KR20240008179A - Pharmaceutical composition for preventing or treating inflammatory disease comprising sulglycotide as active ingredient having enhanced bioavailability and production method thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing sulglycotide with improved bioavailability as an active ingredient and a method for manufacturing the same. The pharmaceutical composition with improved bioavailability of sulglycotide of the present invention It is characterized by achieving pharmacological effects with only two doses per day while reducing the single dose.
In addition, tablets containing sulglycotide with improved bioavailability do not cause problems even when produced continuously in large quantities and have excellent stability even during long-term storage.

Description

Pharmaceutical composition for preventing or treating inflammatory diseases containing sulglycotide with improved bioavailability as an active ingredient and method for manufacturing the same

The present invention relates to a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing sulglycotide with improved bioavailability as an active ingredient, and a method for producing the same. In more detail, the purpose is to provide a pharmaceutical composition and a method of manufacturing the same that can achieve pharmacological effects only by administering twice a day while reducing the single dose of sulglycotide, which is effective in preventing or treating inflammatory diseases. Do it as

Sulglycotide is a sulfur polyester of glycopeptide extracted from the mucous membrane of the stomach or duodenum of pigs, and is used to protect the stomach and duodenum, prevent ulcers, and treat. In particular, sulglycotide is known as a drug used to treat gastric conditions associated with Helicobacter pylori (H. pylori) inflammation.

It has been reported that sulglycotide improves inflammation caused by H. pylori along with significant anti-ulcer activity in the gastrointestinal tract (J. Physiol. Pharmacol. 1999 Jun.; 50(2):197-210). Sulglycotide acts primarily by preventing somastatin-receptor binding and inhibiting the effects of lipopolysaccharide (LPS) produced by bacteria, which causes gastrin overproduction and acid secretion related to subsequent ulcer formation. It is known.

Sulglycotide has been conventionally developed and sold in the form of tablets, and is administered as one 200 mg tablet at a time, or one tablet three times a day (Gliptide Tablet 200 mg ^TM ).

However, despite the fact that patients with gastritis, duodenitis, gastric ulcer, and duodenal ulcer need to take it for a long period of time, a formulation that can be taken twice a day has not yet been developed, so it is recommended for patients who need to take sulglycotide preparations for a long period of time. Inconveniences occurred in guidance and compliance with medication.

As a sulglycotide-related technology, Korean Patent No. 10-1088779 relates to an oral liquid preparation containing sulglycotide as an active ingredient, and more specifically, sulglycotide and sulglycotide in an aqueous medium with an ionic strength of 0.01 to 2.00. An oral liquid formulation having a pH of 6 to 10 containing carbomer as a mucosal adhesive polymer is disclosed.

Korean Patent No. 10-1088781 includes sulglycotide as an active ingredient; and optionally a pH adjusting agent, and an oral liquid formulation having a pH of 6 to 10 is disclosed. These oral liquid preparations have a specific ionic strength and a specific pH range, and have excellent stability, so phase separation and discoloration do not occur even when stored for a long period of time. In addition, it is disclosed that the liquid formulation of the present invention is suitable for patients who have difficulty swallowing and has the advantage of increasing the patient's drug compliance.

Korean Patent No. 10-2270073 discloses a composition for preventing or treating inflammatory bowel disease containing sulglycotide as an active ingredient. Specifically, the group administered the active ingredient sulglycotide had a relatively lower colitis score compared to the control group that induced colitis, the degree of inflammation was low in optical images, and the colon of the control group was reduced by inflammation. It is disclosed that the colon length in the group administered the sulglycotide of the present invention is longer compared to the length.

Korean Patent No. 10-1433428 discloses a complex composition containing sulglycotide as an active ingredient and at least one H2 receptor antagonist selected from the group consisting of ranitidine, famotidine, nizatidine, cimetidine, laputidine, etc. It is starting. Specifically, a multilayer tablet having two or more overlapping layers with different release profiles comprising a first layer containing sulglycotide and a second layer allowing immediate release of the H2 receptor antagonist is prepared, It is disclosed that the stability of the drug is improved and the treatment rate of gastric ulcers etc. is improved by improving the absorption of the active ingredient into the body.

Korean Patent No. 10-1820519 discloses the use of sulglycotide to promote skin wound healing, and a composition for external use containing it, and Korean Patent No. 10-1820519 discloses sulglycotide or a pharmaceutically acceptable salt thereof. Disclosed is a pharmaceutical composition for preventing or treating dry eye syndrome containing.

However, the above documents do not disclose a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing sulglycotide with improved bioavailability as an active ingredient in a dosage form that can be taken twice a day.

Korean Patent No. 10-1088779 Korean Patent No. 10-1088781 Korean Patent No. 10-2270073 Korean Patent No. 10-1433428 Korean Patent No. 10-1820519

J. Physiol. Pharmacol. 1999 Jun.; 50(2):197-210

The purpose of the present invention is to reduce the single dose of sulglycotide, which is effective in preventing or treating inflammatory diseases, while achieving pharmacological effects with only twice daily administration, thereby significantly improving patient compliance. To provide a pharmaceutical composition.

Additionally, an object of the present invention is to provide a method for producing a pharmaceutical composition whose bioavailability does not suffer even when produced continuously in large quantities.

In order to achieve the above object, a pharmaceutical composition for preventing or treating inflammatory diseases for oral administration twice a day containing sulglycotide or a pharmaceutically acceptable salt thereof as an active ingredient is provided.

Additionally, mixing sulglycotide or a pharmaceutically acceptable salt thereof with a disintegrant auxiliary agent, a fluidizing agent, a disintegrating agent, a filler, and a lubricant; Preparing tablets by compressing the mixture into tablets; and coating the tablets; A method for producing a pharmaceutical composition for preventing or treating inflammatory diseases is provided.

The group administered the preparation (150 mg/tablet) containing 150 mg of sulglycotide, the active ingredient of the present invention, twice a day, took the preparation containing 200 mg of sulglycotide (200 mg/tablet, control drug) twice a day. As a result of comparison with when administered 3 times a day, the group administered 2 times a day a formulation containing 150 mg of sulglycotide (150 mg/tablet) disintegrated quickly in the stomach, increasing the speed of drug efficacy. Compared to administering a preparation containing 200 mg of Tide (200 mg/tablet, reference medicine) three times a day, it is applied sufficiently with a smaller amount of active ingredient and a smaller number of administrations, effectively preventing gastric damage (gastritis or gastric ulcer) and duodenum damage. It can be useful as a medicine that helps prevent, treat, and/or improve diseases (such as duodenitis or duodenal ulcer), and can improve patient compliance as it can be taken twice a day.

In addition, the manufacturing method of the present invention has the advantage that bioavailability does not occur even when produced continuously in large quantities.

The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within the scope apparent to those skilled in the art from the contents described below.

Figure 1 is a graph showing the effect of a formulation containing 150 mg of sulglycotide of the present invention on damage to the gastric mucosa in a gastric ulcer animal model.
Figure 2 is a graph showing the effect of a formulation containing 150 mg of sulglycotide of the present invention on the expression of a gastric mucosal inflammatory gene (tumor necrosis factor-α; TNF-α) in a gastric ulcer animal model (beagle dog).

Hereinafter, this specification will be described in more detail.

This is explained in detail as follows. The terms used in this specification are general terms that are currently widely used as much as possible while considering the function in the present invention, but this may vary depending on the intention or precedent of a person skilled in the art, the emergence of new technology, etc. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, rather than simply the name of the term.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the technical field to which the present invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and unless clearly defined in the present application, should not be interpreted in an ideal or excessively formal sense. No.

The numerical range includes the values defined in the range above. Every maximum numerical limit given throughout this specification includes all lower numerical limits as if the lower numerical limit were explicitly written out. Every minimum numerical limit given throughout this specification includes every higher numerical limit as if such higher numerical limit was clearly written. All numerical limits given throughout this specification will include all better numerical ranges within the broader numerical range, as if the narrower numerical limits were clearly written.

Hereinafter, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Additionally, the scope of the present invention cannot be considered limited by the specific description set forth below.

Expressions such as “comprising” used in this specification are understood as open-ended terms that imply the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence containing the expression. It has to be.

The inventors of the present invention were researching and developing a pharmaceutical composition for inflammatory diseases containing sulglycotide as an active ingredient, which can show an improvement effect on inflammatory diseases while reducing the single dose and reducing the number of administrations. When 150 mg/tablet of the active ingredient, sulglycotide, was administered twice a day, compared to when 200 mg/tablet of sulglycotide was administered three times a day, 150 mg/tablet of sulglycotide was 1 When administered twice a day, it disintegrates quickly in the stomach, increasing the speed of drug efficacy. It can be sufficiently applied with a smaller amount of active ingredient and a smaller number of administrations than when 200 mg/tablet of sulglycotide is administered three times a day. The present invention was completed by confirming that it effectively helps prevent, treat, and/or improve stomach damage (gastritis or gastric ulcer) and duodenal damage (duodenitis or duodenal ulcer).

Hereinafter, the present invention will be described in detail.

Pharmaceutical composition for preventing or treating inflammatory diseases containing sulglycotide with improved bioavailability as an active ingredient

The present invention discloses the following pharmaceutical composition.

Specifically, the present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases for oral administration twice a day, comprising sulglycotide or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, the term "sulglycotide" has the structure of the following chemical formula. It is a sulphuric polyester of glycopeptide extracted from pig duodenal mucosa and has affinity for mucoprotein. It combines with mucin of gastric mucus to form a complex, increasing the viscosity of gastric mucus to strengthen the defense ability of the stomach and duodenal mucosa, and prevents self-digestion of the stomach wall by combining with pepsin to inactivate it. do.

In the present invention, sulglycotide, the active ingredient of the pharmaceutical composition, is a drug that is not absorbed through the gastrointestinal tract and exhibits pharmacological effects by reversibly adsorbing to the stomach wall.

[Chemical formula]

In the present invention, sulglycotide can be used in non-salt form or in the form of a pharmaceutically acceptable salt of sulglycotide, which can be appropriately prepared by a person skilled in the art.

In the present invention, the term “active ingredient” refers to a substance or group of substances expected to directly or indirectly express the efficacy and effect of the composition through inherent pharmacological action (including herbal medicines, etc. whose pharmacologically active ingredients, etc. are unknown). means that it contains the main ingredient.

In the present invention, the term “pharmaceutically acceptable” means a substance that is physiologically acceptable and does not cause side effects that cannot be used as a medicine, usually due to gastrointestinal disorders, allergic reactions such as dizziness, or similar reactions when administered to humans. The term “salt” refers to an acid addition salt formed by a pharmaceutically acceptable free acid. Therefore, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, for example, any organic acid selected from oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid; Alternatively, it is preferably in the form of an acid addition salt formed with any inorganic acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, but is not limited thereto.

In the present invention, the term “prevention” refers to any action that suppresses or delays the onset of an inflammatory disease by administering the pharmaceutical composition according to the present invention, and the term “treatment” refers to any action that inhibits or delays the onset of an inflammatory disease by administering the pharmaceutical composition according to the present invention. It refers to any action that improves or beneficially changes the symptoms of an individual suspected of having an inflammatory disease or developing an inflammatory disease.

In the present invention, the pharmaceutical composition is for oral administration twice a day, and if the drug administration method is changed to twice a day through formulation development, there is an advantage that patients' medication compliance can be greatly improved. (Conventionally, 3 times a day)

In the present invention, sulglycotide or a pharmaceutically acceptable salt thereof may be included in an amount of 20 to 60% by weight, preferably 35 to 45% by weight, based on the total weight of the pharmaceutical composition. It is not limited to this.

In the present invention, the pharmaceutical composition may further include one or more selected from the group consisting of disintegrant auxiliaries, fluidizers, disintegrants, fillers and lubricants in addition to the active ingredient sulglycotide or a pharmaceutically acceptable salt thereof. , but is not limited to this.

In the present invention, the disintegration aid may be one or more selected from the group consisting of sodium bicarbonate, sodium carbonate, calcium carbonate, calcium bicarbonate, potassium carbonate, potassium bicarbonate, and ammonium bicarbonate, and is preferably sodium bicarbonate or It may be calcium bicarbonate, but is not limited thereto. In the present invention, the disintegrant auxiliary agent may be included in an amount of 5 to 30% by weight, preferably 9 to 15% by weight, based on the total weight of the pharmaceutical composition, but is not limited thereto.

In the present invention, the fluidizing agent may be at least one selected from the group consisting of colloidal silicon dioxide, magnesium aluminometasilicate (Neusilin US2 ^TM ), magnesium stearate, and talc, and is preferred. It may be a combination of colloidal silicon dioxide (Colloidol Silicon Dioxide) and magnesium aluminometasilicate (Neusilin US2 ^TM ), but is not limited thereto. In the present invention, the fluidizing agent may be included in an amount of 1 to 5% by weight, preferably 2 to 3% by weight, based on the total weight of the pharmaceutical composition, but is not limited thereto.

In the present invention, the disintegrant is crospovidone (e.g. Kollidon CL ^TM ), croscarmellose sodium (e.g. AC-Di-sol ^TM ), low-lipidity hydroxypropyl cellulose (e.g. L-HPC ^TM ), and starch glycol. It may be one or more types selected from the group consisting of sodium acid (Starch 1500 ^TM ), preferably crospovidone (e.g. Kollidon CL ^TM ) or croscarmellose sodium (e.g. AC-Di-sol ^TM ). It is not limited to this. In the present invention, the disintegrant may be included in an amount of 1 to 10% by weight, preferably 5 to 8% by weight, based on the total weight of the pharmaceutical composition, but is not limited thereto.

In the present invention, the filler may be one or more selected from the group consisting of lactose, lactose hydrate (lactose hydrate), modified lactose (e.g. Starlac ^TM ), dextrose, sucrose, starch, and microcrystalline cellulose. , preferably modified lactose (e.g. Starlac ^TM ) or lactose hydrate (lactose hydrate), but is not limited thereto. In the present invention, the filler may be included in an amount of 25 to 50% by weight, preferably 32 to 38% by weight, based on the total weight of the pharmaceutical composition, but is not limited thereto.

In the present invention, the lubricant may be one or more selected from the group consisting of magnesium stearate and talc, preferably a combination of magnesium stearate and talc, but is not limited thereto. In the present invention, the lubricant may be included in an amount of 1 to 6% by weight, preferably 3.5 to 4.5% by weight, based on the total weight of the pharmaceutical composition, but is not limited thereto.

Specifically, the pharmaceutical composition contains 20 to 60% by weight of the active ingredient sulglycotide or a pharmaceutically acceptable salt thereof, 5 to 30% by weight of a disintegrant auxiliary, 1 to 5% by weight of a fluidizing agent, and 1 to 10% by weight of a disintegrant. , may contain 25 to 50% by weight of filler and 1 to 6% by weight of lubricant, and preferably the pharmaceutical composition contains 35 to 45% by weight of sulglycotide or a pharmaceutically acceptable salt thereof, and 9 to 15% by weight of a disintegrant. % by weight, it may include 2 to 3 wt% of a fluidizing agent, 5 to 8 wt% of a disintegrant, 32 to 38 wt% of a filler, and 3.5 to 4.5 wt% of a lubricant. By containing the content within the above range, it disintegrates quickly compared to conventional commercial products, increasing the speed of drug efficacy, and is sufficiently applied even with a lower content of active ingredient and fewer administration times than conventional commercial products, effectively reducing stomach damage (gastritis or gastric ulcer) and It can help prevent, treat and/or improve duodenal damage (duodenitis or duodenal ulcer), and can be continuously produced in large quantities by improving fluidity.

In the present invention, the pharmaceutical composition may further include a coating agent, and especially when the formulation of the pharmaceutical composition is a tablet, it may further include a coating layer as the final outer layer. The coating base may use pharmaceutically acceptable polymers such as cellulose derivatives, polyvinylpyrrolidone, and polyvinyl alcohol as coating materials. Specifically, the cellulose derivatives are for example from the group consisting of methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxyethyl cellulose, ethyl cellulose acetate phthalate and cellulose acetate. It may be one or more components, and preferably, after first coating with a coating solution containing hydroxypropyl cellulose, a coating base based on polyvinyl alcohol (e.g. Colorcon Opadry ^TM 200F) can be used. In the present invention, the coating agent may be included in an amount of 1 to 5% by weight, preferably 3 to 5% by weight, based on the total weight of the pharmaceutical composition, but is not limited thereto.

In the present invention, the pharmaceutical composition may be a solid oral preparation, but is not limited thereto.

In the present invention, the solid oral preparation may be a tablet, film-coated tablet, capsule, or powder, but is not limited thereto.

Specifically, the pharmaceutical composition according to the present invention may be a film-coated tablet, wherein the composition includes 35 to 45% by weight of sulglycotide or a pharmaceutically acceptable salt thereof, 9 to 15% by weight of a disintegrant, and a fluidizing agent. It may include 2 to 3% by weight, 5 to 8% by weight of disintegrant, 32 to 38% by weight of filler, 3.5 to 4.5% by weight of lubricant, and 1 to 5% by weight of coating agent. By containing the content within the above range, it disintegrates quickly compared to conventional commercial products, increasing the speed of drug efficacy, and is sufficiently applied even with a lower content of active ingredient and fewer administration times than conventional commercial products, effectively reducing stomach damage (gastritis or gastric ulcer) and It can help prevent, treat and/or improve duodenal damage (duodenitis or duodenal ulcer), and can be continuously produced in large quantities by improving fluidity.

In the present invention, the pharmaceutical composition may contain 150 mg of sulglycotide. Specifically, compared to the existing commercially available product, Gliptide tablets (200 mg ^TM ), the content of the active ingredient, sulglycotide, is reduced, but it is applied sufficiently, effectively treating stomach damage (gastritis or gastric ulcer) and duodenal damage (duodenitis or duodenal ulcer). It can be useful as a medicine to help prevent, treat and/or improve.

In the present invention, the inflammatory disease may be an inflammatory gastrointestinal disease, specifically an upper gastrointestinal disease, and may be one or more selected from the group consisting of gastritis, duodenitis, gastric ulcer, and duodenal ulcer.

At this time, in the present invention, the term “gastritis” refers to a state in which inflammation or edema of the gastric mucosa occurs. The gastritis may include both acute gastritis and chronic gastritis.

In the present invention, the term “duodenitis” refers to the general term for inflammation occurring in the duodenum.

In the present invention, the term “gastric ulcer” refers to a case in which gastric mucosal damage progresses more severely than gastritis, and the ulcer progresses to the muscle layer due to histologically necrotic defects in the mucosa. At this time, the gastric ulcer may include both acute gastric ulcer and chronic gastric ulcer.

In the present invention, the term “duodenal ulcer” refers to a condition in which the duodenal mucosa is damaged and histologically necrotic mucosal defects occur below the submucosal layer.

The inflammatory gastrointestinal disease may be acute gastritis or gastric ulcer caused by excessive drinking, NSAID use, allergies, etc.

The inflammatory gastrointestinal disease may be chronic gastritis or gastric ulcer caused by aging, stress, long-term drug use, Helicobacter pylori infection, autoimmune mechanism, incorrect eating habits, etc.

Sulglycotide or a pharmaceutically acceptable salt thereof of the present invention contains factors that affect inflammatory responses such as NO (nitric oxide), IL-6 (interleukin-6), TNF-α (tumor necrosis factor alpha) or ICAM ( Inflammatory diseases can be prevented and treated by inhibiting one or more of the production of intercellular adhesion molecules.

Method for producing a pharmaceutical composition for preventing or treating inflammatory diseases containing sulglycotide with improved bioavailability as an active ingredient

The present invention discloses a method for producing the following pharmaceutical combination preparation.

Specifically, the present invention includes the steps of mixing sulglycotide or a pharmaceutically acceptable salt thereof with a disintegrant auxiliary agent, a fluidizing agent, a disintegrant, a filler, and a lubricant; Preparing tablets by compressing the mixture into tablets; and coating the tablets; It relates to a method of producing a pharmaceutical composition for preventing or treating inflammatory diseases, including.

In the present invention, the method for preparing a pharmaceutical composition includes preparing a primary mixture by mixing sulicotide or a pharmaceutically acceptable salt thereof with a fluidizing agent and a disintegrant auxiliary; Preparing a secondary mixture by mixing a filler and a disintegrant into the primary mixture; Preparing a final mixture by mixing a lubricant with the secondary mixture; Preparing tablets by compressing the final mixture into tablets; and coating the tablet.

At this time, the fluidity of the tablet can be improved by using an appropriate amount of fluidizing agent and disintegrant auxiliary, and the disintegration time can be shortened by using an appropriate amount of disintegrant.

The information regarding the pharmaceutical composition described above can be applied to all methods of manufacturing the pharmaceutical composition, unless they contradict each other.

A method for preventing or treating an inflammatory disease comprising administering a therapeutically effective amount of a pharmaceutical composition for the prevention or treatment of an inflammatory disease containing sulglycotide with improved bioavailability as an active ingredient to a subject in need thereof.

The present invention provides a method for preventing inflammatory diseases, comprising administering a therapeutically effective amount of a pharmaceutical composition for preventing or treating inflammatory diseases containing sulglycotide with improved bioavailability as an active ingredient to a subject in need thereof. Or providing a treatment method.

The prevention or treatment method of the present invention not only treats the disease itself before the symptoms appear, but also inhibits or avoids the symptoms by administering a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing the sulglycotide as an active ingredient. It also includes In the management of disease, the prophylactic or therapeutic dosage of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dosage will vary depending on the age, weight, and response of the individual patient. A suitable dosage regimen can be easily selected by one of ordinary skill in the art taking these factors into account. In addition, the method for preventing or treating inflammatory diseases of the present invention includes a pharmaceutical composition for preventing or treating inflammatory diseases containing the sulglycotide as an active ingredient, as well as a therapeutically effective amount of an additional active agent helpful in treating the disease. It may further include the administration of, and the additional active agent may exhibit a synergistic or auxiliary effect with the pharmaceutical composition for preventing or treating inflammatory diseases containing the sulglycotide as an active ingredient.

Specifically, the method for preventing or treating inflammatory diseases includes administering a pharmaceutical composition for preventing or treating inflammatory diseases containing sulglycotide as an active ingredient to a subject in need twice a day, and once. When administered, 150 mg of sulglycotide is administered, with a total of 300 mg administered per day.

In the present invention, the subject may be a mammal, including humans, and mammals, including humans, include mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, and rats.

Use of a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing sulglycotide as an active ingredient for the manufacture of a medicine with an effect for the prevention or treatment of inflammatory diseases

The present invention provides the use of a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing sulglycotide as an active ingredient for the production of a drug having an effect for the prevention or treatment of inflammatory diseases.

Pharmaceutical compositions for the prevention or treatment of inflammatory diseases containing the above sulglycotide as an active ingredient for the manufacture of drugs can be mixed with acceptable adjuvants, diluents, carriers, etc., and are manufactured as a complex preparation with other active agents. The active ingredients may have a synergistic effect.

Use of a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing sulglycotide as an active ingredient for the manufacture of a drug having a preventive or treatment effect on inflammatory diseases

The present invention provides the use of a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing sulglycotide as an active ingredient for the manufacture of a drug having a preventive or treatment effect on inflammatory diseases.

Matters mentioned in the pharmaceutical composition of the present invention, its preparation method, prevention or treatment method, and use are equally applicable unless they contradict each other.

Hereinafter, the present invention will be described in more detail using examples. These examples are only for illustrating the present invention in more detail, and it is obvious to those skilled in the art that the scope of the present invention is not limited thereto.

Example

Film-coated tablets containing 150 mg/tablet of sulglycotide according to Examples 1 to 9 were prepared according to the following manufacturing method with ingredients and contents according to the compositions shown in Tables 1 to 5 below.

Purpose of mixing Raw material name Example 1 Example 2 mg/tablet weight% mg/tablet weight% chief ingredient sulglycotide 150 37.3 150 37.5 Disintegrant aid sodium bicarbonate 40 9.9 40 10 Calcium Bicarbonate - - - - Fluidizing agent Colloidal silicon oxide 5 1.25 2 0.5 magnesium
Aluminometasilicate
(Neusilin ^US2TM ) 7 1.75 6 1.5 disintegrant Crospovidone
(Kollidon ^CLTM ) 20 5 32 8 Croscarmellose Sodium
(AC-Di- ^solTM ) - - - - filler Lactose (Starlac ^TM ) 150 37.3 140 35 lactose hydrate - - - - lubricant talc 7 1.75 7 1.75 Magnesium stearate 7 1.75 7 1.75 Coating mechanism Opadry White 200F 16 4 16 4 sum 402 100 400 100

Purpose of mixing Raw material name Example 3 Example 4 mg/tablet weight% mg/tablet weight% chief ingredient sulglycotide 150 37.5 150 37.5 Disintegrant aid sodium bicarbonate 60 15 60 15 Calcium Bicarbonate - - - - Fluidizing agent Colloidal silicon oxide 2 0.5 2 0.5 magnesium
Aluminometasilicate
(Neusilin ^US2TM ) 6 1.5 6 1.5 disintegrant Crospovidone
(Kollidon ^CLTM ) 20 5 20 5 Croscarmellose Sodium
(AC-Di- ^solTM ) - - - - filler Lactose (Starlac ^TM ) 132 33 128 32 lactose hydrate - - - - lubricant talc 7 1.75 9 2.25 Magnesium stearate 7 1.75 9 2.25 Coating mechanism Opadry White 200F 16 4 16 4 sum 400 100 400 100

Purpose of mixing Raw material name Example 5 Example 6 mg/tablet weight% mg/tablet weight% chief ingredient sulglycotide 150 37.5 150 37.5 Disintegrant aid sodium bicarbonate 40 10 - - Calcium Bicarbonate - - 40 10 Fluidizing agent Colloidal silicon oxide 2 0.5 2 0.5 magnesium
Aluminometasilicate
(Neusilin ^US2TM ) 6 1.5 6 1.5 disintegrant Crospovidone
(Kollidon ^CLTM ) 20 5 20 5 Croscarmellose Sodium
(AC-Di- ^solTM ) - - - - filler Lactose (Starlac ^TM ) 152 38 152 38 lactose hydrate - - - - lubricant talc 7 1.75 7 1.75 Magnesium stearate 7 1.75 7 1.75 Coating mechanism Opadry White 200F 16 4 16 4 sum 400 100 400 100

Purpose of mixing Raw material name Example 7 Example 8 mg/tablet weight% mg/tablet weight% chief ingredient sulglycotide 150 37.5 150 37.5 Disintegration aid sodium bicarbonate 40 10 40 10 Calcium Bicarbonate - - - - Fluidizing agent Colloidal silicon oxide 2 0.5 2 0.5 magnesium
Aluminometasilicate
(Neusilin ^US2TM ) 6 1.5 6 1.5 disintegrant Crospovidone
(Kollidon ^CLTM ) - - 20 5 Croscarmellose Sodium
(AC-Di- ^solTM ) 20 5 - - filler Lactose (Starlac ^TM ) 152 38 - - lactose hydrate - - 152 38 lubricant talc 7 1.75 7 1.75 Magnesium stearate 7 1.75 7 1.75 Coating mechanism Opadry White 200F 16 4 16 4 sum 400 100 400 100

Purpose of mixing Raw material name Example 9 mg/tablet weight% chief ingredient sulglycotide 150 37.5 Disintegrant aid sodium bicarbonate 40 10 Calcium Bicarbonate - - Fluidizing agent Colloidal silicon oxide 2 0.5 magnesium
Aluminometasilicate
(Neusilin ^US2TM ) 6 1.5 disintegrant Crospovidone
(Kollidon ^CLTM ) 20 5 Croscarmellose Sodium
(AC-Di- ^solTM ) - - filler Lactose (Starlac ^TM ) 152 38 lactose hydrate - - lubricant talc 9 2.25 Magnesium stearate 5 1.25 Coating mechanism Opadry White 200F 16 4 sum 400 100

After weighing each ingredient into 1 tablet, the main ingredient, sulglycotide, is first mixed by passing the disintegrant and fluidizing agent through a 30 mesh sieve, and then the disintegrant and filler are passed through a 30 mesh sieve and sieved for the second mixing. After mixing, talc and magnesium stearate as lubricants were passed through a 40 mesh sieve and finally mixed. This mixture was compressed into tablets using a direct compression method to prepare bare tablets.

Thereafter, the coating base was dissolved in purified water to prepare a film coating solution, and then the film coating solution was film-coated on the prepared uncoated tablet to prepare a film-coated tablet.

Comparative example

Comparative Example 1

Film-coated tablets containing 150 mg/tablet of sulglycotide were prepared according to the following manufacturing method with the ingredients and contents according to the composition shown in Table 6 below.

Purpose of mixing Raw material name Comparative Example 1 mg/tablet weight% chief ingredient sulglycotide 150 37.5 Disintegrant aid sodium bicarbonate 40 10 Calcium Bicarbonate - - Fluidizing agent Colloidal silicon oxide - - magnesium
Aluminometasilicate
(Neusilin ^US2TM ) - - disintegrant Crospovidone
(Kollidon ^CLTM ) 20 5 Croscarmellose Sodium
(AC-Di- ^solTM ) - - filler Lactose (Starlac ^TM ) 160 40 lactose hydrate - - lubricant talc 7 1.75 Magnesium stearate 7 1.75 Coating mechanism Opadry White 200F 16 4 sum 400 100

After weighing each ingredient into 1 tablet, the main ingredient, sulglycotide, and the disintegrant auxiliary, sodium bicarbonate, are first mixed by passing them through a 30 mesh sieve, and then the disintegrant, crospovidone, and the filler, lactose, are sieved through a 30 mesh sieve. After passing through a sieve and second mixing, lubricants such as talc and magnesium stearate were passed through a 40 mesh sieve and finally mixed. This mixture was compressed into tablets using a direct compression method to prepare bare tablets.

Thereafter, the coating base was dissolved in purified water to prepare a film coating solution, and then the film coating solution was film-coated on the prepared uncoated tablet to prepare a film-coated tablet.

Comparative Example 2

Film-coated tablets containing 150 mg/tablet of sulglycotide were prepared according to the following manufacturing method with the ingredients and contents according to the composition shown in Table 7 below.

Purpose of mixing Raw material name Comparative Example 2 mg/tablet weight% chief ingredient sulglycotide 150 37.5 Disintegrant aid sodium bicarbonate - - Calcium Bicarbonate 40 10 Fluidizing agent Colloidal silicon oxide One 0.25 magnesium
Aluminometasilicate
(Neusilin ^US2TM ) One 0.25 disintegrant Crospovidone
(Kollidon ^CLTM ) 20 5 Croscarmellose Sodium
(AC-Di- ^solTM ) - - filler Lactose (Starlac ^TM ) 158 39.5 lactose hydrate - - lubricant talc 7 1.75 Magnesium stearate 7 1.75 Coating mechanism Opadry White 200F 16 4 sum 400 100

After weighing each ingredient into 1 tablet, the main ingredient, sulglycotide, the disintegration aid, calcium bicarbonate, and the fluidizing agents, colloidal silicon oxide and magnesium aluminum metasilicate, are sieved through a 30 mesh sieve and mixed for the first time. Crospovidone as a release agent and lactose as a filler were passed through a 30 mesh sieve and sieved for secondary mixing, and then talc and magnesium stearate as lubricants were passed through a 40 mesh sieve and sieved for final mixing. This mixture was compressed into tablets using a direct compression method to prepare bare tablets.

Thereafter, the coating base was dissolved in purified water to prepare a film coating solution, and then the film coating solution was film-coated on the prepared uncoated tablet to prepare a film-coated tablet.

Comparative Example 3

Film-coated tablets containing 150 mg/tablet of sulglycotide were prepared according to the following manufacturing method using the ingredients and contents according to the composition shown in Table 8 below.

Purpose of mixing Raw material name Comparative Example 3 mg/tablet weight% chief ingredient sulglycotide 150 37.5 Disintegrant aid sodium bicarbonate 40 10 Calcium Bicarbonate - - Fluidizing agent Colloidal silicon oxide 2 0.5 magnesium
Aluminometasilicate
(Neusilin ^US2TM ) 6 1.5 disintegrant Crospovidone
(Kollidon ^CLTM ) - - Croscarmellose Sodium
(AC-Di- ^solTM ) 5 1.25 filler Lactose (Starlac ^TM ) 167 41.75 lactose hydrate - - lubricant talc 7 1.75 Magnesium stearate 7 1.75 Coating mechanism Opadry White 200F 16 4 sum 400 100

After weighing each ingredient into 1 tablet, the main ingredient, sulglycotide, the disintegration aid, sodium bicarbonate, and the fluidizing agents, colloidal silicon oxide and magnesium aluminum metasilicate, are passed through a 30 mesh sieve and mixed for the first time. Croscarmellose sodium as a solution and lactose as a filler were passed through a 30 mesh sieve for secondary mixing, and then talc and magnesium stearate as lubricants were passed through a 40 mesh sieve for final mixing. This mixture was compressed into tablets using a direct compression method to prepare bare tablets.

Thereafter, the coating base was dissolved in purified water to prepare a film coating solution, and then the film coating solution was film-coated on the prepared uncoated tablet to prepare a film-coated tablet.

Comparative Example 4

Film-coated tablets containing 150 mg/tablet of sulglycotide were prepared according to the following manufacturing method with the ingredients and contents according to the composition shown in Table 9 below.

Purpose of mixing Raw material name Comparative Example 4 mg/tablet weight% chief ingredient sulglycotide 150 37.5 Disintegrant aid sodium bicarbonate - - Calcium Bicarbonate - - Fluidizing agent Colloidal silicon oxide 2 0.5 magnesium
Aluminometasilicate
(Neusilin ^US2TM ) 6 1.5 disintegrant Crospovidone
(Kollidon ^CLTM ) 25 6.25 Croscarmellose Sodium
(AC-Di- ^solTM ) - - filler Lactose (Starlac ^TM ) - - lactose hydrate 187 46.75 lubricant talc 7 1.75 Magnesium stearate 7 1.75 Coating mechanism Opadry White 200F 16 4 sum 400 100

After weighing each ingredient into 1 tablet, the main ingredient, sulglycotide, and the fluidizing agents, colloidal silicon oxide and magnesium aluminum metasilicate, are first mixed by passing them through a 30 mesh sieve, and then the disintegrant, crospovidone, and the filler, The lactose hydrate was passed through a 30 mesh sieve and sieved for secondary mixing, and then the lubricants, talc and magnesium stearate, were passed through a 40 mesh sieve and sieved for final mixing. This mixture was compressed into tablets using a direct compression method to prepare bare tablets.

Thereafter, the coating base was dissolved in purified water to prepare a film coating solution, and then the film coating solution was film-coated on the prepared uncoated tablet to prepare a film-coated tablet.

control drug

As a reference drug, an existing commercial product, Glipty Tablet 200 mg ^TM , was used.

(Glipty Tablet 200 mg ^TM : Sulglycotide 200 mg/tablet as active ingredient, and additives include Opadry AMB White OY-B-28920, colloidal silicon oxide, lactose hydrate, glycerol palmitostearate, and microcrystalline cellulose. film coated tablet)

Experiment example

Experimental Example 1: Confirmation of the effect of improving gastritis and gastric ulcer in a beagle dog gastric ulcer (stomach damage) model

<Test group settings and drug administration conditions>

Test group: Set as 3 groups with 5 animals in each group.

- Gastric ulcer-inducing group (G1)

- Group administered film-coated tablets of Example 5 (G2)

- Control drug (Gliptide 200 mg tablet ^TM ) administration group (G3)

The gastric ulcer-inducing group (G1) was not administered anything, and the film-coated tablet administered group (G2) of Example 5 and the control drug (Gliptide 200 mg tablet ^TM ) administered group (G3) were treated for 15 days under the following conditions. Drug was administered.

- Group administered film-coated tablets of Example 5 (G2): Repeated oral administration twice a day for 15 days on an empty stomach.

- Control drug (Gliptide 200 mg tablet ^TM ) administration group (G3): Repeated oral administration 3 times a day for 15 days on an empty stomach

In this experiment, in order to review the ethical and efficient management and scientific feasibility of animal experiments, the experiment was conducted with the approval of ChemOn's Laboratory Animal Management Committee (review number: 20-D741).

Experiment method

(1) Measurement of stomach damage

To confirm whether the film-coated tablet prepared according to Example 5 showed improved bioavailability compared to the control drug and was effective in improving gastritis, it was used in beagle dogs (approximately 7 to 10 kg, place of purchase: Woojeong BSC Co., Ltd. (Gwanggyo-ro, Yeongtong-gu, Suwon-si, Gyeonggi-do) 145 Next Generation Convergence Technology Research Institute Building B, 3rd floor)) The experiment was conducted on a gastric ulcer (stomach damage) model.

To induce acute gastric ulcer (stomach damage) in an animal model (beagle dog), first classify them into three groups (G1-G3) as above, and then use endoscopic forceps the day before administering the drug (G2 and G3). It caused an acute gastric ulcer.

Specifically, for acute gastric ulcer induction, beagle dogs were fasted for about 18 hours before inducing gastric ulcer, general anesthesia was administered with alfaxalone (0.02 mg/kg) on the acute gastric ulcer induction day (DAY 0), and isoflurane was administered. ) and anesthetized the beagle dog. After anesthesia, gastric mucosa was removed to a size of 2 mm in diameter and 2 mm in depth using biopsy forceps to cause damage to the gastric mucosa.

Then, gastroscopy (CV) was performed every 3 days (DAY 0, DAY 3, DAY 6, DAY 9, DAY 12, DAY 15) for 15 days starting from the day of inducing acute gastric ulcer (stomach damage) in an animal model (Beagle dog). The presence or absence of gastric ulcer improvement effect in each experimental group was evaluated by confirming the degree of stomach damage through imaging using -150 model, Olympus, Japan.

At this time, the degree of damage to the gastric mucosa was graded from Grade 0 to Grade 10, and the standards are shown in Table 10 below.

division Estimated factor Grade 0 normal gastric mucosa
(Normal stomach wall) Grade 2 Scarring similar to normal gastric mucosa
(A scar with similar to normal gastric wall) Grade 4 Mild erosion with redness
(Insignificant erosion with flare) Grade 6 Severe erosion with redness and swelling
(Severe erosion with flare and swelling) Grade 8 Stomach ulcer with blood spots
(A gastric ulcer with a blood spot) Grade 10 Hemorrhagic gastric lesions
(A bleeding gastric lesion)

(2) Cytokine quantitative polymerase chain reaction (qPCR) analysis

To investigate the expression level of inflammatory disease-related factors at the transcriptional level in an acute gastric ulcer animal model (beagle dog), tissue from the lesion area was extracted on DAY 0 (day of induction), DAY 3, and 15. The extracted tissues were stored in an ultra-low temperature freezer at -80°C until just before qPCR (quantitive polymerase chain reaction) analysis, and tumor necrosis factor-alpha (TNF-α), which plays an important role in immune-mediated inflammatory diseases, was analyzed. did. For DNA extraction, the tissue was dissolved using Proteinase K (intron, cat no. IBS-BP029), and DNA was extracted using a DNA extraction kit (intron, cat no. 17231). qPCR uses custom designed primers for TNF-α. qPCR uses custom designed primers: forward 5′- GAG CCG ACG TGC CAA TG-3′ (SEQ ID NO: 1), reverse 5′- CAA CCC ATC TGA CGG CAC TA-3. ′ (SEQ ID NO: 2) was used. qPCR was performed using SsoAdvanced ^TM Universal SYBR ^® Green reagent and on Bio-Rad's CFX384 ^TM Optics Moduleq qPCR instrument. β-actin was used as a house-keeping control, forward 5′- ATG ACG ATA TCG CTG CGC TT-3′ (SEQ ID NO: 3), reverse 5′- TCG TCC CAC TTG GTG ACG AT- 3′ (SEQ ID NO: 4) primer was used (see Table 11). The obtained values for target gene expression were normalized and quantified to β-actin and compared with the gastric ulcer-induced group (G1) samples.

At this time, the TNF-α measurement value was calculated by applying Student's t-test, a statistical analysis, and on DAY 0, it was assumed that ± standard error was applied to 1.00, the average value of the gastric mucosal ulcer area, and on DAY 3 and DAY 15. The measured values are expressed relatively.

gene primer sequence number TNF-α F: 5′- GAG CCG ACG TGC CAA TG-3′ SEQ ID NO: 1 R: 5′- CAA CCC ATC TGA CGG CAC TA-3′ SEQ ID NO: 2 β-actin F: 5′- ATG ACG ATA TCG CTG CGC TT-3′ SEQ ID NO: 3 R: 5′- TCG TCC CAC TTG GTG ACG AT-3′ SEQ ID NO: 4

result

(1) Result of measuring the degree of damage above

As a result of measuring the ulcerated portion of the gastric mucosa through a gastroscopy, the degree of damage to the gastric mucosa in all groups (G1-G3) was observed to be Grade 10 on DAY 0. In the film-coated tablet-administered group (G2) of Example 5, a statistically significant reduction in gastric damage was observed on DAY 9, 12, and 15 compared to the gastric ulcer-induced group (G1) (i.e., the film-coated tablet-administered group of Example 5 (G2) is statistically significant compared to the gastric ulcer-induced group (G1), and in Figure 1, * means p<0.05 and ** means p<0.01). In the control drug (Glipty Tablet 200 mg ^TM ) administration group (G3), a statistically significant reduction in gastric damage was observed on DAY 6, 9, and 15 compared to the gastric ulcer induction group (G1), and there was a tendency for gastric damage to decrease on DAY 12. was observed (see Table 12, Figure 1).

No statistical difference was observed in the degree of damage to the gastric mucosa in the group (G2) administered with the film-coated tablets of Example 5 compared to the group (G3) administered with the control drug (Gliptide 200 mg tablet ^TM ). The tablet administration group (G2) was confirmed to have the same or higher gastric ulcer treatment effect as the control drug (Gliptide 200 mg tablet ^TM ) administration group (G3).

Based on the above results, the film-coated tablet administration group (G2) of Example 5 is effective in preventing, treating, and/or improving gastritis and gastric ulcers, and is equivalent to or better than the control drug (Gliptide 200 mg tablet ^TM ) administration group (G3). It was confirmed that the above prevention, treatment and/or improvement effects exist.

stomach mucosa group DAY O DAY 3 DAY 6 DAY 9 DAY 12 DAY 15 Gastric ulcer-induced group (G1) 10.00±0.00 8.00±0.00 8.00±0.00 7.60±0.40 6.40±0.40 4.80±0.49 Group administered film-coated tablets of Example 5 (G2) 10.00±0.00 8.00±0.00 7.20±0.49 5.60±0.40 ^** 4.80±0.49 ^* 2.40±0.40 ^** Control drug administration group (G3) 10.00±0.00 8.00±0.00 6.40±0.40 ^* 5.60±0.40 ^** 5.20±0.49 2.80±0.49 ^*

(2) Cytokine quantitative polymerase chain reaction (qPCR) analysis results

Additionally, the results of qPCR analysis using the above tissue are as follows.

As a result of measuring TNF-α in the gastric mucosal ulcer area, the group administered the film-coated tablet of Example 5 (G2) and the group administered the control drug (Gliptide 200 mg tablet ^TM ) (G3) were compared with the gastric ulcer-inducing group (G1) on DAY 3. A tendency to decrease values was observed, and a statistically significant decrease was observed on DAY 15 (that is, the film-coated tablet administration group (G2) of Example 5 was statistically significant compared to the gastric ulcer-induced group (G1) , in Figure 1 * means p<0.05, ** means p<0.01). In addition, a statistically significant decrease was observed in the film-coated tablet administration group (G2) of Example 5 compared to the control drug (Glipty tablet 200 mg ^TM ) administration group (G3) (see Table 13 and Figure 2).

stomach mucosa group DAY 0 DAY 3 DAY 15 Gastric ulcer-induced group (G1) 1.00±0.10 10.77±0.88 5.27±0.84 Group administered film-coated tablets of Example 5 (G2) 1.00±0.12 8.32±1.02 ⁺ 1.00±0.11 ^** Control drug administration group (G3) 1.00±0.17 8.75±0.93 2.82±0.59 ^*

(In Table 13 above, the measured results are expressed as mean ± standard error, and Student's t-test is applied for statistical analysis.

*: Statistically significant compared to G1 group, p<0.05

**: Statistically significant compared to G1 group, p<0.01

+: Statistically significant comparing G2 group and G3 group, P<0.05)

According to the above, when the film-coated tablet of Example 5 was repeatedly orally administered twice a day for 15 days to a beagle dog that had caused a gastric ulcer (stomach damage), gastric damage was improved and TNF-α decreased according to gastroscopy observation. was observed. Therefore, the film-coated tablet administration group (G2) of Example 5 is judged to be effective in preventing, treating, and/or improving gastritis and gastric ulcers, and is equivalent to or effective in the control drug (Glipty Tablet 200 mg ^TM ) administration group (G3). It was found to have an equal or greater therapeutic effect.

Therefore, the film-coated tablet administration group (G2) of Example 5, in which 150 mg/tablet of sulglycotide was administered twice a day, was rapidly disintegrated in the stomach, thereby increasing the rate of drug efficacy, and 200 mg/tablet of sulglycotide was administered twice a day. Compared to the control drug (Gliptide 200 mg tablet ^TM ) administered three times a day, the content of the active ingredient is small compared to the administration group (G3) (the daily dose of sulglycotide can be reduced from 600 mg to 300 mg) ) and a small number of doses (the number of doses per day can be reduced from 3 to 2) is sufficiently absorbed into the upper gastrointestinal tract wall, effectively preventing, treating and/or treating gastritis, duodenitis, gastric ulcer and/or duodenal ulcer. It can be usefully used as a medicine that helps with improvement, and in the case of the preparation containing sulicotide according to the present invention, it can be taken twice a day, confirming that it can be widely used as a preparation with improved patient compliance. did.

Experimental Example 2: Liquidity Evaluation

Experiment method

The angle of repose was measured to confirm the fluidity of the film-coated tablets according to Examples 1 to 9 and the film-coated tablets according to Comparative Examples 1 and 2.

The angle of repose was measured using an angle of repose measuring device (GTB, ERWEKA GmbH) on the manufactured bare well, and the results are shown in angle (°) in Table 14.

result

In the case of manufacturing tablets including sulglycotide by direct compression, sulglycotide is a sulfur polyester of glycopeptide extracted from the mucous membrane of the stomach or duodenum of pigs and has sufficient flowability simply by using an excipient for direct compression. Although it is not easy to obtain, Examples 1 to 9 above were prepared by mixing colloidal silicon dioxide (Colloidol Silicon Dioxide) and magnesium aluminometasilicate (Neusilin US2 ^TM ) as a fluidizing agent to produce tablets containing sulglucotide by direct compression. When manufactured, it was possible to manufacture tablets for direct compression with good fluidity of the mixture (angle of repose 35° or less).

However, Comparative Examples 1 and 2 contained no or 0.5% by weight of a fluidizing agent, and when tablets containing sulglucotide were manufactured by direct compression, the fluidity of the mixture (angle of repose 46° or more) was poor, making it a tablet for direct compression. Manufacturing showed undesirable results.

division Angle of repose (unit: °) Example 1 29 Example 2 35 Example 3 33 Example 4 32 Example 5 30 Example 6 30 Example 7 34 Example 8 32 Example 9 31 Comparative Example 1 57 Comparative Example 2 46

Experimental Example 3: Disintegration time evaluation

Experiment method

The film-coated tablets according to Examples 1 to 9 and the film-coated tablets according to Comparative Examples 3 and 4 were tested according to the disintegration test method (37 ± 2°C, pH 1.2, disintegration test solution 1 of the Korean Pharmacopoeia) among the general test methods of the Korean Pharmacopoeia. A disintegration test was conducted, and the results are shown in Table 15 below.

result

The film-coated tablets of Examples 1 to 9 according to the present invention contain 5 to 8% by weight of crospovidone (e.g., Kollidon CL ^TM ) or croscarmellose sodium (e.g., AC-Di-sol ^TM ) as a disintegrant, and carbonic acid as a disintegrator. Tablets are manufactured by direct pressing with a mixture containing 9 to 15% by weight of sodium hydrogen or calcium bicarbonate and 3 to 5% by weight of magnesium stearate and talc as a lubricant. Film-coated tablets coated with a coating base disintegrate within 30 minutes. It represents time.

However, the film-coated tablet according to Comparative Example 3 contains as little as 1.25% by weight of disintegrant and 10% by weight of disintegrant, and the film-coated tablet according to Comparative Example 4 contains 6.25% by weight of disintegrant and does not contain a disintegrant. However, the film-coated tablets according to Comparative Examples 3 and 4 showed a significantly slower disintegration time (more than 35 minutes) than the film-coated tablets according to Examples 1 to 9.

From the above results, the film-coated tablets of Examples 1 to 9 exhibit pharmacological action by quickly disintegrating and reversibly adsorbing to the stomach wall due to the optimal combination of the type and content of the disintegrant and the type and content of the disintegrant auxiliary, thereby treating upper gastrointestinal diseases. It was confirmed that it can be effective in preventing, treating, and/or improving gastritis, duodenitis, gastric ulcer, and duodenal ulcer.

In particular, the disintegration time of the control drug (Glipty Tablet 200 mg ^TM ) was measured at 40 minutes, and it was confirmed that the disintegration time was significantly delayed compared to the film-coated tablets of Examples 1 to 9 according to the present invention, and the control drug ( Gliptie tablets 200 mg ^TM ) are effective in preventing, treating, and/or improving upper gastrointestinal diseases such as gastritis, duodenitis, gastric ulcer, and duodenal ulcer due to slow reversible adsorption to the stomach wall compared to the film-coated tablets according to Examples 1 to 9. You can expect it to be bad.

Therefore, this suggests that the film-coated tablets according to Examples 1 to 9 can sufficiently replace the reference drug (Glipty Tablet 200 mg ^TM ).

division Disintegration time (unit: minutes) Example 1 23 Example 2 21 Example 3 23 Example 4 25 Example 5 22 Example 6 25 Example 7 26 Example 8 25 Example 9 25 Comparative Example 3 37 Comparative Example 4 35 control drug 40

As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (15)

A pharmaceutical composition for preventing or treating inflammatory diseases for oral administration twice a day, comprising sulglycotide or a pharmaceutically acceptable salt thereof as an active ingredient. According to paragraph 1,
The active ingredient sulglycotide or a pharmaceutically acceptable salt thereof; and
A pharmaceutical composition for the prevention or treatment of inflammatory diseases, characterized in that it further comprises one or more selected from the group consisting of disintegrants, fluidizers, disintegrants, fillers and lubricants. According to paragraph 2,
A pharmaceutical composition for the prevention or treatment of inflammatory diseases, wherein the disintegrant aid is one or more selected from the group consisting of sodium bicarbonate, sodium carbonate, calcium carbonate, calcium bicarbonate, potassium carbonate, potassium bicarbonate, and ammonium bicarbonate. According to paragraph 2,
The fluidizing agent is a pharmaceutical for the prevention or treatment of inflammatory diseases, characterized in that it is one or more selected from the group consisting of colloidal silicon dioxide, magnesium aluminometasilicate, magnesium stearate, and talc. Composition. According to paragraph 2,
A pharmaceutical composition for the prevention or treatment of inflammatory diseases, wherein the disintegrant is at least one selected from the group consisting of crospovidone, croscarmellose sodium, low-density hydroxypropyl cellulose, and sodium starch glycolate. According to paragraph 2,
A pharmaceutical composition for the prevention or treatment of inflammatory diseases, wherein the filler is one or more selected from the group consisting of lactose, lactose hydrate (lactose hydrate), modified lactose, dextrose, sucrose, starch, and microcrystalline cellulose. . According to paragraph 2,
A pharmaceutical composition for preventing or treating inflammatory diseases, wherein the lubricant is at least one selected from the group consisting of magnesium stearate and talc. According to paragraph 2,
The pharmaceutical composition contains 20 to 60% by weight of the active ingredient sulglycotide or a pharmaceutically acceptable salt thereof, 5 to 30% by weight of a disintegrant, 1 to 5% by weight of a fluidizing agent, 1 to 10% by weight of a disintegrant, and 25% filler. A pharmaceutical composition for preventing or treating inflammatory diseases, comprising from 50% by weight to 50% by weight and 1 to 6% by weight of a lubricant. According to paragraph 1,
A pharmaceutical composition for preventing or treating inflammatory diseases, further comprising a coating agent. According to paragraph 1,
A pharmaceutical composition for preventing or treating inflammatory diseases, wherein the coating base is at least one selected from the group consisting of cellulose derivatives, polyvinylpyrrolidone, and polyvinyl alcohol. According to paragraph 1,
A pharmaceutical composition for preventing or treating inflammatory diseases, characterized in that the pharmaceutical composition is a solid oral preparation. According to clause 11,
A pharmaceutical composition for preventing or treating inflammatory diseases, wherein the solid oral preparation is a tablet, film-coated tablet, capsule, or powder. According to paragraph 1,
A pharmaceutical composition for preventing or treating inflammatory diseases, comprising a dose of 150 mg of sulglycotide. According to paragraph 1,
A pharmaceutical composition for preventing or treating inflammatory diseases, wherein the inflammatory disease is at least one selected from the group consisting of gastritis, duodenitis, gastric ulcer, and duodenal ulcer. Mixing sulglycotide or a pharmaceutically acceptable salt thereof with a disintegrant aid, a fluidizing agent, a disintegrant, a filler, and a lubricant;
Preparing tablets by compressing the mixture into tablets; and
Coating the tablet;
A method for producing a pharmaceutical composition for preventing or treating inflammatory diseases, comprising a.