JP6908523B2 - Composition for nebulizer - Google Patents

Description

The present invention relates to a nebulizer composition for treating or preventing an influenza virus infection, which comprises a neuraminidase inhibitory activity of laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof as an active ingredient.

Laninamivir octanoate hydrate exhibits excellent neuraminidase inhibitory activity, is administered to the recipient's respiratory tract, and is retained in the recipient's respiratory tract tissues (upper respiratory tract, lungs, etc.) to cause influenza virus infection. (Patent Documents 1 to 3).

Since laninamivir octanoic acid ester hydrate exhibits an anti-influenza effect by staying in the respiratory tissue of the recipient, laninamivir octanoic acid ester hydrate reaches the respiratory tissue by a parenteral route. Dosage method and dosage form are required. Therefore, a dry powder inhalation preparation is disclosed as a dosage form in which laninamivir octanoic acid ester hydrate is administered by a parenteral route (Patent Document 4).

In the dry powder inhalation preparation, specifically, the powder formulation for inhalation is stored in a container such as a capsule, a blister, a reservoir in a device or a dosing disk, and a single dose of powder is inhaled by the recipient himself / herself. Inhale from the device. However, people with spontaneous breathing difficulties, such as children, the elderly, and patients with impaired respiratory function, may not be able to handle dry powder inhalation preparations properly, and it may be difficult to inhale a sufficient amount of the drug. In addition, it may be difficult for a person with spontaneous dyspnea to secure a sufficient amount of inspiration. For such persons with spontaneous breathing difficulties, it is desired to develop a suitable administration method and dosage form in order to allow a sufficient amount of the drug to reach the respiratory tissue in a stable manner.

In the field of otolaryngology, a nebulizer administration method is known as an administration method that can be reliably inhaled even in children. Also, in the treatment of respiratory diseases such as bronchial asthma and cystic fibrosis, administration by a nebulizer is performed as an administration method that can be reliably inhaled even by children and persons with spontaneous breathing difficulties. Thus, although nebulizers have been widely used in patients, including children, the elderly and those with dyspnea, no composition for nebulizers for influenza virus infections has ever been put on the market. ..

As anti-influenza drugs, especially neurominidase inhibitors, oseltamivir phosphate (trade name Tamiflu, Patent Document 5), Zanamivir hydrate (trade name Relenza, Patent Document 6) and peramivir hydrate (trade name Rapiacta, Patent Document 7). ) Is commercially available.

Tamiflu is an orally administered preparation and is commercially available as a capsule or a dry syrup preparation. Rapiacta is an injection for intravenous drip infusion. Since the route of administration of these drugs is not inhalation, it is not possible to select a nebulizer as the means of administration.

Zanamivir (trade name: Relenza) is an inhalation preparation that requires continuous administration for multiple days. For most patients who do not have a nebulizer, administering Relenza with a nebulizer is burdensome because it requires a visit to the hospital each time it is administered.

It is desired to develop a nebulizer preparation for a nomiraminidase inhibitor that can complete the treatment with as few doses as possible.

Japanese Patent No. 3209946 (US Pat. No. 6,340,702, European Patent No. 823428) Japanese Patent No. 3920041 (US Pat. No. 6,844,363, European Patent No. 12777750) Japanese Patent No. 4205314 (International Publication No. 2001/080892 Pamphlet) Japanese Patent No. 5697199 (Pamphlet of International Publication No. 2010/074113) International Publication No. 96/26933 Pamphlet International Publication No. 91/16320 Pamphlet Japanese Patent No. 4102022 (US Pat. No. 6,503,745, European Patent No. 1040094)

We have been diligently studying drugs for treating / preventing influenza virus infections for many years. As a result, laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof is used as an active ingredient, and the recipient's respiratory tissue (upper respiratory tract, lung, etc.) is selected by appropriately selecting the composition and adjusting the particle size. ) Can be efficiently reached (that is, it has excellent respiratory reachability), and it can be used as an inhalation solution for nebulizers, which has low irritation during inhalation and excellent physical stability. The heading, the present invention was completed.

The present invention
[1] A nebulizer composition containing laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further containing a dispersant and an osmotic pressure regulator.
[2] The nebulizer composition according to the above [1], which contains 1 to 20% by weight of laninamivir octanoic acid ester hydrate.
[3] The nebulizer composition according to the above [1] or [2], which contains 3 to 10% by weight of laninamivir octanoic acid ester hydrate.
[4] The particle size of 50% by weight in the laser diffraction / scattering type particle size distribution measurement method of laninamivir octanoic acid ester hydrate is 5.0 μm or less, and 90% by weight in the laser diffraction / scattering type particle size distribution measurement method. The composition for nebulizer according to any one of the above [1] to [3], wherein the particle size of the above is 12.0 μm or less.
[5] The particle size of 50% by weight in the laser diffraction / scattering type particle size distribution measurement method of laninamivir octanoic acid ester hydrate is 3.2 μm or less, and 90% by weight in the laser diffraction / scattering type particle size distribution measurement method. The composition for nebulizer according to any one of the above [1] to [3], wherein the particle size of the above is 8.0 μm or less.
[6] The dispersant is one or a combination of two selected from the group consisting of polysorbate, sorbitan monolaurate, tyroxapole, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa). The nebulizer composition according to any one of [1] to [5].
[7] The nebulizer composition according to any one of [1] to [5] above, wherein the dispersant is tyroxapole.
[8] The nebulizer composition according to [7] above, wherein the content of tyroxapol is 0.01 to 1% by weight.
[9] The nebulizer composition according to [7] above, wherein the content of tyroxapol is 0.05 to 0.5% by weight.
[10] The composition for a nebulizer according to any one of [1] to [5] above, wherein the dispersant is polyoxyethylene sorbitan monolaurate and sorbitan monolaurate.
[11] In the above [10], the content of polyoxyethylene sorbitan monolaurate is 0.01 to 0.5% by weight, and the content of sorbitan monolaurate is 0.01 to 0.5% by weight. The nebulizer composition described,
[12] In the above [12], the content of polyoxyethylene sorbitan monolaurate is 0.038 to 0.2% by weight, and the content of sorbitan monolaurate is 0.1 to 0.2% by weight. The nebulizer composition described,
[13] The nebulizer composition according to any one of [1] to [12] above, wherein the osmotic pressure regulator is sodium chloride or lactose hydrate.
[14] The nebulizer composition according to any one of [1] to [12] above, wherein the osmotic pressure regulator is sodium chloride.
[15] The nebulizer composition according to any one of [13] or [14] above, wherein the content of sodium chloride is 0.45 to 1.8% by weight.
[16] The nebulizer composition according to the above [13], wherein the content of lactose hydrate is 5 to 10% by weight.
[17] A lyophilized preparation containing laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof as an active ingredient and further containing a dispersant.
[18] The dispersant is one or a combination of two selected from the group consisting of polysorbate, sorbitan monolaurate, tyroxapole, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa). The lyophilized preparation according to the above [17].
[19] The lyophilized preparation according to the above [17], wherein the dispersant is tyrosapol.
[20] The lyophilized preparation according to any one of [17] to [19], which further contains an osmotic pressure regulator.
[21] The content of laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof is 55 to 95% by weight, the content of the dispersant is 1 to 10% by weight, and the osmoregulator The lyophilized preparation according to the above [20], which has a content of 4 to 35% by weight.
[22] A lyophilized preparation consisting of laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof and tyroxapol.
[23] The content of laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof is 93.0 to 98.5% by weight, and the content of tyroxapole is 1.5 to 7.0% by weight. The lyophilized preparation according to the above [22].
[24] A method of spraying and inhaling the nebulizer composition according to any one of the above [1] to [16] using a nebulizer [25] Any one of the above [17] to [23]. A method in which the lyophilized preparation described in the section is dispersed in a suspension solution to form an inhalation solution, and then sprayed and inhaled using a nebulizer.
[26] A prophylactic or therapeutic agent for influenza virus infection, which comprises the composition for a nebulizer according to any one of the above [1] to [16].
[27] A prophylactic or therapeutic agent for influenza virus infection, which comprises an inhalation solution prepared by dispersing the lyophilized preparation according to any one of [17] to [23] in a suspension solution.
[28] The active ingredient contains laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof, and the dose of the active ingredient is 40 to 320 mg in terms of anhydride per administration. The nebulizer composition according to any one of the above [1] to [16].
[29] The active ingredient contains laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof, and the dose of the active ingredient is 80 mg in terms of anhydride per administration. The nebulizer composition according to any one of [1] to [16].
[30] A laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof is contained as an active ingredient, and the dose of the active ingredient is 160 mg in terms of anhydride per administration. The nebulizer composition according to any one of [1] to [16].
[31] The nebulizer composition according to any one of the above [1] to [16] and the above [28] to [30] is applied to a human respiratory organ before the onset of influenza virus. A method of preventing influenza virus infection by spraying and inhaling using.
[32] The nebulizer composition according to any one of the above [1] to [16] and the above [28] to [30] is applied to the human respiratory tract at the onset of influenza virus. How to treat influenza infection by spraying and inhaling with
[33] The lyophilized preparation according to any one of [17] to [23] is dispersed in a suspension solution to prepare an inhalation solution, and a nebulizer is applied to the human respiratory organs before the onset of influenza virus. How to prevent influenza virus infection by spraying and inhaling with
as well as,
[34] The lyophilized preparation according to any one of [17] to [23] is dispersed with a suspension solution to prepare an inhalation solution, and a nebulizer is applied to the human respiratory tract at the onset of influenza virus. It is a treatment method for influenza virus infection by spraying and inhaling using.

The active ingredient of the nebulizer composition of the present invention is laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof. Laninamivir octanoic acid ester hydrate has the following formulas (I) and (II):

Indicated by
(I): (2R, 3R, 4S) -3-acetamido-4-guanidino-2-[(1R, 2R) -2-hydroxy-1-methoxy-3- (octanoyloxy) propyl] -3,4 -Dihydro-2H-pyran-6-carboxylic acid monohydrate,
(II): (2R, 3R, 4S) -3-acetamide-4-guanidino-2-[(1S, 2R) -3-hydroxy-1-methoxy-2- (octanoyloxy) propyl] -3,4 A mixture of -dihydro-2H-pyran-6-carboxylic acid monohydrate.

Since the laninamivir octanoic acid ester hydrate represented by the above formulas (I) and (II) has a guanidino group and a carboxyl group in the molecule, it is pharmacologically bound to an acid or base which is not pharmacologically toxic. Above, an acceptable salt can be formed. "The pharmacologically acceptable salt" of laninamivir octanoic acid ester hydrate means such a salt.

"Pharmically acceptable salts" include, for example, hydrohalogenates such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrates, perchlorates, etc. Inorganic acid salts such as sulfates and phosphates; alkane sulfonates such as methane sulfonates, ethane sulfonates and trifluoromethane sulfonates; benzene sulfonates, p-toluene sulfonates and the like. Arylsulfonates; organic acid salts such as acetates, trifluoroacetates, citrates, tartrates, oxalates, maleates; glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, asparagines Amino acid salts such as acid salts; alkali metal salts such as lithium salt, sodium salt, potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt; aluminum salt, iron salt, zinc salt, copper salt, nickel Metal salts such as salts, cobalt salts; ammonium salts, t-octylamine salts, dibenzylamine salts, morpholinic salts, glucosamine salts, ethylenediamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, procaine salts, ethanol Organic amines such as amine salts, diethanolamine salts, piperazine salts, tetramethylammonium salts, organic ammonium salts and the like can be mentioned, preferably alkali metal salts such as lithium salts, sodium salts and potassium salts; acetates, Organic acid salts such as trifluoroacetate; or inorganic acid salts such as hydrochlorides and sulfates.

Laninamivir octanoic acid ester hydrate and its pharmacologically acceptable salt may absorb water by being left in the air or mixed with water to form a hydrate. Laninamivir octanoic acid ester hydrate and its pharmacologically acceptable salt hydrate refer to such hydrates.

Laninamivir octanoic acid ester hydrates and their pharmacologically acceptable salts have an asymmetric carbon in the molecule and have stereoisomers (including enantiomers and diastereomers). These steric isomers and mixtures thereof (including racemics) in any proportion thereof are included in the active ingredient of the present invention, laninamivir octanoic acid ester hydrate and pharmaceutically acceptable salts thereof.

(2R, 3R, 4S) -3-acetamide-4-guanidino-2-[(1R, 2R) -2-hydroxy-1-methoxy-3- (octanoyloxy) propyl represented by the above formula (I)) ] -3,4-dihydro-2H-pyran-6-carboxylic acid monohydrate, when administered to warm-blooded animals, the acyloxy group at the 3-position of the side chain becomes a hydroxyl group by a metabolic reaction such as hydrolysis. Converted and produced compound (III):

Is known to exhibit pharmacological activity (Patent Document 1 etc.). Further, it is represented by the above formula (II) (2R, 3R, 4S) -3-acetamide-4-guanidino-2-[(1S, 2R) -3-hydroxy-1-methoxy-2- (octanoyloxy). ) Propyl] -3,4-dihydro-2H-pyran-6-carboxylic acid When monohydrate is administered to warm-blooded animals, the acyloxy group at the 2-position of the side chain is a hydroxyl group due to a metabolic reaction such as hydrolysis. Is converted to, and compound (III) is produced in the same manner. In the body of a warm-blooded animal, both compound (I) and compound (II) are converted to the same compound (III), which is an active metabolite.

The particle size of the laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof contained in the composition for nebulizer of the present invention is preferably 50% by weight in the laser diffraction scattering type particle size distribution measurement method. The diameter is 5.0 μm or less, and the particle size of 90% by weight in the laser diffraction / scattering type particle size distribution measurement method is 12.0 μm or less, more preferably 50% by weight in the laser diffraction / scattering type particle size distribution measurement method. The particle size of 90% by weight in the laser diffraction / scattering type particle size distribution measurement method is 8.0 μm or less.

Within this range, the active ingredient of the present invention is particularly inhalable, has high respiratory reach and can pass through the pharynx to the deep lungs, resulting in high and long-term anti-influenza. Exhibits activity.

The composition for nebulizer of the present invention is an inhalation solution for nebulizer containing a dispersant and an osmotic pressure regulator in addition to the above active ingredients.

In the present invention, the dispersant is a compound added in the composition for a nebulizer in order to uniformly disperse the contained compound, particularly the active ingredient, in the liquid. As the dispersant, a surfactant or an emulsifier can be used.

More specifically, as the dispersant, for example, polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan tristearate (Tween 65), or One selected from the group consisting of polysolvate of polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monolaurate (span 20), tyroxapol, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa). An example is a combination of the two types.

Of these, polyoxyethylene sorbitan monolaurate (Tween 20), sorbitan monolaurate (span 20), tyroxapol, and hydroxypropylmethyl cellulose (HPMC) are preferred. Polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) can also be used in combination.

Of these, more preferred is tyroxapol, or a combination of two types, polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20).

Of these, tyroxapol is even more preferred.

The nebulizer composition of the present invention contains an osmotic pressure regulator.

In the present invention, the osmotic pressure regulator is a compound added for adjusting the osmotic pressure of the composition for nebulizer of the present invention, and by selecting a compound used as the osmotic pressure regulator, the nebulizer of the present invention is used. The osmotic pressure of the composition for use can be made equal to the osmotic pressure of body fluids, specifically, body fluids in the oral cavity and respiratory tissues (upper airway, lungs, etc.). By making the nebulizer composition of the present invention isotonic with body fluid, the irritation of the nebulizer composition of the present invention at the time of inhalation can be reduced, and the active ingredient of the present invention capable of reaching the respiratory tissue. The amount (amount of fine particles, FPD) can be increased.

Examples of the osmotic pressure regulator include sodium chloride or lactose hydrate.

Of these, sodium chloride is preferred. Physiological saline can be used as the aqueous solution of sodium chloride.

The volume of the composition for nebulizer of the present invention per inhalation with a nebulizer is preferably 2 to 8 ml, particularly preferably 2 ml.

In the composition for a nebulizer of the present invention, the content of the active ingredient is preferably 1 to 20% by weight, more preferably 3 to 10% by weight. Within this range, a sufficient amount of the active ingredient can be supplied to the respiratory tissues (upper respiratory tract, lungs, etc.) of the recipient who inhaled the nebulizer composition of the present invention.

In the composition for a nebulizer of the present invention, the content of the dispersant varies depending on the compound used. For example, when tyroxapole is used, the content is preferably 0.01 to 1% by weight, more preferably. , 0.05 to 0.5% by weight.

When hydroxypropylmethylcellulose (HPMC) is used as the dispersant, the content is preferably 0.1 to 1% by weight.

When polyoxyethylene sorbitan monolaurate (Tween 20) is used as the dispersant, the content is 0.1 to 0.5% by weight, preferably 0.138 to 0.4% by weight.

When sorbitan monolaurate (span 20) is used as the dispersant, the content is 0.1 to 0.5% by weight, preferably 0.138 to 0.4% by weight.

As the dispersant, polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) may be used in combination. When polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) are used together, the content is preferably 0.038 to polyoxyethylene sorbitan monolaurate (Tween 20). 0.2% by weight, sorbitan monolaurate (span 20) is 0.1 to 0.2% by weight.

This is because the active ingredient exhibits excellent dispersibility in the nebulizer composition of the present invention within this range.

In the composition for nebulizer of the present invention, the content of the osmotic pressure regulator varies depending on the compound used. For example, when sodium chloride is used as the osmotic pressure regulator, sodium chloride is preferably 0.45 to 1.8% by weight in the nebulizer composition of the present invention, and when lactose hydrate is used, the amount of sodium chloride is preferably 0.45 to 1.8% by weight. The lactose hydrate is preferably 5 to 10% by weight.

The lyophilized preparation of the present invention contains laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further contains a dispersant or an osmoregulator. By dispersing the lyophilized preparation of the present invention with a suspension liquid, the composition for a nebulizer of the present invention can be obtained.

The dispersant contained in the lyophilized preparation of the present invention is the same as the dispersant contained in the composition for nebulizer of the present invention.

The osmotic pressure regulator that can be contained in the lyophilized preparation of the present invention is also the same as the osmotic pressure regulator contained in the composition for nebulizer of the present invention.

When the lyophilized preparation of the present invention contains an active ingredient, a dispersant, and an osmotic pressure regulator, the content of the active ingredient contained in the lyophilized preparation is 55 to 95% by weight, and the dispersant is contained. The rate is 1.0 to 10.0% by weight, and the content of the osmotic pressure regulator is 4 to 35% by weight.

In the freeze-dried preparation of the present invention, two kinds can be used in combination as a dispersant. For example, when polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) are used in combination as a dispersant and sodium chloride is used as an osmotic pressure regulator, it is effective contained in a lyophilized preparation. The content of the components is 60 to 90% by weight, the content of polyoxyethylene sorbitan monolaurate (Tween 20) is 0.5 to 5.0% by weight, and the content of sorbitan monolaurate (span 20) is The ratio is preferably 1.5 to 5.0% by weight, and the content of sodium chloride is preferably 8.0 to 30% by weight.

The lyophilized preparation of the present invention may contain only the active ingredient and the dispersant tyroxapol. In such a lyophilized preparation, the content of the active ingredient contained in the lyophilized preparation is 93.0 to 98.5% by weight, and the content of the dispersant is 1.5 to 7.0% by weight. be.

The nebulizer composition of the present invention prepared from the lyophilized preparation of the present invention is administered to a recipient using a nebulizer, preferably a jet nebulizer (also referred to as a compressor nebulizer).

Since the composition for a nebulizer of the present invention has excellent dispersibility of the active ingredient in the composition, it can be accepted even by recipients who have difficulty in spontaneous breathing, such as children, elderly people, and persons with impaired respiratory function. The active ingredient can efficiently reach a person's respiratory tissues (upper respiratory tract, lungs, etc.).

In the nebulizer compositions of the present invention in which the active ingredient has a specific particle size distribution, the active ingredient can reach the recipient's respiratory tissue, especially the upper airway and lungs, and thus has a high and long-term anti-virus. Influenza activity is maintained.

Since the composition for a nebulizer of the present invention is an isotonic solution when administered to a recipient, irritation to respiratory tissues is reduced.

So far, there is no known lyophilized preparation of the inhalation solution. The lyophilized preparation of the present invention is excellent in physical stability, and the composition for nebulizer of the present invention prepared by using the lyophilized preparation stored at normal temperature and pressure for 6 months or more exhibits excellent sprayability. ..

The laninamivir octanoic acid ester hydrate, which is the active ingredient of the composition for nebulizer of the present invention, or a pharmacologically acceptable salt thereof is described in International Publication No. 2008/126943 or International Publication No. 2013/0891668. It can be manufactured according to the method disclosed in the pamphlet or a method equivalent thereto.

As described above, the active ingredient of the composition for nebulizer of the present invention has a particle size of 50% by weight of the active ingredient measured by a laser diffraction / scattering particle size distribution measurement method of 5.0 μm or less and a laser diffraction / scattering particle size. The particle size of the active ingredient of 90% by weight according to the distribution measurement method is preferably 12.0 μm or less. Further, the particle size of the active component of 50% by weight by the laser diffraction / scattering type particle size distribution measurement method is 3.2 μm or less, and the particle size of the active component of 90% by weight by the laser diffraction / scattering type particle size distribution measurement method is 8. More preferably, it is 0.0 μm or less. The laninamivir octanoic acid ester hydrate having such a particle size, or a pharmacologically acceptable salt thereof, is a method disclosed in International Publication No. 2008/126943 or International Publication No. 2013/089168. Alternatively, it can be manufactured according to a method similar thereto.

The lyophilized preparation of the present invention can be produced by the method described below.

The active ingredient produced with a predetermined particle size by the method disclosed in the above-mentioned international publication or a method similar thereto is atomized by a dry pulverization method such as a jet mill. Then, the finely divided active ingredient is combined with the solution obtained by dissolving the dispersant and the osmotic pressure regulator, and the fine particles of the active ingredient are separated by a homogenizer such as Hiscotron or a high-pressure homogenizer such as Emulsiflex or Microfluidizer. The mixture is dispersed, and then the obtained mixed solution is filled in a container and freeze-dried to obtain a freeze-dried preparation.

Alternatively, the finely divided active ingredient and the dispersant dissolved in purified water are combined, and the fine particles of the active ingredient are dispersed by a homogenizer such as Hiscotron or a high-pressure homogenizer such as Emalciflex or Microfluidizer. Then, the obtained suspension is filled in a container and freeze-dried to prepare a freeze-dry preparation.

This method is a production method used when only the active ingredient and the dispersant are contained in the lyophilized preparation.

The lyophilized preparation of the present invention produced in this manner is prepared as a nebulizer composition by adding a suspension liquid to a sealed container and dispersing it.

When the lyophilized preparation contains an active ingredient, a dispersant, and an osmotic pressure regulator, purified water is preferable as the suspension solution.

When the lyophilized preparation contains only the active ingredient and the dispersant, an aqueous solution of the osmoregulator is used as the suspension liquid. Specific examples include an aqueous solution of sodium chloride or a physiological saline solution.

The composition for a nebulizer of the present invention produced in this manner is a suspension-like aqueous liquid preparation.

The nebulizer composition of the present invention produced in this manner is administered to a recipient using a nebulizer, preferably a jet nebulizer (also referred to as a compressor nebulizer).

The dose of the composition for a nebulizer of the present invention is preferably 40 to 320 mg, more preferably 80 to 160 mg, and particularly preferably 160 mg per administration of laninamivir octanoic acid ester in terms of anhydride.

Specifically, the dose of the composition for a nebulizer of the present invention is, for example, 80 mg, 160 mg, 240 mg, 320 mg, preferably 80 mg, per administration of laninamivir octanoic acid ester in terms of anhydride. , 160 mg, particularly preferably 160 mg.

When the composition for nebulizer of the present invention is administered as a preventive agent for influenza virus infection, it is intermittently administered to human respiratory tissue before the onset of influenza virus infection. Inhale the above doses per dose. The dosing interval is, for example, 5 to 10 days, or 1 week.

Here, "before the onset" means a state in which no influenza symptom is observed regardless of the presence or absence of virus infection.

In actual medical practice, prophylactic administration may be performed before the onset of influenza symptoms, regardless of whether or not the patient is infected with the influenza virus. The time of administration of the prophylactic agent of the present invention includes administration before the onset of infection, regardless of the presence or absence of infection.

When the nebulizer composition of the present invention is administered as a therapeutic agent for influenza virus infection, the above-mentioned dose is inhaled into the human respiratory tissue at the onset of influenza virus infection by a single administration.

At the time of onset means that the influenza virus is infected and subjective symptoms such as fever are observed.

A nebulizer, which is an inhalation device, is required for administration of the inhalation solution, and even a recipient who does not have such a device can repeat the administration of the nebulizer composition of the present invention in one dose. There is no need to go to the hospital, and the burden of visiting the recipient is small. Of the neuraminidase inhibitors currently on the market, only laninamivir octanoate hydrate can be combined with a nebulizer as a product because the treatment is completed with a single dose.

Examples and test examples are shown below, and the present invention will be described in more detail.
(Examples 1 to 3) Production of Nebulizer Composition Crystals of laninamivir octanoic acid ester hydrate (hereinafter referred to as an active ingredient) produced according to the production method described in International Publication No. 2008/126943. The pulverized product was pulverized by a jet mill method (supersonic jet crusher (model PJM-100SP), Nippon Pneumatic Industries, Ltd.) to obtain a pulverized product having a particle size distribution shown in Table 1.

Next, a predetermined amount of hydroxypropylmethyl cellulose as a dispersant, lactose hydrate or sodium chloride dissolved in purified water as an osmoregulator, and a predetermined amount of the active ingredient are combined with a homogenizer (Hiscotron (model: model::). NS-50), Nihon Medical Science Instruments Mfg. Co., Ltd.), and then a high-pressure homogenizer (microfluidizer (model: M-110EH), Paulec Co., Ltd.) to disperse, and Examples 1 to 3 A suspension composition was obtained. The obtained composition is shown in Table 2.

＊１：有効成分の無水物としての重量を表す

* 1: Represents the weight of the active ingredient as an anhydride

(Examples 4 and 5) Production of composition for nebulizer A predetermined amount of polyoxyethylene sorbitan monolaurate (Tween 20), sorbitan monolaurate (span 20) and sodium chloride were dissolved in purified water as a dispersant. Pre-dispersed with a homogenizer (Hiscotron) (NS-50, Nihon Medical Science Instruments Mfg. Co., Ltd.) and then dispersed with a microfluidizer (M-110EH, Paulec Co., Ltd.) together with a fixed amount of crushed active ingredient. Then, the suspension-like compositions of Examples 4 and 5 were obtained. The obtained composition is shown in Table 3.

＊１：有効成分の無水物としての重量を表す

* 1: Represents the weight of the active ingredient as an anhydride

(Comparative Example 1) Composition in which Inavir (trade name) inhalation powder is dispersed in purified water 20 mg of commercially available Inavir (trade name) inhalation powder is laninamivir octanoate hydrate and lactose hydrate. It is a composition consisting of. 400 mg of this powder was taken and dispersed in 8 mL of purified water to obtain the composition of Comparative Example 1. The obtained composition is shown in Table 4. In 400 mg of this powder, 80 mg of laninamivir octanoic acid ester hydrate is contained as an anhydride.

＊１：有効成分を無水物として８０ｍｇ含む

* 1: Contains 80 mg of the active ingredient as an anhydride

(Comparative Examples 2 to 3) Composition of Dispersant Only Polyoxyethylene sorbitan monooleate (Tween 80) and / or sodium carboxymethyl cellulose (CMCNa) as a dispersant is dissolved in purified water, and a predetermined amount of pulverized active ingredient is used. Pre-dispersed with a homogenizer (Hiscotron (model: NS-50), Nichion Medical Science Instruments Mfg. Co., Ltd.), and then with a high-pressure homogenizer (microfluidizer (model: M-110EH), Paulec Co., Ltd.). It was dispersed to obtain a suspension-like composition. The obtained composition is shown in Table 5.

＊１：有効成分の無水物としての重量を表す

* 1: Represents the weight of the active ingredient as an anhydride

(Examples 6 and 7) Production of composition for nebulizer and lyophilized preparation A predetermined amount of tyroxapol as a dispersant is mixed with a predetermined amount of sodium chloride dissolved in purified water as an osmoregulator, and a predetermined amount is added. Pre-dispersed with a stirrer (MAZELA Z (model: Z-1100), EYELA) together with the crushed active ingredient, and then dispersed with a high-pressure homogenizer (microfluidizer (model: H-110EH), Paulec Co., Ltd.). , A suspension composition of Example 6 was obtained. Moreover, the obtained composition was freeze-dried using a freeze-dryer (Triomaster II A-04, Kyowa vacuum) to obtain the freeze-dried preparation of Example 7. The composition of the obtained pharmaceutical product is shown in Table 6.

＊１：有効成分の無水物としての重量を表す
＊２：工程中に除去される

* 1: Represents the weight of the active ingredient as an anhydride * 2: Removed during the process

(Examples 8 to 14) Production of lyophilized preparation for nebulizer A predetermined amount of tyroxapol as a dispersant is dissolved in purified water, combined with a predetermined amount of crushed active ingredient, and a stirrer (MAZELA Z (model: Z-1100)). , EYELA), then dispersed with a high-pressure homogenizer (pressure homogenizer (model: LAB1000), SMT Co., Ltd.), and the resulting mixture is lyophilized using a freeze-dryer (Triomaster IIA-04, Kyowa Vacuum). The lyophilized preparations of Examples 8 to 14 were obtained by lyophilization. The composition of the obtained lyophilized preparation is shown in Table 7.

＊１：有効成分の無水物としての重量を表す
＊２：工程中に除去される

* 1: Represents the weight of the active ingredient as an anhydride * 2: Removed during the process

(Examples 15 to 22) Preparation of composition for nebulizer Purified water was added to the lyophilized preparation obtained in Example 7, and physiological saline was added to the lyophilized preparation obtained in Examples 8 to 14 to disperse the mixture. The nebulizer compositions of Examples 15 to 22 were obtained. The obtained composition is shown in Table 8.

(Examples 23 to 25) Preparation of composition having different active ingredient content Of the lyophilized preparation of Example 9 dispersed in 4 mL of physiological saline, 2 mL was injected into a nebulizer to prepare a preparation containing 40 mg of the active ingredient. The lyophilized preparations of Example 23 and Example 9 were dispersed in 1 mL of physiological saline, and two of them were injected into a nebulizer. An inhalation solution for a nebulizer was obtained as Example 25, in which four pharmaceuticals dispersed in 5 mL were injected into a nebulizer. The amount of the active ingredient indicates the weight as an anhydride. The obtained composition is shown in Table 9.

＊１：有効成分を無水物として８０ｍｇ含む
＊２：有効成分の無水物としての重量を表す

* 1: Contains 80 mg of the active ingredient as an anhydride * 2: Represents the weight of the active ingredient as an anhydride.

(Examples 26 to 28) Production of freeze-dried preparation for nebulizer A predetermined amount of tyroxapol as a dispersant is dissolved in purified water, and a jet mill method (supersonic jet crusher (model PJM-100SP)), Nippon Pneumatic Industries Co., Ltd. ), Combined with the prescribed amount of active ingredient, pre-dispersed with a stirrer (seal mixer (model: RC-60G5-2S), Magneo Giken), and then high-pressure homogenizer (pressure homogenizer (model: R5-10.38)). , SMT Co., Ltd.), and the obtained mixture was freeze-dried using a freeze-dryer (freeze-vacuum dryer (model DFB3055-2BS-ST / CIP), ULVAC Co., Ltd.), and Examples 26 to 28 The lyophilized preparation of was obtained. The composition of the obtained lyophilized preparation is shown in Table 10.

＊１：有効成分の無水物としての重量を示す。
＊２：工程中に除去される

* 1: Indicates the weight of the active ingredient as an anhydride.
* 2: Removed during the process

(Examples 29 to 35) Preparation of compositions having different active ingredient contents Of the lyophilized preparation of Example 26 dispersed in 4 mL of physiological saline, 2 mL is injected into a nebulizer, and a nebulizer composition containing 40 mg of the active ingredient. The lyophilized preparation of Example 29 and Example 26 was dispersed in 2 mL of physiological saline and injected into a nebulizer to prepare a nebulizer composition containing 80 mg of the active ingredient.
The lyophilized preparation of Example 26 dispersed in 1 mL of physiological saline was injected into a nebulizer to prepare a composition for a nebulizer containing 160 mg of the active ingredient. The lyophilized preparation of Example 32 and Example 26 was prepared by injecting three pharmaceuticals dispersed in 1 mL of physiological saline into a nebulizer to prepare a composition for a nebulizer containing 240 mg of the active ingredient, and 1 mL of physiological saline was used as the lyophilized preparation. A nebulizer composition containing 320 mg of the active ingredient was prepared by injecting four of them dispersed in (1) into a nebulizer. The composition for a nebulizer containing 80 mg of the active ingredient was injected into the nebulizer. The composition was designated as Example 35. The amount of the active ingredient indicates the weight as an anhydride. The obtained composition is shown in Table 11.

＊１：１バイアル中の有効成分の無水物としての重量を表す
＊２：有効成分の無水物としての重量を表す

* 1: Represents the weight of the active ingredient as an anhydride in a vial * 2: Represents the weight of the active ingredient as an anhydride

(Test method) Respiratory reachability evaluation of drug (measurement method of fine particle amount)
As a simple method for evaluating the respiratory reachability of inhalants in vitro, the method of measuring the amount of fine particles by the next generation impactor (NGI) is widely used (for example, USP37, <1601> products for nebulization-characterization tests and the like. , European Pharmacopoeia 7.3, 2.9.44. Preparations for nebulization: characterization).

This method uses a device for classifying drug particles that have been sucked into the impactor from an inhalation device via a pump. The aspirated drug reaches any of the 10 parts (mouthpiece adapter, induction port, stages 1-7, micro orifice collector (MOC)) that make up the impactor, depending on the particle size. Large particles such as agglomerates are collected in the mouthpiece adapter and induction port. On the other hand, the drug particles having a fine particle size reach any of stages 1 to MOC, but the smaller the particle size, the higher the number of the drug particles, and the drug particles that have passed through the stage 7 are collected by the MOC.

Literature investigating the correlation between drug particle size and the amount of drug delivered to the respiratory tract measured by gun machine chigraphy (Newman SP, Chan HK. In Vitro / In Vivo Comparisons in Pulmonary Drug Delivery. J Aerosol, Glover According to W, Chan HK, Eberl S, et al. Lung Deposition of Mannitol Powder Aerosol in Healthy Subjects. J Aerosol Med. 2006; 19: 522-532. Med Pulm Drug Deliv. 2008; 21: 77-84.) The amount of drug having a particle size of 3 μm to 5 μm or less correlates with the amount of drug delivered to the respiratory organs. In the nebulizer composition of the present invention, the amount of the active ingredient having an aerodynamic particle size of 4.4 μm or less is defined as the amount of fine particles (fine particle dose: FPD) among the amount of the active ingredient contained, and breathing is performed using this parameter. The reachability of the vessel was evaluated.

Since this evaluation is an evaluation of the amount of fine particles, it is also described as an evaluation of the amount of fine particles in the following test examples. The various nebulizer compositions were sprayed using a compressor-type nebulizer device (compressor: Paris Boy N (PARI Japan), nebulizer: Paris LC Plus (PARI Japan)).

(Test Example 1) Evaluation of fine particle amount when Inavir inhalation powder is dispersed in purified water Amount of fine particles in a liquid in which 400 mg of Inavir inhalation powder (containing 80 mg as an anhydride as an active ingredient) is dispersed in 8 mL of purified water. The results of the evaluation are shown in Table 12. The amount of fine particles (FPD) was only 0.4 mg.

(Test Example 2) Suspension of Dispersant Only Table 13 shows the evaluation results of the amount of fine particles of the compositions obtained in Comparative Examples 2 and 3.

(Test Example 3) Effect of osmotic pressure regulator Table 14 shows the results of evaluation of the amount of fine particles of the compositions obtained in Examples 1 to 3. By adding lactose hydrate or sodium chloride in addition to the dispersant hydroxypropylmethylcellulose, a good amount of fine particles was shown.

(Test Example 4) Effect of Dispersant Polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) as dispersants obtained in Examples 4 and 5 in the same manner as in Test Example 3. The amount of fine particles was evaluated for the composition to which was added. The results are shown in Table 15. Even in the system in which both substances were added as dispersants, a good amount of fine particles was shown.

(Test Example 5) Evaluation of fine particle amount of lyophilized preparation A composition containing tyroxapol as a dispersant and an aqueous solution of sodium chloride as an osmoregulator was prepared, and the suspension state (Example 6) and the lyophilized preparation were prepared. Was dispersed in purified water (Example 15), and the amount of fine particles was evaluated. The results are shown in Table 16. Both the composition produced as a suspension and the composition dispersed in an aqueous solution of sodium chloride after freeze-drying showed a good amount of fine particles.

(Test Example 6) Evaluation of stability of lyophilized product The stability of the lyophilized product of Example 7 was evaluated. The evaluation of the amount of fine particles was carried out by the same method as in Example 15 to prepare a nebulizer composition and the above method. Impurities were evaluated by the HPLC method. The results are shown in Table 17. This drug was confirmed to be stable for up to 6 months.

(Test Example 7) Evaluation of Fine Particle Amount of Composition Containing Various Tyroxapol Blending Amounts and Active Ingredients with Various Particle Sizes A composition containing tyroxapole as a dispersant, and fine particles when the particle size of the active ingredient is changed. The amount was evaluated. The results are shown in Table 18. A good amount of fine particles was shown in the range of the amount of tyroxapole and the particle size of the active ingredient in this example.

(Test Example 8)
The lyophilized preparation obtained in Example 9 was dispersed in purified water as Comparative Example 4, and the amount of fine particles was compared with the composition obtained in Example 17. The results are shown in Table 19. It was shown that the amount of fine particles was improved by adding sodium chloride as an osmotic pressure regulator.

(Test Example 9)
Table 20 shows the results of evaluating the amount of fine particles of Examples 17, 23 to 25, 30, and 34 to 35. It was shown that the FPD increased as the active ingredient content increased.

(Test Example 10) Pharmacokinetic study test for healthy adult males For Japanese healthy adult males, a nebulizer composition containing an active ingredient was administered by inhalation once using a nebulizer, and the active ingredient and the active ingredient were effective. The pharmacokinetics of the above-mentioned compound (III) (hereinafter, also referred to as an active metabolite), which is an active metabolite of the component, in plasma and in the alveolar was examined.

Blood was collected before and after inhalation administration of the active ingredient, and the drug concentration in plasma was measured. In addition, after inhalation administration of the active ingredient, intra-alveolar lavage was performed, and drug concentrations in alveolar mucus and alveolar macrophages were measured. The drug concentration was measured for the active ingredient and the active metabolite. A validated liquid chromatography tandem mass spectrometry method was used to measure the drug concentration.

When evaluating only plasma pharmacokinetics, the dosing is a single dose of 40 mg, 80 mg, 160 mg, 240 mg, or 320 mg as the active ingredient (showing the weight as an anhydride; the same applies hereinafter in Test Example 10). It was administered. For dosing, nebulizer compositions adjusted according to Example 29, Example 30, Example 31, Example 32, and Example 33, respectively, were used. In addition, the safety after administration of the nebulizer composition was evaluated.

The concentration of the active metabolite in plasma when the composition containing the active ingredient is administered by inhalation once using a nebulizer for healthy Japanese adult men is the time to reach the maximum plasma concentration (Tmax, median). The plasma was 4.0 to 6.0 hours, and the elimination half-life (T _1/2 , average value) was 58.29 to 165.8 hours. The maximum plasma concentration (Cmax) of the active metabolite in plasma and the area under plasma concentration (AUClast) after administration increased in approximately proportion to the dose. Regarding the safety of a single dose of the nebulizer composition having an active ingredient amount of 40 mg, 80 mg, 160 mg, 240 mg, or 320 mg, findings that pose a safety problem were found from the measurement of vital signs and induced electrocardiogram. There wasn't.

When assessing pharmacokinetics within the alveoli, the dosing was a single dose of 160 mg as the active ingredient. For dosing, a nebulizer composition prepared according to Example 31 was used.

In addition, the safety after administration of the nebulizer composition was evaluated.

After a single inhalation administration of the active ingredient, intra-alveolar lavage was performed using the bronchoalveolar lavage (BAL) method, the intra-alveolar lavage fluid was collected, and the drug concentration in alveolar mucus and alveolar macrophages was collected. Was measured. The concentration of active metabolites in the alveolar mucus showed the highest concentration at the time of the first measurement (4 hours after the start of administration). Its concentration was 1459 ng / mL, which was about 4.2 μM in terms of the molecular weight of the active metabolite (346.34). The concentration 168 hours after the start of administration was 636.1 ng / mL (about 1.8 μM).

_{These values are sufficient for IC 50} values [A (H1N1) pdm09 type: 1.70 nM, A (H3N2) type: 3.98 nM, B type: 14.86 nM] for neuramidase of influenza A and B viruses. It exceeded (Ikematsu H, Kawai N, Iwaki N, et al. Clinical outcome of laninamivir octanoate hydrate for influenza in the 2013-2014 Japanese season. J Infect Chemother. 2015; 21 (11): 802-7.).

The concentration of the active metabolite in the alveolar mucus after a single inhalation administration of the nebulizer composition (active ingredient 160 mg) for healthy Japanese adult men is the reported inhalation powder (effective). The concentration of the active metabolite in the alveolar mucus after a single inhalation of 40 mg of the component) is similar to that of the active metabolite, and both the inhalation powder and the nebulizer composition exceed the _{IC 50 value for a long time after the active component is administered.} The concentration was maintained (Antimicrobial Agents and Chemotherapy 2012, vol.56, No.7, p3873-3878).

From the above pharmacokinetic results, when 40 to 320 mg of the active ingredient was administered by inhalation to a healthy Japanese adult male using a nebulizer, the plasma concentration of the active metabolite increased almost in proportion to the dose. However, systemic exposure was observed with increasing dose.

The active metabolites in the alveolar mucus when 160 mg of the active ingredient was administered once to a healthy Japanese adult male using a nebulizer were type A and B at the time of the first evaluation after administration (4 hours after the start of administration). sufficient excess concentration was observed IC ₅₀ values for the neuraminidase type influenza virus, because its concentration has lasted a long time, likely to develop lasting efficacy was demonstrated.

The approved adult dose of 40 mg of Inavir inhalation powder 20 mg, which is already on the market, has been confirmed to have a therapeutic / preventive effect on influenza A and B virus infections, and a nebulizer composition (effective). Since the pharmacokinetics in the alveolar mucosa after a single dose of 160 mg of the ingredient is not considered to be less than the exposure of the inhaled powder (40 mg of the active ingredient), the nebulizer composition (160 mg of the active ingredient) is type A. And can be expected to have therapeutic / preventive effects on type B influenza virus infection.

(Test Example 11) Comparative test of pharmacokinetics of nebulizer composition and inhaled powder for healthy adult males A nebulizer composition (active ingredient amount 160 mg, weight as an anhydride is shown to Japanese healthy adult males. ) And the inhaled powder (the amount of the active ingredient is 40 mg, the weight as an anhydride is shown) were compared in the pharmacokinetics in the alveolar mucus after a single inhalation administration. As the nebulizer composition, the nebulizer composition prepared according to Example 31 was used. As the inhalation powder, 20 mg of a commercially available inhalation powder of Inavir was used. The results are shown in Table 21.

Ｃｍａｘ、ＡＵＣｉｎｆ、Ｔｍａｘ、及びＴ1/2 は推定値（標準誤差）を示す。

Cmax, AUCinf, Tmax, and T1 / 2 indicate estimated values (standard error).

Regarding the alveolar mucus concentration of the active metabolite of the active ingredient, the maximum plasma concentration (Cmax) tended to be higher when the inhaled powder was administered, but after the time when the maximum plasma concentration (Cmax) was shown, the nebulizer The composition for nebulizer tends to be higher than the inhaled powder, and the area under the plasma concentration-time curve (AUCinf) up to infinity time is about 2.8 times higher in the composition for nebulizer, which is the highest in plasma. No difference was observed in the concentration arrival time (Tmax, median value) and elimination half-life (T1 _/2 , average value) between the nebulizer composition and the inhalation powder.
The maximum plasma concentration (Cmax) of the active metabolite and the area under the plasma concentration-time curve (AUCinf) up to infinity after a single inhalation administration of the nebulizer composition and inhalation powder are the nebulizer composition. Both the inhaled powder and the inhaled powder showed an increase almost proportional to the dose.

The commercially available inhalation powder of Inavir 20 mg is an inhalation powder containing laninamivir octanoate hydrate as an active ingredient, and the amount of the active ingredient is 40 mg (anhydrous), which is the approved dose for children and adults aged 10 years and over. The therapeutic / preventive effect of influenza virus infection has been confirmed.

As shown in Test Example 10 described above, there was no problem in safety with the composition for nebulizer of 80 mg, 160 mg, 240 mg and 320 mg of the active ingredient.

Considering these facts, it was suggested that an active ingredient amount of 80 mg to 320 mg of the nebulizer composition may show a therapeutic / preventive effect on influenza.

(Test Example 12) Examination of arousal function in children and the elderly In order to set the dosage of the nebulizer composition for growing children and the elderly with impaired ventilation function, the children and the elderly were examined. As a subject, the arousal function was measured.

The subjects were healthy children aged 1 to 12 years and elderly people aged 75 and over. In addition, adults aged 20 to 40 years were added as controls. The results are shown in Table 22.

平均値（最小値、最大値）

Average value (minimum value, maximum value)

The tidal volume and minute ventilation (minute ventilation) of children between the ages of 1 and 12 tended to increase with age. Among the children who participated in this study, those who developed influenza virus infection were measured for ventilation at morbidity and compared with normal ventilation, and no significant difference was observed. The results are shown in Table 23.

Therefore, it was suggested that even if a child develops an influenza virus infection, the situation does not cause an extremely low ventilation volume.

For 20 mg of over-the-counter influenza inhalation powder, the approved dose for children under 10 years is the approved dose for children and adults over 10 years, 40 mg of active ingredient (indicating weight as anhydride). ), Which is half the amount of the active ingredient, 20 mg (indicating the weight as an anhydride) has been confirmed to show a therapeutic effect on influenza virus infection.
As shown in Test Example 10, in adults, the nebulizer composition (active ingredient 160 mg) can be expected to have a therapeutic / preventive effect on influenza A and B virus infections of the inhalation powder (active ingredient 40 mg).
Therefore, it is considered that the nebulizer composition may be effective at 80 mg of the active ingredient, which is half of the 160 mg of the effective amount expected to be effective in children and adults aged 10 years or older.

In addition, as shown in Test Example 10, no findings that pose a safety problem were found in Japanese healthy adult males at doses up to an effective dose of 320 mg, and thus it is also effective in children under 10 years of age. It can be expected that the efficacy will be shown when the amount of the component is 80 to 320 mg.

There was no significant difference in arousal function in the elderly compared with adults. Therefore, it was suggested that the nebulizer composition (active ingredient 80-320 mg), which can be expected to have a therapeutic / preventive effect on healthy Japanese adult men, may also have a therapeutic / preventive effect on the elderly.

(Test Example 13) Examination of therapeutic effect in adult patients Conducted as a single-blind comparative study using placebo as a control drug in adults and children aged 10 years or older with influenza A or B virus infection. .. The amount of the active ingredient in the nebulizer composition is 160 mg.

The primary endpoint of therapeutic efficacy is the time of influenza morbidity, i.e., the time from the end of dosing to the first time that all or mild influenza symptoms persist for more than 21.5 hours. do.

(Test Example 14) Examination of therapeutic effect in pediatric patients An open-label open-label study will be conducted in patients with influenza virus infection under 10 years of age. The amount of the active ingredient in the nebulizer composition is 160 mg.

The primary endpoint of therapeutic efficacy is the time of influenza morbidity, i.e., the time from the end of dosing to the first time that all or mild influenza symptoms persist for more than 21.5 hours. do.

Claims (22)

It contains 3 to 10% by weight of laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further contains a dispersant and an osmotic pressure regulator.
The dispersant is a combination of one or two selected from the group consisting of polysorbate, polyoxyethylene sorbitan monolaurate, sorbitan monolaurate, tyroxapol, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa). Is a thing
A composition for a nebulizer in which the osmotic pressure regulator is sodium chloride. The particle size of 50% by weight in the laser diffraction / scattering type particle size distribution measurement method of laninamivir octanoic acid ester hydrate is 5.0 μm or less, and the particle size of 90% by weight in the laser diffraction / scattering type particle size distribution measurement method. The composition for a nebulizer according to claim 1, wherein the particle size is 12.0 μm or less. The particle size of 50% by weight in the laser diffraction scattering type particle size distribution measurement method of lanina mivir octanoic acid ester hydrate is 3.2 μm or less, and the particle size of 90% by weight in the laser diffraction scattering type particle size distribution measurement method. The composition for a nebulizer according to claim 1, wherein the particle size is 8.0 μm or less. The composition for a nebulizer according to any one of claims 1 to 3, wherein the dispersant is tyrosapol. The composition for a nebulizer according to claim 4, wherein the content of tyroxapol is 0.01 to 1% by weight. The composition for a nebulizer according to claim 4, wherein the content of tyroxapol is 0.05 to 0.5% by weight. The composition for a nebulizer according to any one of claims 1 to 3, wherein the dispersant is polyoxyethylene sorbitan monolaurate and sorbitan monolaurate. The nebulizer according to claim 7, wherein the content of polyoxyethylene sorbitan monolaurate is 0.01 to 0.5% by weight, and the content of sorbitan monolaurate is 0.01 to 0.5% by weight. Composition. The nebulizer according to claim 7, wherein the content of polyoxyethylene sorbitan monolaurate is 0.038 to 0.2% by weight, and the content of sorbitan monolaurate is 0.1 to 0.2% by weight. Composition. The composition for a nebulizer according to any one of claims 1 to 9, wherein the content of sodium chloride is 0.45 to 1.8% by weight. It consists of laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof and a dispersant. However, a lyophilized preparation having a content of 93.0 to 98.5% by weight and a content of tyroxapol of 1.5 to 7.0% by weight. It consists of laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof, a dispersant and an osmoregulator, and the content of laninamivir octanoic acid ester hydrate or its pharmacologically acceptable salt is 55. The content of the dispersant is 1 to 10% by weight, the content of the osmoregulator is 4 to 35% by weight, and the content of the dispersant is 1 to 10% by weight.
The dispersant is a combination of one or two selected from the group consisting of polysorbate, polyoxyethylene sorbitan monolaurate, sorbitan monolaurate, tyroxapol, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa). Is a thing
A lyophilized preparation in which the osmotic pressure regulator is sodium chloride. The lyophilized preparation according to claim 12, wherein the dispersant is tyrosapol. A prophylactic or therapeutic agent for influenza virus infection, which comprises the composition for nebulizer according to any one of claims 1 to 10. A prophylactic or therapeutic agent for influenza virus infection, which comprises an inhalation solution prepared by dispersing the lyophilized preparation according to any one of claims 11 to 13 in a suspension solution. Claimed to contain laninamivir octanoic acid ester hydrate or a pharmaceutically acceptable salt thereof as an active ingredient, and the dose of the active ingredient is 40 to 320 mg in terms of anhydride per administration. Item 2. The composition for nebulizer according to any one of Items 1 to 10. Claim 1 which contains laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and the dose of the active ingredient is 80 mg in terms of anhydride per administration. 10. The composition for a nebulizer according to any one of 10. Claim 1 which contains laninamivir octanoic acid ester hydrate or a pharmaceutically acceptable salt thereof as an active ingredient, and the dose of the active ingredient is 160 mg in terms of anhydride per administration. 10. The composition for a nebulizer according to any one of 10. Any one of claims 1 to 10, 16, 17, and 18 for the prevention of influenza virus infection, which is administered by spraying and inhaling into the human respiratory organs before the onset of influenza virus using a nebulizer. The composition for nebulizer according to the section. Any one of claims 1 to 10, 16 , 17, and 18 for the treatment of influenza virus infection, which is administered to the human respiratory tract at the onset of influenza virus by spraying and inhaling with a nebulizer. The nebulizer composition according to the section. An inhalation solution prepared by dispersing the lyophilized preparation according to any one of claims 11 to 13 with a suspension solution, and using a nebulizer in the human respiratory organs before the onset of influenza virus. A nebulizer composition for the prevention of influenza infection, which is sprayed and administered by inhalation. An inhalation solution prepared by dispersing the lyophilized preparation according to any one of claims 11 to 13 with a suspension solution, and using a nebulizer in the human respiratory organs at the onset of influenza virus. A nebulizer composition for the treatment of influenza virus infection, which is sprayed and administered by inhalation.