WO2022220596A1 - Method for preparing sphingosine-1-phosphate receptor agonist- containing oral solid preparation by wet granulation - Google Patents

Abstract

The present invention relates to a method for preparing a sphingosine-1-phosphate receptor agonist-containing oral solid preparation by wet granulation, and more specifically, to a method for preparing an oral solid preparation, wherein the oral solid preparation is prepared by wet granulation by using 1-[1-Chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid of chemical formula 1, or a pharmaceutically acceptable salt thereof, together with sodium lauryl sulfate, as a solubilizing agent.

Description

Method for preparing solid oral dosage form containing sphingosine-1-phosphate receptor agonist by wet granulation method

The present invention relates to a method for preparing an oral solid preparation comprising a sphingosine-1-phosphate receptor agonist by a wet granulation method, and more particularly, to 1-[1-chloro-6 represented by the following formula (1) as an active ingredient -(3-Chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutical thereof It relates to a method for preparing a solid oral dosage form prepared by a wet granulation method using an acceptable salt as a solubilizer together with sodium lauryl sulfate:

[Formula 1]

Sphingosine-1-phosphate (S1P) is produced through the intracellular ceramide pathway, and ceramide, the starting material of this synthetic pathway, has two production pathways, namely, the de novo biosynthetic pathway and It is produced in cells through the degradation of sphingomyelin, a component of the cell membrane. S1P level in each tissue is regulated by two biosynthetic sphingosine kinases (SphKs) and two biodegradable S1P phosphatases (S1P lyase and lysophospholipid phosphatases). The produced substance S1P mediates various cellular responses such as cell proliferation, cytoskeletal organization and migration, adhesion- and tight junction assembly, and morphogenesis. it is known They are present in plasma at high concentrations (100-1000 nM) in a form bound to albumin and other plasma proteins, while in tissues at low concentrations.

S1P binds to the S1P receptor, a G-protein coupled receptor, and exhibits various biological functions. The sub-types of S1P receptors known to date are S1P1 to S1P5. ) receptor) 1, 5, 3, 6 and 8. These S1P receptors are responsible for leukocyte recirculation, neural cell proliferation, morphological changes, migration, endothelial function, vasoregulation and cardiovascular development ( It is known to be involved in various biological functions such as cardiovascular development.

On the other hand, it is generally difficult to prepare a solid formulation having an active dose of a small dose drug to ensure uniformity. The technical problem is how to distribute these drugs uniformly among the large amount of excipient particles.

The simplest way to make tablets is to simply mix all the ingredients as a dry powder and then compress them (direct compression). However, this method is seldom successful with low dose drugs, and a common problem is the separation of the powder mixture during tableting. A variant of this method that has been successful for low dose drugs is known as "trituration" and is sometimes called "sequential mixing" or "interactive mixing". The fine particles of the drug are first mixed with a very small portion of excipient and then the product is continuously mixed with a slightly larger portion of excipient until the desired mixture is obtained. This method relies on a mechanism in which fine drug particles electrostatically attach to larger excipient particles and prevent segregation. This method works well for some drugs, but its success depends on the surface properties of both the drug and the excipient, which is not easy. In addition, in the process of mixing a small amount (dispersion) and then mixing again, there is a possibility that a large amount of active ingredient is contained in the raw material lost during the process.

Another method of formulating a drug with a small dosage is to prepare an active ingredient solution using a solubilizer to ensure content uniformity, and then make a soft capsule formulation. However, due to the sensitivity of gelatin, the main ingredient of soft capsules, to heat and moisture during storage, 1) changes in appearance due to softening and hardening of the capsule shell, 2) adhesion between capsules due to increased adhesion of the capsule shell, 3) rupture of the capsule shell There is a very high risk of deterioration of stability during storage, which is essential as a pharmaceutical, because there are phenomena such as leakage of the internal solution and 4) delayed disintegration due to gelatin crosslinking due to the reaction between the internal solution and the film.

The present invention is 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalen-2-ylmethyl of the formula 1 An object of the present invention is to provide a method for preparing a solid oral dosage form of ]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof with a uniform content and excellent storage stability:

[Formula 1]

In order to solve the above technical problem, the present invention provides an active ingredient 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro -Naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, together with sodium lauryl sulfate as a solubilizing agent, and a wet granulation method for oral solid preparation It provides a manufacturing method of

Hereinafter, the present invention will be described in detail.

According to the present invention i) 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalene-2- as an active ingredient preparing an active ingredient solution by dissolving ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and sodium lauryl sulfate as a solubilizing agent in a solvent; putting a diluent, a binder and a disintegrant into a wet granulator and mixing to prepare a mixture;

ii) adding the active ingredient solution to the mixture obtained in step (i) and then granulating;

iii) drying/sizing the granulated material obtained in step (ii), then adding a lubricant and mixing afterward;

iv) There is provided a method for producing a solid preparation for oral use, comprising compressing the mixture obtained in step (iii) with a tableting machine.

In one embodiment of the present invention, i) 0.2 to 2% by weight of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3 as an active ingredient ,4-Dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and 1 to 5% by weight of sodium lauryl sulfate as a solubilizer are dissolved in a solvent to dissolve the active ingredient preparing a solution; 70 to 90% by weight of a diluent, 2 to 10% by weight of a binder, and 3 to 15% by weight of a disintegrant are placed in a wet granulator and mixed to prepare a mixture;

ii) adding the active ingredient solution to the mixture obtained in step (i) and then granulating;

iii) drying/sizing the granules obtained in step (ii), then adding 0.5 to 3% by weight of a lubricant and post-mixing;

iv) There is provided a method for producing a solid formulation for oral use, characterized in that the mixture obtained in step (iii) is compressed with a tableting machine.

In one embodiment of the present invention, the pharmaceutically acceptable salt is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid , benzoic acid, lactic acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid. In one embodiment of the present invention, the pharmaceutically acceptable salt may be hydrochloric acid.

In one embodiment of the present invention, the solvent in step (i) may be selected from those capable of preparing an active ingredient solution by dissolving the active ingredient and the solubilizing agent, and there is no particular limitation thereto. All of the solvent in step (i) may be evaporated in the step of drying the granules. In one embodiment of the present invention, the solvent in step (i) may be purified water.

In one embodiment of the present invention, the diluent may be selected from lactose or a hydrate thereof, microcrystalline cellulose, and mixtures thereof. In one embodiment of the present invention, the lactose hydrate may be lactose monohydrate.

In one embodiment of the present invention, the binder may be hydroxypropyl cellulose.

In one embodiment of the present invention, the disintegrant may be croscarmellose sodium.

In one embodiment of the present invention, the lubricant may be magnesium stearate.

The oral solid preparation prepared according to the present invention not only has an active ingredient in a uniform content, but also exhibits excellent storage stability by minimizing the generation of related substances of the active ingredient that can be effective even with a small amount of use.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only of one or more embodiments, and the scope of the invention is not limited thereto.

Preparation Example: 1- [1-Chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalen-2-ylmethyl] -piperid Synthesis of din-4-carboxylic acid hydrochloride

1-[1-Chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4 -Carboxylic acid ethyl ester was synthesized according to the method described in Preparation Example 153-1 of International Publication No. WO 2014/129796 A1, the ester was hydrolyzed with NaOH, acidified with HCl, and then crystallized to form hydrochloride (hereinafter referred to as “API ”) was obtained.

Examples 1 to 3: Tablet production by wet granulation method

A solid formulation for oral use was prepared with the composition shown in Table 1 below.

First, an active ingredient solution is prepared by dissolving the API in purified water together with sodium lauryl sulfate. The diluent, binder and solubilizer were placed in a wet granulator and mixed. An active ingredient solution was added to the mixture and granulated. After drying/sizing the obtained granules, a lubricant was added and mixed. The mixture was compressed with a tablet press to obtain tablets containing API.

[Table 1]

Comparative Example: Tablet manufacturing by direct pressing method

Tablets were prepared by mixing the ingredients in the composition of Table 2 below and then directly compressing them.

[Table 2]

Example 4: Measurement of content uniformity

Each of the 10 tablets prepared in Example 2 and Comparative Example was put into a 100 mL volumetric flask, and 70 mL of purified water was added thereto, followed by stirring. After confirming that the tablets were all dissolved, 25 mL of acetonitrile was added, followed by sonication for 5 minutes. After filling up to the mark with acetonitrile, it was filtered with a syringe filter and used as a sample solution.

<HPLC analysis conditions>

1.Column: Inertsil ODS-2 Column (5 μm, 4.6 x 150 mm, GL Sciences Inc.)

2.Detector: 291 nm, UV

3. Temperature: 20℃

4. Mobile phase

Mobile phase A: Acetonitrile/Methanol/H2O/TFA = 45/15/40/0.1 (v/v/v/v)

Mobie phase B: Acetonitrile/Methanol/H2O/TFA = 80/15/5/0.1 (v/v/v/v)

5. Flow Rate: 0.8 mL/min.

6. Injection Volume: 50 μL

7. Gradient Table

8. Total Analysis Time: 25 min.

The results are shown in Table 3.

[Table 3]

As can be seen from Table 3, it was confirmed that the content uniformity in the tablet according to the present invention was superior to that of the comparative example.

Claims (10)

1. i) 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]- as an active ingredient Dissolving piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and sodium lauryl sulfate as a solubilizing agent in a solvent to prepare an active ingredient solution; putting a diluent, a binder and a disintegrant into a wet granulator and mixing to prepare a mixture;

   ii) adding the active ingredient solution to the mixture obtained in step (i) and then granulating;

   iii) drying/sizing the granulated material obtained in step (ii), then adding a lubricant and mixing afterward;

   iv) A method for producing a solid oral preparation comprising compressing the mixture obtained in step (iii) with a tableting machine.
2. According to claim 1,

   i) 0.2 to 2 wt% of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalene- as an active ingredient 2-ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, and 1 to 5% by weight of sodium lauryl sulfate as a solubilizing agent to prepare an active ingredient solution; 70 to 90% by weight of a diluent, 2 to 10% by weight of a binder, and 3 to 15% by weight of a disintegrant are placed in a wet granulator and mixed to prepare a mixture;

   ii) adding the active ingredient solution to the mixture obtained in step (i) and then granulating;

   iii) drying/sizing the granules obtained in step (ii), then adding 0.5 to 3% by weight of a lubricant and post-mixing;

   iv) A method for producing a solid formulation for oral use, characterized in that the mixture obtained in step (iii) is compressed with a tableting machine.
3. According to claim 1, wherein the pharmaceutically acceptable salt is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid , lactic acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid.
4. The method of claim 3, wherein the pharmaceutically acceptable salt is hydrochloric acid.
5. The method of claim 1, wherein the solvent is purified water.
6. The method according to claim 1, wherein the diluent is selected from lactose or a hydrate thereof, microcrystalline cellulose, and mixtures thereof.
7. The method of claim 6, wherein the lactose hydrate is lactose monohydrate.
8. The method according to claim 1, wherein the binder is hydroxypropyl cellulose.
9. The method of claim 1, wherein the disintegrant is croscarmellose sodium.
10. The method of claim 1, wherein the lubricant is magnesium stearate.