1-(5-oxohexyl) theobromine sustained release tablet and preparation method thereof

Abstract

The invention discloses a 1-(5-oxohexyl) theobromine sustained-release tablet, the 1-(5-oxohexyl) theobromine sustained-release tablet is composed of a tablet core and a sustained-release coating layer, the tablet core (based on the total weight of the tablet core) is prepared from the following components in parts by weight: 360-450 parts of 1-(5-oxohexyl) theobromine, 50-200 parts of a skeleton sustained-release material, 5-15 parts of an adhesive and 5-10 parts of a lubricant, the matrix sustained-release material is selected from glyceryl behenate and / or polyoxyethylene, preferably, the matrix sustained-release material is selected from glyceryl behenate and polyoxyethylene, the weight ratio of glyceryl behenate to polyoxyethylene is (0.5-2): 1, and the adhesive is prepared into a 95% ethanol solution of 5% povidone K30.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and specifically relates to an improved 1-(5-oxohexyl) theobromine sustained-release tablet (400 mg) and a preparation method thereof. BACKGROUND

[0002] 1-(5-oxohexyl) theobromine (i.e., pentifylline) is a methylxanthine derivative, which is mainly used for improving blood circulation disorders in the brain and periphery, such as transient ischemic attack, thromboangiitis obliterans, intermittent claudication, etc. With the continuous progress of medical technology, the administration of drugs is also being optimized to better meet the needs of clinical practice.

[0003] At present, the 1-(5-oxohexyl) theobromine preparations on the market are mainly ordinary tablets or injections. These drugs have a fast release rate in the body, which can easily lead to a rapid increase in blood drug concentration, followed by a rapid decline, i.e., the so-called "drug burst" phenomenon. This not only reduces the bioavailability of the drug, but also can cause discomfort or adverse reactions in patients, such as headache, dizziness, nausea, etc. In addition, frequent medication also increases the burden of patients and reduces treatment compliance.

[0004] Although the 1-(5-oxohexyl) theobromine sustained-release tablets on the market can prolong the drug action time to some extent, they still have problems such as low dissolution efficiency, unstable sustained-release effect, etc., which can lead to large fluctuations in drug concentration and easily cause adverse reactions.

[0005] Document 1 (CN 117482063 A) discloses a 1-(5-oxohexyl) theobromine sustained-release tablet, which uses glyceryl monostearate and peach gum as sustained-release materials, and optimizes the preparation process by mixing the raw materials and excipients in multiple times. Specifically, the glyceryl monostearate is mixed with 1-(5-oxohexyl) theobromine to obtain first premixed granules, and the remaining 1-(5-oxohexyl) theobromine is mixed with peach gum and a binder to obtain second premixed granules. Then, the first premixed granules, the second premixed granules, and a lubricant are mixed, so that the main drug 1-(5-oxohexyl) theobromine can be uniformly mixed with the excipients to ensure the uniformity of the drug. Although the 1-(5-oxohexyl) theobromine sustained-release tablet disclosed in document 1 may help to control the release rate of the drug by using glyceryl monostearate and peach gum as sustained-release materials, their biocompatibility and solubility may not be optimal, which can slow down the dissolution and absorption of the drug in the gastrointestinal tract, thereby affecting the bioavailability.

[0006] Document 2 (CN 117919188 A) discloses a 1-(5-oxohexyl) theobromine sustained-release tablet and its improved process, which improves the problem of large granulation viscosity in the wet granulation process of 1-(5-oxohexyl) theobromine sustained-release tablet, selects and adjusts the wetting agent, solves the problem of large product viscosity in the wet granulation process by changing the type of wetting agent. Further use of silicon dioxide as a stabilizer improves the problem of unstable dissolution of 1-(5-oxohexyl) theobromine sustained-release tablet caused by changing the wetting agent. Although document 2 mentions that the problem of large product viscosity in the wet granulation process is solved by changing the type of wetting agent, such change may affect the density and porosity of the granules, and thus affect the release characteristics of the drug. If the selection or amount of the wetting agent is improper, it may cause the granules to be too tight or too loose, which is not conducive to the smooth release of the drug at the predetermined rate, and if the dissolution rate itself is low, it will lead to insufficient absorption of the drug in the gastrointestinal tract, thereby reducing the bioavailability. SUMMARY

[0007] The present application relates to a 1-(5-oxohexyl) theobromine sustained-release tablet (400 mg) and a preparation method thereof, which aims to solve the technical problems of low dissolution efficiency, unstable sustained-release effect, and obvious drug burst phenomenon of 1-(5-oxohexyl) theobromine sustained-release tablets in the prior art, and improve the bioavailability of the drug and the compliance of patients taking the drug.

[0008] Specifically,

[0009] The present application relates to a 1-(5-oxohexyl) theobromine sustained-release tablet, which is composed of a tablet core and a sustained-release coating layer, and the tablet core (based on the total weight of the tablet core) is prepared from the following components in parts by weight:

[0010] 1-(5-oxohexyl) theobromine 360-450 parts by weight,

[0011] 50-200 parts by weight of a matrix sustained-release material,

[0012] 5-15 parts by weight of a binder, and

[0013] 5-10 parts by weight of a lubricant,

[0014] wherein,

[0015] the matrix sustained-release material is selected from glyceryl behenate and / or polyoxyethylene,

[0016] As the above-mentioned 1-(5-oxohexyl) theobromine sustained-release tablet, the matrix sustained-release material is selected from glyceryl behenate and polyoxyethylene, and the weight ratio is (0.5-2):1,

[0017] As the 1-(5-oxohexyl) theobromine sustained-release tablet described above, the polyoxyethylene has a molecular weight of 3.0 x 10 3 ~ 7.0 x 10 3 .

[0018] As the 1-(5-oxohexyl) theobromine sustained-release tablet described above, the binder is povidone.

[0019] As the 1-(5-oxohexyl) theobromine sustained-release tablet described above, the povidone is povidone K30.

[0020] As the 1-(5-oxohexyl) theobromine sustained-release tablet described above, the binder is prepared as a 90-95% ethanol solution of 5-10% povidone K30.

[0021] As the 1-(5-oxohexyl) theobromine sustained-release tablet described above, the binder is prepared as a 95% ethanol solution of 5% povidone K30.

[0022] As the 1-(5-oxohexyl) theobromine sustained-release tablet described above, the glyceryl behenate is a Sugargel series manufactured by British Speciality Chemicals, and the polyoxyethylene is PEG 4000 manufactured by BASF.

[0023] As the 1-(5-oxohexyl) theobromine sustained-release tablet described above, the sustained-release coating layer comprises ethyl cellulose, triethyl citrate, and talc.

[0024] The present application also provides a preparation method of a 1-(5-oxohexyl) theobromine sustained-release tablet, which comprises the following steps:

[0025] Tablet core preparation:

[0026] The powder of 1-(5-oxohexyl) theobromine and ethyl cellulose are weighed and mixed to obtain a mixture, the binder is sprayed on the mixture, and the mixture is continuously stirred and mixed until uniform granules are formed, the granules are sized, a lubricant is added, and the mixture is uniformly mixed again, and a tablet press is used to press the mixed granules into tablets.

[0027] Coating:

[0028] Prepare the coating liquid: weigh ethyl cellulose, triethyl citrate, and talc, and add an appropriate amount of water to prepare the coating liquid.

[0029] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50-80°C, slowly spray the coating liquid, continuously spray the coating, and after the coating is completed, continue to dry until the tablet surface is completely dry.

[0030] Inventive effect

[0031] 1. Stable release: The 400mg 1-(5-oxohexyl)theobromine sustained-release tablets provided by the application can release the drug smoothly within 24 hours, effectively avoid drug burst phenomenon, reduce the fluctuation of blood drug concentration, and improve the bioavailability of the drug.

[0032] 2. Improve efficacy: Stable sustained-release effect helps to maintain the effective concentration of the drug in the body, thereby improving the therapeutic effect, reducing the frequency of medication and adverse reactions.

[0033] 3. Simplify the process: The preparation method described in the application uses fewer auxiliary materials, the prescription process is simple, easy to industrialize production, and the product has high stability. DETAILED DESCRIPTION

[0034] The technical solutions in the embodiments of the present application will be described below. Obviously, the described embodiments are part of the embodiments of the present application, not all embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present application are within the scope of protection of the present application.

[0035] The terms "first", "second", and the like in the specification and claims of the present application are used to distinguish similar objects, not to describe a specific order or sequence. It should be understood that the data used in this way can be interchanged under appropriate circumstances, so that the embodiments of the present application can be implemented in an order other than those illustrated or described herein, and the objects distinguished by "first", "second", etc. are usually a class, not limited to the number of objects, for example, the first object can be one or more. In addition, "and / or" in the specification and claims means at least one of the connected objects, and the character " / ", generally indicates that the objects before and after are in an "or" relationship.

[0036] Example 1

[0037] Ingredients

[0038] Active ingredient: 1-(5-oxohexyl)theobromine 400mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.;

[0039] Sustained-release material: glyceryl behenate and polyoxyethylene, wherein glyceryl behenate (supplier: Croda International Plc, Sugargel series), polyoxyethylene (supplier: BASF, PEG 4000);

[0040] Binder: 5% povidone K30 in 95% ethanol solution, wherein povidone (supplier: Ashland China, Kollidon K30);

[0041] Lubricant: Magnesium stearate (Supplier: Taihei Chemical Industry Co., Ltd.).

[0042] Coating material:

[0043] Ethyl cellulose (Supplier: Ashland China)

[0044] Triethyl citrate (Supplier: BENG BU FENG YUAN TUSHAN PHARMACEUTICAL CO., LTD.)

[0045] Talcum powder (Supplier: Liaoning Jinrui Medicine Talcum Powder Co., Ltd.)

[0046] Preparation method

[0047] Tablet core preparation:

[0048] Weigh 40g of 1-(5-oxohexyl)theobromine powder (for 100 tablets, each containing 400mg), and place it in a mixer. Weigh 80g of glyceryl behenate and polyoxyethylene (weight ratio 1:1), and add them to the mixer. Prepare a 5% povidone K30 solution in 95% ethanol, and use 10% of the total weight of 1-(5-oxohexyl)theobromine, i.e. 4g of ethanol solution, to uniformly spray the mixture as a binder. Turn on the mixer and continue to mix until a uniform granulation is formed. Use an 18-mesh sieve to size the granulation, ensuring that the particle size is moderate. Add 2g of magnesium stearate as a lubricant and mix again. Use a tablet press to compress the mixed granulation into tablets, with appropriate die size and pressure settings. The tablet weight is approximately 1.2g.

[0049] Coating:

[0050] Prepare the coating solution: weigh 10g of ethyl cellulose, 2g of triethyl citrate, and 3g of talcum powder, and add an appropriate amount of water to make the coating solution.

[0051] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, constantly monitoring the appearance of the tablets and the quality of the coating. After coating is complete, continue to dry the tablets at 50°C until the surface is completely dry. Perform appearance inspection and hardness testing on the finished product to ensure compliance with quality standards.

[0052] Inspection and packaging:

[0053] Pack the tablets that meet the standards in aluminum plastic packaging, 10 tablets per plate, and 2 plates per box.

[0054] Example 2

[0055] Ingredients

[0056] Active ingredient: 1-(5-oxohexyl)theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0057] Matrix sustained-release material: glyceryl behenate and polyoxyethylene, wherein, glyceryl behenate (supplier: Croda International Plc, Sugargel series), polyoxyethylene (supplier: BASF, PEG 4000);

[0058] Binder: 95% ethanol solution of 5% povidone K30, wherein, povidone (supplier: Ashland China, Kollidon K30);

[0059] Lubricant: magnesium stearate (supplier: Taihei Chemical Industry Co., Ltd.).

[0060] Coating material:

[0061] Ethyl cellulose (supplier: Ashland China)

[0062] Triethyl citrate (supplier: Bengbu Fengyuan Toshin Pharmaceutical Co., Ltd.)

[0063] Talc (supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0064] Preparation method

[0065] Tablet core preparation:

[0066] Take 1-(5-oxohexyl)theobromine powder 40 g (for preparing 100 tablets, each containing 400 mg), and place it in a mixer. Take glyceryl behenate and polyoxyethylene together, 80 g (weight ratio 1.5:1), and add them to the mixer. Prepare 95% ethanol solution of 5% povidone K30, and use an amount of 10% of the total weight of 1-(5-oxohexyl)theobromine, i.e. 4 g of ethanol solution, and uniformly spray it on the mixture as a binder. Turn on the mixer and continue to mix until uniform granules are formed. Use a 18 mesh sieve to size the granules to ensure proper size. Add 2 g of magnesium stearate as a lubricant and mix again. Use a tablet press to set the appropriate die size and pressure to compress the mixed granules into tablets, with a tablet weight of about 1.2 g.

[0067] Coating:

[0068] Prepare the coating liquid: take ethyl cellulose 10 g, triethyl citrate 2 g, talc 3 g, and add an appropriate amount of water to make the coating liquid.

[0069] Place the above tablet cores in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, constantly monitoring the appearance of the tablets and the quality of the coating. After completing the coating, continue to dry with air blowing at 50°C until the tablet surface is completely dry. Perform appearance inspection and hardness test on the finished product to ensure compliance with quality standards.

[0070] Inspection and packaging:

[0071] The tablets that meet the standards are packaged in aluminum plastic, 10 tablets per plate, and 2 plates per box.

[0072] Example 3

[0073] Ingredients

[0074] Active ingredient: 1-(5-oxohexyl) theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0075] Matrix sustained-release material: glyceryl behenate and polyoxyethylene, wherein glyceryl behenate (supplier: Croda International Plc, Sugargel series), polyoxyethylene (supplier: BASF, PEG 4000);

[0076] Binder: 95% ethanol solution of 5% povidone K30, wherein povidone (supplier: Ashland China, Kollidon K30);

[0077] Lubricant: magnesium stearate (supplier: Taihei Chemical Industry Co., Ltd.).

[0078] Coating material:

[0079] Ethyl cellulose (supplier: Ashland China)

[0080] Triethyl citrate (supplier: Bengbu Fengyuan Toshin Pharmaceutical Co., Ltd.)

[0081] Talc (supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0082] Preparation method

[0083] Tablet core preparation:

[0084] Take 40 g of 1-(5-oxohexyl)theobromine powder (for the preparation of 100 tablets, each containing 400 mg), and place it in a mixer. Take 80 g of glyceryl behenate and polyoxyethylene (weight ratio 0.5:1), and add them to the mixer. Prepare a 5% povidone K30 solution in 95% ethanol, and use 10% of the total weight of 1-(5-oxohexyl)theobromine, i.e. 4 g of the ethanol solution, to uniformly spray the mixture as a binder. Turn on the mixer and continue to mix until uniform granules are formed. Use an 18-mesh sieve to size the granules, ensuring that the size is moderate. Add 2 g of magnesium stearate as a lubricant, and mix again. Use a tablet press to compress the mixed granules into tablets, with appropriate die size and pressure, and the tablets weigh about 1.2 g.

[0085] Coating:

[0086] Prepare the coating solution: take 10 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of talc, and add an appropriate amount of water to make the coating solution.

[0087] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, and monitor the appearance of the tablets and the quality of the coating during this process. After the coating is complete, continue to dry the tablets by blowing air at 50°C until the tablet surface is completely dry. Perform appearance inspection and hardness testing on the finished product to ensure that it meets the quality standards.

[0088] Inspection and packaging:

[0089] Pack the tablets that meet the standards in aluminum plastic packaging, 10 tablets per plate, and 2 plates per box.

[0090] Example 4

[0091] Ingredients

[0092] Active ingredient: 1-(5-oxohexyl)theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd;

[0093] Matrix sustained-release material: glyceryl behenate and polyoxyethylene, where glyceryl behenate (supplier: Croda International Plc, Sugargel series) and polyoxyethylene (supplier: BASF, PEG 4000);

[0094] Binder: 5% povidone K30 solution in 95% ethanol, where povidone (supplier: Ashland China, Kollidon K30);

[0095] Lubricant: Magnesium stearate (Supplier: Taihei Chemical Industry Co., Ltd.)

[0096] Coating material:

[0097] Ethyl cellulose (Supplier: Ashland China)

[0098] Triethyl citrate (Supplier: BENG BU FENG YUAN TUSHAN PHARMACEUTICAL CO., LTD.)

[0099] Talcum powder (Supplier: Liaoning Jinrui Medicine Talcum Powder Co., Ltd.)

[0100] Preparation method

[0101] Tablet core preparation:

[0102] Weigh 40g of 1-(5-oxohexyl)theobromine powder (for 100 tablets, each containing 400mg), and place it in a mixer. Weigh 80g of glyceryl behenate and polyoxyethylene (weight ratio 2:1), and add them to the mixer. Prepare a 5% povidone K30 solution in 95% ethanol, and use 10% of the total weight of 1-(5-oxohexyl)theobromine, i.e. 4g of ethanol solution, to uniformly spray the mixture as a binder. Turn on the mixer and continue to mix until a uniform granulation is formed. Use an 18-mesh sieve to size the granulation, ensuring that the particle size is moderate. Add 2g of magnesium stearate as a lubricant and mix again. Use a tablet press to compress the mixed granulation into tablets with appropriate die size and pressure, and the tablet weight is about 1.2g.

[0103] Coating:

[0104] Prepare the coating solution: weigh 10g of ethyl cellulose, 2g of triethyl citrate, and 3g of talcum powder, and add an appropriate amount of water to make the coating solution.

[0105] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, and monitor the appearance of the tablets and the quality of the coating during this process. After coating is complete, continue to dry the tablets at 50°C until the surface is completely dry. Perform appearance inspection and hardness test on the finished product to ensure that it meets the quality standards.

[0106] Inspection and packaging:

[0107] Pack the tablets that meet the standards in aluminum plastic packaging, 10 tablets per plate, and 2 plates per box.

[0108] Example 5

[0109] Ingredients

[0110] Active ingredient: 400 mg / tablet of 1-(5-oxohexyl) theobromine, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0111] Matrix sustained-release material: glyceryl behenate and polyoxyethylene, wherein glyceryl behenate (supplier: Croda International Plc, Sugargel series), polyoxyethylene (supplier: BASF, PEG 4000);

[0112] Binder: 90% ethanol solution of 10% povidone K30, wherein povidone (supplier: Ashland China, Kollidon K30);

[0113] Lubricant: magnesium stearate (supplier: Taihei Chemical Industry Co., Ltd.).

[0114] Coating material:

[0115] Ethyl cellulose (supplier: Ashland China)

[0116] Triethyl citrate (supplier: Bengbu Fengyuan Chushi Pharmaceutical Co., Ltd.)

[0117] Talc (supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0118] Preparation method

[0119] Tablet core preparation:

[0120] Weigh 40 g of 1-(5-oxohexyl) theobromine powder (for making 100 tablets, each containing 400 mg), and place it in a mixer. Weigh 80 g of glyceryl behenate and polyoxyethylene (weight ratio 1:1) and add them to the mixer. Prepare a 90% ethanol solution of 10% povidone K30, and use an amount of 10% of the total weight of 1-(5-oxohexyl) theobromine, i.e. 4 g of ethanol solution, to uniformly spray on the mixture as a binder. Turn on the mixer and continue to mix until uniform granules are formed. Use an 18-mesh sieve to size the granules to ensure moderate particle size. Add 2 g of magnesium stearate as a lubricant and mix again uniformly. Use a tablet press to compress the mixed granules into tablets with appropriate die size and pressure, and the tablet weight is about 1.2 g.

[0121] Coating:

[0122] Prepare the coating liquid: weigh 10 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of talc, and add an appropriate amount of water to make the coating liquid.

[0123] Place the above tablet cores in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating liquid while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, constantly monitoring the appearance of the tablets and the quality of the coating during this process. After completing the coating, continue to dry with air blowing at 50°C until the tablet surface is completely dry. Perform appearance inspection and hardness test on the finished product to ensure compliance with quality standards.

[0124] Inspection and packaging:

[0125] The tablets that meet the standards are packaged in aluminum plastic, 10 tablets per plate, and 2 plates per box.

[0126] Example 6

[0127] Ingredients

[0128] Active ingredient: 1-(5-oxohexyl) theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0129] Matrix sustained-release material: glyceryl behenate and polyoxyethylene, wherein glyceryl behenate (supplier: Croda International Plc, Sugargel series), polyoxyethylene (supplier: BASF, PEG 4000);

[0130] Binder: 93% ethanol solution of 7% povidone K30, wherein povidone (supplier: Ashland China, Kollidon K30);

[0131] Lubricant: magnesium stearate (supplier: Taihei Chemical Industry Co., Ltd.).

[0132] Coating material:

[0133] Ethyl cellulose (supplier: Ashland China)

[0134] Triethyl citrate (supplier: Bengbu Fengyuan Chushi Pharmaceutical Co., Ltd.)

[0135] Talc (supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0136] Preparation method

[0137] Tablet core preparation:

[0138] Take 40 g of 1-(5-oxohexyl)theobromine powder (for the preparation of 100 tablets, each containing 400 mg), and place it in a mixer. Take 80 g of glyceryl behenate and polyoxyethylene (weight ratio 1:1), and add them to the mixer. Prepare a 7% solution of povidone K30 in 93% ethanol, and use 10% of the total weight of 1-(5-oxohexyl)theobromine, i.e. 4 g of the ethanol solution, to uniformly spray the mixture as a binder. Turn on the mixer and continue to mix until uniform granules are formed. Use an 18-mesh sieve to size the granules, ensuring that the size is appropriate. Add 2 g of magnesium stearate as a lubricant, and mix again. Use a tablet press to compress the mixed granules into tablets, with appropriate die size and pressure, and the tablets weigh about 1.2 g.

[0139] Coating:

[0140] Prepare the coating solution: take 10 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of talc, and add an appropriate amount of water to make the coating solution.

[0141] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, constantly monitoring the appearance of the tablets and the quality of the coating. After the coating is complete, continue to dry the tablets by blowing air at 50°C until the tablet surface is completely dry. Perform appearance inspection and hardness test on the finished product to ensure that it meets the quality standards.

[0142] Inspection and packaging:

[0143] Pack the tablets that meet the standards in aluminum plastic packaging, 10 tablets per plate, and 2 plates per box.

[0144] Example 7

[0145] Ingredients

[0146] Active ingredient: 1-(5-oxohexyl)theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd;

[0147] Matrix sustained-release material: glyceryl behenate and polyoxyethylene, where glyceryl behenate (supplier: Croda International Plc, Sugargel series) and polyoxyethylene (supplier: BASF, PEG 6000);

[0148] Binder: 5% povidone K30 in 95% ethanol, where povidone (supplier: Ashland China, Kollidon K30);

[0149] Lubricant: Magnesium stearate (Supplier: Taihei Chemical Industry Co., Ltd.).

[0150] Coating material:

[0151] Ethyl cellulose (Supplier: Ashland China)

[0152] Triethyl citrate (Supplier: Benge Funguan Chushi Pharmaceutical Co., Ltd.)

[0153] Talcum powder (Supplier: Liaoning Jinrui Medicine Talcum Powder Co., Ltd.)

[0154] Preparation method

[0155] Tablet core preparation:

[0156] Weigh 40 g of 1-(5-oxohexyl) theobromine powder (for 100 tablets, each containing 400 mg), and place it in a mixer. Weigh 80 g of glyceryl behenate and polyoxyethylene (weight ratio 1:1), and add them to the mixer. Prepare a 5% povidone K30 solution in 95% ethanol, and use 10% of the total weight of 1-(5-oxohexyl) theobromine, i.e. 4 g of ethanol solution, to uniformly spray on the mixture as a binder. Turn on the mixer and continue to mix until a uniform granulation is formed. Use an 18-mesh sieve to size the granulation, ensuring that the particle size is moderate. Add 2 g of magnesium stearate as a lubricant and mix again. Use a tablet press to compress the mixed granulation into tablets with appropriate die size and pressure, and the tablet weight is about 1.2 g.

[0157] Coating:

[0158] Prepare the coating solution: weigh 10 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of talcum powder, and add an appropriate amount of water to make the coating solution.

[0159] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, and monitor the appearance of the tablets and the quality of the coating during this process. After coating is complete, continue to dry the tablets at 50°C until the surface is completely dry. Perform appearance inspection and hardness testing on the finished product to ensure that it meets quality standards.

[0160] Inspection and packaging:

[0161] Pack the tablets that meet the standards in aluminum plastic packaging, 10 tablets per plate, and 2 plates per box.

[0162] Comparative example 1

[0163] Ingredients

[0164] Active ingredient: 1-(5-oxohexyl) theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0165] Matrix release material: glyceryl behenate (Supplier: Croda International Plc, Sugargel series);

[0166] Binder: 95% ethanol solution of 5% povidone K30, wherein povidone (Supplier: Ashland China, Kollidon K30);

[0167] Lubricant: magnesium stearate (Supplier: Taihei Chemical Industry Co., Ltd.).

[0168] Coating material:

[0169] Ethyl cellulose (Supplier: Ashland China)

[0170] Triethyl citrate (Supplier: Bengbu Fengyuan Chushi Pharmaceutical Co., Ltd.)

[0171] Talc (Supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0172] Preparation method

[0173] Tablet core preparation:

[0174] Weigh 40 g of 1-(5-oxohexyl) theobromine powder (for making 100 tablets, each containing 400 mg), and place it in a mixer. Weigh 80 g of glyceryl behenate and add it to the mixer. Prepare a 95% ethanol solution of 5% povidone K30, and use an amount of 10% of the total weight of 1-(5-oxohexyl) theobromine, i.e. 4 g of ethanol solution, to uniformly spray on the mixture as a binder. Turn on the mixer and continuously mix until uniform granules are formed. Use an 18-mesh sieve to size the granules to ensure moderate particle size. Add 2 g of magnesium stearate as a lubricant and mix again uniformly. Use a tablet press to set the appropriate die size and pressure to compress the mixed granules into tablets, with a tablet weight of about 1.2 g.

[0175] Coating:

[0176] Prepare the coating liquid: weigh 10 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of talc, and add an appropriate amount of water to make the coating liquid.

[0177] Place the above tablet cores in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, monitoring the tablet appearance and coating quality throughout. After completing the coating, continue to dry with air blowing at 50°C until the tablet surface is completely dry. Inspect the finished product for appearance and hardness, ensuring compliance with quality standards.

[0178] Inspection and packaging:

[0179] Standard-compliant tablets are packaged in aluminum plastic, 10 tablets per plate, and 2 plates per box.

[0180] Comparative example 2

[0181] Ingredients

[0182] Active ingredient: 1-(5-oxohexyl) theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0183] Matrix sustained-release material: polyoxyethylene (supplier: BASF, PEG 4000);

[0184] Binder: 5% povidone K30 in 95% ethanol, where povidone (supplier: Ashland China, Kollidon K30);

[0185] Lubricant: magnesium stearate (supplier: Taihe Chemical Industry Co., Ltd.).

[0186] Coating material:

[0187] Ethyl cellulose (supplier: Ashland China)

[0188] Triethyl citrate (supplier: Bengbu Fengyuan Toshima Pharmaceutical Co., Ltd.)

[0189] Talc (supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0190] Preparation method

[0191] Tablet core preparation:

[0192] Take 40 g of 1-(5-oxohexyl)theobromine powder (for 100 tablets, each containing 400 mg), and place it in a mixer. Take 80 g of polyoxyethylene and add it to the mixer. Prepare a 5% povidone K30 solution in 95% ethanol, and use 10% of the total weight of 1-(5-oxohexyl)theobromine, which is 4 g of ethanol solution, to evenly spray on the mixture as a binder. Turn on the mixer and continue to mix until uniform granules are formed. Use an 18-mesh sieve to size the granules, ensuring that the size is moderate. Add 2 g of magnesium stearate as a lubricant and mix again. Use a tablet press to compress the mixed granules into tablets with appropriate die size and pressure, and the tablet weight is about 1.2 g.

[0193] Coating:

[0194] Prepare the coating solution: take 10 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of talc, and add an appropriate amount of water to make the coating solution.

[0195] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, and monitor the appearance of the tablets and the quality of the coating during this process. After the coating is complete, continue to dry the tablets at 50°C until the surface is completely dry. Perform appearance inspection and hardness test on the finished product to ensure that it meets the quality standards.

[0196] Inspection and packaging:

[0197] Pack the tablets that meet the standards in aluminum plastic packaging, 10 tablets per plate, and 2 plates per box.

[0198] Comparative example 3

[0199] Ingredients

[0200] Active ingredient: 1-(5-oxohexyl)theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd;

[0201] Matrix sustained-release material: glyceryl behenate and polyoxyethylene, where glyceryl behenate (supplier: Croda International Plc, Sugargel series), polyoxyethylene (supplier: Dow Chemical, Polyox WSR N-10);

[0202] Binder: 5% povidone K30 solution in 95% ethanol, where povidone (supplier: Ashland China, Kollidon K30);

[0203] Lubricant: magnesium stearate (supplier: Taihei Chemical Industry Co., Ltd.).

[0204] Coating material:

[0205] Ethyl cellulose (Supplier: Ashland China)

[0206] Triethyl citrate (Supplier: Bengbu Fengyuan Coating Mountain Pharmaceutical Co., Ltd.)

[0207] Talc (Supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0208] Preparation method

[0209] Tablet core preparation:

[0210] Weigh 40g of 1-(5-oxohexyl)theobromine powder (for preparing 100 tablets, each containing 400mg), and place it in a mixer. Weigh 80g of glyceryl behenate and polyoxyethylene (weight ratio 1:1), and add them to the mixer. Prepare a 5% povidone K30 solution in 95% ethanol, and use 10% of the total weight of 1-(5-oxohexyl)theobromine, i.e. 4g of ethanol solution, to uniformly spray on the mixture as a binder. Turn on the mixer and continue to mix until a uniform granulation is formed. Use an 18-mesh sieve to size the granulation, ensuring that the particle size is moderate. Add 2g of magnesium stearate as a lubricant and mix again. Use a tablet press to compress the mixed granulation into tablets, with appropriate die size and pressure settings. The tablet weight is about 1.2g.

[0211] Coating:

[0212] Prepare the coating solution: weigh 10g of ethyl cellulose, 2g of triethyl citrate, and 3g of talc, and add an appropriate amount of water to make the coating solution.

[0213] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, constantly monitoring the appearance of the tablets and the quality of the coating. After coating is complete, continue to dry at 50°C until the tablet surface is completely dry. Perform appearance inspection and hardness testing on the finished product to ensure compliance with quality standards.

[0214] Inspection and packaging:

[0215] Pack the tablets that meet the standards in aluminum plastic packaging, 10 tablets per plate, and 2 plates per box.

[0216] Comparative example 4

[0217] Ingredients

[0218] Active ingredient: 400 mg / tablet of 1-(5-oxohexyl) theobromine, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0219] Matrix sustained-release material: glyceryl behenate and polyoxyethylene, wherein glyceryl behenate (supplier: Croda International Plc, Sugargel series), polyoxyethylene (supplier: BASF, PEG 4000);

[0220] Binder: 95% ethanol solution of 5% povidone K30, wherein povidone (supplier: Ashland China, Kollidon K30);

[0221] Lubricant: magnesium stearate (supplier: Taihei Chemical Industry Co., Ltd.).

[0222] Coating material:

[0223] Ethyl cellulose (supplier: Ashland China)

[0224] Triethyl citrate (supplier: Bengbu Fengyuan Chushi Pharmaceutical Co., Ltd.)

[0225] Talc (supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0226] Preparation method

[0227] Tablet core preparation:

[0228] Weigh 40 g of 1-(5-oxohexyl) theobromine powder (for preparing 100 tablets, each containing 400 mg), and place it in a mixer. Weigh 80 g of glyceryl behenate and polyoxyethylene (weight ratio 3:1) and add them to the mixer. Prepare 95% ethanol solution of 5% povidone K30, and use 10% of the total weight of 1-(5-oxohexyl) theobromine, i.e. 4 g of ethanol solution, to uniformly spray on the mixture as a binder. Turn on the mixer and continue to mix until uniform granules are formed. Use an 18-mesh sieve to size the granules to ensure moderate size. Add 2 g of magnesium stearate as a lubricant and mix again. Use a tablet press to compress the mixed granules into tablets with appropriate die size and pressure, and the tablet weight is about 1.2 g.

[0229] Coating:

[0230] Prepare the coating liquid: weigh 10 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of talc, and add an appropriate amount of water to make the coating liquid.

[0231] Place the above tablet cores in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, constantly monitoring the appearance of the tablets and the quality of the coating. After completing the coating, continue to dry with air blowing at 50°C until the tablet surface is completely dry. Perform appearance inspection and hardness test on the finished product to ensure compliance with quality standards.

[0232] Inspection and packaging:

[0233] The tablets that meet the standards are packaged in aluminum plastic, 10 tablets per plate, and 2 plates per box.

[0234] Comparative example 5

[0235] Ingredients

[0236] Active ingredient: 1-(5-oxohexyl) theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0237] Matrix sustained-release material: glyceryl behenate and polyoxyethylene, wherein glyceryl behenate (supplier: Croda International Plc, Sugargel series), polyoxyethylene (supplier: BASF, PEG 4000);

[0238] Binder: 88% ethanol solution of 12% povidone K30, wherein povidone (supplier: Ashland China, Kollidon K30);

[0239] Lubricant: magnesium stearate (supplier: Taihei Chemical Industry Co., Ltd.).

[0240] Coating material:

[0241] Ethyl cellulose (supplier: Ashland China)

[0242] Triethyl citrate (supplier: Bengbu Fengyuan Toshin Pharmaceutical Co., Ltd.)

[0243] Talc (supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0244] Preparation method

[0245] Tablet core preparation:

[0246] Take 40 g of 1-(5-oxohexyl)theobromine powder (for 100 tablets, each containing 400 mg), and place it in a mixer. Take 80 g of glyceryl behenate and polyoxyethylene (1:1 by weight), and add them to the mixer. Prepare a 12% povidone K30 solution in 88% ethanol, and use 10% of the total weight of 1-(5-oxohexyl)theobromine, which is 4 g of ethanol solution, to uniformly spray the mixture as a binder. Turn on the mixer and continue to mix until uniform granules are formed. Use an 18-mesh sieve to size the granules, ensuring that the size is appropriate. Add 2 g of magnesium stearate as a lubricant, and mix again. Use a tablet press to compress the mixed granules into tablets, with appropriate die size and pressure, and the tablets weigh about 1.2 g.

[0247] Coating:

[0248] Prepare the coating solution: take 10 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of talc, and add an appropriate amount of water to make the coating solution.

[0249] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, and monitor the appearance of the tablets and the quality of the coating during this process. After completing the coating, continue to dry the tablets at 50°C until the surface is completely dry. Perform appearance inspection and hardness testing on the finished product to ensure that it meets the quality standards.

[0250] Inspection and packaging:

[0251] Pack the tablets that meet the standards in aluminum plastic packaging, 10 tablets per plate, and 2 plates per box.

[0252] Comparative example 6

[0253] Ingredients

[0254] Active ingredient: 1-(5-oxohexyl)theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0255] Matrix sustained-release material: glyceryl monostearate and polyoxyethylene, where glyceryl monostearate (supplier: Henan Qinde Pharmaceutical Co., Ltd., 123-94-4) and polyoxyethylene (supplier: BASF, PEG 4000);

[0256] Binder: 5% povidone K30 in 95% ethanol, where povidone (supplier: Ashland China, Kollidon K30);

[0257] Lubricant: magnesium stearate (supplier: Taihei Chemical Industry Co., Ltd.).

[0258] Coating material:

[0259] Ethyl cellulose (Supplier: Ashland China)

[0260] Triethyl citrate (Supplier: Bengbu Fengyuan Coating Mountain Pharmaceutical Co., Ltd.)

[0261] Talc (Supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0262] Preparation method

[0263] Tablet core preparation:

[0264] Weigh 40g of 1-(5-oxohexyl)theobromine powder (for preparing 100 tablets, each containing 400mg), and place it in a mixer. Weigh 80g of glyceryl monostearate and polyoxyethylene (weight ratio 1:1), and add them to the mixer. Prepare a 5% povidone K30 solution in 95% ethanol, and use 10% of the total weight of 1-(5-oxohexyl)theobromine, i.e. 4g of ethanol solution, to uniformly spray on the mixture as a binder. Turn on the mixer and continue to mix until uniform granules are formed. Use an 18-mesh sieve to size the granules, ensuring that the size is appropriate. Add 2g of magnesium stearate as a lubricant and mix again. Use a tablet press to compress the mixed granules into tablets with appropriate die size and pressure, and the tablet weight is about 1.2g.

[0265] Coating:

[0266] Prepare the coating solution: weigh 10g of ethyl cellulose, 2g of triethyl citrate, and 3g of talc, and add an appropriate amount of water to make the coating solution.

[0267] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, and monitor the appearance of the tablets and the quality of the coating during this process. After coating is complete, continue to dry the tablets at 50°C until the surface is completely dry. Perform appearance inspection and hardness test on the finished product to ensure that it meets the quality standards.

[0268] Inspection and packaging:

[0269] Pack the tablets that meet the standards in aluminum plastic packaging, 10 tablets per plate, and 2 plates per box.

[0270] Comparative example 7

[0271] Ingredients

[0272] Active Ingredient: 400 mg / tablet of 1-(5-oxohexyl) theobromine, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0273] Matrix Release Material: glyceryl monostearate and peach gum, wherein glyceryl monostearate (supplier: Henan Qinde Pharmaceutical Co., Ltd., 123-94-4), peach gum (supplier: Shanghai Jinyuan Chemical Co., Ltd.);

[0274] Binder: 95% ethanol solution of 5% povidone K30, wherein povidone (supplier: Ashland China, Kollidon K30);

[0275] Lubricant: magnesium stearate (supplier: Taihei Chemical Industry Co., Ltd.).

[0276] Coating Material:

[0277] Ethyl cellulose (supplier: Ashland China)

[0278] Triethyl citrate (supplier: Bengbu Fengyuan Toshin Pharmaceutical Co., Ltd.)

[0279] Talc (supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0280] Preparation method

[0281] Tablet Core Preparation:

[0282] Weigh 40 g of 1-(5-oxohexyl) theobromine powder (for preparing 100 tablets, each containing 400 mg) and place it in a mixer. Weigh 80 g of glyceryl monostearate and peach gum (weight ratio 1:1) and add it to the mixer. Prepare 95% ethanol solution of 5% povidone K30, and the amount is 10% of the total weight of 1-(5-oxohexyl) theobromine, i.e. 4 g of ethanol solution, evenly sprayed on the mixture as a binder. Turn on the mixer and continue to mix until uniform granules are formed. Use an 18-mesh sieve to size the granules to ensure proper size. Add 2 g of magnesium stearate as a lubricant and mix again. Use a tablet press to set the appropriate die size and pressure to compress the mixed granules into tablets, with a tablet weight of about 1.2 g.

[0283] Coating:

[0284] Prepare the coating liquid: weigh 10 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of talc, and add an appropriate amount of water to make the coating liquid.

[0285] Place the above tablet cores in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, monitoring the tablet appearance and coating quality throughout. After completing the coating, continue to dry with air blowing at 50°C until the tablet surface is completely dry. Inspect the finished product for appearance and hardness, ensuring compliance with quality standards.

[0286] Inspection and packaging:

[0287] Standard tablets are packaged in aluminum plastic, 10 tablets per plate, and 2 plates per box.

[0288] Comparative example 8

[0289] Ingredients

[0290] Active ingredient: 1-(5-oxohexyl) theobromine 400 mg / tablet, supplier: Jilin Hui Kang Pharmaceutical Co., Ltd.

[0291] Matrix sustained-release material: ethyl cellulose (supplier: DuPont, Aquacoat ECD series);

[0292] Binder: 5% povidone K30 in 95% ethanol solution, where povidone (supplier: Ashland China, Kollidon K30);

[0293] Lubricant: magnesium stearate (supplier: Taihe Chemical Industry Co., Ltd.).

[0294] Coating material:

[0295] Ethyl cellulose (supplier: Ashland China)

[0296] Triethyl citrate (supplier: Bengbu Fengyuan Toshima Pharmaceutical Co., Ltd.)

[0297] Talc (supplier: Liaoning Jinrui Medicine Talc Co., Ltd.)

[0298] Preparation method

[0299] Tablet core preparation:

[0300] Take 1-(5-oxohexyl)theobromine powder 40 g (for the preparation of 100 tablets, each containing 400 mg), and place it in a mixer. Weigh 80 g of ethyl cellulose and add it to the mixer. Prepare a 5% povidone K30 solution in 95% ethanol, and use 10% of the total weight of 1-(5-oxohexyl)theobromine, which is 4 g of ethanol solution, to evenly spray on the mixture as a binder. Turn on the mixer and continue to mix until uniform granules are formed. Use an 18-mesh sieve to size the granules, ensuring they are of moderate size. Add 2 g of magnesium stearate as a lubricant and mix again. Use a tablet press to compress the mixed granules into tablets, with appropriate die size and pressure, and the tablets weigh about 1.2 g.

[0301] Coating:

[0302] Prepare the coating solution: Weigh 10 g of ethyl cellulose, 2 g of triethyl citrate, and 3 g of talc, and add an appropriate amount of water to make the coating solution.

[0303] Place the above tablet core in the coating pan, turn on the equipment, and preheat to 50°C. Slowly spray the coating solution while keeping the coating pan rotating to ensure uniform coverage of the tablet surface. Continue spraying until the desired coating thickness is achieved, constantly monitoring the appearance of the tablets and the quality of the coating. After the coating is complete, continue to dry the tablets at 50°C until the surface is completely dry. Perform appearance inspection and hardness test on the finished product to ensure compliance with quality standards.

[0304] Inspection and packaging:

[0305] Pack the tablets that meet the standards in aluminum plastic packaging, 10 tablets per plate, and 2 plates per box.

[0306] Dissolution test

[0307] According to the second method of dissolution and release in Chinese Pharmacopoeia 2020 edition, use 0.1N hydrochloric acid solution 900ml as the dissolution medium, rotate at 50 rpm / min, and follow the operation. Take 1ml sample at 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, do not supplement the liquid, as the test solution.

[0308] According to the high performance liquid chromatography method of Chinese Pharmacopoeia 2020 edition 0512, determine the peak area of the test solution, and calculate the dissolution amount of 1-(5-oxohexyl)theobromine sustained-release tablets per tablet at different times. The results are shown in Table 1.

[0309] Table 1

[0310]

[0311] From the above Table 1, it can be seen that the f2 factors of the 1-(5-oxohexyl) theobromine sustained-release tablets obtained in Examples 1 to 7 are all above 65, while from Comparative Examples 1 to 8, it can be seen that the sustained-release materials used in Comparative Examples 1 to 3 and 6 to 8 are different from those of the present application, the proportion of glyceryl behenate and polyoxyethylene used in Comparative Example 4 exceeds the range of the present application, and the proportion of povidone K30 in the binder used in Comparative Example 5 is increased. The dissolution of these comparative examples is significantly different from that of the examples.

[0312] Bioavailability evaluation

[0313] The bioavailability of the test preparation (1-(5-oxohexyl) theobromine sustained-release tablets 400 mg) was evaluated by comparing the blood concentration-time curves of the test preparation with those of a commercially available reference preparation (same dose). The details are as follows:

[0314] Subject recruitment

[0315] Twelve healthy adult volunteers were recruited, who had no known liver and kidney dysfunction or other diseases that could affect drug metabolism.

[0316] A random double-blind crossover design was used, and the subjects were randomly divided into two groups. In the first phase, one group of subjects received the test preparation, and the other group received the reference preparation. After an elution period of at least two weeks, the two groups of subjects exchanged preparations, and the above steps were repeated.

[0317] Dosing and sample collection

[0318] In the morning, after the subjects had fasted for at least 8 hours, a single dose of 400 mg of 1-(5-oxohexyl) theobromine sustained-release tablets was administered.

[0319] Blood samples were collected at predetermined time points (e.g., 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h) starting from before dosing (baseline) for subsequent analysis.

[0320] Analysis method

[0321] A validated high-performance liquid chromatography-mass spectrometry (LC-MS / MS) method was used to determine the concentration of 1-(5-oxohexyl) theobromine in plasma.

[0322] A standard curve was established with a range from 0 ng / mL to 1000 ng / mL to ensure that the detection limit and the quantification limit meet the requirements of the study.

[0323] Data analysis

[0324] Non-compartmental model analysis was applied to analyze the pharmacokinetic parameters, including: maximum blood concentration (Cmax), blood concentration peak time (Tmax), blood concentration-time curve area (AUC0-t and AUC 0-inf The ratio of geometric means of test formulation and reference formulation and its 90% confidence interval were calculated to assess bioequivalence.

[0325] Table 2: Fasting results (Example 1)

[0326]

[0327] From the above table 2, the 90% confidence interval of the ratio of Cmax, the ratio of AUC(0→t) and the ratio of AUC(0→∞) of the log-transformed values of the self-made product and the reference formulation fell between 80% and 125%. It showed that the self-made product of Example 1 was bioequivalent to the reference formulation.

[0328] Table 3: Fasting results (Comparative Example 4)

[0329]

[0330] From the above table 3, the 90% confidence interval of the ratio of Cmax, the ratio of AUC(0→t) and the ratio of AUC(0→∞) of the log-transformed values of the self-made product and the reference formulation did not fall between 80% and 125%. It showed that the self-made product of Comparative Example 4 was not bioequivalent to the reference formulation.

[0331] The above describes the embodiments of the present application, but the present application is not limited to the above specific embodiments, and the above specific embodiments are only illustrative but not restrictive. Those skilled in the art can make many forms under the inspiration of the present application without departing from the scope of the present application and the scope protected by the claims, which all belong to the protection of the present application.

Claims

1. A 1-(5-oxohexyl)theobromine sustained-release tablet, characterized in that, It consists of a tablet core and a sustained-release coating layer, wherein the tablet core (by total weight of the tablet core) is prepared from the following components in parts by weight: 360-450 parts by weight of 1-(5-oxohexyl)theobromine 50-200 parts by weight of the sustained-release matrix material 5-15 parts by weight of adhesive, and Lubricant: 5-10 parts by weight in, The skeleton sustained-release material is selected from behenicol glycerol and / or polyoxyethylene.

2. The 1-(5-oxohexyl)theobromine sustained-release tablet according to claim 1, wherein, The skeleton sustained-release material is selected from behenicol glycerol ester and polyoxyethylene, and the weight ratio is (0.5~2):

1.

3. The 1-(5-oxohexyl)theobromine sustained-release tablet according to claim 2, wherein, The polyoxyethylene has a molecular weight of 3.0 × 10⁻⁶. 3 ~7.0×10 3 .

4. The 1-(5-oxohexyl)theobromine sustained-release tablet according to claim 1, wherein, The adhesive is polyvinyl chloride.

5. The 1-(5-oxohexyl)theobromine sustained-release tablet according to claim 4, wherein, The povidone is povidone K30.

6. The 1-(5-oxohexyl)theobromine sustained-release tablet according to claim 5, wherein, The adhesive is prepared as a 5-10% solution of 90-95% ethanol in povidone K30.

7. The 1-(5-oxohexyl)theobromine sustained-release tablet according to claim 6, wherein, The adhesive is prepared as a 5% solution of povidone K30 in 95% ethanol.

8. The 1-(5-oxohexyl)theobromine sustained-release tablet according to claim 2, wherein, The behenicol glyceride is the Sugargel series manufactured by British Specialty Chemicals Company, and the polyoxyethylene is PEG 4000 manufactured by BASF.

9. The 1-(5-oxohexyl)theobromine sustained-release tablet according to claim 1, wherein, The sustained-release coating layer comprises: ethyl cellulose, triethyl citrate, and talc.

10. The method for preparing 1-(5-oxohexyl)theobromine sustained-release tablets according to claims 1-9, characterized in that, The method includes the following steps: Core preparation: Weigh out 1-(5-oxohexyl)theobromine powder and ethyl cellulose, mix them to obtain a mixture, spray the binder onto the mixture, and continue stirring and mixing until uniform granules are formed. Granulate the granules, add lubricant, mix again until uniform, and use a tableting machine to compress the mixed granules into tablets. Coating: Prepare the coating solution: Weigh out ethyl cellulose, triethyl citrate, and talc, and add an appropriate amount of water to make the coating solution. Place the tablet cores in a coating pan, turn on the equipment, preheat to 50-80°C, slowly spray the coating solution, continue spraying the coating, and after coating is complete, continue drying until the tablet surface is completely dry.

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