Compositions for oral or nasal use

Abstract

To provide a composition suitable for delivering a biologically active agent to the oral or nasal cavity, the composition allowing stability of the active agent through manufacture and storage while allowing a suitable release profile of the agent.SOLUTION: The composition comprises a biologically active substance, a matrix forming agent comprising β - glucan, and a filler. The composition may further comprise additional additives such as antioxidants, preservatives, taste or flavor enhancers, pH adjusting agents, plasticizers and sweeteners. Methods of making the compositions are also disclosed.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for preparing a matrix-forming composition comprising a biologically active substance, a matrix-forming agent comprising cereal β-glucan, and a loading agent. and a method for preparing the composition for use in the oral or nasal cavity. Regarding. [Background technology]

[0002] Delivery of pharmaceutically active agents to the oral and nasal cavities is generally preferred to obtain rapid onset of treatment and This is the preferred route of administration to avoid metabolic activity in the gastrointestinal system and first-pass metabolism. A number of solid dosage forms, such as Zenji, sublingual tablets, chewing gum, buccal patches or pouches, are available for oral administration. These have been developed to obtain a suitable dosage form for the patient depending on the treatment through the cavity. Solid dosage forms typically contain an active agent, a filler, a binder, a lubricant, and other additives such as mucoadhesive, palatable, or non-pareil components. It contains other ingredients that aid in the release of the active agent, compliance, and release of the active agent.

[0003] Suppliers and developers of smokeless tobacco and nicotine products must notify the public that nicotine is delivered orally or nasally. Tobacco products include, for example, oral chewing tobacco, moist smokeless tobacco, snus and dry snuff, used either intranasally or intranasally; Non-tobacco products include pure nicotine extracted from tobacco or other tobacco-derived products, as exemplified. These drugs rely on synthetic nicotine formulated with additives suitable for oral or nasal dosage forms such as oral Non-tobacco dosage forms for use include, for example, a matrix formulation that acts as a fibrous filler material and a binder. Nicotine (3-(1-methyl-2-pyrrolidinyl)pyridine) may cause heat, It is a volatile compound that easily decomposes under the influence of oxygen and light. to counteract degradation during its manufacture and to maintain adequate storage of nicotine while allowing a desirable release rate of nicotine. Finding a suitable non-tobacco dosage form that provides shelf stability and yet is user-adaptable For these reasons, developers of nicotine dosage forms have sought to Alternatives include long shelf life, desirable release profiles, and high consumer compliance. We are looking for new drugs that support the answer.

[0004] WO2010 / 011445 discloses a method for the delivery of an active substance such as nicotine for oral use. The article discloses a plant fiber product for the purpose of incorporation of alginate as a matrix forming agent. provides the product with the desired release characteristics and adequate stabilization of the liable active substance. provide.

[0005] WO2010 / 104464 discloses a nicotine-containing pouch for use in the oral cavity. The patent discloses alginate particles containing active substances such as cinnamon.

[0006] WO2015 / 051308 and US2015 / 0098996 are primarily concerned with maltodextrins. Tobacco or tobacco containing at least 40% by weight of water-soluble fiber, which is thorin, and less than 15% water However, the shelf life of nicotine or its absorption in the oral cavity is unknown. Nothing is disclosed regarding the release characteristics of cocaine.

[0007] EP1622627 describes a pharmaceutical composition containing cereal β-glucan and a pharmaceutical agent. It has been proposed for use in the oral cavity to deliver drugs such as local anesthetics. However, this document does not claim that such products have been manufactured or actually tested. Therefore, cereal beta-glucans are effective in preventing the entry of liable active substances into the oral or nasal cavity. It is not possible to conclude whether the excipient is suitable for delivery.

[0008] US2010 / 158988 specifies that grains may contain up to 10% (by weight) of fillers. Described is an orally consumable dry dissolvable film or coating based on β-glucan. However, the film is not a nicotine product suitable for oral or nasal delivery of nicotine. EP1790687 does not demonstrate any indication that it may contain nicotine. It describes a similar dry film, but with the same consumer content as a conventional tobacco product. The patent does not teach the use of nicotine in pliance formulations.

[0009] WO2010091649 Tobacco-free nicotine product for intraoral use The pH values ​​are therefore given. The study explored how the stability and release of nicotine can be influenced by the use of selected supportive agents. There is no indication.

[0010] CN10707494 consists of a gum matrix, beta-glucan, sweeteners, and active ingredients. The document discloses a chewing gum containing cellulose lecithin as a cellulose ester.

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

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

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

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

[0015] It is also an object of the present invention to promote the stabilization of active substances that are susceptible to degradation during storage, thereby achieving relatively high To provide a composition that provides a stable product with a long shelf life even in a composition having a water content. This is what we should do.

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

[0017] Yet another object of the present invention is to deliver nicotine to the oral or nasal cavity, thereby providing equivalent and A combination suitable for meeting user expectations of compliance with conventional tobacco products or pharmaceuticals. The purpose is to provide a finished product. [Means for solving the problem]

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

[0019] In this specification of the present invention, a matrix forming agent, together with a filler, The active agent is contained therein and provides a controllable and desirable release profile of the active agent upon contact with the oral or nasal cavity. Stabilizing against liable such drugs while contributing to the profile It can provide a cohesive and homogeneous composition that contributes to its effectiveness. The efficacy and release profile may, in one aspect, be determined by the combination of a filler (e.g., a matrix-forming agent and a filler). This may be caused by an interaction or synergy between the filler and the fibers. The compositions of the invention utilize the interaction between the active substance and the matrix-forming agent to regulate the release rate. The intensity can be adjusted and controlled.

[0020] The matrix-forming agents of the present invention bind biologically active substances in a controlled manner within the composition. For example, if the active substance is nicotine, a controlled amount of nicotine is The nicotine is released, and unbound nicotine and a controlled amount of nicotine are released from the matrix forming agent. The matrix-forming agent can be selected to be slowly and controllably released from the For example, by increasing the amount of matrix forming agent in the composition of the present invention, more The cobalamin is bound and slowly released. Therefore, the composition can be administered orally or nasally. and providing a user with a satisfactory initial dose of nicotine and releasing nicotine from the composition over a predetermined period of time. In the case of nicotine products, matrix formulations can be used to slowly release Various formulations can be used to meet various user compliance requirements.

[0021] In one embodiment, the composition of the present invention contains less than 50% (by weight) of a matrix forming agent, e.g., 4 Less than 0% (by weight) or less than 30% (by weight) and less than 20% (by weight), or 0.1 to 10% (by weight), or 0.5 to 5% (by weight) of a matrix forming agent.

[0022] In other embodiments, the compositions of the present invention contain more than 50% (by weight) of a matrix forming agent, e.g., 5 It contains 0 to 90% (by weight) or 50 to 70% (by weight) of a matrix forming agent.

[0023] Also, as used herein, fillers primarily contribute to the bulk and shape of the composition, e.g., Allows for user compliance in different parts of the cavity and / or convenient distribution of the composition The filler also aids in manufacturing, handling, and administration. Positively interact with the compounding agent to stabilize the drug(s) and induce the desired release profile. Good too.

[0024] The β-glucan of the composition can be obtained from a variety of sources, including grains and yeast, and may contain at least It contains at least 30% β(1-3)β(1-4) glucan, preferably 70 to 99 or approximately It contains almost 100% β(1-3)β(1-4) glucan. β-glucan is obtained from cereals. Preferably, it is obtained from oats, more preferably from oats. Cereal β-glucans are, for example, For example, Journal of Food Science, 2017, 82(9)(GM aheshwari et al) and Chemical Engineering a nd Processing,2014,84,page 90-97(O Benit Purification to a suitable high grade was performed by the method outlined in o-Roman et al. It is possible.

[0025] In one embodiment, the composition of the present invention comprises a matrix comprising at least 50% (by weight) β-glucan. The compositions of the present invention preferably contain alginate and suitable salts thereof, Xanthan, carrageenan, methylcellulose, cudran, pullulan, guar gum, almond At least one food or pharmaceutical grade selected from labia gum and similar polysaccharides a matrix-forming agent further comprising an additional pharmaceutically acceptable gum or gel-forming polysaccharide of Preferably the additional gum is a salt of alginate, more preferably alginate. Sodium glutamate.

[0026] The filler of the composition of the present invention comprises a fibrous material which may be of natural or synthetic origin. Preferably derived from plants, algae or fungi, they may be naturally occurring or bioprocessed or chemically derived. In a preferred embodiment, the fiber material is a plant fiber, more preferably Preferably, the filler comprises natural or modified cellulose fibers, most preferably at least one Contains microcrystalline cellulose.

[0027] In various embodiments, the plant fibers included in the filler include those derived from tea, coffee, tobacco, cocoa, Corn, bamboo, oats, barley, rye, sugar beet, herbs, buckwheat, potatoes, Tomato, eggplant, cauliflower, apple, yerba mate, or one variety of source of cellulose fiber and the like. Plant fibers may be natural or may be derived from a variety of biological or Tobacco fibers may be modified by chemical methods to improve brightness and / or nitrosamine content. The process can be carried out according to various conventional techniques for reduction.

[0028] Microcrystalline cellulose (MCC) suitable for fillers is AVICEL® grade PH-100, PH-102, PH-103, PH-105, PH-112, PH-11 3. PH-200, PH-300, PH-302, VIVACEL (registered trademark) grades 101, 102, 12, 20; EMOCEL® Grades 50M and 90M, H iCel® grades, such as HiCel® 90M, as well as The composition of the present invention preferably contains water-soluble microcrystalline cellulose. For product embodiments, various grades of colloids such as TABULOSE® are used. Grades of microcrystalline cellulose are useful.

[0029] Water-soluble microcrystalline cellulose is preferred in compositions of the invention, e.g., for use in the nasal cavity. For powdered composition embodiments, suitable grades of colloidal microcrystalline cellulose include C As No. 51395-75-6, various brands of A preferred such colloidal gelling MCC is commercially available from TABULOSE®. The product name is FEIYUN XW591.

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

[0031] In an embodiment of the invention relating to a powdered composition for use in the nasal cavity, the filler is at least one selected from the group consisting of cellulose derivatives, starch derivatives, and polyvinylpyrrolidone; The adhesive may comprise a mucoadhesive such as sodium starch glycolate. and cross-linked polyvinylpyrrolidone. In some embodiments, the filler may include guar gum or starch. Suitable starches include thiamin, ... Corn starch, pregelatinized starch, hydroxypropyl starch and modified or non- It is a modified starch.

[0032] In an embodiment of the invention relating to a powdered composition for use in the nasal cavity, the composition comprises 0 0.01~2mm, or 0.05~0.5mm, or 0.02~0.2mm, or 0.01 The composition includes powder particles having a controlled average size (diameter), such as 0.1 mm or less. In this case, particles approaching less than 10 μm (<) may be aerosolized and inadvertently injected into the lungs. Avoid the risk of dispersal and ensure compliance and safety for particles larger than a few mm. The powder particle size is optimized to avoid turbulence and distribution.

[0033] Biologically active substances include therapeutic or non-therapeutic substances that are not generally considered pharmaceuticals, e.g. It may be a naturopathic preparation, a stimulant or a dietary supplement. Examples of therapeutic biologically active agents that can be administered in combination include urinary incontinence agents; anti-inflammatory drugs; Histamines, analgesics, anti-inflammatory drugs, antiemetics, antiepileptic drugs, vasodilators, antitussives and expectorants Drugs, antispasmodics, hormones, diuretics, antihypotensives, bronchodilators, anti-inflammatory steroids, antibiotics Substances, sedatives, CNS active substances, cannabinoids, e.g., Δ9-tetrahydrocannabinol These include steroids (THC) or cannabidiol (CBD), decongestants, laxatives, and antacids. Generally, the composition is used to treat conditions such as loss of consciousness, severe migraine, acute stroke or gastrointestinal obstruction. This leads to the inability to administer conventional tables for They are useful as drug delivery dosage forms for patients suffering from co-morbid conditions. 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 These include acetylsalicylic acid, Russian root and rose root.

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

[0035] In some embodiments, the biologically active substance is nicotine. provides synthetic nicotine and nicotine extracts from tobacco plants, such as Nicotiana tabacum or other plant sources. Any solid or liquid form, including amorphous, crystalline, polymorphic, or other physical form or isomerism. Nicotine or nicotine derivatives in their chemical forms, such as isomers and enantiomers, and any of their The term "nicotine" as used herein includes pharmaceutically acceptable salts, complexes or solvates of the compound. The term also refers to nicotine base and / or its salts, e.g., nicotine hydrochloride, nicotine dihydrochloride , Nicotine Monotartrate, Nicotine Ditartrate, Nicotine Sulfate, Nicotine Zinc Chloride (Monohydrate) Also includes nicotine salicylate) and nicotine salicylate.

[0036] Nicotine is typically present in an amount of about 0.1% (by weight) to about 5% (by weight), calculated as the free base. amount), for example, about 0.1% (by weight) to about 4% (by weight), about 0.1% (by weight) to about 3% (by weight) ), about 0.1% (weight) to about 2% (weight), about 0.1% (weight) to about 1% (weight), about 0 .1% (weight) ~ approx. 0.75% (weight), approx. 0.2% (weight) ~ approx. 0.5% (weight), or It is present at a concentration of about 0.2% (by weight) to about 0.4% (by weight). The nicotine or salt thereof used is preferably of high purity, for example 99.5% purity. .

[0037] The antioxidants in the compositions of the present invention are effective oxidants at a pH of at least 6.5, e.g., 8-9. an antioxidant, preferably the antioxidant is a complex-bound antioxidant, more preferably Antioxidants include alkali and / or alkaline earth metal salts of ascorbate, calcium citrate, Sodium, Calcium Lactate, Calcium Maleate, Calcium Tartrate, Ca-DiNa-E DTA, calcium phosphate, and ammonium citrate; More preferably, the antioxidant is sodium ascorbyl phosphate, calcium ascorbate Sodium, Calcium Ascorbate, Calcium Ascorbyl Phosphate, Ascorbic Acid Most preferably, the antioxidant is an ascorbate selected from magnesium. Calcium scorbate. This type of antioxidant is one whose biologically active substance is nicotine. In some cases it is generally preferred. However, other types of active substances may require suitable storage stability. To achieve this, complementary or different antioxidants or antioxidant systems may be required.

[0038] The composition according to the present invention may contain a plasticizer, a pH adjuster, a preservative, a taste or flavor enhancer, a colorant, and It further comprises at least one additive selected from sweeteners.

[0039] Plasticizers include, for example, polyethylene glycol, propylene glycol, glycerol, and The preferred plasticizer is sorbitol, optionally ly) with a portion of glycerol.

[0040] The pH adjuster is capable of maintaining a pH of at least 6.5 in the composition, and Carbonates, including carbonates, bicarbonates and sesquicarbonates, and acetates phosphate, glycinate, gluconate, borate, glycerophosphate, or citrate Any weak organic acids, other alkalis / alkalis of physiologically acceptable acids such as phosphates Metal salts, metal hydroxides such as sodium hydroxide and potassium hydroxide, and mixtures of these Examples of suitable pH adjusters are sodium bicarbonate and sodium carbonate, and Preferably, the composition has a higher pH (e.g., pH 8 to 9) during production. Preferably, the pH adjuster must be capable of maintaining a pH >6.5 throughout storage and consumption. It must be.

[0041] Preservatives include sorbic acid, sorbates, benzoic acid lactic acid and physiologically acceptable salts. Preservatives can be selected from any food and pharmaceutical industry approved agent. Preferred preservatives are: It is potassium sorbate.

[0042] Taste or flavor enhancers include ammonium chloride; alcohols, esters, aldehydes, and Distillation of chopped flowers, leaves, peels or pulped whole fruits containing a mixture of lactones and solvents Essential oils, including extracts or cold-pressed essential oils; or diluted solutions of essential oils , or for example bergamot, eucalyptus, orange, mandarin, citrus, lemon, Peppermint, mint, menthol, licorice, wintergreen, tobacco, coffee, Synthetic chemical blends that match the desired flavors from chives, limes, apples, peaches, and mixtures thereof. Further examples include brews and blends of and alcoholic beverages, such as cognac, whiskey, rum, gin, sherry, port wine and wine artificial and natural flavors include eucalyptus, licorice, and menthol.

[0043] Coloring agents include indigo carmine, amaranth, erythrosine, carbon black, and dioxide. Dyes containing chemical groups that absorb light, including dyes such as titanium dioxide and any mixtures thereof You can choose from:

[0044] The sweetener may be a natural sweetener that is not fermentable in the mouth, or an artificial sweetener, such as aspartame. cereals, acesulfame K, saccharin, cyclamate, stevia extract and other similar agents It could be.

[0045] In an embodiment of the invention, the composition is a powder composition adapted for delivery to the nasal cavity, and , preferably 0.5 to 5% (by weight) of a matrix-forming agent as defined above, less than 20% (by weight) The powder particles of such a composition contain 0.05 wt. The size range is 1 to 5 mm, or preferably 0.05 to 2 mm. In an embodiment of such a composition, the filler is a water-soluble cellulose, preferably a water-soluble Microcrystalline cellulose, more preferably a combination of water-soluble and water-insoluble microcrystalline cellulose Such compositions may further comprise the active substances, fillers and additives defined above. In one embodiment suitable for nasal use, the composition comprises nicotine and a matrix-forming a filler comprising β-glucan as a binder and at least partially water-soluble cellulose; % (by weight) of water, pH adjusters, antioxidants, preservatives, taste / flavor enhancers and sweeteners and one or more other additives selected from the group consisting of: The composition is a powder having particles less than about 2 mm in size, and comprises nicotine and a matrix a filler comprising β-glucan as a forming agent and at least partially water-soluble cellulose; Less than 20% (by weight) water, pH adjusters, antioxidants, preservatives, taste / flavor enhancers, and and one or more other additives selected from sweeteners. In the present invention, the composition comprises nicotine, β-glucan as a matrix forming agent, and at least part of Partially water-soluble cellulose filler, 1 to 15% (by weight) water, and pH adjuster Sodium bicarbonate, calcium ascorbate as an antioxidant, preservatives, flavor / flavor and one or more other additives selected from a taste enhancer and a sweetener. It is a powder having particles in the size range of

[0046] In an embodiment of the invention, the composition is adapted for delivery to the oral cavity by contact with the mucosa. Such compositions contain less than 50%, preferably 0.1 to 10% (by weight), more preferably contains 0.5-5% (by weight) of the matrix former as defined above, and at least 30% ( % (by weight) of water, preferably 40 to 60% (by weight) of water. In an embodiment, the composition may further comprise active agents, fillers, and additives as defined above. The product preferably contains at least 40% (by weight) of a filler which comprises microcrystalline cellulose. Preferably, such compositions are provided in a form such as a snus product in which a defined amount of the composition is packaged in a pouch. It can be provided as a conventional tobacco product. and a filler containing cocoa, β-glucan as a matrix forming agent, and microcrystalline cellulose. , at least 30% (w) water, pH adjusters, antioxidants, preservatives, taste / flavor enhancers In one embodiment of such a composition, the composition further comprises one or more other additives selected from the group consisting of an anti-inflammatory agent and a sweetener. The formulation is composed of nicotine, β-glucan as a matrix forming agent, and microcrystalline cellulose. and optionally a filler comprising mannitol and / or other vegetable fibers, and 60% (wt) water, pH adjuster, antioxidant, preservative, taste / flavor enhancer and sweetener and one or more other additives selected from the group consisting of: nicotine, β-glucan and one or more other additional pharmaceutical / nutritional agents as defined above. and a matrix forming agent comprising a commercially acceptable gum, microcrystalline cellulose, and optionally onally) a filler containing mannitol and / or other vegetable fibers, and 40-60% (by weight) selected from water, pH adjusters, antioxidants, preservatives, taste / flavor enhancers, and sweeteners and one or more other additives.

[0047] In an embodiment of the invention, the composition is administered as a lozenge or tablet that slowly dissolves upon contact with saliva. The composition is adapted for delivery to the oral cavity. The composition contains less than 30% (by weight) water, preferably contains 1-30% (by weight) water, forming at least 50% matrix as defined above Such compositions further comprise the active substance, fillers and additives defined above. In certain embodiments, the filler may include microcrystalline cellulose, and in certain In this embodiment, the lozenge is provided with a coating containing the active agent, preferably a coating that establishes sustained release. Nicotine-containing coatings designed to provide an initial rapid-dose use before It can have a g.

[0048] In another embodiment of the invention, the composition comprises more than 50% matrix forming agent and the active ingredient The film composition is suitable for transmucosal delivery of high-quality In one embodiment, these compositions have a thickness of 100 mm and optionally contain a plasticizer. The composition contains 0.05 to 20% (by weight), preferably 5 to 10% (by weight) of a filler. Preferably, the filler is microcrystalline cellulose and a plasticizer, and preferably the plasticizer is a sol. The alcohol is selected from at least one of ethanol and glycerol.

[0049] The components and amounts of fillers and other specified additives may be used in a variety of applications, e.g., for oral or nasal use. The force required can vary depending on the desired properties of the final product.

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

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

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

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

[0054] The method may in one alternative include one or more further processing steps of the resulting mixture, e.g. For example, by spray drying to a powder of about 1 mm or less particle size, less than 20% water (by weight) ), for example, 1 to 15% (by weight) of water, to produce a powder composition for nasal administration. It can be configured as follows.

[0055] In another alternative, the method may include filling into pouches, tableting or lozenge forming, extrusion, patting, punching, casting, molding, injection molding, kneading spinning, film, sprayable dosage forms and diluting the resulting product, and forming and mixing the resulting product with a chewing gum base. One or more further processing steps of the mixture to produce a composition for use in the oral cavity. It can be configured to make DETAILED DESCRIPTION OF THE INVENTION

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

[0057] Example 1

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

[0059] A composition of about 800 mg of lactic acid bacteria suitable for packaging in a pouch as a snus-type product for oral use. The unflavored compositions in Table 2, which may have a pH of 0.5, were tested for nicotine stability. 80g samples of the composition of Example 2 and a commercial tobacco-based snus product were incubated at 40°C and relative humidity The comparison was made at 75% for 9 weeks (equivalent to 10 months at 25°C without adjusting for relative humidity). [Table 3]

[0060] Table 3 shows that the β-glucan and antioxidants of the compositions of the present invention significantly increased nicotine stability. This demonstrates that a previous study using a composition similar to that in Table 2 but without antioxidants was performed. The study demonstrates nicotine stability comparable to that of commercially available tobacco-based products. The present invention relates to a method for manufacturing a matrix-forming agent containing β-glucan, which is a composition of the present invention, and a method for manufacturing a matrix-forming agent containing β-glucan. This indicates that the nicotine storage capacity of the β-glucan-containing malic acid is equivalent to that of the β-glucan-containing malic acid. The combination of a trix-forming agent and a chelating antioxidant provides effective long-term nicotine relief. Provide qualitative information.

[0061] Example 2 [Table 4]

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

[0063] The lozenges or tablets are prepared by dry blending all the ingredients in Table 4. The product is transferred to a conventional tablet press, subjected to high pressure and formed into tablets / lozenges. The tablets are spray coated and dried in a coating pan to add sweeteners, flavorings, etc. and similar agents. to (optionally1), containing nicotine to provide an initial dose.

[0064] Example 3

[0065] 0.89% (by weight) nicotine, approximately 41% (by weight) water, 1 as a matrix former or 2% β-glucan. The product was prepared using a substitution method. In step 1, β-glucan was mixed with the filler in the first step and dried. The product from step 1 is mixed dry and the solution of nicotine is added in a third step. ) β-glucan. In step 2, 1 or 2% ( The product from step 2 contains 1% or 2% (by weight) of β-glucan. The product is packaged in a traditional snus pouch and contains microcrystalline cellulose as a filler. Two commercially available tobacco freezers containing β-glucan but not β-glucan as a matrix former were used. - Benchmarked with nicotine products (CP1 and CP2, respectively). , CP1 and CP2 were tested for stability and nicotine release. All products were placed in a heating cabinet at 40°C and 75% humidity for 9 weeks (7 months at room temperature). equivalent to). [Table 5] [Table 6] [Table 7]

[0066] The results in Tables 5 to 7 show that the products according to the present invention containing a matrix-forming agent containing β-glucan , which stabilized both nicotine and pH values ​​during storage significantly better than either CP1 or CP2. The variation in moisture content between products can be attributed to different fillers.

[0067] To test the nicotine release capacity of the compositions according to the invention, pouches containing the product were subjected to a The products were prepared as outlined above in steps 1 and 2 and compared to CP1. The pouches were orally tested and removed after a specified period and processed for residual nicotine. The samples were shredded into a 100 ml glass bottle and exposed to ultrasound for 5 minutes with 5 ml of Milli-Q water. Then, 100 ml of 0.05 M potassium hydroxide solution was added, the sample was shaken, and then The samples were exposed to ultrasound for 60 minutes at 100°C. The samples were shaken overnight on a vibrating table and then the next day for another 30 minutes. The sample is then centrifuged, diluted to the desired level, and an internal standard is added. The average results of three tests are shown below. Shown in Table 8. [Table 8]

[0068] Table 8 shows the effect of the amount of matrix forming agent in the compositions of the present invention on controlling the release rate of nicotine. For example, doubling the amount of beta-glucan from 1 to 2% (by weight) results in an 18% increase in nicotine bound to the matrix forming agent over a 38-minute period. The method for preparing the composition was used to obtain a nicotine-containing matrix-forming agent bound to β-glucan. The results in Table 8 show that the amount of nitrile can be controlled by adding nitrile as the third and final step in the manufacturing process. Adding nicotine together with a matrix-forming agent results in a higher amount of bound nicotine. This shows:

Claims

1. A composition comprising a biologically active substance, a matrix forming agent including β-glucan, and a filler. Compositions for use in the oral or nasal cavity.

2. the pH is at least 6.5 and the biologically active substance is nicotine or a cannabinoid 2. The composition of claim 1, wherein:

3. The β-glucan is preferably at least 30% β(1-3)β(1-4) glucan. and the β-glucan is about 70 to 100% β(1-3)β(1-4) glucan, Preferably it is a cereal β-glucan, preferably a cereal β-glucan obtained from oats 10. The composition of any preceding claim, wherein

4. The matrix forming agent may comprise at least one additional pharmaceutically acceptable gum. , preferably alginate and its salts, xanthan, carrageenan, methylcellulose, Preferably, the additional gum is selected from curdlan and pullulan, and is a salt of alginate. and more preferably sodium alginate. composition.

5. The matrix-forming agent comprises at least 50% (by weight) of cereal β-glucan. The composition according to claim 3 or claim 4.

6. Contains an antioxidant effective at a pH of at least 6.5, preferably effective at a pH of 8-9. Preferably, the antioxidant is a complex-bound antioxidant, preferably ascorbate. Alkali and / or alkaline earth metal salts of calcium citrate, calcium lactate, maleic acid, calcium tartrate, calcium tartrate, Ca-diNa-EDTA, calcium phosphate and and ammonium citrate, more preferably 10. The composition of any one of the preceding claims, wherein is calcium ascorbate.

7. The filler comprises a fibrous material, preferably the fibrous material is a vegetable fiber, more preferably Preferably, the filler comprises natural or modified cellulose fibers, and most preferably at least one 10. The composition of any one of the preceding claims, comprising microcrystalline cellulose.

8. The filler comprises a polyol, preferably mannitol, xylitol, sorbitol maltitol and / or isomaltitol, lactitol and erythritol 10. A composition according to any one of the preceding claims, comprising one or more selected polyols. thing.

9. 9. The method according to claim 8, further comprising the step of adding a filler containing a plant fiber material and 5 to 70% (by weight) of a polyol. Preferably, the filler is mannitol and at least one microcrystalline A composition comprising a hydrophilic cellulose.

10. At least one selected from the group consisting of preservatives, taste or flavor enhancers, pH adjusters, plasticizers, and sweeteners 10. A composition according to any one of the preceding claims, comprising one additive.

11. Contains less than 50% (by weight), preferably less than 40% (by weight) of said matrix forming agent , a composition according to any one of the preceding claims.

12. It is adapted for delivery to the nasal cavity and contains less than 20% water (by weight), preferably 1-15% (by weight).

10. A powder composition according to any one of the preceding claims, comprising water.

13. The composition of claim 12, wherein the powder particles have a particle size of 0.01 to 2 mm.

14. The filler is water-soluble cellulose, preferably water-soluble microcrystalline cellulose, more preferably 13. The composition of claim 12 or claim 13, wherein the composition comprises a combination of water-soluble and water-insoluble microcrystalline cellulose. The composition described in

15. A composition adapted for contact with the mucous membranes of the oral cavity, containing at least 30% (by weight) water and microcrystalline cellulose The composition according to any one of claims 1 to 11, comprising a filler comprising a cellulose acetate.

16. 16. The composition of claim 15, comprising 40 to 60% (by weight) water.

17. Adapted for oral administration as a lozenge or tablet, containing 1 to 30% water (by weight) and a filler comprising at least one of microcrystalline cellulose, plant fiber, and polyol. A composition according to any one of claims 1 to 10, preferably comprises at least 50% (by weight) of said matrix forming agent.

18. Constructed as a film having a thickness of 0.01 to 7 mm suitable for transmucosal delivery of an active agent. and at least 50% (by weight) of said matrix forming agent and optionally a plasticizer. The composition according to any one of claims 1 to 10, comprising an agent.

19. It contains 0.1 to 20% (by weight), preferably 5 to 10% (by weight) of filler, preferably The filler is microcrystalline cellulose and a plasticizer, preferably the plasticizer is sorbitol and glycerol.

20. A method for producing a composition according to any one of claims 1 to 19, comprising the steps of: (i) dry-mixing a filler with at least one of a matrix-forming agent and an antioxidant; And, (ii) mixing the dry mixture with a first aqueous solution containing a pH adjuster; (iii) a second aqueous solution comprising at least one of a preservative, a taste or flavor enhancer, and a sweetener; Adding (iv) adding a third aqueous solution containing one or more biologically active substances, and and mixing all of the ingredients into a mixture with a suitable amount of water.

21. 10. The method of claim 9, wherein the filler is dry mixed with the matrix forming agent and the antioxidant.

20. The method according to claim 20.

22. dry blending the filler and the antioxidant; and 21. The method of claim 20, comprising a tether forming agent and the one or more biologically active substances. Law.

23. The resulting mixture may be subjected to one or more further processing steps to produce a powder composition for intranasal use. powder of less than 2 mm particle size containing less than 15% water (by weight) 23. The method of any one of claims 20 to 22, comprising drying the

24. Filling pouches, tablet or lozenge formation, extrusion, punching, casting, molding, At least one of injection molding, knead spinning, film forming, and mixing with a chewing gum base. The resulting mixture is then further treated with one or more methods to 24. The method of claim 20, wherein the method is adapted to manufacture a composition for use in 10. The method according to claim 1.

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