Dextromethorphan sustained-release dry suspension and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparation preparation, and particularly relates to a dextromethorphan sustained-release dry suspension and a preparation method thereof.The dextromethorphan sustained-release dry suspension at least comprises dextromethorphan used in the form of hydrobromide, and the dry suspension is composed of dextromethorphan sustained-release pellets and dry suspension matrix auxiliary materials, the weight of the dextromethorphan sustained-release pellet in the dry suspension is 10 mg to 45 mg, and the weight ratio of the dextromethorphan sustained-release pellet is 5% to 20%; wherein the dextromethorphan sustained-release pellet is composed of a blank pellet core, a drug carrying layer, an isolating layer and a sustained-release layer from inside to outside, the weight ratio of the sustained-release layer in the dextromethorphan sustained-release pellet is 20-40%, and the sustained-release layer is composed of a sustained-release material, a plasticizer and a pore-foaming agent; the dry suspension matrix auxiliary materials at least comprise a filling agent, a suspending aid and a flavoring agent. The invention provides a dextromethorphan sustained-release dry suspension and a preparation method thereof. The dextromethorphan sustained-release dry suspension has the advantages of being good in taste, convenient to take, good in medication compliance of patients (especially children), accurate in metering, convenient to carry and suitable for industrial production, and the sustained-release effect that the dextromethorphan sustained-release dry suspension only needs to be administered once a day is achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparation preparation, and particularly relates to a dextromethorphan sustained-release dry suspension and a preparation method thereof. Background Art

[0002] Dextromethorphan is a morphine-like central nervous system antitussive. Its hydrobromide salt is used clinically. It is a central antitussive that can inhibit the medulla oblongata cough center and produce an antitussive effect. Its antitussive effect is equal to or slightly stronger than codeine. Long-term use does not cause dependence or tolerance. The structural formula of dextromethorphan is:

[0003]

[0004] In clinical practice, the dextromethorphan preparations that have been marketed include tablets, films and sustained-release suspensions, which can mainly be used to treat coughs caused by upper respiratory tract infections such as colds, acute and chronic bronchitis, and pharyngitis.

[0005] At present, oral preparations of dextromethorphan are all taken three times a day. This is because the existing sustained-release preparations almost completely release the dextromethorphan in about 6 to 8 hours, so the number of times of taking cannot be reduced. For example, the technologies disclosed in the Chinese invention patents "CN106963736A-Dextromethorphan Hydrobromide Sustained-Release Dry Suspension and Preparation Method thereof" and "CN116115584A-A Dextromethorphan Sustained-Release Micropellets and Suspension", although "CN106963736A" believes that its preparations only need to be administered once a day, in fact, the preparation releases 90% of the dextromethorphan at 8 hours and almost completely at 10 hours, and the duration of the drug effect does not meet the requirement of once-a-day administration at all; and the preparation process of "CN106963736A" uses pharmaceutical resin microcapsule technology, but the pharmaceutical resin microcapsule technology has low production efficiency and high cost, and is not suitable for industrial production. In addition, there are oral sustained-release suspension solution dosage forms in the prior art, such as "CN117017911B-A Dextromethorphan Hydrobromide Sustained-Release Suspension and Its Preparation Method", but the liquid preparation is large in size and inconvenient to carry.

[0006] In order to further improve patients' medication compliance and make it easier for children to swallow medication, it is necessary to develop a dextromethorphan sustained-release dry suspension with a longer sustained-release time, so as to reduce the number of medications to once a day and improve patients' medication compliance. Summary of the invention

[0007] The invention provides a dextromethorphan sustained-release dry suspension and a preparation method thereof. The dry suspension contains a therapeutic dose of dextromethorphan, has good taste, is convenient to take, has good medication compliance of patients (especially children), is accurate in metering, has a simple preparation process, is convenient to transport and carry, and is suitable for industrial production.

[0008] The adopted technical scheme is: a dextromethorphan sustained-release dry suspension, comprising at least dextromethorphan used in the form of hydrobromide, the dry suspension consisting of dextromethorphan sustained-release micropellets and dry suspension matrix excipients, the weight of the dextromethorphan sustained-release micropellets in the dry suspension is 10 mg to 45 mg, and the weight proportion is 20 to 60%; the dextromethorphan sustained-release micropellets are composed of a blank core, a drug-loaded layer, an isolation layer and a sustained-release layer from the inside to the outside, the weight proportion of the sustained-release layer in the dextromethorphan sustained-release micropellets is 20 to 40%, and the sustained-release layer is composed of a sustained-release material, a plasticizer and a pore-forming agent; the dry suspension matrix excipients at least include a filler, a suspending agent and a flavoring agent.

[0009] Moreover, the blank pellet core of the dextromethorphan sustained-release microcapsules is composed of one or more of sucrose, microcrystalline cellulose or silicon dioxide; the binder in the drug-carrying layer is composed of one or more of povidone, hydroxypropyl cellulose or hypromellose; and the isolation layer is composed of one or more of polyethylene glycol, hydroxypropyl cellulose or hypromellose.

[0010] Moreover, the sustained-release material of the sustained-release layer is ethyl cellulose or acrylic resin; the plasticizer is polyethylene glycol or triethyl citrate; and the pore-forming agent is composed of one or more of polyethylene glycol, hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

[0011] Moreover, the weight proportions of the dry suspension are: dextromethorphan sustained-release pellets: 5-20%; filler: 50-80%; suspending agent: 0.2-10%; flavoring agent: 1-20%.

[0012] Moreover, the filler is composed of one or more of lactose, microcrystalline cellulose, sucrose powder, mannitol or sorbitol; the suspending agent is composed of one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, xanthan gum or gum arabic; the flavoring agent includes sweeteners and / or spices and flavors, the sweetener is composed of one or more of sucralose, saccharin sodium, maltitol, acesulfame potassium, and steviol glycosides; the spices and flavors are composed of one or more of orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, and grape flavor.

[0013] A method for preparing a dextromethorphan sustained-release dry suspension comprises the following steps:

[0014] Step 1. Add dextromethorphan hydrobromide and drug-loaded layer raw materials to purified water, stir until completely dissolved, and obtain a drug-containing solution; take a blank pill core with a diameter of 0.3-0.6 mm and place it in a fluidized bed, apply the drug by bottom spraying, and control the material temperature to 40-45° C. After the bottom spraying is completed, continue to dry in the fluidized bed until the moisture is within 2% and then take it out to obtain drug-loaded micropills;

[0015] Step 2. Dissolve the isolation layer raw material in purified water and stir until completely dissolved to obtain an isolation layer coating solution; place the drug-loaded micropellets obtained in step 1 in a fluidized bed and coat them by bottom spraying, controlling the material temperature to 40-45°C. After coating, continue drying in the fluidized bed for 15 minutes and then take out to obtain isolation layer micropellets;

[0016] Step 3. Add the sustained-release material and pore-forming agent to a 90% ethanol solution and continue stirring until completely dissolved; then add the plasticizer and continue stirring to obtain a sustained-release layer coating solution; take the isolation layer micropellets obtained in step 2 and place them in a fluidized bed, and coat them by bottom spraying, controlling the material temperature to 35-42° C. After coating, continue drying for 10 minutes to obtain dextromethorphan sustained-release micropellets;

[0017] Step 4. Mix the filler, suspending agent and flavoring agent with the sustained-release pellets in equal amounts for the first time, then add the filler for a second mixing, measure the content of the intermediate, and fill according to the specifications to obtain the dextromethorphan sustained-release dry suspension.

[0018] Moreover, in step 1, the blank pill core is composed of one or more of sucrose, microcrystalline cellulose or silicon dioxide; and the raw material of the drug-carrying layer is composed of one or more of povidone, hydroxypropyl cellulose or hypromellose.

[0019] Moreover, in step 2, the raw material of the isolation layer is composed of one or more of polyethylene glycol, hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

[0020] Moreover, in step 3, the sustained-release material is ethyl cellulose or acrylic resin; the pore-forming agent is composed of one or more of polyethylene glycol, hydroxypropyl cellulose or hydroxypropyl methyl cellulose; and the plasticizer is polyethylene glycol or triethyl citrate.

[0021] Compared with the prior art, the beneficial effects of this technical solution are:

[0022] (1) Through micropellet coating technology, dextromethorphan is released 90% after 15 hours and completely after 24 hours, truly achieving a sustained-release effect with only one dose per day.

[0023] (2) The sustained-release microcapsules are evenly distributed and stable in the preparation, with a simple process and convenient storage and transportation. The preparation method mainly involves applying the drug by bottom spraying in the fluidized bed pot, which is suitable for industrial production and overcomes the problems of low production efficiency and high cost of existing pharmaceutical resin microcapsule technology.

[0024] (3) This product can be used immediately after being prepared, thus avoiding the problems of liquid preparations being inconvenient to carry and inaccurate in dosing.

[0025] (4) By adding flavoring agents to the prescription, the taste of the preparation is further improved, making it easier for children to take. At the same time, single-dose packaging can be carried out according to the minimum dosage for children to avoid overdose and ensure the safety of children's medication.

[0026] (5) Through the layer-by-layer coating method, blank core-drug-loaded pellets-isolation layer pellets-dextromethorphan sustained-release pellets-dextromethorphan sustained-release dry suspension was gradually prepared, as well as the preparation process of the sustained-release layer coating liquid by first mixing the sustained-release material and the pore-forming agent and then mixing the plasticizer, the sustained-release effect with only one dose per day was achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The in vitro release curve of the dextromethorphan sustained-release dry suspension prepared in Example 1;

[0028] Figure 2 The in vitro release curve of the dextromethorphan sustained-release dry suspension prepared in Example 2;

[0029] Figure 3 This is the in vitro release curve of the dextromethorphan sustained-release dry suspension prepared in Example 3. DETAILED DESCRIPTION

[0030] The present invention is described in detail below with reference to the accompanying drawings and embodiments, but the content of the present invention is not limited to the following embodiments.

[0031] Embodiment 1

[0032] (1) Drug-carrying layer prescription and preparation process:

[0033] prescription:

[0034] prescription Dosage(g) Dextromethorphan hydrobromide (calculated as dextromethorphan) 60 Povidone 20 Sucrose pellets (0.4mm) 200 Purified water Moderate

[0035] Preparation process:

[0036] Add dextromethorphan hydrobromide and povidone to purified water and stir until completely dissolved to obtain a drug-containing solution. Place blank sucrose pellet cores in a fluidized bed pot and apply the drug by bottom spraying. Control the material temperature to 40-45°C and apply the drug by bottom spraying. After completion, continue drying in the fluidized bed until the moisture content is within 2% and then take out to obtain drug-loaded micropellets.

[0037] (2) Isolation layer prescription and preparation process

[0038] prescription:

[0039] prescription Dosage(g) Drug-loaded pellets 200 Polyethylene glycol 6000 20 Purified water Moderate

[0040] Preparation process:

[0041] Dissolve polyethylene glycol in purified water and stir until completely dissolved to obtain the isolation layer coating solution. Place the drug-loaded pellets in a fluidized bed and coat them by bottom spraying. Control the material temperature to 40-45°C. After coating, continue drying in the fluidized bed for 15 minutes and then take them out to obtain the isolation layer pellets.

[0042] (3) Sustained-release layer prescription and preparation process

[0043] prescription:

[0044]

[0045]

[0046] Preparation process:

[0047] Add ethyl cellulose and hydroxypropyl cellulose to 90% ethanol solution, continue stirring until completely dissolved, then add triethyl citrate, continue stirring for 10 minutes to obtain the sustained-release layer coating solution. Place the isolation layer pellets in a fluidized bed and coat them by bottom spraying. Control the material temperature at 35-42°C. After coating, continue drying for about 10 minutes to obtain dextromethorphan sustained-release pellets.

[0048] (4) Dry suspension formulation and preparation method

[0049] prescription:

[0050] prescription Dosage(g) Dextromethorphan sustained-release pellets 20 lactose 80 Sucrose powder 140 Hydroxypropylcellulose 20 Xanthan gum 10 Banana flavor 30

[0051] Preparation method:

[0052] After mixing equal amounts of hydroxypropyl cellulose, xanthan gum, banana flavor and dextromethorphan sustained-release micropellets, add lactose and continue mixing, then add sucrose powder and mix, measure the content, and fill into a specification of 30 mg / bag to obtain dextromethorphan sustained-release dry suspension.

[0053] Embodiment 2:

[0054] (1) Drug-carrying layer prescription and preparation process:

[0055] prescription:

[0056] prescription Dosage(g) Dextromethorphan hydrobromide (calculated as dextromethorphan) 30 Hydroxypropyl methylcellulose 30 Microcrystalline cellulose (0.6mm) 200 Purified water Moderate

[0057] Preparation process:

[0058] Add dextromethorphan hydrobromide and hypromellose to purified water and stir until completely dissolved to obtain a drug-containing solution. Place blank microcrystalline cellulose pellets in a fluidized bed pot and apply the drug by bottom spraying. Control the material temperature to 40-45°C and perform bottom spraying. After completion, continue drying in the fluidized bed until the moisture content is within 2% and then take out to obtain drug-loaded pellets.

[0059] (2) Isolation layer prescription and preparation process

[0060] prescription:

[0061] prescription Dosage(g) Drug-loaded pellets 200 Hydroxypropyl methylcellulose 20 Purified water Moderate

[0062] Preparation process:

[0063] Dissolve Hydroxypropyl Methylcellulose in purified water and stir until completely dissolved to obtain the isolation layer coating solution. Place the drug-loaded pellets in a fluidized bed and coat them by bottom spraying. Control the material temperature to 40-45°C. After coating, continue drying in the fluidized bed for 15 minutes and then take them out to obtain the isolation layer pellets.

[0064] (3) Sustained-release layer prescription and preparation process

[0065] prescription:

[0066] prescription Dosage(g) Separator Pellets 200 Acrylic resin 30 Polyethylene glycol 6000 20 Hydroxypropyl methylcellulose 30 Purified water Moderate

[0067] Preparation process:

[0068] Add acrylic resin to 90% ethanol solution, continue stirring until completely dissolved, then add polyethylene glycol 6000 and hydroxypropyl methylcellulose, continue stirring for 10 minutes to obtain the sustained-release layer coating solution. Place the isolation layer pellets in a fluidized bed and coat them by bottom spraying. Control the material temperature at 35-42°C. After coating, continue drying for about 10 minutes to obtain dextromethorphan sustained-release pellets.

[0069] (4) Dry suspension formulation and preparation method

[0070] prescription:

[0071]

[0072]

[0073] Preparation method:

[0074] After mixing equal amounts of sucralose, hydroxypropyl methylcellulose, xanthan gum, cherry flavor, peach flavor and dextromethorphan sustained-release microcapsules, add microcrystalline cellulose and continue to mix, then add mannitol and mix, measure the content, and fill into a specification of 10 mg / bag to obtain dextromethorphan sustained-release dry suspension.

[0075] Embodiment 3:

[0076] (1) Drug-carrying layer prescription and preparation process:

[0077] prescription:

[0078] prescription Dosage(g) Dextromethorphan hydrobromide (calculated as dextromethorphan) 45 Hydroxypropylcellulose 50 Silica pellet core (0.4mm) 200 Purified water Moderate

[0079] Preparation process:

[0080] Add dextromethorphan hydrobromide and hydroxypropyl cellulose to purified water and stir until completely dissolved to obtain a drug-containing solution. Place the blank silica pellet core in the fluidized bed pot and apply the drug by bottom spraying. Control the material temperature to 40-45°C and perform bottom spraying. After completion, continue drying in the fluidized bed until the moisture content is within 2% and then take it out to obtain drug-loaded micropellets.

[0081] (2) Isolation layer prescription and preparation process

[0082] prescription:

[0083]

[0084]

[0085] Preparation process:

[0086] Dissolve hydroxypropyl cellulose in purified water and stir until completely dissolved to obtain the isolation layer coating solution. Place the drug-loaded pellets in a fluidized bed and coat them by bottom spraying. Control the material temperature to 40-45°C. After coating, continue drying in the fluidized bed for 15 minutes and then take them out to obtain the isolation layer pellets.

[0087] (3) Sustained-release layer prescription and preparation process

[0088] prescription:

[0089] prescription Dosage(g) Separator Pellets 200 Ethyl cellulose 40 Triethyl citrate 20 Hydroxypropylcellulose 50 Purified water Moderate

[0090] Preparation process:

[0091] Add ethyl cellulose to 90% ethanol solution, continue stirring until completely dissolved, then add triethyl citrate and hydroxypropyl cellulose, continue stirring for 10 minutes to obtain the sustained-release coating solution. Place the isolation layer pellets in a fluidized bed and coat them by bottom spraying. Control the material temperature at 35-42°C. After coating, continue drying for about 10 minutes to obtain dextromethorphan sustained-release pellets.

[0092] (4) Dry suspension formulation and preparation method

[0093] prescription:

[0094] prescription Dosage(g) Dextromethorphan sustained-release pellets 45 Sucrose powder 140 Sorbitol 50 Hydroxypropylcellulose 10 Gum Arabic 20 Orange flavor 40 Cherry flavor 20

[0095] Preparation method:

[0096] After mixing equal amounts of sorbitol, hydroxypropyl cellulose, gum arabic, orange flavor, cherry flavor and dextromethorphan sustained-release micropellets, add sucrose powder and continue to mix, then add mannitol and mix, measure the content, and fill into a specification of 45 mg / bag to obtain dextromethorphan sustained-release dry suspension.

[0097] Test Example 1

[0098] Sedimentation volume ratio evaluation

[0099] According to the provisions of 0123 of Part IV of the Chinese Pharmacopoeia (2020 Edition), the sedimentation volume ratios of Examples 1-3 were checked.

[0100] Take 5g of dry suspension, add 50ml of water and shake vigorously in a stoppered measuring cylinder for 1 minute. It should be evenly dispersed, and the initial height H0 of the suspension should be recorded. Let it stand for 3 hours, and the final height H of the suspension should be recorded. Calculate according to the following formula: sedimentation volume ratio = H / H0. Observe the dispersibility with the naked eye. If there is no obvious agglomeration or caking, evaluate it with good, good, fair, or poor.

[0101] Suspension performance of Examples 1-3

[0102] Example Liquidity Sedimentation volume ratio Dispersibility 1 good 0.92 good 2 good 0.95 good 3 good 0.99 good

[0103] Test Example 2

[0104] Release determination

[0105] The in vitro release rate was determined by referring to the dissolution and release rate determination method (General Rule 0931 Method 2) of Part IV of the Chinese Pharmacopoeia (2020 Edition), setting the rotation speed to 50 rpm and using 900 ml of pH 6.8 phosphate buffer as the release medium. The in vitro release curves of the dextromethorphan sustained-release dry suspension prepared in Examples 1, 2, and 3 are shown in the attached Figure 1 , 2 3. As can be seen from the figure, the three examples of the product release 90% after 15 hours and completely release after 24 hours, truly achieving a sustained-release effect with only one dose per day.

Claims

1. A dextromethorphan sustained-release dry suspension comprising at least dextromethorphan used in the form of a hydrobromide salt, characterized in that: The dry suspension is composed of dextromethorphan sustained-release microcapsules and dry suspension matrix excipients, wherein the weight proportion of the dextromethorphan sustained-release microcapsules in the dry suspension is 5-20%; wherein the dextromethorphan sustained-release microcapsules are composed of a blank core, a drug-loaded layer, an isolation layer and a sustained-release layer from the inside to the outside, wherein the weight proportion of the sustained-release layer in the dextromethorphan sustained-release microcapsules is 20-40%, and the sustained-release layer is composed of a sustained-release material, a plasticizer and a pore-forming agent; the dry suspension matrix excipients at least include a filler, a suspending agent and a flavoring agent.

2. A dextromethorphan sustained-release dry suspension according to claim 1, characterized in that: The blank pellet core of the dextromethorphan sustained-release micropellets is composed of one or more of sucrose, microcrystalline cellulose or silicon dioxide; the binder in the drug-carrying layer is composed of one or more of povidone, hydroxypropyl cellulose or hypromellose; and the isolation layer is composed of one or more of polyethylene glycol, hydroxypropyl cellulose or hypromellose.

3. A dextromethorphan sustained-release dry suspension according to claim 1, characterized in that: The sustained-release material of the sustained-release layer is ethyl cellulose or acrylic resin; the plasticizer is polyethylene glycol or triethyl citrate; and the pore-forming agent is composed of one or more of polyethylene glycol, hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

4. A dextromethorphan sustained-release dry suspension according to claim 1, characterized in that: The weight proportions of the dry suspension are: dextromethorphan sustained-release pellets: 5-20%; filler: 50-80%; suspending agent: 0.2-10%; Flavoring agent: 1-20%.

5. A dextromethorphan sustained-release dry suspension according to claim 1, characterized in that: The weight of the dextromethorphan sustained-release pellets in the dry suspension is 10 mg to 45 mg.

6. A dextromethorphan sustained-release dry suspension according to claim 1, characterized in that: The filler is composed of one or more of lactose, microcrystalline cellulose, sucrose powder, mannitol or sorbitol; the suspending agent is composed of one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, xanthan gum or gum arabic; the flavoring agent includes sweeteners and / or spices and flavors, and the sweetener is composed of one or more of sucralose, saccharin sodium, maltitol, acesulfame potassium, and steviol glycosides; the spices and flavors are composed of one or more of orange flavor, pineapple flavor, cherry flavor, apple flavor, banana flavor, blueberry flavor, peach flavor, mango flavor, and grape flavor.

7. The method for preparing a dextromethorphan sustained-release dry suspension according to claim 1, characterized in that The following steps are involved: Step 1. Add dextromethorphan hydrobromide and drug-loaded layer raw materials to purified water, stir until completely dissolved, and obtain a drug-containing solution; take a blank pill core with a diameter of 0.3-0.6 mm and place it in a fluidized bed, apply the drug by bottom spraying, and control the material temperature to 40-45° C. After the bottom spraying is completed, continue to dry in the fluidized bed until the moisture is within 2% and then take it out to obtain drug-loaded micropills; Step 2. Dissolve the isolation layer raw material in purified water and stir until completely dissolved to obtain an isolation layer coating solution; place the drug-loaded micropellets obtained in step 1 in a fluidized bed and coat them by bottom spraying, controlling the material temperature to 40-45°C. After coating, continue drying in the fluidized bed for 15 minutes and then take out to obtain isolation layer micropellets; Step 3. Add the sustained-release material and pore-forming agent to a 90% ethanol solution and continue stirring until completely dissolved; then add the plasticizer and continue stirring to obtain a sustained-release layer coating solution; take the isolation layer micropellets obtained in step 2 and place them in a fluidized bed, and coat them by bottom spraying, controlling the material temperature to 35-42° C. After coating, continue drying for 10 minutes to obtain dextromethorphan sustained-release micropellets; Step 4. Mix the filler, suspending agent and flavoring agent with the sustained-release pellets in equal amounts for the first time, then add the filler for a second mixing, measure the content of the intermediate, and fill according to the specifications to obtain the dextromethorphan sustained-release dry suspension.

8. The preparation method according to claim 7, characterized in that: In step 1, the blank pill core is composed of one or more of sucrose, microcrystalline cellulose or silicon dioxide; the raw material of the drug-carrying layer is composed of one or more of povidone, hydroxypropyl cellulose or hypromellose.

9. The preparation method according to claim 7, characterized in that: In step 2, the raw material of the isolation layer is composed of one or more of polyethylene glycol, hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

10. The preparation method according to claim 7, characterized in that: In step 3, the sustained-release material is ethyl cellulose or acrylic resin; the pore-forming agent is composed of one or more of polyethylene glycol, hydroxypropyl cellulose or hydroxypropyl methyl cellulose; and the plasticizer is polyethylene glycol or triethyl citrate.

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