Metoprolol tartrate tablet

Abstract

The invention provides a metoprolol tartrate tablet, and particularly relates to the field of medicines. Comprising 20-40 parts of metoprolol tartrate, 70-100 parts of a filler, 1-5 parts of an adhesive, 8-15 parts of a disintegrating agent and 3-6 parts of a lubricant, weighing the adhesive according to the prescription amount, dispersing the adhesive in absolute ethyl alcohol, adding purified water, and stirring until the adhesive is completely dissolved for later use; the preparation method comprises the following steps: weighing metoprolol tartrate, the filling agent and part of the disintegrating agent according to the prescription amount, putting into a granulator, starting stirring and cutting, and mixing for 20 minutes; starting a wet granulator, adding the adhesive solution for granulation, sieving wet granules after granulation is finished, drying in a fluidized bed until the moisture is less than 5%, and sieving the dried granules to obtain dry granules. And adding an external disintegrating agent and a flow aid into the prepared particles, mixing for 10 minutes, adding a lubricant, and continuously mixing for 10 minutes. And tabletting by using a rotary tablet press to obtain the metoprolol tartrate tablet. The invention effectively solves the problem that the dissolution speed is reduced due to the increase of the hardness of tablets after tabletting.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to a metoprolol tartrate tablet. Background Art

[0002] Metoprolol is a cardioselective β1-adrenoceptor blocker, but at higher plasma concentrations it also inhibits β2-adrenoceptors, which are primarily present on bronchial and vascular smooth muscle.

[0003] The results of clinical pharmacology studies have shown that metoprolol has the following beta-receptor blocking activity: it reduces heart rate and cardiac output at rest and during exercise, reduces systolic blood pressure during exercise, inhibits isoproterenol-induced tachycardia, and reduces reflex orthostatic tachycardia.

[0004] Metoprolol tartrate is a white or off-white crystalline powder, odorless, and bitter; the raw material of this product is very soluble in water, easily soluble in ethanol or chloroform, slightly soluble in anhydrous ethanol, very slightly soluble in acetone, almost insoluble in ether, and easily soluble in glacial acetic acid. Metoprolol tartrate has a very high solubility in water, which can reach 1.5g / mL in actual measurement. However, in traditional wet granulation, starch, dextrin or starch dextrin is mostly used as a binder by dissolving and slurrying with purified water. When preparing metoprolol tartrate granules, it is easy to dissolve and stick. The prepared granules have poor fluidity and are easily affected by moisture and oxidation, which brings difficulties to granulation. Chinese application CN102716091B provides a method for preparing metoprolol tartrate granules, specifically adding resin to the preparation, but it is found that the dissolution result is not ideal in actual application.

[0005] Metoprolol tartrate tablets are ordinary white scored tablets. The original formulation "Betaloc" has a hardness of 30-70N, and the prescription composition is metoprolol tartrate, lactose, microcrystalline cellulose, sodium starch glycolate, povidone, colloidal silicon dioxide and magnesium stearate. The prescription was prepared according to the original research composition, and it was found that the hardness of the tablets gradually increased over time after tableting, and the dissolution rate decreased, resulting in a significant difference between the sample dissolution curve and the original research. Summary of the invention

[0006] The purpose of the present invention is to provide a metoprolol tartrate tablet, optimize the prescription of the existing metoprolol tartrate tablet, adjust the selection of auxiliary materials and the dosage range, provide a metoprolol tartrate tablet and a preparation method thereof, and effectively solve the problem that the hardness of the tablet increases after tabletting and causes the dissolution rate to decrease.

[0007] The present invention provides the following technical solutions:

[0008] A metoprolol tartrate tablet, the mass parts of which are as follows:

[0009] 20-40 parts of metoprolol tartrate, 70-100 parts of filler, 1-5 parts of binder, 8-15 parts of disintegrant, and 3-6 parts of lubricant.

[0010] Preferably, the metoprolol tartrate comprises 25 parts, a filler 90 parts, a binder 3 parts, a disintegrant 10 parts, and a lubricant 4 parts.

[0011] Preferably, the filler is one or more of microcrystalline cellulose, lactose, pregelatinized starch or mannitol.

[0012] Preferably, the filler is microcrystalline cellulose and lactose, and the mass ratio of the microcrystalline cellulose to the lactose is 40-80:10-50.

[0013] Preferably, the mass ratio of the microcrystalline cellulose to the lactose is 50:40.

[0014] Preferably, the binder is one or more of pregelatinized starch, hydroxypropyl methylcellulose or povidone, preferably hydroxypropyl methylcellulose.

[0015] Preferably, the disintegrant is one or more of starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose or sodium starch glycolate, preferably sodium starch glycolate.

[0016] Preferably, the lubricant is one or more of sodium stearyl fumarate, calcium stearate, magnesium stearate or micro-powder silica gel.

[0017] Preferably, the lubricant is magnesium stearate and micro-powder silica gel, and the mass ratio of the magnesium stearate to the micro-powder silica gel is 1-3:1-4.

[0018] Preferably, the mass ratio of the magnesium stearate to the micropowder silica gel is 1.2:2.8.

[0019] Based on the optimization of the prescription made by the present invention, a preparation method of metoprolol tartrate tablets is provided as an example to further ensure the quality of the preparation, and the specific preparation steps are as follows:

[0020] S1. Slurry preparation: Weigh the prescribed amount of adhesive and disperse it in anhydrous ethanol, add purified water, stir until completely dissolved, and set aside.

[0021] S2. Mixing of raw materials and auxiliary materials: Weigh the prescribed amount of metoprolol tartrate, filler and part of disintegrant into a granulator, start stirring and cutting, and mix for 20 minutes.

[0022] S3, granulation, granulation and drying: start the wet granulator, add the binder solution to granulate, sieve the wet granules after granulation, dry them in a fluidized bed until the moisture is less than 5%, and sieve the dried granules to obtain dry granules.

[0023] S4. (Total mixing and tableting: Add an external disintegrant and a glidant to the granules prepared in step (3) and mix for 10 min. Add a lubricant and continue mixing for 10 min.

[0024] S5. Use a rotary tablet press to compress the tablets to obtain metoprolol tartrate tablets.

[0025] Preferably, the concentration of the adhesive solution is 5%-10%, and more preferably, the concentration of the adhesive solution is 8%.

[0026] Preferably, the amount of the disintegrant is 40%-60% of the total mass of the disintegrant, and more preferably, the amount of the disintegrant is 50% of the total mass of the disintegrant.

[0027] Preferably, the granulation is performed by a wet granulator; the drying is fluidized bed drying; in step (2), the wet granulation is performed by a 16-24 mesh screen, and the dry granulation is performed by a 12-18 mesh screen; the drying is performed until the moisture content of the granules is less than 5%.

[0028] Beneficial effects of the present invention:

[0029] The invention optimizes the prescription of the existing metoprolol tartrate tablets, finds that the binder is changed from povidone to hydroxypropyl methylcellulose, magnesium stearate and micro-powder silica gel are selected as lubricants, microcrystalline cellulose and lactose are selected as fillers, sodium carboxymethyl starch is selected as a disintegrant, and the problem that the hardness of the tablet increases after tableting and the dissolution rate is reduced is solved by adjusting the optimization design of the dosage range. DETAILED DESCRIPTION

[0030] Example 1

[0031] Metoprolol tartrate tablets, the prescription is as follows:

[0032] Metoprolol tartrate 25mg, Hydroxypropyl methylcellulose 5mg, Lactose 20mg, Microcrystalline cellulose 70mg,

[0033] Sodium starch glycolate 8mg, magnesium stearate 1mg, micro powder silica gel 1.5mg.

[0034] The preparation steps are as follows:

[0035] ⑴ Preparation of slurry: First, disperse the HPMC in anhydrous ethanol, add purified water, stir until completely dissolved, and prepare an 8% HPMC solution.

[0036] (2) Mixing of raw materials and auxiliary materials: Place metoprolol tartrate, lactose, microcrystalline cellulose and sodium starch glycolate in a wet granulator, start the stirring speed at 30 Hz and the cutting speed at 20 Hz, and mix for 20 minutes.

[0037] ⑶ Granulation: After mixing, add 10% povidone solution to start granulation, start stirring at 30 Hz, cutting at 20 Hz, granulate for 3 minutes, remove from the pot, pass the wet material through a 17-mesh screen of a swing granulator; place the obtained wet granules in a boiling granulation dryer to dry, control the moisture content of the granules to below 5%, stop drying, and remove the material; then pass the dried granules through a 15-mesh screen of a swing granulator for dry granulation to obtain dry granules.

[0038] (4) Tableting: Put the dry granules into a mixer, add sodium carboxymethyl starch and silicon dioxide, mix for 15 minutes, then add magnesium stearate and mix for 10 minutes. After mixing, start tableting to obtain metoprolol tartrate tablets.

[0039] Example 2

[0040] Metoprolol tartrate tablets, the prescription is as follows:

[0041] Metoprolol tartrate 25mg, hypromellose 4mg, lactose 30mg, microcrystalline cellulose 60mg,

[0042] Sodium starch glycolate 12mg, magnesium stearate 1.8mg, micro powder silica gel 2.4mg.

[0043] The preparation steps are as follows:

[0044] ⑴ Preparation of slurry: First, disperse the HPMC in anhydrous ethanol, add purified water, stir until completely dissolved, and prepare an 8% HPMC solution.

[0045] (2) Mixing of raw materials and auxiliary materials: Place metoprolol tartrate, lactose, microcrystalline cellulose and sodium starch glycolate in a wet granulator, start the stirring speed at 30 Hz and the cutting speed at 20 Hz, and mix for 20 minutes.

[0046] ⑶ Granulation: After mixing, add 10% povidone solution to start granulation, start stirring speed 30Hz, cutting speed 20Hz, granulate for 3min, take out of the pot, pass the wet material through the 19-mesh screen of the swing granulator; place the obtained wet granules in a boiling granulation dryer to dry, control the moisture content of the granules to below 5%, stop drying, and discharge; then pass the dried granules through the 17-mesh screen of the swing granulator for dry granulation to obtain dry granules.

[0047] (4) Tableting: Put the dry granules into a mixer, add sodium carboxymethyl starch and silicon dioxide, mix for 15 minutes, then add magnesium stearate and mix for 10 minutes. After mixing, start tableting to obtain metoprolol tartrate tablets.

[0048] Example 3

[0049] Metoprolol tartrate tablets, the prescription is as follows:

[0050] Metoprolol tartrate 25mg, Hydroxypropyl methylcellulose 3mg, Lactose 40mg, Microcrystalline cellulose 50mg,

[0051] Sodium starch glycolate 10mg, magnesium stearate 1.2mg, micro powder silica gel 2.8mg.

[0052] The preparation steps are as follows:

[0053] ⑴ Preparation of slurry: First, disperse the HPMC in anhydrous ethanol, add purified water, stir until completely dissolved, and prepare an 8% HPMC solution.

[0054] (2) Mixing of raw materials and auxiliary materials: Place metoprolol tartrate, lactose, microcrystalline cellulose and sodium starch glycolate in a wet granulator, start the stirring speed at 30 Hz and the cutting speed at 20 Hz, and mix for 20 minutes.

[0055] ⑶ Granulation: After mixing, add 10% povidone solution to start granulation, start stirring at 30 Hz, cutting at 20 Hz, granulate for 3 minutes, remove from the pot, pass the wet material through a 18-mesh screen of a swing granulator; place the obtained wet granules in a boiling granulation dryer to dry, control the moisture content of the granules to below 5%, stop drying, and remove the material; then pass the dried granules through a 14-mesh screen of a swing granulator for dry granulation to obtain dry granules.

[0056] (4) Tableting: Put the dry granules into a mixer, add sodium carboxymethyl starch and silicon dioxide, mix for 15 minutes, then add magnesium stearate and mix for 10 minutes. After mixing, start tableting to obtain metoprolol tartrate tablets.

[0057] Comparative Example 1

[0058] Metoprolol tartrate tablets, the prescription is as follows:

[0059] Metoprolol tartrate 25mg, povidone 5mg, lactose 40mg, microcrystalline cellulose 50mg, sodium starch glycolate 10mg, magnesium stearate 1.2mg, and micronized silica gel 2.8mg.

[0060] The preparation steps are as follows:

[0061] (1) Preparation of slurry: First, prepare a 50% ethanol solution with 19 mg of purified water and 19 mg of ethanol.

[0062] (2) Mixing of raw materials and auxiliary materials: Place metoprolol tartrate, lactose, microcrystalline cellulose, povidone and 50% sodium starch glycolate in a wet granulator, turn on the stirring speed and cutting speed, and mix for 20 minutes.

[0063] ⑶ Granulation: After mixing, add 50% ethanol solution and wet granulate. Then sieve the wet material and dry it in a fluidized bed. The dried granules are sieved again to obtain dry granules.

[0064] (4) Tableting: Put the dry granules into a mixer, add 50% sodium carboxymethyl starch and silicon dioxide, mix for 15 minutes, then add magnesium stearate and mix for 10 minutes. After mixing, start tableting to obtain metoprolol tartrate tablets.

[0065] Comparative Example 2

[0066] Metoprolol tartrate tablets, the prescription is as follows:

[0067] Metoprolol tartrate 25mg, povidone 3mg, lactose 40mg, microcrystalline cellulose 50mg, sodium starch glycolate 10mg, magnesium stearate 1.2mg, and micronized silica gel 2.8mg.

[0068] The preparation steps are as follows:

[0069] Mixing of raw materials and auxiliary materials: Place metoprolol tartrate, lactose, microcrystalline cellulose, povidone and the full amount of sodium carboxymethyl starch in a wet granulator, turn on the stirring speed and cutting speed, and mix for 20 minutes.

[0070] Granulation: After mixing, add water for wet granulation, then sieve the wet material and dry it in a fluidized bed. The dried granules are sieved again to obtain dry granules.

[0071] Tableting: Put the dry granules into a mixer, add silicon dioxide, mix for 15 minutes, then add magnesium stearate and mix for 10 minutes. After mixing, start tableting to obtain metoprolol tartrate tablets.

[0072] The dissolution rates of Examples 1-3 and Comparative Examples 1-2 were measured, and the results are shown in Table 1:

[0073] Dissolution determination method: Take each test preparation and follow the dissolution and release determination method (General Rule 0931 Method 1), use 900ml (100mg, specification) or 500ml (25mg,, 50mg, specification) of sodium chloride hydrochloric acid solution (take 2g of sodium chloride, add 7ml of hydrochloric acid, add water to 1000ml) as the dissolution medium, the speed is 100 revolutions per minute, operate according to the law, after 30 minutes, take out the solution and filter it, and measure the absorbance of the filtrate at 274nm according to the UV-visible spectrophotometry (General Rule 0401); separately accurately weigh an appropriate amount of metoprolol tartrate reference substance, add the dissolution medium to make a solution containing about 100ug per 1ml, and calculate the dissolution amount of each tablet by the same method.

[0074] Table 1 Hardness change results of Examples 1-3 and Comparative Examples 1-2

[0075]

[0076] Table 2 Dissolution results of Examples 1-3 and Comparative Examples 1-2

[0077]

[0078] As can be seen from the above, the prescription and preparation method of the present invention effectively avoid the situation where the hardness of the tablet increases after tableting, and the dissolution rate does not decrease significantly, which is beneficial to improving the bioavailability of the drug and the drug dissolution is complete.

[0079] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A metoprolol tartrate tablet, comprising the following parts by weight: 20-40 parts of metoprolol tartrate, 70-100 parts of a filler, 1-5 parts of a binder, 8-15 parts of a disintegrant, and 3-6 parts of a lubricant.

2. A metoprolol tartrate tablet according to claim 1, characterized in that: The composition comprises 25 parts of metoprolol tartrate, 90 parts of filler, 3 parts of binder, 10 parts of disintegrant and 4 parts of lubricant.

3. A metoprolol tartrate tablet according to claim 1, characterized in that, The filler is one or more of microcrystalline cellulose, lactose, pregelatinized starch or mannitol.

4. A metoprolol tartrate tablet according to claim 3, characterized in that: The filler is microcrystalline cellulose and lactose, and the mass ratio of the microcrystalline cellulose to the lactose is 40-80:10-50.

5. A metoprolol tartrate tablet according to claim 1, characterized in that: The adhesive is one or more of pregelatinized starch, hydroxypropyl methylcellulose or povidone, preferably hydroxypropyl methylcellulose.

6. A metoprolol tartrate tablet according to claim 1, characterized in that: The disintegrant is one or more of starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose or sodium carboxymethyl starch, preferably sodium carboxymethyl starch.

7. A metoprolol tartrate tablet according to claim 1, characterized in that: The lubricant is one or more of sodium stearyl fumarate, calcium stearate, magnesium stearate or micro powder silica gel.

8. A metoprolol tartrate tablet according to claim 1, characterized in that: The lubricant is magnesium stearate and micro-powder silica gel, and the mass ratio of the magnesium stearate to the micro-powder silica gel is 1-3:1-4.

9. A metoprolol tartrate tablet according to claim 1, wherein the preparation method comprises the following steps: S1. Slurry preparation: Weigh the prescribed amount of adhesive and disperse it in anhydrous ethanol, add purified water, stir until completely dissolved, and set aside. S2. Mixing of raw materials and auxiliary materials: Weigh the prescribed amount of metoprolol tartrate, filler and part of disintegrant into a granulator, start stirring and cutting, and mix for 20 minutes. S3, granulation, granulation and drying: start the wet granulator, add the binder solution to granulate, sieve the wet granules after granulation, dry them in a fluidized bed until the moisture is less than 5%, and sieve the dried granules to obtain dry granules. S4, total mixing and tableting: add an external disintegrant and a glidant to the granules prepared in step S3 and mix for 10 min, add a lubricant and continue mixing for 10 min. S5. Use a rotary tablet press to compress the tablets to obtain metoprolol tartrate tablets.

10. A method for preparing metoprolol tartrate tablets according to claim 9, characterized in that: The concentration of the binder solution is 5%-10%. The amount of the disintegrant is 40%-60% of the total mass of the disintegrant; the granulation is performed by a wet granulator; the drying is fluidized bed drying; the wet granulation uses a 16-24 mesh screen, and the dry granulation uses a 12-18 mesh screen; the drying is performed until the moisture content of the granules is less than 5%.

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