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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • 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
  • A61K9/1635—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
  • A61K9/14—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
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system

Definitions

• the present invention provides a pharmaceutical formulation of fingolimod and a copolymer of methacrylic acid and divinylbenzene.
• Fingolimod (2-amino-2-[2-(4-octylphenyl)ethyl]-propane-l,3-diol) of formula (1)
• Fingolimod hydrochloride is sold as a pharmaceutical product under the trade name Gilenya® by Novartis.
• fingolimod hydrochloride is obtainable only as a waxy- or a cotton-like solid with poor filterability and flowability. Because of these properties, such crystal habit is inconvenient for large scale processing and for subsequent formulation into pharmaceutical compositions.
• Other polymorphic forms of fingolimod hydrochloride, forms II and III, as well as a hydrated form are disclosed in WO 2010/055028.
• WO 2012/146980 describes a process for the preparation of amorphous fingolimod hydrochloride in which a pharmaceutical carrier is used.
• a pharmaceutical carrier is used.
• Mentioned pharmaceutical carriers are polyvinylpyrrolidone (povidone or PVP), a hydroxypropyl cellulose (HPC), a hydroxypropyl methylcellulose (hypromellose or HPMC) or a hydroxyethyl cellulose (HEC).
• fingolimod hydrochloride is a compound that easily crystallizes, and in different crystalline forms.
• fingolimod hydrochloride is a compound that easily crystallizes, and in different crystalline forms.
• I European Form
• II III
• Each form has a temperature region at which the respective form is thermodynamically stable.
• room temperature form I is the most stable form
• 40°C form II is most stable
• 65-70°C form III becomes the stable form.
• Polymorph transitions already start to occur from 30°C.
• fingolimod hydrochloride contains several functional groups that may interact with excipients when formulated into pharmaceutical compositions. This may lead to a loss of quality and effectivity during prolonged storage of the composition.
• the marketed Gilenya® capsules need to be stored at a temperature below 30°C in order to minimise the interaction of fingolimod hydrochloride with the mannitol filler.
• compositions comprising a stable form of fingolimod that do not have the disadvantage of loss of quality and effectivity during prolonged storage as mentioned above.
• the present invention relates to a pharmaceutical formulation of fingolimod and a copolymer of methacrylic acid and divinylbenzene.
• a first aspect of the present invention is related to a pharmaceutical formulation comprising a solid composite of fingolimod base and a copolymer of methacrylic acid and divinylbenzene, and one or more pharmaceutically acceptable excipients.
• a second aspect of the present invention relates to a solid composite comprising fingolimod base, intimately associated with the copolymer of methacrylic acid and
• This solid composite may be used for the preparation of the pharmaceutical formulation of the present invention.
• a process for the preparation of the solid composite comprises combining the copolymer with a solution of fingolimod base or a
• a fourth aspect of the present invention relates to a process for the preparation of the pharmaceutical formulation, comprising blending and/or granulating said solid composite with one or more excipients, and filling the blend into capsules or sachets, or compressing the blend into tablets.
• a fifth aspect of the present invention relates to the use of the pharmaceutical formulation or the solid composite of the present invention as a medicament, particularly in the treatment of multiple sclerosis.
• the present invention relates to a solid composite of fingolimod base and a copolymer of methacrylic acid and divinylbenzene, and pharmaceutical formulations comprising this composite and one or more pharmaceutically acceptable excipients.
• the copolymer of methacrylic acid and divinylbenzene to be used in accordance with the present invention is also known under the international non-proprietary name (INN) polacrilex resin.
• Said resin has carboxylic acid groups.
• the carboxylic acid groups are in the H + form.
• Typical examples of commercially available resins include Amberlite IRP-64 and Indion 214.
• fingolimod base is present in a stabilized amorphous form, which means that during stability studies no conversion of amorphous fingolimod base into any crystalline form was observed.
• the solid composite in accordance with the present invention advantageously is in the form of a free-flowing powder, with excellent handling properties and compressibility.
• the solid composite is very suitable to be used for the preparation of pharmaceutical formulations.
• Fingolimod base in the solid composite of the present invention is forming a salt or a complex, i.e., is intimately associated, with the copolymer of methacrylic acid and divinylbenzene, thus preventing the reactive functional groups of fingolimod base from interacting with further excipients.
• the pharmaceutical formulations of the present invention comprise the solid composite of fingolimod base and a copolymer of methacrylic acid and divinylbenzene 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 formulation, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
• the one or more pharmaceutically acceptable excipients are chosen from one or more lubricants, diluents, disintegrants or glidants.
• the one or more pharmaceutically acceptable excipients are chosen from one or more lubricants, diluents, or glidants. In another embodiment of the invention, the one or more pharmaceutically acceptable excipients are chosen from one or more lubricants or diluents. In another embodiment, the one or more acceptable excipients are lubricants only.
• Suitable lubricants to be used in accordance with the present invention include stearic acid, magnesium stearate, glyceryl behenate, glyceryl monostearate, and palmitic acid.
• a preferred lubricant is magnesium stearate.
• the one or more diluents to be used in accordance with the present invention may be polysaccharides, mono- or disaccharides, sugar alcohols or a copolymer of methacrylic acid and divinylbenzene.
• lactose, microcrystalline cellulose, a polacrilex resin or a mixture thereof is used as a diluent.
• Suitable disintegrants to be used in accordance with the present invention include crosscarmelose, crospovidone, and sodium starch glycolate.
• Suitable glidants to be used in accordance with the present invention include colloidal silicon dioxide, powdered cellulose, hydrophobic colloidal silica, magnesium silicate, magnesium trisilicate, sodium stearate, and talc.
• the pharmaceutical formulations of the present invention display dissolution behaviour typical for immediate-release formulations.
• the fingolimod base remains in an amorphous form.
• the present invention further provides a process to prepare a solid composite of fingolimod base and a copolymer of methacrylic acid and divinylbenzene, comprising combining the copolymer with fingolimod base or a pharmaceutically acceptable salt thereof, preferably fingolimod hydrochloride, in a suitable solvent or solvent mixture, followed by optional adjustment of pH and removal of the solvent(s).
• the weight ratio of fingolimod base or a pharmaceutically acceptable salt thereof, preferably fingolimod hydrochloride, to copolymer for preparing the solid composite typically ranges from 1:0.5 to 1: 15, preferably from 1: 1 to 1 :12, more preferably from 1:3 to 1: 12, calculated on fingolimod base.
• the solvent is water or a mixture of water and a polar organic solvent.
• fingolimod hydrochloride is dissolved in an aqueous solution of hydrochloric acid after which the copolymer of methacrylic acid and divinylbenzene is added and the pH of the suspension is adjusted to between 6 and 7.
• Preferred polar organic solvents are alcohols, particularly ethanol or methanol, ethers, particularly tetrahydrofuran, ketones, particularly acetone, and acetonitrile.
• An alternative variant of the process of the present invention comprises adding a solution of fingolimod hydrochloride to the copolymer of methacrylic acid and divinylbenzene.
• the present invention still further provides a process to prepare pharmaceutical
• formulations comprising the solid composite of fingolimod base and a copolymer of methacrylic acid and divinylbenzene according to the present invention.
• the process comprises blending and/or granulating the solid composite of fingolimod base and a copolymer of methacrylic acid and divinylbenzene with one or more pharmaceutically acceptable excipients, followed by filling the blend into capsules or sachets, or compression of the blend into tablets, using equipment and methods well-known to the skilled artisan. Resulting tablets may optionally be coated, using equipment and methods well-known in the art.
• the solid composite and pharmaceutical formulation in accordance with the present invention may be used as a medicament.
• the solid composite and pharmaceutical formulation typically may be used for the treatment of multiple sclerosis.
• the present invention is illustrated by the following Examples.
• Example 1 Weight ratio 1:10 (fingolimod hydrochloride copolymer)
• Flask 1 was brought to pH 4.0 with 1 M NaOH (1 ml)
• Flask 2 was brought to pH 5.0 with 1 M NaOH (2 ml)
• Flask 3 was brought to pH 6.2 with 1 M NaOH (5 ml)
• the remaining 10 ml solution was used as a standard (25 mg/ml). 200 ⁇ was diluted with ACN/0.1 M HC1 to 5 ml (HPLC h01-h02). After stirring overnight at room temperature, the suspensions were filtered over a glass filter. The filtrate was analyzed with HPLC and the residue was washed with water (amount of water depending on original volume; total volume after washing is 20 ml). The combined filtrate was also analyzed with HPLC.
• XRPD shows that all complexes of fingolimod base and Amberlite IRP-64 are amorphous. XRPD was measured at set times after storage of the complexes at 55°C and 90% RH open dish. The results show that the samples were still completely amorphous after 4 weeks of storage. No crystalline fingolimod base was liberated from the complex.
• the complex was made dissolving 13.39 g of fingolimod hydrochloride in 368 g of 0.01 N HCl under mechanical stirring. After complete dissolution, 40.18 g of Amberlite IRP-64 (4% of weight of Amberlite in the formulation) was added slowly. The pH of the suspension was adjusted to between 6 and 7 and the suspension was kept stirring overnight.
• the suspension was used as a granulating liquid in a high shear mixer over the remaining 964.32 g Amberlite IRP-64 (96% of weight of Amberlite in the formulation). Granulation was completed with 800 ml of water. The obtained granulate was dried in a fluid bed and finally was mixed with a 0.5% of magnesium stearate and filled into gelatin capsules.
• Amberlite IRP-64 was granulated in a high shear mixer. Fingolimod hydrochloride was dissolved in 35% of water calculated over the total dry weight. Once fingolimod hydrochloride was completely dissolved the solution was sprayed over the granulated Amberlite IRP-64 in a fluid bed or a high shear mixer and subsequently dried in a fluid bed. The dry powder was mixed with magnesium stearate and the final blend was filled into hard gelatin capsules.
• the capsules were packed in Alu-Alu, duplex or triplex blister and subjected to stability testing at 25°C/60%RH, 30°C/65%RH and 40°C/75%RH in a thermostated chamber.

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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Biomedical Technology (AREA)
• Emergency Medicine (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2013
  • 2013-11-15 WO PCT/EP2013/073902 patent/WO2014013090A2/fr not_active Ceased

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