CN115721621A - Epalrestat sustained-release preparation - Google Patents

Epalrestat sustained-release preparation Download PDF

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CN115721621A
CN115721621A CN202211623293.XA CN202211623293A CN115721621A CN 115721621 A CN115721621 A CN 115721621A CN 202211623293 A CN202211623293 A CN 202211623293A CN 115721621 A CN115721621 A CN 115721621A
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epalrestat
sustained
release
release preparation
cellulose
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徐鹏飞
边聪
周子琳
李海燕
赖才达
王文首
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Beijing Yitai Pharmaceutical Technology Co ltd
Hangzhou Yetai Pharmaceutical Technology Co ltd
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Beijing Yitai Pharmaceutical Technology Co ltd
Hangzhou Yetai Pharmaceutical Technology Co ltd
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Publication of CN115721621A publication Critical patent/CN115721621A/en
Priority to PCT/CN2023/139300 priority patent/WO2024125654A1/en
Priority to CN202311736464.4A priority patent/CN117717532A/en
Priority to CN202311738680.2A priority patent/CN117717533A/en
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Abstract

The invention provides an epalrestat sustained-release preparation. The epalrestat slow-release preparation at least comprises a slow-release floating layer, wherein a hydrogel material in the slow-release floating layer is at least one of polyvinyl alcohol, water swelling cellulose, carrageenan, xanthan gum, guar gum and Arabic gum, and a framework material is at least one of non-water-soluble cellulose, polyvinylpyrrolidone, acrylic resin and polyacrylate. The epalrestat sustained-release preparation has good gastric floating performance, can improve the absorption performance of the epalrestat in vivo, and can replace an epalrestat common tablet which is administrated three times a day by a once-a-day administration mode.

Description

Epalrestat sustained-release preparation
Technical Field
The application relates to an epalrestat preparation, in particular to an epalrestat slow-release preparation.
Background
Epalrestat (5- [ (1Z, 2E) -2-methyl-3-phenyl-2-propenylidene ] -4-oxo-2-thioxo-3-thiazolidineacetic acid) is a reversible, non-competitive inhibitor of aldose reductase which has a selective inhibitory effect on aldose reductase. Clinical studies show that epalrestat can inhibit the accumulation of sorbitol in erythrocytes of patients with diabetic peripheral neuropathy, and can improve subjective symptoms and neurological dysfunction of patients compared with a control group.
Epalrestat is well absorbed by oral administration, but has a short half-life, and the elimination half-life in vivo is about 1 h. Therefore, the currently common epalrestat pharmaceutical preparation is a tablet or a capsule, and the dosage of 50mg is used every time, and the epalrestat pharmaceutical preparation is taken three times a day. The multiple times of taking make the user more easily forget to take the medicine, and further has adverse effect on the treatment effect.
At present, no epalrestat sustained release preparation passing clinical tests is available on the market.
A sustained release formulation of epalrestat to be taken only once a day is disclosed in patent US2018000792 and comprises a water swellable non-pH responsive polymer, an anionic non-cellulose based water swellable polymer and a sugar controlled release agent. In this document, hyparstat is used as API, the remaining adjuvants including hydroxypropyl cellulose, mannitol, hydroxypropyl methylcellulose, methacrylic acid polymers and hydrogenated vegetable oils. The sustained release agent has a good sustained release effect in a buffer solution, but the drug effect in vivo is not specifically disclosed in the patent, and the patent specification states that the preparation is good in dissolution under an alkaline condition and little in dissolution under an acidic condition.
Patent CN104940156 discloses an epalrestat enteric-coated sustained-release tablet, which comprises a single-layer tablet core containing epalrestat or pharmaceutically acceptable salt thereof and sustained-release framework materials and an enteric-coated film. The enteric sustained-release tablet is used for controlling the sustained release of epalrestat in intestinal tracts but not in stomach, almost has no dissolution in acid, and is uniformly released in alkali.
Patent CN112137990 discloses a multi-unit sustained-release epalrestat enteric sustained-release pellet. By adding multiple units such as a gastric-soluble isolation coating layer, a gastric-soluble protective coating layer and the like, the drug damage or burst release condition caused by factors such as gastrointestinal tract environment and the like is reduced, and the drug is continuously released in intestinal tracts.
The conventional epalrestat sustained-release preparations can realize a stable release profile within 24 hours in vitro dissolution measurement, but the absorption of epalrestat in vivo is not disclosed. In fact, because epalrestat is well absorbed in the stomach and the upper section of the small intestine, but is poorly absorbed in the lower section of the small intestine and the large intestine, the above sustained-release agent inhibits the epalrestat from dissolving out under acidic conditions (in the stomach), and controls the epalrestat to dissolve out in the intestinal tract, which results in the epalrestat dissolving out less at the easily absorbed part, and dissolving out a large amount at the poorly absorbed part, and the position of dissolution does not match with the position of absorption, thus easily causing the subject to have difficulty in achieving a specific drug blood concentration after taking the drug, and failing to meet the requirement for sustained-release medication.
In view of the above, there is no epalrestat preparation which can be slowly released from a site (e.g. stomach) where epalrestat is easily absorbed in a human body, thereby maintaining a good blood concentration in a long-term dimension after a subject takes the drug.
Disclosure of Invention
The application relates to an epalrestat sustained-release preparation. The preparation can stay in the stomach for a long enough time and slowly release the epalrestat in the stomach, thereby meeting the requirement of slow release of the epalrestat in vivo.
The epalrestat slow-release preparation designed in the application at least comprises a slow-release floating layer, wherein:
the hydrogel material is at least one of polyvinyl alcohol, water swelling cellulose, carrageenan, xanthan gum, guar gum and Arabic gum;
the skeleton material is at least one of water-insoluble cellulose, polyvinylpyrrolidone, acrylic resin and polyacrylate.
Wherein the hydrogel material is water swelling cellulose, preferably hydroxypropyl methylcellulose K4M.
The mass of the hydrogel material is 0.25-0.4 times of that of epalrestat.
The skeleton material is selected from water-insoluble cellulose, and ethyl cellulose N10 is more preferable.
The framework material adopts ethyl cellulose, so that the floating performance and floating time of the preparation in a water system can be effectively improved, and the prepared epalrestat preparation can be rapidly settled in water by using other framework materials instead, so that the effect of stomach floating cannot be realized.
The mass of the framework material is 0.2 to 0.5 time, preferably 0.3 to 0.5 time of that of the epalrestat.
The epalrestat sustained-release preparation prepared by selecting the hydrogel material and the skeleton material and adjusting the corresponding proportion has good floating performance and sustained-release effect. Meanwhile, in the proportion, the prepared epalrestat sustained-release preparation has a stable state and is not easy to collapse.
Preferably, the epalrestat sustained-release preparation also contains a filling agent, wherein the filling agent is microcrystalline cellulose, and the filling agent is preferably microcrystalline cellulose SH-101 or microcrystalline cellulose 102.
The mass of the filler is 0.2 to 1 time, preferably 0.3 to 0.4 time, or 0.7 to 1 time of the mass of epalrestat.
The material proportion and selection can realize good stomach floating effect and dissolution effect, so that the epalrestat sustained-release preparation can stably float in a medium simulating the stomach (pH1.2) for a long time.
The epalrestat sustained release formulation described herein may or may not optionally include any number of disintegrants, wetting agents, glidants, lubricants.
Preferably, the epalrestat sustained release preparation comprises a disintegrant, preferably crospovidone. The dosage of the disintegrating agent is 0.5 to 0.8 time of the mass of the epalrestat.
Preferably, the adhesive also comprises a binder, wherein the binder is selected from any number of low-viscosity cellulose, acrylic acid polymer, hyaluronic acid, alginic acid, polysaccharide and polysaccharide glycoside, preferably the low-viscosity cellulose, and further preferably hydroxypropyl methyl cellulose E5 or hydroxypropyl cellulose EXF. The dosage of the adhesive is 1/50-1/15 of the mass of the epalrestat.
The lubricant is preferably magnesium stearate, and the mass of the lubricant is 0.005-0.05 times of that of the epalrestat.
The glidant is preferably colloidal silicon dioxide, and the mass of the glidant is 0.005-0.05 times of that of epalrestat.
In conclusion, compared with the prior art, the epalrestat sustained-release preparation provided by the invention has good floating performance and sustained-release performance, has short floating time, long floating time and good dissolution performance, and has good application prospect.
Drawings
FIG. 1 is a graph showing the plasma concentration profiles of epalrestat original and ordinary tablets and epalrestat sustained-release tablets obtained in examples 1-2 and 1-5 in mini-pigs.
Detailed Description
Some noun explanations in this application are explained as follows:
epalrestat refers broadly to a salt of epalrestat or a pharmaceutically acceptable derivative thereof, including co-crystals, salts, free acids, prodrugs (e.g., esters), polymorphs, and solvates of epalrestat.
The hydrogel material refers to a compound or a composition which swells after absorbing water, so that the volume of the tablet is increased, and the floating effect is realized, and can be selected from any number of polyvinyl alcohol, water swelling cellulose, carrageenan, xanthan gum, guar gum, arabic gum, polyvinyl acetate and carbomer.
The water swellable cellulose refers to cellulose containing hydroxyl groups in part, which expands in volume upon absorption of water, and thus functions to provide buoyancy, and includes hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and the like.
The matrix material refers to a component which does not obviously change after being dissolved in water in the sustained-release preparation tablet, has the effects of keeping the tablet shape complete, reducing cracking and the like, and comprises water-insoluble cellulose, polyvinylpyrrolidone, acrylic resin, polyacrylate and the like.
The water-insoluble cellulose refers to a cellulose ether compound which is not dissolved in water.
The technical solution of the present invention will be further described in detail with reference to the following embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the techniques realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1
The epalrestat sustained-release tablet is prepared by a direct tabletting process, and the preparation method comprises the following steps: the raw and auxiliary materials shown in table 1 were weighed in order, mixed thoroughly using a HLS-50 laboratory hopper mixer to obtain mixed granules, and tabletted using an EP200LAWC single-rotation double-layer tablet press and 14.5 × 8.0mm oval punches to obtain epalrestat sustained release tablets.
TABLE 1
Figure BDA0004003340380000041
Figure BDA0004003340380000051
In this embodiment, the materials are selected as follows:
filling agent: microcrystalline cellulose SH101;
hydrogel material: hydroxypropyl methylcellulose K4M;
framework material: ethyl cellulose N10;
adhesive: hypromellose E5;
lubricant: magnesium stearate;
disintegrating agent: crospovidone KCL.
Example 2
The epalrestat sustained-release tablet is prepared by a wet granulation process, and the preparation method comprises the following steps: weighing the raw and auxiliary materials shown in Table 2 in sequence, preparing wet granules containing the medicine by using a Mini-CG experimental wet mixing granulator, drying the wet granules by using an FLZB-0.5 experimental multifunctional fluidized bed to obtain dry granules containing the medicine, fully mixing the dry granules containing the medicine with the additional auxiliary materials to obtain mixed granules, and tabletting by using an EP200LAWC single-rotation double-layer tablet press and a 14.5X 8.0mm oval punch to obtain the epalrestat sustained-release tablet.
TABLE 2
Figure BDA0004003340380000052
In this embodiment, the materials are selected as follows:
filling agent: microcrystalline cellulose SH101;
hydrogel material: hydroxypropyl methylcellulose K4M;
framework material: ethyl cellulose N10;
adhesive: hydroxypropyl methylcellulose E5;
lubricant: magnesium stearate;
disintegrating agent: crospovidone KCL;
glidant preparation: colloidal silica.
Example 3
The epalrestat sustained release formulations prepared in examples 1 and 2 were put into simulated gastric fluid (ph 1.2), and the floating property was measured, and the results are shown in table 3.
TABLE 3
Number of Thickness of the sheet mm Rise time min Sheet form integrity
1-1 5.75 Immediate use Is that
1-2 5.58 Immediate use Is that
1-3 5.6 Immediate use Is that
1-4 5.68 Immediate use Is that
1-5 5.78 Is immediately ready to use Is that
1-6 5.7 Is immediately ready to use Whether or not
1-7 5.71 Is immediately ready to use Whether or not
1-8 5.73 Is immediately ready to use Whether or not
1-9 5.75 Is immediately ready to use Whether or not
1-10 6.15 Immediate use Is that
1-11 6.08 Immediate use Is that
2-1 6.42 Immediate use Is that
2-2 6.73 Is immediately ready to use Is that
2-3 6.59 Is immediately ready to use Is that
The result shows that when the dosage of the hydrogel material is 0.25 to 0.4 times of the mass of the epalrestat and the dosage of the framework material is 0.3 to 0.5 times of the mass of the epalrestat, the prepared epalrestat sustained-release preparation has good preparation performance and bleaching effect.
Example 4
Referring to example 2, hypromellose EXF was selected as a binder, epalrestat sustained-release tablets were prepared and measured for their floating performance according to the method of example 3, the specific component ratios are shown in table 4, and the measurement results are shown in table 5.
TABLE 4
Figure BDA0004003340380000061
TABLE 5
Figure BDA0004003340380000062
Figure BDA0004003340380000071
Example 5
An epalrestat sustained-release tablet was prepared by replacing the filler with microcrystalline cellulose SH102 and the lubricant with sodium stearyl fumarate on the basis of example 1-1. The properties of the tablets obtained by the examination according to the method of example 3 are shown in Table 6.
TABLE 6
Numbering 5
Thickness of the sheet 6.08mm
Time to float Immediate use
Sheet form integrity Is that
Example 6
Table 7 shows the properties of the epalrestat sustained-release tablets prepared by replacing the matrix material with ethylcellulose T10 in example 4-1 and examined by the method of example 3.
TABLE 7
Number of 6
Thickness of the sheet 6.19mm
Time to float Is immediately ready to use
Sheet form integrity Is that
Example 7
Epalrestat double-layer sustained-release tablets comprise a sustained-release floating layer and a quick-release layer. The preparation method of the slow release layer is the same as that of example 1, the relative ratio of the materials of the slow release layers of different preparations is shown in table 8, the quick release layer is prepared by tabletting according to a pharmacopeia method, and the relative ratio of the materials of the quick release layers of the double-layer preparations is the same and is shown in table 9. The mass ratio of the immediate release layer and the sustained release layer and the properties of the tablet are shown in table 10.
TABLE 8
Figure BDA0004003340380000072
TABLE 9
Figure BDA0004003340380000081
TABLE 10
Figure BDA0004003340380000082
The Epalrestat double-layer tablet has good floating performance and complete tablet shape during floating.
Example 8
The epalrestat sustained release tablets prepared by the invention were subjected to floating performance measurement, and the floating time in simulated gastric juice (ph 1.2) was recorded, and the results are shown in table 11.
TABLE 11
Numbering Floating time
1-1 ＞8h
1-2 ＞8h
1-3 ＞8h
1-4 7h
1-5 6h
1-10 6h
1-11 7h
2-1 7h
2-2 7h
4-1 7h
4-2 6h
4-5 ＞8h
4-6 ＞8h
6 120s
The results show that the epalrestat sustained-release tablets prepared by the various methods have good capability of being retained in the stomach under the simulated gastric juice environment when the ethyl cellulose N10 is selected as the framework material. When the framework material is replaced by ethyl cellulose T10, the floating time of the prepared epalrestat sustained-release tablet is only 120s, and the requirement of the gastric floating tablet cannot be met.
Example 9
The absorption of the epalrestat sustained-release preparation of the invention in vivo was studied. The epalrestat sustained release tablets prepared in examples 1-2 and 1-5 and the original conventional tablets were subjected to a biological test and orally administered using a small pig animal model. The sustained-release tablets obtained in examples 1-2 and 1-5 were administered once, and the amount of epalrestat administered once was 150mg, while the conventional epalrestat tablets in the former study were administered once every 8 hours, and the amount of epalrestat administered once was 50mg. The results of the experiment are shown in tables 12 to 14 and FIG. 1.
TABLE 12 Experimental results of the original grinding of the conventional tablets (administration time of 0h, 8h, 16h, respectively)
Figure BDA0004003340380000091
TABLE 13 Experimental results of Epalrestat sustained-release tablets obtained in example 1-2
Figure BDA0004003340380000092
Figure BDA0004003340380000101
TABLE 14 Experimental results of epalrestat sustained-release tablets prepared in examples 1 to 5
Figure BDA0004003340380000102
The result shows that the blood concentration of the epalrestat sustained-release preparation provided by the invention after once daily administration is basically consistent with the blood concentration of the original epalrestat common tablet in the research after three times daily administration, and the epalrestat sustained-release preparation has good sustained-release effect.
It should be noted that the above-mentioned several preferred embodiments are further non-limiting detailed descriptions of the technical solutions of the present invention, and are only used for illustrating the technical concepts and features of the present invention. It is intended that the present invention be understood and implemented by those skilled in the art, and not limited to the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered in the protection scope of the present invention.

Claims (9)

1. The sustained-release epalrestat preparation is characterized by at least comprising a sustained-release floating layer, wherein:
the hydrogel material is at least one of polyvinyl alcohol, water swelling cellulose, carrageenan, xanthan gum, guar gum and Arabic gum;
the skeleton material is at least one selected from water-insoluble cellulose, polyvinylpyrrolidone, acrylic resin and polyacrylate.
2. The epalrestat sustained-release preparation according to claim 1, wherein the hydrogel material is water-swelling cellulose, preferably hydroxypropyl methylcellulose, and more preferably hydroxypropyl methylcellulose K4M.
3. The epalrestat sustained-release preparation according to claim 1, wherein the mass of the hydrogel material is 0.25-0.4 times of the mass of epalrestat.
4. The epalrestat sustained-release preparation according to claim 1, wherein the matrix material is ethyl cellulose N10.
5. The epalrestat sustained-release preparation according to claim 6, wherein the mass of the matrix material is 0.2-0.5 times, preferably 0.3-0.5 times of the mass of epalrestat.
6. The epalrestat sustained-release preparation according to claim 1, characterized by further comprising a filler, wherein the filler is microcrystalline cellulose, preferably microcrystalline cellulose SH-101 or microcrystalline cellulose 102.
7. The epalrestat sustained-release preparation according to claim 6, wherein the mass of the filler is 0.2-1 times of the mass of epalrestat.
8. The epalrestat sustained-release preparation according to claim 7, characterized by further comprising a disintegrant, wherein the mass of the disintegrant is 0.5-0.8 times of the mass of epalrestat.
9. The epalrestat sustained-release preparation according to claim 1, further comprising a binder, wherein the binder is at least one selected from hydroxypropyl methylcellulose E5 and hydroxypropyl cellulose EXF.
CN202211623293.XA 2022-12-16 2022-12-16 Epalrestat sustained-release preparation Pending CN115721621A (en)

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Application Number Priority Date Filing Date Title
CN202211623293.XA CN115721621A (en) 2022-12-16 2022-12-16 Epalrestat sustained-release preparation
PCT/CN2023/139300 WO2024125654A1 (en) 2022-12-16 2023-12-15 Sustained-release epalrestat composition, method for preparing same, and use thereof
CN202311736464.4A CN117717532A (en) 2022-12-16 2023-12-15 Epalrestat gastric floating tablet, and preparation method and application thereof
CN202311738680.2A CN117717533A (en) 2022-12-16 2023-12-15 Epalrestat sustained-release composition, preparation method and application thereof

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WO2024125654A1 (en) * 2022-12-16 2024-06-20 杭州剂泰医药科技有限责任公司 Sustained-release epalrestat composition, method for preparing same, and use thereof

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PT2665477E (en) * 2011-01-20 2016-01-12 Bionevia Pharmaceuticals Inc Modified release compositions of epalrestat or a derivative thereof and methods for using the same
CN102440976A (en) * 2011-12-21 2012-05-09 南京海陵中药制药工艺技术研究有限公司 Epalrestat slow-release tablet and preparation method thereof
CN104940156B (en) * 2015-06-09 2018-06-12 扬子江药业集团南京海陵药业有限公司 Epalrestat enteric-coated sustained-release tablet and preparation method thereof
CN113143880B (en) * 2021-03-10 2022-07-12 河北化工医药职业技术学院 Sustained-release tablet for treating diabetic complications and preparation method thereof
CN115444831B (en) * 2022-10-25 2023-08-22 南京康川济医药科技有限公司 Epalrestat gastric floating tablet and preparation method thereof
CN115721621A (en) * 2022-12-16 2023-03-03 杭州剂泰医药科技有限责任公司 Epalrestat sustained-release preparation

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WO2024125654A1 (en) * 2022-12-16 2024-06-20 杭州剂泰医药科技有限责任公司 Sustained-release epalrestat composition, method for preparing same, and use thereof

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