KR102756994B1 - Co-amorphous form of sacubitril, valsartan, and nicotinamide - Google Patents

Abstract

The present invention relates to a co-amorphous form of sacubitril co-crystal and valsartan, and more specifically, to a sacubitril co-amorphous form in which sacubitril/coformer/valsartan are combined, wherein the coformer is at least one selected from polyethylene glycol, nicotinamide, and caffeic acid.

Description

CO-AMORPHOUS FORM OF SACUBITRIL, VALSARTAN, AND NICOTINAMIDE

The present invention relates to a co-amorphous form of sacubitril, valsartan, and nicotinamide.

As the world ages, the incidence of heart failure is also rising rapidly. In Korea, which is showing a faster aging trend than any other country, the number of heart failure patients increased by more than 22% from 2009 to 2013 over the five years, and the cost of treatment for heart failure also increased by more than 57% from 47.3 billion won in 2009 to 74.3 billion won in 2016. The number of deaths due to heart failure is also increasing rapidly.

Despite the fact that the risk of heart failure is becoming more serious by the day, no drug other than ACE inhibitors had been developed that showed significant effects. In the meantime, a combination drug of sacubitril and valsartan was developed, which garnered attention as a new drug for heart failure introduced 15 years after ACE inhibitors and the first treatment that surpassed ACE inhibitors, and is currently marketed under the trade name Entresto™.

Entresto™ reduces the risk of heart failure through a dual action: valsartan blocks the angiotensin II type 1 receptor, which blocks the harmful effects of angiotensin II on the cardiovascular system; and sacubitril blocks an enzyme called neprilysin, which enhances the heart's protective neurohormonal system.

The active ingredient of Entresto™ is sacubitril/valsartan sodium 2.5 hydrate, the contents of which are disclosed in International Patent Publication No. WO 2007/056546 A1 (Patent Document 1) (whereby the entire contents of the above patent document are incorporated herein as prior art).

However, sacubitril/valsartan sodium 2.5 hydrate has poor stability and water solubility, poor ease of preparation, and in particular, it is difficult to store at room temperature, so there is a problem in storing and preserving sacubitril/valsartan sodium 2.5 hydrate by refrigerating it at 4℃ or lower.

Additionally, Sacubitril itself is known to be an unstable compound that decomposes under acidic and alkaline conditions, and has the problem of being unstable when stored at room temperature and in moisture.

Ultimately, their unstable stability and low solubility issues may lead to problems that lead to reduced absorption rates in the body.

WO 2007/056546 A1 (2007.05.18.)

The purpose of the present invention is to overcome the problems of low stability, water solubility and ease of formulation of sacubitril/valsartan sodium 2.5 hydrate and to provide a new sacubitril/coformer/valsartan co-amorphous which can be usefully used in the treatment of hypertension and heart failure.

The present invention has been devised to solve the problems of the above-described prior art,

As a co-amorphous form of sacubitril/coformer/valsartan,

The present invention provides a co-amorphous sacubitril/co-former/valsartan, characterized in that the co-former comprises at least one selected from polyethylene glycol, nicotinamide, ethylcellulose, and caffeic acid.

In addition, in the present invention, the co-former is ethyl cellulose,

Provided is a co-amorphous form of sacubitril/coformer/valsartan, characterized by a diffraction angle (2θ) on a powder XRD spectrum as shown in Fig. 3.

In addition, in the present invention, the co-former is nicotinamide,

Provided is a co-amorphous form of sacubitril/coformer/valsartan, characterized by a diffraction angle (2θ) on a powder XRD spectrum as shown in Fig. 7.

In addition, in the present invention, the co-former is polyethylene glycol,

Provided is a co-amorphous sacubitril/coformer/valsartan, characterized by a diffraction angle (2θ) on a powder XRD spectrum as shown in Fig. 11.

In addition, in the present invention, the co-former is caffeic acid,

Provided is a co-amorphous sacubitril/coformer/valsartan, characterized by a diffraction angle (2θ) on a powder XRD spectrum as shown in Fig. 15.

In addition, the present invention provides a pharmaceutical composition for treating heart failure comprising the co-formula of the present invention as an effective ingredient.

In addition, a step of preparing a mixed solution by dissolving sacubitril, and at least one co-former selected from polyethylene glycol, nicotinamide, ethyl cellulose and caffeic acid, and valsartan in an organic solvent; and

Provided is a method for producing amorphous sacubitril/coformer/valsartan, comprising a step of evaporating the solvent of the above mixed solution.

In addition, in the manufacturing method of the present invention, the organic solvent is methanol, ethanol, acetone, ethyl methyl ketone, ethyl acetate, n-propyl acetate, dichloromethane, acetonitrile or a mixture thereof, and a method for manufacturing sacubitril/coformer/valsartan co-amorphous is provided.

The sacubitril/coformer/valsartan combination drug according to the present invention has excellent stability, good solubility, particle flow, uniformity, electrostatic force, etc., and thus has advantages in formulation.

In addition, it has excellent form and properties for use as a drug due to its properties such as ease of manufacture, high purity, high stability and low hygroscopicity.

Furthermore, the manufacturing method of the present invention has a simple manufacturing step and operation method, and has a high yield, thereby showing the effect of lowering the manufacturing production cost.

Figure 1 is a powder XRD pattern for sacubitril/ethylcellulose cocrystal.
Figure 2 is a DSC thermogram for sacubitril/ethylcellulose cocrystal.
Figure 3 is a powder XRD pattern for the sacubitril/ethylcellulose/valsartan combination drug.
Figure 4 is a DSC thermogram of the sacubitril/ethylcellulose/valsartan combination drug.
Figure 5 is a powder XRD pattern for sacubitril/nicotinamide cocrystal.
Figure 6 is a DSC thermogram for sacubitril/nicotinamide cocrystal.
Figure 7 is a powder XRD pattern for the sacubitril/nicotinamide/valsartan combination drug.
Figure 8 is a DSC thermogram of the sacubitril/nicotinamide/valsartan combination drug.
Figure 9 is a powder XRD pattern for the sacubitril/polyethylene glycol-6000 cocrystal.
Figure 10 is a DSC thermogram for the sacubitril/polyethylene glycol-6000 cocrystal.
Figure 11 is a powder XRD pattern for the sacubitril/polyethylene glycol-6000/valsartan combination drug.
Figure 12 is a DSC thermogram of the sacubitril/polyethylene glycol-6000/valsartan combination drug.
Figure 13 is a powder XRD pattern for sacubitril/caffeic acid co-crystal.
Figure 14 is a DSC thermogram for sacubitril/caffeic acid co-crystal.
Figure 15 is a powder XRD pattern for the combination drug sacubitril/caffeic acid/valsartan.
Figure 16 is a DSC thermogram of the sacubitril/caffeic acid/valsartan combination drug.
Figure 17 is an XRD pattern of sacubitril powder.
Figure 18 is a DSC thermal analysis diagram for sacubitril.
Figure 19 is an XRD pattern of valsartan powder.
Figure 20 is a DSC thermal analysis diagram for valsartan.
Figure 21 is an XRD pattern of sacubitril/valsartan powder.
Figure 22 is a DSC thermogram for sacubitril/valsartan.
Figure 23 is a photograph comparing the results of solubility tests of examples and comparative examples of the present invention in acetone solvent (listed in the order of comparative example, control group (sacubitril salt-free and valsartan mixture), example 1, example 2, example 3, and example 4 from left to right).
Figure 24 is a photograph comparing the results of solubility tests of examples and comparative examples of the present invention in an acenitrile solvent (listed in the order of comparative example, control group (sacubitril salt-free and valsartan mixture), example 1, example 2, example 3, and example 4 from left to right).
Figures 25 and 26 are graphs showing the results of stability tests.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention is:

It is a co-amorphous form of sacubitril/coformer/valsartan.

The above-mentioned co-former may be at least one selected from polyethylene glycol, nicotinamide, ethyl cellulose, and caffeic acid.

Here, the co-amorphous refers to a solid state in which two or more compound molecules interact but do not form a crystal arrangement.

In particular, the present invention preferably selects valsartan as the angiotensin II inhibitor, and valsartan participates in the crystal structure of a co-former with sacubitril, thereby changing its properties.

As a specific example, when the coformer is polyethylene glycol and nicotinamide, a sacubitril/coformer co-crystal is formed, but when valsartan is added to this, a co-amorphous form is formed.

Although the amorphous form has high solubility, it is generally lower in stability than the crystalline form. However, the co-amorphous form of the present invention has a surprising effect of showing stability equivalent to or greater than that of the crystalline form while having high solubility. A more detailed understanding of this can be confirmed through the examples and experimental examples described below.

The above-mentioned amorphous hollow particle of the present invention can be used in a pharmaceutical composition for treating heart failure, and since it has high stability and solubility, it is easy to store, and improved bioavailability can be expected. In addition, since it has high purity and good particle flow, uniformity, and electrostatic force, it can be usefully used in formulations.

The composition of the present invention can be prepared in various pharmaceutically acceptable dosage forms such as injections and transdermal agents, but oral administration is preferred due to the nature of the desired effect.

Formulations for oral administration include powders, granules, tablets, capsules, soft capsules, and pills.

In particular, when the above formulation is a tablet, it may specifically be a tablet, a film-coated tablet, a sugar-coated tablet, a multilayer tablet, a cored tablet, an inner-core tablet, an orally disintegrating tablet, a chewable tablet, an effervescent tablet, a dispersible tablet, or a dissolving tablet.

Another aspect of the present invention is:

A step of preparing a mixed solution by dissolving sacubitril, and at least one co-former selected from ethylcellulose, nicotinamide, and caffeic acid, and valsartan in an organic solvent; and

A method for producing amorphous sacubitril/coformer/valsartan, comprising a step of evaporating the solvent of the above mixed solution.

The above organic solvent may be a solvent that commonly exhibits a solubility of 40 mg/mL or higher for sacubitril, the co-former, and valsartan, and examples of possible solvents include methanol, ethanol, acetone, ethyl methyl ketone, ethyl acetate, n-propyl acetate, dichloromethane, acetonitrile, or mixtures thereof.

Hereinafter, the present invention will be described in more detail with examples. However, it should be made clear that the following examples are only for the purpose of detailed explanation of the invention and are not intended to limit the scope of the rights thereby.

Example

Example 1 - Sakubitril / Ethyl cellulose / Valsartan Combination drugs manufacturing

After adding 1 g of sacubitril and 10 ml of methylene chloride, the mixture was stirred at room temperature for 20 minutes. Then, 1 g of ethyl cellulose was added and stirred for 30 minutes. After that, all of the methylene chloride was evaporated using a concentrator until crystals were precipitated. A novel sacubitril hollow amorphous form was obtained by vacuum drying at room temperature for more than 24 hours.

0.2 g of sacubitril/ethyl cellulose co-amorphous and 6 ml of methanol (30 V) were added and stirred at room temperature for 20 minutes. Then, valsartan (1.2 eq) was added and stirred for 30 minutes. After that, all methanol was evaporated using a condenser until crystals were precipitated. Then, 2 ml of isopropyl alcohol (10 V) was added and stirred for 20 minutes, and all isopropyl alcohol was evaporated using a condenser. A novel sacubitril/ethyl cellulose/valsartan co-amorphous was obtained by vacuum drying at room temperature for more than 24 hours.

The powder XRD spectrum and differential scanning calorimeter thermogram of the sacubitril/ethylcellulose/valsartan combination drug prepared in Example 1 are attached to FIGS. 3 and 4, respectively.

Example 2 - Sakubitril /nicotinamide/ Valsartan Combination drugs manufacturing

After adding 1 g of Sacubitril and 10 ml of acetone, the mixture was stirred at room temperature for 20 minutes. Then, 1 g of Nicotinamide was added and stirred at 50°C for 30 minutes. After that, all of the acetone was evaporated using a concentrator until crystals were precipitated. A novel Sacubitril co-crystal was obtained by vacuum drying at room temperature for more than 24 hours.

Sacubitril/nicotinamide co-crystal 0.2 g and methanol 6 ml (30 V) were added and stirred at room temperature for 20 minutes. Then, valsartan (1.2 eq) was added and stirred for 30 minutes. After that, all methanol was evaporated using a condenser until crystals were precipitated. Then, 2 ml (10 V) of isopropyl alcohol was added and stirred for 20 minutes, and all isopropyl alcohol was evaporated using a condenser. A novel sacubitril/nicotinamide/valsartan co-crystal amorphous form was obtained by vacuum drying at room temperature for more than 24 hours.

The powder XRD spectrum and differential scanning calorimeter thermogram of the sacubitril/nicotinamide/valsartan combination drug prepared in Example 2 are attached to Figs. 7 and 8, respectively.

Example 3 - Sakubitril / Polyethylene glycol / Valsartan Combination drugs manufacturing

After adding 1 g of sacubitril and 5 ml of methylene chloride, the mixture was stirred at room temperature for 20 minutes. Then, 1 g of polyethylene glycol-6000 (PEG-6000) was added and stirred for 30 minutes. After that, all of the methylene chloride was evaporated using a concentrator until crystals were precipitated. A novel sacubitril co-crystal was obtained by vacuum drying at room temperature for more than 24 hours.

0.2 g of sacubitril/polyethylene glycol-6000 cocrystal and 6 ml of methanol (30 V) were added and stirred at room temperature for 20 minutes. Then, valsartan (1.2 eq) was added and stirred for 30 minutes. After that, all methanol was evaporated using a condenser until crystals were precipitated. Then, 2 ml of isopropyl alcohol (10 V) was added and stirred for 20 minutes, and all isopropyl alcohol was evaporated using a condenser. A novel sacubitril/polyethylene glycol/valsartan cocrystal was obtained by vacuum drying for more than 24 hours at room temperature.

The powder XRD spectrum and differential scanning calorimeter thermogram of the sacubitril/polyethylene glycol/valsartan combination drug prepared in Example 3 are attached to Figs. 11 and 12, respectively.

Example 4 - Sakubitril / Caffeic acid + Valsartan Combination drugs manufacturing

After adding 1 g of sacubitril and 15 ml of methanol, the mixture was stirred at room temperature for 20 minutes. Then, 1 g of caffeic acid was added and stirred for 30 minutes. After that, all methanol was evaporated using a concentrator until crystals were precipitated. A novel sacubitril co-crystal was obtained by vacuum drying at room temperature for more than 24 hours.

0.2 g of sacubitril/caffeic acid co-amorphous was added and 6 ml of methanol (30 V) was stirred at room temperature for 20 minutes. Then, valsartan (1.2 eq) was added and stirred for 30 minutes. After that, all methanol was evaporated using a condenser until crystals were precipitated. Then, 2 ml of isopropyl alcohol (10 V) was added and stirred for 20 minutes, and all isopropyl alcohol was evaporated using a condenser. A novel sacubitril/caffeic acid/valsartan co-amorphous was obtained by vacuum drying at room temperature for more than 24 hours.

The powder XRD spectrum and differential scanning calorimeter thermogram of the sacubitril/caffeic acid/valsartan combination drug prepared in Example 1 are attached to FIGS. 15 and 16, respectively.

Comparative example

LCZ-696, the raw material of commercially available Entresto™

Experimental example

Solubility Test

After dissolving in each solvent, they were left at room temperature for about 1 hour and then observed with the naked eye.

The results are as shown in Figs. 23 and 24. Here, Fig. 23 uses acetone as a solvent, and Fig. 24 uses acetonitrile as a solvent, and they are listed in the following order from left to right: comparative example, control group (sacubitril salt-free and valsartan mixture), example 1, example 2, example 3, and example 4.

As can be seen from the test results, the comparative example showed a cloudy appearance, whereas Examples 1 to 4 all showed a transparent, clear appearance, confirming excellent solubility.

Stability Test

Accelerated testing was conducted for 4 weeks at room temperature, 40℃ temperature, and 75±5% humidity.

The results were as shown in Table 1, Table 2, and Figures 25 and 26 below.

Room temperature 1 week 2 weeks 3 weeks 4 weeks Comparative example 100.00% 100.00% 99.87% 99.85% Control group 100.00% 99.77% 99.73% 99.67% Example 1 100.00% 100.00% 99.93% 99.92% Example 2 100.00% 100.00% 99.86% 99.84% Example 3 100.00% 99.57% 99.52% 99.45% Example 4 100.00% 99.65% 99.60% 99.53%

40℃ 1 week 2 weeks 3 weeks 4 weeks Comparative example 100.00% 100.00% 99.85% 99.78% Control group 99.79% 99.67% 99.55% 99.45% Example 1 100.00% 100.00% 99.92% 99.88% Example 2 100.00% 100.00% 99.89% 99.85% Example 3 99.58% 99.55% 99.47% 99.38% Example 4 99.66% 99.65% 99.52% 99.41%

Claims (7)

Co-amorphous form of sacubitril, valsartan, and nicotinamide. delete delete delete A pharmaceutical composition for treating heart failure, comprising the co-amorphous form of claim 1 as an effective ingredient. delete delete