CN115444831B

CN115444831B - Epalrestat gastric floating tablet and preparation method thereof

Info

Publication number: CN115444831B
Application number: CN202211307218.2A
Authority: CN
Inventors: 王孝伟; 朱春莉; 陈金脱
Original assignee: Nanjing Kang Chuan Ji Pharmatech Co ltd
Current assignee: Nanjing Kang Chuan Ji Pharmatech Co ltd
Priority date: 2022-10-25
Filing date: 2022-10-25
Publication date: 2023-08-22
Anticipated expiration: 2042-10-25
Also published as: CN115444831A

Abstract

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

Background

Epalrestat (Epalrestat), chemical name 5- [ (1 z,2 e) -2-methyl-3-phenyl-2-propenylidene ] -4-oxo-2-thioxo-3-thiazolidineacetic acid, is the only non-competitive ARIs currently marketed, and is mainly used for the treatment of diabetes mellitus and its complications. Epalrestat has absolute therapeutic effect on diabetes-induced neuropathy. It also has therapeutic effects on diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic gastroparesis, cataract, foot ulcer, diabetic macroangiopathy, diabetic microangiopathy, hyperglycemia, and complications such as hyperglycosylated hemoglobin level. Epalrestat has been reported to have protective effects on cardiac muscle and nervous system of non-diabetic patients, and also to have therapeutic and controlling effects on non-diabetes-induced nervous system lesions.

Currently, epalrestat is only an immediate release preparation, and needs to be administered 3 times for 1 day. In order to be able to reduce the number of administrations, increase patient compliance, and achieve therapeutic effects with minimal dosages, the dosage form must be modified. In India, zydus Cadila et al developed a sustained release tablet of 150 mg. Patent CN 104940156A is epalrestat enteric sustained-release tablet, the drug release is slow and non-constant, the influence of the gastrointestinal environment of human body on the absorption and release of the drug is large, and certain blood concentration fluctuation exists. Therefore, epalrestat is prepared into a gastric floating preparation which is taken once a day, the treatment compliance of patients is improved, the phenomenon of large fluctuation of blood concentration is reduced, 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 generating agent, 50-60 parts of filler, 0-60 parts of solubilizer and 20 parts of lubricant.

In some embodiments, the epalrestat gastric-floating tablet comprises 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 generating agent, 50-60 parts of filling agent, 60 parts of solubilizer and 20 parts of lubricant.

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

In some embodiments, the weight ratio of HPMC K4M, HPMC K15M or HPMC K100M to HPMC K100LV is 1:1 to 1:9, preferably 1:3.

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

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

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

In some embodiments, the epalrestat gastric floating tablet, the solubilizer is selected from one or a combination of several of sodium dodecyl sulfate, tween and poloxamer, preferably sodium dodecyl sulfate.

In some embodiments, the lubricant is selected from one or a combination of several of magnesium lauryl sulfate, magnesium stearate, micro silica gel, talc or hydrogenated vegetable oil, preferably magnesium stearate.

In some embodiments, the epalrestat gastric-floating tablet comprises the following ingredients:

in some embodiments, the epalrestat gastric-floating tablet is prepared by coating epalrestat gastric-floating tablet, 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 specific preparation process of the preparation method is as follows:

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

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

(3) Adding lubricant and mixing uniformly; stamping and tabletting;

(4) And weighing gastric-soluble film coating agents according to the prescription amount, respectively dissolving the gastric-soluble film coating agents in the distilled water according to the prescription amount, uniformly mixing the gastric-soluble film coating agents to form coating liquid, and coating the plain tablets in a coating pot to obtain the epalrestat gastric-floating tablets.

Preferably, the tabletting die in the step (3) is a round dimple die with the diameter of 12mm, a 17.5×8.5mm oval dimple die or a 20.35×10.85mm oval dimple die.

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

Drawings

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

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

FIG. 3 is a graph of in vitro cumulative percent release versus time for the epalrestat gastric-floating tablets of examples 1, 6, and 7;

FIG. 4 is a graph of in vitro cumulative percent release versus time for epalrestat gastric floating tablets of examples 1, 8, and 9;

FIG. 5 is a graph of in vitro cumulative percent release versus time for epalrestat gastric-floating tablets of example 1, example 10;

Detailed Description

The present invention will be described in further detail with reference to the following specific embodiments. It should be emphasized that: the following description is merely exemplary in nature and the present invention is not limited to the details of the examples that follow, their implementation may be further modified according to specific requirements.

Method for preparing tablets of examples 1 to 10: sieving the components weighed according to the prescription composition with a 30-mesh sieve, uniformly mixing epalrestat, a framework material, a bleaching aid, a gas generating agent, a filler and a solubilizer, uniformly spraying absolute ethyl alcohol serving as a wetting agent into the mixed powder to prepare a soft material which is agglomerated by hand and is slightly kneaded to be dispersed, sieving the soft material with a 20-mesh sieve, wet granulating, drying in a baking oven at 40 ℃ for 1.0 hour, and sieving the soft material with a 20-mesh sieve to obtain dry granules; adding lubricant and mixing uniformly; circular dimple dies with the diameter of 12mm or 17.5 x 8.5mm elliptical dimple dies or 20.35 x 10.85mm elliptical dimple die tablets; and weighing film coating agents (gastric-soluble type) according to the prescription amount, respectively dissolving the film coating agents in distilled water according to the prescription amount, uniformly mixing the film coating agents to form coating liquid, and placing the plain tablets into a coating pan for coating to obtain the epalrestat gastric-floating tablets.

Method for measuring release degree in examples 1 to 10: according to the fourth rule 0931 dissolution and release measuring method seventh method of Chinese pharmacopoeia 2020 edition, 6 pieces of test sample are placed in 6 reciprocating cylinders, the first 12 hours uses 250mL of pH1.2 hydrochloric acid solution as a release medium, 12 hours-24 hours uses 250mL of pH6.8 phosphoric acid buffer solution as a release medium, the upper screen mesh is 40 meshes, the lower screen mesh is 20 meshes, the reciprocating speed is 10rpm, the temperature is (37+/-0.5), the reciprocating cylinder row numbers are respectively switched between 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours and 24 hours, 20mL of 0.8mol/L sodium phosphate buffer solution is added into the pH1.2 hydrochloric acid release medium to regulate the pH, so that the medicine in the disintegrating fragments in the dissolution cup is dissolved, and the liquid is 10mL. Samples at each sampling point are filtered by a microporous filter membrane with the diameter of 0.45 mu m, the subsequent filtrate is taken to a measuring flask, and phosphate buffer solution with the pH value of 6.8 is used for constant volume and diluted to proper concentration to be used as a test sample solution. Accurately weighing epalrestat raw material medicine 16.67mg to 100ml measuring flask, adding N-N dimethyl amide about 50ml, shaking to dissolve the raw material medicine, fixing volume, and shaking to obtain reference stock solution. Precisely transferring the control stock solution into a measuring flask with volume of 1ml to 50ml, and shaking uniformly by using N-N dimethyl amide to obtain the control solution. The absorbance of the sample solution and the reference solution is measured by ultraviolet spectrophotometry, the detection wavelength is 398nm, and the cumulative release percentage is calculated according to an external standard method.

Example 1

Plain tablet prescription

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

Shading coating film prescription

Composition of the composition	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water and its preparation method	360g

Example 2

Plain tablet prescription

Composition of the composition	Dosage (per tablet)
		Epalrestat	150mg
HPMC K15M	50mg
		HPMC K100LV	150mg
Stearyl alcohol	300mg
		Sodium bicarbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Shading coating film prescription

Example 3

Plain tablet prescription

Shading coating film prescription

Example 4

Plain tablet prescription

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

Shading coating film prescription

Composition of the composition	Dosage (per 100 tablets)
		Opadry 85G66723-CN brown	40g
Water and its preparation method	60g

Example 5

Plain tablet prescription

Shading coating film prescription

Example 6

Plain tablet prescription

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

Shading coating film prescription

Example 7

Plain tablet prescription

Composition of the composition	Dosage (per tablet)
		Epalrestat	150mg
HPMC K4M	50mg
		HPMC K100LV	150mg
Stearyl alcohol	450mg
		Sodium bicarbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Shading coating film prescription

Example 8

Plain tablet prescription

Composition of the composition	Dosage (per tablet)
		Epalrestat	150mg
HPMC K4M	50mg
		HPMC K100LV	150mg
Stearyl alcohol	300mg
		Sodium carbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Shading coating film prescription

Example 9

Plain tablet prescription

Composition of the composition	Dosage (per tablet)
		Epalrestat	150mg
HPMC K4M	50mg
		HPMC K100LV	150mg
Stearyl alcohol	300mg
		Calcium carbonate	90mg
SDS	50mg
		Lactose G200	60mg
Magnesium stearate	20mg

Shading coating film prescription

Example 10

Plain tablet prescription

Shading coating film prescription

Test example 1: comparative examples 1 to 3

The results show (table 1) that the epalrestat gastric floating tablets respectively adopt different types of hypromellose, have significant influence on the release rate of the preparation, the release rate of the epalrestat gastric floating tablets is obviously slowed down by adopting HPMC K15M, and the release rate of the epalrestat gastric floating tablets is further slowed down by adopting HPMC K100M.

TABLE 1 Release of the formulations of examples 1-3 in phosphate buffer pH1.2-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: comparative examples 1, 4 and 5

The results showed (table 2) that epalrestat gastric-floating tablets used different HPMC K4M: HPMC K100LV ratio has an effect on formulation release rate, HPMC K4M: HPMC k100deg.LV=1: the release rate was faster at 3.

Table 2 release of the formulations of example 1, example 4, 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: comparative examples 1, 6 and 7

The results show (Table 3) that the use of different amounts of stearyl alcohol in the epalrestat gastric-floating tablets has an effect on the release rate of the preparation, and that the use amount of stearyl alcohol increases and the release rate slows down.

TABLE 3 Release of the formulations of example 1, example 6, example 7 in phosphate buffer 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: comparative examples 1, 8 and 9

The results show (Table 4) that epalrestat gastric-floating tablets respectively use different types of gas generating agents to influence the release rate of the preparation, and sodium bicarbonate is used as the gas generating agent to release the gas rapidly.

Table 4 release 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: comparative examples 1 and 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 of sodium dodecyl sulfate is obviously accelerated, and the release end point is obviously improved.

TABLE 5 Release curves of the formulations of example 1, example 10 in phosphate buffers 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 float time and hold time in pH1.2 Medium (37.+ -. 0.5 ℃ C.) examples 1 to 10

Sample of	Time/min of float	Duration of float/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 1-6 and FIGS. 1-5, in examples 1-10, example 1 has a faster float time, a longer hold time, a better slow release effect, and a higher slow release end point than the other examples.

Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and 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 the technical solution of the present invention may be modified or equally substituted without departing from the spirit and scope of the technical solution of the present invention, and the scope of the claims of the present invention shall be covered.

Claims

1. The epalrestat gastric floating tablet comprises 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 generating agent, 50-60 parts of filling agent, 60 parts of solubilizer and 20 parts of lubricant;

wherein the framework material is the combination of HPMC K4M and HPMC K100LV, and the weight ratio of the combination is 1:3;

the bleaching aid is stearyl alcohol;

the gas generating agent is sodium bicarbonate, sodium carbonate or calcium carbonate;

the filler is lactose;

the solubilizer is sodium dodecyl sulfate;

the lubricant is magnesium stearate.

2. Epalrestat gastric-floating tablet according to claim 1, characterized in that epalrestat gastric-floating tablet comprises the following components:

3. epalrestat gastric floating tablet according to any one of claims 1-2, characterized in that the epalrestat gastric floating tablet is prepared by coating epalrestat gastric floating tablet element tablets, and the coating agent is selected from gastric soluble opadry.

4. A process for preparing the epalrestat gastric-floating tablet of claim 3, comprising the steps of:

(3) Adding lubricant and mixing uniformly; stamping and tabletting;

(4) And weighing gastric-soluble Opadry, respectively dissolving in distilled water of a prescription amount, uniformly mixing to form coating liquid, and coating the plain tablets in a coating pot to obtain the epalrestat gastric floating tablets.

5. The method of claim 4, wherein the tabletting die of step (3) is a round dimple die with a diameter of 12mm, a 17.5 x 8.5mm oval dimple die, or a 20.35 x 10.85mm oval dimple die.