Cydiodine buccal tablet and preparation method thereof

Abstract

The invention relates to a cydiodine lozenge which comprises the following components: iodine, potassium iodide, menthol, beta-cyclodextrin, cane sugar, hydroxypropyl methylcellulose, magnesium stearate, hydrogenated lecithin and cholesterol. The invention further relates to a preparation method of the cydiodine lozenge. The preparation method comprises the steps of iodine-containing liposome inclusion, menthol inclusion, granulation, total mixing and tabletting. According to the invention, potassium iodide and iodine are mixed to form triiodide ions which are more stable than I2, better in water solubility and lower in volatility; beta-cyclodextrin can embed I2 and physically isolate iodine molecules to inhibit volatilization; hydrogenated lecithin and cholesterol cooperate to form a hydrogenated lecithin bimolecular layer to wrap iodine molecules, so that the volatility is effectively reduced, and the stability is improved.

Description

Technical Field

[0001] This application relates to the field of sildenafil products technology, and in particular to a sildenafil lozenge and its preparation method. Background Technology

[0002] Sildenafil is a broad-spectrum antibacterial disinfectant containing iodine, commonly used for local anti-infection treatment of mucous membranes such as the mouth and throat, and has bactericidal and anti-inflammatory effects; its main component is molecular iodine, which directly destroys the protein structure of pathogenic microorganisms by releasing free iodine, and is often used for chronic pharyngitis, oral ulcers, chronic gingivitis and periodontitis.

[0003] Iodine (I2) is highly volatile at room temperature, and it is especially prone to escaping from tablets under high temperature or open conditions, leading to a decrease in the content of active ingredients. Therefore, there is still room for improvement. Summary of the Invention

[0004] In order to reduce the escape of molecular iodine from sildenafil lozenges and solve the problem of decreased content of active ingredients, this application provides a sildenafil lozenge.

[0005] Firstly, the technical solution adopted in this application for a sildenafil lozenge is as follows: A sildenafil lozenge comprises the following components in parts by weight: 8-10 parts iodine; 16-20 parts potassium iodide; 18-20 servings of menthol; 8-10 parts β-cyclodextrin; 400-420 parts sucrose; 1-2 parts hydroxypropyl methylcellulose; 3-5 parts magnesium stearate; 8-10 parts hydrogenated lecithin; 2-3 servings of cholesterol.

[0006] By adopting the above technical solutions, potassium iodide and iodine can be mixed to form triiodide ions, which are more stable, more water-soluble, and less volatile than I2; β-cyclodextrin can encapsulate I2, physically isolating iodine molecules to inhibit volatilization; hydrogenated lecithin and cholesterol work together to form a hydrogenated lecithin bilayer that encapsulates iodine molecules, effectively reducing volatility and improving stability.

[0007] Preferably, by weight, it further comprises 6-8 parts of methoxy polyethylene glycol-N-hydroxysuccinimide and 0.2-0.3 parts of triethylamine.

[0008] By adopting the above technical solution, the reaction of triethylamine-catalyzed methoxy polyethylene glycol-N-hydroxysuccinimide and hydrogenated lecithin is used to modify hydrogenated lecithin. A protective layer is formed on the surface of hydrogenated lecithin, which significantly reduces iodine volatilization, can also release iodine slowly, prolong the local action time, and reduce mucosal irritation.

[0009] Preferably, by weight, it further comprises 4-7 parts polyvinyl alcohol, 1-4 parts borax and 0.8-1.2 parts 4-iodophenylboronic acid.

[0010] By employing the above technical solution, a borate ester crosslinked hydrogel is prepared by blending 4-iodophenylboronic acid, polyvinyl alcohol, and borax. Polyvinyl alcohol provides a cis-diol structure and introduces arylboronic acid functional groups to participate in dynamic borate ester crosslinking. Iodine groups and iodine molecules have weak interactions between the same halogens, while iodine substituents on the aromatic ring can enhance hydrophobic microdomains and promote I2 enrichment and retention. Borax hydrolysis yields tetrahydroxyborate, providing an alkaline environment and forming additional borate ester crosslinking points with polyvinyl alcohol, enhancing gel strength and stability. The three-dimensional network of the hydrogel physically encapsulates I2 molecules in the pores, and I2 diffusion from the interior to the surface requires passing through the polymer chain and the aqueous phase, extending the release path and achieving effective volatilization suppression.

[0011] Preferably, the polyvinyl alcohol: borax: 4-iodophenylboronic acid ratio is 5:3:1 by weight.

[0012] Secondly, this application provides a method for preparing sildenafil lozenges, which adopts the following technical solution: A method for preparing a sildenafil lozenge includes the following steps: S1. Encapsulation of iodine-containing liposomes; 1) Dissolve hydrogenated lecithin in an anhydrous chloroform / methanol solution with a molar ratio of 2:1, then add cholesterol, and sonicate at 100-200W in a container. Use a rotary evaporator at 40-45℃ under reduced pressure for 30-60 minutes until a uniform, transparent lipid film adheres to the bottle wall. Vacuum dry overnight in a vacuum desiccator to completely remove residual solvent and form a lipid film. An iodine solution prepared by sequentially adding potassium iodide and iodine to deionized water and stirring to dissolve the solution was added to a container in which a lipid film was formed. The solution was then preheated to 50-60°C and stirred in a water bath at 50-60°C for 1-2 hours. Finally, the solution was sonicated at 100-200W for 5-10 minutes in an ice-water bath to obtain iodine-containing liposomes with a particle size of 80-200 nm and uniform distribution. 2) Add 4-5 parts by weight of β-cyclodextrin to the iodine-containing liposomes, keep warm and stir at 80-85℃ until completely dissolved, pass through a 60-mesh sieve, let stand, and collect the solid material; 3) Use a vibrating pellet mill to wet-granulate the solid material through a 20-mesh sieve; 4) Add the granulated particles to a fluidized bed dryer for drying, controlling the inlet air temperature at 65-80℃, and ensuring the particle moisture content does not exceed 4%; 5) The dried granules are granulated by passing them through a 60-mesh sieve using a gyratory pelletizer; S2. Menthol capsules; 1) Add deionized water to the mixing tank, heat to 80-85℃, add the remaining weight of β-cyclodextrin and stir to dissolve, then add menthol and stir to dissolve, pass through a 60-mesh sieve, let stand, and collect the solid material; 2) Use a vibrating pellet mill to wet-granulate the solid material through a 20-mesh sieve; 3) Add the granulated particles to a fluidized bed dryer for drying, with the inlet air temperature controlled at 80-90℃ and the particle moisture content not exceeding 4%; 4) The dried granules are granulated by passing them through a 60-mesh sieve using a vibrating pellet mill; S3. Granulation; 1) Add 1 / 2 sucrose, menthol inclusion granules, iodine-containing liposome inclusion granules and the remaining 1 / 2 sucrose to the wet granulator in sequence, mix for 5 minutes, with the stirring blade speed at 80±20 rpm and the cutting blade speed at 800±200 rpm. 2) Add a 1% binder solution prepared by stirring and dissolving hydroxypropyl methylcellulose in deionized water into the wet granulator; atomization pressure 0.1-0.3 MPa, liquid addition time 10±2 minutes, stirring speed 80±20 rpm, and cutting speed 800±200 rpm. 3) Wet granulation of the material using a vibrating pellet mill through a 20-mesh sieve; 4) Place the granulated wet granules in a fluidized bed for drying, set the inlet air temperature to 70±5℃, and control the granule moisture content to not exceed 3%; 5) Add the dried granules to a vibrating pellet mill and granulate them through a 20-mesh sieve to obtain dry granules; S4. Total Mixing; Add half of the dry granules, magnesium stearate, and the remaining half of the dry granules into the mixer in sequence and mix at 15 rpm for 5 minutes. S5. Tableting; Tableting is performed using a high-speed rotary tablet press with a Φ 10.0mm R13.5 shallow concave die. The theoretical tablet weight is 450mg, with a tablet weight variation of ±5%. The hardness is 7±2kg, and the tableting speed is 60-150KT / h.

[0013] Preferably, step S1 further includes the following steps: Hydrogenated lecithin was dissolved in an anhydrous chloroform / methanol solution with a molar ratio of 2:1; methoxy polyethylene glycol-N-hydroxysuccinimide was added, and triethylamine was added dropwise. The mixture was stirred at room temperature for 7-8 hours under nitrogen protection, the solvent was removed by rotary evaporation, the precipitate was precipitated with cold diethyl ether, and the precipitate was dried under vacuum and passed through a 60-mesh sieve to obtain modified hydrogenated lecithin. Dissolve modified hydrogenated lecithin and cholesterol in 8-10 parts of anhydrous ethanol, and sonicate them in a container at 100-200W. Then, use a rotary evaporator at 40-45℃ under reduced pressure for 30-60 minutes until a uniform and transparent lipid film is formed and adheres to the bottle wall. Vacuum dry overnight to completely remove residual solvent and form a lipid film.

[0014] Preferably, step S3 further includes the following steps: mixing polyvinyl alcohol with deionized water, stirring in a 90°C water bath for 2-3 hours, and cooling to room temperature to obtain a 5% polyvinyl alcohol aqueous solution; Dissolve 4-iodophenylboronic acid in 1 part by weight of 0.1M NaOH aqueous solution, and sonicate at 40℃ for 5-10 minutes until clear to obtain 4-iodophenylboronic acid solution; Borax was dissolved in deionized water to obtain a 100 mM borax solution; Mix 4-7 parts of 5% polyvinyl alcohol aqueous solution and 2-4 parts of borax solution, control pH=9, add 1-3 parts of 4-iodophenylboronic acid solution, shake manually for 10-15s, let stand for 40-100s, and a transparent hydrogel will be formed. Add 1 / 2 sucrose, menthol inclusion granules, iodine-containing liposome inclusion granules, the remaining 1 / 2 sucrose, and transparent hydrogel to the wet granulator in sequence, mix for 5 minutes, with the agitator speed at 80±20 rpm and the cutter speed at 800±200 rpm.

[0015] Preferably, the iodine is pulverized through a 20-mesh sieve, the sucrose is pulverized through a 120-mesh sieve, and the magnesium stearate is pulverized through an 80-mesh sieve.

[0016] In summary, this application includes the following beneficial technical effects: 1. Potassium iodide and iodine can be mixed to form triiodide ions, which are more stable, more water-soluble, and less volatile than I2; β-cyclodextrin can encapsulate I2, physically isolating iodine molecules to inhibit volatilization; hydrogenated lecithin and cholesterol work together to form a hydrogenated lecithin bilayer that encapsulates iodine molecules, effectively reducing volatility and improving stability; 2. The purpose of modifying hydrogenated lecithin is achieved by catalyzing the reaction of triethylamine with methoxy polyethylene glycol-N-hydroxysuccinimide and hydrogenated lecithin. A protective layer is formed on the surface of hydrogenated lecithin, which significantly reduces iodine volatilization, can also release iodine slowly, prolong the local action time, and reduce mucosal irritation. 3,4-Iodophenylboronic acid, polyvinyl alcohol, and borax were blended to prepare a borate ester crosslinked hydrogel. Polyvinyl alcohol provided a cis-diol structure and introduced arylboronic acid functional groups to participate in dynamic borate ester crosslinking. Iodine groups and iodine molecules have weak interactions between the same halogens, while iodine substituents on the aromatic ring can enhance hydrophobic microdomains and promote I2 enrichment and retention. Borax hydrolysis yielded tetrahydroxyborate, providing an alkaline environment and forming additional borate ester crosslinking sites with polyvinyl alcohol, enhancing gel strength and stability. The three-dimensional network of the hydrogel physically encapsulates I2 molecules in the pores. I2 diffusion from the interior to the surface requires passing through the polymer chain and the aqueous phase, extending the release path and achieving effective volatilization suppression. Detailed Implementation

[0017] The following provides a further detailed description of this application.

[0018] In this application, menthol (CAS No. 1490-04-6), β-cyclodextrin (CAS No. 7585-39-9) were provided by Shanghai Aladdin Biochemical Technology Co., Ltd., brand: Aladdin, product number: C425857; sucrose (CAS No. 57-50-1); hydrogenated lecithin (CAS No. 92128-87-5); cholesterol (CAS No. 57-88-5); methoxy polyethylene glycol-N-hydroxysuccinimide (CAS No. 78274-32-5) were provided by Shanghai Yuanye Biotechnology Co., Ltd.; polyvinyl alcohol (CAS No. 9002-89-5); borax (CAS No. 1303-96-4); and 4-iodophenylboronic acid (CAS No. 5122-99-6).

[0019] Unless otherwise specified, all raw materials used in the following embodiments are commercially available.

[0020] Example Example 1: This example discloses a sildenafil lozenge and its preparation method; the sildenafil lozenge includes the following components: iodine, potassium iodide, menthol, β-cyclodextrin, sucrose, hydroxypropyl methylcellulose, magnesium stearate, hydrogenated lecithin and cholesterol, and the content of each component is shown in Table 1 below.

[0021] A method for preparing a sildenafil lozenge includes the following steps: S1. Encapsulation of iodine-containing liposomes; 1) Dissolve hydrogenated lecithin in an anhydrous chloroform / methanol solution with a molar ratio of 2:1, then add cholesterol, and sonicate at 100-200W in a container. Use a rotary evaporator at 40°C under reduced pressure for 30 minutes until a uniform, transparent lipid film adheres to the bottle wall. Vacuum dry overnight in a vacuum desiccator to completely remove residual solvent and form a lipid film. An iodine solution prepared by adding potassium iodide and iodine pulverized through a 20-mesh sieve sequentially to deionized water and stirring to dissolve was added to a container with a lipid film. The solution was preheated to 50°C and stirred in a 50°C water bath for 1 hour. Finally, the solution was sonicated at 100W power for 5 minutes in an ice-water bath to obtain iodine-containing liposomes with a particle size of 80-200 nm and uniform distribution. 2) Add 4 parts by weight of β-cyclodextrin to the iodine-containing liposomes, keep warm and stir at 80°C until completely dissolved, pass through a 60-mesh sieve, let stand, and collect the solid material; 3) Use a vibrating pellet mill to wet-granulate the solid material through a 20-mesh sieve; 4) Add the granulated particles to a fluidized bed dryer for drying, with the inlet air temperature controlled at 65℃ and the particle moisture content not exceeding 4%; 5) The dried granules are granulated by passing them through a 60-mesh sieve using a gyratory pelletizer; S2. Menthol capsules; 1) Add deionized water to the mixing tank, heat to 80°C, add the remaining weight of β-cyclodextrin and stir to dissolve, then add menthol and stir to dissolve, pass through a 60-mesh sieve, let stand, and collect the solid material; 2) Use a vibrating pellet mill to wet-granulate the solid material through a 20-mesh sieve; 3) Add the granulated particles to a fluidized bed dryer for drying, with the inlet air temperature controlled at 80℃ and the particle moisture content not exceeding 4%; 4) The dried granules are granulated by passing them through a 60-mesh sieve using a vibrating pellet mill; S3. Granulation; 1) Crush the sucrose through a 120-mesh sieve, and add the sieved 1 / 2 sucrose / 2 parts by weight of sucrose, menthol inclusion granules, iodine-containing liposome inclusion granules and the remaining 1 / 2 sucrose in sequence into the wet granulation machine. Mix for 5 minutes with the stirring blade speed at 80±20 rpm and the cutting blade speed at 800±200 rpm. 2) Add a 1% binder solution prepared by stirring and dissolving hydroxypropyl methylcellulose in deionized water into the wet granulator; atomization pressure 0.1 MPa, liquid addition time 10±2 minutes, stirring speed 80±20 rpm, and cutting speed 800±200 rpm. 3) Wet granulation of the material using a vibrating pellet mill through a 20-mesh sieve; 4) Place the granulated wet granules in a fluidized bed for drying, set the inlet air temperature to 70±5℃, and control the granule moisture content to not exceed 3%; 5) Add the dried granules to a vibrating pellet mill and granulate them through a 20-mesh sieve to obtain dry granules; S4. Total Mixing; Add half of the dry granules, magnesium stearate pulverized through an 80-mesh sieve, and the remaining half of the dry granules into the mixer in sequence and mix at a speed of 15 rpm for 5 minutes. S5. Tableting; Tableting was performed using a high-speed rotary tablet press with a Φ 10.0mm R13.5 shallow concave die. The theoretical tablet weight was 450mg, with a tablet weight variation of ±5%. The hardness was 7±2kg, and the tableting speed was 60KT / h.

[0022] Example 2: The difference from Example 1 is that this example discloses a sildenafil lozenge and its preparation method; the sildenafil lozenge includes the following components: iodine, potassium iodide, menthol, β-cyclodextrin, sucrose, hydroxypropyl methylcellulose, magnesium stearate, hydrogenated lecithin and cholesterol, and the content of each component is shown in Table 1 below.

[0023] A method for preparing a sildenafil lozenge includes the following steps: S1. Encapsulation of iodine-containing liposomes; 1) Dissolve hydrogenated lecithin in an anhydrous chloroform / methanol solution with a molar ratio of 2:1, then add cholesterol, and sonicate at 150W in a container. Use a rotary evaporator to evaporate at 43°C under reduced pressure for 50 minutes until a uniform and transparent lipid film is formed and adheres to the bottle wall. Vacuum dry overnight in a vacuum desiccator to completely remove residual solvent and form a lipid film. An iodine solution prepared by adding potassium iodide and iodine pulverized through a 20-mesh sieve sequentially to deionized water and stirring to dissolve was added to a container in which a lipid film was formed. The solution was preheated to 55°C and stirred in a 55°C water bath for 1.5 hours. Finally, the solution was sonicated at 150W for 8 minutes in an ice-water bath to obtain iodine-containing liposomes with a particle size of 80-200 nm and uniform distribution. 2) Add 4-5 parts by weight of β-cyclodextrin to the iodine-containing liposomes, keep warm at 83°C and stir until completely dissolved, pass through a 60-mesh sieve, let stand, and collect the solid material; 3) Use a vibrating pellet mill to wet-granulate the solid material through a 20-mesh sieve; 4) Add the granulated particles to a fluidized bed dryer for drying, with the inlet air temperature controlled at 70℃ and the particle moisture content not exceeding 4%; 5) The dried granules are granulated by passing them through a 60-mesh sieve using a gyratory pelletizer; S2. Menthol capsules; 1) Add deionized water to the mixing tank, heat to 83°C, add the remaining weight of β-cyclodextrin and stir to dissolve, then add menthol and stir to dissolve, pass through a 60-mesh sieve, let stand, and collect the solid material; 2) Use a vibrating pellet mill to wet-granulate the solid material through a 20-mesh sieve; 3) Add the granulated particles to a fluidized bed dryer for drying, with the inlet air temperature controlled at 85℃ and the particle moisture content not exceeding 4%; 4) The dried granules are granulated by passing them through a 60-mesh sieve using a vibrating pellet mill; S3. Granulation; 1) Crush the sucrose through a 120-mesh sieve, and add 1 / 2 sucrose by weight, menthol inclusion granules, iodine-containing liposome inclusion granules, and the remaining 1 / 2 sucrose by weight to the wet granulator in sequence. Mix for 5 minutes with the stirring blade speed at 80±20 rpm and the cutting blade speed at 800±200 rpm. 2) Add a 1% binder solution prepared by stirring and dissolving hydroxypropyl methylcellulose in deionized water into the wet granulator; atomization pressure 0.3 MPa, liquid addition time 10±2 minutes, stirring speed 80±20 rpm, and cutting speed 800±200 rpm. 3) Wet granulation of the material using a vibrating pellet mill through a 20-mesh sieve; 4) Place the granulated wet granules in a fluidized bed for drying, set the inlet air temperature to 70±5℃, and control the granule moisture content to not exceed 3%; 5) Add the dried granules to a vibrating pellet mill and granulate them through a 20-mesh sieve to obtain dry granules; S4. Total Mixing; Add half of the dry granules, magnesium stearate pulverized through an 80-mesh sieve, and the remaining half of the dry granules into the mixer in sequence and mix at a speed of 15 rpm for 5 minutes. S5. Tableting; Tableting was performed using a high-speed rotary tablet press with a Φ 10.0mm R13.5 shallow concave die. The theoretical tablet weight was 450mg, with a tablet weight variation of ±5%. The hardness was 7±2kg, and the tableting speed was 120KT / h.

[0024] Example 3: The difference from Example 1 is that this example discloses a sildenafil lozenge and its preparation method; the sildenafil lozenge includes the following components: iodine, potassium iodide, menthol, β-cyclodextrin, sucrose, hydroxypropyl methylcellulose, magnesium stearate, hydrogenated lecithin and cholesterol, and the content of each component is shown in Table 1 below.

[0025] A method for preparing a sildenafil lozenge includes the following steps: S1. Encapsulation of iodine-containing liposomes; 1) Dissolve hydrogenated lecithin in an anhydrous chloroform / methanol solution with a molar ratio of 2:1, then add cholesterol, and sonicate at 200W in a container. Use a rotary evaporator at 45°C under reduced pressure for 60 minutes until a uniform, transparent lipid film is formed and adheres to the bottle wall. Vacuum dry overnight in a vacuum desiccator to completely remove residual solvent and form a lipid film. An iodine solution prepared by adding potassium iodide and iodine pulverized through a 20-mesh sieve sequentially to deionized water and stirring to dissolve was added to a container in which a lipid film was formed. The solution was preheated to 60°C and stirred in a 60°C water bath for 2 hours. Finally, the solution was sonicated at 200W power for 10 minutes in an ice-water bath to obtain iodine-containing liposomes with a particle size of 80-200 nm and uniform distribution. 2) Add 5 parts by weight of β-cyclodextrin to the iodine-containing liposomes, keep warm and stir at 85°C until completely dissolved, pass through a 60-mesh sieve, let stand, and collect the solid material; 3) Use a vibrating pellet mill to wet-granulate the solid material through a 20-mesh sieve; 4) Add the granulated particles to a fluidized bed dryer for drying, with the inlet air temperature controlled at 80℃ and the particle moisture content not exceeding 4%; 5) The dried granules are granulated by passing them through a 60-mesh sieve using a gyratory pelletizer; S2. Menthol capsules; 1) Add deionized water to the mixing tank, heat to 85°C, add the remaining weight of β-cyclodextrin and stir to dissolve, then add menthol and stir to dissolve, pass through a 60-mesh sieve, let stand, and collect the solid material; 2) Use a vibrating pellet mill to wet-granulate the solid material through a 20-mesh sieve; 3) Add the granulated particles to a fluidized bed dryer for drying, with the inlet air temperature controlled at 90℃ and the particle moisture content not exceeding 4%; 4) The dried granules are granulated by passing them through a 60-mesh sieve using a vibrating pellet mill; S3. Granulation; 1) Crush the sucrose through a 120-mesh sieve, and add 1 / 2 sucrose by weight, menthol inclusion granules, iodine-containing liposome inclusion granules, and the remaining 1 / 2 sucrose by weight to the wet granulator in sequence. Mix for 5 minutes with the stirring blade speed at 80±20 rpm and the cutting blade speed at 800±200 rpm. 2) Add a 1% binder solution prepared by stirring and dissolving hydroxypropyl methylcellulose in deionized water into the wet granulator; atomization pressure 0.3 MPa, liquid addition time 10±2 minutes, stirring speed 80±20 rpm, and cutting speed 800±200 rpm. 3) Wet granulation of the material using a vibrating pellet mill through a 20-mesh sieve; 4) Place the granulated wet granules in a fluidized bed for drying, set the inlet air temperature to 70±5℃, and control the granule moisture content to not exceed 3%; 5) Add the dried granules to a vibrating pellet mill and granulate them through a 20-mesh sieve to obtain dry granules; S4. Total Mixing; Add half of the dry granules, magnesium stearate pulverized through an 80-mesh sieve, and the remaining half of the dry granules into the mixer in sequence and mix at a speed of 15 rpm for 5 minutes. S5. Tableting; Tableting was performed using a high-speed rotary tablet press with a Φ 10.0mm R13.5 shallow concave die. The theoretical tablet weight was 450mg, with a tablet weight variation of ±5%. The hardness was 7±2kg, and the tableting speed was 150KT / h.

[0026] Example 4: The difference from Example 1 is that this example discloses a sildenafil lozenge and its preparation method; the sildenafil lozenge includes the following components: iodine, potassium iodide, menthol, β-cyclodextrin, sucrose, hydroxypropyl methylcellulose, magnesium stearate, hydrogenated lecithin, cholesterol, methoxy polyethylene glycol-N-hydroxysuccinimide, triethylamine, polyvinyl alcohol, borax and 4-iodophenylboronic acid, and the content of each component is shown in Table 1 below.

[0027] A method for preparing a sildenafil lozenge includes the following steps: S1. Encapsulation of iodine-containing liposomes; 1) Hydrogenated lecithin was dissolved in an anhydrous chloroform / methanol solution with a molar ratio of 2:1; methoxy polyethylene glycol-N-hydroxysuccinimide was added, followed by dropwise addition of triethylamine. The mixture was stirred at room temperature for 7 hours under nitrogen protection. The solvent was removed by rotary evaporation, and the precipitate was precipitated with cold diethyl ether. After vacuum drying, the precipitate was passed through a 60-mesh sieve to obtain modified hydrogenated lecithin. The precipitate was characterized by infrared spectroscopy at 1150 cm⁻¹. -1 The characteristic peak of the COC asymmetric stretching vibration of methoxy polyethylene glycol-N-hydroxysuccinimide was observed at [location]. Modified hydrogenated lecithin and cholesterol were dissolved in 8 parts of anhydrous ethanol and ultrasonically dissolved in a container at 100W power. The mixture was then rotary evaporated at 40°C under reduced pressure for 30 minutes until a uniform and transparent lipid film was formed and adhered to the bottle wall. The mixture was then vacuum-dried overnight in a vacuum desiccator to completely remove residual solvent and form a lipid film. Iodine was pulverized and passed through a 20-mesh sieve. An iodine solution, prepared by sequentially adding potassium iodide and iodine to deionized water and stirring to dissolve, and preheated to 50°C, was added to a container with a lipid film. The solution was stirred in a 50°C water bath for 1 hour and then sonicated at 100W power for 5 minutes in an ice-water bath to obtain iodine-containing liposomes with a particle size of 80-200 nm and uniform distribution. 2) Add 4 parts by weight of β-cyclodextrin to the iodine-containing liposomes, keep warm and stir at 80°C until completely dissolved, pass through a 60-mesh sieve, let stand, and collect the solid material; 3) Use a vibrating pellet mill to wet-granulate the solid material through a 20-mesh sieve; 4) Add the granulated particles to a fluidized bed dryer for drying, with the inlet air temperature controlled at 65℃ and the particle moisture content not exceeding 4%; 5) The dried granules are granulated by passing them through a 60-mesh sieve using a gyratory pelletizer; S2. Menthol capsules; 1) Add deionized water to the mixing tank, heat to 80°C, add the remaining weight of β-cyclodextrin and stir to dissolve, then add menthol and stir to dissolve, pass through a 60-mesh sieve, let stand, and collect the solid material; 2) Use a vibrating pellet mill to wet-granulate the solid material through a 20-mesh sieve; 3) Add the granulated particles to a fluidized bed dryer for drying, with the inlet air temperature controlled at 80℃ and the particle moisture content not exceeding 4%; 4) The dried granules are granulated by passing them through a 60-mesh sieve using a vibrating pellet mill; S3. Granulation; 1) Mix polyvinyl alcohol with deionized water, stir in a 90°C water bath for 2 hours, and cool to room temperature to obtain a 5% polyvinyl alcohol aqueous solution. Dissolve 4-iodophenylboronic acid in 1 part by weight of 0.1M NaOH aqueous solution, and sonicate at 40°C for 5 minutes until clear to obtain 4-iodophenylboronic acid solution; Borax was dissolved in deionized water to obtain a 100 mM borax solution; Mix 5% polyvinyl alcohol aqueous solution and borax solution, control pH=9, add 4-iodophenylboronic acid solution, shake manually for 10s, let stand for 40s to form a transparent hydrogel. Crush the sucrose through a 120-mesh sieve. Add the sieved 1 / 2 sucrose / 2 parts by weight of sucrose, menthol inclusion granules, iodine-containing liposome inclusion granules, the remaining 1 / 2 sucrose and transparent hydrogel to a wet granulator in sequence. Mix for 5 minutes with the agitator speed at 80±20 rpm and the cutter speed at 800±200 rpm. 2) Add a 1% binder solution prepared by stirring and dissolving hydroxypropyl methylcellulose in deionized water into the wet granulator; atomization pressure 0.1 MPa, liquid addition time 10±2 minutes, stirring speed 80±20 rpm, and cutting speed 800±200 rpm. 3) Wet granulation of the material using a vibrating pellet mill through a 20-mesh sieve; 4) Place the granulated wet granules in a fluidized bed for drying, set the inlet air temperature to 70±5℃, and control the granule moisture content to not exceed 3%; 5) Add the dried granules to a vibrating pellet mill and granulate them through a 20-mesh sieve to obtain dry granules; S4. Total Mixing; Add half of the dry granules, magnesium stearate pulverized through an 80-mesh sieve, and the remaining half of the dry granules into the mixer in sequence and mix at a speed of 15 rpm for 5 minutes. S5. Tableting; Tableting was performed using a high-speed rotary tablet press with a Φ 10.0mm R13.5 shallow concave die. The theoretical tablet weight was 450mg, with a tablet weight variation of ±5%. The hardness was 7±2kg, and the tableting speed was 60KT / h.

[0028] Example 5: The difference from Example 4 is that the content of each component of a sildenafil lozenge is shown in Table 1 below.

[0029] Example 6: The difference from Example 4 is that the content of each component of a sildenafil lozenge is shown in Table 1 below.

[0030] Example 7: The difference from Example 1 is that the components of a sildenafil lozenge also include methoxy polyethylene glycol-N-hydroxysuccinimide and triethylamine.

[0031] Example 8: The difference from Example 7 is that methoxy polyethylene glycol-N-hydroxysuccinimide is replaced with methoxy polyethylene glycol.

[0032] Example 9: The difference from Example 4 is that, by weight parts, the ratio of polyvinyl alcohol: borax: 4-iodophenylboronic acid is 5:3:1, that is, 5 parts by weight of polyvinyl alcohol, 3 parts by weight of borax, and 1 part by weight of 4-iodophenylboronic acid.

[0033] Example 10: The difference from Example 4 is that 4-iodophenylboronic acid is replaced with phenylboronic acid.

[0034] Comparative Example Comparative Example 1: Commercially available iodine tablets were used as the control group.

[0035] Comparative Example 2: The difference from Example 1 is that hydrogenated lecithin is replaced with tripalmitic acid glyceride.

[0036] Comparative Example 3: The difference from Comparative Example 2 is that cholesterol is replaced with cholesterol acetate.

[0037] Table 1. Component content of Examples 1-6 Performance testing (1) Taking Example 6 as an example, finished product samples 1-3 were prepared, and the test results are shown in Table 2 below.

[0038] Table 2 Finished Product Inspection Results (2) Thermogravimetric analysis was performed on each example and comparative example. The samples prepared in each example and comparative example were ground through an 80-mesh sieve to ensure uniform particle size. 5mg was weighed and heated to 150℃ at 10℃ / min under N2 atmosphere. The mass of the sample at this time was measured and the percentage of weight loss was calculated. The results are shown in Table 3 below.

[0039] Table 3. Thermogravimetric analysis results of each embodiment and comparative example. This specific embodiment is merely an explanation of this application and is not intended to limit the scope of protection of this application. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but as long as they are within the scope of the claims of this application, they are protected by patent law.

Claims

1. A lozenge comprising celtioteroi, characterized in that: The composition comprises the following components by weight fraction: 8-10 parts of iodine; 16-20 parts of potassium iodide; 18-20 parts of menthol; 8-10 parts of β-cyclodextrin; 400-420 parts of sucrose; 1-2 parts of hydroxypropyl methyl cellulose; 3-5 parts of magnesium stearate; 8-10 parts of hydrogenated lecithin; 2-3 parts of cholesterol.

2. A lozenge according to claim 1, wherein: It further comprises 6-8 parts of methoxy polyethylene glycol-N-hydroxysuccinimide and 0.2-0.3 parts of triethylamine by weight fraction.

3. A lozenge according to claim 2, wherein: It further comprises 4-7 parts of polyvinyl alcohol, 1-4 parts of borax and 0.8-1.2 parts of 4-iodobenzoic acid by weight fraction.

4. The lozenge according to claim 3, wherein: The polyvinyl alcohol:borax:4-iodobenzoic acid is in a ratio of 5:3:1 by weight fraction.

5. The method of claim 4, wherein the preparation of the cetirizine lozenge is characterized by, It comprises the following steps: S1. Iodine-containing liposome encapsulation; 1) Dissolve the hydrogenated lecithin in a molar ratio of 2:1 anhydrous chloroform / methanol solution, add cholesterol, and ultrasonically dissolve in the container at a power of 100-200W. Use a rotary evaporator to evaporate at 40-45℃ under reduced pressure for 30-60 minutes until a uniform and transparent lipid film is formed and attached to the bottle wall. Vacuumize overnight in a vacuum dryer to completely remove residual solvents and form a lipid film; Add the iodine solution prepared by sequentially adding potassium iodide and iodine to deionized water and stirring to dissolve to the container with the formed lipid film, preheat to 50-60℃, stir in a 50-60℃ water bath for 1-2h, and finally ultrasonically at a power of 100-200W for 5-10min in an ice water bath to obtain iodine-containing liposomes with a particle size of 80-200nm and uniform distribution; 2) Add 4-5 parts of β-cyclodextrin to the iodine-containing liposomes, heat and stir at 80-85℃ until completely dissolved, pass through a 60-mesh sieve, and collect the solid material; 3) Wet granulation of the solid material using a swing granulator through a 20-mesh sieve; 4) Dry the granulated particles in a fluidized bed dryer, control the inlet air temperature at 65-80℃, and the moisture content of the particles should not exceed 4%; 5) Dry granulation of the dried particles using a swing granulator through a 60-mesh sieve; S2. Menthol encapsulation; 1) Add deionized water to the liquid preparation tank, heat to 80-85℃, then add the remaining weight fraction of β-cyclodextrin and stir to dissolve, then add menthol and stir to dissolve, pass through a 60-mesh sieve, and collect the solid material; 2) Wet granulation of the solid material using a swing granulator through a 20-mesh sieve; 3) Dry the granulated particles in a fluidized bed dryer, control the inlet air temperature at 80-90℃, and the moisture content of the particles should not exceed 4%; 4) Dry granulation of the dried particles using a swing granulator through a 60-mesh sieve; S3. Granulation; 1) Add 1 / 2 sucrose, menthol-encapsulated particles, iodine-containing liposome-encapsulated particles, and the remaining 1 / 2 sucrose to the wet granulator in sequence, mix for 5 minutes, and the stirring blade speed is 80±20rpm and the cutting blade speed is 800±200rpm; 2) Add 1% binder solution prepared by dissolving hydroxypropyl methyl cellulose in deionized water into the wet granulator; atomization pressure 0.1-0.3Mpa, liquid addition time 10±2 minutes, stirring blade rotation speed 80±20rpm, cutter rotation speed 800±200rpm; 3) Use the swing granulator to pass the material through a 20 mesh screen for wet granulation; 4) Place the wet granules after the whole granulation in the fluid bed for drying, set the inlet air temperature to 70±5℃, control the moisture content of the granules to be less than 3%; 5) Add the dried granules into the swing granulator to pass through a 20 mesh screen for granulation, to obtain dry granules; S4. Total mixing; Add 1 / 2 dry granules, magnesium stearate, and the remaining 1 / 2 dry granules into the mixer in sequence, mix at a rotation speed of 15rpm for 5 minutes; S5. Tabletting; Use a high-speed rotary tablet press to tablet, use Φ 10.0mm R13.5 shallow concave mold to tablet, the theoretical tablet weight is 450mg, the tablet weight difference is ±5%, the hardness is 7±2kg, and the tabletting speed is 60-150KT / h.

6. A process for the preparation of a cetirizine lozenge according to claim 5, characterized in that: The S1 further comprises the following steps: Dissolve the hydrogenated lecithin in a molar ratio of 2:1 anhydrous chloroform / methanol solution; add methoxypolyethylene glycol-N-hydroxysuccinimide, dropwise add triethylamine, stir at room temperature for 7-8h under nitrogen protection, remove the solvent by rotary evaporation, precipitate with cold ether, pass through a 60 mesh screen after vacuum drying, and obtain modified hydrogenated lecithin; Dissolve the modified hydrogenated lecithin and cholesterol in 8-10 parts of anhydrous ethanol, ultrasonically dissolve in a container at a power of 100-200W, and use a rotary evaporator to rotary evaporate at 40-45℃ under reduced pressure for 30-60 minutes until a uniform and transparent lipid film is formed and attached to the bottle wall; completely remove the residual solvent in a vacuum dryer overnight to form a lipid film.

7. A process for the preparation of a cetirizine lozenge according to claim 5, wherein: The S3 further comprises the following steps: blend polyvinyl alcohol with deionized water, stir in a 90℃ water bath for 2-3h, and cool to room temperature to obtain a 5% polyvinyl alcohol aqueous solution; Dissolve 4-iodobenzoic acid in 1 part by weight of 0.1M NaOH aqueous solution, ultrasonically clarify at 40℃ for 5-10 minutes to obtain a 4-iodobenzoic acid solution; Dissolve borax in deionized water to obtain a 100mM borax solution; Mix 4-7 parts of 5% polyvinyl alcohol aqueous solution and 2-4 parts of borax solution, control the pH to be 9, add 1-3 parts of 4-iodobenzoic acid solution, manually shake for 10-15s, and stand for 40-100s to form a transparent hydrogel; Add 1 / 2 sucrose, menthol-coated granules, iodine-containing liposome-coated granules, the remaining 1 / 2 sucrose, and transparent hydrogel into the wet granulator in sequence, mix for 5 minutes, and the stirring blade rotation speed is 80±20rpm and the cutter rotation speed is 800±200rpm.

8. The method for preparing a sildenafil lozenge according to claim 5, characterized in that: The iodine is crushed to pass through a 20 mesh screen, the sucrose is crushed to pass through a 120 mesh screen, and the magnesium stearate is crushed to pass through an 80 mesh screen.

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