WO2015170939A1 - Préparation pharmaceutique pour une administration par voie orale où son goût est masqué, contenant de la clomipramine - Google Patents

Préparation pharmaceutique pour une administration par voie orale où son goût est masqué, contenant de la clomipramine Download PDF

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Publication number
WO2015170939A1
WO2015170939A1 PCT/KR2015/004660 KR2015004660W WO2015170939A1 WO 2015170939 A1 WO2015170939 A1 WO 2015170939A1 KR 2015004660 W KR2015004660 W KR 2015004660W WO 2015170939 A1 WO2015170939 A1 WO 2015170939A1
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WO
WIPO (PCT)
Prior art keywords
oral administration
clomipramine
exchange resin
cation exchange
acid
Prior art date
Application number
PCT/KR2015/004660
Other languages
English (en)
Korean (ko)
Inventor
전홍렬
권도우
이봉상
박수준
한지영
길명철
김민섭
Original Assignee
주식회사 씨티씨바이오
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 주식회사 씨티씨바이오 filed Critical 주식회사 씨티씨바이오
Priority to JP2017511131A priority Critical patent/JP6577024B2/ja
Priority to EP15789641.6A priority patent/EP3141264A4/fr
Priority to US15/309,620 priority patent/US10213437B2/en
Priority to CN201580036534.2A priority patent/CN106659792B/zh
Priority claimed from KR1020150064918A external-priority patent/KR101601794B1/ko
Publication of WO2015170939A1 publication Critical patent/WO2015170939A1/fr

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Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug

Definitions

  • the present invention relates to a pharmaceutical preparation comprising clomipramine or a pharmaceutically acceptable salt thereof as an active ingredient. More specifically, clomipramine-specific tastes, particularly bitter, spicy and arine tastes are all effectively shielded and contain a pharmaceutically effective amount of clomipramine and can be administered orally, thereby ensuring ease of taking It relates to a pharmaceutical preparation for oral administration using a pramin or a pharmaceutically acceptable salt thereof as an active ingredient, and a preparation method thereof.
  • Clomipramine is a type of selective serotonin reuptake inhibitor (SSRI).
  • Clomipramine is a representative tricyclic antidepressants (TCAs) and is also used as a treatment for premature ejaculation (product name: Annafranil).
  • TCAs tricyclic antidepressants
  • the diagnostic criterion for premature ejaculation is DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision), which by definition defines premature ejaculation on a continuous, repetitive basis, with minimal sexual stimulation. When inserted, it is the situation immediately after insertion.
  • Clomipramine may be administered in the blood, but an oral dosage form is preferable in view of the condition in which premature ejaculation treatment and / or antidepressant is used, and the convenience of carrying and taking due to the nature of the disease.
  • clomipramine hydrochloride is commercially available in tablets containing 10 mg, 15 mg, 25 mg, 50 mg or 75 mg, and a small amount of administration is reported to have little therapeutic effect unlike placebo, for example, to treat effective OCD. 250 mg of clomipramine hydrochloride is recommended daily for a single dose.
  • clomipramine hydrochloride has a characteristic bitter taste and spicy and arine taste, which not only cause discomfort during oral administration but also cause local paralysis symptoms in the oral cavity.
  • Oral dispersible formulations in which the taste is directly felt such as oral soluble films, oral disintegrating tablets, suspensions, suspension tablets, fast disintegrating tablets, oral disintegrating capsules, oral disintegrating granules, oral disintegrating troches, sublingual tablets, It is not easy to prepare powders and / or chewable tablets.
  • Clomipramine hydrochloride along with its characteristic bitter taste, has a strong spicy and astringent taste, as well as a symptom of tongue paralysis.
  • TM masks Taste Masking Agents
  • the problem to be solved by the present invention is to provide a pharmaceutical preparation for oral administration and a method for preparing the same effective for oral administration by effectively masking all the unpleasant taste caused by clomipramine hydrochloride in a small amount (Taste Masking).
  • the present invention comprises a clomipramine or a pharmaceutically acceptable salt thereof as an active ingredient, together with a cation exchange resin and an anionic polymer as a taste masking agent (Taste Masking Agent) It provides a pharmaceutical formulation comprising oral administration and a method for producing the same.
  • the present invention includes clomipramine or a pharmaceutically acceptable salt thereof as an active ingredient, and includes oral administration including a cation exchange resin and an anionic polymer as a taste masking agent.
  • oral administration including a cation exchange resin and an anionic polymer as a taste masking agent.
  • the present invention confirms that the combination of the cation exchange resin and the anionic polymer produces a synergistic effect and is very effective in masking the unique taste of clomipramine (particularly clomipramine hydrochloride) in a small amount. Completed.
  • the pharmaceutical preparations according to the invention may comprise clomipramine derivatives in place of or in combination with clomipramine as an active ingredient. Therefore, the pharmaceutical preparations according to the present invention may include derivatives having pharmaceutical activity equivalent to clomipramine.
  • the term 'clomipramine' includes a free base or a pharmaceutically acceptable salt.
  • a 'pharmaceutically acceptable salt' is a concentration that is relatively nontoxic and harmless to the patient, and any organic or inorganic side effects caused by this salt do not degrade the beneficial efficacy of clomipramine.
  • organic acids, inorganic acids or non-toxic salts can be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as the inorganic acid, and methanesulfonic acid, p-toluene as the organic acid.
  • Acid addition salts can be prepared by conventional methods such as dissolving the compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • the non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride , Acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate, sebacate, Fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methoxybenzoate phthalate , Terephthalate, benzenesulfonate, toluenesulfonate, chlorobenz
  • the cation exchange resin may be used without limitation as long as it does not adversely affect the pharmaceutical activity of clomipramine or a pharmaceutically acceptable salt thereof, and both polyacrylic and polystyrene may be used, for example, meta Cross-linked polymers of methacrylic acid and divinylbenzene (carboxylic acid functional groups and potassium of methacrylic acid form weakly acidic salts) (eg C100HMR ® , C108DR ® , C115HMR ® , C115KMR ® , IRP64 ® , IRP88 ® , INDION204 ® , INDION214 ® , INDION234 ® , INDION234S ® , INDION264 ® , INDION414 ® , INDION464 ® or INDION294 ® (Polycryline Potassium)), cross-linked polymers of styrenesulfonic acid and divinylbenzene (sulfonic
  • the 'anionic polymer' may be used without limitation so long as it does not adversely affect the pharmaceutical activity of clomipramine or a pharmaceutically acceptable salt thereof, and includes both natural anionic polymers and synthetic anionic polymers, for example, alginic acid, As polymers having functional groups of carboxylic acid, sulfonic acid, sulfate ester, phosphate ester, phosphonic acid and salts thereof, pectin and derivatives and salts thereof, cellulose (eg carboxymethylcellulose (CMC)) and derivatives and salts thereof, poly Acrylic acid (eg Eudragit ® ) and its derivatives and salts, galactomannan gums (eg cassia gum, locust bean gum, tara gum, guar gum), carrageenan gum, xanthan gum, tragacand gum, agar, queens Seed gum, starch and derivatives and salts thereof, karaya gum, gum arabic, alginate (eg sodium alginate, propylene glyco
  • the weight ratio of the anion polymer to the cation exchange resin is preferably about 1: 0.07-23, about 1: 0.0.07-22, and about 1: 0.07-21. , About 1: 0.07-20, about 1: 0.07-19, about 1: 0.08-23, about 1: 0.0.08-22, about 1: 0.09-21, about 1: 0.1-20, or about 9: 1 -1 may be 19. If the weight ratio is less than about 1: 0.07 or greater than about 1:23, it is difficult to exert a taste masking effect.
  • the combination of the cation exchange resin and the anionic polymer can effectively mask all the unpleasant tastes of clomipramine in a small amount.
  • the total weight ratio of the cation exchange resin and the anionic polymer as the taste masking component is preferably clomipramine or a pharmaceutical thereof.
  • weight ratio is less than about 1: 0.5, it is difficult to exert a taste masking effect. If the weight ratio is greater than about 1:10, the total weight is increased, which significantly reduces the texture and dosage convenience in the oral cavity. In particular, portability is likely to be offset.
  • the pharmaceutical preparations according to the invention may comprise about 2-150 mg of clomipramine or a pharmaceutically acceptable salt thereof per unit dosage, based on a single unit dose. More specifically, one unit dosage of clomipramine or a pharmaceutically acceptable salt thereof included in the pharmaceutical formulation may vary depending on the specific pharmaceutical use, but the use of clomipramine or a pharmaceutically acceptable salt thereof may vary.
  • a combination of a cation exchange resin and an anionic polymer as a taste masking component within a range of about 2-250 mg of a single dose dose effectively masks the unique taste.
  • the daily dosage is 1 without having to divide the daily dosage into multiple doses.
  • Can be taken in a single dose can be taken just before sexual intercourse, can be changed from a continuous treatment to take the drug at regular intervals from the daily treatment to change the treatment method, so if the problem in the continuous treatment every day.
  • the pharmaceutical preparations according to the present invention can be used without limitation as long as they are a medicinal use of all diseases, disorders and / or symptoms treated by administering clomipramine or a pharmaceutically acceptable salt thereof as an active ingredient, eg, premature ejaculation, OCD, depressive disorder, panic disorder, metamorphosis disorder, aggression, narcolepsy, dysentery, chronic pain, nocturnal enuresis and / or hair growth walls and the resulting symptoms, but may preferably be used for the treatment of premature ejaculation. .
  • 'treatment' refers to any action that improves or advantageously changes a disease, a disorder, and the symptoms caused by administration of a pharmaceutical preparation.
  • the 'treatment' broadly includes the meaning of 'prevention', 'prevention' refers to any action that is suppressed or delayed onset of the disease and the symptoms caused by the administration of the pharmaceutical preparation.
  • the pharmaceutical preparations according to the invention can be formulated for oral administration, for example tablets, films, suspensions, granules, gels, pills, tinctures. ), Decoction, infusion, spirit, fluid, extract, elixir, extract, syrup, powder, fragrance aromatic water), lemonade (lemonade) and the like can be formulated in various forms.
  • the tablet may be, for example, orally disintegrating tablets, mucoadhesive tablets, dispersible tablets, sublingual tablets, buccal tablets, chewing tablets Chewable tablets, dispensing tablets, multilayered tablets, press-coated tablets, effervescent tablets, solution tablets, etc. Can be. And those skilled in the art can be used to variously modify the various tablets as needed.
  • a formulation that immediately feels the unique taste of clomipramine upon oral administration such as a liquid form or a disintegrating formulation in the oral cavity (ie, disintegrating in the oral cavity), such as an orally dispersible formulation such as oral dissolution.
  • a formulation such as a film, oral disintegrating tablet, suspension, suspension tablet, fast disintegrating tablet, oral disintegrating granule, oral disintegrating troche, sublingual tablet, powder and / or chewable tablet, and the situation to be portable
  • the formulation of the pharmaceutical preparation according to the present invention may be preferred oral dissolution film formulations, fast-acting disintegrating tablet formulation or oral disintegrating granule formulation.
  • the orally dissolving film may be used interchangeably with terms such as film, strip, orally disintegrating film, oral cavity, buccal mucosa, sublingual It refers to the dosage form to paste inside and take.
  • Pharmaceutical formulations for oral administration of oral dispersible film formulations according to the present invention has the advantage that it can be taken without water.
  • the pharmaceutical formulation for oral administration according to the present invention When the pharmaceutical formulation for oral administration according to the present invention is formulated into an oral dissolving film, a polymer must be included for film formation in the present invention.
  • the pharmaceutical preparations for oral administration according to the present invention contain a large amount of ionic components, so compatibility with the polymer is important.
  • pullulan hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), starch, polyethylene Glycol-polyvinyl alcohol copolymers, copovidone, hydroxyethyl cellulose, hydroxypropyl p-starch, polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymers, poloxamers or mixtures thereof may be used.
  • the polymer may include 10 to 50% by weight based on the total weight of the dried film, but is not limited thereto.
  • the pharmaceutical formulation may further include a pharmaceutically acceptable carrier that can be added to the pharmaceutical formulation.
  • the pharmaceutically acceptable carrier includes additives such as excipients, disintegrants, binders, lubricants, emulsifiers, suspending agents, stabilizers and the like commonly used in the pharmaceutical field, and if necessary, sweeteners, flavoring and / or coloring agents, etc. It may be added additionally.
  • drugs may be used as an active ingredient in addition to clomipramine or a pharmaceutically acceptable salt thereof, as long as the purpose of the present invention is not impaired.
  • serotonin One or more selected from the group consisting of agonists, cetoronin antagonists, adrenergic agonists, adrenergic antagonists, adrenergic nerve blockers, erectile dysfunction agents, PDE 5-inhibitors, erectile agents and combinations thereof.
  • a person skilled in the art may further select and use various drugs as necessary.
  • the present invention includes a clomipramine or a pharmaceutically acceptable salt thereof as an active ingredient, and includes a cation exchange resin and an anionic polymer together as a taste masking agent.
  • a clomipramine or a pharmaceutically acceptable salt thereof as an active ingredient
  • a cation exchange resin and an anionic polymer together as a taste masking agent.
  • a pharmaceutical preparation for oral administration comprising adding and stirring a cation exchange resin and an anionic polymer to a liquid clomipramine hydrochloride dissolved, it is possible to take without water and clomipramine hydrochloride as an active ingredient It can provide a method for producing a pharmaceutical formulation for oral administration comprising a.
  • the present invention includes a step of adding a mixture of a cation exchange resin and an anionic polymer to a clomipramine or a pharmaceutically acceptable salt thereof in a solvent, and having a taste masking effect having excellent taste masking effect. Formulations are possible.
  • a cation exchange resin and an anionic polymer were added to the liquid clomipramine hydrochloride dissolved and stirred for at least 1 hour.
  • a plasticizer, flavoring agent, coloring agent, sweetening agent, surfactant, and / or diluent is added to the purified water, followed by stirring to dissolve or disperse the same.
  • Homogenizer Ultra turrax T-25, IKA
  • the gas in the film preparation was removed under vacuum conditions, and coated on the PET film to have an appropriate thickness. After drying at 60 ⁇ 80 °C to prepare a film formulation containing clomipramine hydrochloride.
  • TM sensory test was carried out with the same weight formulation prepared.
  • the subject placed a sample of the formulation containing the same unit equivalent amount of clomipramine hydrochloride into the mouth, dissolved and spit out for the same time, and simply rinsed the mouth with the same amount of water. After that, the bitter taste and burning time were recorded separately.
  • the interval between tests for each formulation and sample was set to 3 hours or more and the subject was excluded from the next test when the bitter taste or burning effect was maintained for 3 hours or more.
  • specific evaluation criteria were as follows:
  • the film preparation was prepared by varying the weight ratio of the cation exchange resin, the anionic polymer and the clomipramine hydrochloride to be mixed, and the taste masking effect and the film formulation forming ability were confirmed.
  • Tablet formulations containing clomipramine hydrochloride as an active ingredient were prepared according to the following method using the components according to Table 4, and the taste masking effect and the film formulation forming ability were confirmed.
  • a cation exchange resin and an anionic polymer were added to the liquid clomipramine hydrochloride dissolved and stirred for at least 1 hour.
  • the liquid was filtered and dried to obtain a solid.
  • a binder, a disintegration agent, a diluent, and a lubricant are added to the obtained solid, and then mixed, and a tablet is prepared using a tablet press.
  • the tablets were prepared by varying the weight ratio of the cation exchange resin, the anionic polymer and the clomipramine hydrochloride to be mixed, and the taste masking effect was confirmed.
  • a cation exchange resin and an anionic polymer were added to the liquid clomipramine hydrochloride dissolved and stirred for at least 1 hour.
  • the liquid was filtered and dried to obtain a solid.
  • a binder, a disintegration agent, and a diluent were added to prepare a liquid, and the obtained solid was placed in a fluidized bed granulator and spray dried to prepare granules.
  • granules were prepared by varying the weight ratios of the cation exchange resin, the anionic polymer, and the clomipramine hydrochloride to be mixed, and the taste masking effect was confirmed.

Abstract

La présente invention concerne une préparation pharmaceutique destinée à une administration par voie orale contenant, en tant que principes actifs, de la clomipramine ou un sel pharmaceutiquement acceptable de celle-ci ainsi qu'une résine échangeuse de cations et un polymère anionique comme agents de masquage de goût. L'invention concerne également le procédé de préparation de cette préparation. Selon l'invention, la préparation pharmaceutique peut être administrée par voie orale bien que contenant une quantité pharmaceutiquement efficace de clomipramine car le goût spécifique de la clomipramine, en particulier, tous les goûts amer, épicé et piquant sont masqués de façon efficace, ceci améliorant le confort d'utilisation et la portabilité du médicament.
PCT/KR2015/004660 2014-05-08 2015-05-08 Préparation pharmaceutique pour une administration par voie orale où son goût est masqué, contenant de la clomipramine WO2015170939A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2017511131A JP6577024B2 (ja) 2014-05-08 2015-05-08 味が遮蔽されたクロミプラミン含有経口投与用薬学製剤
EP15789641.6A EP3141264A4 (fr) 2014-05-08 2015-05-08 Préparation pharmaceutique pour une administration par voie orale où son goût est masqué, contenant de la clomipramine
US15/309,620 US10213437B2 (en) 2014-05-08 2015-05-08 Pharmaceutical preparation for masked taste oral administration, containing clomipramine
CN201580036534.2A CN106659792B (zh) 2014-05-08 2015-05-08 含氯丙咪嗪的遮味口服药物制剂

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20140054970 2014-05-08
KR10-2014-0054970 2014-05-08
KR1020150064918A KR101601794B1 (ko) 2014-05-08 2015-05-08 클로미프라민 함유 맛 차폐된 구강 투여용 약학 제제
KR10-2015-0064918 2015-05-08

Publications (1)

Publication Number Publication Date
WO2015170939A1 true WO2015170939A1 (fr) 2015-11-12

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Application Number Title Priority Date Filing Date
PCT/KR2015/004660 WO2015170939A1 (fr) 2014-05-08 2015-05-08 Préparation pharmaceutique pour une administration par voie orale où son goût est masqué, contenant de la clomipramine

Country Status (1)

Country Link
WO (1) WO2015170939A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20020015062A (ko) * 1999-07-08 2002-02-27 에씨팜 유효성분의 맛이 차단되고, 즉시 방출하는 피복된 과립의제조방법
KR101082802B1 (ko) * 2011-08-19 2011-11-11 건일제약 주식회사 8-하이드록시클로미프라민 또는 그의 염을 포함하는 조루의 예방 또는 치료용 약학 조성물
EP2583669A1 (fr) * 2007-10-10 2013-04-24 Rubicon Research Private Limited Comprimés de chlorhydrate de mémantine à dissolution orale et au goût masqué
KR20140029435A (ko) * 2011-04-06 2014-03-10 릴라나 소빅 브르키치크 제약 조성물

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20020015062A (ko) * 1999-07-08 2002-02-27 에씨팜 유효성분의 맛이 차단되고, 즉시 방출하는 피복된 과립의제조방법
EP2583669A1 (fr) * 2007-10-10 2013-04-24 Rubicon Research Private Limited Comprimés de chlorhydrate de mémantine à dissolution orale et au goût masqué
KR20140029435A (ko) * 2011-04-06 2014-03-10 릴라나 소빅 브르키치크 제약 조성물
KR101082802B1 (ko) * 2011-08-19 2011-11-11 건일제약 주식회사 8-하이드록시클로미프라민 또는 그의 염을 포함하는 조루의 예방 또는 치료용 약학 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HAM, WON SIK ET AL.: "Recent Concepts of Premature Ejaculation", KOREAN JOURNAL OF UROLOGY, vol. 49, no. 9, 2008, pages 765 - 774, XP055236793 *
See also references of EP3141264A4 *

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