KR20200073676A - Solid dispersion comprising valsartan and sacubitril and pharmaceutical composition comrising same and method of preparation therof - Google Patents

Abstract

The present invention relates to a solid dispersion comprising Valsartan and Sacubitril, a pharmaceutical composition comprising the same, and a manufacturing method thereof. The solid dispersion and the pharmaceutical composition comprising the same according to the present invention have high stability in an alkaline environment and can be prepared simply. The solid dispersion contains: Valsartan free acid or alkali salt, hydrate, or solvate thereof; Sacubitril free acid ester or alkali salt, hydrate, or solvate thereof; an alkalizing agent; and a hydrophilic polymer.

Description

Solid dispersion comprising valsartan and sacubitril, pharmaceutical composition comprising same, and method for manufacturing same{SOLID DISPERSION COMPRISING VALSARTAN AND SACUBITRIL AND PHARMACEUTICAL COMPOSITION COMRISING SAME AND METHOD OF PREPARATION THEROF}

The present invention relates to a solid dispersion comprising valsartan and sacubitril, a pharmaceutical composition comprising the same, and a method for manufacturing the same. The solid dispersion according to the present invention and the pharmaceutical composition comprising the same have high stability in an alkaline environment and can be easily prepared.

Angiotensin II is a hormone that can constrict blood vessels, cause high blood pressure, and burden the heart. The hormone interacts with a specific receptor on the surface of the target cell. Subtypes of two receptors for angiotensin II have been identified so far, for example angiotensin II type 1 (AT1) and angiotensin II type 2 (AT2). Recently, many efforts have been made to identify substances that bind to the AT1 receptor. An angiotensin receptor blocker (ARB angiotensin II agonist) reduces blood pressure by preventing angiotensin II from binding to its receptors on the walls of blood vessels. It can be used as an antihypertensive agent due to AT1 receptor inhibition or among other indications, particularly for the treatment of congestive heart failure. Neutral endopeptidase (EC 3.4.24.11; enkephalinase; atriopeptidase; NEP) is a zinc-containing metalloprotease that cleaves various peptide substrates on the amino acid side chain of hydrophobic residues (Metalloprotease) , Literature; Pharmacol. Rev., Vol. 45, p87 known). Substrates for this enzyme include, but are not limited to, atrial sodium diuretic peptides (see Atrial natriuretic peptide (ANP) or Atrial natriuretic Factor (ANF) (1993)), brain sodium diuretic peptide (BNP), met- and Leu- And enkephalin, bradykinin, neurokinin A, and endothelin-1. Infusion of ANP in normal subjects causes sodium diuresis and reproducible significant improvements in diuresis, including increased excretion of sodium fraction, increased urine flow rate and glomerular filtration rate. (See J. Hypertension. Vol. 19, P1923 (2001).) However, ANP has a short circulatory half-life, and NEP in the renal cortical membrane has been found to be a major enzyme that causes degradation of the peptide. Peptide, Vol. 9, p173 (1988)), therefore, it is expected that an inhibitor of NEP (neutral endopeptidase inhibitor, NEPi) increases the plasma level of ANP to induce sodium and diuretic effects.

Co-Crystal Complex or prodrug of a double-acting compound or combination, especially two active agents with different mechanisms of action, in particular two active agents with different mechanisms of action, ie angiotensin receptor antagonists and neutral endopepts Supramolecular complexes of tydase inhibitors US Patent Application No. 60/735,093 (application date: 2005.11.9); 60/735,541 (filed on November 10, 2005); No. 60/789,332 (application date: 2006.4.4), and 60/822,086 (application date: 2006.8.11) and international patent application WO2007/056546, and Korean patent application number 10-2015-7033633 (application date) : 2008.11.4), the same application number 10-2007-7015021 (application date: 2006.11.8).

Due to the characteristics of these hypertensive drugs, drugs of various mechanisms must be administered together, and drug administration (Drug Administration Safety) is greatly deteriorated due to inconvenience of taking due to the use of a single agent and confusion of patients, and thus it has been developed and used as a combination drug. Trisodium [3], a supramolecular complex of valsartan and sacubitril, reported in Korean Patent Application No. 10-2015-7033633 (Application Date: 2008.11.4) and Application No. 10-2007-7015021 (Application Date: 2006.11.8) -((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(penta Noyl {2"-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate]hemi-pentahydrate {Trisodium[3-((1S,3R)-1-biphenyl-4- ylmethyl-3-ethoxycarbony-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate)biphenyl-4'-yl-methyl}amino)butylate] hemi-pentahydrate} (LCZ696) showed a tendency to increase unwanted impurities generated in the process of synthesizing ionic or covalently bound supramolecular structures, and to significantly reduce chemical stability. In particular, the material showed a problem in that impurities are generated in a poor manner in an alkaline environment. Therefore, a lot of efforts have been made to improve the stability of the composite of valsartan and sacubitril.

U.S. Patent Application No. 60/735,093 (application date: 2005.11.9) U.S. Patent Application No. 60/735,541 (application date: 2005.11.10) U.S. Patent Application No. 60/789,332 (application date: April 4, 2006) U.S. Patent Application No. 60/822,086 (application date: 2006.8.11) International Patent Publication No. WO2007/056546 Korean Patent Application No. 10-2015-7033633 (application date: 2008.11.4) Korean Patent Application No. 10-2007-7015021 (application date: 2006.11.8) International Patent Publication No. WO1999-055681 Korean Patent Application No. 10-2015-7033633 (application date: 2008.11.4) Korean Patent Application No. 10-2007-7015021 (application date: 2006.11.8)

Pharmacol. Rev., Vol. 45, p87 J. Hypertension. Vol. 19, P1923 (2001) Peptide, Vol. 9, p173 (1988)

The object of the present invention is valsartan free acid (Valsartan free acid) or an alkali salt, hydrate, or solvate thereof; Sacubitril free acid ester or an alkali salt, hydrate or solvate thereof; Alkalizing agents; And to provide a solid dispersion comprising a hydrophilic polymer comprising polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose or mixtures thereof.

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of angiotensin II receptor-related diseases comprising the solid dispersion and a pharmaceutically acceptable additive.

Another object of the present invention provides a pharmaceutical formulation comprising an enteric polymer coating layer surrounding a core layer comprising a pharmaceutical composition.

Another object of the present invention is valsartan free acid or an alkali salt, hydrate, or solvate thereof; Sacubitril free acid ester or alkali salt, hydrate, or solvate thereof; Alkalizing agents; And preparing a solution or suspension comprising a hydrophilic polymer comprising polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof; And it provides a method for producing a pharmaceutical composition for preventing or treating an angiotensin II receptor-related disease comprising the step of drying the solution or suspension.

The present invention is a valsartan free acid represented by the following formula (1) or an alkali salt, hydrate, or solvate thereof; Sacubitril free acid ester represented by Chemical Formula 2 or an alkali salt, hydrate, or solvate thereof; Alkalizing agents; And a hydrophilic polymer comprising polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof.

[Formula 1]

[Formula 2]

The hydrophilic polymer for forming the solid dispersion may be used in an amount of 0.5 to 7 parts by weight compared to 1 part by weight of the active ingredient, but is not limited thereto.

In one embodiment of the present invention, as the alkaline salt, sodium, calcium, cesium, strontium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, alkali metal or alkaline earth metal salts and basic amino acids such as arginine, lysine, ammonia , Primary, secondary, tertiary amine, cyclic amine, and the like, but not limited to, valsartan free acid and sacubitril free acid ester salt.

In the present specification, the solid dispersion includes an alkalizing agent; And polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof, in the hydrophilic polymer, valsartan free acid or an alkali salt, hydrate, or solvate thereof, and sacubit Reel free acid ester or an alkali salt, hydrate, or solvate thereof means dispersed, an alkalizing agent in a pharmaceutically acceptable substrate; And polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof. Valsartan free acid or an alkali salt, hydrate, or solvate and sacubitril thereof in a hydrophilic polymer. The distribution form of the free acid ester or alkali salt, hydrate, or solvate thereof may be dispersed in the form of small particles or very small particles, and may be dispersed on a molecular basis.

The present invention is a valsartan free acid or an alkali salt, hydrate, or solvate thereof; And sacubitril free acid esters or alkali salts, hydrates, or solvates thereof using an alkalizing agent and polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof. When produced in a sieve, a supramolecular complex composed of a simple mixture or ionic or covalent bonds; Trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2 '-(Pentanoyl {2"-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate]hemi-pentahydrate {Trisodium[3-((1S,3R)-1- biphenyl-4-ylmethyl-3-ethoxycarbony-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate)biphenyl-4'-yl-methyl} amino)butylate]hemi-pentahydrate} (LCZ696) is based on the fact that chemical stability is improved.

The solid dispersion according to the present invention exhibits excellent physical properties by increasing the chemical stability of valsartan free acid and sacubitril free acid ester than conventional entresto film coating information, and may be easier to formulate.

The solid dispersion of the present invention contains an alkalizing agent for the purpose of improving the chemical stability of valsartan free acid and sacubitril free acid ester by making the microenvironment in the solid dispersion alkaline.

In one embodiment of the present invention, the alkalizing agent is sodium, potassium, calcium, cesium, strontium, magnesium, zinc, copper, iron, aluminum, hydroxide or carbonate derived from an alkaline earth metal such as lithium, carbonate, phosphoric acid Inorganic alkalizing agents such as cargo, and basic amino acids such as arginine, lysine, and glycine, ammonia, primary, secondary, tertiary amines, cyclic amines, organic alkalizing agents such as N-methyl-D-Glucamine I can be used. However, it is not limited to its base. As the alkalizing agent used in the solid dispersion of the present invention, carbonate or hydroxide such as carbonate or hydroxide of sodium is compared with other alkalizing agents. Valsartan free acid ((2S)-3-methyl-2-[pentanoyl- [[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoic acid) and sacubitril free acid ester (4-{[(2S,4R)-1-(4- Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid).

In one embodiment of the present invention, one or more selected from the group consisting of NaHCO ₃ , Na ₂ CO ₃ and NaOH may be used as the alkalizing agent.

The solid dispersion of the present invention is a hydrophilic polymer that serves to form a solid dispersion and maintain the solid dispersion, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof. It includes. The hydrophilic polymers of the present invention, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and hydroxypropylmethylcellulose, improve the stability of valsartan free acid and sacubitril free acid esters compared to other hydrophilic polymers. It is very good.

The solid dispersion of the present invention is an alkalizing agent, preferably a carbonate or hydroxide of sodium (one or more selected from the group consisting of NaHCO ₃ , Na ₂ CO ₃ and NaOH), polyvinylpyrrolidone, vinylpyrrolidone- Alkaliating agent, preferably when vinyl acetate copolymer, hydroxypropylmethylcellulose or mixtures thereof, preferably polyvinylpyrrolidone is added to improve the chemical stability of valsartan free acid and sacubitril free acid ester Is a carbonate or hydroxide of sodium (one or more selected from the group consisting of NaHCO ₃ , Na ₂ CO ₃ and NaOH); Polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose or mixtures thereof, preferably polyvinylpyrrolidone; And it is preferable to homogeneously and finely mix valsartan free acid and sacubitril free acid ester, and in particular, when preparing a solid dispersion, chemical stability of valsartan free acid and sacubitril free acid ester can be greatly improved. .

The present invention is a valsartan free acid or an alkali salt, hydrate, or solvate thereof; Sacubitril free acid ester or alkali salt, hydrate, or solvate thereof; Alkalizing agents; And preparing a solution or suspension comprising a hydrophilic polymer comprising polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof; And

It provides a method for producing a solid dispersion comprising the step of drying the solution or suspension.

The solid dispersion of the present invention can be prepared by a conventional method for preparing a solid dispersion.

In one embodiment of the present invention, in the drying process of drying the solution or suspension, the present invention has a loss on drying (LOD; Loss of Drying, 105oC, sample weight 5g) of 2% by weight or less (typically 0.5-2 Weight percent), more preferably 1.5 weight percent or less (typically 0.5-1.5 weight percent).

In the process of preparing the solid dispersion according to the present invention, adding 1 to 1.5 equivalents of alkalizing agent to the solution or suspension for preparing the solid dispersion to prevent the decomposition of valsartan free acid and sacubitril free acid ester It is more preferable.

The solid dispersion according to the present invention may also contain valsartan free acid or an alkali salt, hydrate, or solvate thereof; And sacubitril free acid esters or alkali salts, hydrates, or solvates thereof; A solid dispersion of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose or mixtures thereof is first prepared, and thereon an alkalizing agent, preferably a carbonate or hydroxide of sodium (NaHCO ₃ , Na ₂ CO ₃ and one or more solid dispersions selected from the group consisting of NaOH) are spray dried or mixed; Or valsartan free acid or an alkali salt, hydrate, or solvate thereof and sacubitril free acid ester or an alkali salt, hydrate, or solvate thereof; And an alkalizing agent, preferably sodium carbonate or hydroxide (one or more selected from the group consisting of NaHCO ₃ , Na ₂ CO ₃ and NaOH), firstly prepared and polyvinylpyrrolidone, vinylpyrroli on it Don-vinyl acetate copolymer, hydroxypropyl methyl cellulose or a mixture thereof can be prepared by spray drying or mixing. However, it is preferable to prepare a solid dispersion by dissolving or suspending the three components at the same time in terms of mixing uniformity of the three components and most preferably in terms of stability.

For example, polyvinylpyrrolidone is mixed in an organic solvent such as ethanol, acetone, isopropyl alcohol, butanol and alkalinized with water, preferably sodium carbonate or hydroxide (NaHCO ₃ , Na ₂ CO ₃ and NaOH) A mixture of two or more selected from the group consisting of) and mixing two solutions, valsartan free acid or an alkali salt, hydrate, or solvate thereof; And a sacubitril free acid ester or an alkali salt, hydrate, or solvate thereof, and uniformly mixed with an excipient such as lactose and a lubricant such as colloidal silicon dioxide, and dried to prepare solid dispersion granules.

The present invention provides a pharmaceutical composition for preventing or treating an angiotensin II receptor-related disease comprising the solid dispersion and a pharmaceutically acceptable additive.

In one embodiment of the present invention, valsartan free acid or an alkali salt, hydrate, or solvate contained in the solid dispersion; Sakubitril free acid ester or alkali salt, hydrate, or solvate thereof acts as an angiotensin II receptor inhibitor.

In one embodiment of the present invention, the pharmaceutically acceptable additive may be included in a solid dispersion, and may be provided separately from the solid dispersion to constitute a pharmaceutical composition.

The pharmaceutically acceptable is physiologically acceptable, and when administered to humans, it usually does not cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions, and is commonly used in the manufacture of self-medicated pharmaceutical compositions of ordinary skill in the art. It can mean using.

The pharmaceutically acceptable additives may be carriers, excipients, extenders, antioxidants, buffers, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, suspending agents, lubricants, binders, disintegrants, surfactants and preservatives, etc. . For example, the additives include lactose, dextrose, calcium silicate, corn starch, sodium starch glycolate, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate , Dicalcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, methylhydroxybenzoate, propylhydride Hydroxybenzoate, light anhydrous silicic acid, talc, stearic acid, magnesium stearate, calcium stearate, gelatin, mineral oil, saline, aqueous glucose solution, pseudosugar solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, 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 substances listed above, these are only examples, and may be preferably 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 as an oral administration formulation or a parenteral administration formulation, preferably an oral administration formulation.

In the present invention, the preparation for oral administration may be a solid preparation such as a tablet, a pill, a powder, a granule, a capsule, or a liquid preparation such as a suspending agent, an intravenous solution, an emulsion, or a syrup, and preferably a solid preparation. It may be the best, and more preferably, it may be a tablet.

In another embodiment of the invention, the pharmaceutical composition is a granule, capsule or tablet formulation.

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

For example, the present invention also provides that the pharmaceutical composition is an enteric polymer (eg, methacrylic acid copolymer dispersion, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, polyvinyl acetate) It provides a pharmaceutical preparation coated with phthalate, and more preferably, a hydrophilic polymer coating layer (hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidine) between the pharmaceutical composition and the enteric polymer coating layer. Vinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, polyvinyl acetate, polyalkene oxide, polyalkene glycol, polyoxyethylene- It provides a pharmaceutical formulation characterized in that it comprises a polyoxypropylene polymer, diethylamino acetate, aminoalkyl methacrylate copolymer, sodium arginate, gelatin coating layer).

In one embodiment of the present invention, the above-mentioned solid dispersion is mixed with a pharmaceutically acceptable additive to prepare a tablet by direct tableting, or to prepare a tablet by dry granulation after tableting. Can. Examples of the pharmaceutically acceptable additive may be the same as described above, for example, mannitol, croscarmellose sodium, magnesium stearate.

The solid dispersion according to the present invention has excellent physicochemical properties such as processability as a formulation, which are required in the formulation. Therefore, when formulated in the form of tablets or capsules, it is possible to produce tablets or capsules with a uniform pharmacological effect, and there is no problem that the pharmacological effect is reduced 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 additives contained in the pharmaceutical composition is not particularly limited, and can be appropriately adjusted within the content range used for conventional formulation.

In the present invention, the pharmaceutical composition may be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally, or topically), and the dosage is the patient's weight, age, sex, and health status , The range may vary depending on the diet, administration time, administration method, administration period or interval, excretion rate, constitution specificity, property of the formulation, and severity of the disease.

In one embodiment of the present invention, the angiotensin II receptor-related disease is stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina, myocardial infarction, hypertension , For the prevention or treatment of 1 or 2 or more diseases selected from the group consisting of heart failure and inflammation.

In the present invention, the pharmaceutical composition is the valsartan free acid or an alkali salt, hydrate, or solvate thereof; Sacubitril free acid ester or alkali salt, hydrate, or solvate thereof; Alkalizing agents; And other pharmacologically active substances other than a solid dispersion comprising a hydrophilic polymer comprising polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof. The pharmacologically active material is the valsartan free acid or an alkali salt, hydrate, or solvate thereof; It may have the same pharmacological activity as sacubitril free acid ester or an alkali salt, hydrate, or solvate thereof, or other pharmacological activity. Other pharmacologically active substances included in the pharmaceutical composition include amlodipine, lercardipine, nicardipine, simvastatin, atorvastatin, pravastatin, rosuvastatin, and the like. , Linagliptin, Saxagliptin, Teneligliptin, Anagliptin, Melogliptin, Dutogliptin, Gemigliptin and the like, and may be pharmaceutically acceptable salts or mixtures thereof. Preferably amlodipine, rosuvastatin, atorvastatin, hydrochlorothiazide, sitagliptin, vildagliptin, linagliptin and their pharmaceutically acceptable salts or mixtures thereof.

The pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormonal therapy, drug treatment, and biological response modifiers to improve, alleviate, treat, or prevent angiotensin II receptor-related tremors.

The present invention is a valsartan free acid or an alkali salt, hydrate, or solvate thereof; Sacubitril free acid ester or alkali salt, hydrate, or solvate thereof; Alkalizing agents; And preparing a solution or suspension comprising a hydrophilic polymer comprising polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof; And

It provides a method for preparing a pharmaceutical composition for preventing or treating an angiotensin II receptor-related disease, comprising drying the solution or suspension.

In one embodiment of the present invention, in the drying process of drying the solution or suspension, the present invention has a loss on drying (LOD; Loss of Drying, 105oC, sample weight 5g) of 2% by weight or less (typically 0.5-2 Weight percent), more preferably 1.5 weight percent or less (typically 0.5-1.5 weight percent).

For example, polyvinylpyrrolidone is mixed in an organic solvent such as ethanol, acetone, isopropyl alcohol, butanol and alkalinized with water, preferably sodium carbonate or hydroxide (NaHCO ₃ , Na ₂ CO ₃ and NaOH) A mixture of two or more selected from the group consisting of) and mixing two solutions, valsartan free acid or an alkali salt, hydrate, or solvate thereof; And a sacubitril free acid ester or an alkali salt, hydrate, or solvate thereof, and uniformly mixed with an excipient such as lactose and a lubricant such as colloidal silicon dioxide, and dried to prepare solid dispersion granules. The solid dispersion granules can be compressed to prepare a pharmaceutical composition in tablet form.

When using the method of manufacturing a pharmaceutical composition for the prevention or treatment of angiotensin II receptor-related diseases according to the present invention, the active ingredient valsartan free acid or an alkali salt, hydrate, or solvate thereof; And sacubitril free acid esters or alkali salts, hydrates, or solvates thereof, having high stability in an alkaline environment and simple production.

The solid dispersion according to the present invention and the pharmaceutical composition comprising the same have high stability in an alkaline environment and can be easily prepared.

1 is a graph showing the results of evaluation of pharmacokinetic absorption before meals of Dioban (a commercially available formulation of Valsartan) of Example D and Comparative Example 40mg according to the present invention.
Figure 2 is a graph showing the results of the evaluation of pharmacokinetic absorption after meals of Example D and Comparative Example 40mg Diovan (a commercially available formulation of Valsartan) according to the present invention.
3A is an HPLC analysis result of Example D according to the present invention, and FIG. 1B is an HPLC mixing chart of Example D according to the present invention and commercially available 100 mg entreto film coating tablet (Con trol). )to be.

Hereinafter, examples will be described in detail to help understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Experimental Example 1: Polymer Selection

As described in Table 1 below, valsartan free acid ((2S)-3-methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]amino] butanoic acid) and sacubitril free acid ester (4-[[(2S,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4 -oxobutanoic acid) and each polymer were mixed well in a weight ratio of 1:3 and 1:6, then compressed using a roller compacter and sized into No. 20. Since the test deviation may occur even in the heat generated during compression, all conditions were set equally during compression. The prepared granules were put in a brown flask and subjected to a stability test for 1 week under accelerated conditions (40°C, relative humidity (RH) 75%), and the generated relative substances were analyzed by HPLC. The results are summarized in Tables 2 and 3 below.

The analog analysis was performed as follows. Each granule is powdered, and the amounts of 48.6 mg and 51.4 mg, respectively, are accurately weighed as valsartan free acid and sacubitril free acid ester, put into a 100 mL flask, stirred with 10 mL of methanol, and added with 20 mL of phosphate buffer (pH 6.8). After ultrasonic treatment (Ultrasonication). After aligning the same volume with water, the filtrate filtered with a membrane filter was used as a sample solution. After that, it was analyzed by the following HPLC conditions and the peak area of less than 0.05% was not included in the calculation.

[HPLC conditions]

Detector: Ultraviolet absorption photometer (wavelength of measurement 263nm)

Column: Cosmosil 5C18-AR-II, 4.6x150mmx5um or similar column

Mobile phase: Gradient

A: Acetonitrile: Methanol: KH ₂ PO ₄ (pH 3.8) = 30: 50: 20 (v/v)

B: Acetonitrile: Methanol: KH ₂ PO ₄ (pH 3.8) = 50:100: 10 (v/v) mixed solution

Flow rate: 1.0mL/min

Injection Volume: 10um

Sample solution: 0.5mg/mL in mobile phase (0.5mg/mL in mobile phase)

Ingredient name Mixing ratio 1: 3 Mixing ratio 1: 6 One 2 3 4 5 6 7 8 remedy 100 100 100 100 100 100 100 100 HPMC (5cp) 300 - - - 600 - - - HPMC (15cp) - 300 - - - 600 - - L-HPC - - 300 - - - 600 - HPC - - - 300 - - - 600

(Unit: mg)

In Table 1, 100 mg of therapeutic agent means that it contains 48.6 mg of valsartan free acid and 51.4 mg of sacubitril free acid ester.

In Table 1, HPMC 5cp and 15cp refer to hydroxypropyl methylcellulose, which is 5 cp or 15 cp, respectively, when measuring viscosity with a 2 wt% (wt%) aqueous solution at 20°C, and L-HPC is low-substituted-hydroxypropylcellulose. And HPC means hydroxypropylcellulose.

Ingredient name Mixing ratio (w/w%) Single largest impurity
(Single maximum Impurity)
unit (%) Total maximum impurities
(Total maximum Impurity)
unit (%) Initial value Acceleration 1 week Initial value Acceleration 1 week HPMC 5cp 1:3 0.07 0.50 0.31 3.59 HPMC 15cp 1:3 0.09 1.64 0.82 14.01 L-HPC 1:3 0.07 0.92 0.47 6.38 HPC 1:3 0.11 1.15 1.55 7.50

Ingredient name Mixing ratio (w/w%) Single largest impurity
(Single maximum Impurity)
unit (%) Total maximum impurities
(Total maximum Impurity)
unit (%) Initial value Acceleration 1 week Initial value Acceleration 1 week HPMC 5cp 1:6 0.08 0.61 0.01 2.57 HPMC 15cp 1:6 0.12 1.66 0.81 14.48 L-HPC 1:6 0.07 0.76 0.44 4.47 HPC 1:6 0.15 1.23 0.57 7.81

As shown in the results of Tables 2 and 3, the compressed mixture using HPMC 5cp was the most stable in the compressed mixture of valsartan free acid and sacubitril free acid ester and a hydrophilic polymer for solid dispersion formation.

Experimental Example 2: Preparation and evaluation of solid dispersion

A solid dispersion was prepared with the components and contents of Table 4 below. In Example 1, polyvinylpyrrolidone was dissolved in ethanol, and NaHCO ₃ was dissolved in purified water. Valsartan free acid ((2S)-3-methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoic acid) and sacubit in the mixture Reel free acid ester (4-[[(2S,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid) Dissolved. In this solution, lactose and colloidal silicon dioxide were added, mixed uniformly, dried at 40° C., and then sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 2, hydroxypropylmethylcellulose (5cp) was dissolved in ethanol, and NaHCO ₃ was dissolved in purified water. Valsartan free acid and sacubitril free acid ester were added and dissolved in the mixed solution. NaOH, lactose, and colloidal silicon dioxide were added to the solution, dried at 40°C, and then sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 3, polyvinylpyrrolidone was dissolved in ethanol, and Na ₂ CO ₃ was dissolved in purified water. Valsartan free acid and sacubitril free acid ester were added and dissolved in the mixed solution. Lactose and colloidal silicon dioxide were added to the solution, dried at 40° C., and then sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 4, hydroxypropylmethylcellulose (5cp) was dissolved in ethanol, and Na ₂ CO ₃ was dissolved in purified water. Valsartan free acid and sacubitril free acid ester were added and dissolved. NaOH, lactose, and colloidal silicon dioxide were added to the solution, dried at 40°C, and then sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 5, polyvinylpyrrolidone was dissolved in ethanol, and NaOH was mixed with purified water. Valsartan free acid and sacubitril free acid ester were added and dissolved in the mixed solution. In this solution, lactose and colloidal silicon dioxide were added, mixed uniformly, dried at 40° C., and then sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 6, hydroxypropylmethylcellulose (5cp) was dissolved in ethanol, and NaOH was dissolved in purified water. Valsartan free acid and sacubitril free acid ester were added and dissolved in the mixed solution. NaOH, lactose, and colloidal silicon dioxide were added to the solution, dried at 40 ^° C., and then sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 7, polyvinylpyrrolidone was dissolved in ethanol and KOH was dissolved in purified water. The mixed solution was dissolved with the addition of valsartan free acid and sacubitril free acid ester. Lactose and colloidal silicon dioxide were added to the solution, dried at 40°C, and sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 8, hydroxypropylmethylcellulose (5cp) was dissolved in ethanol and KOH was dissolved in purified water. Valsartan free acid and sacubitril free acid ester were added and dissolved in the mixed solution. NaOH, lactose, and colloidal silicon dioxide were added to the solution, dried at 40° C., and then sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 9, polyvinylpyrrolidone was dissolved in ethanol, and Ca(OH) ₂ was dissolved in purified water. Valsartan free acid and sacubitril free acid ester were added and dissolved in the mixed solution. In this solution, lactose and colloidal silicon dioxide were added, mixed uniformly, dried at 40° C., and then sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 10, hydroxypropyl methylcellulose (5cp) was dissolved in ethanol, and Ca(OH) ₂ was dissolved in purified water. Valsartan free acid and sacubitril free acid ester were added and dissolved in the mixed solution. NaOH, lactose, and colloidal silicon dioxide were added to the solution, dried at 40° C., and then sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 11, polyvinylpyrrolidone was dissolved in ethanol, and Mg(OH) ₂ was dissolved in purified water. Valsartan free acid and sacubitril free acid ester were added and dissolved in the mixed solution. In this solution, lactose and colloidal silicon dioxide were added, mixed uniformly, dried at 40° C., and then sieved through a No. 20 sieve to prepare solid dispersion granules. In Example 12, hydroxypropylmethylcellulose (5cp) was dissolved in ethanol, and Mg(OH) ₂ was dissolved in purified water. Valsartan free acid and sacubitril free acid ester were added and dissolved in the mixed solution. NaOH, lactose, and colloidal silicon dioxide were added to the solution, dried at 40° C., and then sieved through a No. 20 sieve to prepare solid dispersion granules.

ingredient Serving Size (mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 remedy 100 100 100 100 100 100 100 100 100 100 100 100 NaHCO ₃ 57 - - - - - - - - - - - NaHCO ₃ 57 - - - - - - - - - - Na ₂ CO ₃ - - 106 - - - - - - - - - Na ₂ CO ₃ - - - 106 - - - - - - - - NaOH - - - - 27 - - - - - - - NaOH - - - - - 27 - - - - - - KOH - - - - - - 38 - - - - - KOH - - - - - - - 38 - - - - Ca(OH) ₂ - - - - - - - - 49 - - - Ca(OH) ₂ - - - - - - - - - 49 - - Mg(OH) ₂ - - - - - - - - - - 56 - Mg(OH) ₂ - - - - - - - - - - - 56 PVP 40 - 40 - 40 - 40 - 40 - 40 - HPMC 5cp - 40 - 40 - 40 - 40 - 40 - 40 NaOH - 27 - 27 - 27 - 27 - 27 - 27 Lactose 80 80 80 80 80 80 80 80 80 80 80 80 Colloidal silicon dioxide 30 30 30 30 30 30 30 30 30 30 30 30 Total 307 334 356 383 277 304 288 315 299 326 306 333

(Unit: mg)

Storage Stability was evaluated in the same manner as Experimental Examples 1 and 2 using Examples 1 to 12, and the results were evaluated by an accelerated 2-week experiment as shown in Table 5.

Sample I.D Initial 1 week 2 weeks Single largest impurity
(Single Maximum Impurity)
unit (%) Total impurities
(Total
Impurity)
unit (%) Single largest impurity
(Single Maximum Impurity)
unit (%) Total impurities
(Total
Impurity)
unit (%) Single largest impurity
(Single Maximum Impurity)
unit (%) Total impurities
(Total
Impurity)
unit (%) Example 1 0.054 0.271 0.277 1.034 0.637 1.678 Example 2 0.048 0.073 0.248 1.678 0.784 1.224 Example 3 0.012 0.042 0.125 0.287 0.295 0.892 Example 4 0.051 0.781 0.134 1.354 0.884 1.015 Example 5 0.084 0.981 0.251 1.984 0.353 3.892 Example 6 0.099 0.258 0.854 2.368 0.756 5.267 Example 7 0.128 0.359 0.756 3.265 0.914 8.014 Example 8 0.201 0.897 0.897 4.561 1.241 9.547 Example 9 0.254 0.789 0.985 5.015 1.854 7.651 Example 10 0.314 0.888 0.452 6.652 1.905 8.482 Example 11 0.657 0.989 1.022 8.984 3.254 10.65 Example 12 0.542 0.933 2.358 9.235 4.125 12.03

In Table 5, 100 mg of therapeutic agent means that it contains 48.6 mg of valsartan free acid and 51.4 mg of sacubitril free acid ester.

In Table 5, HPMC 5cp refers to hydroxypropylmethylcellulose, which is 5 cp or 15 cp, respectively, when measuring viscosity with a 2 wt% (wt%) aqueous solution at 20°C.

As shown in Table 5, when sodium carbonate or hydroxide of NaHCO ₃ or Na ₂ CO _{3 is} included as an alkalizing agent, high storage stability was exhibited. Among them, Examples 3 and 4 using Na ₂ CO ₃ showed the most stable values. In addition, when evaluating the results of Example 3, a solid dispersion using polyvinylpyrrolidine (PVP) showed excellent stability.

Experimental Example 3: Stability evaluation during simple mixing

Test samples were prepared by simply mixing the ingredients using the ingredients and contents of Table 6 below.

ingredient Serving Size (mg) Comparative Example 1 Comparative Example 2 Comparative Example 3 remedy 100 100 100 Polyvinylpyrrolidone 40 - 40 NaOH 27 27 -

(Unit: mg)

In Table 6, 100 mg of therapeutic agent means that it contains 48.6 mg of valsartan free acid and 51.4 mg of sacubitril free acid ester.

Storage stability was evaluated in the same manner as in Experimental Example 3 using Comparative Examples 1 to 3, and the results are shown in Table 7 below.

Sample I.D Initial stability
(Initial stability) 1 week Single largest impurity
(Single Maximum Impurity)
unit (%) Total impurities
(Total
Impurity)
unit (%) Single largest impurity
(Single Maximum Impurity)
unit (%) Total impurities
(Total
Impurity)
unit (%) Comparative Example 1 (therapeutic drug + PVP + NaOH) 0.053 0.244 1.191 9.603 Comparative Example 2 (therapeutic drug + NaOH) 0.055 0.241 0.902 6.768 Comparative Example 3 (Treatment drug + PVP) 0.051 0.251 Dark brown
(Dark Brown Color)

As shown in Table 7, the stability of the valsartan free acid and sacubitril free acid ester did not improve with simple mixing of the components.

Experimental Example 4: Evaluation of the effect of alkalizing agent

As shown in Table 8 below, in the solid dispersion comprising the valsartan free acid and sacubitril free acid ester compound according to the present invention, the effect of the type of alkalizing agent on stability was evaluated. Polyvinyl pyrrolidone (PVP) was dissolved in ethanol and dissolved in therapeutic agents (valsartan free acid and sacubitril free acid ester). In this solution, an alkalinizing agent and colloidal silicon dioxide (Colloid SiO ₂ ) were uniformly mixed and dried at 40° C. to form a No. 20 sieve to prepare a solid dispersion granule.

ingredient Example 13 14 15 16 17 remedy 100 100 100 100 100 PVP 40 40 40 40 40 Alkalizing agent NaHCO ₃ 57 - - - - Na ₂ CO ₃ - 160 - - - NaOH - - 27 - - KOH - - - 38 - Ca(OH) ₂ - - - - 49 Colloidal SiO ₂ 30 30 30 30 30

(Unit: mg)

In Table 8, 100 mg of therapeutic agent means that it contains 48.6 mg of valsartan free acid and 51.4 mg of sacubitril free acid ester.

Storage stability was evaluated in the same manner as in Experimental Example 1 using Examples 13 to 17, and the results are shown in Table 9 below.

Sample I.D Alkalizing agent Initial 1 week Single largest impurity
(Single Maximum Impurity)
unit (%) Total impurities
(Total impurity)
unit (%) Single largest impurity
(Single Maximum Impurity)
unit (%) Total impurities
(Total impurity)
unit (%) Example 13 NaHCO ₃ 0.082 0.295 0.105 0.523 Example 14 Na ₂ CO ₃ 0.021 0.042 0.114 0.301 Example 15 NaOH 0.062 0.370 0.231 0.894 Example 16 KOH 0.111 0.447 0.852 2.596 Example 17 Ca(OH) ₂ 0.087 0.339 0.543 1.786

As shown in Table 9, the solid dispersion using Na ₂ CO ₃ had the best stability.

Experimental Example 5: Effect evaluation according to the content of each component

To the components and contents shown in Table 10, a therapeutic agent (a solid dispersion comprising valsartan free acid and sacubitril free acid ester was prepared. Polyvinylpyrrolidone (PVP) was dissolved in ethanol and NaOH dissolved therein. The purified water was mixed and dissolved in the mixture by adding therapeutic agents (valsartan free acid and sacubitril free acid ester compound) Na ₂ CO ₃ and colloidal silicon dioxide were added to the solution, mixed uniformly, and dried at 40°C. Formed into a No. 20 sieve to prepare a solid dispersion granule.

ingredient Serving Size (mg) Example 18 Example 19 Example 20 Example 21 Example 22 remedy 100 100 100 100 100 Na ₂ CO ₃ 5 5 5 10 5 PVP 100 100 100 100 50 NaOH 200 250 250 250 250 Colloidal silicon dioxide 75 75 0 75 75

(Unit: mg)

In Table 10, 100 mg of therapeutic agent means that it contains 48.6 mg of valsartan free acid and 51.4 mg of sacubitril free acid ester.

Sample I.D Initial 2 weeks Single largest impurity
(Single Maximum Impurity)
unit (%) Total impurities
(Total impurity)
unit (%) Single largest impurity
(Single Maximum Impurity)
unit (%) Total impurities
(Total impurity)
unit (%) Example 18 0.099 0.361 0.149 0.547 Example 19 0.115 0.272 0.138 0.443 Example 20 0.110 0.324 0.121 0.530 Example 21 0.097 0.524 0.171 0.576 Example 22 0.097 0.261 0.155 0.902

As shown in Table 11, when comparing Examples 19 and 20, the presence or absence of colloidal silicon dioxide (Collide SiO ₂ ) does not significantly affect the stability of therapeutic agents (valsartan free acid and sacubitril free acid ester compounds). Does not seem to. In comparison of Examples 18 and 19, and Examples 19 and 21, the higher the amount of NaOH and Na ₂ CO ₃ used, the better the stability of the solid dispersion containing the therapeutic agent (valsartan free acid and sacubitril free acid ester). It was confirmed that when compared to Examples 20 and 22, when PVP was reduced, total relative substances were relatively increased.

Experimental Example 6: Stability evaluation according to moisture content in each manufacturing process

A pharmaceutical composition containing a therapeutic agent (valsartan free acid and sacubitril free acid ester) was prepared according to Table 12 below. .

No. ingredient Serving Size (mg) One Therapeutic agents (valsartan free acid and sacubitril free acid ester 100.0 2 Povidone 60.0 3 Sodium carbonate 60.0 4 Spherical white sugar 138.0 5 Hydroxypropyl methylcellulose 20.0 6 Methacrylic acid copolymer dispersion 238.3 7 Polyethylene glycol 4.0 8 Triethyl citrate 14.3 9 Talc 13.6 10 Colloidal silicon dioxide 1.0 11 Titanium oxide 3.6 Total 652.8

(Unit: mg)

In Table 12, 100 mg of therapeutic agent means that it contains 48.6 mg of valsartan free acid and 51.4 mg of sacubitril free acid ester.

Examples "A" to "E" are povidone dissolved in ethanol, and after dispersing sodium carbonate, and then adding a therapeutic agent (valsartan free acid and sacubitril free acid ester) and dissolving the solution, a fluid bed coater (GPCG 3.1, company name: GLATT) was coated on the spherical white sugar to prepare a solid dispersion granule and dried (primary coating followed by drying). The granules are coated with HPMC, dried (second coated and then dried), and then treated with enteric coating (Encterocoating) with a methacrylic acid copolymer dispersion (dried after tertiary coating) to treat (valsartan free acid and sacubit) Reel free acid ester) containing granules were prepared. Loss of Drying (LOD) (Moisture Balance-Precisa, XM60) measured after each drying process, drying temperature 105° C., Auto Stop, sample weight 5 g is shown in Table 13 below.

Batch No. Example A Example B Example c Example D Example e After the first coating drying * * * 1.91 1.25 After the first coating drying 2.39 2.13 1.21 1.74 1.29 After the first coating drying 1.99 1.72 1.54 1.13 1.28 *After the first coating, the second coating continues without drying.

(Unit: weight%)

In Table 12, 100 mg of therapeutic agent means that it contains 48.6 mg of valsartan free acid and 51.4 mg of sacubitril free acid ester.

The stability evaluation results of Examples “A” to “E” are shown in Tables 14 and 15 below. Table 14 is the result of packaging for 1 week after packaging with PTP (Press Through Package) Al/Al under harsh conditions (60℃, RH 75%) and Table 15 is PTP under accelerated storage conditions (40℃, RH 75%) It is the result of packaging with Al/Al for 6 months.

Batch No. Initial Stability Severe 1 week (Stress test) Single largest impurity
(Single Impurity Maximum)
unit (%) Total impurities
(Total impurity)
unit (%) Single largest impurity
(Single Impurity Maximum)
unit (%) Total impurities
(Total impurity)
unit (%) Example A 0.042 0.145 6.42 18.35 Example B 0.024 0.111 2.39 10.89 Example c 0.047 0.212 0.86 2.91 Example D 0.044 0.209 0.19 0.55 Example e 0.048 0.226 0.16 0.52

Batch No. Initial 3 months 6 months Single largest impurity
(Single Impurity Maximum)
unit (%) Total impurities
(Total impurity)
unit (%) Single largest impurity
(Single Impurity Maximum)
unit (%) Total impurities
(Total impurity)
unit (%) Single largest impurity
(Single Impurity Maximum)
unit (%) Total impurities
(Total impurity)
unit (%) Example B 0.024 0.111 0.332 1.766 - - Example c 0.047 0.212 0.148 1.346 0.213 2.132 Example e 0.048 0.226 0.077 0.494 0.129 1.133

When looking at the results of Tables 14 and 15, Example “D” and Example “E” have improved stability compared to other batches (Example “B”) that did not control the moisture content of the coated granules at each step of the coating process. It showed remarkably improved results. In addition, although it is important to control moisture in all coating steps, it is judged that moisture control in step 1 of the coating process in step 3 has a significant effect on stability, and drying after the first coating is less than 2% LOD, especially less than 1.5%. Setting was the most effective.

Experimental Example 7: Pharmacokinetic absorption evaluation

In order to evaluate the degree of pharmacokinetic absorption of the pharmaceutical preparation according to the present invention, enteric coated tablets as test samples were prepared as shown in Tables 16 and 17 below. Specifically, a solution of dissolving povidone (polyvinylpyrrolidone) in ethanol and dissolving Na ₂ CO ₃ was added, mixed well, and then completely dissolved with a therapeutic agent (valsartan free acid and sacubitril free acid ester) and NaOH in this solution. Some of them were added and dispersed. The solution was sprayed onto colloidal silicon dioxide and NaOH in a fluidized bed to prepare granules. The granules were mixed with the remaining excipients and compressed into tablets to prepare uncoated tablets. Thereafter, HPMC was coated on the prepared tablets using a tablet coater to form a separation layer. Example A was prepared by enteric coating with HPMC P (HP-50) thereon, and Example B was prepared by enteric coating with methacrylic acid ethyl acrylate copolymer (1:1).

No Ingredient (Prescription tablet) Tablet (mg) One remedy 100 2 Povidone 40 3 Na ₂ CO ₃ 160 4 NaOH 27 5 Colloidal silicon dioxide 2.5 6 Microcrystalline cellulose 265.7 7 Crospovidone 25.0 8 Magnesium stearate 5.0 Total Tablet weight 625.2

(unit: %)

In Table 16, 100 mg of therapeutic agent means that it contains 48.6 mg of valsartan free acid and 51.4 mg of sacubitril free acid ester.

No Ingredient (coating prescription) coating Example A Example B One Najung 625.2 625.2 2 Hydroxypropylmethylcellulose 9.8 17.20 3 HPMC P(HP-50) 50.2 - 4 Methacrylic acid copolymer dispersion - 170.3 5 PEG 6000 0.98 2.06 6 TEC - 7.71 7 PG (Phenyl glycine) 4.02 - 8 Talc 8.97 8.85 9 Titanium oxide (TiO ₂ ) - 5.11 Total 699.17 836.41

(unit: %)

The capsules according to the present invention were prepared as shown in Table 18 below. Except for the spherical white sugar used as a seed (Seed), all were prepared by the same prescription and the same recipe. Example C used 850-710um spherical white sugar as a seed, and Example D used 710-600um spherical white sugar. After dissolving povidone in ethanol and dispersing sodium carbonate, a therapeutic agent (valsartan free acid and sacubitril free acid ester) was added, and a completely dissolved solution was sprayed onto spherical white sugar in a fluidized bed to prepare a pellet coated with the main component. HPMC was coated on this pellet to form a separation layer to limit the contact between the main component and the enteric base, and an enteric coated pellet was prepared with a methacrylic acid copolymer dispersion.

No. ingredient Example C Example D One remedy 100 100 2 Povidone 60 60 3 Na ₂ CO ₃ 160 160 4 710-600um per spherical bag - 138 4 850-710um per spherical bag 138 - 5 HPMC 20.0 20.0 6 Methacrylic acid copolymer dispersion 38.3 238.3 7 Polyethylene glycol 4.0 4.0 8 Triethyl citrate 14.3 14.3 9 Talc 13.6 13.6 10 Colloidal silicon dioxide 1.0 1.0 11 Titanium oxide 3.6 3.6 Total 552.8 552.8

Comparative Examples A to D were compared using a commercially available product, 40 mg of dioban (a commercially available formulation of balsatan), as a comparative example. Actual administration of Valsartan in the form of no salt in the exposure (AUC) and Cmax values of Valsartan to enable comparison of exposure to Valsartan between Examples A and D and Dioban of the present invention at different dosage levels Standardized by dose (standardized by mg-equivalent). AUC0-24 values were calculated as ng·h/ml/mg-equivalents of balsatan and compared to the geometric mean. Pharmacokinetic tests were performed before meals, and the test results are shown in Table 19 (enteric coating tablets) and Table 20 (capsule formulations). The results of Tables 19 and 20 below are average values measured after dosing to 12 men around 30 years of age and the results are shown in FIG. 1.

Batch No. Example A Example B Comparative example Cmax(ng/mL) 876.4 739.6 1233 AUC(ng·hr/mL) 7937.3 6131.0 6935 Tmax(hr) 3.0 2.7 1.6

For tablets, Example A coated with HPMC P (HP-50) dissolved at pH 5.0 showed higher Cmax and AUC than Example B coated with a methacrylic acid copolymer dispersion dissolved at pH 5.5. . Compared to the comparative example (commercial entretofilm coated tablet), Example A was Cmax 71.1%, AUC 114.4%, Example B was Cmax 60.0%, AUC 88.3%.

Batch No. Example C Example D Comparative example Cmax(ng/mL) 1084.5 1336.5 1233 AUC(ng·hr/mL) 7397.8 6668.9 6935 Tmax(hr) 1.3 1.5 1.6

In the case of capsules, Cmax and AUC of Example C using pellets having a pellet diameter of 850-710um as a seed, and Example D using pellets having a diameter of 710-600um as a seed, and 40mg of Diovan (a commercially available formulation of Valsartan) were compared. . As a result, both formulations had similar Cmax and AUC when compared with Diovan (a commercially available formulation of Valsartan) of Comparative Example 40 mg. In Example C, Cmax 87.9%, AUC 106.6%, and in Example D, Cmax 108.4%, AUC 96.1%, the absorption rate similar to that of the comparative example was shown. In order to evaluate the pharmacokinetic absorption after a meal, a high-fat diet (750 kcal, fat was about 50% of total calories (41.7 g)) was consumed, and Comparative Example 40 mg of Diovan (a commercially available formulation of Valsartan) and the drug of Example D The dynamic absorption pattern was compared and evaluated, and the results are shown in Table 21 and FIG.

Batch No. Example D Comparative example Cmax(ng/mL) 1059.7 1072.7 AUC(ng·hr/mL) 6056.9 6329.5 Tmax(hr) 2.9 3.1

In the post-prandial bioequivalent test for evaluating the effects of food, the present invention has significantly improved stability in Example D compared to Cmax 98.8% and AUC 95.7% when compared to Diovan (a commercially available formulation of Valsartan) of Comparative Example 40mg It showed an absorption rate similar to the example.

In the evaluation of the pharmacokinetic absorption, LC/MS/MS was used for analysis of therapeutic agents (valsartan free acid and sacubitril free acid ester) in plasma, and sildenafil was used as an internal standard. LC conditions were Column-YMC Hydrosphere C18; Mobile phase-10mM ammonium acetate (Ammonium Acetate): acetonitrile (Acetonitrile) = 10: 90 (v/v); Flow rate-0.2 mL/min; 10 uL of injection volume; Sample temperature-10°C; And column temperature (column temperature)-30 ℃ was the MS condition is the ionization method-Electrospray ionization (ESI) in positive ion mode; MRM (Multiple Reaction Monitering)-Entresto (valsartan and sacubitril compounds) measured by 436.52, 412.49.

Experimental Example 8: HPLC

Example D and Figure 3 prepared by the method described in the present invention was carried out by HPLC of Example D prepared by the method described in the present invention and commercially available 100 mg entretofilm coating tablets (Con trol) and the results are shown in Figure 3 It is shown in. FIG. 3A is the HPLC analysis result of Example D prepared according to the present invention, and FIG. 3B is the HPLC mixing chart of Example D of the present invention and commercially available 100 mg entreto film coating tablet (Con trol) chart). HPLC conditions are as follows.

[HPLC conditions]

Detector: Ultraviolet absorption photometer (wavelength of measurement 263nm)

Column: Cosmosil 5C18-AR-II, 4.6x150mmx5um or similar column

Mobile phase: Gradient

A: Acetonitrile: Methanol: KH ₂ PO ₄ (pH 3.8) = 30: 50: 20 (v/v)

B: Acetonitrile: Methanol: KH ₂ PO ₄ (pH 3.8) = 30:50: 20 (v/v) mixed solution

Flow rate: 1.0mL/min

Injection Volume: 10um

Sample solution: 0.5mg/mL in mobile phase (0.5mg/mL in mobile phase)

Column: Xterra C18 column (4.6x250 mmx5 μm)

Claims (13)

Valsartan free acid or an alkali salt, hydrate or solvate thereof; And sacubitril free acid ester or alkali salts, hydrates or solvates thereof;
Alkalizing agents; And
A solid dispersion comprising a hydrophilic polymer comprising polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof.
According to claim 1,
The alkalizing agent is one or more solid dispersions selected from the group consisting of NaHCO ₃ , Na ₂ CO ₃ and NaOH.
A pharmaceutical composition for the prevention or treatment of angiotensin II receptor-related diseases comprising the solid dispersion according to claim 1 or 2 and a pharmaceutically acceptable additive.
According to claim 3,
The pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of angiotensin II receptor-related disease that is an oral dosage form.
According to claim 3,
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, hypertension, heart failure and inflammation. A pharmaceutical composition for the prevention or treatment of angiotensin II receptor-related diseases that is 1 or 2 or more.
A pharmaceutical preparation comprising an enteric polymer coating layer surrounding a core layer comprising the pharmaceutical composition according to claim 3, wherein the enteric polymer coating layer is a methacrylic acid copolymer, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate A pharmaceutical formulation comprising at least one enteric polymer material selected from the group consisting of succinate, cellulose acetate phthalate, and polyvinyl acetate phthalate.
The method of claim 6,
Pharmaceutical preparation comprising a separation layer between the core layer and the enteric polymer coating layer
The method of claim 7,
The separation layer is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidine-vinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, hydroxymethylcellulose, hydroxy With hydroxyethyl cellulose, hydroxyethyl methyl cellulose, polyvinyl acetate, polyalkene oxide, polyalkene glycol, polyoxyethylene-polyoxypropylene polymer, diethylamino acetate, aminoalkyl methacrylate copolymer, sodium arginate, gelatin It is a hydrophilic polymer layer comprising at least one hydrophilic polymer material selected from the group consisting of, pharmaceutical preparations.
Valsartan free acid or an alkali salt, hydrate or solvate thereof; And sacubitril free acid esters or alkali salts, hydrates or solvates thereof;
Alkalizing agents; And
Hydrophilic polymer comprising polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof
Preparing a solution or suspension comprising; And
A method of preparing a pharmaceutical composition comprising drying the solution or suspension.
The method of claim 8, wherein the drying of the step of drying the solution or suspension is performed until the loss on drying (LOD; Loss of Drying, 105° C., test sample weight 5 g) is 2% by weight or less. Way.
Valsartan free acid or an alkali salt, hydrate or solvate thereof; And sacubitril free acid esters or alkali salts, hydrates or solvates thereof;
Alkalizing agents; And
Hydrophilic polymer comprising polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropylmethylcellulose, or mixtures thereof
A first step of preparing a solution or suspension comprising;
A second step of preparing solid dispersion granules using said solution or suspension; And
A method of manufacturing a pharmaceutical composition comprising a third step of forming an enteric polymer coating layer on the granules,
The enteric polymer coating layer includes one or more enteric polymers selected from the group consisting of methacrylic acid copolymer, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, and polyvinyl acetate phthalate. Phosphorus, a method of manufacturing a pharmaceutical composition.
The method of claim 11,
A method of manufacturing a pharmaceutical composition further comprising forming a separation layer between the second step and the third step.
The method of claim 12,
The separation layer is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidine-vinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, hydroxymethylcellulose, hydroxy With hydroxyethyl cellulose, hydroxyethyl methyl cellulose, polyvinyl acetate, polyalkene oxide, polyalkene glycol, polyoxyethylene-polyoxypropylene polymer, diethylamino acetate, aminoalkyl methacrylate copolymer, sodium arginate, gelatin Method of manufacturing a pharmaceutical composition, which is a hydrophilic polymer layer comprising at least one hydrophilic polymer selected from the group consisting of.

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