Rupatadine fumarate oral liquid and preparation method thereof

Abstract

The invention relates to rupatadine fumarate oral liquid and a preparation method thereof, and belongs to the technical field of medicines. The invention discloses a preparation method of a rupatadine fumarate oral liquid, which comprises the following steps: preparing a phosphate buffer solution, preparing a compound solvent, preparing a main liquid medicine, preparing a liquid medicine, and finally freeze-drying and redissolving to obtain the rupatadine fumarate oral liquid, and the prepared oral liquid has good stability.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and relates to a rupatadine fumarate oral solution and a preparation method thereof. Background Art

[0002] Rupatadine fumarate is a new type of antiallergic drug, mainly used to treat various allergic diseases, including seasonal allergic rhinitis, perennial allergic rhinitis and chronic urticaria. Common forms include capsules, tablets and oral solutions. Compared with capsules and tablets, rupatadine fumarate oral solution is easier to take, and the dosage of the oral solution can also be adjusted according to needs, so patients are more flexible when using it.

[0003] However, rupatadine fumarate oral solution has shown good therapeutic effects in clinical applications, but the stability of the oral solution may affect the long-term storage and use of the drug, especially under environmental changes such as temperature or humidity, the drug ingredients may degrade and be difficult to preserve. Summary of the invention

[0004] The object of the present invention is to provide a rupatadine fumarate oral solution and a preparation method thereof. The present invention further reconstitutes the rupatadine fumarate oral solution after freeze drying, effectively inhibits the growth of microorganisms through freeze drying, maintains its biological activity and efficacy, and at the same time, gives the product a porous structure through freeze drying, which is conducive to subsequent reconstitution. In the preparation of the present invention, a certain amount of mannitol is introduced, which can be used as a flavoring agent and can reduce thermal damage during the freeze drying process, play a role in protecting the drug, and further improve the stability of the drug.

[0005] The purpose of the present invention can be achieved through the following technical solutions: A method for preparing rupatadine fumarate oral solution, comprising the following steps: Step 1, mixing sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water to obtain a phosphate buffer solution; Step 2: After mixing polyethylene glycol 400, glycerol and Tween-80, stir at 280-320 rpm in a 40°C water bath for 10-20 min, add menthol, and continue stirring until completely dissolved to obtain a composite solvent; Step 3, grind rupatadine fumarate, pass through a 100-mesh sieve, add to the compound solvent, stir at 350-450 rpm for 0.8-1.2 h, then add mannitol and potassium sorbate and stir until completely dissolved to obtain a main drug solution; Step 4: add the phosphate buffer solution in step 1 to the main drug solution to adjust the pH to 5.40-5.60, add purified water of the same volume as the main drug solution, stir at 150-250 rpm for 10-20 min, and filter through a 0.22 μm filter membrane to obtain a drug solution; Step 5: After freeze-drying the drug solution, reconstitute it with purified water of an equal volume to the drug solution, and at the same time, add the phosphate buffer solution in step 1 as needed to adjust the pH to be consistent with the pH in step 4, fill it into a pre-sterilized oral liquid bottle, and sterilize it.

[0006] Furthermore, the mass ratio of sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water in step 1 is 0.11-0.13:0.26-0.3:18-22.

[0007] Furthermore, in step 2, the mass ratio of polyethylene glycol 400, glycerol, Tween-80 and menthol is 23-27:14-16:1.8-2.2:0.8-1.2.

[0008] Furthermore, in step 3, the mass ratio of rupatadine fumarate, mannitol, potassium sorbate and the compound solvent is 0.8-1.2:1.9-2.1:0.14-0.18:40-41.

[0009] Furthermore, the specific operation of freeze-drying in step five is pre-freezing at normal pressure, followed by primary drying at a vacuum degree of 10Pa, secondary drying after the vacuum degree reaches 8Pa, and finally tertiary drying at a vacuum degree of 5Pa.

[0010] Furthermore, the pre-freezing temperature and time are -45°C and 3-5h respectively; the primary drying temperature and time are -25°C and 10-14h respectively; the secondary drying temperature and time are 0°C and 5-7h respectively; the tertiary drying temperature and time are 25°C and 2-4h respectively.

[0011] Beneficial effects of the present invention: The present invention further reconstitutes the rupatadine fumarate oral solution after freeze drying, effectively inhibits the growth of microorganisms through freeze drying, maintains its biological activity and efficacy, and at the same time, gives the product a porous structure through freeze drying, which is conducive to subsequent reconstitution. In the preparation of the present invention, a certain amount of mannitol is introduced, which can be used as a flavoring agent and can reduce thermal damage during the freeze drying process, play a role in protecting the drug, and further improve the stability of the drug. DETAILED DESCRIPTION

[0012] In order to further illustrate the technical means and effects adopted by the present invention to achieve the predetermined invention purpose, the specific implementation methods, structures, features and effects of the present invention are described in detail below in combination with the embodiments.

[0013] Sodium dihydrogen phosphate, disodium hydrogen phosphate, polyethylene glycol 400, glycerol, Tween-80 and menthol in all the embodiments and comparative examples of the present invention are directly purchased from the market, and are all purchased from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd.; rupatadine fumarate is directly purchased from the market, and is purchased from Jiangsu Zilong Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group; mannitol is directly purchased from the market, and is purchased from Xi'an Hongyao Pharmaceutical Excipients Co., Ltd.

[0014] Example 1 A method for preparing rupatadine fumarate oral solution. The method for preparing rupatadine fumarate oral solution of this embodiment comprises the following steps: Step 1, mixing sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water to obtain a phosphate buffer solution; Step 2: After polyethylene glycol 400, glycerol and Tween-80 are mixed, the mixture is stirred at 280 rpm in a 40° C. water bath for 10 min, and menthol is added, and the mixture is stirred continuously until completely dissolved to obtain a composite solvent; Step 3, grind rupatadine fumarate, pass through a 100-mesh sieve, add to the compound solvent, stir at 350 rpm for 0.8 h, then add mannitol and potassium sorbate and stir until completely dissolved to obtain a main drug solution; Step 4: add the phosphate buffer solution in step 1 to the main drug solution to adjust the pH to 5.40, add purified water of the same volume as the main drug solution, stir at 150 rpm for 10-20 min, and filter through a 0.22 μm filter membrane to obtain a drug solution; Step 5: After freeze-drying the drug solution, reconstitute it with purified water of an equal volume to the drug solution, and at the same time, add the phosphate buffer solution in step 1 as needed to adjust the pH to be consistent with the pH in step 4, fill it into a pre-sterilized oral liquid bottle, and sterilize it.

[0015] The mass ratio of sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water in step 1 of this embodiment is 0.11:0.26:18.

[0016] The mass ratio of polyethylene glycol 400, glycerol, Tween-80 and menthol in step 2 of this embodiment is 23:14:1.8:0.8.

[0017] The mass ratio of rupatadine fumarate, mannitol, potassium sorbate and the compound solvent in step 3 of this embodiment is 0.8:1.9:0.14:40.

[0018] The specific operation of freeze drying in step five of this embodiment is to pre-freeze at normal pressure, then perform a primary drying at a vacuum degree of 10Pa, perform a secondary drying after the vacuum degree reaches 8Pa, and finally perform a tertiary drying at a vacuum degree of 5Pa.

[0019] The pre-freezing temperature and time of this embodiment are respectively -45°C and 3h; the temperature and time of the first drying are respectively -25°C and 10h; the temperature and time of the second drying are respectively 0°C and 5h; the temperature and time of the third drying are respectively 25°C and 2h.

[0020] Example 2 A method for preparing rupatadine fumarate oral solution. The method for preparing rupatadine fumarate oral solution of this embodiment comprises the following steps: Step 1, mixing sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water to obtain a phosphate buffer solution; Step 2: Mix polyethylene glycol 400, glycerol and Tween-80, stir at 320 rpm in a 40°C water bath for 20 min, add menthol, and continue stirring until completely dissolved to obtain a composite solvent; Step 3, grind rupatadine fumarate, pass through a 100-mesh sieve, add to the compound solvent, stir at 450 rpm for 1.2 h, then add mannitol and potassium sorbate and stir until completely dissolved to obtain a main drug solution; Step 4: add the phosphate buffer solution in step 1 to the main drug solution to adjust the pH to 5.60, add purified water of the same volume as the main drug solution, stir at 250 rpm for 20 min, and filter through a 0.22 μm filter membrane to obtain a drug solution; Step 5: After freeze-drying the drug solution, reconstitute it with purified water of an equal volume to the drug solution, and at the same time, add the phosphate buffer solution in step 1 as needed to adjust the pH to be consistent with the pH in step 4, fill it into a pre-sterilized oral liquid bottle, and sterilize it.

[0021] The mass ratio of sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water in step 1 of this embodiment is 0.13:0.3:22.

[0022] The mass ratio of polyethylene glycol 400, glycerol, Tween-80 and menthol in step 2 of this embodiment is 27:16:2.2:1.2.

[0023] The mass ratio of rupatadine fumarate, mannitol, potassium sorbate and compound solvent in step 3 of this embodiment is 1.2:2.1:0.18:41.

[0024] The specific operation of freeze drying in step five of this embodiment is to pre-freeze at normal pressure, then perform a primary drying at a vacuum degree of 10Pa, perform a secondary drying after the vacuum degree reaches 8Pa, and finally perform a tertiary drying at a vacuum degree of 5Pa.

[0025] The pre-freezing temperature and time in this example are -45°C and 5h respectively; the temperature and time for the first drying are -25°C and 14h respectively; the temperature and time for the second drying are 0°C and 7h respectively; the temperature and time for the third drying are 25°C and 4h respectively.

[0026] Example 3 A preparation method of rupatadine fumarate oral liquid. The preparation method of rupatadine fumarate oral liquid in this example comprises the following steps: Step 1: Mix sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water to obtain a phosphate buffer solution; Step 2: After mixing polyethylene glycol 400, glycerol and Tween-80, stir at 40°C in a water bath at a speed of 300 rpm for 15 min, then add menthol and continue stirring until completely dissolved to obtain a compound solvent; Step 3: Crush rupatadine fumarate and pass through a 100-mesh sieve, then add it to the compound solvent, stir at a speed of 400 rpm for 1 h, then add mannitol and potassium sorbate and stir until completely dissolved to obtain the main medicinal solution; Step 4: Dropwise add the phosphate buffer solution in Step 1 to the main medicinal solution to adjust the pH to 5.50, add purified water with the same volume as the main medicinal solution, stir at a speed of 200 rpm for 15 min, and then pass through a 0.22-μm filter membrane to obtain the medicinal solution; Step 5: After freeze-drying the medicinal solution, re-dissolve it with purified water with the same volume as the medicinal solution, and at the same time dropwise add the phosphate buffer solution in Step 1 as needed to adjust the pH to be consistent with that in Step 4, fill it into a pre-sterilized oral liquid bottle, and sterilize to obtain the product.

[0027] The mass ratio of sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water in Step 1 of this example is 0.12:0.28:20.

[0028] The mass ratio of polyethylene glycol 400, glycerol, Tween-80 and menthol in Step 2 of this example is 23 - 27:14 - 16:1.8 - 2.2:0.8 - 1.2.

[0029] The mass ratio of rupatadine fumarate, mannitol, potassium sorbate and the compound solvent in Step 3 of this example is 1:2:0.16:40.5.

[0030] The specific operation of freeze-drying in Step 5 of this example is to pre-freeze under normal pressure, then conduct the first drying under a vacuum degree of 10 Pa, conduct the second drying after the vacuum degree drops to 8 Pa, and finally conduct the third drying under a vacuum degree of 5 Pa.

[0031] The pre-freezing temperature and time in this example are -45°C and 4 h respectively; the primary drying temperature and time are -25°C and 12 h respectively; the secondary drying temperature and time are 0°C and 6 h respectively; the tertiary drying temperature and time are 25°C and 3 h respectively.

[0032] Example 4 A preparation method of rupatadine fumarate oral liquid. The preparation method of rupatadine fumarate oral liquid in this example comprises the following steps: Step 1: Mix sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water to obtain a phosphate buffer solution; Step 2: Mix polyethylene glycol 400, glycerol and Tween-80, stir at 40°C in a water bath at a speed of 290 rpm for 12 min, then add menthol and continue stirring until completely dissolved to obtain a compound solvent; Step 3: Crush rupatadine fumarate and pass through a 100-mesh sieve, then add it to the compound solvent, stir at a speed of 370 rpm for 0.9 h, then add mannitol and potassium sorbate and stir until completely dissolved to obtain the main medicinal solution; Step 4: Dropwise add the phosphate buffer solution in Step 1 to the main medicinal solution to adjust the pH to 5.45, add purified water with the same volume as the main medicinal solution, stir at a speed of 170 rpm for 13 min, and then pass through a 0.22-μm filter membrane to obtain the medicinal solution; Step 5: After freeze-drying the medicinal solution, re-dissolve it with purified water with the same volume as the medicinal solution, and at the same time dropwise add the phosphate buffer solution in Step 1 as needed to adjust the pH to be the same as that in Step 4, fill it into a pre-sterilized oral liquid bottle, and sterilize to obtain the product.

[0033] The mass ratio of sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water in Step 1 of this example is 0.11:0.27:19.

[0034] The mass ratio of polyethylene glycol 400, glycerol, Tween-80 and menthol in Step 2 of this example is 24:15:1.9:0.9.

[0035] The mass ratio of rupatadine fumarate, mannitol, potassium sorbate and the compound solvent in Step 3 of this example is 0.9:1.95:0.15:40.2.

[0036] The specific operation of freeze-drying in Step 5 of this example is to pre-freeze under normal pressure, then perform primary drying under a vacuum of 10 Pa, perform secondary drying after the vacuum degree drops to 8 Pa, and finally perform tertiary drying under a vacuum of 5 Pa.

[0037] The pre-freezing temperature and time of this embodiment are respectively -45°C and 3.5h; the temperature and time of the first drying are respectively -25°C and 11h; the temperature and time of the second drying are respectively 0°C and 5.5h; the temperature and time of the third drying are respectively 25°C and 2.5h.

[0038] Example 5 A method for preparing rupatadine fumarate oral solution. The method for preparing rupatadine fumarate oral solution of this embodiment comprises the following steps: Step 1, mixing sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water to obtain a phosphate buffer solution; Step 2: After mixing polyethylene glycol 400, glycerol and Tween-80, stir at 310 rpm in a 40°C water bath for 18 min, add menthol, and continue stirring until completely dissolved to obtain a composite solvent; Step 3, grind rupatadine fumarate, pass through a 100-mesh sieve, add to the compound solvent, stir at 420 rpm for 1.1 h, then add mannitol and potassium sorbate and stir until completely dissolved to obtain a main drug solution; Step 4: add the phosphate buffer solution in step 1 to the main drug solution to adjust the pH to 5.55, add purified water of the same volume as the main drug solution, stir at 230 rpm for 18 min, and filter through a 0.22 μm filter membrane to obtain a drug solution; Step 5: After freeze-drying the drug solution, reconstitute it with purified water of an equal volume to the drug solution, and at the same time, add the phosphate buffer solution in step 1 as needed to adjust the pH to be consistent with the pH in step 4, fill it into a pre-sterilized oral liquid bottle, and sterilize it.

[0039] The mass ratio of sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water in step 1 of this embodiment is 0.13:0.29:21.

[0040] The mass ratio of polyethylene glycol 400, glycerol, Tween-80 and menthol in step 2 of this embodiment is 26:15.5:2.1:1.1.

[0041] The mass ratio of rupatadine fumarate, mannitol, potassium sorbate and compound solvent in step 3 of this embodiment is 1.1:2.05:0.17:40.7.

[0042] The specific operation of freeze drying in step five of this embodiment is to pre-freeze at normal pressure, then perform a primary drying at a vacuum degree of 10Pa, perform a secondary drying after the vacuum degree reaches 8Pa, and finally perform a tertiary drying at a vacuum degree of 5Pa.

[0043] The pre-freezing temperature and time of this embodiment are respectively -45°C and 4.5h; the temperature and time of the first drying are respectively -25°C and 13h; the temperature and time of the second drying are respectively 0°C and 6.5h; the temperature and time of the third drying are respectively 25°C and 3.5h.

[0044] Comparative Example 1 On the basis of Example 3, polyethylene glycol 400 in step 2 was removed and replaced with polyethylene glycol 600 of equal weight, and other conditions remained the same as in Example 3.

[0045] Comparative Example 2 On the basis of Example 3, Tween-80 in step 2 was removed and replaced with polyethylene glycol 400 of equal weight, and other conditions remained the same as in Example 3.

[0046] Comparative Example 3 On the basis of Example 3, the mass ratio of rupatadine fumarate, mannitol, potassium sorbate and the compound solvent was changed to 1:1.8:0.16:40.5, and other conditions remained the same as in Example 3.

[0047] Comparative Example 4 On the basis of Example 3, the pH of step 4 was changed to 5.35, and other conditions remained the same as in Example 3.

[0048] Comparative Example 5 On the basis of Example 3, while keeping other conditions the same, the preparation method of rupatadine fumarate oral solution was changed to the following steps: Step 1, mixing sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water to obtain a phosphate buffer solution; Step 2: After mixing polyethylene glycol 400, glycerol and Tween-80, stir at 300 rpm in a 40° C. water bath for 15 min, add menthol, and continue stirring until completely dissolved to obtain a composite solvent; Step 3, grind rupatadine fumarate, pass through a 100-mesh sieve, add to the compound solvent, stir at 400 rpm for 1 hour, then add mannitol and potassium sorbate and stir until completely dissolved to obtain a main drug solution; Step 4: Add the phosphate buffer solution in step 1 to the main drug solution to adjust the pH to 5.5, add purified water of the same volume as the main drug solution, stir at 200 rpm for 15 minutes, filter through a 0.22 μm filter membrane to obtain the drug solution, fill it into a pre-sterilized oral liquid bottle, and sterilize it.

[0049] Comparative Example 6 On the basis of Example 3, while keeping other conditions the same, the freeze-drying operation of step five is changed to: pre-freezing at normal pressure, followed by primary drying under a vacuum degree of 10 Pa, and finally secondary drying under a vacuum degree of 5 Pa, wherein the pre-freezing temperature and time are -45°C and 4h respectively; the primary drying temperature and time are -25°C and 18h ​​respectively; the secondary drying temperature and time are 25°C and 3h respectively.

[0050] The rupatadine fumarate oral solution prepared in Examples 1-5 and Comparative Examples 1-6 was used as a sample, 10 mL of each sample was taken and placed under accelerated conditions (40° C., RH 75.0%), and the pH value of each group of samples was measured at 0 day and 3 months to evaluate the stability of the oral solution. Each group of samples was measured in parallel 3 times and the average value was taken. The measurement results are recorded in Table 1 below.

[0051] Table 1 pH value measurement results

[0052] As shown in Table 1, the pH of the rupatadine fumarate oral solution prepared by the present invention has no significant change after 3 months of accelerated storage, indicating that the oral solution has good stability.

[0053] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technical personnel in this field can make some changes or modify the technical contents disclosed above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any indirect modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for preparing rupatadine fumarate oral solution, characterized in that: The preparation method of the rupatadine fumarate oral solution comprises the following steps: Step 1, mixing sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water to obtain a phosphate buffer solution; Step 2: Mix polyethylene glycol 400, glycerol and Tween-80, stir at 280-320 rpm in a 40°C water bath for 10-20 min, add menthol, and continue stirring until completely dissolved to obtain a composite solvent; Step 3, grind rupatadine fumarate, pass through a 100-mesh sieve, add to the compound solvent, stir at 350-450 rpm for 0.8-1.2 h, then add mannitol and potassium sorbate and stir until completely dissolved to obtain a main drug solution; Step 4: add the phosphate buffer solution in step 1 to the main drug solution to adjust the pH to 5.40-5.60, add purified water of the same volume as the main drug solution, stir at 150-250 rpm for 10-20 min, and filter through a 0.22 μm filter membrane to obtain a drug solution; Step 5: After freeze-drying the drug solution, reconstitute it with purified water of an equal volume to the drug solution, and at the same time, add the phosphate buffer solution in step 1 as needed to adjust the pH to be consistent with the pH in step 4, fill it into a pre-sterilized oral liquid bottle, and sterilize it.

2. The method for preparing rupatadine fumarate oral solution according to claim 1, characterized in that: The mass ratio of sodium dihydrogen phosphate, disodium hydrogen phosphate and purified water in step 1 is 0.11-0.13:0.26-0.3:18-22.

3. The method for preparing rupatadine fumarate oral solution according to claim 1, characterized in that: The mass ratio of polyethylene glycol 400, glycerol, Tween-80 and menthol in step 2 is 23-27:14-16:1.8-2.2:0.8-1.

2.

4. The method for preparing rupatadine fumarate oral solution according to claim 1, characterized in that: The mass ratio of rupatadine fumarate, mannitol, potassium sorbate and the compound solvent in step 3 is 0.8-1.2:1.9-2.1:0.14-0.18:40-41.

5. The method for preparing rupatadine fumarate oral solution according to claim 1, characterized in that: The specific operation of freeze drying in step 5 is pre-freezing at normal pressure, followed by primary drying at a vacuum degree of 10Pa, secondary drying after the vacuum degree reaches 8Pa, and finally tertiary drying at a vacuum degree of 5Pa.

6. The method for preparing rupatadine fumarate oral solution according to claim 5, characterized in that: The pre-freezing temperature and time are -45°C and 3-5h respectively; the primary drying temperature and time are -25°C and 10-14h respectively; the secondary drying temperature and time are 0°C and 5-7h respectively; the tertiary drying temperature and time are 25°C and 2-4h respectively.

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