nasal appeal.

[0044] In one embodiment suitable for oral use, the composition comprises: nicotine, alginate 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 other excipients selected from one or more 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 formers; a filler comprising microcrystalline cellulose and optionally other plant fibers; 40 to 60% by weight of water; a pH adjuster; an antioxidant comprising ammonium citrate; and other excipients selected from one or more 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 other plant fibers; 40 to 60% by weight water; a pH adjuster; an antioxidant comprising ammonium citrate; and other excipients selected from one or more 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 a matrix former; 40 to 90% by weight of a filler comprising microcrystalline cellulose and optionally other plant fibers; 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 other excipients selected from one or more 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 a matrix forming agent; a filler comprising microcrystalline cellulose and optionally plant fiber; 40 to 60% by weight of water; sodium bicarbonate as a pH adjuster; ammonium citrate as an antioxidant; and other excipients selected from one or more preservatives, taste / flavor enhancers, and sweeteners.

[0049] In yet another embodiment, the composition comprises: 0.5 to 1.5 weight percent nicotine; 0.5 to 1 weight percent antioxidant comprising ammonium citrate, preferably triammonium citrate; 0.5 to 10 weight percent matrix former; 40 to 50 weight percent filler; 40 to 50 weight percent water; and other excipients selected from one or more pH adjusters, preservatives, taste / flavor enhancers, and sweeteners.

[0050] In an embodiment of the invention suitable as a lozenge that dissolves gradually in the mouth, the composition comprises: nicotine; 1 to 30% by weight of water; 50 to 90% by weight of a matrix former comprising alginate and optionally other matrix formers as defined; an antioxidant comprising ammonium citrate; and 1 to 40% by weight of a filler.

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

[0052] In one embodiment suitable for nasal administration, the composition is a powder having a particle size of less than about 2 mm and comprising: nicotine; alginate and a suitable salt thereof as a matrix forming agent; a filler comprising at least partially water-soluble cellulose; less than 20% by weight of water; a pH adjuster; a chelate-forming antioxidant; and other excipients selected from one or more preservatives, taste / flavor enhancers, and sweeteners.

[0053] In another embodiment suitable for nasal use, the composition is a powder having a particle size of 0.01 to 2 mm, comprising: nicotine; alginate and suitable salts thereof 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 adjuster; a chelate-forming antioxidant, preferably ammonium citrate as an antioxidant; and other excipients selected from one or more preservatives, taste / flavor enhancers, and sweeteners.

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

[0055] In another general aspect, the present invention relates to a method for producing a composition for oral and nasal administration. The method comprises dry-mixing a filler with at least one of a matrix forming agent, an antioxidant, and optionally a taste or flavor enhancer; mixing the dry mix 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 added components with a suitable amount of water (e.g., at least 30% by weight of water) to form a mixture.

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

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

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

[0059] In another alternative, the method can be configured to produce a composition for oral use by subjecting the resulting mixture to one or more further processing steps utilizing at least one of the following: filling in pouches, forming into tablets or lozenges, extrusion, stamping, casting, molding, injection molding, kneading, spinning, film forming, dilution into a sprayable dosage form, shaping, and mixing with a chewing gum base.

[0060] Detailed and exemplary description of the invention

[0061] As used in the summary and exemplary content herein, weight percent (wt %) means the weight percent of the total composition.

[0062] Table 1 below further shows examples of oral or nasal compositions comprising suitable excipients.

[0063] Table 1

[0064] Element use Amount (weight %) water humidify 2-70％ Sodium chloride smell <15％ microcrystalline cellulose Fillers 5-95％ Sodium bicarbonate / sodium carbonate pH adjusters <2％ Sodium alginate Matrix forming agent <5％ Ammonium chloride Flavor <2％ Potassium sorbate preservative <0.2％ Xylitol sweeteners <5％ Acesulfame K / Stevia sweeteners <0.5％ Menthol / Spearmint / Lemon / Other Flavor <8％ Triammonium citrate, CAS No. 3458-72-8 antioxidants <5％ Nicotine Active agent <20％

[0065] Table 2 shows specific examples of the composition products prepared by the method.

[0066] Table 2

[0067]

[0068] Example 1

[0069] The nicotine stability of a composition according to Table 2, which contains no flavoring, approximately 1% nicotine, has a pH of 8.5, and is suitable for packaging in pouches as a snus-type product for oral use, was tested. 80 g of the composition of Table 2 was compared to a sample of a commercial tobacco-based snus product (see Table 3) at 40°C and 75% relative humidity over the course of 9 weeks (equivalent to 10 months at 25°C). For the compositions shown in Table 3, equal amounts of different chelate-forming antioxidants and non-complex-forming antioxidants were compared to the commercial product.

[0070] Table 3

[0071]

[0072] Table 3 shows that the sodium alginate and antioxidant of the present composition significantly increase nicotine stability. This result indicates that the matrix-forming agent comprising sodium alginate of the present composition has a nicotine retention capacity comparable to that of natural tobacco fiber. In this example, the positive effect of ammonium citrate compared to calcium ascorbate can also be seen. Table 3 also shows the negative impact of the non-complex-forming antioxidant BHT (butylated hydroxytoluene). In short, the combination of a matrix-forming agent comprising alginate and a composite adhesive antioxidant provides effective long-term stability of nicotine.

[0073] Example 2

[0074] Products with approximately 1% nicotine by weight were prepared using the two specific methods outlined above according to Table 2. In Method 1, sodium alginate was dry-mixed with an MCC filler in a first step, and a nicotine solution was added in a third step. The product from Method 1 contained 0.7% sodium alginate by weight. In Method 2, sodium alginate was added to the nicotine-containing solution as a third step. The product from Method 2 contained 0.7% sodium alginate. The products were packaged in conventional snus pouches and used as a benchmark against a commercially available tobacco-free nicotine product, CP1, which contains microcrystalline cellulose as a filler but no sodium alginate as a matrix-forming agent. The products prepared according to the present invention and CP1 were studied for stability and nicotine release.

[0075] To test the nicotine-releasing capacity of the compositions of the present invention, pouches containing the product were prepared using Methods 1 and 2 as described above and compared to CP1. The product was orally administered to subjects, removed after a defined period of time, and processed to preserve the nicotine. The consumed pouches were cut into 100ml glass bottles and exposed to ultrasound for 5 minutes along with 5ml of Milli-Q water. Thereafter, 100ml of 0.05M potassium hydroxide solution was added, the sample shaken, and then exposed to ultrasound for 60 minutes. The sample was shaken on a vibration table overnight and exposed to ultrasound for an additional 30 minutes the following day. The sample was then centrifuged and diluted to the desired concentration, an internal standard was added, and the sample was analyzed by LC / MS / MS. The average results of the three tests are shown in Table 4 below.

[0076] Table 4

[0077]

[0078] Table 4 shows that the amount of matrix forming agent in the composition of the present invention can be used to control the release rate of nicotine. Alternative methods of manufacturing the composition can be used to control the amount of nicotine bound to the alginate of the matrix forming agent. The results in Table 8 show that when nicotine is added together with the matrix forming agent as the third (final) step in the manufacturing process, the amount of bound nicotine obtained is higher.

[0079] Example 3

[0080] To further evaluate the stabilizing effect of the antioxidants of the present invention, products containing approximately 1% nicotine by weight were prepared according to the formulation in Table 2 and Method 1 of Example 2. These products were prepared with and without ammonium citrate as an antioxidant and compared to the same commercially available product (CP1) in Example 2. For stability testing, all products were placed in a heating cabinet at 40°C and 75% humidity for 9 weeks (representing 7 months at room temperature). The test results for nicotine loss, pH, and water content are shown in Tables 5 to 7 below.

[0081] Table 5

[0082]

[0083] Table 6

[0084]

[0085] Table 7

[0086]

[0087] The results in Tables 5-7 demonstrate the stabilizing ability of the compositions of the present invention comprising ammonium citrate antioxidant.

Claims

1. A composition for oral or nasal use at a pH of at least 6.5, comprising: nicotine as an active agent, a matrix forming agent comprising alginate, a filler, and an antioxidant, wherein the antioxidant is a composite binder at a pH of at least 6.5, the antioxidant comprising at least one ammonium citrate or an ammonium citrate salt.

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 gum is selected from the group consisting of beta-glucan, xanthan gum, 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 alginate.

5. The composition of any one of claims 1 to 3, comprising 5 to 95% by weight of a filler comprising at least one plant fiber.

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

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

8. The composition of claim 5, 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 isomalt, lactitol and erythritol.

10. The composition according to any one of claims 1 to 3, comprising at least one excipient selected from the group consisting of preservatives, taste or flavor enhancers, pH adjusters, plasticizers, and sweeteners.

11. The composition of any one of claims 1 to 3, comprising less than 50% by weight of the matrix forming agent.

12. The composition of any one of claims 1 to 3, comprising less than 40% by weight of the matrix forming agent.

13. A composition according to any one of claims 1 to 3 suitable for delivery to the nasal cavity comprising less than 20% by weight water.

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

15. The composition of claim 13, wherein the composition comprises powder particles having a size range of 0.01 to 2 mm.

16. The composition of claim 13, wherein the filler comprises a water-soluble cellulose.

17. The composition of claim 13, wherein the filler comprises water-soluble microcrystalline cellulose.

18. The composition of claim 13, wherein the filler comprises a combination of water-soluble and water-insoluble microcrystalline cellulose.

19. A composition according to any one of claims 1 to 3, suitable for contact with oral mucosa, comprising at least 30% by weight of water and a filler comprising at least one of microcrystalline cellulose and other plant fibers.

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

21. The composition of claim 19 comprising 40 to 60% by weight of water.

22. The composition according to any one of claims 1 to 3, which is suitable for contact with oral mucosa, comprising less than 40% by weight of water and a filler selected from at least one of microcrystalline cellulose and other plant fibers.

23. The composition of claim 22, wherein the composition comprises 1 to 40% by weight water.

24. The composition of any one of claims 1 to 3 configured as a film suitable for transmucosal delivery of an active agent, said film having a thickness of 0.01 to 7 mm, comprising at least 50% by weight of said matrix forming agent and optionally a plasticizer.

25. The composition of claim 24 comprising 0.1 to 20% by weight of a filler.

26. The composition of claim 24 comprising 5 to 10% by weight of a filler.

27. The composition of claim 24, wherein the filler is microcrystalline cellulose and a plasticizer.

28. The composition of claim 27, wherein the plasticizer is selected from at least one of sorbitol and glycerol.

29. The composition of any one of claims 1 to 3, wherein the alginate is sodium alginate.

30. A method of making the composition of any one of claims 1 to 29, comprising: (i) dry mixing a bulking agent with a matrix forming agent, an antioxidant and optionally at least one taste or flavor enhancer; (ii) mixing the obtained dry mixture with a first aqueous solution comprising 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 comprising an active agent.

31. A method of making the composition of any one of claims 1 to 29, comprising: (i) dry mixing a bulking agent, an antioxidant, and optionally at least one taste or flavor enhancer; (ii) mixing the obtained dry mixture with a first aqueous solution comprising 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 comprising a matrix forming agent and an active agent.

32. A method as claimed in claim 30 or 31 , configured to produce a powder composition for nasal use by subjecting the resulting mixture to one or more further processing steps, said processing steps comprising drying to a powder having a particle size of less than 2 mm with less than 15% by weight of water.

33. The method of claim 30 or 31, configured to produce a composition for oral use by subjecting the resulting mixture to one or more further processing methods utilizing at least one of: filling in pouches, forming tablets or lozenges, extrusion, stamping, casting, molding, kneader spinning, film forming, and mixing with a chewing gum base.

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