JP2023174307A - Pharmaceutical compositions - Google Patents

Abstract

To provide a pharmaceutical composition comprising S-(+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione in a form other than a type B crystal form as an active ingredient.SOLUTION: Provided is a compound (I) in amorphous form or in A-type or M-type crystal form.SELECTED DRAWING: None

Description

PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions.

Patent Document 1 describes a solid form containing (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione. is disclosed and states that the compound exists in multiple crystalline or amorphous solid forms. Also disclosed are pharmaceutical compositions comprising a solid form selected from a plurality of solid forms of the compound.

Patent Document 2 describes (+)-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-4-acetylaminoisoindoline-1,3-dione or its pharmaceuticals. A pharmaceutical composition is disclosed that includes a salt acceptable as a filler; a filler; a disintegrant; and a lubricant.

Currently, pharmaceuticals containing S-(+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione as an active ingredient As a composition, Otezla (registered trademark) tablets are commercially available. Hereinafter, Otezla (registered trademark) tablets will be referred to as a commercially available preparation.

Special table 2011-515463 Special table 2015-506356

Commercially available Otezla® tablets are S-(+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1, Among the multiple crystal forms of 3-dione, only the B type crystal form is used as an active ingredient. Therefore, from the viewpoint of increasing the selection of drugs available to users, there is room for consideration in using the above-mentioned compounds in crystalline forms other than type B as active ingredients in pharmaceutical compositions.

One aspect of the present invention provides S-(+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoiso in a form other than Form B crystal form. An object of the present invention is to provide a pharmaceutical composition containing indoline-1,3-dione as an active ingredient.

The present inventors have conducted extensive research in order to achieve the above object. As a result, multiple forms of S-(+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione were present. Among them, the present inventors have discovered that an amorphous form or a crystalline form of type A or type M can be suitably used as an active ingredient of a pharmaceutical composition, and have completed the present invention.

In order to solve the above problems, a pharmaceutical composition according to one aspect of the present invention contains one form of the compound of formula (I) as a main component of the active ingredient, and the form is an amorphous form, or A type or M type crystal form, and the A type crystal form is 2θ (°) = 8.1 ± 0.2, 15.2 ± 0.2, 17.4 ± 0.2, 23 It has a powder X-ray diffraction pattern containing peaks at 2θ(°)=5.3±0.2, 8.6±0.2 and 25.1±0.2. 4±0.2, 9.8±0.2, 13.98±0.2, 14.85±0.2, 16.64±0.2, 19.59±0.2, 21.46± It has a powder X-ray diffraction pattern containing peaks of 0.2, 27.23±0.2.

According to one aspect of the invention, S-(+)-2-[1-(3-ethoxy A pharmaceutical composition containing 4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione as a main active ingredient can be provided.

FIG. 3 shows differential scanning calorimeter (DSC) plots and powder X-ray structure diffraction (XRD) plots of Compound 1-1 and Compound 1-2. FIG. 2 is a diagram showing differential scanning calorimetry (DSC) and powder X-ray structure diffraction (XRD) plots of unground compound 1-3, ground compound 1-3, and compound 1-4. FIG. 2 is a diagram showing the dissolution rate (%) of the pharmaceutical compositions of Examples 1 to 2 and 17 and Comparative Example 1. FIG. 3 is a diagram showing the dissolution rate (%) of the pharmaceutical compositions of Examples 3 to 14 and Comparative Example 3. FIG. 3 is a graph showing the dissolution rate (%) of the pharmaceutical compositions of Examples 15 to 16 and Comparative Examples 2 and 4 to 5. FIG. 3 is a diagram showing an equation used to calculate an effective particle size range that exhibits a dissolution rate equivalent to that of a commercially available preparation at 45 minutes after the start of elution. FIG. 2 is a diagram showing an equation used to calculate an effective particle size range that exhibits a dissolution rate equivalent to that of a commercially available preparation at 60 minutes after the start of elution.

<Characteristics of the pharmaceutical composition>
A pharmaceutical composition according to one aspect of the present invention contains one form of the compound of chemical formula (I) (hereinafter simply referred to as "compound (I)") as a main active ingredient, and the above form is a non-form. It is a crystalline form, or an A-type or M-type crystal form, and the A-type crystal form is 2θ (°) = 8.1 ± 0.2, 15.2 ± 0.2, 17.4 ± 0. The M-type crystal form has a powder X-ray diffraction pattern containing peaks at 2θ(°)=5.3±0. 2, 8.4±0.2, 9.8±0.2, 13.98±0.2, 14.85±0.2, 16.64±0.2, 19.59±0.2, It has a powder X-ray diffraction pattern containing peaks of 21.46±0.2 and 27.23±0.2.

The pharmaceutical composition according to one aspect of the present invention can contain Compound (I) in an amorphous form or a crystalline form of type A or type M as a main active ingredient.

From the above, the number of options for pharmaceutical compositions containing compound (I) as an active ingredient increases. Therefore, it will be possible to contribute to Goal 3 of the United Nations-led Sustainable Development Goals (SDGs), ``Good health and well-being for all.''

<Compound (I)>
Compound (I) is S-( +)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione.

Since the S-enantiomer of Compound (I) has a higher pharmacological effect than the R-enantiomer, it is preferably enantiomerically pure from the viewpoint of enhancing the pharmacological effect. "Enantiomerically pure" means R-(-)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3- This means that it does not substantially contain dione. "Substantially free of" means R The content of (-)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione is 20% by mass or less, 10 It means not more than 5% by weight, not more than 3% by weight, or not more than 1% by weight.

The form of compound (I) is an amorphous form or a crystalline form of type A or type M.

Amorphous forms are also referred to as amorphous. The amorphous form is characterized by having an endothermic peak at 78° C. or higher and 96° C. or lower in differential scanning calorimetry.

The crystal morphology of type A is 2θ(°)=8.1±0.2, 15.2±0.2, 17.4±0.2, 23.6±0.2 and 25.1±0. It is a crystalline form with a powder X-ray diffraction pattern containing two peaks. The crystal morphology of type A is 2θ(°)=8.1±0.1, 15.2±0.1, 17.4±0.1, 23.6±0.1 and 25.1±0. A crystalline form having a powder X-ray diffraction pattern containing one peak is preferred. Powder X-ray diffraction can be performed by a known method.

Form A crystal form has a melting point of 158.17°C. Further, when the mass change of the sample was measured by thermogravimetric analysis (TGA) by applying a heat load at 25° C. to 140° C., the mass change rate was 0.05241%. On the other hand, the crystal form of type B has a melting point of 157.64° C. and a mass change rate by TGA of 0.2482%. From this, it can be said that the A-type crystal form has higher thermal stability than the B-type crystal form. Therefore, pharmaceutical compositions containing Compound (I) in Form A crystalline form as the main active ingredient are more stable to heat than commercial preparations containing Compound (I) in Form B crystalline form as an active ingredient. This has the effect of improving.

The crystal morphology of type M is 2θ (°) = 5.3 ± 0.2, 8.4 ± 0.2, 9.8 ± 0.2, 13.98 ± 0.2, 14.85 ± 0. It is a crystalline form with a powder X-ray diffraction pattern containing peaks of 2, 16.64±0.2, 19.59±0.2, 21.46±0.2, 27.23±0.2. The crystal morphology of type M is 2θ (°) = 5.3 ± 0.1, 8.4 ± 0.1, 9.8 ± 0.1, 13.98 ± 0.1, 14.85 ± 0. 1, 16.64 ± 0.1, 19.59 ± 0.1, 21.46 ± 0.1, 27.23 ± 0.1 peaks. preferable. Powder X-ray diffraction can be performed by a known method.

The M-type crystal form has a melting point of 92.3°C.

(Particle size of compound (I))
When compound (I) is in the A-type or M-type crystal form, it is preferably in the form of a fine powder. When Compound (I) is in the M-type crystal form, it is preferably more finely powdered than when it is in the A-type crystal form. The particle size of Compound (I) in the A-type or M-type crystal form is not particularly limited, but since the particle size affects the elution of Compound (I), the particle size should be adjusted so as to exhibit the desired elution behavior. Adjustment is preferred.

In one embodiment, the pharmaceutical composition according to one aspect of the present invention preferably has a dissolution behavior equivalent to that of a commercially available preparation containing the B-type crystalline form of Compound (I) as an active ingredient. In this case, from the viewpoint of controlling the elution rate, the particle size of Compound (I) in an amorphous form, or in an A-type or M-type crystal form is preferably 10 μm or more. In addition, from the viewpoint of preventing the dissolution rate from decreasing too much compared to the commercially available preparations, the particle size of Compound (I) in the amorphous form, or the A-type or M-type crystalline form should be 60 μm or less. preferable.

Here, in this specification, "particle size" refers to the median diameter (D ₅₀ ), for example, by laser diffraction method (measurement method: dry method) using a particle size distribution measuring device (Mastersizer 3000, manufactured by Malvern Panalytical). It can be calculated by measuring and analyzing using Mie scattering theory. Note that the median diameter (D ₅₀ ) is the maximum particle diameter below which 50% of the sample volume falls, and is the median diameter in volume units.

<Composition of pharmaceutical composition>
(active ingredient)
A pharmaceutical composition according to one aspect of the present invention contains one form of compound (I) as a main active ingredient. Here, the term "main ingredient of active ingredients" means the ingredient in the largest amount among the ingredients contained as active ingredients. For example, in one aspect of the present invention, the term "main ingredient of active ingredients" means The content of compound (I) relative to the total mass of is 90% by mass or more, 95% by mass or more, 96% by mass or more, 97% by mass or more, 98% by mass or more, 99% by mass or more, or 100% by mass.

The content of the active ingredient contained in the pharmaceutical composition according to one aspect of the present invention can be appropriately set depending on the purpose. However, major changes in tablet shape or content to achieve bioequivalence with commercially available formulations can be risky. Therefore, it is preferable that the mass of the active ingredient contained in the pharmaceutical composition is similar to that of commercially available preparations. This also applies when the total mass of the pharmaceutical composition is reduced compared to the original formulation, such as by making tablets smaller.

(Ingredients other than active ingredients)
The pharmaceutical composition according to one aspect of the present invention preferably contains an excipient, a binder, a disintegrant, and a lubricant in addition to compound (I).

Excipients include, but are not particularly limited to, crystalline cellulose, lactose, cornstarch, and the like. Only one type of excipient may be used, or a combination of multiple types may be used. Hereinafter, (i) crystalline cellulose or lactose and (ii) corn starch are referred to as excipient (i) and excipient (ii), respectively. From the viewpoint of minimizing hydrolysis of the active ingredient, it is preferable to use excipients with low water content. Examples of excipients with low water content include anhydrous lactose, granulated corn starch, and partially pregelatinized starch, which have low water activity values. Further, the excipient is preferably a combination of microcrystalline cellulose and cornstarch, or a combination of lactose and cornstarch, from the viewpoint of minimizing hydrolysis of the active ingredient.

When a combination of excipients (i) and (ii) is included as an excipient, the mass ratio of excipient (i) and excipient (ii) can be adjusted as appropriate. For example, when the mass of excipient (ii) is 1, the mass of excipient (i) can be 3 or more.

The mass of excipients contained in the pharmaceutical composition is not particularly limited, and it depends on the dosage form of the pharmaceutical composition, the total mass of the pharmaceutical composition, the content of active ingredients contained in the pharmaceutical composition, and the pharmaceutical composition. It can be adjusted as appropriate depending on the content of additives other than excipients contained in the composition. As an example, when the pharmaceutical composition is a solid preparation, the content of excipients based on the total mass of the pharmaceutical composition may be 65% by mass or more, 70% by mass or more, and 85% by mass or more. It may be less than % by mass.

The binder is not particularly limited, but may be, for example, at least one binder selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hypromellose, methylcellulose, and polyvinyl alcohol, or a combination of multiple binders. The binder is also preferably polyvinylpyrrolidone.

The mass of the binder contained in the pharmaceutical composition is not particularly limited, and depends on the dosage form of the pharmaceutical composition, the total mass of the pharmaceutical composition, the content of active ingredients contained in the pharmaceutical composition, and the pharmaceutical composition. Depending on the content of additives other than the binder contained in the product, the dissolution behavior of the active ingredient can be adjusted as appropriate within a range that can be made equivalent to that of commercially available preparations. As an example, when the pharmaceutical composition is a solid preparation, the content of the binder relative to the total mass of the pharmaceutical composition is 4.0% by mass or more, from the viewpoint of making the dissolution behavior of the active ingredient equivalent to that of commercially available preparations. The content may be 20% by mass or less, or may be 8.0% by mass or less.

The disintegrant is not particularly limited, but includes, for example, cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, low-substituted hydroxypropylcellulose, carmellose, partially pregelatinized starch, croscarmellose sodium, and carmellose calcium. It may be at least one selected from the group consisting of: Further, from the viewpoint of making the dissolution behavior of the active ingredient equivalent to that of commercially available preparations, the disintegrant is preferably crospovidone.

The mass of the disintegrant contained in the pharmaceutical composition is not particularly limited, and depends on the dosage form of the pharmaceutical composition, the total mass of the pharmaceutical composition, the content of active ingredients contained in the pharmaceutical composition, and the pharmaceutical composition. Depending on the content of additives other than the disintegrant contained in the product, the dissolution behavior of the active ingredient can be adjusted as appropriate within a range that can be made equivalent to that of commercially available preparations. As an example, when the pharmaceutical composition is a solid preparation, the disintegration rate can be controlled and the dissolution behavior of the active ingredient can be made equivalent to that of commercially available preparations, so that the content of the disintegrant is 10% by mass based on the total mass of the pharmaceutical composition. % or less, or 4.0% by mass or less. Further, it may be 1.2% by mass or more.

The lubricant is not particularly limited, but may be, for example, at least one selected from the group consisting of magnesium stearate, calcium stearate, fumaric acid, talc, wax, and the like. Preferably, the lubricant is magnesium stearate.

The mass of the lubricant contained in the pharmaceutical composition is not particularly limited, and depends on the dosage form of the pharmaceutical composition, the total mass of the pharmaceutical composition, the content of active ingredients contained in the pharmaceutical composition, and the pharmaceutical composition. Depending on the content of additives other than the lubricant contained in the composition, the dissolution rate of the active ingredient can be adjusted as appropriate within a controllable range. As an example, when the pharmaceutical composition is a solid preparation, from the viewpoint of controlling the dissolution rate of the active ingredient, the content of the lubricant with respect to the total mass of the pharmaceutical composition is 0.5% by mass or more, 1.5% by mass % or less is preferable.

A preferred pharmaceutical composition contains, based on the total weight of the pharmaceutical composition, Compound (I) at 9.0% by mass or more and 11% by mass or less, crystalline cellulose at 55% by mass or more and 65% by mass or less, and cornstarch at 15% by mass. % or more and 25% by mass or less, polyvinylpyrrolidone 4.0% or more and 8.0% by mass or less, crosslinked polyvinylpyrrolidone 2.0% or more and 4.0% by mass or less, magnesium stearate 0.5% A pharmaceutical composition containing 1.5% by mass or more and 1.5% by mass or less.

Another preferable pharmaceutical composition includes compound (I) in an amount of 9.0% by mass or more and 11% by mass or less, lactose in a range of 55% by mass or more and 65% by mass or less, and corn starch in a proportion of 15% by mass or less based on the total mass of the pharmaceutical composition. 4.0 to 8.0 mass% of polyvinylpyrrolidone, 2.0 to 4.0 mass% of crosslinked polyvinylpyrrolidone, 0.0 to 4.0 mass% of magnesium stearate. A pharmaceutical composition containing 5% by mass or more and 1.5% by mass or less.

The pharmaceutical composition according to one aspect of the present invention may further contain a fluidizing agent in addition to compound (I).

The pharmaceutical composition according to one aspect of the present invention may contain any pharmaceutically acceptable component as long as it does not interfere with the effect of compound (I). Examples of optional components include surfactants, antioxidants, foaming agents, acidulants, sweeteners, flavoring agents, coloring agents, and fragrances. Any component may be used alone or in combination of two or more.

The dosage form of the pharmaceutical composition according to one aspect of the present invention is not particularly limited, and may be a solid preparation or a liquid preparation. Examples of solid preparations include oral solid preparations such as tablets, hard capsules, soft capsules, granules, powders, pills, dry syrups, and orally disintegrating tablets. Since one embodiment of the present invention has excellent solubility, solid preparations can be more suitably employed. In addition, the dosage form of the pharmaceutical composition according to one aspect of the present invention is suitable for intraoral use because the tablet can be disintegrated with only saliva in the oral cavity and is easy to take even for elderly people, children, and patients who have difficulty swallowing. A disintegrating tablet is preferred.

The pharmaceutical composition according to one aspect of the present invention can be manufactured by a known method depending on the dosage form.

〔summary〕
The pharmaceutical composition according to aspect 1 of the present invention contains one form of the compound of formula (I) as the main active ingredient, and said form is an amorphous form or a crystalline form of form A or form M. The crystal morphology of type A is 2θ (°)=8.1±0.2, 15.2±0.2, 17.4±0.2, 23.6±0.2 and 25. It has a powder X-ray diffraction pattern including a peak of 1 ± 0.2, and the crystal form of the M type is 2θ (°) = 5.3 ± 0.2, 8.4 ± 0.2, 9.8 ±0.2, 13.98±0.2, 14.85±0.2, 16.64±0.2, 19.59±0.2, 21.46±0.2, 27.23±0 It has a powder X-ray diffraction pattern containing a peak of .2.

In aspect 1, the pharmaceutical composition according to aspect 2 of the present invention is preferably an orally disintegrating tablet.

The pharmaceutical composition according to aspect 3 of the present invention, in aspect 1 or 2, comprises an excipient, a binder, a disintegrant, and a lubricant, and the excipient contains the following (i) and (ii). at least one selected from the group consisting of: (i) crystalline cellulose or lactose; (ii) corn starch; and the disintegrating agent is a group consisting of cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, low-substituted hydroxypropylcellulose, carmellose, partially pregelatinized starch, croscarmellose sodium, and carmellose calcium. The lubricant is preferably magnesium stearate.

In the pharmaceutical composition according to aspect 4 of the present invention, in any one of aspects 1 to 3, the content of the compound of chemical formula (I) based on the total mass of the pharmaceutical composition is 5.0% by mass or more, It is preferably 15% by mass or less.

In the pharmaceutical composition according to aspect 5 of the present invention, in aspect 3, the content of the excipient relative to the total mass of the pharmaceutical composition is preferably 65% by mass or more and 85% by mass or less.

In the pharmaceutical composition according to aspect 6 of the present invention, in aspect 3, the content of the binder relative to the total mass of the pharmaceutical composition is preferably 4.0% by mass or more and 20% by mass or less.

In the pharmaceutical composition according to aspect 7 of the present invention, in aspect 3, the content of the disintegrant with respect to the total mass of the pharmaceutical composition is preferably 10% by mass or less.

In the pharmaceutical composition according to aspect 8 of the present invention, in aspect 3, the content of the lubricant relative to the total mass of the pharmaceutical composition is preferably 1.5% by mass or less.

In the pharmaceutical composition according to aspect 9 of the present invention, in any one of aspects 1 to 8, the particle size of the compound of chemical formula (I), which is the crystal form of type A, is 20 μm or more and 60 μm or less. It is preferable.

In the pharmaceutical composition according to aspect 10 of the present invention, in aspect 3, the compound of the chemical formula (I) is contained in an amount of 9.0% by mass or more and 11% by mass or less, based on the total mass of the pharmaceutical composition, and the crystalline cellulose. 55% by mass or more and 65% by mass or less, the cornstarch by 15% by mass or more and 25% by mass or less, the polyvinylpyrrolidone by 4.0% by mass or more and 8.0% by mass or less, and the crosslinked polyvinylpyrrolidone by 2.0% by mass. It is preferable that the magnesium stearate is contained in an amount of 0.5% by mass or more and 1.5% by mass or less.

In the pharmaceutical composition according to aspect 11 of the present invention, in aspect 3, the compound of the chemical formula (I) is contained in an amount of 9.0% by mass or more and 11% by mass or less, and the lactose is 55% by mass or more and 65% by mass or less, the cornstarch by 15% by mass or more and 25% by mass or less, the polyvinylpyrrolidone by 4.0% by mass or more and 8.0% by mass or less, and the crosslinked polyvinylpyrrolidone by 2.0% by mass. % or more and 4.0% by mass or less, and preferably 0.5% by mass or more and 1.5% by mass or less of the magnesium stearate.

EXAMPLES Below, embodiments of the present invention will be described in more detail with reference to Examples. Of course, the present invention is not limited to the following embodiments, and it goes without saying that various modifications can be made to the details. Furthermore, the present invention is not limited to the embodiments described above, and various changes can be made within the scope of the claims, and the present invention also includes embodiments obtained by appropriately combining the disclosed technical means. falls within the technical scope of the invention. Additionally, all documents mentioned herein are incorporated by reference.

[Identification of the form of compound (I)]
Compound (I) in amorphous form, Compound (I) in Form B crystalline form, Compound (I) in Form A crystalline form and Compound (I) in Form M crystalline form were procured from drug substance manufacturers. For convenience of explanation, Compound (I) in amorphous form will be referred to as Compound 1-1, Compound (I) in Form B crystal form will be referred to as Compound 1-2, and Compound (I) in Form A crystal form will be referred to as Compound 1-1. 1-3 and M-type crystal forms of Compound (I) are referred to as Compound 1-4.

Differential scanning calorimetry (DSC) or powder X-ray structure diffraction (XRD) plots of Compound 1-1, Compound 1-2, Compound 1-3, and Compound 1-4 are shown in FIGS. 1 and 2.

(Measurement by DSC)
Measurement was carried out according to the following measuring device and measurement conditions.
<Measuring device>
Differential scanning calorimeter (manufactured by TA Instruments, model: Discovery DSC25)
<Measurement conditions>
Heating rate: 10℃/min, 25-300℃

(Measurement of powder X-ray structural diffraction)
Measurement was carried out according to the following measuring device and measurement conditions.
<Measuring device>
X-ray diffraction measurement device (Rigaku Co., Ltd., Smart Lab)
<Measurement conditions>
X-ray diffraction measurement: 40kV, 30mA
Parallel beam method: 3-45deg
Speed: 8.2deg/min Step: 0.02deg
Entrance slit: 1mm
Light receiving optical element: 0.114deg

As shown in FIG. 1, Compound 1-1 showed a DSC plot of an amorphous form, and Compound 1-2 showed a DSC and XRD plot of a crystalline form of Form B. Further, as shown in FIG. 2, Compound 1-3 showed a DSC and XRD plot of the A-type crystal form, and Compound 1-4 showed a DSC plot of the M-type crystal form.

Note that the XRD plot of Compound 1-1 in FIG. 1 is partially edited and cited from FIG. 1 of International Publication No. 2015/173792. The XRD plot of compound (I) in amorphous form shows the pattern shown in FIG. In addition, the XRD plot of Compound 1-4 in FIG. 2 is quoted from FIG. 8 of Japanese Patent Publication No. 2018-516912 with some modifications. The XRD plot of Compound (I) in crystalline form M shows the pattern shown in FIG.

[Preparation of fine powder]
Compound 1-3 was ground to prepare a fine powder. Specifically, the crude drug substance was pulverized using a medicine spoon, and a fine powder was prepared using a jet mill pulverizer (manufactured by Hosokawa Micron Co., Ltd., model 50ASII) under the following conditions.
<Crushing conditions>
Supply pressure: 0.5~0.6MPa
Grinding pressure: 0.4-0.5MPa

FIG. 2 shows the results of DSC and XRD of the pulverized compound 1-3 obtained by pulverizing the compound 1-3 into a fine powder.

[Measurement of particle size]
The median diameter (D ₅₀ ) of each compound was measured using a particle size distribution measuring device (Mastersizer 3000, manufactured by Malvern Panalytical). The measurement was performed in a dry manner, and the analysis was performed using Mie scattering theory. The particle size of Compound (I) in amorphous form was measured by laser diffraction particle size distribution measurement method.

[Preparation of pharmaceutical composition]
(Examples 1 to 17)
In Examples 1 to 17, orally disintegrating tablets were manufactured according to Formulation Examples 1 to 17 shown in Table 1 below, respectively. The content of each component listed in Table 1 is shown in parts by mass. Each component was weighed out according to the amounts shown in Table 1, and mixed using an agate mortar. In Examples 1 to 17, the mixed powder was manually compressed into tablets with a diameter of 6.5 mm and a mass of 100 mg.

(Comparative Examples 1 to 3)
Comparative Examples 1 to 3 each used a commercially available formulation (Otezla tablets, manufactured by Amgen Corporation). Comparative Examples 1 and 3 are tablets with a mass of 104 mg, which contain 10 mg of Compound (I) in the B-type crystal form. Moreover, Comparative Example 2 is a tablet with a mass of 312 mg, which contains 30 mg of Compound (I) in the B-type crystal form.

(Comparative Examples 4-5)
Comparative Examples 4 to 5 were the same as Examples 1 to 17 except that orally disintegrating tablets were manufactured according to Comparative Formulation Examples 1 to 2 listed in Table 2 below, respectively, with a tablet diameter of 6.5 mm and a mass of 100 mg. Each tablet was obtained. Note that the content of each component listed in Table 2 is shown in parts by mass.

[Test Example 1: Confirmation of elution behavior of pharmaceutical compositions using various forms of compounds]
Using the pharmaceutical compositions of Examples 1 to 2 and 17 and Comparative Example 1, the elution behavior of pharmaceutical compositions containing each form of Compound (I) as the main active ingredient was confirmed.

<Test conditions>
Test solution: 900 mL of 0.15% SDS buffer (pH 6.8)
Sample collection time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes Rotation speed: 50 rpm
Test method: Paddle method

The elution rate (%) was calculated using the following formula.
Dissolution rate (%) = Content of compound (I) dissolved in test solution (mg) / Content of compound (I) in tablet (mg) x 100

The results are shown in Figure 3. The vertical axis of FIG. 3 shows the elution rate (%), and the horizontal axis shows the collection time (min). As shown in FIG. 3, the pharmaceutical compositions of Examples 1 to 2 and 17 containing Compound (I) in an amorphous form or in an A-type or M-type form as the main active ingredient are B It was found that the formulation exhibited good dissolution behavior similar to that of the commercially available formulation of Comparative Example 1 containing the crystalline form of Compound (I) as an active ingredient. Therefore, Compound (I) in an amorphous form, or in a Form A or M form, which has the same dissolution behavior as a commercially available preparation containing Form B crystalline form of Compound (I) as an active ingredient, can be used as an active ingredient. It was possible to provide a pharmaceutical composition containing as a main component.

[Test Example 2: Dissolution test of pharmaceutical composition using A-type crystal compound]
Using the pharmaceutical compositions of Examples 3 to 14 and Comparative Example 3, the elution behavior of pharmaceutical compositions containing the A-type crystalline form of Compound (I) as the main active ingredient was confirmed.

The same test method and conditions as in Test Example 1 were used, except that a further sample was collected 90 minutes after the start of elution.

The results are shown in Figure 4. The vertical axis of FIG. 4 shows the elution rate (%), and the horizontal axis shows the collection time (min). Further, Table 3 shows the elution rate (%) 90 minutes after the start of elution.

As shown in FIG. 4 and Table 3, the pharmaceutical compositions of Examples 3 to 14 containing Compound (I) in Form A crystal form as the main active ingredient contain Compound (I) in Form B crystal form. It was found that it exhibited good dissolution behavior similar to that of the commercial preparation of Comparative Example 3 containing as an active ingredient. Therefore, a pharmaceutical composition containing Compound (I) in Form A crystalline form as the main active ingredient has the same behavior as a commercially available preparation containing Form B crystalline Form Compound (I) as an active ingredient. I was able to provide it.

[Test Example 3: Disintegration test]
A disintegration test was conducted using the orally disintegrating tablets of Examples 3 to 14.

The disintegration test was conducted according to the United States Pharmacopeia (USP). Using a disintegration tester (NT-1HM, manufactured by Toyama Sangyo Co., Ltd.) and a Magstar Bath (TMB-81, manufactured by Toyama Sangyo Co., Ltd.), the disintegration time of each pharmaceutical composition was measured, and the average value was calculated. .
<Test conditions>
Test solution: artificial saliva (1.44g/L NaCl, 1.47g/L KCl, 0.3% Tween80)

The results are shown in Table 4.

The US Food and Drug Administration (FDA) provides guidance that the in vitro disintegration time of orally disintegrating tablets is approximately 30 seconds or less when tested in accordance with USP. As shown in Table 4, the orally disintegrating tablets of Examples 3 to 14 were found to disintegrate within 30 seconds. Therefore, it was possible to provide an orally disintegrating tablet that complies with FDA guidelines.

[Test Example 4: Dissolution test of pharmaceutical compositions based on differences in particle size]
Using the pharmaceutical compositions of Examples 15 to 16 and Comparative Examples 2 and 4 to 5, elution of pharmaceutical compositions containing Compound (I) in A-type crystal form with different particle sizes as the main active ingredient I confirmed the behavior.

The test method and conditions are the same as Test Example 2.

The results are shown in Figure 5. The vertical axis of FIG. 5 shows the elution rate (%), and the horizontal axis shows the collection time (min). It was found that as the particle size of compound (I) increases, the elution rate of compound (I) decreases.

From the results of the obtained dissolution rate (%), the effective range of particle diameter in which dissolution behavior equivalent to that of the commercial preparation of Comparative Example 2 could be obtained was calculated.

The particle size effective range was calculated by the following method. That is, the relationship between the particle size of Compound (I) used and the final elution rate (%) was plotted, and the slope and intercept were calculated. Next, from the slope and intercept, the effective particle size range within which similarity to the original formulation could be obtained was calculated.

Figure 6 shows the equation for calculating the effective particle size range that shows a dissolution rate equivalent to that of a commercially available formulation at 45 minutes after the start of elution. The equation for calculating the range is shown in FIG. From the equations shown in Figures 6 and 7, when the particle size of Compound (I) in the A-type crystal form is 20 μm or more and 60 μm or less, the elution behavior is equivalent to that of a commercially available preparation containing Compound (I) as an active ingredient. I understand.

From the above results, it was found that Compound (I) in the amorphous form, or in the A-type or M-type crystalline form, has the same dissolution behavior as a commercially available preparation containing the B-type crystalline Compound (I) as an active ingredient. It was shown that it was possible to provide a pharmaceutical composition containing the active ingredient as a main component.

INDUSTRIAL APPLICABILITY The present invention can be used as a pharmaceutical composition in place of commercially available preparations containing the B-type crystalline form of Compound (I) as an active ingredient.

Claims (11)

Containing one form of the compound of formula (I) as the main active ingredient,
The form is an amorphous form or a crystalline form of type A or type M,
The crystal form of the A type is 2θ (°) = 8.1 ± 0.2, 15.2 ± 0.2, 17.4 ± 0.2, 23.6 ± 0.2 and 25.1 ± 0. It has a powder X-ray diffraction pattern containing a peak of .2,
The crystal form of the M type is 2θ (°) = 5.3 ± 0.2, 8.4 ± 0.2, 9.8 ± 0.2, 13.98 ± 0.2, 14.85 ± 0 .2, 16.64±0.2, 19.59±0.2, 21.46±0.2, 27.23±0.2.

The pharmaceutical composition according to claim 1, which is an orally disintegrating tablet. Contains excipients, binders, disintegrants, and lubricants;
The excipient is at least one selected from the group consisting of the following (i) and (ii):
(i) crystalline cellulose or lactose;
(ii) corn starch;
The binder is at least one selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hypromellose, methylcellulose, and polyvinyl alcohol,
The disintegrant is at least one member selected from the group consisting of cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate, low-substituted hydroxypropylcellulose, carmellose, partially pregelatinized starch, croscarmellose sodium, and carmellose calcium. and
The pharmaceutical composition according to claim 1, wherein the lubricant is magnesium stearate. The pharmaceutical composition according to claim 1, wherein the content of the compound of the chemical formula (I) based on the total mass of the pharmaceutical composition is 5.0% by mass or more and 15% by mass or less. The pharmaceutical composition according to claim 3, wherein the content of the excipient with respect to the total mass of the pharmaceutical composition is 65% by mass or more and 85% by mass or less. The pharmaceutical composition according to claim 3, wherein the content of the binder with respect to the total mass of the pharmaceutical composition is 4.0% by mass or more and 20% by mass or less. The pharmaceutical composition according to claim 3, wherein the content of the disintegrant with respect to the total mass of the pharmaceutical composition is 10% by mass or less. The pharmaceutical composition according to claim 3, wherein the content of the lubricant with respect to the total mass of the pharmaceutical composition is 1.5% by mass or less. The pharmaceutical composition according to any one of claims 1 to 8, wherein the compound of formula (I) in the form A crystal has a particle size of 20 μm or more and 60 μm or less. Based on the total mass of the pharmaceutical composition,
9.0% by mass or more and 11% by mass or less of the compound of the chemical formula (I),
The crystalline cellulose is 55% by mass or more and 65% by mass or less,
The corn starch is 15% by mass or more and 25% by mass or less,
The polyvinylpyrrolidone is 4.0% by mass or more and 8.0% by mass or less,
2.0% by mass or more and 4.0% by mass or less of the crosslinked polyvinylpyrrolidone,
The pharmaceutical composition according to claim 3, containing the magnesium stearate in an amount of 0.5% by mass or more and 1.5% by mass or less. Based on the total mass of the pharmaceutical composition,
9.0% by mass or more and 11% by mass or less of the compound of the chemical formula (I),
The lactose is 55% by mass or more and 65% by mass or less,
The corn starch is 15% by mass or more and 25% by mass or less,
The polyvinylpyrrolidone is 4.0% by mass or more and 8.0% by mass or less,
2.0% by mass or more and 4.0% by mass or less of the crosslinked polyvinylpyrrolidone,
The pharmaceutical composition according to claim 3, containing the magnesium stearate in an amount of 0.5% by mass or more and 1.5% by mass or less.

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