KR102201396B1 - Phamaceutical composition comprising Fimasartan - Google Patents

Abstract

The present invention relates to fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; And it relates to a pharmaceutical composition for the prevention or treatment of angiotensin-2-receptor-related diseases comprising a soluble polymer. The pharmaceutical composition according to the present invention increases the solubility of fimasartan and increases dissolution, thereby improving bioavailability.

Description

Pharmaceutical composition comprising Fimasartan {Phamaceutical composition comprising Fimasartan}

The present invention relates to fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; And it relates to a pharmaceutical composition for preventing or treating diseases related to angiotensin-2-receptor comprising a soluble polymer. The pharmaceutical composition according to the present invention can increase solubility and increase bioavailability without using a separate surfactant for solubilization.

In the pharmaceutical field, in addition to the pharmacological activity of the drug, the physicochemical properties of the drug also have an important influence on the effect of the drug.

For example, no matter how excellent the pharmacological activity is, if the drug is poorly soluble, the drug does not dissolve well when taken orally, making it difficult for the drug to exert its effect. This is because the dissolution of the drug is difficult, so that the formulation is not easy, and even if the drug is formulated, the dispersion of the drug dissolution rate between the formulations may be large due to low solubility, and a problem of low dissolution rate may occur.

In addition, no matter how excellent the pharmacological activity is, if the bioavailability of the drug is low, the concentration of the drug in the blood is low when administered orally, so that sufficient therapeutic effect cannot be obtained.In order to obtain sufficient therapeutic effect, the amount of drug administered orally is not As a result, there may be a problem that the convenience of taking medication is reduced or side effects are accompanied.

Therefore, in order to exert a sufficient effect even for a drug having excellent pharmacological activity, a number of methods have been attempted to improve the solubility of the drug and the bioavailability according to oral administration.

Fimasartan is a high blood pressure drug, an angiotensin II receptor antagonist, and is commercially available in three doses of 30, 60, and 120 mg under the brand name of Canabra, and its main component is fimasartan potassium salt.

The fimasartan has excellent pharmacological activity, but has low solubility, so it has been used in the form of fimasartan potassium salt for its improvement.

However, as previously mentioned, when physicochemical properties such as solubility are excellent, there are various advantages such as an increase in bioavailability. In order to improve the above bioavailability, solubilization technology is sometimes used. As an example of the solubilization technology, a fat-soluble base and a surfactant are used together, for example, SEDDS (Self-Emulsifying Drug Delivery System), SMEDDS (self-microemulsifying drug delivery system). However, this technique has a problem in that the size of the formulation is increased, which may cause difficulty swallowing, and side effects such as allergy may be caused by the use of a surfactant.

Therefore, many efforts have been made to improve the solubility and bioavailability of the potassium fimasartan salt.

International Patent Publication No. WO1999-055681

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

The present invention is fimasartan represented by the following formula (1), a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; And it provides a pharmaceutical composition for the prevention or treatment of angiotensin-2-receptor-related diseases comprising a soluble polymer.

[Formula 1]

The pharmaceutical composition according to the present invention increases the solubility of fimasartan and increases dissolution, thereby improving bioavailability. In the case of fimasartan, as a poorly soluble drug, its solubility is low, making it difficult to formulate and its bioavailability was not sufficiently high. Therefore, in order to exhibit sufficient therapeutic effect through oral administration, fimasartan must be contained in a high content in the formulation, and as a result, there was a problem that the patient's medication convenience was deteriorated, and in consideration of these points, fimasartan potassium salt was used. Has been. The pharmaceutical composition according to the present invention has excellent physicochemical and pharmacological properties required for a drug such as solubility or bioavailability, and exhibits superior physical properties than the conventional fimasartan potassium salt formulation, making it easier to formulate, and convenience for patient taking. Can be improved. In addition, the solubility can be increased without the use of a surfactant, and side effects derived from the surfactant can be reduced.

In one embodiment of the present invention, the content of the soluble polymer may be 0.1 parts by weight or more based on 1 part by weight of fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof. In another embodiment, the content of the soluble polymer may be 0.15 parts by weight or more based on 1 part by weight of fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof. Specifically, the composition contains fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof in an amount of 0.1 parts by weight to 10 parts by weight, more specifically 0.15 parts by weight to 5 parts by weight or less, Can include.

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 containing one or two or more functional groups selected from the group consisting of a hydroxy group, an amine group, and a carboxyl group.

In one embodiment of the present invention, the hydrophilic polymer is hydroxyalkylmethyl cellulose (eg, hydroxypropylmethylcellulose), hydroxyalkylcellulose (eg, hydroxypropylcellulose and hiroxyethylcellulose), Carboxymethylcellulose, sodium carboxymethyl cellulose, cellulose succinate (e.g., hydroxypropylmethylcellulose acetate succinate), cellulose phthalate (e.g., hydroxypropylmethylcellulose phthalate), polymethacrylate (e.g. , Eudragit (registered trademark)), polyhydroxyalkylacrylate, polyhydroxyalkylmethacrylate, polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate public It may be one or two or more selected from the group consisting of coalescence, chitosan, alginic acid, and salts thereof, and dextrin, but is not limited thereto.

In another embodiment, the soluble polymer is hydroxyalkylmethylcellulose, polyvinyl alcohol (PVA), hydroxyalkylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyhydroxyalkyl It may be one or two or more selected from the group consisting of methacrylate, cyclodextrin, and polymethacrylate, but 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 1 selected from the group consisting of hydroxypropylmethylcellulose (HPMC) polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), and Eudragit EPO. It may be a species or two.

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

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

In one embodiment of the present invention, the pharmaceutically acceptable salt of fimasartan is selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonate salts, amino acid salts and amine salts. Specifically, inorganic salts made of calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid and sulfuric acid, inorganic acid salts, acetic acid, trifluoroacetic acid, citric acid, maleic acid , Succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, tartaric acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid , Mandelic acid, muxic acid, pamoic acid, pantothenic acid, organic acid salt, methanesulfonic acid, ethanesulfonic acid, ethane disulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, naphthalenedisulfonic acid or naphthalene There are sulfonates prepared with sulfonic acid, amino acid salts prepared with glycine, arginine, lysine, etc., and amine salts prepared with trimethylamine, meglumine, triethylamine, ammonia, pyridine, picoline, choline, etc. The types of salts meant in the present invention are not limited by these listed salts.

The hydrate of fimasartan or its pharmaceutically acceptable salts of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. The hydrate may contain 1 equivalent or more, that is, 1 to 5 equivalents of water based on 1 equivalent of fimasartan or a salt thereof.

The solvate of fimasartan or a pharmaceutically acceptable salt thereof of the present invention may include a stoichiometric or non-stoichiometric amount of a solvent bonded by an intermolecular force.

The hydrate of fimasartan or a pharmaceutically acceptable salt thereof according to the present invention may be monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, and the like, preferably trihydrate.

In one embodiment of the present invention, the fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof is composed of fimasartan free base, fimasartan potassium trihydrate, fimasartan potassium monohydrate and fimasartan sodium salt. Can be selected from the group. Specifically, the pharmaceutically acceptable salt of fimasartan may be fimasartan potassium or fimasartan sodium. Specifically, the pharmaceutically acceptable hydrate of fimasartan or a salt of fimasartan may be fimasartan potassium monohydrate or fimasartan calcium trihydrate.

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

The pharmaceutically acceptable means physiologically acceptable and when administered to a human, usually does not cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions, and when manufacturing a pharmaceutical composition by a person having ordinary knowledge in the field, It can mean to use.

The pharmaceutically acceptable additives may be carriers, excipients, bulking agents, antioxidants, buffers, fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, suspending agents, surfactants and preservatives. For example, the additives are lactose, dextrose, calcium silicate, corn starch, starch sodium glycolate, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate , Dicalcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, stearic acid, magnesium stearate, calcium stearate, gelatin, mineral oil , Saline solution, aqueous glucose solution, a similar sugar solution, alcohol, glycol, ether (eg, polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, or a mixture thereof. However, additives that may be included in the composition according to the present invention are not limited to the above-listed substances, and these are only examples, and preferably mannitol, dicalcium phosphate, and sodium starch glycolate.

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

In the present invention, the formulation for oral administration may be a solid formulation such as a tablet, a pill, a powder, a granule, or a capsule, or a liquid formulation such as a suspension, a liquid formulation, an emulsion, or a syrup, preferably a solid formulation. It may be the first, more preferably a tablet.

In another embodiment of the present invention, the pharmaceutical composition is in the form of granules, capsules or tablets.

In the present invention, the granules, capsules or tablets can be prepared by a conventional manufacturing method.

The pharmaceutical composition according to the present invention is excellent in physicochemical properties required for pharmaceuticals such as processability as a formulation. Therefore, when formulated in a form such as a tablet or capsule, a tablet or capsule having a uniform pharmacological effect can be produced, and there is no problem that the pharmacological effect is deteriorated during the formulation process. Therefore, it is possible to economically produce a formulation having excellent medicinal efficacy and uniform pharmacological effect.

In the present invention, the content of the additive included in the pharmaceutical composition is not particularly limited, and may be appropriately adjusted within the content range used for conventional formulation.

In the present invention, the pharmaceutical composition may be administered orally or parenterally (for example, intravenous, subcutaneous, intraperitoneal or topically applied), and the dosage may be the patient's weight, age, sex, and health. The range may vary depending on the condition, diet, administration time, administration method, administration period or interval, excretion rate, constitutional specificity, the nature of the formulation, and the severity of the disease.

In one embodiment of the present invention, the angiotensin II receptor-related diseases are stroke, stroke, cerebral hemorrhage, cerebral infarction, Alzheimer's, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension. , It is for the prevention or treatment of one or more diseases selected from the group consisting of heart failure and inflammation.

In the present invention, the pharmaceutical composition comprises the fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; And other pharmacologically active substances in addition to the soluble polymer. The pharmacologically active substance may have the same pharmacological activity as the fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or may have other pharmacological activities. Other pharmacologically active substances included in the pharmaceutical composition are amlodipine, lercardipine, nicardipine, simvastatin, atorvastatin, pravastatin, rosuvastatin, and other hyperlipidemia treatment agents, metformin, hydrochlorothiazide, sitagliptin, vildagle. Diabetes treatment agents such as liptin, linagliptin, saxagliptin, teneligliptin, anagliptin, melogliptin, dutogliptin, gemigliptin, etc. may be pharmaceutically acceptable salts or mixtures thereof, More preferably, amlodipine, rosuvastatin, atorvastatin, hydrochlorothiazide, sitagliptin, vildagliptin, linagliptin, and may be a pharmaceutically acceptable salt thereof or a mixture thereof.

The pharmaceutical composition of the present invention may be used alone or in combination with surgery, hormone therapy, drug therapy, and methods of using a biological response modifier to improve, alleviate, treat or prevent angiotensin II receptor-related pain.

Fimasartan, a pharmaceutically acceptable salt, hydrate or solvate thereof according to the present invention; And the angiotensin-2-receptor-related disease prevention or treatment pharmaceutical composition comprising a soluble polymer increases solubility without the use of a separate surfactant, thereby improving bioavailability and reducing side effects from surfactants. .

Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

Example 1: Measurement of solubility of pharmaceutical compositions at pH 1.2

After mixing the potassium fimasartan trihydrate and the soluble polymer of Table 1 at a weight ratio of 1:1 at pH1.2, after 24 hours while stirring at room temperature using a stirrer (500 rpm), the solution was taken and filtered through a 0.45 μm filter. After analyzing the solubility of fimasartan potassium using HPLC, the results are shown in Table 1.

Hereinafter, A is fimasartan potassium 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 solubility of fimasartan potassium trihydrate was improved in the pharmaceutical composition according to the present invention at pH 1.2.

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

After adding fimasartan potassium salt and HPMC in a weight ratio of 1:0.15, 1:0.3, 1:0.5, and 1:1, respectively, at pH1.2, solution after 24 hours while stirring at room temperature (500rpm) using a stirrer. Table 2 shows the results of analyzing the solubility of fimasartan potassium using HPLC after filtration through a 0.45 μm filter.

Hereinafter, 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 solubility of fimasartan potassium trihydrate is improved in the pharmaceutical composition according to the present invention at pH 1.2.

Example 3: Measurement of solubility of pharmaceutical compositions at pH 4.0

After adding fimasartan potassium trihydrate and various kinds of soluble polymers in a weight ratio of 1:1 at pH4.0, after 24 hours while stirring at room temperature using a stirrer (500 rpm), the solution was taken and filtered through a 0.45 μm filter. Table 3 shows the results of analyzing the solubility of fimasartan potassium using HPLC.

Hereinafter, 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 solubility of fimasartan potassium trihydrate was improved in the pharmaceutical composition according to the present invention at pH 4.0.

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

After adding fimasartan potassium salt and HPMC in a weight ratio of 1:0.15, 1:0.3, 1:0.5, and 1:1, respectively, at pH 4.0, solution after 24 hours while stirring at room temperature (500 rpm) using a stirrer. Table 4 shows the results of analyzing the solubility of fimasartan potassium using HPLC after filtration through a 0.45 μm filter.

Hereinafter, 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 solubility of fimasartan potassium trihydrate was improved in the pharmaceutical composition according to the present invention at pH 4.0.

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

Fimasartan and various types of soluble polymers are mixed at a weight ratio of 1:1 at pH 1.2 and pH 4.0 and added. After 24 hours while stirring at room temperature using a stirrer (500 rpm), the solution is taken and filtered through a 0.45 μm filter. The results of analyzing the solubility using HPLC are shown in Tables 5 and 6, respectively.

Hereinafter, A is fimasartan, and B, C, D, and E are the same as those defined in Example 1.

[Table 5]

[Table 6]

From the results of Tables 5 and 6, it was confirmed that the solubility of fimasartan was improved in the pharmaceutical composition according to the present invention.

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

Fimasartan sodium salt and various kinds of soluble polymers are mixed in a weight ratio of 1:1 at pH 1.2 and pH 4.0, and then stirred at room temperature using a stirrer (500 rpm), and after 24 hours, the solution is taken with a 0.45 μm filter. The results of analyzing the solubility using HPLC after filtration are shown in Tables 7 and 8, respectively.

Hereinafter, A is fimasartan sodium salt, 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 fimasartan sodium salt 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

After adding fimasartan potassium trihydrate and various surfactants at a weight ratio of 1:0.5 at pH 1.2, after 24 hours while stirring at room temperature using a stirrer (500 rpm), the solution was taken and filtered through a 0.45 μm filter, followed by HPLC Table 9 shows the results of analyzing the solubility.

Hereinafter, A is the same as defined in Example 1.

[Table 9]

Looking at the results of Table 9, it was confirmed that the solubility of the pharmaceutical composition according to the present invention in the same conditions as the experiment was 0.089 mg/ml, which was significantly improved compared to the solubility of the pharmaceutical composition containing a 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, hydrate or solvate thereof; And
A pharmaceutical composition for preventing or treating diseases related to angiotensin-2-receptor comprising a hydrophilic polymer, wherein the content of the hydrophilic polymer is fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, based on 1 part by weight 0.15 parts by weight or more and 10 parts by weight or less,
The hydrophilic polymer is hydroxypropylmethylcellulose,
The angiotensin-2-receptor-related diseases include stroke, stroke, stroke, cerebral infarction, cerebral infarction, Alzheimer's, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina, myocardial infarction, hypertension, heart failure and inflammation. Angiotensin-2-receptor-related disease prevention or treatment composition that is one or more diseases selected from. delete delete delete delete The method of claim 1,
The pharmaceutically acceptable salt of fimasartan is selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonates, amino acid salts, and amine salts. Pharmaceuticals for preventing or treating diseases related to angiotensin-2-receptors Composition. The method of claim 1,
The fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof is selected from the group consisting of fimasartan, fimasartan potassium salt trihydrate, and fimasartan sodium salt to prevent or treat angiotensin-2-receptor-related diseases Pharmaceutical composition for use. The method of claim 1,
The pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of angiotensin-2-receptor-related diseases that are oral administration formulations. The method of claim 1,
The pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of angiotensin-2-receptor-related diseases that are in the form of granules, capsules or tablets. delete