Pharmaceutical compositions containing particle-size-controlled sphingosine-1-phosphate receptor agonists

Abstract

The present invention relates to a pharmaceutical composition comprising a particle size controlled sphingosine-1-phosphate receptor agonist, more specifically, to a pharmaceutical composition 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 pharma- ceutically acceptable salt thereof as an active ingredient, and a pharma- ceutically acceptable carrier, wherein the particle size d(0.9) of the active ingredient is 60 μm or less.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing a particle-size-controlled sphingosine-1-phosphate receptor agonist, more specifically, a pharmaceutical composition comprising a compound represented by the following formula (1): [ka] or a pharmaceutically acceptable salt thereof, wherein the particle size d(0.9) of the active ingredient is 60 μm or less. [Background technology]

[0002] Sphingosine-1-phosphate (S1P) is produced via the intracellular ceramide pathway, starting from ceramide. Ceramide is produced via two pathways: the de novo biosynthetic pathway and the de novo biosynthetic pathway. Ceramide is also produced by the intracellular degradation of sphingomyelin, a cell membrane component. S1P levels in various tissues are regulated by two biosynthetic sphingosine kinases (SphKs) and two biodegradative S1P phosphatases (S1P lyase and lysophospholipid phosphatase). S1P, produced via the phosphorylation of sphingosine by Sphingosine kinases, is known to mediate various cellular responses, including cell proliferation, cytoskeletal organization and migration, adhesion and tight junction assembly, and morphogenesis. S1P is present at high concentrations (100–1000 nM) in plasma bound to plasma proteins, including albumin, and at lower concentrations in tissues.

[0003] S1P binds to G-protein-coupled receptors, called S1P receptors, and exhibits various biological functions. Currently, S1P receptor subtypes, S1P1 to S1P5, are known, and are named endothelial differentiation gene receptors (EDG) 1, 5, 3, 6, and 8, respectively. S1P receptors are known to be involved in various biological functions, such as leukocyte recirculation, neuronal proliferation, morphological changes, migration, endothelial function, blood pressure regulation, and cardiovascular development.

[0004] On the other hand, in the preparation of pharmaceuticals, particle size specifications must be set to ensure uniformity and efficacy of the active ingredient. Specifically, when the content of the active ingredient is low, particle size specifications must be set to ensure uniformity of the active ingredient in each formulation and its pharmacokinetic properties. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention relates to a compound represented by the following formula (1): [ka] The object of the present invention is to provide a pharmaceutical composition which uniformly contains 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid represented by the formula: or a pharmaceutically acceptable salt thereof, and which can ensure pharmacokinetic properties that show sufficient efficacy. [Means for solving the problem]

[0006] In order to solve the above technical problems, the present invention provides a pharmaceutical composition comprising 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 as an active ingredient, and a pharmaceutically acceptable carrier, wherein the particle size d(0.9) of the active ingredient is 60 μm or less.

[0007] The present invention will be described in detail below.

[0008] According to the present invention, there is provided a pharmaceutical composition comprising 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 as an active ingredient, and a pharmaceutically acceptable carrier, wherein the particle size d(0.9) of the active ingredient is 60 μm or less.

[0009] In this specification, "particle size d(0.9)" means that 90% of the particle volume has a diameter within a specific particle size d range. Specifically, it means that the particle size (d(0.9)) at which the cumulative frequency of the volume distribution, accumulating from small particles, reaches 90% is within the specific diameter d range.

[0010] In one embodiment of the present invention, the active ingredient can be micronized to have a particular particle size, for example, In one embodiment of the present invention, micronization of the active ingredient can be achieved by methods known in the art, for example, milling.

[0011] In one embodiment of the present invention, the lower limit of the particle size d(0.9) is not particularly limited and may be, for example, 0 μm or more, 2 μm or more, or 5 μm or more, but is not limited thereto. In one embodiment of the present invention, the particle size d(0.9) of the active ingredient is 5 to 60 μm.

[0012] In one embodiment according to the present invention, the pharmaceutically acceptable salt may be selected from the group consisting of 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.

[0013] In one embodiment according to the present invention, the pharmaceutically acceptable carrier is a diluent, a binder, a lubricant, and / or a disintegrant. In one embodiment according to the present invention, the diluent is lactose or a hydrate thereof, the binder is hydroxypropyl cellulose, the lubricant is sodium stearyl fumarate, and the disintegrant is croscarmellose sodium. In one embodiment according to the present invention, the pharmaceutical composition may further contain other additives, such as colorants, flavors, flavorings, sweeteners, coating agents, etc., as necessary.

[0014] The pharmaceutical composition according to the present invention is suitable for the prevention or treatment of diseases associated with sphingosine-1-phosphate receptors. In one embodiment according to the present invention, the pharmaceutical composition can be used for the treatment of autoimmune disorders, including multiple sclerosis. In one embodiment according to the present invention, the pharmaceutical composition can be used for the prevention or treatment of diseases caused by unwanted lymphocyte infiltration associated with sphingosine-1-phosphate. In one embodiment according to the present invention, the pharmaceutical composition can be used for the prevention or treatment of immunoregulatory disorders. In one embodiment according to the present invention, the immunoregulatory disorder may be, for example, an autoimmune disease or a chronic inflammatory disease selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), arteriosclerosis, atherosclerosis, scleroderma, and autoimmune hepatitis, but is not limited to these. [Effects of the Invention]

[0015] The pharmaceutical composition according to the present invention contains a sphingosine-1-phosphate receptor agonist in suitable uniformity, and can provide a medicament that exhibits sufficient efficacy. [Brief explanation of the drawings]

[0016] [Figure 1] 1 is a graph showing the change in blend uniformity over time. [Figure 2] 1 is a graph showing a comparison of in vitro dissolution patterns in various buffer solutions. [Figure 3] 1 is a graph showing a comparison of pharmacokinetic properties (plasma concentration) depending on particle size. [Example]

[0017] The present invention will now be described in more detail with reference to the following examples, but it should be understood that the scope of protection of the present invention is not limited to the examples.

[0018] Preparation Example: Synthesis of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid hydrochloride According to the method described in Preparation Example 153-1 of WO2014 / 129796 A1, 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, and the ester was hydrolyzed with NaOH, acidified with HCl, and then crystallized to obtain the hydrochloride salt (hereinafter referred to as "Compound 1").

[0019] Example 1: Tablet production The ingredients were mixed according to the composition in Table 1 below, and then tablets were prepared by direct compression. [Table 1]

[0020] Example 2: Measurement of uniformity changes In order to confirm the change in uniformity during mixing due to the particle size distribution of the active ingredient, the active ingredient was pulverized to prepare samples having various particle size distributions as shown in Table 2 below. [Table 2] The active ingredients having different particle size distributions in Table 2 were mixed in the compositions in Table 1, and then the degree of mixing uniformity was measured. The results are shown in FIG.

[0021] As can be seen from FIG. 1, smaller particle sizes are more advantageous for uniform mixing.

[0022] Example 3: In Vitro Dissolution Rate Measurement Active ingredients with different particle size distributions shown in Table 3 below were filled into gelatin capsules, and the dissolution rate over time was measured at various pH levels in fasting stimulated gastric fluid (FaSSGF) and fasting stimulated intestinal fluid (FaSSIF, V2). [Table 3] The results are shown in Figure 2. Figure 2 confirms that, although the degree of dissolution varies depending on the solution conditions, there is a difference in dissolution rate depending on particle size under in vitro conditions.

[0023] Example 4: Measurement of pharmacokinetic properties In this study, a crossover design was used in which all three types of tablets (active ingredients with particle sizes of Samples 5 to 7) were administered to male beagle dogs. Each of the three types of tablets was administered once, with a 14-day washout period. Each dose was administered with 50 mL of water while maintaining a fasting state for at least 14 hours. The results are shown in Figure 3.

[0024] As can be seen from Figure 3, it was confirmed that the pharmacokinetic (PK) properties differ depending on the particle size of the API, and it was determined that a particle size d(0.9) based on Cmax of 60 μm or less shows pharmacokinetic bioequivalence and stable efficacy.

Claims

1. The present invention relates to a pharmaceutical composition comprising 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 as an active ingredient, and a pharmaceutically acceptable carrier, and further comprising a diluent, a binder, a lubricant, and a disintegrant, wherein the particle size d(0.9) of the active ingredient is 5 to 60 μm or less, the diluent is lactose or a hydrate thereof, the binder is hydroxypropyl cellulose; the lubricant is sodium stearyl fumarate, A pharmaceutical composition wherein the disintegrant is croscarmellose sodium.

2. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable acid salt is selected from the group consisting of 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.

3. 3. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable salt is hydrochloride.

4. 2. The pharmaceutical composition of claim 1, wherein the hydrate of lactose is lactose monohydrate.

5. 10. The pharmaceutical composition of claim 1 for use in the treatment of autoimmune disorders, including multiple sclerosis.

6. 2. The pharmaceutical composition according to claim 1, which is for use in the prevention or treatment of a disease caused by unwanted lymphocyte infiltration associated with sphingosine-1-phosphate.

7. The pharmaceutical composition according to claim 1, which is for use in the prevention or treatment of immunoregulatory disorders.

8. 8. The pharmaceutical composition of claim 7, wherein the immunoregulatory disorder is an autoimmune disease or chronic inflammatory disease selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), arteriosclerosis, atherosclerosis, scleroderma, and autoimmune hepatitis.

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