WO2022034914A1 - Préparation pharmaceutique solide facilement soluble et son procédé de production - Google Patents

Préparation pharmaceutique solide facilement soluble et son procédé de production Download PDF

Info

Publication number
WO2022034914A1
WO2022034914A1 PCT/JP2021/029747 JP2021029747W WO2022034914A1 WO 2022034914 A1 WO2022034914 A1 WO 2022034914A1 JP 2021029747 W JP2021029747 W JP 2021029747W WO 2022034914 A1 WO2022034914 A1 WO 2022034914A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
soluble solid
solid dispersion
easily soluble
solid preparation
Prior art date
Application number
PCT/JP2021/029747
Other languages
English (en)
Japanese (ja)
Inventor
隆行 入江
匡明 澤
亮 寺川
Original Assignee
カルナバイオサイエンス株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by カルナバイオサイエンス株式会社 filed Critical カルナバイオサイエンス株式会社
Publication of WO2022034914A1 publication Critical patent/WO2022034914A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to an easily soluble solid preparation of a poorly soluble drug and a method for producing the same. More specifically, 2- (3- ⁇ 4-amino-6-[(1-methyl-1H-pyrazole-4-yl) amino] -1,3,5-triazine-2-yl ⁇ -2- (hydroxy)
  • the present invention relates to an easily soluble solid preparation comprising a solid dispersion of methyl) phenyl) -6-cyclopropyl-8-fluoroisoquinoline-1 (2H) -one (Compound A) and a method for producing the same.
  • Inhibitors against various protinkinases are widely used as molecular-targeted therapeutic agents for cancer and immunoinflammatory diseases, and for example, agents having an inhibitory effect on Bruton's tyrosine kinase (BTK) (BTK).
  • Imbruvica (trademark, generic name, ibrutinib) (BTK inhibitor) has been used as a therapeutic agent for relapsed or refractory chronic lymphocytic leukemia.
  • Compound A is a BTK inhibitor newly created by the inventors of the present application, and is a disease known to be associated with an abnormal cellular response mediated by BTK, for example, an autoimmune disease or an inflammatory disease.
  • a compound useful as a drug for cancers such as bone diseases and lymphomas (Patent Document 1 below).
  • compound A has extremely low solubility in water, when orally administered as a solid preparation such as a capsule filled with compound A or a normal tablet, the dissolution property is poor and therefore it is not sufficiently absorbed into blood. , It has a drawback of low bioavailability, and in order to use compound A as an orally-administered preparation as a BTK inhibitor, an easily soluble solid preparation having excellent oral absorbability is required. ing.
  • Various methods are known as a method for producing a poorly soluble solid preparation of a poorly soluble drug. For example, a poorly soluble drug is dispersed in an inert carrier (hereinafter, simply referred to as a carrier) in an amorphous state, so-called.
  • a method for producing an easily soluble solid preparation as a solid dispersion is known.
  • a method for producing a solid dispersion a method in which a drug and a carrier are dissolved in a solvent and then spray-dried to form a solid dispersion (spray-drying method), or a method in which the drug and the carrier are put into an extruder are placed in a sparingly soluble drug.
  • a method of co-melting by applying shearing force while heating above the melting point of the above, extruding from the die, cooling and solidifying (hot melt extrusion method) or dissolving the drug and carrier in a solvent and then adding to the poor solvent.
  • Various production methods are known, such as a method of precipitating and drying to form a solid dispersion (co-precipitation method). No formulation using the manufacturing technology of is reported.
  • An object of the present invention is to provide an easily soluble solid preparation characterized by containing a solid dispersion of compound A and a method for producing the same.
  • the present inventors have made compound A amorphized in a specific carrier by a spray-drying method.
  • the present invention was completed by finding that the solid dispersion of compound A can remarkably improve the elution of compound A and that the easily soluble solid preparation containing the solid dispersion can solve the problems of the present invention.
  • the easily soluble solid preparation containing the compound A as an active ingredient of the present invention According to the easily soluble solid preparation containing the compound A as an active ingredient of the present invention and the method for producing the same, the elution property is remarkably improved by amorphizing the compound A in a carrier to form a solid dispersion. It was confirmed by the dissolution test using the easily soluble solid preparation of the present invention and the oral administration test performed using an animal (dog) that the oral absorbability and bioavailability can be improved. From this, the easily soluble solid preparation containing the compound A of the present invention as an active ingredient can exert an excellent effect as a BTK inhibitor.
  • FIG. 1 is a diagram showing the results of the dissolution test of Test Example 1, in which the vertical axis indicates the elution amount ( ⁇ M) of compound A and the horizontal axis indicates the elapsed time (minutes).
  • the present invention is achieved as follows.
  • the present invention comprises organic compound A (Patent Document 1) produced by the production method found by the present inventors and various high molecular weight polymers (carriers) that can be usually used as a carrier for a solid dispersion. After dissolving in a solvent and then amorphizing compound A into a carrier by a spray-drying method and confirming that compound A is in an amorphous state in the obtained carrier, the obtained solid dispersion is used. It is achieved by producing an easily soluble solid preparation containing the target compound A by subjecting it to a normal formulation step.
  • various water-soluble polymers for example, hypromellose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, copovidone, etc.
  • enteric polymers eg, hypromellose phthalate ester, hypromellose acetate succinate, dried methacrylic acid copolymer LD, etc.
  • compound A is in the solid dispersion. It becomes an amorphous state, the elution property is remarkably improved as compared with the compound A (drug substance), and the drawback of low bioavailability is improved.
  • the elution property is particularly improved as compared with other solid dispersions, and the solid composition (solid dispersion).
  • HPMCP TM hypromellose phthalate ester
  • the disadvantage of low bioavailability is improved, and the amorphous compound A in the solid preparation is less likely to transfer to the crystalline form during storage, and the storage stability is stable. Is also excellent.
  • the hypromellose phthalate (HPMCP) suitably used in the present invention has a structure in which a hydrophobic carboxybenzoyl group is introduced into hypromellose (hydroxypropylmethylcellulose; HPMC), so that HPMCP is soluble in water. It dissolves in an organic solvent. It is also used as an enteric coating agent because it does not dissolve in the stomach due to the carboxyl group of the carboxybenzoyl group, but can usually be dissolved in the small intestine, which is the maximum absorption site of the drug.
  • HPMC hydroxypropylmethylcellulose
  • the small intestine is the longest organ in the human body consisting of the duodenum, jejunum, and ileum, and since the absorption site differs depending on the drug, the carboxybenzoyl group of HPMCP is used to control the elution in the small intestine.
  • HPMCPs of the type (HP-50) that dissolves at around pH 5.0 and the type (HP-55) that dissolves at around pH 5.5 are commercially available, but the carrier of compound A is pH5.
  • a type (HP-55) HPMCP that dissolves around 5.5 is preferred.
  • the presence of compound A in the carrier in an amorphous state can be confirmed by powder X-ray diffraction measurement, temperature-modulated DSC analysis and the like.
  • the easily soluble solid preparation of the present invention can use compound A and various water-soluble and enteric-soluble polymers that can be used as pharmaceutically acceptable pharmaceutical additives as carriers, but HPMCP is preferable, and HPMCP is particularly preferable. (HP-55) is preferable.
  • the carrier is dissolved in an organic solvent at a ratio of 0.5 to 5 parts by weight, preferably 0.8 to 3 parts by weight, particularly preferably 1 part by weight with respect to compound A (1 part by weight), and then spray-dried. After amorphizing compound A by the method and confirming that compound A is in an amorphous state in the obtained solid composition (solid dispersion), it is easy to contain compound A by a usual formulation method. Soluble solid formulations can be produced.
  • HPMCP when HPMCP is used as the carrier, the HPMCP is dissolved in an organic solvent at a ratio of 0.8 to 3 parts by weight, particularly preferably 1 part by weight with respect to compound A (1 part by weight), and then spray-dried. After amorphizing compound A and confirming that compound A is in an amorphous state in the obtained solid composition (solid dispersion), an easily soluble solid containing compound A by a usual formulation method.
  • the formulation can be manufactured.
  • the easily soluble solid preparation of the present invention can be formed into a dosage form such as a capsule, a tablet, a granule, or a fine granule, if necessary.
  • various pharmaceutically acceptable excipients, disintegrants, lubricants, colorants, and flavoring agents can be appropriately blended for various formulations, if necessary.
  • examples of these compounding agents include starch such as lactose and cornstarch, crystalline cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, calcium carboxymethyl cellulose, talc, magnesium stearate and the like.
  • the organic solvent used in the present invention is not particularly limited, but usually, a mixed solvent of dichloromethane and methanol that dissolves compound A and the carrier can be used.
  • the mixing ratio is a volume ratio of methanol of 0.5 to 2, preferably 0.8 to 1.2 with respect to dichloromethane 1.
  • the dose of the pharmaceutical product of the present invention can be appropriately increased or decreased according to the type, severity, age, gender, body weight, etc. of the patient, but is usually in the range of 10 mg to 2400 g per day in adults, which is 1 It can be orally administered once a day, or in two or three divided doses.
  • the capsule according to one embodiment of the present invention is suitable as the dosage form of the preparation of the present invention because it is easy to adjust the dosage according to the type, symptom and age of the disease. Not particularly limited.
  • Test Example 1 The effect of the pharmaceutical product of the present invention was evaluated using various solid dispersions of compound A.
  • the solid dispersions of Examples 1 to 8 were subjected to the elution test.
  • compound A drug substance
  • dissolution test the second solution of the dissolution test (pH 6.8) of the Japanese Pharmacopoeia was used as the dissolution test solution
  • dissolution test solution (30 ml, 37 ° C.) was added to 40 mg of each of the above solid dispersions, and sampling was performed over time (sampling). 5,15,30,60 and 120 minutes), the elution amount of compound A was determined by UV measurement. The measurement results are shown in FIG.
  • the solid dispersion of the present invention showed a remarkable improvement in dissolution property as compared with the drug substance of compound A, but HPMCP (HP-55) was selected as the carrier with compound A.
  • HPMCP HP-55
  • the solid dispersion of the combination had the most remarkable improvement in elution, and the only increase in the amount of compound A elution was observed even after 120 minutes had passed. Therefore, particularly in the case of the easily soluble solid preparation of the present invention consisting of a solid dispersion of compound A and HPMCP (HP-55), the supersaturated state of compound A is maintained for a long time in the small intestine where the drug is easily absorbed. The drawback of low bioavailability is improved.
  • Test Example 2 (dissolution test) The elution test of the solid dispersion of Example 9 was carried out in the same manner as in Test Example 1. As a result, the solid dispersion of Example 9 showed almost the same improvement in elution as the solid dispersion of Example 1 even though the amount of the carrier was reduced to one-third of that of Example 1. ..
  • Example 1 Compound A (1 g) was dissolved in a mixed solvent of 250 ml each of dichloromethane and methanol, and then 3 g of HPMCP (HP-55) was added and dissolved to prepare a feed solution. Then, the feed liquid was spray-dried using a mini spray dryer at an input heat temperature of 75 ° C., an exhaust heat temperature of 50 ° C., a spray nitrogen flow rate of 350 (L / h), and a feed flow rate of 5 (mL / min). By subjecting the powder to a vacuum drying step at room temperature for 20 hours, a solid dispersion of Compound A was obtained in a yield of about 82%.
  • HPMCP HP-55
  • the obtained solid dispersion showed a halo pattern in the powder X-ray diffraction test, no crystal peak was observed, no melting point peak was observed in the temperature-modulated DSC analysis, and a glass transition point (140.22 ° C.) was observed. It was confirmed that the compound A was in an amorphous state in HPMCP (HP-55) (carrier).
  • the powder X-ray diffraction test and the temperature-modulated DSC analysis were performed under the following conditions. Powder X-ray diffraction test: 2 ⁇ : 5-40 degrees, step width: 0.01 degrees, step time: 0.02 seconds
  • Temperature-modulated DSC analysis temperature range: 0-300 ° C, temperature rise rate: 5 ° C / min, Modulation width: 1.43 ° C
  • Examples 2-8 A solid dispersion of compound A was obtained in the yield shown in Table 3 in the same manner as in Example 1 except that the polymers shown in Table 2 were used as carriers instead of HPMCP (HP-55) of Example 1.
  • the obtained solid dispersion showed a halo pattern in the powder X-ray diffraction test, no crystal peak was observed, no melting point peak was observed in the temperature-modulated DSC analysis, and the glass transition point shown in Table 3 was observed. It was confirmed that the compound A was in an amorphous state.
  • Example 9 Compound A (4 g) was dissolved in a mixed solvent of 1000 ml each of dichloromethane and methanol, and then 4 g of HPMCP (HP-55) was added and dissolved to prepare a feed solution. Then, the feed liquid is spray-dried using a mini spray dryer with a spray nitrogen flow rate of 350 (L / h) and a feed flow rate of 5 (mL / min) while controlling the heat input temperature so that the exhaust heat temperature becomes 50 ° C. The obtained powder was subjected to a vacuum drying step at room temperature for 20 hours to obtain a solid dispersion of Compound A in a yield of about 71%.
  • HPMCP HP-55
  • the obtained solid dispersion showed a halo pattern in the powder X-ray diffraction test, no crystal peak was observed, no melting point peak was observed in the temperature-modulated DSC analysis, a glass transition point was observed, and HPMCP (HP-55). It was confirmed that the compound A was in an amorphous state in the (carrier).
  • Example 10 By filling the capsule with 30 mg of the solid dispersion obtained in Example 9, a capsule containing compound A (15 mg) was obtained.
  • the compound A is made into a solid dispersion to be in an amorphous state and the elution property is remarkably improved by oral absorption. Since it was confirmed by an oral administration test by an animal (dog) using the easily soluble solid preparation of the present invention that the sex and bioavailability can be improved, the amorphous state using the compound A of the present invention as an active ingredient.
  • the easily soluble solid preparation contained in the above can exert an excellent effect as a BTK inhibitor.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Inorganic Chemistry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne : une préparation pharmaceutique solide facilement soluble qui est caractérisée en ce qu'elle contient, en tant qu'inhibiteur BTK, une dispersion solide d'une 2-(3-{4-amino-6-[(1-méthyl-1H-pyrazole-4-yl)amino]-1,3,5-triazine-2-yl}-2-(hydroxyméthyl)phényl)-6-cyclopropyl-8-fluoroisoquinoléine-1(2H)-one utile ; et un procédé de production de la préparation pharmaceutique solide facilement soluble.
PCT/JP2021/029747 2020-08-13 2021-08-12 Préparation pharmaceutique solide facilement soluble et son procédé de production WO2022034914A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020-136820 2020-08-13
JP2020136820 2020-08-13

Publications (1)

Publication Number Publication Date
WO2022034914A1 true WO2022034914A1 (fr) 2022-02-17

Family

ID=80247927

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/029747 WO2022034914A1 (fr) 2020-08-13 2021-08-12 Préparation pharmaceutique solide facilement soluble et son procédé de production

Country Status (1)

Country Link
WO (1) WO2022034914A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015012149A1 (fr) * 2013-07-26 2015-01-29 カルナバイオサイエンス株式会社 Nouveau dérivé triazine
JP2015531365A (ja) * 2012-09-28 2015-11-02 オンコエシックス エスエー チエノトリアゾロジアゼピン化合物を含む医薬製剤
JP2018507896A (ja) * 2015-03-10 2018-03-22 シオノギ インク． 固体分散体
JP2019070000A (ja) * 2012-01-13 2019-05-09 エックススプレイ ファーマ パブリーク・アクチエボラグＸＳｐｒａｙ Ｐｈａｒｍａ ＡＢ（ｐｕｂｌ） 少なくとも１種のプロテインキナーゼ阻害剤及び少なくとも１種のポリマー性安定化マトリックス形成性成分の安定な非晶質のハイブリッドナノ粒子を含む医薬組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019070000A (ja) * 2012-01-13 2019-05-09 エックススプレイ ファーマ パブリーク・アクチエボラグＸＳｐｒａｙ Ｐｈａｒｍａ ＡＢ（ｐｕｂｌ） 少なくとも１種のプロテインキナーゼ阻害剤及び少なくとも１種のポリマー性安定化マトリックス形成性成分の安定な非晶質のハイブリッドナノ粒子を含む医薬組成物
JP2015531365A (ja) * 2012-09-28 2015-11-02 オンコエシックス エスエー チエノトリアゾロジアゼピン化合物を含む医薬製剤
WO2015012149A1 (fr) * 2013-07-26 2015-01-29 カルナバイオサイエンス株式会社 Nouveau dérivé triazine
JP2018507896A (ja) * 2015-03-10 2018-03-22 シオノギ インク． 固体分散体

Similar Documents

Publication Publication Date Title
JP5794650B2 (ja) 難溶性薬物の溶解性改善製剤
WO2001095912A1 (fr) Compositions permettant de reguler la plage et/ou la vitesse de liberation du ph
JP2018035171A (ja) 医薬製剤
KR20150097792A (ko) 개선된 생체이용률을 갖는 약학 조성물
TWI790364B (zh) 包含烷基硫酸鈉之醫藥組合物
EP3389633B1 (fr) Compositions pharmaceutiques comprenant un dérivé de phénylaminopyrimidine
US20220056012A1 (en) Amorphous form of a malt1 inhibitor and formulations thereof
WO2022034914A1 (fr) Préparation pharmaceutique solide facilement soluble et son procédé de production
US20230174493A1 (en) Solid Dispersions of Amorphous 3,4-Diphenyl-4,5-Dihydro-1H-Pyrazole Derivatives, Compositions Comprising them and Uses Thereof as Cannabinoid CB1 Receptor Inhibitors
CN117337170A (zh) 包含(4s)-24-氯-4-乙基-73-氟-35-甲氧基-32,5-二氧代-14-(三氟甲基)-32h-6-氮杂-3(4,1)-吡啶-1(1)-[1,2,3]三唑-2(1,2),7(1)-二苯七蕃-74-甲酰胺的药物剂型
JP7370126B2 (ja) エルロチニブを有効成分とする医薬錠剤
AU2017209981A1 (en) Process of preparing active pharmaceutical ingredient salts
WO2019030691A1 (fr) Compositions extrudées d'enzalutamide
JP2020075924A (ja) エルロチニブを有効成分とする医薬錠剤
JP6739275B2 (ja) ゲフィチニブを有効成分とする医薬組成物
JP2020090456A (ja) エルロチニブを有効成分とする医薬錠剤
CN113350349B (zh) 奥拉帕尼溶出增强组合物
TW202404585A (zh) 含有匹密特匹（Pimitespib）之醫藥組合物
CA3200729A1 (fr) Composition pharmaceutique comprenant du meloxicam
TW202341973A (zh) 治療性化合物、調配物、及其用途
TW202408463A (zh) 醫藥組合物
WO2022162687A1 (fr) Compositions pharmaceutiques comprenant du nilotinib
JP2023008994A (ja) アピキサバンの溶出性の改善方法
JP2020075923A (ja) エルロチニブを有効成分とする医薬錠剤
NZ623628B2 (en) Solid oral pharmaceutical formulations comprising amorphous (S)-methyl (1- ((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-1-isopropy1-1H-pyrazo1-4-yl)pyrimidin-2-yl)amino)propan-2-yl)carbamate (Compound A)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21855993

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21855993

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP