Buccal product and preparation method thereof

Abstract

The invention discloses a buccal product and a preparation method thereof, the buccal product comprises an active component, the active component comprises room temperature ionic liquid, and the room temperature ionic liquid comprises nicotine ions. In the application, the nicotine is in an ion pair state instead of a free state, so that the chemical stability of the nicotine can be improved, and meanwhile, the volatilization loss is reduced; in addition, the fat solubility of the ionic liquid is remarkably improved, the ionic liquid is easily absorbed by a human body, and the bioavailability is further improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of food or medicine, in particular to a mouth product and a preparation method thereof. BACKGROUND

[0002] The mouth product is a new type of oral delivery system designed to release active ingredients in the oral cavity and be absorbed by the human body, usually in the form of powder, film, patch, sachet, etc. placed in the oral cavity, then dissolved and release active ingredients (such as nicotine), and absorbed through the oral mucosa. It has the advantages of precise dosage, rapid onset, portability, etc. However, the existing mouth product has low bioavailability of active ingredients. SUMMARY

[0003] To solve the problem of low bioavailability of active ingredients of the existing mouth product, the present application provides a mouth product and a preparation method thereof, which helps to improve the bioavailability of active ingredients.

[0004] The present application discloses a mouth product, which comprises an active ingredient, and the active ingredient comprises a room temperature ionic liquid, and the room temperature ionic liquid comprises a nicotine ion.

[0005] In an implementation manner of the present application, the room temperature ionic liquid further comprises at least one of the following: a bistrifluoromethylsulfonylimide ion, a trifluoroacetate ion, and a 1-butyl-3-methylimidazole ion.

[0006] In an implementation manner of the present application, the mouth product further comprises a loading structure, and the active ingredient is loaded on the surface and / or inside of the loading structure.

[0007] In an implementation manner of the present application, the loading structure comprises a nanofiber membrane, and the active ingredient is loaded on the surface and / or inside of the nanofiber membrane, wherein the nanofiber membrane comprises a base material, a fiber forming aid, and a plasticizing humectant.

[0008] In an implementation manner of the present application, the base material comprises at least one of the following: gelatin, collagen, silk fibroin, and methyl cellulose; and / or the fiber forming aid comprises at least one of the following: polyethylene oxide, polyvinyl alcohol, polyacrylonitrile, and pullulan; and / or the plasticizing humectant comprises at least one of the following: glycerol, polyethylene glycol, sorbitol, and acetyl triethyl citrate; and / or the nanofiber membrane comprises, in terms of mass fraction, 40-60 parts of the base material, 20-30 parts of the fiber forming aid, and 5-10 parts of the plasticizing humectant; and / or the nanofiber membrane is formed by electrospinning.

[0009] In an implementation form of the application, the oral chewing article further comprises a penetration enhancer, the penetration enhancer being dispersed on the surface layer of the nanofiber membrane; and / or, the oral chewing article further comprises a flavoring microsphere, the flavoring microsphere being dispersed on the surface layer of the nanofiber membrane.

[0010] In an implementation form of the application, the penetration enhancer comprises at least one of sodium glycocholate, lecithin; and / or, the penetration enhancer comprises liposome particles, the liposome particles having a particle size of 80nm-120nm; and / or, the flavoring microsphere comprises at least one of a sweetener, a cooling agent, a salty agent, an acid agent, an aromatic agent.

[0011] The application further discloses a preparation method of an oral chewing article, for preparing the oral chewing article according to any one of claims 1-7, the preparation method comprising: obtaining an active ingredient, the active ingredient comprising a room temperature ionic liquid containing nicotine ions; and loading the active ingredient into a loading structure.

[0012] In an implementation form of the application, the obtaining of the active ingredient comprises: obtaining nicotine hydrochloride; and reacting the nicotine hydrochloride with an anion agent to generate a room temperature ionic liquid containing nicotine cations, wherein the anion agent comprises a bistrifluoromethylsulfonylimide salt and / or a trifluoroacetate salt; or, the obtaining of the active ingredient comprises: reacting nicotine with a cation agent to generate a room temperature ionic liquid containing nicotine anions, wherein the cation agent comprises a 1-butyl-3-methylimidazolium chloride salt.

[0013] In an implementation form of the application, the loading of the active ingredient into the loading structure comprises any one of the following methods: (I) preparing a nanofiber membrane by electrospinning, i.e., obtaining the loading structure, and immersing the nanofiber membrane in the room temperature ionic liquid; (II) using the room temperature ionic liquid as an oil phase carrier, using a fiber material solution as an aqueous phase carrier, mixing the oil phase carrier and the aqueous phase carrier to form an emulsion, and using the emulsion to perform electrospinning to form a nanofiber membrane, wherein the fibers of the nanofiber membrane are wrapped with the room temperature ionic liquid; (III) dissolving the room temperature ionic liquid and the fiber material in a common solvent to obtain a blended solution, and using the blended solution to perform electrospinning to form a nanofiber membrane, wherein the fibers of the nanofiber membrane are wrapped with the room temperature ionic liquid inside and on the surface; and / or, the loading structure comprises a nanofiber membrane, and the preparation method further comprises at least one of the following steps: (I) sprinkling a penetration enhancer on the surface of the nanofiber membrane; (II) preparing a flavoring microsphere, sprinkling the flavoring microsphere on the surface of the nanofiber membrane, and performing hot-pressing compounding; (III) cutting the nanofiber membrane into a preset shape.

[0014] The application has the following beneficial effects:

[0015] The oral use article of the present application, the active ingredient includes a room temperature ionic liquid, the room temperature ionic liquid includes nicotine ions. Among them, the room temperature ionic liquid refers to a salt composed of anions and cations at room temperature or near room temperature, also known as low temperature molten salt. In the form of room temperature ionic liquid, nicotine is in the form of ion pair rather than free state, which can improve the chemical stability of nicotine and reduce the loss of volatilization; in addition, the liposolubility of ionic liquid is significantly improved, which is easy to be absorbed by the human body, thereby facilitating the improvement of bioavailability. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 A scanning electron microscope image of the nanofiber membrane of Example 1 of the present application is shown. DETAILED DESCRIPTION

[0017] The application will be described in further detail below with specific embodiments in conjunction with the accompanying drawings. In the following embodiments, many details are described in order to make the application better understood. However, those skilled in the art can easily recognize that some of the features can be omitted in different cases, or can be replaced by other materials or methods. In some cases, some operations related to the application are not shown or described in the specification in order to avoid the core part of the application being overwhelmed by too much description, and it is not necessary to describe these related operations in detail for those skilled in the art, they can fully understand the related operations according to the description in the specification and the general technical knowledge in the art.

[0018] In addition, the features, operations or characteristics described in the specification can be combined in any appropriate way to form various embodiments. At the same time, the steps or actions in the method description can also be sequentially adjusted or adjusted in a manner that those skilled in the art can easily see. Therefore, the various sequences in the specification and drawings are only for the purpose of clearly describing a certain embodiment, and do not mean that the sequence is necessary, unless otherwise stated that a certain sequence must be followed.

[0019] The serial numbers of the components in this paper, such as "first", "second", etc., are only used to distinguish the described objects, and do not have any sequence or technical meaning.

[0020] The existing oral products, the active ingredient (nicotine) is in the form of free form, the liposolubility and permeability of nicotine is poor, and further leads to low bioavailability. In addition, the traditional oral film usually uses hydroxypropyl methyl cellulose (HPMC) as the film-forming matrix, and HPMC will swell rapidly after being exposed to water, forming a layer of viscous and dense gel on the surface of the film. This gel layer will block the mutual penetration of water and active ingredients, and further make the release rate and bioavailability of the active ingredient difficult to meet the demand. The present application provides an oral product and a preparation method thereof, which has at least one of the following advantages: (1) Ionic liquid drug loading system: the nicotine is in the form of room temperature ionic liquid (IL), which is beneficial to improve the liposolubility and permeability of nicotine, improve the bioavailability, and make it faster through the oral mucosa absorption. (2) Nanofiber support structure: the electrospinning technology is used to construct a porous nanofiber film as a drug loading skeleton, which can effectively load room temperature ionic liquid, and is beneficial to ensure the rapid release and absorption of drugs in the oral cavity. (3) Flavor layer: the surface layer of the nanofiber film has flavor microspheres, which realize the taste experience of "sweet first and medicine later" through the time release system, so as to improve the user experience.

[0021] In an embodiment, the oral product includes an active ingredient and a support structure.

[0022] In an embodiment, the active ingredient includes a room temperature ionic liquid. The room temperature ionic liquid includes nicotine ions. The nicotine ions are nicotine in ionic form.

[0023] In an embodiment, the room temperature ionic liquid can further include a first ion combined with the nicotine ion. The first ion can be obtained by dissociation of a first compound. The first ion can include at least one of the following: bis(trifluoromethylsulfonyl)imide ion, trifluoroacetate ion, 1-butyl-3-methylimidazolium ion. Among them, nicotine can act as a cation donor, nicotine as an organic base, the tertiary amine nitrogen in the pyrrolidine ring can act as the main proton accepting site, bis(trifluoromethylsulfonyl) sodium or sodium trifluoroacetate can act as an anion agent to provide protons H + , and further undergo proton transfer reaction to form room temperature ionic liquid Nic + NTf2 - (melting point -10℃) or room temperature ionic liquid Nic + TFA-(melting point -5℃). While 1-butyl-3-methylimidazolium ion ([BMIM] + ) can act as a cation donor, nicotine can act as an anion acceptor to obtain room temperature ionic liquid [BMIM] + [Nic] - In addition, the asymmetry of the molecular structure of nicotine can hinder the close and regular arrangement of ions in the crystal lattice, and further inhibit crystallization, which is beneficial to form room temperature ionic liquid.

[0024] In an embodiment, the room temperature ionic liquid can be obtained from 10-30 parts by mass of nicotine and 15-45 parts by mass of the first compound. For example, it can include 10 parts, 20 parts, or 30 parts of nicotine and 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, or 45 parts of the first compound.

[0025] In an embodiment, the method for preparing the room temperature ionic liquid can include obtaining nicotine hydrochloride; and reacting the nicotine hydrochloride and an anion agent to obtain the room temperature ionic liquid containing nicotine cation; wherein the anion agent includes a bistrifluoromethanesulfonimide salt and / or a trifluoroacetate salt. The nicotine hydrochloride can be obtained commercially or prepared by oneself. In the method for preparing the room temperature ionic liquid, nicotine serves as a cation donor, and the tertiary amine nitrogen in the pyrrolidine ring of nicotine can serve as a main proton accepting site. The bistrifluoromethanesulfonimide sodium and the trifluoroacetate sodium can serve as anion agents to provide protons H + , and then a proton transfer reaction occurs to form the room temperature ionic liquid Nic + NTf2 - (melting point -10℃) or the room temperature ionic liquid Nic + TFA - (melting point -5℃).

[0026] In an embodiment, the method for preparing the room temperature ionic liquid can include reacting nicotine and a cation agent to obtain the room temperature ionic liquid containing nicotine anion; wherein the cation agent includes 1-butyl-3-methylimidazolium chloride. In the preparation method, 1-butyl-3-methylimidazolium ion ([BMIM] + ) serves as a cation donor, and nicotine serves as an anion acceptor to obtain the room temperature ionic liquid [BMIM] + [Nic] - .

[0027] In an embodiment, the active ingredient is loaded on the loading structure. The active ingredient can be loaded on the surface of the loading structure, or loaded in the interior of the loading structure, or loaded on both the surface and the interior of the loading structure.

[0028] In an embodiment, the loading structure includes a nanofiber membrane. The nanofiber membrane can be formed by electrospinning. It should be noted that the present application can effectively load the active ingredient and ensure the rapid release and absorption of the active ingredient in the oral cavity by loading the active ingredient on the nanofiber membrane.

[0029] In an embodiment, the nanofiber membrane comprises a base material, a fiber forming aid, and a plasticizing humectant. The base material can serve as a matrix for the nanofibers, providing structural support. The fiber forming aid can adjust the viscosity and improve the fiber morphology, reducing beading defects and forming a uniform nanofiber network. The plasticizing humectant can provide moisture retention and increase the plasticity of the nanofibers.

[0030] In an embodiment, the base material comprises at least one of gelatin, collagen, silk fibroin, and methyl cellulose. Thus, a good support can be provided as a base material.

[0031] In an embodiment, the fiber forming aid comprises at least one of polyethylene oxide, polyvinyl alcohol, polyacrylonitrile, and pullulan. Thus, the viscosity can be adjusted and the fiber morphology can be improved.

[0032] In an embodiment, the plasticizing humectant comprises at least one of glycerol, polyethylene glycol, sorbitol, and acetyl triethyl citrate. Thus, moisture retention and fiber plasticity can be increased.

[0033] In an embodiment, the nanofiber membrane comprises 40-60 parts by mass of the base material. For example, the nanofiber membrane can comprise 40, 45, 50, 55, or 60 parts by mass of the base material.

[0034] In an embodiment, the nanofiber membrane comprises 20-30 parts by mass of the fiber forming aid. For example, the nanofiber membrane can comprise 20, 25, or 30 parts by mass of the fiber forming aid.

[0035] In an embodiment, the nanofiber membrane comprises 5-10 parts by mass of the plasticizing humectant. For example, the nanofiber membrane can comprise 5, 8, or 10 parts by mass of the plasticizing humectant.

[0036] In an embodiment, the oral product comprises 40-60 parts by mass of the base material, 20-30 parts by mass of the fiber forming aid, and 5-10 parts by mass of the plasticizing humectant.

[0037] In an embodiment, the oral product further comprises a penetration enhancer. The penetration enhancer is dispersed on the surface layer of the nanofiber membrane. Thus, the mucosal permeability can be enhanced, and the bioavailability of the active ingredient can be improved.

[0038] In an embodiment, the penetration enhancer comprises liposome particles. The liposome particles have a particle size of 80-120 nm.

[0039] In an embodiment, the penetration enhancer comprises sodium glycocholate, lecithin, and a mixture of sodium glycocholate and lecithin. In an embodiment, the penetration enhancer comprises sodium glycocholate and lecithin, and the mass ratio of sodium glycocholate to lecithin can be 7:3.

[0040] In an embodiment, the oral use article can comprise 1 part to 5 parts of the penetration enhancer by mass fraction. For example, 1 part, 2 parts, 3 parts, 4 parts, or 5 parts of the penetration enhancer can be included.

[0041] In an embodiment, the oral use article further comprises a flavoring microsphere. The flavoring microsphere is dispersed on the surface layer of the nanofiber membrane. In this way, the flavoring microsphere can be released first to improve the taste.

[0042] In an embodiment, the flavoring microsphere comprises at least one of the following flavoring substances: a sweetener, a cooling agent, a salty agent, an acid agent, and an aromatic agent. The sweetener can comprise at least one of xylitol, sorbitol, mannitol, isomalt, lactitol, maltitol, isomaltulose, hydrogenated starch hydrolysate, erythritol, maltotriitol, aspartame, acesulfame potassium, sodium saccharin, sucralose, neotame, cyclamate, alitame, steviol glycoside, arabitol, and momordica grosvenori. The cooling agent can comprise at least one of menthol, menthol derivatives, WS-3, and WS-23. The aromatic agent can comprise at least one of bergamot essence, eucalyptus essence, citrus essence, lemon essence, peppermint essence, mint essence, menthol, liquorice essence, wintergreen essence, tobacco essence, coffee essence, vanilla essence, lime essence, apple essence, peach essence, mango essence, cherry essence, blueberry essence, strawberry essence, cola essence, cinnamon essence, cassia essence, and watermelon essence. The salty agent can comprise at least one of sodium chloride, potassium chloride, yeast extract, and seaweed extract. The acid agent can comprise at least one of citric acid, acetic acid, lactic acid, malic acid, tartaric acid, and ascorbic acid. The sweetener, the cooling agent, the salty agent, the acid agent, and the aromatic agent can also be other kinds of edible substances, which will not be listed here.

[0043] In an embodiment, the flavoring microsphere comprises a carrier. The material of the carrier can be a water-soluble crystalline sugar alcohol, for example, the material of the carrier can be mannitol. The carrier can be spherical or spheroid structure. The flavoring substance can be dispersed in the carrier, and / or the flavoring substance can be located inside the carrier. For example, the flavoring microsphere can comprise a structure in which the outer shell is a porous or dense matrix formed by mannitol (water-soluble crystalline sugar alcohol), the core is menthol oil, the outer shell wraps the core, and the sweetener sucralose is dispersed in the mannitol matrix.

[0044] In an embodiment, the oral use article can comprise 30 parts to 50 parts of the flavoring microsphere by mass fraction. For example, 30 parts, 35 parts, 40 parts, 45 parts, or 50 parts of the flavoring microsphere can be included.

[0045] In some embodiments, the oral use article can be in the form of a lozenge, a mouth dissolving film, a mouth pouch, a chewing gum, or the like. Various designs can be made according to user needs, which will not be described herein.

[0046] In a specific embodiment, the method for preparing the oral use article comprises: obtaining an active ingredient, and loading the active ingredient into a loading structure.

[0047] In a specific embodiment, the active ingredient comprises a room temperature ionic liquid containing nicotine ions.

[0048] In a specific embodiment, the obtaining of the active ingredient comprises: obtaining nicotine hydrochloride, and reacting the nicotine hydrochloride with an anion agent to generate a room temperature ionic liquid containing nicotine cations; wherein the anion agent comprises a bistrifluoromethylsulfonylimide salt and / or a trifluoroacetate salt.

[0049] In a specific embodiment, the obtaining of the active ingredient comprises: reacting nicotine with a cation agent to generate a room temperature ionic liquid containing nicotine anions; wherein the cation agent comprises a 1-butyl-3-methylimidazolium chloride salt.

[0050] In a specific embodiment, the loading of the active ingredient into the loading structure comprises any one of the following methods: (I) preparing a nanofiber membrane by electrospinning, i.e., obtaining the loading structure, and immersing the nanofiber membrane in the room temperature ionic liquid; (II) using the room temperature ionic liquid as an oil phase carrier, using a solution containing a fiber material as an aqueous phase carrier, mixing the oil phase carrier and the aqueous phase carrier to form an emulsion, and using the emulsion to perform electrospinning to form a nanofiber membrane, wherein the fibers in the nanofiber membrane are wrapped with the room temperature ionic liquid inside; (III) dissolving the room temperature ionic liquid and the fiber material in a common solvent to obtain a blended solution, and using the blended solution to perform electrospinning to form a nanofiber membrane, wherein the fibers in the nanofiber membrane have the room temperature ionic liquid inside and on the surface.

[0051] In a specific embodiment, the method for preparing the oral use article further comprises: sprinkling a penetration enhancer on the surface of the nanofiber membrane, so that the penetration enhancer is dispersed on the surface layer of the nanofiber membrane, which can help to enhance the mucosal permeability and improve the bioavailability of the active ingredient.

[0052] In a specific embodiment, the method for preparing the oral use article further comprises: preparing flavored microspheres, sprinkling the flavored microspheres on the surface of the nanofiber membrane, and performing hot-pressing compounding, so that the flavored microspheres are dispersed on the surface layer of the nanofiber membrane, which can enable the flavored microspheres to be released first to improve the taste. The conditions for hot-pressing compounding can be: hot-pressing at 80°C for 10 seconds. In this way, the flavored microspheres can be more firmly combined on the surface of the nanofiber membrane.

[0053] In a specific embodiment, the nanofiber membrane is cut into a preset shape. The preset shape can be selected according to user needs or product applications, and can be a regular shape such as a rectangle, a circle, an ellipse, a heart shape, or an irregular shape such as a leaf shape, a cartoon image shape, etc. For example, the nanofiber membrane can be cut into a square of 10 mm x 10 mm to facilitate attachment to the user's oral mucosa for use.

[0054] The application will be further described in detail below through specific experimental processes and experimental data examples. The following examples are only further illustrations of the application and should not be construed as limiting the application. In the present examples, unless otherwise specified, the reagents and instruments used are ordinary commercially available, and the experimental operations are performed according to the product instructions and conventional experimental specifications.

[0055] [Example 1]

[0056] (1) Preparation of a mouthpiece:

[0057] 1. Take nicotine 15 g and lithium bis(trifluoromethanesulfonyl)imide (LiNTf2) 15 g, respectively;

[0058] Preparation of nicotine hydrochloride:

[0059] Nicotine (free base) + HCl → Nic + Cl - + H2O

[0060] Nicotine (free base) is mixed with hydrochloric acid, and water is evaporated to obtain solid nicotine hydrochloride Nic + Cl - . Among them, the free base refers to the neutral molecular state of nicotine, at this time, the basic nitrogen atom (mainly the tertiary amine nitrogen on the pyrrolidine ring) in the molecule does not combine with an additional proton (H + ); Nic + refers to the protonated nicotine molecule with a positive charge, also known as a nicotine onium ion;

[0061] Ion exchange reaction:

[0062] Nic + Cl - + LiNTf2 → Nic + NTf2 - + LiCl↓ Nic + Cl - + LiNTf2 → Nic + NTf2 - + LiCl↓

[0063] Nic + Cl -and mixed with lithium bis-trifluoromethanesulfonimide (LiNTf2), the reaction product is Nic + NTf2 - and mixed with lithium chloride (LiCl), purified by extraction with dichloromethane to remove LiCl, and rotary evaporation to obtain pure Nic + NTf2 - Room temperature ionic liquid

[0064] 2. Take gelatin 40 g, polyethylene oxide (molecular weight Mw≈300000) 20 g, glycerol 6 g, dissolve in 200 mL deionized water, then add the IL mixture, stir evenly;

[0065] 3. Electrospinning: voltage 15 kV, push rate 0.8 mL / h, aluminum foil receiver distance 12 cm; Figure 1 The scanning electron microscope image of the nanofiber membrane of Example 1 of the present application is shown, and the SEM image shows that the nanofiber membrane has a layered structure, and the fiber diameter is 200±50 nm;

[0066] 4. Liposome (penetration enhancer) preparation and loading: dissolve sodium glycocholate (0.7 g) and lecithin (0.3 g) in chloroform, rotary evaporation to form a film, after hydration, extrude through a polycarbonate membrane with a pore size of 100 nm to obtain a liposome suspension (concentration 5 mg / mL). Load the liposome: evenly spray the liposome suspension on the surface of the nanofiber membrane (spraying amount: 0.1 mL / cm 2 ), dry at 25°C for 30 minutes;

[0067] 5. Preparation of flavored microspheres: take mannitol (D50=50 μm) 30 g, peppermint oil 1 g and sucralose 0.15 g, homogenize (20000 rpm, 5 min) and then spray dry (inlet temperature 120°C);

[0068] 6. Evenly spread the flavored microspheres on the nanofiber membrane, and hot-press at 80°C for 10 seconds to composite;

[0069] 7. Laser cutting into 10 mm x 10 mm square patches.

[0070] (2) Performance test:

[0071] ① Test method:

[0072] Dissolution test method: slurry method. Dissolution medium: artificial saliva: phosphate buffer with pH 6.8 (simulating oral environment); dissolution temperature: 37°C; rotation speed: 50 rpm; dissolution volume: 500 mL; test procedure: place the lozenge to be tested into the basket, place the basket into the water tank of the dissolution tester, add artificial saliva to ensure that the solution level is higher than the starting position of the basket, start the dissolution tester, and take samples at specific time points; then detect the nicotine content of the sample solution taken at the specific points by high performance liquid chromatography (HPLC).

[0073] Bitterness test method: electronic tongue is used to detect the bitterness value, with a full score of 10.

[0074] Oral residual rate test: volunteer test.

[0075] In vitro permeation experiment: Franz cell: pig oral mucosa, 37°C, pH 6.8; TR146 cells; TEER (trans epithelial electrical resistance) and Papp (apparent permeability coefficient) are determined. High performance liquid chromatography is used to detect nicotine. MTT method is used to measure cell toxicity.

[0076] 2. Test results:

[0077] Dissolution: 98.5% released in 5 minutes;

[0078] Bitterness value: 1.8 / 10 (detected by electronic tongue);

[0079] Human oral residual test: 3 / 10 volunteers reported slight coolness, no sticky feeling;

[0080] In vitro permeation test: mucosal permeability: Papp= 2.36 x 10 -6 cm / s (p < 0.05 vs. comparative example); cell layer permeability: Papp= 1.89 x 10 -6 cm / s, TEER decreased by 28.4%; the lozenge of Example 1 has good safety. In summary, the lozenge of Example 1 has the characteristics of rapid permeation, and the predicted human BA (bioavailability) is about 65%.

[0081] [Example 2]

[0082] (1) Preparation of lozenge:

[0083] 1. Take 12 g of nicotine and 20 g of 1-butyl-3-methylimidazolium chloride ([BMIM] + Cl - ) respectively;

[0084] Reaction:

[0085] [BMIM]+Cl-+ nicotine → [BMIM] +[Nic] - + HCl [BMIM] + Cl-+ nicotine -> [BMIM] + [Nic] - + HCl

[0086] Mixing nicotine and 1-butyl-3-methylimidazolium chloride, the reaction product is [BMIM] + [Nic] - and HCl, to obtain room temperature ionic liquid [BMIM] + [Nic] - ;

[0087] 2. Take gelatin 50 g, polyethylene oxide (molecular weight Mw≈200000), glycerol 7.5 g, 25 g is dissolved in 250 mL deionized water, then the room temperature ionic liquid is added, and stirred uniformly;

[0088] 3. Electrospinning: voltage 16 kV, push rate 1.0 mL / h, aluminum foil receiver distance 15 cm;

[0089] 4. Liposome preparation and loading: make sodium glycocholate (0.7 g), lecithin (0.3 g) dissolved in chloroform, rotary evaporation into a film, after hydration, extruded through a polycarbonate membrane with a pore size of 100 nm, to obtain a liposome suspension (concentration 5 mg / mL). Load the liposome: evenly spray the liposome solution on the surface of the nanofiber membrane (spraying amount: 0.1 mL / cm 2 ), dry at 25°C for 30 minutes;

[0090] 5. Preparation of flavored microspheres: take mannitol (D50=50μm) 35 g, peppermint oil 1.5 g and sucralose 0.2 g, homogenize (20000 rpm, 5 min) and then spray dry (inlet temperature 125°C);

[0091] 6. Uniformly spread the flavored microspheres on the nanofiber membrane, and hot-press at 85°C for 12 seconds to composite;

[0092] 7. Laser cutting into 15mm×15mm square patches.

[0093] (2) Performance test:

[0094] Test method same as example 1, test results as follows:

[0095] Dissolution: 99% released in 5 minutes;

[0096] Bitterness value: 2.1 / 10 (electronic tongue detection);

[0097] Human oral cavity residue test: 2 / 10 volunteers reported obvious cooling sensation, no sticky feeling;

[0098] In vitro permeation test: Mucosal permeability: Papp= 2.1 x 10 -6 cm / s (p<0.05 vs. comparative example); cell layer permeability: Papp= 1.8 x 10 -6 cm / s, TEER drop 31%; the oral patch of Example 2 has good safety. In summary, the oral patch of Example 2 has the feature of fast permeation, predicting human BA (bioavailability) of about 68%.

[0099] [Comparative Example]: Traditional film

[0100] (1) Preparation of the oral patch:

[0101] 1. Disperse 30 g of film-forming material HPMC (E5) in 300 mL of deionized water at 80°C, stir until completely dissolved (about 1 h), cool to room temperature;

[0102] 2. Add 10 g of nicotine, 5 g of plasticizer glycerol, 1 g of solubilizer triethyl citrate, homogenize (5000 rpm, 5 min) to form a uniform slurry, to obtain a coating liquid;

[0103] 3. Film coating: use an automatic coating machine to coat the film on a PET substrate (wet film thickness 500 μm);

[0104] 4. Drying: hot air drying at 50°C for 2 h, to obtain a dry film thickness of about 100 ± 10 μm (calibrated by thickness gauge);

[0105] 5. Flavor microsphere compounding: prepare the flavored microspheres in the same way as in Example 1, and uniformly spread them on the surface of the dry film, and hot-press at 80°C for 10 seconds for compounding;

[0106] 6. Laser cutting into 10 mm x 10 mm square patches.

[0107] (2) Performance test:

[0108] Test method same as Example 1, test results as follows:

[0109] Dissolution: 35% released in 5 minutes;

[0110] Bitterness value: 6.5 / 10 (detected by electronic tongue);

[0111] Human oral residue test: 8 / 10 volunteers reported obvious film-like residues, which needed to be deliberately swallowed (reason: the HPMC gel layer cannot be completely dissolved in the oral cavity, forming sticky gel fragments, resulting in poor user experience);

[0112] In vitro permeation test: Mucosal permeability: Papp= 0.5 x 10 -6 cm / s; cell layer permeability: Papp= 0.4 x 10-6 cm / s, 5% drop in TEER; safety results: safe, no cytotoxicity. Overall, the mouthpiece of the comparative example permeated more slowly, predicting a human BA (bioavailability) of about 25%.

[0113] The above description is further to the application in conjunction with specific embodiments, and cannot be deemed to limit the specific implementation of the application to these descriptions. For those skilled in the art to which the application belongs, some simple deductions or replacements can be made without departing from the concept of the application.

Claims

1. A mouthpiece, characterized in that The oral preparation comprises an active ingredient, the active ingredient comprising a room temperature ionic liquid, the room temperature ionic liquid comprising nicotine ions.

2. A smokeless tobacco product according to claim 1, wherein The room temperature ionic liquid further comprises at least one of the following: bis-trifluoromethanesulfonimide ions, trifluoroacetate ions, 1-butyl-3-methylimidazolium ions.

3. A smokeless tobacco product according to claim 1, wherein The oral preparation further comprises a loading structure, the active ingredient being loaded on the surface and / or inside of the loading structure.

4. A smokeless tobacco product according to claim 3, wherein The loading structure comprises a nanofiber membrane, the active ingredient being loaded on the surface and / or inside of the nanofiber membrane, wherein the nanofiber membrane comprises a base material, a fiber forming aid, and a plasticizing humectant.

5. A smokeless tobacco product according to claim 4, wherein The base material comprises at least one of the following: gelatin, collagen, silk fibroin, methyl cellulose; And / or, the fiber forming aid comprises at least one of the following: polyethylene oxide, polyvinyl alcohol, polyacrylonitrile, pullulan; And / or, the plasticizing humectant comprises at least one of the following: glycerol, polyethylene glycol, sorbitol, acetyl triethyl citrate; And / or, the nanofiber membrane comprises, in terms of mass fraction: 40-60 parts of the base material, 20-30 parts of the fiber forming aid, and 5-10 parts of the plasticizing humectant; And / or, the nanofiber membrane is formed by electrospinning.

6. A smokeless tobacco product according to claim 4, wherein The oral preparation further comprises a penetration enhancer, the penetration enhancer being dispersed on the surface layer of the nanofiber membrane; And / or, the oral preparation further comprises a flavoring microsphere, the flavoring microsphere being dispersed on the surface layer of the nanofiber membrane.

7. A smokeless tobacco product according to claim 6, wherein The penetration enhancer comprises at least one of the following ingredients: sodium glycocholate, lecithin; And / or, the penetration enhancer comprises liposome particles, the particle size of the liposome particles being 80-120 nm; And / or, the flavoring microsphere comprises at least one of the following: a sweetener, a cooling agent, a salty agent, an acidic agent, and an aromatic agent.

8. A method of making a mouthpiece, characterized in that A method for preparing the oral preparation according to any one of claims 1-7, the method comprising: obtaining an active ingredient, the active ingredient comprising a room temperature ionic liquid comprising nicotine ions; loading the active ingredient into a loading structure.

9. The production method according to claim 8, wherein The obtaining of the active ingredient comprises: obtaining nicotine hydrochloride, and reacting the nicotine hydrochloride with an anion agent to generate a room temperature ionic liquid containing nicotine cations, wherein the anion agent comprises bis-trifluoromethanesulfonimide salt and / or trifluoroacetate salt; Or, the obtaining of the active ingredient comprises: reacting nicotine with a cation agent to generate a room temperature ionic liquid containing nicotine anions, wherein the cation agent comprises 1-butyl-3-methylimidazolium chloride salt.

10. The production method according to claim 8, wherein The loading of the active ingredient into the loading structure includes any one of the following methods: (I) preparing a nanofiber membrane by electrospinning, i.e. obtaining the loading structure, and immersing the nanofiber membrane in the room-temperature ionic liquid; (II) taking the room-temperature ionic liquid as an oil phase carrier, taking a solution including a fiber material as an aqueous phase carrier, mixing the oil phase carrier and the aqueous phase carrier to form an emulsion, and using the emulsion to perform electrospinning to form a nanofiber membrane, wherein the fibers in the nanofiber membrane are wrapped with the room-temperature ionic liquid inside; (III) dissolving the room-temperature ionic liquid and the fiber material in a common solvent to obtain a blended solution, and using the blended solution to perform electrospinning to form a nanofiber membrane, wherein the fibers in the nanofiber membrane have the room-temperature ionic liquid inside and on the surface; And / or, the loading structure includes a nanofiber membrane, and the preparation method further includes at least one of the following steps: (I) sprinkling a penetration enhancer on the surface of the nanofiber membrane; (II) preparing flavored microspheres, sprinkling the flavored microspheres on the surface of the nanofiber membrane, and performing hot-pressing compounding; (III) cutting the nanofiber membrane into a preset shape.

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