KR20190118400A - Novel salt of sugammadex and preparation method thereof - Google Patents

Abstract

The present invention relates to novel salts of sugammadex and a preparation method thereof. Specifically, the present invention relates to: metal salts such as sugammadex magnesium salts, calcium salts and potassium salts; organic salts such as lysine, arginine, meglumine and diolamine; and a preparation method thereof.

Description

Novel salt of sugammadex and preparation method

The present invention relates to novel salts of Sugarmadex and methods for their preparation. Specifically, the present invention is a metal salt such as sugar maddex magnesium salt, calcium salt, potassium salt; And organic salts such as lysine, arginine, meglumine, diolamine, and methods for producing the same.

Sugammadex is 6-per-deoxy-6-per- (2-carboxyethyl) thio-gamma-cyclodextrin, and has the structure of Formula 5 below.

<Formula 5>

Sugamadex is a drug that has a reversible effect of neuromuscular blockade induced by rocuronium, vecuronium, and pancuronium, the neuromuscular blocking agents (NMBA) used for general anesthesia. to be. In other words, it reverses drug-induced neuromuscular blockade and reduces the amount of neuromuscular blocker capable of binding to nicotinic receptors in neuromuscular junctions.

In addition, Sugarmadex is a "gamma-cyclodextrin" derivative as shown in Formula 5, and is a conical three-dimensional structure with a polar hydroxyl group inside and a carboxy group on the outside. This structural feature blocks the muscle relaxation action by enclosing the steroidal relaxant in a capsule form to form a 1: 1 conjugate to inhibit the effect. Particularly, the neuromuscular blocker is known to have a high binding constant with rocuronium, because its dissociation constant is very high and its dissociation constant is very low.

^Bridion®® , a product containing "Sugardex dex sodium salt" as an active ingredient, is commercially available from Korea.

Korean Patent Registration Publication No. 10-0716524 discloses a method for preparing sugar maddex sodium. Examples of the present invention disclose a method for preparing a sugarmadex sodium salt obtained by reacting 3-mercapto propionic acid with iodide gamma-cyclodextrin in the presence of sodium hydroxide and dimethylformamide. Another embodiment discloses a method for preparing an iodide intermediate through the reaction of gamma-cyclodextrin and iodine in the presence of triphenylphosphine and dimethylformamide, but triphenylphosphine oxide, which is difficult to remove, is produced as a by-product. There are disadvantages.

In International Patent Publication No. 2012/025937, phosphorus pentachloride and gamma-cyclodextrin are reacted to synthesize chloro gamma-cyclodextrin intermediates, and the sugarmadex sodium salt is reacted with 3-mercaptopropionic acid in the presence of sodium chloride and dimethylformamide. It is disclosed that it is obtained through a coupling reaction of.

In addition, International Patent Publication No. 2014/125501 discloses that a sugarmadex sodium salt is produced by the coupling reaction of 3-mercapto propionic acid and a chlorolated intermediate in the presence of sodium methoxide and dimethylformamide. In addition, International Patent Publication No. 2016/194001 discloses a method for synthesizing sugarmadex in the form of free acid.

However, sugarmadex sodium salts contain sodium, which can cause problems due to sodium overdosing in patients requiring sodium dietary control, such as cardiovascular disease.

In addition, sugarmadex used as an intravenous injection should satisfy physicochemical criteria such as good solubility and stability. In other words, when the drug is administered intravenously, the blood concentration can be obtained immediately, but it is important that the drug remains in solution after injection and that no precipitate is formed in the vascular system. Since the solubility in the aqueous solution is low in the form of the sugar maddex free acid, it is necessary to secure sufficient solubility. Therefore, it was attempted to develop other salts that are pharmaceutically applicable to intravenous injection while increasing solubility, but not sugarmadex free acid or sodium salt.

Therefore, the present inventors have developed a new sugarmadex salt having little change in properties in solid and aqueous solution and minimizing the generation of flexible substances.

The present invention seeks to provide a novel salt of Sugarmadex, which must be a salt that has physicochemical characteristics such as excellent solubility and stability, can be mass-produced in high purity, and can be used for intravenous infusion.

The present invention provides a novel salt of sugarmadex represented by the following formula (1) or (2), which is a drug that can be used as a drug for reversing drug-induced neuromuscular blockade.

[Formula 1]

[Formula 2]

In the present invention, A of Formula 1 may be potassium, arginine, lysine, diolamine, or meglumine, and B of Formula 2 may be magnesium or calcium, but is not limited thereto.

In order to commercially produce the novel salts of sugar maddex of the present invention, mono-addition salts or mono-addition salts or sugars of sugar maddex are added by adding mono-monic acid addition salts or di-anion salts as starting materials. A method of preparing a dexionic divalent addition salt; Alternatively, the present invention provides a method for preparing a dicatalytic divalent salt of sugar maddex through a cation exchange reaction using a sugar maddex monocationic addition salt as a starting material.

That is, the novel salt of the present invention may be in the form of a sugar maddex monocationic salt of formula (3), or a sugar maddex dicationic salt of formula (4).

[Formula 3]

[Formula 4]

Sugarmadex free acid used in the present invention may be crystalline or amorphous, and the sugarmadex base addition salt according to the present invention may also be crystalline or amorphous.

The novel salts of the sugarmadex of the present invention have an increase in the amount of the individual analogues of less than 0.1% and the total amount of the total analogues of less than 1% for 30 weeks under long-term storage conditions of 25 ℃ ± 2 ℃, RH 65% ± 5% It is preferable.

The novel salts of the sugarmadex of the present invention have an increase in the amount of the individual analogues of less than 0.1% and the total amount of the total analogues of less than 1% for 30 weeks under accelerated storage conditions of 40 ℃ ± 2 ℃, RH 75% ± 5% It is preferable.

The novel salts of Sugarmadex of the present invention preferably increase the total amount of analogues to less than 1% for 30 weeks under severe storage conditions of 60 ° C ± 2 ° C.

The novel salts of sugarmadex according to the present invention

(a) dissolving a form of sugarmadex capable of forming a salt, and a pharmaceutically acceptable salt, in a solvent selected from the group consisting of polar protic solvents, polar aprotic solvents, and mixtures thereof;

(b) adding anti-solvent to the solution to produce a solid; And

(c) recovering the resulting solid.

Specifically, as shown in Scheme 1 below, the sugarmadex free acid is dissolved in a polar protic solvent, a polar aprotic solvent or a mixture thereof together with a pharmaceutically acceptable anti-salt and then reacted, and an antisolvent is added thereto. It can be prepared by solidification.

Scheme 1

Also, as shown in Scheme 2 below, the sugarmadex monocationic addition salt may be prepared by carrying out a cation exchange reaction with a pharmaceutically acceptable salt which is a dicationic addition salt.

Scheme 2

Specifically, the method for producing the sugar maddex base addition salt,

(1) dissolving and reacting sugarmadex free acid and a pharmaceutically acceptable salt in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent, and a mixed solvent thereof; and

(2) solidifying the sugar maddex base addition salt by adding an anti-solvent to the solution in which the reaction of step 1 is completed; And

(3) recovering the resulting solid.

Another method for preparing a sugar maddex base addition salt is

(1) A pharmaceutically acceptable anti-salt, which is a sugar maddex monocationic addition salt and a dicationic addition salt, is dissolved in a solvent selected from the group consisting of a polar protic solvent, a polar aprotic solvent, and a mixed solvent thereof. Reacting, and

(2) solidifying the sugar maddex base addition salt by adding an anti-solvent to the solution in which the reaction of step 1 is completed; And

(3) recovering the resulting solid.

The pharmaceutically acceptable salt used in Scheme 1 may be a monocationic substance, in which one sugarmadex molecule and eight cationic substances may bind, and may be used in an amount of at least 8.0 equivalents based on one equivalent sugarmadex. Can be.

The monocationic material may be an organic amine or a material represented by the following Chemical Formula 6.

The organic amine may be lysine, arginine, diolamine or meglumine, but is not limited thereto and may include all forms of carboxylic acid.

[Formula 6]

In Chemical Formula 6,

A can be potassium or lithium and X can be halogen, hydroxy, acetate, carboxylate, sulfate, nitrate, triflate or derivatives thereof.

The pharmaceutically acceptable salt used in Scheme 2 is a dicationic material, which can be combined with one molecule of sugarmadex and four cationic materials, and is used in an amount of at least 4.0 equivalents based on one equivalent of sugarmadex. Can be.

The dicationic material may be a material represented by the following formula (7).

[Formula 7]

In Chemical Formula 7,

B is magnesium or calcium and X can be halogen, hydroxy, acetate, carboxylate, sulfate, nitrate, triflate or derivatives thereof.

The polar protic solvents used in Schemes 1 and 2 are water, methyl alcohol, ethyl alcohol, isopropyl alcohol, t-butyl alcohol, sec-butyl alcohol, n-butyl alcohol, n-amyl alcohol and mixed solvents thereof. It is possible to use a single solvent or a mixed solvent selected from the group consisting of. As a polar aprotic solvent that can be used in the above Schemes 1 and 2, a solvent selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, and a mixed solvent thereof, or a mixed solvent may be used.

The polar protic solvent and the polar aprotic solvent may be used in an amount of 1 to 50 ml per 1 g of sugar maddex, and preferably 5 to 20 ml.

The antisolvents used in Schemes 1 and 2 are methyl alcohol, ethyl alcohol, isopropyl alcohol, t-butyl alcohol, sec-butyl alcohol, n-butyl alcohol, n-amyl alcohol, heptane, toluene, diethyl ether, iso Propyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate and mixed solvents thereof. The antisolvent may be used in an amount of 5 to 50 ml per 1 g of Sugarmadex, and preferably in an amount of 10 to 30 ml.

The novel salts of sugarmadex of the present invention may be prepared at -10 to 70 ° C, most preferably at 5 to 50 ° C.

The present invention relates to a pharmaceutical composition for inverting drug-induced neuromuscular blockade, comprising a novel salt of sugar maddex of the present invention as an active ingredient. In particular, the compositions of the present invention may be administered intravenously.

The novel salts of the sugarmadex of the present invention are pharmaceutically safe and possess suitable physicochemical properties as injections. In addition, it is easy to mass-produce with a simple manufacturing process, and has excellent pharmaceutical and pharmaceutical properties such as stability and solubility, so that it can be immediately administered by in vivo through high bioavailability, thereby preventing drug-induced neuromuscular blockade. It can be usefully used as an active ingredient of a dedicated medicine.

Figure 1 is an XRD analysis of the sugar maddex potassium salt prepared in Example 1.
Figure 2 is an XRD analysis of the sugar maddex magnesium salt (crystalline form) prepared in Example 2-1.
3 is an XRD analysis result of the sugar maddex magnesium salt (amorphous) prepared in Example 2-2.
4 is an XRD analysis result of the sugar maddex calcium salt (crystalline Form A) prepared in Example 3-1.
5 is an XRD analysis result of the sugar maddex calcium salt (crystalline Form B) prepared in Example 3-2.
6 is an XRD analysis result of the sugar maddex calcium salt (amorphous) prepared in Example 3-3.
7 is an XRD analysis result of the sugar maddex arginine salt prepared in Example 4. FIG.
8 is an XRD analysis result of the sugar maddex lysine salt prepared in Example 5. FIG.
9 is an XRD analysis result of the sugar maddex diolamine salt prepared in Example 6. FIG.
10 is an XRD analysis result of the sugar maddex meglumine salt prepared in Example 7.
11 is an XRD analysis result of sugar maddex sodium salt.
12 shows the results of XRD analysis of sugarmadex free acid (crystalline form).
Fig. 13 shows the results of XRD analysis of sugarmadex free acid (amorphous).
14 is a nuclear magnetic resonance analysis ( ¹ H NMR) of the sugar maddex potassium salt prepared in Example 1.
15 is a nuclear magnetic resonance analysis ( ¹ H NMR) of the sugar maddex magnesium salt prepared in Example 2.
16 is a nuclear magnetic resonance analysis ( ¹ H NMR) of the sugar maddex calcium salt prepared in Example 3.
Figure 17 shows the results of nuclear magnetic resonance analysis ( ¹ H NMR) of the sugar maddex arginine salt prepared in Example 4.
18 shows the results of nuclear magnetic resonance analysis ( ¹ H NMR) of the sugar maddex lysine salt prepared in Example 5. FIG.
19 is a nuclear magnetic resonance analysis ( ¹ H NMR) of the sugar maddex diolamine salt prepared in Example 6.
20 is a nuclear magnetic resonance analysis ( ¹ H NMR) of the sugar maddex meglumine salt prepared in Example 7
21 is a nuclear magnetic resonance analysis ( ¹ H NMR) of the sugar maddex sodium salt.
Figure 22 shows the results of nuclear magnetic resonance analysis ( ¹ H NMR) of sugar maddex free acid.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

In addition, the reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea and TCI Korea, unless otherwise noted, HLPC was used Waters Water 9595 from the company, and XRD measurement was Bruker X-ray Diffractometer (XRD) D8 ADVANCE was used and ¹ H NMR was measured using a 400 ultraShield NMR Spectrometer from Bruker.

Example 1

Preparation of Sugarmadex Potassium Salt

30.0 g of sugarmadex free acid was added to 300.0 mL of purified water, and the mixture was stirred at room temperature. Then, the mixture was dissolved completely while 1.1 equivalent of KOH was slowly added thereto. 1,500.0 mL of methanol was slowly added to the reaction solution to precipitate a solid. The stirred solution was stirred for 2 hours, and the resulting solid was filtered, washed with 100 mL of methanol, and dried to give 27.6 g of sugarmadex potassium salt.

Yield: 79.57%

Salt content: 13.47%

-Melting point: 230.2 ℃

Purity: 96.58% by HPLC

¹ H NMR (400 MHz, D 2 O-d 4): 5.22 (m, 1 H); 4.10-4.05 (m, 1 H); 3.99-3.95 (m, 1 H); 3.69-3.63 (m, 2 H); 3.17-3.14 (m, 1 H); 3.03-2.98 (m, 1 H); 2.90-2.86 (m, 2 H); 2.58-2.46 (m, 2H) ppm.

Example 2

Preparation of Sugarmadex Magnesium Salt

1. Preparation of Sugarmadex Magnesium Salt

3.0 g of sugarmadex potassium salt was added to 24.0 mL of purified water to dissolve it, and a solution of 30.0 equivalents of magnesium chloride in 6.0 mL of purified water was slowly added dropwise to the reaction solution. After stirring for 30 minutes, 60.0 mL of ethanol was slowly added dropwise and stirred for about 2 hours. The resulting solid was filtered, washed with 6.0 mL of ethanol and dried to give 2.35 g of sugarmadex magnesium salt (crystalline).

Yield: 86.54%

Salt content: 4.65%

-Melting point: 274.6 ℃

Purity: 96.58% by HPLC

¹ H NMR (400 MHz, D 2 O-d 4): 5.18 (m, 1 H); 4.08-4.04 (m, 1 H); 3.96-3.92 (m, 1 H); 3.68-3.61 (m, 2 H); 3.19-3.16 (m, 1 H); 3.03-2.98 (m, 1 H); 2.90-2.86 (m, 2 H); 2.58-2.46 (m, 2H) ppm.

2. Preparation of Sugarmadex Magnesium Salt

2.0 g of sugarmadex free acid was added to 30.0 mL of purified water, and the mixture was stirred while slowly adding 4.0 equivalents of magnesium methoxide after stirring at room temperature. The mixture was filtered fine to remove suspended solids. To the clear solution obtained, 30.0 mL of methanol was slowly added dropwise and stirred for about 2 hours. The resulting solid was filtered, washed with 10.0 mL of methanol and dried to give 1.38 g of sugarmadex magnesium salt (amorphous).

Yield: 66.03%

Salt content: 4.34%

3. Preparation of Sugarmadex Magnesium Salt

2.0 g of sugarmadex free acid was added to 3.0 mL of purified water, and the mixture was stirred while slowly adding 4.0 equivalents of magnesium hydroxide after stirring at room temperature. The mixture was filtered fine to remove suspended solids. To this clear solution, 40.0 mL of methanol was slowly added dropwise and stirred for about 2 hours. The resulting solid was filtered, washed with 6.0 mL of ethanol and dried to give 1.36 g of sugarmadex magnesium salt (amorphous).

Yield: 65.07%

Salt content: 4.25%

Example 3

Preparation of Sugarmadex Calcium Salts

1. Preparation of Sugarmadex Calcium Salt

24.0 g of sugarmadex potassium salt was added to 240.0 mL of purified water and dissolved at room temperature, followed by stirring while slowly adding 10.0 equivalents of calcium chloride. The reaction solution was subjected to microfiltration to remove suspended solids. 350.0 mL of methanol was slowly injected into the obtained clear solution, followed by stirring for about 2 hours. The resulting solid was filtered, washed with 80.0 mL of methanol and dried to give 20.25 g of Sugarmadex calcium salt (crystalline Form A).

Yield: 90.36%

Salt content: 7.28%

-Melting point: 285.4 ℃

Purity: 96.57% by HPLC

¹ H NMR (400 MHz, D 2 O-d 4): 5.16 (m, 1H); 4.07-4.02 (m, 1 H); 3.95-3.90 (m, 1 H); 3.66-3.58 (m, 2 H); 3.18-3.15 (m, 1 H); 3.01-2.96 (m, 1 H); 2.89-2.85 (m, 2 H); 2.52-2.46 (m, 2H) ppm.

2. Preparation of Sugarmadex Calcium Salt

3.0 g of sugarmadex potassium salt was added to 30.0 mL of purified water, dissolved, and stirred at 60 ° C for 1 hour. 10.0 equivalents of calcium chloride was slowly added to the reaction solution, cooled to room temperature, and filtered to remove suspended solids. 45.0 mL of methanol was slowly added to the obtained clear solution, followed by stirring for about 2 hours. The resulting solid was filtered, washed with 10.0 mL of methanol and dried to give 2.95 g of Sugarmadex calcium salt (crystalline Form B).

Yield: 91.45%

Salt content: 7.24%

3. Preparation of Sugarmadex Calcium Salt

3.0 g of sugarmadex free acid was added to 30.0 mL of purified water, and the mixture was stirred while slowly adding 4.0 equivalents of calcium hydroxide after stirring at room temperature. The mixture was microfiltered to remove suspended solids. To this clear solution, 45.0 mL of methanol was slowly added dropwise and stirred for about 2 hours. The resulting solid was filtered, washed with 10.0 mL of methanol and dried to give 2.98 g of sugarmadex calcium salt (amorphous).

Yield 92.26%

Salt content: 7.22%

4. Preparation of Sugarmadex Calcium Salt

 3.0 g of sugarmadex free acid was added to 30.0 mL of purified water, and the mixture was stirred while slowly adding 4.0 equivalents of calcium methoxide after stirring at room temperature. The mixture was microfiltered to remove suspended solids. To this clear solution, 45.0 mL of methanol was slowly added dropwise and stirred for about 2 hours. The resulting solid was filtered, washed with 10.0 mL of methanol and dried to give 2.48 g of sugarmadex calcium salt (amorphous).

Yield: 76.78%

Salt content: 7.24%

Example 4

Preparation of Sugarmadex Arginine Salts

2.0 g of sugarmadex free acid was added to 15.0 mL of purified water, and the mixture was stirred while slowly adding 8.0 equivalents of arginine after stirring at room temperature. The mixture was microfiltered to remove suspended solids. The obtained clear solution was lyophilized for about 72 hours to obtain 3.37 g of sugarmadex arginine salt.

-Melting point: 122.3 ℃

Purity: 99.28% by HPLC

¹ H NMR (400 MHz, D 2 O-d 4): 5.21 (m, 1 H); 4.10-4.06 (m, 1 H); 3.99-3.94 (m, 1 H); 3.67-3.65 (m, 2 H); 3.58-3.55 (m, 1 H); 3.25-.22 (m, 1 H); 3.16-.14 (m, 1 H); 3.04-2.99 (m, 1 H); 2.90-2.86 (m, 2 H); 2.57-2.45 (m, 2 H); 1.87-1.59 (m, 4H) ppm.

Example 5

Preparation of Sugarmadex Lysine Salt

  2.0 g of sugarmadex free acid was added to 15.0 mL of purified water, and the mixture was stirred while slowly adding 8.0 equivalents of lysine after stirring at room temperature. The mixture was microfiltered to remove suspended solids. The obtained clear solution was lyophilized for about 72 hours to obtain 3.15 g of Sugarmadex lysine salt.

-Melting point: 94.1 ℃

Purity: 99.17% by HPLC

¹ H NMR (400 MHz, D ₂ Od ₄ ): 5.22 (m, 1H); 4.11-4.06 (m, 1 H); 3.99-3.95 (m, 1 H); 3.70-3.63 (m, 2 H); 3.59-3.55 (m, 1 H); 3.17-.14 (m, 1 H); 3.04-2.99 (m, 3 H); 2.90-2.85 (m, 2 H); 2.57-2.45 (m, 2 H); 1.83-1.67 (m, 4 H); 1.55-1.35 (m, 2H) ppm.

Example 6

Preparation of Sugarmadex Diolamine Salts

2.0 g of sugarmadex free acid was added to 15.0 mL of purified water, and the mixture was stirred while slowly adding 8.0 equivalents of diolamine after stirring at room temperature. The mixture was microfiltered to remove suspended solids. The obtained clear solution was lyophilized for about 72 hours to obtain 2.82 g of sugarmadex diolamine salt.

-Melting point: 251.7 ℃

Purity: 98.98% by HPLC

¹ H NMR (400 MHz, D 2 O-d 4): 5.20 (m, 1 H); 4.09-4.05 (m, 1 H); 3.98-3.93 (m, 4 H); 3.80-3.77 (m, 4 H); 3.69-3.63 (m, 2 H); 3.16-.13 (m, 1 H); 3.02-2.98 (m, 5 H); 2.89-2.86 (m, 2 H); 2.56-2.44 (m, 2 H); ppm.

Example 7

Preparation of Sugarmadex Meglumine Salt

2.0 g of sugarmadex free acid was added to 15.0 mL of purified water, and the mixture was stirred while slowly adding 8.0 equivalents of meglumine after stirring at room temperature. The mixture was microfiltered to remove suspended solids. The obtained clear solution was lyophilized for about 72 hours to obtain 3.54 g of sugarmadex meglumine salt.

-Melting point: 59.1 ℃

Purity: 99.30% by HPLC

¹ H NMR (400 MHz, D 2 O-d 4): 5.22 (m, 1 H); 4.10-4.06 (m, 1 H); 4.05-4.00 (m, 1 H); 3.98-3.95 (m, 1 H); 3.85-3.75 (m, 3 H); 3.71-3.64 (m, 4 H); 3.16-3.13 (m, 1 H); 3.04-2.93 (m, 3 H); 2.90-2.86 (m, 2 H); 2.61 (s, 3 H); 2.55-2.47 (m, 2 H); ppm.

[Test Example 1]

Solid Stability Test of Sugarmadex Salts

The stability test of a drug means to check the stability of a certain quality over time in a certain condition in order to set the storage method and the period of use of the drug. In other words, the validity period of the product is established by setting the appropriate standard, evaluating the significant change based on the analysis method, and evaluating the conformity of the standard.

The sugar maddex base addition salt, sodium salt and free acid of the present invention were subjected to stability experiments under storage conditions according to ICH guidelines and analyzed using high performance liquid chromatography (HPLC) analysis. To 3 are shown.

Long-term storage condition (25 ℃ ± 2 ℃, RH 65% ± 5%) division Early 4 Weeks 12 Weeks 30 Weeks 30 weeks △% Sugarmadex Magnesium Salt (crystalline) 98.78% 98.70% 98.72% 98.78% -0.0% Sugarmadex Calcium Salt (crystalline) 99.47% 99.49% 99.51% 99.35% -0.1% Sugarmadex Sodium Salt (crystalline) 99.46% 99.44% 98.88% 99.37% -0.1% Sugarmadex Free Acid (crystalline) 99.16% 99.20% 98.92% 98.66% 0.5%

As shown in Table 1, the sugar maddex base addition salt of the present invention showed a very small change in purity as a result of a stability test for 30 weeks under long-term conditions, and confirmed to have an excellent stability equivalent to that of sugar maddex sodium salt. It became.

Accelerated storage conditions (40 ° C ± 2 ° C, RH 75% ± 5%) division Early 4 Weeks 12 Weeks 30 Weeks 30 weeks △% Sugarmadex Magnesium Salt (crystalline) 98.78% 98.67% 98.64% 98.58% -0.2% Sugarmadex Calcium Salt (crystalline) 99.47% 99.53% 99.49% 99.41% -0.1% Sugarmadex Sodium Salt (crystalline) 99.46% 99.51% 99.03% 99.34% -0.1% Sugarmadex Free Acid (crystalline) 99.16% 98.53% 98.05% 95.97% 3.2%

As shown in Table 2, the sugar maddex base addition salt of the present invention showed a very small change in purity as a result of the stability test for 30 weeks under accelerated conditions, and confirmed to have an excellent stability equivalent to the sugar maddex sodium salt. It became.

Severe storage conditions (60 ℃ ± 2 ℃) division Early 4 Weeks 12 Weeks 30 Weeks 30 weeks △% Sugarmadex Magnesium Salt (crystalline) 98.78% 98.58% 97.86% 98.05% -0.7% Sugarmadex Calcium Salt (crystalline) 99.47% 99.52% 99.39% 98.75% -0.7% Sugarmadex Sodium Salt (crystalline) 99.46% 99.40% 98.77% 99.07% 0.4% Sugarmadex Free Acid (crystalline) 99.16% 95.15% 89.05% 80.79% -18.4%

As shown in Table 3, the sugar maddex base addition salt of the present invention showed a very small change in purity as a result of a 30-week stability test under severe conditions, and confirmed to have an excellent stability equivalent to that of sugar maddex sodium salt. It became.

[Test Example 2]

Solubility Analysis

The solubility of sugarmadex base addition salt, sodium salt and free acid of the present invention was measured. In the solubility test method, 500 μl of purified water or pH 7.4 solution was added to about 500 mg of each sample. After stirring for 12 hours, filtering with PVDF, and diluting to constant magnification, a calibration curve (range: 100 ~ 3,000 ㎍ / mL) was prepared by the following HPLC method, and the concentration of saturated solution was obtained from the first function of the calibration curve.

[HPLC Test Equipment Operating Conditions]

  1) Detector: UV absorbance photometer (wavelength: 200 nm)

  2) Column: column equal to C18 (3 um, 2.0 * 150 mm)

  3) Column temperature: constant temperature around 40 ℃

  4) Injection volume: 2.5 μL

  5) Flow rate: 0.3 mL / min

  6) Mobile phase: Buffer: Acetonitrile (85:18)

  7) Buffer: Dissolve 2.0 g of sodium dihydrogen phosphate in 1 L of purified water and titrate pH 3.0 with diluted phosphate solution.

The results tested by the solubility test method are shown in Table 4 below.

Dissolution condition Solubility (mg / ml) Sugarmadex
Potassium salt
(Crystalline) Sugarmadex
Magnesium salt
(Crystalline) Sugarmadex
Calcium salt
(Crystalline) Sugarmadex
Sodium salt
(Crystalline) Sugarmadex
Free acid
(Crystalline) Purified water More than 1000mg 500mg or more More than 300mg 500mg or more 21mg pH 7.4 More than 1000mg 500mg or more More than 300mg 500mg or more 23mg

In addition, the solubility of the sugar maddex lysine salt, arginine salt, diolamine salt and meglumine salt of the present invention was measured by the same method as above, and the test results are shown in Table 5 below.

Dissolution condition Solubility (mg / ml) Sugarmadex
Lysine salt
(Amorphous) Sugarmadex
Arginine
(Amorphous) Sugarmadex
Diolamine salt
(Amorphous) Sugarmadex
Meglumine salt
(Amorphous) Purified water More than 1000mg More than 1000mg More than 1000mg More than 1000mg pH 7.4 More than 1000mg More than 1000mg More than 1000mg More than 1000mg

As shown in Table 5, it was confirmed that the base addition salt except the sugar maddex free acid has a high solubility in the experimental range, through which the sugar maddex base addition salt of the present invention is a product of sugar maddex in the intravenous injection. It can be seen that very advantageous.

Claims (11)

The novel salt of sugarmadex represented by the following general formula (1) or (2).
[Formula 1]

[Formula 2]

(A in Formula 1 is potassium, arginine, lysine, diolamine or meglumine, and B in Formula 2 is a pharmaceutically acceptable salt that is magnesium or calcium)
The novel salt of sugarmadex according to claim 1, which is crystalline or amorphous.
The novel salt of Sugarmadex according to claim 1, wherein the total amount of analogue is less than 1% for 30 weeks at 25 ° C ± 2 ° C and RH 65% ± 5%.
The novel salt of Sugarmadex according to claim 1, wherein the total amount of analogue is less than 1% for 30 weeks at an accelerated storage condition of 40 ° C ± 2 ° C and RH 75% ± 5%.
The novel salt of Sugarmadex according to claim 1, wherein the total amount of analogue is less than 1% for 30 weeks under severe storage conditions of 60 ° C ± 2 ° C.
A process for the preparation of the novel salt of sugarmadex according to claim 1 comprising the following steps:
(a) dissolving the sugarmadex free acid or sugarmadex monocationic addition salt, and a pharmaceutically acceptable salt in a solvent selected from the group consisting of polar protic solvents, polar aprotic solvents, and mixtures thereof ;
(b) adding anti-solvent to the solution to produce a solid; And
(c) recovering the resulting solid.
The method of claim 6, wherein the polar protic solvent is selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, t-butyl alcohol, sec-butyl alcohol, n-butyl alcohol and n-amyl alcohol And, wherein the polar aprotic solvent is at least one selected from the group consisting of N, N-dimethylformamide and dimethylsulfoxide.
The method of claim 6, wherein the antisolvent is methyl alcohol, ethyl alcohol, isopropyl alcohol, t-butyl alcohol, sec-butyl alcohol, n-butyl alcohol, n-amyl alcohol, heptane, toluene, diethyl ether, isopropyl A process for preparing a novel salt of sugarmadex, characterized in that at least one is selected from the group consisting of ether, t-butylmethylether, ethyl acetate and isopropyl acetate.
7. The process for producing novel salts of sugarmadex according to claim 6, which is prepared at -10 to 70 deg.
The pharmaceutical composition for inverting drug-induced neuromuscular blockade, comprising the novel salt of sugarmadex of claim 1 as an active ingredient.
The pharmaceutical composition of claim 10, wherein the composition is administered intravenously.

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