Midazolam maleate orally disintegrating tablet and preparation method thereof

Abstract

The invention belongs to the technical field of first-aid calming medicinal preparations, and relates to a midazolam maleate orally disintegrating tablet and a preparation method thereof. The midazolam maleate orally disintegrating tablet is prepared from midazolam maleate, a filling agent, a disintegrating agent, a lubricating agent and dithiothreitol. According to the midazolam maleate orally disintegrating tablet and the preparation method thereof, the formula and the preparation process of the midazolam maleate orally disintegrating tablet are optimized, the stability of midazolam maleate is effectively improved, the content of related substances in an acceleration test is low, effective components are stable, and in addition, due to good control in the aspects of the formula, the process and the like, the disintegration speed of the medicine in the mouth and the taking experience of a patient are effectively balanced.

Description

Technical Field

[0001] The invention belongs to the technical field of emergency sedative drug preparations, and particularly relates to a midazolam maleate orodisintegrating tablet and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] In the field of modern medical emergency, rapid and effective control of patients' emergency symptoms is crucial to saving lives and improving prognosis. Various emergency medical conditions, such as status epilepticus, severe agitation and delirium, and mental stress caused by acute cardiovascular events, urgently need fast-acting drug intervention.

[0004] Midazolam is a 7-chloro-1,3-diaza[2,3,5]benzo[1,4]diazepine pyridine-2-one compound with high lipophilicity, which makes it quick and obvious when entering the central nervous system. It has good anxiolytic, sedative, anticonvulsant and other pharmacological activities. Midazolam exerts its sedative effect by acting on the cerebral cortex and other parts of the central nervous system. It binds to γ-aminobutyric acid (GABA) receptors, enhances the inhibitory effect of GABA, and then inhibits nerve conduction. GABA receptors are the main inhibitory receptors in the central nervous system. Enhancing the effect of GABA will lead to a decrease in neural activity, thereby playing a sedative, anxiolytic, anticonvulsant and muscle relaxant role. Midazolam maleate is the hydrochloride form of midazolam. The double salt formed with maleic acid can improve the water solubility of midazolam.

[0005] Chinese patent publication number CN103932999A discloses a midazolam maleate dispersible tablet comprising: 7.5 parts by weight of midazolam maleate, 15 to 80 parts by weight of microcrystalline cellulose, 8 to 12 parts by weight of micropowdered silica gel, 25 to 40 parts by weight of a binder, 1.5 to 3 parts by weight of a moisture-isolating lubricant such as magnesium stearate or calcium stearate, and 5 to 12 parts by weight of a flavoring agent.

[0006] Traditional midazolam maleate preparations, such as ordinary tablets, have some limitations. For some special patient groups, such as elderly patients, children, patients with dysphagia, and patients who cannot swallow normally in emergency medical conditions, it is difficult to take ordinary tablets, which may lead to poor patient compliance and even delay treatment. As a new form of drug preparation, orodisintegrating tablets can quickly disintegrate and disperse in the mouth, without the need for water, and can effectively solve the above problems. It is not only convenient for patients to take, especially for those who have difficulty swallowing traditional tablets, but also can take effect quickly, improve the bioavailability of drugs, and reduce the first-pass effect in the gastrointestinal tract.

[0007] However, due to its physical and chemical properties, such as low melting point and sensitivity to light and heat, midazolam maleate faces many challenges in the preparation of orally disintegrating tablets. For example, how to ensure the stability of the drug and prevent its degradation or deterioration during the preparation process, while ensuring that the orally disintegrating tablets have good taste, rapid disintegration performance, and appropriate hardness and other quality indicators, is the focus and difficulty of current research. Summary of the invention

[0008] From the perspective of the balance between the stability of midazolam maleate and the disintegration rate and the patient's taking experience, the present invention improves the preparation process and formula of midazolam maleate orodisintegrating tablets, overcomes the problems of the prior art such as slow onset of action and poor stability, and provides a midazolam maleate orodisintegrating tablet with high stability, fast onset of action and good taking experience.

[0009] Specifically, the formula of the orally disintegrating midazolam maleate tablets of the present invention is: 5 to 15 parts by weight of midazolam maleate, 40 to 180 parts by weight of filler, 15 to 30 parts by weight of disintegrant, 0.5 to 2.5 parts by weight of lubricant, and 2 to 5 parts by weight of dithiothreitol.

[0010] Furthermore, the filler is selected from one or more of starch, microcrystalline cellulose, lactose, mannitol, hydroxypropyl methylcellulose, calcium carbonate, and calcium phosphate; the disintegrant is selected from one or more of carboxymethyl starch sodium, hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, sodium tripolyphosphate, maltodextrin, and low-substituted hydroxypropyl methylcellulose; the lubricant is selected from one or more of stearic acid, magnesium stearate, talc, silicon dioxide, polydimethylsiloxane, polyethylene glycol 4000, and polyethylene glycol 6000; preferably, the filler is starch, microcrystalline cellulose, and calcium carbonate; the disintegrant is sodium tripolyphosphate and maltodextrin; and the lubricant is polyethylene glycol 4000.

[0011] In addition, in order to improve the taste of the orodisintegrating midazolam maleate tablets, a flavoring agent may be added, wherein the flavoring agent is selected from one or more of aspartame, sucralose, glucose, and essence.

[0012] The present invention also provides a method for preparing the above-mentioned midazolam maleate orally disintegrating tablets, comprising the following steps:

[0013] (1) dissolving dithiothreitol in an appropriate amount of solvent to form a dithiothreitol solution for later use;

[0014] (2) mixing midazolam maleate with 1 / 4 to 1 / 2 weight portion of a disintegrant, adding a dithiothreitol solution, and granulating to obtain a drug-loaded particle core;

[0015] (3) The remaining disintegrant, filler, lubricant and drug-loaded particles are mixed and coated, tableted and dried to obtain the product.

[0016] Compared with the prior art, the technical effects of the present invention are:

[0017] The invention optimizes the formula and preparation process of the midazolam maleate orodisintegrating tablets, especially improves the addition of dithiothreitol and the adding method. On the one hand, the stability of midazolam maleate is effectively improved. Before and after the accelerated test, the orodisintegrating tablets of midazolam maleate of the invention have low content of related substances and stable effective ingredients. On the other hand, the formula and process of the invention are well controlled, and the disintegration speed of the drug in the mouth and the taking experience of the patient are effectively balanced. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 : Structural formula of impurity I.

[0019] Figure 2 : Changes in the content of impurity I in the accelerated test examples 1 to 10 midazolam maleate orally disintegrating tablets and comparative examples 1 to 4 midazolam maleate orally disintegrating tablets. DETAILED DESCRIPTION

[0020] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0021] Example 1 Midazolam Maleate Orally Disintegrating Tablets

[0022] formula:

[0023]

[0024]

[0025] Preparation method:

[0026] (1) Dissolve dithiothreitol in 20 ml of ethanol to form a dithiothreitol solution for later use;

[0027] (2) mixing midazolam maleate with 1 / 3 weight portion of a disintegrant, adding a dithiothreitol solution, and granulating to obtain a drug-loaded particle core;

[0028] (3) The remaining disintegrant, filler, lubricant and drug-loaded particles are mixed and coated, tableted and dried to obtain the product.

[0029] Example 2 Midazolam Maleate Orally Disintegrating Tablets

[0030] formula:

[0031]

[0032] Preparation method:

[0033] (1) Dissolve dithiothreitol in 10 ml of ethanol to form a dithiothreitol solution for later use;

[0034] (2) mixing midazolam maleate with 1 / 4 weight portion of a disintegrant, adding a dithiothreitol solution, and granulating to obtain a drug-loaded particle core;

[0035] (3) The remaining disintegrant, filler, lubricant and drug-loaded particles are mixed and coated, tableted and dried to obtain the product.

[0036] 5-15 parts by weight of midazolam maleate, 40-180 parts by weight of filler, 15-30 parts by weight of disintegrant, 0.5-2.5 parts by weight of lubricant, and 2-5 parts by weight of dithiothreitol.

[0037] Example 3 Midazolam maleate orally disintegrating tablets

[0038] formula:

[0039]

[0040] Preparation method:

[0041] (1) Dissolve dithiothreitol in 30 ml of ethanol to form a dithiothreitol solution for later use;

[0042] (2) mixing midazolam maleate with 1 / 2 weight portion of a disintegrant, adding a dithiothreitol solution, and granulating to obtain a drug-loaded particle core;

[0043] (3) The remaining disintegrant, filler, lubricant and drug-loaded particles are mixed and coated, tableted and dried to obtain the product.

[0044] Examples 4-7 Midazolam Maleate Orally Disintegrating Tablets

[0045]

[0046]

[0047] Preparation method:

[0048] (1) Dissolve dithiothreitol in 20 ml of ethanol to form a dithiothreitol solution for later use;

[0049] (2) mixing midazolam maleate with 1 / 3 weight portion of a disintegrant, adding a dithiothreitol solution, and granulating to obtain a drug-loaded particle core;

[0050] (3) The remaining disintegrant, filler, lubricant and drug-loaded particles are mixed and coated, tableted and dried to obtain the product.

[0051] Examples 8-10 Midazolam Maleate Orally Disintegrating Tablets

[0052] formula:

[0053]

[0054] Preparation method:

[0055] (1) Dissolve dithiothreitol in 20 ml of ethanol to form a dithiothreitol solution for later use;

[0056] (2) mixing midazolam maleate with 1 / 3 weight portion of a disintegrant, adding a dithiothreitol solution, and granulating to obtain a drug-loaded particle core;

[0057] (3) The remaining disintegrant, filler, lubricant, and flavoring agent are mixed and coated with the drug-carrying particles, compressed into tablets, and dried to obtain the product.

[0058] Comparative Example 1 Midazolam Maleate Orally Disintegrating Tablets

[0059] formula:

[0060]

[0061] Preparation method:

[0062] (1) mixing midazolam maleate with 1 / 3 weight portion of a disintegrant, and dry granulating the mixture to obtain drug-loaded granule cores;

[0063] (2) The remaining disintegrant, filler, lubricant and drug-loaded particles are mixed and coated, tableted and dried to obtain the product.

[0064] Comparative Example 2 Midazolam Maleate Orally Disintegrating Tablets

[0065] formula:

[0066]

[0067] Preparation method:

[0068] (1) Dissolve dithiothreitol in 20 ml of ethanol to form a dithiothreitol solution for later use;

[0069] (2) mixing midazolam maleate with 1 / 3 weight portion of a disintegrant, adding a dithiothreitol solution, and granulating to obtain a drug-loaded particle core;

[0070] (3) The remaining disintegrant, filler, lubricant and drug-loaded particles are mixed and coated, tableted and dried to obtain the product.

[0071] Comparative Example 3 Midazolam Maleate Orally Disintegrating Tablets

[0072] formula:

[0073]

[0074] Preparation method:

[0075] (1) mixing midazolam maleate with 1 / 3 weight portion of a disintegrant, and dry granulating the mixture to obtain drug-loaded granule cores;

[0076] (3) The remaining disintegrant, filler, lubricant, and dithiothreitol are mixed and coated with the drug-loaded particles, compressed into tablets, and dried to obtain the product.

[0077] Comparative Example 4 Midazolam Maleate Orally Disintegrating Tablets

[0078] formula:

[0079]

[0080]

[0081] Preparation method:

[0082] Midazolam maleate, dithiothreitol, a disintegrant, a filler and a lubricant are mixed and the mixture is prepared by a direct tableting method to obtain the tablet.

[0083] The related substances in the orally disintegrating tablets of midazolam maleate are determined according to the high performance liquid chromatography method (General Rule 0512) of the Chinese Pharmacopoeia. Test solution: Take an appropriate amount of fine powder of this product, add mobile phase and ultrasonically treat to dissolve the midazolam maleate and prepare a solution containing 0.5 mg of midazolam per 1 ml. Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute to the scale with mobile phase, and shake well. System suitability solution Take an appropriate amount of midazolam maleate reference substance and midazolam impurity I reference substance, add mobile phase to dissolve and dilute to prepare a solution containing 10 μg of midazolam and impurity I per 1 ml. Chromatographic conditions: octadecylsilane bonded silica gel is used as filler; phosphate buffer (mix the same volume of 0.1mol / L phosphoric acid solution and 0.03mol / L triethylamine solution, and adjust the pH value of the mixture to 3.5 with 0.1mol / L sodium hydroxide solution)-methanol (35:65) is used as mobile phase; detection wavelength is 220nm; column temperature is 40℃; injection volume is 10μl. System suitability requirements: In the system suitability solution chromatogram, the separation degree between the midazolam peak and the impurity I peak should be greater than 3.0. Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram to 3 times the retention time of the main component peak.

[0084] The content of midazolam maleate orally disintegrating tablets is determined according to the high performance liquid chromatography method (General Rule 0512) of the "Chinese Pharmacopoeia". Test solution: Take 20 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount (equivalent to approximately 10 mg of midazolam), place in a 100 ml volumetric flask, add mobile phase and ultrasonically dissolve the midazolam maleate, dilute to the scale with the mobile phase, shake well, filter, and take the filtrate. Reference solution: Take the midazolam maleate reference substance, accurately weigh, add mobile phase to dissolve and quantitatively dilute to make a solution containing approximately 0.12 mg per 1 ml. System suitability solution, chromatographic conditions and system suitability requirements: see under related substances. Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate according to the midazolam peak area by the external standard method, and multiply the result by 0.7373, which is C 18 H 13 C l FN3 content.

[0085] Accelerated test: The orodisintegrating tablets of midazolam maleate of Examples 1 to 10 and the orodisintegrating tablets of midazolam maleate of Comparative Examples 1 to 4 were used as test samples and placed at a temperature of 40±2°C and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the first, second, third and sixth months of the test to detect the contents of related substances and active ingredients.

[0086] Table 1 Active ingredient content of midazolam maleate orally disintegrating tablets

[0087]

[0088] Table 1 shows that in the accelerated test, the content of the active ingredient in the orally disintegrating tablets of midazolam maleate of Examples 1 to 10 of the present invention remains substantially unchanged, indicating that the drug is relatively stable in a high temperature and high humidity environment, has good chemical stability, does not undergo significant degradation or deterioration, and can maintain effectiveness and safety for a relatively long time.

[0089] Figure 2 The impurity content changes in the midazolam maleate orodisintegrating tablets of Examples 1 to 10 and Comparative Examples 1 to 4 were accelerated. The impurity content in the midazolam maleate orodisintegrating tablets of Examples 1 to 10 of the present invention is low and remains basically unchanged in the accelerated test, which shows that the control of the formula and process of the present invention is good, the stability of the active ingredient in the storage environment is high, and the generation of impurities is effectively suppressed.

[0090] Table 2 Disintegration time and hardness quality evaluation of midazolam maleate orally disintegrating tablets

[0091]

[0092]

[0093] The disintegration time limit of orally disintegrating tablets is less than 30s, which is an ideal range, especially for drugs that need to take effect quickly. A short disintegration time can improve the patient's medication compliance, and is particularly suitable for the elderly, children or patients with dysphagia. The disintegration time limit of the orally disintegrating tablets of midazolam maleate in Examples 1 to 10 of the present invention can be controlled within this range before and after the accelerated test, ensuring the speed and effect of the drug dissolving in the oral cavity. It is more appropriate to control the hardness of orally disintegrating tablets at around 50N. Too low hardness may cause the tablets to be easily broken or damaged during transportation and storage. Too high hardness may affect the rapid disintegration of the tablets and reduce the patient's comfort when taking the medicine. The hardness of the orally disintegrating tablets of midazolam maleate in Examples 1 to 10 of the present invention can be controlled at around 50N before and after the accelerated test, effectively balancing the drug disintegration speed in the mouth and the patient's taking experience.

Claims

1. A midazolam maleate orally disintegrating tablet, characterized in that: The formula of the midazolam maleate orally disintegrating tablet is: 5-15 parts by weight of midazolam maleate, 40-180 parts by weight of a filler, 15-30 parts by weight of a disintegrant, 0.5-2.5 parts by weight of a lubricant, and 2-5 parts by weight of dithiothreitol.

2. The orodisintegrating midazolam maleate tablet according to claim 1, characterized in that: The filler is selected from one or more of starch, microcrystalline cellulose, lactose, mannitol, hydroxypropyl methylcellulose, calcium carbonate, and calcium phosphate; preferably, the filler is starch, microcrystalline cellulose, and calcium carbonate.

3. The orodisintegrating tablet of midazolam maleate according to claim 1, characterized in that: The disintegrant is selected from one or more of sodium carboxymethyl starch, hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, polymer cross-linked polyvinyl pyrrolidone, sodium tripolyphosphate, maltodextrin, and low-substituted hydroxypropyl methylcellulose; preferably, the disintegrant is sodium tripolyphosphate or maltodextrin.

4. The orodisintegrating tablet of midazolam maleate according to claim 1, characterized in that: The lubricant is selected from one or more of stearic acid, magnesium stearate, talc, silicon dioxide, polydimethylsiloxane, polyethylene glycol 4000, and polyethylene glycol 6000; preferably, the lubricant is polyethylene glycol 4000.

5. The orodisintegrating tablet of midazolam maleate according to any one of claims 1 to 4, characterized in that The formula of the midazolam maleate orally disintegrating tablet is: 7.5 parts by weight of midazolam maleate, 80 parts by weight of starch, 20 parts by weight of microcrystalline cellulose, 10 parts by weight of calcium carbonate, 15 parts by weight of sodium tripolyphosphate, 5 parts by weight of maltodextrin, 1 part by weight of polyethylene glycol 4000, and 2-5 parts by weight of dithiothreitol.

6. The orodisintegrating tablet of midazolam maleate according to claim 1, characterized in that: A flavoring agent may also be added to the midazolam maleate orodisintegrating tablet.

7. The orodisintegrating tablet of midazolam maleate according to claim 6, characterized in that: The flavoring agent is selected from one or more of aspartame, sucralose, glucose and essence.

8. A method for preparing the orally disintegrating midazolam maleate tablet according to claim 1, characterized in that: The preparation method comprises the following steps: (1) dissolving dithiothreitol in an appropriate amount of solvent to form a dithiothreitol solution for later use; (2) mixing midazolam maleate with 1 / 4 to 1 / 2 weight portion of a disintegrant, adding a dithiothreitol solution, and granulating to obtain a drug-loaded particle core; (3) The remaining disintegrant, filler, lubricant and drug-loaded particles are mixed and coated, tableted and dried to obtain the product.

9. The preparation method according to claim 8, characterized in that: The amount of disintegrant in step (2) is 1 / 3 part by weight.

10. The preparation method according to claim 8, characterized in that: The solvent is ethanol.

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