Pharmaceutical composition containing trisulfide compound

Abstract

Disclosed is a pharmaceutical composition comprising a specific trisulfide compound and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of silica gel-based carriers and saccharides.

Description

Pharmaceutical compositions containing trisulfide compounds

[0001] The present disclosure relates to pharmaceutical compositions containing trisulfide compounds.

[0002] Compounds containing a covalent bond structure formed by three consecutive sulfur atoms are called trisulfide compounds. Trisulfide compounds have redox capabilities depending on the valence of the constituent sulfur atoms, and are therefore expected to have various physiologically active functions. For example, Non-Patent Document 1 describes that administration of polysulfides reduced neurodegeneration in Parkinson's disease model mice.

[0003] Patent Document 1 describes pantethine trisulfide, a type of trisulfide compound. Patent Document 2 describes a trisulfide compound and its inclusion complex. Patent Document 3 describes a method for producing glutathione trisulfide, a type of trisulfide compound.

[0004] International Publication No. 2022 / 045052 International Publication No. 2022 / 045212 International Publication No. 2021 / 200487

[0005] Fumiaki Nagashima et al., "Sulfide:quinone oxidoreductase ameliorates neurodegeneration in a murine model of Parkinson's disease", Redox Biology, 59:102562 (2023).

[0006] In a pharmaceutical composition, the storage stability of the active ingredient in the composition affects the amount of the active ingredient at the time of administration to a subject after the pharmaceutical composition is manufactured, and therefore may affect the therapeutic effect of the pharmaceutical composition. For example, if the active ingredient has high hygroscopicity (deliquescent), in a pharmaceutical composition in which the hygroscopicity has not been improved, the active ingredient will absorb moisture and decompose during storage, resulting in a decrease in the effective concentration of the active ingredient in the administered subject.

[0007] Furthermore, ease of handling of a pharmaceutical composition, as typified by fluidity, has a significant impact on the convenience of patients when taking the composition or the efficiency of dividing and packaging the pharmaceutical composition into doses suitable for administration. In particular, if the pharmaceutical composition has low fluidity, it becomes difficult to ingest, divide, or measure out an accurate amount, which may result in the administration of an unintended dose or cause a partial loss of the pharmaceutical composition due to adhesion to equipment.

[0008] The present disclosure aims to provide pharmaceutical compositions containing trisulfide compounds.

[0009] The present inventors have found that a pharmaceutical composition containing a trisulfide compound and a specific pharmaceutically acceptable carrier has excellent storage stability and is easy to handle.

[0010] The present disclosure relates to, for example, the following: [1] A pharmaceutical composition containing a trisulfide compound and a pharmaceutically acceptable carrier, wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof; (Wherein, X is —OR １ or -NR ２ R ３ indicates R １ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ２ and R ３each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxy group.) A pharmaceutical composition comprising at least one selected from the group consisting of a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof; and glutathione trisulfide or a pharmaceutically acceptable salt thereof; wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of a silica gel-based carrier and a saccharide. [2] The pharmaceutical composition according to [1], wherein X in formula (1) is -OH. [3] The pharmaceutical composition according to [1] or [2], wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof. [4] The pharmaceutical composition according to any one of [1] to [3], wherein the pharmaceutically acceptable carrier is a silica gel-based carrier. [5] The pharmaceutical composition according to any one of [1] to [4], wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable carrier is a silica gel-based carrier. [6] The pharmaceutical composition according to any one of [1] to [5], wherein the silica gel-based carrier is a hydrophilic silica gel-based carrier. [7] The pharmaceutical composition according to any one of [1] to [5], wherein the silica gel-based carrier is a hydrophobic silica gel-based carrier. [8] The pharmaceutical composition according to any one of [1] to [7], wherein the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is 2:1 to 1:50. [9] The pharmaceutical composition according to any one of [1] to [8], wherein the pharmaceutical composition is for oral or transdermal administration.

[10] The pharmaceutical composition according to any one of [1] to [9], wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, powder, ointment, cataplasm, or gel.

[11] The pharmaceutical composition according to any one of [1] to

[10] , wherein the pharmaceutical composition is a tablet, capsule, granule, or powder.

[12] The pharmaceutical composition according to [1], wherein the pharmaceutically acceptable carrier is a sugar.

[13] The pharmaceutical composition according to [1] or

[12] , wherein the pharmaceutically acceptable carrier is lactose.

[14] The pharmaceutical composition according to [1],

[12] , or

[13] , wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable carrier is lactose.

[15] The pharmaceutical composition according to any one of claims [1] and

[12] to

[14] , wherein the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is 1:1 to 1:20.

[16] The pharmaceutical composition according to any one of [1] and

[12] to

[15] , wherein the pharmaceutical composition is for oral administration, pulmonary administration, nasal administration, buccal administration, rectal administration, or vaginal administration.

[17] The pharmaceutical composition according to any one of [1] and

[12] to

[16] , wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, powder, inhalation powder, nasal powder, sublingual tablet, troche, drop, suppository, or vaginal suppository.

[18] The pharmaceutical composition according to any one of [1] and

[12] to

[17] , wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, powder, inhalable powder, or nasal powder.

[19] The pharmaceutical composition according to any one of [1] to

[18] , wherein the pharmaceutical composition is in the form of a carrier-adsorbed composition.

[20] The pharmaceutical composition according to any one of [1] to

[19] , wherein the pharmaceutical composition is in powder form.

[21] The pharmaceutical composition according to any one of [1] to

[20] , wherein the increase in mass after standing for 240 hours in air at a temperature of 25±1.5°C and a relative humidity of 43.0±3.5% is 2.0% or less.

[22] The pharmaceutical composition according to any one of [1] to

[21] , wherein the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is such that the increase in mass after standing for 240 hours in air at a temperature of 25±1.5°C and a relative humidity of 43.0±3.5% is 2.0% or less.

[23] The pharmaceutical composition according to any one of [1] to

[22] , wherein the mass increase of the composition is 6.0% or less when the composition is left standing in air at a temperature of 25±1.5°C and a relative humidity of 59.0±5.5% for 240 hours.

[24] The pharmaceutical composition according to any one of [1] to

[23] , wherein the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is such that the mass increase of the composition is 6.0% or less when the composition is left standing in air at a temperature of 25±1.5°C and a relative humidity of 59.0±5.5% for 240 hours.

[25] Use or application of a pharmaceutically acceptable carrier in improving the storage stability and ease of handling of a trisulfide compound in a pharmaceutical composition, wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof; Formula (1): (Wherein, X is —OR １ or -NR ２ R ３ indicates R １ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ２ and R ３ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxy group.) or a pharmaceutically acceptable salt thereof; and glutathione trisulfide or a pharmaceutically acceptable salt thereof; wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of silica gel-based carriers and saccharides.

[26] The use or application according to

[25] in suppressing moisture absorption and improving fluidity of a trisulfide compound in a pharmaceutical composition.

[27] A method for improving ease of handling while improving the storage stability of the trisulfide compound in a pharmaceutical composition, comprising combining a trisulfide compound with a pharmaceutically acceptable carrier, wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof; (Wherein, X is —OR １ or -NR ２ R ３ indicates R １ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ２ and R ３each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxy group.) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof; and glutathione trisulfide or a pharmaceutically acceptable salt thereof; wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of silica gel-based carriers and saccharides.

[28] The method according to

[27] , which is a method for improving fluidity while suppressing moisture absorption of a trisulfide compound in a pharmaceutical composition.

[29] The use or application according to

[25] or

[26] , or the method according to

[27] or

[28] , wherein the trisulfide compound is pantethine trisulfide or a pharmaceutically acceptable salt thereof.

[30] The use or application according to

[25] ,

[26] or

[29] , or the method according to

[27] ,

[28] or

[29] , wherein the pharmaceutically acceptable carrier is a silica gel-based carrier, and the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is 2:1 to 1:50.

[31] The use or application according to

[25] ,

[26] or

[29] , or the method according to

[27] ,

[28] or

[29] , wherein the pharmaceutically acceptable carrier is lactose, and the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is 1:1 to 1:20.

[32] The use or application according to any one of

[25] ,

[26] and

[29] to

[31] , or the method according to any one of

[27] to

[31] , wherein the pharmaceutical composition is a carrier-adsorbed composition.

[33] The use or application according to any one of

[25] ,

[26] , and

[29] to

[32] , or the method according to any one of

[27] to

[32] , wherein the pharmaceutical composition is in powder form.

[34] The use or application according to any one of

[25] ,

[26] , and

[29] to

[33] , or the method according to any one of

[27] to

[33] , comprising allowing the pharmaceutical composition to increase in mass by 2.0% or less when left standing in air at a temperature of 25±1.5°C and a relative humidity of 43.0±3.5% for 240 hours.

[35] The use or application according to any one of

[25] ,

[26] , and

[29] to

[34] , or the method according to any one of

[27] to

[34] , comprising adjusting the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition to a mass ratio that achieves a mass increase of 2.0% or less when the pharmaceutical composition is left standing in air at a temperature of 25±1.5°C and a relative humidity of 43.0±3.5% for 240 hours.

[36] The use or application according to any one of

[25] ,

[26] , and

[29] to

[35] , or the method according to any one of

[27] to

[35] , comprising adjusting the pharmaceutical composition so that a mass increase of 6.0% when the pharmaceutical composition is left standing in air at a temperature of 25±1.5°C and a relative humidity of 59.0±5.5% for 240 hours.

[37] The use or application according to any one of

[25] ,

[26] , and

[29] to

[36] , or the method according to any one of

[27] to

[36] , comprising adjusting the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition to a mass ratio that achieves an increase in mass of 6.0% or less when the pharmaceutical composition is left standing in air at a temperature of 25±1.5°C and a relative humidity of 59.0±5.5% for 240 hours.

[0011] According to the present disclosure, there is provided a pharmaceutical composition containing a trisulfide compound. According to the present disclosure, there is provided a pharmaceutical composition containing a trisulfide compound and a pharmaceutically acceptable carrier.

[0012] According to the present disclosure, it is possible to provide a pharmaceutical composition containing a trisulfide compound that has excellent storage stability and is easy to handle. According to the present disclosure, it is possible to provide a pharmaceutical composition containing a trisulfide compound that has excellent storage stability (e.g., deliquescence) and is easy to handle, even without a coating for improving moisture resistance or fluidity.

[0013] 1 is a diagram showing the results of a moisture absorption test of a pharmaceutical composition containing PTN-SSS and a pharmaceutical composition containing PTN-SSS under a relative humidity condition of about 20% in Test Example 1. 2 is a diagram showing the results of a moisture absorption test of a pharmaceutical composition containing PTN-SSS and a pharmaceutical composition containing PTN-SSS under a relative humidity condition of about 40% in Test Example 1. 3 is a diagram showing the results of a moisture absorption test of a pharmaceutical composition containing PTN-SSS and a pharmaceutical composition containing PTN-SSS under a relative humidity condition of about 60% in Test Example 1. 4 is a diagram showing the properties of a pharmaceutical composition containing PTN-SSS and a pharmaceutical composition containing PTN-SSS under a relative humidity condition of about 60% after a moisture absorption test. 5 is a diagram showing the stability of a pharmaceutical composition containing PTN-SSS, a drug substance of PTN-SSS, and an aqueous solution of PTN-SSS under a high temperature condition of 40°C in Test Example 2. 1 is a diagram showing the change over time in the value (%) obtained by relativizing the peak area derived from PTN-SS, which was formed under the same conditions as in Test Example 2, with the peak area derived from PTN-SSS, in Test Example 5. FIG. 2 is a diagram showing the change over time in the value (%) obtained by relativizing the peak area derived from PTN-SSSS, which was formed under the same conditions as in Test Example 2, with the peak area derived from PTN-SSS, in Test Example 5.

[0014] Hereinafter, embodiments for carrying out the present disclosure will be described, but the present disclosure is not limited to the following embodiments.

[0015] One embodiment of the present disclosure relates to a pharmaceutical composition containing a trisulfide compound and a pharmaceutically acceptable carrier. The pharmaceutical composition according to one embodiment of the present disclosure contains the trisulfide compound as an active ingredient. The pharmaceutical composition according to one embodiment of the present disclosure contains a therapeutically effective amount of the trisulfide compound.

[0016] <Trisulfide Compound> The trisulfide compound according to one embodiment of the present disclosure is pantethine trisulfide or a pharmaceutically acceptable salt thereof; wherein X is —OR １ or -NR ２ R ３ indicates R １ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ２ and R３ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxy group.] or a pharmaceutically acceptable salt thereof; and glutathione trisulfide or a pharmaceutically acceptable salt thereof. These trisulfide compounds may be contained in the pharmaceutical composition in a form other than the free form or a pharmaceutically acceptable salt thereof, and may be contained in the form of, for example, a solvate thereof (e.g., a hydrate).

[0017] In the present disclosure, examples of pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with amino acids such as arginine.

[0018] Pantethine trisulfide is represented by the following formula (2A): Pantethine trisulfide can be prepared, for example, according to the method described in Patent Document 1.

[0019] Glutathione trisulfide is represented by the following formula (2): Glutathione trisulfide can be prepared, for example, according to the method described in Patent Document 3.

[0020] The pharmaceutically acceptable salts of glutathione trisulfide and pantethine trisulfide are preferably amino acid salts or alkali metal salts, more preferably arginine salts or sodium salts. The pharmaceutically acceptable salts of compound (1) are preferably salts with alkali metals, more preferably sodium salts.

[0021] Compound (1) can be prepared, for example, according to the method described in Patent Document 2.

[0022] In one embodiment, compound (1) is represented by formula (3): A compound represented by the formula １ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.], and R １ may be, for example, a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. １ is a hydrogen atom, and in this case, the compound represented by formula (3) is lipoic acid trisulfide represented by formula (4).

[0023] In another embodiment, compound (1) is represented by formula (5): A compound represented by the formula ２ and R ３ R each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxy group. １ and R ２ R may be a hydrogen atom or an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. These alkyl groups may have one or both of an amino group and a carboxy group as a substituent. １ and R ２ may be, for example, a group represented by formula (6) (where * represents a bond). Specific examples of the compound represented by formula (5) include, for example, R ２ and R ３ are both hydrogen atoms, R ２ is a hydrogen atom and R ３ is a group represented by formula (6).

[0024] In a preferred embodiment, the trisulfide compound according to the present disclosure may be pantethine trisulfide or a pharmaceutically acceptable salt thereof, compound (1) or a pharmaceutically acceptable salt thereof, or glutathione trisulfide or a pharmaceutically acceptable salt thereof; in a more preferred embodiment, pantethine trisulfide or a pharmaceutically acceptable salt thereof, or glutathione trisulfide or a pharmaceutically acceptable salt thereof; and in a particularly preferred embodiment, pantethine trisulfide or a pharmaceutically acceptable salt thereof.

[0025] The pharmaceutically acceptable carrier according to one embodiment of the present disclosure is at least one selected from the group consisting of silica gel-based carriers and sugars.

[0026] The silica gel carrier of the pharmaceutical composition of the present disclosure may be any carrier that can be used as a pharmaceutically acceptable carrier, such as fumed silica or colloidal silica, and in a preferred embodiment, fumed silica.

[0027] The silica gel carrier according to the present disclosure may be, for example, a hydrophobic (i.e., surface-treated) or hydrophilic (i.e., surface-untreated) silica gel carrier. When the silica gel carrier according to the present disclosure is hydrophobic, the surface treatment is not particularly limited as long as it is one that is normally performed by a person skilled in the art, and may be, for example, dimethylsilyl modification, trimethylsilyl modification, octylsilyl modification, or dimethylpolysiloxane modification. In a preferred embodiment, it may be dimethylsilyl modification, and the dimethylsilyl modification may be performed by surface treatment using dimethyldichlorosilane.

[0028] The specific surface area of ​​the fumed silica, which is a silica gel-based carrier according to the pharmaceutical composition of the present disclosure, measured by the BET method (the method of Brunauer, Emmett, and Teller) is, for example, 30 to 1000 m ２ / g, 45-660m ２ / g, 60-500m ２ / g or 90 to 330 m ２ / g, and may be, for example, 30 to 400 m ２ / g, 45-260m ２ / g, 60-200m ２ / g or 90 to 130m ２ / g.

[0029] The pH of a 4% aqueous dispersion of fumed silica, which is a silica gel-based carrier according to the pharmaceutical composition of the present disclosure, may be, for example, 3.0 to 7.0, 3.3 to 6.5, 3.6 to 6.0, or 3.8 to 5.5.

[0030] The specific gravity of fumed silica, which is a silica gel-based carrier in the pharmaceutical composition of the present disclosure, may be, for example, 10 to 250 g / L, 20 to 125 g / L, 25 to 100 g / L, or 40 to 60 g / L.

[0031] Examples of silica gel carriers for the pharmaceutical composition of the present disclosure include the AEROSIL® series (EVONIK), the SYLOID® series (GRACE), and the CAB-O-SIL® series (CABOT). In a preferred embodiment, the carrier may be the AEROSIL® series. In a more preferred embodiment, the carrier may be AEROSIL® R972, AEROSIL® 300, or AEROSIL® 200. In a particularly preferred embodiment, the carrier may be AEROSIL® R972. AEROSIL® R972 is a hydrophobic fumed silica that has been surface-treated with dimethyldichlorosilane and has a specific surface area of ​​90 to 130 m as measured by the BET method. ２ / g, pH in a 4% aqueous dispersion is 4.0 to 5.5, and apparent specific gravity is approximately 50 g / L. AEROSIL® 300 is a hydrophilic fumed silica with a BET specific surface area of ​​270 to 330 m ２ The pH of a 4% aqueous dispersion is 3.8 to 4.3, and the apparent specific gravity is approximately 50 g / L.

[0032] The saccharide in the pharmaceutical composition of the present disclosure is not particularly limited as long as it is a saccharide that can be used as a pharmaceutically acceptable carrier, and may be, for example, a monosaccharide, an oligosaccharide, or a polysaccharide. In a preferred embodiment, it may be a monosaccharide or an oligosaccharide, and in a more preferred embodiment, it may be a monosaccharide or a disaccharide. In the present disclosure, oligosaccharides refer to saccharides (disaccharides to hexasaccharides) formed by glycosidic bonds between 2 to 6 monosaccharides, and polysaccharides refer to saccharides formed by glycosidic bonds between 7 or more monosaccharides.

[0033] The saccharide in the pharmaceutical composition of the present disclosure may have a molecular weight of, for example, 10,000 or less, 3,000 or less, 1,000 or less, 500 or less, or 350 or less.

[0034] Examples of monosaccharides used in the pharmaceutical composition of the present disclosure include glucose (grape sugar), fructose (fruit sugar), xylitol, D-sorbitol, and D-mannitol. Examples of oligosaccharides used in the pharmaceutical composition of the present disclosure include lactose (milk sugar), sucrose (cane sugar), maltose (malt sugar), trehalose, and cyclodextrin. Examples of polysaccharides used in the pharmaceutical composition of the present disclosure include starch, hypumellose, and dextran. In one embodiment of the present disclosure, the saccharide used in the pharmaceutical composition may be a saccharide other than cyclodextrin.

[0035] The sugar in the pharmaceutical composition of the present disclosure may be, for example, lactose (milk sugar), glucose (dextrose), sucrose (cane sugar), maltose (malt sugar), or trehalose, and in a preferred embodiment, it may be lactose or sucrose, and in a more preferred embodiment, it may be lactose.

[0036] In the pharmaceutical composition according to an embodiment of the present disclosure, the trisulfide compound may be pantethine trisulfide or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable carrier may be a silica gel-based carrier. In the pharmaceutical composition according to an embodiment of the present disclosure, the trisulfide compound may be pantethine trisulfide or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable carrier may be a saccharide.

[0037] In the pharmaceutical composition according to one embodiment of the present disclosure, the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier may be 2:1 to 1:50, 2:1 to 1:20, 2:1 to 1:9, 1.8:1 to 1:6, 1.6:1 to 1:4, 1.4:1 to 1:2, or 1.2:1 to 1:1.2. When the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier is within the above range, moisture absorption in the pharmaceutical composition is suppressed and handling becomes easier. The mass of the trisulfide compound in the above mass ratio may be the mass converted into the free form.

[0038] In a pharmaceutical composition according to one embodiment of the present disclosure, when the pharmaceutically acceptable carrier is a silica gel-based carrier, the mass ratio of the trisulfide compound to the silica gel-based carrier may be 2:1 to 1:50, 2:1 to 1:20, 2:1 to 1:9, 1.8:1 to 1:6, 1.6:1 to 1:4, 1.4:1 to 1:2, or 1.2:1 to 1:1.2. When the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier is within the above range, moisture absorption in the pharmaceutical composition is suppressed and handling becomes easier. The mass of the trisulfide compound in the above mass ratio may be the mass converted into the free form.

[0039] In a pharmaceutical composition according to one embodiment of the present disclosure, when the pharmaceutically acceptable carrier is a saccharide, the mass ratio of the trisulfide compound to the saccharide may be 1:1 to 1:20, 1:1 to 1:14, 1:1 to 1:9, 1:1 to 1:6, 1:1 to 1:4, 1:1 to 1:2, or 1:1 to 1:1.2. When the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier is within the above range, moisture absorption in the pharmaceutical composition is significantly suppressed. The mass of the trisulfide compound in the above mass ratio may be the mass converted into the free form.

[0040] In addition to the trisulfide compound and a pharmaceutically acceptable carrier, the pharmaceutical composition according to one embodiment of the present disclosure may further contain additives as other components. Examples of additives include stabilizers such as amino acids (e.g., L-arginine), water-soluble polymers (e.g., HES (hydroxyethyl starch), PVP (polyvinylpyrrolidone)), and nonionic surfactants (e.g., polysorbate, poloxamer), isotonicity agents such as sodium chloride, and excipients such as glycine and table salt.

[0041] The dosage of the trisulfide compound in administering the pharmaceutical composition according to one embodiment of the present disclosure is preferably 0.5 to 800 mg per kg of body weight per day (0.5 to 800 mg / kg / day), more preferably 1 to 400 mg / kg / day, and even more preferably 2 to 200 mg / kg / day.

[0042] The pharmaceutical composition according to one embodiment of the present disclosure may be administered 1 to 8 times a day or 1 to 4 times a day, which is believed to reduce the burden of medication on patients and improve medication compliance.

[0043] The pharmaceutical composition according to one embodiment of the present disclosure may be for example, oral, transdermal, pulmonary, ocular, nasal, buccal, rectal, or vaginal administration. In other words, the pharmaceutical composition according to one embodiment of the present disclosure may be in a form suitable for oral, transdermal, pulmonary, ocular, nasal, buccal, rectal, or vaginal administration. In the pharmaceutical composition according to one embodiment of the present disclosure, when the pharmaceutically acceptable carrier is a silica gel-based carrier, the pharmaceutical composition may be for example, oral or transdermal administration, and in a preferred embodiment, oral administration. In the pharmaceutical composition according to one embodiment of the present disclosure, when the pharmaceutically acceptable carrier is a sugar, the pharmaceutical composition may be for example, oral, pulmonary, ocular, nasal, buccal, rectal, or vaginal administration, and in a preferred embodiment, oral administration.

[0044] The pharmaceutical composition according to one embodiment of the present disclosure may be in the form of, for example, tablets, capsules, granules, powders, ointments, poultices, gels, inhalation powders, nasal powders, sublingual tablets, lozenges, drops, suppositories, or vaginal suppositories. In the pharmaceutical composition according to one embodiment of the present disclosure, when the pharmaceutically acceptable carrier is a silica gel-based carrier, the pharmaceutical composition may be in the form of, for example, tablets, capsules, granules, powders, ointments, poultices, or gels, and in a preferred embodiment, may be in the form of tablets, capsules, granules, or powders. In the pharmaceutical composition according to one embodiment of the present disclosure, when the pharmaceutically acceptable carrier is a sugar, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, granules, powder, inhalation powder, nasal spray powder, sublingual tablet, troche, drop, suppository, or vaginal suppository; in a preferred embodiment, it may be in the form of a tablet, capsule, granule, powder, inhalation powder, or nasal spray powder; and in a more preferred embodiment, it may be in the form of a tablet, capsule, granule, or powder. In these cases, the tablet, capsule, granule, or powder may be for oral administration, the ointment or cataplasm may be for transdermal administration, the gel may be for ophthalmic, nasal, buccal, or vaginal administration, the inhalation powder may be for pulmonary administration, the nasal spray powder may be for nasal administration, the sublingual tablet, troche, or drop may be for buccal administration, the suppository may be for rectal administration, and the vaginal suppository may be for vaginal administration.

[0045] The pharmaceutical composition according to one embodiment of the present disclosure may be a carrier-adsorbed composition. That is, the pharmaceutical composition according to one embodiment of the present disclosure may be a composition in which a trisulfide compound and other additives as components are adsorbed onto a pharmaceutically acceptable carrier. In the present disclosure, a carrier-adsorbed composition is distinguished from a solid dispersion using a polymer. The pharmaceutical composition according to one embodiment of the present disclosure may be in powder form.

[0046] The pharmaceutical composition according to one embodiment of the present disclosure has reduced hygroscopicity. In the present disclosure, reduced hygroscopicity may mean, for example, that when left standing in air at a temperature of 25±1.5°C and a relative humidity of 43.0±3.5% for 240 hours, the increase in mass is 2.0% or less, 1.5% or less, or 1.0% or less, or that the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is such that the above-mentioned mass increase is achieved. In the present disclosure, "hygroscopicity is suppressed" may mean, for example, that the increase in mass when the pharmaceutical composition is left standing in air at a temperature of 25±1.5°C and a relative humidity of 43.0±3.5% for 240 hours is 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, or 20% or less of the increase in mass when the active ingredient of the trisulfide compound contained in the pharmaceutical composition is left standing under similar conditions; or the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is a mass ratio that achieves the above-mentioned increase in mass. In the present disclosure, "hygroscopicity is suppressed" may mean, for example, that when left standing for 240 hours in air at a temperature of 25±1.5°C and a relative humidity of 59.0±5.5%, the increase in mass is 6.0% or less, 5.0% or less, 4.5% or less, 4.0% or less, 3.0% or less, 2.0% or less, or 1.0% or less, or that the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is a mass ratio that achieves the above-mentioned mass increase. In the present disclosure, "having reduced hygroscopicity" may mean, for example, that the increase in mass when the pharmaceutical composition is left standing for 240 hours in air at a temperature of 25±1.5°C and a relative humidity of 59.0±5.5% is 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, or 20% or less of the increase in mass when the trisulfide compound bulk substance contained in the pharmaceutical composition is left standing under similar conditions, or that the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is such that the above-mentioned increase in mass is achieved. Furthermore, by further formulating such a pharmaceutical composition whose hygroscopicity has been reduced by containing a carrier into a moisture-proof formulation, such as a capsule, it is possible to obtain a formulation with even better moisture resistance.

[0047] A pharmaceutical composition according to an embodiment of the present disclosure has excellent storage stability. In the present disclosure, a pharmaceutical composition having excellent storage stability may, for example, mean that the moisture absorption described above in the pharmaceutical composition is suppressed. Furthermore, in the present disclosure, a pharmaceutical composition having excellent storage stability may, for example, mean that the rate of decomposition of the trisulfide compound when left standing in air at 40°C under light-shielded conditions for 14 days is 18% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, or 2% or less.

[0048] A pharmaceutical composition according to one embodiment of the present disclosure has excellent fluidity. In the present disclosure, a pharmaceutical composition having excellent fluidity may have, for example, an angle of repose (static angle of repose) of 45° or less, 40° or less, 35° or less, 30° or less, or 25° or less. Furthermore, in the present disclosure, a pharmaceutical composition having excellent fluidity may have, for example, a compressibility of 25% or less, 20% or less, 15% or less, 13% or less, 10% or less, or 9% or less. The angle of repose may be a value measured according to, for example, the method described in "Japanese Pharmacopoeia, 18th Edition, Reference Information, Powder Fluidity <G2-3-171>."

[0049] The pharmaceutical composition according to one embodiment of the present disclosure is easy to handle (easy to handle). In the present disclosure, the ease of handling of a pharmaceutical composition may mean, for example, that the pharmaceutical composition has excellent fluidity as described above. Furthermore, in the present disclosure, the ease of handling of a pharmaceutical composition may include, for example, suppression of excessive increase in viscosity and formation of lumps, reduced adhesion to medicine spoons and packaging devices, and reduced scattering due to wind, etc.

[0050] Another aspect of the present disclosure is the use or application of a pharmaceutically acceptable carrier in improving the storage stability and ease of handling of a trisulfide compound in a pharmaceutical composition. In one embodiment, the use or application may be the use or application of a trisulfide compound in suppressing moisture absorption and improving flowability in a pharmaceutical composition. In these cases, the trisulfide compound, pharmaceutically acceptable carrier, and pharmaceutical composition may be the same as those used in the pharmaceutical composition according to one embodiment of the present disclosure described above.

[0051] Another aspect of the present disclosure is a method for improving the ease of handling while improving the storage stability of a trisulfide compound in a pharmaceutical composition, comprising combining a trisulfide compound with a pharmaceutically acceptable carrier. In one embodiment, the method may be a method for improving the fluidity of the trisulfide compound in a pharmaceutical composition while suppressing moisture absorption. In one embodiment, the method may be a method for improving the ease of handling while improving the storage stability of a trisulfide compound in a pharmaceutical composition containing a trisulfide compound, which may involve adding at least one carrier selected from the group consisting of silica gel-based carriers and saccharides to the pharmaceutical composition. In these cases, the trisulfide compound, the pharmaceutically acceptable carrier, and the pharmaceutical composition may be the same as those used in the pharmaceutical composition according to one embodiment of the present disclosure described above.

[0052] In one embodiment of these uses, applications, or methods, the pharmaceutically acceptable carrier is a silica gel-based carrier, and the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is 2:1 to 1:50, 2:1 to 1:20, 2:1 to 1:9, 1.8:1 to 1:6, 1.6:1 to 1:4, 1.4:1 to 1:2, or 1.2:1 to 1:1.2. When the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier is within the above range, moisture absorption in the pharmaceutical composition is suppressed and handling becomes easier. The mass of the trisulfide compound in the above mass ratio may be the mass converted into the free form.

[0053] In one embodiment of these uses, applications, or methods, the pharmaceutically acceptable carrier is lactose, and the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier in the pharmaceutical composition is 1:1 to 1:20, 1:1 to 1:14, 1:1 to 1:9, 1:1 to 1:6, 1:1 to 1:4, 1:1 to 1:2, or 1:1 to 1:1.2. When the mass ratio of the trisulfide compound to the pharmaceutically acceptable carrier is within the above range, moisture absorption in the pharmaceutical composition is significantly suppressed. The mass of the trisulfide compound in the above mass ratio may be the mass converted into the free form.

[0054] The present disclosure will be described in more detail below using examples, but the present disclosure is not limited to the following examples.

[0055] In the following examples, pantethine trisulfide is also referred to as PTN-SSS. In the following examples, pantethine is also referred to as PTN-SS. PTN-SS is a compound represented by the following structural formula: In the following examples, pantethine tetrasulfide is also referred to as PTN-SSSS. PTN-SSSS is a compound in which one more sulfur atom is inserted in a linear chain at the trisulfide site of PTN-SSS, and is represented by the following structural formula:

[0056] The PTN-SSS used in the following examples was prepared according to the method described in Patent Document 1.

[0057] Preparation Example 1: Preparation of a composition containing PTN-SSS and a silica gel-based carrier After dissolving 1 g of PTN-SSS in 10 mL of methanol, AEROSIL 300 or AEROSIL R972 was added to the solution so that the mass ratio of PTN-SSS to AEROSIL 300 or AEROSIL R972 was 2:1, 1:1, 1:4, or 1:9, and the mixture was stirred for 30 minutes. Thereafter, the methanol was distilled off under reduced pressure, and the mixture was dried under reduced pressure.

[0058] Preparation Example 2: Preparation of a composition containing PTN-SSS and sugars After dissolving 1 g of PTN-SSS in 10 mL of methanol, lactose was added to the solution so that the mass ratio of PTN-SSS to lactose was 2:1, 1:1, 1:4, or 1:9, and the mixture was stirred for 30 minutes. Thereafter, methanol was distilled off under reduced pressure, and the mixture was dried under reduced pressure.

[0059] Test Example 1: Moisture absorption test of compositions containing PTN-SSS The storage stability (hygroscopicity, deliquescence) was evaluated based on the change in mass under relative humidity conditions of approximately 20%, 40%, and 60% for PTN-SSS and the compositions prepared in Preparation Examples 1 and 2. To evaluate hygroscopicity, samples prepared in Preparation Examples 1 and 2 were stored in a desiccator with a constant humidity level maintained by the saturated salt method, and their weights were measured for 72 hours after the start of storage, and the amount of moisture absorption was calculated from the change in weight.

[0060] Figure 1 shows the results of mass change under conditions of approximately 20% relative humidity (25.0±2.5%, humidity adjusted by the saturated salt method using saturated potassium acetate aqueous solution). Figure 2 shows the results of mass change under conditions of approximately 40% relative humidity (43.0±3.5%, humidity adjusted by the saturated salt method using saturated potassium carbonate aqueous solution). Figure 3 shows the results of mass change under conditions of approximately 60% relative humidity (59.0±5.5%, humidity adjusted by the saturated salt method using saturated potassium iodide aqueous solution). Figure 4 also shows photographs of each composition 72 hours after the start of the test under conditions of approximately 60% relative humidity. As shown in Figures 1 to 3, the control PTN-SSS experienced an increase in mass under conditions of approximately 40% and approximately 60% relative humidity, and continued to absorb moisture even after 10 days. Furthermore, even at a relative humidity of approximately 20%, deliquescence of PTN-SSS was confirmed, and the solid state could not be maintained. In contrast, compositions containing PTN-SSS and a sugar (lactose) in a mass ratio of 1:1 or greater, and compositions containing PTN-SSS and a silica gel carrier (AEROSIL 300, AEROSIL R972) in a mass ratio of 2:1 or greater, did not experience the same mass increase as PTN-SSS even at relative humidity levels of approximately 40% and approximately 60%, suppressing moisture absorption and allowing the composition to remain in a powder state for 10 days. Specifically, at a relative humidity of approximately 40%, the mass increase of the composition after 10 days was suppressed to 2.0% or less, and at a relative humidity of approximately 60%, the mass increase of the composition after 10 days was suppressed to 6.0% or less, 5.0% or less, and 4.5% or less. These results demonstrate that a composition containing a trisulfide compound and a sugar or silica gel-based carrier as a pharmaceutically acceptable carrier has reduced hygroscopicity and excellent storage stability.

[0061] Test Example 2: Stability test of compositions containing PTN-SSS at high temperatures The stability at high temperatures was tested for PTN-SSS (base material), an aqueous solution of PTN-SSS, a composition containing PTN-SSS and silica gel, and the compositions prepared in Preparation Examples 1 and 2. The aqueous solution of PTN-SSS was a group that simulated the case where the base material of PTN-SSS had absorbed moisture, and the PTN-SSS was set at a high concentration (80%).

[0062] As the aqueous solution of PTN-SSS used in Test Example 2, 80% PTN-SSS was prepared by weighing out 245 mg of PTN-SSS and adding 61 μL of purified water. 50% PTN-SSS (silica gel) was prepared by dissolving 1 g of PTN-SSS in 10 mL of methanol, adding the solution to silica gel (Kanto Chemical, Silica Gel 60N, spherical, neutral) so that the mass ratio of PTN-SSS to silica gel was 1:1, stirring for 30 minutes, and then distilling off the methanol under reduced pressure and drying under reduced pressure.

[0063] Each sample was weighed into a brown 20 mL screw tube bottle and stored in a thermostatic chamber at 40°C. Sampling was performed appropriately from the start of the stability test, and the HPLC purity was measured by HPLC until the 14th day. The HPLC analysis conditions were as follows. Detector: Ultraviolet absorption photometer (measurement wavelength: 220 nm) Column: LiChrosorb RP-18 (Kanto Chemical, 4.0 x 250 mm, 5 μm) Column temperature: Constant temperature around 40°C Mobile phase A: Phosphoric acid aqueous solution (pH 3) Mobile phase B: Methanol Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 1 to control the concentration gradient. Flow rate: 0.6mL / min Injection volume: 10μL

[0064] The results are shown in Figure 5. In Figure 5, 50% (lactose) indicates a composition in which the mass ratio of PTN-SSS to lactose is 1:1, 50% (AEROSIL) indicates a composition in which the mass ratio of PTN-SSS to AEROSIL300 is 1:1, 20% (lactose) indicates a composition in which the mass ratio of PTN-SSS to lactose is 1:4, and 20% (AEROSIL) indicates a composition in which the mass ratio of PTN-SSS to AEROSIL300 is 1:4. According to FIG. 5, in the aqueous solution of PTN-SSS, the PTN-SSS content decreased to 85% or less after 14 days at 40°C, whereas in the composition containing PTN-SSS and a sugar or silica gel-based carrier as a pharmaceutically acceptable carrier, no significant decrease in the PTN-SSS content was observed. This demonstrates that compositions containing a trisulfide compound and a sugar or silica gel-based carrier as a pharmaceutically acceptable carrier are stable under high-temperature conditions and have excellent storage stability.

[0065] Test Example 3: Ease of handling of compositions containing PTN-SSS The powder properties and handling of the compositions obtained in Test Example 1 after 72 hours, the photograph of which is shown in FIG. 4, and the compositions after being left to stand for 72 hours under conditions of relative humidity of about 20% or about 40%, as in FIG. 4, were visually inspected.

[0066] The results under a relative humidity condition of approximately 60% (60% RH) are shown in Table 2. The results under relative humidity conditions of approximately 40% (40% RH) and approximately 20% (20% RH) are shown in Table 3. In Tables 2 and 3, A indicates extremely good handling, B indicates good handling, and C indicates not very good handling. Also, in Tables 2 and 3, 1) indicates that the product was not powdered and was highly viscous, 2) indicates that the product was easy to handle but formed clumps upon absorbing moisture and adhered to a medicine spoon or the like, and 3) indicates that the amount of carrier was large and the product was prone to being blown around in a slight breeze, making it somewhat difficult to handle. The results in Tables 2 and 3 revealed that the composition containing a sugar to PTN-SSS in a mass ratio of 1:1 to 1:9 and the composition containing a silica gel-based carrier to PTN-SSS in a mass ratio of 2:1 to 1:9 were compositions with superior ease of handling.

[0067]

[0068]

[0069] Test Example 4: Fluidity of composition containing PTN-SSS The fluidity of the composition containing PTN-SSS and silica gel, and the compositions prepared in Preparation Examples 1 and 2 was evaluated.

[0070] Based on the measurement method described in "The Japanese Pharmacopoeia, 18th Edition, Reference Information, Powder Fluidity <G2-3-171>", the angle of repose and compressibility were measured according to the protocol described below.

[0071] Measurement of the angle of repose 1. The funnel was set at a height of approximately 2 cm from the bottom onto which the powder was dropped. 2. The powder was dropped and the height of the mound of powder that formed was measured. 3. The length of the bottom was measured. 4. The angle of repose was calculated using the following formula.

[0072] Measurement of compressibility 1. The powder was gently placed in a 10 mL measuring cylinder. 2. The loose bulk density (V ０ 3. The measuring cylinder was tapped until the volume stopped changing. 4. The packed bulk density (V ｆ 5. The compressibility was calculated using the following formula:

[0073] The angle of repose and compressibility were measured for compositions in which the mass ratio of PTN-SSS to carriers (lactose, AEROSIL 300, AEROSIL R972) was 1:1 to 1:9, and for the carrier alone, and the results are shown in Tables 4 and 5, respectively. Table 6 shows general fluidity scales for the angle of repose and compressibility, which were used as the criteria for evaluating whether fluidity was good in Tables 4 and 5. In Tables 4 and 5, 1) indicates that blocking occurred and measurement was impossible. The angle of repose for a composition in which the mass ratio of PTN-SSS to silica gel was 1:4 was 23° and the compressibility was 8.5. These results demonstrate that compositions containing a sugar to PTN-SSS in a mass ratio of 1:4 to 1:9 and compositions containing a silica gel-based carrier to PTN-SSS in a mass ratio of 1:1 to 1:9 are compositions with excellent fluidity.

[0074]

[0075]

[0076]

[0077] Test Example 5: Test for inhibiting the formation of decomposition products of a composition containing PTN-SSS under high temperature conditions The types and amounts of decomposition products were analyzed by HPLC in the stability test under high temperature conditions in Test Example 2. As a result, PTN-SS and PTN-SSSS were detected as decomposition products of PTN-SSS, while no compound resulting from the elimination of pantoic acid due to hydrolysis of the amide bond was detected.

[0078] Fig. 6 is a graph showing the time-dependent change in the value (%) relative to the peak area derived from PTN-SS produced under the same conditions as in Test Example 2, calculated by dividing the peak area derived from PTN-SSS by the peak area derived from PTN-SSS. Fig. 7 is a graph showing the time-dependent change in the value (%) relative to the peak area derived from PTN-SSSS produced under the same conditions as in Test Example 2, calculated by dividing the peak area derived from PTN-SSS by the peak area derived from PTN-SSS. Figs. 6 and 7 show that, in the aqueous solution of PTN-SSS, PTN-SS and PTN-SSSS were significantly produced over time, whereas in the composition further containing a sugar or silica gel-based carrier as a pharmaceutically acceptable carrier, no significant production of these conversion products was observed.

[0079] It is known that in PTN-SS, compounds resulting from the elimination of pantoic acid due to hydrolysis of amide bonds are produced as thermal decomposition products. In contrast, in the thermal decomposition test of PTN-SSS in this test example, the production of such compounds resulting from the elimination of pantoic acid was not detected. Unexpectedly, in a composition containing PTN-SSS and a sugar or silica gel-based carrier as a pharmaceutically acceptable carrier, the production of thermal decomposition products (PTN-SS, PTN-SSSS) that have completely different structures and production mechanisms from the thermal decomposition products of PTN-SS was significantly suppressed. This result was even more unexpected in light of the fact that the production of thermal decomposition products was significantly suppressed for PTN-SSS, which is less stable than PTN-SS.

Claims

1. A pharmaceutical composition comprising a trisulfide compound and a pharma- ceutical acceptable carrier, wherein the trisulfide compound is pantethine trisulfide or a pharma- ceutical acceptable salt thereof; Formula (1): (Wherein, X is -OR １ Or -NR ２ R ３ indicates R １ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R ２ and R ３ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of an amino group and a carboxy group; and glutathione trisulfide or a pharma- ceutically acceptable salt thereof; wherein the pharma- ceutically acceptable carrier is at least one selected from the group consisting of a silica gel-based carrier and a saccharide.

2. The pharmaceutical composition according to claim 1, wherein X in formula (1) is -OH.

3. The pharmaceutical composition of claim 1, wherein the trisulfide compound is pantethine trisulfide or a pharma- ceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 1, wherein the pharma- ceutically acceptable carrier is a silica gel-based carrier.

5. The pharmaceutical composition according to claim 1, wherein the trisulfide compound is pantethine trisulfide or a pharma- ceutically acceptable salt thereof, and the pharma- ceutically acceptable carrier is a silica gel-based carrier.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the mass ratio of the trisulfide compound to the pharma- ceutically acceptable carrier in the pharmaceutical composition is 2:1 to 1:

50.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is for oral or transdermal administration.

8. The pharmaceutical composition of claim 1, wherein the pharma- ceutically acceptable carrier is a saccharide.

9. The pharmaceutical composition of claim 1, wherein said pharma- ceutically acceptable carrier is lactose.

10. The pharmaceutical composition of claim 1, wherein the trisulfide compound is pantethine trisulfide or a pharma- ceutically acceptable salt thereof and the pharma- ceutically acceptable carrier is lactose.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein the mass ratio of the trisulfide compound to the pharma- ceutically acceptable carrier in the pharmaceutical composition is 1:1 to 1:

20.

12. The pharmaceutical composition according to any one of claims 8 to 10, wherein the pharmaceutical composition is for oral, pulmonary, nasal, buccal, rectal or vaginal administration.

13. The pharmaceutical composition according to any one of claims 1 to 5 and 8 to 10, which is a carrier-adsorbed composition.

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