KR20240063039A - Novel co-complex comprising valsartan and sacubitril - Google Patents

Abstract

The present invention relates to a novel co-complex of sacubitril/valsartan calcium salt hydrate consisting of sacubitril and valsartan. Specifically, the present invention provides a novel co-complex of sacubitril and valsartan calcium hydrate to solve the pharmaceutical problems of sacubitril and valsartan pharmaceuticals. In addition, the present invention evaluates the specific volume, particle size, solubility, stability, release pattern, and hygroscopicity according to the crystallinity of the co-composite to provide a co-composite having a crystallinity degree with excellent solubility and stability.

Description

Novel co-complex comprising valsartan and sacubitril}

The present invention relates to a novel sacubitril/valsartan calcium salt hydrate (co-complex) composed of sacubitril and valsartan, which has specific properties such as specific volume, particle size, solubility, stability, release pattern, and hygroscopicity depending on the crystallinity of the co-complex. , pharmacokinetic parameters, etc. are evaluated to provide a co-complex with excellent pharmaceutical properties.

Heart failure, which accounts for a significant portion of the world's medical burden, is a disease in which the heart's function deteriorates and fails to supply sufficient blood to the entire body. It is caused by various causes such as coronary artery disease, high blood pressure, atrial fibrillation, and heart valve disease. Drugs such as blockers, diuretics, aldosterone antagonists, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers are used as drugs related to heart failure.

Beta blockers are drugs that block beta receptors and play a role in reducing the burden on the heart by reducing heart rate and myocardial contractility, and are caused by angiotensin II receptor blockers (ARB), angiotensin converting enzyme inhibitors, and chymase inhibitors Renin-angiotensin-aldosterone system (RAAS) inhibition plays a role in reducing cardiac load and peripheral hypertension, which worsen the progression of heart failure disease. However, despite the above effects, these beta blockers and RAAS inhibitors are unable to solve the problem of high heart failure incidence and mortality.

Neprilysin (NEP) acts to inactivate and decompose bradykinin, which plays a role in dilating blood vessels, and natriuretic peptides (atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP)). It is an enzyme. Proteins such as ANP protect heart muscle cells, relax blood vessels to promote the flow of oxygenated blood, and reduce the risk of high blood pressure through natriuresis. Therefore, neprilysin inhibitors can be used as a treatment for heart failure by inhibiting the effect of neprilysin in decomposing proteins such as ANP.

Due to its pharmacological mechanism, neprilysin inhibitors are expected to serve as an excellent treatment for heart failure disease when used together with the RAAS inhibitors. However, when neprilysin inhibitors are used together with angiotensin-converting enzyme inhibitors, the risk of angioedema increases. It has been confirmed that it does. Entresto tablets, which are used together with a neprilysin inhibitor and angiotensin receptor blocker, are composed of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin receptor blocker, and are widely used as a treatment for chronic heart failure.

Meanwhile, the dissolution of a drug is affected by a wide variety of factors such as solubility, oil/water partition coefficient, molecular weight, and crystal form. Among these, the crystal form of the drug is an important factor that determines the dissolution rate, and the amorphous form is often faster than the crystalline form. It is known that

Novartis' Korean Patent No. 10-1432821 discloses a co-crystal of valsartan-sacubitril trisodium 2.5 hydrate and describes the 2θ value of XRD crystal analysis and its preparation method for the crystal form, but the detailed values or drawings There is no specific mention of.

Entresto tablets contain valsartan-sacubitril trisodium 2.5 hydrate of Korean Patent No. 10-1432821 as an active ingredient. However, despite its excellent effect on heart failure, valsartan-sacubitril trisodium 2.5 hydrate has poor stability and stability. Due to its low solubility, it faces several limitations in the pharmaceutical manufacturing process.

Accordingly, in order to overcome the formulation disadvantages of valsartan-sacubitril, the present inventors developed a co-complex agent with excellent dissolution characteristics and stability, and completed the present invention.

The present invention provides a novel co-complex of sacubitril and valsartan calcium salt hydrate in order to solve the pharmaceutical problems of valsartan-sacubitril pharmaceuticals.

The present invention seeks to solve problems with solubility and stability by providing a co-complex consisting of sacubitril, valsartan, calcium and water in a ratio of 1:1:1.5:4 and having a crystallinity of 30% to 80%. .

The present invention provides a co-complex composed of sacubitril, valsartan, calcium and water in a ratio of 1:1:1.5:4, and the co-complex has a crystallinity of 30% to 80%.

The crystallinity may preferably be 40% to 80%, and more preferably 58% to 77%.

Additionally, the co-complex may have a solubility of 4 mg/mL or more at pH 1.2.

Additionally, the co-complex may have a solubility of 10 mg/mL or more at pH 4.

Additionally, the co-complex may have a solubility of 20 mg/mL or more at pH 6.8.

Additionally, the co-complex may have a solubility of 7 mg/mL or more in purified water.

In addition, the co-complex has a total of related substances that do not exceed 0.1 in a severe stability test at 60°C for 7 days, and the impurity (2R,4S)-4-[(4-hydroxy-4-oxo-butanoyl ) The amount of amino]-2-methyl-5-(4-phenylphenyl)pentanoic acid does not exceed 0.05.

The present invention also relates to co-complexes prepared by a method comprising:

(1) preparing sacubitril/valsartan ammonium salt by mixing sacubitril monoammonium salt, valsartan free acid, and aqueous ammonia; and

(2) Preparing sacubitril/valsartan calcium salt by adding a calcium source to the prepared sacubitril/valsartan ammonium salt.

The calcium source may be one or more selected from the group consisting of calcium chloride, calcium hydroxide, calcium carbonate, and calcium acetate, but is not limited thereto.

This invention

(1) preparing sacubitril/valsartan ammonium salt by mixing sacubitril monoammonium salt, valsartan free acid, and aqueous ammonia; and

(2) adding a calcium source to the sacubitril/valsartan ammonium salt prepared above to produce sacubitril/valsartan calcium salt, where sacubitril, valsartan, calcium, and water are mixed in a ratio of 1:1:1.5:4. It relates to a method for producing a co-composite, characterized in that it is made in proportion and has a crystallinity of 30% to 80%.

The present invention provides a novel co-complex comprising sacubitril and valsartan, 1.5 calcium (Ca) and 4 water molecules (H ₂ O), and the co-complex of the present invention is sacubitril By solving the physicochemical and pharmaceutical problems of valsartan drugs and having excellent dissolution characteristics and stability, it can be provided as an excellent medicine.

Figure 1 shows the sacubitril release rate according to the crystallinity of the present invention.
Figure 2 shows the valsartan release rate according to the crystallinity of the present invention.

The term "co-complex" used in the present invention refers to a simple mixture of two or more substances that does not have a certain crystal structure, but has a certain particle size, solubility, hygroscopicity, and release pattern depending on the degree of crystallinity. Distinguished. In particular, the co-complex of the present invention consists of sacubitril, valsartan, calcium and water in a ratio of 1:1:1.5:4 and has a crystallinity of 30% to 80%, more preferably 40% to 80%. It has a crystallinity degree of , and most preferably has a crystallinity degree of 58% to 77%.

As used herein, the term “crystallinity” refers to the proportion of the substance present in crystalline form in the co-complex.

The term “cumulative particle size distribution percentage 90% (d90)” used in the present invention refers to the particle size at the point where the cumulative total is 90% in the cumulative particle size distribution according to the particle size distribution system.

The term "related substances" used in the present invention refers to substances that are likely to be included in the raw drug product synthesis process or the transportation and storage process of finished drugs, and are impurities to the main active ingredient that can be used for quality assessment of finished drugs. means.

The term "severe stability test" used in the present invention refers to a test to identify decomposition products of pharmaceuticals under severe conditions and to quantify the decomposition products after storing samples at 60°C for 7 days.

Hereinafter, with reference to the attached drawings, embodiments and examples of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present application may be implemented in various forms and is not limited to the embodiments and examples described herein.

Throughout the specification of the present application, when a part “includes” a certain component, this means that it may further include other components rather than excluding other components unless specifically stated to the contrary.

The present invention will be described in more detail through examples below. However, the examples below are for illustrative purposes only and are not intended to limit the scope of the present invention.

[Production Example 1]

Preparation of Co-complex

100 g (0.232 mol) of sacubitril hemicalcium salt was placed in a 2L three-neck round flask, and 1L of ethyl acetate (10 mL/g) and 230 mL (0.46 mol, 2 eq) of 2N aqueous hydrochloric acid solution were sequentially added. After stirring at room temperature for 10 minutes, the mixture was allowed to stand and the organic layer was separated. It was washed twice with 200 mL (2 ml/g) of water, 100 g (1 g/g) of anhydrous sodium sulfate was added, stirred for 30 minutes, filtered, and the filtrate was concentrated.

1L (10 mL/g) of acetone was added to the concentrated oil obtained above, 36 mL (1 eq) of 25% ammonia water was added, and the mixture was stirred at 25°C for 1 hour. The resulting crystals were filtered and washed with 200 mL of acetone to obtain 85 g of sacubitril monoammonium salt (yield 85.6%, ammonium content 3.97%).

50 g of sacubitril monoammonium salt obtained above was placed in a 3L three-necked round flask, and 1.5L (30 mL/g) of water was added. While stirring at room temperature, 36 mL (2 eq) of 25% ammonia water was added, and 64.29 g (1.265 eq) of valsartan was sequentially added. It was stirred for 10 minutes to dissolve clearly and then filtered to remove impurities. It was washed with 0.5L (10V) of water, 68.6 g (4 eq) of calcium chloride dihydrate was added, and stirred at 25°C for 1 hour. The resulting crystals were filtered and dried under vacuum at 50°C to obtain 108.2 g (yield 95%) of sacubitril/valsartan calcium salt hydrate (co-complex) as shown below.

[Test Example 1]

Co-complex component analysis

In the process of preparing the co-complex according to Preparation Example 1, valsartan was excluded and pure amorphous sacubitril-calcium was secured. In addition, in the same process, sacubitril was excluded and pure crystalline valsartan-calcium was secured. Component analysis of the co-complex of the present invention was performed using the two samples obtained by the above method as standards.

The contents of sacubitril-calcium and valsartan-calcium in the co-complex were measured using HPLC analysis, HPLC was used as the analysis device, and the analysis conditions were as follows.

(1) Preparation of standard solution: Precisely weigh 10.2 mg of sacubitril-calcium and 12.9 mg of valsartan-calcium, place in a 100 mL volumetric flask, dissolve in diluent (D.W: Acetonitrile=2:8), and mark.

(2) Preparation of sample solution: Accurately weigh 10 mg of the co-complex, place in a 100 mL volumetric flask, dissolve in diluent, and mark.

(3) Analysis conditions

① Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 254 nm)

② Column: CAPCELL PAK C18 MG type (4.6 Х 250 mm, 5 μm)

③ Flow rate: 1.0 mL/min

④ Injection volume: 10 μL

⑤ Column temperature: constant temperature around 40℃

⑥ Detection order: Valsartan - Sacubitril

⑦ Mobile phase A: mixture of purified water, acetonitrile, and trifluoroacetic acid (950:50:1, v/v/v)

⑧ Mobile phase B: Acetonitrile and trifluoroacetic acid mixture (1000:1, v/v)

⑨ Mobile phase ratio A:B = 40:60

As a result of measuring the contents of sacubitril-calcium (Sacu-Ca) and valsartan-calcium (Val-Ca) in the co-complex according to the above analysis conditions, sacubitril constituting the co-complex is shown in Table 1 below. -The contents of calcium and valsartan-calcium showed an error of less than 0.1% compared to the standard product, and through this, it was confirmed that the co-complex was composed of sacubitril-calcium and valsartan-calcium at an exact molar ratio of 1:1.

[Test Example 2]

Crystallinity evaluation

In order to prepare samples with various degrees of crystallinity, the cocomplex prepared according to Preparation Example 1 was dissolved in methanol (MeOH) and then crystallized through a concentration process. The crystallized sample was dried and then ground to prepare Example 1.

In addition, Examples 2 to 4 were prepared by including Example 5 and Example 1 prepared according to Preparation Example 1 at the ratios of 37.5:62.5, 62.5:37.5, and 75:25, respectively.

In addition, Example 7 was prepared by mixing crystalline sacubitril-calcium and crystalline valsartan-calcium at a molar ratio of 50:50, and Example 6 was prepared by mixing Example 7 and Example 1 at a molar ratio of 80:20. did.

The crystallinity of the present invention was measured using the following equipment and analysis conditions.

Analysis device: BRUKER D8 ADVANCE

Analysis conditions: 40kV, 40mA, 4~40 degree, Cu KaI - 1.5148Å

Software: DIFFRAC.EVA (V5.2)

The crystallinity degrees of sacubitril-calcium and valsartan-calcium were 72.6% and 84.4%, respectively, and the crystallinity degrees of Examples 1-7 are shown in Table 2.

[Test Example 3]

Cost volume and particle size evaluation

In general, the physical properties of a drug, such as particle size, can affect the release, solubility, hygroscopicity, and stability of the drug, and specific volume and particle size were measured using the following methods.

To measure the specific volume of Example 1-7, 1 to 2 g of each sample was placed in a 10 mL measuring cylinder, and the specific volume was measured by tap filling more than 100 times until there was no change in volume. In addition, in order to analyze the particle size of Examples 1-7, the particle size was analyzed using a laser diffraction test. About 100 mg of each sample was dispersed in 10 mL of ethyl acetate (EA), sonicated for 1 minute, and stirred for 2 minutes. Wet analysis was performed, and the specific volume and particle size analysis results measured using the above method are shown in Table 3 below.

As shown in Table 3, Examples 1 to 7 showed similar specific volumes, and Examples 2 to 7 showed a higher particle size distribution compared to Example 1.

[Test Example 4]

Solubility test evaluation

To evaluate the solubility of the co-complex according to its crystallinity, solubility tests were conducted on samples at pH 1.2, 4.0, 6.8, and purified water. The above example sample was added in excess to each pH solution to create a supersaturated solution and dissolved in a shaking incubator for 24 hours at 37°C. Then, a certain amount was taken, filtered, diluted with a diluent to analyze the content, and substituted into the linear equation. The concentration was calculated and the results are shown in Table 4 below.

As shown in Table 4, the samples of Examples 1 to 7 showed similar solubility at pH 1.2, 4.0, 6.8, and purified water, and the samples of Examples 4 to 7 had excellent solubility at all pH and purified water. You can see that

[Test Example 5]

Stability test evaluation

In order to evaluate the stability of the co-complex according to the crystallinity degree, a severe stability test (60°C, 3 days) was conducted on examples with different crystallinity degrees, and is shown in Table 5 below. In this case, the impurity A in Table 5 was It refers to (2R,4S)-4-[(4-hydroxy-4-oxo-butanoyl)amino]-2-methyl-5-(4-phenylphenyl)pentanoic acid as a hydrolyzate of sacubitril. .

As shown in Table 5, it can be seen that the change in the amount of impurity A and total related substances is the largest in Example 1, and the change in the amount of impurity A and total related substances is small in Examples 2 to 7. You can.

As shown in Table 6, it can be seen that the change in the amount of impurity A and total related substances is the largest in Example 1, and the change in the amount of impurity A and total related substances is small in Examples 2 to 7. You can.

In addition, when comparing according to Article 21 of the Pharmaceutical Equivalence Test Standards notified by the Ministry of Food and Drug Safety and the criteria for determining equivalence of dissolution patterns in Annex 6, when the value of the similarity factor is 50 or more, it is judged to be equivalent. In the above test example, when the dissolution patterns of Example 5 were compared with the control group, Examples 2 to 4 and Examples 6 to 7 were judged to be equivalent to Example 5 with a similarity factor of 50 or more, but Example 1 It can be seen that the similarity factor is less than 50, which is not equivalent to Example 5.

As shown in Table 7, the 14-day stress stability test results were similar to the 3-day and 7-day results, showing that Example 1 showed the greatest change in the amount of impurity A and total related substances, and Example 2 It was found that there was little change in the amount of impurity A and total related substances in to 7.

[Test Example 6]

Emission profile evaluation

To confirm the drug release rate according to crystallinity, a test was conducted according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia, and the content was analyzed using HPLC. A standard solution was prepared using Example 5 and analyzed under the following conditions.

(1) Drug release test conditions: Korean Pharmacopoeia Dissolution Test Method 2 (Paddle Method)

(2) Preparation of standard solution: Accurately weigh about 128.05 mg of sacubitril/valsartan calcium salt hydrate standard (111.11 mg as sacubitril/valsartan) into a 50 mL volumetric flask, and add diluent (mixture of water and acetonitrile (50:1) 50)) was added and ultrasonic shaken to completely dissolve, and then marked. Take 5 mL of the above solution, put it in a 50 mL volumetric flask, add 7.5 mL of acetonitrile, mark it as a dissolution test solution with pH 4.5, and use the filtered solution as a standard solution.

(3) Preparation of test solution: Each example sample corresponding to 200 mg of sacubitril and valsartan was placed in an eluent vessel, and 5 mL of the eluate was taken at each specified time and supplemented with the same amount of test solution. The collected eluate was filtered through a 0.45 μm PVDF syringe filter, and the content was analyzed through HPLC using the sample solution.

(4) Analysis conditions

① Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 254 nm, HPLC system)

② Column: X-Bridge C18 (4.6 × 150 mm, 5 μm) or equivalent column

③ Column temperature: constant temperature around 40℃

④ Sample temperature: constant temperature around 10℃

⑤ Injection volume: 10 μL

⑥ Flow rate: 1.0 mL/min

⑦ Mobile phase: Mixture of mobile phase A and mobile phase B (1:1)

(a) Mobile phase A: purified water, a mixture of acetonitrile and trifluoroacetic acid (950:50:1), (b) Mobile phase B: a mixture of acetonitrile and trifluoroacetic acid (1000:1)).

The sacubitril release test results analyzed under the above conditions are shown in Figure 1 and Table 8 below, and the release test results of valsartan are shown in Figure 2 and Table 9 below.

As shown in Figure 1 and Table 8, it can be seen that Examples 3 to 5 are faster than other examples in terms of initial release rate, and Examples 2 to 7 show similar release rates at the end of release. However, Example 1 showed a low release rate. Therefore, it can be seen that Examples 3 to 5 show excellent release patterns with respect to the sacubitril drug release rate.

In addition, when comparing according to Article 21 of the Pharmaceutical Equivalence Test Standards notified by the Ministry of Food and Drug Safety and the criteria for determining equivalence of dissolution patterns in Annex 6, when the value of the similarity factor is 50 or more, it is judged to be equivalent. In the above test example, when the dissolution patterns of Example 5 were compared with the control group, Examples 2 to 4 and Examples 6 to 7 were judged to be equivalent to Example 5 with a similarity factor of 50 or more, but Example 1 It can be seen that the similarity factor is less than 50, which is not equivalent to Example 5.

As shown in Figure 2 and Table 9, it can be seen that Examples 3 to 7 are faster than other examples in terms of initial release rate, and Examples 2 to 7 show similar release rates at the end of release. However, Example 1 showed a low release rate. Therefore, it can be seen that Examples 3 to 7 show excellent release patterns with respect to the valsartan drug release rate.

In addition, when comparing the dissolution patterns of Example 5 with the control group, Examples 3 to 4 and Examples 6 to 7 had a similarity factor of 50 or more and were determined to be equivalent to Example 5, but Examples 1 to 2 It can be seen that the similarity factor is less than 50, which is not equivalent to Example 5.

[Test Example 7]

Hygroscopicity evaluation

To evaluate hygroscopicity according to crystallinity, a hygroscopicity test was conducted on examples with different crystallinity degrees, and the results are shown in Table 10 below.

As shown in Table 10, it can be seen that Examples 6 and 7, which have a high degree of crystallinity, exhibit low hygroscopicity compared to other examples.

[Test Example 8]

Rat pharmacokinetic evaluation

In order to evaluate the pharmacokinetic parameters according to the degree of crystallinity, a pharmacokinetic test was performed on three examples with different degrees of crystallinity, and the results are shown in Tables 11 and 12 below.

As shown in Tables 11 and 12, all pharmacokinetic parameters of sacubitril and valsartan of Example 3 (crystallinity 58.6%), Example 5 (crystallinity 64.4%), and Example 7 (crystallinity 76.4%) were similar to those of sacubitril and valsartan. The significance level (p-value) according to the crystallinity of valsartan calcium salt hydrate was greater than 0.05. Therefore, it can be seen that they are equivalent to each other in the corresponding crystallinity range.

Claims (13)

A co-complex composed of sacubitril, valsartan, calcium and water in a ratio of 1:1:1.5:4, wherein the co-complex has a crystallinity of 30% to 80%.
The co-complex according to claim 1, wherein the degree of crystallinity is 40% to 80%.
The co-complex according to claim 1, wherein the degree of crystallinity is 58% to 77%.
The co-complex according to claim 1, wherein the co-complex has a solubility of 4 mg/mL or more at pH 1.2.
The co-complex according to claim 1, wherein the co-complex has a solubility of 10 mg/mL or more at pH 4.
The co-complex according to claim 1, wherein the co-complex has a solubility of 20 mg/mL or more at pH 6.8.
The co-complex according to claim 1, wherein the co-complex has a solubility in purified water of 7 mg/mL or more.
The co-composite according to claim 1, wherein the total amount of related substances in the co-composite does not exceed 0.1 in a severe stability test at 60°C for 7 days.
The method of claim 1, wherein the co-complex contains the impurity (2R,4S)-4-[(4-hydroxy-4-oxo-butanoyl)amino]-2-methyl in a stress stability test at 60°C for 7 days. -A co-complex characterized in that the amount of 5-(4-phenylphenyl)pentanoic acid does not exceed 0.05.
The co-complex according to claim 1, characterized in that it is prepared by a method comprising:
(1) preparing sacubitril/valsartan ammonium salt by mixing sacubitril monoammonium salt, valsartan free acid, and aqueous ammonia; and
(2) Preparing sacubitril/valsartan calcium salt by adding a calcium source to the prepared sacubitril/valsartan ammonium salt.
The method of claim 10, wherein the calcium source is a co-complex, characterized in that at least one selected from the group consisting of calcium chloride, calcium hydroxide, calcium carbonate, and calcium acetate. .
(1) preparing sacubitril/valsartan ammonium salt by mixing sacubitril monoammonium salt, valsartan free acid, and aqueous ammonia; and
(2) Preparing sacubitril and valsartan calcium salts by adding a calcium source to the prepared sacubitril and valsartan ammonium salts.
A method for producing a co-complex comprising sacubitril, valsartan, calcium and water in a ratio of 1:1:1.5:4 and having a degree of crystallinity of 30% to 80%.

The method of claim 12, wherein the calcium source is calcium chloride, calcium hydroxide, calcium carbonate, and calcium acetate.