Methimazole pulvis or powder and preparation method therefor

Abstract

The present disclosure relates to a methimazole pulvis or powder and a preparation method therefor. By means of combining a solid dispersion technique with a micronization modification and secondary crushing process, a drug powder with a high dispersity is prepared, so that the specific surface area of the drug is increased, the dissolution rate of the drug is increased, the absorption rate is increased, and the bioavailability is improved. Other sweetening agents are also added to a preparation, a methimazole pulvis or powder which can be directly administrated and completely covers the bitter taste and the peculiar smell of the drug is prepared, and the drug can be administrated without water.

Description

A kind of methimazole powder or dust and preparation method thereof Technical Field

[0001] The present disclosure relates to the field of pharmaceutical preparations, and in particular to a methimazole direct-take powder or dust and a preparation method thereof. Background Art

[0002] Hyperthyroidism (Hyperthyroidism) is caused by an overactive thyroid gland, significantly increasing the synthesis and secretion of thyroid hormones. This excess of T3 and T4 in the bloodstream leads to increased excitability of a range of systems, including the nervous, circulatory, and digestive systems, accompanied by hypermetabolism, resulting in thyrotoxicosis. The prevalence of hyperthyroidism varies depending on age, gender, and ethnicity, with higher rates seen in women, those with a family history of the condition, and those who have experienced trauma or infection. Bacterial infections such as tonsillitis and pneumonia; traumatic injuries; external mental and physical stress; frequent fatigue and exhaustion; pregnancy; and excessive iodine intake and consumption of high-iodine products can also contribute to hyperthyroidism.

[0003] The clinical manifestations of hyperthyroidism are mainly a series of high metabolic symptoms such as increased appetite, weight loss, fear of heat, sweating, palpitations and excitement. Among them, local nerve and vascular excitation is enhanced, and different degrees of thyroid enlargement, exophthalmos, hand tremors and heart murmurs may occur as corresponding characteristics. In severe cases, hyperthyroid crisis may occur, and coma may even endanger life safety.

[0004] The primary treatment for hyperthyroidism is thiourea drugs, primarily imidazoles and thiouracils. Methimazole (MMI) is a representative of the former, while propylthiouracil (PTU) is a representative of the latter. Propylthiouracil reduces the conversion of T4 to T3 in peripheral tissues by inhibiting 5′ deiodinase activity, but it is more hepatotoxic than methimazole. Therefore, propylthiouracil is the preferred treatment for severe cases, thyroid storm, early pregnancy, or those allergic to methimazole. In other cases, methimazole should be considered the preferred drug.

[0005] Surgery and radioactive iodine (RAI) treatment often lead to permanent hypothyroidism, necessitating lifelong thyroid hormone replacement therapy. Antithyroid medications remain the preferred treatment for childhood hyperthyroidism, with methimazole tablets being the preferred option. Adverse reactions are dose-dependent, so strict dosage control is essential for children. Tablets are typically available in 5mg and 10mg strengths, which present limitations for long-term, low-dose treatment.

[0006] Currently, methimazole is commercially available in tablet and ointment formulations. Methimazole tablets can cause systemic adverse reactions during use, including nausea, vomiting, upper abdominal discomfort, arthritis, and vasculitis. A small number of people have developed systemic side effects such as hepatitis, pneumonia, nephritis, liver damage, granulocytopenia, and vasculitis affecting the kidneys while taking methimazole tablets. Therefore, the dosage of methimazole tablets must be strictly controlled. Compared to tablets, methimazole ointment significantly reduces systemic toxic side effects due to its transdermal administration. However, since this formulation is a conventional ointment and methimazole is highly water-soluble, the primary challenge in transdermal administration is how to ensure drug penetration of the lipid-soluble stratum corneum. Therefore, to improve transdermal permeability, ointments primarily incorporate large amounts of penetration enhancers to enhance methimazole's ability to penetrate the skin. However, high concentrations of penetration enhancers can be irritating to the skin, making them more susceptible to local adverse reactions, especially with long-term use. Therefore, both methimazole tablets and ointments have certain limitations in their application. Summary of the Invention

[0007] In one aspect, the present disclosure provides a methimazole powder or dust, comprising methimazole and other pharmaceutically acceptable carriers. The solid preparation can be taken without water.

[0008] Furthermore, the solid dispersion material is selected from natural high molecular polymers with low melting points, such as waxes, glyceryl monostearate, polycaprolactone polyols, polyethylene glycols, and the like.

[0009] Furthermore, the low melting point refers to a melting point ≤ 100°C.

[0010] Furthermore, the solid dispersion material is selected from one or more of glyceryl mono- and distearate, stearyl alcohol, and glyceryl behenate.

[0011] In the above-mentioned methimazole powder or dust, the pharmaceutically acceptable carrier includes one or more of a sweetener and a filler.

[0012] Furthermore, the sweetener and filler are selected from one or more of erythritol, sorbitol, maltitol, mannitol, lactitol, sucralose and the like.

[0013] Furthermore, the sweetener is selected from sucralose. Furthermore, the mass percentage of sucralose in each unit of the preparation is 1%-5%, preferably 2%-4%.

[0014] Furthermore, the sweetener is selected from erythritol. Furthermore, the mass percentage of erythritol in each unit of the preparation is 40%-50%, preferably 42%-48%.

[0015] Furthermore, the sweetener is selected from mannitol. Furthermore, the mass percentage of mannitol in each unit of the preparation is 40%-50%, preferably 42%-48%.

[0016] Furthermore, in the methimazole powder or dust disclosed herein, the mass percentage of the methimazole raw material in each unit preparation is 0.1%-0.5%, preferably 0.1%-0.3%; the mass percentage of the solid dispersion material is 3%-8%, preferably 4%-6%.

[0017] Furthermore, the methimazole powder or dust of the present disclosure further comprises a filler selected from one or more of erythritol, lactose, mannitol, sorbitol, and the like.

[0018] On the other hand, the present disclosure also provides a method for preparing the methimazole powder or dust, comprising:

[0019] Preparation of solid dispersion: Melt methimazole in solid dispersion material at high temperature to form a yellow, clear and transparent eutectic mixture;

[0020] Solidification: The above mixture is solidified at low temperature to obtain a white solid;

[0021] Secondary crushing: The obtained white solid is transferred to a multifunctional crusher for primary crushing; at the same time, it passes through a certain number of metal woven sieves; then it is transferred to a flat air flow crusher for secondary crushing; at the same time, it passes through a certain number of metal woven sieves;

[0022] Mixing: Add other pharmaceutically acceptable excipients together with the secondary pulverized product into a multifunctional pulverizer for shear mixing, and then pass through a certain number of metal woven sieves for diffusion mixing.

[0023] Furthermore, the methimazole of the present disclosure is subjected to a crushing step before being added to the molten solid dispersion material. Further preferably, the crushed material is passed through a 120-mesh sieve.

[0024] Furthermore, methimazole is added to the molten solid dispersion material and stirred to ensure uniform mixing.

[0025] Furthermore, in the mixing step, other pharmaceutically acceptable excipients are mixed with the secondary pulverized product by using an equal amount incremental addition method, and then added into the multifunctional pulverizer.

[0026] Furthermore, the preparation method also includes a filling step.

[0027] Furthermore, in the preparation method, the secondary pulverization uses a multifunctional pulverizer and a flat airflow pulverizer. Furthermore, the flat airflow pulverizer has a Venturi (sample delivery) pressure of 2-6 bar, preferably 3-5 bar; an annular (centrifugal) pressure of 2-6 bar, preferably 2-5 bar; and a sample delivery speed of 5-7 (approximately 35-45 g / h), preferably 5-6 (approximately 35-40 g / h).

[0028] In another aspect, the present disclosure further provides a method for using a drug, specifically a method for using the aforementioned methimazole powder or dust. The methimazole powder or dust disclosed herein is a direct-take dosage form. That is, the powder or powder can be taken directly without drinking water.

[0029] In yet another aspect, the present disclosure further provides a method for treating hyperthyroidism, comprising administering the methimazole powder or dust to a patient in need thereof, the patient including but not limited to a pediatric patient, an adult patient, and an elderly patient.

[0030] In another aspect, the present disclosure also provides use of the methimazole powder or dust in preparing a medicament for treating hyperthyroidism. Beneficial effects:

[0031] The present disclosure provides a methimazole powder or dust and its preparation process, addressing the shortcomings of existing methimazole pharmaceuticals. By combining solid dispersion technology with a micronized, modified, and two-stage pulverization process, a highly dispersed drug powder is prepared, increasing the drug's specific surface area, boosting its dissolution rate, and improving its absorption rate, thereby enhancing its bioavailability.

[0032] Furthermore, the addition of other sweeteners to the formulation allows for the preparation of a direct-dose methimazole powder or dust that completely masks the bitterness and odor of the drug, while also breaking the habit of taking the drug with water. Its solubility is reflected in the drug powder's small, fine, and uniform particle size, which increases its surface area and solubility, improving the drug's dissolution rate to a certain extent. This makes it particularly suitable for administration in special environments where water is inconvenient, and for children, the elderly, and other individuals with swallowing difficulties.

[0033] Furthermore, the technical solution disclosed in the present invention also solves the problem in the prior art that methimazole drugs need to strictly control the dosage of methimazole. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG1 is an optical microscope image of the powder of the present disclosure after primary comminution.

[0035] FIG2 is an optical microscope image of the powder of the present disclosure after secondary pulverization.

[0036] FIG3 is a diagram showing the particle size distribution of the powder of the present disclosure after secondary pulverization.

[0037] FIG4 is a DSC spectrum of Experimental Example 1. DETAILED DESCRIPTION

[0038] In order to more clearly illustrate the embodiments of the present disclosure or the technical solutions in the prior art, the terms and implementation methods required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the implementation method described below is only one implementation method of the present disclosure. For ordinary technicians in this field, other implementation methods can also be obtained based on these drawings.

[0039] I. Terminology

[0040] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the present disclosure belongs.

[0041] As used herein, the articles "a" and "an" refer to one or more than one (ie, to at least one) of the grammatical object to which the article refers. For example, "an element" means one element or more than one element.

[0042] As used herein, the term "about" refers to and encompasses a specified value and a range greater than or less than that value. In certain embodiments, the term "about" can refer to a variation of ±0.1%, ±0.5%, ±1%, ±2%, ±3%, ±4%, ±5%, ±6%, ±7%, ±8%, ±9%, or ±10%. In certain embodiments, where applicable, the term "about" refers to a specified value ± one standard deviation of that value.

[0043] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0044] The terms "comprising," "consisting essentially of," or variations thereof, used throughout the specification and claims mean that all recited elements or groups of elements are included, and optionally, other elements of similar or different properties to the recited elements that do not significantly alter the basic or novel properties of a specified dosage regimen, method, or composition.

[0045] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0046] II. Detailed description of specific implementation plan

[0047] In one aspect, the present disclosure provides a methimazole powder or dust and a method for preparing the same. The method comprises using solid dispersion technology and a two-stage pulverization process. Methimazole is co-melted with a solid dispersion material and then subjected to a two-stage pulverization process using solid dispersion technology and micronization modification to produce a highly dispersed pharmaceutical powder.

[0048] Specifically, the methimazole powder or dust disclosed herein comprises methimazole, a solid dispersion material, and a pharmaceutically acceptable carrier. The solid dispersion material is selected from natural high-molecular-weight polymers with a low melting point, particularly natural high-molecular-weight polymers with a melting point of ≤100°C, such as waxes, glyceryl monostearate, polycaprolactone polyols, and polyethylene glycol polymers. The solid dispersion material in the disclosed technical solution is preferably one or more of glyceryl mono- and distearate, stearyl alcohol, and glyceryl behenate.

[0049] The active ingredient in the disclosed powder is methimazole, also known as methimazole, with a molecular formula of C4H6N2S. It is a white or yellowish-white crystalline powder with a slight odor and a slightly bitter taste. For powders administered orally, it is necessary to add suitable other pharmaceutical carriers or adjuvants to cover or eliminate the peculiar smell of methimazole. In addition, according to the preparation requirements, adjuvants such as other fillers and diluents can also be added to the powder.

[0050] Preferably, the methimazole powder or dust of the present disclosure includes a sweetener. The sweetener is used to mask the odor of the drug, including bad smell and bitterness. Useful sweeteners include one or more of erythritol, sorbitol, maltitol, mannitol, lactitol, sucralose, etc.

[0051] Erythritol tastes similar to sucrose, yet is mild and pure without an unpleasant aftertaste, making it an excellent flavoring agent / sweetener. When combined with the intense sweetener sucralose, erythritol exhibits a synergistic effect, significantly enhancing sweetness and flavor, resulting in a superior taste. It can also mask some of the unpleasant odors and undesirable properties of high-intensity sweeteners, resolving the bitter taste of methimazole APIs and making it easier for patients to swallow. Erythritol also contains no reducing aldehyde groups, making it highly stable to heat and acid, and highly compatible with APIs. It also has low hygroscopicity, remaining moisture-resistant at 20°C and 90% relative humidity. Erythritol powder also exhibits excellent flowability and stability, ensuring the smooth flow of the direct-use powder. Furthermore, erythritol absorbs significant amounts of heat during dissolution, exerting a significant cooling effect. This effect imparts a cooling sensation upon oral dissolution, enabling the entire formulation to be swallowed without water, improving patient compatibility.

[0052] Mannitol is stable in both solid and liquid states, and does not react with low-temperature weak acids and bases. Its low hygroscopicity also does not affect the stability of the API. Mannitol and other polyols are calorie-free, pose no risk of weight gain or tooth decay, and can significantly enhance the flavor of formulations through the cooling sensation produced by their dissolution, a degree of sweetness, and a creamy texture.

[0053] In some embodiments, the sweetener is selected from sucralose. Further, the mass percentage of sucralose per unit of preparation is 1%-5%, preferably 1.5%-4.5%, 2%-4%, 2.5%-3.5%. More preferably, it is 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%.

[0054] In some embodiments, the sweetener is selected from erythritol. Further, the mass percentage of erythritol per unit of preparation is 40%-50%, preferably 41%-49%, 42%-48%, 43%-47%, 44%-46%. More preferably, it is 40%, 40.5%, 41%, 41.5%, 42%, 42.5%, 43%, 43.5%, 44%, 44.5%, 45%, 45.5%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%, 49.5%, 50%.

[0055] In some embodiments, the sweetener is selected from mannitol. Further, the mass percentage of mannitol per unit of preparation is 40%-50%, preferably 41%-49%, 42%-48%, 43%-47%, 44%-46%. More preferably, it is 40%, 40.5%, 41%, 41.5%, 42%, 42.5%, 43%, 43.5%, 44%, 44.5%, 45%, 45.5%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%, 49.5%, 50%.

[0056] In some embodiments, the methimazole powder or dust of the present disclosure has a mass percentage of methimazole API per unit of preparation of 0.1%-0.5%, preferably 0.1%-0.3%, 0.1%-0.2%; and a mass percentage of solid dispersion material of 3%-8%, preferably 3.5%-7%, 4%-6%, 4.5%-5%. More preferably, the mass percentages are 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, and 0.5%.

[0057] Furthermore, the methimazole powder or dust of the present disclosure may also include other pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers include, but are not limited to, fillers, diluents, and the like. Fillers or diluents are the types of fillers or diluents that can be used in conventional oral preparations, including, but not limited to, lactose, microcrystalline cellulose, starch, mannitol, and sorbitol.

[0058] On the other hand, the present disclosure also provides a method for preparing the methimazole powder or dust, comprising:

[0059] Preparation of solid dispersion: Melt methimazole in solid dispersion material at high temperature to form a yellow, clear and transparent eutectic mixture;

[0060] Solidification: The above mixture is solidified at low temperature to obtain a white solid;

[0061] Secondary crushing: The obtained white solid is transferred to a multifunctional crusher for primary crushing; at the same time, it passes through a certain number of metal woven sieves; then it is transferred to a flat air flow crusher for secondary crushing; at the same time, it passes through a certain number of metal woven sieves;

[0062] Mixing: Add other pharmaceutically acceptable excipients together with the secondary pulverized product into a multifunctional pulverizer for shear mixing, and then pass through a certain number of metal woven sieves for diffusion mixing.

[0063] Furthermore, the methimazole of the present disclosure is subjected to a crushing step before being added to the molten solid dispersion material. Further preferably, the crushed material is passed through a 120-mesh sieve.

[0064] Furthermore, methimazole is added to the molten solid dispersion material and stirred to ensure uniform mixing.

[0065] Furthermore, in the mixing step, other pharmaceutically acceptable excipients are mixed with the secondary pulverized product by using an equal amount incremental addition method, and then added into the multifunctional pulverizer.

[0066] Furthermore, the screening in the secondary crushing is preferably through a 120-mesh metal sieve.

[0067] Furthermore, the diffusion mixing in the mixing step is preferably passed through a 20-30 mesh sieve.

[0068] Furthermore, the preparation method of the methimazole powder or dust disclosed herein also includes a filling step.

[0069] Furthermore, in the preparation method, the secondary pulverization uses a multifunctional pulverizer and a flat airflow pulverizer. Furthermore, the flat airflow pulverizer has a Venturi (sample delivery) pressure of 2-6 bar, preferably 3-5 bar; an annular (centrifugal) pressure of 2-6 bar, preferably 2-5 bar; and a sample delivery speed of 5-7 (approximately 35-45 g / h), preferably 5-6 (approximately 35-40 g / h).

[0070] On the other hand, the present disclosure also provides a method for using a drug, specifically a method for using the aforementioned methimazole powder or powder. The methimazole powder or powder disclosed herein is a direct-take powder or direct-take powder. That is, it is a powder or powder that can be taken directly without drinking water. Direct-take powder or direct-take powder is a new type of preparation that can be taken without water. It is mainly prepared using solid dispersion technology. The raw material methimazole is uniformly dispersed in a solid carrier material to form a low-melting mixture during solidification and cooling, and then micronized and surface-modified, and then pulverized in two stages to prepare a drug powder with high dispersion. After the drug is micronized, the specific surface area of ​​the drug can be increased, the dissolution rate of the drug can be increased, and the absorption rate can be increased, thereby improving bioavailability.

[0071] The methimazole direct-take powder or direct-take powder provided by the present disclosure stimulates saliva secretion in the oral cavity and is conducive to rapid swallowing, so that the patient can swallow without drinking water during the taking process, and the taking process has no bad taste and bitterness, effectively improving medication compliance, increasing the applicable population of patients, and ensuring that the preparation tastes good throughout the whole process, realizing the technical characteristics of swallowing without water, while reducing the possibility of hygroscopicity of the drug during production and storage by adding other excipients, and increasing the stability of the preparation. Thus, the methimazole direct-take powder or direct-take powder disclosed in the present disclosure solves the adaptability problem existing in conventional methimazole oral preparations.

[0072] In yet another aspect, the present disclosure further provides a method for treating hyperthyroidism, comprising administering the methimazole powder or dust to a patient in need thereof, the patient including but not limited to a pediatric patient, an adult patient, and an elderly patient.

[0073] In another aspect, the present disclosure further provides use of the methimazole powder or methimazole dust in preparing a medicament for treating hyperthyroidism.

[0074] The technical solution disclosed in the present invention also solves the defects existing in the use of methimazole drugs in the prior art, such as insufficient taste masking after taking the drug, extremely poor taste, poor medication compliance, the need to wash it down with water, which makes it inconvenient to take the drug, and the need to strictly control the dosage of methimazole.

[0075] In some embodiments, a methimazole powder and a preparation method thereof disclosed herein are as follows:

[0076] Table 1: Methimazole powder according to 100 units of preparation:

[0077] Preparation process:

[0078] Preparation of solid dispersion: Place the mono- and distearic glyceryls in a beaker and heat in a water bath at 70-80°C while stirring magnetically at 15-25 rpm. When the mono- and distearic glyceryls are completely melted and become yellow and clear, add the crushed methimazole API passed through a 120-mesh sieve. Stop heating when the drug is evenly dissolved in the mono- and distearic glyceryls.

[0079] Solidification: The simple eutectic formed by the two is cooled at 0℃ to -20℃ and solidifies for 6-12 hours to form a hard white solid;

[0080] Crushing: transfer the white solid to a multifunctional crusher for primary crushing, pass through a 20-30 mesh sieve, and then use a flat airflow crusher for secondary crushing. The Venturi (sample delivery) pressure is 3-5 bar, the annular (centrifugal) pressure is 2-4 bar, the sample delivery speed is 5-6 gears (about 35-40g / h), and pass through a 100-120 mesh metal woven sieve;

[0081] Mixing: Initially mix sucralose, erythritol, and mannitol with the secondary pulverized product using an equal-volume incremental addition method. Before initial mixing, sucralose, erythritol, and mannitol are screened through a 120-mesh sieve. After initial mixing, shear mix the mixture in a multi-purpose grinder and finally pass through a 20-30 mesh metal woven sieve for further mixing.

[0082] Filling: obtain methimazole powder.

[0083] The disclosed technical solution adopts solid dispersion technology. By melting method, the solid carrier material with low melting point is first heated and melted, and then the high melting point raw material drug is added thereto. After the drug is evenly dispersed in the solid carrier material, it is taken out and cooled and solidified. Then, the solid is placed at a certain temperature and becomes brittle. The key to this method is that it is necessary to cool rapidly by high temperature so that multiple colloidal crystal nuclei are rapidly formed to obtain highly dispersed drugs, and the solid solution formed by the melting method can melt the high melting point raw material drug at a lower temperature so that it can be prepared at a temperature significantly lower than the melting point of the raw material drug. At the same time, the heating temperature needs to be about 10 ℃ -20 ℃ higher than the solid carrier material, which can accelerate the speed of solid carrier melting, reduce process cost, and is simple and easy. The high temperature rapid cooling refers to cooling the material from 70 ℃ to room temperature, such as 25 ℃, within 30 minutes. The 25 ℃ eutectic obtained is placed at 0 ℃ -25 ℃ for 6-12 hours.

[0084] The technical solution disclosed in the present invention also performs secondary pulverization through the surface modification of micropowders, sequentially using a multifunctional pulverizer for primary pulverization and a flat airflow pulverizer for secondary pulverization. After coarse pulverization, the low eutectic is subjected to high-speed airflow impact and mutual collision of materials in the airflow pulverizer to achieve the purpose of fine pulverization, thereby increasing the specific surface area of ​​the drug, increasing the dissolution rate of the drug, and improving the absorption rate, thereby improving bioavailability.

[0085] The disclosed technical solution combines solid dispersion technology with a two-stage pulverization process to produce a drug powder with a particle size of 100-125 μm. As the drug particle size decreases, its saturated solubility increases, its diffusion concentration gradient increases, and its surface area in contact with the dissolution medium also increases, effectively increasing the drug's dissolution rate. This allows the drug preparation to stimulate saliva secretion in the mouth, facilitate rapid swallowing, and thus improve the drug's bioavailability.

[0086] The disclosed technical solution utilizes solid dispersion technology to highly disperse the drug within a solid carrier, forming a dispersed system in solid form. This increases the drug's solubility and dissolution rate, thereby improving bioavailability. The melt preparation method shortens the drug's heating time. The carrier material is first heated and melted, followed by the addition of the crushed drug and quenching to form a solid. This solid is then left at a certain temperature to become brittle and easily breakable.

[0087] The technical solution disclosed in the present invention is to improve the pulverization process of the preparation, through the secondary pulverization process of micronized surface modification, firstly, a multifunctional pulverizer is used for primary pulverization, and the material is mechanically pulverized mainly by the shear pulverization and diffusion pulverization principles of the multifunctional pulverizer, and the surface of the obtained particles is not round and has edges and corners (see Figure 1). The secondary pulverization adopts flat air flow pulverization, and the material is pulverized due to the mutual impact, collision and friction between particles and the inner wall of the machine. The solid after the primary pulverization is polished for the second time in the flat air flow pulverizer, and the waxy layer is fully extended, and the raised part of the surface of the small particle is turned into a spherical shape during the impact process (see Figure 2). At the same time, the waxy material is fully deformed and extended during the impact process to tightly wrap the drug, and a low eutectic powder with a particle size of 100-125um is obtained (see Figure 3). The above-mentioned images and particle size distribution measurements are obtained based on the product of Example 3.

[0088] The following examples or comparative examples are intended to better explain or illustrate the methimazole powder of the present invention, but do not constitute a limitation or restriction on the scope of protection of this application.

[0089] Unless otherwise specified, the reagents and equipment used in this disclosure are conventional and commercially available.

[0090] Example 1

[0091] Table 2: Methimazole powder according to 100 units of preparation:

[0092] Preparation process:

[0093] Preparation of solid dispersion: Place the mono- and distearic glyceryl in a beaker and heat in a water bath at 70-80°C while stirring magnetically at 15-25 rpm. When the mono- and distearic glyceryl is completely melted and becomes a yellow, clear state, add the methimazole API crushed to 120 mesh. Stop heating when the drug is evenly dissolved in the mono- and distearic glyceryl.

[0094] Solidification: The simple eutectic formed by the two is cooled at 0℃ to -20℃ and solidifies for 6-12 hours to form a hard white solid;

[0095] Crushing: transfer the white solid to a multifunctional crusher for primary crushing, pass through a 20-30 mesh sieve, and then use a flat airflow crusher for secondary crushing. The Venturi (sample delivery) pressure is 3-5 bar, the annular (centrifugal) pressure is 2-4 bar, the sample delivery speed is 5-6 gears (about 35-40g / h), and pass through a 100-120 mesh metal woven sieve;

[0096] Mixing: Initially mix sucralose, erythritol, and the secondary pulverized product using an equal-volume incremental addition method. Before initial mixing, sucralose and erythritol are screened through a 120-mesh sieve. After initial mixing, shear mix the sucralose and erythritol in a multi-purpose grinder and then pass through a 20-30 mesh metal woven sieve for further mixing.

[0097] Filling: obtain methimazole powder.

[0098] Example 2

[0099] Table 3: Methimazole powder according to 100 units of preparation:

[0100] Preparation process:

[0101] Preparation of solid dispersion: Place the mono- and distearic glyceryl in a beaker and heat in a water bath at 70-80°C while stirring magnetically at 15-25 rpm. When the mono- and distearic glyceryl is completely melted and becomes a yellow, clear state, add the methimazole API crushed to 120 mesh. Stop heating when the drug is evenly dissolved in the mono- and distearic glyceryl.

[0102] Solidification: The simple eutectic formed by the two is cooled at 0℃ to -20℃ and solidifies for 6-12 hours to form a hard white solid;

[0103] Crushing: Transfer the white solid to a multifunctional crusher for crushing and pass through a 100-120 mesh metal woven sieve;

[0104] Mixing: Initially mix sucralose, erythritol, and mannitol with the secondary pulverized product using an equal-volume incremental addition method. Before initial mixing, sucralose, erythritol, and mannitol are screened through a 120-mesh sieve. After initial mixing, shear mix the sucralose, erythritol, and mannitol in a multi-purpose grinder and then pass through a 20-30 mesh metal woven sieve for further mixing.

[0105] Filling: obtain methimazole powder.

[0106] Example 3

[0107] Table 4: Methimazole powder according to 100 units of preparation:

[0108] Preparation process:

[0109] Preparation of solid dispersion: Place the mono- and distearic glyceryl in a beaker and heat in a water bath at 70-80°C while stirring magnetically at 15-25 rpm. When the mono- and distearic glyceryl is completely melted and becomes a yellow, clear state, add the methimazole API crushed to 120 mesh. Stop heating when the drug is evenly dissolved in the mono- and distearic glyceryl.

[0110] Solidification: The simple eutectic formed by the two is cooled at 0℃ to -20℃ and solidifies for 6-12 hours to form a hard white solid;

[0111] Crushing: transfer the white solid to a multifunctional crusher for primary crushing, pass through a 20-30 mesh sieve, and then use a flat airflow crusher for secondary crushing. The Venturi (sample delivery) pressure is 3-5 bar, the annular (centrifugal) pressure is 2-4 bar, the sample delivery speed is 5-6 gears (about 35-40g / h), and pass through a 100-120 mesh metal woven sieve;

[0112] Mixing: Initially mix sucralose, erythritol, and mannitol with the secondary pulverized product using an equal-volume incremental addition method. Before initial mixing, sucralose, erythritol, and mannitol are screened through a 120-mesh sieve. After initial mixing, shear mix the sucralose, erythritol, and mannitol in a multi-purpose grinder and then pass through a 20-30 mesh metal woven sieve for further mixing.

[0113] Filling: obtain methimazole powder.

[0114] Example 4

[0115] Table 5: Methimazole powder according to 100 units of preparation:

[0116] Preparation process:

[0117] Preparation of solid dispersion: Place the glyceryl behenate in a beaker and heat in a water bath at 70-80°C while stirring magnetically at 15-25 rpm. When the glyceryl behenate is completely melted and becomes a yellow, clear state, add methimazole API crushed to 120 mesh. Stop heating when the drug is evenly dissolved in the glyceryl behenate.

[0118] Solidification: The simple eutectic formed by the two is cooled at 0℃ to -20℃ and solidifies for 6-12 hours to form a hard white solid;

[0119] Crushing: transfer the white solid to a multifunctional crusher for primary crushing, pass through a 20-30 mesh sieve, and then use a flat airflow crusher for secondary crushing. The Venturi (sample delivery) pressure is 3-5 bar, the annular (centrifugal) pressure is 2-4 bar, the sample delivery speed is 5-6 gears (about 35-40g / h), and pass through a 100-120 mesh metal woven sieve;

[0120] Mixing: Initially mix sucralose, erythritol, and mannitol with the secondary pulverized product using an equal-volume incremental addition method. Before initial mixing, sucralose, erythritol, and mannitol are screened through a 120-mesh sieve. After initial mixing, shear mix the sucralose, erythritol, and mannitol in a multi-purpose grinder and then pass through a 20-30 mesh metal woven sieve for further mixing.

[0121] Filling: Filling gives methimazole powder.

[0122] Example 5

[0123] Table 6: Methimazole powder according to 100 units of preparation:

[0124] Preparation process:

[0125] Preparation of solid dispersion: Place the octadecanol in a beaker and heat in a water bath at 70-80°C while stirring magnetically at 15-25 rpm. When the octadecanol is completely melted and becomes a yellow, clear state, add the methimazole API crushed to 120 mesh. Stop heating when the drug is evenly dissolved in the octadecanol.

[0126] Solidification: The simple eutectic formed by the two is cooled at 0℃ to -20℃ and solidifies for 6-12 hours to form a hard white solid;

[0127] Crushing: transfer the white solid to a multifunctional crusher for primary crushing, pass through a 20-30 mesh sieve, and then use a flat airflow crusher for secondary crushing. The Venturi (sample delivery) pressure is 3-5 bar, the annular (centrifugal) pressure is 2-4 bar, the sample delivery speed is 5-6 gears (about 35-40g / h), and pass through a 100-120 mesh metal woven sieve;

[0128] Mixing: Initially mix sucralose, erythritol, and mannitol with the secondary pulverized product using an equal-volume incremental addition method. Before initial mixing, sucralose, erythritol, and mannitol are screened through a 120-mesh sieve. After initial mixing, shear mix the sucralose, erythritol, and mannitol in a multi-purpose grinder and then pass through a 20-30 mesh metal woven sieve for further mixing.

[0129] Filling: Filling gives methimazole powder.

[0130] Experimental Example 1

[0131] In order to verify whether the melting point is reproducible when preparing solid dispersions using large doses of raw materials, this experiment accurately weighed 2.0 mg of methimazole powder prepared in Example 3, as well as the reference raw material methimazole, the reference solid dispersion material mono- and di-stearate glyceryl, and the reference product of 1 mg of methimazole melted in 10 mg of mono- and di-stearate glyceryl, placed them in a crucible, covered the crucible, and placed in the S position of the DSC analyzer; an empty crucible was covered with a crucible lid as a blank control and placed in the R position of the DSC analyzer, and the DSC spectra of Example 3 and the reference were obtained, respectively, as shown in Figure 4.

[0132] The thermodynamic properties of methimazole, mono- and distearic glyceryl, and methimazole melted in mono- and distearic glyceryl (Example 3 and reference substance) were determined respectively by DSC. It was found through the spectrum that the methimazole bulk drug had a melting peak at about 146-148°C (see the red line in FIG4 ), and the solid dispersion material mono- and distearic glyceryl had a melting peak at about 62-66°C (see the blue line in FIG4 ). The DSC spectrum of the methimazole melted in mono- and distearic glyceryl of Example 3 had a melting peak at about 58°C, indicating that the two formed a simple eutectic (see the black line in FIG4 ), and methimazole was uniformly dispersed in mono- and distearic glyceryl. The reference substance 1 mg methimazole melted in the 10 mg mono- and distearic glyceryl product had a melting peak at about 55°C (see the green line in FIG4 ).

[0133] Since the prescribed dosage of methimazole is very low, when the maximum meltable dosage of methimazole was added to mono- and distearic glycerol, a melting peak was found at the same temperature, indicating that the two may have formed a simple eutectic.

[0134] Experimental Example 2

[0135] 2-1 Taste Evaluation

[0136] The pharmaceutical preparations prepared in Examples 1-5 were tested by 10 male volunteers aged 20-30 and 10 female volunteers aged 20-30. Dysphagia, sandy feeling, mouth ulcer, bad odor, and residual particles were used as evaluation indicators. Indicators with the above sensations were marked as 1, and indicators without the above sensations were marked as 0.

[0137] Based on the above evaluation rules, the evaluation results are shown in Table 7 below:

[0138] Table 7: Taste evaluation

[0139] For Examples 4-5, 10% of the volunteers reported issues such as a gritty feeling, a sticky mouth, and powdery residue. However, for Examples 1 and 3, all volunteers reported that the amount and speed of saliva secretion after the drug entered the mouth met the requirements for swallowing. The drug was taken within 2 minutes, and there was no unpleasant taste. Due to individual variability, some individual particles were broken, resulting in a slight bitter taste in the mouth, but this was within an acceptable range. Overall, the drug met quality requirements for taste masking and swallowing.

[0140] 2-2 Simulated oral dissolution test method

[0141] The preparation of Example 3 (600 mg) was placed in 20 mL of purified water at 37°C and pH 6.6-7.1 to simulate oral dissolution. The mixture was magnetically stirred at 5 rpm for 20 seconds, removed from the container, dried at 60°C, and passed through a homemade 150-mesh container. Weight loss was measured. The results showed that the amount undissolved in the solvent accounted for less than 5% of the total preparation. Specific experimental results are shown in Table 8.

[0142] Table 8: Oral dissolution results

[0143] Conclusion: Methimazole powder stimulates saliva secretion in the mouth, facilitating rapid swallowing and enabling patients to swallow without water. It also provides no unpleasant taste or bitterness, effectively improving medication compliance and broadening the patient population. Furthermore, the formulation maintains a pleasant taste throughout the entire process, achieving the technical advantage of swallowing without water.

[0144] 2-3 Hygroscopicity test

[0145] (1) Place a supersaturated sodium chloride solution in a glass desiccator and leave it at room temperature to allow the internal humidity to balance and form environments with different relative humidity. At this time, the relative humidity of the desiccator is 75%;

[0146] (2) Dry the methimazole powder prepared in Examples 1-5 to constant weight. Take 1.0 g of the methimazole powder that has been dried to constant weight and place it in a flat weighing bottle of constant weight and accurately weigh it. Open the weighing bottle cap and place it in the above-mentioned desiccator with a relative humidity of 75%. Weigh it after 48 hours and calculate the moisture absorption rate. The calculation formula is: Moisture absorption rate (%) = (weight after moisture absorption - weight before moisture absorption) / weight before moisture absorption × 100%. The hygroscopicity results are shown in Table 9.

[0147] Table 9: Hygroscopicity results

[0148] As shown in Table 9, the methimazole powder prepared in the embodiment of the present disclosure has low hygroscopicity, which indicates that the technical solution of the present disclosure effectively reduces the hygroscopicity of the methimazole powder, and that embodiment 3 of the present invention is the best embodiment.

[0149] 2-4 Release Test

[0150] For Examples 1-5, dissolution curves were determined using purified water as the dissolution medium. The dissolution method employed a paddle method, with a rotation speed of 50 rpm, a temperature of 37 ± 0.5°C, and a dissolution medium volume of 100 ml. 5 mL samples were taken at 5, 15, 30, and 45 min, and 5 mL of solution was replenished simultaneously. The solution was aspirated at the specified sampling point and filtered through a 0.45 μm microporous membrane. The content was determined using ultraviolet light, and the test results are shown in Table 10.

[0151] Table 10: Methimazole powder dissolution test results in each implementation

[0152] The drug dissolution rate of Examples 1-5 reached about 95% or even higher within 5 minutes, indicating that the methimazole direct-use powder prepared by the process of the present invention has good drug dissolution and release and high bioavailability.

[0153] 2-5 Stability test

[0154] (1) Test material: methimazole powder prepared in Examples 1-5.

[0155] (2) Test method: Place the product in commercial packaging at a temperature of 25±2°C and a relative humidity of 60±10% for 6 months. Take samples at 0, 3, and 6 months respectively. According to the quality standard of methimazole powder, test its properties, identification, moisture, particle size, loss on drying, related substances, content, etc.

[0156] (3) Test results: The stability test results are shown in Table 11 (0-month stability test) and Table 12 (6-month stability test).

[0157] Table 11: 0-month stability test

[0158] Table 12: Six-month stability test

[0159] The above description is only an embodiment of the present disclosure and does not limit the present disclosure in any form or substance. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present disclosure, and these improvements and supplements should also be regarded as the scope of protection of the present disclosure. Any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the spirit and scope of the present invention by using the technical content disclosed above are all equivalent embodiments of the present disclosure; at the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present disclosure are still within the scope of the technical solution of the present disclosure.

Claims

1. A methimazole powder or dust comprising methimazole, a solid dispersion material and a pharmaceutically acceptable carrier, wherein the solid preparation can be taken without water.

2. The powder or dust according to claim 1, wherein the solid dispersion material is selected from natural high molecular polymers with low melting points; preferably waxes, glyceryl monostearate, polycaprolactone polyols, and polyethylene glycols.

3. The powder or dust according to claim 1 or 2, wherein the solid dispersion material is one or more of glyceryl mono- and distearate, stearyl alcohol, and glyceryl behenate.

4. The powder or dust according to any one of claims 1 to 3, wherein the pharmaceutically acceptable carrier comprises one or more of a sweetener, a filler, and a diluent.

5. The powder or dust according to claim 4, wherein the sweetener is selected from one or more of erythritol, sorbitol, maltitol, mannitol, lactitol, sucralose and the like.

6. The powder or dust according to any one of claims 1 to 5, wherein the mass percentage of methimazole raw material in the unit preparation is 0.1%-0.5%, preferably 0.1%-0.3%.

7. The powder or dust according to any one of claims 1 to 6, wherein the mass percentage of the solid dispersion material in the unit preparation is 3% to 8%, preferably 4% to 6%.

8. the preparation method of the described methimazole powder or dust of any one of claim 1-7, comprising: Preparation of solid dispersion: Melt methimazole in solid dispersion material at high temperature to form a yellow, clear and transparent eutectic mixture; Solidification: The above mixture is solidified at low temperature to obtain a white solid; Secondary crushing: The obtained white solid is transferred to a multifunctional crusher for primary crushing; at the same time, it passes through a certain number of metal woven sieves; then it is transferred to a flat air flow crusher for secondary crushing; at the same time, it passes through a certain number of metal woven sieves; Mixing: Add other pharmaceutically acceptable excipients together with the secondary pulverized product into a multifunctional pulverizer for shear mixing, and then pass through a certain number of metal woven sieves for diffusion mixing.

9. The preparation method according to claim 8, further comprising a pulverizing step before methimazole is added to the molten solid dispersion material.

10. The preparation method according to claim 8 or 9, wherein the low-temperature solidification in the solidification step refers to gradually solidifying the liquid obtained after heating and melting by placing it at a low temperature to form a solid dispersion with a three-dimensional network structure.

11. The preparation method according to claim 10, wherein the low temperature solidification comprises the steps of cooling the material from 70°C to 25°C within 30 minutes, and placing the obtained eutectic at 25°C at 0°C-25°C for 6-12 hours.

12. The preparation method according to any one of claims 8 to 11, wherein: In the mixing step, other pharmaceutically acceptable excipients are mixed with the secondary pulverized product by using an equal amount incremental addition method, and then added into the multifunctional pulverizer.

13. A method for treating hyperthyroidism, comprising administering to a patient in need thereof the methimazole powder or dust according to any one of claims 1 to 7 or the methimazole powder or dust prepared by the preparation method according to any one of claims 8 to 12.

Images