CN110548014B - Epalrestat double-layer osmotic pump controlled release tablet and preparation method thereof - Google Patents

Abstract

The invention provides an epalrestat double-layer osmotic pump controlled release tablet and a preparation method thereof. The osmotic pump consists of a drug-containing layer, a boosting layer and a coating film; the weight percentage of the medicine-containing layer is as follows: 30-40% of epalrestat, 30-50% of swelling agent, 1-10% of pH regulator, 5-15% of solubilizer and 1-3% of lubricant; the boosting layer comprises the following components in percentage by weight: 60-75% of swelling agent, 5-30% of osmotic pressure active substance and 1-3% of lubricant; the semipermeable coating film comprises the following components: the dosage of each 100 tablets is composed of 5-15 g of semipermeable polymer material and 0.5-3 g of water-soluble pore-forming agent. The epalrestat double-layer osmotic pump controlled release tablet can realize the constant-speed release of the drug in vivo, the drug release behavior is not influenced by factors such as medium environment pH value, enzyme, gastrointestinal motility, food and the like, the stability of blood concentration can be maintained, the toxic and side effect of the drug is reduced, the administration frequency is reduced, and the compliance of patients is improved.

Description

Epalrestat double-layer osmotic pump controlled release tablet and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an epalrestat double-layer osmotic pump controlled release tablet and a preparation method thereof.

Background

Diabetic Peripheral Neuropathy (DPN) is a common chronic complication of diabetes, the course of the disease is long, and after the disease occurs, both the nerve center and Peripheral local nerves of a patient are damaged, and Peripheral Neuropathy is the most common in clinical practice, and is mainly lesion of distal sensory nerves. DPN is not the main cause of death of the diabetic patients, but can cause the disability risk of the patients to rise, and serious patients can develop diabetic foot and acromelic gangrene, so that amputation and disability are caused, and the survival quality of the patients is adversely affected.

The polyol pathway is a pathogenesis of diabetic peripheral neuropathy, and Aldose Reductase (ARIs) can reduce sorbitol flux through the polyol pathway, thereby treating diabetic peripheral neuropathy. Epalrestat (Epalrestat) is chemically known as 5- [ (1Z,2E) -2-methyl-3-phenyl-2-propenylidene ] -4-oxo-2-thioxo-thiazolidine acetic acid and is a reversible aldose reductase inhibitor. Can selectively inhibit glucose produced by polyol metabolism, and control sorbitol level, thereby continuously enhancing nerve function of patients. In addition, epalrestat can increase the density of myelinated fibers, the area of axons, the thickness of myelin sheaths of nerves and the like, improve blood supply of nerves, promote the content of inositol in nerve blocks to rise rapidly, and further improve the sensory conduction speed of the median nerve and the common peroneal nerve.

Epalrestat tablets were developed by the japanese national minister and were first marketed in japan in 1992. At present, only 3 enterprises in Yangziang pharmaceutical industry, Shandongdin marine biopharmaceutical industry and Beijing Youyiji special pharmaceutical industry, which are in national batch, produce common preparations with the specification of 50mg, and the common preparations need to be administrated 3 times a day during treatment, thereby bringing inconvenience to patients, and simultaneously causing great fluctuation of effective blood concentration and great toxic and side effects. Subsequently, the report of an epalrestat sustained-release preparation appears, the CN 104940156A enteric-coated sustained-release tablet has slow and non-constant drug release speed, 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 controlled release preparation which is taken once a day, so that the treatment compliance of a patient can be improved, the phenomenon of large blood concentration fluctuation can be avoided or reduced to the maximum extent by a unique zero-order drug release mode, and the toxic and side effects are reduced. The osmotic pump controlled release preparation is one of the most ideal controlled release technologies with the current effect, the medicine does not depend on physiological factors such as pH value, gastric motility, emptying time and the like to a great extent, and the safety and the effectiveness of the medicine are greatly improved.

Disclosure of Invention

The epalrestat osmotic pump preparation prepared by the method has zero-order release kinetics drug release characteristics, can release drugs at a constant speed within 8 hours, is beneficial to maintaining long-term and efficient blood concentration in vivo and improving the drug treatment effect.

The invention is realized by the following technical scheme: the osmotic pump preparation comprises a drug-containing layer tablet core, a boosting layer tablet core, a semipermeable membrane and a single drug release pore on the surface of a controlled release tablet at one side of a drug-containing layer; the weight percentage of the medicine-containing layer is as follows: 30-40% of epalrestat, 35-50% of swelling agent, 1-10% of pH regulator, 5-15% of solubilizer and 1-3% of lubricant; the boosting layer comprises the following components in percentage by weight: 60-75% of swelling agent, 5-30% of osmotic pressure active substance and 1-3% of lubricant; the semipermeable coating film comprises the following components: every 100 tablets are composed of 5-15 g of semipermeable polymer material and 0.5-3 g of water-soluble pore-forming agent; the weight gain of the coating is 5 to 15 percent of the weight of the tablet core; the aperture of the small hole is 0.6 mm-1.2 mm.

The epalrestat double-layer osmotic pump controlled release tablet provided by the invention has the advantages that the swelling agent of the drug-containing layer is selected from one or a combination of more of PEO N10, PEO N80 and PEO N750.

The epalrestat double-layer osmotic pump controlled release tablet provided by the invention has the advantages that the pH regulator is selected from one or more of sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, sodium citrate and magnesium oxide.

The epalrestat double-layer osmotic pump controlled release tablet provided by the invention is characterized in that the solubilizer is selected from one or a combination of a plurality of sodium dodecyl sulfate, tween and poloxamer.

The epalrestat double-layer osmotic pump controlled release tablet provided by the invention is prepared by combining one or more of osmotic pressure active substances of sodium chloride, potassium chloride, lactose, sodium sulfate, magnesium sulfate and mannitol.

According to the epalrestat double-layer osmotic pump controlled release tablet, the boosting layer swelling agent is selected from one or a combination of more of PEO N12K, PEO N60K, WSR 301, WSR 303 and WSR Coagulant.

The epalrestat double-layer osmotic pump controlled release tablet provided by the invention has the advantages that the coloring agent is selected from one or a combination of iron oxide red and iron oxide yellow.

The epalrestat double-layer osmotic pump controlled release tablet provided by the invention is characterized in that the lubricant is selected from one or more of magnesium stearate, talcum powder, magnesium lauryl sulfate, superfine silica gel powder and polyethylene glycol.

The epalrestat double-layer osmotic pump controlled release tablet provided by the invention is characterized in that the semipermeable high polymer material is selected from one or a combination of more of cellulose acetate, acrylic resin and ethyl cellulose.

The epalrestat double-layer osmotic pump controlled release tablet provided by the invention has the advantages that the pore-forming agent is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol, propylene glycol, water-soluble inorganic salt and polyvinylpyrrolidone.

The epalrestat double-layer osmotic pump controlled release tablet is characterized by comprising the following preparation processes:

(1) the preparation process of the medicine-containing layer comprises the following steps: mixing epalrestat with a pH regulator, a solubilizer and a swelling agent, adding a wetting agent to prepare a soft material, sieving with a 40-mesh sieve for granulation, drying, sieving with the 40-mesh sieve for size stabilization, adding a lubricant, and uniformly mixing; the preparation process of the boosting layer comprises the following steps: mixing swelling agent, osmotic pressure active substance and coloring agent, adding wetting agent to make into soft material, sieving with 24 mesh sieve, granulating, drying, sieving with 24 mesh sieve, grading, adding lubricant, mixing, sequentially adding the medicine-containing layer granule and the boosting layer granule into 12mm round dimple punch, and pressing into double-layer osmotic pump tablet core.

(2) Weighing the semipermeable high polymer material and the water-soluble pore-forming agent according to the prescription amount, respectively dissolving the semipermeable high polymer material and the water-soluble pore-forming agent in acetone and distilled water of the prescription amount, uniformly mixing the semipermeable high polymer material and the water-soluble pore-forming agent to form a coating solution, placing the tablet core into a coating pot for coating, and punching holes with the diameter of 0.6-1.2 mm on one side of a drug-containing layer of the coated tablet by using a laser punching machine to obtain the epalrestat double-layer osmotic pump controlled release tablet.

The preparation has the following advantages: by utilizing the advanced membrane pore technology, the purpose of zero-order constant-speed release of the medicament is achieved by adjusting the prescriptions of the tablet core and the coating membrane and taking the osmotic pressure difference between the inside and the outside of the coating membrane as the main medicament release power, and the peak valley phenomenon of the blood concentration of a common preparation is effectively avoided; the preparation has the advantages of reduced administration frequency, reduced adverse side effect, and improved patient compliance, and the preparation has no influence on drug release behavior due to gastrointestinal peristalsis, pH value, gastric emptying, etc.

Drawings

FIG. 1 is a graph of percentage in vitro cumulative release versus time for the double layer osmotic pump controlled release tablet of epalrestat of example 1;

FIG. 2 is a graph of percentage in vitro cumulative release versus time for the double layer osmotic pump controlled release tablet of epalrestat of example 2;

FIG. 3 is a graph of percentage in vitro cumulative release versus time for the double layer osmotic pump controlled release tablet of example 3;

FIG. 4 is a graph of percentage in vitro cumulative release versus time for the double layer osmotic pump controlled release tablet of example 4;

FIG. 5 is a graph of percentage in vitro cumulative release versus time for the double layer osmotic pump controlled release tablet of example 5;

FIG. 6 is a graph of percentage in vitro cumulative release versus time for the double layer osmotic pump controlled release tablet of example 6;

FIG. 7 is a graph of percentage in vitro cumulative release versus time for the double layer osmotic pump controlled release tablet of example 7;

FIG. 8 is a graph of percentage in vitro cumulative release versus time for the double layer osmotic pump controlled release tablet of example 8;

FIG. 9 is a graph of percentage in vitro cumulative release versus time for the double layer osmotic pump controlled release tablet of example 8;

FIG. 10 is a graph of percentage in vitro cumulative release versus time for the double layer osmotic pump controlled release tablet of example 8.

Detailed Description

Example 1

(1) Drug-containing layer (per tablet):

(2) boost layer (per sheet):

(3) semipermeable membrane coating liquid composition (every 1000 tablets)

(4) Composition of moisture-proof coating liquid

Appropriate amount of Opaba 85G662723-CN

Example 1-example 10 preparation of epalrestat bilayer osmotic pump controlled release tablets:

(1) pulverizing the raw materials to particle diameter D₉₀About 50 μm. Sieving the adjuvants with 40 mesh sieve. Preparing medicine-containing layer particles: weighing raw and auxiliary materials according to the prescription amount, and uniformly mixing by an equivalent progressive method to obtain premixed powder. Adding appropriate amount of wetting agent to make into soft material, sieving with 40 mesh sieve, granulating, drying at 40 deg.C for 2 hr, and sieving with 40 mesh sieve. Adding the lubricant in the prescription amount and mixing uniformly. Preparing boosting layer particles: weighing the auxiliary materials according to the prescription amount, and uniformly mixing by an equivalent progressive method to obtain premixed powder. Adding appropriate amount of wetting agent to make into soft material, sieving with 24 mesh sieve, granulating, drying at 40 deg.C for 2 hr, and sieving with 24 mesh sieve. Adding the lubricant in the prescription amount and mixing uniformly.

(2) Tabletting: and (4) avoiding light. And pressing the medicine-containing layer mixture and the boosting layer mixture into a double-layer tablet core by adopting a double-tabletting technology. The diameter of the tablet core is 12mm, and the hardness is 6-8 kg.

(3) Coating a controlled release coating film: the tablet cores were coated with semipermeable membrane coating solution with a weight gain of 12.5%. The coated product was aged at 40 ℃ for 24 h.

(4) Laser drilling: and (3) punching a drug release hole with the aperture of 0.6-1.2 mm on the controlled release coating film at the circle center position on one side of the drug-containing layer by using a laser drilling machine for the aged osmotic pump tablet.

(5) Coating a gastric coating film: the perforated core was coated with gastric film coating solution.

Example 1-example 10 determination of the release rate of epalrestat bilayer osmotic pump controlled release tablets:

according to the second method of the determination method of the dissolution rate and the release degree of 0931 in the fourth part of the pharmacopoeia 2015 edition, the epalrestat double-layer osmotic pump controlled release tablet is placed in a dissolution cup, 900mL of degassed phosphate buffer solution with the pH value of 6.8 is used as a release medium, the rotating speed is 100rpm, the temperature is (37 +/-0.5) DEG C, 10mL of the release medium is taken in 1h, 2h, 4h, 6h, 8h, 12h and 24h respectively, meanwhile, an equivalent amount of isothermal fresh medium is supplemented, the fresh medium is filtered by a 0.45 mu m microporous filter membrane, and the absorbance of the subsequent filtrate is determined at 398nm by using an ultraviolet spectrophotometer after the subsequent filtrate is diluted; in addition, a proper amount of reference substance is precisely weighed, the cumulative release percentage is calculated by the same method, and the requirement is met.

Example 2

(1) Drug-containing layer (per tablet):

(2) boost layer (per sheet):

(3) semipermeable membrane coating liquid composition (every 1000 tablets)

(4) Composition of moisture-proof coating liquid

Appropriate amount of Opaba 85G662723-CN

The release rate of the epalrestat bilayer osmotic pump controlled release tablet of example 1 is shown in fig. 1. The release rate of the epalrestat bilayer osmotic pump controlled release tablet of example 2 is shown in fig. 2. Therefore, the release end point of the epalrestat can be obviously improved by adding the sodium dodecyl sulfate into the medicine-containing layer.

Example 3

(1) Drug-containing layer (per tablet):

(2) boost layer (per sheet):

(3) semipermeable membrane coating liquid composition (every 1000 tablets)

(4) Composition of moisture-proof coating liquid

Appropriate amount of Opaba 85G662723-CN

Example 4

(1) Drug-containing layer (per tablet):

(2) boost layer (per sheet):

(3) semipermeable membrane coating liquid composition (every 1000 tablets)

(4) Composition of moisture-proof coating liquid

Appropriate amount of Opaba 85G662723-CN

The release rate of the epalrestat bilayer osmotic pump controlled release tablet of example 3 is shown in fig. 3. The release rate of the epalrestat bilayer osmotic pump controlled release tablet of example 4 is shown in fig. 4. Na (Na)₂CO₃Effect ratio of NaHCO as pH regulator₃Good results are obtained. Not only can meet the requirement of the early-stage nearly zero-order release, but also can meet the requirement of complete release. From the release profile, Na₂CO₃The dosage is in positive correlation with the release speed and the release terminal point.

Example 5

(1) Drug-containing layer (per tablet):

(2) boost layer (per sheet):

(3) semipermeable membrane coating liquid composition (every 1000 tablets)

(4) Composition of moisture-proof coating liquid

Appropriate amount of Opaba 85G662723-CN

Example 6

(1) Drug-containing layer (per tablet):

(2) boost layer (per sheet):

(3) semipermeable membrane coating liquid composition (every 1000 tablets)

(4) Composition of moisture-proof coating liquid

Appropriate amount of Opaba 85G662723-CN

The release rate of the epalrestat bilayer osmotic pump controlled release tablet of example 5 is shown in fig. 5. The release rate of the epalrestat bilayer osmotic pump controlled release tablet of example 6 is shown in fig. 6. As can be seen, the release of WSR N-750 was significantly slower than that achieved using WSR N-10, since WSR N-750 had a much higher viscosity than WSR N-10, which would hinder drug release.

Example 7

(1) Drug-containing layer (per tablet):

(2) boost layer (per sheet):

(3) semipermeable membrane coating liquid composition (every 1000 tablets)

(4) Composition of moisture-proof coating liquid

Appropriate amount of Opaba 85G662723-CN

The release rate of the epalrestat bilayer osmotic pump controlled release tablet of example 7 is shown in fig. 7. When the dosage of the sodium chloride reaches a certain range, the dosage of the sodium chloride is increased, so that the release result is not greatly influenced.

Example 8

(1) Drug-containing layer (per tablet):

(2) boost layer (per sheet):

(3) semipermeable membrane coating liquid composition (every 1000 tablets)

(4) Composition of moisture-proof coating liquid

Appropriate amount of Opaba 85G662723-CN

Example 9

(1) Drug-containing layer (per tablet):

(2) boost layer (per sheet):

(3) semipermeable membrane coating liquid composition (every 1000 tablets)

(4) Composition of moisture-proof coating liquid

Appropriate amount of Opaba 85G662723-CN

Example 10

(1) Drug-containing layer (per tablet):

(2) boost layer (per sheet):

(3) semipermeable membrane coating liquid composition (every 1000 tablets)

(4) Composition of moisture-proof coating liquid

Appropriate amount of Opaba 85G662723-CN

The release rate of the epalrestat bilayer osmotic pump controlled release tablet of example 8 is shown in fig. 8. The release rate of the epalrestat bilayer osmotic pump controlled release tablet of example 9 is shown in fig. 9. The release rate of the epalrestat bilayer osmotic pump controlled release tablet of example 10 is shown in fig. 10, which shows that the larger the amount of PEG in the coating powder in a certain range, the faster the release rate.

Claims (3)

1. An epalrestat double-layer osmotic pump controlled release tablet comprises a tablet core consisting of a drug-containing layer and a boosting layer, a semipermeable coating membrane outside the tablet core, and a drug release pore on the semipermeable membrane at one side of the drug-containing layer; the medicine-containing layer is characterized by comprising the following components in percentage by weight: 30-40% of epalrestat, 30-50% of swelling agent, 1-10% of pH regulator, 5-15% of solubilizer and 0.1-3% of lubricant; the boosting layer comprises the following components in percentage by weight: 60 to 75 percent of swelling agent, 5 to 30 percent of osmotic pressure active substance and 0.1 to 3 percent of lubricant; the semipermeable coating film comprises the following components: every 100 tablets are composed of 5-15 g of semipermeable polymer material and 0.5-3 g of water-soluble pore-forming agent; the weight gain of the coating is 5 to 15 percent of the weight of the tablet core; the aperture of the small hole is 0.6 mm-1.2 mm;

the swelling agent of the drug-containing layer is one or a combination of more of PEO N10 and PEO N80;

the pH regulator is selected from one or more of sodium carbonate, disodium hydrogen phosphate, sodium citrate and magnesium oxide;

the solubilizer is selected from one or a combination of several of sodium dodecyl sulfate, tween and poloxamer;

the osmotic pressure active substance is selected from one or more of sodium chloride, potassium chloride, lactose, sodium sulfate, magnesium sulfate and mannitol;

the boosting layer swelling agent is selected from one or a combination of more of PEO N12K, PEO N60K, WSR 301 and WSR 303;

the lubricant is selected from one or more of magnesium stearate, talcum powder, magnesium lauryl sulfate, superfine silica gel powder and polyethylene glycol;

the semipermeable high polymer material is selected from one or a combination of more of cellulose acetate, acrylic resin and ethyl cellulose; the pore-forming agent is selected from one or a combination of several of hydroxypropyl methylcellulose, polyethylene glycol, propylene glycol, water-soluble inorganic salt and polyvinylpyrrolidone.

2. The epalrestat bi-layer osmotic pump controlled release tablet of claim 1, wherein the boosting layer further comprises a coloring agent, and the coloring agent is one or a combination of several selected from red iron oxide and yellow iron oxide.

3. A method for preparing the epalrestat bi-layer osmotic pump controlled release tablet of claim 2, comprising the steps of:

(1) the preparation process of the medicine-containing layer comprises the following steps: mixing epalrestat with a pH regulator, a solubilizer and a swelling agent, adding a wetting agent to prepare a soft material, sieving with a 40-mesh sieve for granulation, drying, sieving with the 40-mesh sieve for size stabilization, adding a lubricant, and uniformly mixing; the preparation process of the boosting layer comprises the following steps: mixing swelling agent, osmotic pressure active substance and coloring agent, adding wetting agent to prepare soft material, sieving with 24 mesh sieve for granulation, drying, sieving with 24 mesh sieve for granulation, adding lubricant, mixing, sequentially adding the medicine-containing layer granule and the boosting layer granule into 12mm round dimple punch, and pressing to obtain a double-layer osmotic pump tablet core;

(2) weighing the semipermeable high polymer material and the water-soluble pore-forming agent according to the prescription amount, respectively dissolving the semipermeable high polymer material and the water-soluble pore-forming agent in acetone and distilled water of the prescription amount, uniformly mixing the semipermeable high polymer material and the water-soluble pore-forming agent to form a coating solution, placing the tablet core into a coating pot for coating, and punching holes with the diameter of 0.6-1.2 mm on one side of a drug-containing layer of the coated tablet by using a laser punching machine to obtain the epalrestat double-layer osmotic pump controlled release tablet.

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