EP3073996A1 - Composition pharmaceutique comprenant de l'ivabradine amorphe - Google Patents

Composition pharmaceutique comprenant de l'ivabradine amorphe

Info

Publication number
EP3073996A1
EP3073996A1 EP14802452.4A EP14802452A EP3073996A1 EP 3073996 A1 EP3073996 A1 EP 3073996A1 EP 14802452 A EP14802452 A EP 14802452A EP 3073996 A1 EP3073996 A1 EP 3073996A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
ivabradine
adsorbate
composition according
porous carrier
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Withdrawn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
EP14802452.4A
Other languages
German (de)
English (en)
Inventor
Rolf Keltjens
Jacobus Theodorus Henricus EUPEN VAN
Bernard Herman RIETMAN
Deepak Murpani
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.)
Byondis BV
Original Assignee
Synthon Biopharmaceuticals BV
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 Synthon Biopharmaceuticals BV filed Critical Synthon Biopharmaceuticals BV
Priority to EP14802452.4A priority Critical patent/EP3073996A1/fr
Publication of EP3073996A1 publication Critical patent/EP3073996A1/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Withdrawn legal-status Critical Current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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • 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
    • A61K9/143—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 inorganic compounds
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the compound is a pharmaceutically active compound used for the treatment of stable angina pectoris and chronic heart failure.
  • the compound was discovered by Adir and is disclosed in EP534859.
  • the compound may form acid addition salts, for instance Ivabradine hydrochloride, which is the active ingredient in the medicinal product sold under the brand name Corlentor® and Procoralan® by Laboratoires Servier.
  • Ivabradine hydrochloride exhibits polymorphism.
  • WO2006092493 discloses polymorph ⁇ of ivabradine hydrochloride, its process of preparation and compositions comprising this polymorph. Polymorph ⁇ is the most stable form and is present in the marketed tablets.
  • Other polymorphic forms of ivabradine hydrochloride are disclosed in WO2005110993, WO2006092491, WO2006092492, WO2006092494, WO2007042656, WO2007042657 and WO2013064307. The prior art thus teaches that ivabradine hydrochloride crystallizes very easily.
  • amorphous ivabradine hydrochloride is very hygroscopic and is therefore not suitable for use on pharmaceutical production scale.
  • compositions comprising ivabradine, or a pharmaceutically acceptable salt thereof, which are stable and suitable for use on a commercial scale.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an amorphous adsorbate of ivabradine, or a pharmaceutically acceptable salt thereof, on a porous carrier and one or more pharmaceutically acceptable excipients.
  • It also provides a process for preparing said adsorbate by combining ivabradine, or a pharmaceutically acceptable salt thereof, with a porous carrier in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s).
  • the invention provides a process for preparing said pharmaceutical composition comprising mixing or granulating said adsorbate with one or more excipients, followed by compression into tablets.
  • Said pharmaceutical composition may be used as a medicament, particularly in the treatment of stable angina pectoris and chronic heart failure.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an adsorbate of ivabradine, or a pharmaceutically acceptable salt thereof, on a porous carrier and one or more pharmaceutically acceptable excipients.
  • Drags that can exist in either an amorphous or crystalline form tend to crystallize over time when present in an amorphous state because the crystalline form of the drug is a lower- energy state than the amorphous form.
  • the adsorbate of the present invention containing ivabradine, or a pharmaceutically acceptable salt thereof is present in a stabilized amorphous form, which means that during stability studies no conversion into any crystalline form was observed even under stress conditions.
  • the weight ratio of ivabradine, or a pharmaceutically acceptable salt thereof, to porous carrier in the adsorbate ranges from about 1: 1 to about 1:8, preferably from 1:1 to 1:3.
  • the porous carrier is selected from the group consisting of metal oxides, metal silicates, metal phosphates, metal carbonates, zeolites and molecular sieves. More preferably the porous carrier is a metal oxide. Examples of suitable metal oxides are silicon dioxide, titanium dioxide, zinc dioxide, zinc oxide and aluminium oxide. Most preferred, the porous carrier is porous silicon dioxide, also known as silica. Typical examples of commercially available silicas are Syloid® 350 XDP and Syloid® 3150 XDP, characterized by a pore volume of >1.70 ml/g and an average particle size of 48-66 microns and 120-170 microns respectively.
  • the porous carrier has a high surface area, meaning that the carrier has a surface area of at least 20 m 2 /g, preferably at least 50 m 2 /g, more preferably at least 100 m 2 /g, and most preferably at least 180 m 2 /g.
  • the surface area of the porous carrier may be measured using standard procedures.
  • One exemplary method is by low-temperature nitrogen adsorption, based on the Brunauer, Emmett and Teller (BET) method, well known in the art.
  • BET Brunauer, Emmett and Teller
  • the aforementioned silicas Syloid® 350 XDP and Syloid® 3150 XDP have typical surface areas of 320 m 2 /g.
  • ivabradine, or a pharmaceutically acceptable salt thereof, in the adsorbate is amorphous.
  • a major portion of ivabradine, or a pharmaceutically acceptable salt thereof means that at least 60% of the drug is in amorphous form, rather than a crystalline form.
  • ivabradine, or a pharmaceutically acceptable salt thereof, in the adsorbate is at least 80% in amorphous form. More preferably, ivabradine, or a
  • ivabradine, or a pharmaceutically acceptable salt thereof, in the adsorbate is "almost completely amorphous" meaning that the amount of ivabradine, or a pharmaceutically acceptable salt thereof, in the amorphous form is at least 90% as measured by powder X-ray diffraction or any other standard quantitative measurement. Most preferably, ivabradine, or a pharmaceutically acceptable salt thereof, in the adsorbate is in a completely amorphous form within the detection limits of the techniques used for characterization, like powder X-ray diffraction.
  • the adsorbate in accordance with the present invention advantageously is in the form of a free-flowing powder, with excellent handling properties and stable morphology.
  • the adsorbate is very suitable to be used for the preparation of pharmaceutical compositions.
  • compositions of the present invention comprise the adsorbate of ivabradine, or a pharmaceutically acceptable salt thereof, on a porous carrier and one or more pharmaceutically acceptable excipients.
  • the excipients to be used in accordance with the present invention are well-known to and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are chosen from one or more binders, diluents, disintegrants, glidants, lubricants, stabilizers, surface active agents or pH-adjusting agents.
  • compositions of the present invention display dissolution behavior typical for immediate-release formulations.
  • compositions of the present invention the adsorbate of ivabradine, or a pharmaceutically acceptable salt thereof, on a porous carrier remains in the amorphous form.
  • the present invention further provides a process to prepare an adsorbate of ivabradine, or a pharmaceutically acceptable salt thereof, on a porous carrier, comprising combining the carrier with ivabradine, or a pharmaceutically acceptable salt thereof, in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s), using equipment and methods well-known in the art.
  • the solvent or solvent mixture is water, a polar organic solvent or a mixture of water and a polar organic solvent.
  • ivabradine, or a pharmaceutically acceptable salt thereof is dissolved in water or a mixture of water and a polar organic solvent and the porous carrier is added to this solution.
  • Preferred polar organic solvents are alcohols, particularly ethanol or methanol, ethers, particularly tetrahydrofuran, ketones, particularly acetone and acetonitrile.
  • water or a mixture of an alcohol and water is used.
  • Another method to prepare an adsorbate of ivabradine, or a pharmaceutically acceptable salt thereof, on a porous carrier comprises a thermal process.
  • ivabradine, or a pharmaceutically acceptable salt thereof is melted and then applied on the porous carrier, for example in a thin- screw extruder.
  • the carrier is insoluble in the process environment used to form the adsorbate. That is, where the adsorbate is formed by solvent processing, the carrier does not dissolve in the solvent. Where the adsorbate is formed by a melt or thermal process, the carrier has a sufficiently high melting point that it does not melt.
  • the present invention still further provides a process to prepare pharmaceutical compositions comprising an adsorbate of ivabradine, or a pharmaceutically acceptable salt thereof, on a porous carrier and one or more pharmaceutically acceptable excipients.
  • the process comprises mixing or granulating the adsorbate with one or more pharmaceutically acceptable excipients, followed by compression into tablets, using equipment and methods well-known to the skilled artisan.
  • the pharmaceutical composition in accordance with the present invention may be used as a medicament.
  • the pharmaceutical composition typically may be used in the treatment of stable angina pectoris and chronic heart failure.
  • the present invention is illustrated by the following Examples.
  • Example 1 ivabradine hydrochloride: Syloid 350 XDP (weight ratio 1:3)
  • XRPD data showed that the isolated adsorbate was fully amorphous.
  • XRPD analysis performed 4 weeks after subjecting the powder in open dish to 55°C/90% RH and 2 months to 40°C /75% RH showed that the adsorbate was still fully amorphous.
  • Example 2 ivabradine hydrochloride: Syloid 350 XDP (weight ratio 1:2)
  • ivabradine hydrochloride 0.5 g was dissolved in 4 ml of water. 1.0 g of Syloid 350 XDP was added and the suspension was stirred for 10 minutes. Stirring was stopped and the mixture was allowed to stand at ambient temperature for 1 hour. The suspension was concentrated in vacuo. The residue was dried over night at 40°C under vacuum.
  • XRPD data showed that the isolated adsorbate was fully amorphous.
  • Example 3 ivabradine hydrochloride: Syloid 3150 XDP (weight ratio 1:3)
  • ivabradine hydrochloride 0.5 g was dissolved in 5 ml of water. 1.5 g of Syloid 3150 XDP was added and the suspension was stirred for 10 minutes. Stirring was stopped and the mixture was allowed to stand at ambient temperature for 1 hour. The suspension was concentrated in vacuo. The residue was dried over night at 40°C under vacuum.
  • Example 4 ivabradine hydrochloride: Syloid 350 XDP (weight ratio 1:1)
  • 51.63 g of ivabradine hydrochloride was dissolved in 415 ml of water. The solution was added to 51.63 g of Syloid 350 XDP and the resulting suspension was heated in a high shear mixer, until the solvent started to evaporate. The residue was dried using a fluid bed.
  • XRPD data showed that the isolated adsorbate was fully amorphous.
  • XRPD analysis performed 2 weeks after subjecting the powder in open dish to 55°C/90% RH showed that the adsorbate was still fully amorphous.
  • the resulting granulate/blend was sieved. Microcrystalline cellulose (89.6 wt%) and croscarmellose sodium (3.0 wt%) were added by mixing, followed by the addition of magnesium stearate (0.5 wt%). The powder blend obtained in this way was compacted into tablets. Tablets with a total weight of 240 mg, containing 7.5 mg of ivabradine (referring to the amount of free base) were obtained.
  • Example 5 ivabradine hydrochloride: Syloid 350 XDP (weight ratio 1:2)
  • ivabradine hydrochloride 43.02 g was dissolved in 344 ml of water. The solution was added to 86.04 g of Syloid 350 XDP and the resulting suspension was heated in a high shear mixer, until the solvent started to evaporate. Part of the residue was dried using the high shear mixer (by evaporation), whereas the other part of the residue was dried using a fluid bed. The granulates/blends obtained by each of the drying processes, were sieved. Microcrystalline cellulose (86.2 wt%) and croscarmellose sodium (3.0 wt ) were added to the
  • XRPD data showed that the isolated adsorbates and the tablets were fully amorphous.
  • XRPD analysis performed 2 weeks after subjecting the adsorbates in open dish to 55°C/90% RH showed that the powders were still fully amorphous.
  • Tablets showed a fast dissolution at pH 1.2 and 4.5.
  • Example 6 ivabradine hydrochloride: Syloid 350 XDP (weight ratio 1:5)
  • ivabradine hydrochloride 10.33 g was dissolved in 205.5 ml of water. The solution was added to 51.60 g of Syloid 350 XDP and the resulting suspension was heated and dried in a high shear mixer. The resulting granulate/blend was sieved. Microcrystalline cellulose (75.9 wt%) and croscarmellose sodium (3.0 wt%) were added by mixing, followed by the addition of magnesium stearate (0.5 wt%). The powder blend obtained in this way was compacted into tablets. Tablets with a total weight of 240 mg, containing 7.5 mg of ivabradine (referring to the amount of free base) were obtained.

Abstract

La présente invention concerne une composition pharmaceutique comprenant de l'adsorbat d'ivabradine amorphe, ou son sel pharmaceutiquement acceptable de celui-ci, et un ou plusieurs excipients pharmaceutiquement acceptables. L'invention porte en outre sur l'utilisation de ladite composition en tant que médicament, en particulier dans le traitement de l'angine de poitrine stable et de l'insuffisance cardiaque chronique.
EP14802452.4A 2013-11-28 2014-11-25 Composition pharmaceutique comprenant de l'ivabradine amorphe Withdrawn EP3073996A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP14802452.4A EP3073996A1 (fr) 2013-11-28 2014-11-25 Composition pharmaceutique comprenant de l'ivabradine amorphe

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP13194884 2013-11-28
PCT/EP2014/075485 WO2015078845A1 (fr) 2013-11-28 2014-11-25 Composition pharmaceutique comprenant de l'ivabradine amorphe
EP14802452.4A EP3073996A1 (fr) 2013-11-28 2014-11-25 Composition pharmaceutique comprenant de l'ivabradine amorphe

Publications (1)

Publication Number Publication Date
EP3073996A1 true EP3073996A1 (fr) 2016-10-05

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EP14802452.4A Withdrawn EP3073996A1 (fr) 2013-11-28 2014-11-25 Composition pharmaceutique comprenant de l'ivabradine amorphe

Country Status (2)

Country Link
EP (1) EP3073996A1 (fr)
WO (1) WO2015078845A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3122362A1 (fr) * 2014-03-27 2017-02-01 Laboratorio Chimico Internazionale S.p.A. Adsorbats d'ivabradine
US10507204B2 (en) 2014-12-19 2019-12-17 Synthon B.V. Pharmaceutical composition comprising amorphous lenalidomide

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011157722A2 (fr) * 2010-06-14 2011-12-22 Ratiopharm Gmbh Composition contenant de l'ivabradine solide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2015078845A1 *

Also Published As

Publication number Publication date
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