Probucol tablet and preparation method thereof

Abstract

The invention provides a probucol tablet and a preparation method thereof, and belongs to the technical field of medicine, the probucol tablet is composed of a tablet core and a coating film, the tablet core contains a bulk drug, a filler, a surfactant, a disintegrating agent, a first lubricant and a second lubricant, and the probucol tablet is prepared by a preparation method of hot melt extrusion granulation. According to the probucol tablet, copovidone serves as a filling agent, laurel sorbitan serves as a surface active agent, colloidal silicon dioxide serves as a first lubricating agent, magnesium stearate serves as a second lubricating agent, and cross-linked carboxymethyl cellulose serves as a disintegrating agent. According to the probucol tablet prepared by the invention, the dissolution rate, bioavailability and stability of probucol are improved, the blood fat reducing curative effect of the medicine is improved, the administration dosage can be reduced, and the adverse reaction of the medicine is reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceuticals, and in particular to a probucol tablet and a preparation method thereof. Background Art

[0002] Cardiovascular disease is one of the most common and serious diseases that endangers human health (especially the middle-aged and elderly). Dyslipidemia is an important risk factor for atherosclerosis, coronary heart disease and other cardiovascular and cerebrovascular diseases.

[0003] Probucol is also known as probucol. It is a white or off-white crystalline powder with a special odor. Its chemical name is 4,4'-[(1-methylethylidene) disulfide]bis[2,6-di(1,1-dimethylethyl)phenol], and it is used clinically as a lipid-lowering drug. Its chemical structure is as follows:

[0004]

[0005] Probucol has the effects of regulating blood lipids and resisting lipid peroxidation. Probucol reduces blood cholesterol and low-density lipoprotein by reducing cholesterol synthesis and promoting cholesterol decomposition; it strengthens the reverse transport of blood high-density lipoprotein cholesterol by changing the properties and functions of high-density lipoprotein subtypes, affecting the functions of phospholipid cholesterol acyltransferase, cholesterol lipid transfer protein and apolipoprotein E, and restoring the lipidated cholesterol / total cholesterol ratio to normal; it inhibits the adhesion of monocytes to endothelial cells by inhibiting the expression of intercellular adhesion factor-1 and P-selectin. Therefore, probucol can prevent atherosclerosis and the cardiovascular and cerebrovascular diseases caused by it. At the same time, probucol has a significant anti-lipid peroxidation effect, which can inhibit the gene expression of inflammatory factors and atherogenic factors and free radical-mediated inflammation, improve endothelial vasodilation function, thereby inhibiting the formation of foam cells and atherosclerotic plaques, and regressing or reducing atherosclerotic plaques. Therefore, probucol can resist restenosis after angioplasty and has the effect of eliminating xanthelasma. Studies have not found that probucol has carcinogenic or mutagenic effects.

[0006] Probucol has low solubility and its absorption rate in the human body is slow, requiring about 18 hours to reach maximum absorption. The drug effect takes a long time to take effect and there is a high incidence of gastrointestinal discomfort and diarrhea. Summary of the invention

[0007] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a probucol tablet and a preparation method thereof. The present invention aims to improve the solubility, bioavailability and lipid-lowering efficacy of probucol, reduce the dosage, and thus reduce the adverse reactions of the drug.

[0008] In order to solve the problems existing in the prior art, the present invention adopts the following solution. The probucol tablet comprises a tablet core and a coating film, and the components and contents thereof are as follows:

[0009]

[0010] Further, as a preferred embodiment of the present invention, the components and contents are as follows:

[0011]

[0012] Furthermore, the probucol tablet preferably comprises the following components in parts by mass: 200 parts of probucol, 80 parts of copovidone, 16 parts of sorbitan laurate, 16 parts of cross-linked carboxymethyl cellulose, 3.2 parts of colloidal silicon dioxide, 6.4 parts of magnesium stearate, and 9.6 parts of film coating premix.

[0013] The probucol tablet of the present invention is prepared by hot melt extrusion method.

[0014] Preferably, the hot melt extrusion method comprises the following steps:

[0015] (1) Weigh the raw and excipient materials according to the prescription amount and set aside;

[0016] (2) Heat the sorbitan in a water bath and keep it heated for later use.

[0017] (3) Add probucol, copovidone and colloidal silicon dioxide into a wet granulator and mix them evenly, then add the sorbitan laurate maintained in the heated state in (2) to granulate, and pass the granulated intermediate through an 18-mesh sieve for later use.

[0018] (4) Add the granules obtained in step (3) into a hot melt extruder, set the temperature at 120-125° C., and prepare a hot melt extrusion intermediate. The extrudate should be a transparent strip.

[0019] (5) The intermediate after hot melt extrusion is crushed and passed through a 30-mesh sieve. After the crushing is completed, cross-linked sodium carboxymethyl cellulose and magnesium stearate are added and mixed evenly for use.

[0020] (6) The granules obtained in step (5) are compressed into tablets and coated with a film coating premix, with the coating increasing the weight by 2 to 3%, to obtain a finished product.

[0021] Preferably, during the hot melt extrusion process of step (4), when the extrudate is transparent, the hot melt extrusion intermediate is collected, and in step (5), the intermediate after hot melt extrusion is cooled and then crushed and sieved.

[0022] Compared with the prior art, the present invention adopts a hot melt extrusion process to prepare probucol tablets, selects copolyvidone as a filler, selects laurel sorbitan as a surfactant, adds colloidal silicon dioxide as a lubricant during granulation, and adds magnesium stearate as a lubricant during total mixing. By optimizing the details in the hot melt extrusion process and the amount of raw materials and auxiliary materials added, the obtained probucol tablets can improve the dissolution, bioavailability and stability of the probucol tablets, improve the lipid-lowering efficacy of the drug, and at the same time, because the solubility, bioavailability and stability of the drug are improved, the dosage can be further reduced, thereby reducing the side effects of the drug and improving the safety of medication. The dissolution of multiple batches of probucol tablets prepared by the preparation method of the present invention is fast, and can be completely dissolved, and it is easy to master the dosage; the components in the drug are stable under high temperature and high humidity (60±2°C, RH75±5%) conditions, and there is no obvious growth of related substances.

[0023] The dissolution rate and stability of the probucol tablets prepared by the preparation method of the present invention are significantly better than those of samples prepared by other prescriptions or other processes. DETAILED DESCRIPTION

[0024] The following examples provide those of ordinary skill in the art with an understanding of how to make and evaluate the present invention, which are exemplary of the present disclosure and are not intended to limit the scope of the invention. Although every effort has been made to ensure accuracy with respect to numerical values ​​(e.g., amounts, temperatures, etc.), some errors and deviations should be considered. Unless otherwise stated, temperatures are in ° C or at ambient temperature, and pressures are at or near atmospheric pressure.

[0025] The preparation method for the disclosed compound described in the present embodiment is one of many methods, and there are many other methods for the preparation method of the disclosed compound in the present application, and the present application does not limit the scope. Therefore, those skilled in the art of the present disclosure can easily modify the described method or use different methods to prepare one or more of the disclosed compounds. The following method is only exemplary, and temperature, catalyst, concentration, reactant composition, and other process conditions can be changed, and for the desired compound, those skilled in the art of the present disclosure can easily select suitable reactants and conditions for preparation.

[0026] The raw materials and auxiliary materials used in the present invention can all be purchased from the market, the model of copovidone is VA64, the model of colloidal silicon dioxide is Aerosil 200Pharma, the model of anhydrous calcium hydrogen phosphate is A150, and the model of magnesium stearate is SH-YM-H.

[0027] Example 1: Preparation of Probucol Tablets Using Hot Melt Extrusion Formulation Process

[0028]

[0029] Preparation method:

[0030] Weigh the raw and auxiliary materials according to the prescription amount and set aside;

[0031] Heat the sorbitan laurel in a water bath for 10 min to maintain the sorbitan laurel at 70°C for later use.

[0032] Probucol, copovidone and colloidal silicon dioxide were added into a wet granulator and mixed evenly, and then sorbitan laurel was added and granulated for 2 minutes. The intermediate after granulation was passed through an 18-mesh sieve for later use.

[0033] The obtained particles are added to a hot melt extruder, and the temperature is set at 120-125° C. to prepare a hot melt extrusion intermediate. When the extrudate is transparent, the extrudate is collected, and the extrudate is cooled and then crushed and passed through a 30-mesh sieve. After the crushing is completed, cross-linked sodium carboxymethyl cellulose and magnesium stearate are added and mixed evenly for use.

[0034] The obtained granules are compressed into tablets using a tablet press to obtain tablet cores, and then the tablet cores are coated with a film coating premix, and the coating weight gain is controlled to be 2-3% to obtain a finished product.

[0035] Comparative Example 1: Preparation of Probucol Tablets Using a Conventional Wet Granulation Process

[0036]

[0037] Preparation method:

[0038] Weigh the raw and auxiliary materials according to the prescription amount and set aside;

[0039] Preparation of adhesive: Heat the laurel sorbitan in a water bath for 10 minutes, then add an appropriate amount of purified water to prepare a 25% concentration aqueous solution for use.

[0040] Wet granulation: Add probucol, copovidone and colloidal silicon dioxide into a wet granulator and mix evenly, then add the prepared binder and granulate for 2 minutes, dry the intermediate after granulation and sieve it with an 18-mesh screen, add cross-linked sodium carboxymethyl cellulose and magnesium stearate to the obtained granules, mix evenly and set aside.

[0041] Tableting and coating: The obtained granules are compressed into tablets using a tablet press to obtain tablet cores, and then the tablet cores are coated with a film coating premix, and the coating weight gain is controlled to be 2-3% to obtain the finished product.

[0042] Comparative Example 2: Replacement of filler

[0043]

[0044] The preparation method is the same as that in Example 1, and the finished product can be prepared normally.

[0045] Comparative Example 3: Replacement of surfactant

[0046]

[0047]

[0048] The preparation method is the same as that in Example 1, and the finished product can be prepared normally.

[0049] Comparative Example 4: Using only one lubricant

[0050]

[0051] The preparation method is the same as that of Example 1. In Comparative Examples 09 to 10, only one lubricant is used, and the prepared granules have serious sticking problems during tableting, so qualified finished products cannot be successfully prepared; in Comparative Example 11, colloidal silicon dioxide is added during the total mixing, and magnesium stearate is added during granulation. The prepared granules still have sticking problems during tableting, and qualified finished products cannot be successfully prepared.

[0052] Therefore, the use of two lubricants is also one of the advantages of the present invention. The two lubricants are preferably colloidal silicon dioxide and magnesium stearate, and the colloidal silicon dioxide needs to be added during granulation, while the magnesium stearate needs to be added during total mixing.

[0053] Example 2 Dissolution Experiment

[0054] Eleven batches of probucol tablets prepared according to Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 3 and a batch of commercially available probucol tablets (specification: 250 mg, trade name: Lorelco; manufacturer: Otsuka Pharmaceutical Co., Ltd., Japan) were subjected to dissolution experiments. According to the dissolution test method of the Chinese Pharmacopoeia, the paddle method was used at 100 rpm in 900 ml of a 40% n-propanol solution at 37±0.5°C to test the dissolution curve of the probucol tablets. The test results are as follows:

[0055]

[0056]

[0057] The commercially available product has a dissolution rate of only 70% in 45 minutes, while the dissolution rate of samples from batches 01 to 03 prepared using the present invention is faster, reaching more than 85% in 45 minutes, and can be completely dissolved in 90 minutes, indicating that the prescription composition and preparation method provided by the present invention can effectively accelerate the dissolution.

[0058] The dissolution results of Comparative Examples 01 to 03 were significantly lower than those of Examples 01 to 03, so the preparation method provided by the present invention is significantly better than the ordinary wet granulation process.

[0059] The dissolution results of Comparative Examples 04 to 06 were all lower than those of Examples 01 to 03, but higher than those of Comparative Examples 01 to 03, indicating that the selection of filler type and preparation method have an impact on the dissolution of probucol. Selecting copolyvidone as the filler and adopting a hot melt extrusion preparation process can accelerate the dissolution of copolyvidone.

[0060] The dissolution results of Comparative Examples 07 to 08 were lower than those of Examples 01 to 03, indicating that the selection of surfactants would also affect the dissolution of probucol. The selection of sorbitan laurel as surfactant, combined with other raw materials and preparation methods of the present invention, could improve the dissolution of probucol.

[0061] Example 4

[0062] The probucol tablets of Example 01-03 and Comparative Example 01-03 were placed in aluminum-plastic packaging and a commercial product (specification: 250 mg, trade name: Lorelco; manufacturer: Otsuka Pharmaceutical Co., Ltd., Japan) under high temperature and high humidity (60±2°C, RH75±5%) for 10 days and 30 days, and the changes of related substances in the samples were detected by HPLC. The test results are shown in the following table:

[0063]

[0064]

[0065] From the above results, it can be seen that the related substances of the samples of batches 01 to 03 prepared in Example 1 are very stable, while the related substances of batches 01 to 03 of the comparative examples prepared using the wet granulation process increase slightly, indicating that the stability of the probucol tablets prepared using the present invention is better.

[0066] Example 5

[0067] Beagle dog pharmacokinetic study:

[0068] The samples of batch 01, batch 02 and batch 01 of comparative example 1 of the present invention were respectively used for pharmacokinetic test using beagle dogs, and commercially available drugs (specification: 250 mg, trade name: Lorelco; manufacturer: Otsuka Pharmaceutical Co., Ltd., Japan) were used as controls. The beagle dogs were fasted for 12 hours before administration and had free access to water during the test. 2 ml of blood was taken at 0, 0.5, 3, 6, 9, 12, 18, 24, 36, 48, 72, and 120 hours after administration (heparin was added to the blood vessels), centrifuged (5000r / min, 10min), and the supernatant plasma was taken. The concentration of probucol in plasma was detected by LC / MS / MS method, and the statistical analysis of the average pharmacokinetic parameters was as follows:

[0069]

[0070] From the above results, we can know that:

[0071] The absorption peak time of the samples of Example 01 and Example 02 is faster than that of the commercially available drugs and Comparative Example 01, and the maximum blood drug concentration and the area under the drug-time curve of Example 01 are greater than those of the commercially available drugs and Comparative Example 01, indicating that the absorption efficiency and bioavailability of the probucol tablets prepared by the present invention are significantly improved, and the blood drug concentration of the commercially available product can be achieved using a lower dosage.

[0072] Example 6

[0073] Rabbit adverse reaction experiment:

[0074] The 02 batch samples prepared in Example 1 of the present invention were used to conduct adverse reaction experiments on rabbits, and a commercially available drug (specification: 250 mg, trade name: Lorelco; manufacturer: Otsuka Pharmaceutical Co., Ltd., Japan) was used as a control. 40 rabbits were divided into two groups and fed normally. One group was fed with the sample prepared in Example 1, and the other group was fed with the control drug once a day for one week. The statistical data are as follows.

[0075]

[0076] From the above results, it can be seen that the incidence of gastrointestinal discomfort or diarrhea caused by the samples of Example 02 batch is significantly lower than that of the control drug.

[0077] In combination with Example 5 and Example 6, it can be seen that the probucol tablets prepared by the present invention can achieve the same blood drug concentration as the commercially available product at a reduced dosage, and can also reduce the adverse reactions of the drug. Therefore, the probucol tablets prepared by the present invention have improved solubility and bioavailability, and can reduce the adverse reactions of the drug by reducing the dosage.

[0078] The above-mentioned embodiments only express several implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A probucol tablet, characterized in that: It consists of a tablet core and a coating film. The tablet core contains a raw material, a filler, a surfactant, a disintegrant, a first lubricant and a second lubricant. The probucol tablet is prepared by a hot melt extrusion method. The probucol tablet includes the following components in parts by weight:

2. The probucol tablet according to claim 1, characterized in that: The filler is copolyvidone.

3. The probucol tablet according to claim 1, characterized in that: The surfactant is sorbitan laurel.

4. The probucol tablet according to claim 3, characterized in that: The first lubricant is colloidal silicon dioxide, and the second lubricant is magnesium stearate.

5. The probucol tablet according to claim 4, characterized in that: The disintegrant is cross-linked carboxymethyl cellulose.

6. A method for preparing the probucol tablets according to claim 5, characterized in that: The steps include: (1) Weigh the raw and auxiliary materials according to the required amount; (2) heating the sorbitan laurel in a water bath and keeping the heated state for later use; (3) adding probucol, copovidone and colloidal silicon dioxide into a wet granulator and mixing them evenly, then adding the sorbitan laurel maintained in the heated state in step (2) to granulate, and sieving the intermediate after granulation for later use; (4) adding the particles obtained in step (3) into a hot melt extruder, setting the temperature at 120-125° C., to prepare a hot melt extrusion intermediate; (5) crushing and screening the intermediate after hot melt extrusion, and adding cross-linked sodium carboxymethyl cellulose and magnesium stearate to mix evenly after the crushing is completed; (6) The granules obtained in step (5) are compressed into tablets and coated with a film coating premix, with the coating increasing the weight by 2 to 3%, to obtain a finished product.

7. The preparation method according to claim 6, characterized in that: In step (2), the water bath heating temperature is 70°C.

8. The preparation method according to claim 6, characterized in that: In step (3), the granulated intermediate is passed through an 18-mesh sieve for later use; during the hot melt extrusion process of step (4), when the extrudate is transparent, the hot melt extruded intermediate is collected; in step (5), the hot melt extruded intermediate is cooled and then crushed; the mesh number of the crushed and sieved sieve is 30 mesh.

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