Fingolimod oral liquid composition and use thereof

Abstract

An oral liquid composition containing fingolimod or a pharmaceutically acceptable salt thereof. The oral liquid composition at least comprises: fingolimod or a pharmaceutically acceptable salt thereof, cyclodextrin, a metal complexing agent, and water, wherein the mass ratio of the cyclodextrin to the fingolimod or the pharmaceutically acceptable salt thereof is 70-200:1, and the composition has a pH of 3-6. By means of adding the metal complexing agent, providing the specific amount of cyclodextrin, and controlling the pH of the composition, the problems of physical and chemical instability of fingolimod in the oral liquid composition caused by of iron ion leaching in the production line, long-time storage, environmental change, etc. are solved.

Description

Fingolimod oral liquid composition and application thereof

[0001] The present invention claims priority from the prior application filed on May 13, 2024, entitled “A fingolimod oral liquid composition and its application” and application number 202410590969.2. The contents of the above-mentioned prior application are incorporated into this text by reference. Technical Field

[0002] The present application relates to the field of biomedicine, and specifically to a fingolimod oral liquid composition and its application. Background Art

[0003] Fingolimod (CAS No. 162359-55-9, chemical name 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol) is an S1P (sphingosine-1-phosphate) receptor modulator that can block the outflow of lymphocytes from secondary lymphoid organs and prevent reactive lymphocytes from entering the central nervous system. Clinically, it can mainly prevent the relapse of multiple sclerosis and the development of physical disability.

[0004] Among the various compositions of fingolimod and its salts, oral solid compositions such as capsules and orally disintegrating tablets have been marketed, but no oral liquid preparation products have been marketed. Therefore, there is a need to develop oral liquid compositions to improve patient compliance.

[0005] However, since oral liquid compositions usually need to be stored for a long time and the storage or transportation environment requirements are generally not strict to facilitate market circulation, the stability of the preparation, especially good long-term stability, is particularly important for the quality assurance of oral liquid compositions.

[0006] In actual pharmaceutical production lines, liquid compositions containing fingolimod or its salts inevitably come into contact with production line equipment (such as stainless steel), which may release iron ions to varying degrees. The inventors surprisingly discovered that, because the alkyl aromatic hydrocarbons in fingolimod are easily oxidized to form ketones, these iron ions catalyze the oxidation of fingolimod, and even trace amounts of iron ions can affect the stability of the fingolimod liquid composition.

[0007] Summary of the Invention

[0008] In view of this, the present invention provides a long-term stable and weather-resistant fingolimod oral liquid composition, and the technical solution is as follows.

[0009] The present invention provides a fingolimod oral liquid composition, comprising the following components:

[0010] (A) 0.0001-0.5% of fingolimod or a pharmaceutically acceptable salt thereof;

[0011] (B) cyclodextrin, wherein the mass ratio of the cyclodextrin to fingolimod or a pharmaceutically acceptable salt thereof is 70-200:1;

[0012] (C) 0.01-1% of a metal complexing agent; and

[0013] (D) Water;

[0014] The pH of the oral liquid composition is 3-6.

[0015] Preferably, the cyclodextrin in the oral liquid composition is selected from at least one of natural cyclodextrin, branched cyclodextrin, alkyl cyclodextrin or hydroxyalkyl cyclodextrin.

[0016] The natural cyclodextrin of the present invention is selected from at least one of α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin.

[0017] As used herein, "branched cyclodextrins" refer to natural cyclodextrin rings with glycosyl groups (e.g., glucose, maltose, cellobiose, lactose, sucrose, galactose, glucosamine, etc.) attached to them. Branched cyclodextrins are formed by the enzyme pullulanase, which binds glycosyl groups to the natural cyclodextrin rings. For example, branched cyclodextrins can be formed by attaching one, two, or three or more glucose groups in natural cyclodextrin to glucose or other glycosyl groups via an oxygen atom at position 6, forming an α,1→6 bond.

[0018] The "alkylcyclodextrin" referred to in the present invention refers to a product in which the hydrogen atoms of the hydroxyl groups in natural cyclodextrin are replaced by alkyl groups. For example, the alkyl group can be C 1-8 Specifically, the alkyl group may be a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group or an octyl group.

[0019] The "hydroxyalkyl cyclodextrin" referred to in the present invention refers to a product in which the hydrogen atom of the hydroxyl group in the natural cyclodextrin is replaced by a hydroxyalkyl group. For example, the hydroxyalkyl group can be C 1-8 Specifically, the hydroxyalkyl group may be a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group, a hydroxyhexyl group, a hydroxyheptyl group or a hydroxyoctyl group having 1 to 6 hydroxyl groups.

[0020] Preferably, in the fingolimod oral liquid composition, the content of fingolimod or a pharmaceutically acceptable salt thereof is 0.001-0.1%, preferably 0.005-0.05%.

[0021] Preferably, the mass ratio of the cyclodextrin to fingolimod or its pharmaceutically acceptable salt in the oral liquid composition is 70-100:1.

[0022] Preferably, the fingolimod or a pharmaceutically acceptable salt thereof is fingolimod hydrochloride or fingolimod dodecylsulfonate.

[0023] Preferably, the fingolimod or a pharmaceutically acceptable salt thereof is fingolimod hydrochloride.

[0024] Preferably, the content of the metal complexing agent in the oral liquid composition is 0.05-0.5%, preferably 0.1-0.2%.

[0025] Preferably, the cyclodextrin in the oral liquid composition is hydroxypropyl-β-cyclodextrin.

[0026] Preferably, the metal complexing agent in the oral liquid composition is selected from at least one of disodium edetate or sodium calcium edetate, more preferably disodium edetate.

[0027] Preferably, the oral liquid composition further contains:

[0028] (E) a buffering agent, wherein the buffering agent is used in an amount such that the pH of the oral liquid composition is 3-6.

[0029] Preferably, the buffer in the oral liquid composition is selected from at least one of citric acid and its hydrates, disodium hydrogen phosphate and its hydrates, sodium citrate and its hydrates, phosphates and their hydrates, malic acid, tartaric acid, hydrochloric acid or sodium hydroxide; the buffer is preferably selected from at least one of citric acid and its hydrates, disodium hydrogen phosphate and its hydrates or sodium citrate and its hydrates.

[0030] Preferably, the amount of the buffer in the oral liquid composition is 0.03-3%.

[0031] Preferably, the oral liquid composition may further contain other pharmaceutical excipients, wherein the other pharmaceutical excipients are selected from at least one of preservatives, sweeteners or aromatics.

[0032] Preferably, the dosage of the other pharmaceutical excipients is 0.01-20%, preferably 0.1-10%.

[0033] The present invention also provides use of any of the aforementioned oral liquid compositions in the preparation of a medicament or preparation for treating an S1P-mediated disease, such as an immune disease. Preferably, the disease is multiple sclerosis. DETAILED DESCRIPTION

[0034] In the following description, numerous specific details are provided to provide a more thorough understanding of the present invention. However, it will be apparent to those skilled in the art that the present invention may be practiced without one or more of these details. In other instances, certain technical features well known in the art are not described to avoid confusion with the present invention.

[0035] Unless otherwise specified, "%" herein refers to mass volume percentage (g / mL), and "part(s)" refers to parts by weight.

[0036] The following describes the implementation of the present invention in detail with reference to the definitions of terms:

[0037] I. Oral liquid composition

[0038] The oral liquid composition of the present invention comprises the following components:

[0039] (A) 0.0001-0.5% of fingolimod or a pharmaceutically acceptable salt thereof;

[0040] (B) cyclodextrin, wherein the mass ratio of the cyclodextrin to fingolimod or a pharmaceutically acceptable salt thereof is 70-200:1;

[0041] (C) 0.01-1% of a metal complexing agent; and

[0042] (D) Water;

[0043] The pH of the oral liquid composition is 3-6.

[0044] (A) Active pharmaceutical ingredient

[0045] In some embodiments, the pharmaceutically active ingredient of the present invention includes fingolimod or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the pharmaceutically active ingredient of the present invention is fingolimod or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the pharmaceutically acceptable salt of the present invention refers to a salt prepared from a base or acid that is acceptable for administration to a patient. For fingolimod, the salt may be derived from a pharmaceutically acceptable inorganic acid or organic acid. Specifically, pharmaceutically acceptable inorganic or organic acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, pyrophosphoric acid, hydrobromic acid, hydroiodic acid, and nitric acid; and organic acids such as citric acid, fumaric acid, gluconic acid, glutamic acid, lactic acid, maleic acid, malic acid, mandelic acid, oxalic acid, pantothenic acid, succinic acid, tartaric acid, acetic acid, sulfonic acid, alkylsulfonic acid, naphthalenesulfonic acid, etc. Fingolimod of the present invention is particularly preferably a salt derived from hydrochloric acid or dodecylsulfonic acid.

[0048] The content of fingolimod or its pharmaceutically acceptable salt in the oral liquid composition of the present invention is 0.0001-0.5%, 0.0005-0.2%, 0.001-0.1%, 0.002-0.09%, 0.005-0.08%, 0.006-0.05% or 0.008-0.03%, for example, it can be 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.011%, 0.012%, 0.013%, 0.015%, 0.02%, 0.025%, etc.

[0049] (B) Cyclodextrin

[0050] In some embodiments, the cyclodextrin of the present invention can be a natural cyclodextrin, a branched cyclodextrin, an alkyl cyclodextrin or a hydroxyalkyl cyclodextrin, such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dodecakis-2,6-O-methyl-α-cyclodextrin, tetradecakis-2,6-O-methyl-β-cyclodextrin, hexadecakis-2,6-O-methyl-γ-cyclodextrin, tetradecakis-2,6-O-ethyl-β-cyclodextrin, α-cyclodextrin etherified by 2-hydroxypropyl moiety, β-cyclodextrin etherified by 2-hydroxypropyl moiety (HP-β-CD), or a branched α-cyclodextrin or branched β-cyclodextrin obtained by binding glucose or maltose by α-1,6-glycosidic bond.

[0051] In some embodiments, the cyclodextrins of the present invention are selected from the group consisting of β-cyclodextrins.

[0052] In some embodiments, the cyclodextrin of the present invention is selected from hydroxyalkyl-β-cyclodextrins, such as hydroxypropyl-β-cyclodextrin or 2-hydroxypropyl partially etherified β-cyclodextrin.

[0053] In some embodiments, the mass ratio of the cyclodextrin of the present invention to fingolimod or its pharmaceutically acceptable salt is 70-200:1, 70-100:1, or 70-80:1. For example, the content of cyclodextrin can be 75, 80, 85, 90, 95, 100, 105, 110, 120, 150, 180 times the content of fingolimod or its pharmaceutically acceptable salt. Only an appropriate content of cyclodextrin can ensure the stability of the oral liquid composition of the present invention.

[0054] (C) Metal complexing agent

[0055] The metal complexing agent of the present invention refers to an agent that can complex with metal ions to stabilize them.

[0056] In some embodiments, the metal complexing agent of the present invention can complex Fe3+ .

[0057] In some embodiments, the metal complexing agent of the present invention is selected from sodium citrate, disodium edetate, sodium calcium edetate, gentisate ethanolamine or oxyquinoline sulfate, etc. In some embodiments, the metal complexing agent of the present invention is disodium edetate.

[0058] In some embodiments, the metal complexing agent of the present invention is present in an oral liquid composition at an amount of 0.01-1%, 0.02-0.8%, 0.05-0.5%, 0.08-0.3%, or 0.1-0.2%.

[0059] (D) Water

[0060] Water is the main solvent of the oral liquid composition of the present invention, and its amount can ensure that all components in the composition have long-term weathering stability.

[0061] In some embodiments, the volume of a single dose of the oral liquid composition of the present invention can be 0.1-500 mL, for example, 0.2 mL, 0.5 mL, 1 mL, 2 mL, 5 mL, 10 mL, 20 mL, 50 mL, 100 mL, 120 mL, 150 mL, 200 mL, 250 mL, etc. The above volumes are obtained by adding water to the composition to make up the volume.

[0062] (E) Buffer

[0063] The pH of the oral liquid composition of the present invention is 3-6, for example, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, etc.

[0064] In some embodiments, the pH is controlled by adding a pH buffer to the oral liquid composition.

[0065] In some embodiments, the buffer is selected from at least one of citric acid and its hydrates, disodium hydrogen phosphate and its hydrates, sodium citrate and its hydrates, phosphates and its hydrates, malic acid, tartaric acid, hydrochloric acid or sodium hydroxide.

[0066] In some embodiments, the buffer is selected from at least one of citric acid and its hydrates, disodium hydrogen phosphate and its hydrates, or sodium citrate and its hydrates.

[0067] In some embodiments, the amount of buffer in the oral liquid composition is 0.03-3%, for example, 0.05%, 0.1%, 0.2%, 0.5%, 1%, 1.5%, 2%, 2.5% or 2.8%.

[0068] (F) Other pharmaceutical excipients

[0069] Other auxiliary materials may be added as needed without affecting the oral liquid composition of the present invention.

[0070] In some embodiments, the content of the excipient in the composition may be 0.01-20% or 0.1-10%.

[0071] The pharmaceutical excipients that may be added to the present invention may include, for example, at least one of a preservative, a sweetener, and a flavoring agent.

[0072] In some embodiments, the preservative of the present invention is selected from at least one of benzoic acid, sorbic acid or sodium benzoate, preferably sodium benzoate. In some embodiments, the content of the preservative in the composition may be 0.01-0.5%.

[0073] In some embodiments, to improve the taste of the composition, a sweetener may be added, such as sorbitol, mannitol, sucralose, or at least one of aspartame and saccharin sodium, preferably at least one of mannitol or sucralose. In some embodiments, the sweetener may be present in the composition in an amount of 0.2-10%.

[0074] In some embodiments, a fragrance can be added to improve the taste of the composition, such as at least one of sweet orange flavor, strawberry flavor, orange flavor, vanilla flavor, or mixed fruit flavor. In some embodiments, the fragrance can be present in an amount of 0-5% in the composition.

[0075] II Preparation

[0076] The pharmaceutical composition of the present invention can be prepared into an oral liquid preparation.

[0077] In some embodiments, the volume of a single dose of the oral liquid formulation of the present invention can be 0.1-500 mL, for example, 0.2 mL, 0.5 mL, 1 mL, 2 mL, 5 mL, 10 mL, 20 mL, 50 mL, 100 mL, 120 mL, 150 mL, 200 mL, 250 mL, etc. The above volumes are obtained by adding water to the composition to make up the volume.

[0078] III Application

[0079] The pharmaceutical composition or formulation of the present invention can be used to treat a disease, such as an immune disease. In some embodiments, the disease is multiple sclerosis.

[0080] The present invention solves the problem of instability of oral liquid compositions caused by iron ion leaching from the production line, long-term storage, changes in the storage environment, etc. by adding a metal chelating agent and a specific amount of cyclodextrin to the fingolimod liquid composition and controlling the pH of the composition. This results in a new dosage form with potential for large-scale clinical production - an oral liquid, which improves patient compliance.

[0081] The pharmaceutical composition or formulation of the present invention has good long-term stability, including physical and / or chemical stability. Furthermore, the pharmaceutical composition or formulation of the present invention also has good weather resistance, including high temperature resistance and / or low temperature resistance.

[0082] The term "chemical stability" means that the composition has almost no changes in the relevant substances after being stored at an elevated temperature of 60°C for at least 30 days.

[0083] The term "physical stability" means that the composition does not precipitate crystals after being stored at low temperature (2-8°C for 10 days).

[0084] The term "related substances" refers to impurities such as starting materials, intermediates, polymers, side reaction products introduced during the preparation of the pharmaceutical composition, and degradation products during storage.

[0085] The term "reporting limit" is the minimum limit for impurity reporting, that is, impurities above this limit need to have their content reported.

[0086] The present invention is further described in detail below through specific examples.

[0087] raw material

[0088] Fingolimod hydrochloride: a raw material with a purity greater than 99.0% that meets the requirements of the United States Pharmacopoeia.

[0089] Hydroxypropyl-β-cyclodextrin: molecular weight 1431-1806, in compliance with the Chinese Pharmacopoeia pharmaceutical excipients.

[0090] Other reagents were purchased from Sinopharm Chemical Reagent Co., Ltd. and used directly.

[0091] Detection method

[0092] Impurity detection:

[0093] Detection instrument: High performance liquid chromatograph: Agilent, model: Agilent 1260.

[0094] Detection process: The solvent was acetonitrile-0.1% phosphoric acid solution (50:50).

[0095] Preparation of test solution: Take an appropriate amount of each example sample, dissolve it in the above solvent and quantitatively dilute it to make a solution containing about 0.8 mg of each example sample per 1 ml.

[0096] Preparation of control solution: Take an appropriate amount of fingolimod hydrochloride reference substance calibrated with accurate content and quantitatively dilute it with solvent to prepare a solution containing approximately 4 μg of fingolimod hydrochloride per 1 ml.

[0097] Preparation of sensitivity solution: Take 1 ml of the control solution, place it in a 10 ml volumetric flask, dilute it to the scale with solvent, and shake well.

[0098] System suitability solution: Take 6 mg of fingolimod hydrochloride mixed reference substance (including fingolimod hydrochloride and various impurities, USP standard), place it in a 10 ml volumetric flask, dilute to the scale with diluent, and shake well.

[0099] Chromatographic conditions: Octadecylsilane bonded silica gel as filler (Prontosil 120-3-C18 ACE-EPS (150 mm × 3 mm, 3 μm) or equivalent performance column); 0.1% phosphoric acid as mobile phase A, acetonitrile as mobile phase B, gradient elution as shown in the table below; column temperature, 40°C; detection wavelength, 215 nm; flow rate, 0.8 ml / min; injection volume, 5 μl.

[0100] System suitability requirements: In the system suitability solution chromatogram, the order of peak elution should be fingolimod hexyl homologue, fingolimod heptyl homologue, fingolimod, O-acetyl fingolimod, fingolimod nonyl homologue, fingolimod decyl homologue, 3-phenylethyl homologue, and 2-phenylethyl homologue. The resolution between the O-acetyl fingolimod peak and the fingolimod nonyl homologue peak should be no less than 1.2. In the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height should be no less than 10.

[0101] Determination method: Accurately measure the test solution and control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0102] Effect of pH of the composition of Examples 1-5

[0103] Fingolimod hydrochloride pharmaceutical compositions were prepared according to the formulation shown in Table 1. The specific method was as follows: hydroxypropyl-β-cyclodextrin was added to a certain amount of purified water to obtain a solution, fingolimod hydrochloride was then added to the solution to dissolve it, and the other excipients were added in sequence, stirred to dissolve, and finally purified water was added to the volume. Each example composition was sealed in an ampoule and stored at 60°C for 30 days before being tested for impurity content.

[0104] Table 1

[0105] *Reporting limit: 0.05%.

[0106] **For the test data of Example 3, the maximum single impurity and total impurity were 0.05% at day 0, and less than 0.05% at days 10 and 30, which are acceptable errors affected by instrument precision, etc.

[0107] It can be seen that pH has a great influence on the chemical stability of the fingolimod hydrochloride oral solution of the present invention, and the pharmaceutical composition with a pH between 3 and 6 has good high temperature stability.

[0108] Examples 6-10

[0109] Fingolimod hydrochloride pharmaceutical compositions were prepared according to the formulation shown in Table 2, using the same method as in Example 1. The pharmaceutical compositions of each example were sealed in glass bottles and refrigerated at 2-8°C for 5 or 10 days. The bottles were then placed in a dark room under a vertical umbrella light at an illumination of 1000 lx and observed horizontally for the presence of crystals.

[0110] Table 2 Effect of the dosage of hydroxypropyl-β-cyclodextrin

[0111] It can be seen that the weight ratio of hydroxypropyl-β-cyclodextrin to fingolimod hydrochloride has a great influence on the physical stability of the pharmaceutical composition of the present invention. When the above ratio is above 70, the pharmaceutical composition of the present invention has good physical stability.

[0112] Effect of Complexing Agents in Examples 11-14

[0113] In order to simulate the environment of the pharmaceutical composition production line, a trace amount of Fe was added to the formulation. 3+ .

[0114] The fingolimod hydrochloride pharmaceutical composition was prepared according to the prescription in Table 3. The specific method was the same as that in Example 1, except that a specific amount of FeCl3 was added before the volume was fixed. The prepared pharmaceutical composition of each example was sealed in an ampoule and placed under light conditions (illuminance of 4500 lx ± 500 lx, the total illumination of the light source should be not less than 1.2 × 10 6 lux·hr, near-ultraviolet lamp energy is not less than 200W·hr / m 2 ) was placed for 10 days and its related substances were detected.

[0115] It can be seen that the stability of the pharmaceutical composition of the present invention is easily affected by the iron ions leached in the production line, and the addition of a complexing agent can improve the chemical stability of the pharmaceutical composition.

[0116] In the above embodiments, all technical solutions that fall within the scope of the present invention are within the scope of protection of the present invention. It should be noted that for those skilled in the art, several improvements and modifications that do not depart from the principles of the present invention should also be considered within the scope of protection of the present invention.

Claims

1. An oral liquid composition comprising the following components: (A) 0.0001-0.5% of fingolimod or a pharmaceutically acceptable salt thereof; (B) cyclodextrin, wherein the mass ratio of the cyclodextrin to fingolimod or a pharmaceutically acceptable salt thereof is 70-200:1; (C) 0.01-1% of a metal complexing agent; and (D) Water; The pH of the oral liquid composition is 3-6.

2. The oral liquid composition according to claim 1, wherein the cyclodextrin is selected from at least one of natural cyclodextrin, branched cyclodextrin, alkyl cyclodextrin or hydroxyalkyl cyclodextrin.

3. The oral liquid composition according to claim 1, wherein: The content of fingolimod or its pharmaceutically acceptable salt is 0.001-0.1%, preferably 0.005-0.05%; Preferably, the mass ratio of the cyclodextrin to fingolimod or its pharmaceutically acceptable salt is 70-100:1; Preferably, the fingolimod or a pharmaceutically acceptable salt thereof is fingolimod hydrochloride or fingolimod dodecyl sulfonate; Preferably, the fingolimod or a pharmaceutically acceptable salt thereof is fingolimod hydrochloride; Preferably, the content of the metal complexing agent is 0.05-0.5%, preferably 0.1-0.2%.

4. The oral liquid composition according to any one of claims 1 to 3, wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin; preferably, the metal complexing agent is selected from at least one of disodium edetate or sodium calcium edetate, preferably disodium edetate.

5. The oral liquid composition according to any one of claims 1 to 3, wherein the oral liquid composition further comprises: (E) a buffering agent, wherein the buffering agent is used in an amount such that the pH of the oral liquid composition is 3-6.

6. The oral liquid composition according to claim 5, wherein the buffer is selected from at least one of citric acid and its hydrates, disodium hydrogen phosphate and its hydrates, sodium citrate and its hydrates, phosphates and their hydrates, malic acid, tartaric acid, hydrochloric acid or sodium hydroxide; the buffer is preferably selected from at least one of citric acid and its hydrates, disodium hydrogen phosphate and its hydrates, sodium citrate and its hydrates.

7. The oral liquid composition according to claim 6, wherein the buffer is used in an amount of 0.03-3%.

8. The oral liquid composition according to any one of claims 1 to 3, wherein the oral liquid composition further contains other pharmaceutical excipients, and the other pharmaceutical excipients are selected from at least one of preservatives, sweeteners or aromatics.

9. The oral liquid composition according to claim 8, wherein the amount of the other pharmaceutical excipients is 0.01-20%, preferably 0.1-10%.

10. Use of the oral liquid composition according to any one of claims 1 to 9 in the preparation of a medicament or preparation for treating a disease mediated by S1P, such as an immune disease, preferably the disease is multiple sclerosis.

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