Solid pharmaceutical preparation of nitric acid 2-(4-methylthiazol-5-yl) ethyl ester hydrochloride

Abstract

The invention discloses a solid particle of double-membrane nitric acid 2-(4-methylthiazol-5-yl) ethyl ester hydrochloride and a solid pharmaceutical preparation prepared from the solid particle. The solid particle is a drug-containing particle sequentially coated with an oily membrane and a high polymer material membrane. According to the invention, a double-membrane strategy is adopted, and the problems of content reduction and easy degradation caused by sublimation of a main drug are effectively solved through a membrane protection barrier formed by a fat-soluble material and a high polymer material.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a solid drug particle containing 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and a solid drug formulation thereof. Technical Background

[0002] Neurodegenerative diseases are a group of chronic illnesses characterized by the gradual loss of neurons and myelin sheaths, leading to functional decline. These diseases cause a gradual deterioration of the nervous system, affecting cognitive, motor, emotional, and sensory functions. Common neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, vascular dementia, amyotrophic lateral sclerosis (ALS), and Huntington's disease. The causes of neurodegenerative diseases are complex, involving multiple factors such as gene mutations, oxidative stress, mitochondrial dysfunction, abnormal immune responses, inflammation, and excitotoxicity. These diseases are irreversible; patients gradually lose their daily living abilities as the disease progresses, and may eventually die from complications.

[0003] 2-(4-methylthiazol-5-yl)ethyl nitrate exhibits pharmacological effects such as inhibiting the expression of inflammatory factors, particularly TNF-α, synergistically increasing the activation of receptors by amino acid neurotransmitters, releasing NO through metabolism in vivo, and exerting vasodilatory effects. These effects can alleviate individual neurodegeneration, achieve neuroprotection, and / or enhance cognition. It can be used for the prevention and / or treatment of the aforementioned cardiovascular and cerebrovascular diseases and neurodegenerative diseases. 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride (chemical structure shown below) is a white or off-white powder, readily soluble in water, readily soluble in methanol, soluble in ethanol, very slightly soluble in acetone, and insoluble in diethyl ether, ethyl acetate, and dichloromethane. It has certain sublimation properties and is easily degraded under certain temperature conditions to a specific known 5-(2-chloroethyl)-4-methylthiazolium (impurity C).

[0004]

[0005] Patent document CN 110433161 A discloses a tablet containing 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride or 2-(4-methylthiazol-5-yl)ethyl nitrate maleate. It employs a direct powder compression process, where all excipients are sieved through a 100-mesh sieve. The active pharmaceutical ingredient is ground into powder, then mixed with fillers and disintegrants, followed by the addition of a lubricant and compression into tablets. In industrial-scale production, due to the significant sublimation properties of the active pharmaceutical ingredient, there is substantial content loss during preparation and storage. Furthermore, the prepared tablets are greatly affected by storage temperature, making them prone to impurity C formation. Additionally, the active pharmaceutical ingredient is corrosive to machinery.

[0006] Patent document CN 118662462 B developed a tablet of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride using glyceryl monostearate as a protectant. The addition of the protectant solved the sticking and corrosion of equipment during the industrial production of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride. Although the addition of the protectant slowed down the sublimation and chemical degradation of the active pharmaceutical ingredient to some extent, long-term stability tests (30℃±2℃, 65%±5%RH) showed that the tablets prepared with glyceryl monostearate as a protectant still had stability problems such as content reduction due to active pharmaceutical ingredient sublimation and easy degradation. Therefore, the prepared tablets need to be stored under low-temperature conditions to fully ensure the stability of content and related substances.

[0007] Therefore, how to effectively overcome the pharmaceutical defects of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, such as its easy sublimation and chemical degradation, and to ensure its good stability under normal storage conditions, remains the main factor limiting the commercial production of this drug. Summary of the Invention

[0008] To overcome the shortcomings of the existing technology, the present invention provides a new formulation strategy that uses a double membrane barrier to effectively solve the problem of drug content reduction due to drug sublimation, thereby avoiding the low-temperature limitation of the prepared product on storage temperature and improving product stability.

[0009] Specifically, the technical solution of the present invention is as follows:

[0010] In a first aspect, the present invention provides solid particles containing 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, wherein the solid particles are drug-containing particles sequentially coated with an oily film and a polymeric material film, and specifically comprise 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, an oily film material, a polymeric material, a filler, and a binder. The oily film is a fat-soluble material selected from one or more of vegetable oils and tocopherols, preferably one or more of wheat germ oil, sunflower seed oil, camellia seed oil, and tocopherols. The polymeric material is selected from one or more of hydroxypropyl methylcellulose, polyoxyethylene, polyvinyl alcohol, and copovidone.

[0011] The solid particles containing 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride are prepared by the following method: 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride is granulated with an ethanol solution containing an oily film material to obtain drug-containing core particles with an oily film; the drug-containing core particles, polymer material, filler and binder are then mixed and granulated, and dried and sized to obtain the final product.

[0012] The mass ratio of oily membrane material to 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride in the solid particles is 1:2.5 to 20; the mass percentage of polymeric membrane material in the solid particles is 10% to 51%.

[0013] The filler and binder in the solid particles containing 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride account for 27% to 82% of the total mass of the solid particles.

[0014] The filler in the solid particles containing 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride is selected from one or more of lactose, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, starch, paste, sucrose, sorbitol, and potassium dihydrogen phosphate; the binder is selected from one or more of polyvinylpyrrolidone, pregelatinized starch, and hydroxypropyl cellulose.

[0015] A solid pharmaceutical preparation of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride is prepared from the above-mentioned solid particles containing 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride.

[0016] The solid pharmaceutical preparation containing 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride further comprises one or more of the following: fillers, binders, flow aids, and lubricants.

[0017] The filler in the solid pharmaceutical preparation containing 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride is selected from one or more of lactose, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, starch, paste, sucrose, sorbitol, and potassium dihydrogen phosphate; the binder is selected from one or more of povidone, pregelatinized starch, and hydroxypropyl cellulose; the flow aid is selected from one or more of silica and talc; and the lubricant is selected from one or more of magnesium stearate and sodium stearate fumarate.

[0018] In a specific example of the present invention, the solid particles comprise 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, an oily membrane material, a hydrophilic polymer material, a filler, and a binder, wherein the mass ratio of the oily membrane material to the 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride is 1:2.5 to 20, the polymer membrane material accounts for 10% to 51% of the mass percentage of the solid particles, and the filler and binder account for 27% to 82% of the mass percentage of the solid particles.

[0019] More preferably, the solid particles comprise 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, an oily membrane material, a hydrophilic polymer material, a filler, and a binder, wherein the mass ratio of the oily membrane material to 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride is 1:2.5 to 10, the polymer membrane material accounts for 20% to 40% of the mass of the solid particles, and the filler and binder account for 30% to 70% of the mass of the solid particles.

[0020] The solid pharmaceutical preparation containing 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride is in the form of powder, granules, tablets or capsules.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] 1. Due to the easy degradation and sublimation of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride, conventional inclusion techniques, such as cyclodextrin inclusion, while mitigating drug sublimation to some extent, suffer from low inclusion rates, easy degradation during drying, and poor flowability of the inclusion compound. This invention employs a dual-membrane barrier strategy, sequentially coating the product with an oily membrane and a polymeric material membrane. This not only solves the stability issues related to product degradation and sublimation but also avoids the problems of low inclusion rates and complex preparation processes associated with traditional cyclodextrin inclusion techniques.

[0023] 2. The dual-membrane barrier of the present invention can improve the chemical stability of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride under high temperature conditions, and the content of impurity C under accelerated conditions at 40°C does not exceed 1.5%, avoiding the harsh requirements of ambient temperature on product storage conditions and improving product safety. Detailed Implementation

[0024] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. The reagents and raw materials used in this invention are readily available through conventional means, and unless otherwise specified, they are used in accordance with conventional methods in the art or as per the product instructions. Furthermore, any methods or materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0026] Example 1

[0027] Tablet formulation composition:

[0028] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 100 30.3 Hydroxypropyl methylcellulose 80 24.2 Wheat germ oil 10 3.0 Mannitol 120 36.3 Pregelatinized starch 10 3.0 silicon dioxide 5 1.5 magnesium stearate 5 1.5 total 330 100.0

[0029] Preparation method: First, add the prescribed amount of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and half of the prescribed amount of mannitol to a high-shear wet granulation pot for premixing. Dissolve the prescribed amount of wheat germ oil in an appropriate amount of anhydrous ethanol and spray granulate. After drying at 40°C, premix the granules coated with the drug-containing oily film with the remaining mannitol, 3 / 4 of the prescribed amount of pregelatinized starch and hydroxypropyl methylcellulose in a high-shear wet granulation pot. Dissolve the remaining prescribed amount of pregelatinized starch in an appropriate amount of 35% ethanol to prepare a binder solution. Fully wet the hydroxypropyl methylcellulose, granulate, dry and granulate. Add the prescribed amount of silica and magnesium stearate, mix evenly, and then compress into tablets using a rotary tablet press (average tablet weight is about 330 mg).

[0030] Example 2

[0031] Tablet formulation composition:

[0032] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 50 16.7 Copolyvinylpyrrolidone 150 50.0 Sunflower seed oil 12.5 4.2 microcrystalline cellulose 70 23.3 Hydroxypropyl cellulose 10 3.3 silicon dioxide 3.5 1.2 magnesium stearate 4 1.3 total 300 100.0

[0033] Preparation process: First, add the prescribed amount of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and half of the prescribed amount of microcrystalline cellulose to a high-shear wet granulation pan for premixing. Dissolve the prescribed amount of sunflower seed oil in an appropriate amount of anhydrous ethanol and spray granulate. After drying at 40°C, premix the particles coated with the drug-containing oily film, copovidone, and the remaining microcrystalline cellulose in a high-shear wet granulation pan. Dissolve hydroxypropyl cellulose in an appropriate amount of 75% ethanol to prepare a binder solution. Fully wet the copovidone, granulate, dry, and granulate. Add the prescribed amount of silica and magnesium stearate, mix evenly, and then compress into tablets using a rotary tablet press (average tablet weight is about 300 mg).

[0034] Example 3

[0035] Capsule prescription composition:

[0036] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 100 40.0 Hydroxypropyl methylcellulose 60 24.0 Tocopherol 5 2.0 lactose 70 28.0 Povidone K30 9 3.6 silicon dioxide 3 1.2 magnesium stearate 3 1.2 total 250 100.0

[0037] Preparation process: First, add the prescribed amount of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and half of the prescribed amount of lactose to a high-shear wet granulation pot for premixing. Dissolve the prescribed amount of tocopherol in an appropriate amount of anhydrous ethanol and spray granulate. After drying at 40°C, premix the granules coated with the drug-containing oily film, hydroxypropyl methylcellulose, and the remaining lactose in a high-shear wet granulation pot. Dissolve povidone K30 in an appropriate amount of 95% ethanol to prepare a binder solution. Fully wet the hydroxypropyl methylcellulose, granulate, dry, and granulate. Add the prescribed amount of silica and magnesium stearate, mix evenly, and fill No. 3 capsules (containing approximately 250 mg of contents) to obtain the final product.

[0038] Example 4

[0039] Granule formulation composition:

[0040] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 10 5.0 Polyoxyethylene 20 10.0 Camellia seed oil 5 2.5 dextrin 157 78.5 Povidone K30 4.5 2.25 silicon dioxide 1.5 0.75 Sodium stearate 2 1.0 total 200 100.0

[0041] Preparation process: First, add the prescribed amount of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and 10% of the prescribed amount of dextrin to a high-shear wet granulation pot for premixing. Dissolve camellia seed oil in an appropriate amount of anhydrous ethanol and spray granulate. After drying at 40℃, premix the granules coated with the drug-containing oily film, polyoxyethylene and the remaining dextrin in a high-shear wet granulation pot. Dissolve povidone K30 in an appropriate amount of 95% ethanol to prepare a binder solution. Fully wet the polyoxyethylene, granulate, dry and granulate. Add the prescribed amount of silica and sodium stearate fumarate, mix evenly, and package using a granulation packaging machine to obtain the final product.

[0042] Example 5

[0043] Powder formulation composition:

[0044] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 10 10.0 Polyoxyethylene 13 13.0 Tocopherol 4 4.0 sucrose 70 70.0 Povidone K30 1.5 1.5 silicon dioxide 0.5 0.4 magnesium stearate 1 1.0 total 100 100.0

[0045] Preparation process: First, the prescribed amount of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and 1 / 3 of the prescribed amount of sucrose are added to a high-shear wet granulation pot for premixing. The prescribed amount of tocopherol is dissolved in an appropriate amount of anhydrous ethanol and then spray-granulated. After drying at 40°C, the granules coated with the drug-containing oily film, polyoxyethylene, and the remaining sucrose are premixed in a high-shear wet granulation pot. A binder solution is prepared by dissolving povidone K30 in an appropriate amount of 70% ethanol. The polyoxyethylene is fully wetted, granulated, dried, and granulated into a fine powder. The prescribed amount of silica and magnesium stearate are added, mixed evenly, and then packaged using a packaging machine to obtain the final product.

[0046] Comparative Example 1: Patent CN 118662462 B uses glyceryl monostearate as a protective agent.

[0047] Tablet formulation composition:

[0048] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 10 10.0 lactose 83 83.0 Low-substituted hydroxypropyl cellulose 5 5.0 Glyceryl monostearate 1.4 1.4 magnesium stearate 0.6 0.6 total 100 100.0

[0049] Preparation process: Premix the prescribed amount of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride with glyceryl monostearate, then add lactose, low-substituted hydroxypropyl cellulose and magnesium stearate, mix again, and compress into tablets using a rotary tablet press to obtain the final product.

[0050] Comparative Example 2: Formulation with low dosage of oily film material

[0051] Tablet formulation composition:

[0052] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 100 40.0 Hydroxypropyl methylcellulose 60 24.0 Tocopherol 2 0.8 lactose 73 29.2 Povidone K30 9 3.6 silicon dioxide 3 1.2 magnesium stearate 3 1.2 total 250 100.0

[0053] Preparation process: The prescribed amount of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and half of the prescribed amount of lactose are premixed in a high-shear wet granulation pot. The prescribed amount of wheat germ oil is dissolved in an appropriate amount of anhydrous ethanol and spray-granulated. After drying at 40°C, the granules coated with the drug-containing oily film are premixed with the remaining lactose and hydroxypropyl methylcellulose in a high-shear wet granulation pot. A binder solution is prepared by dissolving povidone K30 in an appropriate amount of 95% ethanol. The hydroxypropyl methylcellulose is fully wetted, granulated, dried, and sized. The prescribed amount of silica and magnesium stearate are added and mixed evenly. The mixture is then compressed into tablets using a rotary tablet press (average tablet weight is about 250 mg).

[0054] Comparative Example 3: Formulation with low dosage of polymer membrane material

[0055] Tablet formulation composition:

[0056] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 10 5.3 Polyoxyethylene 10 5.3 Camellia seed oil 5 2.6 dextrin 152 80.0 Povidone K30 5 2.6 silicon dioxide 3 1.6 Sodium stearate 5 2.6 total 190 100.0

[0057] Preparation process: Premix 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride (prescribed amount) and 10% dextrin (prescribed amount) in a high-shear wet granulation pan. Dissolve camellia seed oil (prescribed amount) in an appropriate amount of anhydrous ethanol and spray granulate. Dry at 40℃. Then, premix the granules coated with the drug-containing oily film with the remaining dextrin and polyoxyethylene in a high-shear wet granulation pan. Dissolve povidone K30 in an appropriate amount of 95% ethanol to prepare a binder solution. Thoroughly wet the polyoxyethylene, granulate, dry, and granulate. Add silica and sodium stearate fumarate (prescribed amount), mix evenly, and compress using a rotary tablet press (average tablet weight approximately 190 mg). Comparative Example 4: Formulations prepared from different polymeric materials (ethyl cellulose).

[0058] Tablet formulation composition:

[0059] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 100 100.0 Ethyl cellulose 80 80.0 Wheat germ oil 10 10.0 Mannitol 70 70.0 Povidone K30 10 10.0 silicon dioxide 5 5.0 magnesium stearate 5 5.0 total 280 280.0

[0060] Preparation process: The prescribed amount of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and half of the prescribed amount of mannitol are premixed in a high-shear wet granulation pot. The prescribed amount of wheat germ oil is dissolved in an appropriate amount of anhydrous ethanol and spray-granulated. After drying at 40°C, the granules coated with the drug-containing oily film are premixed with the remaining mannitol and ethyl cellulose in a high-shear wet granulation pot. The binder solution is prepared by dissolving povidone K30 in an appropriate amount of 95% ethanol. The granules are fully wetted with glyceryl monostearate, dried, and sized. The prescribed amounts of silica and magnesium stearate are added and mixed evenly. The mixture is then compressed into tablets using a rotary tablet press (average tablet weight is approximately 280 mg).

[0061] Comparative Example 5: Formulations prepared from different polymeric materials (hydroxyethyl cellulose)

[0062] Tablet formulation composition:

[0063] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 100 100.0 Hydroxyethyl cellulose 80 80.0 Wheat germ oil 10 10.0 Mannitol 70 70.0 Povidone K30 10 10.0 silicon dioxide 5 5.0 magnesium stearate 5 5.0 total 280 280.0

[0064] Preparation process: The prescribed amount of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and half of the prescribed amount of mannitol are premixed in a high-shear wet granulation pot. The prescribed amount of wheat germ oil is dissolved in an appropriate amount of anhydrous ethanol and spray-granulated. After drying at 40°C, the granules coated with the drug-containing oily film are premixed with the remaining mannitol and hydroxyethyl cellulose in a high-shear wet granulation pot. The binder solution is prepared by dissolving povidone K30 in an appropriate amount of 95% ethanol. The granules are fully wetted with glyceryl monostearate, dried, and sized. The prescribed amount of silica and magnesium stearate are added and mixed evenly. The mixture is then compressed into tablets using a rotary tablet press (average tablet weight is about 280 mg).

[0065] Comparative Example 6: Case without oily film material

[0066] Tablet formulation composition:

[0067] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 100 40.0 Hydroxypropyl methylcellulose 60 24.0 lactose 75 30.0 Povidone K30 9 3.6 silicon dioxide 3 1.2 magnesium stearate 3 1.2 total 250 100.0

[0068] Preparation process: Add the prescribed amounts of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride, hydroxypropyl methylcellulose, and lactose to a high-shear wet granulation pan for premixing. Dissolve povidone K30 in an appropriate amount of 95% ethanol to prepare a binder solution. After fully wetting and granulating the hydroxypropyl methylcellulose, dry and granulate it. Add the prescribed amounts of silica and magnesium stearate, mix evenly, and then compress the mixture into tablets using a rotary tablet press (average tablet weight is approximately 250 mg).

[0069] Comparative Example 7: Tablets prepared using cyclodextrin inclusion complex technology

[0070] Tablet formulation composition:

[0071] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 50 20.0 Hydroxypropyl methylcellulose 45 18.0 Hydroxypropyl-β-cyclodextrin 100 40.0 lactose 40 16.0 Povidone K30 9 3.6 silicon dioxide 3 1.2 magnesium stearate 3 1.2 total 250 100.0

[0072] Preparation process: 1) Preparation of hydroxypropyl-β-cyclodextrin inclusion complex of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride: Add the prescribed amount of hydroxypropyl-β-cyclodextrin to the reaction vessel, add purified water and stir to dissolve, maintain the temperature inside the vessel at 35℃, and stir to obtain a clear cyclodextrin solution; weigh the prescribed amount of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride, slowly add it to the above-stirred cyclodextrin solution, continue stirring for 1 hour after the addition is complete, cool and let stand, filter, place the filter in a vacuum drying oven to dry, and obtain 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride inclusion complex;

[0073] 2) Preparation of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride tablets: Granulate the obtained 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride inclusion complex, pass it through a 60-mesh sieve, and mix it evenly with the prescribed amount of lactose, povidone K30 and hydroxypropyl methylcellulose in a wet granulator. Then add an appropriate amount of water, granulate by high-speed shearing, dry and granulate through a 30-mesh sieve. Then mix it evenly with silica and magnesium stearate, and compress it into tablets to obtain the final product.

[0074] Comparative Example 8: Formulation first coated with a polymer membrane material and then coated with an oily film.

[0075] Tablet formulation composition:

[0076] composition Dosage (g) Weight percentage (%) 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride 100 30.3 Hydroxypropyl methylcellulose 80 24.2 Wheat germ oil 10 3.0 Mannitol 120 36.3 Povidone K30 10 3.0 silicon dioxide 5 1.5 magnesium stearate 5 1.5 total 330 100.0

[0077] Preparation process: The prescribed amount of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and half the prescribed amount of dextrin and hydroxypropyl methylcellulose are premixed in a high-shear wet granulation pan. A binder solution is prepared by dissolving povidone K30 in an appropriate amount of 95% ethanol. The hydroxypropyl methylcellulose is fully moistened, granulated, dried, and sized. Then, the drug-containing granules are premixed with the remaining dextrin in a high-shear wet granulation pan. Wheat germ oil is dissolved in an appropriate amount of anhydrous ethanol and spray-granulated. After drying at 40°C, the granules are sized. Finally, the prescribed amount of silicon dioxide and magnesium stearate are added, and the tablets are compressed using a rotary tableting machine (average tablet weight is about 330 mg) to obtain the final product.

[0078] Test method and sample detection for the content of Example 1

[0079] The content of the sample was determined by high performance liquid chromatography (HPLC).

[0080] Chromatographic conditions: Octadecylsilane-bonded silica gel (Alltima C18, 4.6×250mm, 5μm) was used as the stationary phase; 0.1% formic acid solution was used as mobile phase A; methanol was used as mobile phase B; gradient elution was used; the flow rate was 0.8 ml / min; the column temperature was 40℃; the detection wavelength was 247 nm; the injection volume was 20 μL; the theoretical plate number, calculated based on the 2-(4-methylthiazolyl-5-yl)ethyl nitrate peak, was not less than 5000.

[0081] Take an appropriate amount of the test sample, accurately weigh it, grind it into a fine powder, accurately weigh an appropriate amount of the fine powder (approximately equivalent to 50 mg of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride) and place it in a 50 ml volumetric flask. Add an appropriate amount of solvent [water-methanol (1:1)], shake to fully wet the sample, and dilute to the mark with the solvent. Shake well. Take 1 ml of the solution and place it in a 10 ml volumetric flask. Dilute to the mark with water, shake well, filter, and collect the filtrate. Take an appropriate amount of 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride reference standard and prepare a reference solution containing approximately 100 μg of the main component per ml using the same method. Calculate the content of the main component of the test sample by peak area using the external standard method.

[0082] Samples from Examples 1-5 and Comparative Examples 1-8 were taken, and their contents were determined according to the above-described content testing method. The specific test results are shown in the table below:

[0083]

[0084]

[0085] The experimental results show that the contents of the samples prepared in Examples 1-5 are close to 100% of the theoretical labeled contents, indicating that the use of oily membrane materials and polymeric membrane materials in the technical solution of this invention can effectively reduce the loss caused by drug sublimation during the preparation process. Comparative Example 1 uses the prior art with glyceryl monostearate as a protective agent, and Comparative Example 7 uses the prior art cyclodextrin inclusion technology, showing a significant loss of drug content (approximately 5%). Comparative Example 2 uses a low amount of oily membrane material, and Comparative Example 6 does not use any oily membrane material, showing that the effect of oily membrane material in reducing drug content loss is relatively limited. Comparative Example 3 uses a low amount of polymeric material, showing that oily membrane material plays a major role in reducing drug content loss. Comparative Examples 4 and 5 use ethyl cellulose and hydroxyethyl cellulose as polymeric film-forming materials, showing a significant loss of drug content (approximately 5%), indicating that the type of polymeric film-forming material affects the effectiveness of the film-forming barrier. Comparative Example 8 involves the sequential exchange of polymeric membrane and oily membrane inside and outside, showing that it can effectively reduce drug loss during the preparation process.

[0086] Experimental Example 2: Analytical Methods and Detection of Related Substances

[0087] High performance liquid chromatography (HPLC) was used to detect related substances in the sample.

[0088] Chromatographic conditions: Octadecylsilane-bonded silica gel (Alltima C18, 4.6×250mm, 5μm) was used as the stationary phase; 0.1% formic acid solution was used as mobile phase A; methanol was used as mobile phase B; gradient elution was used; the flow rate was 0.8 ml / min; the column temperature was 40℃; the detection wavelength was 247 nm; the injection volume was 20 μL; the theoretical plate number, calculated based on the 2-(4-methylthiazolyl-5-yl)ethyl nitrate peak, was not less than 5000.

[0089] Take an appropriate amount of the test sample, accurately weigh it, grind it into a fine powder, accurately weigh an appropriate amount of the fine powder (approximately equivalent to 50 mg of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride) and place it in a 50 ml volumetric flask. Add an appropriate amount of solvent [water-methanol (1:1)], shake to fully wet the sample, and dilute to the mark with the solvent. Sonicate for 15 min, cool to room temperature, dilute to the mark with the solvent, shake well, filter, and take the filtrate as the test solution. Accurately measure 0.5 ml of the test solution into a 500 ml volumetric flask, dilute to the mark with the solvent, shake well, and use as the control solution. Accurately measure the reference solution and the test solution, and inject them separately into the liquid chromatograph. Record the chromatograms. Except for the solvent peak and the main component peak of 2-(4-methylthiazol-5-yl)ethyl nitrate, detect impurities A, B, and C at a wavelength of 247 nm (relative retention times of 0.40, 0.91, and 1.05, respectively). Calculate the impurities using the main component self-comparison method with correction factors (correction factors of 1.19, 1.05, and 1.09, respectively). Impurity A should not exceed 1.0%, impurity B should not exceed 1.0%, impurity C should not exceed 3.0%, other maximum single impurities should not exceed 0.5%, and total impurities should not exceed 5.0%.

[0090] Samples from Examples 1-5 and Comparative Examples 1-8, as well as the active pharmaceutical ingredient used in the preparation, were taken and the relevant substances in the samples were determined according to the above-mentioned methods for testing related substances. The specific test results are shown in the table below:

[0091]

[0092] Note: ND - Not detected.

[0093] Compared with the raw material before preparation, the total impurities in each example and comparative example increased to varying degrees, indicating that the main component of this product is prone to degradation, mainly generating impurity C. Compared with the related substances in Examples 1-5, the related substances in samples prepared with lower oil film material content (Comparative Example 2) and without oil film material (Comparative Example 6) all met the quality standard requirements, but the total impurities increased significantly, especially impurity C. This suggests that although the oil film material has a limited effect on drug sublimation loss, it significantly improves drug stability and reduces drug degradation. Although glyceryl monostearate was used as a protective agent in Comparative Example 1, its protective effect on the main component was weak during preparation, resulting in a large increase in impurity C. Comparative Example 7 used conventional cyclodextrin molecular inclusion, which had a poor stabilizing effect on the main component, resulting in a large increase in impurity C. Comparative Example 3 was a case of low polymeric film material content. Comparative Examples 4 and 5 used ethyl cellulose and hydroxyethyl cellulose as polymeric film-forming materials, and the results showed that the polymeric film material had a relatively small impact on drug stability. Comparative Example 8 involved the sequential exchange of the inner and outer sides of the polymer membrane and the oil membrane. While this effectively reduced drug sublimation loss during preparation, it also decreased drug stability and increased impurity content. Combined with the results of Experimental Example 2, this demonstrates that the oil membrane in the present invention can improve drug stability and reduce the formation of related substances during preparation, while the polymer membrane can reduce drug sublimation loss. Furthermore, the inner and outer order of the oil membrane barrier and the polymer membrane barrier is also a key factor in improving drug stability.

[0094] Experiment Example 3: Stability Test

[0095] The 2-(4-methylthiazol-5-yl)ethyl nitrate hydrochloride preparations prepared in Examples 1, 2, Comparative Examples 1, and Comparative Examples 5-8 were packaged in aluminum-plastic blister packs and placed under accelerated testing conditions of 40℃±2℃ and 75%±5% humidity. The accelerated stability of the samples was investigated according to the methods described in the quality standard. The experimental results are as follows:

[0096]

[0097] The results above show that, under accelerated testing conditions, although the content of the tablets prepared in Examples 1 and 2 of this invention decreased slightly, and impurity C and total impurities showed a certain increasing trend, they were all within the proposed quality standards. This indicates that the polymeric film-forming material and oily material in the examples can effectively control the sublimation and chemical degradation of the drug. The tablets prepared in Comparative Examples 1, 6, 7, and 8 gradually changed from white to pale yellow or yellow during stable storage, and the increase in various impurities was relatively significant. This indicates that the formulation did not contain oily film material or the oily film material was not effectively coated with the active pharmaceutical ingredient. The prepared formulation samples are prone to chemical degradation, leading to significant changes in tablet properties. In Comparative Example 5, although the formulation also contained a certain amount of hydroxyethyl cellulose polymer material, the tablet content gradually decreased during stable storage, indicating that the hydroxyethyl cellulose polymer material failed to effectively form a film to block drug sublimation, resulting in drug loss through sublimation during stable storage. Furthermore, based on the stability data of Comparative Example 7, the cyclodextrin inclusion technology did not provide good protection for the main component. Under accelerated conditions, there was significant sublimation, and the increase in impurities was more pronounced, even exceeding the limits. Based on the stability data of Comparative Example 8, although coating with a polymer film followed by an oil film was beneficial to inhibiting the sublimation of the active ingredient to some extent, the changes in impurities did not provide a good stabilizing effect on the chemical stability of the active ingredient.

[0098] Based on the disclosure of this invention, those skilled in the art can apply this invention to the fullest extent. Therefore, the above preferred embodiments are merely illustrative and are not intended to limit the scope of this invention in any way.

Claims

1. A solid particle of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride, characterized in that... The solid particles are drug-containing particles sequentially coated with an oily film and a polymeric material film. The solid particles include 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride, an oily film material, a polymeric material, a filler, and a binder. The oily film is a fat-soluble material selected from one or more of vegetable oils and tocopherols. The polymeric film material is selected from one or more of hydroxypropyl methylcellulose, polyoxyethylene, polyvinyl alcohol, and copovidone.

2. The solid particles as described in claim 1, characterized in that... The drug-containing core particles with an oily membrane are prepared by granulation of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride and an ethanol solution containing an oily membrane material. The drug-containing core particles, polymer material, filler and binder are then mixed and granulated, and dried and sized to prepare the final product.

3. The solid particles as described in claim 1 or 2, characterized in that... The mass ratio of the oily membrane material to 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride is 1:2.5~20. The fat-soluble material is selected from one or more of wheat germ oil, sunflower seed oil, camellia seed oil, and tocopherol. The mass percentage of the polymer membrane material in the solid particles is 10%~51%.

4. The solid particles as described in claim 3, characterized in that... The mass ratio of the oily membrane material to 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride is 1:2.5~10, and the mass percentage of the polymer membrane material in the solid particles is 20%~40%.

5. The solid particles as described in claim 1 or 2, characterized in that... The mass percentage of fillers and binders in solid particles is 27% to 82%.

6. The solid particles as described in claim 5, characterized in that... The mass percentage of fillers and binders in solid particles is 30% to 70%.

7. The solid particles according to claim 1 or 2, characterized in that... The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, starch, paste, sucrose, sorbitol, and potassium dihydrogen phosphate; the binder is selected from one or more of povidone, pregelatinized starch, and hydroxypropyl cellulose.

8. A solid pharmaceutical preparation of 2-(4-methylthiazolyl-5-yl)ethyl nitrate hydrochloride, characterized in that... It is prepared using the solid particles described in any one of claims 1-7.

9. The solid pharmaceutical preparation according to claim 8, characterized in that... It also includes one or more of the following: fillers, adhesives, flow aids, and lubricants.

10. The solid pharmaceutical preparation according to claim 9, characterized in that... The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, disodium hydrogen phosphate, starch, paste, sucrose, sorbitol, and potassium dihydrogen phosphate; the binder is selected from one or more of povidone, pregelatinized starch, and hydroxypropyl cellulose; the flow aid is selected from one or more of silica and talc; and the lubricant is selected from one or more of magnesium stearate and sodium stearate fumarate.

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