EP3554481A1 - Matrice pouvant être directement mise sous forme de comprimé pour la production de comprimés présentant une libération de substance active prolongée - Google Patents

Matrice pouvant être directement mise sous forme de comprimé pour la production de comprimés présentant une libération de substance active prolongée

Info

Publication number
EP3554481A1
EP3554481A1 EP17842357.0A EP17842357A EP3554481A1 EP 3554481 A1 EP3554481 A1 EP 3554481A1 EP 17842357 A EP17842357 A EP 17842357A EP 3554481 A1 EP3554481 A1 EP 3554481A1
Authority
EP
European Patent Office
Prior art keywords
grained
fine
tablet
hpmc
release
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP17842357.0A
Other languages
German (de)
English (en)
Inventor
Gudrun BIRK
Guenter Moddelmog
Thorsten Wedel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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 Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP3554481A1 publication Critical patent/EP3554481A1/fr
Withdrawn legal-status Critical Current

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to tablets of extremely long duration
  • Polyvinyl alcohols are synthetic polymers used in the following
  • Parteck ® SRP 80 a polyvinyl alcohol-quality, which is sold commercially, and which is a respect and compressibility
  • retarding agent usually a cumulative release of about 10 to 12 hours (90 to 100% final drug release). However, some users want an even more delayed in-vitro
  • a further object is to use a pulverulent, active ingredient-containing mixture with the above-mentioned, optimized PVA type (PVA 40-88) as carrier material for the production of active ingredient-containing tablets for
  • PCT / EP2016 / 001430 and PCT / EP2016 / 001431 disclose that drug-containing matrix retard tablets can be prepared using these co-mixtures which, in addition to good galenic tablet properties, have drug release over 12 hours with cumulative in vitro drug release from 80 to 100% show.
  • the co-mixtures which, in addition to good galenic tablet properties, have drug release over 12 hours with cumulative in vitro drug release from 80 to 100% show.
  • Tablet hardness Furthermore, it is shown in these applications that for these tablets, the drug release is largely independent of the pH in the range of pH 1 to 7 and the alcohol content (0 to 40% by volume) of the release media. These are all factors that Prerequisites for preventing possible "dose-dumping" effects.
  • Microcrystalline cellulose (MCC) and hydroxypropylmethylcelluloses (HPMCs) of different viscosities show good compression properties and greatly delayed in vitro drug release.
  • Dissolution rate of the matrix itself is further delayed, while at the same time, however, the diffusion of the drug from the tablet is slowed down.
  • microcrystalline celluloses with the addition of further hydrophilic polymers, in particular of hydroxypropylmethylcelluloses
  • the formulator is enabled in a simple process (direct tabletting) to influence the in vitro release profiles of prolonged-release tablets by a simple mixing of an active ingredient (API) with a PVA / HPMC / MCC premix, and the
  • Mixing ratios of the three components may be said to be "extreme" prolongation of drug release
  • Especially advantageous over formulas based on HPMC alone are the significantly higher bulk and tamping densities of the PVA / HPMC / MCC combinations that allow for smaller size tablets to get at the same weight.
  • Propranololtabletten show a particularly prolonged or particularly strongly retarded in vitro drug delivery.
  • the drug developer obtains a quick way to make drug tablets with an extremely delayed in vitro release profile, and an active ingredient in a low-mixing mixing method with the premix consisting of the above three components, and be able to formulate the desired tablets by direct compression.
  • Blending of these co-mixtures with the active ingredient here by way of example with propranolol HCl, and other additives and compression at 5, 10, 20 and 30 kN pressing force followed by galenic
  • Extended-release tablets are made by direct tableting.
  • very particularly preferably Co-mixtures consisting of the powdered PVA 40-88 (Parteck ® SRP 80, Merck KGaA, Germany) or 26-88 with HPMC Methocel ® K4M and K100M (both DOW), in combination with MCC Vivapur ® 102 (JRS), wherein the components PVA, HPMC and MCC preferably in the weight ratios of 50: 35 are used, and as preferred: 15: 45.5: 4.5 to 50
  • Retardation matrices are used.
  • compositions are kept in a closed 5 minutes
  • Average data (arithmetic mean values) from 20 tablet measurements per pressing force. The measurements are made one day after the tablet is made.
  • Tablet mass average (arithmetic mean) of the weighing of 20 tablets for each force: Multicheck ® 5.1 (Erweka, Germany.) With Balance Sartorius CPA 64 (from Sartorius, Germany.). The measurements are made one day after the tablet is made.
  • ERWEKA DT70 release device equipped with Apparatus 2 (Paddle Apparatus according to Ph.Eur.), ERWEKA, Germany
  • Samples are taken after 15, 30, 45, 60 minutes and then every hour up to 12 hours or additionally after 17, 22, 27, 32, 37 and 42
  • PVA 26-88 polyvinyl alcohol 26-88 suitable for use as excipient EMPROVE ® exp Ph Eur, USP, JPE, Article no.
  • PVA 40-88 polyvinyl alcohol 40-88, suitable for use as excipient EMPROVE ® exp Ph Eur, USP, JPE,
  • Tablettiermatrix can be used.
  • stamping dies and thus also no constant tablet weight at high rotational speeds of the (rotary) tableting machines.
  • fine-grained PVAs can ensure a homogeneous distribution of the active ingredient in the tablet without the occurrence of segregation effects. This is for the assurance of
  • Retardation matrices crushed i. be ground.
  • the desired particle size is generated empirically, in particular by varying the grinding temperature, i. By running in-process controls of the particle size, the milling conditions are varied until the desired grain size is obtained.
  • Microcrystalline cellulose (Vivapur ® Type MCP 102 Premium, microcrystalline cellulose, Ph Eur, NF, JP, JRS Pharma, Rosenberg, Germany Particle distribution determined by laser diffraction with dry dispersion (1 bar counterpressure):
  • HPMC K4M Methocel ® K4M Premium CR hydroxypropyl
  • Blends PVA 40-88, MCC and HPMC K100M Examples A to D and Comparisons 1 and 2, respectively
  • Blends PVA 40-88, MCC and HPMC K4M Examples E to H and Comparison 3, respectively
  • step 1 Preparation and galenic characterization of the co-mixtures Examples A to J and Comparisons 1 to 4:
  • Blends of the mixtures according to tables Table 1 a Blends PVA 40-88, MCC and HPMC K100M: Examples A to D and Comparisons 1 and 2, respectively
  • Table 1 b Blends PVA 40-88, MCC and HPMC K4M: Examples E to H and Comparisons 1 and 3, respectively
  • Table 2a Blends PVA 40-88, MCC and HPMC K1 OOM:
  • Table 2b Blends PVA 40-88, MCC and HPMC K4M:
  • step 2 composition, preparation and galenic
  • Table 3a Composition (in% by weight) of propranolol HCl
  • Table 3c Composition (in% by weight) of propranolol HCl
  • Tablet hardness, tablet mass, tablet height, tablet abrasion and necessary ejection force Tablet hardness, tablet mass, tablet height, tablet abrasion and necessary ejection force.
  • Table 4a Tablettier Scheme the propranolol HCl prolonged-release tablets under
  • FIG. 1 a graphically shows the press force tablet hardness profiles of the examples and comparisons for better illustration.
  • FIG. 1 a Press force tablet hardness profiles of propranolol HCl
  • Table 4b Tablettier Scheme the propranolol HCl prolonged-release tablets under
  • FIG. 1 b graphically illustrates the press force tablet hardness profiles of the examples and comparisons for better illustration.
  • FIG. 1 b Press force tablet hardness profiles of propranolol HCl
  • Table 4c Tabletting data of propranolol HCl prolonged-release tablets using the premixes of Examples I and J and Comparisons 2 and 4
  • FIG. 1 c graphically illustrates the compression force tablet hardness profiles of the examples and comparisons for ease of illustration.
  • Figure 1 c Press force tablet hardness profiles of propranolol HCl
  • FIG. 2a graphically depicts the releases at pH 6.8 from Table 5a for better illustration.
  • FIG. 2a In vitro release data of the tablets from the experiments
  • the cumulative amounts of released propranolol HCl (in%) from the tablets are given at 20 kN pressing force over 42 hours.
  • FIG. 2b In vitro release data of the tablets of Examples E to H and of Comparisons 1 and 3 at pH 6.8 over 42 hours
  • the cumulative amounts of released propranolol HCl (in%) from the tablets are given at 20 kN pressing force over 12 hours.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des comprimés présentant une libération de substance active nettement prolongée, leur composition particulière et leur production.
EP17842357.0A 2016-12-14 2017-12-11 Matrice pouvant être directement mise sous forme de comprimé pour la production de comprimés présentant une libération de substance active prolongée Withdrawn EP3554481A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16204112 2016-12-14
PCT/EP2017/082122 WO2018108764A1 (fr) 2016-12-14 2017-12-11 Matrice pouvant être directement mise sous forme de comprimé pour la production de comprimés présentant une libération de substance active prolongée

Publications (1)

Publication Number Publication Date
EP3554481A1 true EP3554481A1 (fr) 2019-10-23

Family

ID=57570015

Family Applications (1)

Application Number Title Priority Date Filing Date
EP17842357.0A Withdrawn EP3554481A1 (fr) 2016-12-14 2017-12-11 Matrice pouvant être directement mise sous forme de comprimé pour la production de comprimés présentant une libération de substance active prolongée

Country Status (12)

Country Link
US (1) US20190307698A1 (fr)
EP (1) EP3554481A1 (fr)
JP (1) JP2020510626A (fr)
KR (1) KR20190095373A (fr)
CN (1) CN110381927A (fr)
AR (1) AR110685A1 (fr)
AU (1) AU2017375712A1 (fr)
BR (1) BR112019012104A2 (fr)
CA (1) CA3046834A1 (fr)
MX (1) MX2019005546A (fr)
PH (1) PH12019500992A1 (fr)
WO (1) WO2018108764A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114126408A (zh) * 2019-05-31 2022-03-01 戴纳立制药公司 嘧啶基氨基-吡唑化合物的改良释放配制品和治疗方法
GR1010024B (el) * 2020-05-06 2021-06-01 Φαρματεν Α.Β.Ε.Ε. Φαρμακευτικο σκευασμα ελευθερο συντηρητικου για οφθαλμικη χορηγηση που περιλαμβανει βριμονιδινη
WO2023171730A1 (fr) 2022-03-10 2023-09-14 三菱ケミカル株式会社 Composition pharmaceutique, comprimé pharmaceutique et son procédé de fabrication

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050250838A1 (en) * 2004-05-04 2005-11-10 Challapalli Prasad V Formulation for sustained delivery
DE102004062257A1 (de) * 2004-12-23 2006-07-06 Merckle Gmbh Direkt verpresste Indapamid-Tabletten mit verzögerter Wirkstofffreisetzung
KR100762847B1 (ko) * 2006-01-27 2007-10-04 씨제이 주식회사 멀티플 유닛 타입 서방성 경구 제제 및 그 제조방법
NZ600123A (en) * 2009-11-30 2015-04-24 Aptalis Pharmatech Inc Compressible-coated pharmaceutical compositions and tablets and methods of manufacture
DK3174530T3 (en) 2014-07-30 2018-11-26 Merck Patent Gmbh DIRECT COMPATIBLE POLYVINYL ALCOHOLS
KR20170038039A (ko) 2014-07-30 2017-04-05 메르크 파텐트 게엠베하 분상, 직접 압축성 유형의 폴리비닐 알코올
KR20170036768A (ko) 2014-07-30 2017-04-03 메르크 파텐트 게엠베하 미세결정성 셀룰로오스를 포함하는 직접 압축성 조성물

Also Published As

Publication number Publication date
PH12019500992A1 (en) 2019-11-25
AR110685A1 (es) 2019-04-24
KR20190095373A (ko) 2019-08-14
BR112019012104A2 (pt) 2019-10-29
MX2019005546A (es) 2019-08-12
CN110381927A (zh) 2019-10-25
JP2020510626A (ja) 2020-04-09
WO2018108764A1 (fr) 2018-06-21
US20190307698A1 (en) 2019-10-10
AU2017375712A1 (en) 2019-08-01
CA3046834A1 (fr) 2018-06-21

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