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
  • A61K9/2022—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
  • 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

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 product.
• 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. Moreover, it was experienced in our laboratory that polymorphic transitions of ivabradine hydrochloride take place rather easily, especially in pharmaceutical composition. Amorphous ivabradine hydrochloride and methods for its preparation are disclosed in WO2008146308, CN101597261 and CN101463008. We observed in our laboratory that 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 a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co-) polymer and one or more pharmaceutically acceptable excipients, wherein ivabradine, or a pharmaceutically acceptable salt thereof, is in an amorphous form.
• the invention provides a process for preparing said pharmaceutical composition comprising mixing or granulating said solid composite 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 a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer and one or more pharmaceutically acceptable excipients, wherein ivabradine, or a pharmaceutically acceptable salt thereof, is in an amorphous form.
• ivabradine, or a pharmaceutically acceptable salt thereof, and the acrylate (co)polymer are preferably intimately associated, meaning that there is attractive interaction between the active pharmaceutical ingredient and the (co)polymer.
• the weight ratio of ivabradine, or a pharmaceutically acceptable salt thereof, to (co)polymer in the solid composite typically ranges from 1: 1 to 1:8, preferably from 1: 1 to 1:3.
• the acrylate (co)polymer is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate with a ratio of 2: 1 : 1.
• Typical examples of such a commercially available cationic copolymer are Eudragit® E PO, Eudragit® E 100 and Eudragit® E 12,5.
• the acrylate (co)polymer is a copolymer of methacrylic acid and divinylbenzene, and is known under the international nonproprietary name (INN) polacrilex or polacrilin resin.
• INN international nonproprietary name
• the carboxylic acid groups of the polacrilex resin are in the H+ form, while the polacrilin resin is supplied as the potassium salt.
• Typical examples of commercially available polacrilex resins include
• Amberlite® IRP64 and Indion® 214 examples of commercially available polacrilin resins include Amberlite® IRP88 and Indion® 294.
• At least a major portion of ivabradine, or a pharmaceutically acceptable salt thereof, in the solid composite is amorphous.
• the term "a major portion" of ivabradine, or a pharmaceutically acceptable salt thereof, in the solid composite is amorphous.
• 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 solid composite is substantially amorphous.
• substantially amorphous means that the amount of ivabradine, or a pharmaceutically acceptable salt thereof, in amorphous form is at least 80%.
• ivabradine, or a pharmaceutically acceptable salt thereof, in the solid composite 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.
• 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 solid composite is substantially amorphous.
• the solid composite in accordance with the present invention advantageously is in the form of a free-flowing powder, with excellent handling properties and stable morphology.
• the solid composite is very suitable to be used for the preparation of pharmaceutical compositions.
• compositions of the present invention comprise the solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer and one or more pharmaceutically acceptable excipients.
• the excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art.
• the dosage form chosen for the pharmaceutical composition the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
• the dosage form is an immediate-release tablet and 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, ivabradine, or a pharmaceutically acceptable salt thereof remains in the amorphous form.
• the present invention further provides a process to prepare a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer, comprising combining the (co)polymer 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.
• isolation of the solid composite may also be established by filtration.
• 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 a polar organic solvent, water or a mixture of water and a polar organic solvent and the acrylate (co)polymer is added to this solution.
• Preferred polar organic solvents are alcohols, particularly ethanol or methanol, ethers, particularly tetrahydrofuran, ketones, particularly acetone and acetonitrile.
• an alcohol, water or a mixture of an alcohol and water is used.
• the present invention still further provides a process to prepare pharmaceutical compositions comprising a solid composite of ivabradine, or a pharmaceutically acceptable salt thereof, and an acrylate (co)polymer and one or more pharmaceutically acceptable excipients.
• the process comprises mixing or granulating the solid composite with one or more pharmaceutically acceptable excipients, followed by compression into tablets, using equipment and methods well-known to the skilled artisan.
• the composite, in solution was spray-dried onto one of the main excipients, e.g. the diluent, and the resulting granulate/blend was mixed with one or more pharmaceutically acceptable excipients, followed by compression into tablets.
• 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: Eudragit® E PO (weight ratio 1:1)
• ivabradine hydrochloride was dissolved in 41.50 g of ethanol (96%). 5.16 g of Eudragit® E PO was added. The solution was spray-dried on 134.43 g of microcrystalline cellulose. The resulting granulate/blend was sieved and 4.50 g of croscarmellose sodium was added by mixing, followed by the addition of 0.75 g magnesium stearate. The powder blend 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.
• the XRPD patterns of the tablets do not show any reflections in accordance with crystalline ivabradine hydrochloride.
• XRPD analysis performed 1 week after subjecting the tablets in open dish to 55°C/90% RH and 1 month to 40°C /75% RH showed that the tablets still do not show any reflections in accordance with crystalline ivabradine hydrochloride.
• Tablets showed a fast dissolution at pH 1.2, 4.5 and 6.8.
• Example 2 ivabradine hydrochloride: Eudragit® E PO (weight ratio 1:2)
• ivabradine hydrochloride was dissolved in 75.00 g of ethanol (96%). 10.33 g of Eudragit® E PO was added. The solution was spray-dried on 129.26 g of microcrystalline cellulose. The resulting granulate/blend was sieved and 4.50 g of croscarmellose sodium was added by mixing, followed by the addition of 0.75 g magnesium stearate. The powder blend 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.
• the XRPD patterns of the tablets do not show any reflections in accordance with crystalline ivabradine hydrochloride.
• XRPD analysis performed 1 week after subjecting the tablets in open dish to 55°C/90 RH and 1 month in alu/alu packaging to 40°C /75 RH showed that the tablets still do not show any reflections in accordance with crystalline ivabradine hydrochloride.
• ivabradine hydrochloride was dissolved in 185.00 g of ethanol (96%). 25.80 g of Eudragit® E PO was added. The solution was spray-dried on 113.81 g of microcrystalline cellulose. The resulting granulate/blend was sieved and 4.50 g of croscarmellose sodium was added by mixing, followed by the addition of 0.75 g magnesium stearate. The powder blend 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.
• the XRPD patterns of the tablets do not show any reflections in accordance with crystalline ivabradine hydrochloride.
• XRPD analysis performed 1 week after subjecting the tablets in open dish to 55°C/90% RH and 1 month to 40°C /75% RH showed that the tablets still do not show any reflections in accordance with crystalline ivabradine hydrochloride.
• Tablets showed a fast dissolution at pH 4.5 and 6.8.
• the composites were prepared by making a slurry of ivabradine hydrochloride and Amberlite® in water. The pH of the slurry was adjusted with either 0.1 M aqueous sodium hydroxide or 2.0 M aqueous hydrochloride to either 4-5 or 6-8 (see table 1). The slurries were stirred at ambient temperature over night. The composite was isolated by filtration, washed with water and dried at air.
• Example 4 ivabradine hydrochloride: Amberlite® IRP64 (weight ratio 1:3)
• Tablets were prepared with the ivabradine hydrochloride:Amberlite® IRP64 (weight ratio 1:3) solid composite, obtained as described in example 3. The composition of the tablets is shown in table 2.
• Ivabradine hydrochloride Amberlite® IRP64 (weight ratio 1:3) 15.0
• Lactose monohydrate granulate (Supertab 30 GR) 64.0
• the solid composite of ivabradine hydrochloride Amberlite® IRP64 (weight ratio 1:3) was mixed with Aerosil 200 VV and part of the lactose monohydrate granulate (Supertab 30 GR) for 10 minutes in a Turbula mixer at 22 rpm. The pre-mix was sieved over a 0.5 mm sieve. Pregelatinized starch (Starch 1500) and the rest of the lactose monohydrate granulate (Supertab 30 GR) were added and mixing was continued for 10 minutes. Magnesium stearate was sieved over a 0.6 mm sieve, added and mixed for 3 minutes at 22 rpm. Tablets were compressed.

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• 2014
  • 2014-12-19 WO PCT/EP2014/078819 patent/WO2015091992A1/en active Application Filing
  • 2014-12-19 EP EP14815382.8A patent/EP3082772A1/de not_active Withdrawn

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