WO2023193745A1

WO2023193745A1 - Dextromethorphan-quinidine orally disintegrating tablet and use thereof

Info

Publication number: WO2023193745A1
Application number: PCT/CN2023/086493
Authority: WO
Inventors: 戴莉香; 裘少君; 殷乐; 陈强欣; 李海燕; 陈红敏; 赖才达; 王文首
Original assignee: 北京剂泰医药科技有限公司; 杭州剂泰医药科技有限责任公司
Priority date: 2022-04-06
Filing date: 2023-04-06
Publication date: 2023-10-12
Also published as: CN114469882B; CN114469882A

Abstract

A dextromethorphan-quinidine orally disintegrating tablet, a preparation method therefor and use thereof in preparing drugs for treating and/or preventing pseudobulbar affect, dysphagia, drooling or language disorders, and cognitive defects in patients with nervous system diseases. The dextromethorphan-quinidine orally disintegrating tablet comprises dextromethorphan, a pharmaceutically acceptable salt thereof or a hydrate thereof, quinidine, a pharmaceutically acceptable salt thereof or a hydrate thereof, a flavoring agent and a disintegrating agent, wherein the addition of the flavoring agent eases the problem that dextromethorphan and quinidine taste intensely bitter; the prepared orally disintegrating tablet easily disintegrates, solving the problem of dysphagia in patients with nervous system diseases and also improving the patients' medication experience.

Description

A kind of dextromethorphan quinidine orally disintegrating tablet and its application

Cross-references to related applications

This invention claims the priority of the earlier application submitted to the State Intellectual Property Office of China on April 6, 2022 with the patent application number 202210353658.5 and the invention title being "A Dextromethorphan Quinidine Orally Disintegrating Tablet and its Application". The entirety of this earlier application is incorporated herein by reference.

Technical field

The present invention relates to the field of pharmaceutical preparations, and specifically relates to an orally disintegrating tablet containing dextromethorphan and quinidine and its preparation method and application.

Background technique

Dextromethorphan hydrobromide and quinidine sulfate are a compound drug developed by Avanir Pharmaceuticals Inc to treat pseudobulbar affect (PBA). It was first approved by the FDA in October 2010. The drug is the first and only drug used to treat PBA, also known as emotional incontinence, which is mainly secondary to neurological diseases such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and stroke. Sudden involuntary crying or laughing.

Dextromethorphan and quinidine taste very bad, bitter and numbing, and are currently available in capsule form. Patients with neurological diseases often have symptoms such as difficulty swallowing and salivation. Studies have shown that the incidence of dysphagia in patients with Parkinson's disease is 11-87%. More than 50% of patients with acute cerebral infarction are accompanied by varying degrees of dysphagia. The prevalence of dysphagia among stroke patients is approximately 51-73%. PBA patients basically have difficulty swallowing, so capsules are not suitable for PBA patients. Swallowing capsules increases the pain of these patients.

CN113209042, CN107072990 and Journal of Affective Disorders (2014), 167, 333-335 disclose dextromethorphan quinidine capsules and ordinary tablets, which cannot meet the medication needs of patients with dysphagia.

Pharm Dev Technol. 24(6), 711-719, 2019, disclosed that the lubricant sodium stearyl fumarate in dextromethorphan hydrobromide orally disintegrating tablets can play an enhanced taste-masking effect. Chem.Pharm.Bull.50(12), 1589-1593, 2002, disclosed the masking of quinidine optical isomer quinid by sucralose, aspartame, sodium chloride, phosphatidic acid and tannic acid. The taste effect and possible taste-masking mechanism indicate that the use of electronic sensors (electronic tongues) and human tasters can obtain consistent bitter taste assessment results. However, the two above-mentioned taste-masking related documents do not disclose the taste-masking of the dextromethorphan-quinidine composition. The invention of this application In previous studies, people found that after adding different concentrations of commonly used flavoring agents to the dextromethorphan-quinidine composition, the evaluation results of the electronic tongue showed that the bitterness, sourness and other tastes of the composition were basically not improved, so it was necessary to test the dextromethorphan-quinidine composition. The taste-masking of dextromethorphan-quinidine compositions was studied in depth.

In summary, in order to alleviate patients' pain, there is an urgent need to develop a new dosage form that can simultaneously satisfy taste masking and ease of swallowing.

Contents of the invention

The purpose of the present invention is to solve the problems in the prior art and provide a dextromethorphan quinidine orally disintegrating tablet with good taste and disintegration speed and high dissolution rate, its preparation method and application.

The object of the present invention can be achieved through the following technical solutions:

The invention provides an orally disintegrating tablet of dextromethorphan and quinidine, which contains dextromethorphan, a pharmaceutically acceptable salt thereof or a hydrate thereof, quinidine, a pharmaceutically acceptable salt thereof or a hydrate thereof. substances, flavoring agents and disintegrating agents.

The "dextromethorphan" in the dextromethorphan and quinidine orally disintegrating tablets described in the present invention refers to dextromethorphan, its pharmaceutically acceptable salts or its hydrates, including but not limited to hydrobromide, salts Acid salt, phosphate, hydroiodide, nitrate, formate, sulfate, acetate, propionate, butyrate, trifluoroacetate, p-toluenesulfonate, lysine salt, N,N'dibenylethylenediamine salt, procaine salt, chloroprocaine salt, diethylene glycolamine salt, ethylenediamine salt, meglumine salt, lithium salt, sodium salt, potassium salt, calcium salt Salt, magnesium salt or hydrate of the above salt, preferably hydrobromide, hydrochloride, phosphate, hydroiodide or hydrate of the above salt, more preferably hydrobromide or hydrobromide hydrate ; "Quinidine" refers to quinidine, its pharmaceutically acceptable salts or its hydrates, including but not limited to sulfate, polygalacturonate, hydrochloride, hydroiodide, hydrobromide Salt, phosphate, nitrate, oxalate, p-toluenesulfonate, gluconate, lysine salt, N,N'dibenylethylenediamine salt, procaine salt, chloroprocaine salt , diethylene glycol amine salt, ethylenediamine salt, meglumine salt, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt or hydrates of the above salts, preferably sulfate, polygalacturonate , hydrochloride or hydrate of the above salt, more preferably sulfate or sulfate hydrate.

Both dextromethorphan and quinidine have poor taste, and both dextromethorphan and quinidine taste bitter and numbing. In order to prepare easily acceptable orally disintegrating tablets and improve patient compliance, it is necessary to add flavoring agents in addition to disintegrating agents.

In a preferred embodiment, the flavoring agent of the dextromethorphan and quinidine orally disintegrating tablets provided by the present invention is one or more of sweeteners, flavors and sour agents, preferably containing at least one sweet taste. agent.

The inventor of the present application discovered during the early development process that the fragrance of the essence is difficult to blend with the taste of the raw material medicine, which has a taste-masking effect. The bitterness, numbing taste and the smell of the essence are all relatively obvious in the prepared preparation, and the sour taste is The agent can improve the taste of orally disintegrating tablets, but it is not enough to meet the taste-masking requirements. Only sweeteners can achieve a good taste-masking effect.

In order to obtain the optimal taste-masking prescription based on the addition of sweeteners, we combined high-throughput experiments with computer artificial intelligence to select easily available sweeteners, flavors, sourants and their combinations, from possible From the sample data of more than a thousand taste-masking combinations, the influence of each excipient on the taste-masking effect of dextromethorphan and quinidine was obtained.

In a preferred embodiment, the sweetener of the dextromethorphan quinidine orally disintegrating tablets provided by the present invention is sucrose or its derivatives, aspartame, fructose, steviol glycosides, mannitol or sorbitol. One or more, preferably one or more of sucrose or its derivatives, aspartame, fructose or steviol glycosides, more preferably one or more of sucralose or aspartame.

Using the results of high-throughput screening experiments as data, computer artificial intelligence analysis shows that the taste-masking effect of sweeteners is not necessarily related to their sweetness. Furthermore, sucralose, aspartame, fructose, sucrose, steviol glycosides, sorbitol or mannitol all have a positive impact on the taste-masking effect. Among them, sucralose and aspartame have similar effects on the taste-masking effect, about 2-3 times that of fructose, sucrose or steviol glycosides, 3-4 times that of sorbitol or mannitol, and more powerful than dextromethorphan The preferred sweetener for nitin taste masking.

In a preferred embodiment, the flavor of the dextromethorphan quinidine orally disintegrating tablets provided by the present invention is one or more of sweet orange flavor, mint flavor, milk flavor and strawberry flavor, preferably sweet orange flavor. , one or more of mint flavor or milk flavor, more preferably one or more of sweet orange flavor or mint flavor.

On the basis of adding sweeteners, adding flavors can improve the medication experience of medicines. Furthermore, with the addition of sweeteners, sweet orange flavor, mint flavor and milk flavor all have a positive impact on the taste masking of dextromethorphan and quinidine, while strawberry flavor has a negative impact.

In addition, the inventor of the present application conducted raw material and auxiliary material compatibility testing on various flavoring agents before high-throughput screening of flavoring agents. The results showed that cherry flavor, pineapple flavor and vitamin C would lead to an increase in impurities under the test conditions and had poor compatibility with dextromethorphan and quinidine, so they were not selected. The sweetener steviol glycoside itself will have new impurities and cannot meet the compatibility requirements of raw materials and excipients, so it is not selected.

In a preferred embodiment, the sour agent of the dextromethorphan quinidine orally disintegrating tablets provided by the present invention is sodium carbonate, potassium carbonate, sodium chloride, potassium chloride, sodium hydroxide, vitamin C, citric acid, One or more lactic acids are preferably one or more sodium carbonate, potassium carbonate, sodium chloride, potassium chloride, and sodium hydroxide, and more preferably sodium chloride or sodium carbonate.

The sour agent can increase the decomposition of saliva in the oral cavity, supplement the saliva consumed when the orally disintegrating tablets of dextromethorphan and quinidine disintegrate in the oral cavity, and improve the taste of the orally disintegrating tablets.

In a preferred embodiment, the flavor screening method for dextromethorphan quinidine orally disintegrating tablets provided by the present invention includes the following steps:

(1) Preparing an aqueous solution of dextromethorphan, its pharmaceutically acceptable salt or its hydrate and quinidine, its pharmaceutically acceptable salt or its hydrate;

(2) Prepare an aqueous solution of flavoring agents;

(3) Use the Halton sampling method to select some samples for high-throughput experiments. Add the aqueous solutions prepared in steps (1) and (2) to the well plates. After mixing evenly, test the taste masking effect and obtain the taste masking results. ; Among them, artificial taste is preferred for testing the taste-masking effect;

(4) Use computer artificial intelligence to build a model based on the taste masking results to obtain a flavoring agent with good flavor correction effect.

The present invention adopts a method that combines high-throughput experiments and computer artificial intelligence. Compared with traditional experimental methods, the taste-masking effect of each taste-masking excipient on dextromethorphan-quinidine can be obtained efficiently and intuitively.

In the early stage of research and development, the inventor of the present application used an electronic tongue to test the taste-masking effect of the taste-masking prescription. It was found that unlike the taste-masking effect of a single prescription of quinil in the prior art, for the dextromethorphan-quinidine composition, after adding different concentrations of commonly used flavoring agents, the evaluation results of the electronic tongue all showed that the composition had a bitter taste. There is basically no improvement in the taste such as sourness and dextromethorphan. It may be that the taste-masking mechanism of the dextromethorphan-quinidine combination is inconsistent with the taste-masking mechanism of quinid or the bitter taste of dextromethorphan-quinidine is too great. Therefore, this application uses the oral taste of volunteers. way to obtain more accurate taste masking results.

In a preferred embodiment, the disintegrating agent of the dextromethorphan quinidine orally disintegrating tablets provided by the present invention is crospovidone, sodium carboxymethyl starch, low-substituted cellulose, and low-substituted hydroxypropylcellulose. , one or more of crospovidone, croscarmellose sodium, preferably at least crospovidone, more preferably crospovidone or crospovidone and croscarmellose Sodium methylcellulose combination.

Due to the addition of hygroscopic flavoring agents, the disintegration properties of dextromethorphan and quinidine are greatly affected. The inventor of the present application found that when the disintegrant contains crospovidone, especially when the disintegrant is crospovidone or crospovidone and croscarmellose sodium, the orally disintegrating tablets It can disintegrate within 40s and has good disintegration performance.

In a preferred embodiment, the weight of the disintegrant of the dextromethorphan and quinidine orally disintegrating tablets provided by the present invention accounts for 10-35% of the total weight of the dextromethorphan and quinidine orally disintegrating tablets, preferably 20 -30%.

As mentioned above, because the taste of dextromethorphan and quinidine is too bad, the added flavoring agent is highly hygroscopic and the dosage is large, which leads to the need to add more disintegrants to ensure the disintegration of the orally disintegrating tablets. When the dosage of disintegrant is more than 10%, the requirement of disintegration of orally disintegrating tablets within 60 seconds can be met. When the mass content of the disintegrant is more than 20%, the disintegration time can be within 40 seconds.

In a preferred embodiment, the dextromethorphan quinidine orally disintegrating tablets provided by the present invention also contain one or more of lubricants and fillers.

In a preferred embodiment, the lubricant is colloidal silica, sodium stearyl fumarate, magnesium stearate, polymer One or more of ethylene glycol, magnesium lauryl sulfate, hydrogenated vegetable oil, talc, and micronized silica gel, preferably one or more of colloidal silica and sodium stearyl fumarate.

In a preferred embodiment, the filler is one of microcrystalline cellulose, mannitol, xylitol, starch, powdered sugar, saccharin, lactose, pregelatinized starch, calcium sulfate, calcium hydrogen phosphate, and calcium carbonate. One or more, preferably one or more of microcrystalline cellulose, xylitol, and mannitol.

The invention also provides a preparation method of dextromethorphan quinidine orally disintegrating tablets, which includes the following steps:

(1) Mix dextromethorphan, its pharmaceutically acceptable salt or its hydrate, quinidine, its pharmaceutically acceptable salt or its hydrate with a lubricant, sieve, and add fillers and flavorings. Mix the agent and disintegrant, sieve them, then add lubricant and mix;

(2) Granulate the mixture obtained in step (1) using a dry granulator to obtain mixture granules;

(3) Mix the granules prepared in step (2) with a lubricant and a disintegrating agent;

(4). Compress the mixture obtained in step (3) into tablets to obtain dextromethorphan-quinidine orally disintegrating tablets.

Another object of the present invention is to provide a dextromethorphan and quinidine orally disintegrating tablet prepared for the treatment and/or prevention of pseudobulbar mood, dysphagia, salivation or language disorders, and cognitive defects in patients with neurological diseases. uses in.

Compared with the prior art, the present invention achieves the following unexpected technical effects:

1. The present invention provides a dextromethorphan-quinidine preparation that is easy to swallow and has good taste-masking effect.

2. The present invention combines high-throughput screening experiments with computer artificial intelligence to efficiently and accurately obtain the impact of each flavoring agent on the taste-masking effect of dextromethorphan-quinidine.

3. When hygroscopic flavoring agents are added to the orally disintegrating tablets provided by the present invention, the disintegration time is short and the taste is easy to accept, which greatly improves the medication experience of patients with neurological diseases.

Description of the drawings

Figure 1 is an important factor analysis diagram of the high-throughput experimental results of the screening of flavoring agents of the present invention.

Detailed ways

The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following examples are only illustrative and explain the present invention and should not be construed as limiting the scope of the present invention. All technologies implemented based on the above contents of the present invention are covered by the scope of protection intended by the present invention.

Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

Example 1

Weigh 20mg dextromethorphan hydrobromide, 10mg quinidine sulfate and 2mg colloidal silica, mix and sieve, add 32mg mannitol, 16mg xylitol, 40mg microcrystalline cellulose, 10mg crospovidone , 10mg croscarmellose sodium, 4mg sucralose and 4mg peppermint flavor, mix and sieve, mix again, add 2mg sieved sodium stearyl fumarate, mix well and use dry granulation mechanism grain. Then add 10 mg of screened crospovidone, 10 mg of screened croscarmellose sodium and 2 mg of screened sodium stearyl fumarate, mix evenly and press into tablets to obtain dextromethorphan quinine Nidin is an orally disintegrating tablet.

Example 2

Weigh 20mg dextromethorphan hydrobromide, 10mg quinidine sulfate and 2mg colloidal silica, mix and sieve, add 32mg mannitol, 16mg xylitol, 40mg microcrystalline cellulose, 20mg crospovidone , 4mg sucralose and 4mg peppermint flavor, mix and sieve, mix again, add 2mg sieved sodium stearyl fumarate, mix well and use a dry granulator to granulate. Then add 20 mg of screened crospovidone and 2 mg of screened sodium stearyl fumarate, mix evenly and press the tablets to obtain dextromethorphan quinidine orally disintegrating tablets.

Example 3

Weigh 20mg dextromethorphan hydrobromide, 10mg quinidine sulfate and 2mg colloidal silica, mix and sieve, add 32mg mannitol, 16mg xylitol, 40mg microcrystalline cellulose, 20mg crospovidone , 4mg aspartame and 4mg mint flavor, mix and sieve, mix again, add 2mg of sieved sodium stearyl fumarate, mix well and use a dry granulator to granulate. Then add 20 mg of screened crospovidone and 2 mg of screened sodium stearyl fumarate, mix evenly and press the tablets to obtain dextromethorphan quinidine orally disintegrating tablets.

Example 4

Weigh 20mg dextromethorphan hydrobromide, 10mg quinidine sulfate and 2mg colloidal silica, mix and sieve, add 32mg mannitol, 16mg xylitol, 24mg microcrystalline cellulose, 20mg crospovidone , 20mg sucrose and 4mg mint flavor, mix and sieve, mix again, add 2mg sieved sodium stearyl fumarate, mix well and use a dry granulator to granulate. Then add 20 mg of screened crospovidone and 2 mg of screened sodium stearyl fumarate, mix evenly and press the tablets to obtain dextromethorphan quinidine orally disintegrating tablets.

Example 5

Select commonly used sweeteners, flavors and sour agents shown in Table 1, and prepare them into aqueous solutions with a concentration of 10.4 mg/mL. Select any three of them and ensure that they contain at least one sweetener. There are a total of 1,372 flavoring prescriptions. Halton sampling method was used to select 251 groups of samples for high-throughput experiments. The selected samples are shown in Table 2.

Add the flavoring solutions of the combinations shown in Table 2 to the well plates of the high-throughput experimental device. Each flavoring solution Take 0.1 mL, add 0.5 mL of dextromethorphan hydrobromide aqueous solution (10.4 mg/mL) and 0.5 mL of quinidine sulfate aqueous solution (5.2 mg/mL) into each well, mix evenly, and perform artificial taste. The tasting steps are as follows:

Volunteers should not eat, drink, or chew gum for at least 1 hour before the test, and rinse their mouths with deionized water. Use a dropper to draw 1 mL of sample into your mouth, hold the sample solution in your mouth for 5 seconds and rinse your mouth so that the taste sensing areas at the base and sides of the tongue can fully feel the taste of the drug, spit it out, and rinse your mouth with deionized water until there is no odor in your mouth before proceeding to the next time. experiment.

Volunteers rated the bitterness, numbness, sourness and sweetness of the prescription they tasted on a 10-point scale. The higher the score, the stronger the corresponding taste. Bitterness and numbness are scored as negative values, sourness and sweetness are scored as positive values, and the four scores are added to obtain a comprehensive score.

Table 1

Table 2

The taste results of 251 prescriptions were modeled using computer artificial intelligence (sour value<5, -5<bitter value<0, -5<numbing value<0, and the comprehensive score>0 is a positive sample, otherwise it is a negative sample sample), and analyze the characteristic importance of each excipient, the results are shown in Figure 1. In Figure 1, the SHAP value > 0 indicates that the point may be a positive sample. The larger the value, the greater the possibility of becoming a positive sample. At the same time, the dark dots in the figure indicate that the prescription contains this excipient, and the light dots indicate that the prescription does not contain this excipient.

The importance of the characteristics of various excipients was quantitatively analyzed to obtain the contribution of various excipients to the flavoring effect of dextromethorphan and quinidine, that is, the influence. The results are shown in Table 3.

table 3

Combining Figure 1 and Table 3, it can be concluded that sucralose, aspartame, fructose, sucrose, steviol glycosides, sorbitol or mannitol have a positive impact on the taste-masking effect. Among them, sucralose and aspartame Batame has a similar effect on the flavoring effect, about 2-3 times that of fructose, sucrose or stevia glycosides, and 3-4 times that of mannitol or sorbitol. With the addition of sweeteners, the strawberry essence in the flavor and the citric acid and lactic acid in the sour agent still have a negative impact on the taste-masking effect.

Example 6

Use the same flavoring agent and add different disintegrants to prepare a blank prescription without active ingredients, and examine the disintegration time. The results are shown in Table 4.

Table 4

The results show that when the disintegrant contains cross-linked povidone, a satisfactory disintegration effect can be achieved.

Example 7

According to the same preparation method as Example 1, formulas with different disintegrant contents were prepared and their disintegration times were measured. The results are shown in Table 5.

table 5

The results show that the orally disintegrating tablets prepared by the present invention can meet the disintegration time requirements of orally disintegrating tablets. As the content of crospovidone in the prescription increases, the disintegration rate of the orally disintegrating tablets increases. In order to ensure the disintegration time within 40 seconds and ensure the taste-masking effect, the content range of the disintegrant is selected to be 20-30% (w%).

Example 8

The orally disintegrating tablets prepared according to the present invention are tested in enzyme-free simulated gastric juice (pH 1.2) (temperature 37.0°C ± 0.5°C) using the first method (basket method) of the four dissolution and release determination methods in the 2020 version of the Chinese Pharmacopoeia For the dissolution of dextromethorphan hydrobromide and quinidine sulfate, samples were taken at 5 min, 10 min and 30 min respectively, and the dissolution rate (%) was determined by high performance liquid chromatography. Taking the orally disintegrating tablet prepared in Example 4 as an example, The dissolution data are shown in Table 6.

Table 6

The results show that the orally disintegrating tablets obtained by the present invention have very good dissolution rates in enzyme-free simulated gastric juice (pH 1.2). At 5 minutes, the dissolution rates of dextromethorphan hydrobromide and quinidine sulfate have reached More than 90%, meeting the dissolution requirements of immediate-release preparations.

Comparative ratio

Comparative example 1

The sweetener in Example 1 was removed, and the remaining components remained unchanged to prepare dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets.

Comparative example 2

The sweetener in Example 2 or 3 was replaced with mannitol to prepare dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets.

Comparative Example 3-4

With reference to the prescription proportions in Example 2-3 of patent document CN1720917A, dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets were prepared.

Comparative example 3 prescription table:

Comparative Example 4 Prescription Table

Comparative example 5

Dextromethorphan hydrobromide orally disintegrating tablets containing 20 mg of dextromethorphan hydrobromide were prepared according to the prescription in Example 3 of patent document CN1720917A. The prescription table is as follows:

Comparative example 6

The sweetener in Example 2 or 3 was replaced with saccharin sodium to prepare dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets.

Comparative Example 7: Analysis of taste masking effect

Each prepared orally disintegrating tablet was tasted manually to evaluate the taste-masking effect. Ten volunteers were selected for each batch of drugs to conduct the experiment.

The taste method is as follows: volunteers moisten their mouths before taking the medicine. Place the tablet on the upper part of the tongue, move the tongue until the tablet lumps disappear, and then spit the medicine out. Record the numbness and bitterness of the slices you taste. Rinse your mouth until no bitter taste remains in your mouth before tasting the next batch of tablets.

Since some tablets have a strong numbing smell, and the numbing smell has a certain hysteresis effect, the accumulation of numbing smell from multiple batches of tablets will have an impact on the subsequent evaluation of the numbing taste. Therefore, when volunteers feel an obvious numbing smell, they need to wait until the numbing smell occurs. Eliminate and proceed to the next batch of taste experiments.

After taste experiments, the taste masking effects of each embodiment and comparative example are obtained as follows in Table 7

Table 7

The results show that using the dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets prepared in Examples 1-3 of the present application, the numbness of the tongue is basically covered, and 7-10 people think it is not bitter. In contrast, when the sweetener in Example 1 of the present application is removed or the sweetener in Examples 2-3 is replaced with mannitol, the number of people who are not bitter is 0. For Comparative Example 2, even half of the volunteers It is considered extremely bitter and has a strong numbing taste. It can be seen that the addition of the sweetener sucralose or aspartame in this application plays a very important role in the taste-masking effect.

Compared with the patent document CN1720917A, the taste-masking effect of Example 3 of the patent document CN1720917A, which only masks the taste of dextromethorphan hydrobromide orally disintegrating tablets, is unsatisfactory. It can be seen that the patent document CN1720917A does not pay attention to the orally disintegrating tablets. The taste masking effect. When quinidine sulfate is added according to the formula of patent document CN1720917A, although the numbness of the tongue is basically covered, only 2-3 people think it is not bitter, that is, the bitter taste is not well covered.

In addition, the inventor also selected saccharin sodium with relatively high sweetness (300-600 sweetness relative to sucrose) to prepare a formula and conducted a taste experiment. The experimental results showed that although the numbness of the tongue was basically covered, there was as much as 8 people thought that the medicinal taste was bitter; correspondingly, only 3 people thought that aspartame, which has a relative sweetness lower than saccharin (the sweetness relative to sucrose is 200), was bitter or extremely bitter. This experiment further proves that for dextromethorphan hydrobromide and quinidine sulfate orally disintegrating tablets, the selection of sweeteners needs to rely on specific experimental evaluations and cannot be selected solely based on conventional indicators such as relative sweetness.

In summary, the technical solution of the present application has obvious advantages in the taste-masking effect of dextromethorphan hydrobromide and quinidine sulfate compared with the technical solution without adding sweetener and the patent document CN1720917A.

It should be pointed out that the above-mentioned preferred embodiments are further non-limiting detailed descriptions of the technical solutions of the present invention, and are only used to illustrate the technical concepts and features of the present invention. The purpose is to enable those familiar with the technology to understand the content of the present invention and implement it, but does not limit the scope of protection of the present invention. All equivalent changes or modifications made based on the spirit and essence of the present invention should be included in the protection scope of the present invention.

Claims

An orally disintegrating tablet of dextromethorphan and quinidine, characterized by: containing dextromethorphan, a pharmaceutically acceptable salt thereof or a hydrate thereof, quinidine, a pharmaceutically acceptable salt thereof or a hydrate thereof, and flavoring agents and disintegrants.
The orally disintegrating tablet according to claim 1, wherein the flavoring agent is one or more of a sweetener, an essence and a sour agent, and preferably contains at least one sweetener.
The orally disintegrating tablet according to claim 2, wherein the sweetener is one or more of sucrose or its derivatives, aspartame, fructose, steviol glycosides, mannitol or sorbitol, Preferably it is one or more of sucrose or its derivatives, aspartame, fructose or steviol glycosides, more preferably one or more of sucralose or aspartame, more preferably dextromethorphan, The mass ratio of quinidine and sucralose or aspartame is 5:2.5:1, or the prescription ratio of sucralose or aspartame is 2.33%; the flavors are sweet orange flavor, mint flavor, milk One or more of the flavors or strawberry flavors, preferably one or more of the sweet orange flavor, mint flavor or milk flavor, more preferably one or more of the sweet orange flavor or mint flavor; said The sour agent is one or more of sodium carbonate, potassium carbonate, sodium chloride, potassium chloride, sodium hydroxide, citric acid, and lactic acid, preferably sodium carbonate, potassium carbonate, sodium chloride, potassium chloride, hydrogen One or more types of sodium oxide, more preferably sodium chloride or sodium carbonate.
The orally disintegrating tablet according to claim 1, wherein the disintegrating agent is crospovidone, sodium carboxymethyl starch, low-substituted cellulose, low-substituted hydroxypropylcellulose, or cross-linked polyvinylpyrrolidone. , one or more of croscarmellose sodium, preferably containing at least crospovidone, more preferably crospovidone or crospovidone and croscarmellose sodium The combination.
The orally disintegrating tablet according to claim 1, wherein the weight of the disintegrant accounts for 10%-35% of the total weight of the orally disintegrating tablet, preferably 20-30%.
The orally disintegrating tablet according to claim 1, further comprising one or more of a lubricant and a filler.
The orally disintegrating tablet according to claim 6, wherein the lubricant is colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, polyethylene glycol, magnesium lauryl sulfate, and hydrogenated vegetable oil. , one or more of talc powder and micronized silica gel, preferably one or more of colloidal silica and sodium stearyl fumarate; the filler is microcrystalline cellulose, xylitol, One or more of mannitol, starch, powdered sugar, saccharin, lactose, pregelatinized starch, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, preferably one of microcrystalline cellulose, xylitol or mannitol Kind or variety.
A method for preparing orally disintegrating tablets as claimed in claim 1, characterized in that: comprising the following steps:

(1) Mix dextromethorphan, its pharmaceutically acceptable salt or its hydrate, quinidine, its pharmaceutically acceptable salt or its hydrate with a lubricant, sieve, and add fillers and flavorings. Mix the agent and disintegrant, sieve them, then add lubricant and mix;

(2) Granulate the mixture obtained in step (1) using a dry granulator to obtain mixture granules;

(3) Mix the granules prepared in step (2) with a lubricant and a disintegrating agent;

(4). Compress the mixture obtained in step (3) into tablets to obtain dextromethorphan-quinidine orally disintegrating tablets.
A kind of dextromethorphan quinidine orally disintegrating tablet as claimed in claim 1 in the preparation of drugs for treating and/or preventing pseudobulbar mood, dysphagia, salivation or language disorders, and cognitive defects in patients with neurological diseases. the use of.