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EP2477605A1 - Préparations pharmaceutiques solides à dissolution rapide contenant des copolymères amphiphiles à base de polyéthers en combinaison avec des tensioactifs - Google Patents

Préparations pharmaceutiques solides à dissolution rapide contenant des copolymères amphiphiles à base de polyéthers en combinaison avec des tensioactifs

Info

Publication number
EP2477605A1
EP2477605A1 EP10754472A EP10754472A EP2477605A1 EP 2477605 A1 EP2477605 A1 EP 2477605A1 EP 10754472 A EP10754472 A EP 10754472A EP 10754472 A EP10754472 A EP 10754472A EP 2477605 A1 EP2477605 A1 EP 2477605A1
Authority
EP
European Patent Office
Prior art keywords
dosage forms
surfactants
surfactant
polyether
weight
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Withdrawn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
EP10754472A
Other languages
German (de)
English (en)
Inventor
Karl Kolter
Dejan Djuric
Stefan Fischer
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.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Priority to EP10754472A priority Critical patent/EP2477605A1/fr
Publication of EP2477605A1 publication Critical patent/EP2477605A1/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Withdrawn legal-status Critical Current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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • the present invention relates to solid pharmaceutical preparations of amphiphilic copolymers and sparingly water-soluble active ingredients in combination with surfactants, which are able to influence the stability of the formulation and / or the release of the active ingredients.
  • Solubilization is understood to mean the solubilization of substances which are soluble or insoluble in a particular solvent, in particular water, by surface-active compounds, the solubilizers. Such solubilizers are able to convert poorly water-soluble or water-insoluble substances in clear, at most opalescent aqueous solutions, without this undergoes a change in the chemical structure of these substances.
  • solid solution refers to a state in which a substance is dispersed colloidally or, ideally, molecularly dispersed in a solid matrix such as a polymer matrix .
  • solid solutions for example, when used in solid pharmaceutical dosage forms of a poorly soluble drug to an improved release of the drug.
  • An important requirement of such solid solutions is that they are stable even when stored for a long time, ie, that the active ingredient does not crystallize out.
  • the capacity of the solid solution in other words the ability to form stable solid solutions with the highest possible active ingredient contents, is of importance.
  • WO 2007/051743 discloses the use of water-soluble or water-dispersible copolymers of N-vinyllactam, vinyl acetate and polyethers as solubilizers for pharmaceutical, cosmetic, food-processing, agro-technical or other technical applications. Therein it is generally described that the corresponding graft polymers can also be processed in the melt with the active ingredients.
  • the object of the present invention was to find an improved process and thus improved preparations of substances which are sparingly soluble in water and which, with good bioavailability, enable a stable suspension of the release. Accordingly, a process for the preparation of formulations of sparingly water-soluble biologically active substances in a polymer matrix based on copolymers obtained by free-radically initiated polymerization of a mixture of i) 30 to 80 wt .-% N-vinyl lactam,
  • iii) 10 to 50% by weight of a polyether, with the proviso that the sum of i), ii) and iii) is equal to 100% by weight, which process is characterized in that surfactants are added during processing.
  • preferred polymers are obtained from: i) 30 to 70% by weight of N-vinyllactam
  • Polymers used with particular preference are obtainable from: i) 40 to 60% by weight of N-vinyllactam
  • Very particularly preferably used polymers are obtainable from i) 50 to 60 wt .-% N-vinyl lactam
  • iii) from 10 to 20% by weight of a polyether. It is also true for the preferred and particularly preferred compositions that the sum of the components i), ii), and iii) is equal to 100% by weight.
  • N-vinyllactam are N-vinylcaprolactam or N-vinylpyrrolidone or mixtures thereof. Preference is given to using N-vinylcaprolactam.
  • the graft is polyether.
  • Suitable polyethers are preferably polyalkylene glycols.
  • the polyalkylene glycols may have molecular weights of from 1000 to 100,000 D [daltons], preferably from 1500 to 35,000 D, more preferably from 1,500 to 10,000 D. The molecular weights are determined on the basis of the measured according to DIN 53240 OH number.
  • the preferred polyalkylene glycols also include those which are alkylated at one or both OH end groups.
  • Suitable alkyl radicals are branched or unbranched C to C22-alkyl radicals, preferably C 1 -C 6 -alkyl radicals, for example methyl, ethyl, n-butyl, isobutyl, pentyl, hexyl, octyl, nonyl, decyl , Dodecyl, tridecyl or octadecyl radicals.
  • General processes for the preparation of the novel graft copolymers are known per se.
  • the preparation is carried out by free-radically initiated polymerization, preferably in solution, in nonaqueous, organic solvents or in mixed nonaqueous / aqueous solvents.
  • Suitable preparation processes are described, for example, in WO 2007/051743 and WO 2009/013202, to the disclosure of which reference is expressly made with regard to the preparation process.
  • the melt thus obtained can then be cooled and granulated.
  • a so-called hot break or cooling takes place under air or inert gas, for example, on a Teflon or chain belt and subsequent granulation of the cooled melt strand.
  • air or inert gas for example, on a Teflon or chain belt and subsequent granulation of the cooled melt strand.
  • it can also be a cooling in a solvent, in which the polymers are not significantly soluble.
  • Suitable twin-screw extruders may have a screw diameter of 16 to 70 mm and a length of 25 to 40 D. ,
  • the resulting extrudate strands can be processed into granules with a granulator and these can in turn be further comminuted (ground) into a powder.
  • the granules or powder can be filled into capsules or pressed into tablets using conventional tableting excipients. In this case, further release-controlling adjuvants can also be used.
  • water-soluble high glass transition temperature polymers such as e.g. Polyvinyl pyrroli- don with K values of 17 to 120, hydroxyalkyl or hydroxalkyl used. Too high a glass transition temperature of the formulation can be lowered by adding plasticizers.
  • plasticizers are suitable, which are also used for pharmaceutical coatings, such. Triethyl citrate, tributyl citrate, acetyltributyl citrate, triacetin, propylene glycol, polyethylene glycol 400, dibutyl sebacate, glycerol monostearate, lauric acid, cetylstearyl alcohol.
  • substances which are sparingly soluble in water are preferably to be understood as meaning biologically active substances such as pharmaceutical active substances for humans and animals, cosmetic or agrochemical active substances or nutritional supplements or dietary active substances.
  • fillers e.g. inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium or calcium carbonate, calcium or magnesium phosphates or organic fillers such as lactose, sucrose, sorbitol, mannitol may be added.
  • inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium or calcium carbonate, calcium or magnesium phosphates or organic fillers such as lactose, sucrose, sorbitol, mannitol may be added.
  • Suitable plasticizers are, for example, triacetin, triethyl citrate, glycerol monostearate, low molecular weight polyethylene glycols or poloxamers.
  • Visual inspection of the stable solid solutions reveals no amorphous constituents.
  • the visual inspection can be done with a light microscope both with and without a polarizing filter at 40x magnification.
  • preparations can also with the aid of XRD (X-ray diffraction) and
  • the preparations obtained by the process according to the invention are amorphous, which means that the crystalline proportions of the biologically active substance are less than 5% by weight.
  • the amorphous state is checked by DSC or XRD. Such an amorphous state may also be referred to as an amorphous state.
  • the inventive method allows the production of stable preparations with high drug loading.
  • Feed 2 10.44 g of tert-butyl perpivalate (75% strength by weight in aliphatic mixture)
  • the twin-screw extruder used to prepare the formulations described in the Examples below had a screw diameter of 16 mm and a length of 40D.
  • the entire extruder was made up of 8 individually heatable cylinder blocks.
  • the prepared solid solutions were examined for crystallinity and amorphicity using XRD (X-ray diffractometry) and DSC (Differential Scanning Calorimetry) using the following equipment and conditions:
  • Measuring instrument Diffractometer D 8 Advance with 9-fold sample changer (Fa.Bruker / AXS)

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)

Abstract

Formes posologiques contenant des préparations de substances actives peu solubles dans l'eau dans une matrice polymérique composée de copolymères de polyéther, lesdits copolymères de polyéther étant obtenus par polymérisation par amorçage radicalaire d'un mélange composé de 30 à 80 % en poids de N-vinyl-lactame, de 10 à 50 % en poids de polyéther, et d'au moins un tensioactif, et dans lesquelles la substance peu soluble dans l'eau est présente sous forme amorphe dans la matrice polymérique.
EP10754472A 2009-09-18 2010-09-13 Préparations pharmaceutiques solides à dissolution rapide contenant des copolymères amphiphiles à base de polyéthers en combinaison avec des tensioactifs Withdrawn EP2477605A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10754472A EP2477605A1 (fr) 2009-09-18 2010-09-13 Préparations pharmaceutiques solides à dissolution rapide contenant des copolymères amphiphiles à base de polyéthers en combinaison avec des tensioactifs

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP09170706 2009-09-18
EP10754472A EP2477605A1 (fr) 2009-09-18 2010-09-13 Préparations pharmaceutiques solides à dissolution rapide contenant des copolymères amphiphiles à base de polyéthers en combinaison avec des tensioactifs
PCT/EP2010/063369 WO2011032907A1 (fr) 2009-09-18 2010-09-13 Préparations pharmaceutiques solides à dissolution rapide contenant des copolymères amphiphiles à base de polyéthers en combinaison avec des tensioactifs

Publications (1)

Publication Number Publication Date
EP2477605A1 true EP2477605A1 (fr) 2012-07-25

Family

ID=43302040

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10754472A Withdrawn EP2477605A1 (fr) 2009-09-18 2010-09-13 Préparations pharmaceutiques solides à dissolution rapide contenant des copolymères amphiphiles à base de polyéthers en combinaison avec des tensioactifs

Country Status (6)

Country Link
US (1) US20120178827A1 (fr)
EP (1) EP2477605A1 (fr)
JP (1) JP2013505211A (fr)
CN (1) CN102548540A (fr)
BR (1) BR112012005938A2 (fr)
WO (1) WO2011032907A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9032390B2 (en) * 2008-07-29 2015-05-12 Qualcomm Incorporated Framework versioning
US8636929B2 (en) 2010-05-21 2014-01-28 Basf Se Nanoporous foamed active compound-containing preparations based on pharmaceutically acceptable thermoplastically workable polymers
EP2463327A3 (fr) * 2010-12-10 2015-06-03 Basf Se Procédé de fabrication de granulés comprenant au moins un composant soluble dans l'eau
CN104510707A (zh) * 2013-09-26 2015-04-15 博瑞生物医药技术(苏州)有限公司 一种泊沙康唑固体分散体及其制备方法
WO2016071434A1 (fr) * 2014-11-05 2016-05-12 Abbott Laboratories Gmbh Procédés pour produire des compositions à profil de sécurité d'emploi amélioré comprenant de la pancréatine et des compositions adaptées à un usage pharmaceutique

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005053066A1 (de) * 2005-11-04 2007-05-10 Basf Ag Verwendung von Copolymeren als Solubilisatoren für in Wasser schwerlöslichen Verbindungen
EP2173781A1 (fr) * 2007-07-26 2010-04-14 Basf Se Procédé de fabrication de copolymères à base de polyéthers sous forme solide pouvant être obtenus par polymérisation-greffage en solution
WO2010112489A2 (fr) * 2009-03-31 2010-10-07 Basf Se Procédé de production de préparations de substances difficilement solubles dans l'eau
BRPI1010550B1 (pt) * 2009-05-13 2019-11-05 Basf Se formas de dosagem, e, processo para a produção de preparações para formas de dosagem de substâncias ativas fracamente solúveis em água

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011032907A1 *

Also Published As

Publication number Publication date
CN102548540A (zh) 2012-07-04
BR112012005938A2 (pt) 2016-03-15
US20120178827A1 (en) 2012-07-12
WO2011032907A1 (fr) 2011-03-24
JP2013505211A (ja) 2013-02-14

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