WO2001097803A1 - Preparations pharmaceutiques comportant du racecadotril (acetorphane) - Google Patents

Preparations pharmaceutiques comportant du racecadotril (acetorphane) Download PDF

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Publication number
WO2001097803A1
WO2001097803A1 PCT/EP2001/007007 EP0107007W WO0197803A1 WO 2001097803 A1 WO2001097803 A1 WO 2001097803A1 EP 0107007 W EP0107007 W EP 0107007W WO 0197803 A1 WO0197803 A1 WO 0197803A1
Authority
WO
WIPO (PCT)
Prior art keywords
racecadotril
pharmaceutical
formulation
granulate
pharmaceutical granulate
Prior art date
Application number
PCT/EP2001/007007
Other languages
English (en)
Inventor
Nathalie Claude Marianne Barges Causeret
Jean-Philippe Giraud
Original Assignee
Laboratoire Glaxosmithkline
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 Laboratoire Glaxosmithkline filed Critical Laboratoire Glaxosmithkline
Priority to AU2001266084A priority Critical patent/AU2001266084A1/en
Publication of WO2001097803A1 publication Critical patent/WO2001097803A1/fr

Links

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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/009—Sachets, pouches characterised by the material or function of the envelope
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • 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
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals

Definitions

  • the present invention relates to novel formulations of the compound racecadotril, and their use in the treatment of diarrhoea.
  • Racecadotril is the compound of structure (I) in the form of a racemate:
  • Racecadotril has recently been launched onto the market in a number of countries under the tradename HIDRASEC (trademark of S ⁇ iithkline Beecham pic).
  • the marketed form is in the form of a dry powder filled into a hard gelatin capsule.
  • certain disadvantages are associated with the formulations as noted below.
  • Racecadotril is a hydrophobic, or water-hating, compound and as such has proved difficult to formulate into stable and acceptable dosage formulations.
  • granules of suitable hardness generally have improved flow characteristics that are important for efficient capsule filling.
  • racecadotril can be formulated into granules using a starch disintegrant having particular characteristics, to provide granules of suitable hardness so as to provide free flowing stable granules for filling into hard gelatin capsules.
  • the granules of the present invention can be used to provide dry powder formulations for direct ingestion, and dry powder formulations for reconstitution into a suspension formulation.
  • suspension formulations is a valuable and convenient dosage form for dosing to paediatric patients, and one which has not been achievable before due to the inherent hydrophobic nature of the active ingredient racecadotril.
  • the present invention therefore provides in a first aspect, a pharmaceutical granulate formulation comprising racecadotril, in association with, at least one diluent, at least one lubricant, and a starch based intragranular disintegrant having the following characteristics:
  • the intragranular disintegrant is a gelatinised maize starch having the above noted characteristics.
  • the intragranular disintegrant is a gelatinised maize starch having:
  • the intragranular disintegrant is selected from C*pharm 93000 gelatinised maize starch, Lycatab 15c gelatinised maize starch, or Starch 1500 gelatinised maize starch
  • the intragranular disintegrant is C*pharm 93000 gelatinised maize starch.
  • C*pharm 93000 is a trademark of gelatinised maize starch (Direct compressible starch) and available form CERESTAR at CERESTAR France SA , 14 Bd General Leclerc- 92572 Neuilly-sur-Seine, Lycatab 15c is a trademark of gelatinised maize starch, and is available from Roquette Company at ROQUETTE FRERES 62136 LESTREM, France, Starch 1500 is a trademark of gelatinised maize starch and is available from COLORCON at Colorcon France - 62-70 rue Yvan Tourguenieff 78 380 BOUGIVAL FRANCE)
  • Suitable diluents will be apparent to those skilled in the art, and include for example, silicon dioxide, microcrystalline cellulose, dicalcium phosphate, sorbitol, lactose, calcium carbonate and magnesium carbonate.
  • the diluent is lactose.
  • Suitable lubricants will be apparent to those skilled in the art, and include for example, long chain fatty acids such as stearic acid or salts thereof, in particular group II metal salts such as magnesium or calcium, or amorphous silicon such as Aerosil R 972 or Aerosil 200, sodium benzoate or sodium laurylsulphate. Either a single lubricant can be used, or a combination of diluents to achieve the desired flow characteristics for the granulates. Preferred in the present invention is magnesium stearate in combination with aerosil R 972.
  • the ratio, of diluent, lubricants and disintegrant will depend on the hardness and flow characteristics to be achieved.
  • preferred combinations of the components, and their respective proportions in the granulates are as follows.
  • the present invention comprises a process for the manufacture of a pharmaceutical granulate, as hereinbefore disclosed, which process comprises mixing the ingredients of the granulate together in powder form under dry conditions, and then compacting the mixture into granulates by conventional dry powder compaction techniques, for example by pressing, rolling, slugging extrusion etc, under a suitable pressure for the compaction process, for example, 30-200 KN, e.g., 35-65 KN, preferably 45-50 KN.
  • the presently claimed granulate is particularly suited to manufacture via slugging, in particular it has been found that a single slugging step is generally sufficient to provide granulates of the required hardness. It is generally necessary to mill and sieve the compacted mixture after compaction so as to achieve a suitable size fraction of granulate. In particular, particles of particle size of from 1 to 2 mm are preferred, most preferred the particles are milled and sieved to a fraction size of around 1.25mm
  • the granulates described herein can be filled into hard gelatin capsules suitable for oral administration.
  • capsules can be prepared so as to contain i to 125 mg of active ingredient, preferably from 80 to 125 mg, most preferably 100 mg per capsule size n°2.
  • larger amounts of active can be included if the capsule size is increased as for example capsule size n°l, 0, or 0+ etc.
  • the granulates of the present invention are suitable for use in the preparation of other pharmaceutical formulations, for example, they may be provided as free flowing granulated formulations for use in dry powder sachets containing a single dose of racecadotril.
  • Such dosage forms may be suitable for dosing direct to patients without reconstitution with water.
  • a single sachet will provide a dose of from 1 to 100 mg of racecadotril, preferably 6 to 30mg of racecadotril and preferably 6, 10, 18 and 30 mg of racecadotril.
  • the dry powder form may be provided as a form suitable for reconstitution with water to provide suspension formulations of racecadotril.
  • the dry granulate would be provided in a bottle providing sufficient compound for a course of treatment on reconstitution. Such a course would preferably be over several days, so that once the suspension has been made up, a full course is available. It is to be noted that, the provision of a dry powder form, and a suspension formulation forms a further aspect of the invention.
  • formulations of racecadotril, in particular as suspension formulations had not been known due to the hydrophobic nature of the compound making the provision of suspensions a difficult technical hurdle to overcome.
  • Suitable sweetening agents include for example, aspartame, K acesulphame, saccharine, ammonium glycyrrizinate, sodium cyclamate and sucrose.
  • Suitable thickening agents include for example Xantham gum, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, Guar Gum , carbopol 974 P, hydroxymethylpropylcellulose and silica gel. Suitable combinations of sweetening and thickening agents will of course be within the scope of the skilled formulator and depend on the precise nature of the final formulation desired.
  • coloring agents may added to improve the compliance of the patients
  • Diluents may be added to improve the suitability for filling into bottles.
  • Suitable diluents include, for example, silica gel, sorbitol, lactose and mannitol.
  • preservatives include for example sodium benzoate, parabens (such as propylparahydroxybenzoate and methylparahydroxybenzoate) and potassium sorbate.
  • a spray drying step can also be included.
  • the granules can be spray dried either with a solution of an amphiphilic compound such as glycerol formal or a derivative thereof, without further drying, or with dimethylpolysiloxane or lecithine emulsions followed by a drying step.
  • the invention further provides pharmaceutical granulate formulations as described hereinabove for use an active pharmaceutical substance.
  • the invention further provides active granulate formulations as described above, for use in the treatment of diarrhoea.
  • the invention further provides a method of treatment of diarrhoea in mammals which comprises administration to the mammal of an effective amount of a pharmaceutical granulate formulation as described hereinabove.
  • the granulates of racecadotril are prepared according to the procedure described in example 1, calibrated on a 1.25mm, sieve and then milled on an Apex machine or Frewitt to the reduced size suitable for filling into sachets .
  • the remaining excipients are added to the granulates to form a blend for filling into sachets.
  • the sachets are then sealed until administration.
  • racecadotril The granulates of racecadotril are prepared according to the procedure described in example 1, calibrated on a 1.25mm sieve and then milled on an Apex machine or

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur une nouvelle préparation pharmaceutique granulaire comportant un antidiarrhéique, au moins un diluant, au moins un lubrifiant, et un agent de désintégration des granulés aux caractéristiques définies.
PCT/EP2001/007007 2000-06-23 2001-06-20 Preparations pharmaceutiques comportant du racecadotril (acetorphane) WO2001097803A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001266084A AU2001266084A1 (en) 2000-06-23 2001-06-20 Pharmaceutical preparations comprising racecadotril (acetorphan)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0015490.6 2000-06-23
GBGB0015490.6A GB0015490D0 (en) 2000-06-23 2000-06-23 Novel formulations

Publications (1)

Publication Number Publication Date
WO2001097803A1 true WO2001097803A1 (fr) 2001-12-27

Family

ID=9894320

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2001/007007 WO2001097803A1 (fr) 2000-06-23 2001-06-20 Preparations pharmaceutiques comportant du racecadotril (acetorphane)

Country Status (3)

Country Link
AU (1) AU2001266084A1 (fr)
GB (1) GB0015490D0 (fr)
WO (1) WO2001097803A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001097801A2 (fr) * 2000-06-23 2001-12-27 Societe Civile Bioprojet Formulation
FR2900823A1 (fr) * 2006-05-15 2007-11-16 Bioprojet Soc Civ Ile Nouvelle forme d'administration du racecadotril.
WO2009022893A1 (fr) * 2007-07-27 2009-02-19 ESPINOSA ABDALA, Leopoldo de Jesús Composition pharmaceutique comprenant la combinaison d'un agent antimicrobien et d'un agent inhibiteur sélectif de l'enzyme encéphalinase, indiquée pour la lutte contre, ainsi que le traitement de, la diarrhée aiguë d'origine bactérienne
CN101103960B (zh) * 2006-07-14 2010-12-08 海南盛科生命科学研究院 一种含有消旋卡多曲的干混悬剂及其制备方法
CN102166197A (zh) * 2011-04-25 2011-08-31 四川百利药业有限责任公司 消旋卡多曲颗粒及其生产工艺
EP2462922A1 (fr) * 2010-12-10 2012-06-13 Bioprojet Nouvelle forme d'administration pour inhibiteurs de l'enképhalinase
CN104356036A (zh) * 2014-11-07 2015-02-18 山东齐都药业有限公司 消旋卡多曲α 晶型及其制备方法
EP2918268A1 (fr) 2014-03-10 2015-09-16 Galenicum Health S.L. Compositions pharmaceutiques comprenant un agent actif
EP2949318A1 (fr) 2014-05-26 2015-12-02 Galenicum Health S.L. Compositions pharmaceutiques comprenant du racécadotril
WO2016069871A1 (fr) 2014-10-29 2016-05-06 Johnson & Johnson Consumer Inc. Particules de cadotril
WO2016128098A1 (fr) * 2015-02-09 2016-08-18 Rivopharm Sa Formulation pharmaceutique de racécadotril
US9636300B2 (en) 2013-03-15 2017-05-02 Johnson & Johnson Consumer Inc. Racecadotril lipid compositions
US10039712B2 (en) 2012-06-28 2018-08-07 Johnson & Johnson Consumer Inc. Racecadotril lipid compositions
WO2018163195A1 (fr) * 2017-03-06 2018-09-13 Athena Drug Delivery Solutions Pvt Ltd. Composition pharmaceutique comprenant du racécadotril et son procédé de préparation
WO2022103269A2 (fr) 2020-11-16 2022-05-19 Pharmamatch B.V. Formulation de granulé pharmaceutique et son procédé de préparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0038758A1 (fr) * 1980-04-17 1981-10-28 Societe Civile Bioprojet Dérivés d'acides aminés et leur application thérapeutique
EP0318377A2 (fr) * 1987-11-24 1989-05-31 Societe Civile Bioprojet Nouveaux composés énantiomères dérivés d'amino-acides, leur procédé de préparation et leurs applications thérapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0038758A1 (fr) * 1980-04-17 1981-10-28 Societe Civile Bioprojet Dérivés d'acides aminés et leur application thérapeutique
EP0318377A2 (fr) * 1987-11-24 1989-05-31 Societe Civile Bioprojet Nouveaux composés énantiomères dérivés d'amino-acides, leur procédé de préparation et leurs applications thérapeutiques

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001097801A3 (fr) * 2000-06-23 2002-09-12 Ile Bioprojet Soc Civ Formulation
WO2001097801A2 (fr) * 2000-06-23 2001-12-27 Societe Civile Bioprojet Formulation
US8318203B2 (en) 2006-05-15 2012-11-27 Bioprojet Form of administration of racecadotril
FR2900823A1 (fr) * 2006-05-15 2007-11-16 Bioprojet Soc Civ Ile Nouvelle forme d'administration du racecadotril.
WO2007132091A1 (fr) * 2006-05-15 2007-11-22 Bioprojet Nouvelle forme d'administration du racecadotril
EA014707B1 (ru) * 2006-05-15 2011-02-28 Биопроже Новая форма введения рацекадотрила
AP2627A (en) * 2006-05-15 2013-03-26 Bioprojet Soc Civ New form of administration of racecadotril
CN101103960B (zh) * 2006-07-14 2010-12-08 海南盛科生命科学研究院 一种含有消旋卡多曲的干混悬剂及其制备方法
WO2009022893A1 (fr) * 2007-07-27 2009-02-19 ESPINOSA ABDALA, Leopoldo de Jesús Composition pharmaceutique comprenant la combinaison d'un agent antimicrobien et d'un agent inhibiteur sélectif de l'enzyme encéphalinase, indiquée pour la lutte contre, ainsi que le traitement de, la diarrhée aiguë d'origine bactérienne
WO2012076691A1 (fr) * 2010-12-10 2012-06-14 Bioprojet Nouvelle forme d'administration d'un inhibiteur de l'enképhalinase
EP2462922A1 (fr) * 2010-12-10 2012-06-13 Bioprojet Nouvelle forme d'administration pour inhibiteurs de l'enképhalinase
US20130331423A1 (en) * 2010-12-10 2013-12-12 Bioprojet Form of Administration of Enkephalinase Inhibitor
EA022730B1 (ru) * 2010-12-10 2016-02-29 Биопроже Новая форма введения ингибитора энкефалиназы
US9439853B2 (en) 2010-12-10 2016-09-13 Bioprojet Form of administration of enkephalinase inhibitor
AP3787A (en) * 2010-12-10 2016-08-31 Bioprojet Soc Civ New form of administration of enkephalinase inhibitor
CN102166197B (zh) * 2011-04-25 2012-09-05 四川百利药业有限责任公司 消旋卡多曲颗粒及其生产工艺
CN102166197A (zh) * 2011-04-25 2011-08-31 四川百利药业有限责任公司 消旋卡多曲颗粒及其生产工艺
US10039712B2 (en) 2012-06-28 2018-08-07 Johnson & Johnson Consumer Inc. Racecadotril lipid compositions
US9801819B2 (en) 2012-06-28 2017-10-31 Johnson & Johnson Consumer Inc. Racecadotril compositions
US9636300B2 (en) 2013-03-15 2017-05-02 Johnson & Johnson Consumer Inc. Racecadotril lipid compositions
EP2918268A1 (fr) 2014-03-10 2015-09-16 Galenicum Health S.L. Compositions pharmaceutiques comprenant un agent actif
EP2949318A1 (fr) 2014-05-26 2015-12-02 Galenicum Health S.L. Compositions pharmaceutiques comprenant du racécadotril
US10022349B2 (en) 2014-10-29 2018-07-17 Johnson & Johnson Consumer Inc. Cadotril particles
WO2016069871A1 (fr) 2014-10-29 2016-05-06 Johnson & Johnson Consumer Inc. Particules de cadotril
CN104356036A (zh) * 2014-11-07 2015-02-18 山东齐都药业有限公司 消旋卡多曲α 晶型及其制备方法
AU2015382526B2 (en) * 2015-02-09 2020-09-10 Rivopharm Sa Pharmaceutical formulation of racecadotril
EA035038B1 (ru) * 2015-02-09 2020-04-21 Ривофарма Са Лекарственная форма препарата рацекадотрил
CN107438431A (zh) * 2015-02-09 2017-12-05 瑞沃制药股份公司 消旋卡多曲的药物制剂
CN107438431B (zh) * 2015-02-09 2020-12-15 瑞沃制药股份公司 消旋卡多曲的药物制剂
US20180028448A1 (en) * 2015-02-09 2018-02-01 Rivopharm Sa Pharmaceutical Formulation of Racecadotril
US10188607B2 (en) 2015-02-09 2019-01-29 Rivopharm Sa Pharmaceutical formulation of racecadotril
WO2016128098A1 (fr) * 2015-02-09 2016-08-18 Rivopharm Sa Formulation pharmaceutique de racécadotril
KR20180129807A (ko) * 2017-03-06 2018-12-05 아테나 파르마쎄티크 에스에이에스 라세카도트릴을 포함하는 약학 조성물 및 이를 제조하는 방법
US20200061014A1 (en) * 2017-03-06 2020-02-27 Athena Pharmaceutiques Sas A pharmaceutical composition comprising racecadotrl and process for preparing the same
WO2018163195A1 (fr) * 2017-03-06 2018-09-13 Athena Drug Delivery Solutions Pvt Ltd. Composition pharmaceutique comprenant du racécadotril et son procédé de préparation
KR102195776B1 (ko) 2017-03-06 2020-12-29 아테나 파르마쎄티크 에스에이에스 라세카도트릴을 포함하는 약학 조성물 및 이를 제조하는 방법
WO2022103269A2 (fr) 2020-11-16 2022-05-19 Pharmamatch B.V. Formulation de granulé pharmaceutique et son procédé de préparation
WO2022103269A3 (fr) * 2020-11-16 2022-06-23 Pharmamatch B.V. Formulation de granulé pharmaceutique et son procédé de préparation
NL2026905B1 (en) * 2020-11-16 2022-06-30 Pharmamatch B V Pharmaceutical granulate formulation and method for the preparation thereof

Also Published As

Publication number Publication date
AU2001266084A1 (en) 2002-01-02
GB0015490D0 (en) 2000-08-16

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