Encapsulated formulation

Abstract

To provide a new medicine for the prevention and / or treatment of COVID-19, which is a disease based on SARS-CoV-2 infection.SOLUTION: The present invention provides an encapsulated formulation containing (a) cepharanthine having an average particle size of 0.5-10 μm and (b) lactose having an average particle size of 1-200 μm.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a capsule containing cepharanthine. [Background technology]

[0002] COVID-19 (Japanese name: novel coronavirus infection) is an infectious disease caused by the 2019 novel coronavirus (SARS-CoV-2). COVID-19 was confirmed to have occurred in Wuhan, People's Republic of China in November 2019 and reported to the WHO in December of the same year, and has since spread worldwide. Symptoms include fever, dry cough, fatigue, phlegm, shortness of breath, sore throat, headache, muscle pain, joint pain, abnormal smell, and abnormal taste, and in severe cases, pneumonia worsens, leading to respiratory failure and death. There are still many unknowns about the virus, such as its infectiousness and the rate at which it becomes severe when contracted. In addition, because it is a new type of virus, effective treatments are still being sought, causing anxiety around the world. To date, many existing drugs have been screened, and recently, cepharanthine has been shown to be a promising treatment for COVID-19 (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] https: / / www.tus.ac.jp / mediarelations / archive / 20200422_9837.html Summary of the Invention [Problem to be solved by the invention]

[0004] The objective of the present invention is to provide a new pharmaceutical agent for the prevention and / or treatment of COVID-19, a disease caused by SARS-CoV-2 infection. [Means for solving the problem]

[0005] Cepharanthine is currently used in the form of powder and tablet preparations for oral administration, as well as in the form of injections. The present inventors came up with the idea of ​​applying cepharanthine, which is considered to be an effective drug for suppressing SARS-CoV-2 infection, to the site most commonly infected by SARS-CoV-2. As a result, they found that the object can be achieved by making cepharanthine into an inhalant that can be applied directly to the lower respiratory tract, and also found that an inhalant that can efficiently supply cepharanthine directly to the lower respiratory tract can be obtained by making the particle size of cepharanthine 0.5 to 10 μm. As a result of further investigation, they found that a capsule for inhalation powder with excellent storage stability can be obtained by encapsulating cepharanthine with a particle size of 0.5 to 10 μm and lactose with a particle size of 1 to 200 μm, and thus completed the present invention.

[0006] That is, the present invention provides the following inventions [1] to [5]. [1] A capsule containing (a) cepharanthine having a particle size of 0.5 to 10 μm and (b) lactose having a particle size of 1 to 200 μm. [2] The capsule formulation according to [1], wherein the mass ratio (a / b) of the components (a) and (b) is 0.001 to 0.5. [3] The capsule formulation according to [1] or [2], which is a capsule formulation for powder inhalation. [4] A capsule according to any one of [1] to [3], wherein the content of ingredient (a) in one capsule is 0.01 to 40 mg. [5] A capsule according to any one of [1] to [4], wherein component (b) is lactose hydrate. Effect of the Invention

[0007] The capsule preparation of the present invention contains fine cepharanthin powder and lactose, has excellent storage stability of cepharanthin, and when used as a powder inhalation preparation, can efficiently supply cepharanthin to the lower respiratory tract. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The capsule preparation of the present invention contains (a) cepharanthin having a particle size of 0.5 to 10 μm and (b) lactose having a particle size of 1 to 200 μm.

[0009] Cepharanthine, component (a) used in the present invention, is a chemical substance with the chemical name 6',12'-Dimethoxy-2,2'-dimethyl-6,7-[methylenebis(oxy)]oxyacanthan, and is a type of alkaloid that can be extracted from Cepharanthaea gracilis, Cepharanthaea quinata, Cepharanthaea japonica, etc. Cepharanthin is used to treat radiation-induced leukopenia, alopecia areata, alopecia pityriasis, serous otitis media, and viper bites. When cepharanthin is made into an inhalant as in the present invention, in addition to these indications, it is particularly useful as an infection suppressant for SARS-CoV-2 and as a preventive and / or therapeutic agent for COVID-19.

[0010] In the present invention, cepharanthine may be either chemically synthesized or extracted from Cepharantha nigricans, Cepharantha quinata, Cepharantha quinata, etc. When extracted from Cepharantha nigricans, it is also possible to use Cepharantha quinata extracts containing, in addition to cepharantha, other alkaloids other than cepharantha such as isotetrandrine, cyclaine, and berbamine. Cepharantha and Cepharantha quinata extracts are commercially available and can be purchased for use, and Cepharantha quinata extracts can be produced from Cepharantha nigricans by using known methods.

[0011] In order to apply the cepharanthin used in the present invention to the lower respiratory tract (trachea, bronchi, lungs), from the viewpoint of the reachability of the cepharanthin to the lower respiratory tract, the particle size is preferably 0.5 to 10 μm, more preferably 1 to 8 μm, and even more preferably 2 to 8 μm. The particle size means the cumulative frequency 50% diameter obtained by a laser diffraction scattering type particle size distribution measurement method (Partica LA-950V2: Horiba, Ltd.) (hereinafter, sometimes referred to as D50). This particle size can be adjusted by pulverization, sieving, etc. during production.

[0012] The content of cepharanthin in one capsule is the amount for one administration, and is preferably 0.01 to 40 mg, more preferably 0.1 to 30 mg, and even more preferably 1 to 20 mg. The capsules can be taken 1 to 3 times a day, 1 to 8 capsules (preferably 1 to 4 capsules, particularly preferably 1 to 2 capsules) before meals, between meals, after meals, before going to bed, etc.

[0013] The lactose of component (b) used in the present invention is an excipient. As the lactose, lactose hydrate is preferably used. Considering the accessibility of cepharanthin to the lower respiratory tract and storage stability, the particle size of lactose is preferably 1 to 200 μm, more preferably 1 to 180 μm. This particle size can be adjusted by pulverization, sieving, etc. during production.

[0014] In addition, it is more preferable to use a mixture of (b1) fine lactose having a particle size of 1 to 50 μm and (b2) lactose having a particle size of 50 to 200 μm in terms of the ability of cepharanthin to reach the lower respiratory tract and storage stability. Here, the particle size of the fine lactose is preferably 1 to 40 μm, more preferably 1 to 30 μm, and even more preferably 1 to 20 μm. The particle size of the lactose having a particle size of 50 to 200 μm is preferably 70 to 180 μm, more preferably 80 to 160 μm, and even more preferably 100 to 150 μm. In addition, the content mass ratio (b1 / b2) of the fine lactose to the lactose having a particle size of 50 to 200 μm is preferably 0.0001 to 0.5, more preferably 0.001 to 0.2, and even more preferably 0.01 to 0.1.

[0015] The content mass ratio (a / b) of component (a) to component (b) is preferably 0.001 to 0.5, more preferably 0.005 to 0.25, and even more preferably 0.01 to 0.1, from the viewpoints of the ability of cepharanthin to reach the lower respiratory tract, storage stability, and ease of powder inhalation.

[0016] In addition to the above-mentioned components (a) and (b), the capsule preparation of the present invention may contain, in addition to the above-mentioned components (a) and (b), acetic acid, phosphoric acid, boric acid, citric acid, tartaric acid, lactic acid, aspartic acid, histidine, arginine, lysine, glycine, glutamic acid, ε-aminocaproic acid, sulfuric acid and pharma- ceutically acceptable salts thereof, pH adjusters such as sodium hydroxide and hydrochloric acid, parabens such as methyl parahydroxybenzoate and propyl parahydroxybenzoate, preservatives such as benzalkonium chloride and chlorobutanol, stabilizers such as sodium cromoglycate, preservatives such as carthregin and phenol, sodium bisulfite, sodium edetate, chloride, etc. It is also possible to contain stabilizers such as sodium, carmellose sodium, xylitol, glycerin, creatinine, magnesium stearate, nicotinamide, macrogol (600, 4000, etc.), tocopherol and its derivatives, sodium nitrite, sodium sulfite, ascorbic acid, etc., bases such as oleic acid, purified oleic acid, purified water, etc., solubilizers such as absolute ethanol, solvents such as water for injection, etc., and the content of these substances is preferably 5% by mass or less, more preferably 3% by mass or less, and even more preferably 2% by mass or less of the total amount of the capsule contents.

[0017] The capsule of the present invention is preferably a hard capsule, and the shell thereof may be gelatin, hydroxypropyl methylcellulose, polyvinyl alcohol copolymer, pullulan, etc., with hydroxypropyl methylcellulose being particularly preferred from the viewpoint of stability. Commercially available products include, for example, Japanese Pharmacopoeia Gelatin Capsules (Qualicaps Co., Ltd.) containing PEG (macrogol), and Qualy V, which is based on hydroxypropyl methylcellulose. TM (Qualicaps Co., Ltd.) and Vcaps TM Plus (Lonza Japan Co., Ltd.), PONDAC based on polyvinyl alcohol copolymer TM Capsules (Nissin Kasei Co., Ltd.), NPcaps based on pullulan TM (Lonza Japan Co., Ltd.) and others.

[0018] The capsule of the present invention can be used as an oral administration agent, but is preferably used as an inhalable powder capsule from the viewpoint of delivering cepharanthin to the lower respiratory tract. When using the capsule of the present invention, an appropriate tool or device for inhalation administration may be used.

[0019] A specific example of an apparatus for inhalation administration of the powdered inhalation capsule of the present invention is a dry powder inhaler (hereinafter, abbreviated as DPI). The device used for the powdered inhalation capsule of the present invention can be one that is commonly used as a DPI. For example, the device can be a monohaler, a handyhaler, a Breezhaler, a flowcaps, etc.

[0020] The capsules are preferably supplied as pharmaceuticals in an airtight package further containing an inert gas and / or an oxygen scavenger. In the present invention, the term "airtight package" refers to a package that can substantially prevent solids and liquids from entering from outside the package under normal handling, transportation, storage, etc., and is a concept that includes "airtight container" and "sealed container" defined in the General Rules of the 18th Revised Japanese Pharmacopoeia. The package may be of either a fixed or irregular shape, and specific examples include bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, etc. In the present invention, a combination of these may also be used, and specific examples include a form in which the capsule is first packaged in a PTP package and then packaged in a pillow package.

[0021] The packaging material (raw material) for the airtight packaging body is not particularly limited as long as it can normally exhibit moisture-proofing properties, and materials used in the pharmaceutical and food industries for the purpose of preventing moisture from entering the contents that are sensitive to water can be used as appropriate. Examples of materials for the bottle body used in bottle packaging include glass, plastics (polyester, polyethylene (including low density (LDPE) and high density (HDPE)), polycarbonate, polystyrene, polypropylene, etc.), metals (aluminum), etc. Examples of materials for the stopper and lid include plastics (polyester, polyethylene, polycarbonate, polystyrene, polypropylene, etc.), metals (aluminum), etc. When packaging in a bottle, for example, a suitable number of the capsules are stored in a commercially available bottle, and then the bottle is sealed with a suitable stopper or lid. The size of the bottle may be appropriately selected according to the number of capsules to be stored, and the capacity of the bottle is, for example, about 10 to 500 mL, preferably 14 to 400 mL, and more preferably 24 to 350 mL. Examples of materials for bottle packaging are polyethylene and polypropylene, more preferably low density polyethylene (LDPE) and high density polyethylene (HDPE), and particularly preferably high density polyethylene (HDPE).

[0022] Examples of packaging materials used in SP packaging, PTP packaging, pillow packaging, stick packaging, and the like include biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), glucose modified PET (PET-G), biaxially oriented nylon (ONy, PA), cellophane, paper, low density polyethylene (LDPE), linear low density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), non-oriented polypropylene (CPP, IPP), ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially oriented polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC), cyclic polyolefin (COC), non-oriented nylon (CNy), polycarbonate (PC), polystyrene (PS), rigid polyvinyl chloride (VSC), and other resins, as well as metal foils such as aluminum foil (AL), and two or more of these may be appropriately combined to form a multilayer structure. Examples of such a multilayer structure include a laminate of PVC and PVDC (PVC / PVDC, hereinafter abbreviated as such), PVC / PVDC / PE / PVC, PVC / PVDC / PE / PVDC / PVC, CPP / COC / CPP, PVC / AL, CPP / AL, CPP / CPP / CPP, etc. Methods for forming such a multilayer structure include known lamination methods such as extrusion lamination, dry lamination, coextrusion lamination, thermal lamination, wet lamination, non-solvent lamination, and heat lamination. Packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. are preferably polyvinyl chloride and aluminum foil.

[0023] The capsule of the present invention can be further packaged in an airtight package and supplied as a medicine.Specific examples include bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, etc.The capsule of the present invention can also be packaged in a PTP package, which is then further packaged in a pillow package.

[0024] The capsule of the present invention can be used as an infection suppressant for SARS-CoV-2 and a preventive and / or therapeutic drug for COVID-19, in addition to the indications of cepharanthin, which are alopecia areata, alopecia pityroides, serous otitis media, and viper bites. The dosage varies depending on the patient's weight, age, sex, symptoms, etc., but is usually in the range of 1 to 20 mg of cepharanthin per day for adults. In addition, when the capsule of the present invention is used as an infection suppressant for SARS-CoV-2 and a preventive and / or therapeutic drug for COVID-19, it can also be used in combination with an anti-HIV drug such as nelfinavir. EXAMPLES

[0025] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0026] Reference example 1 98.5 g of lactose hydrate was added to 1.5 g of cepharanthine (particle size: 1.2 μm: measured by laser diffraction method) ground in a jet mill, and mixed with Hyflex Glar (HF-GS-2J, manufactured by Fukae Powtec Co., Ltd.) 0.1 g of the obtained powder was filled into a capsule to produce an inhalation powder.

[0027] Reference Comparative Example 1 98.5 g of lactose hydrate was added to 1.5 g of unground cepharanthine (particle size: 50 μm: measured by laser diffraction method) and mixed with Hyflex Glar (HF-GS-2J, manufactured by Fukae Powtec Co., Ltd.) 0.1 g of the obtained powder was filled into a capsule to produce an inhalation powder.

[0028] Test Example 1 The Stage 2 display rate (%) and fine particle dose (FPD) (%) were measured using a Monohaler device for the dry powder inhalants obtained in Reference Example 1 and Reference Comparative Example 1. The results are shown in Table 1. (1)Stage2 display rate (%) The Stage 2 indication rate, which indicates the airway reach rate, was calculated using the Twin Impinger, an in vitro evaluation device for inhaled drugs. (2) Fine particle amount (FPD) (%) The evaluation was carried out using the multi-stage liquid impinger device 1 in accordance with the aerodynamic particle size measurement method for inhalants in the Japanese Pharmacopoeia, 17th Edition, Second Supplement.

[0029] [Table 1]

[0030] As is clear from the results in Table 1, the inhalable powder of Reference Example 1 had a high Stage 2 display rate (%) and fine particle dose (FPD) (%) of approximately 30%, indicating that cepharanthin is capable of reaching the deep lungs. On the other hand, in the case of unpulverized cepharanthin in Reference Comparative Example 1, the Stage 2 display rate (%) and fine particle dose (FPD) (%) were low at about 3%, suggesting that it would be difficult for cepharanthin to reach the deep lungs.

[0031] Reference example 2 [Sample 1] 2 g of cepharanthin (D50: 133 μm) was placed in a glass bottle (standard 2K bottle) and used as sample 1. [Sample 2] 2 g of cepharanthin (D50: 3.5 μm) pulverized with a jet mill was placed in a glass bottle (standard 2K bottle) to prepare sample 2. [Sample 3] 2 g of cepharanthine (D50: 3.5 μm) ground in a jet mill and 18 g of lactose hydrate (D50: 134 μm, product name: InhaLac TM 120) were mixed and placed in a glass bottle (standard 2K bottle) to prepare Sample 3. [Sample 4] 2 g of cepharanthine (D50: 3.5 μm) ground in a jet mill and 18 g of lactose hydrate (D50: 8.1 μm, product name: InhaLac TM 400) were mixed and placed in a glass bottle (2K standard bottle) to prepare Sample 4.

[0032] Test Example 2 The percentage of decomposition products (related substances) derived from cepharanthin in each of the above samples was measured using an HPLC device before and after storage at 80°C for 3 days. Specifically, the percentage of cepharanthin related substances was measured as the area percentage (%) of the total peak area derived from cepharanthin and its related substances. Then, from the percentages (%) of cepharanthin-related substances in each sample obtained before the start of storage and after storage at 80°C for 3 days, the increase rate (%) of cepharanthin-derived decomposition products in each sample was calculated according to the following formula. Increase rate (%) of decomposition products derived from cepharanthin = (proportion (%) of cepharanthin-related substances after storage at 80°C for 3 days) - (proportion (%) of cepharanthin-related substances before storage)

[0033] <Measurement of decomposition products> The amount of decomposition products was determined by liquid chromatography under the following conditions. Detector: Ultraviolet spectrophotometer (measurement wavelength: 284 nm) Column temperature: constant temperature around 40℃ Column: Octadecylsilylated silica gel for liquid chromatography (4.6 mm x 15 cm, φ5 μm) Mobile phase: Acetonitrile / diluted triethylamine (1→2000) mixture (1:1)

[0034] The results obtained are shown in Table 2. From Table 2, it was found that the storage stability of cepharanthin decreased when it was made into a fine powder. The storage stability of cepharanthin also decreased when it was mixed with lactose.

[0035] [Table 2]

[0036] Manufacturing Example 1 2 g of cepharanthine (D50: 3.5 μm) ground with a jet mill, 17.26 g of lactose hydrate (D50: 134 μm, product name: InhaLac TM120, sold by MEGGLE GmbH & CO.KG), and 0.74g of lactose hydrate (D50: 8.1 μm, product name: InhaLac TM 400, sold by MEGGLE GmbH & CO.KG) to obtain a powder.

[0037] Example 1 The powder obtained in Production Example 1 was placed in No. 3 HPMC capsules (product name: Vcaps) so that each capsule contained 100 mg. TM The mixture was filled into 200 capsules (white, sold by Lonza Japan Co., Ltd.). The obtained 5 capsules were placed in a glass bottle (standard 2K bottle) to prepare a pharmaceutical preparation.

[0038] Comparative Example 1 100 mg of the powder obtained in Preparation Example 1 was placed in a glass bottle (standard 2K bottle) to prepare a pharmaceutical preparation.

[0039] Test Example 3 The proportion of cepharanthine-derived analogues in each of the above samples was measured using an HPLC device before and after storage at 60°C for two weeks.

[0040] [Table 3]

[0041] From Table 3, it was found that storage stability was improved by encapsulating (a) cepharanthin having an average particle size of 0.5 to 10 μm and (b) lactose having an average particle size of 1 to 200 μm in a capsule.

[0042] Manufacturing Example 2 Mix 5.0 g of cepharanthin (D50: 133 μm) and 5.0 g of lactose hydrate (D50: 134 μm, product name: InhaLac) in a jet mill. TM 120, sold by MEGGLE GmbH & CO.KG) was pulverized to obtain a pulverized product (average particle size: 2.6 μm). 4.0 g of the pulverized product and 16.0 g of lactose hydrate (D50: 134 μm, product name: InhaLac TM120, sold by MEGGLE GmbH & CO.KG) to obtain a powder.

[0043] Production Example 3 Mix 5.0 g of cepharanthin (D50: 133 μm) and 5.0 g of lactose hydrate (D50: 134 μm, product name: InhaLac) in a jet mill. TM 120, sold by MEGGLE GmbH & CO.KG) was pulverized to obtain a pulverized product (average particle size: 2.6 μm). 2.0 g of the pulverized product and 18.0 g of lactose hydrate (D50: 134 μm, product name: InhaLac TM 120, sold by MEGGLE GmbH & CO.KG) to obtain a powder.

[0044] Production Example 4 Mix 5.0 g of cepharanthin (D50: 133 μm) and 5.0 g of lactose hydrate (D50: 134 μm, product name: InhaLac) in a jet mill. TM 120, sold by MEGGLE GmbH & CO.KG) was pulverized to obtain a pulverized product (average particle size: 2.6 μm). 0.4 g of the pulverized product and 19.6 g of lactose hydrate (D50: 134 μm, product name: InhaLac TM 120, sold by MEGGLE GmbH & CO.KG) to obtain a powder.

[0045] Examples 2 to 4 The powders obtained in the above Production Examples 2 to 4 were placed into No. 3 HPMC capsules (product name: Vcaps) so that each capsule contained 100 mg of powder. TM The mixture was filled into a 100% ethanolamine Plus (white, sold by Lonza Japan Co., Ltd.) to prepare 20 capsules, which were designated as Examples 2 to 4.

Claims

1. A capsule formulation containing (a) cepharanthin having an average particle size of 0.5 to 10 μm and (b) lactose having an average particle size of 1 to 200 μm.

2. 2. The capsule according to claim 1, wherein the mass ratio (a / b) of the components (a) and (b) is 0.001 to 0.

5.

3. 3. The capsule according to claim 1 or 2, which is a capsule for dry powder inhalation.

4. The capsule according to any one of claims 1 to 3, wherein the content of component (a) in one capsule is 1 to 40 mg.

5. 5. The capsule according to claim 1, wherein the component (b) is lactose hydrate.

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