Oral soluble film and preparation method thereof

Abstract

The invention discloses an oral soluble film and a preparation method thereof.The oral soluble film comprises a first film layer, a second film layer and a third film layer which are sequentially arranged in a stacked mode, the first film layer comprises a first film forming agent, the third film layer comprises a third film forming agent, and at least one of the first film layer and the third film layer comprises a first functional substance; the second layer of film comprises a second film-forming agent and a second functional substance, the disintegration speed of the first layer of film and the third layer of film is higher than that of the second layer of film, and the peak reaching time of the first functional substance is earlier than that of the second functional substance. According to the oral soluble film provided by the invention, the functional substances in different film layers have different release rates, so that the requirements of users can be better met.

Description

Technical Field

[0001] The present application relates to the technical field of oral products, and in particular to an orally disintegrating film and a preparation method thereof. Background Art

[0002] Oral products, such as oral nicotine products, contain the active ingredient nicotine (nicotine or its derivatives) and are typically placed in the mouth in the form of powder, film, or pouches. The product then dissolves and releases the active ingredient, which is absorbed through the oral mucosa, thereby alleviating nicotine withdrawal symptoms during smoking cessation. Oral nicotine products are a new type of rapid oral nicotine delivery system with advantages such as precise dosage, rapid onset, and portability. They are widely used in smoking cessation aids and metabolic regulation.

[0003] Orally disintegrating film is a thin film product, usually made of soluble materials, containing a certain amount of functional substances. It can dissolve in the mouth and release the functional substances when used.

[0004] However, current orally dissolving films usually have a single release rate and cannot meet the needs of users. Summary of the Invention

[0005] The present application provides an orally disintegrating film and a preparation method thereof, which are used to solve the problem that existing orally disintegrating films generally have a single release rate and cannot meet the usage needs of users.

[0006] The present application discloses an orally disintegrating film, comprising a first film layer, a second film layer, and a third film layer stacked in sequence, wherein the first film layer comprises a first film-forming agent, the third film layer comprises a third film-forming agent, at least one of the first film layer and the third film layer comprises a first functional substance, the second film layer comprises a second film-forming agent and a second functional substance, the disintegration rates of the first film layer and the third film layer are higher than the disintegration rates of the second film layer, and the peak time of the first functional substance is earlier than the peak time of the second functional substance.

[0007] In one implementation of the present application, at least one of the first membrane and the third membrane includes a porous structure.

[0008] In one implementation of the present application, the porosity of the porous structure is greater than or equal to 60%; and / or the pore size of the porous structure is 5 μm to 20 μm; and / or the porous structure is a freeze-dried porous structure.

[0009] In one implementation of the present application, the second layer of film includes a cross-linked network structure.

[0010] In one implementation of the present application, the first layer of film further comprises at least one of the following: a support agent, a sweetener, a cooling agent, and a fragrance; and / or the third layer of film further comprises at least one of the following: a support agent, a sweetener, a cooling agent, and a fragrance; and / or the second layer of film further comprises at least one of the following: a sustained-release agent, a sweetener, a cooling agent, and a fragrance.

[0011] In one implementation of the present application, the first film-forming agent includes at least one of the following: hydroxypropyl methylcellulose, polyvinyl alcohol, pullulan, gelatin, chitosan, polyvinyl pyrrolidone, and sodium carboxymethyl cellulose; and / or, the second film-forming agent includes at least one of the following: hydroxypropyl methylcellulose, polyvinyl alcohol, pullulan, gelatin, chitosan, polyvinyl pyrrolidone, and sodium carboxymethyl cellulose; and / or, the third film-forming agent includes at least one of the following: hydroxypropyl methylcellulose, polyvinyl alcohol, pullulan, gelatin, chitosan, polyvinyl pyrrolidone, and sodium carboxymethyl cellulose; and / or, the first functional substance includes at least one of the following: nicotine and nicotine derivatives; and / or, the second functional substance includes at least one of the following: nicotine and nicotine derivatives; and / or, the support includes mannitol; and / or, the sustained-release agent includes sodium alginate and a calcium salt, wherein the calcium salt is a neutral or alkaline calcium salt.

[0012] In one implementation of the present application, the first layer of film and the third layer of film have the same components. In the orally disintegrating film, the first layer of film and the third layer of film together include, by weight: 20 to 25 parts of the first film-forming agent, 8 to 12 parts of the first functional substance, 5 to 8 parts of a support agent, 0.8 to 1.2 parts of a sweetener, and 0.3 to 0.6 parts of a cooling agent; the second layer of film includes: 10 to 15 parts of the second film-forming agent, 5 to 8 parts of the second functional substance, 15 to 20 parts of sodium alginate, 0.5 to 1 part of a calcium salt, 0.8 to 1.2 parts of a sweetener, and 0.3 to 0.6 parts of a cooling agent.

[0013] In one implementation of the present application, the thickness ratio of the first film layer, the second film layer, and the third film layer is 0.8-1.2:1.8-2.2:0.8-1.2.

[0014] The present application also discloses a method for preparing an orally disintegrating film, comprising: obtaining a first film-forming liquid, and applying the first film-forming liquid to form a first film; obtaining a second film-forming liquid, and applying the second film-forming liquid to form a second film; obtaining a third film-forming liquid, and applying the third film-forming liquid to form a third film; stacking the first film, the second film, and the third film in sequence to obtain a three-layer composite film, and then obtaining the orally disintegrating film; wherein the first film comprises a first film-forming agent, the third film comprises a third film-forming agent, at least one of the first film and the third film comprises a first functional substance, the second film comprises a second film-forming agent and a second functional substance, the disintegration rates of the first film and the third film are higher than the disintegration rate of the second film, and the peak time of the first functional substance is earlier than the peak time of the second functional substance.

[0015] In one implementation of the present application, the first film-forming liquid and the third film-forming liquid have the same components, and the preparation method includes: preparing the first film and the third film: applying the first film-forming liquid and the third film-forming liquid respectively to form wet films, freeze-drying, and obtaining the first film and the third film respectively; preparing the second film and compounding: applying the second film-forming liquid to form a wet film, drying, and when the total drying time is 40% to 80%, stacking the first film, the second film and the third film in sequence to obtain the three-layer composite film; drying: drying the three-layer composite film to obtain the orally disintegrating film.

[0016] The beneficial effects of this application are:

[0017] The orally disintegrating film of the present application includes a three-layer structure, wherein the first layer of film or the third layer of film located on the outside preferentially contacts the saliva in the oral cavity during use, and the first layer of film and the third layer of film disintegrate at a faster rate, thereby allowing the first functional substance located in the first layer of film and / or the third layer of film to be released faster; the second layer of film located in the middle disintegrates at a slower rate, thereby allowing the second layer of film to provide the second functional substance more slowly; the peak time of the first functional substance is earlier than the peak time of the second functional substance, that is, the release rate of the first functional substance is faster than the release rate of the second functional substance. The functional substances have different release rates, which can help better meet the user's usage needs. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The figure shows a schematic structural diagram of the orally disintegrating film involved in the present application.

[0019] Figure 2 The nicotine release curve of the orally disintegrating film according to the embodiment of the present application is shown. DETAILED DESCRIPTION

[0020] The present invention is further described in detail below by specific embodiments in conjunction with the accompanying drawings. In the following embodiments, many detailed descriptions are intended to enable the present application to be better understood. However, those skilled in the art can readily appreciate that some of the features may be omitted in different circumstances, or may be replaced by other materials or methods. In some cases, some operations related to the present application are not shown or described in the specification. This is to avoid the core of the present application being overwhelmed by excessive descriptions, and for those skilled in the art, it is not necessary to describe these related operations in detail. They can fully understand the related operations based on the description in the specification and the general technical knowledge in the art.

[0021] In addition, the features, operations, or characteristics described in the specification may be combined in any appropriate manner to form various embodiments. Furthermore, the steps or actions in the method description may be reordered or adjusted in a manner readily apparent to those skilled in the art. Therefore, the various sequences in the specification and drawings are provided solely for the purpose of clearly describing a particular embodiment and are not intended to be mandatory, unless otherwise specified.

[0022] The serial numbers assigned to the components in this document, such as "first", "second", etc., are only used to distinguish the objects described and do not have any order or technical meaning.

[0023] Currently, most of the orally disintegrating film products on the market adopt a single-layer structure design. Although they can achieve rapid disintegration or sustained release, the release rate is single (either a rapid-release orally disintegrating film or a sustained-release orally disintegrating film), and it is difficult to take into account the dual needs of rapid release and sustained release. Specifically, conventional single-layer rapid-release orally disintegrating films have technical defects: the dense structure formed by the ordinary film-forming process leads to slow disintegration, resulting in the functional substances therein not being released in time, and unable to be quickly absorbed by the oral mucosa and enter the blood circulation to produce effects. Conventional single-layer sustained-release orally disintegrating films usually rely on a single polymer material (such as HPMC) to adjust the release rate by viscosity, but cannot form a dynamic cross-linking structure, and the sustained-release time is limited. The existing single-layer structure orally disintegrating film is a single-peak release, and has the following limitations: it is impossible to achieve the dual needs of rapid release and sustained sustained release, resulting in a short duration of rapid-release products, too slow release of sustained-release products at the entrance, poor user experience or the need for frequent use. In addition, it is difficult for traditional coating processes to accurately construct multi-layer functional structures, the interlayer bonding is poor, the sustained-release effect is unstable, and the process control is insufficient.

[0024] In view of this, the present application creatively proposes an orally dissolving film and a preparation method thereof. The orally dissolving film of the present application has functional substances with different release rates, which can help better meet the usage needs of users.

[0025] In a specific embodiment, the present application provides an orally disintegrating film 100 .

[0026] In one embodiment, the orally disintegrating film 100 has a multi-layer structure.

[0027] Figure 1 The structural diagram of the orally dissolving film 100 involved in this application is shown in FIG. Figure 1 As shown, in a specific embodiment, the orally disintegrating film 100 can have a three-layer structure, including a first film layer 10, a second film layer 20, and a third film layer 30. The first film layer 10, the second film layer 20, and the third film layer 30 can be stacked in sequence, that is, the second film layer 20 is located between the first film layer 10 and the third film layer 30.

[0028] In one embodiment, the first film 10 or the third film 30 has a higher disintegration rate than the second film 20. Disintegration rate refers to the rate at which a film decomposes or dissolves. In one embodiment, the disintegration rates of both the first film 10 and the third film 30 are higher than the disintegration rate of the second film 20. It should be noted that the first film 10 and the third film 30 are located on either side of the second film 20. During use, saliva first contacts the first and third films 10, 30, causing them to disintegrate and release the first functional substance, providing immediate gratification. The second film 20 disintegrates more slowly, providing sustained gratification.

[0029] In one embodiment, at least one of the first film 10 and the third film 30 includes a first functional substance. For example, both the first film 10 and the third film 30 may include the first functional substance. Alternatively, only the first film 10 or only the third film 30 may include the first functional substance. When both the first film 10 and the third film 30 include the first functional substance, the specific type and concentration of the first functional substance in the first film 10 may be the same as or different from that in the third film 30.

[0030] In one embodiment, the second film 20 includes a second functional substance.

[0031] In one embodiment, the first functional substance reaches its peak release time earlier than the second functional substance. Peak release time refers to the time required for the functional substance to reach 80% of its total mass. In other words, the release rate of the functional substance (first functional substance) in the first film 10 or the third film 30 is higher than the release rate of the functional substance (second functional substance) in the second film 20.

[0032] In a specific embodiment, the first functional substance may include at least one of nicotine and nicotine derivatives, for providing a sense of satisfaction.

[0033] In a specific embodiment, the second functional substance may include at least one of nicotine and nicotine derivatives, for providing a sense of satisfaction.

[0034] In a specific embodiment, nicotine includes natural nicotine and synthetic nicotine. Nicotine derivatives may include one or more of nicotine salts, nicotine in a matrix such as a sugar matrix or an organometallic complex, a nicotine-resin combination, a nicotine inclusion complex, and non-covalently bound nicotine. Non-covalently bound nicotine includes nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, nicotine benzoate, and the like. Nicotine derivatives also include nicotine containing substituents, such as hexamethyl nicotine, hexamethyl nicotine lactate, hexamethyl nicotine malate, hexamethyl nicotine salicylate, hexamethyl nicotine cyclodextrin embedded complex, hexamethyl nicotine hydrochloride, hexamethyl nicotine dihydrochloride, hexamethyl nicotine tartrate, hexamethyl nicotine tartrate dihydrate, hexamethyl nicotine sulfate, hexamethyl nicotine zinc chloride, and hexamethyl nicotine benzoate. One or more mixtures thereof.

[0035] In a specific embodiment, the first functional substance or the second functional substance may also be selected from other substances with medical or other specific uses, such as vitamins, capsaicin, caffeine, etc., to meet the needs of different users.

[0036] In a specific embodiment, the first functional substance or the second functional substance can also be selected from other alkaloids or amino acids, for example, alkaloids such as tobacco, coffee, and tea.

[0037] In a specific embodiment, the first membrane 10 and / or the third membrane 30 may have a porous structure. Figure 1 As described above, the first film 10 and the third film 30 may have pores 11. The number of pores 11 may be multiple. Thus, during use, saliva can more quickly penetrate into the first film 10 and the third film 30, causing the first film 10 and the third film 30 to disintegrate and release the first functional substance.

[0038] In one embodiment, the porous structure can be a freeze-dried porous structure. That is, the porous structure can be obtained through freeze-drying technology. Freeze-drying (freeze-drying) involves freezing a water-containing substance into a solid state and then sublimating the ice directly into water vapor under vacuum conditions, thereby removing the water and forming a porous structure in the material.

[0039] In one embodiment, the first membrane 10 and / or the third membrane 30 may be a through-porous structure. In other words, the pores 11 may penetrate both the upper and lower surfaces of the first membrane 10 or the upper and lower surfaces of the third membrane 30 .

[0040] In a specific embodiment, the pores 11 can be interconnected, closed, or independent. The size of the pores 11 can range from nanometers to millimeters. For example, the size of the pores 11 can be 1 nm to 100 nm.

[0041] In one embodiment, the porosity of the first film 10 can be 50% to 80%. For example, the porosity of the first film 10 can be 50%, 60%, 70%, or 80%. It should be noted that porosity refers to the ratio of the pore volume in a material to the total volume.

[0042] In a specific embodiment, the porosity of the third film 30 may be 50% to 80%. For example, the porosity of the third film 30 may be 50%, 60%, 70% or 80%.

[0043] In one embodiment, the porosity of the first membrane 10 or the third membrane 30 is greater than or equal to 60%. Porosity refers to the ratio of the pore volume to the total volume of a material. In this application, the first membrane 10 or the third membrane 30 has a higher porosity. Thus, during use, saliva can penetrate more quickly and cause the first membrane 10 or the third membrane 30 to disintegrate.

[0044] In a specific embodiment, the pore structure 11 may have a pore diameter of 5 μm to 20 μm.

[0045] In a specific embodiment, the second film layer 20 may have a cross-linked network structure, thereby enabling sustained release of the second functional substance through the cross-linked network structure, providing a lasting sense of satisfaction.

[0046] In one embodiment, the first film 10 includes a first film-forming agent.

[0047] In one embodiment, the second film 20 includes a second film-forming agent.

[0048] In one embodiment, the third film 30 includes a third film-forming agent.

[0049] In a specific embodiment, the first film-forming agent may include at least one of the following: hypromellose, polyvinyl alcohol, pullulan, gelatin, chitosan, polyvinyl pyrrolidone, and sodium carboxymethyl cellulose.

[0050] In a specific embodiment, the third film-forming agent may include at least one of the following: hypromellose, polyvinyl alcohol, pullulan, gelatin, chitosan, polyvinyl pyrrolidone, and sodium carboxymethyl cellulose.

[0051] In a specific embodiment, the second film-forming agent may include at least one of the following: hypromellose, polyvinyl alcohol, pullulan, gelatin, chitosan, polyvinyl pyrrolidone, and sodium carboxymethyl cellulose.

[0052] In one embodiment, the first film-forming agent or the third film-forming agent may be Hydroxypropyl Methylcellulose E5. HPMC E5 has a viscosity of approximately 5 mPa·s in a 2% aqueous solution. Its relatively low viscosity makes it suitable for applications requiring relatively low viscosity and can serve as the porous substrate for the first film 10 or the third film 30.

[0053] In one specific embodiment, the second film-forming agent may be Hydroxypropyl Methylcellulose E50. HPMC E50 has a viscosity of approximately 50 mPa·s in a 2% aqueous solution, making it suitable for applications requiring high viscosity. It can serve as the base material for the second film 20 and improve the bonding strength between the second film 20 and other film layers. Furthermore, Hydroxypropyl Methylcellulose E50 exhibits a synergistic sustained-release effect.

[0054] In a specific embodiment, the first membrane 10 may further include a proppant.

[0055] In a specific embodiment, the third membrane 30 may further include a proppant. The proppant of the first membrane 10 and the third membrane 30 may be the same.

[0056] In a specific embodiment, the proppant may include mannitol. It should be noted that mannitol has the following functions: protecting structural integrity, helping to maintain the three-dimensional structure of the sample, and reducing physical damage caused by ice crystal formation and sublimation during the freeze-drying process; increasing stability: mannitol can increase the glass transition temperature (Tg) of the sample, making it easier for the sample to remain in a glassy state during the freeze-drying process, which helps reduce the risk of recrystallization and thus protect the sample from oxidation and degradation; improving resolubility: mannitol can make the freeze-dried sample easier to resolubilize, can promote the rapid dissolution of the orally dissolving film, can help restore the original fluidity and uniformity of the sample, and ensure the effective release of functional substances, sweeteners, cooling agents, etc.; reducing collapse: in the secondary drying stage of the late freeze-drying stage, mannitol can help maintain the structure of the sample and prevent collapse caused by excessive removal of residual water; improving aesthetics: mannitol can make the surface of the freeze-dried product smoother and flatter, reducing wrinkling or deformation, and improving the overall aesthetics and texture of the product. In summary, mannitol can help improve the stability of orally disintegrating films, improve the disintegration rate and uniformity, and protect functional substances.

[0057] In a specific embodiment, the second film 20 may further include a sustained-release agent.

[0058] In a specific embodiment, the sustained-release agent may include sodium alginate and calcium salt. It should be noted that sodium alginate can form a three-dimensional cross-linked network with calcium ions, thereby delaying the disintegration time, which is beneficial to the sustained release of functional substances and sweeteners, fragrances, cooling agents, etc. in the second layer of film 20. The present application can significantly prolong the disintegration time by forming a cross-linked network with sodium alginate. In addition, sodium alginate can increase the viscosity of the film-forming liquid, thereby increasing the bonding strength with other film layers. It should also be noted that by adding calcium salt as a calcium ion source, the cross-linking rate can be precisely controlled; when the orally disintegrating film 100 is in use, the calcium ions contained in the saliva itself can also combine with sodium alginate to form a three-dimensional cross-linked network, further delaying the disintegration and the release of the second functional substance.

[0059] In a specific embodiment, the molecular weight of sodium alginate may be 80 kDa to 120 kDa.

[0060] In one embodiment, the calcium salt is a neutral or alkaline calcium salt. Thus, the calcium salt can also act as a pH regulator to neutralize the taste of nicotine, and nicotine is better absorbed in an alkaline environment.

[0061] In one specific embodiment, the calcium salt includes at least one of the following: calcium chloride, calcium citrate, calcium carbonate, calcium hydrogen phosphate, calcium gluconate, calcium lactate, and calcium sulfate. It should be noted that the above calcium salts are common commercial calcium salts with good taste and safety. For example, calcium citrate dissociates into calcium ions under acidic conditions (nicotine derivatives such as nicotine tartrate are inherently acidic, or by additional pH adjustment), thereby crosslinking the sodium alginate.

[0062] In one specific embodiment, at least one of the first film 10, the second film 20, and the third film 30 may further include at least one of the following: a sweetener, a flavoring agent, and a cooling agent. It should be noted that the sweetener, cooling agent, and flavoring agent in the first film 10, the second film 20, and the third film 30 may be independently selected. For example, the sweetener in the first film 10 may be xylitol, and the sweetener in the second film 20 may be sucralose.

[0063] In a specific embodiment, the sweetener may include at least one of xylitol, sorbitol, mannitol, iglesia, lactitol, maltitol, isomalt, hydrogenated starch hydrolysate, erythritol, maltotriitol, aspartame, acesulfame potassium, saccharin sodium, sucralose, neotame, cyclamate, alitame, steviol glycosides, arabitol, and monk fruit sweetener. Other edible-grade substances may also be selected, which will not be detailed here.

[0064] In a specific embodiment, the fragrance may include at least one of essence, natural essential oil, and natural extract. The essence is an edible essence, which may include at least one of bergamot essence, eucalyptus essence, citrus essence, lemon essence, peppermint essence, mint essence, menthol, licorice 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, vanilla essence, and watermelon essence. Other types of edible essences may also be used, which will not be detailed here.

[0065] In a specific embodiment, the cooling agent may include at least one of menthol, a menthol derivative, WS-3, and WS-23.

[0066] In one embodiment, the thickness ratio of the first film 10, the second film 20, and the third film 30 may be 0.8-1.2:1.8-2.2:0.8-1.2. For example, the thickness ratio of the first film 10, the second film 20, and the third film 30 may be 0.8:1.8:0.8 or 1:2:1.

[0067] In one embodiment, the third film 30 may be the same as the first film 10. For example, the third film 30 may have the same components, proportions, and film thickness as the first film 10.

[0068] In a specific embodiment, the orally disintegrating film 100 may include 20 to 25 parts by weight of the first film-forming agent or the third film-forming agent. For example, the orally disintegrating film 100 may include 20, 21, 22, 23, 24, or 25 parts by weight of the first film-forming agent or the third film-forming agent.

[0069] In a specific embodiment, the orally disintegrating film 100 may include 8 to 12 parts by weight of the first functional substance. For example, the orally disintegrating film 100 may include 8, 9, 10, 11, or 12 parts by weight of the first functional substance.

[0070] In a specific embodiment, the orally dissolving film 100 may include 5 to 8 parts by weight of a proppant. For example, the orally dissolving film 100 may include 5, 6, 7, or 8 parts by weight of a proppant.

[0071] In a specific embodiment, the orally disintegrating film 100 may include 10 to 15 parts by weight of the second film-forming agent. For example, the orally disintegrating film 100 may include 10, 11, 12, 13, 14, or 15 parts by weight of the second film-forming agent.

[0072] In a specific embodiment, the orally dissolving film 100 may include 5 to 8 parts by weight of the second functional substance. For example, the orally dissolving film 100 may include 5, 6, 7, or 8 parts by weight of the second functional substance.

[0073] In a specific embodiment, the orally disintegrating film 100 may include 15 to 20 parts by weight of sodium alginate. For example, the orally disintegrating film 100 may include 15, 16, 17, 18, 19, or 20 parts by weight of sodium alginate.

[0074] In a specific embodiment, the orally dissolving film 100 may include 0.5 to 1 part of calcium salt by weight. For example, the orally dissolving film 100 may include 0.5, 0.6, 0.7, 0.8, 0.9 or 1 part of calcium salt by weight.

[0075] In a specific embodiment, the orally dissolving film 100 may include 0.8 to 2.4 parts by weight of a sweetener. For example, the orally dissolving film 100 may include 0.8, 1, 1.5, 2, or 2.4 parts by weight of a sweetener.

[0076] In a specific embodiment, the orally dissolving film 100 may include 0.3 to 1.2 parts by weight of a cooling agent. For example, the orally dissolving film 100 may include 0.3, 0.5, 1, or 1.2 parts by weight of a cooling agent.

[0077] In a specific embodiment, the orally dissolving film 100 may further include other ingredients. In some embodiments, the orally dissolving film may further include a plasticizer to improve the toughness of the orally dissolving film and prevent the film from being too brittle. The plasticizer may include at least one of the following: glycerol, sorbitol, propylene glycol, polyethylene glycol, xylitol. In some embodiments, the orally dissolving film may further include a solubilizer. The solubilizer may include at least one of the following: polyethylene glycol (e.g., PEG-200, PEG-400, PEG-600, etc.), Tween (e.g., Tween-20, Tween-80, etc.), poloxamer. In some embodiments, the orally dissolving film may further include a pH regulator. The pH regulator may include at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and magnesium carbonate. In some embodiments, the orally dissolving film may further include a pigment to improve the appearance of the product.

[0078] In a specific embodiment, the disintegration time of the first film 10 or the third film 30 may be ≤15 seconds.

[0079] In a specific embodiment, the disintegration time of the second film 20 may be 15 minutes to 20 minutes.

[0080] In a specific embodiment, the orally disintegrating film 100 with a multi-layer structure of the present application has good process stability, and the film thickness uniformity CV is ≤3%.

[0081] In a specific embodiment, the orally disintegrating film 100 with a multi-layer structure of the present application can meet the dual requirements of rapid release and sustained release, releasing ≥35% of the functional substance within 30 seconds and releasing about 80% of the functional substance within 15 minutes.

[0082] In a specific embodiment, the orally dissolving film 100 with a multi-layer structure of the present application has an improved taste experience, and the sweetener and the cooling agent are continuously released for more than 10 minutes.

[0083] In a specific embodiment, the orally disintegrating film 100 of the present application has at least one of the following characteristics: Bimodal release: the outer quick-release layer realizes the rapid release of nicotine within 30 seconds (≥35%), and the middle sustained-release layer extends the effect to more than 15 minutes through ionic cross-linking. Different layers of the orally disintegrating film have different release rates, which can help meet the user's needs for immediate inhalation and continuous absorption. Taste optimization: sweetener (sucralose) and cooling agent (WS-23) are added to the middle layer in the same proportion to maintain the continuous release of sweeteners and cooling agents for more than ten minutes. Process stability: low-temperature freeze-drying technology forms a porous quick-release layer, and sodium alginate-calcium ion cross-linking technology enhances the structural stability of the sustained-release layer; in addition, sodium alginate can increase the viscosity of the film-forming liquid, thereby improving the bonding strength with other film layers.

[0084] In a specific embodiment, the present application provides a method for preparing an orally disintegrating film 100 (hereinafter sometimes referred to as "preparation method"). It should be noted that the ingredients, dosages, etc. involved in the preparation method can refer to the above description of the orally disintegrating film 100.

[0085] In a specific embodiment, the preparation method may include the following steps: obtaining a first film-forming liquid and applying the first film-forming liquid to form a first film 10 (step S1), obtaining a second film-forming liquid and applying the second film-forming liquid to form a second film 20 (step S2), obtaining a third film-forming liquid and applying the third film-forming liquid to form a third film (step S3), and sequentially stacking the first film 10, the second film 20, and the third film 30 to obtain a three-layer composite film, thereby obtaining an orally disintegrating film 100 (step S4);

[0086] In a specific embodiment, step S1 may include: applying the first film-forming liquid to form a wet film, and freeze-drying the wet film to obtain the first film layer 10 .

[0087] In a specific embodiment, step S3 may include: applying the third film-forming liquid to form a wet film, and freeze-drying the wet film to obtain the third film layer 30 .

[0088] In a specific embodiment, step S2 may include: applying a second film-forming liquid containing a sustained-release agent to form a wet film, and drying the wet film to obtain a second film layer 20 .

[0089] In a specific embodiment, when the total drying time of the second film 20 is 40% to 80%, the first film 10, the second film 20 and the third film 30 are sequentially stacked to obtain a three-layer composite film.

[0090] In a specific embodiment, step S4 may include: drying the three-layer composite film to obtain the orally disintegrating film 100 .

[0091] In a specific embodiment, the preparation method may include the following steps: preparing the first film 10 and the third film 30: applying the first film-forming liquid and the third film-forming liquid respectively to form wet films, freeze-drying, and obtaining the first film 10 and the third film 30 respectively; preparing the second film 20 and compounding: applying the second film-forming liquid to form a wet film, drying, and when the total drying time is 40% to 80%, stacking the first film 10, the second film 20 and the third film 30 in sequence to obtain a three-layer composite film; drying: drying the three-layer composite film to obtain an orally disintegrating film 100.

[0092] In one embodiment, the preparation method further comprises preparing a membrane-forming solution: adding each component to a solvent and homogenizing at a speed of 10,000 to 15,000 rpm for 15 to 30 minutes. The solvent may be water. The membrane-forming solution includes a first membrane-forming solution, a second membrane-forming solution, and a third membrane-forming solution.

[0093] In one embodiment, the first membrane-forming liquid and the third membrane-forming liquid have the same components.

[0094] In a specific embodiment, the freeze-drying conditions may include: freezing at -25°C to -50°C for 3 to 5 hours, and vacuum drying for 12 to 36 hours.

[0095] In a specific embodiment, the coating parameters of the first film-forming liquid or the third film-forming liquid may include: coating speed: 5 mm / s, coating distance: 400 mm, scraper / plane temperature: 35±2° C., thickness: 0.1±10% mm.

[0096] In one embodiment, the first film 10 and the third film 30 have the same thickness.

[0097] In a specific embodiment, the coating parameters of the second film-forming liquid may include: coating speed: 5 mm / s, coating distance: 400 mm, scraper / plane temperature: 35±2° C., thickness: 0.2±10% mm.

[0098] In one specific embodiment, in step S2, after the wet film is formed by coating, the wet film is dried until the film solidifies and stops flowing, and then the three-layer film is laminated and stacked. For example, the lamination and stacking of the three-layer film can be performed when the total drying time reaches 40% to 80%. This helps to improve the structural stability of the three-layer composite film.

[0099] In one embodiment, the orally disintegrating film 100 is prepared by the above-mentioned preparation method.

[0100] The present invention is further described in detail below by specific experimental process and experimental data examples. The following examples are only used to further illustrate the present invention and should not be construed as limiting the present invention. In the present embodiment, unless otherwise specified, the reagents and instruments used are all commercially available, and the experimental operations are all carried out in accordance with the product specifications and conventional experimental specifications.

[0101] (1) Preparation of orally disintegrating film:

[0102] Homogenize the components (12000 rpm, 20 minutes) according to the ratios shown in the table below to prepare the membrane-forming solutions for different layers:

[0103] Film-forming solution for the first or third film:

[0104]

[0105] The second film-forming solution:

[0106]

[0107]

[0108] Preparation of the First and Third Film Layers: Coating: The film-forming solution for the first or third film layer was applied to a coating surface at a coating speed of 5 mm / s, a coating distance of 400 mm, a doctor blade / surface temperature of 35 ± 2°C, and a thickness of 0.1 ± 10% mm. Freeze-drying: A porous immediate-release layer (i.e., the first and third film layers, respectively) was prepared using a low-temperature freeze-drying process (pre-freezing at -40°C for 4 hours, followed by vacuum drying at 0.1 mbar for 24 hours).

[0109] Preparation of the second film: coating the film-forming liquid of the second film onto the coating plane, coating speed: 5 mm / s, coating distance: 400 mm, scraper / plane temperature: 35±2°C, thickness: 0.2±10% mm.

[0110] Composite: Dry the second film. Before the second film dries (when the wet film solidifies and does not flow), stack the first, second, and third films in sequence to form a three-layer composite film. Pre-cure at 40°C for 30 minutes, with a total thickness of 0.5±5% mm.

[0111] Drying: The three-layer composite film was dried in stages to relieve stress: main drying at 55°C for 60 minutes, followed by equilibration at 25°C for 12 hours.

[0112] Cutting and packaging: Cut into appropriate size and package.

[0113] (2) Nicotine dissolution curve test:

[0114] Experimental purpose: To verify the nicotine release characteristics of the orally disintegrating film of this application in a simulated oral environment (pH 6.8, 37°C) to ensure that it meets the bimodal release target: immediate release phase: release ≥35% nicotine within 30 seconds; sustained release phase: cumulative release ≥80% within 15 minutes.

[0115] Samples: The three-layer composite orally dissolving film of this example, the traditional sustained-release (single-layer) orally dissolving film, and the traditional quick-release (single-layer) orally dissolving film. The traditional sustained-release (single-layer) orally dissolving film is a single-layer structure, which differs from the second layer of the example in that sodium alginate and calcium citrate are not used (only HPMC E50 is used as the sustained-release material), and the other materials and their amounts are the same as those of the second layer of the example 1. After coating, the film is dried to obtain a single-layer structure. The traditional quick-release (single-layer) orally dissolving film is a single-layer structure, which differs from the first or third layer of the example in that no freeze-drying treatment is performed, and the materials and their amounts are the same as those of the first or third layer of the example 1. After coating, the film is dried to obtain a single-layer structure.

[0116] Reagent: Saliva (pH 6.8, containing 0.5% SDS)

[0117] Apparatus: Dissolution apparatus (USPII paddle method, 37±0.5°C, 50 rpm), HPLC system (C18 column, mobile phase: acetonitrile-phosphate buffer (pH 3.0, volume ratio 70:30), detection wavelength 260 nm).

[0118] Experimental Method: Preheat 500 mL of saliva to 37°C and add it to the dissolution cup. Secure the sample to be tested (the three-layer composite orally dissolving film of this example or a conventional single-layer orally dissolving film) to the bottom of the dissolution apparatus paddle and start the apparatus (50 rpm). Take 5 mL of saliva at the following time points (while replenishing the fluid): 0.5, 1, 3, 5, 7, 10, and 15 minutes. Filter the sample through a 0.22 μm filter membrane, and measure nicotine concentration by HPLC.

[0119] Data analysis: Calculation of cumulative release: Cumulative release rate (%) = [(total nicotine content detection concentration × dissolution medium volume) ÷ total nicotine content] × 100.

[0120] Release curve fitting: The first-order kinetic model (Weibull equation) was used.

[0121] Results: Nicotine release rate results are shown in the table below, and release curves are shown in Figure 2 , Figure 2 The nicotine release curve of the orally disintegrating film according to the embodiment of the present application is shown. Figure 2 In the figure, the top curve (KRZY000012) is the nicotine dissolution curve of the traditional immediate-release (single-layer) orally dissolving film, the middle curve (KRZY000013) is the nicotine dissolution curve of the orally dissolving film of this embodiment, and the bottom curve (KRZY000014) is the nicotine dissolution curve of the traditional sustained-release (single-layer) orally dissolving film.

[0122]

[0123] As can be seen from the above, the oral dissolving film of the present application has outstanding performance in the release verification of the rapid release and sustained release stages. At 0.5 minutes, its nicotine release rate reached 36.2%, meeting the rapid release target of releasing ≥35% within 30 seconds. The traditional single-layer sustained-release oral dissolving film did not release at this time. Although the traditional single-layer rapid-release oral dissolving film has rapid release, it lacks a subsequent sustained-release design. At 15 minutes, the cumulative release rate of the oral dissolving film of the present application was 82.50%, meeting the sustained-release requirement of cumulative release >80% within 15 minutes, while the traditional single-layer sustained-release oral dissolving film was only 66.50%. The traditional rapid-release oral dissolving film was unable to achieve long-term sustained release due to its excessively rapid release (96.10% in 15 minutes). From the perspective of release behavior, the peak time of the oral dissolving film of the present application was extended to 5 minutes, which is more suitable for sustained-release requirements than the peak time of 1-2 minutes of the traditional single-layer rapid-release oral dissolving film. Moreover, the release was stable after 15 minutes, and only slightly increased to 83.00% after 30 minutes. The release controllability was significantly better than the control group.

[0124] (3) Sweetener and cooling agent dissolution test:

[0125] Experimental purpose: To verify the release characteristics of sucralose and WS-23 in the orally disintegrating film of this example, compare the release differences with those of traditional single-layer orally disintegrating films, and analyze the sustained release effect of taste components.

[0126] Samples: The three-layer composite orally disintegrating film of this example (containing 1.0% sucralose and 0.5% WS-23, n=6); conventional rapid-release orally disintegrating film (containing the same dosage of sucralose and WS-23, n=6). The conventional rapid-release (single-layer) orally disintegrating film is a single-layer structure. Compared with the first or third layer of the film of the example, it is not freeze-dried. The materials and amounts used are the same as those of the first or third layer of the film of Example 1. After coating, drying is performed to obtain a single-layer structure film.

[0127] Reagent: Saliva (pH 6.8, containing 0.5% SDS).

[0128] Instruments: dissolution apparatus (USPⅡ paddle method, 37±0.5℃, rotation speed 50rpm), HPLC system (C18 column, sucralose detection wavelength 210nm, WS-23 detection wavelength 275nm), 0.22μm filter membrane.

[0129] Experimental Methods: 500 mL of saliva was preheated to 37°C and added to the dissolution cup. The sample was fixed to the bottom of the dissolution apparatus and the instrument was started. 5 mL samples were taken at 0.5, 1, 3, 5, 7, 10, and 15 minutes (with 5 mL of saliva at the same temperature added simultaneously). The samples were filtered through a 0.22 μm filter and then tested. The concentrations of sucralose and WS-23 in the filtrate were determined by HPLC. The mobile phase was acetonitrile-phosphate buffer (pH 3.0, 40:60 volume ratio), the flow rate was 1.0 mL / min, and the injection volume was 20 μL.

[0130] Data analysis: Release rate (%) = (test concentration × dissolution medium volume) ÷ total added amount × 100.

[0131] result:

[0132]

[0133] Traditional orally disintegrating films release sucralose and WS-23 rapidly, with release rates exceeding 68% in 0.5 minutes and reaching over 79.4% in 1 minute. Subsequent release slows, making it difficult to maintain a long-lasting mouthfeel. The orally disintegrating film of the present invention, through its structural design, delays release, achieving a sucralose release rate of 38.5% and a WS-23 release rate of 41.2% in 0.5 minutes. After 15 minutes, the release rates of sucralose and WS-23 reach 91.0% and 91.5%, respectively. This results in a flatter release curve and prolonged sweetness and cooling sensations, demonstrating the advantages of the orally disintegrating film of this embodiment in regulating the release of taste components.

[0134] In summary, the present invention successfully achieves the bimodal release characteristics of nicotine through innovative three-layer membrane structure design and process technology. The outer layer / inner layer uses low-temperature freeze-drying technology to form a porous quick-release layer (porosity ≥ 60%), which releases ≥ 35% nicotine within 30 seconds and quickly delivers sweeteners and cooling agents. The middle layer uses sodium alginate-calcium ion dynamic cross-linking to construct a sustained-release network, with a cumulative release of 82.5% in 15 minutes, effectively extending the duration of action. Experimental data show that the present invention meets the requirements of rapid onset in the quick-release stage, and continuous and stable release in the sustained-release stage. At the same time, the release time of sweeteners and cooling agents is extended to more than 10 minutes, significantly improving the user experience.

[0135] Compared with traditional single-layer orally disintegrating films, this application breaks through the technical bottleneck of being unable to take into account both rapid release and sustained release. Through process optimization, it achieves film thickness uniformity CV≤3%, significantly improving product stability and controllability.

[0136] The above content is a further detailed description of the present application in conjunction with specific implementation methods, and the specific implementation of the present application cannot be considered to be limited to these descriptions. For ordinary technicians in the technical field to which the present application belongs, several simple deductions or substitutions can be made without departing from the concept of the present application.

Claims

1. An orally disintegrating film, characterized in that: The invention comprises a first film layer, a second film layer and a third film layer stacked in sequence, wherein the first film layer comprises a first film-forming agent, the third film layer comprises a third film-forming agent, at least one of the first film layer and the third film layer comprises a first functional substance, the second film layer comprises a second film-forming agent and a second functional substance, the disintegration speed of the first film layer and the third film layer is higher than the disintegration speed of the second film layer, and the peak time of the first functional substance is earlier than the peak time of the second functional substance.

2. The orally dissolving film according to claim 1, wherein At least one of the first membrane and the third membrane comprises a porous structure.

3. The orally dissolving film according to claim 2, wherein The porosity of the porous structure is greater than or equal to 60%; and / or, the pore size of the porous structure is 5 μm to 20 μm; And / or, the porous structure is a freeze-dried porous structure.

4. The orally dissolving film according to claim 1, wherein The second film layer includes a cross-linked network structure.

5. The orally dissolving film according to claim 1, wherein The first film further comprises at least one of the following: a support agent, a sweetener, a cooling agent, and a fragrance; and / or, the third film further comprises at least one of the following: a support agent, a sweetener, a cooling agent, and a fragrance; And / or, the second film layer further comprises at least one of the following: a sustained-release agent, a sweetener, a cooling agent, and a fragrance.

6. The orally dissolving film according to claim 5, wherein The first film-forming agent comprises at least one of the following: hypromellose, polyvinyl alcohol, pullulan, gelatin, chitosan, polyvinyl pyrrolidone, and sodium carboxymethyl cellulose; and / or, the second film-forming agent comprises at least one of the following: hydroxypropyl methylcellulose, polyvinyl alcohol, pullulan, gelatin, chitosan, polyvinyl pyrrolidone, sodium carboxymethyl cellulose; and / or, the third film-forming agent comprises at least one of the following: hydroxypropyl methylcellulose, polyvinyl alcohol, pullulan, gelatin, chitosan, polyvinyl pyrrolidone, sodium carboxymethyl cellulose; and / or, the first functional substance comprises at least one of the following: nicotine and nicotine derivatives; and / or, the second functional substance comprises at least one of the following: nicotine and nicotine derivatives; and / or, the proppant comprises mannitol; And / or, the sustained-release agent comprises sodium alginate and calcium salt, wherein the calcium salt is a neutral or alkaline calcium salt.

7. The orally dissolving film according to claim 1, wherein The first layer of film has the same components as the third layer of film. In the orally disintegrating film, the first layer of film and the third layer of film together include, by weight: 20 to 25 parts of the first film-forming agent, 8 to 12 parts of the first functional substance, 5 to 8 parts of a support agent, 0.8 to 1.2 parts of a sweetener, and 0.3 to 0.6 parts of a cooling agent; the second layer of film includes: 10 to 15 parts of the second film-forming agent, 5 to 8 parts of the second functional substance, 15 to 20 parts of sodium alginate, 0.5 to 1 part of a calcium salt, 0.8 to 1.2 parts of a sweetener, and 0.3 to 0.6 parts of a cooling agent.

8. The orally dissolving film according to claim 1, wherein The thickness ratio of the first film layer, the second film layer and the third film layer is 0.8-1.2:1.8-2.2:0.8-1.

2.

9. A method for preparing an orally dissolving film, characterized in that: include: Obtaining a first film-forming liquid, and applying the first film-forming liquid to form a first film; obtaining a second film-forming liquid, and applying the second film-forming liquid to form a second film; obtaining a third film-forming liquid, and applying the third film-forming liquid to form a third film; stacking the first film, the second film and the third film in sequence to obtain a three-layer composite film, thereby obtaining the orally disintegrating film; Among them, the first film layer includes a first film-forming agent, the third film layer includes a third film-forming agent, at least one of the first film layer and the third film layer includes a first functional substance, the second film layer includes a second film-forming agent and a second functional substance, the disintegration rates of the first film layer and the third film layer are higher than the disintegration rate of the second film layer, and the peak time of the first functional substance is earlier than the peak time of the second functional substance.

10. The preparation method according to claim 9, characterized in that The first membrane-forming liquid and the third membrane-forming liquid have the same components, and the preparation method includes: preparing the first film and the third film: coating the first film-forming liquid and the third film-forming liquid to form wet films, and freeze-drying the films to obtain the first film and the third film respectively; preparing the second film layer and laminating the film: applying the second film-forming liquid to form a wet film, drying the film, and laminating the first film layer, the second film layer, and the third film layer in sequence when the total drying time is 40% to 80% to obtain the three-layer composite film; Drying: drying the three-layer composite film to obtain the orally disintegrating film.

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