WO2021227146A1

WO2021227146A1 - N-[8-(2-hydroxybenzoyl)amino]monopotassium octanoate crystal compound, and preparation method therefor and use thereof

Info

Publication number: WO2021227146A1
Application number: PCT/CN2020/094002
Authority: WO
Inventors: 张发满
Original assignee: 台州浦凯医药科技有限公司
Priority date: 2020-05-14
Filing date: 2020-06-02
Publication date: 2021-11-18
Also published as: CN111517980B; CN111517980A

Abstract

The present invention belongs to the technical field of medicine. Specifically, disclosed is an N-[8-(2-hydroxybenzoyl)amino]monopotassium octanoate crystal compound, and a preparation method therefor and the use thereof. The crystal compound has a high purity, a low impurity content, good stability, low moisture absorption, and good liquidity. The crystal compound can be prepared into solid oral preparations, such as capsules and tablets, with pharmaceutically active compounds such as small molecules or polypeptides, thereby improving the oral bioavailability of the drugs in the preparations. Moreover, a composition containing the crystal compound and sodium ion organic or inorganic salts can further improve the bioavailability of pharmaceutically active compounds.

Description

N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound, preparation method and application

Technical field

The invention belongs to the technical field of medicine, and specifically relates to a N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound, a preparation method and an application.

Background technique

N-[8-(2-hydroxybenzoyl)amino] monosodium octanoate (SNAC) has a wide range of applications in facilitating the delivery of various active agents. At present, there are a large number of research documents on different crystal forms, different preparation methods and application methods of SNAC in the prior art. For example, CN102001962B discloses six polymorphic forms and one amorphous form of monosodium N-[8-(2-hydroxybenzoyl)amino]octanoic acid crystals. The polymorphic forms include two hydrates of SNAC, methanol Solvates and ethanol solvates. At the same time, a pharmaceutical composition containing them, a preparation method thereof, and a method of using them to promote the delivery of active agents are disclosed.

However, at present, there are few reports on the research of the N-[8-(2-hydroxybenzoyl)amino]monopotassium octanoate (KNAC) compound involved in the present invention. In particular, there are almost no reports on the research of KNAC crystal form and its application methods in promoting the delivery of active agents.

Summary of the invention

The technical problem to be solved by the present invention is to aim at the research blank of N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium in the prior art, and the compound and its preparation method and its active agent in promoting In order to find a technical solution that can replace or surpass the clinical application effect of SNAC.

In order to solve the above technical problems, the present invention first discloses the crystal form of potassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid. The X-ray powder diffraction patterns of the crystal form compound are at 7.24, 24.53, and 20.91. , 20.41, 6.24, 19.92, 19.69 and 26.62 show characteristic diffraction peaks at the reflection angle of 2θ±0.2°.

Furthermore, the present invention also discloses the X-ray powder diffraction pattern of the N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound as shown in FIG. 1.

At the same time, the present invention also discloses a preparation method of the N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound, which includes the following steps:

(1) Take compound N-[8-(2-hydroxybenzoyl)amino]octanoic acid, add a benign solvent, and configure to form a suspension;

(2) Apply a constant magnetic field in the horizontal direction of the suspension of step (1), and under the constant magnetic field condition, drop a high-concentration potassium hydroxide aqueous solution, and maintain the system temperature at 25-60 during the dropping process ℃;

(3) After the dripping is completed, add the poor solvent;

(4) Let stand;

(5) Cool down to below room temperature and filter;

(6) Vacuum drying to constant weight to obtain monopotassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid as a crystalline compound.

The room temperature mentioned here means 25°C. And the following mentioned here includes this number.

Preferably, the benign solvent in step (1) is an organic alcohol solution, particularly preferably methanol, ethanol, and isopropanol. It is worth noting that it is preferable to select only one solvent to add when adding a benign solvent, and not to mix two or more solvents.

Preferably, the poor solvent in the step (3) is an aliphatic hydrocarbon solvent, and more preferably n-hexane and n-heptane.

At the same time, as a preference, the present invention also discloses that in the step (5), the poor solvent in the step (3) is further used to wash the filter cake.

It is further preferred that the mass percentage concentration of potassium hydroxide in step (2) is 10% to saturation.

At the same time, as a preferred technical solution, the temperature in the step (2) is 30-50°C.

In a preferred technical solution, the intensity of the magnetic field in the step (2) is 0.8T.

In addition, the present invention further discloses the application of the N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound in the preparation of pharmaceutical compositions, and the pharmaceutical compositions include N-[8-(2-hydroxybenzoyl)amino]caprylic acid monopotassium crystal compound, sodium salt and any compound with pharmacological activity.

The compounds with pharmacological activity mentioned here refer to small molecules with oral bioavailability less than 80%, polypeptides with less than 50 amino acids, and their derivatives modified by chemical or biological means.

Preferably, in the pharmaceutical composition, the mixing ratio of sodium salt and N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound is such that the sodium salt and N-[ The mixing equivalent ratio of the 8-(2-hydroxybenzoyl)amino]octanoic acid monopotassium crystal compound is in the range of 0.5:1 to 1.5:1.

Further preferably, in the pharmaceutical composition, the mixing ratio of the sodium salt and the N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound is that the sodium salt and the N- The mixing equivalent ratio of the [8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound is in the range of 0.8:1 to 1.2:1.

More preferably, in the pharmaceutical composition, the mixing ratio of sodium salt and N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound is as follows: The mixing equivalent ratio of the N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound is in the range of 0.9:1 to 1.1:1.

The aforementioned sodium salt may be an organic sodium salt or an inorganic sodium salt.

The aforementioned pharmaceutical composition can be prepared into oral preparations such as capsules, tablets, granules and powders according to the preparation methods in the prior art.

The N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound disclosed by the invention has the advantages of simple preparation process, high product purity, low impurity content, good stability and the like. At the same time, the crystalline compound is not easy to absorb moisture, has good fluidity, and can significantly control and improve its fluidity through frequently-corrected formulation technical means, and has superior application prospects in formulation production.

At the same time, the N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound disclosed in the present invention and the pharmaceutically active compound together form a pharmaceutical composition, which can promote the delivery of the active agent and has an excellent promoting active agent Delivery capacity. Used in conjunction with sodium salt, it can significantly improve the oral bioavailability of active pharmaceutical compounds. It shows better drug delivery capability than KNAC and SNAC.

Description of the drawings

Figure 1 is an X-ray powder diffraction pattern of N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound powder.

Detailed ways

In order to better understand the present invention, we will further illustrate the present invention in conjunction with specific embodiments below.

Unless otherwise specified, the reagents used in the examples are all commercially available reagents.

The term "KNAC" as used herein refers to monopotassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid and its crystalline compounds.

The term "SNAC" as used herein refers to monosodium N-[8-(2-hydroxybenzoyl)amino]caprylic acid and its crystalline compounds.

Example 1 Preparation of N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound

Take 1.0 kg of N-[8-(2-hydroxybenzoyl)amino]caprylic acid, add 3L of anhydrous methanol (or anhydrous ethanol, or anhydrous isopropanol) to the reaction kettle to obtain a suspension, and then A constant magnetic field with a magnetic field strength of 0.8 T was applied to the resulting suspension in the horizontal direction. A 20% potassium hydroxide aqueous solution with a good configuration number and a mass percentage concentration of 20% is added dropwise to the KNAC suspension under the condition of 30-50°C. The equivalent of potassium hydroxide added is 80%-90% of the equivalent of N-[8-(2-hydroxybenzoyl)amino]caprylic acid. After the addition is complete, stir for 10-30 minutes to make the system change from turbid to clear. Then, under heat preservation conditions, n-hexane (or n-heptane) is added dropwise, and the volume ratio of n-hexane to methanol is 1:1, which is 3L. After the dripping is completed, the temperature of the system is naturally lowered to below room temperature, and the mixture is stirred for 2-4 hours. After filtration (or suction filtration), the filter cake is washed with n-hexane and dried in vacuum to a constant weight to obtain N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound.

Example 2 Determination of crystal form of N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound

The crystalline compound obtained in Example 1 was pulverized into powder. Then, the powder was measured by X-ray diffractometry.

The powder X-ray diffraction detection conditions used are: instrument D8Advance powder crystal X-ray diffractometer from Bruker, Germany; radiation source Cu-Kα; scanning speed 2°/min; scanning range 3-60°.

The obtained powder X-ray diffraction pattern is shown in Figure 1, and the data is shown in Table 1.

Table 1: The characteristic XRPD peaks of the crystal form of KNAC (expressed in degrees 2θ)

Example 3

In this example, we prepared a pharmaceutical composition by mixing SNAC and KNAC with semaglutide respectively, and investigated the effect of KNAC as a delivery agent.

Semaglutide refers to N-ε ²⁶ -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanylamino)-4(S)-carboxy Butyrylamino]ethoxy)ethoxy]acetamido)ethoxy]ethoxy)ethoxy][Aib8,Arg34]GLP-1-(7-37) peptide.

The added sodium carboxymethyl cellulose is a filler and pure water is a dispersant, both of which are required for formulation formation.

3.1 Prepare SNAC according to the method disclosed in CN102001962B, and grind the SNAC to a uniform powder, and mix with semaglutide at a weight ratio of 30:1 (semaglutide 20mg, SNAC600mg). Then take an appropriate amount of filler sodium carboxymethyl cellulose (1000 mg) and add it to the above mixture. Add an appropriate amount of pure water (3000ml) to the final mixture to disperse, and apply a rotating force to intermittently oscillate to make it uniformly dispersed, and a composition A is obtained.

3.2 Take the KNAC obtained in Example 1, grind to a uniform powder, and mix with Semaglutide in a weight ratio of 30:1 (Semaglutide 20mg, KNAC600mg). Then take an appropriate amount of filler sodium carboxymethyl cellulose (1000 mg) and add it to the above mixture. Add an appropriate amount of pure water (3000 ml) to the final mixture to disperse, and apply a rotating force to intermittently oscillate to make it uniformly dispersed, and a composition B is obtained.

3.3 Take the KNAC obtained in Example 1, grind to a uniform powder, and mix with Semaglutide in a weight ratio of 30:1 (Semaglutide 20mg, KNAC600mg). Next, take the solid sodium bicarbonate (or sodium chloride) and add it in an equivalent ratio of 1:1 to KANC. Finally, take an appropriate amount of filler sodium carboxymethyl cellulose (1000 mg) and add it to the above mixture. Add an appropriate amount of pure water (3000ml) to the final mixture to disperse, and apply a rotating force to intermittently oscillate to make it uniformly dispersed, and a composition C is obtained.

3.4 Comparison of the inhibition rate of semaglutide blood glucose in different pharmaceutical compositions on the blood glucose of mice

Experimental animals: 12 male db/db mice, weighing about 27.0±1.0g. Divide evenly into three groups, with four animals in each group.

Experimental method: Before the administration, blood was taken from the tail of each mouse through a blood extractor, and the blood glucose value was measured and recorded with a blood glucose meter to obtain the origin blood glucose value.

According to the average body weight, the pharmaceutical composition A, the pharmaceutical composition B, and the pharmaceutical composition C prepared in 5.1, 5.2, and 5.3 above were respectively administered to the mice through an oral administration device. Two hours after the administration, blood was taken from the tail of each mouse, and the blood glucose value was measured and recorded with a blood glucose meter to obtain the fasting blood glucose value. After the blood was collected, the mice were fed. About 4 hours after the mice had eaten, blood was taken from the tail of each mouse, and the blood glucose level was measured and recorded with a blood glucose meter to obtain the postprandial blood glucose level.

According to the origin blood glucose value, fasting blood glucose value, and postprandial blood glucose value, the blood glucose inhibition rate of the mice was calculated respectively, and the calculation results are shown in Table 2.

Table 2:

The results showed that the average fasting blood glucose inhibition rate was 44.9% after 2 hours of administration of composition A, and the inhibition rate ranged from 39.8% to 50.9%; the average blood glucose inhibition rate 4 hours after a meal was 39.1%, and the inhibition rate ranged from 37.9% to 40.2%. . Two hours after the administration of composition B, the average fasting blood glucose inhibition rate is 23.7%, and the inhibition rate ranges from 18.9% to 27.6%; the average blood glucose inhibition rate 4 hours after a meal is 20.1%, and the inhibition rate ranges from 15.8% to 24.9%. Two hours after the administration of composition C, the average fasting blood glucose inhibition rate is 49.3%, and the inhibition rate ranges from 42.9% to 53.2%; the average blood glucose inhibition rate 4 hours after a meal is 43.2%, and the inhibition rate ranges from 40.9% to 46.3%.

Based on the above data, it can be seen that both composition A and composition B have an effect on the blood sugar inhibition of db/db mice, but the blood sugar inhibition effect of composition A in db/db mice is better than that of composition B of. Composition C is based on composition B, adding a fixed amount of sodium salt (sodium bicarbonate or sodium chloride). The results show that the blood sugar inhibitory effect of composition C in db/db mice is not inferior (or better) than composition A, which indicates that KNAC has a good delivery ability after being combined with sodium salt, and sodium salt can significantly improve The delivery ability of KNAC makes it more widely used for the preparation of delivery formulations.

The above are the specific embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications are also regarded as the protection scope of the present invention.

Claims

N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound, characterized in that: the X-ray powder diffraction pattern of the crystalline compound is 7.24, 24.53, 20.91, 20.41, 6.24, 19.92, 19.69 and 26.62 show characteristic diffraction peaks at 2θ±0.2° reflection angles.
The N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound according to claim 1, wherein the crystalline compound has an X-ray powder diffraction as shown in Figure 1 Atlas.
The preparation method of N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound as claimed in claim 1 or 2, characterized in that it comprises the following steps:

(1) Take compound N-[8-(2-hydroxybenzoyl)amino]octanoic acid, add a benign solvent, and configure to form a suspension;

(2) Apply a constant magnetic field in the horizontal direction of the suspension of step (1), and under the constant magnetic field condition, drop a high-concentration potassium hydroxide aqueous solution, and maintain the system temperature at 25-60 during the dropping process ℃;

(3) After the dripping is completed, add the poor solvent;

(4) Let stand;

(5) Cool down to below room temperature and filter;

(6) Vacuum drying to constant weight to obtain monopotassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid as a crystalline compound.
The method for preparing monopotassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystalline compound according to claim 3, wherein any one or more of the following reaction conditions are selected:

A: The benign solvent in step (1) is an organic alcohol solution, and methanol, ethanol, and isopropanol are particularly preferred; it is worth noting that it is preferable to add only one solvent when adding a benign solvent without mixing the two. One or more than two solvents.

B: The poor solvent in the step (3) is an aliphatic hydrocarbon solvent, more preferably n-hexane and n-heptane.

C: In the step (5), the poor solvent in the step (3) is further used to wash the filter cake.

D: The mass percentage concentration of potassium hydroxide in step (2) is 10% to saturation.

E: The temperature in the step (2) is 30-50°C.

F: The intensity of the magnetic field in the step (2) is 0.8T.
The use of the N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound according to claim 1 or 2 in the preparation of a pharmaceutical composition, characterized in that: the pharmaceutical composition comprises N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound and any compound with pharmacological activity.
The use of the monopotassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid crystal compound in the preparation of a pharmaceutical composition according to claim 5, characterized in that it further comprises a sodium salt.
The use of the monopotassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid crystalline compound in the preparation of a pharmaceutical composition according to claim 6, wherein the sodium salt is an organic sodium salt or an inorganic Sodium salt.
The use of the monopotassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid crystal compound in the preparation of pharmaceutical compositions according to claim 6, characterized in that: in the pharmaceutical composition, sodium salt The mixing ratio with N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound is based on sodium ion, sodium salt and N-[8-(2-hydroxybenzoyl)amino] The mixing equivalent ratio of the monopotassium caprylate crystal compound is in the range of 0.5:1 to 1.5:1;

Further preferably, in the pharmaceutical composition, the mixing ratio of the sodium salt and the N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound is that the sodium salt and the N- The mixing equivalent ratio of [8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound is in the range of 0.8:1 to 1.2:1;

More preferably, in the pharmaceutical composition, the mixing ratio of sodium salt and N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound is as follows: The mixing equivalent ratio of the N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystal compound is in the range of 0.9:1 to 1.1:1.
The use of the monopotassium N-[8-(2-hydroxybenzoyl)amino]caprylic acid crystal compound in the preparation of pharmaceutical compositions according to claim 5 or 6, characterized in that: the compound with pharmacological activity refers to Oral bioavailability of small molecules less than 80%, polypeptides of less than 50 amino acids, and their derivatives modified by chemical or biological means.
The use of the N-[8-(2-hydroxybenzoyl)amino] octanoic acid monopotassium crystalline compound in the preparation of a pharmaceutical composition according to claim 5 or 6, characterized in that the preparation form of the pharmaceutical composition is Allowed oral preparations, especially capsules, tablets, granules and powders.