WO2011039369A2 - Amorphous forms of a 2-amino-4-(4-fluorobenzylamino)phenylcarbamate derivative - Google Patents

Amorphous forms of a 2-amino-4-(4-fluorobenzylamino)phenylcarbamate derivative Download PDF

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Publication number
WO2011039369A2
WO2011039369A2 PCT/EP2010/064694 EP2010064694W WO2011039369A2 WO 2011039369 A2 WO2011039369 A2 WO 2011039369A2 EP 2010064694 W EP2010064694 W EP 2010064694W WO 2011039369 A2 WO2011039369 A2 WO 2011039369A2
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Prior art keywords
retigabine
packaging
pharmaceutically acceptable
pharmaceutical formulation
amorphous solid
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PCT/EP2010/064694
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French (fr)
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WO2011039369A3 (en
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Monica Benito Velez
Ernesto Duran Lopez
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Medichem S.A.
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Publication of WO2011039369A2 publication Critical patent/WO2011039369A2/en
Publication of WO2011039369A3 publication Critical patent/WO2011039369A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids
    • C07C271/08Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate 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
    • A61K9/146Intimate 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat

Definitions

  • Retigabine (Compound I) is the international commonly accepted name for ethyl 2-amino-4-(4-fluorobenzylamino)phenylcarbamate, and has an empirical formula of C 16 His FN 3 O 2 , and a molecular weight of 303.33 g/mol.
  • Retigabine is a pharmaceutical substance with anticonvulsive, antipyretic and analgesic activity, and can thus be used in pharmaceutical preparations.
  • the non-proprietary name retigabine has been superseded by ezogabine.
  • CNS Drug Rev. 2005, 11, 1 describes the dihydrochloride salt of retigabine to be hygroscopic and unstable under medium to long-term storage at -18°C. It also describes that retigabine is preferably stored as the free base, isolated from light. The tendency of retigabine to easily oxidize upon contact with air during solubilization as the free base is also described.
  • Figure 1 illustrates the X-ray powder diffractogram (XRD) of an amorphous form of retigabine comprising a mixture of retigabine and polyvinylpyrrolidone, as obtained in Example 1.
  • XRD X-ray powder diffractogram
  • Figure 2 illustrates the XRD of an amorphous form of retigabine comprising a mixture of retigabine and polyvinylpyrrolidone as obtained in Example 1 , and after one month of storage at room temperature in a closed glass vial.
  • Figure 3 illustrates the XRD of an amorphous form of retigabine comprising a mixture of retigabine and polyvinylpyrrolidone, as obtained in Example 4.
  • Figure 4 illustrates the XRD of an amorphous form of retigabine comprising a mixture of retigabine and hydroxypropyl methylcellulose phthalate, as obtained in Example 11.
  • Figure 5 illustrates the XRD of an amorphous form of retigabine comprising a mixture of retigabine and hydroxypropyl methylcellulose phthalate, as obtained in Example 12.
  • the invention relates to a stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, to processes for preparing the same, and to solid pharmaceutical compositions or formulations comprising the same.
  • the invention also provides a stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, and a pharmaceutical formulation comprising the same, stabilized in a container or packaging.
  • the invention relates to a method for storing or packaging an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, and a pharmaceutical formulation comprising the same.
  • the invention relates to a method of stabilization of an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, and a pharmaceutical formulation comprising the same.
  • retigabine can be obtained in an amorphous stable form when mixed with at least one pharmaceutically acceptable carrier. Further, the inventors have shown that stable solid retigabine amorphous as such can not be successfully obtained (See reference examples 1-5). According to the present invention, therefore, there is provided a stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier.
  • the mixture according to the present invention is particularly stable, meaning that the retigabine is stable in its amorphous form.
  • the inventors have shown that the amorphous mixture of retigabine according to the present invention is stable in its amorphous form after storage for at least one month at room temperature and in a closed glass vial, and after storage in an aluminium foil bag for at least 6 months under accelerated stability testing conditions (i.e. 40°C and 75% RH).
  • the amorphous mixture of retigabine according to the present invention is substantially chemically stable after storage in an aluminium foil bag for at least 6 months under accelerated stability testing conditions (i.e. 40°C and 75% RH) and in an inert atmosphere.
  • the amorphous mixture of retigabine according to the present invention shows an enhanced solubility profile compared to the known solid retigabine forms (i.e. crystalline modifications A, B, and C).
  • the amorphous solid mixture of retigabine of the invention shows a solubility increasing of more than 200% as compared to the lowest soluble crystalline modification of retigabine (i.e. modification C), and a solubility increasing of more than 60% as compared to the highest soluble crystalline modification of retigabine (i.e. modification B).
  • the mixture is particularly easy to manipulate.
  • the stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the present invention preferably has a polymeric carrier as a pharmaceutically acceptable carrier.
  • the term "polymer” is used conventionally, meaning a compound that is made of monomers connected together to form a larger molecule.
  • a polymer generally consists of at least about 20 monomers connected together. Thus, the molecular weight of the polymer generally will be about 2000 daltons or more.
  • the polymer should be inert, in the sense that it does not chemically react with the drug in an adverse manner, and should be pharmaceutically acceptable.
  • the at least one pharmaceutically acceptable carrier of the stable amorphous solid mixture according to the present invention is preferably a polymeric carrier suitable for instant release or modified release formulation, and more preferably is at least one from the group consisting of gelatines, ovalbumin, soybean proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), PVP-vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mann
  • the polymeric carrier suitable for instant release or modified release formulation of the stable amorphous solid mixture according to the present invention preferably has the functionality of being a stabilizer agent of the amorphous retigabine and an agent that controls or modifies the release of the amorphous retigabine in a pharmaceutical formulation.
  • agent that controls or modifies the release is understood to define an agent that regulates the release and/or the rate of dissolution of the active pharmaceutical ingredient retigabine upon administration to a subject.
  • the solid amorphous solid mixture comprising amorphous retigabine of the present invention can be suitable for an instant or a modified release solid pharmaceutical formulation.
  • the said pharmaceutically acceptable carrier is suitable not only for stabilizing the amorphous retigabine within the solid mixture, but also is suitable for preparing an instant or modified release formulation of said stable amorphous solid mixture.
  • the at least one pharmaceutically acceptable carrier of the stable amorphous solid mixture according to the present invention is preferably an enteric polymer.
  • An enteric polymer as used herein is meant to describe a polymer which is poorly soluble in water at a pH of about 4.5 or less (i.e. the pH of the stomach) and which is soluble in water at a pH of greater than about 5 (i.e. the pH of the lower gastrointestinal tract).
  • An enteric polymer is amphiphilic in nature, meaning that it has hydrophilic and hydrophobic portions, and also contains ionisable portions that are capable of being ionised at a pH of greater than about 5, so constituting at least a portion of the hydrophilic portions of the polymer.
  • the enteric polymer is at least one from the group consisting of polyvinylacetate phthalate, hydroxypropylmethylcellulose acetate succinate (HPMC-AS), cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, hydroxypropylmethylcellulose phthalate (HPMCP), polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methylacrylate-methacrylic acid-octyl acrylate copolymer, methylcellulose (MC), ethylcellulose (EC), cellulose acetate propionate, methylvinylether-maleic anhydride copolymers, and Eudragit E (a basic butylmethacrylate copolymer). It is preferred that the enteric poly
  • the enteric polymer of the stable amorphous solid mixture according to the present invention preferably has the functionality of being a stabilizer agent of the amorphous retigabine and an agent for retarding release in the gastric environment in a pharmaceutical formulation.
  • agent for retarding the release in the gastric environment is meant to describe an agent that bypasses the release of the active ingredient into the gastric environment, so that the retigabine is first exposed to an environment of the lower gastrointestinal tract.
  • the said enteric polymer is suitable not only for stabilizing the amorphous retigabine within the solid mixture, but also is suitable for preparing an extended release formulation of said stable amorphous solid mixture. Therefore, the solid amorphous mixture of the invention can be suitable for an extended release solid pharmaceutical formulation.
  • the stable amorphous solid mixture according to the present invention can comprise combinations of several pharmaceutically acceptable carriers, wherein said carriers are carriers suitable for instant release or modified release formulation or polymeric enteric carriers as hereinbefore described. Therefore, the specific selection, combination, properties and content ratio of the various pharmaceutically acceptable carriers within the amorphous mixture described above may not only stabilize the amorphous retigabine but may also regulate the release and/or the rate of dissolution of the active pharmaceutical ingredient retigabine in a pharmaceutical formulation.
  • the stable amorphous solid mixture according to the present invention can be suitable for preparing an extended and/or an instant or modified release solid pharmaceutical formulation.
  • the amorphous forms of retigabine of the invention can be characterized by means of Powder X-ray diffraction pattern (XRD).
  • the stable amorphous solid mixture according to the present invention is preferably characterized by showing an X-ray powder diffraction pattern showing a broad peak at between about 4 and about 44 (20°). Also, the stable amorphous solid mixture according to the present invention can be characterized by showing an X-ray powder diffraction pattern lacking discernible or sharp peaks and/or by showing an X-ray powder diffraction pattern being substantially the same as any of the XRD depicted in Figures 1 to 5.
  • Figures 1 to 3 illustrate the X-ray powder diffraction pattern (2 ⁇ ) ( ⁇ 0.2°) of amorphous solid mixtures of retigabine and polyvinylpyrrolidone.
  • Figures 4 and 5 illustrate the X-ray powder diffraction pattern (2 ⁇ ) ( ⁇ 0.2°) of amorphous solid mixtures of retigabine and hydroxypropyl methylcellulose phthalate.
  • the powder X-ray diffraction patterns (i.e. XRD diffractograms) of the amorphous solid mixtures according to the present invention were obtained by means of a RX SIEMENS D5000 diffractometer.
  • the stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier according to the present invention preferably has a ratio of the at least one pharmaceutically acceptable carrier to the retigabine of at least about 1 :2 (w/w). More preferably, the stable amorphous solid mixture of the invention has a ratio of the at least one pharmaceutically acceptable carrier to the retigabine of between about 1 :2 to about 2: 1 (w/w).
  • the stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier according to the present invention is preferably obtained by a process comprising: (a) removing the solvent from a solution or dispersion of retigabine and the at least one pharmaceutically acceptable carrier; or (b) melt extruding a mixture of retigabine and the at least one pharmaceutically acceptable carrier; or (c) grinding a mixture of retigabine and the at least one pharmaceutically acceptable carrier; or (d) lyophilizing a mixture of retigabine and the at least one pharmaceutically acceptable carrier; or (e) hot melting a mixture of retigabine and the at least one pharmaceutically acceptable carrier in fluid bed granulator.
  • the preparation of the stable amorphous solid mixture of the present invention is preferably carried out by the process (a) of the invention above, and said process preferably comprises: (i) treating retigabine with the at least one pharmaceutically acceptable carrier in the presence of a suitable solvent, to obtain a solution, and (ii) removing the solvent from the solution.
  • the solvent of the step (i) of the process of the invention above is preferably an organic solvent, and still preferably is a C1-C5 alcohol solvent, a C3-C10 ketone solvent, or mixtures thereof. More preferably, the solvent of the step (i) of the process above is methanol, ethanol, acetone, or mixtures thereof. Also, the solvent may comprise water.
  • the removing the solvent from the solution of step (ii) of the process of the invention above can be carried out by standard methods known in the art such as, for example, distilling the solution, spray drying the solution, or precipitating the amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier from the solution and either filtering or decanting the suspension.
  • the removing the solvent from the solution of step (ii) of the process of the invention above is carried out by spray drying the solution. More precisely, in the spray drying the solution the solvent is preferably methanol, ethanol or acetone; the inlet temperature is preferably of between about 20-200 °C, and more preferably of about 65-115 °C; and the feed rate is preferably of between about 1-25 mL/min, and more preferably of about 3.5 mL/min; and so the outlet temperature is preferably of between about 20-120 °C, and more preferably of about 45-80 °C. In an alternative preferred embodiment, the removing the solvent from the solution of step (ii) of the process of the invention above is carried out by distilling the solution.
  • the distilling the solution is preferably carried out by rotary evaporation (rotavapping).
  • the removing the solvent from the solution of step (ii) of the process of the invention above can be carried out by any additional drying step known in the art, such as vacuum drying and oven drying.
  • the retigabine used for preparing the amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the process above can be either retigabine obtained by a known method, for example retigabine in crystalline modifications A, B, or C, or mixtures thereof.
  • the said in crystalline modifications A, B, or C, or mixtures thereof can be prepared by following any of the methods described in the art, such as the processes described in U.S. patent No. 6,538,151.
  • the retigabine can be directly used in solution or dispersion as directly obtained from any synthetic preparation described in the art.
  • Another aspect of the invention includes a pharmaceutical composition comprising a stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier according to the invention. Therefore, the invention also relates to a solid pharmaceutical formulation comprising stable amorphous retigabine and one or more pharmaceutically acceptable carriers.
  • a solid pharmaceutical formulation comprising said amorphous solid mixture of retigabine of the invention is advantageous over a solid pharmaceutical formulation comprising any of the crystalline modifications of retigabine described in the art, because the amorphous solid mixture of retigabine of the invention dissolves better (i.e. about 200- 60% better. See Example 15), which is a key factor for the bioavailability of the active substance in the body.
  • compositions as described herein are meant to define any mixture for pharmaceutical use, which can be referred to in the art as
  • the solid pharmaceutical formulation according to the present invention is meant to comprise an effective amount of solid amorphous retigabine substantially as hereinbefore described, optionally, together with a pharmaceutically acceptable carrier or excipient therefor.
  • effective amount means an amount of amorphous retigabine which is capable of providing an anticonvulsive, antipyretic and / or analgesic therapeutic effect.
  • pharmaceutically acceptable carrier or excipient is meant that the carrier or excipient must be compatible with amorphous retigabine and not to be deleterious to a recipient thereof.
  • the stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the invention above can be directly used as a pharmaceutical formulation.
  • the solid pharmaceutical formulation according to the present invention comprises: (i) a nucleus comprising the stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the invention above; and (ii) one or more additional pharmaceutical acceptable carriers; and/or (iii) one or more coating layers.
  • the formulation nucleus comprising the amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the invention above can comprise combinations of several pharmaceutically acceptable carriers, wherein said pharmaceutically acceptable carriers are preferably polymeric carriers suitable for instant release or modified release formulation or polymeric enteric carriers as described above. Therefore, the selection, specific combination, properties and content ratio of the various pharmaceutically acceptable carriers within the formulation nucleus described above may not only stabilize the amorphous retigabine but may also regulate the release and/or the rate of dissolution of the active pharmaceutical ingredient retigabine.
  • the solid pharmaceutical formulation of the invention may comprise one or more coating layers which may additionally contribute to regulate the release and/or the rate of dissolution of the active pharmaceutical ingredient retigabine upon administration to a subject.
  • the coating layers for use in the pharmaceutical formulation of the invention are preferably film coating layers, meaning that the film is formed by polymers, wherein said film coating layers can be formulations of organic solvent-based solution of polymers, aqueous solutions or dispersions of polymers, hot melt systems, or powder coatings.
  • the said polymers used in the said coating layers can be water soluble polymers, water insoluble polymers, and polymers used in enteric coatings.
  • the coating layers for use in instant release pharmaceutical formulation preferably comprise a polymeric carrier suitable for instant release formulation, and more preferably is at least one from the group consisting of gelatines, ovalbumin, soybean proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), PVP-vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a vinylpyrrolidone- vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, Isomalt, cycl
  • the coating layers for use in extended release pharmaceutical formulation preferably comprise an enteric polymer, and more preferably the enteric polymer is at least one from the group consisting of polyvinylacetate phthalate, hydorxypropylmethylcellulose acetate succinate (HPMC-AS), cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methylacrylate-methacrylic acid-octyl acrylate copolymer, methylcellulose (MC), ethylcellulose (EC), cellulose acetate propionate, methylvinylether-maleic anhydride copolymers, and Eudragit
  • each coating layer of the pharmaceutical formulation of the invention above can also comprise combinations of different polymeric carriers suitable for instant release formulation or enteric polymers, as hereinbefore described, which may additionally contribute to regulate the release and/or the rate of dissolution of the active pharmaceutical ingredient retigabine upon administration to a subject.
  • the solid the pharmaceutical formulation comprising amorphous retigabine of the present invention can relate to an extended and/or an instant or modified release solid pharmaceutical formulation.
  • instant or immediate release pharmaceutical formulation as used herein is meant to describe a pharmaceutical formulation such that the active ingredient is immediately released upon administration to a subject.
  • modified or controlled release pharmaceutical formulation as used herein is meant to describe a pharmaceutical formulation such that the active ingredient is delivered at a relatively constant level over a sustained period of time, upon administration to a subject, based on delaying the rate of dissolution or the release of the active ingredient.
  • extended release pharmaceutical formulation as used herein is meant to describe a pharmaceutical formulation such that the release of the active ingredient is retarded into the gastric environment, so that the retigabine is first exposed to an environment of the lower gastrointestinal tract.
  • the additional pharmaceutical acceptable carriers of paragraph (ii) of the solid pharmaceutical formulation according to the present invention are at least one from the group consisting of pharmaceutically acceptable bulking agents, binders, disintegrants, lubricants, surfactants, drug delivery matrices, release modifying agents, glidants, diluents, vehicles, buffers, stabilizers, tonicity agents, coloring agents, flavouring agents, sweeteners, cryoprotectants, lyoprotectants, anti-oxidants, chelating agents, and preservatives.
  • Pharmaceutically acceptable carriers are well known in the art and are described in, for example, Remington: The Science and Practice of Pharmacy, A. R. Gennaro, ed., Lippincott Williams & Wilkins; 20 th edition (December 15, 2000).
  • Suitable pharmaceutically acceptable formulations according to the present invention are preferably in the form of solid compositions, such as a powder or lyophilized product for inclusion in a suspension or dispersion for an injectable formulation, or powder for an oral suspension, suppositories, tablets, coated tablets such as film coated tablets, non coated tablets, orodispersible tablets, pellets, pills, granules, capsules, or mini-tablets in capsules.
  • the solid pharmaceutical formulation of the invention is in the form of a film coated tablet.
  • retigabine is light sensitive in solid form, since it is described that retigabine is preferably isolated from light on storage. However, the stability of the solid retigabine upon contact with air is not reported. The inventors have now also found that the amorphous solid mixture of retigabine of the present invention is susceptible to oxidation upon contact with the atmosphere.
  • the inventors have additionally surprisingly found that the chemical stability of the amorphous solid mixture of retigabine of the present invention can be dramatically affected by the oxygen content in a surrounding environment. Degradation has been particularly observed by the worsening of the chemical purity (i.e. at least between about 11-18%) of the solid amorphous mixtures of retigabine of the invention when stored in contact with atmospheric oxygen in a closed aluminium foil bag for at least 6 months under accelerated stability testing conditions (i.e. 40°C and 75% RH). Surprisingly, when keeping the same mixtures under an inert atmosphere, no substantial worsening of the chemical purity is observed (i.e. only 0.5% of worsening).
  • inert atmosphere as used herein is understood to comprise an atmosphere which is essentially free of oxygen.
  • essentially free of oxygen is meant to refer that the oxygen content within the surrounding environment (i.e. in a closed container or packaging) is less than 1%, preferably less than 0.1%, more preferably less than 0.01%, and even more preferably is free of oxygen.
  • the present invention therefore, provides an additional improvement in stability of the amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier according to the present invention as illustrated by a substantial chemical stability, as measured by HPLC. Equally, the said improvement can be used to stabilize the chemical purity of the solid pharmaceutical formulation comprising the said amorphous solid mixture according to the present invention.
  • the present invention provides an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, or a solid pharmaceutical formulation thereof, as described hereinbefore, which is stabilized or substantially stabilized by storage in an enclosed container or packaging wherein inert atmosphere is provided within the container or packaging and/or wherein the container or packaging is a substantially gas exchange non-permeable enclosed container or packaging.
  • the amorphous solid mixture, or solid pharmaceutical formulation thereof, stabilized in an enclosed container or packaging as hereinbefore described is preferably stored in the absence of light.
  • the enclosed container or packaging as described above is preferably also a substantially light non-permeable enclosed container or packaging.
  • the inert atmosphere provided in the amorphous solid mixture, or solid pharmaceutical formulation thereof, stabilized in an enclosed container or packaging as hereinbefore described is preferably provided by the presence of a suitable amount of an oxygen scavenger; and/or by the provision of vacuum or of an inert gas atmosphere, in the said enclosed container or packaging.
  • the inert gas is preferably nitrogen or argon.
  • the oxygen scavenger is preferably a chemical compound that reacts with oxygen, and more preferably is an iron powder compound or ascorbic acid. Even more preferably, the iron powder compound is an AgelessTM sachet.
  • the enclosed container or packaging for the amorphous solid mixture of the invention is preferably a gas exchange non-permeable metal or glass or plastic container or packaging. More preferably, the enclosed gas exchange non-permeable container or packaging is an Aluminium foil bag or sachet.
  • the amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the invention can be firstly stored in a gas exchange permeable glass or plastic container or packaging (i.e. polyethylene plastic bag) which is turn stored within the gas exchange non-permeable metal or glass or plastic container or packaging, so as to avoid any potential damage of the gas exchange non-permeable metal or glass or plastic container or packaging to the mixture, especially when the gas exchange non-permeable container or packaging is a metal container or packaging.
  • the gas exchange non-permeable metal or glass or plastic container or packaging can have an internal polymeric layer to avoid damage to the mixture, so that the intermediate gas exchange permeable glass or plastic container or packaging is not necessary.
  • the enclosed container or packaging for the solid pharmaceutical formulation comprising the amorphous solid mixture of the invention is preferably selected from the group consisting a non-permeable blister, such as an Al / Al blister, or an Al-polychloro-3-fluoroethylene homopolymer / PVC laminate blister, an aluminum foil, a glass or plastic bottle, and a glass or plastic vial.
  • a non-permeable blister such as an Al / Al blister, or an Al-polychloro-3-fluoroethylene homopolymer / PVC laminate blister, an aluminum foil, a glass or plastic bottle, and a glass or plastic vial.
  • the invention in another aspect, relates to a method for storing or packaging an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, or a solid pharmaceutical formulation thereof, as hereinbefore described, in an enclosed container or packaging, wherein the storing or packaging procedure is carried out in an inert atmosphere; and/or the container or packaging is a substantially gas exchange non-permeable enclosed container or packaging.
  • the invention relates to a method for stabilization of an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, or a solid pharmaceutical formulation thereof, as hereinbefore described, said method comprising storing or packaging the solid mixture, or the solid pharmaceutical formulation thereof, in an enclosed container or packaging, wherein the enclosed container or packaging has inert atmosphere as hereinbefore described; and/or the container or packaging is a substantially gas exchange non-permeable enclosed container or packaging.
  • the container or packaging of the methods above is a substantially light non-permeable enclosed container or packaging; and/or the storing or packaging procedure in said methods is carried out in the absence of light.
  • the present invention further provides amorphous solid mixture of retigabine substantially as hereinbefore described, for use in the treatment of a disease state alleviated by administration of retigabine, in particular for the treatment of epilepsy.
  • the present invention also provides a method of treatment of a disease state alleviated by administration of retigabine, in particular epilepsy, which method comprises administering to the patient an effective amount of amorphous solid mixture of retigabine substantially as hereinbefore described.
  • the chromatographic separation was carried out in a Waters Sunfire CI 8, 5 ⁇ , 4.6 x 250 mm column at 30°C.
  • the mobile phase was a filtered and degassed mixture of buffer solution and methanol (35:65).
  • the buffer solution was prepared by dissolving about 0.5 mL of thiethylamine in 500 mL of water, and then adjusting the pH to 7.1 with acetic acid.
  • the chromatograph was equipped with a 254nm detector, and the flow rate was 0.8mL per minute.
  • the test samples (10 ⁇ ) were prepared by dissolving the appropriate amount of sample in mobile phase in order to obtain 1.0 mg of retigabine per mL.
  • the chromatograph was run for at least 45 minutes.
  • Example 1 Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
  • Retigabine (0.5005 g) and polyvinylpyrrolidone (1.0033 g) were dissolved in 7 mL methanol at room temperature. The solution was filtered and concentrated to dryness in a rotary evaporator. The residue obtained was smoothly ground.
  • Example 2 Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
  • Retigabine (0.5015 g) and polyvinylpyrrolidone (0.5017 g) were dissolved in 12 mL methanol at room temperature. The solution was filtered and concentrated to dryness in a rotary evaporator. The residue obtained was smoothly ground.
  • XRD amorphous form, substantially similar to Figure 1.
  • XRD after one month of storage at room temperature in a closed glass vial amorphous form, substantially similar to Figure 2.
  • Example 3 Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
  • Retigabine (0.5004 g) and polyvinylpyrrolidone (0.4998 g) were dissolved in 20 mL ethanol at room temperature. The solution was filtered and concentrated to dryness in a rotary evaporator. The residue obtained was smoothly ground.
  • Example 4 Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
  • Polyvinylpyrrolidone (Plasdone K29/32) (5.0048 g) was dissolved in methanol (50 mL). Then, retigabine (5.0221 g) was added and methanol was added to complete dissolution (the total volume of methanol was 100 mL). The solution was filtered and spray dried using a Buchi B290 spray dryer. The amorphous solid mixture of retigabine and polyvinylpyrrolidone was recovered.
  • inlet temperature (actual reading) 90 °C
  • outlet temperature (actual reading) 67 °C
  • aspirator 100% (equivalent to approximately 35 m 3 /hour)
  • nitrogen flow 30 mm (equivalent to approximately 360 L/hour).
  • the peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
  • Example 5 Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
  • Polyvinylpyrrolidone (Plasdone K29/32) (10.0044 g) was dissolved in methanol (50 mL). Then, retigabine (5.0122 g) was added and methanol was added to complete dissolution (the total volume of methanol was 80 mL). The solution was filtered and spray dried using a Buchi B290 spray dryer. The amorphous solid mixture of retigabine and polyvinylpyrrolidone was recovered.
  • inlet temperature (actual reading) 90 °C
  • outlet temperature (actual reading) 66-67 °C
  • aspirator 100% (equivalent to approximately 35 m 3 /hour)
  • nitrogen flow 30 mm (equivalent to approximately 360 L/hour).
  • the peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
  • Example 6 Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
  • inlet temperature (actual reading) 90°C
  • outlet temperature (actual reading) 60°C
  • aspirator 100%
  • nitrogen flow 30 mm (equivalent to approximately 360 L/hour).
  • the peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
  • Example 7 Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
  • inlet temperature (actual reading) 90°C
  • outlet temperature (actual reading) 61°C
  • aspirator 100%) (equivalent to approximately 35 m 3 /hour)
  • nitrogen flow 30 mm (equivalent to approximately 360 L/hour).
  • the peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
  • inlet temperature (actual reading) 110°C
  • outlet temperature (actual reading) 67°C
  • aspirator 100% (equivalent to approximately 35 m 3 /hour)
  • nitrogen flow 30 mm (equivalent to approximately 360 L/hour).
  • the peristaltic pump to feed the product solution was set to 25% (equivalent to approximately 8.75 mL/min).
  • Example 9 Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
  • Example 10 Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
  • inlet temperature (actual reading) 70°C
  • outlet temperature (actual reading) 50°C
  • aspirator 100% (equivalent to approximately 35 m 3 /hour)
  • nitrogen flow 20 mm (equivalent to approximately 240 L/hour).
  • the peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
  • Example 11 Preparation of an amorphous solid mixture of retigabine and hydroxypropylmethylcellulose phthalate
  • Retigabine (0.5853 g) was dissolved in acetone (3 mL) at room temperature and under nitrogen. Then hydroxypropylmethylcellulose phthalate (HPMCP HP-55) (0.5820 g) was added and acetone was added to complete dissolution (total volume of acetone was 7 mL). The solution was concentrated to dryness in a rotary evaporator. The residue obtained was smoothly ground.
  • HPMCP HP-55 hydroxypropylmethylcellulose phthalate
  • Example 12 Preparation of an amorphous solid mixture of retigabine and hydroxypropylmethylcellulose phthalate
  • Example 13 Amorphous stability study under accelerated stability testing conditions of the amorphous solid mixture of retigabine and PVP
  • Example 7 A sample corresponding to the amorphous solid mixture of retigabine and PVP obtained in Example 7 was stored in a polyethylene bag which in turn was stored in an Aluminium foil bag under accelerated stability testing conditions (40°C and 75% RH) for 6 months.
  • the amorphous stability of the sample was measured by XRD. The obtained results are shown in Table 1 below.
  • Example 14 Chemical stability study under accelerated stability testing conditions of the amorphous solid mixture of retigabine and PVP
  • Samples corresponding to the amorphous solid mixture of retigabine and PVP obtained in Examples 6 and 7 were stored in a polyethylene bag which in turn was stored in an Aluminium foil bag, either in the presence or in the absence of an agelessTM oxygen scavenger sachet (placed between the polyethylene bag external layer and the Aluminium foil bag internal layer), under accelerated stability testing conditions (40°C and 75% RH) for 6 months.
  • the chemical stability of the sample was measured by HPLC. The obtained results are shown in Table 2 below.
  • Example 15 Comparative solubility studies for crystalline and amorphous forms or retigabine
  • Retigabine (150 mg) was dissolved in acetone (1,5 mL) at room temperature. The solution was evaporated in a rotary evaporator to dryness. The residue was collected.
  • Retigabine (150 mg) was dissolved in methanol (2 mL) at room temperature. The solution was evaporated in a rotary evaporator to dryness. The residue was collected.
  • Retigabine (4 g) was dissolved in acetone (30 mL). The solution was filtered and spray dried using a Buchi B290 spray dryer. The solid residue was recovered.
  • inlet temperature (actual reading) 101°C
  • outlet temperature (actual reading) 72°C
  • aspirator 100% (equivalent to approximately 35 m 3 /hour)
  • nitrogen flow 35 mm (equivalent to approximately 420 L/hour).
  • the peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
  • Retigabine (3.15 g) was dissolved in ethanol (15 mL) at reflux. The solution was filtered and spray dried using a Buchi B290 spray dryer. The solid residue was recovered.
  • inlet temperature (actual reading) 130°C
  • outlet temperature (actual reading) 96°C
  • aspirator 100%
  • nitrogen flow 30 mm
  • peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
  • Retigabine (3 g) was dissolved in acetone (20 mL). The solution was filtered and spray dried using a Buchi B290 spray dryer. The solid residue was recovered.
  • inlet temperature (actual reading) 60°C
  • outlet temperature (actual reading) 51°C
  • aspirator 100%) (equivalent to approximately 35 m 3 /hour)
  • nitrogen flow 30 mm (equivalent to approximately 360 L/hour).
  • the peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).

Abstract

The invention relates to a stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, to processes for preparing the same, to solid pharmaceutical formulations comprising the same, and to said mixture or formulation stabilized in a container or packaging.

Description

AMORPHOUS FORMS OF A 2-AMINO-4-(4- FLUOROBENZYLAMINO)PHENYLCARBAMATE DERIVATIVE
This application claims the benefit of priority of the United States Provisional Application No. 61/248,224, filed 2 October 2009, the United States Provisional Application No. 61/257,930, filed 4 November 2009, and the United States Provisional Application No. 61/306,196, filed 19 February 2010).
BACKGROUND OF THE INVENTION
Retigabine (Compound I) is the international commonly accepted name for ethyl 2-amino-4-(4-fluorobenzylamino)phenylcarbamate, and has an empirical formula of C16 His FN3O2, and a molecular weight of 303.33 g/mol.
Figure imgf000003_0001
Retigabine is a pharmaceutical substance with anticonvulsive, antipyretic and analgesic activity, and can thus be used in pharmaceutical preparations. In the United States of America, the non-proprietary name retigabine has been superseded by ezogabine.
The preparation of retigabine dihydro chloride and similar compounds is disclosed in U.S. Patent No. 5,384,330.
CNS Drug Rev. 2005, 11, 1 describes the dihydrochloride salt of retigabine to be hygroscopic and unstable under medium to long-term storage at -18°C. It also describes that retigabine is preferably stored as the free base, isolated from light. The tendency of retigabine to easily oxidize upon contact with air during solubilization as the free base is also described.
U.S. patent No. 6,538,151 describes three different crystalline forms of retigabine, denominated therein as modifications A, B, and C, and also provides processes for preparing the same. BRIEF DESCRIPTION OF THE FIGURES
Figure 1 illustrates the X-ray powder diffractogram (XRD) of an amorphous form of retigabine comprising a mixture of retigabine and polyvinylpyrrolidone, as obtained in Example 1.
Figure 2 illustrates the XRD of an amorphous form of retigabine comprising a mixture of retigabine and polyvinylpyrrolidone as obtained in Example 1 , and after one month of storage at room temperature in a closed glass vial.
Figure 3 illustrates the XRD of an amorphous form of retigabine comprising a mixture of retigabine and polyvinylpyrrolidone, as obtained in Example 4.
Figure 4 illustrates the XRD of an amorphous form of retigabine comprising a mixture of retigabine and hydroxypropyl methylcellulose phthalate, as obtained in Example 11.
Figure 5 illustrates the XRD of an amorphous form of retigabine comprising a mixture of retigabine and hydroxypropyl methylcellulose phthalate, as obtained in Example 12.
BRIEF SUMMARY OF THE INVENTION
The invention relates to a stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, to processes for preparing the same, and to solid pharmaceutical compositions or formulations comprising the same.
The invention also provides a stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, and a pharmaceutical formulation comprising the same, stabilized in a container or packaging.
Additionally, the invention relates to a method for storing or packaging an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, and a pharmaceutical formulation comprising the same.
In a further aspect, the invention relates to a method of stabilization of an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, and a pharmaceutical formulation comprising the same. DETAILED DESCRIPTION OF THE INVENTION
The inventors have now surprisingly found that retigabine can be obtained in an amorphous stable form when mixed with at least one pharmaceutically acceptable carrier. Further, the inventors have shown that stable solid retigabine amorphous as such can not be successfully obtained (See reference examples 1-5). According to the present invention, therefore, there is provided a stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier.
The mixture according to the present invention is particularly stable, meaning that the retigabine is stable in its amorphous form. Namely, the inventors have shown that the amorphous mixture of retigabine according to the present invention is stable in its amorphous form after storage for at least one month at room temperature and in a closed glass vial, and after storage in an aluminium foil bag for at least 6 months under accelerated stability testing conditions (i.e. 40°C and 75% RH). Also, the amorphous mixture of retigabine according to the present invention is substantially chemically stable after storage in an aluminium foil bag for at least 6 months under accelerated stability testing conditions (i.e. 40°C and 75% RH) and in an inert atmosphere. Furthermore, the amorphous mixture of retigabine according to the present invention shows an enhanced solubility profile compared to the known solid retigabine forms (i.e. crystalline modifications A, B, and C). Namely, the amorphous solid mixture of retigabine of the invention shows a solubility increasing of more than 200% as compared to the lowest soluble crystalline modification of retigabine (i.e. modification C), and a solubility increasing of more than 60% as compared to the highest soluble crystalline modification of retigabine (i.e. modification B). In addition the mixture is particularly easy to manipulate.
The stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the present invention preferably has a polymeric carrier as a pharmaceutically acceptable carrier. The term "polymer" is used conventionally, meaning a compound that is made of monomers connected together to form a larger molecule. A polymer generally consists of at least about 20 monomers connected together. Thus, the molecular weight of the polymer generally will be about 2000 daltons or more. The polymer should be inert, in the sense that it does not chemically react with the drug in an adverse manner, and should be pharmaceutically acceptable.
In an aspect, the at least one pharmaceutically acceptable carrier of the stable amorphous solid mixture according to the present invention is preferably a polymeric carrier suitable for instant release or modified release formulation, and more preferably is at least one from the group consisting of gelatines, ovalbumin, soybean proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), PVP-vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, Isomalt, cyclodextrins such as cc-cyclodextrins, β-cyclodextrins, γ- cyclodextrins, and hydroxyl-propyl- -cyclodextrins, sodiumcarboxymethylcellulose, sodium alginate, xantham gum, caavageenan, locust bean gum (ceratonia), chitosan, guar gum, cross-linked high amylase starch, and cross-linked polyacrylic acid (carbopol). It is preferred that the polymeric carrier suitable for instant release or modified release formulation of the stable amorphous solid mixture according to the present invention is polyvinylpyrrolidone (PVP).
The polymeric carrier suitable for instant release or modified release formulation of the stable amorphous solid mixture according to the present invention preferably has the functionality of being a stabilizer agent of the amorphous retigabine and an agent that controls or modifies the release of the amorphous retigabine in a pharmaceutical formulation. The term "agent that controls or modifies the release" is understood to define an agent that regulates the release and/or the rate of dissolution of the active pharmaceutical ingredient retigabine upon administration to a subject. Therefore, based on the selection of the polymeric carrier suitable for instant release or modified release formulation as described above, their specific combination, properties and content ratio, the solid amorphous solid mixture comprising amorphous retigabine of the present invention can be suitable for an instant or a modified release solid pharmaceutical formulation. Namely, the said pharmaceutically acceptable carrier is suitable not only for stabilizing the amorphous retigabine within the solid mixture, but also is suitable for preparing an instant or modified release formulation of said stable amorphous solid mixture.
In an alternative aspect, the at least one pharmaceutically acceptable carrier of the stable amorphous solid mixture according to the present invention is preferably an enteric polymer. An enteric polymer as used herein is meant to describe a polymer which is poorly soluble in water at a pH of about 4.5 or less (i.e. the pH of the stomach) and which is soluble in water at a pH of greater than about 5 (i.e. the pH of the lower gastrointestinal tract). An enteric polymer is amphiphilic in nature, meaning that it has hydrophilic and hydrophobic portions, and also contains ionisable portions that are capable of being ionised at a pH of greater than about 5, so constituting at least a portion of the hydrophilic portions of the polymer. More preferably, the enteric polymer is at least one from the group consisting of polyvinylacetate phthalate, hydroxypropylmethylcellulose acetate succinate (HPMC-AS), cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, hydroxypropylmethylcellulose phthalate (HPMCP), polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methylacrylate-methacrylic acid-octyl acrylate copolymer, methylcellulose (MC), ethylcellulose (EC), cellulose acetate propionate, methylvinylether-maleic anhydride copolymers, and Eudragit E (a basic butylmethacrylate copolymer). It is preferred that the enteric polymer of the stable amorphous solid mixture according to the present invention is hydroxypropylmethylcellulose phthalate (HPMCP).
The enteric polymer of the stable amorphous solid mixture according to the present invention preferably has the functionality of being a stabilizer agent of the amorphous retigabine and an agent for retarding release in the gastric environment in a pharmaceutical formulation. The term "agent for retarding the release in the gastric environment" as used herein is meant to describe an agent that bypasses the release of the active ingredient into the gastric environment, so that the retigabine is first exposed to an environment of the lower gastrointestinal tract. Namely, the said enteric polymer is suitable not only for stabilizing the amorphous retigabine within the solid mixture, but also is suitable for preparing an extended release formulation of said stable amorphous solid mixture. Therefore, the solid amorphous mixture of the invention can be suitable for an extended release solid pharmaceutical formulation.
The stable amorphous solid mixture according to the present invention can comprise combinations of several pharmaceutically acceptable carriers, wherein said carriers are carriers suitable for instant release or modified release formulation or polymeric enteric carriers as hereinbefore described. Therefore, the specific selection, combination, properties and content ratio of the various pharmaceutically acceptable carriers within the amorphous mixture described above may not only stabilize the amorphous retigabine but may also regulate the release and/or the rate of dissolution of the active pharmaceutical ingredient retigabine in a pharmaceutical formulation. Thus, the stable amorphous solid mixture according to the present invention can be suitable for preparing an extended and/or an instant or modified release solid pharmaceutical formulation. The amorphous forms of retigabine of the invention can be characterized by means of Powder X-ray diffraction pattern (XRD). The stable amorphous solid mixture according to the present invention is preferably characterized by showing an X-ray powder diffraction pattern showing a broad peak at between about 4 and about 44 (20°). Also, the stable amorphous solid mixture according to the present invention can be characterized by showing an X-ray powder diffraction pattern lacking discernible or sharp peaks and/or by showing an X-ray powder diffraction pattern being substantially the same as any of the XRD depicted in Figures 1 to 5.
Figures 1 to 3 illustrate the X-ray powder diffraction pattern (2Θ) (± 0.2°) of amorphous solid mixtures of retigabine and polyvinylpyrrolidone. Figures 4 and 5 illustrate the X-ray powder diffraction pattern (2Θ) (± 0.2°) of amorphous solid mixtures of retigabine and hydroxypropyl methylcellulose phthalate.
The powder X-ray diffraction patterns (i.e. XRD diffractograms) of the amorphous solid mixtures according to the present invention were obtained by means of a RX SIEMENS D5000 diffractometer. The measurements were carried out under technical characteristics as set out below. Namely, the determinations were done with the RX SIEMENS D5000 diffractometer with a vertical goniometer, a copper anodic tube, and radiation CuKa , λ= 1, 54056 A.
In a further aspect, the stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier according to the present invention preferably has a ratio of the at least one pharmaceutically acceptable carrier to the retigabine of at least about 1 :2 (w/w). More preferably, the stable amorphous solid mixture of the invention has a ratio of the at least one pharmaceutically acceptable carrier to the retigabine of between about 1 :2 to about 2: 1 (w/w).
In another aspect, the stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier according to the present invention is preferably obtained by a process comprising: (a) removing the solvent from a solution or dispersion of retigabine and the at least one pharmaceutically acceptable carrier; or (b) melt extruding a mixture of retigabine and the at least one pharmaceutically acceptable carrier; or (c) grinding a mixture of retigabine and the at least one pharmaceutically acceptable carrier; or (d) lyophilizing a mixture of retigabine and the at least one pharmaceutically acceptable carrier; or (e) hot melting a mixture of retigabine and the at least one pharmaceutically acceptable carrier in fluid bed granulator.
In another further aspect, the preparation of the stable amorphous solid mixture of the present invention is preferably carried out by the process (a) of the invention above, and said process preferably comprises: (i) treating retigabine with the at least one pharmaceutically acceptable carrier in the presence of a suitable solvent, to obtain a solution, and (ii) removing the solvent from the solution.
The solvent of the step (i) of the process of the invention above is preferably an organic solvent, and still preferably is a C1-C5 alcohol solvent, a C3-C10 ketone solvent, or mixtures thereof. More preferably, the solvent of the step (i) of the process above is methanol, ethanol, acetone, or mixtures thereof. Also, the solvent may comprise water.
The removing the solvent from the solution of step (ii) of the process of the invention above can be carried out by standard methods known in the art such as, for example, distilling the solution, spray drying the solution, or precipitating the amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier from the solution and either filtering or decanting the suspension.
Preferably, the removing the solvent from the solution of step (ii) of the process of the invention above is carried out by spray drying the solution. More precisely, in the spray drying the solution the solvent is preferably methanol, ethanol or acetone; the inlet temperature is preferably of between about 20-200 °C, and more preferably of about 65-115 °C; and the feed rate is preferably of between about 1-25 mL/min, and more preferably of about 3.5 mL/min; and so the outlet temperature is preferably of between about 20-120 °C, and more preferably of about 45-80 °C. In an alternative preferred embodiment, the removing the solvent from the solution of step (ii) of the process of the invention above is carried out by distilling the solution. The distilling the solution is preferably carried out by rotary evaporation (rotavapping). Alternatively, the removing the solvent from the solution of step (ii) of the process of the invention above can be carried out by any additional drying step known in the art, such as vacuum drying and oven drying.
The retigabine used for preparing the amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the process above can be either retigabine obtained by a known method, for example retigabine in crystalline modifications A, B, or C, or mixtures thereof. The said in crystalline modifications A, B, or C, or mixtures thereof can be prepared by following any of the methods described in the art, such as the processes described in U.S. patent No. 6,538,151. Also, the retigabine can be directly used in solution or dispersion as directly obtained from any synthetic preparation described in the art.
Another aspect of the invention includes a pharmaceutical composition comprising a stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier according to the invention. Therefore, the invention also relates to a solid pharmaceutical formulation comprising stable amorphous retigabine and one or more pharmaceutically acceptable carriers.
Since the present inventors have found that the stable amorphous solid mixture of retigabine according to the present invention shows an enhanced solubility profile as compared to the crystalline modifications of retigabine described in the art, a solid pharmaceutical formulation comprising said amorphous solid mixture of retigabine of the invention is advantageous over a solid pharmaceutical formulation comprising any of the crystalline modifications of retigabine described in the art, because the amorphous solid mixture of retigabine of the invention dissolves better (i.e. about 200- 60% better. See Example 15), which is a key factor for the bioavailability of the active substance in the body.
The term pharmaceutical composition as described herein is meant to define any mixture for pharmaceutical use, which can be referred to in the art as
pharmaceutical mixture, composition or formulation.
The solid pharmaceutical formulation according to the present invention is meant to comprise an effective amount of solid amorphous retigabine substantially as hereinbefore described, optionally, together with a pharmaceutically acceptable carrier or excipient therefor. The term "effective amount" as used herein means an amount of amorphous retigabine which is capable of providing an anticonvulsive, antipyretic and / or analgesic therapeutic effect. By "pharmaceutically acceptable carrier or excipient" is meant that the carrier or excipient must be compatible with amorphous retigabine and not to be deleterious to a recipient thereof.
In an aspect, the stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the invention above can be directly used as a pharmaceutical formulation.
In a preferred aspect, the solid pharmaceutical formulation according to the present invention comprises: (i) a nucleus comprising the stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the invention above; and (ii) one or more additional pharmaceutical acceptable carriers; and/or (iii) one or more coating layers.
The formulation nucleus comprising the amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the invention above can comprise combinations of several pharmaceutically acceptable carriers, wherein said pharmaceutically acceptable carriers are preferably polymeric carriers suitable for instant release or modified release formulation or polymeric enteric carriers as described above. Therefore, the selection, specific combination, properties and content ratio of the various pharmaceutically acceptable carriers within the formulation nucleus described above may not only stabilize the amorphous retigabine but may also regulate the release and/or the rate of dissolution of the active pharmaceutical ingredient retigabine.
Also, the solid pharmaceutical formulation of the invention may comprise one or more coating layers which may additionally contribute to regulate the release and/or the rate of dissolution of the active pharmaceutical ingredient retigabine upon administration to a subject.
The coating layers for use in the pharmaceutical formulation of the invention are preferably film coating layers, meaning that the film is formed by polymers, wherein said film coating layers can be formulations of organic solvent-based solution of polymers, aqueous solutions or dispersions of polymers, hot melt systems, or powder coatings. The said polymers used in the said coating layers can be water soluble polymers, water insoluble polymers, and polymers used in enteric coatings.
The coating layers for use in instant release pharmaceutical formulation preferably comprise a polymeric carrier suitable for instant release formulation, and more preferably is at least one from the group consisting of gelatines, ovalbumin, soybean proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), PVP-vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a vinylpyrrolidone- vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, Isomalt, cyclodextrins such as cc-cyclodextrins, β-cyclodextrins, γ- cyclodextrins, and hydroxyl-propyl- -cyclodextrins, sodiumcarboxymethylcellulose, sodium alginate, xantham gum, caavageenan, locust bean gum (ceratonia), chitosan, guar gum, cross-linked high amylase starch, and cross-linked polyacrylic acid (carbopol).
The coating layers for use in extended release pharmaceutical formulation preferably comprise an enteric polymer, and more preferably the enteric polymer is at least one from the group consisting of polyvinylacetate phthalate, hydorxypropylmethylcellulose acetate succinate (HPMC-AS), cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methylacrylate-methacrylic acid-octyl acrylate copolymer, methylcellulose (MC), ethylcellulose (EC), cellulose acetate propionate, methylvinylether-maleic anhydride copolymers, and Eudragit E (a basic butylmethacrylate copolymer).
Also, each coating layer of the pharmaceutical formulation of the invention above can also comprise combinations of different polymeric carriers suitable for instant release formulation or enteric polymers, as hereinbefore described, which may additionally contribute to regulate the release and/or the rate of dissolution of the active pharmaceutical ingredient retigabine upon administration to a subject.
Therefore, based on the specific selection, combination, properties and content ratio of the various pharmaceutically acceptable carriers within the formulation nucleus, and/or within the extra-nucleus, and based on the selection, composition and number of the coating layers, the solid the pharmaceutical formulation comprising amorphous retigabine of the present invention can relate to an extended and/or an instant or modified release solid pharmaceutical formulation.
The term "instant or immediate release pharmaceutical formulation" as used herein is meant to describe a pharmaceutical formulation such that the active ingredient is immediately released upon administration to a subject.
The term "modified or controlled release pharmaceutical formulation" as used herein is meant to describe a pharmaceutical formulation such that the active ingredient is delivered at a relatively constant level over a sustained period of time, upon administration to a subject, based on delaying the rate of dissolution or the release of the active ingredient.
The term "extended release pharmaceutical formulation" as used herein is meant to describe a pharmaceutical formulation such that the release of the active ingredient is retarded into the gastric environment, so that the retigabine is first exposed to an environment of the lower gastrointestinal tract.
In another aspect, the additional pharmaceutical acceptable carriers of paragraph (ii) of the solid pharmaceutical formulation according to the present invention are at least one from the group consisting of pharmaceutically acceptable bulking agents, binders, disintegrants, lubricants, surfactants, drug delivery matrices, release modifying agents, glidants, diluents, vehicles, buffers, stabilizers, tonicity agents, coloring agents, flavouring agents, sweeteners, cryoprotectants, lyoprotectants, anti-oxidants, chelating agents, and preservatives. Pharmaceutically acceptable carriers are well known in the art and are described in, for example, Remington: The Science and Practice of Pharmacy, A. R. Gennaro, ed., Lippincott Williams & Wilkins; 20th edition (December 15, 2000).
Suitable pharmaceutically acceptable formulations according to the present invention are preferably in the form of solid compositions, such as a powder or lyophilized product for inclusion in a suspension or dispersion for an injectable formulation, or powder for an oral suspension, suppositories, tablets, coated tablets such as film coated tablets, non coated tablets, orodispersible tablets, pellets, pills, granules, capsules, or mini-tablets in capsules. Preferably, the solid pharmaceutical formulation of the invention is in the form of a film coated tablet.
It is known from the prior art that retigabine is light sensitive in solid form, since it is described that retigabine is preferably isolated from light on storage. However, the stability of the solid retigabine upon contact with air is not reported. The inventors have now also found that the amorphous solid mixture of retigabine of the present invention is susceptible to oxidation upon contact with the atmosphere.
The inventors have additionally surprisingly found that the chemical stability of the amorphous solid mixture of retigabine of the present invention can be dramatically affected by the oxygen content in a surrounding environment. Degradation has been particularly observed by the worsening of the chemical purity (i.e. at least between about 11-18%) of the solid amorphous mixtures of retigabine of the invention when stored in contact with atmospheric oxygen in a closed aluminium foil bag for at least 6 months under accelerated stability testing conditions (i.e. 40°C and 75% RH). Surprisingly, when keeping the same mixtures under an inert atmosphere, no substantial worsening of the chemical purity is observed (i.e. only 0.5% of worsening). Namely, substantial stability of the chemical purity has been particularly observed for the solid amorphous mixtures of retigabine when stored in contact with atmospheric oxygen within a permeably gas-exchange polyethylene (PE) bag which at the same time was stored in an aluminium foil bag for at least 6 months under accelerated stability testing conditions (i.e. 40°C and 75% RH) and in the presence of a suitable amount of an oxygen scavenger (i.e. Ageless™ ZPT-300 bag) so that to ensure that the atmosphere within the aluminium foil bag is an inert atmosphere.
The term "inert atmosphere" as used herein is understood to comprise an atmosphere which is essentially free of oxygen. By essentially free of oxygen is meant to refer that the oxygen content within the surrounding environment (i.e. in a closed container or packaging) is less than 1%, preferably less than 0.1%, more preferably less than 0.01%, and even more preferably is free of oxygen.
The present invention, therefore, provides an additional improvement in stability of the amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier according to the present invention as illustrated by a substantial chemical stability, as measured by HPLC. Equally, the said improvement can be used to stabilize the chemical purity of the solid pharmaceutical formulation comprising the said amorphous solid mixture according to the present invention.
Accordingly, the present invention provides an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, or a solid pharmaceutical formulation thereof, as described hereinbefore, which is stabilized or substantially stabilized by storage in an enclosed container or packaging wherein inert atmosphere is provided within the container or packaging and/or wherein the container or packaging is a substantially gas exchange non-permeable enclosed container or packaging.
The amorphous solid mixture, or solid pharmaceutical formulation thereof, stabilized in an enclosed container or packaging as hereinbefore described is preferably stored in the absence of light. In another embodiment, the enclosed container or packaging as described above is preferably also a substantially light non-permeable enclosed container or packaging.
In yet another embodiment, the inert atmosphere provided in the amorphous solid mixture, or solid pharmaceutical formulation thereof, stabilized in an enclosed container or packaging as hereinbefore described is preferably provided by the presence of a suitable amount of an oxygen scavenger; and/or by the provision of vacuum or of an inert gas atmosphere, in the said enclosed container or packaging.
In a further embodiment, the inert gas is preferably nitrogen or argon.
In yet a further embodiment, the oxygen scavenger is preferably a chemical compound that reacts with oxygen, and more preferably is an iron powder compound or ascorbic acid. Even more preferably, the iron powder compound is an Ageless™ sachet.
In another embodiment, the enclosed container or packaging for the amorphous solid mixture of the invention is preferably a gas exchange non-permeable metal or glass or plastic container or packaging. More preferably, the enclosed gas exchange non-permeable container or packaging is an Aluminium foil bag or sachet.
The amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier of the invention can be firstly stored in a gas exchange permeable glass or plastic container or packaging (i.e. polyethylene plastic bag) which is turn stored within the gas exchange non-permeable metal or glass or plastic container or packaging, so as to avoid any potential damage of the gas exchange non-permeable metal or glass or plastic container or packaging to the mixture, especially when the gas exchange non-permeable container or packaging is a metal container or packaging. Also, the gas exchange non-permeable metal or glass or plastic container or packaging can have an internal polymeric layer to avoid damage to the mixture, so that the intermediate gas exchange permeable glass or plastic container or packaging is not necessary.
In another embodiment, the enclosed container or packaging for the solid pharmaceutical formulation comprising the amorphous solid mixture of the invention is preferably selected from the group consisting a non-permeable blister, such as an Al / Al blister, or an Al-polychloro-3-fluoroethylene homopolymer / PVC laminate blister, an aluminum foil, a glass or plastic bottle, and a glass or plastic vial.
In another aspect, the invention relates to a method for storing or packaging an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, or a solid pharmaceutical formulation thereof, as hereinbefore described, in an enclosed container or packaging, wherein the storing or packaging procedure is carried out in an inert atmosphere; and/or the container or packaging is a substantially gas exchange non-permeable enclosed container or packaging.
In yet another aspect, the invention relates to a method for stabilization of an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier, or a solid pharmaceutical formulation thereof, as hereinbefore described, said method comprising storing or packaging the solid mixture, or the solid pharmaceutical formulation thereof, in an enclosed container or packaging, wherein the enclosed container or packaging has inert atmosphere as hereinbefore described; and/or the container or packaging is a substantially gas exchange non-permeable enclosed container or packaging.
Preferably, the container or packaging of the methods above is a substantially light non-permeable enclosed container or packaging; and/or the storing or packaging procedure in said methods is carried out in the absence of light.
The present invention further provides amorphous solid mixture of retigabine substantially as hereinbefore described, for use in the treatment of a disease state alleviated by administration of retigabine, in particular for the treatment of epilepsy. The present invention also provides a method of treatment of a disease state alleviated by administration of retigabine, in particular epilepsy, which method comprises administering to the patient an effective amount of amorphous solid mixture of retigabine substantially as hereinbefore described.
Specific examples
General Experimental Conditions:
The solid retigabine used in the Examples described herein was obtained by following the teachings of the methods described in U.S. patent No. 6,538, 151. X-ray Powder Diffraction (XRD)
The XRD diffractograms were obtained using a RX SIEMENS D5000 diffractometer with a vertical goniometer, a copper anodic tube, and radiation CuKa , λ= 1, 54056 A.
HPLC Method
The chromatographic separation was carried out in a Waters Sunfire CI 8, 5μιη, 4.6 x 250 mm column at 30°C.
The mobile phase was a filtered and degassed mixture of buffer solution and methanol (35:65). The buffer solution was prepared by dissolving about 0.5 mL of thiethylamine in 500 mL of water, and then adjusting the pH to 7.1 with acetic acid.
The chromatograph was equipped with a 254nm detector, and the flow rate was 0.8mL per minute. The test samples (10 μί) were prepared by dissolving the appropriate amount of sample in mobile phase in order to obtain 1.0 mg of retigabine per mL. The chromatograph was run for at least 45 minutes.
Example 1: Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
Retigabine (0.5005 g) and polyvinylpyrrolidone (1.0033 g) were dissolved in 7 mL methanol at room temperature. The solution was filtered and concentrated to dryness in a rotary evaporator. The residue obtained was smoothly ground.
Analytical data: XRD: amorphous form, see Figure 1. XRD after one month of storage at room temperature in a closed glass vial: amorphous form, see Figure 2.
Example 2: Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
Retigabine (0.5015 g) and polyvinylpyrrolidone (0.5017 g) were dissolved in 12 mL methanol at room temperature. The solution was filtered and concentrated to dryness in a rotary evaporator. The residue obtained was smoothly ground.
Analytical data: XRD: amorphous form, substantially similar to Figure 1. XRD after one month of storage at room temperature in a closed glass vial: amorphous form, substantially similar to Figure 2. Example 3: Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
Retigabine (0.5004 g) and polyvinylpyrrolidone (0.4998 g) were dissolved in 20 mL ethanol at room temperature. The solution was filtered and concentrated to dryness in a rotary evaporator. The residue obtained was smoothly ground.
Analytical data: XRD: amorphous form, substantially similar to Figure 1.
Example 4: Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
Polyvinylpyrrolidone (Plasdone K29/32) (5.0048 g) was dissolved in methanol (50 mL). Then, retigabine (5.0221 g) was added and methanol was added to complete dissolution (the total volume of methanol was 100 mL). The solution was filtered and spray dried using a Buchi B290 spray dryer. The amorphous solid mixture of retigabine and polyvinylpyrrolidone was recovered.
The following parameters were used in the spray drying: inlet temperature (actual reading) = 90 °C, outlet temperature (actual reading) = 67 °C, aspirator = 100% (equivalent to approximately 35 m3/hour), nitrogen flow = 30 mm (equivalent to approximately 360 L/hour). The peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
Analytical data: XRD: amorphous form, see Figure 3.
Example 5: Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
Polyvinylpyrrolidone (Plasdone K29/32) (10.0044 g) was dissolved in methanol (50 mL). Then, retigabine (5.0122 g) was added and methanol was added to complete dissolution (the total volume of methanol was 80 mL). The solution was filtered and spray dried using a Buchi B290 spray dryer. The amorphous solid mixture of retigabine and polyvinylpyrrolidone was recovered.
The following parameters were used in the spray drying: inlet temperature (actual reading) = 90 °C, outlet temperature (actual reading) = 66-67 °C, aspirator = 100% (equivalent to approximately 35 m3/hour), nitrogen flow = 30 mm (equivalent to approximately 360 L/hour). The peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
Analytical data: XRD: amorphous form, substantially similar to Figure 3.
Example 6: Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
Polyvinylpyrrolidone (Plasdone K29/32) (10.05 g) was dissolved in methanol (40 mL). Then retigabine (10.01 g) was added and methanol was added to complete dissolution (total volume of methanol was 160 mL). The solution was filtered and spray dried using a Buchi B290 spray dryer. 15.04 g of solid were recovered (Yield: 75.0 %). HPLC purity: 99.07%
The following parameters were used in the spray drying: inlet temperature (actual reading) = 90°C, outlet temperature (actual reading) = 60°C, aspirator = 100%) (equivalent to approximately 35 m3/hour), nitrogen flow = 30 mm (equivalent to approximately 360 L/hour). The peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
Analytical data: XRD: amorphous form, substantially similar to Figure 1.
Example 7: Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
Polyvinylpyrrolidone (Plasdone K29/32) (10.32 g) was dissolved in methanol (50 mL). Then retigabine (5.19 g) was added and methanol was added to complete dissolution (total volume of methanol was 80 mL). The solution was filtered and spray dried using a Buchi B290 spray dryer. 11.24 g of solid were recovered (Yield: 74.9 %). HPLC purity: 98.97%.
The following parameters were used in the spray drying: inlet temperature (actual reading) = 90°C, outlet temperature (actual reading) = 61°C, aspirator = 100%) (equivalent to approximately 35 m3/hour), nitrogen flow = 30 mm (equivalent to approximately 360 L/hour). The peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
Analytical data: XRD: amorphous form, substantially similar to Figure 1. Example 8: Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
Retigabine (130.18 g) and polyvinylpyrrolidone (Plasdone K29/32) (130.14 g) were mixed and dissolved in methanol (2,325 L). The resulting solution was filtered and spray dried using a Buchi B290 spray drier. 213.9 g of solid were recovered (Yield: 89%). HPLC purity: 99.79%
The following parameters were used in the spray drying: inlet temperature (actual reading) = 110°C, outlet temperature (actual reading) = 67°C, aspirator = 100% (equivalent to approximately 35 m3/hour), nitrogen flow = 30 mm (equivalent to approximately 360 L/hour). The peristaltic pump to feed the product solution was set to 25% (equivalent to approximately 8.75 mL/min).
Analytical data: XRD: amorphous form, substantially similar to Figure 1.
Example 9: Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
Retigabine (10.09 g) was dissolved in methanol (200 mL). Then polyvinylpyrrolidone (Plasdone K29/32) (5.00 g) was added and methanol was added to complete dissolution (total volume of methanol was 80 mL). The resulting solution was filtered and spray dried using a Buchi B290 spray dryer. 10.60 g of solid were recovered (Yield: 70.2 %). HPLC purity: 98.18%
The following parameters were used in the spray drying: inlet temperature
(actual reading) = 110°C, outlet temperature (actual reading) = 74°C, aspirator = 100% (equivalent to approximately 35 m3/hour), nitrogen flow = 30 mm (equivalent to approximately 360 L/hour). The peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
Analytical data: XRD: amorphous form, substantially similar to Figure 1.
Example 10: Preparation of an amorphous solid mixture of retigabine and polyvinylpyrrolidone
Retigabine (10.00 g) was dissolved in methanol (170 mL). Then polyvinylpyrrolidone (Plasdone K29/32) (10.02 g) was added and methanol was added to complete dissolution (total volume of methanol was 200 mL). The resulting solution was filtered and spray dried using a Buchi B290 spray dryer. 14.03 g of solid were recovered (Yield: 70.1 %). HPLC purity: 98.28%.
The following parameters were used in the spray drying: inlet temperature (actual reading) = 70°C, outlet temperature (actual reading) = 50°C, aspirator = 100% (equivalent to approximately 35 m3/hour), nitrogen flow = 20 mm (equivalent to approximately 240 L/hour). The peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
Analytical data: XRD: amorphous form, substantially similar to Figure 1.
Example 11: Preparation of an amorphous solid mixture of retigabine and hydroxypropylmethylcellulose phthalate
Retigabine (0.5853 g) was dissolved in acetone (3 mL) at room temperature and under nitrogen. Then hydroxypropylmethylcellulose phthalate (HPMCP HP-55) (0.5820 g) was added and acetone was added to complete dissolution (total volume of acetone was 7 mL). The solution was concentrated to dryness in a rotary evaporator. The residue obtained was smoothly ground.
Analytical data: XRD: amorphous form, see Figure 4.
Example 12: Preparation of an amorphous solid mixture of retigabine and hydroxypropylmethylcellulose phthalate
Retigabine (0.5333 g) was dissolved in methanol (11 mL) at room temperature and under nitrogen. Then hydroxylpropylmethylcellulose phthalate (HPMCP HP-55) (0.5356 g) was added. The mixture was stirred for 30 min and concentrated to dryness in a rotary evaporator. The residue obtained was smoothly ground. 0.96 g solid was recovered (Yield: 89.3%).
Analytical data: XRD: amorphous form, see Figure 5.
Example 13: Amorphous stability study under accelerated stability testing conditions of the amorphous solid mixture of retigabine and PVP
A sample corresponding to the amorphous solid mixture of retigabine and PVP obtained in Example 7 was stored in a polyethylene bag which in turn was stored in an Aluminium foil bag under accelerated stability testing conditions (40°C and 75% RH) for 6 months. The amorphous stability of the sample was measured by XRD. The obtained results are shown in Table 1 below.
Figure imgf000023_0002
Table 1
Example 14: Chemical stability study under accelerated stability testing conditions of the amorphous solid mixture of retigabine and PVP
Samples corresponding to the amorphous solid mixture of retigabine and PVP obtained in Examples 6 and 7 were stored in a polyethylene bag which in turn was stored in an Aluminium foil bag, either in the presence or in the absence of an ageless™ oxygen scavenger sachet (placed between the polyethylene bag external layer and the Aluminium foil bag internal layer), under accelerated stability testing conditions (40°C and 75% RH) for 6 months. The chemical stability of the sample was measured by HPLC. The obtained results are shown in Table 2 below.
Figure imgf000023_0001
Ageless™
Example 7 ZPT-300 99.79 99.26 -0.53%
sachet
Table 2
Example 15: Comparative solubility studies for crystalline and amorphous forms or retigabine
The solubility study of the prior art retigabine modifications A, B and C, and of the amorphous solid mixture of retigabine and PVP from Examples 7 and 9 were conducted in water at room temperature. The solid was added in portions to water at room temperature for 24 h until suspension was observed. Then, an aliquot was filtered through a 0.22 μιη filter syringe and analysed by HPLC. The obtained results are shown in Table 3 below.
Figure imgf000024_0001
Table 3
Reference Example 1
Retigabine (150 mg) was dissolved in acetone (1,5 mL) at room temperature. The solution was evaporated in a rotary evaporator to dryness. The residue was collected.
Analytical data: XRD: Retigabine crystalline modification B. Reference Example 2
Retigabine (150 mg) was dissolved in methanol (2 mL) at room temperature. The solution was evaporated in a rotary evaporator to dryness. The residue was collected.
Analytical data: XRD: mixture of crystalline modifications A and B.
Reference Example 3
Retigabine (4 g) was dissolved in acetone (30 mL). The solution was filtered and spray dried using a Buchi B290 spray dryer. The solid residue was recovered.
The following parameters were used in the spray drying: inlet temperature (actual reading) = 101°C, outlet temperature (actual reading) = 72°C, aspirator = 100% (equivalent to approximately 35 m3/hour), nitrogen flow = 35 mm (equivalent to approximately 420 L/hour). The peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
Analytical data: XRD: Retigabine crystalline modification B.
Reference Example 4
Retigabine (3.15 g) was dissolved in ethanol (15 mL) at reflux. The solution was filtered and spray dried using a Buchi B290 spray dryer. The solid residue was recovered.
The following parameters were used in the spray drying: inlet temperature (actual reading) = 130°C, outlet temperature (actual reading) = 96°C, aspirator = 100%) (equivalent to approximately 35 m3/hour), nitrogen flow = 30 mm (equivalent to approximately 360 L/hour). The peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
Analytical data: XRD: Retigabine crystalline modification B.
Reference Example 5
Retigabine (3 g) was dissolved in acetone (20 mL).The solution was filtered and spray dried using a Buchi B290 spray dryer. The solid residue was recovered.
The following parameters were used in the spray drying: inlet temperature (actual reading) = 60°C, outlet temperature (actual reading) = 51°C, aspirator = 100%) (equivalent to approximately 35 m3/hour), nitrogen flow = 30 mm (equivalent to approximately 360 L/hour). The peristaltic pump to feed the product solution was set to 10% (equivalent to approximately 3.5 mL/min).
Analytical data: XRD: Retigabine crystalline modification B.

Claims

Claims:
1. A stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier.
2. The stable amorphous solid mixture of claim 1, wherein the at least one pharmaceutically acceptable carrier is a polymeric carrier.
3. The stable amorphous solid mixture of any of claims 1 and 2, wherein the at least one pharmaceutically acceptable carrier is a polymeric carrier for instant or modified release formulation.
4. The stable amorphous solid mixture of any of claims 1 to 3, wherein the pharmaceutically acceptable carrier is a stabilizer agent of the amorphous retigabine and an agent that controls the release of the amorphous retigabine in a pharmaceutical formulation.
5. The stable amorphous solid mixture of any of claims 3 and 4, wherein the pharmaceutically acceptable carrier is at least one from the group consisting of gelatines, ovalbumin, soybean proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxy ethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), PVP-vinylacetate-copolymer (PVP- VA), Kollidon VA 64 (a vinylpyrrolidone- vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, Isomalt, cyclodextrins such as cc-cyclodextrins, β- cyclodextrins, γ-cyclodextrins and hydroxyl-propyl- -cyclodextrins, sodiumcarboxymethylcellulose, sodium alginate, xantham gum, caavageenan, locust bean gum (ceratonia), chitosan, guar gum, cross-linkedhighamylase starch, and cross- linked polyacrylic acid (carbopol).
6. The stable amorphous solid mixture of claim 5, wherein the pharmaceutically acceptable carrier is polyvinyl pyrrolidone (PVP).
7. The stable amorphous solid mixture of any of claims 1 and 2, wherein the at least one pharmaceutically acceptable carrier is an enteric polymer.
8. The stable amorphous solid mixture of any of claims 1, 2, and 7, wherein the pharmaceutically acceptable carrier is a stabilizer agent of the amorphous retigabine, and an agent for retarding release in the gastric environment in a pharmaceutical formulation.
9. The stable amorphous solid mixture of any of claims 7 and 8, wherein the enteric polymer is at least one from the group consisting of polyvinylacetate phathalate, hydroxypropylmethylcellulose acetate succinate (HPMC-AS), cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacylic acid copolymer, methylacrylate-methacrylic acid-octyl acrylate copolymer, methylcellulose, ethylcellulose, cellulose acetate propionate, methylvinylether-maleic anhydride copolymers, and Eudragit E (a basic butylmethacrylate copolymer).
10. The stable amorphous solid mixture of claim 9, wherein the enteric polymer is hydroxypropylmethylcellulose phthalate (HPMCP).
11. The stable amorphous solid mixture of any of claims 1 to 10, wherein the X- ray powder diffraction pattern shows a broad peak at between about 4 and about 44 (20°).
12. The stable amorphous solid mixture of any of claims 1 to 11, wherein the ratio of the at least one pharmaceutically acceptable carrier to the retigabine is at least about 1 :2 (w/w).
13. The stable amorphous solid mixture of claim 12, wherein the ratio of the at least one pharmaceutically acceptable carrier to the retigabine is between about 1 :2 to about 2: 1 (w/w).
14. A process for preparing the stable amorphous solid mixture of any of claims 1 to 13, said process comprising:
(a) removing the solvent from a solution or dispersion of retigabine and the at least one pharmaceutically acceptable carrier; or
(b) melt extruding a mixture of retigabine and the at least one pharmaceutically acceptable carrier; or
(c) grinding a mixture of retigabine and the at least one pharmaceutically acceptable carrier; or
(d) lyophilizing a mixture of retigabine and the at least one pharmaceutically acceptable carrier; or
(e) hot melting a mixture of retigabine and the at least one pharmaceutically acceptable carrier in fluid bed granulator.
15. The process of claim 14, wherein the process (a) comprises:
(i) treating retigabine with the at least one pharmaceutically acceptable carrier in the presence of a solvent to obtain a solution; and (ii) removing the solvent from the solution.
16. The process of claim 15, wherein the retigabine of step (i) is retigabine in crystalline modifications A, B, or C, or mixtures thereof.
17. The process of any of claims 15 and 16, wherein the solvent is an organic solvent.
18. The process of claim 17, wherein the organic solvent is a C1-C5 alcohol solvent, a C3-C10 ketone solvent, or mixtures thereof.
19. The process of any of claims 17 and 18, wherein the organic solvent is methanol, ethanol, acetone, or mixtures thereof.
20. The process of any of claims 15 to 19, wherein the step (ii) comprises spray drying the solution.
21. The process of any of claims 15 to 20, wherein the step (ii) comprises spray drying a solution of retigabine in methanol, ethanol or acetone, at an inlet temperature between about 20-200 °C, at a feed rate of between about 1-25 mL/min, and at an outlet temperature of between about 20-120 °C.
22. The process of any of claims 15 to 19, wherein the step (ii) comprises distilling the solution.
23. A solid pharmaceutical formulation comprising the stable amorphous solid mixture of any of claims 1 to 13.
24. A solid pharmaceutical formulation comprising stable amorphous retigabine and one or more pharmaceutically acceptable carriers.
25. A solid pharmaceutical formulation comprising:
(i) a nucleus comprising the stable amorphous solid mixture as defined in any of claims 1 to 13; and
(ii) one or more pharmaceutical acceptable carriers; and/or
(iii) one or more coating layers.
26. The solid pharmaceutical formulation of claim 25, wherein the coating layer is an instant or modified release coating layer.
27. The solid pharmaceutical formulation of claim 26, wherein the instant release coating layer comprises a polymeric carrier.
28. The solid pharmaceutical formulation of claim 27, wherein the polymeric carrier is at least one from the group consisting of gelatines, ovalbumin, soybean proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), PVP-vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, Isomalt, cc-cyclodextrins, β-cyclodextrins, γ-cyclodextrins and hydroxyl- propyl- -cyclodextrins, sodiumcarboxymethylcellulose, sodium alginate, xantham gum, caavageenan, locust bean gum (ceratonia), chitosan, guar gum, cross- linkedhighamylase starch, and cross-linked polyacrylic acid (carbopol).
29. The solid pharmaceutical formulation of claim 25, wherein the coating layer is an extended release coating layer.
30. The solid pharmaceutical formulation of claim 29, wherein the extended release coating layer comprises an enteric polymer.
31. The solid pharmaceutical formulation of claim 30, wherein the enteric polymer is at least one from the group consisting of polyvmylacetate phathalate, hydorxypropylmethylcellulose acetate succinate (HPMC-AS), cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, hydroxypropylmethylcellulose phthalate, polyvmylacetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacylic acid copolymer, methylacrylate-methacrylic acid-octyl acrylate copolymer, methylcellulose, ethylcellulose, cellulose acetate propionate, methylvinylether-maleic anhydride copolymers, and Eudragit E.
32. The solid pharmaceutical formulation of any of claims 23 to 31, wherein the one or more pharmaceutical acceptable carriers is at least one from the group consisting of pharmaceutically acceptable bulking agents, binders, disintegrants, lubricants, surfactants, drug delivery matrices, release modifying agents, glidants, diluents, vehicles, buffers, stabilizers, tonicity agents, coloring agents, flavouring agents, sweeteners, cryoprotectants, lyoprotectants, anti-oxidants, chelating agents, and preservatives.
33. The solid pharmaceutical formulation of any of claims 23 to 32, which is in the form of a powder for inclusion in a suspension or dispersion for an injectable formulation.
34. The solid pharmaceutical formulation of any of claims 23 to 32, which is in the form of a powder for an oral suspension.
35. The solid pharmaceutical formulation of any of claims 23 to 32, which is in the form of a tablet, a coated tablet, a non coated tablet, an orodispersible tablet, a pellet, a pill, a granule, a capsule, or a mini-tablet in a capsule.
36. The solid pharmaceutical formulation of claim 35, which is in the form of a film coated tablet.
37. A stable amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier as defined in any of claims 1 to 13, or a solid pharmaceutical formulation thereof as defined in any of claims 23 to 35, which is stored in an enclosed container or packaging wherein inert atmosphere is provided within the container or packaging and/or the container or packaging is a substantially gas exchange non-permeable enclosed container or packaging.
38. The stable amorphous solid mixture, or the solid pharmaceutical formulation thereof, of claim 37 which is stored in the absence of light.
39. The stable amorphous solid mixture, or the solid pharmaceutical formulation thereof, of any of claims 37 and 38 wherein the enclosed container or packaging is also a substantially light non-permeable enclosed container or packaging.
40. The stable amorphous solid mixture, or the solid pharmaceutical formulation thereof, of any of claims 37 to 39, wherein the inert atmosphere is provided by the presence of a suitable amount of an oxygen scavenger; and/or the provision of vacuum or of an inert gas atmosphere, in the container or packaging.
41. The stable amorphous solid mixture, or the solid pharmaceutical formulation thereof, of claim 40 wherein the inert gas is nitrogen or argon.
42. The stable amorphous solid mixture, or the solid pharmaceutical formulation thereof, of claim 40 wherein the oxygen scavenger is an iron powder compound or ascorbic acid.
43. The stable amorphous solid mixture of any of claims 37 to 42, wherein the enclosed container or packaging is a gas exchange non-permeable metal or glass or plastic container or packaging.
44. The stable amorphous solid mixture of claim 43, wherein the enclosed gas exchange non-permeable container or packaging is an Aluminium foil bag or sachet.
45. The solid pharmaceutical formulation of any of claims 37 to 42, wherein the enclosed container or packaging is selected from the group consisting of non- permeable blisters, such as an Al / Al blister, an Al-polychloro-3-fluoroethylene homopolymer / PVC laminate blister, an aluminum foil, a glass or a plastic bottle, and a glass or a plastic vial.
46. A method for storing or packaging an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier as defined in any of claims 1 to 13, or a solid pharmaceutical formulation thereof as defined in any of claims 23 to 35, in an enclosed container or packaging, wherein the storing or packaging procedure is carried out in an inert atmosphere; and/or the container or packaging is a substantially gas exchange non-permeable enclosed container or packaging.
47. A method for stabilization of an amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier as defined in any of claims 1 to 13, or a solid pharmaceutical formulation thereof as defined in any of claims 23 to 35, said method comprising storing or packaging the solid mixture, or the solid pharmaceutical formulation thereof, in an enclosed container or packaging, wherein the enclosed container or packaging has an inert atmosphere; and/or the container or packaging is a substantially gas exchange non-permeable enclosed container or packaging.
48. The method of any of claims 46 and 47, wherein the container or packaging is a substantially light non-permeable enclosed container or packaging; and/or the storing or packaging procedure is carried out in the absence of light.
49. Use of amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier according to any of claims 1 to 13, for the treatment of a disease state alleviated by administration of retigabine, in particular for the treatment of epilepsy.
50. A method of treatment of a disease state alleviated by administration of retigabine, in particular epilepsy, which method comprises administering to the patient an effective amount of amorphous solid mixture of retigabine and at least one pharmaceutically acceptable carrier according to any of claims 1 to 13.
PCT/EP2010/064694 2009-10-02 2010-10-01 Amorphous forms of a 2-amino-4-(4-fluorobenzylamino)phenylcarbamate derivative WO2011039369A2 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102241608A (en) * 2011-05-12 2011-11-16 天津市汉康医药生物技术有限公司 Retigabine compound and composition thereof
US20120053238A1 (en) * 2009-03-17 2012-03-01 Ratiopharm Gmbh Solid retigabine in non-crystalline form
WO2013008250A2 (en) * 2011-07-01 2013-01-17 Dr.Reddys Laboratories Limited. Crystalline form of retigabine and processes for mixture of retigabine crystalline modifications
CN102964273A (en) * 2012-12-06 2013-03-13 北京英科博雅科技有限公司 Novel retigabine crystal form F and preparation method thereof
WO2014023270A1 (en) 2012-08-09 2014-02-13 Zentiva, K.S. Salts or co-crystals of ethyl n-[2-amino-4-[(4-fluorophenyl)methylamino]-phenyl]carbamate
CN107049979A (en) * 2011-09-30 2017-08-18 持田制药株式会社 Easy taking solid pharmaceutical preparation
WO2019032319A1 (en) * 2017-08-07 2019-02-14 SE Tylose USA, Inc. Pharmaceutical composition in solid extruded form
CN114760990A (en) * 2019-12-02 2022-07-15 泽农医药公司 Pediatric immediate release formulation of the potassium channel opener Ezogatabine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5384330A (en) 1992-01-08 1995-01-24 Asta Medica Aktiengesellschaft Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes for their preparation and pharmaceutical compositions containing them
US6538151B1 (en) 1997-01-20 2003-03-25 Asta Medica Aktiengesellschaft Modifications of 2-amino-4-(4-fluorobenzylamino)-1-ethoxycarbonylaminobenzene, and processes for their preparation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6733764B2 (en) * 2000-06-14 2004-05-11 Alain Martin Immunostimulator anti-cancer compounds and methods for their use in the treatment of cancer
WO2002080898A2 (en) * 2001-04-04 2002-10-17 Wyeth Methods for treating hyperactive gastric motility
DE102009013611A1 (en) * 2009-03-17 2010-09-23 Ratiopharm Gmbh Solid retigabine in non-crystalline form

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5384330A (en) 1992-01-08 1995-01-24 Asta Medica Aktiengesellschaft Pharmaceutically active 1,2,4-triamino-benzene derivatives, processes for their preparation and pharmaceutical compositions containing them
US6538151B1 (en) 1997-01-20 2003-03-25 Asta Medica Aktiengesellschaft Modifications of 2-amino-4-(4-fluorobenzylamino)-1-ethoxycarbonylaminobenzene, and processes for their preparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 15 December 2000, LIPPINCOTT WILLIAMS & WILKINS
CNS DRUG REV., vol. 11, 2005, pages 1

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120053238A1 (en) * 2009-03-17 2012-03-01 Ratiopharm Gmbh Solid retigabine in non-crystalline form
CN102241608A (en) * 2011-05-12 2011-11-16 天津市汉康医药生物技术有限公司 Retigabine compound and composition thereof
WO2013008250A2 (en) * 2011-07-01 2013-01-17 Dr.Reddys Laboratories Limited. Crystalline form of retigabine and processes for mixture of retigabine crystalline modifications
WO2013008250A3 (en) * 2011-07-01 2013-03-07 Dr.Reddys Laboratories Limited. Crystalline form of retigabine and processes for mixture of retigabine crystalline modifications
CN107049979A (en) * 2011-09-30 2017-08-18 持田制药株式会社 Easy taking solid pharmaceutical preparation
CN107049979B (en) * 2011-09-30 2020-08-14 持田制药株式会社 Easily administrable solid preparation
WO2014023270A1 (en) 2012-08-09 2014-02-13 Zentiva, K.S. Salts or co-crystals of ethyl n-[2-amino-4-[(4-fluorophenyl)methylamino]-phenyl]carbamate
CN102964273B (en) * 2012-12-06 2014-04-02 北京英科博雅科技有限公司 Novel retigabine crystal form F and preparation method thereof
CN102964273A (en) * 2012-12-06 2013-03-13 北京英科博雅科技有限公司 Novel retigabine crystal form F and preparation method thereof
WO2019032319A1 (en) * 2017-08-07 2019-02-14 SE Tylose USA, Inc. Pharmaceutical composition in solid extruded form
CN110913914A (en) * 2017-08-07 2020-03-24 Se纤维素美国公司 Pharmaceutical composition in solid extruded form
CN110913914B (en) * 2017-08-07 2023-08-29 Se纤维素美国公司 Pharmaceutical composition in solid extruded form
CN114760990A (en) * 2019-12-02 2022-07-15 泽农医药公司 Pediatric immediate release formulation of the potassium channel opener Ezogatabine

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