Dextromethorphan hydrobromide quinidine sulfate capsule and preparation method thereof

Abstract

The invention relates to a dextromethorphan hydrobromide quinidine sulfate capsule and a preparation method thereof. The dextromethorphan hydrobromide quinidine sulfate capsule comprises dextromethorphan hydrobromide, quinidine sulfate, a filling agent, a disintegrating agent, a flow aid, a lubricating agent and a capsule shell. The preparation process comprises the following steps: uniformly mixing the active ingredients with part of the auxiliary materials, preparing into particles through dry granulation, adding the lubricant, mixing, and filling into capsules. According to the dextromethorphan hydrobromide quinidine sulfate capsule and the preparation method thereof, the novel crystal form of quinidine sulfate found and disclosed for the first time is adopted, under the specific prescription, the stability of a preparation composition is improved and is kept consistent with the dosage form of an original research medicine, meanwhile, the dextromethorphan hydrobromide quinidine sulfate capsule provided by the invention is simple in preparation process, the quality of products between batches and in batches is stable, and the dextromethorphan hydrobromide quinidine sulfate capsule is suitable for industrial mass production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical oral solid preparations, and relates to a hydrobromide dextromethorphan quinidine sulfate capsule and a preparation method thereof. BACKGROUND

[0002] As a classic class I antiarrhythmic drug, quinidine sulfate was developed due to the high incidence of cardiovascular diseases and the urgent need for effective treatment drugs. In clinical practice, atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia and other arrhythmias are common cardiovascular emergencies. Patients often experience symptoms such as palpitations, chest tightness, dizziness, and in severe cases, heart failure, thromboembolism and other complications, and even life-threatening. Traditional treatment methods such as electrical conversion and drug conversion can temporarily correct arrhythmia, but the recurrence rate is high, and there is a lack of effective drugs for long-term maintenance therapy. Quinidine sulfate can effectively control ectopic rhythm and prevent arrhythmia recurrence by inhibiting myocardial cell membrane sodium channels, prolonging the effective refractory period, and reducing automaticity, becoming an indispensable treatment option in clinical practice. With the intensification of population aging (the proportion of people over 60 years old worldwide has reached 13%, and China is as high as 18.7%), the number of patients with cardiovascular diseases continues to grow (the number of patients with cardiovascular diseases in China has exceeded 300 million).

[0003] The molecular formula of quinidine sulfate is (C 20 H 24 N2O6)·H2SO4·2H2O, and the molecular weight is 782.96. Its chemical structural formula is as follows: 。

[0004] The development of dextromethorphan was due to the concern about the addiction of opioid antitussive drugs (such as morphine and codeine) in the mid-20th century. Morphine has a strong central antitussive effect, but long-term use can cause serious problems such as physiological dependence and withdrawal symptoms, and cannot be used as a daily cough medicine for long-term use. In search of a substitute drug that is "effective in cough but has no addiction", scientists at Hoffmann-La Roche initiated a structural modification study. By adjusting the chemical structure of morphine, the active site related to addiction was removed while the inhibition of the cough center was retained. Finally, dextromethorphan hydrobromide was successfully synthesized in the 1950s. Dextromethorphan inhibits the excitability of the medullary cough center and blocks the cough reflex pathway of the vagus nerve, thereby rapidly relieving cough symptoms. In 1958, the U.S. Food and Drug Administration (FDA) approved dextromethorphan as an over-the-counter drug (OTC), which quickly became one of the most commonly used cough medicines in the world due to its significant antitussive effect and lack of addiction (at the prescribed dose).

[0005] The molecular formula of dextromethorphan hydrobromide is C 18 H 25NO·HBr·H2O, with a molecular weight of 370.33, and its chemical structure is as follows: .

[0006] NUEDEXTA is a combination drug of dextromethorphan hydrobromide and quinidine sulfate developed by Avanir pharmaceuticals Inc. for treating pseudobulbar affect (PBA), which was first approved by FDA in October 2010 and by EU on June 25, 2013. The drug is the first and only one for treating PBA, which is also known as emotional incontinence, mainly secondary to nervous system diseases such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and stroke, and is characterized by sudden and unconscious crying or laughing. Quinidine sulfate itself is sensitive to light and has poor stability, and the existing public data also have this problem for the quinidine sulfate raw material used in the drug preparation.

[0007] Therefore, a dextromethorphan hydrobromide quinidine sulfate capsule and a preparation method thereof are designed to overcome the above problems. SUMMARY

[0008] The purpose of the present application is to overcome the deficiencies in the prior art and provide a dextromethorphan hydrobromide quinidine sulfate capsule and a preparation method thereof. The present application uses a newly discovered new crystal form of quinidine sulfate raw material, which has better stability in the finished product of the preparation composition prepared under specific prescription conditions with dextromethorphan hydrobromide and pharmaceutical excipients, and is consistent with the dosage form (capsule) of the original preparation, greatly enhancing the practicability of the dextromethorphan hydrobromide quinidine sulfate capsule.

[0009] The present application is realized by the following technical scheme: a dextromethorphan hydrobromide quinidine sulfate capsule, which comprises dextromethorphan hydrobromide, quinidine sulfate, disintegrant, filler, lubricant, glidant and capsule shell, wherein the prescription composition ratio of the capsule is as follows: Dextromethorphan hydrobromide: 20-30 mg after drying and purifying; Quinidine sulfate: 10-20 mg after drying and purifying; Filler: 75-90 %; Disintegrant: 2-5 %; Glidant: 0.5-2 %; Lubricant: 0.5-2 %.

[0010] As a preferred, the disintegrant is one or more of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose.

[0011] As preferred, the filler is one or more of lactose monohydrate, starch, sucrose, pregelatinized starch, microcrystalline cellulose, mannitol, sorbitol, erythritol, calcium carbonate.

[0012] As preferred, the lubricant is one or more of magnesium stearate, stearic acid, colloidal silicon dioxide, sodium stearyl fumarate.

[0013] As preferred, the glidant is colloidal silicon dioxide.

[0014] As preferred, the material of the capsule shell is hydroxypropyl methyl cellulose capsule.

[0015] A preparation method of dextromethorphan hydrobromide quinidine sulfate capsules, the method comprising the following steps: Step 1): the dextromethorphan hydrobromide, quinidine sulfate and disintegrant are uniformly premixed and sieved, and then the filler and the glidant are poured into a three-dimensional mixer and mixed uniformly, and then the lubricant is added and mixed; Step 2): the mixture obtained in step 1) is granulated using a dry granulator to obtain a mixture granule; Step 3): the granule prepared in step 2) is mixed with the lubricant; Step 4): the granule obtained in step 3) is filled into a capsule according to the prescription amount.

[0016] As preferred, the sieve used for sieving in step 1) is 40-50 mesh, and the parameters for the first mixing are: rotation speed 10 rpm, time 25-35 min; the parameters for the second mixing are: rotation speed 10 rpm, time 5 min.

[0017] As preferred, the parameters for the dry granulation in step 2) are as follows: the feeding speed of the dry granulation is 20-50 rpm, the pressure roller gap is 0.8-20 mm, the pressure roller pressure is 30-80 bar, the pressure roller rotation speed is 5-20 rpm, the primary screen mesh size is 4*4 mm, the primary crushing rotation speed is 80-120 rpm, the secondary screen mesh size is 0.8 mm, and the secondary crushing rotation speed is 100-150 rpm.

[0018] As preferred, the parameters for the mixing in step 3) are: rotation speed 10 rpm, time 5 min.

[0019] The beneficial effects of the present application are as follows: 1) The capsule and the preparation method thereof provided by the present application use a new crystal form of quinidine sulfate raw material which is first discovered, and under specific prescription conditions, the preparation composition prepared by the dextromethorphan hydrobromide and the pharmaceutical excipients significantly improves the stability of the preparation, and the prepared preparation does not have batch differences and batch differences, and the product quality is stable and controllable.

[0020] 2) The application mixes the dextromethorphan hydrobromide and quinidine sulfate with the disintegrant first, and then mixes with other excipients, which not only ensures the uniform distribution of the raw materials, the uniformity of mixing within the standard range, but also ensures the release of dextromethorphan hydrobromide and quinidine sulfate, so that the dissolution of the raw materials is more stable. DETAILED DESCRIPTION

[0021] In order to make those skilled in the art more clearly understand the purpose, technical scheme and advantages of the present application, the present application will be further described below in conjunction with examples.

[0022] In the description of the present application, it should be understood that the orientation or position relationship indicated by the terms such as "up", "down", "left", "right", "inner", "outer", "horizontal", "vertical" and the like is only for the convenience of describing the present application, and does not indicate or imply that the device or element referred to must have a particular orientation, so it cannot be understood as a limitation on the present application.

[0023] The present application will be described in detail as follows: a dextromethorphan hydrobromide quinidine sulfate capsule, the capsule contains dextromethorphan hydrobromide, quinidine sulfate, disintegrant, filler, lubricant, glidant and capsule shell, wherein the prescription composition ratio of the capsule is as follows: Dextromethorphan hydrobromide: 20-30 mg after drying and purifying; Quinidine sulfate: 10-20 mg after drying and purifying; Filler: 75~90 %; Disintegrant: 2~5 %; Glidant: 0.5~2 %; Lubricant: 0.5~2 %.

[0024] The disintegrant is one or more of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, more preferably one of cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose.

[0025] The filler is one or more of monohydrate lactose, starch, sucrose, pregelatinized starch, microcrystalline cellulose, mannitol, sorbitol, erythritol, calcium carbonate, more preferably one or more of monohydrate lactose, microcrystalline cellulose, mannitol.

[0026] The lubricant is one or more of magnesium stearate, stearic acid, micro-powder silica gel, sodium stearate fumarate.

[0027] The glidant is colloidal silicon dioxide.

[0028] The material of the capsule shell is hydroxypropyl methyl cellulose capsule.

[0029] A preparation method of dextromethorphan hydrobromide quinidine sulfate capsules, the method comprises the following steps: Step 1): the dextromethorphan hydrobromide, quinidine sulfate and disintegrating agent are uniformly premixed and sieved, and then the filler and the glidant are poured into a three-dimensional mixer and uniformly mixed, and then the lubricant is added and mixed; Step 2): the mixture obtained in step 1) is granulated using a dry granulator to obtain a mixture granule; Step 3): the granule prepared in step 2) is mixed with the lubricant; Step 4): the granule obtained in step 3) is filled into a capsule according to the prescription amount.

[0030] The sieve used for sieving in step 1) is 40-50 mesh, preferably 40 mesh, the parameters for the first mixing are: rotation speed 10 rpm, time 25-35 min; the parameters for the second mixing are: rotation speed 10 rpm, time 5 min.

[0031] The parameters for the dry granulation in step 2) are as follows: the feeding speed of the dry granulation is 20-50 rpm, the pressure roller gap is 0.8-20 mm, the pressure roller pressure is 30-80 bar, the pressure roller rotation speed is 5-20 rpm, the primary screen aperture is 4*4 mm, the primary crushing rotation speed is 80-120 rpm, the secondary screen aperture is 0.8 mm, and the secondary crushing rotation speed is 100-150 rpm.

[0032] The parameters for the mixing in step 3) are: rotation speed 10 rpm, time 5 min.

[0033] Example 1 The prescription of this example is shown in Table 1 below: Table 1

[0034] The preparation process is as follows: 1) weighing: weigh the prescription amount of raw materials and auxiliary materials for standby; 2) premixing: the dextromethorphan hydrobromide, quinidine sulfate and cross-linked povidone are uniformly premixed and sieved, and then the lactose monohydrate, microcrystalline cellulose and colloidal silicon dioxide are poured into a three-dimensional mixer, the mixing speed is set to 10 rpm, and the time is 30 min, then the inner-added magnesium stearate is added and mixed, the mixing speed is set to 10 rpm, and the time is 5 min; 3) dry granulation: the obtained mixture is granulated using a dry granulator, and the preferred dry granulation parameters are set to obtain a mixture granule; 4) total mixing: the mixture granule obtained by dry granulation is mixed with the added magnesium stearate, the mixing speed is set to 10 rpm, and the time is 5 min; 5) Filling: the standard filling amount is converted according to the sample content, and the filling amount control range is ±5%.

[0035] Example 2 The prescription of this example is shown in Table 2 below: Table 2

[0036] Preparation is carried out according to the method of Example 1.

[0037] Example 3 The prescription of this example is shown in Table 3 below: Table 3

[0038] Preparation is carried out according to the method of Example 1.

[0039] Example 4 The prescription of this example is shown in Table 4 below: Table 4

[0040] Preparation is carried out according to the method of Example 1.

[0041] It can be known from the above examples that the disclosed dextromethorphan hydrobromide and quinidine sulfate capsule and the preparation method thereof have good stability, small batch-to-batch difference, simple process operation, and are suitable for industrial production, and have far-reaching significance for the development and utilization of solid preparation drugs.

[0042] The specific examples described herein are merely illustrative of the principles of the present application and their efficacy, and are not intended to limit the present application. Any person skilled in the art can modify or change the above examples without departing from the spirit and scope of the present application. Therefore, all equivalent modifications or changes made by those skilled in the art without departing from the spirit and technical idea disclosed by the present application should be covered by the claims of the present application.

Claims

1. A capsule containing dextromethorphan hydrobromide and quinidine sulfate, characterized in that, The capsule contains dextromethorphan hydrobromide, quinidine sulfate, a disintegrant, a filler, a lubricant, a flow aid, and a capsule shell, wherein the formulation of the capsule is as follows: Dextromethorphan hydrobromide: 20-30 mg after drying and purification; Quinidine sulfate: 10-20 mg on dry and pure basis; Filler: 75~90%; Disintegrant: 2-5%; Flow aid: 0.5~2%; Lubricant: 0.5~2%.

2. The dextromethorphan hydrobromide and quinidine sulfate capsules according to claim 1, characterized in that, The disintegrant is one or more of crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone polyvinylpyrrolidone, and crospovidone carboxymethyl cellulose.

3. The dextromethorphan hydrobromide and quinidine sulfate capsules according to claim 1, characterized in that, The filler is one or more of the following: lactose monohydrate, starch, sucrose, pregelatinized starch, microcrystalline cellulose, mannitol, sorbitol, erythritol, and calcium carbonate.

4. The dextromethorphan hydrobromide and quinidine sulfate capsules according to claim 1, characterized in that, The lubricant is one or more of magnesium stearate, stearic acid, micronized silica gel, and sodium stearate fumarate.

5. The dextromethorphan hydrobromide and quinidine sulfate capsules according to claim 1, characterized in that, The flow aid is colloidal silica.

6. The dextromethorphan hydrobromide and quinidine sulfate capsules according to claim 1, characterized in that, The capsule shell is made of hydroxypropyl methylcellulose.

7. The method for preparing dextromethorphan hydrobromide and quinidine sulfate capsules according to any one of claims 1-6, characterized in that, The method includes the following steps: Step 1): After premixing dextromethorphan hydrobromide, quinidine sulfate and disintegrant evenly, sieve them, pour them together with filler and flow aid into a three-dimensional mixer and mix evenly, then add lubricant and mix. Step 2): Granulate the mixture obtained in Step 1) using a dry granulation machine to obtain mixture granules; Step 3): Mix the granules obtained in Step 2) with the lubricant; Step 4): Fill the capsules with the granules obtained in Step 3) according to the prescription amount.

8. The method for preparing dextromethorphan hydrobromide and quinidine sulfate capsules according to claim 7, characterized in that, The sieve used for sieving in step 1) is 40-50 mesh. The parameters for the first mixing are: rotation speed 10 rpm, time 25-35 min; the parameters for the second mixing are: rotation speed 10 rpm, time 5 min.

9. The method for preparing dextromethorphan hydrobromide and quinidine sulfate capsules according to claim 7, characterized in that, The parameters for dry granulation in step 2) are as follows: the feed rate for dry granulation is 20-50 rpm, the gap between the pressure rollers is 0.8-20 mm, the pressure of the pressure rollers is 30-80 bar, the rotation speed of the pressure rollers is 5-20 rpm, the aperture of the primary screen is 4*4 mm, the rotation speed of the primary crushing is 80-120 rpm, the aperture of the secondary screen is 0.8 mm, and the rotation speed of the secondary crushing is 100-150 rpm.

10. The method for preparing dextromethorphan hydrobromide and quinidine sulfate capsules according to claim 7, characterized in that, The mixing parameters in step 3) are: rotation speed 10 rpm, time 5 min.

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