Buccal tablet for refreshing mind, restoring consciousness and refreshing oral cavity and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a buccal tablet for refreshing and refreshing oral cavity and a preparation method thereof. The lozenge comprises a plain tablet and a shell, the plain tablet comprises internal phase particles, an internal phase particle coating layer and an auxiliary agent, the internal phase particles use sodium carboxymethyl cellulose and cross-linked povidone to construct a quick release skeleton, quick release type and slow release type caffeine and theanine are used as refreshing components, and poloxamer is supplemented to enhance infiltration, so that quick absorption and continuous release of caffeine are realized, and the effect of refreshing the mind is achieved; the nerve stimulation caused by caffeine is relieved through theanine; according to the inner-phase particle coating layer, a sustained-release framework is constructed by hydroxypropyl methylcellulose and hydroxy propyl cellulose, a micropore channel is formed through polyethylene glycol, sustained release of fermented ginsenoside is promoted, the anti-fatigue capacity is enhanced, the refreshing time effect is prolonged, cineole and limonene are released, a cool feeling is generated, peculiar smells are covered, and the refreshing effect is improved. And lactobacillus rhamnosus is supplemented to inhibit the reproduction of harmful bacteria in the oral cavity so as to reduce peculiar smell, so that the effects of quickly refreshing, persistently refreshing and freshening the oral cavity are realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a refreshing lozenge and a preparation method thereof. BACKGROUND

[0002] In the current fast-paced life and work environment, refreshing and keeping the oral cavity fresh have become the general needs of the public. The existing related products on the market, such as traditional lozenges, chewing gums or functional beverages, often have obvious limitations in the comprehensiveness, durability and experience of the efficacy. Specifically, most refreshing products rely on the single rapid release of ingredients such as caffeine, which can quickly take effect but has a short duration and is prone to cause palpitations, anxiety and other discomfort due to the sudden rise and fall of blood drug concentration. At the same time, its oral cavity freshening function is mostly limited to providing a short-term cooling sensation through ingredients such as menthol or relying on fragrances to mask odors, which cannot regulate the oral flora from the microecological root, resulting in superficial and easily repeated freshening effects. In addition, the simple mixing of refreshing and freshening functions in the dosage form design often ignores the optimal release kinetics of different ingredients, for example, the refreshing ingredients need to achieve a balance between rapid onset and smooth maintenance, while the freshening ingredients need to consider both immediate sensation and long-term effect. This technical deficiency makes it difficult for existing products to meet the comprehensive expectations of rapid onset, long-lasting effect, mild comfort and root freshening. SUMMARY

[0003] In view of the deficiencies of the prior art, the purpose of the present application is to provide a refreshing lozenge and a preparation method and application thereof, which comprises inner phase particles, inner phase particle coating layer and outer shell. The inner phase particles are constructed with low-viscosity sodium carboxymethyl cellulose and cross-linked povidone to form a rapid-release skeleton, with rapid-release and sustained-release caffeine and theanine as the core refreshing ingredients, and supplemented with poloxamer to enhance the penetration effect, achieving rapid absorption and sustained release of caffeine, and relieving the possible nerve stimulation caused by caffeine through theanine. The inner phase particle coating layer is constructed with hydroxypropylmethyl cellulose and low-substituted hydroxypropyl cellulose to form a sustained-release skeleton, and the gel permeability is regulated by polyethylene glycol. The released fermented ginsenosides can enhance the anti-fatigue ability to prolong the refreshing time, and the released eucalyptol and limonene activate the TRPM8 channel to produce a cooling sensation and mask odors, supplemented by lactobacillus rhamnosus to inhibit the reproduction of harmful bacteria in the oral cavity to reduce odors, thereby achieving the effects of rapid refreshing, long-lasting refreshing and freshening the oral cavity.

[0004] To achieve the above purpose, the present application adopts the following technical solutions:

[0005] In a first aspect, the present application provides a lozenge for refreshing the mouth, the lozenge comprising a base and a shell; the base comprising an inner phase granule, an inner phase granule coating layer and an auxiliary agent; the shell comprising a film forming agent; the inner phase granule comprising immediate-release caffeine, sustained-release caffeine, theanine and excipients; the inner phase granule coating layer comprising a fat-soluble inclusion compound, a probiotic inclusion compound and additives; the auxiliary agent comprising anhydrous erythritol and magnesium stearate; the excipients comprising sodium carboxymethyl cellulose, cross-linked povidone, poloxamer 188, colloidal silica, povidone and anhydrous erythritol; the fat-soluble inclusion compound comprising eucalyptol, limonene, fermented ginsenoside and HP-β-cyclodextrin (hydroxypropyl-β-cyclodextrin); the probiotic inclusion compound comprising freeze-dried Lactobacillus rhamnosus powder, maltodextrin, gum arabic and vitamin E; and the additives comprising hypromellose, hydroxypropyl cellulose, polyethylene glycol, citric acid, colloidal silica and hydroxypropyl cellulose.

[0006] Further, the mass ratio of the tablet and the shell is (101.45-118.26):(9-11); the mass ratio of the inner phase granules, the coating layer of the inner phase granules and the auxiliary agent in the tablet is (45.8-52.6):(50.45-59.26):(5.2-6.4); the mass ratio of the rapidly-released caffeine, the slowly-released caffeine, the theanine and the excipient in the inner phase granules is (0.43-0.53):(1.0-1.24):(1.6-2.0):(42.77-48.83); the mass ratio of the fat-soluble inclusion compound, the probiotic inclusion compound and the additive in the coating layer of the inner phase granules is (22.7-27.7):(9-11):(18.54-20.46); the mass ratio of the sodium carboxymethyl cellulose, the crosslinked povidone, the poloxamer 188, the microcrystalline silica, the povidone and the anhydrous erythritol in the excipient is (6.8-8.2):(1.8-2.2):(0.45-0.55):(0.27-0.33):(0.45-0.55):(33-37); the mass ratio of the eucalyptol, the limonene, the fermented ginsenoside and the HP-β-cyclodextrin in the fat-soluble inclusion compound is (1.8-2.2):(0.9-1.1):(5.4-6.6):(14.6-17.8); the mass ratio of the Lactobacillus rhamnosus freeze-dried bacteria powder, the maltodextrin, the gum arabic and the vitamin E in the probiotic inclusion compound is (1.8-2.2):(4.5-5.5):(2.7-3.3):(0.27-0.33); the mass ratio of the hypromellose, the hydroxypropyl cellulose, the polyethylene glycol, the citric acid, the microcrystalline silica and the sodium alginate in the additive is (12.6-15.4):(2.7-3.3):(0.45-0.55):(0.09-0.11):(0.63-0.77):(2.0-2.3); the mass ratio of the anhydrous erythritol and the magnesium stearate in the auxiliary agent is (4.5-5.5):(0.7-0.9); the film-forming agent is the hypromellose, and the viscosity of 2% aqueous solution of the hypromellose at 25℃ is 3.6-5.4 mPa·s.

[0007] Further, the viscosity of 2% aqueous solution of the sodium carboxymethyl cellulose in the excipient at 25℃ is 5-20 mPa·s; the K value of the povidone in the excipient is 27-32; the average degree of substitution of the HP-β-cyclodextrin in the fat-soluble inclusion compound is 0.6-0.8; the viscosity of 2% aqueous solution of the hypromellose in the additive at 25℃ is 3500-4500 mPa·s; the degree of substitution of the hydroxypropyl cellulose in the additive is 7%-12%; the molecular weight of the polyethylene glycol in the additive is 5000-7000; the viscosity of 2% aqueous solution of the sodium alginate in the additive at 25℃ is 30-80 mPa·s.

[0008] In a second aspect, the present application provides a preparation method of a lozenge for refreshing the mind and clearing the oral cavity, comprising the following steps:

[0009] S1, mix sodium carboxymethyl cellulose, cross-linked povidone, instant-release caffeine, slow-release caffeine, theanine, poloxamer 188, micro-silica gel, povidone, anhydrous erythritol and ethanol solution, spray dry, dry, and obtain an inner phase granule;

[0010] S2, mix eucalyptol, limonene, fermented ginsenoside, HP-β-cyclodextrin and the first deionized water, stir, high-pressure homogenize, freeze-dry, sieve, and obtain a fat-soluble inclusion compound; mix lactobacillus rhamnosus freeze-dried bacteria powder, maltodextrin, gum arabic, vitamin E and the second deionized water, spray dry, and obtain a probiotic inclusion compound;

[0011] S3, mix hydroxypropyl methylcellulose K4M, hydroxypropyl cellulose, polyethylene glycol, citric acid, micro-silica gel, add the fat-soluble inclusion compound and the probiotic inclusion compound under stirring, and obtain an outer phase mixture; mix the outer phase mixture, sodium alginate and deionized water, shear, and obtain an outer phase suspension;

[0012] S4, spray the outer phase suspension to the surface of the inner phase granule, dry, and obtain a coated inner phase granule; mix the coated inner phase granule, anhydrous erythritol and magnesium stearate, press into tablets, and obtain a blank tablet; mix hydroxypropyl methylcellulose and ethanol solution, and obtain a coating liquid; spray the coating liquid to the surface of the blank tablet, solidify and dry at the spraying temperature, sieve, and obtain a lozenge for refreshing the mind and clearing the oral cavity.

[0013] In a feasible implementation scenario, in S1, the instant-release caffeine is made by airflow crushing of caffeine under the conditions of crushing pressure 0.7-0.9 MPa and feeding rate 10-15 kg / h, and the particle size is ≤5 μm; the particle size of the slow-release caffeine is 80-120 μm.

[0014] The viscosity of 2% aqueous solution of sodium carboxymethyl cellulose at 25℃ is 5-20 mPa·s, and because of the short molecular chain and strong hydrophilicity, it can quickly absorb water, swell and collapse after encountering saliva, while cross-linked povidone (PVPP) can accelerate the disintegration of the skeleton by virtue of the strong capillary force generated in the swelling of the cross-linked network structure, and the two together form a transient dispersion channel, providing a physical basis for the release of functional ingredients. By introducing poloxamer 188 as a non-ionic surfactant, the hydrophilic segment in its molecule can interact with the phospholipid molecules on the cell membrane of the oral mucosa, temporarily increasing the permeability of the membrane and promoting the absorption of subsequent ingredients.

[0015] The micronized instant-release caffeine has a significantly increased specific surface area, rapidly dissolves into free molecules in saliva, penetrates the mucosal epithelial cells with the help of the penetration of poloxamer, rapidly enters the blood circulation and reaches the central nervous system, blocks the adenosine-mediated sedative signal by competitive binding of adenosine receptors, and rapidly awakens the nervous excitement state; while the sustained-release caffeine retains the original particle size, which makes it difficult to be rapidly dissolved in the initial stage of the skeleton disintegration, but is gradually released with the slow dispersion of the internal residual structure, continuously supplements the caffeine concentration, avoids the palpitation, anxiety caused by the rapid rise of blood drug concentration, or the fatigue rebound caused by the rapid drop. Theanine enters the central nervous system through the blood-brain barrier, promotes the synthesis of inhibitory neurotransmitters such as gamma-aminobutyric acid, and at the same time reduces the excessive release of excitatory neurotransmitters such as norepinephrine, balances the stimulating effect of caffeine, and the alpha brain waves induced by theanine can make people remain relaxed in a state of wakefulness, achieving the mild effect of refreshing without excitement. In addition, the povidone with a K value of 27-32 binds the powders in the internal phase into stable particles through intermolecular hydrogen bonding, avoiding too much fine powder in the granulation process; the micro-powder silica gel reduces the friction between particles through adsorption, ensuring uniform fluidity during tabletting; anhydrous erythritol as a low-calorie sweetener provides a refreshing taste, and its crystal structure can enhance the mechanical strength of the particles, avoiding breakage during transportation.

[0016] In a feasible implementation case, in the S1, the mass-volume ratio of the instant-release caffeine and the ethanol solution is (0.43-0.53) kg:(32-38) L, and the mass fraction of the ethanol solution is 30 wt.%; the parameters of the spray drying are: the inlet air temperature is 115-125℃, the outlet air temperature is 55-65℃, and the atomization pressure is 0.3-0.5 MPa; the drying step is: drying at a temperature of 60℃ and a wind speed of 1.5-2.0 m / s for 8-12 min; the particle size of the internal phase particles is 120-150 μm.

[0017] Spray drying granulation is the key to the formation of the functional structure of the inner phase particles. In the temperature difference environment of the inlet air temperature and the outlet air temperature, the ethanol on the surface of the droplet evaporates rapidly due to high temperature, forming a hard shell, while the internal solvent slowly diffuses to the surface, eventually forming a porous particle. The inlet air temperature is to ensure the instantaneous solidification of the droplet, to avoid the aggregation of the instant caffeine due to the micronization of the small particle size under long time heating, and the outlet air temperature is to protect the activity of theanine and povidone. The pores of the formed porous structure provide channels for saliva penetration, which not only retains the rapid disintegration potential of low viscosity sodium carboxymethyl cellulose and PVPP, but also realizes the gradient release of the components through the pore size difference of the large surface pore and the small internal pore, that is, the instant caffeine can be quickly dissolved through the surface large pore, and the slow-release caffeine needs to gradually penetrate the internal small pore, and the residual structure of the matrix material delays the release. The subsequent drying process makes the particles in a boiling state by air flow, which ensures the fluidity, matrix stability and subsequent disintegration performance of the inner phase particles, and lays a foundation for the stable play of the quick refreshing function.

[0018] In a feasible implementation scenario, in S2, the mass-volume ratio of eucalyptol and the first deionized water is (1.8-2.2) kg:(72-88) L; the temperature of the stirring is 48-52℃, the stirring speed is 450-550 r / min, and the stirring time is 20-30 min; the pressure of the high-pressure homogenization is 27-33 MPa, and the high-pressure homogenization time is 8-12 min; the temperature of the freeze drying is-40℃, and the freeze drying time is 24-30 h; the mesh number of the sieving is 80 meshes.

[0019] The inclusion complex of fat-soluble ingredients is the key carrier to realize long-acting refreshing and synergistic refreshing, and its core lies in the protection and controlled release regulation of HP-β-cyclodextrin molecular inclusion properties on fat-soluble ingredients. HP-β-cyclodextrin is a cyclic molecule formed by 7 glucose units connected by glycosidic bonds, with a hydrophobic cavity inside and a hydrophilic surface due to the dense arrangement of hydroxyl groups. This internal hydrophobic and external hydrophilic structure can form a stable inclusion complex with eucalyptol, limonene, and fermented ginsenosides through van der Waals force and hydrophobic interaction. This inclusion complex can significantly reduce the volatility of eucalyptol and limonene, and improve the water solubility of fermented ginsenosides, allowing them to be uniformly dispersed in the outer phase matrix, avoiding uneven release due to hydrophobic aggregation.

[0020] In the oral environment, as saliva gradually penetrates, the HP-β-cyclodextrin outer hydroxyl group combines with water molecules, the inclusion complex structure gradually disintegrates, and the wrapped ingredients: eucalyptol and limonene contact the oral mucosa, can specifically activate the transient receptor potential cation channel M8 type, after the channel is activated, it triggers calcium ion influx, produces cold signal and transmits to the central nervous system, forming a cool feeling; at the same time, the natural citrus and eucalyptus aroma of the two can directly mask the volatile sulfur compounds and other odor components in the oral cavity, achieving instant freshness. Fermented ginsenosides are absorbed into the body through the mucosa, and their active ingredients can promote the synthesis and release of neurotransmitters such as dopamine and 5-hydroxytryptamine in the brain, enhance the central nervous system's tolerance to fatigue signals, and form a functional complement with sustained excitement of the internal phase of caffeine. Caffeine focuses on blocking inhibitory signals, while fermented ginsenosides focus on enhancing excitatory signal transmission, and the two work together to prolong the refreshing effect.

[0021] In a feasible implementation scenario, in S2, the viable cell count of the Lactobacillus rhamnosus freeze-dried bacterial powder is 1.0×109-1.0×1010 CFU / g, the mass-volume ratio of the Lactobacillus rhamnosus freeze-dried bacterial powder and the second deionized water is (1.8-2.2) kg:(45-55) L, and the parameters of the spray drying are as follows: the inlet air temperature is 75-85°C, the outlet air temperature is 42-48°C, and the atomization pressure is 0.2-0.4 MPa.

[0022] The probiotic inclusion complex realizes long-acting oral freshness through the viable cell protection-bacterial flora regulation mechanism, and the core is the protection and controlled release of Lactobacillus rhamnosus by the composite wall material. As the main wall material, the glucose units in the maltodextrin molecules can form a network structure through hydrogen bonds, wrap the bacterial powder and quickly solidify during spray drying to form a dense shell; the high-molecular-weight polysaccharide chains of gum arabic can cross-link with maltodextrin to enhance the mechanical strength of the wall material and resist the high-temperature impact during drying. Vitamin E as an antioxidant can scavenge free radicals generated during spray drying and storage, prevent the oxidation and destruction of bacterial cell membrane lipids, and greatly improve the survival rate of Lactobacillus rhamnosus freeze-dried bacterial powder.

[0023] After entering the oral cavity, the water in the saliva gradually dissolves the composite wall material, and the maltodextrin is dissolved first due to its good water solubility, releasing part of the viable cells, and the slow dissolution of gum arabic continuously releases the remaining bacteria. Lactobacillus rhamnosus, as an oral beneficial bacterium, can regulate the balance of bacterial flora in the following ways: first, it competes with Streptococcus mutans, Porphyromonas gingivalis and other acid-producing harmful bacteria for carbohydrate nutrients in the oral cavity, inhibiting their proliferation; second, it metabolizes and produces lactic acid and other acidic substances, reducing the local pH in the oral cavity to below 5.5, creating an environment that is not conducive to the survival of harmful bacteria; third, it secretes bacteriocins and other antibacterial substances to directly kill some harmful bacteria. This mechanism, which reduces the production of odors from the source, complements the immediate masking of odors by the lipid-soluble inclusion complex, and continuously produces a fresh effect, thereby solving the problem of repeated odor masking by traditional lozenges relying on fragrances.​

[0024] In a possible implementation, in the S3, the stirring speed is 13-17 r / min, and the stirring time is 16-24 min; the mass / volume ratio of the sodium alginate to the deionized water is (2.0-2.3) kg:(70-90) L; the shearing speed is 1800-2200 rpm, and the shearing time is 25-35 min; and the viscosity of the outer phase suspension is 2000-3000 mPa·s.

[0025] The hydroxypropyl methyl cellulose with a viscosity of 3500-4500 mPa·s in a 2% aqueous solution at 25°C is a high-molecular-weight cellulose ether, and the molecular chain slowly swells after being hydrated by the hydroxyl groups to form a gel matrix with viscoelasticity, which can provide sustained structural support for the outer phase to avoid rapid disintegration of the buccal tablet during the buccal process; the low-substituted hydroxypropyl cellulose (L-HPC) with a degree of substitution of 7%-12% contains a small amount of hydroxypropyl substituents in the molecule, has weak hydrophilicity but extremely strong water-swellable capacity, and the particles in the gel matrix can swell several times in volume by absorbing water and tear a large number of microporous channels in the matrix; by introducing polyethylene glycol as a water-soluble porogen, uniform dispersion can be achieved in the gel matrix, and after dissolution in saliva, additional pores are formed to cooperatively regulate the permeability of the gel network with the micropores of L-HPC, and by adjusting the ratio of the three, the release period of the outer phase composition can be adjusted to match the long-acting functional requirements.

[0026] The outer phase mixture is prepared by uniformly mixing the fat-soluble inclusion compound, the probiotic inclusion compound and other excipients to ensure consistent functional ingredient content in each buccal tablet. In terms of taste adjustment, citric acid stimulates the sour taste receptors of the taste buds in the mouth to neutralize the sweetness of anhydrous erythritol, forming a refreshing taste with a balance of sour and sweet. In terms of the structure of the buccal tablet, the crystal structure of anhydrous erythritol can increase the flowability of the outer phase mixture, ensuring uniform filling during tablet pressing; the physical adsorption of the micro-powder silica gel reduces the cohesive force between particles, further improving the flowability of the outer phase and avoiding differences in tablet weight during tablet pressing; vitamin E protects the active ingredients of the fat-soluble inclusion compound in the outer phase by antioxidant action to prevent oxidation and deterioration during storage.

[0027] In a possible implementation, in the S4, the spraying step is: spraying the outer phase suspension at a rate of 4-6 mL / min on the surface of the inner phase particles under the conditions of an inlet air temperature of 55-60°C and an atomization pressure of 0.08-0.12 MPa; the drying temperature is 55-60°C, and the drying time is 8-12 min.

[0028] The inner phase particles are kept in suspension and rolling in fluidized state, ensuring the outer phase suspension is sprayed on the surface of the inner phase particles at a uniform rate. This dynamic contact mode can avoid local accumulation or over-thick coating, and make the outer phase material form a functional layer with uniform thickness on the surface of each inner phase particle. After the spraying, the fluidized drying process removes the moisture in the outer phase suspension through continuous air circulation, and promotes the gel materials such as hypromellose and low-substitution hydroxypropyl cellulose in the outer phase functional layer to solidify and form a continuous support gel matrix and microporous channels in the matrix, which are coordinated with the pore-forming effect of polyethylene glycol to build a sustained-release structure for precisely controlling the release rate. The solidified outer phase functional layer is tightly combined with the inner phase particles, which neither hinders the rapid dispersion of the inner phase fast-release matrix upon contact with saliva, nor prevents the slow release of the liposoluble inclusion compounds and probiotic inclusion compounds through the gel network of the outer phase, thus forming a functional system with fast response of the inner core and sustained action of the outer layer.

[0029] The addition of anhydrous erythritol and magnesium stearate to the coated inner phase particles and mixing is a key step to ensure the quality and stability of the tablet. As a filler, the rigid particles of anhydrous erythritol can fill the gaps between the particles, reduce the risk of particle agglomeration caused by the viscosity of the outer phase functional layer, and significantly improve the flowability of the mixed particles. This ensures that the particles can be uniformly filled into the die hole during tabletting, avoiding differences in tablet weight caused by uneven distribution of materials, and ensuring the consistency of the content of active ingredients in each tablet. At the same time, anhydrous erythritol has good compressibility and can deform plastically when pressed, tightly combining with the particles and compensating for the elastic defects of the gel material in the outer phase, thus avoiding tablet cracking or loosening. As a lubricant, magnesium stearate forms a lubricating film on the surface of the particles by adsorption, reducing the frictional resistance between the mixed particles and the die and die hole of the tablet press, preventing sticking and reducing energy loss during tabletting, ensuring the integrity of the tablet and the smoothness of the surface, and providing a stable substrate for subsequent film coating.

[0030] In a feasible implementation scenario, in the S4, the mass-volume ratio of the hypromellose and ethanol solution is (9-11) kg:(52-78) L; the mass fraction of the ethanol solution is 80 wt.%; the spraying step is: spraying at a rate of 4.5-5.5 mL / min under the conditions of an inlet air temperature of 58-62 ℃ and an outlet air temperature of 33-37 ℃; the solidification and drying time is 15-25 min; and the mesh size of the sieving is 2-3 mesh.

[0031] The film coating realizes double protection and taste optimization of the lozenge by forming a continuous film on the surface of the tablet. The coating solution formed by dissolving hydroxypropyl methyl cellulose in ethanol solution quickly forms a film during the spraying process with the evaporation of the solvent. The low viscosity characteristics ensure that the film uniformly covers the surface of the tablet without pinholes or bare areas. The formed film has a dense network structure that can effectively isolate humidity and oxygen in the external environment. On the one hand, it prevents the caffeine and theanine in the inner phase from caking or degrading due to moisture absorption, ensuring the stability of the refreshing ingredients. On the other hand, it reduces the contact between the probiotic inclusion complex in the outer phase and oxygen, delays the oxidation and inactivation of the bacterial cells, and prolongs the shelf life of the product. At the same time, the film has a smooth texture that can cover the fine roughness on the surface of the tablet caused by particle compression, reducing the friction and irritation to the oral mucosa during sucking, and improving the comfort of taking. More importantly, the film can slowly dissolve in the oral saliva, neither hindering the gradual disintegration of the tablet during sucking, nor providing physical protection for the tablet during storage and transportation, ultimately forming a functional and stable lozenge product with excellent experience.

[0032] Compared with the prior art, the beneficial effects of the present application are as follows:

[0033] The present application synchronously realizes the effects of quick refreshing, long-lasting refreshing and freshening the oral cavity by preparing a lozenge for refreshing and refreshing the oral cavity. The inner phase particles serve as a quick response refreshing unit, and the low viscosity carboxymethyl cellulose sodium and cross-linked povidone are used to construct a fast release skeleton. The skeleton quickly disperses in saliva, and the fast release caffeine with small particle size and high solubility quickly penetrates the oral mucosa under the penetration of the permeation aid poloxamer 188, and quickly relieves fatigue by blocking the adenosine receptors of the central nervous system. At the same time, the sustained-release caffeine slowly dissolves by relying on the moderate resistance of the skeleton, realizing continuous supply, thereby avoiding the sudden rise and fall of the effect; in addition, theanine can promote the generation of alpha brain waves and regulate the balance of neurotransmitters, and cooperatively relieve the stimulation reaction caused by caffeine, ensuring a mild and stable refreshing process.

[0034] The inner phase granule coating layer serves as a long-acting maintenance and refreshing functional unit. A sustained-release skeleton is constructed by using hydroxypropyl methyl cellulose and low-substituted hydroxypropyl cellulose. The hydroxypropyl methyl cellulose in the skeleton swells moderately after being exposed to water to form a supporting gel matrix, and the low-substituted hydroxypropyl cellulose produces a large number of microporous channels in the matrix through strong water absorption and swelling, and the additive polyethylene glycol further adjusts the gel network permeability by dissolving the pores formed, thereby promoting the sustained release of fermented ginsenosides and enhancing the central nervous anti-fatigue ability, and the sustained-release caffeine in the inner phase granule prolongs the refreshing time effect in cooperation; and the released eucalyptol and limonene produce a cooling sensation by activating the transient receptor potential cation channel M8 type, and the natural aroma masks the oral odor to achieve instant odor removal; on this basis, lactobacillus rhamnosus can inhibit the reproduction of harmful bacteria after entering the oral cavity, thereby reducing the generation of odor from the source. The traditional lozenge has the problems of strong stimulation, short time effect, and repeated refreshing effect, and the comprehensive advantages of rapid refreshing, long-lasting refreshing, and oral cavity refreshing are achieved. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 The figure is a composition schematic diagram of the refreshing and refreshing oral cavity lozenge of the present application.

[0036] Figure 2 The figure is a caffeine cumulative dissolution curve diagram of the refreshing and refreshing oral cavity lozenge of the present application. DETAILED DESCRIPTION

[0037] In order to make the technical problems, technical solutions and beneficial effects of the present application more clear and explicit, the present application will be further described in detail below in conjunction with the embodiments. However, this should not be understood as limiting the scope of the present application to the following examples. Without departing from the method idea of the present application, all other embodiments obtained by those skilled in the art without making creative labor are within the scope of protection of the present application.

[0038] The singular forms "is", "or", "a", "any" and "the" used in the present application are intended to include the plural forms, unless the context clearly indicates otherwise. In addition, if the terms "first", "second" appear, they are only used for description purposes, and cannot be understood as indicating or implying relative importance.

[0039] Example 1

[0040] As Figure 1 shown, a preparation method of the refreshing and refreshing oral cavity lozenge, comprising the following steps:

[0041] S1, take 1.6 kg of caffeine, of which 0.48 kg of caffeine is air flow pulverized under the conditions of a pulverizing pressure of 0.8 MPa and a feeding rate of 12 kg / h, and pulverized to a particle size of ≤5 μm as a fast-release caffeine, and the remaining 1.12 kg of caffeine is kept as original particle size as a slow-release caffeine. 0.48 kg of the fast-release caffeine, 1.12 kg of the slow-release caffeine, 1.8 kg of theanine, 7.5 kg of sodium carboxymethylcellulose (2% aqueous solution viscosity at 25℃ is 20 mPa·s), 2 kg of crosslinked povidone, 0.5 kg of poloxamer 188, 0.3 kg of micro-silica gel, 0.5 kg of povidone K30, and 35 kg of anhydrous erythritol are mixed, 35 L of 30% ethanol solution is added, and spray drying granulation is performed under the conditions of an air inlet temperature of 120℃, an air outlet temperature of 60℃, and an atomization pressure of 0.4 MPa, followed by fluidized bed drying at 60℃ for 10 min at a wind speed of 1.7 m / s to obtain an inner phase granule;

[0042] S2, 2 kg of eucalyptol, 1 kg of limonene, and 6 kg of fermented ginsenosides are mixed, 16.2 kg of HP-β-cyclodextrin with a degree of substitution of 0.6 is added, dissolved in 80 L of deionized water, and stirred in a water bath at 50℃ and 500 r / min for 15 min, while 300 W of ultrasonic treatment is applied for 15 min, followed by high-pressure homogenization at 30 MPa for 10 min, and -40℃ freeze drying for 27 h, and then sieved through a 80-mesh sieve to obtain a fat-soluble ingredient inclusion compound; 2 kg of freeze-dried Lactobacillus rhamnosus (Sichuan Provincial Microbial Resource Platform Culture Collection Center, strain number: SICC1.1515), 5 kg of malt dextrin, 3 kg of gum arabic, and 0.3 kg of vitamin E are mixed, and spray drying granulation is performed under the conditions of an air inlet temperature of 80℃, an air outlet temperature of 45℃, and an atomization pressure of 0.2 MPa to obtain a probiotic inclusion compound;

[0043] S3, 14 kg of hydroxypropyl methylcellulose K4M, 3 kg of hydroxypropyl cellulose with a degree of substitution of 10%, 0.5 kg of polyethylene glycol 6000, 0.1 kg of citric acid, and 0.7 kg of micro-silica gel are put into a three-dimensional motion mixer, and mixed at a speed of 15 r / min for 10 min, followed by the addition of 25.2 kg of the fat-soluble inclusion compound and 10 kg of the probiotic inclusion compound, and continued mixing at 15 r / min for 10 min to obtain an outer phase mixture; 2.1 kg of sodium alginate (2% aqueous solution viscosity at 25℃ is 30 mPa·s) is dissolved in 10 L of deionized water to obtain a sodium alginate solution, and the outer phase mixture and 70 L of deionized water are added, and high-speed shearing is performed at a speed of 2000 rpm for 30 min to form an outer phase suspension with a viscosity of 2500 mPa·s;

[0044] S4, under the conditions of an inlet air temperature of 58℃ and an atomization pressure of 0.1 MPa, the outer phase suspension is sprayed onto the surface of the inner phase particles in a fluidized state at a constant rate of 5 mL / min, after the spraying is completed, the drying is continued for 10 min at a temperature of 58℃ in a fluidized state, to obtain coated inner phase particles; the coated inner phase particles are transferred into a V-type mixer, 5 kg of anhydrous erythritol and 0.8 kg of magnesium stearate are added, and mixing is performed at a rotating speed of 15 r / min for 10 min, to obtain mixed particles, and then a rotary tablet press is used to compress the mixed particles into a tablet core. 10 kg of hydroxypropyl methylcellulose E5 is dissolved in 65 L of an 80% ethanol solution by mass fraction, to obtain a coating liquid, and the tablet core is uniformly sprayed with the coating liquid on the surface thereof at a spraying speed of 5 mL / min under the conditions of an inlet air temperature of 60℃, an outlet air temperature of 36℃, and a rotating speed of 10 rpm, after the spraying is completed, the solidification and drying are continued for 20 min at the spraying temperature, and screening is performed through a 2.5-mesh screen, to obtain a refreshing oral cavity-containing tablet.

[0045] Example 2

[0046] As shown in Figure 1 , a preparation method of a refreshing oral cavity-containing tablet, comprising the following steps:

[0047] S1, 1.43 kg of caffeine is taken, wherein 0.43 kg of caffeine is airflow pulverized under the conditions of a pulverizing pressure of 0.7 MPa and a feeding rate of 10 kg / h, to a particle size of ≤5 μm, as a quick-release type caffeine, and the remaining 1.0 kg of caffeine is reserved for the original particle size, as a slow-release type caffeine. 0.43 kg of the quick-release type caffeine, 1.0 kg of the slow-release type caffeine, 1.6 kg of theanine, 6.8 kg of carboxymethyl cellulose sodium (a 2% aqueous solution has a viscosity of 5 mPa·s at 25℃), 1.8 kg of cross-linked povidone, 0.45 kg of poloxamer 188, 0.27 kg of micro-powder silica gel, 0.45 kg of povidone K30, and 33 kg of anhydrous erythritol are mixed, 33 L of a 30% ethanol solution by mass fraction is added, and spray drying granulation is performed under the conditions of an inlet air temperature of 115℃, an outlet air temperature of 55℃, and an atomization pressure of 0.3 MPa, and then the fluidized bed drying is performed at 60℃ and a wind speed of 1.5 m / s for 8 min, to obtain inner phase particles;

[0048] S2, 1.8 kg of eucalyptol, 0.9 kg of limonene and 5.4 kg of fermented ginsenosides were mixed, 14.6 kg of HP-β-cyclodextrin with a degree of substitution of 0.7 was added, dissolved in 72 L of deionized water, and stirred in a water bath at 48℃ and 450 r / min for 20 min, while 300 W ultrasonic treatment was applied for 15 min, then homogenized at 27 MPa for 8 min, freeze-dried at-40℃ for 24 h, and sieved through an 80-mesh sieve to obtain a fat-soluble ingredient inclusion compound; 1.8 kg of freeze-dried Lactobacillus rhamnosus (Sichuan Provincial Microbial Resource Platform Strain Preservation Center, strain number: SICC1.1515) powder, 4.5 kg of malt dextrin, 2.7 kg of acacia gum and 0.27 kg of vitamin E were mixed, and dissolved in 45 L of deionized water, and spray dried to granulate under the conditions of an inlet air temperature of 75℃, an outlet air temperature of 42℃, and an atomization pressure of 0.2 MPa to obtain a probiotic inclusion compound;

[0049] S3, 12.6 kg of hydroxypropyl methyl cellulose K4M, 2.7 kg of hydroxypropyl cellulose with a degree of substitution of 7%, 0.45 kg of polyethylene glycol 6000, 0.09 kg of citric acid and 0.63 kg of colloidal silica were put into a three-dimensional motion mixer, and mixed at a speed of 15 r / min for 10 min, then 22.7 kg of fat-soluble inclusion compound and 9 kg of probiotic inclusion compound were added, and mixed at 15 r / min for another 10 min to obtain an external phase mixture; 2.0 kg of sodium alginate (2% aqueous solution with a viscosity of 80 mPa·s at 25℃) was dissolved in 10 L of deionized water to obtain a sodium alginate solution, and the external phase mixture and 70 L of deionized water were added and high-speed sheared at a speed of 2000 rpm for 30 min to form an external phase suspension with a viscosity of 2000 mPa·s;

[0050] S4, the external phase suspension was sprayed onto the surface of the internal phase particles in a fluidized state at a constant rate of 4 mL / min under the conditions of an inlet air temperature of 55℃ and an atomization pressure of 0.08 MPa, and after the spraying was completed, the coated internal phase particles were dried in a fluidized state at a temperature of 55℃ for 8 min to obtain coated internal phase particles; the coated internal phase particles were transferred to a V-type mixer, 4.5 kg of anhydrous erythritol and 0.7 kg of magnesium stearate were added, and mixed at a speed of 15 r / min for 10 min to obtain mixed particles, and then the mixed particles were compressed into tablets using a rotary tablet press. 9 kg of hydroxypropyl methyl cellulose E5 was dissolved in 52 L of 80% ethanol solution to obtain a coating liquid, and the tablets were uniformly sprayed with the coating liquid at a spraying speed of 4.5 mL / min on the surface of the tablets under the conditions of an inlet air temperature of 58℃, an outlet air temperature of 33℃, a rotation speed of 8 rpm, and after the spraying was completed, the tablets were further solidified and dried at the spraying temperature for 15 min, and sieved through a 2-mesh sieve to obtain refreshing oral cavity containing tablets.

[0051] Example 3

[0052] As Figure 1 shown, a preparation method of a lozenge for refreshing the oral cavity, comprising the following steps:

[0053] S1, take 1.77 kg of caffeine, wherein 0.53 kg of caffeine is airflow pulverized under the conditions of a pulverizing pressure of 0.9 MPa and a feeding rate of 15 kg / h, and the particle size is ≤5 μm, as a fast-release caffeine, and the remaining 1.24 kg of caffeine is kept as the original particle size, as a slow-release caffeine. Mix 0.53 kg of the fast-release caffeine, 1.24 kg of the slow-release caffeine, 2.0 kg of theanine, 8.2 kg of carboxymethyl cellulose sodium (2% aqueous solution viscosity at 25°C is 10 mPa·s), 2.2 kg of cross-linked povidone, 0.55 kg of poloxamer 188, 0.33 kg of micro-silica gel, 0.55 kg of povidone K30, and 37 kg of anhydrous erythritol, add 38 L of a 30% ethanol solution, and perform spray drying granulation under the conditions of an air inlet temperature of 125°C, an air outlet temperature of 65°C, and an atomization pressure of 0.5 MPa, and then perform fluidized bed drying at 60°C and a wind speed of 2.0 m / s for 12 min to obtain an inner phase granule;

[0054] S2, mix 2.2 kg of eucalyptol, 1.1 kg of limonene, and 6.6 kg of fermented ginsenosides, add 17.8 kg of HP-β-cyclodextrin with a degree of substitution of 0.8, dissolve in 88 L of deionized water, perform water bath stirring at 52°C and 550 r / min for 30 min, apply 300 W ultrasonic treatment for 15 min at the same time, then perform high-pressure homogenization at 33 MPa for 12 min, freeze dry at -40°C for 30 h, and pass through an 80-mesh sieve to obtain a fat-soluble ingredient inclusion compound; mix 2.2 kg of freeze-dried Lactobacillus rhamnosus (Sichuan Provincial Microbial Resource Platform Strain Preservation Center, strain number: SICC1.1515) bacterial powder, 5.5 kg of malt dextrin, 3.3 kg of gum arabic, and 0.33 kg of vitamin E, dissolve in 55 L of deionized water, and perform spray drying granulation under the conditions of an air inlet temperature of 85°C, an air outlet temperature of 48°C, and an atomization pressure of 0.4 MPa to obtain a probiotic inclusion compound;

[0055] S3, 15.4 kg of hypromellose K4M, 3.3 kg of hydroxypropyl cellulose with a degree of substitution of 12%, 0.55 kg of polyethylene glycol 6000, 0.11 kg of citric acid and 0.77 kg of fumed silica were put into a three-dimensional motion mixer, and mixed at a speed of 15 r / min for 10 min, then 27.7 kg of fat-soluble inclusion compound and 11 kg of probiotic inclusion compound were added, and the mixing was continued at 15 r / min for 10 min to obtain an external phase mixture; 2.0-2.3 kg of sodium alginate (2% aqueous solution at 25℃, viscosity 50 mPa·s) was dissolved in 10 L of deionized water to obtain a sodium alginate solution, and the external phase mixture and 70 L of deionized water were added, and high-speed shearing was carried out at a speed of 2200 rpm for 35 min to form an external phase suspension with a viscosity of 3000 mPa·s;

[0056] S4, the external phase suspension was sprayed onto the surface of the internal phase particles in a fluidized state at a constant speed of 6 mL / min under the conditions of an inlet air temperature of 60℃ and an atomization pressure of 0.12 MPa, and after the spraying was completed, the drying was continued for 12 min at a temperature of 60℃ in a fluidized state to obtain coated internal phase particles; the coated internal phase particles were transferred to a V-type mixer, 5.5 kg of anhydrous erythritol and 0.9 kg of magnesium stearate were added, and mixed at a speed of 15 r / min for 10 min to obtain mixed particles, and then the mixed particles were compressed into tablets using a rotary tablet press. 11 kg of hypromellose E5 was dissolved in 78 L of an 80% ethanol solution to obtain a coating liquid, and the coating liquid was uniformly sprayed onto the surface of the tablets at a spraying speed of 5.5 mL / min under the conditions of an inlet air temperature of 62℃, an outlet air temperature of 37℃, a rotation speed of 12 rpm, and after the spraying was completed, the solidification and drying were continued for 25 min at the spraying temperature, and the tablets were screened through a 3-mesh sieve to obtain refreshing oral cavity containing tablets.

[0057] Comparative Example 1

[0058] A method for preparing refreshing oral cavity containing tablets, the implementation steps and parameters are different from those of Example 1, and there is no immediate-release caffeine, and all the caffeine is in the original particle size without micronization, and the remaining steps and parameters are the same.

[0059] Comparative Example 2

[0060] A method for preparing refreshing oral cavity containing tablets, the implementation steps and parameters are different from those of Example 1, and the external phase does not add low-substituted hydroxypropyl cellulose, but only uses hypromellose K4M, and the remaining steps and parameters are the same.

[0061] Comparative Example 3

[0062] A preparation method of a lozenge for refreshing the mind and clearing the oral cavity, wherein the implementation steps and parameters are different from those of Example 1 in that the fat-soluble inclusion compound is not added with HP-β-cyclodextrin for inclusion, i.e., eucalyptol, limonene and fermented ginsenosides are directly added, and the remaining steps and parameters are the same.

[0063] Comparative Example 4

[0064] A preparation method of a lozenge for refreshing the mind and clearing the oral cavity, wherein the implementation steps and parameters are different from those of Example 1 in that the inner phase does not add cross-linked povidone, but only uses low-viscosity sodium carboxymethyl cellulose, and the remaining steps and parameters are the same.

[0065] Performance test:

[0066] In-vitro dissolution test: take the lozenges for refreshing the mind and clearing the oral cavity prepared in Examples 1-3 and Comparative Examples 1-4, respectively, and directly place them in the dissolution cup of the dissolution instrument. Through simulated saliva, 6.80 g of potassium dihydrogen phosphate and 1.79 g of sodium phosphate dibasic are dissolved in 1000 mL of purified water, filtered through a 0.22 μm filter to remove impurities, and then ultrasonic degassing is performed to remove dissolved air to prepare a pH 6.8 phosphate buffer medium. The temperature is maintained at 37℃, and the rotation speed is 50 r / min. Sampling is performed at the following time points: 0.5 min, 1 min, 2 min, 5 min, 10 min, 15 min, 20 min, 25 min, and 30 min for caffeine detection. At each time point, 5 mL of sample is taken from 1 / 2 below the liquid surface, and an equal amount of fresh buffer medium is added simultaneously. After filtration through a 0.45 μm filter, HPLC detection is performed, and the cumulative dissolution rate is calculated using the formula: cumulative dissolution rate (%) = (cumulative dissolution amount of caffeine in the lozenge / initial total amount of caffeine in the lozenge) x 100%. The test data are shown in Table 1. Figure 2

[0067] In-vitro refreshing ingredient release test: take the lozenges for refreshing the mind and clearing the oral cavity prepared in Examples 1-3 and Comparative Examples 1-4, and add 500 mL of pH 6.8 phosphate buffer prepared in the dissolution test. Place in a 37℃ constant temperature water bath with a magnetic stirring speed of 50 r / min to simulate saliva flow. Sampling is performed at 0.5 min, 1 min, 2 min, 5 min, 10 min, 15 min, 20 min, 25 min, and 30 min, with 5 mL of sample taken at each time point. An equal amount of medium is added simultaneously, filtered through a 0.45 μm filter, extracted with diethyl ether, and detected by GC-MS. The cumulative release rate of eucalyptol and limonene is calculated by the characteristic peak area using the formula: cumulative release rate (%) = (cumulative release amount of eucalyptol and limonene in the lozenge / initial total amount of eucalyptol and limonene in the lozenge) x 100%.

[0068] ​Stability test: the refreshing and refreshing oral cavity lozenges prepared in examples 1-3 and comparative examples 1-4 were divided into initial group and accelerated group: the initial group was detected immediately; the accelerated group was packaged with aluminum plastic blister to simulate the commercial packaging, and was placed in an accelerated test box with a set temperature of 40℃ and a relative humidity of 75%, and was placed for 3 months, during which the appearance, deliquescence, discoloration and cracking were observed every week. After 3 months, the accelerated group and the initial group were detected synchronously to determine the retention rate of the key ingredients:

[0069] Caffeine retention rate: 3 lozenges were taken from the initial group and the accelerated group respectively, ground into powder, weighed 0.5g, added with 50mL methanol for ultrasonic extraction for 30min, filtered, and the filtrate was detected by HPLC to calculate the content and the retention rate = (average content of the accelerated group / average content of the initial group) x 100%; Lactobacillus rhamnosus live bacteria retention rate: 3 lozenges were taken from the initial group and the accelerated group respectively, ground and weighed 1g, added with 9mL sterile normal saline, gradient diluted to times, 100μL of the diluted solution was spread on MRS agar medium, and was cultured at 37℃ in anaerobic condition for 48h, and the number of colonies was counted, and the live bacteria retention rate = (average number of live bacteria of the accelerated group / average number of live bacteria of the initial group) x 100%; Eucalyptol retention rate: 3 lozenges were taken from the initial group and the accelerated group respectively, and the treatment method was the same as that of caffeine, and GC detection was used to calculate the content and the retention rate.

[0070] Table 1 Performance test results of the refreshing and refreshing oral cavity lozenges prepared in examples 1-3 and comparative examples 1-4

[0071]

[0072] From table 1 and Figure 2 It can be seen that the cumulative dissolution rate of caffeine and the cumulative release rate of eucalyptol and limonene of the lozenges of examples 1-3 are higher than those of comparative examples 1-4, and the stability of the lozenges within three months is higher than that of comparative examples 1-4, which indicates that the rapid onset ability, long-acting controlled release effect and ingredient stability of the lozenges prepared in examples 1-3 are better than those of comparative examples 1-4.

[0073] The comparative example 1 does not perform micronization on part of the caffeine, only retains the original particle size of caffeine, resulting in the lack of immediate-release performance of caffeine. Micronization can increase the specific surface area, rapidly dissolve after contacting saliva, and cooperate with the rapid disintegration of the inner phase skeleton structure to achieve early rapid release, providing the basis for instant refreshment. The lack of immediate-release caffeine design means that even if the inner phase skeleton disintegrates normally, the dissolution rate of large particle size caffeine is much lower than that of small particle size, resulting in insufficient early release efficiency and inability to achieve the effect of rapid refreshment. However, the inclusion design of the outer phase controlled-release structure and the refreshing ingredient is not affected, so the long-term release and the basic release of the refreshing ingredient change little, which further shows that the micronization of the immediate-release caffeine is the key to ensuring the early refreshment effect, and its function is specific and does not interfere with the action of other systems.

[0074] The comparative example 2 does not add L-HPC in the outer phase, which destroys the balance of the gel skeleton and the pore-forming agent in the controlled release. L-HPC, as a high-swelling ingredient, can construct microporous channels in the gel skeleton formed by hydroxypropyl methyl cellulose, providing a sustained release path for the caffeine sustained-release part and the refreshing ingredient, and adjusting the internal humidity of the skeleton to create stable survival conditions for probiotics. After the lack of L-HPC, the outer phase gel skeleton is dense due to the lack of channels, which not only hinders the release of subsequent ingredients, resulting in the interruption of long-term effect, but also destroys the anaerobic dry environment of probiotics due to the high internal humidity, reducing the stability of live bacteria. This result confirms the dual role of L-HPC in the outer phase controlled release and probiotic protection, and its synergy with the gel skeleton is the core of ensuring the multifunctionality of the outer phase.

[0075] The comparative example 3 does not make the liposoluble ingredients such as eucalyptol and limonene into inclusion compounds, directly adding them to the outer phase, which breaks the balance and stability of release. The hydrophobic cavity of the inclusion compound wraps the liposoluble ingredients, on the one hand, slowing down the dissolution rate after contacting saliva, avoiding the excessive cooling sensation caused by the large release in the early stage, and ensuring the sustained release in the later stage to maintain the long-term refreshing; on the other hand, it isolates oxygen and humidity, prevents the oxidation and volatilization of the ingredients during storage, and ensures stability. After the lack of inclusion treatment, the liposoluble ingredients are not protected by the structure, and are released rapidly after contacting saliva, resulting in excessive early effect and later interruption, and are easily oxidized during storage, with a significant decrease in stability. This shows that the inclusion process is the key to balancing the release rhythm and stability of liposoluble ingredients, directly affecting the sustainability and reliability of the refreshing effect.

[0076] The comparative example 4 does not add PVPP in the internal phase, resulting in weakening of the disintegration ability in the internal phase. PVPP as a high-efficiency disintegrant can quickly swell by absorbing water after contacting saliva, generating strong disintegration force, rapidly destroying the internal phase skeleton structure, dispersing and dissolving the micronized immediate-release caffeine in time, and providing a structural basis for early rapid release. After the absence of PVPP, the disintegration ability of the low-viscosity binder alone cannot quickly disperse the internal phase particles, resulting in the micronized immediate-release caffeine being wrapped by the skeleton, being difficult to contact saliva, and the early release efficiency decreasing, and the rapid refreshing effect being delayed. The controlled-release structure of the external phase and the inclusion design of the refreshing ingredients are not affected, which further shows that PVPP is the core of ensuring the rapid disintegration of the internal phase and the release of the immediate-release ingredient, and directly determines the realization efficiency of the early refreshing effect.

[0077] The comparative examples 1-4 lack the micronized immediate-release caffeine, L-HPC, PVPP, and the inclusion process of the fat-soluble ingredients, resulting in the early dissolution efficiency of caffeine decreasing, the long-acting release stagnating, the internal phase skeleton disintegration rate slowing down, and the ingredient stability decreasing, which collectively shows that there are obvious short boards in the rapid onset ability, long-acting controlled-release effect, ingredient stability, and structural disintegration efficiency.

[0078] The above results show and describe the basic principles and main features of the present application and the advantages of the present application.

[0079] The embodiments of the present application are described above in combination with the drawings, but the present application is not limited to the above-mentioned specific embodiments, and the above-mentioned specific embodiments are only illustrative and not limiting. Those skilled in the art can make many forms under the inspiration of the present application without departing from the purpose of the present application and the scope protected by the claims, and these all belong to the protection of the present application.

Claims

1. A lozenge for refreshing the mind and clearing the mouth, characterized in that, The lozenge comprises a plain tablet and a shell; the plain tablet comprises inner phase particles, an inner phase particle coating layer, and excipients; the shell comprises a film-forming agent; the inner phase particles comprise immediate-release caffeine, sustained-release caffeine, theanine, and excipients; the inner phase particle coating layer comprises a fat-soluble inclusion complex, a probiotic inclusion complex, and additives; the excipients comprise anhydrous erythritol and magnesium stearate; the excipients comprise sodium carboxymethyl cellulose, crospovidone, poloxamer 188, micronized silica gel, povidone, and anhydrous erythritol; the fat-soluble inclusion complex comprises eucalyptol, limonene, fermented ginsenosides, and HP-β-cyclodextrin; the probiotic inclusion complex comprises *Lactobacillus rhamnosus* freeze-dried bacterial powder, maltodextrin, gum arabic, and vitamin E; the additives comprise hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, citric acid, micronized silica gel, and sodium alginate.

2. The lozenge for refreshing the mind and clearing the mouth according to claim 1, characterized in that, The mass ratio of the uncoated tablet to the outer shell is (101.45-118.26):(9-11); the mass ratio of the inner phase particles, the inner phase particle coating layer, and the excipients in the uncoated tablet is (45.8-52.6):(50.45-59.26):(5.2-6.4); the mass ratio of immediate-release caffeine, sustained-release caffeine, theanine, and excipients in the inner phase particles is (0.43-0.53):(1.0-1.24):(1.6-2.0):(42.77-48.83). The mass ratio of the lipid-soluble inclusion complex, probiotic inclusion complex, and additives in the inner phase particle coating layer is (22.7-27.7):(9-11):(18.54-20.46). The mass ratio of sodium carboxymethyl cellulose, crospovidone, poloxamer 188, micronized silica gel, povidone, and anhydrous erythritol in the excipients is (6.8-8.2):(1.8-2.2):(0.45-0.55):(0.27-0.33):(0.45-0.55):(33-37). The mass ratio of eucalyptol, limonene, fermented ginsenosides, and HP-β-cyclodextrin in the inclusion complex is (1.8-2.2):(0.9-1.1):(5.4-6.6):(14.6-17.8); the mass ratio of *Lactobacillus rhamnosus* freeze-dried bacterial powder, maltodextrin, gum arabic, and vitamin E in the probiotic inclusion complex is (1.8-2.2):(4.5-5.5):(2.7-3.3):(0.27-0.33); the additives include hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyethylene glycol. The mass ratio of glycol, citric acid, micronized silica gel, and sodium alginate is (12.6-15.4):(2.7-3.3):(0.45-0.55):(0.09-0.11):(0.63-0.77):(2.0-2.3); the mass ratio of anhydrous erythritol and magnesium stearate in the additives is (4.5-5.5):(0.7-0.9); the film-forming agent is hydroxypropyl methylcellulose, and the viscosity of a 2% aqueous solution of hydroxypropyl methylcellulose at 25°C is 3.6-5.4 mPa·s.

3. The lozenge for refreshing the mind and clearing the mouth according to claim 2, characterized in that, The viscosity of a 2% aqueous solution of sodium carboxymethyl cellulose in the excipients is 5-20 mPa·s at 25°C; the K value of povidone in the excipients is 27-32; the average degree of substitution of HP-β-cyclodextrin in the fat-soluble inclusion complex is 0.6-0.8; the viscosity of a 2% aqueous solution of hydroxypropyl methylcellulose in the additives is 3500-4500 mPa·s at 25°C; the degree of substitution of hydroxypropyl cellulose in the additives is 7%-12%; the molecular weight of polyethylene glycol in the additives is 5000-7000; and the viscosity of a 2% aqueous solution of sodium alginate in the additives is 30-80 mPa·s at 25°C.

4. A method for preparing a lozenge for refreshing the mind and clearing the mouth as described in any one of claims 1-3, characterized in that, Includes the following steps: S1. Sodium carboxymethyl cellulose, crospovidone, immediate-release caffeine, sustained-release caffeine, theanine, poloxamer 188, micronized silica gel, povidone, anhydrous erythritol and ethanol solution are mixed, spray-dried and dried to obtain internal phase particles. S2. Eucalyptol, limonene, fermented ginsenosides, HP-β-cyclodextrin and first deionized water are mixed, stirred, homogenized under high pressure, freeze-dried, and sieved to obtain a fat-soluble inclusion complex; Lactobacillus rhamnosus freeze-dried powder, maltodextrin, gum arabic, vitamin E and second deionized water are mixed and spray-dried to obtain a probiotic inclusion complex. S3. Hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, citric acid, and micronized silica gel are mixed, and a fat-soluble inclusion complex and a probiotic inclusion complex are added while stirring to obtain an external phase mixture; the external phase mixture, sodium alginate, and deionized water are mixed and sheared to obtain an external phase suspension; S4. Spray the external phase suspension onto the surface of the internal phase particles and dry to obtain coated internal phase particles; mix the coated internal phase particles, anhydrous erythritol and magnesium stearate, compress into tablets to obtain uncoated tablets; mix hydroxypropyl methylcellulose and ethanol solution to obtain coating solution; spray the coating solution onto the surface of the uncoated tablets, cure and dry at the spraying temperature, and sieve to obtain a lozenge for refreshing the mind and clearing the mouth.

5. The method for preparing a lozenge for refreshing the mind and clearing the mouth according to claim 4, characterized in that, In step S1, the immediate-release caffeine is produced by air-jet milling of caffeine under a milling pressure of 0.7-0.9 MPa and a feed rate of 10-15 kg / h, with a particle size ≤ 5 μm; the sustained-release caffeine has a particle size of 80-120 μm; the mass-to-volume ratio of the immediate-release caffeine to the ethanol solution is (0.43-0.53) kg:(32-38) L, and the mass fraction of the ethanol solution is 30 wt.%; the spray drying parameters are: inlet air temperature 115-125℃, outlet air temperature 55-65℃, and atomization pressure 0.3-0.5 MPa; the drying step is: drying at a temperature of 60℃ and a wind speed of 1.5-2.0 m / s for 8-12 min; the particle size of the internal phase particles is 120-150 μm.

6. The method for preparing a lozenge for refreshing the mind and clearing the mouth according to claim 4, characterized in that, In step S2, the mass-to-volume ratio of eucalyptol to the first deionized water is (1.8-2.2) kg: (72-88) L; the stirring temperature is 48-52℃, the stirring speed is 450-550 r / min, and the stirring time is 20-30 min; the high-pressure homogenization pressure is 27-33 MPa, and the high-pressure homogenization time is 8-12 min; the freeze-drying temperature is -40℃, and the freeze-drying time is 24-30 h; the sieve mesh size is 80 mesh.

7. The method for preparing a lozenge for refreshing the mind and clearing the mouth according to claim 4, characterized in that, In step S2, the viable count of the Lactobacillus rhamnosus freeze-dried powder is ≥1×10⁻⁶. 10 CFU / g; the mass-to-volume ratio of the Lactobacillus rhamnosus freeze-dried bacterial powder to the second deionized water is (1.8-2.2) kg: (45-55) L; the parameters of the spray drying are: inlet air temperature 75-85℃, outlet air temperature 42-48℃, and atomization pressure 0.2-0.4 MPa.

8. The method for preparing a lozenge for refreshing the mind and clearing the mouth according to claim 4, characterized in that, In step S3, the stirring speed is 13-17 r / min, and the stirring time is 16-24 min; the mass-to-volume ratio of sodium alginate to deionized water is (2.0-2.3) kg:(70-90) L; the shearing speed is 1800-2200 rpm, and the shearing time is 25-35 min; the viscosity of the external phase suspension is 2000-3000 mPa·s.

9. The method for preparing a lozenge for refreshing the mind and clearing the mouth according to claim 4, characterized in that, In step S4, the spraying step is as follows: under the conditions of an air inlet temperature of 55-60℃ and an atomization pressure of 0.08-0.12MPa, the external phase suspension is sprayed onto the surface of the internal phase particles at a rate of 4-6mL / min; the drying temperature is 55-60℃ and the drying time is 8-12min.

10. The method for preparing a lozenge for refreshing the mind and clearing the mouth according to claim 4, characterized in that, In step S4, the mass-to-volume ratio of hydroxypropyl methylcellulose to ethanol solution is (9-11) kg: (52-78) L; the mass fraction of ethanol solution is 80 wt.%; the spraying step is as follows: spraying at a rate of 4.5-5.5 mL / min under the conditions of inlet air temperature of 58-62℃, outlet air temperature of 33-37℃, and rotation speed of 8-12 rpm; the curing and drying time is 15-25 min; and the sieve mesh size is 2-3 mesh.

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