KR101132977B1 - Stable pharmaceutical composition comprising trimebutine and prokinetic agent - Google Patents

Abstract

The present invention provides a pharmaceutical composition comprising trimebutin and a prokinetic agent as an active ingredient, and includes 1 to 25 parts by weight of an organic acid as a stabilizer based on 100 parts by weight of trimebutin. The pharmaceutical composition according to the present invention can effectively inhibit the formation of the decomposition product of trimebuterin as an active ingredient by containing an organic acid as a stabilizer, and has excellent stability.

Description

Stable pharmaceutical composition comprising trimebutine and prokinetic agent

The present invention relates to a pharmaceutical composition comprising trimebuterin and a prokinetic agent as an active ingredient, and relates to a pharmaceutical composition having excellent stability by significantly reducing the degradation products of the active ingredient trimebuterin.

Functional dyspepsia refers to a clinical syndrome in which the patient presents symptoms of the digestive system even when no organic lesions are found in the stomach itself. The types include upper gastrointestinal and lower gastrointestinal tracts. In particular, the overwhelmingly large upper gastrointestinal tract in Korea includes heartburn, burping, nausea, vomiting, indigestion, epigastric discomfort after eating, and gastric abdominal pain on an empty stomach. Lower gastrointestinal tract diseases include postoperative ileus, irritable bowel syndrome in the lower gastrointestinal tract, constipation and diarrhea.

As a therapeutic agent for functional digestive disorders, various drugs targeting serotonin, cholecystokinin, opioid receptor, muscaric receptor, and the like have been developed and used. Specifically, a gastrointestinal motility regulator known as a prokinetic agent is used for the treatment of functional digestive disorders. The prokinetic agents include metoclopramide, which is a paraaminobenzoic acid derivative; Domperidone, a benzimidazole derivative; Benzamide derivatives are cisapride, mosapride, itopride, clebopride, levosulpride and the like. As other gastrointestinal motility regulators, Korean Patent Registration No. 10-0500372 discloses bicyclic benzamides of 3- or 4-substituted 4- (aminomethyl) -piperidine derivatives, and European Patent Nos. 0,309,043, EP 0,299,566 and WO 97/11054 also disclose compounds having gastrointestinal motility stimulating activity. However, most prokinetic agents have a concern that the effect of improving gastrointestinal motility is concentrated on promoting the discharge of the upper gastrointestinal tract, which may cause dysfunction such as diarrhea or constipation due to imbalance with the motor function of the lower gastrointestinal tract. In addition, if there is a digestive disorder in both the upper and lower parts of the gastrointestinal tract, there is a limit to solve them at the same time by conventional prokinetic agents.

On the other hand, trimebuterin agonist enkephalin receptor agonists are known as a drug that acts to regulate the gastrointestinal muscle movement to regulate the enhanced or reduced gastrointestinal motility by acting on the enkephalin receptor (regulator). The gastrointestinal motility improving activity of trimebutin mainly acts on the lower intestinal tract. The present inventors have described trimebutin as an enkephalin receptor agonist; We have designed a composite composition of prokinetic agents such as cisapride, mosapride, and itofride, and found that the composite composition has a general purpose of improving gastrointestinal motility activity acting on both upper and lower gastrointestinal tract regions (2008). Filed December 8, Korean Patent Application No. 2008-0124068). The complex composition is an agent obtained by mixing trimebutin, an enkephalin receptor agonist that acts on the receptors of the peripheral gastrointestinal tract, and a prokinetic agent that promotes the movement of the upper gastrointestinal tract. Competence improves synergistically.

The inventors of the present invention, while conducting a study on a combination formulation containing trimebuterin and prokinetic agents as active ingredients, not only is the stability of trimebuterin increased due to increased degradation products during storage, but also prokenetic agents such as etopriide When combined with, it was observed that the degradation products of trimebutin were further increased. The present inventors have conducted various studies to solve the problems in stability, and surprisingly, when using an organic acid such as citric acid as a stabilizer, it is possible to significantly suppress the generation of decomposition products of trimebuterin, having excellent stability It has been found that the design of a combination formulation of trimebuterin and prokinetic agents is possible.

It is therefore an object of the present invention to provide a combination formulation of trimebutin with a prokinetic agent having excellent stability.

According to one aspect of the invention, a pharmaceutical composition comprising trimebutin and a prokinetic agent as an active ingredient, 1 to 25 parts by weight, preferably 5 to 20 parts by weight based on 100 parts by weight of trimebutin There is provided a pharmaceutical composition comprising a negative organic acid as a stabilizer.

The organic acid may be at least one selected from the group consisting of citric acid, tartaric acid, succinic acid, glutamic acid, aspartic acid, oxalic acid, malic acid, acetic acid, sorbic acid, ascorbic acid, and lactic acid. In addition, the prokinetic agent may be at least one selected from the group consisting of mosapride or a salt thereof, an itopride or a salt thereof, and a cisapride or a salt thereof, and the weight ratio of the trimebutin and the prokinetic agent is 30: 1. It may be in the range of 2: 1.

The pharmaceutical composition according to the present invention may be in the form of solid oral preparations selected from the group consisting of powders, granules, pellets, tablets, and capsules, and more preferably in tablet form.

The pharmaceutical composition of the present invention, if necessary, mannitol, lactose, sucrose, erythritol, isomalt, maltitol, xylitol, sorbitol, trehalose, dextrose, microcrystalline cellulose, corn starch, potato starch, wheat starch, dextrin, Excipients selected from the group consisting of methylcellulose, glucose, and fructose; At least one binder selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and ethyl cellulose; Disintegrating agents selected from the group consisting of sodium starch glycolate, corn starch, starch, crospovidone, croscarmellose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose; Or one or more lubricants selected from the group consisting of silicon dioxide, colloidal silicon dioxide, magnesium stearate, talc, sodium stearyl fumarate, stearic acid, glyceryl behenate, and magnesium aluminometa silicate.

The pharmaceutical composition according to the present invention can effectively inhibit the formation of the decomposition product of trimebuterin as an active ingredient by containing an organic acid as a stabilizer, and it is possible to design a complex formulation of trimebuterin and prokinetic agent having excellent stability. Do.

Figure 1 shows the results of the stability test for 2 weeks at 60 ℃ / 75% RH harsh conditions for the tablets of Comparative Example 1 and Examples 1 to 8.
Figure 2 shows the results of a stability test for two weeks at 60 ℃ / 75% RH harsh conditions for the tablets of Comparative Examples 3, 9 and 10.
Figure 3 shows the results of the stability test for 2 weeks at 60 ℃ / 75% RH harsh conditions for the tablets of Comparative Examples 2, Examples 11 and 12.

As used herein, the term "prokinetic agent" refers to a drug that enhances the rate of intestinal passage of intestinal contents by improving the frequency and / or strength of contraction of the gastrointestinal tract. The prokinetic agent is metoclopramide (paratobenzoic acid derivative); Domperidone, a benzimidazole derivative; Benzamide derivatives cisapride, mosapride, itopride, clebopride, levosulpride and the like. In addition, Korean Patent Registration No. 10-0500372, European Patent No. 0,309,043, European Patent No. 0,299,566, International Patent No. WO97 / 11054 and the like has a compound having a gastrointestinal motility activity. The prokinetic agent may preferably be cisapride or salt thereof, mosapride or salt thereof, itopride or salt thereof, clevopride or salt thereof, or levosulphride or salt thereof, which is preferably a benzamide derivative. May be cisapride or a salt thereof, mosapride or a salt thereof, or an itopride or a salt thereof. In addition, the prokinetic agents (including salt forms) listed above include without limitation their hydrates, solvates or various crystalline forms.

The present invention provides a pharmaceutical composition comprising trimebutin and a prokinetic agent as an active ingredient, and includes 1 to 25 parts by weight of an organic acid as a stabilizer based on 100 parts by weight of trimebutin.

The organic acid used as a stabilizer functions to inhibit the production of decomposition products of trimebutin by prokinetic agents. The organic acid may be at least one selected from the group consisting of citric acid, tartaric acid, succinic acid, glutamic acid, aspartic acid, oxalic acid, malic acid, acetic acid, sorbic acid, ascorbic acid, and lactic acid. The content of the organic acid may be in the range of 1 to 25 parts by weight, preferably 5 to 20 parts by weight, based on 100 parts by weight of trimebutin. When the content of the organic acid is less than 1 part by weight, the effect of improving stability of trimebutin may not be satisfactory. If it exceeds 20 parts by weight, it may cause irritation at the time of taking, and unnecessary organic acid may be absorbed into the body.

In addition, the content of trimebuterin and prokinetic agents may be used in an amount known as a therapeutically effective amount. For example, the content per unit dosage form of trimebutin may be 50-300 mg, preferably about 100 mg. Among prokinetic agents, for example, the content per unit dosage form of the mosapride or salt thereof may be 1-20 mg (as free base), preferably about 5 mg (as free base), and the unit dosage form of itopride or salt thereof The sugar content can be 10-100 mg (as free base), preferably about 50 mg (as free base), and the content per unit dosage of cisapride or salt thereof is 1-30 mg (as free base), preferably May be about 10 mg (as free base). Thus, the weight ratio of trimebutin and prokinetic agent may be determined in view of the therapeutically effective amount described above, and may be, for example, in the range of 30: 1 to 2: 1.

The pharmaceutical composition according to the present invention may be in the form of solid oral preparations selected from the group consisting of powders, granules, pellets, tablets, and capsules, and more preferably in tablet form. In addition, the pharmaceutical composition according to the present invention may further contain additives conventionally used in the pharmaceutical field, for example, conventional excipients, binders, disintegrants, lubricants and the like as necessary.

The excipients include mannitol, lactose, sucrose, erythritol, isomalt, maltitol, xylitol, sorbitol, trehalose, dextrose, microcrystalline cellulose, corn starch, potato starch, wheat starch, dextrin, methylcellulose, glucose, and One or more may be selected from fructose, preferably d-mannitol may be used. The binder may be at least one selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and ethyl cellulose, and preferably hydroxypropyl cellulose may be used. . In addition, the disintegrant may be at least one selected from the group consisting of sodium starch glycolate, corn starch, starch, crospovidone, croscarmellose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, preferably Sodium starch glycolate can be used. The lubricant may be at least one selected from the group consisting of silicon dioxide, colloidal silicon dioxide, magnesium stearate, talc, sodium stearyl fumarate, stearic acid, glyceryl behenate, and magnesium aluminometa silicate.

The pharmaceutical composition according to the present invention may be prepared in the form of an oral solid formulation using the above-mentioned ingredients, that is, trimebutin, a prokinetic agent, and an organic acid, and, if necessary, additives commonly used in the pharmaceutical field. Can be. For example, the pharmaceutical compositions of the present invention may be prepared in tablet form by wet granulation, using trimebutin, prokinetics, organic acids, and additives. The granules obtained in the course of tablet formulation comprise all of trimebutin, a prokinetic agent, and an organic acid; Include trimebuterin and prokinetic agents (in this case, the obtained granules are mixed with an organic acid and compressed into tablets); Trimebuterin and an organic acid may be included (in this case, the obtained granules are mixed with a prokinetic agent and compressed into tablets).

In one embodiment, the pharmaceutical composition of the present invention comprises the steps of (a) preparing a granule containing trimebuterin and a prokinetic agent; And (b) tableting a mixture of the granules, organic acids, and pharmaceutically acceptable additives. The granules of step (a) may be prepared by wet granulation or dry granulation. For example, the granules may be prepared from a mixture of trimebutin, a prokinetic agent (e.g., a mosapride or salt thereof), and a pharmaceutically acceptable additive, to form a binding solution (e.g., hydroxypropylcellulose solution). Can be obtained by drying the prepared wet granules by conventional drying methods such as hot air drying, spray drying and the like.

In another embodiment, the pharmaceutical composition of the present invention comprises the steps of (a ') preparing a granule containing trimebuterin and an organic acid; And (b ') tableting a mixture of the granules, prokinetic agents (or granules of prokinetic agents), and pharmaceutically acceptable additives. The granules of step (a ') may be prepared by wet granulation or dry granulation. For example, the granules are typically prepared from wet granules prepared using a binder solution (e.g., hydroxypropylcellulose solution) from a mixture of trimebutin, an organic acid, and a pharmaceutically acceptable additive. It can be obtained by drying by, for example, hot air drying, spray drying and the like. The mixture of step (b ') is a mixture of granules, prokinetics, and pharmaceutically acceptable additives obtained in step (a'), preferably the prokinetic agent is in the form of granules of prokinetic agents, for example It is excellent in terms of tableting to be mixed in the form of etopriide (or salt thereof) granules obtained according to a conventional granulation process.

In another embodiment, the pharmaceutical compositions of the present invention may be obtained by tableting trimebuterin, prokinetic agents and organic acids, together with pharmaceutically acceptable additives. In addition, the pharmaceutical compositions of the present invention can be obtained by tableting granules containing trimebutin, a prokinetic agent and an organic acid, together with pharmaceutically acceptable additives.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example 1-3.

Tablets were prepared according to the ingredients and contents in Table 1 below. In Table 1, the content of each component represents the weight per unit (mg). After trimmebutin, mosapride, citric acid, colloidal silicon, mannitol and sodium starch glycolate were mixed evenly at 500 rpm for 3 minutes in a high speed stirring mixer (NMG-1L), hydroxypropyl cellulose was purified. Wet granules were prepared using a binder solution obtained by dissolving at about 27% w / w. The obtained wet granules were dried in an oven at 60 ° C. for 3 hours, and then mixed together with sodium starch glycolate, mannitol and sodium stearyl fumarate in a plastic bag for 10 minutes, and tableted with a single tablet press (Fette F1) to prepare a tablet. .

Ingredient Example 1 Example 2 Example 3 Trimebuterin 100 100 100 Mosapride 5.29 5.29 5.29 Mannitol (Added during granulation) 32.71 27.71 17.71 Mannitol (added after mixing) 37 37 37 Citric acid 5 10 20 Hydroxypropylcellulose 4 4 4 Sodium starch glycolate (added during granulation) 4 4 4 Sodium starch glycolate (added during post-mixing) 4 4 4 Colloidal Silicon Oxide 4 4 4 Sodium stearyl fumarate 4 4 4 Gross weight 200 200 200

Example 4-8.

Tablets were prepared according to the ingredients and contents in Table 2 below. In Table 2, the content of each component represents the weight per unit (mg). After trimmebutin, mosapride, colloidal silicon acid, mannitol, and sodium starch glycolate are evenly mixed at 500 rpm for 3 minutes in a high speed stirring mixer (NMG-1L), hydroxypropyl cellulose is added to purified water. Wet granules were prepared using the binder solution obtained by dissolving at 27% w / w. The obtained wet granules were dried in an oven at 60 ° C. for 3 hours, and then mixed together with an organic acid, sodium starch glycolate, mannitol, and sodium stearyl fumarate in a plastic bag for 10 minutes, and tableted with a single tablet press (Fette F1). Prepared.

Ingredient Example 4 Example 5 Example 6 Example 7 Example 8 Trimebuterin 100 100 100 100 100 Mosapride 5.29 5.29 5.29 5.29 5.29 Mannitol (Added during granulation) 27.71 27.71 27.71 27.71 27.71 Mannitol (added after mixing) 37 37 37 37 37 Citric acid 10 - - - - Tartaric acid - 10 - - - Suche mountain - - 10 - - Glutamic acid - - - 10 - Aspartic acid - - - - 10 Hydroxypropylcellulose 4 4 4 4 4 Sodium starch glycolate
(Added during granulation) 4 4 4 4 4 Sodium starch glycolate
(Added after mixing) 4 4 4 4 4 Colloidal Silicon Oxide 4 4 4 4 4 Sodium stearyl fumarate 4 4 4 4 4 Gross weight 200 200 200 200 200

Example 9-10.

Tablets were prepared according to the ingredients and contents in Table 3 below. In Table 3, the content of each component represents the weight per unit (mg). After trimmebutin, organic acid (citric acid or tartaric acid), mannitol and sodium starch glycolate were mixed evenly for 3 minutes at 500 rpm in a high speed stirring mixer (NMG-1L), hydroxypropyl cellulose was added to purified water for about 27 minutes. Wet granules were prepared using the binder solution obtained by dissolving in% w / w, and then dried in an oven at 60 ° C. for 3 hours to obtain granules (trimebutin-granules). Separately, wet granules of etopriide were prepared using a binding solution obtained by dissolving hydroxypropyl cellulose in ethanol at about 30% w / w, and then dried in an oven at 60 ° C. for 3 hours to form etopriride. -Granules were obtained. The trimebutin granules, itopride granules, mannitol, sodium starch glycolate, colloidal silicon oxide and sodium stearyl fumarate were mixed in a plastic bag for 10 minutes, and then tableted with a single tablet press (Fette F1) to prepare tablets. It was.

Ingredient Example 9 Example 10 Trimebuterin 100 100 Itopride 50 50 Mannitol (Added during granulation) 27.25 27.25 Mannitol (added after mixing) 39 39 Citric acid 12.5 - Tartaric acid - 12.5 Hydroxypropyl cellulose
(Added when preparing trimerbutin-granule) 3 3 Hydroxypropyl cellulose
(Added during preparation of Itopride granules) 2 2 Sodium starch glycolate (added during granulation) 5 5 Sodium starch glycolate (added after mixing) 5 5 Colloidal Silicon Oxide 1.25 1.25 Sodium stearyl fumarate 5 5 Gross weight 250 250

Example 11-12.

Tablets were prepared according to the ingredients and contents in Table 4 below. In Table 4, the content of each component represents the weight per unit (mg). After trimembootin, cisapride, colloidal silicon acid, mannitol and sodium starch glycolate are mixed evenly at 500 rpm for 3 minutes in a high-speed stirring mixer (NMG-1L), hydroxypropyl cellulose is added to purified water. Wet granules were prepared using the binder solution obtained by dissolving at 27% w / w. The obtained wet granules were dried in an oven at 60 ° C. for 3 hours, and then mixed together with an organic acid, sodium starch glycolate, mannitol, and sodium stearyl fumarate in a plastic bag for 10 minutes, and tableted with a single tablet press (Fette F1). Prepared.

Ingredient Example 11 Example 12 Trimebuterin 100 100 Cisapride 10 10 Mannitol (Added during granulation) 30 30 Mannitol (added after mixing) 30 30 Suche mountain 10 - Glutamic acid - 10 Hydroxypropylcellulose 4 4 Sodium starch glycolate (added during granulation) 4 4 Sodium starch glycolate (added after mixing) 4 4 Colloidal Silicon Oxide 4 4 Sodium stearyl fumarate 4 4 Gross weight 200 200

Comparative Examples 1 and 2

Tablets were prepared according to the ingredients and contents in Table 5 below. In Table 5, the content of each component represents the weight per unit (mg). After trimmebutin, a prokinetic agent (mosaphride or cisapride), colloidal silicon, mannitol and sodium starch glycolate were evenly mixed at 500 rpm for 3 minutes in a high speed stirring mixer (NMG-1L), Wet granules were prepared using a binder obtained by dissolving oxypropylcellulose in about 27% w / w in purified water. The obtained wet granules were dried in an oven at 60 ° C. for 3 hours, and then mixed together with sodium starch glycolate, mannitol and sodium stearyl fumarate in a plastic bag for 10 minutes, and tableted with a single tablet press (Fette F1) to prepare a tablet. .

Ingredient Comparative Example 1 Comparative Example 2 Trimebuterin 100 100 Mosapride 5.29 - Cisapride - 10 Mannitol (Added during granulation) 37.71 35 Mannitol (added after mixing) 37 35 Hydroxypropylcellulose 4 4 Sodium starch glycolate (added during granulation) 4 4 Sodium starch glycolate (added during post-mixing) 4 4 Colloidal Silicon Oxide 4 4 Sodium stearyl fumarate 4 4 Gross weight 200 200

Comparative Example 3

Tablets were prepared according to the ingredients and contents in Table 6 below. In Table 6, the content of each component represents the weight per unit (mg). After trimebuterin, mannitol and sodium starch glycolate were evenly mixed for 3 minutes at 500 rpm in a high speed stirring mixer (NMG-1L), hydroxypropyl cellulose was dissolved in purified water at about 27% w / w. Using the obtained binder, wet granules were prepared, and then dried in an oven at 60 ° C. for 3 hours to obtain granules (trimebutin-granules). Separately, wet granules of etopriide were prepared using a binding solution obtained by dissolving hydroxypropyl cellulose in ethanol at about 30% w / w, and then dried in an oven at 60 ° C. for 3 hours to form etopriride. -Granules were obtained. The trimebutin granules, itopride granules, mannitol, sodium starch glycolate, colloidal silicon oxide and sodium stearyl fumarate were mixed in a plastic bag for 10 minutes, and then tableted with a single tablet press (Fette F1) to prepare tablets. It was.

Ingredient Comparative Example 3 Trimebuterin 100 Itopride 50 Mannitol (Added during granulation) 39.75 Mannitol (added after mixing) 39 Hydroxypropyl cellulose (added in the preparation of trimebutin granules) 3 Hydroxypropyl Cellulose (Added in Preparation of Itopride Granules) 2 Sodium starch glycolate (added during granulation) 5 Sodium starch glycolate (added after mixing) 5 Colloidal Silicon Oxide 1.25 Sodium stearyl fumarate 5 Gross weight 250

Test Example-Stability Test

The tablets obtained in Examples 1 to 12 and Comparative Examples 1 to 3 were subjected to stability tests for 2 weeks under severe conditions of 60 ° C./75% RH in sealed HDPE containers. The analogue of trimebutin was analyzed by HPLC using a C ₁₈ 250 × 4.6 mm column at 254 nm wavelength. The temperature of the column was 40 ° C., and the flow rate was 1.0 ml / min. The stability test results are as shown in FIGS.

Tablets containing trimebutin and mosapride that do not contain an organic acid produce 0.44% of the maximum individual softener of trimebuterin and 0.5% of the total softener after 2 weeks under severe conditions of 60 ° C / 75% RH. According to the invention, tablets containing organic acids exhibited high stability with a significant reduction in the maximum individual flexible and total analogues (see FIG. 1). In particular, the tablet prepared in Example 3 containing 20 mg of citric acid had the highest level of individual flexible substance of trimebutin at 0.07% after 2 weeks under severe conditions of 60 ° C./75% RH, resulting in the highest level of total flexible substance of 0.08%. Stability was shown.

Tablets containing trimebutin and itopride containing no organic acid produced 0.82% of the maximum individual softeners of trimebutin and 0.87% of the total analogues after 2 weeks under severe conditions of 60 ° C / 75% RH. According to the invention, tablets containing organic acids showed high stability, with a significant reduction in the maximum individual softeners and total softeners (see FIG. 2). In particular, even in tablets prepared separately from granules of the active ingredient (for example, tablets containing trimebutin and itoparate), it is very notable that the organic acid reduces the production of the tribbutin analog.

Tablets containing trimebutin and cisapride that do not contain an organic acid yield 0.54% of the maximum individual softener of trimebutin and 0.62% of the total softener after 2 weeks under severe conditions of 60 ° C / 75% RH. According to the invention, tablets containing organic acids exhibited high stability, with a significant reduction in the maximum individual softeners and total softeners (see FIG. 3).

Claims (8)

A pharmaceutical composition comprising trimebutin and a prokinetic agent as an active ingredient, comprising 1 to 25 parts by weight of an organic acid as a stabilizer based on 100 parts by weight of trimebutin, wherein the organic acid is citric acid, tartaric acid, or succinic acid. , Glutamic acid, aspartic acid, oxalic acid, malic acid, acetic acid, sorbic acid, ascorbic acid, and lactic acid. The pharmaceutical composition according to claim 1, wherein the content of the organic acid is in the range of 5 to 20 parts by weight based on 100 parts by weight of trimebbutin. delete The pharmaceutical composition according to claim 1 or 2, wherein the prokinetic agent is selected from the group consisting of mosapride or salts thereof, itopride or salts thereof, and cisapride or salts thereof. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of the trimebuterin and the prokinetic agent is in the range of 30: 1 to 2: 1. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is in the form of an oral solid preparation selected from the group consisting of powders, granules, pellets, tablets, and capsules. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is in tablet form. The method of claim 7, wherein mannitol, lactose, sucrose, erythritol, isomalt, maltitol, xylitol, sorbitol, trehalose, dextrose, microcrystalline cellulose, corn starch, potato starch, wheat starch, dextrin, methylcellulose, glucose And one or more excipients selected from the group consisting of fructose;
At least one binder selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and ethyl cellulose;
Disintegrating agents selected from the group consisting of sodium starch glycolate, corn starch, starch, crospovidone, croscarmellose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose; or
At least one glidant selected from the group consisting of silicon dioxide, colloidal silicon dioxide, magnesium stearate, talc, sodium stearyl fumarate, stearic acid, glyceryl behenate, and magnesium aluminometa silicate. Pharmaceutical composition.

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