Nicotine-loaded composition

Abstract

The present invention relates to a composition comprising nicotine and / or a nicotine salt and calcium silicate, wherein the composition is placed in a pouch, wherein the pouch is for placement in the oral cavity.

Description

Technical Field

[0001] This invention relates to specific compositions comprising nicotine and calcium silicate, and in particular, to providing nicotine-loaded compositions and their uses. Background Technology

[0002] There is a demand for nicotine products, primarily as a substitute for tobacco. Therefore, it is essential to determine suitable formulations of nicotine, ideally meeting several criteria. First, nicotine should be released along a specific curve, and in the case of products intended for oral administration or inhalation of vapor, it should provide the best possible user experience. Typically, this involves a rapid release of nicotine from the formulation to provide an immediate pleasurable "hit," followed by a sustained release over a period to prolong the experience. Furthermore, nicotine itself is an oily liquid, difficult to handle, store, and formulate, thus usually requiring some diluent or carrier to physically contain the composition within the carrier used for its administration. Additionally, nicotine is readily oxidatively degraded, so the loaded form should exhibit improved stability. Moreover, the composition should be able to accommodate other materials beneficial to its use; for example, the incorporation of certain flavoring ingredients.

[0003] The aforementioned properties can be achieved through carrier materials for nicotine, many examples of which are known in the art. For example, nicotine loaded on an ion-exchange resin (Polacrilex) is a commercial product used in gums and hard lozenges for oral delivery of nicotine. The use of microcrystalline cellulose and / or compressible sugar alcohol particles as carriers for nicotine-releasing chewable tablets has also been previously described. Alternatively, solid lipid particles can be used as carriers in nicotine powder compositions. Furthermore, an inorganic mineral filler material has been previously disclosed as a carrier based on natural or precipitated calcium carbonate to provide nicotine-containing chewing gum or granular materials for controlled release. However, generally, the carriers described in the prior art are only applicable to orally administered products. Manufacturers typically offer their nicotine alternatives in various forms, thus requiring them to use different nicotine powder compositions for their various products, increasing production costs.

[0004] A known nicotine formulation, such as those used in sachets or tablets, consists of a mixture of tartrate or other salts of nicotine and an alkali (e.g., sodium bicarbonate), which releases free nicotine upon reaction with water. However, this undesirably produces a salty taste and leads to the intake of large amounts of sodium, which can affect the user's blood pressure.

[0005] Therefore, the object of the present invention is to alleviate the above-mentioned problems. Summary of the Invention

[0006] According to one aspect of the invention, a composition comprising nicotine and / or nicotine salts and calcium silicate is provided.

[0007] According to another aspect of the invention, a composition comprising nicotine and / or nicotine salts and calcium silicate is provided, wherein the composition is placed in a sachet for placement in the oral cavity.

[0008] According to another aspect of the invention, a premixed composition is provided comprising about 5 wt% to about 70 wt% calcium silicate and about 5 wt% to about 70 wt% nicotine, wherein the nicotine content is expressed as an equal amount of nicotine and / or nicotine provided in the form of nicotine salts.

[0009] According to another aspect of the invention, a formulation comprising the premix described herein is provided, wherein the formulation comprises about 0.05 wt% to about 5 wt% nicotine, wherein the nicotine content is expressed as an equal amount of nicotine and / or nicotine salts provided in the form of nicotine.

[0010] According to another aspect of the invention, a formulation comprising the premix described herein is provided, wherein the formulation comprises about 0.07 wt% to about 15 wt% of the premix composition, preferably about 0.1 wt% to about 10 wt%.

[0011] According to another aspect of the invention, tablets are provided that comprise the compositions, premixed compositions or formulations of the invention as described herein.

[0012] According to another aspect of the invention, chewing gum is provided that comprises a composition, premixed composition or formulation according to the invention described herein.

[0013] According to another aspect of the invention, a tablet is provided comprising the composition, premixed composition or formulation of the invention as described herein.

[0014] According to another aspect of the invention, a heat-not-burn product is provided, comprising a composition, premixed composition or formulation according to the invention described herein.

[0015] According to another aspect of the invention, a pouch is provided containing the compositions, premixed compositions, or formulations of the invention as described herein.

[0016] According to another aspect of the invention, a method for preparing compositions, premixed compositions or formulations according to the invention is provided, the method comprising mixing nicotine and / or nicotine salts with calcium silicate.

[0017] According to another aspect of the invention, a method for preparing a composition, premixed composition, or formulation is provided, the method comprising pretreating calcium silicate with carbon dioxide prior to mixing nicotine and / or nicotine salts with calcium silicate.

[0018] According to another aspect of the invention, a method for preparing a composition, premixed composition or formulation is provided, the method comprising mixing calcium silicate, water and nicotine and / or nicotine salt.

[0019] According to another aspect of the invention, a method for preparing a composition, premixed composition, or formulation is provided, the method comprising mixing calcium silicate with carbon dioxide and nicotine and / or nicotine salts. Detailed Implementation

[0020] The present invention relates first to a composition comprising nicotine and / or nicotine salts and calcium silicate, wherein the composition is placed in a sachet for placement in the oral cavity.

[0021] Calcium silicate has been found to provide a useful carrier for nicotine, suitable for oral administration compositions and for use in inhalation devices. This carrier is effective both in carrying nicotine from oil into easily handled solid powder formulations and in providing a medium from which nicotine is easily released to the user.

[0022] Furthermore, using calcium silicate as a carrier allows the composition to be used with additional ingredients, such as flavorings and other ingredients needed to enhance the user experience.

[0023] In addition, no additional alkali (such as sodium bicarbonate) is required, so you don't ingest large amounts of sodium when consuming nicotine.

[0024] Compositions comprising calcium silicate and nicotine have been described in the prior art. However, the purpose of calcium silicate in prior art formulations is not to load nicotine, but rather to improve the physical properties of the resulting composition, such as improving flow properties. For the purposes used in the prior art, calcium silicate is typically used in a low percentage, but in order to provide a loaded form of nicotine, calcium silicate is used in a higher percentage. Furthermore, calcium silicate has not been used in prior art for nicotine sachet formulations. Similarly, in the prior art, nicotine is present in a low percentage in the composition, while in this invention, nicotine is present in a higher percentage to provide a loaded form of nicotine, particularly to provide a premix.

[0025] RCFuisz's patent application US2018 / 0084820 relates to fully soluble, non-filament melt-spun compositions with a tobacco content of 1-70%. Considering that the nicotine content in tobacco is typically around 1%, these compositions generally contain less than 1% nicotine. Although these compositions contain calcium silicate, its purpose is to improve the flowability of the mixture for uniform processing, and their application is only specified at most 10%, preferably 3-5%. Examples show calcium silicate in the range of 2-4%. Apart from the presence of relatively low proportions of nicotine and calcium silicate, these compositions are designed to dissolve completely in the mouth without the aid of saliva, and are therefore significantly different from the pouch compositions of this invention.

[0026] Similarly, RCFuisz's Australian patent AU2014 / 202362B2 relates to a sheet-like, non-aqueous, extrudable composition comprising a thermoplastic polymer for delivering bioactive products, such as nicotine, through contact with the user's mucous membranes. It relates to compositions containing a total tobacco content of 75 mg. Assuming the tobacco contains approximately 1% nicotine, this indicates that these compositions contain approximately 0.75 mg of nicotine. Additionally, typical embodiments in the patent contain 25% tobacco; this implies approximately 0.25% nicotine. Although some components in the composition include calcium silicate, its purpose is as a flow agent to promote flowability and uniformity and consistency of the finished product. Likewise, it is used only in relatively small amounts, ranging from 2-6% in the examples. While the patent does not explicitly describe compositions containing both nicotine and calcium silicate, it describes compositions containing both nicotine and starch, noting that silicate can be used in place of starch. Nevertheless, apart from the relatively low proportions of nicotine and calcium silicate in its compositions, the compositions are designed to dissolve directly through contact with the user's oral mucosa. This patent does not use a pouch that can be placed in the mouth to contain the formulation; in fact, this would prevent its composition from directly contacting the oral mucosa to which it is intended. While the patent mentions that the composition can be in a pouch, these only refer to pouches that can be used as packaging embodiments, from which the composition is removed by the user for use; such pouches are not saliva-permeable and are not intended for placement in the mouth. It is noteworthy that this patent compares its product to snuff-type products from other companies, and notably, the composition in this patent, containing 75mg of tobacco, produces a higher plasma nicotine content and is therefore superior in performance compared to snuff-type products containing 2mg of nicotine. Other companies' snuff-type products use saliva-permeable pouches. Assuming they claim their products are superior, this effectively teaches a far cry from the concept of using their extrudable compositions in saliva-permeable pouches.

[0027] Patent application GB2016897A by RGBayless et al. relates to a combustible tobacco alternative smoking material comprising nicotine encapsulated in a combustible polysaccharide material, which can then be mixed with particulate organic fillers. One example shows approximately 2.2 parts of microencapsulated nicotine citrate, representing approximately 20% nicotine, in approximately 75g of other ingredients (e.g., fillers). Clearly, the proportion of nicotine in the overall composition is less than 1%, similar to tobacco. As possible filler materials, they list any of 14 cations with 9 anions, preferably 6 cations (one of which is "calcium") and 8 anions (one of which is "silicate"); however, silicate is not one of the three most preferred anions. Furthermore, specific filler materials they list include sodium silicate, calcium aluminate, and calcium carbonate, and it can be inferred that they have not specifically studied calcium silicate and therefore do not know what specific properties calcium silicate would impart to the resulting composition. Furthermore, the composition is designed to encapsulate nicotine within a polysaccharide, thereby keeping the filler separate from the nicotine, and is equivalent to a premix of only nicotine and polysaccharide, which, according to the description, is subsequently mixed with the filler material. Moreover, the given composition is intended solely as a substitute for combustible tobacco used in smoking; the role of the inorganic material in other types of formulations used for nicotine administration, such as sachets placed in the mouth, is unknown.

[0028] U.S. Patent Application 2014 / 0246033 by L. Daehne et al. describes a heat-not-burning system in which the device includes a reservoir in which nicotine is adsorbed within nanoparticles of a material such as glass, silicate, or aluminum silicate, and the reservoir has a macroporous structure that allows airflow, so that when the reservoir area is heated, the vaporized nicotine is released into the airflow for the user to inhale. However, although the specification mentions "silicate," the patent does not exemplify any use of calcium silicate. The patent focuses primarily on aluminum trisilicate. Furthermore, the patent only relates to a heat-not-burning device as a component for generating a vapor stream containing nicotine. The patent does not provide information on the utility that could be converted into other forms of nicotine delivery; in particular, the patent makes no suggestion of any utility of silicates in compositions ingested into the oral cavity, or the effectiveness of nicotine release due to the entry of saliva rather than heating the solid. One argument in the patent is that nicotine present in nanoporous particles is more stable; however, our observations of calcium silicate suggest that nicotine thus adsorbed is less stable against oxidative degradation, and other stabilizers, such as water, glycerol, carbon dioxide, or ethanol, should be added to improve its stability, as described below. This may reflect the behavioral differences between the type of silicate involved in their invention and the calcium silicate used in this invention. Furthermore, very different properties are required for formulations intended for placement in the oral cavity, such as those permeable to saliva. Aluminum silicate is undesirable for use in oral cavity compositions due to its toxicity.

[0029] An example of calcium silicate suitable for use in this invention is (i) Tomita Pharmaceutical Co., Ltd. PS-200 ( PS-200 of Tomita Pharmaceutical Co Ltd), Tokushima, Japan, (ii) R, also Tomita Pharmaceutical Co., Ltd., (iii) Evonik Resource Efficiency GmbH 250 Precipitated Calcium Silicate NF, Hanau-Wolfgang, Germany; and (iv) MLAIndustries, 'Hydrated Calcium Silicate BP / USP', Kanpur, India.

[0030] The preferred form of calcium silicate used in this invention is produced by Tomita Pharmaceutical under the trade name [trade name missing]. Synthetic calcium silicate for sale. Compared with other known calcium silicates, It has a relatively open structure, which allows it to adsorb large amounts of nicotine / nicotine salts. However, for the purposes of this invention, any form of calcium silicate can be used.

[0031] Preferably, the sachet is a saliva-permeable sachet. This facilitates the release of nicotine from the sachet, as nicotine is water-soluble.

[0032] Preferably, the pouch is a heat-sealable pouch, and more preferably a heat-sealable nonwoven pouch. This type of pouch allows saliva to quickly reach the nicotine because the pouch does not need to dissolve the nicotine before entering the mouth.

[0033] Preferably, the width of the pouch is in the range of about 8 mm to about 20 mm, more preferably, about 10 mm to about 16 mm, for example, about 14 mm. Preferably, the length of the pouch is in the range of about 20 mm to about 40 mm, more preferably, about 25 mm to about 35 mm, for example, about 30 mm. This size is advantageous for placing the pouch in the mouth, for example, between the cheek and gums or between the lips and gums.

[0034] Preferably, the sachet is placed in the mouth between the cheek and gums and / or between the lips and gums, preferably between the cheek and gums. This is the appropriate location for the absorption of nicotine from the sachet into the body.

[0035] Preferably, the composition in the sachet comprises about 0.5 wt% to about 4 wt% calcium silicate and about 0.5 wt% to about 2 wt% nicotine, wherein the nicotine content is expressed as an equal amount of nicotine provided in the form of nicotine and / or nicotine salts. This is a suitable amount of nicotine stabilized by calcium silicate and absorbed orally.

[0036] Preferably, the sachet contains about 100 mg to about 500 mg of the composition, and more preferably, the sachet contains about 200 mg to about 400 mg of the composition. This content means that the sachet and the composition are of suitable size for delivering nicotine into the user's mouth.

[0037] Preferably, the composition is used in a tobacco alternative product. The compositions and premixed compositions of the present invention allow nicotine to be used in any tobacco alternative product (e.g., heated tobacco products, lozenges, tablets, sachets, and / or chewing gum), in which powder may be used.

[0038] Preferably, the nicotine is selected from synthetic nicotine or nicotine extracted from tobacco. Preferably, the nicotine salt is formed from synthetic nicotine or nicotine extracted from tobacco. Synthetic nicotine has a higher purity than nicotine extracted from tobacco, but both can be used in the compositions of the present invention. The compositions of the present invention may contain only synthetic nicotine, only nicotine extracted from tobacco, or a mixture of both.

[0039] Preferably, the weight ratio of nicotine / nicotine salt to calcium silicate is in the range of about 5%:about 95% to about 75%:about 25%. The term "nicotine / nicotine salt" refers to nicotine and / or nicotine salt.

[0040] Preferably, the nicotine content is expressed as an equal amount of nicotine and / or nicotine provided in the form of nicotine salts.

[0041] Preferably, the weight ratio of nicotine / nicotine salt to calcium silicate is in the range of about 10%: about 90% to about 70%: about 30%.

[0042] Preferably, the weight ratio of nicotine / nicotine salt to calcium silicate is in the range of about 25%: about 75% to about 60%: about 40%.

[0043] To avoid any doubt, the scope mentioned herein refers to the range of raw materials used in the production of the final product. For example, the final mixture formulation for sachet applications may contain only about 0.75% by weight and about 1.5% by weight of nicotine.

[0044] Furthermore, when calculating the scope of this article, components other than those named should be ignored when considering proportions. For example, a composition may contain nicotine, calcium silicate, and flavoring agents. However, when considering the ratio of nicotine to calcium silicate, the amount of flavoring agents present should be ignored.

[0045] Preferably, the composition is used to stabilize nicotine in the composition. It has been found that the compositions of the present invention stabilize nicotine, thus providing an extended shelf life for any product containing the composition.

[0046] As used herein, the terms “stable,” “stabilized,” “stabilization,” or any derivatives of the word “stable” mean that the nicotine in a composition exhibits less degradation than the nicotine in a composition that does not contain the stabilizing ingredient. For example, “stable” as used herein may mean that a composition exhibits minimal signs of degradation (e.g., less than 10% nicotine oxidation) over a period of more than two months, whereas a composition not so indicated may exhibit more than 10% nicotine oxidation during the same period. Such nicotine oxidation produces degradation products such as myosmine, nicotine-N-oxide, and cotinine.

[0047] Preferably, the composition further comprises an acid, ethanol, carbon dioxide, glycerol, or any combination thereof.

[0048] Using one of these ingredients in the compositions of the present invention improves the stability of nicotine while maintaining good nicotine release for relevant applications.

[0049] Preferably, the acid is selected from pyruvic acid, benzoic acid, acetylpropionic acid, citric acid, gluconic acid, glucuronic acid, ribonucleic acid, arabinoic acid, or galactonic acid.

[0050] Preferably, the acid is a hydroxy acid, such as a glycolic acid (e.g., gluconic acid), glucuronic acid, ribonucleic acid, arabinoic acid, and galactobionic acid. Preferably, the acid is citric acid or gluconic acid.

[0051] Preferably, the acid reacts with nicotine to form a nicotine salt. The formation of the nicotine salt can improve the stability of nicotine.

[0052] Preferably, the composition comprises about 5% to about 70% by weight of nicotine / nicotine salt, about 5% to about 70% by weight of calcium silicate, and about 5% to about 90% by weight of acid.

[0053] Preferably, the composition comprises about 5% to about 65% by weight of nicotine / nicotine salt, about 10% to about 60% by weight of calcium silicate, and about 10% to about 80% by weight of acid.

[0054] Preferably, the composition comprises about 10% to about 55% by weight of nicotine / nicotine salt, about 14% to about 50% by weight of calcium silicate, and about 15% to about 72% by weight of acid.

[0055] Preferably, when nicotine is loaded onto calcium silicate at a concentration of about 1 wt% to 20 wt%, gluconic acid is present at a content of about 5 wt% to 75 wt% (based on 50% water). Preferably, when nicotine is loaded onto calcium silicate together with citric acid, the concentration of citric acid is at most about 50 wt%.

[0056] Preferably, the composition comprises about 5% to about 70% by weight of nicotine / nicotine salt, about 5% to about 70% by weight of calcium silicate, and about 5% to about 90% by weight of ethanol.

[0057] Preferably, the composition comprises about 5% to about 65% by weight of nicotine / nicotine salt, about 10% to about 60% by weight of calcium silicate, and about 10% to about 80% by weight of ethanol.

[0058] Preferably, the composition comprises about 10% to about 55% by weight of nicotine / nicotine salt, about 14% to about 50% by weight of calcium silicate, and about 15% to about 72% by weight of ethanol.

[0059] Preferably, the composition comprises about 5% to about 80% by weight of nicotine / nicotine salt, about 5% to about 50% by weight of calcium silicate, and about 5% to about 50% by weight of glycerol.

[0060] Preferably, the composition comprises about 20% to about 65% by weight of nicotine / nicotine salt, about 10% to about 40% by weight of calcium silicate, and about 10% to about 35% by weight of glycerol.

[0061] Preferably, the composition comprises about 30% to about 60% by weight of nicotine / nicotine salt, about 10% to about 35% by weight of calcium silicate, and about 15% to about 25% by weight of glycerol.

[0062] Compositions prepared using glycerin can impart a smooth taste / feel to the product, which is preferred by the user.

[0063] Preferably, the weight ratio of nicotine / nicotine salt to carbon dioxide is in the range of about 90%:10% to about 50%:50%. The carbon dioxide content indicated herein refers to the content used in the production of the composition, not the content of carbon dioxide molecules that may be generated. For example, when producing the compositions of the present invention, carbon dioxide may react with calcium silicate to form calcium carbonate and silicon dioxide; CO2 atoms are still present, but not as carbon dioxide. As shown in the examples, the use of carbon dioxide reduces the content of impurities in nicotine.

[0064] Preferably, the composition comprises carbon dioxide and glycerol. Glycerol increases the solubility of carbon dioxide.

[0065] Preferably, the composition comprises a powder component and a particulate component, wherein the composition is in the form of a powder component and / or a particulate component, preferably in the form of a powder component and a particulate component. Preferably, the powder component releases nicotine faster than the particulate component. Preferably, the powder is a free-flowing powder. This has the advantage of providing a rapid initial nicotine release, followed by sustained nicotine release. An advantage of the present invention is that compositions can be formulated to give a desired release profile.

[0066] This invention relates to a premixed composition comprising about 5 wt% to about 70 wt% calcium silicate and about 5 wt% to about 70 wt% nicotine, wherein the nicotine content is expressed as an equal amount of nicotine and / or nicotine provided in the form of nicotine salts. This composition contributes to the stability of nicotine and facilitates its release into the body. Its advantage is that the premix can be used in a variety of nicotine products disclosed herein.

[0067] Preferably, the premixed composition comprises about 20 wt% to about 60 wt% calcium silicate and about 10 wt% to about 60 wt% nicotine, wherein the nicotine content is expressed as an equal amount of nicotine provided in the form of nicotine and / or nicotine salts.

[0068] Preferably, the premixed composition further comprises carbon dioxide. The use of carbon dioxide has been shown to increase the stability of nicotine.

[0069] Preferably, the premixed composition further comprises water, preferably about 5 wt% to about 30 wt% water, more preferably about 10 wt% to about 25 wt% water. The use of water has been shown to increase the stability of nicotine.

[0070] This invention relates to formulations comprising the premix described herein, wherein the formulation contains about 0.05 wt% to about 5 wt% nicotine, wherein the nicotine content is expressed as an equal amount of nicotine and / or nicotine salts provided in the form of nicotine, preferably about 0.2 wt% to about 3 wt% nicotine. This indicates that the premix can be used to prepare formulations for end-user applications. Its advantage is that the same premix can be used to prepare different formulations.

[0071] The present invention relates to formulations comprising the premix described herein, wherein the formulation comprises about 0.07 wt% to about 15 wt% of the premix composition, preferably about 0.1 wt% to about 10 wt%.

[0072] The preferred features of the compositions described herein also relate to premixes and formulations.

[0073] Premixed compositions prepared using ethanol are preferably used in the production of formulations for chewing gum and tablets. Such compositions can also be used in heat-non-combustible devices. The ethanol flavor can be satisfactory if present, and / or it can facilitate formulation preparation by partially dissolving some excipients to fuse the composition together. If desired, ethanol can be removed by evaporation during the preparation of the final formulation.

[0074] Preferably, the premixed composition is used in heat-not-burning products. Unlike other electronic nicotine release systems, heat-not-burning products require heating a solid composition to release nicotine and provide a vapor stream. Therefore, the compositions of the present invention are used in powder form in heat-not-burning devices. For this purpose, it is useful that, upon heating, the components of the composition do not decompose to form impurities in the vapor that could be harmful or impair the user experience. In this regard, by using an inorganic material as a carrier, namely calcium silicate or calcium carbonate, organic impurities are not released into the vapor.

[0075] The compositions, premixed compositions or formulations of the present invention can be used in heated non-combustible devices as components that release nicotine vapors for inhalation by the user when heated.

[0076] Preferably, the composition, premixed composition, or formulation is used in patches, sachets, lozenges, tablets, or chewing gum.

[0077] It has been found that the compositions, premixed compositions, and formulations of the present invention do not exhibit significant discoloration over time. A problem with some prior art compositions is that when they change color, it becomes visible through the fabric of the pouch, hindering use. This problem has led to the development of colored pouches to conceal the composition. However, for the compositions of the present invention, white, semi-transparent pouches can be used.

[0078] Patches, sachets, lozenges, tablets, or chewing gum may contain compositions, premixed compositions, or formulations according to the invention in the form of free-flowing powder and / or granules. If both free-flowing powder and granule forms are present, the free-flowing powder will provide the initial nicotine shock, after which nicotine will be slowly released from the granules.

[0079] The granular form can be produced by any method known to those skilled in the art. An example of such a method is to mix a free-flowing powder produced by the method of the present invention with microcrystalline cellulose and hydroxypropyl cellulose and / or hydroxypropyl methylcellulose. The nicotine release profile can be altered as needed to manufacture this granular form.

[0080] This invention relates to patches, sachets, lozenges, chewing gum, and / or tablets comprising compositions, premixed compositions, or formulations according to the invention described herein.

[0081] The compositions or premixed compositions of the present invention can be used in a variety of products, which means that manufacturers only need to produce a single formulation as a raw material product, which can reduce production costs.

[0082] The chewing gum described herein preferably further comprises gum base, diluent, flow aid, flavoring agent, sweetener, lubricant, binder, plasticizer, solvent, coating, colorant, surface polishing agent, or a combination of two or more thereof, preferably gum base particles, sorbitol, colloidal silica, flavoring agent, sweetener, acesulfame potassium, HPMC, sucralose, polysorbate 80, xylitol, gum arabic, titanium dioxide, carnauba wax, or a combination of two or more thereof.

[0083] Typically, a sachet is placed between the cheek and gums, releasing nicotine which is absorbed through the oral mucosa, providing a direct pathway into the bloodstream once released. Similarly, lozenges and gums can be placed or moved around the mouth. The compositions, premixed compositions, and formulations of the present invention provide advantageous release profiles for sachets, lozenges, tablets, and chewing gum because they offer an immediate release of nicotine, followed by sustained release.

[0084] This invention relates to heated tobacco products comprising compositions, premixed compositions, or formulations of the invention as described herein. Another method of providing nicotine as a tobacco substitute is by means of nicotine-containing vapor from a suitable device. The compositions, premixed compositions, or formulations of the invention can be used in any suitable device, including electronic cigarettes and heated tobacco products. Heated tobacco products typically contain tobacco, but by using the compositions of the invention, heated tobacco technology can deliver nicotine to the user without the use of tobacco.

[0085] In this specification, embodiments have been described in a manner that allows for clear and concise description; however, it should be understood that embodiments may be combined or separated in different ways without departing from the invention.

[0086] In this specification, the term "about" means ±20%, more preferably ±10%, even more preferably ±5%, and most preferably ±2%.

[0087] The composition may also contain conventional additives, such as stabilizers, humectants, emulsifiers, flavoring agents, buffers, etc.

[0088] Liquid formulations can be prepared by dissolving or suspending the active ingredient in water or other suitable carriers. Tablets and granules can be coated using conventional methods.

[0089] For oral administration, the composition may be in the form of soft gelatin capsules or tablets and typically includes an inert diluent or edible carrier. Compatible binders and / or excipients may be part of the composition. Tablets, lozenges, pills, capsules, troches, sachets, etc., may contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch, lactose, maltitol, or gum arabic; disintegrants, such as alginate, Primogel, or corn starch; lubricants, such as magnesium stearate or sterotes; flow aids, such as colloidal silica; sweeteners, such as sucrose, saccharin, or acesulfame potassium; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings. Additionally or optionally, the composition may contain glycerin to regulate smooth release in the oral cavity, and / or bind or coat powders obtained in other ways to improve physical properties, nicotine release profiles, or the stability of the nicotine contained therein.

[0090] Compositions containing appropriately formulated compounds may be included in containers, packages, or dispensers along with instructions for use.

[0091] According to another aspect of the invention, a method for preparing the compositions or premixed compositions described herein is provided, the method comprising mixing nicotine and / or nicotine salts with calcium silicate. Preferably, the method is used to prepare stable nicotine.

[0092] Preferably, the method further includes mixing nicotine and / or nicotine salts with an acid, ethanol, carbon dioxide, glycerol, or a combination thereof to form a solution before mixing the solution with calcium silicate.

[0093] Preferably, when the method uses ethanol, the method further includes a step of evaporating the ethanol after the mixing step.

[0094] Preferably, the solution is homogeneous before being mixed with calcium silicate.

[0095] Preferably, the solution is introduced into the calcium silicate incrementally. Alternatively, the calcium silicate may be introduced into the solution incrementally.

[0096] Preferably, mixing continues until a free-flowing powder is obtained.

[0097] Free-flowing powders can be used in a variety of applications / devices / products.

[0098] Free-flowing powder can be formed into granular form by any method known to those skilled in the art. An example of such a method is to mix free-flowing powder produced by the method of the present invention with microcrystalline cellulose and hydroxypropyl cellulose and / or hydroxypropyl methylcellulose.

[0099] According to another aspect of the invention, a method for preparing a nicotine composition is provided, the method comprising pretreating calcium silicate with carbon dioxide prior to mixing nicotine and / or nicotine salts with calcium silicate.

[0100] According to another aspect of the invention, a method for preparing a composition, premixed composition, or formulation is provided, the method comprising mixing calcium silicate, water, and nicotine and / or nicotine salt, preferably wherein the composition, premixed composition, or formulation contains about 5 wt% to about 30 wt% water, more preferably about 10 wt% to about 25 wt% water. Preferably, the calcium silicate is pretreated with hydrogen peroxide before being mixed with nicotine and / or nicotine salt.

[0101] Preferably, the method includes pretreating calcium silicate with water and carbon dioxide before mixing nicotine and / or nicotine salts with calcium silicate, wherein the composition, premixed composition or formulation contains about 5 wt% to about 30 wt% water, preferably about 10 wt% to about 25 wt% water.

[0102] According to another aspect of the invention, a method for preparing a nicotine composition is provided, the method comprising mixing calcium silicate with carbon dioxide and nicotine and / or nicotine salts.

[0103] Carbon dioxide can be introduced along with nicotine during formulation preparation, or calcium silicate can be pretreated with carbon dioxide to reduce its alkalinity before the introduction of nicotine and before the introduction of nicotine alone. Carbon dioxide is believed to react on the surface of the calcium silicate support to form calcium carbonate, thereby forming a stable nicotine composition. In this respect, the introduction of carbon dioxide to adjust the alkalinity of calcium silicate is particularly valuable for heat-not-burn applications. Carbon dioxide can also be used as a propellant for nicotine from the support during use in heat-not-burn applications. The use of glycerol and / or ethanol can also be used in heat-not-burn applications because they provide thermally stable compositions.

[0104] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. These changes and modifications can be made without departing from the spirit and scope of the invention and without diminishing its incidental advantages. Therefore, such changes and modifications are intended to be covered by the appended claims.

[0105] Example embodiments of the invention will now be described. It should be understood that the examples below, which include nicotine and an acid (e.g., gluconic acid or citric acid), preferably result in the in-situ formation of nicotine salts.

[0106] Example 1. Nicotine and gluconate supported on calcium silicate superior

[0107] By 50g of PS-200 grade nicotine was mixed with 25g of nicotine and 125g of 50% gluconic acid aqueous solution to obtain a free-flowing powder representing 12.5% ​​by weight of nicotine. First, the gluconic acid was weighed using a 1-liter wide-necked container on a balance, the nicotine was added, and the mixture was stirred. Then, the Florite powder was added in batches while the container was rotated. Finally, the container was capped, and the mixture was shaken vigorously.

[0108] Using a similar method, prepare products containing... A mixture of PS-200 grade (25g), nicotine (25g) and 50% gluconic acid aqueous solution (125g), representing 14.3% by weight of nicotine, but the mixture has a paste-like characteristic.

[0109] Example 2. Nicotine loaded on calcium silicate Stability (with and without gluconic acid)

[0110] exist PS-200 level and Mixtures of 10 wt%, 20 wt%, and 50 wt% nicotine were prepared at R grade.

[0111] exist PS-200 or A mixture of nicotine and 50% gluconic acid aqueous solution (2 equivalents) prepared from 0.25 g nicotine, 1.21 g 50% gluconic acid aqueous solution, and 1.04 g Florite, containing 10% nicotine by weight, showed no nicotine degradation after 2 and 4 months. In contrast, without gluconic acid, HPLC analysis of the 20% nicotine sample after three months showed that the PS-200 grade sample had degraded by 10%, and the R-grade sample by 18%, and the samples became noticeably yellow.

[0112] The initial content of the nicotine impurity, mesmin, used in these experiments was 0.14%. After 5 months, when gluconic acid was used in combination with PS-200 and R-grade Florite, the content of mesmin was 0.20% and 0.32%, respectively; no other impurities were found. After 6 months, when using PS-200 and R-grade Florite, the content of mesmin was 0.22% and 0.49%, respectively, and the content of cotinine was 0.03% and 0.04%, respectively, while both samples showed 0.02% nicotine N-oxide.

[0113] Example 3. Nicotine and gluconate loaded on calcium silicate Taste test

[0114] Taste tests using a sample containing gluconic acid from Example 2 showed rapid release of nicotine from the composition. This is consistent with dissolution studies (see Example 7).

[0115] Example 4. Nicotine and citric acid supported on calcium silicate Stability on

[0116] The composition on Florite (PS-200 or R grade) consisted of 25% w / w nicotine and 0.5 equivalent citric acid; 4.8 g of anhydrous citric acid was mixed with 7.1 g of water, and 8.1 g of nicotine was added. 12.4 g of Florite was then added, and the mixture was thoroughly mixed to obtain a free-flowing powder. The initial content of the impurity, mesmin, was 0.14%. After 2 weeks, the mesmin content in both grades of Florite decreased to 0.04%, and no impurity was observed. After 5 weeks, no degradation was observed in either sample.

[0117] Example 5. Preparative-scale synthesis of nicotine and gluconic acid supported on calcium silicate.

[0118] The composition is prepared by mixing the following substances:

[0119] A: (S)-nicotine (synthetic nicotine) (31.25 g, 0.192 mol), gluconic acid (50% aqueous solution, 156.25 g, 0.398 mol), and calcium silicate (62.5 g, PS200-level); and

[0120] B: (S)-nicotine (50.0 g, 0.308 mol), gluconic acid (50% aqueous solution, 125.0 g, 0.319 mol) and calcium silicate (75.0 g); PS200-level).

[0121] Compositions A and B represent 12.5% ​​and 20.0% wt% nicotine, respectively. Nicotine and gluconic acid were mixed until a homogeneous solution was formed, then slowly introduced into calcium silicate powder over 5 minutes using a planetary mixer. Mixing was continued for another 15 minutes to obtain a free-flowing powder, which was collected in a sealed plastic bag. After 15 days of storage, the resulting powder showed no discoloration. Dissolution studies were conducted by stirring the sample in 900 mL of phosphate buffer at pH 7.4. Compositions according to formulation A released 93.0% and 92.6% nicotine after 2 minutes, 94.1% and 94.3% after 4 minutes, and 98.1% and 99.3% after 8 minutes. Compositions according to formulation B released 89.8% nicotine after 2 minutes, 93.6% after 4 minutes, and 99.2% after 8 minutes.

[0122] Example 6. Preparation of granule formulation using cellulose-loaded nicotine / gluconic acid.

[0123] The premix is ​​composition A (12.5% ​​by weight of nicotine) from Example 5.

[0124] Granule formulations are made from the following components:

[0125] (i) Premix (32.0 g), microcrystalline cellulose PH102 (210.5 g), hydroxypropyl cellulose (Klucel-LF, 7.5 g);

[0126] (ii) Premix (16.0 g), microcrystalline cellulose PH102 (226.5 g), hydroxypropyl cellulose (HPC; Klucel-LF, 7.5 g);

[0127] (iii) Premix (32.0 g), microcrystalline cellulose PH102 (209.5 g), hydroxypropyl methylcellulose (HPMC; low viscosity, 8.75 g);

[0128] (iv) Premix (24.0 g), microcrystalline cellulose PH102 (340.0 g), hydroxypropyl methylcellulose (low viscosity, 11.25 g);

[0129] (v) Premix (48.0 g), microcrystalline cellulose PH102 (319.5 g), hydroxypropyl methylcellulose (low viscosity, 7.5 g);

[0130] (vi) Premix (24.0 g), microcrystalline cellulose PH102 (343.5 g), hydroxypropyl methylcellulose (low viscosity, 7.5 g).

[0131] These granular compositions contain 1.6% by weight nicotine (i, iii, v) or 0.8% by weight nicotine (ii, iv, vi). In preparation, a 5% w / w solution of the binder (HPC or HPMC) is prepared using purified water and thoroughly mixed to obtain a clump-free, translucent solution. Separately, measured amounts of the nicotine premix and microcrystalline cellulose are mixed at medium speed using a planetary mixer. The binder solution is then introduced via a peristaltic pump at a rate of 3 to 4 grams per minute, and mixing continues until uniform granules are obtained. The granules are then sieved to remove any lumps and placed on trays to dry overnight at 50°C, and packaged in double-layered plastic bags.

[0132] Example 7. A sachet formulation containing nicotine and gluconic acid on calcium silicate.

[0133] Based on the contents in Table 1, the granules from Example 6 were used together with the premix from Example 5 to prepare a composition for sachet formulations:

[0134] Table 1

[0135]

[0136] Flavorings are marked with an asterisk in the table. Liquid flavorings were first processed by co-processing with the premix. Excipients (maltitol, gum arabic, and acesulfame potassium) were each sieved through a 20-mesh sieve. Then, according to the table above, the nicotine premix, granules, diluent, binder, and sweetener were mixed at medium speed for 15 minutes in a conical mixer. The premix containing the flavorings was then added and mixed for 15 minutes, followed by packaging the final blend. Dissolution studies were performed by stirring the final blend in 900 mL of phosphate buffer at pH 7.4 and analyzing the mixture by HPLC. The samples released 89.0%–94.3% nicotine after 2 minutes, 92.6%–94.8% after 4 minutes, and 95.4%–98.3% after 8 minutes. The final blend was finally filled into heat-sealable nonwoven pouches (3.5cm × 1.5cm) using a metering device, pouch filling and sealing machine, with a target filling weight of 400mg (±5%) of the final blend per pouch.

[0137] Example 8. Preparative-scale synthesis of nicotine and citric acid supported on calcium silicate

[0138] The composition is prepared by mixing the following components:

[0139] A: Nicotine (63.1g, 0.39mol), anhydrous citric acid (37.4g, 0.195mol), water (55.3g), and calcium silicate (94.2g, PS200 level) and

[0140] B: Nicotine (100.0g, 0.62mol), anhydrous citric acid (30.0g, 0.156mol), water (30.0g), calcium silicate (60.0g).

[0141] These mixtures contained 25% by weight (A) and 45% by weight (B), respectively, of nicotine. They were mixed using the same method as in Example 5, and the products were stored in sealed plastic bags. No discoloration was observed after 15 days. Dissolution studies were conducted by stirring the samples in 900 mL of phosphate buffer at pH 7.4. The composition according to formulation A released 96.1% of the nicotine after 2 minutes and 100% of the nicotine after 4 minutes.

[0142] Example 9. Preparation of granule formulation using cellulose-loaded nicotine / citric acid.

[0143] The premix is ​​composition A (25% by weight of nicotine) from Example 8.

[0144] Granule formulations are made from the following components:

[0145] (i) Premix (24.0 g), microcrystalline cellulose PH102 (337.9 g), hydroxypropyl methylcellulose (low viscosity, 13.1 g);

[0146] (ii) Premix (12.0 g), microcrystalline cellulose PH102 (351.75 g), hydroxypropyl methylcellulose (low viscosity, 11.25 g).

[0147] The obtained nicotine contents were (i) 1.6 wt% and (ii) 0.8 wt%, respectively. The mixing method was the same as in Example 6.

[0148] Example 10. A sachet formulation containing nicotine and citric acid on calcium silicate.

[0149] Based on the contents in Table 2, the granules from Example 9 (or (i) 6 mg of nicotine in the 400 mg sachet mixture, or (ii) 3 mg) were used together with the premix (A) from Example 8 to prepare a composition for sachet formulation.

[0150] Table 2

[0151]

[0152]

[0153] The method was the same as in Example 7. After stirring in 900 mL of phosphate buffer at pH 7.4 for 2 minutes, the dissolution rate of the substance contained in the sachet was determined by HPLC using a C-18 column, and the release rate was more than 85%.

[0154] Example 11. Evaluation of nicotine release from sachets containing nicotine and citric acid on calcium silicate.

[0155] Evaluation was conducted using five prototype sample sachets containing 400 mg of a blend from Example 10, which contained 3 mg of nicotine and had deer hoof grass flavoring (first data column of the table in Example 10), with only the nicotine delivery sensation recorded.

[0156] Table 3 shows the time intervals (in seconds) between the occurrence of the indicated events following “active sucking and gentle chewing”. This sensation is advantageous, with sufficiently early initial delivery and nicotine release duration.

[0157] Table 3 (Time unit is seconds)

[0158]

[0159] Example 12. Preparative-scale synthesis of nicotine and glycerol supported on calcium silicate

[0160] The composition is prepared by mixing the following components:

[0161] A: Nicotine (18.0g, 0.11mol), glycerol (9.0g, 0.10mol), calcium silicate (9.0g); R-level);

[0162] B: Nicotine (24.0g, 0.15mol), Glycerin (6.0g, 0.065mol), Calcium Silicate (10.0g);

[0163] C: Nicotine (90.0g, 0.55mol), Glycerin (45.0g, 49mol), Calcium Silicate (45.0g).

[0164] These mixtures contained A: 50% by weight nicotine, B: 60% by weight nicotine, and C: 50% by weight nicotine, respectively. They were mixed using the same method as in Example 5, and the products were stored in sealed plastic bags. No discoloration was observed after 15 days. Dissolution studies were conducted by stirring the samples in 900 mL of phosphate buffer at pH 7.4. The composition according to formulation C released 93.0% nicotine after 2 minutes. HPLC analysis showed that 95.0% nicotine was released after 4 minutes and 99.4% after 8 minutes.

[0165] Example 13. Preparation of granule formulation using cellulose-loaded nicotine / glycerol.

[0166] The premix is ​​composition C (50% by weight nicotine) from Example 12. The granule formulation is made from the following components:

[0167] (i) Premix (12.0 g), microcrystalline cellulose PH102 (349.9 g), hydroxypropyl methylcellulose (low viscosity, 13.1 g);

[0168] (ii) Premix (12.0 g), microcrystalline cellulose PH102 (355.5 g), hydroxypropyl methylcellulose (low viscosity, 7.5 g).

[0169] The nicotine content of the granule formulations in (i) and (ii) is 1.6% by weight. The mixing method is the same as in Example 6.

[0170] Example 14. A sachet formulation containing nicotine and glycerin on calcium silicate.

[0171] Based on the contents in Table 4, the granules from Example 13 were used to prepare the composition for the sachet formulation:

[0172] Table 4

[0173]

[0174] The method was the same as in Example 7. After stirring for 2 minutes in a phosphate buffer solution (900 mL) at pH 7.4, more than 85% of the substances contained in the sachet were released.

[0175] Users prefer the 6mg citrus flavoring.

[0176] Example 15. Preparative-scale synthesis of nicotine and ethanol supported on calcium silicate

[0177] By mixing nicotine (18.0 g, 0.11 mol), ethanol (200.0 g), and calcium silicate (72.0 g); The composition was prepared (Grade R). The composition contained 6.0 wt% nicotine. Calcium silicate was loaded into a planetary mixer and slowly stirred while an ethanolic solution of nicotine was introduced via a peristaltic pump at a rate of 4 g / min. After stirring for another 15 minutes, a homogeneous powder was obtained and collected in a sealed plastic bag. The composition showed no discoloration after 15 days of storage. Dissolution studies were conducted by stirring the sample in 900 mL of phosphate buffer at pH 7.4. It released 93.9% of the nicotine after 2 minutes, 97.9% after 4 minutes, and 98.4% after 8 minutes.

[0178] Imagine this composition used in chewing gum and tablet formulations, as well as in heat-not-burn devices, where ethanol can typically be removed by evaporation as part of the final formulation.

[0179] Example 16. Characteristics of Nicotine Pouch Blends

[0180] The composition of the nicotine pouch blends is shown in Table 5 below.

[0181] Table 5

[0182]

[0183] Nicotine premixes contain calcium silicate loaded with gluconic acid or citric acid, respectively. Nicotine on the surface.

[0184] The binder composition was prepared by mixing HPMC with purified water and stirring at 100 RPM to form a clump-free, translucent solution. Weighed microcrystalline cellulose was loaded into a planetary mixer and mixed at medium speed for 15 minutes. The translucent solution was added to the planetary mixer at an additional rate of 3 to 4 grams per minute using a peristaltic pump, and granulation was carried out at medium speed. After granulation, the composition was sieved and placed on a tray to dry overnight at 50°C. The dried granules were sieved and packaged in double-layered plastic bags.

[0185] The final nicotine blend was prepared by sieving all excipients (sorbitol, gum arabic, and sweetener) separately through a 20-mesh sieve and collecting them separately in double-layered plastic bags. Place the placebo granules (for batches A and C only), nicotine premix, and sieved excipients into a double-cone mixer and mix at medium speed for 15 minutes. Add the flavoring mixture to the mixer and mix at medium speed for 15 minutes. Pack the final blend into double-layered plastic bags.

[0186] The final blend is filled into heat-sealable nonwoven pouches and properly sealed using a suitable metering device. The target fill weight per pouch is 250 mg ± 10%.

[0187] Table 6 shows the characteristics of the nicotine pouch blends. ND indicates not detected, BQL indicates below quantifiable levels, and LOD indicates loss on drying. The data shows that the content of nicotine degradation products is either undetectable or below quantifiable levels. This indicates that nicotine exists in a stable form.

[0188] Table 6

[0189]

[0190]

[0191] Example 17: Evaluation of soluble, insoluble, and diluent-containing nicotine sachets prepared by direct blending:

[0192] The composition of the nicotine pouch blends is shown in Table 7 below.

[0193] Table 7

[0194]

[0195] The nicotine premix contains nicotine loaded onto calcium silicate (Florite) with gluconic acid or citric acid, respectively.

[0196] The final nicotine blend was prepared by sieving all excipients (sorbitol, gum arabic, and sweetener) separately through a 20-mesh sieve and collecting them separately in double-layered plastic bags. The nicotine premix and sieved excipients were then placed in a double-cone mixer and mixed at medium speed for 15 minutes. The flavoring mixture was added to a blender and mixed at medium speed for 15 minutes. The final blend was then placed in double-layered plastic bags.

[0197] The final blend is filled into heat-sealable nonwoven pouches and properly sealed using a suitable metering device. The target fill weight per pouch is 250 mg ± 10%.

[0198] Table 8 shows the characteristics of the nicotine pouch blends. The data shows that the content of nicotine degradation products is either undetectable or below quantifiable levels. This indicates that nicotine exists in a stable form.

[0199] Table 8

[0200]

[0201] Example 18: Stability results of nicotine pouch blends

[0202] The nicotine blend compositions in the pouches were stored with the compositions described in Examples 16 and 17 at 25°C for 4 months. Their nicotine degradation products were then analyzed, and the results are shown in Table 9. The results showed that the content of nicotine degradation products was very low.

[0203] Table 9

[0204]

[0205]

[0206] Example 19: Nicotine release characteristics in nicotine pouches (in vivo):

[0207] The nicotine release characteristics of each batch of product were evaluated using three sachets. Users were instructed to place the sachet between their gums and lips for up to 30 minutes or 1 hour. Table 10 shows the flexibility of the compositions, as they can be customized to provide the desired nicotine release profile. Zyn and On are commercially available products. Some calcium silicate compositions have release profiles similar to those of the commercially available product Zyn (i.e., slow), while some calcium silicate compositions have release profiles similar to those of the commercially available product On (i.e., faster). Furthermore, compositions treated with CO2 gave very rapid release profiles. NA indicates that the nicotine in the sample was consumed too quickly and the measurement window was not reached. The compositions of the present invention have the advantage of providing customized release profiles. They achieve this without requiring soluble buffers to modulate nicotine release. The disadvantage of commercially available products Zyn and On is that they contain soluble buffers, and these buffers introduce an undesirable salty taste.

[0208] Table 10

[0209]

[0210]

[0211] Table 10A shows the formulation details for Y1. Table 13 shows the formulation details for AA4 and AA6.

[0212] Table 10A

[0213] 4mg granules mg / unit Nicotine premix (S2 citric acid) 4 mg equivalent 16.00 Microcrystalline cellulose 102 229 Hydroxypropyl methylcellulose (low viscosity); 5.00 Granulation stage weight 250.00 8mg final blend – batch 076 mg / unit Granules (4 mg equivalent, from ZNP / SYN / 021) 250.00 Additional nicotine equivalent in the premix - 4 mg 16.00 Sorbitol 56.50 Gum Arabic 5.00 sweeteners 2.50 Citrus Mint (Spice Blend) 20.00 Final particle weight 350.00

[0214] Example 20: Data Extraction

[0215] The release of nicotine from nonwoven pouches was analyzed using water or artificial saliva. 20g of water or artificial saliva was placed in a petri dish, and filter paper was placed on top. The pouch was placed on the filter paper and left for 5 minutes. The pouch was then removed, and the concentration of nicotine in the water or artificial saliva was measured to calculate the amount of dissolved nicotine. It was observed that a greater release of nicotine was achieved when artificial saliva was used. The free-flowing powder composition G1 showed a higher release than the particulate composition C1. This indicates that the compositions can be formulated to produce either rapid or slow-release nicotine.

[0216] Table 11

[0217]

[0218] Example 21: Stability results of nicotine premixes under three strategies under different storage conditions

[0219] The data in Table 12 show that nicotine exhibits greater stability over time compared to glycerol when using citric acid or gluconic acid. This is presumably due to the formation of nicotine salts when using gluconic acid or citric acid.

[0220] Table 12

[0221]

[0222] Example 22: Stability data of compositions treated with and without carbon dioxide

[0223] Table 13 below shows the compositions. The initial compositions AA1-AA6 according to Table 13 were kept overnight at a carbon dioxide pressure of 4-5 bar generated by adding dry ice, and then the pressure was released. In the experiments, nicotine was not present in the initial compositions of AA1-AA4 and AA6, but was added after carbon dioxide treatment. Compositions AA18-AA23 were not subjected to any carbon dioxide treatment. For all experiments, calcium silicate (Tomita...) The composition contains 20 grams each of PS-200 grade and nicotine. After 4-5 days, observe the color of the resulting composition and test the nicotine degradation products content as a measure of oxidative degradation. Some compositions also include water, ethanol, or glycerin.

[0224] A few days later, the color of the resulting compositions and the content of nicotine-N-oxides, representing the content of nicotine oxidative degradation products, were tested. The best-performing samples were those when the compositions were pretreated with carbon dioxide and additionally included one of water, ethanol, or glycerin, and when nicotine was added after carbon dioxide treatment.

[0225] The data further showed low levels of nicotine degradation products, indicating that the nicotine is stabilized by the composition. Batch AA1 was yellow, while batches AA2 through AA6 were white. This suggests that the advantage of using water, ethanol, or glycerin in the batches is less nicotine degradation.

[0226] Table 13

[0227]

[0228] Table 14

[0229]

[0230] Table 14 shows the nicotine degradation products and compares the premixed compositions treated with and without carbon dioxide. The data show that carbon dioxide treatment reduced the overall content of nicotine degradation products, indicating that nicotine had been stabilized. Furthermore, the inclusion of water in the premixed compositions further stabilized the nicotine.

[0231] Example 23. Further measurements of nicotine oxidative degradation loaded on various calcium silicates

[0232] The measurement results of impurities generated by the oxidative degradation of nicotine loaded on calcium silicate are shown in Table 15. This indicates that different forms of calcium silicate can be used in this invention. Impurities generated by the oxidative degradation of nicotine stabilized by citric acid or gluconic acid on various calcium silicate materials were measured. The calcium silicate material is Tomita. -PS-200, Tomite -R class, Evonik 250 and MLA Industries Hydrated Calcium Silicate. For up to six months after composition preparation, only a few samples showed a cotinine content of 0.02% relative to nicotine. Surprisingly, the mysmine impurity detected in nicotine decreased from an initial 0.14% to 0.04-0.12% in several samples.

[0233] Table 15

[0234]

[0235]

[0236] Example 24. A heat-resistant, non-combustible composition

[0237] By mixing S-nicotine (synthetic) (1.0 g), 50% gluconic acid aqueous solution (5.0 g), and calcium silicate ( The composition was prepared using PS-200 grade (3.0g), glycerin, and tobacco flavoring (0.1g). A 250-300mg sample containing 10-12mg of nicotine was placed in the chamber of a PODA vaporizer heated non-combustible device (podalifestyle.com) and tested. When inhaled at moderate temperatures, nicotine produces a strong sensation.

[0238] Example 25: Composition of nicotine lozenges prepared by direct mixing and pressing process

[0239] Table 16 shows the nicotine premixed compositions used.

[0240] Table 16

[0241] Nicotine premixed citric acid Composition % 6mg 4mg 2mg nicotine 25 6 4 2 Citric acid 15 4 2 1 water 22 5 4 2 Florite PS 200 38 9 6 3 100 24 16 8

[0242] Nicotine tablet preparation procedure:

[0243] Step 1 (Screening): Screen all excipients through a 20-mesh sieve and collect them into double-layered plastic bags.

[0244] Step 2 Mixing 1: Load 25% of the sieved mannitol 200SD, sorbitol, xanthan gum, HPMC and nicotine premix into a double cone mixer and mix at medium speed for 15 minutes.

[0245] Step 2 Mixing 2: Add the sieved colloidal silica, aspartame, masking agent and flavoring to the above steps, and mix with the materials from Step 2 in an octagonal mixer at 12 RPM for 20 minutes.

[0246] Step 3: Lubrication: Add the lubricant to the mixture from the previous step and mix at medium speed for 5 minutes. Pack the final blend into a double-layered plastic bag.

[0247] Step 4: Pressing: Press the lubricated blend using the respective punches.

[0248] Table 17 shows the formulas used.

[0249] Table 17

[0250]

[0251]

[0252] Example 26: A composition of nicotine tablets prepared using wet granulation, blending, and compression processes.

[0253] Table 16 shows the nicotine premixed compositions used.

[0254] Nicotine tablet preparation procedure:

[0255] Adhesive preparation

[0256] Step 1: Transfer the weighed purified water to a glass container, place it in the center of the glass container with a stirrer, and stir at the optimal speed (RPM). Gradually add the weighed binder to the above steps and mix thoroughly until a lump-free, translucent solution is obtained.

[0257] Granulation

[0258] Step 2: Weigh out the nicotine premix, mannitol, xanthan gum and HPMC dry binder and put them into a planetary mixer and mix at medium speed for 15 minutes.

[0259] Step 3: Using a peristaltic pump, gradually add the granulation solution from Step 1 to Step 2 at an additional rate of 2 to 4 grams per minute, and granulate at a medium speed. Continue mixing until the granulation endpoint is reached.

[0260] Step 4: After reaching the granulation endpoint, sieve the granules and place them on a tray for drying. Dry the granules using fluidized air at 50°C, with a target LOD NMT of 3.0%.

[0261] Step 5: Screen the dried particles through a #20 mesh sieve and collect the #20 residue for grinding. Grind the retained particles using a multi-mill equipped with a 1.5mm sieve, and then sieve the ground particles through a #20 mesh sieve.

[0262] Blending and Lubrication

[0263] Step 1 (Screening): Screen all excipients through a 20-mesh sieve and collect them into double-layered plastic bags.

[0264] Step 2 (Mix 1): The drug particles from Step 1, the sieved excipients (silica, acesulfame potassium, flavoring agent and flavoring) are loaded into a double cone mixer and mixed at 12 RPM for 30 minutes.

[0265] Step 3 (Mix 2): Add the lubricant magnesium stearate mixture to the above step and mix at 12 RPM for 5 minutes. Pack the final blend into a double-layered plastic bag.

[0266] Pressing: The lubricated blend is pressed using its own punch. Table 18 shows the formulations used.

[0267] Table 18

[0268]

[0269] Example 27: Preparation of chewing gum containing nicotine premix. Table 16 shows the nicotine premix composition used. Nicotine chewing gum preparation procedure:

[0270] Step 1 (Screening): Screen all excipients through a 20-mesh sieve and collect them into double-layered plastic bags.

[0271] Step 2 Mixing 1: Load the sieved gum base particles, flavor premix, sorbitol, sweetener and nicotine premix 25 into a double cone mixer and mix at medium speed for 15 minutes.

[0272] Step 2 Mixing 2: Add the sieved colloidal silica to the above steps and mix it together with the material from Step 2 in an octagonal mixer at 12 RPM for 10 minutes.

[0273] Step 3: Lubrication: Add the lubricant to the mixture from the previous step and mix at medium speed for 5 minutes. Pack the final blend into a double-layered plastic bag.

[0274] Pressing: Use a 14.5mm×13.5mm rectangular punch to press the lubricated granules.

[0275] Table 19 shows the formulas used.

[0276] Table 19

[0277]

[0278] Example 28: Preparation method of nicotine chewing gum (including core gum, bottom coating, and crunchy sugar coating)

[0279] Table 16 shows the nicotine premixed compositions used.

[0280] Method: The preparation method of the core chewing gum is the same as that of Example QB, and the preparation methods of the bottom coating and sugar coating are in accordance with the standard sugar coating procedure.

[0281] Table 20 shows the formulas used.

[0282] Table 20

[0283]

Claims

1. A premixed composition comprising: (a) 20 wt% to 65 wt% nicotine, 10 wt% to 40 wt% calcium silicate, and 10 wt% to 35 wt% glycerol; or (b) 5 wt% to 65 wt% nicotine, 10 wt% to 60 wt% calcium silicate, and 10 wt% to 80 wt% acid; wherein the acid is selected from pyruvic acid, benzoic acid, levulinic acid, citric acid, gluconic acid, glucuronic acid, ribonic acid, arabinonic acid, or galactonic acid; or (c) 5 wt% to 65 wt% nicotine, 10 wt% to 60 wt% calcium silicate, and 10 wt% to 80 wt% ethanol; or (d) 20 wt% to 60 wt% calcium silicate and 10 wt% to 60 wt% nicotine, wherein the calcium silicate has been pretreated with carbon dioxide, or the premixed composition is prepared by a method comprising mixing calcium silicate with carbon dioxide and nicotine; the weight ratio of nicotine to carbon dioxide is in the range of 90%:10% to 50%:50%. The nicotine content is expressed as an equal amount of nicotine provided in the form of nicotine and / or nicotine salts.

2. The premixed composition according to claim 1, wherein the nicotine is synthetic nicotine or nicotine extracted from tobacco, wherein when the premixed composition comprises (b) or (c), the weight ratio of nicotine to calcium silicate is in the range of 10%:90% to 75%:25%, wherein the nicotine content is expressed as an equal amount of nicotine and / or nicotine provided in the form of nicotine salts.

3. The premixed composition according to claim 1, wherein when the premixed composition comprises (b), (c) or (d), the weight ratio of nicotine to calcium silicate is in the range of 25%:75% to 75%:25%, wherein the nicotine content is expressed as an equal amount of nicotine and / or nicotine provided in the form of nicotine salts.

4. The premixed composition according to claim 1, wherein the premixed composition comprises (a), (b) or (c), and the calcium silicate has been pretreated with carbon dioxide, or the premixed composition is prepared by a method comprising mixing calcium silicate with carbon dioxide and nicotine.

5. The premixed composition according to claim 1, wherein the premixed composition comprises (d) and further comprises an acid, ethanol, glycerol, or any combination thereof.

6. The premixed composition according to claim 1, wherein the premixed composition comprises (a) and further comprises an acid, ethanol, or a combination thereof.

7. The premixed composition according to claim 1, wherein the premixed composition comprises (b), and further comprises ethanol, glycerol, or a combination thereof.

8. The premixed composition according to claim 1, wherein the premixed composition comprises (c), and further comprises an acid, glycerol, or a combination thereof.

9. The premixed composition according to any one of claims 1 to 3, wherein the premixed composition further comprises water.

10. A formulation comprising a premixed composition according to any one of claims 1 to 9, wherein the formulation comprises 0.05 wt% to 5 wt% nicotine, wherein the nicotine content is expressed as an equal amount of nicotine and / or nicotine provided in the form of nicotine salts.

11. The formulation according to claim 10, wherein the formulation or the premixed composition is in the form of a powder component and / or a particulate component.

12. A tablet comprising a premixed composition according to any one of claims 1, 2, 4, 5, 7 or 8, or a formulation according to claim 10 or 11.

13. A chewing gum comprising a premixed composition according to any one of claims 1, 2, 4, 5, 7 or 8, or a formulation according to claim 10 or 11.

14. A tablet comprising a premixed composition according to any one of claims 1, 2, 4, 5, 7 or 8, or a formulation according to claim 10 or 11.

15. A heat-resistant, non-flammable product comprising a premixed composition according to any one of claims 1, 2, 4, 5, 7 or 8, or a formulation according to claim 10 or 11.

16. A sachet comprising a premixed composition according to any one of claims 1, 2, 4, 5, 7 or 8, or a formulation according to claim 10 or 11.

17. A patch comprising a premixed composition according to any one of claims 1, 2, 4, 5, 7 or 8, or a formulation according to claim 10 or 11.

18. A lozenge comprising a premixed composition according to any one of claims 1, 2, 4, 5, 7 or 8, or a formulation according to claim 10 or 11.

19. A pill comprising a premixed composition according to any one of claims 1, 2, 4, 5, 7 or 8, or a formulation according to claim 10 or 11.

20. A capsule comprising a premixed composition according to any one of claims 1, 2, 4, 5, 7 or 8, or a formulation according to claim 10 or 11.

21. A method for preparing the premixed composition according to claims 1-9, the method comprising mixing calcium silicate with nicotine.

22. The method of claim 21, wherein the method further comprises mixing in water.

23. The method of claim 22, wherein the method further comprises mixing nicotine and / or nicotine salt with an acid, ethanol or glycerol to form a solution prior to mixing the solution with calcium silicate.

24. The method of claim 23, wherein the solution is homogeneous prior to mixing with calcium silicate.

25. The method according to claim 23 or 24, wherein the solution is incrementally introduced into the calcium silicate.

26. The method according to claim 23 or 24, wherein mixing continues until a free-flowing powder is obtained.

27. The method of claim 21, wherein the method comprises pretreating the calcium silicate with carbon dioxide prior to mixing the nicotine and / or nicotine salt with the calcium silicate.

28. The method of claim 21, wherein the method comprises mixing calcium silicate with carbon dioxide and nicotine and / or nicotine salts.

29. The method of claim 21, further comprising pretreating the calcium silicate with water and carbon dioxide prior to mixing the nicotine and / or nicotine salt with the calcium silicate.

30. The method of claim 29, wherein 5 wt% to 30 wt% water is used for the pretreatment.

31. A method for preparing the formulation of claim 10 or 11, the method comprising mixing nicotine with calcium silicate.

32. The method of claim 31, wherein the formulation further comprises a stabilizer, a wetting agent, an emulsifier, a flavoring agent, and / or a buffer.

33. The method of claim 31, wherein the formulation comprises 0.07 wt% to 15 wt% of the premixed composition.

Images