Mirdodrine hydrochloride tablet and preparation method thereof

Abstract

The invention discloses a midodrine hydrochloride tablet and a preparation method thereof, and belongs to the field of medicine preparation, the midodrine hydrochloride tablet comprises midodrine hydrochloride, ethyl cellulose, hydroxypropyl methylcellulose, lactose, microcrystalline cellulose and magnesium stearate; the preparation method comprises the following steps: sieving ethyl cellulose with a 80-mesh sieve; sieving other raw materials with a 100-mesh sieve; the preparation method comprises the following steps: dissolving ethyl cellulose in absolute ethyl alcohol, fully stirring, and adding trimethylhydroxysilane; adding midodrine hydrochloride into the absolute ethyl alcohol containing ethyl cellulose and hydroxypropyl methylcellulose, and stirring to form wet particles; the wet particles are subjected to ultraviolet radiation; mixing the wet granules with lactose, microcrystalline cellulose and magnesium stearate to prepare tablets; performing drying treatment on the tablets; according to the midodrine hydrochloride tablet and the preparation method thereof disclosed by the invention, the slow-release effect can be improved under the condition that a small amount of ethyl cellulose is used, and the problem of insufficient slow-release effect in the prior art is solved.

Description

Technical Field

[0001] The invention relates to the field of midodrine hydrochloride tablet medicines, in particular to a midodrine hydrochloride tablet and a preparation method thereof. Background Art

[0002] Midodrine hydrochloride is a selective peripheral α1-adrenaline receptor agonist that stimulates vascular smooth muscle and increases blood pressure through its active metabolite desglymidodrine. It is widely used clinically to treat orthostatic hypotension and female stress urinary incontinence.

[0003] In addition, midodrine hydrochloride is chemically sensitive and easily degraded by moisture. Conventional tablets may be affected by environmental humidity or light during storage, resulting in loss of active ingredients or increase in impurities. Its raw materials need to be strictly protected from light and sealed, and the content of glycine and related impurities (such as residual solvents such as methanol and acetonitrile) in the preparation needs to be controlled. Therefore, it is of urgent clinical significance to develop a sustained-release preparation that can prolong the efficacy, reduce the number of dosing times and improve stability.

[0004] At present, the realization of sustained-release preparations mainly relies on skeleton materials, coating technology or osmotic pump systems, but their application in midodrine hydrochloride still faces the following challenges. Although conventional skeleton tablets can delay drug release, the high water solubility of midodrine hydrochloride can easily lead to an initial burst release, causing a sudden increase in blood drug concentration and increasing the risk of supine hypertension.

[0005] Ethyl cellulose is widely used as a sustained-release agent in pharmaceutical preparations, but it also has some shortcomings in practical applications, mainly including the following aspects: if ethyl cellulose is used too little, the sustained-release effect will be insufficient, but if it is used too much, it will limit the final release effect. Usually, in order to improve the sustained-release effect, ethyl cellulose is usually mixed with some fillers, but on the one hand, it increases the process, and on the other hand, while improving the sustained-release effect, it will also lead to a decrease in the final release concentration. Summary of the invention

[0006] The purpose of the present invention is to solve the problems existing in the prior art and disclose a midodrine hydrochloride tablet, which can improve the sustained-release effect when the amount of ethyl cellulose used is small.

[0007] In parts by weight: Midodrine hydrochloride: 5-10 parts; Ethyl cellulose: 9-15 parts; Hydroxypropyl methylcellulose: 4-10 parts; Lactose: 20-50 parts; Microcrystalline cellulose: 3-15 points; Magnesium stearate: 0.5-2 parts; Among the preferred embodiments, the invention comprises, by weight: Midodrine hydrochloride: 6-8 parts; Ethyl cellulose: 9-10 parts; Hydroxypropyl methylcellulose: 4-5 parts; Lactose: 20-40 parts; Microcrystalline cellulose: 3-10 parts; Magnesium stearate: 0.8-1.5 parts; 0.3-8 parts of trimethylhydroxysilane.

[0008] The present application also discloses a method for preparing a midodrine hydrochloride tablet, which is used to prepare the above-mentioned midodrine hydrochloride tablet, and the steps are as follows: Step 1: Pass ethyl cellulose through an 80-mesh sieve; pass other raw materials through a 100-mesh sieve; Step 2: dissolve ethyl cellulose and hydroxypropyl methyl cellulose in anhydrous ethanol, stir well, and add trimethylhydroxysilane; Step 3, adding midodrine hydrochloride to the anhydrous ethanol containing ethyl cellulose and hydroxypropyl methylcellulose, stirring to form wet granules; and irradiating the wet granules with ultraviolet light; Step 4: mixing the wet granules with lactose, microcrystalline cellulose and magnesium stearate to prepare tablets; Step 5: Dry the tablets.

[0009] In a preferred embodiment, the ratio of ethyl cellulose to hydroxypropyl methyl cellulose and anhydrous ethanol is 1:5, and ethyl cellulose is fully dissolved in anhydrous ethanol.

[0010] In a preferred embodiment, the ultraviolet irradiation time is 1-3 hours.

[0011] The present application reduces the amount of ethyl cellulose used in the existing formula and adds trimethylhydroxysilane in the preparation process in combination with ultraviolet irradiation, thereby not only improving the sustained-release effect but also increasing the final release amount. DETAILED DESCRIPTION

[0012] The present invention is described in detail below.

[0013] Comparative Example 1: Raw material formula: midodrine hydrochloride: 8g, ethyl cellulose: 15g, lactose: 40g; microcrystalline cellulose: 5g, magnesium stearate: 1g.

[0014] Preparation method: The ethyl cellulose is passed through an 80-mesh sieve; other raw materials are passed through a 100-mesh sieve; ethyl cellulose is dissolved in anhydrous ethanol (1:5), and stirred sufficiently; midodrine hydrochloride is added to the anhydrous ethanol containing ethyl cellulose, and stirred to form wet granules; the wet granules are mixed with lactose, microcrystalline cellulose, and magnesium stearate to prepare tablets, and the tablets are dried.

[0015] Embodiment 1: Raw material formula: midodrine hydrochloride: 8g, ethyl cellulose: 15g, lactose: 40g; microcrystalline cellulose: 5g, magnesium stearate: 1g, trimethylhydroxysilane 3g.

[0016] Preparation method: The ethyl cellulose is passed through an 80-mesh sieve; other raw materials are passed through a 100-mesh sieve; ethyl cellulose is dissolved in anhydrous ethanol (1:5), fully stirred, midodrine hydrochloride is added to the anhydrous ethanol containing ethyl cellulose, trimethylhydroxysilane is added, and stirred to form wet granules; the wet granules are irradiated with ultraviolet light for 3 hours; the wet granules are mixed with lactose, microcrystalline cellulose, and magnesium stearate to prepare tablets, and the tablets are dried.

[0017] Dissolution test method: paddle method, rotation speed 50-75 rpm, pH = 4.5 acetate buffer, temperature: 37 ± 0.5 ° C, dissolution was measured at 1 / 2 / 4 / 6 / 8 / 12 hours.

[0018] Example 2: Change the 15g ethyl cellulose in the raw materials of Comparative Example 1 to: 10g ethyl cellulose, 5g hydroxypropyl methylcellulose. Preparation method: ethyl cellulose is passed through an 80-mesh sieve; other raw materials are passed through a 100-mesh sieve; ethyl cellulose and hydroxypropyl methylcellulose are dissolved in anhydrous ethanol (the ratio of the mixture of ethyl cellulose, hydroxypropyl methylcellulose and ethanol is 1:5), and stirred thoroughly; midodrine hydrochloride is added to the anhydrous ethanol containing ethyl cellulose, and stirred to form wet granules; the wet granules are mixed with lactose, microcrystalline cellulose and magnesium stearate to prepare tablets, and the tablets are dried.

[0019] Example 3: 3 g of trimethylhydroxysilane was added to Example 2, and ultraviolet irradiation was added. The preparation method is as follows: ethyl cellulose was sieved through an 80-mesh sieve; other raw materials were sieved through a 100-mesh sieve; ethyl cellulose and hydroxypropyl methylcellulose were dissolved in anhydrous ethanol (1:5), and stirred thoroughly; midodrine hydrochloride was added to the anhydrous ethanol containing ethyl cellulose, trimethylhydroxysilane was added, and stirred to form wet granules; the wet granules were irradiated with ultraviolet light for 3 hours; the wet granules were mixed with lactose, microcrystalline cellulose, and magnesium stearate to prepare tablets, and the tablets were dried.

[0020] Example 4: The trimethylhydroxysilane in Example 3 is modified to triethylhydroxysilane. The preparation method is as follows: The preparation method is as follows: ethyl cellulose is passed through an 80-mesh sieve; other raw materials are passed through a 100-mesh sieve; ethyl cellulose and hydroxypropyl methylcellulose are dissolved in anhydrous ethanol (1:5), fully stirred, midodrine hydrochloride is added to the anhydrous ethanol containing ethyl cellulose, triethylhydroxysilane is added, and stirred to form wet granules; the wet granules are irradiated with ultraviolet light for 3 hours; the wet granules are mixed with lactose, microcrystalline cellulose, and magnesium stearate to prepare tablets, and the tablets are dried.

[0021] Table 1 Dissolution test results Test results: Comparison between Example 1 and Comparative Example 1 shows that, from the test results of the dissolution rate, the sustained-release effect of midodrine hydrochloride after adding trimethylhydroxysilane and ultraviolet irradiation is basically unchanged; From the comparison between Comparative Example 1 and Example 2, it is found that after replacing ethyl cellulose with a mixture of ethyl cellulose and hypromellose, the sustained-release effect is significantly improved.

[0022] From the comparison between Example 3 and Example 2, after ethyl cellulose was replaced by a mixture of ethyl cellulose and hydroxypropyl methylcellulose, and trimethylhydroxysilane was added and irradiated, the sustained-release effect was further significantly improved.

[0023] From the results of Example 4, it can be seen that when trimethylhydroxysilane is replaced by triethylhydroxysilane, the functions of the two are basically the same. It can be seen that the sustained release effect is improved to a certain extent, but the effect is less than that of Example 3, and the final release degree is reduced.

[0024] The inventors have found that midodrine hydrochloride can not only be used as a drug for increasing blood pressure, but in some cases, it can also improve the effect of metformin in treating diabetes.

[0025] Example 5: Raw material formula: midodrine hydrochloride: 15g, metformin: 30g; ethyl cellulose: 14g, magnesium stearate: 1g.

[0026] Preparation method: pass ethyl cellulose through an 80-mesh sieve; pass other raw materials through a 100-mesh sieve; dissolve ethyl cellulose in anhydrous ethanol (1:5), stir thoroughly, add midodrine hydrochloride to the anhydrous ethanol containing ethyl cellulose, stir to form wet granules; mix the wet granules with metformin and magnesium stearate to prepare tablets, and dry the tablets.

[0027] Example 6: Raw material formula; metformin: 30 g; ethyl cellulose: 14 g, magnesium stearate: 1 g, tablets are prepared according to the method of Example 5.

[0028] Example 7: Raw materials: midodrine hydrochloride: 10 g; ethyl cellulose: 14 g; metformin: 30 g, hypromellose: 5 g; lactose: 26 g; microcrystalline cellulose: 4 g; magnesium stearate: 1 g.

[0029] The ethyl cellulose is passed through an 80-mesh sieve; other raw materials are passed through a 100-mesh sieve; ethyl cellulose is dissolved in anhydrous ethanol (1:5), fully stirred, midodrine hydrochloride is added to the anhydrous ethanol containing ethyl cellulose, and stirred to form wet granules; the wet granules are irradiated with ultraviolet light for 3 hours; the wet granules are mixed with lactose, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate, and metformin to prepare tablets, and the tablets are dried.

[0030] Drug Experiments Fifty male induced diabetic model mice, weighing between 20-25 g, were randomly divided into 5 groups, 10 mice in each group, namely group A, group B, group C, group D, and control group.

[0031] Group A: Take 20g of mouse corn food, grind 5mg of metformin into powder, mix it evenly with 20g of corn food, and feed it evenly to the 10 mice in Group B to ensure that the mice eat completely.

[0032] Group B: Take 20 g of corn food for mice, grind 7.5 mg of the tablets prepared in Example 6 into drug powder, mix it with corn, and feed it evenly to 10 mice in Group B to ensure that the mice eat completely.

[0033] Group C: Grind the tablets prepared in Example 5 into drug powder, take 20g of corn as mouse food, take 10mg of drug powder and mix thoroughly with corn, and feed evenly to 10 mice in Group A to ensure that the mice are fully fed. Group D: Take 20 g of corn food for mice, grind 15 mg of the drug of Example 7 into powder, mix evenly with 20 g of corn food, and feed evenly to 10 mice in Group B to ensure that the mice eat completely.

[0034] The above four groups of drugs ate normally after feeding the drugs.

[0035] Control group: normal diet.

[0036] The above drug group was fed with drugs once a day for 5 consecutive weeks. After the last drug administration, the animals stopped eating for 12 hours and then took glucose solution (2g / kg). Blood sugar was measured 60 minutes later. The results were as follows: Results: In the control group, mice did not take any drugs, and the blood glucose concentration was as high as 27.5. In group A, mice took metformin powder, and the results showed that the symptoms of diabetes were improved. In group B, the blood glucose concentration had no significant effect compared with group A, indicating that ethylcellulose and magnesium stearate did not improve the effect of metformin in treating diabetes. In group C, the blood glucose concentration decreased, indicating that midodrine hydrochloride can synergistically improve the therapeutic effect of metformin in treating diabetes.

[0037] The blood glucose concentration in Group D was significantly reduced, which proves that the drug in Example 7 has a significant effect on the treatment of diabetes. It may be that the improvement of the sustained-release effect has a certain improvement on the therapeutic effect of the drug.

[0038] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes and apply it to other fields. However, any simple modification, equivalent change and modification made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A midodrine hydrochloride tablet, characterized in that: In parts by weight: Midodrine hydrochloride: 5-10 parts; Ethyl cellulose: 9-15 parts; Hydroxypropyl methylcellulose: 4-10 parts; Lactose: 20-50 parts; Microcrystalline cellulose: 3-15 points; Magnesium stearate: 0.5-2 parts; 0.3-8 parts of trimethylhydroxysilane.

2. The midodrine hydrochloride tablet according to claim 1, characterized in that In parts by weight: Midodrine hydrochloride: 6-8 parts; Ethyl cellulose: 9-10 parts; Hydroxypropyl methylcellulose: 4-5 parts; Lactose: 20-40 parts; Microcrystalline cellulose: 3-10 points; Magnesium stearate: 0.8-1.5 parts; 0.3-8 parts of trimethylhydroxysilane.

3. The midodrine hydrochloride tablet according to claim 1, characterized in that According to weight, 30-50 parts of metformin are also included.

4. A method for preparing midodrine hydrochloride tablets, characterized in that: For preparing the midodrine hydrochloride tablets according to claim 1, the steps are as follows: Step 1: Pass ethyl cellulose through an 80-mesh sieve; pass other raw materials through a 100-mesh sieve; Step 2: dissolve ethyl cellulose and hydroxypropyl methyl cellulose in anhydrous ethanol, stir well, and add trimethylhydroxysilane; Step 3, adding midodrine hydrochloride to the anhydrous ethanol containing ethyl cellulose and hydroxypropyl methylcellulose, drying, and stirring to form wet granules; and subjecting the wet granules to ultraviolet radiation; Step 4: mixing the wet granules with lactose, microcrystalline cellulose and magnesium stearate to prepare tablets; Step 5: Dry the tablets.

5. The method for preparing the midodrine hydrochloride tablet according to claim 4, characterized in that: The ratio of ethyl cellulose to anhydrous ethanol is 1:

10.

6. The method for preparing the midodrine hydrochloride tablet according to claim 5, characterized in that: The ultraviolet radiation time is 1-3 hours.

7. The method for preparing the midodrine hydrochloride tablet according to claim 6, characterized in that: The ratio of the ethyl cellulose to the hypromellose is 2:1.

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