WO2014013090A2 - Formulation comprising amorphous fingolimod - Google Patents

Formulation comprising amorphous fingolimod Download PDF

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Publication number
WO2014013090A2
WO2014013090A2 PCT/EP2013/073902 EP2013073902W WO2014013090A2 WO 2014013090 A2 WO2014013090 A2 WO 2014013090A2 EP 2013073902 W EP2013073902 W EP 2013073902W WO 2014013090 A2 WO2014013090 A2 WO 2014013090A2
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WIPO (PCT)
Prior art keywords
fingolimod
copolymer
solid composite
divinylbenzene
formulation
Prior art date
Application number
PCT/EP2013/073902
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French (fr)
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WO2014013090A3 (en
Inventor
Deepak Murpani
Reinerus Gerardus Gieling
Lisardo ÁLVAREZ FERNÁNDEZ
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Synthon B.V.
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Publication of WO2014013090A2 publication Critical patent/WO2014013090A2/en
Publication of WO2014013090A3 publication Critical patent/WO2014013090A3/en

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    • 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.

Abstract

The present invention relates to a solid composite of fingolimod base and a copolymer of methacrylic acid and divinylbenzene, a pharmaceutical formulation comprising said composite and the use of either the solid composite or pharmaceutical formulation as a medicament, particularly for the treatment of multiple sclerosis.

Description

FORMULATION COMPRISING AMORPHOUS FINGOLIMOD
BACKGROUND OF THE INVENTION
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)
Figure imgf000002_0001
is a pharmaceutically active compound used for the treatment of multiple sclerosis. It may form stable acid addition salts, of which fingolimod hydrochloride is the most common one. Fingolimod hydrochloride is sold as a pharmaceutical product under the trade name Gilenya® by Novartis.
The compound was discovered by Yoshitomi and is disclosed in EP 0627406. In this publication, a stable crystalline form of fingolimod hydrochloride is obtained by recrystallization from a solution in ethanol. In Example 5 of WO 00/27798, crystals of fingolimod hydrochloride were obtained by crystallization from a mixture of ethyl acetate and ethanol. In Example 3 thereof, crystals were obtained by precipitation after concentration of the ethanolic solution.
However, after repeating the crystallization processes of the above prior art the present inventors observed that 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. Mentioned pharmaceutical carriers are polyvinylpyrrolidone (povidone or PVP), a hydroxypropyl cellulose (HPC), a hydroxypropyl methylcellulose (hypromellose or HPMC) or a hydroxyethyl cellulose (HEC).
The prior art thus teaches that fingolimod hydrochloride is a compound that easily crystallizes, and in different crystalline forms. However, there exists an enantiotropic relationship between the reported forms I (EP 0627406), II and III. Each form has a temperature region at which the respective form is thermodynamically stable. At room temperature form I is the most stable form, at about 40°C form II is most stable, and above 65-70°C form III becomes the stable form. Polymorph transitions already start to occur from 30°C.
In addition, 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. E.g., 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.
Thus, in view of the prior art cited above there is a need for 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. BRIEF DESCRIPTION OF THE INVENTION
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
divinylbenzene. This solid composite may be used for the preparation of the pharmaceutical formulation of the present invention.
In a third aspect, a process for the preparation of the solid composite is provided. The process comprises combining the copolymer with a solution of fingolimod base or a
pharmaceutically acceptable salt thereof, preferably fingolimod hydrochloride, in a suitable solvent or solvent mixture, optionally adjusting the pH to between 6 and 7, followed by removal of the solvent(s).
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. DETAILED DESCRIPTION OF THE INVENTION
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. Typically, the carboxylic acid groups are in the H+ form. Typical examples of commercially available resins include Amberlite IRP-64 and Indion 214.
In the solid composite of the present invention, 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. Preferably, the one or more pharmaceutically acceptable excipients are chosen from one or more lubricants, diluents, disintegrants or glidants.
In one embodiment of the present invention, 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. Preferably, 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. During preparation and storage of the pharmaceutical formulations of the present invention 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.
Preferably, the solvent is water or a mixture of water and a polar organic solvent. In an advantageous variant of the process of the present invention, 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.
EXAMPLES
Example 1 - Weight ratio 1:10 (fingolimod hydrochloride copolymer)
Preparation of the intimate association/complex
In a 50 ml volumetric flask, 1.25 g fingolimod hydrochloride was weighed. The flask was filled with demi water to 50 ml. The clear solution was divided into portions of 10 ml with volumetric pipette.
Four portions of the solution (containing fingolimod hydrochloride (0.25 g, 0.727 mmol)) were added to separate flasks and a copolymer of methacrylic acid and divinylbenzene (i.e. Amberlite IRP-64) (2.5 g) was added to each flask. The suspensions were stirred.
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)
To flask 4 was added one equivalent of 1 M NaOH (0.73 ml), pH 3.5.
The remaining 10 ml solution was used as a standard (25 mg/ml). 200 μΐ 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.
Results
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.
Example 2 - Weight ratio 1:3 (fingolimod hydrochloride copolymer)
Preparation of the intimate association/complex
In a 250 ml beaker, 100 g of 0.01 N HC1 was weighed. 3.57 g of fingolimod hydrochloride was weighed and added to the beaker under magnetic stirring. The solution was maintained under stirring during 20 minutes to ensure complete dissolution. The concentration of fingolimod was quantified in a 5 ml sample. 10.18 g of Amberlite IRP-64 was added to the solution slowly under vigorous magnetic stirring. The pH of the suspension was adjusted adding 6 ml of NaOH 2N to a final pH between 6 and 7. Samples of 5 ml were taken at preset times to check the kinetics of complex formation.
The samples were centrifuged immediately after being taken and the supernatant was analysed to check the absence of free fingolimod base. Example 3 - Wet granulation with formation of fingolimod:Amberlite intimate association/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.
Example 4 - Wet granulation with fingolimod hydrochloride solution
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.
The contents of fingolimod as well as of impurities were determined by HPLC.
The results of the stability study were as follows: 25 °C / 60% RH; time (months)
0 (%) 1 (%)
Alu-Alu Assay 99.6 99.2
Impurity (total) 8.2 -
Duplex Assay 99.6 99.5
Impurity (total) 8.2 -
Triplex Assay 99.6 101.4
Impurity (total) 8.2 -
Figure imgf000011_0001
40 °C / 75% RH; time (months)
0 (%) 1 (%) 2 (%)
Alu-Alu Assay 99.6 98.3 95.1
Impurity (total) 8.2 4.4 4.3
Duplex Assay 99.6 97.5 93.5
Impurity (total) 8.2 5.7 5.4
Triplex Assay 99.6 100.0 94.8
Impurity (total) 8.2 5.0 5.7

Claims

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.
The formulation according to claim 1, wherein the solid composite comprises fingolimod base intimately associated or complexed with the copolymer of methacrylic acid and divinylbenzene.
A solid composite consisting of fingolimod base intimately associated or complexed with a copolymer of methacrylic acid and divinylbenzene.
The formulation or composite according to any one of claims 1 to 3, wherein the copolymer of methacrylic acid and divinylbenzene is a polacrilex resin.
The formulation or composite according to any one of claims 1 to 4 comprising amorphous fingolimod base.
A process for preparing the solid composite according to any one of claims 3 to 5 comprising combining the copolymer with a solution of fingolimod base or a
pharmaceutically acceptable salt thereof, preferably fingolimod hydrochloride, in a suitable solvent or solvent mixture, optionally adjusting the pH to between 6 and 7, followed by removal of the solvent(s).
The process according to claim 6, wherein the weight ratio of fingolimod to copolymer 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 process according to claim 6 or 7, wherein the solvent is water, aqueous HC1 or a mixture of water and a polar organic solvent.
9. A process for preparing the pharmaceutical formulation according to claim 1 or 2 comprising blending and/or granulating the solid composite according to any one of claims 3 to 5 with one or more pharmaceutically acceptable excipients, and filling the blend into capsules or sachets, or compressing the blend into tablets.
10. Use of the solid composite according to any one of claims 3 to 5 for preparing the
pharmaceutical formulation according to claim 1, 2, 4 or 5.
11. The pharmaceutical formulation according to claim 1, 2, 4 or 5 or the solid composite according to any one of claims 3 to 5 for use as a medicament.
12. The formulation or solid composite according to claim 11 for use in the treatment of
multiple sclerosis.
PCT/EP2013/073902 2013-05-06 2013-11-15 Formulation comprising amorphous fingolimod WO2014013090A2 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150165057A1 (en) * 2013-01-15 2015-06-18 Sun Pharmaceutical Industries Ltd. Fingolimod containing stable composition
WO2016042493A1 (en) 2014-09-19 2016-03-24 Aizant Drug Research Pvt. Ltd Pharmaceutical compositions of fingolimod

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008037421A2 (en) * 2006-09-26 2008-04-03 Novartis Ag Pharmaceutical compositions comprising an s1p modulator
EP2198857A1 (en) * 2008-12-19 2010-06-23 Ratiopharm GmbH Oral dispersible tablet
EP2505589A1 (en) * 2011-04-01 2012-10-03 Johann Wolfgang Goethe-Universität Frankfurt am Main Novel sphingolipid heterocyclic compounds as modulators of sphingolipid signaling and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008037421A2 (en) * 2006-09-26 2008-04-03 Novartis Ag Pharmaceutical compositions comprising an s1p modulator
EP2198857A1 (en) * 2008-12-19 2010-06-23 Ratiopharm GmbH Oral dispersible tablet
EP2505589A1 (en) * 2011-04-01 2012-10-03 Johann Wolfgang Goethe-Universität Frankfurt am Main Novel sphingolipid heterocyclic compounds as modulators of sphingolipid signaling and uses thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150165057A1 (en) * 2013-01-15 2015-06-18 Sun Pharmaceutical Industries Ltd. Fingolimod containing stable composition
US9173948B2 (en) * 2013-01-15 2015-11-03 Sun Pharamaceutical Industries, Ltd. Fingolimod containing stable composition
US9717800B2 (en) 2013-01-15 2017-08-01 Sun Pharmaceutical Industries Ltd. Fingolimod containing stable composition
WO2016042493A1 (en) 2014-09-19 2016-03-24 Aizant Drug Research Pvt. Ltd Pharmaceutical compositions of fingolimod

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