Composition for nasal administration

Abstract

With respect to a pharmaceutical composition for nasal administration containing a pharmaceutical active ingredient targeting the brain, the purpose of the present invention is to provide: a formulation prescription design, which improves the adhesion efficiency to an olfactory region in the nasal cavity; and a formulation prescription for improving the bioavailability of resveratrol. The composition for nasal administration, which is a particulate composition, contains particles containing (A) a pharmaceutical active ingredient targeting the brain and (B) a binder. By designing the average particle diameter of the particles to 15-30 μm, the amount of adhesion to the olfactory region relative to the amount of adhesion to the concha region in the nasal cavity can be remarkably improved. By adding (A1) rifamycin to a nasal administration composition containing (A2) resveratrol, the bioavailability of the component (A2) can be improved.

Description

Nasal administration composition

[0001] The present invention relates to a composition for nasal administration. Specifically, the present invention relates to a particulate composition for nasal administration that has improved adhesion efficiency to the olfactory region in the nasal cavity in order to non-invasively deliver an active pharmaceutical ingredient to the brain, and to a composition for nasal administration that improves the bioavailability of resveratrols.

[0002] Active pharmaceutical ingredients (hereinafter also referred to as "API") administered via nasal administration are not only localized in the nasal cavity, but also distributed to the systemic circulation via blood vessels present under the nasal mucosa and to the nasal cavity via nerve pathways. Meanwhile, the mucociliary clearance system present in the nasal cavity acts as a biological defense mechanism, and also serves to remove foreign substances such as drugs to the pharyngeal side.

[0003] In other words, the nasal retention of a nasally administered drug is a property that affects the delivery site of the nasally administered API, and therefore, in designing a nasally administered drug, it is recognized that it is extremely important to understand this nasal retention in addition to the nasal mucosa permeability of the nasally administered drug.

[0004] A 3D model (in vitro nasal cast model) is sometimes used to evaluate the intranasal properties of nasally administered drugs. However, the in vitro nasal cast model does not accurately represent the in vivo surface properties of the nasal cavity, including the influence of mucociliary clearance. Therefore, with the aim of establishing the in vitro nasal cast model as a tool for predicting in vivo nasal deposition, analytical methods have been developed to quantify radioactivity deposited in the in vitro nasal cast model and predict in vivo scintigraphic deposition (Non-Patent Document 1).

[0005] Carbrera et al., Development of In Vitro Nasal Cast Imaging Techniques to Predict In Vivo Nasal Deposition, Respiratory Drug Delivery Europe2017, 325-328

[0006] <1> As mentioned above, research into the design of nasally administered drugs has focused on retention in the nasal cavity.

[0007] Here, nasal drops (nasally administered drugs) have different delivery targets, such as local delivery in the nasal cavity, systemic delivery via the systemic circulation, or local delivery to the brain, depending on the type of active pharmaceutical ingredient (hereinafter also referred to as "API") contained therein. The desired effect is achieved by the API attached to the nasal vestibule and turbinate areas in the nasal cavity in the case of local delivery in the nasal cavity, the turbinate area in the nasal cavity in the case of systemic delivery via the systemic circulation, or the olfactory area in the nasal cavity in the case of local delivery to the brain. In other words, the location in the nasal cavity to which the API should be attached varies depending on the delivery target.

[0008] On the other hand, if the amount of API attached to sites other than the intranasal site where the API is to be attached increases, not only will the delivery efficiency to the target decrease, but side effects may also occur. For example, in the case of an API intended for local delivery to the brain, if the amount of API attached to other sites increases, not only will the delivery efficiency to the brain decrease, but side effects may also worsen due to increased transfer to the liver via the systemic circulation.

[0009] In designing a nasally administered drug, the inventors focused on the properties that affect the delivery site of an API after nasal administration, not only the physical properties of the nasally administered drug, retention in the nasal cavity, and permeability to the nasal mucosa, but also the property of which part of the nasal cavity the drug adheres to. In particular, in the case of an API that targets the brain, it is desirable to increase the amount of the API that adheres to the olfactory region relative to the amount that adheres to the nasal turbinate region in the nasal cavity in order to improve delivery efficiency to the brain and prevent liver damage due to transfer to the liver via the systemic circulation.

[0010] Therefore, a first object of the present invention is to provide a pharmaceutical composition for nasal administration containing a brain-targeting active pharmaceutical ingredient for non-invasively delivering the component (A) to the brain, which has a formulation design that improves the adhesion efficiency to the olfactory region in the nasal cavity.

[0011] <2> Resveratrol, a functional ingredient, acts as a NAD +Since its identification as a plant-derived substance that activates the dependent protein deacetylase 1 (SIRT1), resveratrol has attracted attention as a potential therapeutic agent for various diseases. However, resveratrol itself has the problem of very low bioavailability.

[0012] Therefore, a second object of the present invention is to provide a formulation that improves the bioavailability of resveratrols.

[0013] First, the present inventors have found that by designing a pharmaceutical composition for nasal administration containing a brain-targeting active pharmaceutical ingredient as a particulate composition in which the average particle size of particles containing the active pharmaceutical ingredient is 15 to 30 μm, it is possible to significantly improve the amount of adhesion to the olfactory area relative to the amount of adhesion to the turbinate area in the nasal cavity.

[0014] Secondly, the present inventors have found that by combining resveratrols with rifamycins in a nasal administration composition, the bioavailability of resveratrols via nasal administration is improved.

[0015] The present invention was completed through further investigation based on these findings.

[0016] That is, the present invention provides a first invention (Items 1 to 14, 18 to 22) and a second invention (Items 15 to 17) of the following aspects: Item 1. A particulate composition for nasal administration for non-invasively delivering component (A) to the brain, comprising particles comprising (A) a brain-targeting active pharmaceutical ingredient and (B) a binder, the particles having an average particle size of 15 to 30 μm. Item 2. The particulate composition for nasal administration according to Item 1, wherein component (A) is at least one of (A1) a rifamycin represented by the following formula (I), and (A2) a resveratrol selected from the group consisting of resveratrol, resveratrol ester, and resveratrol glucoside: Item 3. The particle composition for nasal administration according to Item 1 or 2, wherein the component (B) is at least one of (B1) a cellulose-based binder in which at least a portion of the hydrogen atoms constituting the hydroxyl groups of cellulose are substituted with a substituent selected from the group consisting of an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, and an alkylcarbonyl group, and (B1) a vinyl-based binder selected from the group consisting of polyvinylpyrrolidone and polyvinyl alcohol. Item 4. The particle composition for nasal administration according to any one of Items 1 to 3, wherein the component (B) is (B1) a cellulose-based binder in which at least a portion of the hydrogen atoms constituting the hydroxyl groups of cellulose are substituted with a substituent selected from the group consisting of an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, and an alkylcarbonyl group. Item 5. The particle composition for nasal administration according to any one of Items 1 to 4, further comprising (C) a cyclodextrin selected from the group consisting of cyclodextrin and cyclodextrin derivatives in which at least a portion of the hydrogen atoms constituting the hydroxyl groups of the cyclodextrin are substituted with an alkyl group and / or a hydroxyalkyl group. Item 6. Item 7. The particle composition for nasal administration according to any one of Items 1 to 5, further comprising (D) ascorbic acid. Item 7. The particle composition for nasal administration according to any one of Items 1 to 6, wherein the content of component (A) is 40 to 90% by weight. Item 8. The particle composition for nasal administration according to any one of Items 1 to 7, wherein the content of component (B) is 0.1 to 0.8 parts by weight per part by weight of component (A). Item 9. The particle composition for nasal administration according to any one of Items 1 to 8, wherein the content of component (C) is 0.05 to 0.3 parts by weight per part by weight of component (A). Item 10. The particle composition for nasal administration according to any one of Items 1 to 9, wherein the particles are a spray-dried product of a liquid material containing component (A) and component (B). Item 11. The particle composition for nasal administration according to any one of Items 1 to 10, wherein the particles are deposited more in the olfactory region than in the turbinate region of the nasal cavity upon nasal administration. Item 12. Item 12. A particle composition for nasal administration according to any one of Items 1 to 11, wherein 45% by weight or more of the particles sprayed into the nasal cavity by nasal administration are deposited in the olfactory region.Item 13. A method for improving the adhesion efficiency of a particulate composition for nasal administration to the olfactory region in the nasal cavity, the particulate composition containing particles comprising (A) a brain-targeting active pharmaceutical ingredient and (B) a binder, and for non-invasively delivering component (A) to the brain, the method comprising a step of controlling the average particle size of the particles to 15 to 30 μm. Item 14. The method according to Item 13, wherein the step comprises spray-drying a liquid material containing component (A) and component (B), the liquid material containing 1 to 7% by weight of solids in an aqueous solution of ethanol, isopropanol, and / or methanol. Item 15. A composition for nasal administration comprising (A1) a rifamycin represented by the following formula (I), and (A2) a resveratrol selected from the group consisting of resveratrol, resveratrol esters, and resveratrol glucoside, the composition being used for applications utilizing the physiological activity of component (A2). Item 16. The composition for nasal administration according to Item 15, which is a particle composition. Item 17. A method for improving the bioavailability of component (A2) in a composition for nasal administration containing a resveratrol selected from the group consisting of resveratrol, resveratrol esters, and resveratrol glucoside, comprising blending (A1) a rifamycin represented by the following formula (I) together with component (A2) into the composition for nasal administration: Item 18. A method of nasal administration comprising nasally administering a particulate composition for nasal administration for non-invasively delivering component (A) to the brain, the particulate composition containing particles comprising (A) a brain-targeting active pharmaceutical ingredient and (B) a binder, the particles having an average particle size of 15 to 30 μm, so that the particles adhere more to the olfactory region than to the turbinate region of the nasal cavity. Item 19. The method of nasal administration according to Item 18, wherein the composition is administered nasally to a subject in need of prevention or treatment of central nervous system disease, ischemic cerebrovascular disease, psychiatric disorder, pain, metabolic disease, or malignant tumor. Item 20. Use of a particulate composition containing particles comprising component (A) and (B) a binder, the particles having an average particle size of 15 to 30 μm, for the manufacture of a particulate composition for non-invasively delivering component (A) a brain-targeting active pharmaceutical ingredient to the brain by nasal administration. Item 21. Item 21. A particle composition for non-invasively delivering (A) a brain-targeting active pharmaceutical ingredient to the brain by nasal administration, the particle composition comprising particles comprising the component (A) and (B) a binder, the particles having an average particle size of 15 to 30 μm. Item 22. The nasal administration method according to Item 18, the use according to Item 20, or the particle composition according to Item 21, wherein 45% by weight or more of the particles sprayed into the nasal cavity are deposited in the olfactory region.

[0017] According to the first aspect of the present invention, the efficiency of a pharmaceutical composition for nasal administration containing a brain-targeting active pharmaceutical ingredient to adhere to the olfactory region in the nasal cavity can be improved.

[0018] According to the second invention, the bioavailability of resveratrols can be improved.

[0019] 1 shows the intracerebral concentration of rifampicin per dose when the first intranasal particle composition of the present invention was administered to rabbits. 2 shows the intracerebral concentration of resveratrol per dose when the first intranasal particle composition of the present invention was administered to rabbits.

[0020] [1] [1-1. Particulate composition for nasal administration] The particulate composition for nasal administration of the first invention is for non-invasively delivering an active pharmaceutical ingredient to the brain, and is characterized in that it contains particles comprising (A) a brain-targeting active pharmaceutical ingredient (hereinafter also referred to as "component (A)") and (B) a binder (hereinafter also referred to as "component (B)"), and the average particle size of the particles is 15 to 30 μm. The particulate composition for nasal administration of the first invention can improve the efficiency of adhesion to the olfactory region in the nasal cavity. Specifically, by nasal administration, the particles can adhere more to the olfactory region than to the turbinate region in the nasal cavity. In a preferred embodiment, the particulate composition for nasal administration of the first invention further comprises (C) a cyclodextrin (hereinafter also referred to as "component (C)").

[0021] [1-1-1. (A) Brain-Targeting Active Pharmaceutical Ingredient] The particulate composition for nasal administration of the first invention contains, as component (A), a brain-targeting active pharmaceutical ingredient. The particulate composition for nasal administration of the first invention efficiently adheres to the olfactory region in the nasal cavity and transfers component (A) from the olfactory region mucosa to the brain via the trigeminal nerve. Therefore, the component (A) is not limited as long as it is an active pharmaceutical ingredient that targets the brain. Examples of the component (A) include (A1) rifamycins (hereinafter also referred to as "component (A1)"), (A2) resveratrols (hereinafter also referred to as "component (A2)"), and the drugs shown in the table below.

[0022]

[0023]

[0024]

[0025]

[0026]

[0027] The component (A) may contain one of these active pharmaceutical ingredients alone or a combination of two or more of them.

[0028] Among these active pharmaceutical ingredients, the component (A) is preferably at least one of the component (A1) and the component (A2), and more preferably the component (A1).

[0029] (A1) Rifamycins Rifamycins are compounds represented by the following formula (I) and salts thereof.

[0030] The salt of rifamycins is not particularly limited as long as it forms a salt with the compound represented by formula (I) and is pharmaceutically acceptable. Examples include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, salts of pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.), inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), and organic acid salts (acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.). These salts may be used alone or in combination of two or more.

[0031] The component (A1) may contain one or more of the rifamycins represented by formula (I). Among these rifamycins, preferred are rifampicin and rifapentine.

[0032] (A2) Resveratrols The resveratrols are selected from the group consisting of resveratrol, resveratrol esters, and resveratrol glucosides. Specifically, the resveratrols are represented by the following formula (II):

[0033] Resveratrol is represented by the formula (II), R 4 , R 5 , and R 6 is a hydrogen atom; and the resveratrol ester is represented by the formula (II), 4 , R 5 , and R 6 are each independently a hydrogen atom or an alkylcarbonyl group, and R 4 , R 5 , and R 6 is an alkylcarbonyl group; and resveratrol glucoside is a compound represented by the formula (II), 4 , R 5 , and R 6 are each independently a hydrogen atom or a glucosyl group, and R 4 , R 5 , and R 6 At least one of these is a glucosyl group.

[0034] The component (A2) may contain one resveratrol compound represented by formula (II) alone or in combination of two or more. Among these resveratrol compounds, resveratrol is preferred. The resveratrol may be purified from a plant extract such as lingonberry extract, grape extract, bilberry extract, Japanese knotweed extract, or melinjo extract, or may be obtained by chemical synthesis, genetic engineering, or microbiological methods.

[0035] Content of Component (A) The content of component (A) in the particle composition for nasal administration of the first present invention is not particularly limited, and may be, for example, 40% by weight or more, preferably 50% by weight or more, more preferably 58% by weight or more, 63% by weight or more, 65% by weight or more, 68% by weight or more, or 70% by weight or more in total. The upper limit of the content of component (A) is also not particularly limited, and may be, for example, 90% by weight or less, preferably 80% by weight or less, more preferably 75% by weight or less, and even more preferably 72% by weight or less, 70% by weight or less, 68% by weight or less, 66% by weight or less, 64% by weight or less, or 62% by weight or less.

[0036] Specific ranges of the content of component (A) in the particle composition for nasal administration of the first present invention include, for example, a total amount of 40 to 90% by weight, 40 to 80% by weight, 40 to 75% by weight, 50 to 72% by weight, 58 to 72% by weight, 63 to 72% by weight, 65 to 72% by weight, 68 to 72% by weight, 70 to 72% by weight, 68 to 70% by weight, 58 to 68% by weight, 58 to 66% by weight, 58 to 64% by weight, or 58 to 62% by weight.

[0037] [1-1-2. (B) Binder] The particle composition for nasal administration of the first aspect of the present invention contains a binder as component (B). The binder is not particularly limited, and preferred examples include a cellulose-based binder (B1) (hereinafter also referred to as "component (B1)") and a vinyl-based binder (B2) (hereinafter also referred to as "component (B2)"). As component (B), one type of binder may be contained alone, or two or more types may be contained in combination.

[0038] Among these components (B), component (B1) is preferred from the viewpoint of improving the adhesion efficiency to the olfactory region.

[0039] (B1) Cellulose-based binder The cellulose-based binder is a binder in which at least some of the hydrogen atoms constituting the hydroxyl groups of cellulose are substituted with alkyl groups (-R 7 group), hydroxyalkyl group (-R 8 OH), alkoxyalkyl groups (-R 9 OR 10 group), and alkylcarbonyl group (—COR 11 The cellulose derivative is substituted with a substituent selected from the group consisting of cellulose ethers, ...

[0040] R 7 represents an alkyl group having 1 to 3 carbon atoms, preferably a methyl group or an ethyl group. 8 represents an alkylene group having 2 to 3 carbon atoms, and preferably represents a —CH—CH(CH)— group or a —CH—CH— group. 9 R has 1 to 3 carbon atoms, preferably a —CH—CH(CH)— group or a —CH—CH— group, and more preferably a —CH—CH— group. 10represents an alkyl group having 1 to 3 carbon atoms, preferably a methyl group or an ethyl group, and more preferably a methyl group. 11 represents an organic group, and preferably includes an alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms; an aryl group having a carboxyl group and having 6 to 12 carbon atoms, preferably 6 carbon atoms; an alkyl group having a carboxyl group and having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and more preferably, -COR 11 Examples of such groups include acyl groups of monovalent acids such as acetyl (-COCH), and acyl groups of divalent acids such as phthaloyl (-CO-CH-COH) and succinyl (-CO-CHCH-COH). Cellulose derivative molecules may contain one type of these substituents alone or a combination of two or more types.

[0041] The component (B1) may contain one of these cellulose derivatives alone or a combination of two or more of them.

[0042] Among these cellulose derivatives, from the viewpoint of improving the efficiency of adhesion to the olfactory region, preferred are methyl cellulose, ethyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, methylhydroxyethyl cellulose, and esters thereof, more preferred are hypromellose and esters thereof, and even more preferred is hypromellose.

[0043] Hypromellose is also called hydroxypropyl methylcellulose (HPMC). Hypromellose is a mixed methyl and hydroxypropyl ether of cellulose. The degree of substitution type of hypromellose used in the first present invention is not particularly limited, and examples thereof include 1828, 2208, 2906, and 2910. In the degree of substitution type, the first two digits indicate the average degree of methoxy substitution, and the last two digits indicate the average degree of hydroxypropoxy substitution. The viscosity grade of hypromellose (viscosity of a 2 wt% aqueous solution at 20°C) is also not particularly limited, and examples thereof include 2.5 to 140,000. These hypromelloses may be used alone or in combination of two or more. From the viewpoint of improving the efficiency of adhesion to the olfactory region, preferred are those having a degree of substitution of 2910 and / or those having a viscosity grade of preferably 3.2 to 10,000, more preferably 3.6 to 4,000, even more preferably 5.2 to 50, still more preferably 5.2 to 17.5, and particularly preferably 5.2 to 7.0.

[0044] Examples of hypromellose esters include hypromellose phthalate (HPMCP) and hypromellose acetate succinate (HPMCAS). These esters may be used alone or in combination of two or more. Hypromellose phthalate (HPMCP) is a monophthalate ester of hypromellose. The degree of substitution of hypromellose phthalate is not particularly limited, but examples include 220824 and 200731. Regarding the degree of substitution, the first two digits indicate the average degree of methoxy substitution, the middle two digits indicate the average degree of hydroxypropoxy substitution, and the last two digits indicate the average degree of carboxybenzoyl substitution. These hypromellose esters may be used alone or in combination of two or more.

[0045] (B2) Vinyl-Based Binder The vinyl-based binder is a vinyl-based polymer selected from the group consisting of polyvinylpyrrolidone and polyvinyl alcohol.

[0046] The component (B2) may contain one of these vinyl polymers alone, or may contain two or more of them in combination.

[0047] Among these vinyl polymers, polyvinylpyrrolidone is preferable from the viewpoint of improving the efficiency of adhesion to the olfactory region.

[0048] Polyvinylpyrrolidone is a polymer of N-vinyl-2-pyrrolidone. The K value of the polyvinylpyrrolidone used in the first invention is not particularly limited, but may be, for example, 15 to 40. The K value is a viscosity characteristic value correlated with molecular weight, and is a numerical value calculated by applying the relative viscosity value (25°C) measured with a capillary viscometer to the Fikentscher formula. These polyvinylpyrrolidones may be used alone or in combination of two or more. From the viewpoint of improving the adhesion efficiency to the olfactory region, polyvinylpyrrolidones having a K value of preferably 20 to 37, more preferably 25 to 35, are preferred.

[0049] Polyvinyl alcohol is a saponified product of polyvinyl ester. The saponification degree of polyvinyl alcohol is preferably 80 mol % or more, more preferably 90 mol % or more. These polyvinyl alcohols may be used alone or in combination of two or more.

[0050] Content of Component (B) The content of component (B) in the particle composition for nasal administration of the first present invention is not particularly limited, but can be, for example, 10% by weight or more in total, and from the viewpoint of improving the efficiency of adhesion to the olfactory region, preferably 15% by weight or more, more preferably 20% by weight or more, even more preferably 25% by weight or more, and even more preferably 28% by weight or more. The upper limit of the content of component (B) is also not particularly limited, but can be, for example, 50% by weight or less, and from the viewpoint of improving the efficiency of adhesion to the olfactory region, preferably 45% by weight or less, more preferably 40% by weight or less, even more preferably 35% by weight or less, and even more preferably 32% by weight or less.

[0051] Specific ranges of the content of component (B) in the particle composition for nasal administration of the first present invention include, for example, a total amount of 10 to 50% by weight, 15 to 45% by weight, 20 to 40% by weight, 25 to 35% by weight, or 28 to 32% by weight.

[0052] The ratio of component (B) per 1 part by weight of component (A) is not particularly limited, but a total amount of, for example, 0.1 part by weight or more can be obtained, and from the viewpoint of improving the efficiency of adhesion to the olfactory region, the ratio is preferably 0.2 parts by weight or more, more preferably 0.3 parts by weight or more, even more preferably 0.4 parts by weight or more, 0.45 parts by weight or more, or 0.48 parts by weight or more. The upper limit of the ratio of component (B) is also not particularly limited, but for example, the ratio can be 0.8 parts by weight or less, preferably 0.7 parts by weight or less, more preferably 0.6 parts by weight or less, even more preferably 0.55 parts by weight or less, or 0.52 parts by weight or less.

[0053] Specific ranges for the ratio of component (B) per 1 part by weight of component (A) include, for example, 0.1 to 0.8 parts by weight, 0.2 to 0.7 parts by weight, 0.3 to 0.6 parts by weight, 0.4 to 0.55 parts by weight, 0.45 to 0.52 parts by weight, or 0.48 to 0.52 parts by weight in total.

[0054] [1-1-3. (C) Cyclodextrins] The particle composition for nasal administration of the first invention preferably contains a cyclodextrin as component (C). Cyclodextrins are known as absorption enhancers in powder compositions for nasal administration, and can be incorporated into the particle composition for nasal administration of the first invention for the purpose of improving the efficiency of adhesion to the olfactory region.

[0055] The cyclodextrins are selected from the group consisting of cyclodextrin and cyclodextrin derivatives in which at least some of the hydrogen atoms constituting the hydroxyl groups of the cyclodextrin (specifically, the hydroxyl groups at the 2-, 3-, and 6-positions of the glucose residue) are substituted with alkyl groups and / or hydroxyalkyl groups.

[0056] Cyclodextrin is a cyclic oligosaccharide consisting of glucopyranose units with α-1,4 bonds. Examples of cyclodextrin include α-cyclodextrin (a cyclic oligosaccharide consisting of six glucose units), β-cyclodextrin (a cyclic oligosaccharide consisting of seven glucose units), and γ-cyclodextrin (a cyclic oligosaccharide consisting of eight glucose units).

[0057] Examples of alkyl groups as substituents on cyclodextrin derivatives include alkyl groups having 1 to 4 carbon atoms, more specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and / or t-butyl. Examples of hydroxyalkyl groups as substituents on cyclodextrin derivatives include hydroxyalkyl groups having 1 to 4 carbon atoms, more specifically hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxybutyl, 2-hydroxyisobutyl, dihydroxymethyl, and / or 2,2-dihydroxyethyl.

[0058] Specific examples of cyclodextrin derivatives in which at least a portion of the hydrogen atoms constituting the hydroxyl groups of cyclodextrin are substituted with alkyl groups include methylated α-cyclodextrin, methylated β-cyclodextrin, methylated γ-cyclodextrin, dimethyl-α-cyclodextrin, dimethyl-β-cyclodextrin, dimethyl-γ-cyclodextrin, etc. Specific examples of cyclodextrin derivatives in which at least a portion of the hydrogen atoms constituting the hydroxyl groups of cyclodextrin are substituted with hydroxyalkyl groups include hydroxypropyl-α-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxybutyl-β-cyclodextrin, etc.

[0059] As the component (C), one of these cyclodextrins may be contained alone, or two or more of them may be contained in combination.

[0060] Among these cyclodextrins, from the viewpoint of improving the efficiency of attachment to the olfactory region, preferred are β-cyclodextrin and its derivatives (specifically, methylated β-cyclodextrin, dimethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxybutyl-β-cyclodextrin, etc.), or cyclodextrin derivatives having a hydroxyalkyl group as a substituent (hydroxypropyl-α-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, etc.). More preferred are cyclodextrin derivatives having a hydroxyalkyl group as a substituent of γ-cyclodextrin, still more preferred are hydroxypropyl-β-cyclodextrin and hydroxybutyl-β-cyclodextrin, still more preferred are (2-hydroxypropyl)-β-cyclodextrin and (2-hydroxybutyl)-β-cyclodextrin, and particularly preferred is (2-hydroxypropyl)-β-cyclodextrin.

[0061] When the particle composition for nasal administration of the first present invention contains component (C), its content is not particularly limited, but may be, for example, 3% by weight or more in total, and from the viewpoint of improving the efficiency of adhesion to the olfactory region, it is preferably 5% by weight or more, more preferably 7% by weight or more, even more preferably 8% by weight or more, and even more preferably 9% by weight or more. The upper limit of the content of component (C) is also not particularly limited, but may be, for example, 20% by weight or less, and from the viewpoint of improving the efficiency of adhesion to the olfactory region, it is preferably 15% by weight or less, more preferably 13% by weight or less, even more preferably 12% by weight or less, and even more preferably 11% by weight or less.

[0062] When the first particulate composition for nasal administration of the present invention contains component (C), specific ranges of the content include, for example, a total amount of 3 to 20% by weight, 5 to 15% by weight, 7 to 13% by weight, 8 to 12% by weight, and 9 to 11% by weight.

[0063] Furthermore, when the particle composition for nasal administration of the first present invention contains component (C), the ratio of component (C) per 1 part by weight of component (A) is not particularly limited, but a total amount of, for example, 0.05 part by weight or more can be obtained, and from the viewpoint of improving the efficiency of adhesion to the olfactory region, it is preferably 0.1 part by weight or more, more preferably 0.12 parts by weight or more, even more preferably 0.14 parts by weight or more, or 0.16 parts by weight or more. The upper limit of the ratio of component (C) is also not particularly limited, but it is, for example, 0.3 parts by weight or less, preferably 0.25 parts by weight or less, more preferably 0.2 parts by weight or less, and even more preferably 0.18 parts by weight or less.

[0064] When the first particle composition for nasal administration of the present invention contains component (C), specific ranges for the ratio of component (C) per 1 part by weight of component (A) include, for example, a total amount of 0.05 to 0.3 parts by weight, 0.1 to 0.3 parts by weight, 0.12 to 0.25 parts by weight, 0.14 to 0.2 parts by weight, or 0.16 to 0.18 parts by weight.

[0065] [1-1-4. (D) Ascorbic Acid] The particulate composition for nasal administration of the first invention preferably contains ascorbic acid as component (D). Ascorbic acid is known as an absorption enhancer in powder compositions for nasal administration, and can be added to the particulate composition for nasal administration of the first invention for the purpose of improving the efficiency of adhesion to the olfactory region.

[0066] When the particle composition for nasal administration of the first present invention contains component (D), its content is not particularly limited, but may be, for example, 3% by weight or more in total, and from the viewpoint of improving the efficiency of adhesion to the olfactory region, it is preferably 5% by weight or more, more preferably 7% by weight or more, even more preferably 8% by weight or more, and even more preferably 9% by weight or more. The upper limit of the content of component (D) is also not particularly limited, but may be, for example, 20% by weight or less, and from the viewpoint of improving the efficiency of adhesion to the olfactory region, it is preferably 15% by weight or less, more preferably 13% by weight or less, even more preferably 12% by weight or less, and even more preferably 11% by weight or less.

[0067] When the first particulate composition for nasal administration of the present invention contains component (D), specific ranges of the content include, for example, a total amount of 3 to 20% by weight, 5 to 15% by weight, 7 to 13% by weight, 8 to 12% by weight, and 9 to 11% by weight.

[0068] Furthermore, when the particle composition for nasal administration of the first present invention contains component (D), the ratio of component (D) per 1 part by weight of component (A) is not particularly limited, but a total amount of, for example, 0.05 part by weight or more can be obtained, and from the viewpoint of improving the efficiency of adhesion to the olfactory region, it is preferably 0.1 part by weight or more, more preferably 0.12 parts by weight or more, even more preferably 0.14 parts by weight or more, or 0.16 parts by weight or more. The upper limit of the ratio of component (D) is also not particularly limited, but it is, for example, 0.3 parts by weight or less, preferably 0.25 parts by weight or less, more preferably 0.2 parts by weight or less, even more preferably 0.18 parts by weight or less.

[0069] When the first particle composition for nasal administration of the present invention contains component (D), specific ranges for the ratio of component (D) per 1 part by weight of component (A) include, for example, a total amount of 0.05 to 0.3 parts by weight, 0.1 to 0.3 parts by weight, 0.12 to 0.25 parts by weight, 0.14 to 0.2 parts by weight, or 0.16 to 0.18 parts by weight.

[0070] [1-1-5. Other Components] The particle composition for nasal administration of the first aspect of the present invention may or may not contain other components, such as pharmacologically acceptable bases, mucosal adhesion promoters, mucosal absorption promoters, binders other than component (B), and / or additives, which are acceptable for nasal administration compositions, in addition to the above-mentioned component (A) and component (B), or the further component (C) and / or component (D) which are blended as necessary.

[0071] Specific examples of these other ingredients, which may or may not be contained, include cellulose derivatives (crystalline cellulose, cellulose acetate, carmellose sodium, etc.); vinyl polymers (polyacrylic acid, carboxyvinyl polymer, etc.); polysaccharides (alginic acid or its salts, dextrin, starch, carrageenan, tamarind seed gum, guar gum, locust bean gum, gum arabic, karaya gum, chitosan, etc.); synthetic polymers (polylactic acid, polyethylene, polyethylene terephthalate, polyvinyl chloride, etc.); polyvalent metal compounds (carbonate calcium, barium sulfate, hydroxyapatite, talc, silicon dioxide, titanium oxide, etc.); higher fatty acids having 12 or more carbon atoms, their esters or salts (hardened oil, hydrogenated soybean oil, carnauba wax, white beeswax, sucrose fatty acid esters, stearic acid, stearates, etc.), surfactants (nonionic surfactants, etc.), lubricants, pH adjusters (citric acid, glycine, etc.), preservatives, antiseptics (parahydroxybenzoates, benzalkonium chloride, phenol, chlorobutanol, etc.), odorants (menthol, citrus flavor, etc.), etc. As other components, one of these components may be contained alone, or two or more may be contained in combination.

[0072] From the viewpoint of improving the efficiency of adhesion to the olfactory region, it is preferable that the composition does not contain lactose (including lactose hydrate).

[0073] [1-1-6. Formulation] The particle composition for nasal administration of the first aspect of the present invention contains particles containing component (A) and component (B), or, if necessary, component (C) and / or component (D).

[0074] The average particle size of the particles is 15 to 30 μm. From the viewpoint of further improving the ratio of the amount of adhesion to the olfactory region to the amount of adhesion to the nasal turbinate region, preferred average particle sizes of the particles are 17 to 25.5 μm, 17 to 25 μm, or 17.5 to 24.5 μm, more preferably 19.5 to 23.2 μm, or 20 to 23 μm. The average particle size is the 50% cumulative value (D 50 )

[0075] The particle size distribution width (D 90 -D 10 ) / D 50 ) is, for example, 0.8 to 1.9, 0.85 to 1.55, 0.85 to 1.4, or 0.85 to 1.3. 10 and D 90 are the 10% integrated value and the 90% integrated value, respectively, determined from the volume-based particle size distribution measured by a laser diffraction / scattering method.

[0076] The form of the particles is not particularly limited, but is preferably a spray-dried product of a liquid material containing component (A) and component (B), or further component (C) and / or component (D) as necessary.

[0077] The particle composition for nasal administration of the first aspect of the present invention can be filled into a container for nasal administration. As the container for nasal administration, a commercially available container, specifically a pressurized container for metered injection, can be used.

[0078] [1-1-7. Manufacturing method] The particle composition for nasal administration of the first aspect of the present invention can be manufactured by a known granulation method using the above-mentioned component (A) and component (B), or component (C) and / or component (D) which are further blended as necessary.

[0079] Preferably, the first particle composition for nasal administration of the present invention can be produced by spray-drying a liquid material containing the above-mentioned components (A) and (B), or further components (C), (D), and / or other components that are optionally blended.

[0080] The liquid medium used in the liquid material is not particularly limited, but examples include aqueous solutions of one or more organic solvents selected from the group consisting of ethanol, isopropanol, and methanol. The organic solvent concentration of these aqueous solutions is not particularly limited, but examples include 60 to 95% by volume, preferably 65 to 90% by volume, more preferably 68 to 87% by volume, and even more preferably 70 to 85% by volume. The solids concentration in the liquid material is not particularly limited, but examples include 1 to 7% by weight, preferably 2 to 6% by weight, more preferably 2.5 to 5.5% by weight, and even more preferably 2.5 to 4% by weight, or 2.5 to 3.5% by weight.

[0081] As for the spray drying conditions, the inlet temperature of the spray dryer is, for example, 102 to 110°C, preferably 103 to 109°C, and more preferably 104 to 108°C.

[0082] [1-1-8. Uses] The particulate composition for nasal administration of the first aspect of the present invention is used as a pharmaceutical for preventing or treating central nervous system disorders, ischemic cerebrovascular disorders, psychiatric disorders, pain, metabolic disorders, or malignant tumors.

[0083] Examples of central nervous system diseases include Alzheimer's disease (AD), tauopathy [frontotemporal lobar degeneration (FTLD) such as Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), AD, etc.], synucleinopathy [dementia with Lewy bodies (DLB), Parkinson's disease (PD), multiple system atrophy (MSA), etc.], amyotrophic lateral sclerosis, etc., and preferably Alzheimer's disease (AD), tauopathy [frontotemporal lobar degeneration (FTLD) such as Pick's disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), AD, etc.], synucleinopathy [dementia with Lewy bodies (DLB), Parkinson's disease (PD), multiple system atrophy (MSA), etc.], amyotrophic lateral sclerosis, etc.

[0084] Examples of ischemic cerebrovascular disorders include cerebral embolism, transient cerebral ischemia, subclavian steal syndrome, lateral medullary syndrome, cerebral thrombosis, lacunar infarction, reversible ischemic neurological disorder, cerebral infarction, circle of Willis occlusion, hypoxic encephalopathy, sinus venous thrombosis, and postoperative spinal cord ischemia. Preferred examples include cerebral embolism, transient cerebral ischemia, subclavian steal syndrome, lateral medullary syndrome, cerebral thrombosis, lacunar infarction, reversible ischemic neurological disorder, and cerebral infarction.

[0085] Examples of mental disorders include schizophrenia, schizoaffective disorder, bipolar disorder (mania and / or depression), depression, major depression, psychotic episode, autism, autism spectrum disorder, fragile X syndrome, and pervasive developmental disorder, and preferably include schizophrenia, schizoaffective disorder, bipolar disorder (mania and / or depression), depression, major depression, psychotic episode, autism, and autism spectrum disorder.

[0086] Examples of pain include cancer pain, pain caused by chemotherapy treatment, nerve pain, pain caused by other events (wounds, surgery, etc.) or diseases, and preferably cancer pain, pain caused by chemotherapy treatment, and nerve pain.

[0087] The metabolic disease is not particularly limited as long as it is a disease associated with abnormalities in the maintenance of brain homeostasis or a disease that may be associated with abnormalities in the maintenance of brain homeostasis, and examples include obesity, fatty liver, dyslipidemia, hypertension, coronary artery disease, hepatitis, and type 2 diabetes.

[0088] The malignant tumor is not particularly limited as long as it is a primary brain tumor, a metastatic brain tumor, or a disease that may be a metastatic brain tumor, and examples thereof include liver cancer, bone cancer, pancreatic cancer, skin cancer, oral cancer, head and neck cancer, breast cancer, lung cancer (including small cell and non-small cell lung cancer), cutaneous or intraocular malignant melanoma, kidney cancer, uterine cancer, ovarian cancer, colorectal cancer, colon cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, pediatric cancer, bladder cancer, kidney or ureter cancer, renal pelvis cancer, brain tumor, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers (including those induced by asbestos), hematologic malignancies (including multiple myeloma, lymphocytic lymphoma, B-cell lymphoma, Hodgkin's lymphoma / primary mediastinal B-cell lymphoma, non-Hodgkin's lymphoma, acute myeloid lymphoma, chronic myeloid leukemia, chronic lymphoid leukemia, follicular lymphoma, generalized large B-cell lymphoma, Burkitt's lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, mycosis fungoides, anaplastic large cell lymphoma, T-cell lymphoma, and precursor T-lymphoblastic lymphoma).

[0089] In addition, the particulate composition for nasal administration of the first aspect of the present invention can also be used as a pharmaceutical for the applications listed in the application columns of Tables 1 to 4.

[0090] The first particle composition for nasal administration of the present invention is administered to mammals, preferably humans. By nasally administering the first particle composition for nasal administration of the present invention, particles containing a pharmaceutical active ingredient adhere to the olfactory region of the nasal cavity in greater amounts than to the turbinate region. This improves delivery efficiency to the brain and suppresses side effects caused by increased transfer to the liver via systemic circulation. Preferably, the ratio of the amount of particles containing a pharmaceutical active ingredient adhering to the olfactory region relative to the amount adhering to the turbinate region of the nasal cavity is 1.5 or more, preferably 1.8 or more, more preferably 2 or more, even more preferably 2.5 or more, and even more preferably 3 or more. Furthermore, the amount of particles to be adhering to the olfactory region of the sprayed particles is, for example, 45% by weight or more, preferably 48% by weight or more, more preferably 50% by weight or more, even more preferably 52% by weight or more, and even more preferably 53% by weight or more.

[0091] The dose of the particulate composition for nasal administration of the first present invention is, for example, 20 to 600 mg / body, preferably 60 to 500 mg / body, more preferably 100 to 400 mg / body, 150 to 300 mg / body, or 200 to 270 mg / body per day in terms of the total amount of component (A). The dose of the particulate composition for nasal administration of the first present invention is, for example, 10 to 300 mg / body, preferably 30 to 250 mg / body, more preferably 50 to 200 mg / body, 80 to 150 mg / body, or 110 to 130 mg / body per day in terms of the doses of components (A1) and (A2), respectively.

[0092] [1-2. Method for Improving Efficiency of Adhesion to the Olfactory Region in the Nasal Cavity] As described above, in a composition for nasal administration, the efficiency of adhesion to the olfactory region in the nasal cavity can be improved by controlling the average particle diameter of particles comprising (A) an active pharmaceutical ingredient that targets the brain and (B) a binder to a predetermined range of 15 to 30 μm. Therefore, the first invention also provides a method for improving the efficiency of adhesion to the olfactory region in the nasal cavity of a particulate composition for nasal administration containing particles comprising (A) an active pharmaceutical ingredient that targets the brain and (B) a binder, the method comprising the step of controlling the average particle diameter of the particles to 15 to 30 μm.

[0093] The average particle size of the particles may be controlled by a known method. Preferably, as described in "1-1-7. Production method" of "1-1. Particulate composition for nasal administration" above, the liquid material to be used for spray drying may be prepared using the liquid medium described above, the liquid material may be prepared to have the solid content concentration described above, and the liquid material may be sprayed at the temperature described above (the inlet temperature of the spray dryer).

[0094] [1-3. Nasal Administration Method] The particulate composition for nasal administration described above in "1-1. Particulate Composition for Nasal Administration" can improve the efficiency of adhesion to the olfactory region in the nasal cavity by nasal administration. Therefore, the first invention also provides a nasal administration method in which a particulate composition for nasal administration containing particles comprising (A) an active pharmaceutical ingredient that targets the brain and (B) a binder, the particles having an average particle size of 15 to 30 μm, is nasally administered to a subject in need of prevention or treatment of a central nervous system disease, so that the particles adhere more to the olfactory region than to the turbinate region in the nasal cavity.

[0095] The amount of particles adhering to the olfactory region by the first nasal administration method of the present invention (specifically, the ratio of the amount of particles containing a pharmaceutical active ingredient adhering to the olfactory region to the amount adhering to the turbinate region in the nasal cavity, and the amount of particles sprayed that are allowed to adhere to the olfactory region) is as described above in "1-1-8. Uses" of "1-1. Particle composition for nasal administration."

[0096] [2] [2-1. Composition for nasal administration] The composition for nasal administration of the second invention comprises (A1) a rifamycin and (A2) a resveratrol selected from the group consisting of resveratrol, resveratrol esters, and resveratrol glucoside, and is used for applications utilizing the physiological activity of component (A2). The composition for nasal administration of the second invention can improve the bioavailability of the resveratrol.

[0097] [2-1-1. Component (A1) and Component (A2)] In the composition for nasal administration of the second invention, details of the component (A1) and the component (A2) are the same as those described in "(A1) Rifamycins" and "(A2) Resveratrols" of the particulate composition for nasal administration of the first invention, respectively.

[0098] The content of component (A2) in the composition for nasal administration of the second invention is not particularly limited, but may be, for example, 20% by weight or more, preferably 25% by weight or more, more preferably 28% by weight or more, 30% by weight or more, or 35% by weight or more. The content of component (A) is not particularly limited in its upper limit, but may be, for example, 45% by weight or less, preferably 40% by weight or less, more preferably 37% by weight or less, and even more preferably 35% by weight or less, 32% by weight or less, or 30% by weight or less.

[0099] The content of component (A1) contained in the composition for nasal administration of the second present invention is not particularly limited and may be set appropriately depending on the desired degree of improvement in bioavailability. For example, the content of component (A1) per part by weight of component (A2) is 0.2 to 1.5 parts by weight, preferably 0.4 to 1.4 parts by weight, more preferably 0.6 to 1.3 parts by weight, and even more preferably 0.8 to 1.2 parts by weight.

[0100] [2-1-2. Other Components] The composition for nasal administration of the second invention may consist of the above-mentioned component (A1) and component (A2), or may contain additives and / or bases depending on the formulation. The additives and bases that the composition for nasal administration of the second invention may contain are not particularly limited as long as they are pharmaceutically acceptable, but preferably include at least one of the binder (B) described in "1-1-2. (B) Binder" of the particulate composition for nasal administration of the first invention, the cyclodextrins (C) described in "1-1-3. (C) Cyclodextrins," the ascorbic acid (D) described in "1-1-4. (D) Ascorbic Acid," and the other components described in "1-1-5. Other Components," and more preferably include the component (B) and the component (C). Details of the component (B), the component (C), the component (D), and other components are as described above in the respective sections.

[0101] [2-1-3. Formulation] The nasal composition of the second invention can be in any formulation form as long as it is suitable for nasal administration. The nasal composition of the second invention may be, for example, either in the form of particles (powder) or a liquid, but is preferably in the form of particles (powder).

[0102] When the second composition for nasal administration of the present invention is in the form of particles (powder), the average particle size, particle size distribution width, and morphology of the particles are not particularly limited, but preferably include the average particle size, particle size distribution width, and / or morphology described in "1-1-6. Formulation form" of the particle composition for nasal administration of the first present invention above.

[0103] The composition for nasal administration of the second aspect of the present invention can be filled into a container for nasal administration. As the container for nasal administration, a commercially available container, specifically a pressurized container for metered injection, can be used.

[0104] [2-1-4. Production method] The composition for nasal administration of the second aspect of the present invention can be produced from the above-mentioned components (A1) and (A2), or further components (B), (C), (D), and / or other components, which are blended as necessary, by a known method.

[0105] When the second composition for nasal administration of the present invention is a particulate composition, it can preferably be produced by the granulation method described in "1-1-7. Production method" for the particulate composition for nasal administration of the first invention.

[0106] [2-1-5. Uses] The nasal composition of the second invention has improved bioavailability of the component (A2) compared to a composition not containing the component (A1). Therefore, the nasal composition of the second invention is used in applications that utilize the physiological activity of the component (A2). Applications that utilize the physiological activity of the component (A2) preferably exclude applications that utilize the physiological activity of the component (A1).

[0107] The applications utilizing the physiological activity of component (A2) are not particularly limited, but include SIRT1 activation and the like.

[0108] Specific examples of applications utilizing the physiological activity of component (A2) include metabolic diseases, musculoskeletal diseases, chronic obstructive pulmonary diseases, and malignant tumors.

[0109] Metabolic diseases include obesity, fatty liver, dyslipidemia, hypertension, coronary artery disease, hepatitis, and type 2 diabetes.

[0110] Examples of musculoskeletal diseases include degenerative myopathy, Paget's disease of bone (PDB), osteoarthritis, and osteoporosis, with osteoporosis being preferred.

[0111] Chronic obstructive pulmonary diseases include chronic bronchitis, emphysema, pulmonary hypertension, interstitial pulmonary fibrosis, airway inflammation, and cystic fibrosis, and preferably chronic bronchitis.

[0112] Malignant tumors include liver cancer, bone cancer, pancreatic cancer, skin cancer, oral cancer, head and neck cancer, breast cancer, lung cancer (including small cell and non-small cell lung cancer), cutaneous or intraocular malignant melanoma, kidney cancer, uterine cancer, ovarian cancer, colorectal cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, pediatric cancer, bladder cancer, kidney or ureter cancer, renal pelvis cancer, brain tumor, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell carcinoma, environmentally induced cancer (including those induced by asbestos), hematologic malignancies (including multiple myeloma, lymphocytic lymphoma, B-cell lymphoma, Hodgkin's lymphoma / primary mediastinal B-cell lymphoma, non-Hodgkin's lymphoma, acute myeloid lymphoma, chronic myeloid leukemia, chronic lymphoid leukemia, follicular lymphoma, generalized large B-cell lymphoma, Burkitt's lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, mycosis fungoides, anaplastic large cell lymphoma, T-cell lymphoma, and precursor T-lymphoblastic lymphoma).

[0113] The dose of the second composition for nasal administration of the present invention is not particularly limited, but may be, for example, 0.1 to 10 mg / kg, preferably 0.2 to 5 mg / kg, more preferably 0.3 to 1 mg / kg, and even more preferably 0.4 to 0.7 mg / kg, or 0.4 to 0.65 mg / kg per day in terms of the human dose of component (A2).

[0114] [2-2. Method for Improving the Bioavailability of Resveratrols] As described above, the bioavailability of the component (A2) in a composition for nasal administration can be improved by nasally administering the component (A1) together with the component (A2). Therefore, the second invention also provides a method for improving the bioavailability of the component (A2) in a composition for nasal administration containing a resveratrol selected from the group consisting of resveratrol, resveratrol esters, and resveratrol glucoside, which comprises blending the composition for nasal administration with the component (A2) and (A1) a rifamycin represented by the following formula (I):

[0115] In the second invention, "improving the bioavailability of the (A2) component" means improving the bioavailability compared to when the (A2) component is administered nasally alone (i.e., not together with the (A1) component). Furthermore, "improving bioavailability" means increasing the area under the blood concentration-time curve (AUC), increasing the maximum blood concentration (Cmax), and / or shortening the time to reach the maximum blood concentration (Tmax), preferably at least improving Cmax and shortening Tmax. More preferably, it means increasing AUC, improving Cmax, and shortening Tmax.

[0116] In the method for improving the bioavailability of resveratrols according to the second aspect of the present invention, details of the components (A1) and (A2), components other than the components (A1) and (A2) that may be contained in the composition for nasal administration, as well as the formulation, production method, and uses of the composition for nasal administration are as described above in "2-1. Composition for nasal administration."

[0117] The present invention will be explained in more detail below by showing examples, but the present invention is not limited to these examples.

[0118] Test Example 1 (1) Preparation of the first particulate composition for nasal administration according to the present invention The components shown in Table 6 were dissolved in the indicated liquid medium to the indicated solids concentration (wt%), and the resulting liquid material was freeze-dried using a Procept (Zelzate, BE) 4M8-TriX spray dryer equipped with a nitrogen closed loop recirculation unit (N2CL) and a Huber 050w-H chiller for solvent recovery. The aqueous solution was atomized using an ultrasonic nozzle. The inlet nitrogen flow rate was 0.60 m 3 / min, the inlet gas temperature was 104-106°C, the outlet temperature was 75-85°C, and the cyclone inlet temperature was 65-75°C. The obtained particle composition for nasal administration was cooled using a collection container (100 mL glass-Duran bottle with a PTFE-lined PBT cap).

[0119] (2) Particle characteristics of particulate compositions for nasal administration The particle sizes of the particulate compositions for nasal administration were measured using a Mastersizer 3000 laser diffraction particle size distribution analyzer manufactured by Malvern Panalytical (measurement principle: laser diffraction / scattering method). The results are shown in Table 6.

[0120] (3) Test Method A nasal administration device (Unidose Nasal Powder System, manufactured by Aptar) was filled with a particle composition for nasal administration. A Caucasian male nasal cavity model (Alberta Idealized Nasal Inlet: AINI, manufactured by Aptar) was placed on a horizontal stand, and a total of 20 mg was administered to both nostrils (two shots) per dose. The insertion depth of the device from the nostril was 5 mm, and the spray angle was 45 degrees from the horizontal plane. Each particle composition for nasal administration was tested three times.

[0121] (4) Evaluation of Adhesion Efficiency After spraying the particulate composition for nasal administration, the nasal cavity model was disassembled into its individual parts (olfactory region part, turbinate part, vestibule part, and nasopharynx part), and the particulate composition for nasal administration deposited in each of the olfactory region part and turbinate region part was recovered with a solvent. The recovered solvent was subjected to HPLC-UV to quantify the amount of adhered component (A). The amount of adhered component (A) was calculated as the relative value (%) of the quantitative value of component (A) deposited in each part, assuming the administered amount of component (A) to be 100%, and the average value obtained in each of three tests was used. The ratio of the amount of adhered component (%) in the olfactory region part to the amount of adhered component (%) in the turbinate region part was calculated as the adhesion ratio. In the case of particulate compositions for nasal administration (Examples 2-1 and 2-2) containing both the component (A1) and the component (A2) as the component (A), the adhesion amount (%) was defined as the average value of the adhesion amount (%) of the component (A1) and the adhesion amount (%) of the component (A2), and the adhesion amount ratio was defined as the average value of the adhesion amount ratio of the component (A1) and the adhesion amount ratio of the component (A2). The results are shown in Table 6.

[0122]

[0123] As shown in Table 6, the particulate compositions for nasal administration in all Examples were able to ensure that more than half of the particles sprayed into the nasal cavity adhered to the olfactory region, demonstrating excellent local delivery to the brain. Furthermore, the particulate compositions for nasal administration in all Examples also had a high ratio of the amount of particles adhering to the olfactory region relative to the amount of particles adhering to the turbinate region in the nasal cavity, demonstrating improved delivery efficiency to the brain and the ability to suppress liver damage due to transfer to the liver via the systemic circulation. Among these Examples, when comparing compositions with the same composition except for component (A), it was found that the smaller the average particle diameter (D50), the higher the amount of particles adhering to the olfactory region (i.e., better local delivery to the brain) and the higher the ratio of the amount of particles adhering to the olfactory region relative to the amount of particles adhering to the turbinate region in the nasal cavity (i.e., improved delivery efficiency to the brain and excellent performance in suppressing liver damage due to transfer to the liver via the systemic circulation).

[0124] Test Example 2 Particulate compositions for nasal administration according to the first aspect of the present invention (Examples 1-3, 2-3, 3-2) and compositions for oral administration (Comparative Examples 1, 2, 3) shown in Table 7 were prepared.

[0125] New Zealand White rabbits (4-5 months old) were administered each composition listed in Table 7 once daily for 8 days. The intranasal administration dose of 1.7 mg / kg / day to rabbits is 5 mg / body / day, which, based on brain weight (rabbit brain: 11 g, human brain: 1400 g), translates to a human dose of 127 mg / body / day for noninvasive brain delivery of the active ingredient. Brain tissue samples were collected 2-3 hours after administration on Day 8. Components (A1) and (A2) in the brain tissue were analyzed by LCMS. The brain concentrations of components (A1) and (A2) obtained were divided by the dose and converted to brain concentrations per dose (ng / g / dose). The brain concentrations of component (A1) per unit dose are shown in Figure 1, and the brain concentrations of component (A2) per unit dose are shown in Figure 2.

[0126]

[0127] As shown in Figures 1 and 2, the brain concentration per unit dose obtained by nasal administration (Examples 1-3, 2-3, and 3-2) was significantly higher than the brain concentration per unit dose obtained by oral administration (Comparative Examples 1, 2, and 3). As shown in Figure 2, particularly for resveratrol, the remarkable improvement in brain concentration per dose compared to oral administration was significantly greater. Furthermore, as shown in Figure 2, the brain concentration per dose obtained in Example 3-2 was higher than that obtained in Example 2-3. This is evidence that Example 3-2 had a smaller average particle diameter than Example 2-3, resulting in a higher amount of adhesion to the olfactory region and therefore superior local delivery to the brain.

[0128] [Test Example 3] The particulate compositions for nasal administration (Examples 1-3, 3-2, and Example 2-3 according to the second aspect of the present invention) and compositions for oral administration (Comparative Examples 1, 2, and 3) shown in Table 8 were prepared.

[0129] Each composition was administered once daily to New Zealand White rabbits (4-5 months old) for 8 days at the doses shown in Table 8. Blood samples were collected on Day 1 and Day 7, and Cmax, Tmax, and AUC were calculated. The results are shown in Table 8. Note that the intranasal administration dose of 1.7 mg / kg / day to rabbits is equivalent to a human dose of 0.63 mg / kg / day based on body surface area from the perspective of bioavailability.

[0130]

[0131] As shown in Table 8, when comparing the particulate composition for nasal administration of Example 3-2, which is a single preparation of the (A2) component, with the particulate composition for nasal administration of Example 2-3, which is a combination preparation containing the (A1) component together with the (A2) component, the particulate composition for nasal administration of Example 2-3, which is a combination preparation, showed an increase in AUC, a significant increase in Cmax, and a significant decrease in Tmax for the (A2) component, indicating that the bioavailability of the (A2) component was significantly improved.

[0132] In contrast, when the composition for oral administration of Comparative Example 3, which is a single preparation of the component (A2), is compared with the composition for oral administration of Comparative Example 2, which is a combination preparation containing the component (A1) together with the component (A2), the composition for oral administration of Comparative Example 2, which is a combination preparation, showed a decrease in AUC and Cmax for the component (A2), and also an increase in Tmax, indicating that the bioavailability of the component (A2) was actually decreased. Furthermore, when comparing the particulate composition for nasal administration of Example 1-3, which is a single preparation of component (A1), with the particulate composition for nasal administration of Example 2-3, which is a combination preparation containing component (A2) together with component (A1), in the particulate composition for nasal administration of Example 2-3, which is a combination preparation, the AUC for component (A1) increased on Day 1 but decreased on Day 7, the Cmax increased slightly on Day 1 but decreased significantly on Day 7, and the Tmax was significantly extended on both Day 1 and Day 7, and therefore a satisfactory improvement in the bioavailability of component (A1) was not observed. When the composition for oral administration of Comparative Example 1, which is a single preparation of component (A1), is compared with the composition for oral administration of Comparative Example 2, which is a combination preparation containing component (A2) together with component (A1), the AUC of component (A1) in the composition for oral administration of Comparative Example 2, which is a combination preparation, decreased on both Day 1 and Day 7, and there was no significant difference in Cmax and Tmax, and therefore no improvement in bioavailability was observed.

[0133] In other words, the significant improvement in the bioavailability of the component (A2) observed in the combined preparation of Example 2-3, compared with the single preparation of Example 3-2, was found to be the result of the component (A1) contributing to the improvement in the bioavailability of the component (A2), and was also found to be an effect unique to a nasally administered composition.

Claims

1. A particulate composition for nasal administration for non-invasively delivering component (A) to the brain, comprising particles comprising (A) a brain-targeting active pharmaceutical ingredient and (B) a binder, the particles having an average particle size of 15 to 30 μm.

2. The particulate composition for nasal administration described in claim 1, wherein the component (A) is at least one of (A1) a rifamycin represented by the following formula (I) and (A2) a resveratrol selected from the group consisting of resveratrol, resveratrol ester, and resveratrol glucoside:

3. The particle composition for nasal administration described in claim 1, wherein the component (B) is at least one of (B1) a cellulose-based binder in which at least a portion of the hydrogen atoms constituting the hydroxyl groups of cellulose are substituted with a substituent selected from the group consisting of an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, and an alkylcarbonyl group, and (B1) a vinyl-based binder selected from the group consisting of polyvinylpyrrolidone and polyvinyl alcohol.

4. The particulate composition for nasal administration described in claim 1, wherein component (B) is (B1) a cellulose-based binder in which at least a portion of the hydrogen atoms constituting the hydroxyl groups of cellulose are substituted with a substituent selected from the group consisting of alkyl groups, hydroxyalkyl groups, alkoxyalkyl groups, and alkylcarbonyl groups.

5. The particulate composition for nasal administration described in claim 1, further comprising (C) a cyclodextrin selected from the group consisting of cyclodextrin and cyclodextrin derivatives in which at least a portion of the hydrogen atoms constituting the hydroxyl groups of the cyclodextrin are substituted with alkyl groups and / or hydroxyalkyl groups.

6. The particulate composition for nasal administration according to claim 1, further comprising (D) ascorbic acid.

7. A particulate composition for nasal administration according to claim 1, wherein the content of component (A) is 40 to 90% by weight.

8. A particulate composition for nasal administration according to claim 1, wherein the content of component (B) is 0.1 to 0.8 parts by weight per part by weight of component (A).

9. A particulate composition for nasal administration according to claim 1, wherein the content of component (C) is 0.05 to 0.3 parts by weight per part by weight of component (A).

10. A particulate composition for nasal administration according to claim 1, wherein the particles are a spray-dried product of a liquid material containing the component (A) and the component (B).

11. A particle composition for nasal administration as described in claim 1, which, upon nasal administration, causes the particles to adhere more to the olfactory region of the nasal cavity than to the turbinate region.

12. A particle composition for nasal administration as described in claim 1, which is intended to ensure that 45% by weight or more of the particles sprayed into the nasal cavity adhere to the olfactory region when administered nasally.

13. A method for improving the adhesion efficiency of a particulate composition for nasal administration, which contains particles comprising (A) a brain-targeting active pharmaceutical ingredient and (B) a binder, and which non-invasively delivers said ingredient (A) to the brain, to the olfactory region in the nasal cavity, the method comprising the step of controlling the average particle size of the particles to be 15 to 30 μm.

14. The method of claim 13, wherein the step comprises spray drying a liquid material comprising the (A) component and the (B) component, the liquid material containing 1 to 7% by weight of solids in an aqueous solution of ethanol, isopropanol, and / or methanol.

15. A composition for nasal administration comprising (A1) a rifamycin compound represented by the following formula (I) and (A2) a resveratrol compound selected from the group consisting of resveratrol, resveratrol esters, and resveratrol glucoside, and used for applications utilizing the physiological activity of the (A2) component.

16. The composition for nasal administration according to claim 15, which is a particulate composition.

17. A method for improving the bioavailability of (A2) a resveratrol selected from the group consisting of resveratrol, resveratrol esters, and resveratrol glucoside in a composition for nasal administration, comprising blending (A1) a rifamycin represented by the following formula (I) together with (A2) the composition for nasal administration.

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