CN115444831A - Epalrestat gastric floating tablet and preparation method thereof - Google Patents

Abstract

The invention relates to an epalrestat gastric floating tablet and a preparation method thereof, the epalrestat gastric floating tablet prepared by the invention has good slow release effect, active ingredients are slowly released at a constant speed, and in-vitro tests show slow release characteristics; the invention adopts an effervescent mechanism, can quickly float in the solution, and the floating time is less than 5min; the invention takes hydroxypropyl methylcellulose as hydrophilic slow-release framework material and the bleaching aid as dissolution type slow-release framework material, effectively controls the drug rate and achieves slow and constant-speed release.

Description

Epalrestat gastric floating tablet and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to an epalrestat gastric floating tablet and a preparation method thereof.

Background

Epalrestat (Epalrestat), chemical name 5- [ (1z, 2e) -2-methyl-3-phenyl-2-propenylidene ] -4-oxo-2-thioxo-3-thiazolidine acetic acid, is currently the only non-competitive ARIs on the market, and is mainly used for treating diabetes and its complications. Epalrestat has absolute therapeutic effect on neuropathy induced by diabetes. It can be used for treating diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic gastroparesis, cataract, foot ulcer, diabetic macroangiopathy, diabetic microangiopathy, hyperglycemia, and hyperglycosylated hemoglobin level. Epalrestat has been reported in the literature to have protective effects on the myocardium and nervous system of non-diabetic patients, and simultaneously has therapeutic and control effects on non-diabetic induced nervous system disorders.

At present, epalrestat only has a quick-release preparation, and needs to be administrated 1 day and 3 times. In order to be able to reduce the number of administrations, increase patient compliance and achieve therapeutic effects with a minimum dose, the dosage form has to be modified. In India, zydus Cadila et al developed sustained release tablets of 150mg specification. The patent CN 104940156A is an epalrestat enteric-coated sustained-release tablet, the slow and non-constant drug release is realized, the gastrointestinal environment of a human body has large influence on the absorption and release of the drug, and certain blood concentration fluctuation exists. Therefore, the epalrestat is prepared into the gastric floating preparation which is taken once a day, so that the treatment compliance of a patient is improved, the phenomenon of large fluctuation of blood concentration is reduced, the toxic and side effects are reduced, and the safety and the effectiveness of the medicine are improved.

Disclosure of Invention

The invention provides an epalrestat gastric floating tablet, which comprises the following components in parts by weight: 150 parts of epalrestat, 200 parts of framework material, 150-450 parts of bleaching aid, 90 parts of gas producing agent, 50-60 parts of filler, 0-60 parts of solubilizer and 20 parts of lubricant.

In some embodiments, the epalrestat gastric floating tablets comprise the following components in parts by weight: 150 parts of epalrestat, 200 parts of framework material, 150-300 parts of bleaching aid, 90 parts of gas producing agent, 50-60 parts of filler, 60 parts of solubilizer and 20 parts of lubricant.

In some embodiments, the matrix material is selected from one or a combination of HPMC K4M, HPMC K15M, HPMC K100 LV; preferably HPMC K4M, HPMC K15M or a combination of HPMC K100M and HPMC K100LV, more preferably a combination of HPMC K4M and HPMC K100 LV.

In some embodiments, the weight ratio of HPMC K4M, HPMC K15M or HPMC K100M in combination with HPMC K100LV is 1.

In some embodiments, the bleaching aid is selected from stearic acid, stearyl alcohol, or a combination of one or more of glyceryl stearate; octadecanol is preferred.

In some embodiments, the gas generating agent is selected from one or a combination of sodium bicarbonate, sodium carbonate, and calcium carbonate, preferably sodium bicarbonate.

In some embodiments, the filler is selected from one or a combination of lactose, microcrystalline cellulose, starch, or dextrin, preferably lactose.

In some embodiments, the epalrestat gastric floating tablet, the solubilizer is selected from one or more of sodium dodecyl sulfate, tween and poloxamer, and the sodium dodecyl sulfate is preferred.

In some embodiments, the lubricant is selected from magnesium lauryl sulfate, magnesium stearate, silica gel micropowder, talc, and hydrogenated vegetable oil, preferably magnesium stearate.

In some embodiments, epalrestat gastric raft tablets are comprised of the following:

in some embodiments, said epalrestat gastric floating tablets are prepared by coating epalrestat gastric floating tablet plain tablets, and the coating agent is selected from gastric-soluble opadry.

On the other hand, the invention also provides a preparation method of the epalrestat gastric floating tablet, which comprises the following steps:

the preparation method is wet granulation.

Further, the preparation method comprises the following specific preparation processes:

(1) Weighing the components according to the prescription composition of the components in the epalrestat gastric floating tablets;

(2) Sieving the weighed components with a 30-mesh sieve, uniformly mixing epalrestat, a framework material, a bleaching aid, a gas generating agent, a filling agent and a solubilizer, preparing a soft material by using absolute ethyl alcohol, sieving with a 20-mesh sieve, carrying out wet granulation, drying in an oven at 40 ℃ for 1.0 hour, and sieving with a 20-mesh sieve, carrying out dry granulation;

(3) Adding a lubricant and mixing uniformly; punching a die and tabletting;

(4) Weighing the gastric-soluble film coating agent according to the prescription amount, respectively dissolving the gastric-soluble film coating agent in the distilled water according to the prescription amount, uniformly mixing to form a coating solution, and coating the plain tablets in a coating pan to obtain the epalrestat gastric floating tablets.

Preferably, the tableting die of step (3) is a circular dimple die, 17.5 x 8.5mm elliptical dimple die or 20.35 x 10.85mm elliptical dimple die of 12mm diameter.

The invention has the beneficial effects that: the epalrestat gastric floating tablet has good slow release effect, active ingredients are slowly released at a constant speed, and the slow release characteristic is shown in vitro tests; the invention adopts an effervescent mechanism, can quickly float in the solution, and the floating time is less than 5min; the invention takes hydroxypropyl methylcellulose as hydrophilic slow-release framework material and the bleaching aid as dissolution type slow-release framework material, effectively controls the drug rate and achieves slow and constant-speed release.

Drawings

FIG. 1 is a graph of percentage in vitro cumulative release versus time for gastric floating epalrestat tablets of examples 1-3;

FIG. 2 is a graph of percentage in vitro cumulative release versus time for gastric floating epalrestat tablets of examples 1, 4 and 5;

FIG. 3 is a plot of percentage in vitro cumulative release versus time for epalrestat gastric floating tablets of example 1, example 6, and example 7;

FIG. 4 is a plot of percentage in vitro cumulative release versus time for epalrestat gastric floating tablets of example 1, example 8, and example 9;

FIG. 5 is a graph of percentage in vitro cumulative release versus time for gastric floating epalrestat tablets of examples 1 and 10;

Detailed Description

The present invention will be described in further detail with reference to specific embodiments. It should be emphasized that: the following description is merely exemplary in nature and is not intended to limit the invention to the particular embodiments described herein, as the practical conditions employed in the embodiments may be further modified in accordance with specific requirements.

Example 1-example 10 tablet preparation method: screening the components weighed according to the prescription composition by a 30-mesh sieve, uniformly mixing the epalrestat, the framework material, the bleaching aid, the gas generating agent, the filling agent and the solubilizer, uniformly spraying the mixture into the mixed powder by adopting absolute ethyl alcohol as a wetting agent to prepare a soft material which is held by hands to be agglomerated and is scattered by light kneading, carrying out wet granulation on the soft material by a 20-mesh sieve, drying the wet granulation by an oven at 40 ℃ for 1.0 hour, and screening the dry granulation by the 20-mesh sieve; adding a lubricant and mixing uniformly; circular 12mm diameter dimple die or 17.5 x 8.5mm oval dimple die or 20.35 x 10.85mm oval dimple die tablet; weighing the film coating agent (gastric soluble type) according to the prescription amount, respectively dissolving the film coating agent (gastric soluble type) in the distilled water according to the prescription amount, uniformly mixing to form a coating solution, and placing the plain tablets in a coating pot for coating to obtain the epalrestat gastric floating tablets.

Methods for measuring the release rate in examples 1 to 10: according to a seventh reciprocating cylinder method of a method for measuring the dissolution rate and the release degree of 0931 in the four general guidelines of the 2020 edition of Chinese pharmacopoeia, 6 tablets of a test article are taken and placed in 6 reciprocating cylinders, 250mL of a hydrochloric acid solution with the pH value of 1.2 is taken as a release medium in the first 12h, 250mL of a phosphate buffer solution with the pH value of 6.8 is taken as a release medium in 12 h-24 h, the number of upper meshes is 40, the number of lower meshes is 20, the reciprocating speed is 10rpm, the temperature is (37 +/-0.5) DEG C, the row number of the reciprocating cylinders is respectively switched among 2h,4h,6h,8h,12h, 116h and 24h, 20m0.8mol/L of sodium phosphate buffer solution is added into the hydrochloric acid release medium with the pH value of 1.2 to adjust the pH value, so that the medicine in the disintegrating fragments in a dissolution cup is dissolved, and 10mL of the solution is taken. Filtering each sample point with 0.45 μm microporous membrane, adding the filtrate into a measuring flask, diluting to desired volume with phosphate buffer solution with pH of 6.8, and diluting to appropriate concentration to obtain sample solution. Precisely weighing 16.67mg of epalrestat raw material medicine into a 100ml measuring flask, adding about 50ml of N-N dimethyl amide, shaking to dissolve the raw material medicine, fixing the volume, and shaking uniformly to obtain a reference substance stock solution. Precisely transferring 1ml to 50ml of the reference substance stock solution into a measuring flask, metering the volume by using N-N dimethyl amide, and shaking up to obtain the reference substance solution. And measuring the absorbance of the test solution and the reference solution by adopting an ultraviolet spectrophotometry, detecting the wavelength at 398nm, and calculating the cumulative release percentage by adopting an external standard method.

Example 1

Plain tablet prescription

Composition of	Dosage (each tablet)
		Epalrestat	150mg
HPMC K4M	50mg
		HPMC K100LV	150mg
Octadecanol	300mg
		Sodium bicarbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Light-shading coating film prescription

Make up of	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water (W)	360g

Example 2

Plain tablet prescription

Composition of	Dosage (each tablet)
		Epalrestat	150mg
HPMC K15M	50mg
		HPMC K100LV	150mg
Octadecanol	300mg
		Sodium bicarbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Light-shading coating film prescription

Composition of	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water (I)	360g

Example 3

Plain tablet prescription

Light-shading coating film prescription

Composition of	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water (I)	360g

Example 4

Plain tablet prescription

Composition of	Dosage (per tablet)
		Epalrestat	150mg
HPMC K4M	100mg
		HPMC K100LV	100mg
Octadecanol	300mg
		Sodium bicarbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Light-shading coating film prescription

Composition of	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water (W)	60g

Example 5

Plain tablet prescription

Light-shading coating film prescription

Composition of	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water (W)	360g

Example 6

Plain tablet prescription

Composition of	Dosage (per tablet)
		Epalrestat	150mg
HPMC K4M	50mg
		HPMC K100LV	150mg
Octadecanol	150mg
		Sodium bicarbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Light-shading coating film prescription

Make up of	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water (I)	360g

Example 7

Plain tablet prescription

Make up of	Dosage (per tablet)
		Epalrestat	150mg
HPMC K4M	50mg
		HPMC K100LV	150mg
Octadecanol	450mg
		Sodium bicarbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Light-shading coating film prescription

Make up of	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water (I)	360g

Example 8

Plain tablet prescription

Make up of	Dosage (each tablet)
		Epalrestat	150mg
HPMC K4M	50mg
		HPMC K100LV	150mg
Octadecanol	300mg
		Sodium carbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Light-shading coating film prescription

Composition of	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water (I)	360g

Example 9

Plain tablet prescription

Make up of	Dosage (each tablet)
		Epalrestat	150mg
HPMC K4M	50mg
		HPMC K100LV	150mg
Octadecanol	300mg
		Calcium carbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Light-shading coating film prescription

Make up of	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water (W)	360g

Example 10

Plain tablet prescription

Light-shading coating film prescription

Composition of	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water (W)	360g

Test example 1: comparison of examples 1 to 3

The results (table 1) show that the release rate of the preparation is significantly influenced by respectively adopting different types of hypromellose, the release rate is significantly reduced by adopting HPMC K15M, and the release rate is further reduced by adopting HPMC K100M.

TABLE 1 Release of the formulations of examples 1 to 3 in phosphate buffer at pH1.2 to pH6.8

Time	Example 1	Example 2	Example 3
				2h	9.97％	8.62％	7.80％
4h	20.83％	16.53％	11.44％
				6h	33.75％	22.08％	14.51％
8h	42.29％	27.49％	17.20％
				12h	57.05％	37.27％	20.84％
16h	75.29％	52.58％	29.83％
				24h	94.47％	74.41％	48.97％

Test example 2: comparison of example 1, example 4 and example 5

The results show (table 2) that epalrestat gastric floating tablets were prepared using different HPMC K4M: the HPMC K100LV ratio has an effect on the release rate of the formulation, using HPMC K4M: HPMC K100LV =1: the release rate is faster at 3.

TABLE 2 Release rates of the formulations of example 1, example 4 and example 5 in phosphate buffer at pH1.2-pH6.8

Time	Example 1	Example 4	Example 5
				2h	9.97％	8.77％	10.38％
4h	20.83％	18.33％	17.64％
				6h	33.75％	28.26％	25.78％
8h	42.29％	36.40％	32.96％
				12h	57.05％	47.78％	44.65％
16h	75.29％	65.13％	66.89％
				24h	94.47％	88.58％	89.13％

Test example 3: comparison of examples 1, 6 and 7

The results show (table 3) that the use of different amounts of octadecanol in epalrestat gastric-floating tablets has an effect on the release rate of the preparation, with the amount of octadecanol increasing and the release rate decreasing.

TABLE 3 Release Rate of the formulations of example 1, example 6 and example 7 in phosphate buffer at pH1.2-pH6.8

Time	Example 1	Example 6	Example 7
				2h	9.97％	10.07％	8.64％
4h	20.83％	21.72％	16.90％
				6h	33.75％	33.18％	26.68％
8h	42.29％	42.38％	35.76％
				12h	57.05％	56.97％	45.26％
16h	75.29％	73.93％	58.87％
				24h	94.47％	98.86％	83.76％

Test example 4: comparison of example 1, example 8 and example 9

The results show (table 4) that epalrestat gastric floating tablets respectively adopt different types of gas generating agents to influence the release rate of the preparation, and adopt sodium bicarbonate as the gas generating agent to have higher release rate.

TABLE 4 Release Rate of the formulations of example 1, example 8, example 9 in phosphate buffer at pH1.2-pH6.8

Time	Example 1	Example 8	Example 9
				2h	9.97％	10.80％	10.12％
4h	20.83％	21.88％	19.10％
				6h	33.75％	30.55％	27.87％
8h	42.29％	43.13％	40.12％
				12h	57.05％	55.01％	54.68％
16h	75.29％	72.54％	70.56％
				24h	94.47％	92.46％	90.98％

Test example 5: comparison of example 1 and example 10

The results show (table 4) that the addition of sodium dodecyl sulfate to epalrestat gastric floating tablets has a significant effect on the release rate of the preparation, the release rate is significantly accelerated by adding sodium dodecyl sulfate, and the release endpoint is significantly improved.

TABLE 5 Release Profile of the formulations of example 1 and example 10 in phosphate buffer at pH1.2-pH6.8

Time	Example 1	Example 10
			2h	9.97％	7.79％
4h	20.83％	14.67％
			6h	33.75％	18.98％
8h	42.29％	22.65％
			12h	57.05％	30.86％
16h	75.29％	45.79％
			24h	94.47％	59.99％

TABLE 6 bleaching initiation and sustaining times of examples 1-10 in pH1.2 medium (37. + -. 0.5 ℃ C.)

Sample (I)	Rise time/min	Float sustaining time/h
			Example 1	＜0.5	＞12h
Example 2	＜1.0	＞12h
			Example 3	＜1.0	＞12h
Example 4	＜0.5	＞12h
			Example 5	＜0.5	＞12h
Example 6	＜0.5	＞10h
			Example 7	＜0.5	＞12h
Example 8	＜0.5	＞12h
			Example 9	＜0.5	＞12h
Example 10	＜0.5	＞12h

As shown in tables 1 to 6 and FIGS. 1 to 5, in examples 1 to 10, the bleaching time of example 1 was faster than that of the other examples, the bleaching duration was longer, the sustained-release effect was good, and the sustained-release end point was higher.

Finally, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that various changes and modifications may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (10)

1. The epalrestat gastric floating tablet comprises the following components in parts by weight: 150 parts of epalrestat, 200 parts of framework material, 150-450 parts of bleaching aid, 90 parts of gas producing agent, 50-60 parts of filler, 0-60 parts of solubilizer and 20 parts of lubricant.

2. The epalrestat gastric floating tablet of claim 1, which is characterized in that the components of the epalrestat gastric floating tablet comprise the following components in parts by weight: 150 parts of epalrestat, 200 parts of framework material, 150-300 parts of bleaching aid, 90 parts of gas producing agent, 50-60 parts of filler, 60 parts of solubilizer and 20 parts of lubricant.

3. The epalrestat gastric floating tablet of claim 1, wherein the framework material is selected from one or a combination of more of HPMC K4M, HPMC K15M, HPMC K100M or HPMC K100 LV; preferably HPMC K4M, HPMC K15M, or a combination of HPMC K100M and HPMC K100LV, more preferably a combination of HPMC K4M and HPMC K100 LV; preferably, the weight ratio of the frame material HPMC K4M, HPMC K15M or HPMC K100M to HPMC K100LV is 1.

4. The epalrestat gastric floating tablet of claim 1, wherein the bleaching aid is selected from one or a combination of stearic acid, stearyl alcohol or glyceryl stearate; preferably octadecanol; preferably, the gas generating agent is selected from one or more of sodium bicarbonate, sodium carbonate and calcium carbonate, and sodium bicarbonate is preferred.

5. The epalrestat gastric floating tablet of claim 1, wherein the filler is selected from one or a combination of lactose, microcrystalline cellulose, starch or dextrin, preferably lactose; preferably, the solubilizer is selected from one or a combination of several of sodium dodecyl sulfate, tween and poloxamer, and the sodium dodecyl sulfate is preferred.

6. The epalrestat gastric floating tablet according to claim 1, characterized in that the lubricant is selected from one or a combination of more of magnesium lauryl sulfate, magnesium stearate, silica gel micropowder, talcum powder or hydrogenated vegetable oil, and preferably magnesium stearate.

7. The epalrestat gastric floating tablet of claim 1, wherein the epalrestat gastric floating tablet comprises the following components:

8. the epalrestat gastric floating tablet of claims 1-7, wherein the epalrestat gastric floating tablet is prepared by coating an epalrestat gastric floating tablet plain tablet, and the coating agent is selected from gastric soluble opadry.

9. The method for preparing epalrestat gastric floating tablets of claim 1, comprising the following steps:

(1) Weighing the components according to the prescription composition of the components in the epalrestat gastric floating tablets;

(2) Screening the weighed components with a 30-mesh sieve, uniformly mixing the epalrestat, the framework material, the bleaching aid, the gas producing agent, the filler and the solubilizer, preparing a soft material by using absolute ethyl alcohol, screening with a 20-mesh sieve, carrying out wet granulation, drying in an oven at 40 ℃ for 1.0 hour, screening with a 20-mesh sieve, and carrying out dry granulation;

(3) Adding a lubricant and mixing uniformly; punching a die and tabletting;

(4) Weighing the gastric-soluble film coating agent according to the prescription amount, respectively dissolving the gastric-soluble film coating agent in the distilled water according to the prescription amount, uniformly mixing to form a coating solution, and coating the plain tablets in a coating pan to obtain the epalrestat gastric floating tablets.

10. The method of claim 9, wherein the tableting die of step (3) is a circular 12mm diameter dimple die, a 17.5 x 8.5mm elliptical dimple die, or a 20.35 x 10.85mm elliptical dimple die.

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