KR20170061616A - New salt of fimasartan - Google Patents

Abstract

The present invention provides a novel salt of Pimassartan having excellent solubility, bioavailability and physicochemical properties, a method for producing the same, and a pharmaceutical composition containing the same.

Description

NEW SALT OF FIMASARTAN < RTI ID = 0.0 >

The present invention relates to novel salts of Pimalactan. More particularly to a novel salt of Pimassartan having excellent physical and chemical properties such as stability and non-hygroscopicity as well as excellent solubility and bioavailability.

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, the drug is poorly soluble in the case of ingestion, and the drug is hardly effective. 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.

In addition, the drug should satisfy physicochemical standards such as excellent stability, non-hygroscopicity and processability in formulation as well as excellent solubility and bioavailability, and studies on new salts of Pimassartan capable of satisfying the above properties have been continuously carried out have.

Pimassartan is a hypertensive drug that is an angiotensin II receptor antagonist. Canavra is marketed in three doses under the trade name of 30, 60, and 120 mg. Its main ingredient is Pimacartan potassium salt.

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

However, as already mentioned above, an excellent physicochemical property such as solubility has an advantage such as an increase in bioavailability. If the physicochemical properties such as stability, non-hygroscopicity and processability as a formulation are excellent, mass production is easy, .

Therefore, much efforts have been made to develop new salts which are superior in solubility and bioavailability than the potassium salt potassium salt, and exhibit excellent properties such as drug stability, non-hygroscopicity, and processability as a dosage form.

Korean Patent Registration No. 100354654 Korean Patent Registration No. 100617953

It is an object of the present invention to provide novel salts of Pimassartan.

It is an object of the present invention to provide a process for the preparation of novel salts of Pimasartan.

It is an object of the present invention to provide a pharmaceutical composition comprising a novel salt of Pimalactan.

The present invention provides new novel salts of Pimacaltan.

In the present invention, the new salt of Pimasartan may be an amine salt of Pimasartan.

The present invention provides an amine salt of Pimersartan or a hydrate or solvate thereof.

The Pimacartan amine salt or a hydrate or solvate thereof according to the present invention exhibits excellent solubility and bioavailability and is excellent in stability and non-hygroscopicity, and thus has excellent formability as a formulation and excellent drug efficacy.

The present invention provides a meglumine salt of Pimacartan or a hydrate or solvate thereof.

The meglumine salt of Pimalactan according to the present invention may be a compound represented by the following general formula (1).

[Chemical Formula 1]

In the above formula (1), R ₁ and R ₂ may be H, R ₃ may be CH _3, and R ₄ may be CH ₂ (CHOH) ₄ CH ₂ OH.

The present invention provides an ammonium salt of Pimersartan or a hydrate or solvate thereof.

The ammonium salt of Pimasartan according to the present invention may be a compound represented by the above formula (1), wherein R _1, R ₂ , R ₃ and R ₄ is H.

The present invention provides an arginine salt of Pimersartan or a hydrate or solvate thereof.

The arginine salt of Pimassartan according to the present invention may be a compound represented by the following formula (2).

(2)

The novel salts of Pimassartan according to the present invention, the Pimassartan meglumine salt, the Pimassartan ammonium salt, the Pimassartan arginine salt, or the hydrate or solvate thereof, have excellent therapeutic effects even when administered in a small amount exhibiting high bioavailability when orally administered And the medicinal convenience of the patient can be remarkably improved. In addition, the pharmaceutical and physico-chemical properties such as stability, non-hygroscopicity and processability as formulations are increased and are suitable for the production of pharmaceutical formulations.

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 high content of phimassartan must be contained in the preparation. As a result, there is a problem that the convenience of the patient's medication is deteriorated. Considering this point, the use of the phimassartan potassium salt Has come. Pimersartan meglumine salt, Pimersartan ammonium salt, Pimethaltan arginine salt or a hydrate or solvate thereof is excellent in physicochemical and pharmacological properties required for a drug such as solubility or bioavailability, and is superior to conventional Pimacartan potassium salt And is easier to formulate and improves the patient's medication convenience.

In addition, the Pimersartan meglumine salt, the Pimersartan ammonium salt, the Pimersartan arginine salt or the hydrate or solvate thereof is non-hygroscopic and exhibits excellent stability in the solid state, so that the preparation can maintain a uniform content over a long period of time.

In the present invention, the above-mentioned Pima saccharide amine salt, preferably Pima saccharganeglumin salt, ammonium salt or arginine salt may be a crystal.

In the present invention, the above-mentioned Pimassaran meglumine salt, ammonium salt or arginine salt may be anhydrous crystal or hydrate, and may be, for example, a dihydrate of a pimecartan meglumine salt.

In the present invention, the meglumine salt, the ammonium salt or the arginine salt of the palmatartan includes all the geometric isomers, optical isomers and racemates of the meglumine salt, ammonium salt or arginine salt of Pimasartan.

The present invention provides a process for preparing the amine salt of the palmatalkane, or a hydrate or solvate thereof.

The method

Preparing a reaction product comprising a solvent and a salt of Pimasartan or a salt thereof; And

And adding an amine to the reactant. ≪ Desc / Clms Page number 3 >

In the present invention, the step of preparing the reactant may be a step of mixing the above-described Pimasartan or a salt thereof with the above solvent.

In the present invention, the amine salt of Pimasartan may be a meglumine salt, an ammonium salt or an arginine salt of Pimasartan, and the amine added to the reaction may be meglumine, ammonium or arginine.

In the present invention, the method may further include heating and stirring. The heating and stirring may be carried out with the addition of amine to the reactants.

In the present invention, the heating may be carried out at 20 ° C to 80 ° C, preferably at 25 ° C to 65 ° C.

In the present invention, the solvent may include an organic solvent. The organic solvent may be ethyl acetate, ethanol, acetonitrile, methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanol, tetrahydrofuran, 1,4-dioxane, methyl acetate, , Preferably ethyl acetate, ethanol, isopropanol, acetonitrile, tetrahydrofuran, or a mixture thereof, more preferably acetonitrile.

In the present invention, the solvent may further comprise water together with an organic solvent. For example, the solvent may be a mixture of acetonitrile and water. In this case, the volume ratio of acetonitrile and water may be about 30 to 10: 1.

In the present invention, the starting material for the production of the above-mentioned phimacartan amine salt, or a hydrate or solvate thereof, is a palmasaltan or a pirasaltan salt. When the starting material is a salt of Pimacartan, it may be a Pimacartan potassium salt, preferably Pimacartan.

In the present invention, the method may further include adding an amine and then adding an organic solvent. The step of adding the organic solvent may be performed after the precipitation of the amine is performed. The kind of the organic solvent is as described above. The organic solvent added to the reactant may be the same as or different from the organic solvent described above, preferably acetonitrile.

The present invention provides a composition comprising the palmatartan amine salt, or a hydrate or solvate thereof.

In the present invention, the Pimacartan amine salt may be a Pimassartan meglumine salt, an ammonium salt or an arginine salt.

In the present invention, the composition according to the present invention may be used as a pharmaceutical composition for the treatment of stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, Or a pharmaceutical composition for treating or preventing renal failure.

In the present 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, For use, see Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA.

The additive 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, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Wherein the aqueous solution is selected from the group consisting of methylcellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, stearic acid, magnesium stearate, calcium stearate, gellan tin, mineral oil, Alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, or mixtures thereof. However, the additives that may be included in the composition according to the present invention are not limited to the above listed materials, and they are merely illustrative.

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.

The Pimacartan amine salt or a hydrate or solvate thereof according to the present invention is excellent in stability, solubility in various solvents, non-hygroscopic, and excellent physico-chemical 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.

When the pharmaceutical composition of the present invention is formulated into an oral solid preparation, examples of the additives to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate , Gelatin, talc, and the like.

When the pharmaceutical composition is formulated into a liquid preparation for oral administration, various additives such as water, a simple diluent such as liquid paraffin, a wetting agent, a sweetener, a fragrance, a preservative, an antiseptic and a colorant may be added to the pharmaceutical composition have.

When the pharmaceutical composition of the present invention is prepared in the form of an injection, the additive may include water, saline solution, glucose aqueous solution, pseudosugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, Rides, and the like.

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

In the present invention, the pharmaceutical composition may contain the pimetic saline meglumine salt, the pimetic saline ammonium salt or the pimetic saline arginine salt to a content of about 1 mg to 240 mg, preferably about 5 to 180 mg , And more preferably 10 to 120 mg.

In the present invention, the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically), and the dose may vary depending on the patient's weight, age, 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. For example, oral administration may be carried out so that the dosage of pimecaran is about 1 to 240 mg, preferably 5 to 180 mg, more preferably 10 to 120 mg per day on the basis of a general adult of about 60 kg, Or may be applied once or several times.

In the present invention, the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically), and the dose may vary depending on the patient's weight, age, 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. For example, oral administration may be carried out so that the dosage of pimecaran is about 1 to 240 mg, preferably 5 to 180 mg, more preferably 10 to 120 mg per day on the basis of a general adult of about 60 kg, Or may be applied once or several times.

In the present invention, the pharmaceutical composition may further comprise a pharmacologically active substance other than a pharmacartan amine salt, specifically, a phimassartan meglumine salt, a pirassalant ammonium salt, or a pirasaltan arginine salt. The pharmacologically active substance may have the same pharmacological activity as the above-mentioned palmatisartum glucuronide salt, palmatartan ammonium salt or pirasalactan arginine salt, or may have other pharmacological activity. Other pharmacologically active substances included in the pharmaceutical composition include, but are not limited to, agents for treating hyperlipemia such as amlodipine, lercardipine, nicardipine, simvastatin, atorvastatin, pravastatin, rosuvastatin, metformin, hydrochlorothiazide, 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, ditogliptin, 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 diseases, or in combination with methods using surgery, hormone therapy, drug therapy and biological response modifiers.

The novel phthalic anhydride amine salt according to the present invention has excellent solubility or bioavailability and is excellent in therapeutic effect and is excellent in physicochemical properties such as adhesiveness, hygroscopicity and flowability, is easy to formulate, and has excellent content uniformity And economical, mass production can be carried out easily and effectively.

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 > Preparation of pimeticatan meglumine salt

In a 25 ml flask, 2.60 g of Pimersartan, 15 ml of acetonitrile and 0.7 ml of purified water was added and 0.98 g of meglumine was added while stirring at 50 캜 with stirring. When precipitation occurs at this temperature, add 10 ml of acetonitrile. Stirred at room temperature for 1 hour and then filtered to give a solid product which was washed with 2 ml acetonitrile. The obtained solid was dried at 43 캜 for 1 day to obtain a dihydrate of 3.52 g of the palmasaltan meglumine salt.

Yield: 98.5%

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.49 (m, 1H), 7.38 (m, 2H), 7.29 (m, 1H), 7.06 (d, 2H), 6.94 (d, 2H), 4.00 ( 2H), 1.24 (m, 2H), 0.78 (m, 2H), 2.95 (m, 2H) , 3H).

Example 2 Preparation of Pimacartan Ammonium Salt

In a 250 ml flask, add 20.8 g of Pimassartan and 80 ml of acetonitrile and add 7.60 g of ammonia solution (10.9 wt%, ammonia gas is collected in methanol). When the precipitate was formed while stirring with heating to 50 DEG C, the reaction product was further stirred at room temperature for 2.5 hours and filtered to obtain a solid product, which was washed twice with 4 ml of acetonitrile. The obtained solid was dried at 43 DEG C for 16 hours to obtain 19.53 g of a castor oil ammonium salt.

Yield: 94.3%

^{1 H NMR (400MHz, DMSO-} d 6): δ 7.66 (m, 2H), 7.56 (m, 2H), 7.06 (m, 4H), 5.27 (s, 2H), 3.78 (s, 2H), 3.60 ( (d, 6H), 2.58 (m, 2H), 2.15 (s, 3H), 1.54 (m, 2H), 1.26 (m, 2H), 0.81

Example 3 Preparation of Pima Saltan Arginine Salt

In a 25 ml flask, 0.52 g of Pimersartan, 2.5 ml of ethanol and 0.25 ml of water was added and 0.17 g of L-arginine was added with stirring. 10 ml of acetonitrile was added at room temperature to form a precipitate. After stirring for an additional 1 hour at room temperature, the solid was obtained by filtration and washed with 2 ml acetonitrile / isopropyl ether (5: 5) mixed solvent. The obtained solid was dried at 43 DEG C for 1 day to obtain 0.49 g of the Pimersartan L-arginine salt.

Yield: 72.8%

^{1 H NMR (400MHz, DMSO-} d 6): δ 9.02 (br, 1H), 7.85-7.52 (m, 6H), 7.39-7.29 (m, 4H), 7.05 (d, J = 8.0Hz, 2H), 3H), 3.41 (s, 3H), 3.32 (t, J = 5.6 Hz, 1H), 6.96 (s, 2H) (M, 2H), 0.82 (t, J < RTI ID = 0.0 > = 7.2 Hz, 3H).

Experimental Example 1 Measurement of solubility

 The solubility of the pegmatrazine meglumine salt prepared in Example 1 and the pimassartan arginine salt prepared in Example 3 and the Pimasartan potassium salt (Boryung Pharmaceutical Co., Ltd.) were measured according to the method described in Korean Pharmacopoeia.

To the supernatant, supernatant was added to the aqueous solution of phosphoric acid of pH 1.2, pH 4.0 aqueous solution of phosphoric acid, and aqueous solution of pH 6.8 until the supersaturation of the pegmatacanthmalginine salt prepared in Example 1, , And the mixture was stirred at 25 ° C ± 3 ° C for 24 hours and allowed to stand for 1 hour to stabilize. The solution was then analyzed by liquid chromatography (HPLC) and the amount dissolved was determined on the basis of the free base. The results are shown in Table 1 below.

[Table 1]

As can be seen from the above Table 1, the Pimersartan meglumine salt of Example 1 exhibited a high solubility of 3 to 50 times at all pH as compared to the conventional Pimersartan potassium salt, The arginine salt exhibited similar solubilities to potassium salt at pH 1.2 compared to the conventional castor potassium salt salt and showed high solubilities of 10 and 50 times at pH 4.0 and 6.8, respectively.

<Experimental Example 2> Measurement of bioavailability

Using the beagle dogs, the bioavailability of the Pimersartan meglumine salt and arginine salt of Examples 1 and 3 and the Pimersartan potassium salt (Boryung Pharmaceutical Co., Ltd.) was measured.

Ten dogs of 10 beagles were divided into Groups 1 to 3, and fasted for one day.

On the other hand, capsules 1 (meglumine salt), capsules 2 (arginine salt) and 30 mg of Pimersartan potassium salt, which were filled with gelatin capsules, respectively, with 30 mg of the palmasaltan meglumine salt and arginine salt obtained in Examples 1 and 3, A filled capsule 3 was prepared.

Capsule 1 containing 30 mg of Pimersartan glucosamine salt in Group 1, Capsule 2 containing 30 mg of Pimersartan arginine salt in Group 2, Capsule 3 containing 30 mg of Pimersartan potassium salt in Group 3, 1 capsule / One dog was orally taken and immediately taken at a dose of 30 mL / 1 of negative water. Blood samples were collected from the dorsal veins of beagle dogs immediately after 10 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after drug and water intake. free base) were measured and their pharmacokinetic parameters were obtained.

The results are shown in Table 2 below.

[Table 2]

As can be seen in Table 2 above, the pimassartan meglumine salt and arginine salt according to the present invention showed a higher blood concentration as compared to the pimecartan potassium salt. In particular, when administered in the same amount, it was found that about 6 times Cmax and about 3 times the AUC for the meglumine salt, about 7 times Cmax and about twice the AUC for the arginine salt.

Therefore, it can be seen that the salt of the present invention is remarkably excellent in bioavailability as compared with the conventional salt of Pimasartan potassium salt, and as a result, a remarkably high therapeutic effect can be obtained.

Claims (14)

Pimacartan amine salt or a hydrate or solvate thereof. The pharmaceutical composition according to claim 1, wherein the Pimacartan amine salt is a Pimacartan meglumine salt, an Ammonium salt or an Arginine salt, or a hydrate or solvate thereof. 4. The pharmaceutical composition according to claim 1, wherein the crystalline form of the phthalic anhydride amine salt or a hydrate or solvate thereof. 4. The pharmaceutical composition according to claim 3, wherein the Pimacartan amine salt is a crystalline anhydrous Pimacartan amine salt or a hydrate or solvate thereof. 3. The method of claim 2, wherein the paramasartan meglumine salt is a parassal saline meglumine salt or a hydrate or solvate thereof, which is a dihydrate of a megasartan meglumine salt. Preparing a reaction product comprising a solvent and a salt of Pimasartan or a salt thereof; And
And adding an amine to the reactant. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; 7. The method according to claim 6, wherein the amine is meglumine, ammonia or arginine, or a hydrate or solvate thereof. 7. The method of claim 6, wherein the solvent is selected from the group consisting of ethyl acetate, ethanol, acetonitrile, methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanol, tetrahydrofuran, &Lt; / RTI &gt; 9. The method of claim 8, wherein the solvent further comprises water. A pharmaceutical composition comprising a Pimacartan amine salt or a hydrate or solvate thereof. 11. The pharmaceutical composition according to claim 10, wherein the Pimacartan amine salt is a Pimacartan meglumine salt, an ammonium salt or an arginine salt. 11. The method of claim 10, wherein the pharmaceutical composition is selected from the 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, 0.0 &gt; and / or &lt; / RTI &gt; at least one disease selected from the group consisting of renal failure. 11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition further comprises a pharmacologically active substance different from the palmasaltan amine salt. The pharmaceutical composition according to claim 13, wherein the pharmacologically active substance is selected from the group consisting of amlodipine, lercardipine, nicardipine, simvastatin, atorvastatin, pravastatin, rosuvastatin, metformin, hydrochlorothiazide, &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.