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Espacenet

Description: KR20170061493 (A) ― 2017-06-05

NEW SALT OF FIMASARTAN

Description of KR20170061493 (A)

The EPO does not accept any responsibility for the accuracy of data and information
originating from other authorities than the EPO; in particular, the EPO does not guarantee
that they are complete, up-to-date or fit for specific purposes.

FIELD OF THE INVENTION [0001 ] The present invention relates to novel salts of
Pimasartan . And more particularly to novel salts of Pimassarthan 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 have an important influence on 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 effects 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 drug
product may be large and the dissolution rate may be low due to low solubility.

In addition, even when the pharmacological activity is excellent, the bioavailability of the
drug is low, the concentration of the drug in the blood during oral administration is low, so
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that a sufficient therapeutic effect can not be obtained. 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 sufficient effect.

Pimassartan is a hypertensive drug that is an angiotensin II receptor antagonist. Canvasra

is marketed in three doses, 30, 60 and 120 mg under the trade name, and its main
ingredient is Pimersartan potassium salt.

The Pimassartan has excellent pharmacological activity but has low solubility and has
been used in the form of a 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 a new salt that can exhibit excellent
physical properties in terms of solubility and bioavailability rather than the potassium salt
potassium salt.

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

The object of the present invention is to provide a novel salt of Pimersartan .

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 Pimasartan.

The present invention provides new novel salts of Pimassartan.

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

In the present invention, the palmaline amine salt may be cholinic salt of Pimacartan.

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The present invention provides a palmasaltan cholinic salt or a hydrate or solvate thereof.

The Pima saccharan choline salt according to the present invention may be a compound
represented by the following formula (1).

Image Omitted]

The novel salt of Pimersartan according to the present invention, the Pimersartan choline
salt or its hydrate or solvate, is remarkably excellent in solubility. In addition, the
pimecartan cholinic salt can exhibit a high therapeutic effect even when it is used in a
small amount which shows a high bioavailability when orally administered, thus remarkably
improving the convenience of patient's medication.

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 should be included in the preparation. As a result, there is a problem that
the convenience of medication is lowered. As a result, Has come. Pima saccharan choline
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 conventional castor potassium salt and is more easily
formulated, The convenience of medicines can be improved.

In addition, the castor oil chalcine 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 pimicatane, which is the amine salt of the castor
oil, may be anhydrous crystals.

The present invention provides a process for preparing a choline salt of pimicatan, or
anhydrate or solvate thereof, which is an amine salt of said palmatartan.

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The method comprises

the steps of: preparing a reactant comprising a solvent and a salt of Pimasartan or a salt
thereof; 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
palmatalkane or a salt thereof with the 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 heating after adding a choline or
choline salt. For example, the heating can be performed at 20 ° C to 80 ° C, preferably at
25 ° C to 65 ° C.

In the present invention, the method may further include a step of performing 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 organic

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solvent.

The present invention provides a composition comprising the choline salt of Pimersartan,
or the hydrate or solvate thereof, which is 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 undue toxicity, usually without causing 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, But are not limited to, water, 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 these
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
preparation, preferably, an oral preparation.

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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 coloring agent
and the like 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, aqueous glucose solution,
pseudosugar solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid,
fatty acid ester, 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 be determined depending on the patient's body 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, it may be orally
administered so that the dosage of Pimacartan is about 1 to 240 mg, preferably 5 to 180
mg, more preferably 10 to 120 mg per day based on a general adult of about 60 kg, May
be applied once or several times.

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In the present invention, the pharmaceutical composition may further comprise a drug
other than the 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 antidiabetic drugs such as
amlodipine, lercardipine, nicardipine, simvastatin, atorvastatin, pravastatin, rosuvastatin,
metformin, Or a pharmaceutically acceptable salt thereof, or a mixture thereof, for the
treatment of diabetes such as glycoprotein, glutathione, saxagliptin, teneligliptin,
anagliptin, meloglyptin, twotogliptin and gemigliptin, May be amlodipine, rosuvastatin,
atorvastatin, hydrochlorothiazide, cytarglyptin, 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 phimassartan, which is a novel pharmacartan amine 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. It should be noted,
however, that the following examples are illustrative of the present invention and are not
intended to limit the scope of the present invention. Embodiments of the present invention
are provided to more fully describe the present invention to those skilled in the art.

Example 1

20.8 g of Pimassartan and 100 ml of ethyl acetate were added to a 500 ml flask, and
11.85 g of a choline hydroxide solution (45% methanol solution) was added thereto. While
heating with stirring at 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
solid obtained was dried at 43 ° C for 16 hours to give 23.01 g of the castaxol cholamine
salt.

Yield: 92.4%

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<1> H NMR (400MHz, DMSO-d6): δ 7.48 (m, 1H), 7.38 (m, 2H), 7.29 (m, 1H), 7.02 (d,
2H), 6.94 (d, 2H), 2.13 (s, 2H), 5.60 (s, 1H), 5.21 (s, 2H), 3.51 (m, 3H), 3.37 (d, ), 2.07 (s,
IH), 1.51 (m, 2H), 0.78 (t, 3H).

EXPERIMENTAL EXAMPLE 1 Measurement of Solubility The solubility of the

palmasaltan cholinic salt prepared in Example 1 and the palmasal potassium salt
(Boryung Pharma Co., Ltd.) was measured according to the method described in the
KPP.

The pima saccharan choline salt and the pima sacchar 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, Stirring was continued for 24 hours and
allowed to stand for 1 hour to stabilize. Then, the solution was analyzed by liquid
chromatography (HPLC) and the dissolved amount was measured on the basis of free
base. The results are shown in Table 1 below.

Table 1 (Unit: mg / mL)

[image]

As can be seen from the above Table 1, Example 1 Pima saltan choline salts are any pH
from 10 times to 100 times as high in comparison with the conventional castor saltan
potassium salt of Solubility.

EXPERIMENTAL EXAMPLE 2 Measurement of Bioavailability The bioavailability

of the pimacartan choline salt and the pimecartan potassium salt (Boryung
Pharmaceutical Co., Ltd.) of Example 1 was measured using a beagle dog.

Ten dogs of 10 beagles were divided into Group 1 and Group 2, and fasted for one day.

On the other hand, Capsule 1, which was filled with gelatin capsules, and Capsule 2, which
was filled with 30 mg of Pimersartan potassium salt in gelatin capsules, was prepared.

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One capsule / one capsule of Capsule 2 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 then immediately taken at a dose of 30 mL / 1 of negative water. After
that, blood samples were taken from the sagittal 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 the pharmacokinetic parameters
were obtained.

The results are shown in Table 2 below.

Table 2

[image]

As can be seen from the above Table 2, the Pima saccharan cholin salt according to the
present invention showed a higher blood concentration as compared with the Pima sacal
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 pimacatan cholinic salt according to the present
invention is remarkably excellent in bioavailability as compared with the conventional
castor potassium salt, and as a result, a remarkably high therapeutic effect can be
obtained.

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