KR20190064210A - Phamaceutical composition comprising Fimasartan - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating an angiotensin 2 receptor-related disease, comprising: fimasartan, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof; and a soluble polymer. The pharmaceutical composition according to the present invention increases a solubility of fimasartan and increases elution thereof, thereby improving bioavailability thereof.

Description

FIELD OF THE INVENTION The present invention relates to a phamaceutical composition comprising Fimasartan,

The present invention relates to fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; And a soluble polymer. The present invention also relates to a pharmaceutical composition for preventing or treating an angiotensin-2 receptor-related disease. The pharmaceutical compositions according to the present invention can increase solubility and increase bioavailability without the use of separate surfactants for solubilization.

In addition to the pharmacological activity of the drug in the pharmaceutical field, the physicochemical properties of the drug also play an important role in the efficacy of the drug.

For example, even if the pharmacological activity is excellent, if the drug is poorly soluble, it is difficult for the drug to exert its effect because the drug is not dissolved well when ingested orally. This is because the drug is difficult to dissolve because the drug is difficult to dissolve, and even if the drug is formulated, the drug dissolution rate between the preparations may be large and the dissolution rate may be low due to low solubility.

In addition, even when the pharmacological activity is excellent, when the bioavailability of the drug is low, a sufficient therapeutic effect can not be obtained because the concentration of the drug is low in the blood during oral administration. In order to obtain a sufficient therapeutic effect, Which may result in lowered convenience of medication or side effects.

Therefore, even if a drug has excellent pharmacological activity, many attempts have been made to improve the solubility of the drug and the bioavailability by oral administration in order to exhibit a sufficient effect.

Pimassartan is a hypertensive drug that is an angiotensin II receptor antagonist. Kanabra is available in three doses, 30, 60 and 120 mg under the trade name, and its main ingredient is Pimassartan potassium salt.

The Pimassartan has excellent pharmacological activity but has low solubility and has been used in the form of Pimassartan potassium salt for its improvement.

However, as has been pointed out earlier, excellent physico-chemical properties such as solubility have various advantages such as an increase in bioavailability. Solubilization techniques may also be used to improve bioavailability. Examples of the solubilization technique include a self-emulsifying drug delivery system (SEDDS) and a self-microemulsifying drug delivery system (SMEDDS) using a liposoluble base and a surfactant together. However, such a technique has a problem in that the size of the preparation is large, which may cause difficulty in swallowing, and side effects such as allergy may be caused by the use of a surfactant.

Thus, much effort has been made to improve the solubility and bioavailability of the potassium salts of potassium palmitate.

International Patent Publication No. WO999-055681

It is an object of the present invention to provide a pharmaceutical composition comprising fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; And a soluble polymer. The present invention also provides a pharmaceutical composition for preventing or treating angiotensin-2-receptor related diseases. The pharmaceutical compositions according to the present invention can increase solubility and increase bioavailability without the use of surfactants for solubilization.

The present invention relates to a fimasartan represented by the following general formula (1), a pharmaceutically acceptable salt, a hydrate or a solvate thereof; And a pharmaceutical composition for preventing or treating an angiotensin-2 receptor-related disease comprising a soluble polymer.

[Chemical Formula 1]

The pharmaceutical composition according to the present invention improves the bioavailability by increasing the solubility and increasing the elution of the Pimacartan. In the case of Pimassartan, the solubility as a poorly soluble drug was so low that formulation was not easy and bioavailability was not sufficiently high. Therefore, in order to exhibit a sufficient therapeutic effect through oral administration, the content of the phimassartan must be high in the preparation. As a result, the convenience of the patient's medication is deteriorated. In view of this, Has come. The pharmaceutical composition according to the present invention is excellent in physicochemical and pharmacological properties required for a drug such as solubility or bioavailability, exhibits physical properties superior to those of conventional Picalsartan potassium salt preparations, is more easily formulated, Can be improved. In addition, the solubility can be increased without the use of a surfactant, thereby reducing adverse effects derived from the surfactant.

In one embodiment of the present invention, the content of the soluble polymer may be 0.1 part by weight or more based on 1 part by weight of the palmasaltan, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. In another embodiment, the content of the soluble polymer may be at least 0.15 part by weight relative to 1 part by weight of the palmasaltan, its pharmaceutically acceptable salt, its hydrate or solvate thereof. Specifically, the composition may contain 0.1 to 10 parts by weight, more specifically 0.15 to 5 parts by weight, of the soluble polymer with respect to 1 part by weight of Pimassartan, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof .

In one embodiment of the present invention, the soluble polymer is a hydrophilic polymer.

In one embodiment of the present invention, the soluble polymer includes a unit having one or more functional groups selected from the group consisting of a hydroxyl group, an amine group and a carboxyl group.

In one embodiment of the present invention, the hydrophilic polymer is selected from the group consisting of hydroxyalkylmethylcellulose (e.g., hydroxypropylmethylcellulose), hydroxyalkylcellulose (e.g., hydroxypropylcellulose and hydroxyethylcellulose), hydroxyethylcellulose Carboxymethylcellulose, sodium carboxymethylcellulose, cellulose succinate (for example, hydroxypropylmethylcellulose acetate succinate), cellulose phthalate (for example, hydroxypropylmethylcellulose phthalate), polymethacrylate (Eudragit TM), polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates, polyvinyl alcohols, polyvinyl pyrrolidone, vinyl pyrrolidone / vinyl acetate aerials Chitosan, alginic acid and its salts, and dextrin. May be one kind or two or more kinds, but is not limited thereto.

In another embodiment, the soluble polymer is selected from the group consisting of hydroxyalkylmethylcellulose, polyvinylalcohol (PVA), hydroxyalkylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyhydroxyalkyl Methacrylate, cyclodextrin, and polymethacrylate. However, the present invention is not limited thereto.

In an embodiment of the present invention, the polymethacrylate is eudragit EPO.

In one embodiment of the present invention, the soluble polymer is selected from the group consisting of hydroxypropylmethylcellulose (HPMC) polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), and Eudragit EPO Species or two species.

In one embodiment of the present invention, the pharmaceutically acceptable salt of Pimassartan may mean a salt commonly used in the pharmaceutical industry.

In one embodiment of the present invention, the pharmaceutically acceptable salt of Pimassartan may mean a salt commonly used in the pharmaceutical industry.

In one embodiment of the invention, the pharmaceutically acceptable salts of the palmatalkane are selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonic acid salts, amino acid salts and amine salts. Specifically, inorganic ion salts prepared from calcium, potassium, sodium and magnesium, inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid and sulfuric acid and the like, acetic acid, trifluoroacetic acid, Wherein the organic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrobromic acid, hydrobromic acid, hydrobromic acid, hydrobromic acid, hydrobromic acid, hydrobromic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, tartaric acid, Benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, naphthalenedisulfonic acid, or naphthalenesulfonic acid, or a salt thereof with an organic acid salt such as malic acid, mandelic acid, mucic acid, Sulfonic acid salts prepared with sulfonic acid and the like, amino acid salts prepared with glycine, arginine, lysine and the like, and amino acid salts such as trimethylamine, meglumine, triethylamine, ammonia, pyridine, picoline, choline And the like. However, the types of the salts represented by the present invention are not limited by the listed salts.

The hydrates of the castazatins of the present invention or pharmaceutically acceptable salts thereof may contain stoichiometric or non-stoichiometric amounts of water that are bound by non-covalent intermolecular forces. The hydrate may contain at least 1 equivalent, i. E. 1 to 5 equivalents of water, based on 1 equivalent of Pimacartan or a salt thereof.

Solvates of the palmatalkine or pharmaceutically acceptable salts thereof of the present invention may include stoichiometric or non-stoichiometric amounts of solvent bound by intermolecular forces.

The hydrates of Pimassalta or a pharmaceutically acceptable salt thereof according to the present invention may be monohydrate, dihydrate, trihydrate, dihydrate, pentahydrate, etc., preferably trihydrate.

In one embodiment of the present invention, the Pimassartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, comprises a Pimassartan free base, Pimassartan potassium trihydrate, Pimassartan potassium monohydrate, and Pimassartan sodium salt Can be selected from the group. Specifically, the pharmaceutically acceptable salt of the palmatartan may be potassium palmitate or sodium palmitate sodium. Specifically, the pharmaceutically acceptable hydrate of the salt of Pimasartan or Pimacartan may be Pimassartan potassium monohydrate or Pimassalant calcium trihydrate.

In one embodiment of the invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable additive.

Such pharmacologically acceptable is physiologically acceptable and is generally administered to humans without the usual occurrence of gastrointestinal disorders, allergic reactions such as dizziness, or similar reactions, It can mean to use.

The pharmaceutically acceptable excipient may be a carrier, an excipient, an extender, an antioxidant, a buffer, a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a suspending agent, a surfactant and an antiseptic agent. For example, the additive may be selected from the group consisting of lactose, dextrose, calcium silicate, corn starch, sodium starch glycolate, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate , Calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, stearic acid, magnesium stearate, calcium stearate, gellan tin, Glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, or mixtures thereof. However, additives which may be included in the compositions according to the present invention are not limited to the above listed materials, but are merely illustrative and preferably include mannitol, dicalcium phosphate, sodium starch glycolate.

The pharmaceutical composition of the present invention may be formulated according to a conventional method, and may be prepared into an oral preparation or a parenteral administration preparation, and preferably it may be an oral administration preparation.

In the present invention, the pharmaceutical preparations for oral administration may be solid preparations such as tablets, pills, powders, granules and capsules, or liquid preparations such as suspensions, solutions, emulsions and syrups, More preferably, it may be a tablet.

In another embodiment of the invention, the pharmaceutical composition is a formulation of granules, capsules or tablets.

In the present invention, the above granules, capsules or tablets can be produced by a usual production method.

The pharmaceutical composition according to the present invention is excellent in physicochemical properties required for formulation such as processability as a formulation. Therefore, when formulating into the form of tablets or capsules, tablets or capsules with uniform pharmacological effects can be produced, and there is no problem that the pharmacological effect is lowered during the formulation process. Therefore, it is possible to economically produce an agent having a superior pharmacological effect and a uniform pharmacological effect.

In the present invention, the content of the additive contained in the pharmaceutical composition is not particularly limited and may be appropriately controlled within the range of contents used for usual formulation.

In the present invention, the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically), and the dose may be appropriately determined depending on the body weight, age, sex, The range may vary depending on the condition, diet, time of administration, method of administration, duration or interval of administration, excretion rate, sickness specificity, nature of the preparation, severity of the disease and the like.

In one embodiment of the present invention, the angiotensin II receptor-related disease is selected from the group consisting of stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, , Heart failure, and inflammation.

In the present invention, the pharmaceutical composition comprises the above-mentioned Pimacartan, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And a pharmacologically active substance other than the soluble polymer. The pharmacologically active substance may have the same pharmacological activity as the castazate, its pharmaceutically acceptable salt, its hydrate or solvate, or may have other pharmacological activity. The other pharmacologically active substances contained in the pharmaceutical composition may be selected from the group consisting of therapeutic agents for hyperlipidemia such as amlodipine, lercardipine, nicardipine, simvastatin, atorvastatin, pravastatin and rosuvastatin, metformin, hydrochlorothiazide, cytarglyptin, Or a pharmaceutically acceptable salt thereof, or a mixture of these, for the treatment of diabetes such as lipid, lignin, linagliptin, saxagliptin, teneligliptin, anagliptin, meloglyptin, twotogliptin, gemigliptin, More preferably amlodipine, rosuvastatin, atorvastatin, hydrochlorothiazide, cytarglyptin, bilagogliptin, linagliptin, and pharmaceutically acceptable salts thereof or a mixture thereof.

The pharmaceutical composition of the present invention can be used alone, for improving, alleviating, treating or preventing angiotensin II receptor-related progression, or in combination with methods using surgery, hormone therapy, drug therapy and biological response modifiers.

Fimasartan, a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the present invention; And a soluble polymer can be used to increase solubility without the use of a separate surfactant to improve bioavailability and reduce side effects from surfactants. .

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Example 1: Determination of the solubility of a pharmaceutical composition at pH 1.2

The mixture of potassium sorbate of potassium palmitate and the soluble polymer of the following Table 1 was mixed at a weight ratio of 1: 1, and the mixture was stirred at 500 rpm using a stirrer. After 24 hours, the solution was filtered through a 0.45 μm filter The results of analysis of the solubility of potassium palmitate using HPLC were shown in Table 1.

In the following, A is the potassium palate trihydrate, B is HPMC, C is PVA, D is HPC and E is Eudragit EPO.

[Table 1]

From the results of Table 1, it was confirmed that the pharmaceutical composition according to the present invention improved the solubility of Pimersartan potassium trihydrate at pH 1.2.

Example 2: Determination of solubility according to the content of soluble polymer at pH 1.2

The mixture of potassium sorbate potassium salt and HPMC was mixed at a weight ratio of 1: 0.15, 1: 0.3, 1: 0.5 and 1: 1, respectively, at pH 1.2 and 24 hours after stirring at room temperature (500 rpm) Was filtered through a 0.45 μm filter, and the solubility of potassium palate was analyzed by HPLC. The results are shown in Table 2.

In the following, A and B are the same as those defined in Example 1.

[Table 2]

From the results of Table 2, it was confirmed that the pharmaceutical composition according to the present invention improved the solubility of the Pimersartan potassium trihydrate at pH 1.2.

Example 3: Determination of the solubility of a pharmaceutical composition at pH 4.0

The mixture of Pimassartan potassium trihydrate and various kinds of soluble polymers was mixed at a weight ratio of 1: 1 and the mixture was stirred at 500 rpm using a stirrer. After 24 hours, the solution was filtered through a 0.45 μm filter Table 3 shows the results of analysis of the solubility of potassium palmitate using HPLC.

In the following, A, B, C, D and E are the same as those defined in Example 1.

[Table 3]

From the results of Table 3, it was confirmed that the pharmaceutical composition according to the present invention improved the solubility of Pimersartan potassium trihydrate at pH 4.0.

Example 4: Determination of solubility according to the content of soluble polymer at pH 1.2

The mixture of Pimassartan potassium salt and HPMC was mixed at a weight ratio of 1: 0.15, 1: 0.3, 1: 0.5 and 1: 1, respectively, to pH 4.0 and then stirred for 24 hours at room temperature using a stirrer (500 rpm) Was filtered through a 0.45 μm filter, and the solubility of potassium palate was analyzed by HPLC. The results are shown in Table 4.

In the following, A and B are the same as those defined in Example 1.

[Table 4]

From the results of Table 4, it was confirmed that the pharmaceutical composition according to the present invention improved the solubility of Pimersartan potassium trihydrate at pH 4.0.

Example 5: Determination of solubility according to soluble polymer content at pH 1.2 and pH 4.0

Pima saccharide and various kinds of soluble polymer were mixed in a weight ratio of 1: 1 at pH 1.2 and pH 4.0, and the mixture was stirred at room temperature (500 rpm) using a stirrer. After 24 hours, the solution was filtered through a 0.45 μm filter The results of solubility analysis using HPLC are shown in Tables 5 and 6, respectively.

B, C, D, and E are the same as those defined in Example 1, below.

[Table 5]

[Table 6]

As a result of the above Tables 5 and 6, it was confirmed that the solubility of the Pimacartan was improved in the pharmaceutical composition according to the present invention.

Example 6: Determination of solubility according to the content of soluble polymer at pH 1.2 and pH 4.0

Pimasartan sodium salt and various kinds of soluble polymers were mixed in a weight ratio of 1: 1 at pH 1.2 and pH 4.0, and the mixture was stirred at room temperature (500 rpm) using a stirrer. After 24 hours, the solution was filtered through a 0.45 μm filter After filtration, the solubility was analyzed by HPLC and the results are shown in Tables 7 and 8, respectively.

In the following, A is a sodium salt of Pimasartan and B, C, D and E are the same as defined in Example 1.

[Table 7]

[Table 8]

From the results of Tables 7 and 8, it was confirmed that the solubility of the sodium salt of Pimersacan sodium was improved in the pharmaceutical composition according to the present invention.

Comparative Example 1: Measurement of solubility according to the content of surfactant at pH 1.2 and pH 4.0

The mixture of Pimassartan potassium trihydrate and various kinds of surfactant was mixed at a weight ratio of 1: 0.5, and the mixture was stirred at 500 rpm using a stirrer. After 24 hours, the solution was filtered through a 0.45 μm filter, followed by HPLC The results are shown in Table 9. < tb > < TABLE >

In the following, A is the same as defined in Example 1.

[Table 9]

From the results of Table 9, it was confirmed that the solubility of the pharmaceutical composition according to the present invention under the same conditions as the above test was 0.089 mg / ml, which was significantly improved as compared with the solubility of the pharmaceutical composition containing the surfactant.

Therefore, the pharmaceutical composition according to the present invention can increase the solubility without using a separate surfactant, thereby increasing the bioavailability.

Claims (10)

Fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; And
Wherein the composition contains a soluble polymer. The method according to claim 1,
Wherein the content of the soluble polymer is at least 0.1 part by weight based on 1 part by weight of Pimacartan, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. The method according to claim 1,
Wherein the soluble polymer is a hydrophilic polymer. 2. A pharmaceutical composition for preventing or treating angiotensin-2-receptor related disease, wherein the soluble polymer is a hydrophilic polymer. The method according to claim 1,
Wherein the soluble polymer comprises a unit comprising one or more functional groups selected from the group consisting of a hydroxyl group, an amine group and a carboxy group; and a pharmaceutical composition for preventing or treating angiotensin-2 receptor related disease. The method according to claim 1,
The soluble polymer is selected from the group consisting of hydroxyalkylmethylcellulose, hydroxyalkylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, cellulose succinate, cellulose phthalate, polymethacrylate, polyhydroxyalkyl acrylate, polyhydroxyalkylmethacrylate , Polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, chitosan, alginic acid and salts thereof, and dextrin, which is at least one selected from the group consisting of angiotensin- A pharmaceutical composition for preventing or treating a receptor-related disease. The method according to claim 1,
Wherein the pharmaceutically acceptable salt of Pimassartan is selected from the group consisting of an inorganic ion salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt, and an amine salt; and a pharmaceutical composition for preventing or treating angiotensin- Composition. The method according to claim 1,
The pharmaceutical composition according to claim 1, wherein the Pimassartan, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof is selected from the group consisting of Pimassartan, Pimassartan potassium salt trihydrate and Pimassartan sodium salt. A pharmaceutical composition. The method according to claim 1,
Wherein the pharmaceutical composition is an orally administered preparation. The method according to claim 1,
Wherein said pharmaceutical composition is in the form of granules, capsules or tablets. The method according to claim 1,
The angiotensin-2 receptor-related disease is a group consisting of stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes mellitus, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, Or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the prevention or treatment of angiotensin-2 receptor related disease.