JP7503420B2 - Pharmaceutical composition containing fingolimod, and its manufacturing method and stabilization method - Google Patents

Description

The present invention relates to a pharmaceutical composition containing fingolimod as an active ingredient, a hard capsule containing the same, and a method for producing the same. The present invention relates to a method for stabilizing a pharmaceutical composition containing fingolimod.

Fingolimod is a compound represented by the following formula (I), and its chemical name is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol. Fingolimod acts as a functional antagonist of sphingosine 1-phosphate receptor 1, exhibits immunosuppressive activity, and is used to treat multiple sclerosis. Patent Document 1 describes a tablet containing fingolimod hydrochloride as an active ingredient.

Patent Publication No. 2018-502168

Fingolimod is known to be a compound that does not have very good storage stability. Generally, active pharmaceutical ingredients are organic compounds, and temperature (heat) is a factor that significantly affects the storage stability of the active ingredient. In addition, pharmaceutical additives that are mixed with the active ingredient also affect storage stability. The present invention aims to provide a pharmaceutical composition containing fingolimod that has excellent storage stability and a method for producing the same.

The present inventors discovered that erythritol is a pharmaceutical additive that has a small effect on fingolimod when mixed with it, and that a pharmaceutical composition containing fingolimod and erythritol has excellent temperature stability, and thus completed the present invention. Thus, the present invention provides a pharmaceutical composition containing fingolimod or a pharma- ceutical acceptable salt or solvate thereof, and erythritol. The present invention also provides a hard capsule formulation containing fingolimod or a pharma-ceutical acceptable salt or solvate thereof as an active ingredient, in which the pharmaceutical composition is filled in a capsule.

The present invention provides a method for producing a pharmaceutical composition containing fingolimod or a pharma- ceutically acceptable salt or solvate thereof, comprising the steps of mixing fingolimod or a pharma- ceutically acceptable salt or solvate thereof with erythritol, and mixing the mixed powder obtained in the mixing step with magnesium stearate.

The present invention provides a method for producing a hard capsule formulation containing fingolimod or a pharma- ceutically acceptable salt or solvate thereof as an active ingredient, the method comprising the steps of mixing fingolimod or a pharma- ceutically acceptable salt or solvate thereof with erythritol, mixing the mixed powder obtained in the mixing step with magnesium stearate to obtain a pharmaceutical composition containing fingolimod or a pharma- ceutically acceptable salt or solvate thereof, and filling the pharmaceutical composition into a capsule.

The present invention provides a method for stabilizing a pharmaceutical composition containing fingolimod or a pharma- ceutically acceptable salt or solvate thereof by incorporating erythritol.

The present invention provides a pharmaceutical composition containing fingolimod that has excellent storage stability and a method for producing the same.

The pharmaceutical composition of this embodiment contains fingolimod or a pharma- ceutically acceptable salt or solvate thereof as an active ingredient. A pharma-ceutically acceptable salt of fingolimod refers to a salt formed from the compound represented by the above formula (I) and an organic or inorganic acid, which is acceptable for administration to mammals, including humans. Examples of such pharma-ceutically acceptable salts include hydrochloride, sulfate, acetate, phosphate, methanesulfonate, and fumarate. Among these, fingolimod hydrochloride is preferred.

A pharma- ceutically acceptable solvate of fingolimod refers to a solid molecule formed from the compound represented by formula (I) above and a solvent that is acceptable for administration to mammals, including humans. Examples of such solvents include water, acetic acid, and ethanol.

Hereinafter, the term "fingolimod" includes the compound represented by the above formula (I) and its pharma- ceutically acceptable salts and solvates, unless otherwise specified. In this embodiment, the content of fingolimod in the pharmaceutical composition is, for example, 0.01% by weight or more and 20% by weight or less, and preferably 0.5% by weight or more and 5% by weight or less.

The fingolimod used in this embodiment preferably has a drug substance particle size _D50 of 8 μm or more and 28 μm or less. The drug substance particle size can be measured using, for example, a laser diffraction scattering type particle size distribution measuring device or an image analyzer.

The pharmaceutical composition of this embodiment contains erythritol as a pharmaceutical additive. In this embodiment, by forming a pharmaceutical composition containing fingolimod and erythritol, the production and promotion of the production of fingolimod analogues is suppressed and stability against temperature is improved. The content of erythritol in the pharmaceutical composition is, for example, 75% by weight or more and 99.9% by weight or less, and preferably 90% by weight or more and 99.5% by weight or less.

In this embodiment, if necessary, a pharmaceutical additive other than erythritol may be further included. Such pharmaceutical additives can be appropriately selected from pharma- ceutically acceptable lubricants, excipients, disintegrants, binders, sweeteners, colorants, and the like. In this embodiment, it is preferable to further include a lubricant. Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, light anhydrous silicic acid, and talc. One type of lubricant may be used, or two or more types may be combined. Among them, magnesium stearate is particularly preferable. The content of the lubricant in the pharmaceutical composition is, for example, 0.01% by weight or more and 5% by weight or less, and preferably 0.5% by weight or more and 3% by weight or less.

The pharmaceutical composition of this embodiment is preferably substantially free of D-mannitol. Here, "substantially free" means that, if any, D-mannitol is contained in the pharmaceutical composition, it is in a small amount, and D-mannitol is not actively added. Examples of cases in which a small amount of D-mannitol is contained include cases in which it is mixed in as an impurity, or in which a small amount is produced as a result of some kind of chemical reaction or decomposition of a contained component.

The pharmaceutical composition of this embodiment preferably consists essentially of fingolimod, erythritol, and magnesium stearate. Such a pharmaceutical composition can be suitably used as the contents (filling composition) of a hard capsule. Here, "consisting essentially of fingolimod, erythritol, and magnesium stearate" means that the pharmaceutical composition contains only small amounts of components other than fingolimod, erythritol, and magnesium stearate, if any, and that these components are not actively added. Examples of cases in which such components are contained in small amounts include cases in which they are mixed in as impurities in trace amounts, and cases in which they are generated in trace amounts through some kind of chemical reaction or decomposition of the contained components.

The pharmaceutical composition of this embodiment can be produced as follows. First, fingolimod and erythritol are mixed. The resulting mixed powder is then mixed with magnesium stearate to obtain the pharmaceutical composition of this embodiment. Mixing may be performed by sieving or using a known powder mixer.

In this embodiment, fingolimod may be a fingolimod dilution that has been prepared by mixing it with erythritol in advance. By using dilution, weighing errors can be reduced. The dilution may be prepared in stages. For example, fingolimod bulk powder and erythritol may be mixed to prepare a 2-10 fold dilution (10-50% fingolimod powder), and this dilution and erythritol may be further mixed to prepare a 4-100 fold dilution (1-25% fingolimod powder). The dilution preparation process is not limited to two stages, and may be three or more stages. The three-stage dilution preparation process may, for example, mix fingolimod bulk powder and erythritol to prepare a 2-10 fold dilution, mix the resulting dilution with an excipient to prepare a 4-100 fold dilution, and mix the resulting dilution with an excipient to prepare an 8-200 fold dilution. Additionally, the powder may be prepared by mixing the bulk fingolimod with erythritol and a portion of the magnesium stearate.

The scope of the present invention also includes a pharmaceutical preparation containing the pharmaceutical composition of the present embodiment. The dosage form of the pharmaceutical preparation is not particularly limited as long as it is a solid dosage form, and examples thereof include hard capsules, tablets, and granules. Among these, hard capsules are preferred because they do not require pressurization or drying in the formulation process. Therefore, in this embodiment, hard capsules containing fingolimod or a pharma- ceutical acceptable salt or solvate thereof as an active ingredient, in which the pharmaceutical composition is filled in a capsule, are particularly preferred.

In the hard capsule formulation of this embodiment, the content of fingolimod per capsule is, for example, from 0.05 mg to 10 mg, preferably from 0.1 mg to 5 mg, and more preferably from 0.2 mg to 1 mg.

The capsules into which the pharmaceutical composition is filled are not particularly limited, so long as they are hard capsules made from a pharma- ceutical acceptable capsule base such as gelatin or hydroxypropylmethylcellulose. The capsule shell may contain a pharma- ceutical acceptable colorant such as titanium oxide or iron oxide. The size of the capsule is not particularly limited as long as it can be filled with a therapeutically effective amount of fingolimod, and examples of the size include capsules No. 2, No. 3, No. 4, or No. 5 as described in the Japanese Pharmacopoeia.

The hard capsule of this embodiment can be produced as follows. First, fingolimod and erythritol are mixed. Next, the resulting mixed powder is mixed with magnesium stearate to obtain the pharmaceutical composition of this embodiment. Mixing may be performed by sieving or using a known powder mixer. The resulting pharmaceutical composition is then filled into a capsule to obtain the hard capsule of this embodiment. The method of filling a capsule with a powder is known per se, and for example, any of the disc, compress, and Auger type filling machines can be used. The hard capsule of this embodiment may be packaged in PTP packaging, bottle filling, aluminum packaging, or the like.

The scope of the present invention also includes a method for stabilizing a pharmaceutical composition containing fingolimod. This method involves adding erythritol as a pharmaceutical additive to a pharmaceutical composition containing fingolimod as an active ingredient. As shown in Test Example 1 described below, erythritol is an additive that is less susceptible to interactions when added to fingolimod. Furthermore, as shown in Test Example 2 described below, a composition containing erythritol and fingolimod has improved thermal stability. As a result, the production and promotion of the production of analogues of fingolimod is suppressed in the pharmaceutical composition.

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[Test Example 1]
The effects of adding various pharmaceutical additives to fingolimod hydrochloride were investigated by a compatibility test.

1. Sample preparation Erythritol, powdered reduced maltose syrup, and potato starch were used as pharmaceutical additives. Fingolimod hydrochloride (10 mg) and each additive (3000 mg) were filled into polypropylene centrifuge tubes and mixed. For comparison, centrifuge tubes containing only fingolimod hydrochloride (10 mg) were prepared. These centrifuge tubes were stored for one month at an ambient temperature of 40°C and a relative humidity of 75% RH (open).

2. Purity test (measurement of related substances)
An amount corresponding to 10 mg of fingolimod was taken from the centrifuge tube, and a mixture (3:1) of phosphoric acid solution diluted 1:1000 and acetonitrile was added, shaken, and ultrasonicated. This liquid was filtered through a membrane filter to obtain a sample solution. The sample solution was tested by liquid chromatography under the following test conditions. Each peak area of the sample solution was measured by the automatic integration method, and their amounts were calculated by the area percentage method.

<Test conditions>
・Detector: Ultraviolet spectrophotometer (measurement wavelength: 215 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was packed with 3.5 μm phenylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 35°C Mobile phase A: water/acetonitrile/phosphoric acid/triethylamine mixture (900:100:2:1)
Mobile phase B: Acetonitrile/water/phosphoric acid/triethylamine mixture (900:100:2:1)
Flow rate: 1.0 mL per minute

3. Results Table 1 shows the amount (%) of total related substances for each sample. The total related substances are the sum of all related substances detected. In the table, "Start time" indicates the result at the start of storage of the centrifuge tubes filled with each sample.

In Table 1, the results for fingolimod only show the stability of fingolimod hydrochloride itself, since no additives were mixed in. As shown in Table 1, when erythritol was used, the total amount of related compounds after one month of storage at 40°C and 75% RH (open) was significantly lower than when powdered reduced maltose syrup and potato starch were used. This suggests that a stable fingolimod-containing pharmaceutical composition can be obtained by using erythritol as a pharmaceutical additive to be mixed with fingolimod.

[Test Example 2]
The temperature stability of a pharmaceutical composition containing fingolimod hydrochloride, erythritol or powdered reduced maltose syrup, and magnesium stearate was investigated.

1. Preparation of samples Fingolimod hydrochloride (392 mg), erythritol (32536 mg), and magnesium stearate (672 mg) were filled into a glass bottle and mixed to obtain a mixed powder of the Example. Fingolimod hydrochloride (392 mg), powdered reduced maltose syrup (32536 mg), and magnesium stearate (672 mg) were filled into a glass bottle and mixed to obtain a mixed powder of the Comparative Example. The glass bottles filled with each mixed powder were stored in a sealed state at an ambient temperature of 70°C for 3, 6, or 9 days.

2. Purity test (measurement of related substances)
Six pieces of this product were taken, and a mixture (3:1) of phosphoric acid solution diluted 1:1000 and acetonitrile was added, shaken, and ultrasonicated. This liquid was filtered through a membrane filter to obtain a sample solution. The sample solution was tested by liquid chromatography under the same test conditions as in Test Example 1. The peak areas of each of the sample solutions were measured by automatic integration, and their amounts were calculated by the area percentage method. Table 2 shows the total amount of affinity (%) for each sample. In the table, "Start time" indicates the result at the start of storage of the glass bottle filled with each sample.

As shown in Table 2, in the comparative example containing powdered reduced maltose syrup, the increase in related substances was significant and the temperature stability was poor. On the other hand, in the example containing erythritol, the production of related substances was significantly suppressed compared to the comparative example. This suggests that by combining fingolimod, erythritol, and magnesium stearate, a fingolimod-containing pharmaceutical composition with excellent storage stability can be obtained.

[Preferred formulation example]
As a preferred example of the formulation of the pharmaceutical composition and pharmaceutical preparation of this embodiment, the formulation of a hard capsule (amount of ingredients per capsule) is shown in Table 3. The "filling composition" in the table is the content of the hard capsule, and corresponds to the pharmaceutical composition of this embodiment.

The hard capsules in Table 3 were produced as follows. Fingolimod hydrochloride was mixed with 5 times the amount of erythritol. The resulting mixed powder was sieved through a 30 mesh sieve. The sieve was washed with erythritol in an amount 4 times the amount of fingolimod hydrochloride. The remaining erythritol was further added and mixed. Magnesium stearate was added and mixed. The resulting mixed powder was filled into capsules to obtain hard capsules (major axis 15.9 mm, minor axis 5.8 mm).

Claims (4)

A hard capsule containing fingolimod or a pharma- ceutical acceptable salt or solvate thereof as an active ingredient, the hard capsule comprising a pharmaceutical composition containing fingolimod or a pharma- ceutical acceptable salt or solvate thereof and erythritol filled in a capsule. 10. The hard capsule of claim 1, wherein the pharmaceutical composition further comprises magnesium stearate . 3. The hard capsule according to claim 1 or 2, wherein the pharmaceutical composition is substantially free of D-mannitol . mixing fingolimod or a pharma- ceutically acceptable salt or solvate thereof with erythritol;
mixing the mixed powder obtained in the mixing step with magnesium stearate to obtain a pharmaceutical composition containing fingolimod or a pharma- ceutically acceptable salt or solvate thereof;
and filling the pharmaceutical composition into a capsule.