KR20170061493A - New salt of fimasartan - Google Patents
New salt of fimasartan Download PDFInfo
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- KR20170061493A KR20170061493A KR1020150166616A KR20150166616A KR20170061493A KR 20170061493 A KR20170061493 A KR 20170061493A KR 1020150166616 A KR1020150166616 A KR 1020150166616A KR 20150166616 A KR20150166616 A KR 20150166616A KR 20170061493 A KR20170061493 A KR 20170061493A
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- South Korea
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- salt
- pharmaceutical composition
- choline
- cholinic
- rti
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Abstract
The present invention provides a novel salt of Pimassarthan having excellent solubility and bioavailability, a method for producing the same, and a pharmaceutical composition containing the same.
Description
The present invention relates to novel salts of Pimalactan. And more particularly to a novel salt of Pimassartan having good 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, 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. 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 has been pointed out earlier, excellent physico-chemical properties such as solubility have various advantages such as an increase in bioavailability.
Therefore, much efforts have been made to develop new salts which can exhibit excellent physical properties in terms of solubility and bioavailability rather than the potassium salt potassium salt.
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.
In the present invention, the palmaline amine salt may be cholinic salt of Pimasartan.
The present invention provides a palmasaltan cholinic salt or a hydrate or solvate thereof.
The pimecatan cholinic salt according to the present invention may be a compound represented by the following general formula (1).
[Chemical Formula 1]
The novel salt of Pimersartan according to the present invention, the Pimersartan cholinic salt or its hydrate or solvate, is remarkably excellent in solubility. In addition, the pimecartan cholinic salt can exhibit a superior therapeutic effect even when administered in a small amount, which shows a high bioavailability when orally administered, and thus the convenience of the patient can be remarkably improved.
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. The pimecartan cholinic salt or a hydrate or solvate thereof is excellent in physicochemical and pharmacological properties required for a drug such as solubility and bioavailability, exhibits physical properties superior to those of a conventional castor potassium salt and is more easily formulated, The convenience of medication can be improved.
In addition, the pimecartan cholinic salt or its hydrate or solvate is non-hygroscopic and exhibits excellent stability in the solid state, so that the formulation can maintain a uniform content over a long period of time.
In the present invention, the choline salt of the pimicatane, which is the amine salt of the castor oil, may be a crystal.
In the present invention, the choline salt of pimicatan, which is the amine salt of the castor oil, may be anhydrous crystals.
The present invention provides a method for preparing a choline salt of pimicatan, or anhydrate or solvate thereof, which is an amine salt of the said palmatalkane.
The method
Preparing a reaction product comprising a solvent and a salt of Pimasartan or a salt thereof; And
And adding a choline or choline salt to the reactant.
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 choline salt may be choline hydroxide (choline hydroxide). For example, a solution containing choline hydroxide may be added to the reaction, and preferably the solution containing choline hydroxide may be a methanol solution containing choline hydroxide.
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 ethyl acetate.
In the present invention, when the organic solvent is a water-miscible solvent, the solvent may further include water in addition to the organic solvent.
In the present invention, the starting material for the preparation of the choline salt of the phimassartan amine salt is the palmasaltan or the phimacartin 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 a step of heating after adding a choline or choline salt. For example, the heating may be performed at 20 캜 to 80 캜, preferably at 25 캜 to 65 캜.
In the present invention, the method may further include a step of heating, and then an organic solvent is added. The kind of the organic solvent is as described above. The added organic solvent may be the same as or different from the above-mentioned organic solvent.
The present invention provides a composition comprising the cholinic salt of Pimersartan, or the hydrate or solvate thereof, of the Pimacartan amine 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.
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, a colorant, 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 pimicatanamine salt in an amount 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 further comprise a drug other than a palmasaltan cholinic salt. The drug may have the same pharmacological activity as the castazate cholinic salt or may have other pharmacological activities. Other drugs included in the pharmaceutical composition include antihyperlipidemic agents such as amlodipine, lercardipine, nicardipine, simvastatin, atorvastatin, pravastatin and rosuvastatin, metformin, hydrochlorothiazide, cytarglyptin, Or a pharmaceutically acceptable salt thereof, or a mixture thereof, for the treatment of diabetes such as glycoprotein, glutinin, saxagliptin, teneligliptin, anagliptin, melogliptin, twotogliptin and gemigliptin, May be amlodipine, rosuvastatin, atorvastatin, hydrochlorothiazide, sitagliptin, bilagogliptin, linagliptin, and pharmaceutically acceptable salts or mixtures 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 choline salt of Pimasartan, which is a novel Pimacaltanamine salt according to the present invention, is excellent in solubility and bioavailability, is excellent in therapeutic effect, is easy to formulate, and can greatly improve convenience for patients.
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 >
In a 500 ml flask, 20.8 g of Pimassartan and 100 ml of ethyl acetate are added and 11.85 g of a choline hydroxide solution (45% methanol solution) is added. While heating with stirring to 50 DEG C, 280 ml of ethyl acetate was added. When a precipitate is formed at this temperature, it is stirred for another 2 hours at room temperature and filtered to obtain a solid product, which is washed twice with 5 ml of ethyl acetate. The obtained solid was dried at 43 DEG C for 16 hours to obtain 23.01 g of a castaxol cholamine salt.
Yield: 92.4%
1 H NMR (400MHz, DMSO- d 6): δ 7.48 (m, 1H), 7.38 (m, 2H), 7.29 (m, 1H), 7.02 (d, 2H), 6.94 (d, 2H), 5.60 ( 2H), 2.13 (s, 3H), 2.07 (s, 2H), 3.51 (m, 3H) , ≪ / RTI > 1H), 1.51 (m, 2H), 0.78 (t, 3H).
Experimental Example 1 Measurement of solubility
The solubility of the phimacartan cholinic salt prepared in Example 1 and the Pimersartan potassium salt (Boryung Pharm) was measured according to the method described in Korean Pharmacopoeia.
The phimacartan cholinic salt and the pimecartan potassium salt prepared in Example 1 were added to an aqueous phosphoric acid solution of pH 1.2, a pH 4.0 aqueous phosphoric acid solution and a pH 6.8 aqueous phosphoric acid solution, respectively, until they were supersaturated. Lt; / RTI > for 1 hour and stabilized. 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 (Unit: mg / mL)
As can be seen from the above Table 1, the Pima Sartan cholinic salt of Example 1 exhibited a high solubility of about 10 to 100 times at all pH values as compared with the conventional Pimasartan potassium salt.
<Experimental Example 2> Measurement of bioavailability
Using a beagle dog, the bioavailability of the pimecartan cholin salt and the pimecartan potassium salt of Example 1 (Boryung Pharmaceutical Co., Ltd.) was measured.
Five dogs of 10 beagles were divided into Group 1 and Group 2 and fasted for one day.
On the other hand, Capsule 1 in which 30 mg of the palmasaltan cholinic salt obtained in Example 1 was filled in gelatin capsules and 30 mg of Pimersartan potassium salt in capsule was filled in gelatin capsules.
One capsule / per capsule of Capsule 1 containing 30 mg of Pima saccharin cholinic salt was administered to Group 1 and 30 mg of Pimersartan potassium salt was administered to Group 2, 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 pima sacatan cholin salt according to the present invention showed a higher blood concentration as compared to the pimacartan potassium salt. In particular, it was found that Cmax of 5 times or more and AUC of 3 times or more even when administered in the same amount.
Therefore, it can be seen that the pima saccharan cholin salt according to the present invention is remarkably superior in bioavailability as compared with the conventional castor potassium salt, and as a result, it can exhibit a remarkably high therapeutic effect.
Claims (10)
And adding a choline or choline salt to said reactant. ≪ RTI ID = 0.0 > 11. < / RTI >
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150166616A KR20170061493A (en) | 2015-11-26 | 2015-11-26 | New salt of fimasartan |
| PCT/KR2016/013727 WO2017091041A1 (en) | 2015-11-26 | 2016-11-25 | Novel salt of fimasartan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020150166616A KR20170061493A (en) | 2015-11-26 | 2015-11-26 | New salt of fimasartan |
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| Publication Number | Publication Date |
|---|---|
| KR20170061493A true KR20170061493A (en) | 2017-06-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020150166616A KR20170061493A (en) | 2015-11-26 | 2015-11-26 | New salt of fimasartan |
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| KR (1) | KR20170061493A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110037998A (en) * | 2018-01-16 | 2019-07-23 | 镇学初 | Purposes of the melbine salt in treatment cerebral infarction |
| KR102022694B1 (en) * | 2019-02-20 | 2019-09-18 | 주식회사 네비팜 | Pharmaceutical composition |
| KR20190123607A (en) | 2018-04-24 | 2019-11-01 | (주)국전약품 | Fimasartan Tromethamine Salt and Pharmaceutical Composition Comprising the Same |
| KR20200058865A (en) * | 2018-11-20 | 2020-05-28 | 보령제약 주식회사 | Bilyaer tablets and method of preparing bilyaer tablet |
| WO2024049275A1 (en) * | 2022-09-02 | 2024-03-07 | Rexpharmtech Co., Ltd | Novel benfotiamine choline salt |
-
2015
- 2015-11-26 KR KR1020150166616A patent/KR20170061493A/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110037998A (en) * | 2018-01-16 | 2019-07-23 | 镇学初 | Purposes of the melbine salt in treatment cerebral infarction |
| KR20190123607A (en) | 2018-04-24 | 2019-11-01 | (주)국전약품 | Fimasartan Tromethamine Salt and Pharmaceutical Composition Comprising the Same |
| KR20200058865A (en) * | 2018-11-20 | 2020-05-28 | 보령제약 주식회사 | Bilyaer tablets and method of preparing bilyaer tablet |
| WO2020106020A1 (en) * | 2018-11-20 | 2020-05-28 | 보령제약 주식회사 | Bilayer tablet and preparation method therefor |
| KR102022694B1 (en) * | 2019-02-20 | 2019-09-18 | 주식회사 네비팜 | Pharmaceutical composition |
| WO2024049275A1 (en) * | 2022-09-02 | 2024-03-07 | Rexpharmtech Co., Ltd | Novel benfotiamine choline salt |
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