WO2022220593A1 - Directly compressible pharmacological composition comprising sphingosine-1-phosphate receptor agonist - Google Patents

Abstract

The present invention relates to a directly compressible pharmacological composition comprising a sphingosine-1-phosphate receptor agonist and, more specifically, to a pharmacological composition for direct compression, comprising 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid of formula 1 or a pharmacologically acceptable salt thereof as an active ingredient, and comprising lactose or a hydrate thereof as a diluent, hydroxypropyl cellulose as a binder, sodium stearyl fumarate as a lubricant, and croscarmellose sodium as an excipient.

Description

Pharmaceutical composition for direct tableting comprising a sphingosine-1-phosphate receptor agonist

The present invention relates to a pharmaceutical composition for direct tableting comprising a sphingosine-1-phosphate receptor agonist, and more particularly, 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, diluent It relates to a pharmaceutical composition for direct tableting comprising raw lactose or a hydrate thereof, hydroxypropyl cellulose as a binder, sodium stearyl fumarate as a lubricant and sodium croscarmellose as a disintegrant:

[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 levels in each tissue are 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 high concentrations (100-1000 nM) in plasma bound to albumin and other plasma proteins, whereas in tissues, they are present in 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, a typical oral solid preparation is directly compressed into tablets after mixing all the ingredients by direct compression (direct compression) method; Dry granulation method in which the mixture is kneaded, granulated and sieved to produce dry granules, and then compressed into tablets; And water or organic solvent is used to make a binding solution, add to the mixture, knead, granulate, dry, and sieve to produce wet granules, and then compress to make tablets. It can be manufactured using wet granulation. have.

In the case of the direct tableting method, since there are few process steps, the manufacturing cost is reduced and the loss of the active ingredient is small, and since it does not require a solvent, it can be expected to improve the stability of the active ingredient, which is unstable to heat or humidity. However, it is necessary to select a specific excipient in order to impart properties necessary for direct compression, and in particular, in tablets containing a relatively small amount of active ingredient, it may be difficult to prepare a tablet with a uniform content.

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 ]-Piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof is to provide a composition that can be prepared by a direct tableting method with stability in a uniform content:

[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 is combined with a specific excipient to ensure stability with a uniform content of the active ingredient, direct tableting method It provides a composition that can be prepared by

Hereinafter, the present invention will be described in detail.

According to one aspect of the present invention, 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalene-2 as an active ingredient -ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, lactose or a hydrate thereof as a diluent, hydroxypropyl cellulose as a binder, sodium stearyl fumarate as a lubricant, and A pharmaceutical composition for tableting by direct compression comprising croscarmellose sodium as a disintegrant is provided.

In one embodiment of the present invention, the pharmaceutical composition for direct tableting is 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)- as an active ingredient 0.2 to 2% by weight of 3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, 85.25 to 90.55% by weight of lactose or a hydrate thereof as a diluent; It may include 4.5 to 5.5 wt% of hydroxypropyl cellulose as a binder, 0.75 to 1.25 wt% of sodium stearyl fumarate as a lubricant, and 4 to 6 wt% of croscarmellose sodium as a disintegrant.

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 lactose hydrate may be lactose monohydrate.

In one embodiment of the present invention, the pharmaceutical composition may be compressed at a pressure of 5 to 11 kN. In one embodiment of the present invention, when the molding pressure is less than 5 kN, proper friability may not be secured, and when the molding pressure exceeds 11 kN, the hardness decreases due to increased repulsion between the components and an increase in friability.

In one embodiment of the present invention, the pharmaceutical composition may further include a coating agent. In one embodiment of the present invention, the coating agent may be a polyvinyl alcohol-based (PVA-based) coating agent or a hydroxypropyl methyl cellulose-based (HPMC-based) coating agent, but is not limited thereto. In one embodiment of the present invention, the hydroxypropyl methyl cellulose-based coating agent, for example, Opadry™ may be used, but is not limited thereto.

According to another aspect of the present invention, 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-dihydro-naphthalene- 2-ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, lactose or its hydrate as a diluent, hydroxypropyl cellulose as a binder, sodium stearyl fumarate as a lubricant and cross as a disintegrant Provided is a method for preparing a solid oral dosage form comprising a sphingosine-1-phosphate receptor agonist, which is directly tableted after mixing with sodium carmellose.

In one embodiment of the present invention, the preparation method is 1- [1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3,4-di as an active ingredient Hydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof 0.2 to 2% by weight, lactose or its hydrate as a diluent 85.25 to 90.55% by weight, hydroxypropyl as a binder 4.5 to 5.5 wt% of cellulose, 0.75 to 1.25 wt% of sodium stearyl fumarate as a lubricant, and 4 to 6 wt% of croscarmellose sodium as a disintegrant may be mixed.

In one embodiment of the present invention, the tableting may be performed at a pressure of 5 to 11 kN. In one embodiment of the present invention, when the molding pressure is less than 5 kN, proper friability may not be secured, and when the molding pressure exceeds 11 kN, the hardness decreases due to increased repulsion between the components. and an increase in friability.

The pharmaceutical composition according to the present invention enables the production of a solid oral preparation containing a sphingosine-1-phosphate receptor agonist through a direct tableting process, thereby reducing manufacturing cost and loss of active ingredients with fewer process steps However, it is possible to provide the active ingredient in a state in which stability is ensured in a uniform content.

1 is a comparison of main effects plots and interaction plots under high-temperature and high-humidity conditions (80°C/75%RH) for the impurity of RRT 0.62.

2 is a comparison of the main effect plot and the interaction plot of high temperature and high humidity conditions (80°C/75%RH) for the impurity of RRT 0.72.

3 is a graph measuring the change in hardness according to pressure during direct tableting.

4 is a graph measuring the change in the degree of wear and tear according to the pressure during direct tableting.

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.

Example 1: Preparation of tablets

After mixing the ingredients in the composition shown in Table 1 below, tablets were prepared by direct compression.

[Table 1]

Example 2: content uniformity

The API and excipients were mixed using a 3D mixer in the composition of Table 2 below.

[Table 2]

After taking a sample from 10 places of the mixture obtained above and measuring the content of the main component, the % difference between the theoretical value and the actual value is summarized and shown in Table 3. As a result of the confirmation, it was confirmed that the above formulation constituted a homogeneous mixture.

[Table 3]

Example 3: Stability Study

The tablets prepared with the composition of Table 2 were stored in an HDPE bottle by 50 tablets under severe conditions, and then stability against changes in content was measured, and the results are shown in Table 4.

[Table 4]

From the above results, it was confirmed that the tablet according to the present invention had adequate stability even under severe conditions.

comparative example

With the composition of Table 5 below, a mixture containing microcrystalline cellulose instead of lactose monohydrate as a diluent and magnesium stearate as a lubricant instead of Pruv was prepared in the same manner as in Example 2.

[Table 5]

In addition, as in Example 2, a sample was taken from 10 places of the mixture obtained above and the content of the main component was measured, and the % difference between the theoretical value and the actual value was summarized and shown in Table 6. As a result of the confirmation, it was confirmed that the above formulation constituted a homogeneous mixture.

[Table 6]

In addition, after stability measurement in the same manner as in Example 3, the results are shown in Table 7.

[Table 7]

From the above results, it is possible to obtain a homogeneous mixture similar to the formulation based on lactose in the case of a formulation based on microcrystalline cellulose, but at humidity (70°C/75%RH) and heat (80°C/50%RH) was found to be very sensitive to changes in

Example 4: Confirmation of stability according to component content

This experiment was conducted to check how the CQA (content, uniformity of content, dissolution, related substances) was affected when the ratio of excipients was changed. The experimental design was fractional factorial design, 200 g/batch, and the excipient range setting criteria were as follows according to the SUPAC-IR guideline (level 1 change, total dosage form weight criteria).

- API: 0.2 to 1.5 mg/tablet

- HPC-L (Binder) ± 0.5%

- Croscarmellose sodium(CCS) (Disintegrant) ± 1%

- Pruv (Lubricant) ± 0.25%

In the case of Pruv, the level 1 change standard of the SUPAC guideline is ±1%, but it was arbitrarily set to ±0.25% because tableting was impossible without Pruv.

[Table 8]

A comparison of main effects plots and interaction plots under high-temperature and high-humidity conditions (80°C/75%RH) for the impurity of RRT 0.62 is shown in FIG. 1 . A comparison of the main effect plot and the interaction plot of the high temperature and high humidity conditions (80°C/75%RH) for the impurity of RRT 0.72 is shown in FIG. 2 .

As can be seen from the main effect diagram of Figure 1, HPC-L and Pruv lowered the impurity of RRT 0.62 at 80 ℃ / 75% RH, croscamellose sodium (CCS) at 80 ℃ / 75% RH The impurity of RRT 0.62 was increased, and the lower the API capacity, the higher the impurity of RRT 0.62 at 80℃/75%RH. From the interaction diagram of FIG. 1, when the content of Pruv is low, HPC-L does not affect the amount of impurity, but when the content of Pruv is high, HPC-L has an impurity of RRT 0.62 at 80°C/75%RH When the API content was high, HPC-L did not affect the amount of impurity, but when the API content was low, it was confirmed that HPC-L lowered the impurity of RRT 0.62.

In addition, as can be seen from the main effect diagram of Figure 2, CCS lowered the impurity of RRT 0.72 at 80 ℃ / 75% RH, HPC-L and Pruv increased the impurity of RRT 0.72 at 80 ℃ RH, API The lower the dose, the higher the impurity of RRT 0.72 at 80°C/75%RH. From the interaction diagram of FIG. 2, when the content of pruv is low, HPC-L does not increase the impurity, whereas when the content of pruv is high, HPC-L increases the impurity of RRT 0.72 at 80°C/75%RH knew what to do

Example 5: Setting of tableting process conditions

For tablet molding, it is necessary to secure a certain level of friability to prepare for deformation (damage) of the formulation during flow. Accordingly, the changes in hardness and friability of the tablet according to the compression force during direct hitting were measured, and the results are shown in FIGS. 3 and 4 , respectively. As can be seen from FIG. 3, the hardness is decreased and the friability is increased due to the increase in repulsion between the components constituting the molding at a pressure exceeding about 11 kN. In addition, as can be seen from FIG. 4, it was not possible to secure an appropriate degree of friability during molding at a pressure of less than about 5 kN. From the above results, it was confirmed that the proper molding range should be set to 5 to 11 kN.

Example 6: Confirmation of stability for film-coated tablets

After preparing uncoated tablets with the composition shown in Table 9 below, three different types of film coatings were performed.

[Table 9]

The prepared film-coated tablets were stored under severe conditions to confirm their stability. It was confirmed through the change of organic impurities (RRT 0.80) of RRT 0.80 under the following analysis conditions. The results are shown in Table 10.

[Table 10]

From the above results, it was confirmed that the film-coated tablet using the composition of the present invention had adequate stability even under severe conditions.

Example 8: Confirmation of Long-Term Stability for Compositions

In order to confirm the long-term storage stability of the composition of the present invention, film-coated tablets were prepared with the composition of Table 11. The manufacturing method was first prepared by using a direct pressing method for tablets containing from API to Pruv, and then coating was completed using a water-based coating method.

[Table 11]

Storage stability of the prepared tablets was confirmed at room temperature and accelerated storage conditions. Table 12 shows the results of analysis on changes in content and organic impurities during the storage stability test.

[Table 12]

From the above results, it was confirmed that the composition of the present invention has adequate stability even under long-term storage conditions.

Claims (8)

1. 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperid as active ingredient Direct tableting comprising din-4-carboxylic acid or a pharmaceutically acceptable salt thereof, lactose or a hydrate thereof as a diluent, hydroxypropyl cellulose as a binder, sodium stearyl fumarate as a lubricant, and sodium croscarmellose as a disintegrant pharmaceutical composition for
2. The method of claim 1, wherein 0.2 to 2% by weight of the active ingredient, 85.25 to 90.55% by weight of the diluent, 4.5 to 5.5% by weight of the binder, 0.75 to 1.25% by weight of the lubricant and 4 to 6% by weight of the disintegrant. pharmaceutical composition.
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, characterized in that the pharmaceutical composition is selected from the group consisting of.
4. The pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable salt is hydrochloric acid.
5. The pharmaceutical composition according to claim 1, wherein the lactose hydrate is lactose monohydrate.
6. The pharmaceutical composition according to claim 1, characterized in that the tablet is compressed at a pressure of 5 to 11 kN.
7. The pharmaceutical composition according to claim 1, further comprising a coating agent.
8. The pharmaceutical composition according to claim 7, wherein the coating agent is a polyvinyl alcohol-based (PVA-based) coating agent or a hydroxypropyl methyl cellulose-based (HPMC-based) coating agent.

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